Summary

Persons with diabetes make up the fastest growing group of kidney dialysis and transplant recipients in the United States. In 1985, when the first edition of Diabetes in America was published, 20,961 persons with diabetes were receiving renal replacement therapy, representing 29% of all new cases of end-stage renal disease (ESRD). By 2012, 239,837 persons with diabetes were on renal replacement therapy, accounting for 44% of all new ESRD cases. The increased count reflects growth in diabetes prevalence and increased access to dialysis and transplantation. Those with a primary diagnosis of diabetes have lower survival relative to other causes of ESRD, primarily because of the coexistent morbidity associated with diabetes, particularly cardiovascular diseases (CVD). While survival on dialysis has slowly improved across modalities since the 1990s, it remains reduced in persons with diabetes, half of whom die within 3 years of beginning dialysis in the United States. Similar to persons with ESRD in general, the leading causes of death among adults with diabetes who started dialysis in 1995–2009 were CVD (58% of the deaths) and infections (13% of the deaths). Kidney transplant recipients with diabetes have much better survival than those on dialysis, indicating a significant impact of the type of renal replacement therapy (transplant versus dialysis) on long-term survival.

Kidney failure affects about 1% of persons with diabetes in the United States. A considerably higher proportion, about 40%, have less severe kidney disease. Since the second edition of Diabetes in America was published in 1995, a wealth of new information has contributed substantially to the understanding of kidney disease associated with diabetes. In 2002, the National Kidney Foundation’s Kidney Disease Outcome Quality Initiative published a uniform definition of chronic kidney disease (CKD) and classification of its stages irrespective of underlying cause, thus providing a common language for defining both the severity and prognosis of kidney disease. The definition and classification of CKD were subsequently updated and refined by the Kidney Disease: Improving Global Outcomes in 2012. Accordingly, CKD is classified based on both albuminuria and glomerular filtration rate (GFR) categories, and together with kidney failure, these conditions are collectively referred to as CKD, regardless of etiology. In addition, the Kidney Disease: Improving Global Outcomes recommends using equations to estimate GFR (eGFR), which include the routinely obtained variables serum creatinine, age, sex, and race/ethnicity. The use of serum cystatin C, an endogenous filtration marker less influenced than serum creatinine by variations in muscle mass, diet, and tubular secretion, has emerged as an alternative or an adjunct to serum creatinine-based equations, particularly in persons with diabetes, in whom early kidney disease is often characterized by elevated GFR.

Since the late 1990s, new molecular mechanisms have been defined that are helping to explain the development and progression of diabetic kidney disease. Glomerular structural lesions were found to explain 95% of the variability in albumin excretion and 78% of GFR variability. The latter percentage increased to 92% by adding indices of glomerular-tubular junction abnormalities and interstitial expansion to the regression models. Podocyte injury appears to play an essential role in the progression of diabetic nephropathy. In persons with either type 1 or type 2 diabetes, podocyte changes may occur even before the increase in albuminuria, suggesting that diabetes itself may induce podocyte alterations.

Much has also been written about the prognostic implications of CKD. Elevated albuminuria and low GFR are associated with ESRD, fatal and nonfatal CVD, and all-cause mortality. A meta-analysis of 1,024,977 participants (nearly 13% with diabetes) from 30 general population and high-risk cardiovascular cohorts and 13 CKD cohorts indicated that while the absolute risks for all-cause and CVD mortality are higher in the presence of diabetes, the relative risks of ESRD or death by eGFR and albuminuria are similar with or without diabetes. These findings underscore the importance of kidney disease per se as a predictor of important clinical outcomes, regardless of the underlying cause of kidney disease. New biomarkers of diabetic kidney disease appear to have additional prognostic information beyond that provided by albuminuria. These markers include kidney injury molecule 1, liver fatty acid-binding protein, N-acetyl-β-D-glucosaminidase, neutrophil gelatinase-associated lipocalin, β-trace protein, β₂-microglobulin, and tumor necrosis factor receptors 1 and 2.

Many concepts about risk factors for CKD illustrated in this chapter have not changed since 1995, and where they have, those changes are discussed. In particular, major advances have been made in elucidating the genetic and epigenetic complexity of CKD, which contributed to defining cellular metabolic memory and the understanding of the longlasting effects of strict glycemic control observed in persons with type 1 diabetes or type 2 diabetes.

Improvements in the management of persons with diabetes and CKD have extended the time course from onset of severe albuminuria to ESRD and reduced the occurrence of CVD. In type 1 diabetes, the combined Diabetes Control and Complications Trial (DCCT) and its long-term follow-up, the Epidemiology of Diabetes Interventions and Complications (EDIC) observational study, indicated that intensive early metabolic control reduced the risk of impaired GFR by 50% and of CVD outcomes by 42%, with a specific 57% decrease in myocardial infarction, stroke, or death from CVD, effects that were partly mediated by the reduced incidence of diabetic kidney disease. Among persons with type 2 diabetes, a meta-analysis of randomized controlled trials indicated that more intensive glycemic control (glycosylated hemoglobin [A1c] <7%) was associated with a significant 10% reduction in albuminuria but had no effects on mortality, kidney failure, or other vascular outcomes. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, targeting an A1c level <6.0% in the intensive intervention arm, reported an increased risk of CVD death for intensive versus conventional glycemic control, although it remains unclear whether this effect was related to more hypoglycemic episodes, the use of additional hypoglycemic medicines, or to the target glycemic level itself. Likewise, the modest gains in intermediate outcomes in the intensive treatment arms of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) and the Veterans Affairs Diabetes (VADT) trial were counterbalanced by a twofold to threefold higher risk of severe hypoglycemia. Together, these trials indicate that glycemic control is extremely useful up to a point, but more aggressive glycemic control may be harmful. Similarly, for blood pressure control, 2014–2015 recommendations by the guideline-writing groups endorse less intensive and more individualized blood pressure targets for diabetes and CKD than in the past. Persons with diabetes and CKD require multidisciplinary management involving a combination of treatments and behavioral adjustments to delay progression of CKD and to prevent the associated complications. The Steno-2 study, a landmark prospective, randomized trial in Denmark, demonstrated that compared with conventional treatment, intensive multifactorial intervention led to 46% lower death rate, 56% less severe albuminuria, 43% lower incidence of diabetic retinopathy, and 47% lower incidence of autonomic neuropathy during the 13.3-year study period.

Introduction

Important progress has been made since 1995, when the previous edition of Diabetes in America was published, in understanding the course and determinants of diabetic kidney disease and in its treatment (1,2,3,4,5,6,7). Widely accepted criteria for staging of chronic kidney disease (CKD) have been developed, based on the assessment of albuminuria and estimated glomerular filtration rate (eGFR) (7)—estimates of GFR and CKD staging criteria had not yet been developed in 1995. Nevertheless, kidney disease is still a major cause of morbidity and mortality in persons with diabetes, as indicated by the dramatic increase in the number of persons receiving renal replacement therapy since the 1980s. Increased availability of dialysis and transplants and the rising prevalence of diabetes are primarily responsible for this trend. Because kidney disease in diabetes is strongly associated with cardiovascular disease (CVD) and the development of end-stage renal disease (ESRD), the combined cost incurred by CKD and diabetes is associated with a greater percentage of the Medicare budget than that associated with congestive heart failure alone (2). For people with diabetes and kidney disease, the overall Medicare expenditures were approximately $25 billion in 2011 (2).

Projected increases in diabetes prevalence and the increasing frequency of both type 1 and type 2 diabetes in young people threaten to reverse the modest progress achieved with available treatments. Not only is the course of kidney disease in youth-onset type 2 diabetes more aggressive than in type 1 diabetes (4,5), but the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study suggests it may also be more treatment resistant than kidney disease in adults with type 2 diabetes (6). Although the development of new therapeutic options is essential for improving the management of this complex disease, diabetes prevention may ultimately offer the greatest benefit for stemming the rising tide of diabetic kidney disease.

This chapter has been updated to incorporate the substantial advances made in the past 20 years in the understanding of the pathogenesis, course, and management of CKD in persons with diabetes. It is not a systematic review of the literature but draws from recent publications that did perform such reviews. It also reflects the opinions of the authors about the challenges that may face persons with diabetes and CKD and those who care for them.

Definition, Measurements, and Classification

CKD attributable to diabetes, referred to as diabetic kidney disease, is defined by reduced kidney function or the presence of kidney damage for at least 3 months, regardless of kidney function (7). Kidney damage is ascertained by increased urinary markers, such as albuminuria, or by abnormal urinary sediment, abnormal imaging studies, or kidney biopsy (7). The clinical diagnosis of diabetic kidney disease is based largely on the finding of elevated excretion of urinary albumin in a person with diabetes in the absence of other kidney disease.

Persons are classified as having elevated albuminuria if the albumin-to-creatinine ratio (ACR) in at least two urine samples collected within 3–6 months is ≥30 mg/g in the absence of clinical or laboratory evidence of urinary tract infection (7). Elevated albuminuria, the earliest marker of diabetic nephropathy, is frequently associated with a progressive decline in kidney function and a high risk for kidney failure and CVD. Although albuminuria is a continuous risk factor, it is often arbitrarily divided into moderately increased albuminuria (ACR 30–299 mg/g)—generally characterized by stable kidney function and a greater risk for higher levels of albuminuria than an ACR <30 mg/g—and severely increased albuminuria (ACR ≥300 mg/g), associated with arterial hypertension and a high risk of kidney failure (Table 22.1) (8). Moderate albuminuria is also referred to as microalbuminuria, and severe albuminuria as macroalbuminuria, overt nephropathy, or clinical proteinuria. Because albuminuria occurs as a continuum, the American Diabetes Association (ADA) recommends simply using the term albuminuria for an ACR ≥30 mg/g (9). Urinary albumin excretion can be determined from 24-hour, overnight, or shorter urine collection periods; however, urinary ACR measured in a first morning void specimen is highly correlated with the 24-hour albumin excretion rate and is therefore an established and recommended way to assess urinary albumin excretion. Differences in methods of urine collection, albumin and creatinine measurements, reporting of results, and lack of standardized reference intervals for ACR often make comparisons between studies difficult.

TABLE 22.1

Albuminuria Categories According to KDIGO Classification.

TABLE 22.2

Kidney Function Categories According to KDIGO Classification.

Reduced kidney function is defined by a GFR <60 mL/min/1.73 m², and kidney failure by a GFR <15 mL/min/1.73 m² (Table 22.2) (7,8). Accurate determination of GFR is best achieved by infusing special markers into the bloodstream that are filtered at the glomerulus, but not secreted or reabsorbed by the tubules (e.g., inulin, iothalamate, iohexol, or ⁵¹Cr-EDTA), and measuring their disappearance from the blood or their appearance in the urine. Because such testing is laborious and expensive to use in large populations, the National Kidney Foundation (NKF) recommends using equations to estimate GFR that include the routinely obtained variables serum creatinine, age, sex, and race/ethnicity. The Modification of Diet in Renal Disease (MDRD) study equation (10) is the most widely used equation for estimating GFR in adults in the office setting and is reasonably accurate when the estimate is <60 mL/min/1.73 m² (11). Precision is lower and bias is higher at higher eGFR values, due in part to declining precision of creatinine measurement at its lower concentrations (12). The newer Chronic Kidney Disease Epidemiology Collaboration equation uses the same variables as the MDRD equation but with reduced bias and similar precision at higher eGFR values, thereby reducing the rate of false-positive results at levels ≥60 mL/min/1.73 m², i.e., the rate of classifying persons to eGFR <60 mL/min/1.73 m² (13). The use of serum cystatin C, an endogenous filtration marker that is less influenced than serum creatinine by variations in muscle mass, diet, and tubular secretion is being explored as an alternative or an adjunct to serum creatinine-based equations, particularly in persons with diabetes, in whom early kidney disease is often characterized by elevated GFR. Regardless of etiology, CKD is classified based on both albuminuria and eGFR categories (Figure 22.1).

In persons with diabetes, CKD may or may not represent diabetic kidney disease, as illustrated in Table 22.3 (14). In those with type 1 diabetes of ≥10 years duration, CKD should be attributed to diabetic kidney disease (14). Among persons with type 2 diabetes in particular, an eye examination is a useful, simple, and noninvasive test for discerning the presence of diabetic kidney disease (15,16). A meta-analysis of 2,012 pooled patients indicated that diabetic retinopathy has a sensitivity of 0.65 (95% confidence interval [CI] 0.62–0.68) and specificity of 0.75 (95% CI 0.73–0.78) for diabetic kidney disease (15). The presence of diabetic retinopathy in those with severe albuminuria is strongly suggestive of diabetic kidney disease, whereas the absence of diabetic retinopathy in those with normal or moderate albuminuria and GFR <60 mL/min/1.73 m² suggests nondiabetic CKD (15,17). Nondiabetic causes of CKD should be considered under the circumstances listed in Table 22.4 (14).

Figure 22.1 illustrates the Kidney Disease: Improving Global Outcomes (KDIGO) CKD classification that reflects prognosis based on the combined measures of GFR and albuminuria (8,18). The risk associations of GFR and albuminuria categories with renal, cardiovascular, and all-cause mortality outcomes are reviewed in the following sections. For screening and management of kidney disease in persons with diabetes, the NKF and the ADA recommend annual ACR screening starting at 5 years duration of type 1 diabetes and at diagnosis of type 2 diabetes (8,19). Serum creatinine measurements and eGFR reporting are recommended at least annually in adults with diabetes, regardless of ACR level.

TABLE 22.3

Likelihood of Chronic Kidney Disease Due to Diabetic Kidney Disease, by Levels of GFR and Albuminuria.

FIGURE 22.1

Classification of Chronic Kidney Disease to Indicate Prognosis Based on the Combined Measures of Albuminuria and Estimated Glomerular Filtration Rate. CKD stages based on both albuminuria and GFR levels are indicated in each cell. Symbols rank adjusted (more...)

TABLE 22.4

Situations That Prompt Consideration of Nondiabetic Cause(s) of Chronic Kidney Disease.

Pathophysiology and Clinical Course

Diabetic kidney disease typically progresses through a number of phases in which albumin or protein excretion increases, and GFR may rise and subsequently falls, frequently culminating in uremia or ESRD (Figure 22.2) (20,21). A diagram of the typical clinical progression of diabetic kidney disease and some of the factors contributing to it is shown in Figure 22.3 (22,23,24,25,26,27,28,29). The clinical manifestations of kidney disease are similar in both type 1 and type 2 diabetes. The major histologic changes of diabetic kidney disease and their relationships with kidney disease progression are discussed in detail in the Morphometry section.

Albumin Excretion

Urinary albumin excretion is usually normal at the diagnosis of type 1 diabetes, except when ketoacidosis is present. Moderate albuminuria in the early years of diabetes is associated with poor metabolic control but is frequently transitory (21,30,31,32,33,34) and rarely persistent in the first 5 years (35). With treatment, normalization of albuminuria occurs in 58% of persons with type 1 diabetes (36), whereas persistent regression without treatment is observed in 16% (37). Glycosylated hemoglobin (A1c) <8% (<64 mmol/mol), systolic blood pressure <115 mmHg, and low levels of both cholesterol (<198 mg/dL [<5.13 mmol/L]) and triglycerides (<145 mg/dL [<1.64 mmol/L]) are associated with the regression of albuminuria (36). Persons with persistent moderate albuminuria often progress to severe albuminuria (34) over a period of 10–20 years (3%–4% per year) (37,38), with hypertension and proliferative retinopathy also developing with advancing disease. Once overt nephropathy develops, albuminuria regression is less frequent (34,39), and the GFR generally falls at a variable rate (2–20 mL/min/year) (37).

Because the onset of type 2 diabetes is more insidious, poor glycemic control and elevated blood pressure may be present for several years before diagnosis, and therefore, elevated albuminuria is also frequently present at diabetes diagnosis. Approximately 3% of newly diagnosed persons with type 2 diabetes have severe albuminuria (37). The course of urinary protein excretion in type 2 diabetes is more heterogeneous than in persons with type 1 diabetes, in part reflecting a greater heterogeneity of kidney lesions due to the relatively higher prevalence of nondiabetic kidney disease, a consequence of the older age at onset of diabetes (40,41). About 25% of persons with type 2 diabetes have moderate albuminuria after 10 years, and 50% of those who develop moderate albuminuria do so within 20 years of diagnosis (37).

FIGURE 22.2

Outline of the Natural History of Diabetic Kidney Disease in Persons With Type 1 Diabetes. Figure is based on data from 20 men, all of whom developed nephropathy; time between the first examination and follow-up averaged 12±3 years; not all persons (more...)

Glomerular Hemodynamic Function

In healthy adults, the GFR ranges from 90 to 120 mL/min/1.73 m², is stable through mid-adult life, and declines by approximately 1 mL/min per year after age 50 years, with the onset of global kidney sclerosis (42,43,44). The onset of diabetes is associated with hemodynamic changes in the kidney circulation that lead to increased renal plasma flow, glomerular capillary hyperperfusion, and an increased glomerular transcapillary hydraulic pressure gradient (Figures 22.4 and 22.5) (45,46,47,48,49,50,51).

Glomerular capillary hypertension and the ensuing increase in filtration pressure are partly responsible for the elevation of GFR, but various other glomerular and tubular factors also influence the magnitude of the hyperfiltration (52,53,54). The prevalence of hyperfiltration, generally defined as a GFR of at least two standard deviations above the mean GFR in persons with normal glucose tolerance, varies from 40% to 60% in persons with type 1 diabetes and from 7% to 73% in those with type 2 diabetes (26,55,56,57,58,59). The large variations in these estimates are attributed mostly to differences in age, race/ethnicity, glycemic control, duration of diabetes, absence of diet standardization, and methodologies used to measure and report GFR among different populations. In addition, simple single compartment models of plasma disappearance curves will overestimate GFR, and other methods are needed to accurately measure GFR and define its normal range.

Several investigators have reported a relationship between hyperfiltration and the subsequent development of moderate albuminuria and progressive nephropathy (60,61,62), but others have not (24,25,63). Hyperfiltration may also reflect a generalized vascular dysfunction related to diabetes that in turn predisposes to diabetic nephropathy (64,65).

After the initial elevation at onset of diabetes, GFR decreases to a near normal range in response to metabolic control in both type 1 and type 2 diabetes (66,67,68,69), but usually not to levels found in nondiabetic persons (47,69,70,71). In some, this reversal could reflect the initiation of progressive kidney disease, as suggested by the appearance of global glomerular sclerosis and the fall in single-nephron filtration coefficient (72); in others, it could represent a purely functional change in kidney vasomotion associated with improvement in diabetes control or simply the intrinsic variability in GFR in the absence of significant histopathologic changes (73). Distinguishing between these two potential causes of GFR decline requires either observation of GFR over a long period of time to determine whether it plateaus, reverses direction, or continues to decline to pathologic levels, or attention to other biomarkers, including albuminuria.

FIGURE 22.3

Risk Factors For and Clinical Course of Kidney Disease in Diabetes. The thick horizontal arrows represent the reversibility of albuminuria with progressive kidney disease. BMI, body mass index; BP, blood pressure; ESRD, end-stage renal disease; GFR, glomerular (more...)

FIGURE 22.4

Mean Glomerular Filtration Rate in Men With Newly Diagnosed Type 1 Diabetes and No Diabetes. Subjects were 31 nondiabetic men and 11 men with newly diagnosed and untreated type 1 diabetes; horizontal lines are mean±standard deviation. The mean (more...)

Coincident with the initial elevation of GFR at the diagnosis of diabetes is slightly elevated urinary albumin excretion, although levels in the moderate albuminuria range or above are usually seen only after several years of diabetes (Figure 22.3) (22). The GFR in persons with moderate albuminuria is higher, on average, than in those with normal urinary albumin excretion (74,75). In those with severe albuminuria, it is lower, although in type 2 diabetes, GFR may still be within the normal range (76,77). Cross-sectional data suggest that GFR declines in persons with severe albuminuria, reflecting progressive glomerulosclerosis and loss of filtration surface area. Longitudinal studies confirm this hypothesis (78,79). The absence of albuminuria, however, does not preclude the presence of progressive kidney damage (see the section Incidence of Elevated Urinary Albumin Excretion) (80).

Kidney hemodynamic alterations induced by hyperglycemia and hypertension are believed to cause mechanical stretch and shear stress on endothelial cells and the mesangium, activating complex biochemical pathways that increase extracellular matrix production, hyperglycemia-induced injury, and podocyte damage and loss. These alterations ultimately lead to defects in selective glomerular capillary permeability, albuminuria, protein extravasation into the glomerular mesangium, expansion of mesangial matrix, and glomerulosclerosis (81,82,83,84,85,86,87,88).

Morphometry

The histologic changes in the kidneys of persons with type 1 diabetes and CKD are well described, typically homogenous, and predict development of elevated albuminuria, ESRD, and cardiovascular death (89,90,91). On the other hand, the kidney lesions underlying CKD in type 2 diabetes are more heterogeneous (92,93). Whether the natural history of CKD in diabetes varies by histologic lesion remains unknown, although longitudinal studies suggest a relationship between renal lesions and GFR decline (94,95). This section reviews the morphometric characteristics of diabetic kidney disease.

FIGURE 22.5

Glomerular Filtration Rate and Renal Plasma Flow in Individuals With Type 2 Diabetes and Without Diabetes. GFR and effective renal plasma flow were measured in 110 persons with type 2 diabetes and 32 nondiabetic subjects; mean values are shown for each (more...)

To appear in the urine, albumin must cross each layer of the glomerular filtration barrier consisting of the endothelial surface layer, fenestrated endothelial cells, glomerular basement membrane, and the glomerular epithelial cells or podocytes. Elevated albuminuria is an early clinical indicator of diabetic kidney disease, reflecting at the glomerular level the destruction of the endothelial surface layer (96,97,98,99), reduction in size and density of endothelial cell fenestrations (100,101,102), and thickening of the basement membranes. Subsequent mesangial expansion and podocyte injury and detachment further increase albuminuria, decreasing the available capillary filtration surface and leading to glomerulosclerosis. In addition to the glomerular morphologic lesions, diabetes progressively affects the kidney tubules, interstitium, and arterioles.

One of the earliest structural abnormalities in diabetes is thickening of the glomerular and tubular basement membranes due to excessive deposition of normal extracellular matrix components (85,93,103,104). Glomerular basement membrane thickening strongly correlates with albuminuria and less with GFR, suggesting that it is a good indicator of early diabetic kidney disease. This alteration is followed by an increase in the mesangial volume per glomerulus (fractional mesangial volume), primarily through expansion of the mesangial matrix, with the increase in the volume fraction of the mesangial cellular component playing a secondary role (105). The fractional mesangial volume is correlated inversely with GFR, and positively with ACR and hypertension (57,104,106), and is therefore a strong predictor of progressive kidney dysfunction (Figure 22.6) (107). Virtually all persons with type 1 diabetes and advanced kidney disease have markedly thickened glomerular basement membrane and diffuse mesangial expansion. About 25% of persons with >10 years of diabetes duration present with Kimmelstiel-Wilson nodules, which are rounded, paucicellular, lamellated accumulations of mesangial matrix at the periphery of the glomerulus (108,109). Kimmelstiel-Wilson lesions correlate with longer diabetes duration, higher serum creatinine, and more severe diabetic retinopathy (110). Mesangial expansion changes the architecture of the glomerular tuft, restricts the cellular component, distorts and occludes glomerular capillaries, decreasing the available capillary filtration surface and contributing to the decline in kidney function. Glomerular hypertrophy may compensate for the loss of filtration surface area, providing a means by which GFR is maintained in progressive kidney disease (111).

FIGURE 22.6

Glomerular Basement Membrane and Fractional Mesangial Volume by Albuminuria in Persons With Type 1 Diabetes. GBM width and Vv(Mes/glom) in 88 normoalbuminuric (NA), 17 moderately albuminuric (MA), and 19 proteinuric (P) persons with type 1 diabetes. Normoalbuminuria (more...)

Podocyte injury appears to play an essential role in the progression of diabetic nephropathy. The podocyte with its extended foot processes, provides structural support for the glomerular capillaries, as well as hydraulic resistance, and prevents the escape of proteins into the urinary space (112). With glomerular hypertrophy, the podocytes, which have a limited proliferative potential (113,114,115,116), stretch their foot processes more broadly to maintain coverage of the expanded glomerular basement membrane, a compensatory mechanism believed to influence their functional integrity (117). In addition, glomerular endothelial cell dysfunction, which precedes podocyte injury (100), appears to contribute to the latter through several mechanisms, including protein overload and toxicity at the podocyte level due to saturation of clearance mechanisms (118), increased shear stress (97), decreased endothelial nitric oxide synthase (eNOS) expression and activity (119,120), and production of cytokines, proteoglycans, and growth factors (100). Podocytes are known to absorb excess albumin arriving in the surrounding urinary space, and this increased workload may initiate inflammatory signaling and contribute to changes in podocyte-associated molecules and foot process effacement (121,122). Sustained mechanical stress and glomerular hypertension may ultimately lead to podocyte detachment and loss in the urine, leaving areas of bare glomerular basement membrane that further enhance loss of protein (Figure 22.7) (102). These denuded areas may initiate glomerular-tubular junction abnormalities and focal or global glomerular sclerosis (103). In persons with either type 1 (123) or type 2 diabetes (102,124), podocyte changes may occur even before the increase in ACR, suggesting that diabetes itself may induce podocyte alterations. In a study of persons with type 2 diabetes, moderate albuminuria was associated with 20% and severe albuminuria with 40% podocyte loss relative to normal albuminuria (117). Moreover, individuals with moderate albuminuria had a 35% decline in the number of podocytes per glomerulus, and half of them progressed to severe albuminuria during 4 years of follow-up (72). Similarly, a lower number of podocytes and changes in the shape of the remaining podocytes were found in persons with type 2 diabetes and elevated ACR when compared with those with normal ACR and similar fractional mesangial volume, indicating that changes in podocyte structure and density occur early during diabetic nephropathy and contribute to albuminuria. Other cross-sectional and experimental studies have reported similar findings (115,125). Some data suggest a repair mechanism via recruitment of parietal epithelial cells that is overwhelmed when podocyte loss exceeds a modest threshold (126,127,128). Consequently, significant damage to the podocytes is a potential starting point for irreversible glomerular injury in diabetic kidney disease.

FIGURE 22.7

Peripheral Glomerular Capillaries From Pima Indians With Type 2 Diabetes. Transmission electron microscopy, × 11,280. (A) Intact podocyte foot processes (P) attached to glomerular basement membrane (GBM). (B) Local podocyte detachment (PD) and (more...)

Interstitial expansion, in contrast with mesangial expansion, primarily involves a cellular component represented by T lymphocytes and macrophages that infiltrate the interstitium, with subsequent fibrosis and declining GFR (129,130). Efferent and afferent arteriolar hyalinosis, consisting of intramural accumulations of plasma proteins and lipids within kidney arterioles, may occur within a few years of diabetes onset (104,131,132). Although afferent arteriolar hyalinosis is less specific to diabetic nephropathy, both lesions are associated with increased albumin excretion and progression of kidney disease. Similar exudative lesions may occur in the glomerular capillaries (hyalinosis), Bowman’s capsule (capsular drops) (133,134), or proximal convoluted tubules and are generally associated with advanced diabetic nephropathy (104).

Abnormalities of the glomerular-tubular junction, typically associated with proteinuria (135), include focal adhesions, atrophic tubules, or atubular glomeruli.

These lesions further contribute to the loss of kidney function in diabetes. Advanced diabetic kidney disease is characterized by a marked reduction in the number of functioning glomeruli and further compensatory enlargement of those that remain functional. This stage is associated with markedly reduced GFR.

The intra- and extraglomerular morphologic changes described in this section progress at variable rates. Nonetheless, in one study, glomerular structural lesions explained 95% of the variability in albumin excretion and 78% of GFR variability (107,135). The latter percentage increased to 92% by adding indices of glomerular-tubular junction abnormalities and interstitial expansion to the regression models (135).

Albuminuria, however, is neither a sensitive nor specific early biomarker of progression to ESRD, and the absence of albuminuria does not exclude the presence of relatively advanced diabetic renal lesions and progressive kidney damage (136,137,138,139,140,141,142,143,144). New biomarkers of diabetic kidney disease appear to have additional prognostic information beyond that provided by albuminuria. These markers include kidney injury molecule 1 (KIM-1), liver fatty acid-binding protein (L-FABP), N-acetyl-β-D-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL) (145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161), β-trace protein, β₂-microglobulin (162,163,164), and tumor necrosis factor receptors 1 and 2 (165,166,167,168,169,170,171,172). Tumor necrosis factor-alpha receptor 1 and receptor 2 consistently enhance the discrimination of the survival models for ESRD beyond that achievable by the clinically recognized risk factors in persons with type 1 or type 2 diabetes (165,166,167,168,169,170,171,172). Evaluation of other biomarkers in relation to diabetic kidney disease often shows conflicting results (145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161). This may be due to differences in study design, inclusion of persons without diabetes, use of surrogate or composite outcomes, or incomplete covariate adjustment in risk models (161).

Selective Glomerular Permeability

The glomerular capillary wall serves as a filter that discriminates among molecules on the basis of size, electrical charge, and configuration. Studies of glomerular filtrate collected by micropuncture or narrow size fractioning of exogenous polymers, such as dextran, indicate that albuminuria is primarily the result of impairment of the electrostatic barrier within the glomerulus, consequent to a decrease in endothelial cell glycocalyx (173,174) and heparan sulfate content of the glomerular basement membrane (175,176), and by changes in size selectivity across the glomerular capillary wall (Figure 22.8) (56,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193).

A comparison of the mean dextran sieving profiles in 43 initially microalbuminuric Pima Indians with type 2 diabetes, who were followed for up to 8 years, showed no difference in the size selectivity of the glomerular filtration barrier between participants with moderate albuminuria and long-term normoalbuminuric control subjects (194). However, participants with severe albuminuria after 4 years of follow-up had a significantly higher fractional clearance of the large-radius test molecules than normoalbuminuric controls, with a reduction at the low-radius end, as shown in Figure 22.9. When the macromolecular shunt was analyzed as a function of albumin excretion, an abrupt transition was apparent at an ACR of approximately 3,000 mg/g (Figure 22.10), whereas the contribution of the shunt in the moderate albuminuria range was very small. These data suggest that permselectivity defects in the glomerular filtration barrier have little or no role in the development of moderate albuminuria. By contrast, a primary contributor to severe albuminuria is the shunt resulting from the presence of large pores within the glomerular capillary wall through which plasma proteins can easily pass (195,196,197,198). Morphometric data in participants with severe albuminuria identified a significant correlation between the shunt magnitude and podocyte foot process width (p=0.027) (Figure 22.11) (194), which was not discernible in participants with moderate albuminuria. A similar size-selectivity defect has been reported in type 1 diabetes (190,195). These findings are consistent with the view that permselectivity defects responsible for increased albumin excretion may be focal and likely due to podocyte foot process effacement and simplification and, possibly, to defective intercellular junctions (199).

With the application in the late 1990s of multiphoton fluorescence techniques to kidney research, direct imaging of the structure and function of living kidney tissue was possible (200). In some studies, this technique revealed what appeared to be a much higher albumin glomerular sieving coefficient than was calculated or measured by micropuncture, prompting some investigators to propose alternative explanations for the facilitated urinary clearance of albumin in diabetic kidney disease (200,201), including the idea that elevated albuminuria is the result of a proximal tubular cell dysfunction in retrieving and degrading albumin and does not reflect an alteration in glomerular permselectivity (201,202). Later studies using improved imaging techniques do not support this concept and confirm that glomerular filtration barrier permeability to macromolecules is largely restricted to areas of podocyte damage (203,204,205).

FIGURE 22.8

Fractional Dextran Clearance Profile in Pima Indians With and Without Type 2 Diabetes. The figure compares the fractional dextran clearance profile in persons with type 2 diabetes and those with normal glucose tolerance. Fractional dextran clearances (more...)

FIGURE 22.9

Dextran Sieving Curves in Pima Indians With Type 2 Diabetes. Sieving coefficient was measured in 31 persons with diabetes and severe albuminuria at 48 months follow-up (▵) and 11 diabetic controls with long-term normoalbuminuria (○). Lines (more...)

FIGURE 22.10

Graph of the Shunt Magnitude as a Function of Albuminuria. The shunt magnitude parameter (ω₀) as a function of albuminuria, as reflected by (A) the fractional clearance of albumin and (B) the urinary albumin-to-creatinine ratio (A/C)—for (more...)

FIGURE 22.11

Relationship Between Shunt Magnitude and Mean Podocyte Foot Process Width. Shunt magnitude (ω₀) and mean foot process width in 10 persons with severe albuminuria who had kidney biopsies.

Elevated Urinary Albumin Excretion

As noted earlier in this chapter, urinary albumin excretion is often increased at the diagnosis of both types of diabetes but frequently returns to normal with the institution of glycemic control (21,30,31,32). Persistent albuminuria at the onset of type 2 diabetes, however, may reflect diabetes that has remained undiagnosed for years (32) or the presence of kidney disease unrelated to diabetes, since other kidney diseases are common at the ages when type 2 diabetes typically develops. On the other hand, elevated urinary albumin excretion is found in persons with impaired glucose tolerance (206,207,208), raising the possibility that hyperglycemia, even at levels below those diagnostic of diabetes, is sometimes associated with kidney abnormalities.

Prevalence of Elevated Urinary Albumin Excretion

The prevalence of elevated albuminuria (ACR ≥30 mg/g) in the U.S. adult population with self-reported diabetes was 35.9%, 32.6%, and 29.3% based on a one-time random spot urine measurement collected for the National Health and Nutrition Examination Surveys (NHANES) 1988–1994, 1999–2004, and 2007–2012, respectively (Table 22.5) (1). When measured in a first morning void sample, the prevalence of ACR ≥30 mg/g in NHANES 2009–2010 participants with self-reported diabetes was 15.7% (95% CI 12.3%–19.0%) (209) (prevalences of moderate albuminuria 11.9%, 95% CI 9.7%–14.4%, and severe albuminuria 3.8%, 95% CI 2.2%–6.4%, were computed in a new analysis for Diabetes in America, 3rd edition). These estimates were significantly lower than the 24.1% prevalence (95% CI 19.8%–28.2%) of ACR ≥30 mg/g obtained from a random spot urine in the same population (prevalences of moderate albuminuria 19.3%, 95% CI 16.0%–23.1%, and severe albuminuria 4.8%, 95% CI 3.1%–7.4%, were computed in a new analysis for Diabetes in America). Prevalence of elevated ACR was significantly lower in the NHANES population without diabetes (6.2%, 95% CI 4.9%–7.5%, in random urine samples and 3.7%, 95% CI 2.9%–4.5%, in first morning voids) (209). As mentioned in the Definition, Measurements, and Classification section, ACR measurement in first morning urine is a more reliable indicator of albumin excretion, since it correlates better with the 24-hour albumin excretion rate (AER) than the ACR measured in random spot urine. This suggests that ACR measurements based on single random spot urine specimens—the standard measurement in the NHANES—likely overestimate the frequency of elevated ACR in the general population (210,211,212).

Because of the high intraindividual variation of ACR, both NKF and ADA guidelines (8,9,19) recommend confirmation of elevated albuminuria in a repeat measurement—either first morning void or random urine sample. The prevalence of persistent albuminuria, defined as elevated ACR in two consecutive random urine measurements within 2 weeks, was 15.9% in adults with diabetes (defined by A1c ≥6.5% [≥48 mmol/mol] or use of glucose-lowering medicines) in the NHANES 2009–2014, lower than the 20.8% prevalence in the NHANES III (1988–1994) (age, sex, and race/ethnicity adjusted prevalence ratio 0.76, 95% CI 0.65–0.89) (213). This overall change was due to lower albuminuria prevalence in adults age <65 years and non-Hispanic whites over time. By contrast, the prevalence of low eGFR increased during the same time in the overall population with diabetes. Trends in persistent albuminuria and eGFR <60 mL/min/1.73 m² in the general U.S. population with diabetes are shown in Table 22.6 by age group (213). The prevalence of low eGFR in the U.S. population with diabetes has increased over time among non-Hispanic white and black adults (Table 22.7) (213).

By design, the NHANES does not differentiate the type of diabetes, and results in the adult population with self-reported diabetes may largely reflect the experience of persons with type 2 diabetes. In a new analysis of NHANES 1999–2010 data conducted for Diabetes in America, the prevalence of CKD by type of diabetes was estimated using a published algorithm (214) to define persons with type 1 diabetes (Table 22.8). Results showed a higher prevalence of CKD in those with type 2 diabetes than in those with type 1 diabetes, regardless of sex, and a higher prevalence in non-Hispanic blacks than in non-Hispanic whites. CKD was also more frequent in persons with hypertension or CVD, regardless of type of diabetes.

In the Pittsburgh Epidemiology of Diabetes Complications (EDC) study, the prevalences of both moderate and severe albuminuria were higher in the 210 men than the 180 women diagnosed with type 1 diabetes between 1950 and 1964 (moderate albuminuria prevalence: 75% in men vs. 53.8% in women, p=0.001; severe albuminuria prevalence: 53.1% in men vs. 32.0% in women, p=0.002) (Figure 22.12) (215). In the cohort with diabetes onset between 1965 and 1980 (260 men and 283 women), sex differences in some CKD risk factors diminished, as did the differences in albuminuria prevalence (moderate albuminuria: 42.6% in men vs. 41.9% in women, p=0.9; severe albuminuria: 18.1% in men vs. 22.4% in women, p=0.3) (Figure 22.12). The prevalence of albuminuria in a population-based study of 706 insulin-treated subjects in Wisconsin with diabetes onset at age <30 years, presumably mostly persons with type 1 diabetes, is shown in Table 22.9 (216). The overall prevalence was 21.2% for moderate albuminuria (≥0.03–0.29 g albumin/L) and 21.1% for severe albuminuria (≥0.30 g albumin/L). In the Finnish Diabetic Nephropathy (FinnDiane) study (217), moderate albuminuria was present in 12% and severe albuminuria in 14% of adult clinic-based patients with type 1 diabetes, lower than the prevalences of 23% (31–299 mg albumin/24 hours) and 19% (≥300 mg albumin/24 hours) found in 876 clinic-based patients in Denmark (218). Figure 22.13 shows the prevalence of albuminuria in these clinic-based patients in Denmark as a function of the duration of diabetes. The prevalence data reported in the studies above are higher than those reported in a nationwide cohort of Norwegians with type 1 diabetes (19% for moderate albuminuria, 15–200 mg/min; 7.8% for severe albuminuria, >200 mg/min) (219), in an observational study from the Swedish National Registry (12.2% for moderate albuminuria; 7.4% for severe albumin-uria) (220), or in the type 1 diabetes population in Germany (3.3% for moderate albuminuria, ACR ≥2.5 mg/mmol; 0.2% for severe albuminuria, ACR ≥35 mg/mmol) (221). The differences are likely due to the shorter duration of diabetes and better metabolic control in the latter studies, which included observations after the year 2002.

TABLE 22.5

Prevalence of Chronic Kidney Disease in Adults Age ≥20 Years, by Age, Sex, Race/Ethnicity, and Risk Factor Categories, U.S., 1988–1994, 1999–2004, and 2007–2012.

TABLE 22.6

Prevalence of Albuminuria and Decreased Glomerular Filtration Rate in Adults Age ≥20 Years With Diabetes, by Age and Time Period, U.S., 1988–2014.

A cross-sectional, clinic-based study of 24,151 patients from 33 countries worldwide with type 2 diabetes, mean diabetes duration of 8 years, and without previously known albuminuria found overall prevalences of moderate and severe albuminuria of 39% and 10%, respectively (222). Compared with whites, who had the lowest prevalence of albuminuria, Asian and Hispanic patients had nearly twice the odds of albuminuria (adjusted odds ratios [OR] 1.8, 95% CI 1.59–1.97, and OR 1.7, 95% CI 1.47–1.94, respectively). African patients were younger and had shorter duration of diabetes than other racial/ethnic groups, but the odds of albuminuria were 1.5-fold higher than in whites (95% CI 1.20–1.83), who had the lowest A1c levels and the highest frequency of antihypertensive, lipid-lowering, and anticoagulant or antiplatelet usage. Among Pima Indians with type 2 diabetes (207), 26% had moderate albuminuria (ACR 30–299 mg/g) and 21% had severe albuminuria (ACR ≥300 mg/g), and in the population on the Western Pacific island of Nauru (208), 41% had moderate albuminuria (ACR 30–299 mg/mL) and 31% had severe albuminuria (ACR ≥300 mg/mL). Figure 22.14 shows the prevalence of moderate and severe albuminuria in Pima Indians according to duration of diabetes (207). Although different methods and definitions of urinary albumin excretion were employed in these studies, other factors must be invoked to explain the large differences in the prevalence of elevated urinary albumin excretion in these different groups. Additional contributing factors may include racial/ethnic differences, as well as differences in duration of diabetes, blood pressure and metabolic control, diet, and perhaps genetic susceptibility to diabetic kidney disease.

TABLE 22.7

Prevalence of Albuminuria and Decreased Glomerular Filtration Rate in Adults Age ≥20 Years With Diabetes, by Race/Ethnicity and Time Period, U.S., 1988–2014.

TABLE 22.8

Crude Prevalence of Chronic Kidney Disease Stages 1–5 in Adults Age ≥20 Years, by Type of Diabetes, U.S., 1999–2010.

Incidence of Elevated Urinary Albumin Excretion

Moderate albuminuria predicts the development of severe albuminuria in persons with type 1 (223,224,225,226,227) or type 2 diabetes (228,229,230,231). In type 1 diabetes, persistent albuminuria rarely develops in the first 10 years after diagnosis (232,233,234). The rate of progression to severe albuminuria is highest between 10 and 20 years duration of diabetes, and subsequently, the incidence rate declines (130,219,235). In the Diabetes Control and Complications Trial (DCCT), the cumulative incidence of persistent moderate albuminuria was 14%, 33%, and 38% at 10, 20, and 30 years duration of diabetes, respectively, among persons assigned to conventional treatment (mean A1c 9.6% [81 mmol/mol]), higher than among those in the intensive treatment arm (10%, 21%, 25%, respectively; mean A1c 8.9% [74 mmol/mol]). In the 325 participants with incident moderate albuminuria who were followed for up to 23 years, the 10-year cumulative incidence was 28% for severe albuminuria, 15% for impaired eGFR (eGFR <60 mL/min/1.73 m² at two consecutive study visits), and 4% for ESRD (33). The 10-year cumulative incidence of regression to normoalbuminuria, however, was also common, at 40%. Lower levels of A1c, blood pressure, low-density lipoprotein (LDL) cholesterol, and triglycerides and absence of retinopathy were associated with reduced risk of kidney disease progression.

In type 2 diabetes, the incidence of elevated albuminuria in relation to diabetes duration is more difficult to characterize because of the uncertainty in dating the onset of diabetes in most studies. No relationship between duration of type 2 diabetes and the incidence of proteinuria was found in the Mayo Clinic population in Rochester, Minnesota (236), whereas in Wisconsin (237), a relationship between diabetes duration and incidence of proteinuria was stronger in persons who received insulin than in those who did not. In Pima Indians, in whom the duration of type 2 diabetes is known with greater accuracy because of systematic periodic oral glucose tolerance testing in the population, the age-sex-adjusted incidence of proteinuria, defined as urinary protein-to-creatinine ratio ≥0.5 g/g, was strongly related to duration of diabetes (238).

FIGURE 22.12

Sex- and Cohort-Specific Prevalence of Moderate and Severe Albuminuria, Pittsburgh Epidemiology of Diabetes Complications Study. Moderate albuminuria, albumin excretion rate of 30–300 mg/24 hours; severe albuminuria, albumin excretion rate >300 (more...)

FIGURE 22.13

Prevalence of Elevated Urinary Albumin Excretion, By Duration of Type 1 Diabetes. Moderate albuminuria is defined as 31–299 mg/24 hours and severe albuminuria as ≥300 mg/24 hours.

TABLE 22.9

Prevalence of Moderate Albuminuria and Severe Albuminuria in Men and Women With Type 1 Diabetes and Without Diabetes, Wisconsin Epidemiologic Study of Diabetic Retinopathy, 1984–1986.

A secular decline in the incidence of diabetic kidney disease has been described in type 1 diabetes (239,240,241,242,243,244). In the EDC study (241), the cumulative incidence of diabetic nephropathy, defined as persistent AER >200 µg/min in timed urine collections, was 37% lower in the 179 participants diagnosed with diabetes in 1975–1980 than in the 339 participants diagnosed in 1965–1974, after 20 years of diabetes. Among those with >25 years of diabetes duration, the declining trend was not statistically significant (Figure 22.15). The favorable trend disappeared in those with diabetes duration >35 years. Nevertheless, significant reductions in both mortality and ESRD rates in this population suggest a slower progression to kidney failure with improved management of diabetes complications. Comparable data have been reported for persons with type 1 diabetes in Sweden (242), where the cumulative incidence of persistent albuminuria (≥1 positive test by Albustix) after 20 years of diabetes decreased from 28% in persons diagnosed with type 1 diabetes in 1961–1965 to 6% in those diagnosed in 1980–1985. Furthermore, none of the 51 persons in whom type 1 diabetes was diagnosed in 1976–1980 developed persistent albuminuria during 12–16 years of follow-up. Figure 22.16 shows the cumulative incidence of persistent albuminuria in these cohorts according to the calendar year of diagnosis of diabetes. The decline in the cumulative incidence coincided with improvement in glycemic control compar-able to that in the intensively treated group in the DCCT study (245). These findings were replicated in the Steno Diabetes Center cohort from Denmark (243,244). The cumulative incidence of diabetic kidney disease, defined as persistent albuminuria, declined from 31.1% in those with onset of type 1 diabetes in 1965–1969 to 13.7% in those with onset of diabetes in 1979–1984, the most significant decline occurring in the most recent cohort (Figure 22.17) (244). This change paralleled a significant trend for earlier initiation of antihypertensive treatment following the onset of diabetes, expansion of renin-angiotensin-aldosterone system (RAAS) inhibitor usage, and sustained improvement in mean blood pressure.

FIGURE 22.14

Prevalence of Elevated Urinary Albumin Excretion in Pima Indians, By Duration of Diabetes, 1982–1988. Moderate albuminuria is defined as 31–299 mg/24 hours and severe albuminuria as ≥300 mg/24 hours.

In contrast with type 1 diabetes, no secular decline in the incidence of proteinuria has been reported in type 2 diabetes. The 10-year cumulative incidence of persistent proteinuria in the predominantly Caucasian population age ≥40 years of Rochester, Minnesota, remained 12% in those diagnosed with type 2 diabetes in 1970–1979 (n=483) and those diagnosed in 1980–1989 (n=680) (246). The 20-year cumulative incidence of proteinuria reported in this study, however, was 41%, higher than the 25% cumulative incidence reported in an earlier Rochester study of individuals diagnosed with diabetes in 1945–1969 (236). These secular differences may be related in part to differences in age distributions and in diabetes diagnosis criteria between the studies. In the Pima Indian longitudinal study, in which the population was screened approximately every 2 years using 2-hour oral glucose tolerance testing, the incidence of proteinuria rose between 1967 and 2002 in response to the longer average duration of diabetes in this population in recent years (Table 22.10) (247).

The progression of kidney disease in persons with newly diagnosed type 2 diabetes in the United Kingdom Prospective Diabetes Study (UKPDS) is presented in Figure 22.18 (248,249). The rate of progression to the next level of kidney disease severity (moderate albuminuria, severe albuminuria, or elevated plasma creatinine or renal replacement therapy) was 2%–2.8% per year; the risk of death increased with increasing severity of kidney disease, with an annual rate of 1.4% for subjects with no nephropathy, 3.0% for those with moderate albuminuria, 4.6% for those with severe albuminuria, and 19.2% with elevated plasma creatinine or renal replacement therapy. Individuals with severe albuminuria were more likely to die in any year than to develop kidney failure. Progression from no nephropathy to severe albuminuria or more advanced kidney disease was low (0.1%), as was progression from moderate albumin-uria to elevated plasma creatinine or renal replacement therapy.

Although moderate albuminuria is associated historically with an inexorable progression to severe albuminuria and a decrease in the GFR of 10–15 mL/min/year, leading to ESRD (250,251), a substantial proportion of persons with type 1 or type 2 diabetes and moderate albuminuria spontaneously regress to normoalbuminuria. This observation suggests that moderate albuminuria represents reversible kidney injury rather than the onset of an inevitable progression to ESRD. In a prospective observational study of persons with type 1 diabetes and moderate albuminuria, only 19% developed severe albuminuria, whereas 59% regressed to normal albuminuria after 6 years of follow-up (36). The incidence of albuminuria reported in predominantly white populations with type 1 diabetes is lower and the rate of regression higher than those reported in African Americans with type 1 diabetes for a similar time period (252,253). The 6-year cumulative incidence of moderate albumin-uria (AER 20–200 µg/min) in 473 African Americans with type 1 diabetes was 26.0% (95% CI 20.9%–31.6%), and of severe albuminuria (AER ≥200 µg/min) 16.9% (95% CI 12.6%–21.8%), with an overall incidence of elevated albuminuria of 42.9% (95% CI 36.9%–50.0%) (Figure 22.19) (252). Among the 370 African Americans with ACR <200 µg/min at baseline, 23.5% (95% CI 19.3%–28.2%) progressed to severe albuminuria. Overall, 33.5% progressed to a worse albuminuria category, and 8.5% improved either spontaneously or due to treatment with angiotensin-converting enzyme (ACE) inhibitors or other antihypertensive medicines.

FIGURE 22.15

Incidence of Kidney Disease in Persons With Type 1 Diabetes, Pittsburgh Epidemiology of Diabetes Complications Study, 1986–2000, and Steno Clinic Population, 1933–1984. Kidney disease is defined as an albumin excretion rate >200 (more...)

FIGURE 22.16

Cumulative Incidence of Persistent Albuminuria in Persons With Type 1 Diabetes Diagnosed Before Age 15 Years, by Duration of Diabetes. Persistent albuminuria is defined as ≥1 positive by Albustix. Subjects are divided into four groups based on (more...)

FIGURE 22.17

Cumulative Incidence of Diabetic Nephropathy by Period of Onset of Type 1 Diabetes Diagnosed Before Age 15 Years, by Duration of Diabetes.

TABLE 22.10

Incidence of Proteinuria in Three Independent Time Periods Among Pima Indians With Type 2 Diabetes, by Diabetes Duration and Proportion of Person-Years Accumulating in Short and Long Duration Categories, 1967–2002.

In general, the proportion of persons with type 2 diabetes who regress from moderate albuminuria to normoalbuminuria is 30%–54%, while the frequency of progression to overt proteinuria is 12%–36% (254,255,256). Moderate albuminuria of short duration, use of RAAS inhibitors, lower A1c (<6.9% [<52 mmol/mol]), and systolic blood pressure <129 mmHg are independently associated with regression. A higher likelihood of progression than regression of diabetic kidney disease was found in a large population-based study of persons with type 2 diabetes and hypertension, all members of a managed care organization (257), who had at least two ACR measurements during a mean follow-up of 5 years. At baseline, 57% had normal ACR (<3.4 mg/mmol), 31% had moderate albuminuria (3.4–33.8 mg/mmol), and 12% had severe albuminuria (≥33.9 mg/mmol). Among those with normal ACR at baseline, 46% developed elevated ACR by the end of follow-up; of those with moderate albumin-uria, 20% developed severe albuminuria, whereas 21% regressed to normal ACR; and among those with severe albuminuria, 4% developed ESRD and 31% regressed to moderate albuminuria. When included in a multivariable adjusted model, duration of diabetes, antihypertensive treatment, body mass index (BMI), A1c, and being African American were positively associated with progression to elevated ACR, whereas age, GFR, systolic blood pressure, and treatment with RAAS inhibitors were positively associated with progression to ESRD in persons with severe albuminuria. Among 750 American Indians from Arizona, Oklahoma, and North and South Dakota age 45–74 years in the Strong Heart Study, albuminuria was measured in 1989–1991 (baseline), 1993–1995 (second examination), and 1997–1999 (third examination) (258). Among those with normal ACR at baseline, 67% remained so and 33% developed elevated albuminuria (29% moderate albuminuria and 4% severe albuminuria) by the second examination. More participants with normal albuminuria at the second examination remained normoalbuminuric (77%), and 23% developed elevated albuminuria (19% moderate albuminuria and 4% severe albuminuria) by the third examination, suggesting a decline in onset of kidney disease in the later years. Risk factors for onset of elevated albuminuria were higher A1c, systolic blood pressure, higher baseline ACR, smoking, hypoglycemic treatment, and longer diabetes duration. Participants with a baseline ACR between 10 and 30 mg/g had nearly threefold higher risk of elevated ACR over a 4-year period (OR 2.7, 95% CI 1.9–3.9) than those with baseline ACR <5 mg/g (258). The cumulative incidence of elevated ACR increased with duration of diabetes (p<0.01) and was similar in men and women in the three study centers (Figure 22.20).

FIGURE 22.18

Chronic Kidney Disease Progression in Persons With New-Onset Type 2 Diabetes, United Kingdom Prospective Diabetes Study, 1977–1997. Percentages represent annual rates with 95% confidence intervals.

Diabetic Kidney Disease as a Risk Factor for ESRD, Cardiovascular Disease, and Death

A new analysis of the NHANES 1999–2004 conducted for Diabetes in America showed that elevated albuminuria and low GFR are associated with ESRD, fatal and nonfatal CVD, and all-cause mortality (Table 22.11). For albuminuria, these associations are a continuum, starting at levels well below the 30 mg/g threshold that defines moderate albuminuria (259,260,261,262). Among American Indians age 45–74 years in the Strong Heart Study (259) who were free of CVD at baseline, ACR <30 mg/g was a strong and independent predictor of all cardiovascular events, including nonfatal and fatal CVD, and these associations were similar in individuals with or without diabetes. In those with diabetes, the adjusted risks for all, nonfatal, and fatal CVD events increased by 20% (hazard ratio [HR] 1.20, 95% CI 1.07–1.34), 13% (HR 1.13, 95% CI 0.99–1.28), and 48% (HR 1.48, 95% CI 1.17–1.87), respectively, for each doubling of ACR within the normal range.

Among persons with diabetes participating in the NHANES III, those with the highest ACR levels (ACR ≥300 mg/g) and lowest eGFR (eGFR 15–59 mL/min/1.73 m²) had a 2.7-fold higher risk for cardiovascular mortality and a 2.5-fold higher risk for all-cause mortality, relative to those with normal ACR and eGFR ≥90 mL/min/1.73 m² (263). Similar associations were found in participants without diabetes; however, those with diabetes had greater absolute risks for these outcomes. Adjustments for diabetes duration and cardiovascular risk factors did not change the significance of these associations, suggesting that CKD is a risk amplifier, with much of the excess CVD in diabetes occurring in persons with diabetic kidney disease.

FIGURE 22.19

Six-Year Incidence of Any Proteinuria in African American Men and Women With Type 1 Diabetes, by Duration of Diabetes at the Baseline Examination, New Jersey 725 Study, 1993–1998.

FIGURE 22.20

Four-Year Cumulative Incidence of Elevated Albuminuria in American Indians, by Duration of Diabetes, Sex, and Study Site, Strong Heart Study. ACR, albumin-to-creatinine ratio.

Nearly all of the excess mortality associated with either type of diabetes is found in persons with severe albuminuria (35,264,265), primarily from kidney disease or CVD in type 1 diabetes (264,266), from CVD in whites with type 2 diabetes (267), and from CVD or kidney disease in Pima Indians with type 2 diabetes (265,268). The 20-year mortality in 658 persons with type 1 diabetes in the EDC study is shown in Tables 22.12 and 22.13 (269). Individuals who maintained normal levels of albumin excretion had near-normal survival (standardized mortality ratio [SMR] 1.2, 95% CI 0.5–1.9), and they were more likely to die from non-diabetes-related causes than individuals who had elevated albuminuria (AER ≥20 µg/min) (269). Other studies in persons with more than 30 years duration of type 1 diabetes show similar associations (270,271).

An analysis of secular trends in the incidence of ESRD and mortality in patients with type 1 diabetes and severe albumin-uria from the Joslin Clinic, however, found no significant decline in pre-ESRD death rate, progression to ESRD, or post-ESRD death rate from 1991 to 2004, despite both widespread adoption of kidney protective treatments during the same period and significant improvements in blood pressure and total serum cholesterol concentration (272,273). Sixty-nine percent of either pre- or post-ESRD excess mortality was attributable to CVD. Moderate and severe albuminuria independently predicted all-cause mortality in a monotonic fashion in the FinnDiane cohort, a cohort representing 16% of the population with type 1 diabetes in Finland (217). During 7 years of follow-up, the overall death rate in persons with moderate albuminuria was nearly three times that observed in the general Finnish population (adjusted SMR 2.8, 95% CI 2.0–4.2), with CVD representing 56% of these deaths. Severe albuminuria was associated with nine times the death rate observed in the age- and sex-matched general population (adjusted SMR 9.2, 95% CI 8.1–10.5), 45% of these being caused by CVD. Indeed, the impact of albuminuria level on mortality risk was equivalent to that of preexisting macrovascular disease, as defined by a history of myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, stroke, carotid surgery, peripheral revascularization, or amputation for critical limb ischemia. Other major causes of death included infections and cancer. By contrast, overall death rates in persons with normal ACR were equivalent to those in the general population (adjusted SMR 0.8, 95% CI 0.5–1.1), regardless of diabetes duration, indicating that diabetic kidney disease is a major driver of excess mortality in type 1 diabetes. Irrespective of albuminuria level, the eGFR was independently associated with mortality, but in a U-shaped fashion, as shown in Figure 22.21 (217), possibly reflecting confounding from other morbid conditions unrelated to kidney disease at high eGFR levels. The non-linear association reflects serum creatinine confounding due to such factors as low or reduced muscle mass, increased tubular secretion, and extrarenal elimination of creatinine. Moreover, measurement imprecision is greater at lower concentrations of serum creatinine, compounding the difficulty of interpreting serum creatinine levels in those with normal or high-normal GFR (274).

TABLE 22.11

Crude All-Cause and Cause-Specific Death Rates in Adults With Diabetes and Chronic Kidney Disease, U.S., 1999–2004.

TABLE 22.12

Death Rates in Persons With Type 1 Diabetes by Sex, Age, Race, and Baseline Kidney Damage Categories, Pittsburgh Epidemiology of Diabetes Complications Study, 1986–2008.

Likewise, in type 2 diabetes, death rates due to both overall and cardiovascular causes are greatly increased with elevated albuminuria (275,276,277,278). Among 1,993 Pima Indians (55.9% with type 2 diabetes, the only type of diabetes occurring in this population, even at young ages) followed for a median of 11 years, death rates from natural causes increased with worsening kidney function in both nondiabetic and diabetic subjects (268). Figure 22.22 shows that death rates in nondiabetic and diabetic subjects without kidney disease were virtually identical and increased similarly with worsening kidney disease in both groups, suggesting that kidney disease rather than diabetes per se is the major determinant of increased mortality among the diabetic population. The higher overall mortality in those with longer duration of diabetes is due primarily to the greater proportion of person-years of follow-up falling in the categories of worse kidney function (Figure 22.22C). The presence of kidney disease was associated with excess mortality from diabetic kidney disease, CVD, infections, and malignancy in the Pima Indians with diabetes and from infections in those without diabetes. In a cross-sectional analysis including American Indians with type 2 diabetes in the Strong Heart Study (685 with normal albuminuria, 519 with moderate albumin-uria, and 372 with severe albuminuria), participants with severe albuminuria were more likely to experience left ventricular systolic and diastolic dysfunction than those with normal ACR (Figure 22.23) (279). Further, among 4,081 American Indians, 45% with diabetes, reduced eGFR (<90 mL/min/1.73 m²) was associated with increased risk of CVD events, including coronary heart disease, stroke, and heart failure during a median follow-up of 15 years (280). The associations between eGFR measure and CVD events were attenuated after adjusting for albuminuria.

TABLE 22.13

Mortality Risk and Standardized Mortality Ratios in Participants With Type 1 Diabetes, Pittsburgh Epidemiology of Diabetes Complications Study, 1986–2008.

FIGURE 22.21

Risk of Death Associated With Estimated Glomerular Filtration Rate in Type 1 Diabetes. Relative hazard computed in persons with type 1 diabetes: (A) without end-stage renal disease, (B) with normal albuminuria, (C) with moderate albuminuria, and (D) with (more...)

Fewer studies have focused on the noncardiovascular causes of mortality associated with diabetic kidney disease. Persons with CKD are three to four times more likely to have a poor prognosis after acquiring infections than the non-CKD population (281,282,283). Persons with diabetes have a higher risk of community-acquired lower respiratory tract infection, pneumonia, and sepsis with declining eGFR and increasing ACR, independent of age, sex, smoking status, and comorbid conditions of diabetes (282). Among hemodialysis patients with diabetes, adjusted hospitalization rates for infections are 0.5 per patient-year (1), similar to the rate of hospitalizations for CVD and higher than among patients with ESRD due to other causes than diabetes. Infections represented the second leading cause of death (15.9%) after CVD (55.8%) among those who initiated hemodialysis between 1995 and 2009 due to diabetes; the leading fatal infections on dialysis were septicemia and pneumonia (284). Other causes of death in this cohort were malignancy (2.8%), withdrawal from dialysis (5.2%), and unknown or unidentified causes (9.6%). The leading causes of death were the same for each racial/ethnic group (284). Although some reports suggest that both kidney disease, particularly ESRD, and diabetes increase the risk of death from several types of cancer (285,286,287), this is not a uniform finding (288,289,290,291).

Quantitative information about ACR adds significant predictive value to eGFR about the risk of death or ESRD, and therefore, using both ACR and eGFR is significantly better for predicting these outcomes than using either measure alone (292,293,294). An analysis conducted in 10,640 persons with type 2 diabetes enrolled in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial (293) showed similar contributions of high ACR and low eGFR to cardiovascular and kidney events (Figure 22.24). These findings concur with those from a systematic review of the association between microvascular and macrovascular disease in type 2 diabetes (295), which showed an approximately twofold increased risk for cardiovascular events associated with albuminuria or reduced eGFR (Table 22.14) (260,295,296,297,298,299,300,301,302,303,304,305,306,307,308). The strength of these associations remained after adjustments for multiple confounders, suggesting that microvascular and macro-vascular disease in type 2 diabetes may share similar pathophysiologic mechanisms. A meta-analysis of 1,024,977 participants (nearly 13% with diabetes) from 30 general population and high-risk cardiovascular cohorts and 13 CKD cohorts indicated that while the absolute risks for all-cause and cardiovascular mortality are higher in the presence of diabetes, the relative risks of ESRD or death by eGFR and ACR are similar with or without diabetes (309). These findings underscore the importance of kidney disease per se as a predictor of important clinical outcomes, regardless of the underlying cause of kidney disease. Additional information about mortality and causes of death in persons with diabetes can be found in Chapter 35 Mortality in Type 1 Diabetes and Chapter 36 Mortality Trends in Type 2 Diabetes.

FIGURE 22.22

Trends in Age-Sex-Adjusted Death Rates From Natural Causes and Cardiovascular Disease in American Indians With and Without Diabetes, by Severity of Kidney Disease. Trends in age- and sex-adjusted death rates from (A) natural causes and (B) cardiovascular (more...)

FIGURE 22.23

Prevalence of Subnormal Left Ventricular Midwall Shortening and Diastolic Dysfunction in American Indians With Type 2 Diabetes, by Albuminuria, Strong Heart Study, 1993–1995. Comparison between each group was made using chi-squared statistics (more...)

FIGURE 22.24

Association of (A) Urinary Albumin-to-Creatinine Ratio and (B) Estimated Glomerular Filtration Rate Levels During Follow-Up With the Risk for Cardiovascular Events. Closed and open squares represent hazard ratios (HRs) in subgroups for eGFR <60 (more...)

TABLE 22.14

Prospective Studies With at Least 200 Type 2 Diabetes Subjects That Evaluated Hard Cardiovascular Endpoints.

End-Stage Renal Disease

Prevalence of Diabetic ESRD

Kidney failure or ESRD is the most advanced stage of CKD, requiring renal replacement therapy, such as dialysis or kidney transplant, for survival. Since 1988, all persons receiving treatment for ESRD, regardless of age and insurance coverage, are included in the United States Renal Data System (USRDS) registry (1). Consequently, the annual data report published by the USRDS contains the most complete and reliable information on treated ESRD in the United States. Table 22.15 summarizes the incidence and prevalence of treated ESRD according to demographic characteristics, primary diagnosis, and treatment modality in the United States in 2012 (1). In that year, 114,813 new cases of dialysis and transplant were added to the national registry, of which 50,534 (44%) had kidney disease attributed to diabetes. Diabetes is the single largest cause of ESRD in the United States (Figure 22.25) (1). In 1985, the adjusted prevalence of treated ESRD attributed to diabetes was 103 cases per million population, these patients accounting for 19% of prevalent treated ESRD in the United States; by 2012, the prevalence had risen to 731 cases per million population, representing 35% of prevalent treated ESRD in the United States (44% of dialysis patients and 23% of kidney transplant patients) (Table 22.15) (1). An increasing prevalence of diabetes and improved CVD survival are responsible, in part, for this growth (Figure 22.26) (310). About 30% of persons with type 1 diabetes and 10%–40% of those with type 2 diabetes eventually develop kidney failure. Because type 2 is the predominant type of diabetes, it also far exceeds type 1 diabetes as the cause of diabetes-related ESRD. Of the 239,837 prevalent cases of ESRD with diabetes at the end of 2012, type 2 diabetes was responsible for 207,145 (86%) (Table 22.16) (1).

TABLE 22.15

Summary Statistics on Reported End-Stage Renal Disease Treatment, by Age, Sex, Race/Ethnicity, and Primary Diagnosis, U.S., 2012.

FIGURE 22.25

Trends in Incident ESRD Cases and ESRD Incidence Rate, by Primary Diagnosis of ESRD, 1980–2012. ESRD, end-stage renal disease. * Adjusted for age, sex, and race. Standardized to the 2011 U.S. population.

FIGURE 22.26

Incident ESRD Cases (Line), and Increase in ESRD Attributable to Increased Prevalence of Diabetes, Improved Survival Following Myocardial Infarction and Stroke, and U.S. Population Growth in 1991 (Bars). ESRD, end-stage renal disease.

TABLE 22.16

Prevalence of Reported End-Stage Renal Disease, by Primary Diagnosis, Sex, and Race/Ethnicity, U.S., 2008–2012.

Survival of Persons With Diabetic ESRD

Persons with CKD who progress to ESRD receive renal replacement therapy, including hemodialysis, peritoneal dialysis, or kidney transplant, in order to survive. Those with a primary diagnosis of diabetes have lower survival relative to other causes of ESRD (1), primarily because of the coexistent morbidity associated with diabetes, particularly cardiovascular diseases (321,322,323,324), which continue to advance during the course of renal replacement therapy. One- and five-year survival rates in persons with diabetic ESRD are presented by age, sex, race/ethnicity, and primary diagnosis in Appendices 22.1 and 22.2 (1). While survival on dialysis has slowly improved across modalities since the 1990s (Figure 22.28), it remains reduced in persons with diabetes, half of whom die within 3 years of beginning dialysis in the United States (Appendix 22.3) (1). Among incident ESRD patients with a primary diagnosis of type 1 diabetes, first-year mortality declined from 13% in 2001–2005 to 8% in 2006–2010, while the proportion of first-year kidney transplants remained stable at 8% (1).

TABLE 22.17

Incidence Rates of Reported End-Stage Renal Disease Due to Diabetes, by Age, Sex, and Race/Ethnicity, 1985–2012.

FIGURE 22.27

Sex-Adjusted Incident Rates of End-Stage Renal Disease Due to Diabetes, by Age (Years) and Race/Ethnicity, U.S., 1980–2012. Rates are 3-year rolling averages. Data are standardized to the 2011 U.S. population. Af Am, African American; Hisp, Hispanic. (more...)

TABLE 22.18

Incidence of Reported End-Stage Renal Disease, by Primary Diagnosis, Sex, and Race/Ethnicity, U.S., 2008–2012.

African Americans (325,326), Hispanics (327), Asians (1), and American Indians (1,328) treated for diabetic ESRD have a lower risk of death compared with whites (Appendix 22.4) (1). Among patients on hemodialysis due to diabetic kidney disease, the risk of death was 31% lower in American Indian, African American, or Hispanic patients compared with whites and 38% lower in Asians. Among American Indians, those with full Indian blood ancestry had the lowest adjusted risk of death compared with whites (HR 0.58, 95% CI 0.55–0.61) (Figure 22.29) (284). The risk of death increased to 0.95 (95% CI 0.82–1.11) in those with less than one-quarter American Indian ancestry (284), suggesting that hereditary factors play a role in how patients respond to dialysis treatment. Similarly, a study conducted in white, African American, and Hispanic incident dialysis patients between 1995 and 2009 showed lowest mortality risk in Hispanics, intermediate in African Americans, and highest in non-Hispanic whites (326). Although patients with diabetes were not analyzed separately, the survival advantage persisted in older patients who were more likely to have diabetes as a cause of ESRD. Similar to persons with ESRD in general, the leading causes of death among adults with diabetes who started dialysis in 1995–2009 were CVD, representing 58% of the deaths, and infections, representing 13% of the deaths; malignancy accounted for 3% and withdrawal from dialysis for 5% of the deaths. Nonetheless, the adjusted annual death rate in patients with diabetes as a primary cause of ESRD improved steadily since 1985, more so than among patients with other causes of ESRD (Appendix 22.5) (1).

FIGURE 22.28

Five- and Ten-Year Survival for Incident Persons With Diabetes, by End-Stage Renal Disease Treatment Modality, U.S., 1985–2007. Adjusted for age, sex, race, and primary diagnosis. Reference cohort is 2011 incident ESRD population. HD and CAPD/CCPD (more...)

Kidney transplant recipients with diabetes have much better survival than those on dialysis, as shown in Figure 22.28 (1). In 2012, the adjusted death rate in those with diabetes-related kidney transplant was 45 cases per 1,000 person-years at risk, significantly lower than the 186 cases per 1,000 person-years among those on dialysis, and lower even than the 88 cases per 1,000 person-years among those on the waiting list for kidney transplant, although the transplant candidates are presumably similar in other respects to those who receive transplants (329,330). The lifespan increase after kidney transplant was greater among persons with ESRD due to diabetes than to other causes (331), indicating a significant impact of the type of renal replacement therapy (transplant versus dialysis) on long-term survival.

FIGURE 22.29

Hazard Ratios for Death From Any Cause Among Non-Hispanic American Indians With Diabetes at Initiation of Hemodialysis, by Degree of American Indian Ancestry. Information on American Indian ancestry was obtained from the IHS patient database. The reference (more...)

Risk Factors for Diabetic Kidney Disease

Numerous risk factors have been identified for the development and progression of diabetic kidney disease. In this section, the evidence for some of the more prominent factors is reviewed.

Hypertension

High blood pressure is related to diabetic kidney disease in many cross-sectional and longitudinal studies of both type 1 and type 2 diabetes. In type 1 diabetes, this relationship frequently reflects elevation of blood pressure in response to kidney disease (362,363,364,365); whereas in type 2 diabetes, the onset of hypertension generally precedes diabetic kidney disease and is often associated with obesity. The risk of kidney disease is three times as high in persons with type 1 diabetes who have a hypertensive parent as in those whose parents are not hypertensive (Figure 22.35) (366). In addition, those with kidney disease have a higher prevalence of parental hypertension and a higher mean arterial blood pressure during adolescence (367). Increased blood pressure during sleep may herald the development of moderate albuminuria in adolescents and young adults with type 1 diabetes, as shown in Figure 22.36 (368). In that study, blood pressure was monitored at 2-year intervals for up to 9 years or as long as the ACR was in the normal range; a ratio of ≤0.9 between the mean nighttime systolic pressure and the mean daytime systolic pressure defined the dipping during sleep. Moderate albuminuria did not develop in those with poor metabolic control in whom blood pressure remained normal, suggesting that nocturnal elevation in blood pressure may identify those with type 1 diabetes who are most susceptible to progression of kidney disease.

FIGURE 22.30

Four-Year Incidence of Proteinuria in Type 1 Diabetes, By Glycosylated Hemoglobin (A1c) Level, Wisconsin, 1980–1986. Proteinuria is defined as urinary protein excretion ≥0.30 g/L, determined by reagent strip. Conversions for A1c values (more...)

FIGURE 22.31

Incidence of Proteinuria in Pima Indians With Type 2 Diabetes, by OGTT Glucose Level and Diabetes Duration. Incidence of proteinuria (protein-to-creatinine ratio ≥1.0 g/g) by duration of diabetes in 480 Pima Indians with type 2 diabetes, according (more...)

In Pima Indian offspring with type 2 diabetes, the prevalence of proteinuria was similar if neither parent or only one parent had hypertension (8.9% and 9.4%, respectively) but was significantly higher if both parents had hypertension (18.8%), after adjustment for age, sex, duration of diabetes, and 2-hour postload plasma glucose concentration in the offspring and diabetes in the parents (369). The odds for proteinuria in the offspring when both parents had hypertension was 2.2 times (95% CI 1.2–4.2) that when only one parent had hypertension. This relationship was present even when controlled for the effects of blood pressure and its treatment in the offspring. In addition, higher blood pressure before the onset of type 2 diabetes was related to a higher prevalence of elevated albuminuria after the onset of diabetes, suggesting that blood pressure plays a causal role in the development of diabetic kidney disease (Figure 22.37) (370).

Sodium-lithium countertransport activity, a genetically influenced trait, is often higher in persons with essential hypertension and in those whose parents have essential hypertension (371,372,373,374). In type 1 diabetes, elevated rates of countertransport activity are reported in persons with moderate albuminuria or proteinuria (Figure 22.38) (375,376,377,378), elevated GFR (379), and proliferative retinopathy (380). These findings suggest that diabetic persons with hypertension and with elevated sodium-lithium countertransport activity are at greater risk for CKD and possibly other microvascular complications, although these findings have not been uniformly confirmed (378,381,382). Few studies assessed this relationship in those with type 2 diabetes; some found an association between higher sodium-lithium countertransport activity and albumin-uria (383,384,385), and others did not (386,387).

Lipids

Many of the abnormalities in plasma lipoproteins associated with kidney disease are sequelae of kidney dysfunction, yet dyslipidemia may also play a role in the pathogenesis of glomerular injury (388,389,390). Persons with diabetes and predialysis CKD typically have significant hypertriglyceridemia, elevated LDL, and low high-density lipoprotein (HDL) cholesterol levels. These abnormalities are more pronounced in persons with severe albuminuria than those with moderate albuminuria (33,391,392,393) but tend to subside with progression to uremia and dialysis (Table 22.19) (394). Besides quantitative changes, lipid particles in people with diabetes change qualitatively; LDL and HDL particles tending to be smaller and denser with advancing CKD (393,395).

FIGURE 22.32

Pathways for Potential Interactions Between Glucose Metabolism and Hemodynamic Factors Leading to Diabetic Nephropathy. PKC, protein kinase C; TGF-β, transforming growth factor beta; VEGF, vascular endothelial growth factor.

In type 1 diabetes, LDL cholesterol predicted progression of diabetic kidney disease as defined by a doubling of albuminuria or a decline in creatinine clearance in excess of 3 mL/min/year (396). In that study, LDL cholesterol was associated with elevated albuminuria after nearly 9 years of follow-up; a higher triglyceride content of very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) particles predicted worsening of moderate albuminuria, whereas smaller LDL size was associated with declining kidney function in persons with severe baseline albuminuria. These findings suggest that specific lipids or lipid profiles may influence the onset or progression of diabetic kidney disease, although these findings have not been consistently observed (340,397,398,399).

In type 2 diabetes, prospective studies with long follow-up found that LDL cholesterol increases the risk for severe albuminuria (400) and ESRD (401). In a post hoc analysis of 1,061 persons with type 2 diabetes included in the Reduction of Endpoints in Non-insulin dependent diabetes with the Angiotensin II Antagonist Losartan (RENAAL) study, the risk of ESRD was 32% higher for each 50 mg/dL (1.30 mmol/L) increase in LDL cholesterol concentration and 67% higher for each 100 mg/dL (2.59 mmol/L) increase in total cholesterol concentration; lowering LDL cholesterol concentrations with a statin reduced the 1-year risk of ESRD, although concurrent treatment with losartan, an angiotensin receptor blocker (ARB), likely contributed to improving this outcome by reducing both lipid levels and ACR (401). Elevated plasma triglycerides are associated with increased risk for both moderate and severe albuminuria (400) and with ESRD in type 2 diabetes (402). In addition, low concentrations of HDL cholesterol predict increased risk of albuminuria progression in persons with type 2 diabetes and moderate albuminuria (403,404). In the UKPDS, each mmol/L decline in HDL cholesterol increased the risk of doubling of serum creatinine concentration nearly threefold (HR 2.78, 95% CI 1.01–7.68) 15 years after the diagnosis of type 2 diabetes (400). The Strong Heart Study examined the relationship between plasma lipoprotein concentrations and the risk of elevated albuminuria (ACR ≥30 mg/g) in 671 American Indians with type 2 diabetes who were followed for a mean of 3.9 years (405). At baseline, small LDL (particle size <254 Å, measured by gradient gel electrophoresis) was present in 38% men and 25% women, and large LDL (particle size ≥257 Å) was present in 50% men and 61% women. A low HDL cholesterol concentration was associated with elevated ACR in women only (OR 0.56, 95% CI 0.32–0.98) after adjustment for age, duration of diabetes, hypoglycaemic treatment, A1c, study site, degree of Indian heritage, mean arterial blood pressure, baseline albumin excretion, insulin concentration, BMI, alcohol consumption, and physical activity. The association between HDL cholesterol and increased ACR in women was largely explained by a HDL cholesterol concentration <0.9 mmol/L, with little additional effect at higher HDL concentrations (Figure 22.39) (405). No other lipids were found to increase the risk of incident albuminuria; high levels of total and VLDL triglycerides and small LDL size were positively, but not significantly, associated with abnormal albuminuria. In the absence of a standard measure of insulin resistance, however, the study could not determine whether low HDL cholesterol itself, insulin resistance, or other correlated variables are most prominently increasing the risk of nephropathy (405).

FIGURE 22.33

Morphometric Measurements in Kidney and Skeletal Muscle From Identical Twins Discordant for Type 1 Diabetes. (A) Basement membrane width (nm) and (B) fractional volume of the mesangium (%). Values for twins without diabetes (●) are linked to values (more...)

FIGURE 22.34

Renal Histologic Changes at Baseline and 5 and 10 Years After Pancreas Transplantation. (A) Thickness of the GBM, (B) thickness of TBM, (C) mesangial fractional volume, and (D) mesangial matrix fractional volume are shown before (baseline) and after pancreas (more...)

Dyslipidemia might contribute to onset and progression of diabetic kidney disease through mechanisms similar to those responsible for arterial atherogenesis (389,406,407). The diabetic environment facilitates glomerular production of triglycerides and cholesterol, which appear to cause kidney injury both directly by accumulating in the cellular and extracellular structures and indirectly by stimulating the expression of prosclerotic, proliferative, and proinflammatory cytokines (85,390,406). Hypercholesterolemia may impair the kidney’s hemodynamic responses and tubular function by decreasing nitric oxide production and/or increasing superoxide activity in the kidney (408,409,410,411,412), with resulting antidiuretic and antinatriuretic effects (413). Although not directly affecting GFR, these actions may play a role in the development of systemic hypertension associated with diabetes (413). Oxidized LDL and free fatty acids can cause structural and functional damage to podocytes by inducing mitochondrial dysfunction and accumulation of reactive oxygen species (414), suggesting a direct causal role in the development and progression of proteinuria. Experimental rodent models of type 1 and type 2 diabetes indicate that down-regulation of glomerular ATP-binding cassette transporter (ABCA1) expression can lead to excessive cholesterol accumulation in podocytes (415,416). Under normal conditions, ABCA1 mediates the efflux of cholesterol to lipid-poor apolipoproteins (primarily Apo A1) to form HDLs. This mechanism has also been demonstrated in glomerular transcripts from persons with diabetic kidney disease when compared with living normal controls (417,418). Nevertheless, a definitive role for dyslipidemia in the development and progression of diabetic kidney disease in humans remains to be established.

FIGURE 22.35

Mean Blood Pressure in Parents of Persons With Type 1 Diabetes and With or Without Proteinuria. Family study of diabetes, including 26 surviving parents of 17 persons with type 1 diabetes and proteinuria and parents of 17 matched persons without diabetes (more...)

FIGURE 22.36

Nocturnal Systolic Blood Pressure According to Albuminuria and Level of Glycosylated Hemoglobin (HbA_1c) in Type 1 Diabetes. (A) Nocturnal systolic pressure in 14 subjects who subsequently developed moderate albuminuria (microalbuminuria) and in 61 subjects (more...)

Dietary Protein

In epidemiologic studies, higher-protein diets are associated with development of diabetes, as well as with greater risk of kidney damage or loss of function, especially in individuals with diabetes, hypertension, and/or reduced kidney function. These risks are mainly confined to animal meat intake. Vegetable or dairy proteins do not appear to adversely affect kidney health (419,420).

In experimental models, excessive protein intake causes kidney vasodilation and glomerular hyperperfusion with a resulting increase in the intraglomerular pressure that leads to proteinuria and glomerular damage (421,422). In addition, long-term high protein intake accelerates structural and functional injury in models of diabetic kidney disease, whereas low-protein diets offer kidney protection (423,424,425,426,427,428). Physiologic studies in humans confirm the hyperfiltration response found in animal studies, but only in the presence of chronic hyperglycemia (429,430). On the other hand, dietary protein of animal origin may be a significant source of advanced glycation endproducts, particularly when cooked at high temperatures or in fat (431). In vitro studies indicate that advanced glycation endproducts can produce kidney damage through a variety of mechanisms even from the very early stages of kidney disease, but their contribution to disease progression is still unclear. Two other studies explored the association between CKD and dietary acid load, a surrogate for the intake of acid-inducing foods (rich in animal proteins) versus base-inducing foods (fruits and vegetables), quantified as the net acid excretion estimated from 24-hour dietary recall (432), and between CKD and metabolic acidosis (433). The former found that higher dietary acid load among 12,293 U.S. adult participants in the NHANES 1999–2004 was associated with eGFR <60 mL/min/1.73 m² or elevated albuminuria in participants with hypertension and in those without hypertension or diabetes. Older age, poverty, black race, and male sex, but not diabetes, were significantly associated with an increasing level of net acid excretion in this population. In the latter study (including 21% persons with diabetes), serum bicarbonate level ≤22 mEq/L was associated with a 54% higher risk of eGFR decline during a median follow-up of 3.4 years after adjustment for baseline eGFR and clinical, demographic, and socioeconomic patient characteristics. Since this study had no information on patients’ diet or medication during the follow-up, the findings cannot be attributed directly to dietary protein intake.

FIGURE 22.37

Prevalence of Elevated Albuminuria in Pima Indians After Diagnosis of Type 2 Diabetes, by Blood Pressure Before Onset of Diabetes. Elevated albuminuria is defined by urinary albumin-to-creatinine ratio ≥100 mg/g. Participants with the highest (more...)

FIGURE 22.38

Correlation of Sodium-Lithium Countertransport Activity With Nephropathy. Sodium-lithium (Na-Li) countertransport activity measured in 21 persons with type 1 diabetes and normoalbuminuric matched controls. Diabetic nephropathy is defined by a urinary (more...)

Thus, although a theoretical case can be made for the impact of dietary protein on the development of diabetic kidney disease, no observational data in humans unequivocally support such a role.

Smoking

A cross-sectional analysis of 61,675 participants in the NKF’s Kidney Early Evaluation Program (KEEP), 27.1% of whom had CKD, identified smoking along with obesity, diabetes, hypertension, and CVD as significant factors associated with CKD (434). Similarly, in 14,632 participants in the NHANES 1999–2004, 15.3% of whom had CKD, current smoking increased the odds of CKD by 31% (434).

TABLE 22.19

Changes in Lipids, Lipoproteins, Apo A, and Apo B, by Stages of Chronic Kidney Disease.

In a large population-based study, maternal smoking during pregnancy increased the odds of albuminuria in the full-term offspring who later developed type 1 diabetes by threefold, independent of low birth weight or blood pressure levels (435). In young persons with type 1 diabetes who smoked, the risk of albuminuria was nearly threefold higher than in nonsmokers (436). Likewise, the frequency of proteinuria (>500 mg/24 hours) was twice as high in smokers as in nonsmokers of similar age, duration of type 1 diabetes, A1c, and prevalence of hypertension (437). On the other hand, no relationship was observed between smoking and GFR decline in a longitudinal study of type 1 diabetic persons with albuminuria and serial ⁵¹Cr-EDTA GFR measurements over a median follow-up of 7 years (Figure 22.40) (438), although other smaller studies identified an association (439,440,441).

In men with type 2 diabetes, cigarette smoking was associated with higher A1c and ACR levels in a dose-dependent fashion (442), with nearly one-half of the heavy smokers having A1c >9% (>75 mmol/mol) and ACR ≥30 mg/g. The odds of elevated ACR were 2.8–3.2 times as high in those smoking more than 15 pack-years than in nonsmokers, regardless of age, blood pressure control, or diabetes duration (Figure 22.41). This and other studies in type 2 diabetes suggest that smoking is associated with kidney damage regardless of blood pressure control and treatment with RAAS inhibitors (443,444). Smoking also increased the risk of moderate or severe albuminuria (adjusted OR 1.50, 95% CI 1.21–1.86) after 5 years of follow-up in a large population-based study of persons with type 2 diabetes and no kidney disease at baseline from the Swedish National Diabetes Registry, although no association was found with the rate of kidney function decline (445).

FIGURE 22.39

Effect of Serum HDL Cholesterol Concentration on the Incidence of Albuminuria in American Indians With Type 2 Diabetes, Strong Heart Study, 1989–1996. Effect of HDL cholesterol concentration on the incidence of albuminuria (ACR ≥30 mg/g) (more...)

Nicotine promotes the proliferation of mesangial cells and upregulates specific molecules involved in extracellular matrix production (446,447). In db/db mice, exposure to tobacco smoke for 8 weeks induces significant mesangial expansion and increases TGF-β and fibronectin expression compared with nonexposed mice (447). These changes, however, are not accompanied by significant changes in urinary albumin excretion. Experimental prenatal exposure to smoking results in neonates whose kidneys are proportionally smaller and exhibit reduced thickness of proximal tubule cuboidal epithelium, dysmorphia of the proximal and distal convoluted tubules, and immature glomeruli (448). In addition to nicotine, mainstream cigarette combustion produces over 4,000 compounds, including reactive oxygen species, carbon monoxide, nitric oxide, toxic metals, and polycyclic aromatic hydrocarbons, which may add to an already increased susceptibility to kidney disease in persons with diabetes (449). Although the precise mechanisms are unclear, tobacco smoking is known to cause vasoconstriction, impair platelet function and coagulation, and alter blood pressure (450,451). Given that persons with diabetes already have widespread vascular damage as a consequence of their diabetes (452), smoking may serve to accelerate the process.

FIGURE 22.40

Impact of Smoking Habit on Kidney Function, Adjusted for Difference in Blood Pressure Between Groups, Steno Clinic, 1983–1997. GFR was measured yearly by the ⁵¹Cr-EDTA plasma clearance technique. In 301 persons with type 1 diabetes and severe (more...)

Periodontal Disease

Periodontal disease, which often occurs in the absence of diabetes, is also a frequent complication of diabetes (462), contributing to poor glycemic control, low-grade chronic systemic inflammation, and increased risk of macro-vascular and microvascular complications (462,463,464). (See also Chapter 31 Oral Health and Diabetes.) Because diabetes is the leading cause of ESRD, periodontitis is frequently present among dialysis patients, increasing the risk for cardiovascular death (463,465). Severity of periodontitis and being edentulous predicted severe albuminuria and ESRD in a dose-dependent manner among adults with type 2 diabetes followed for a median of 9 years (466). A study investigating the relationships between diabetes, periodontal disease, and CKD in the NHANES 1988–1994 population suggested a bidirectional relationship between CKD and periodontal disease, with periodontitis increasing the risk of CKD both directly and mediated by hypertension and duration of diabetes, and CKD having a direct effect on periodontitis (467). Control of periodontal infection in diabetic adults improves A1c level (462) and reduces the concentration of various markers of inflammation, coagulation, and adhesion (468,469). Whether such control also reduces the onset or progression of diabetic kidney disease is not known.

FIGURE 22.41

Adjusted Odds Ratios of Albuminuria in Males With Type 2 Diabetes, Overall and by Age, Blood Pressure, Duration of Diabetes, and Smoking Habit, DMIDS Project, 2003–2007. The reference group, nonsmokers, is represented by the horizontal line. Study (more...)

Drug Nephrotoxicity

Between 1999 and 2002, 27% of adults in the United States reported habitual use of analgesic and nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin (470). Cumulative toxicity from prolonged exposure to these drugs is a possible cause of chronic kidney disease, particularly among the elderly and those with diabetes, underlying volume depletion, heart failure, or preexisting kidney dysfunction (471,472,473,474,475). NSAIDs are cyclooxygenase (COX) inhibitors that reduce prostaglandin production in the kidneys and elsewhere. Because kidney perfusion in persons with kidney dysfunction is maintained, in part, by the local synthesis of vasodilating prostaglandins (475,476,477,478), changes in blood flow due to inhibition of prostaglandin synthesis may be responsible for ischemia/reperfusion injury and worsening kidney dysfunction (479,480). Tubulointerstitial changes associated with analgesic use may also influence the progression of a number of kidney diseases (481,482). No data are available comparing the nephrotoxicity profile of various NSAIDs; indomethacin is suggested to cause more hyperkalemia (483) and acute kidney injury (484) than other NSAIDs, and nephritic syndrome is more often associated with fenoprofen (485). Nonetheless, lifetime use of nonnarcotic analgesics among 1,697 women participating in the Nurses’ Health Study was not associated with significant changes in kidney function, even in those who used high doses of these drugs (486). Similarly, among 11,032 initially healthy men in the Physicians’ Health Study (487), moderate analgesic use had an insignificant effect on serum creatinine levels or creatinine clearance over a 14-year period. Subgroup analyses that included those with a history of diabetes or hypertension also found no associations between kidney function decline and consumption of NSAIDs. On the other hand, annual intake of 105–365 acetaminophen pills doubled the odds of ESRD in 242 persons with diabetes, and a cumulative lifetime intake of ≥1,000 tablets nearly tripled the odds (Table 22.20) (475). Interestingly, the introduction of eGFR reporting in the health records of a Scottish population resulted in reduced prescribing of NSAIDs and a significant improvement in eGFR among those who stopped taking NSAIDs, suggesting that eGFR reporting may result in safer prescribing (488).

FIGURE 22.42

Effect of Youth-Onset Type 2 Diabetes on Incidence of End-Stage Renal Disease in Pima Indians, by Diabetes Duration and Age, 1965–2002. Participants were observed from onset of diabetes to outcome or December 2002. Youth-onset type 2 diabetes (more...)

TABLE 22.20

Risk of End-Stage Renal Disease in Persons With Diabetes, By Use of Acetaminophen, Aspirin, and Nonsteroidal Anti-Inflammatory Drugs.

A variety of other commonly used or prescribed medicines have been associated with kidney injuries, including tubulointerstitial and glomerular lesions (489). Two main mechanisms of interaction with kidney structures have been described: direct cellular toxicity and immune-mediated injury. Direct glomerular cell injury was associated with nodular glomerulosclerosis, thrombotic microangiopathy, minimal change disease, and focal segmental glomeruloscrerosis (490). Immune-mediated drug injuries include lupus-like renal lesions, ANCA (anti-neutrophil cytoplasmic antibodies)-related pauci-immune vasculitis, secondary membranous nephropathy, and minimal change disease (Table 22.21) (490). These injuries and the related clinical parameters are generally reversible after withdrawing the offending drug. Nonetheless, establishing a causal link between drug exposure and the development of renal pathology is often difficult, due to lack of specific markers, recall bias, underlying diseases, heterogeneity of symptoms, and physicians’ unfamiliarity with the renal effects caused by certain drugs.

Contrast-induced nephropathy is one of the most commonly reported causes of acute kidney failure in hospitalized patients. Those with diabetes and GFR <60 mL/min/1.73 m² are at particularly increased risk for contrast-induced nephropathy, especially with use of high-osmolar iodinated contrast media (491).

Autonomic Neuropathy

In the United States, between 25% and 28% of adults age ≥40 years with diabetes have peripheral neuropathy (492). Sympathetic neuropathy with ensuing alteration of glomerular vascular resistance is assumed to hasten deterioration of kidney function in persons with autonomic neuropathy (493). Whether autonomic neuropathy per se is part of the pathogenic process leading to diabetic kidney disease or is a reflection of the severity of diabetes is unclear (493,494,495). Nonetheless, the two complications of diabetes occur together frequently. One study reported that half of the deaths in those with type 1 diabetes and autonomic neuropathy were attributed to diabetic kidney disease (496 More information about diabetic neuropathy is provided in Chapter 23 Peripheral and Autonomic Neuropathy in Diabetes.

TABLE 22.21

Drug-Induced Glomerular Lesions.

Pregnancy

Among women with normal kidney function, regardless of the presence or absence of diabetes, pregnancy is associated with a rise in GFR of about 50% that persists through the 37th week of gestation (274,497) and is accompanied by a moderate increase in urinary protein excretion (274,498). Table 22.22 summarizes ACR and kidney function characteristic of nondiabetic and diabetic pregnancies (499). Most diabetic women with nephropathy have successful pregnancy outcomes. Those with advanced kidney disease, poor glycemic control, or hypertension, however, are at increased risk of pregnancy complications and subsequent deterioration in kidney function (497).

Although neither pregnancy nor parity adversely affect the course of early diabetic kidney disease (500), the few available studies suggest that women with more severe kidney impairment may be at greater risk of progression to ESRD. In a retrospective review of pregnant women with type 1 diabetes, a creatinine clearance <90 mL/min or a urinary protein excretion >1 g/day during the first 20 weeks of gestation was associated with a greater decline in kidney function at approximately 3 years after delivery than in those with less severe nephropathy during early pregnancy (18.9 mL/min/year compared with 6.6 mL/min/year) (501). On average, the creatinine clearance declined from 120±53.1 mL/min (mean±standard deviation) in the first weeks of pregnancy to 77.9±45.4 mL/min at the 3-year follow-up (p=0.01); follow-up proteinuria remained unchanged from the initial measurement during pregnancy (2.94±4.26 g/24 hours vs. 1.74±1.33 g/24 hours, p=0.25) (Table 22.23) (501). Eight of the 34 women who had a follow-up examination maintained a proteinuria level >3 g/24 hours (501). Mothers with advanced kidney disease were more likely to experience preeclampsia and have offspring with low birth weight. Worsening of preexisting diabetic kidney disease was also reported among women with type 1 diabetes who were followed for up to 26 years (502). In this study, morbidity and mortality remained higher in women with pregnancies than in those without 10 years after their last delivery (502). Preeclampsia is more frequent in women with diabetes and is associated with 7.7-fold higher odds of subsequent CKD than in those with normotensive pregnancies (503).

TABLE 22.22

Kidney Function During and After Pregnancy, by Presence or Absence of Diabetes.

TABLE 22.23

Serial Creatinine Clearance and 24-Hour Proteinuria Measurements During and After Pregnancy in Participants With Type 1 Diabetes, 1988–1994.

Familial and Genetic Factors

Familial aggregation of diabetic kidney disease and racial/ethnic differences in disease susceptibility suggest a genetic predisposition to diabetic kidney disease. Three initial studies reported familial clustering of diabetic kidney disease (518,519,520). In one study, nephropathy was reported in 83% of the diabetic siblings of persons with type 1 diabetes and kidney disease, but in only 17% of the diabetic siblings of persons with type 1 diabetes without kidney disease (Figure 22.45) (518). Moreover, 41% of the affected siblings of persons with kidney disease had ESRD. A similar study in persons with type 1 diabetes found kidney disease in 33% of the diabetic siblings of diabetic persons with kidney disease but in only 10% of the diabetic siblings of persons without kidney disease (519). Familial clustering is also found in type 2 diabetes. In two generations of Pima Indians with type 2 diabetes (520), the frequency of proteinuria in the diabetic offspring was higher if both diabetic parents had proteinuria than if neither did, and if one parent had proteinuria, the prevalence was intermediate (Figure 22.46).

FIGURE 22.43

Cumulative Incidence of Diabetic End-Stage Renal Disease Among Pima Indians, by Offspring’s Age and Duration of Diabetes, According to Exposure to Diabetes in Utero, 1965–2006.

A number of candidate genes have been identified that may be related to diabetic kidney disease. In Pima Indians, a potential susceptibility locus for ESRD was found within the plasmocytoma variant 1 (PVT1) gene (521), which was confirmed in subjects of European descent with type 1 diabetes (522). Genome-wide association studies of subjects with type 1 diabetes in the Genetics of Kidneys in Diabetes (GoKinD) study (523) found single nucleotide polymorphisms (SNPs) in the FERM domain-containing protein 3 (FRMD3) gene and near the cysteinyl-tRNA synthetase (CARS) gene associated with diabetic kidney disease, defined by overt proteinuria or ESRD. These associations were confirmed in the DCCT/Epidemiology of Diabetes Interventions and Complications (EDIC) prospective study of type 1 diabetes (524), and susceptibility loci near CARS were common to both types of diabetes (525). Engulfment and cell motility 1 (ELMO1) loci were associated with diabetic kidney disease in European (526) and Japanese (527) individuals with type 1 diabetes and in African Americans with ESRD due to type 2 diabetes (528). The Family Investigation of Nephropathy and Diabetes (FIND) study (529) collected DNA and cell lines from European American, African American, American Indian, and Hispanic American families in whom type 2 diabetes was the predominant cause of kidney disease. For all ethnicities combined, the strongest evidence for linkage to diabetic kidney disease was on the long arm of chromosomes 7, 14, 18, and on the short arm of chromosome 10; to ACR on the long arm of chromosomes 2, 7, and 15; and to eGFR on the long arm of chromosomes 1, 7, and 8 (530,531).

FIGURE 22.44

Association Between Birth Weight and Chronic Kidney Disease. The horizontal dashed line represents the reference birth weight (2,500–3,999 g). Birth weight is based on Washington state birth records from 1987–2008. Chronic kidney disease (more...)

FIGURE 22.45

Kidney Status of Siblings of Type 1 Diabetes Probands, by Diabetic Nephropathy. Probands with diabetic nephropathy were persons with kidney transplant for diabetic ESRD; probands without diabetic nephropathy were persons with albumin excretion rate <45 (more...)

A meta-analysis assessing the effects of all genetic variants associated with severe albuminuria or ESRD found 24 reproducible genetic variants associated with diabetic kidney disease (Figure 22.47) (532). These genetic variants are involved in the renin-angiotensin system, polyol pathway, oxidative stress, inflammation, angiogenesis, glomerular filtration barrier defects, cell growth, differentiation, and apoptosis, supporting their roles in the pathogenesis of diabetic kidney disease (532). Albuminuria and, to a greater degree, GFR are heritable (533), but the actual genes responsible for diabetic kidney disease remain elusive. Although these findings are not universal, they do suggest that genetic factors may predispose some individuals to a higher risk of diabetic kidney disease than others.

FIGURE 22.46

Prevalence of Proteinuria in Offspring, by Number of Parents With Proteinuria, Pima Indians. Proteinuria is defined as urinary protein excretion ≥1 g protein/24 hours. Data are adjusted for age, systolic blood pressure, diabetes duration, and (more...)

FIGURE 22.47

Genetic Variants Reproducibly Associated With Diabetic Nephropathy. (A) All genetic variants in or near a gene that were reproduced in an independent study and significantly associated with diabetic nephropathy after meta-analysis. (B) All genetic variants (more...)

In addition to specific genetic factors, the multifaceted cross-talk between genes and environmental factors can induce tissue-specific epigenetic changes, i.e., heritable changes in gene expression without alterations in the DNA sequence that can lead to aberrant gene regulation expressed as pathologic phenotype. Epigenetic changes include DNA cytosine methylation, histone posttranslational modifications in chromatin, and noncoding RNAs, all of which can modulate diabetes complications through alterations in gene expression (534). Through epigenetic mechanisms, for example, cells acquire metabolic memory of prior hyperglycemic exposure that appears to mediate the development and progression of diabetic kidney disease (535,536). Hyperglycemia-induced epigenetic aberrations alter transcription factors involved in the expression of genes mediating the pathogenesis of diabetic kidney disease (Figure 22.48) (534). Several microRNAs and certain long noncoding RNAs also have regulatory roles in diabetic kidney disease, including promoting/modulating fibrotic gene expression in renal cells by targeting transcription repressors (535). Although the mechanisms of such cellular memory are not entirely elucidated, its presence is supported by the regression of morphologic lesions in diabetic kidneys after a long period of normoglycemia following pancreas transplantation (361). Similarly, the longlasting effects of previous strict glycemic control observed in persons with type 1 diabetes in the DCCT or type 2 diabetes in the UKPDS could be attributed to cellular metabolic memory. Therapeutic approaches targeting TGF-β, angiotensin II type 1 receptor, or microRNAs can block some of the events involved in the pathogenesis of diabetic kidney disease, suggesting the need for novel therapies.

FIGURE 22.48

Signaling and Epigenetic Networks Involved in the Pathogenesis of Diabetic Complications and Metabolic Memory. Metabolic and hemodynamic disorders associated with diabetes can upregulate growth factors and lipids that trigger signaling pathways, transcription (more...)

Treatment of Diabetic Kidney Disease

A number of large, well-designed clinical trials have examined the effects of treatments on the onset and progression of kidney disease in persons with diabetes. The results of these trials helped inform and refine clinical practice guidelines for the management of persons with diabetes and kidney disease. This section summarizes the current understanding of renoprotective treatments in those with diabetes.

Metabolic Control

Epidemiologic studies indicate that hyperglycemia plays a fundamental role in the development of diabetic kidney disease, as reviewed previously in this chapter. A number of clinical trials examined the effect of metabolic control on the course of diabetic kidney disease (244,524,537,538,539,540,541,542,543,544,545,546,547,548,549,550,551,552).

In type 1 diabetes, evidence that intensive treatment of hyperglycemia prevents elevation of albuminuria or delays its progression comes from the combined DCCT and its long-term follow-up, the EDIC observational study (524,542). In the DCCT, 1,441 persons with type 1 diabetes were randomly divided into two groups, half receiving intensive insulin therapy and the other half receiving conventional therapy. Participants were followed for a mean of 6.5 years (245). Intensive insulin therapy reduced the risks of moderate albuminuria (≥40 mg/24 hours) and severe albuminuria (≥300 mg/24 hours) by 39% and 54%, respectively. Figure 22.49 shows the cumulative incidence of moderate and severe albuminuria among persons in the DCCT. At the end of the randomization period, the two treatment groups were followed for 8 more years, on average, during the EDIC study to determine the long-term effects of intensive treatment on kidney disease (524). Despite the fact that the difference in A1c levels achieved during the DCCT (7.4% [57 mmol/mol] in the intensive treatment vs. 9.1% [76 mmol/mol] in the conventional treatment group, p<0.01) disappeared promptly during the EDIC study, the beneficial effect of early intensive treatment persisted for 8 years after the end of randomization, with 57% lower adjusted risk for moderate albuminuria and 84% lower risk for severe albuminuria in the former intensively treated group relative to the conventionally treated group (Figure 22.50) (524). In later analyses, although the risk of ESRD did not differ significantly between treatment groups during 22 years of combined follow-up (0.5 cases/1,000 person-years in the intensive treatment and 1.1 cases/1,000 person-years in the conventional treatment group, p=0.10) (542), intensive early metabolic control reduced the risk of impaired GFR, defined as a sustained eGFR <60 mL/min/1.73 m², by 50% (95% CI 18%–69%, p=0.0006). Intensive metabolic control also reduced CVD outcomes by 42%, with a specific 57% decrease in myocardial infarction, stroke, or death from CVD—effects that were partly mediated by the reduced incidence of diabetic kidney disease (543).

The long-term positive effect of intensive glycemic control—the “glycemic legacy”—observed in persons with type 1 diabetes followed in the DCCT/EDIC study (543) was confirmed in those with type 2 diabetes in the UKPDS who were followed for up to 10 years after randomization to an intensively treated or standard care group (544), suggesting that glycemic control is more likely to reduce long-term microvascular and macrovascular complications when introduced early (545,546). The level of glycemic control achieved in the UKPDS was similar to that achieved in the DCCT. Among persons with type 2 diabetes, a meta-analysis of randomized controlled trials (547) exploring the effect of even more intensive glycemic control on microvascular and macrovascular outcomes indicated that more intensive glucose lowering was associated with a significant reduction in the rate of moderate albuminuria only (risk ratio 0.90, 95% CI 0.85–0.96) but had no effects on mortality, kidney failure, or other vascular outcomes. Baseline characteristics and mean A1c levels achieved during standard and intensive glycemic therapy in these clinical trials are shown in Table 22.24 (547,548,549,550,551,552,553). The modest gains in intermediate outcomes across these studies were counterbalanced by a twofold to threefold higher risk of severe hypoglycemia that required the intervention of another person in the intensive treatment arms of the Action to Control Cardiovascular Risk in Diabetes (ACCORD), ADVANCE, and Veterans Affairs Diabetes Trial (VADT) trials (Table 22.25) (551,552,553). The ACCORD trial, targeting an A1c level <6.0% (<42 mmol/mol) in the intensive intervention arm, reported an increased risk of cardiovascular death for intensive versus conventional glycemic control, although it remains unclear whether this effect was related to more hypoglycemic episodes, the use of additional hypoglycemic medicines, or to the target glycemic level itself. Significant weight gain in those receiving intensive treatment might also have offset the beneficial effects of the lower A1c levels. Together, these trials indicate that glycemic control is extremely useful up to a point, but more aggressive glycemic control may be harmful (554).

FIGURE 22.49

Cumulative Incidence of Moderately Elevated Albuminuria and Severe Albuminuria in Participants With Type 1 Diabetes, Diabetes Control and Complications Trial. Moderate albuminuria is defined as an albumin excretion rate ≥40 mg/24 hours; severe (more...)

Persons with advanced kidney disease experience reduced gluconeogenesis and impaired kidney clearance of insulin and certain oral hypoglycemic drugs (555), potentially increasing the likelihood of severe hypoglycemia, particularly when associated with inadequate food intake. Furthermore, because A1c may underestimate the level of glycemia in uremic patients, due to the shortened lifespan of red blood cells and treatment with erythropoietin, establishing an optimal target A1c in uremic patients remains challenging (556,557). Persons with GFR <60 mL/min/1.73 m² or on dialysis often have higher glycemic levels than expected for a given A1c, albeit with a wide variation in the glucose/A1c relationship (558,559,560,561,562,563). The Dialysis Outcomes and Practice Patterns Study (DOPPS) (564) found a U-shaped association between A1c and all-cause mortality in hemodialysis patients with type 1 or type 2 diabetes. The lowest death rates were associated with A1c levels 7%–7.9% (53–63 mmol/mol), comparable to those found in a population-based study of patients with diabetes and GFR <60 mL/min/1.73 m² who were not on dialysis (565). Another study using time-dependent modeling of A1c values in patients with diabetes on dialysis found similar nonlinear associations with mortality (566). Nevertheless, A1c remains the best clinical marker of long-term glycemic control in persons with diabetes and CKD, particularly if combined with self-monitoring of blood glucose (554). Alternatives to A1c, including measurement of glycated albumin and fructosamine, may be of greater value in these persons, but their clinical value is still being explored.

FIGURE 22.50

Differences in Glycosylated Hemoglobin (A1c) Level and Prevalence and Incidence of Moderate and Severe Albuminuria, by Randomized Treatment Group at the End of the Diabetes Complications and Control Trial and Each Year in the Epidemiology of Diabetes (more...)

Blood Pressure Control

Blood pressure control, particularly with RAAS inhibitors, significantly decreases the risk of progression from moderate albuminuria to severe albuminuria, increases the rate of regression from moderate albuminuria to normoalbuminuria, and decreases the risk of heart failure and overall cardiovascular outcomes in persons with diabetic kidney disease, regardless of type of diabetes (567,568,569). Although several types of antihypertensive drugs are effective in ameliorating the progression of diabetic kidney disease, including beta blockers, non-dihydropyridine calcium channel blockers, diuretics, and RAAS inhibitors, the purported relationship between increased intraglomerular pressure and proteinuria that is mediated by RAAS components, as well as their association with virtually every aspect of kidney disease progression, has prompted many investigators to examine the effect of RAAS inhibitors, including primarily ACE inhibitors and ARB, on the progression of diabetic kidney disease.

TABLE 22.24

Characteristics of Persons With Type 2 Diabetes Included in Randomized Controlled Studies of Intensive Versus Conventional Glycemic Treatment.

TABLE 22.25

Effect of Intensive Versus Conventional Glycemic Control on Kidney Outcomes in Type 2 Diabetes.

A landmark study of 409 mostly hypertensive persons with type 1 diabetes and urinary protein excretion ≥500 mg/24 hours, who were randomized to receive either captopril (an ACE inhibitor) or placebo, found a 48% lower risk of doubling of serum creatinine concentration in the captopril group than in the placebo group after a median follow-up of 3 years (570). The risk of the combined endpoints of death, dialysis, and transplantation was 50% lower (Figure 22.51). A significant renoprotective effect of captopril, however, was limited to those with baseline serum creatinine concentrations ≥1.5 mg/dL. No long-term studies have examined the renoprotective efficacy of ARBs in type 1 diabetes and advanced kidney disease. In persons with type 1 diabetes and lesser levels of ACR, with or without hypertension, randomized controlled studies demonstrate that RAAS inhibitors do not prevent increases in ACR, serum creatinine, or ESRD during up to 5 years of follow-up (Table 22.26) (552,570,571,572,573,574,575,576,577,578,579,580,581,582,583,584,585,586,587). Moreover, when given to normoalbuminuric, normotensive persons with type 1 diabetes, these treatments do not reduce the rate of expansion of the mesangium over a period of 4–5 years (571).

In hypertensive persons with type 2 diabetes and severe albuminuria, the RENAAL study (580) and the Irbesartan Diabetic Nephropathy Trial (IDNT) (581) reported results that were similar to those in persons with type 1 diabetes and severe albuminuria (Table 22.26) (570). The RENAAL study reported a 25% lower risk of doubling of serum creatinine and a 28% decrease in ESRD compared with placebo; the IDNT found a 33% lower risk of doubling of serum creatinine compared with placebo and a 37% lower risk compared with amlodipine. The Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria (IRMA 2) study found that high-dose irbesartan prevented new severe albuminuria in hypertensive persons with moderate ACR levels (579). Although none of these three ARB trials found significant reductions in ESRD incidence during the intervention periods, several cost-benefit analyses based on the IDNT and the cost of medicine and ESRD treatment specific to the United States, Canada, and several European countries, consistently predicted both long-term survival advantage and higher cost-effectiveness with ARB than with other treatments (588). These benefits might be due in part to less comorbidity associated with RAAS treatment, such as heart failure and retinopathy, and in part to lower ESRD incidence when longer time periods are considered. No long-term studies have examined the renoprotective efficacy of ACE inhibitors in persons with type 2 diabetes and ACR ≥300 mg/g. Dual RAAS blockade is at least as effective as monotherapy in reducing blood pressure and albuminuria in persons with diabetes (584,589,590) but is less well tolerated by persons without hypertension or diabetes (582). The Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) (587) and Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) (591) trials found an excess risk of acute kidney injury and hyperkalemia with dual RAAS therapy, without a significant cardiovascular and renal benefit. Further, even after 5 years of treatment, albuminuria increased to pretreatment levels soon after the withdrawal of these drugs (571,572,573). This observation suggests the need for longer periods of normalization of both ACR and glycemic levels to achieve a durable treatment effect on underlying disease processes or more sensitive early markers of kidney disease progression.

FIGURE 22.51

Effect of Captopril on Incidence of Kidney Disease in Persons With Type 1 Diabetes and Proteinuria, 1987–1992. The Collaborative Study included 409 subjects with type 1 diabetes and urinary protein excretion ≥500 mg/24 hours, who were (more...)

TABLE 22.26

Randomized Controlled Studies of Renin-Angiotensin System Inhibitors.

Adding the direct renin inhibitor aliskiren to an ARB (losartan) in persons with type 2 diabetes, hypertension, and ACR ≥300 mg/g more effectively reduced mean urinary ACR than losartan alone (20%, 95% CI 9%–30%, p<0.001) (592); the mean eGFR decline during the 24-week study period also tended to be lower in the aliskiren group (2.4 mL/min/1.73 m² in the aliskiren group vs. 3.8 mL/min/1.73 m² in the placebo group, p=0.07). The Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE), a subsequent, larger study in persons with type 2 diabetes, CKD, and high cardiovascular risk was stopped early due to therapeutic futility and increased risk of stroke and other adverse events (593). Neither ALTITUDE nor VA NEPHRON-D were continued long enough to establish efficacy and remained underpowered for their primary CVD and renal outcomes. Based on their other findings, however, dual RAAS blockade is contraindicated due to safety concerns (554).

In a meta-analysis exploring the benefit of intensive (achieved systolic blood pressure ≤135 mmHg) versus standard (achieved systolic blood pressure ≤140 mmHg) blood pressure targets in subjects with type 2 diabetes, the former was associated with significant 17% and 27% reductions in the odds for moderate and severe albuminuria, respectively (594). For persons with severe albuminuria (>3 g/24 hours), a post hoc analysis from the MDRD study indicated better kidney outcomes with a lower blood pressure goal (<130/80 mmHg) (595). Whereas stringent blood pressure targets lowered the risk for stroke and death, the few studies reporting ESRD or doubling of serum creatinine showed no benefits for these outcomes, suggesting the importance of individualizing blood pressure goals in persons with diabetes to account for the presence and severity of CKD, age, and associated cardiovascular risk. Moreover, ACE inhibitors and beta blockers may be less effective in controlling blood pressure and reducing albuminuria in African Americans than in whites (596,597,598), suggesting that different drug combinations may be more effective in slowing progression of kidney disease in African Americans (599,600).

Table 22.27 shows the Eighth Joint National Committee’s (JNC 8) recommendations for management of hypertension in the population with diabetes and CKD in comparison with other guidelines (600,601,602,603,604). The thresholds and goals recommended by the guideline-writing groups differ within a narrow range, with 2014–2015 recommendations endorsing less intensive and more individualized blood pressure targets for diabetes and CKD than in the past. In elderly persons, in particular, antihypertensive treatment should be individualized, taking into consideration such factors as frailty, comorbidities, and albuminuria (Figure 22.52) (600). There is consensus on the initial use of RAAS treatment in persons with albuminuria, but not for those without elevated albuminuria.

Control of Blood Lipids

Persons with diabetes and CKD typically have an atherogenic lipid profile, characterized by low concentrations of HDL cholesterol, high concentrations of small, dense LDL cholesterol particles and triglycerides (393,605,606,607). Treatment with lipid-lowering medicines, particularly statins, can reduce the high cardiovascular risk in this population. There is no conclusive evidence, however, that such treatment also affects progression of diabetic kidney disease (608,609,610,611). The Study of Heart and Renal Protection (SHARP) (612) is the largest randomized controlled trial in persons with CKD (average eGFR 27 mL/min/1.73 m²) to demonstrate that a lipid-lowering strategy with a statin plus ezetimibe significantly reduces major atherosclerotic events, such as coronary death, myocardial infarction, nonhemorrhagic stroke, and arterial revascularization procedures, compared with placebo (HR 0.83, 95% CI 0.74–0.94). The relative effect on these outcomes was similar in persons with or without diabetes, although the study was not adequately powered for subgroup analyses—only 23% of the 9,438 participants had diabetes. The study detected no effect of lipid-lowering treatment on the frequency of doubling of the baseline serum creatinine concentration or progression to ESRD. This and other studies (613,614,615) found no cardiovascular benefit of statin therapy when it was initiated in persons with diabetes after the onset of dialysis. By contrast, lipid-lowering therapy appears highly beneficial in reducing cardiovascular events in diabetic and nondiabetic persons with a functioning kidney transplant (616).

TABLE 22.27

Guideline Comparisons of Blood Pressure Goals and Drug Therapy for Adults With Hypertension.

FIGURE 22.52

2014 Hypertension Guideline Management Algorithm, Eighth Joint National Committee. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; CKD, chronic kidney disease; DBP, diastolic blood pressure; (more...)

Other lipid-changing medicines may be of value in the management of persons with diabetes and CKD. The Veterans Affairs High-density lipoprotein Intervention Trial (VA-HIT) (617) reported in a post hoc analysis that gemfibrozil reduced risk of major cardiovascular events by 42% compared with placebo in persons with GFR <75 mL/min/1.73 m² and diabetes. The Diabetes Atherosclerosis Intervention Study (DAIS) (618) and the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study (619,620) both found that fenofibrate significantly lowered the risk of new-onset moderate albuminuria and promoted regression from moderate to normal albuminuria compared with placebo in persons with type 2 diabetes. On the other hand, fenofibrate did not change the risk of progression from moderate to severe albuminuria.

Dietary Modification

In animals with experimental diabetes, reduced protein intake protects against hyperfiltration and progressive sclerosis of functioning glomeruli (621,622). In persons with type 1 diabetes and normal urinary albumin excretion, short-term dietary protein restriction favorably modifies glomerular hemodynamic function, and in those with moderate albuminuria, it also reduces urinary albumin excretion (623,624,625,626,627). Similar effects were found in persons with clinical proteinuria (Table 22.28) (628,629,630,631). The largest of these studies (632) randomized 82 persons with type 1 diabetes, severe albuminuria, and prerandomization GFR decline of 7.1 mL/min/year to usual-protein diet (1.02 g/kg/day, 95% CI 0.95–1.10) and reduced-protein diet (0.89 g/kg/day, 95% CI 0.83–0.95) (p=0.005) for a period of 4 years. At the end of the study, the CVD-adjusted risk of ESRD or death was 0.23 (95% CI 0.07–0.72, p=0.01) in the group receiving the reduced-protein diet compared with the group receiving the usual diet (Figure 22.53), suggesting that even moderate protein restriction, which moves intakes from excess toward the norm, provides benefits beyond conventional drug therapy in these persons.

TABLE 22.28

Clinical Trials of the Effect of Dietary Protein Reduction on the Course of Diabetic Nephropathy in Persons With Type 1 Diabetes and Severe Albuminuria.

FIGURE 22.53

Cumulative Incidence of End-Stage Renal Disease or Death in Persons With Type 1 Diabetes, by Protein Intake. Eighty-two persons with severe albuminuria were randomized to usual-protein diet and low-protein diet. The numbers at the bottom of the figure (more...)

Fewer studies are available in persons with type 2 diabetes. A study of the efficacy of dietary protein restriction in 160 persons with type 2 diabetes and moderate albuminuria or ≥5 years duration of diabetes found no beneficial effect of protein restriction on albuminuria or eGFR over a mean follow-up of 28 months (633). In fact, a protein intake restricted to 0.8 g/kg/day could not be effectively achieved beyond the first 6 months of the study, reflecting the inconvenience associated with a strict dietary regimen that may outweigh the benefits of such therapy. A systematic review of randomized studies (634) concluded that a reduced-protein diet in persons with CKD associated with either type of diabetes had no significant effect on kidney function relative to normal protein consumption, despite improvements in proteinuria and A1c, and that dietary protein restriction may significantly increase the risk for malnutrition in those with more advanced CKD (635). On the other hand, studies evaluating a reduction or alteration of protein intake in persons with diabetes and CKD are generally small (under 100 subjects), of short duration (<2 years), have limited documentation on the quality of protein (animal or vegetable), fat and carbohydrate intake, and evaluate intermediate outcomes, i.e., albuminuria and eGFR, rather than major health outcomes.

Sodium intake is a major contributor to blood pressure increase. According to the Institute of Medicine (636), about 75% of dietary sodium intake is obtained from preprocessed foods or is added to restaurant food during preparation, and only about 25% comes from natural sources or is added by the consumer. The Dietary Guidelines for Americans (637) recommends that persons age ≥51 years, African Americans, and persons with hypertension, diabetes, or CKD limit their sodium intake to 1,500 mg daily. In the NHANES 2005–2008, virtually all (99.4%) of those encouraged to limit their sodium intake exceeded the recommended limit on a daily basis (638). Although sodium reduction has a positive impact on blood pressure in persons with diabetes (639), its long-term effect on kidney outcomes remains unclear. Most individuals may benefit from a Dietary Approaches to Stop Hypertension (DASH) diet, a reduced sodium diet emphasizing fruits, vegetables, low-fat dairy foods, whole grains, nuts, poultry, fish, and smaller amounts of red meat and refined sugars than the typical diet in the United States (640). The DASH diet reflects a shift towards whole-diet approaches to the management of CKD in diabetes that integrates multiple healthful eating goals simultaneously, without a focus on single nutrients. In addition to lowering blood pressure, a DASH-type diet reduced kidney function loss over 11 years in women from the Nurses’ Health Study with mildly decreased eGFR, an effect primarily associated with reduced red meat intake (641). Nonetheless, the DASH diet may not be suitable, without modification, for persons with GFR <60 mL/min/1.73 m² because of its high content of potassium (4.5 g/day), phosphorus (1.7 g/day), and protein (1.4 g/kg/day).

Other Kidney Diseases Associated With Diabetes

Infections

Urinary Tract Infections

Persons with diabetes may be more susceptible to infections of the urinary tract. Autopsy studies from the preantibiotic era (654,655,656,657,658) reported 10%–20% prevalence of histologic pyelonephritis in persons with diabetes, five times that of persons without diabetes. Not only was the frequency of urinary tract infection greater in those with diabetes at that time, but the infections were often more serious and protracted (655). With the introduction of effective antimicrobial therapy, the frequency and severity of urinary tract infections may have diminished (659). Additional information about urinary tract infections in persons with diabetes is provided in Chapter 28 Urologic Diseases and Sexual Dysfunction in Diabetes and Chapter 30 Infections Associated With Diabetes.

Table 22.29 presents the prevalence of asymptomatic bacteriuria in persons with and without diabetes from several different clinic- or hospital-based populations (660,661,662,663,664,665,666,667,668,669,670,671,672,673,674,675,676,677). In a systematic review and meta-analysis of published data since 1966, women with diabetes have about three times the frequency of bacteriuria as nondiabetic women (OR 2.6, 95% CI 1.6–4.1), and men with diabetes have about four times the frequency of bacteriuria as healthy control subjects (OR 3.7, 95% CI 1.3–10.2) (660,665,666,670,678,679,680,681,682,683,684,685). Some studies report a longer duration of diabetes in women with asymptomatic bacteriuria than in those without (pooled difference 0.17 years, 95% CI 0.03–0.31, p=0.01), but the same review found no difference in A1c (660). Some studies show a relationship between asymptomatic bacteriuria in diabetic persons and the more frequent development of genitourinary tract infections (677,686,687,688,689), but others show no relationship (659,690). In most studies, the microorganisms causing asymptomatic bacteriuria in persons with diabetes are similar to those causing bacteriuria in nondiabetic persons (659), but a survey of 514 diabetic and 405 nondiabetic subjects found that nearly half of the diabetic subjects with bacteriuria were infected by bacteria other than E. coli, whereas all but one case of bacteriuria in the nondiabetic subjects were caused by E. coli (679). The prevalence of asymptomatic bacteriuria is not influenced by the type of diabetes (659,660).

TABLE 22.29

Prevalence of Asymptomatic Bacteriuria in Populations With and Without Diabetes.

The prevalences of cystitis and pyelonephritis in 550 women with type 1 diabetes in the UroEDIC survey—EDIC year 10 subjects surveyed for urologic complications of type 1 diabetes—were 15% and 3% during the preceding 12 months (691). Table 22.30 presents risk factors for urinary tract infections in this cohort. The prevalence of cystitis in UroEDIC women was similar to that in nondiabetic white women age 20–59 years from the NHANES III. Among the men in UroEDIC, the prevalence of urinary tract infections was 4% for cystitis and 0% for pyelonephritis, too low to be included in the risk factor evaluation.

HIV

Diabetes and hypertension associated with HIV infection are described as risk factors for the development of HIV-associated immune complex kidney disease (692,693,694). While hypertension may be a consequence of HIV-related kidney disease, the association with diabetes appears to be mediated by post-infectious glomerulonephritis (692,695). A cross-sectional comparison of persons with type 2 diabetes with and without HIV infection and persons with HIV infection only is presented in Table 22.31 (696). Among the 73 HIV-infected persons with type 2 diabetes, the combination of diabetes, higher HIV viral load, and antiretroviral treatment with abacavir was a significant predictor of ACR ≥30 mg/g. Antiretroviral therapy has nephrotoxic effects, including tubulointerstitial nephropathies, proximal tubular dysfunction, Fanconi’s syndrome, and nephrogenic diabetes insipidus (697). Chapter 6 Other Specific Types of Diabetes provides additional information about the relationship of diabetes with HIV infection and drugs for HIV therapy.

TABLE 22.30

Adjusted Odds Ratios for Cystitis and Pyelonephritis in Women With Type 1 Diabetes Participating in the Uro-EDIC Survey, 2002–2004.

Renal Papillary Necrosis

Impaired blood flow to the inner medulla and papilla of the kidney can lead to anoxic damage and ultimately to renal papillary necrosis. Sloughing of the renal papilla may ensue, which can obstruct the renal pelvis. Individuals may remain asymptomatic or develop flank pain and renal colic. Historically, the prevalence of renal papillary necrosis at autopsy is 20–30 times as great in persons with diabetes as in those without (698). Among persons with diabetes, it occurs bilaterally in half of the cases and is 2.5 times as frequent in women as in men (655,656,699). Moreover, persons with diabetes and acute pyelonephritis are at particularly high risk of renal papillary necrosis. In one study, 27% of diabetic subjects with renal papillary necrosis at autopsy also had acute fulminant pyelonephritis (656). A review of the medical records of the 165 patients diagnosed with renal papillary necrosis at the Mayo Clinic between 1976 and 1992 showed that among patient groups with diabetes, analgesic abuse, or urinary tract infections, the diagnosis was more frequent in women than men (700). The 10-year survival rate from the time of diagnosis was significantly lower for patients with diabetes than without (44% vs. 77%), and progression to ESRD was more frequent in the presence of diabetes.

TABLE 22.31

Demographic and Clinical Characteristics of Subjects With HIV, Diabetes, and Both HIV and Diabetes, 2007–2009.

Conclusions

Chronic kidney disease is a public health problem that affects nearly 14% of the U.S. population and is disproportionately distributed among minority and disadvantaged groups. Most risk factors for CKD are modifiable; therefore, public health strategies targeting these factors may significantly reduce the disease burden.

Diabetes is the leading cause of CKD, and the increasing prevalence of diabetes together with improved availability of dialysis and transplants have sustained a continued rise in the proportion of CKD attributable to diabetes since the 1980s. In persons with type 1 diabetes, the incidence of CKD has declined in parallel with a significant trend for earlier initiation of antihypertensive treatment following the onset of diabetes, expansion of RAAS inhibitor usage, and sustained improvements in glycemic control. On the other hand, in persons with type 2 diabetes, the incidence of CKD does not appear to be declining, possibly due to the higher number and prevalence of CKD risk factors associated with type 2 diabetes that outweigh current treatment options or their effectiveness. An ever-increasing number of persons with diabetes, 91% of whom have type 2 diabetes, are requiring renal replacement therapy, at enormous cost to patients, their families, and to society.

Improved management of hyperglycemia, hypertension, hyperlipidemia, and albuminuria have dramatically slowed progression to ESRD, as illustrated by a level incidence of ESRD attributed to diabetes since 2005. Trends in the incidence of ESRD due to diabetes, however, differ broadly by age and race/ethnicity. At the national level, the incidence of ESRD in persons with a primary diagnosis of diabetes remains higher in African Americans, Mexican Americans, Asians, and American Indians than in whites, with the highest rates being found in African Americans and American Indians.

List of Abbreviations

A1c

glycosylated hemoglobin

ABCA1

ATP-binding cassette transporter

ACCORD

Action to Control Cardiovascular Risk in Diabetes

ACE

angiotensin-converting enzyme

ACR

albumin-to-creatinine ratio

ADA

American Diabetes Association

ADVANCE

Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation

AER

albumin excretion rate

ALTITUDE

Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints

ARB

angiotensin receptor blocker

ATP

adenosine triphosphate

BMI

body mass index

CI

confidence interval

CKD

chronic kidney disease

CVD

cardiovascular disease

DASH

Dietary Approaches to Stop Hypertension

DCCT

Diabetes Control and Complications Trial

DNA

deoxyribonucleic acid

EDC

Epidemiology of Diabetes Complications study

EDIC

Epidemiology of Diabetes Interventions and Complications study

EDTA

ethylenediaminetetraacetic acid

eGFR

estimated glomerular filtration rate

ESRD

end-stage renal disease

FinnDiane

Finnish Diabetic Nephropathy study

GFR

glomerular filtration rate

HDL

high-density lipoprotein

HIV

human immunodeficiency virus

HR

hazard ratio

IDNT

Irbesartan Diabetic Nephropathy Trial

KDIGO

Kidney Disease: Improving Global Outcomes

KEEP

Kidney Early Evaluation Program

LDL

low-density lipoprotein

MDRD

Modification of Diet in Renal Disease

NHANES

National Health and Nutrition Examination Survey

NKF

National Kidney Foundation

NSAID

nonsteroidal anti-inflammatory drugs

OR

odds ratio

RAAS

renin-angiotensin-aldosterone system

RENAAL

Reduction of Endpoints in Non-insulin dependent diabetes with the Angiotensin II Antagonist Losartan

SMR

standardized mortality ratio

TGF-β

transforming growth factor beta

UKPDS

United Kingdom Prospective Diabetes Study

UroEDIC

ancillary study of urologic complications in the DCCT/EDIC cohort

USRDS

United States Renal Data System

VA NEPHRON-D

Veterans Affairs Nephropathy in Diabetes

VLDL

very low-density lipoprotein

References

1.

United States Renal Data System: USRDS 2014 Annual Data Report: an Overview of the Epidemiology of Kidney Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2014. Disclaimer: The data reported here have been supplied by the United States Renal Data System (USRDS). The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the U.S. government.

2.

United States Renal Data System: USRDS 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, 2013. Disclaimer: The data reported here have been supplied by the United States Renal Data System (USRDS). The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the U.S. government.

3.

Centers for Disease Control and Prevention: Prevalence of chronic kidney disease and associated risk factors—United States, 1999–2004. MMWR Morb Mortal Wkly Rep 56:161–165, 2007 [PubMed: 17332726]

4.

Yokoyama H, Okudaira M, Otani T, Sato A, Miura J, Takaike H, Yamada H, Muto K, Uchigata Y, Ohashi Y, Iwamoto Y: Higher incidence of diabetic nephropathy in type 2 than in type 1 diabetes in early-onset diabetes in Japan. Kidney Int 58:302–311, 2000 [PubMed: 10886575]

5.

Dart AB, Martens PJ, Rigatto C, Brownell MD, Dean HJ, Sellers EA: Earlier onset of complications in youth with type 2 diabetes. Diabetes Care 37:436–443, 2014 [PubMed: 24130346]

6.

TODAY Study Group, Zeitler P, Hirst K, Pyle L, Linder B, Copeland K, Arslanian S, Cuttler L, Nathan DM, Tollefsen S, Wilfley D, Kaufman F: A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med 366:2247–2256, 2012 [PMC free article: PMC3478667] [PubMed: 22540912]

7.

National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 39(2 Suppl 1):S1–S266, 2002 [PubMed: 11904577]

8.

Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group: KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 3:1–150, 2013

9.

American Diabetes Association: Microvascular complications and foot care. Sec. 10. In “Standards of Medical Care in Diabetes—2017.” Diabetes Care 40(Suppl 1):S88–S89, 2017 [PMC free article: PMC5481974] [PubMed: 28522554]

10.

Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D: A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461–470, 1999 [PubMed: 10075613]

11.

Stevens LA, Coresh J, Feldman HI, Greene T, Lash JP, Nelson RG, Rahman M, Deysher AE, Zhang YL, Schmid CH, Levey AS: Evaluation of the Modification of Diet in Renal Disease Study equation in a large, diverse population. J Am Soc Nephrol 18:2749–2757, 2007 [PubMed: 17855641]

12.

Miller WG: Estimating glomerular filtration rate. Clin Chem Lab Med 47:1017–1019, 2009 [PubMed: 19728841]

13.

Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration): A new equation to estimate glomerular filtration rate. Ann Intern Med 150:604–612, 2009 [PMC free article: PMC2763564] [PubMed: 19414839]

14.

National Kidney Foundation: KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kidney Dis 49(Suppl 2):S1–S180, 2007 [PubMed: 17276798]

15.

He F, Xia X, Wu XF, Yu XQ, Huang FX: Diabetic retinopathy in predicting diabetic nephropathy in patients with type 2 diabetes and renal disease: a meta-analysis. Diabetologia 56:457–466, 2013 [PubMed: 23232641]

16.

Tuttle KR, Bakris GL, Bilous RW, Chiang JL, de Boer IH, Goldstein-Fuchs J, Hirsch IB, Kalantar-Zadeh K, Narva AS, Navaneethan SD, Neumiller JJ, Patel UD, Ratner RE, Whaley-Connell AT, Molitch ME: Diabetic kidney disease: a report from an ADA Consensus Conference. Diabetes Care 37:2864–2883, 2014 [PMC free article: PMC4170131] [PubMed: 25249672]

17.

Wolf G, Muller N, Mandecka A, Muller UA: Association of diabetic retinopathy and renal function in patients with types 1 and 2 diabetes mellitus. Clin Nephrol 68:81–86, 2007 [PubMed: 17722706]

18.

Levey AS, de Jong PE, Coresh J, El Nahas M, Astor BC, Matsushita K, Gansevoort RT, Kasiske BL, Eckardt KU: The definition, classification and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int 80:17–28, 2011 [PubMed: 21150873]

19.

American Diabetes Association: Standards of medical care in diabetes—2017. Diabetes Care 40(Suppl 1):S1–S131, 2017

20.

Molitch ME: Management of early diabetic nephropathy. Am J Med 102:392–398, 1997 [PubMed: 9217622]

21.

Mogensen CE: Prediction of clinical diabetic nephropathy in IDDM patients. Alternatives to microalbuminuria? Diabetes 39:761–767, 1990 [PubMed: 2191882]

22.

Nelson RG, Knowler WC, Pettitt DJ, Bennett PH: Kidney diseases in diabetes. In Diabetes in America. 2nd ed. Harris MI, Cowie CC, Stern MP, Boyko EJ, Reiber GE, Bennett PH, Eds. Bethesda, MD, National Institutes of Health, NIH Pub No. 95-1468, 1995, p. 349–400

23.

Ruggenenti P, Porrini EL, Gaspari F, Motterlini N, Cannata A, Carrara F, Cella C, Ferrari S, Stucchi N, Parvanova A, Iliev I, Dodesini AR, Trevisan R, Bossi A, Zaletel J, Remuzzi G; GFR Study Investigators: Glomerular hyperfiltration and renal disease progression in type 2 diabetes. Diabetes Care 35:2061–2068, 2012 [PMC free article: PMC3447826] [PubMed: 22773704]

24.

Ficociello LH, Perkins BA, Roshan B, Weinberg JM, Aschengrau A, Warram JH, Krolewski AS: Renal hyperfiltration and the development of microalbuminuria in type 1 diabetes. Diabetes Care 32:889–893, 2009 [PMC free article: PMC2671109] [PubMed: 19196883]

25.

Thomas MC, Moran JL, Harjutsalo V, Thorn L, Waden J, Saraheimo M, Tolonen N, Leiviska J, Jula A, Forsblom C, Groop PH; FinnDiane Study Group: Hyperfiltration in type 1 diabetes: does it exist and does it matter for nephropathy? Diabetologia 55:1505–1513, 2012 [PubMed: 22322918]

26.

Moriya T, Tsuchiya A, Okizaki S, Hayashi A, Tanaka K, Shichiri M: Glomerular hyperfiltration and increased glomerular filtration surface are associated with renal function decline in normo- and microalbuminuric type 2 diabetes. Kidney Int 81:486–493, 2012 [PubMed: 22157655]

27.

Murussi M, Gross JL, Silveiro SP: Glomerular filtration rate changes in normoalbuminuric and microalbuminuric type 2 diabetic patients and normal individuals. A 10-year follow-up. J Diabetes Complications 20:210–215, 2006 [PubMed: 16798471]

28.

Chaiken RL, Eckert-Norton M, Bard M, Banerji MA, Palmisano J, Sachimechi I, Lebovitz HE: Hyperfiltration in African-American patients with type 2 diabetes. Cross-sectional and longitudinal data. Diabetes Care 21:2129–2134, 1998 [PubMed: 9839105]

29.

Brenner BM, Lawler EV, Mackenzie HS: The hyperfiltration theory: a paradigm shift in nephrology. Kidney Int 49:1774–1777, 1996 [PubMed: 8743495]

30.

Mogensen CE, Christensen CK, Vittinghus E: The stages in diabetic renal disease. With emphasis on the stage of incipient diabetic nephropathy. Diabetes 32(Suppl 2):64–78, 1983 [PubMed: 6400670]

31.

Martin P, Hampton KK, Walton C, Tindall H, Davies JA: Microproteinuria in type 2 diabetes mellitus from diagnosis. Diabet Med 7:315–318, 1990 [PubMed: 1692521]

32.

Mogensen CE: A complete screening of urinary albumin concentration in an unselected diabetic out-patient clinic population. Diabetic Nephropathy 2:11–18, 1983

33.

de Boer IH, Rue TC, Cleary PA, Lachin JM, Molitch ME, Steffes MW, Sun W, Zinman B, Brunzell JD; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group, White NH, Danis RP, Davis MD, Hainsworth D, Hubbard LD, Nathan DM: Long-term renal outcomes of patients with type 1 diabetes mellitus and microalbuminuria: an analysis of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications cohort. Arch Intern Med 171:412–420, 2011 [PMC free article: PMC3085024] [PubMed: 21403038]

34.

Hovind P, Tarnow L, Rossing P, Jensen BR, Graae M, Torp I, Binder C, Parving HH: Predictors for the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: inception cohort study. BMJ 328:1105, 2004 [PMC free article: PMC406322] [PubMed: 15096438]

35.

Viberti GC, Walker JD, Pinto JL: Diabetic nephropathy. In International Textbook of Diabetes Mellitus. 1st ed. Alberti KG, DeFronzo RA, Keen H, Zimmet P, Eds. New York, John Wiley & Sons, 1992, p. 1267–1328

36.

Perkins BA, Ficociello LH, Silva KH, Finkelstein DM, Warram JH, Krolewski AS: Regression of microalbuminuria in type 1 diabetes. N Engl J Med 348:2285–2293, 2003 [PubMed: 12788992]

37.

Parving HH, Mauer M, Fioretto P, Rossing P, Ritz E: Diabetic nephropathy. In Brenner & Rector’s The Kidney. 9th ed. Taal MW, Chertow GM, Marsden PA, Skorecki K, Yu AS, Brenner BM, Eds. Philadelphia, Saunders Elsevier, 2011, p. 1411–1443

38.

Mogensen CE, Poulsen PL: Epidemiology of microalbuminuria in diabetes and in the background population. Curr Opin Nephrol Hypertens 3:248–256, 1994 [PubMed: 7922249]

39.

Jerums G, Panagiotopoulos S, Premaratne E, MacIsaac RJ: Integrating albuminuria and GFR in the assessment of diabetic nephropathy. Nat Rev Nephrol 5:397–406, 2009 [PubMed: 19556994]

40.

Parving HH, Gall MA, Skott P, Jorgensen HE, Lokkegaard H, Jorgensen F, Nielsen B, Larsen S: Prevalence and causes of albuminuria in non-insulin-dependent diabetic patients. Kidney Int 41:758–762, 1992 [PubMed: 1513098]

41.

Sharma SG, Bomback AS, Radhakrishnan J, Herlitz LC, Stokes MB, Markowitz GS, D’Agati VD: The modern spectrum of renal biopsy findings in patients with diabetes. Clin J Am Soc Nephrol 8:1718–1724, 2013 [PMC free article: PMC3789339] [PubMed: 23886566]

42.

Lindeman RD: Overview: renal physiology and pathophysiology of aging. Am J Kidney Dis 16:275–282, 1990 [PubMed: 2220770]

43.

Tan JC, Busque S, Workeneh B, Ho B, Derby G, Blouch KL, Sommer FG, Edwards B, Myers BD: Effects of aging on glomerular function and number in living kidney donors. Kidney Int 78:686–692, 2010 [PMC free article: PMC3353650] [PubMed: 20463656]

44.

Hoang K, Tan JC, Derby G, Blouch KL, Masek M, Ma I, Lemley KV, Myers BD: Determinants of glomerular hypofiltration in aging humans. Kidney Int 64:1417–1424, 2003 [PubMed: 12969161]

45.

Hostetter TH, Rennke HG, Brenner BM: The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies. Am J Med 72:375–380, 1982 [PubMed: 7036732]

46.

Ditzel J, Schwartz M: Abnormally increased glomerular filtration rate in short-term insulin-treated diabetic subjects. Diabetes 16:264–267, 1967 [PubMed: 6023168]

47.

Brochner-Mortensen J: Glomerular filtration rate and extracellular fluid volumes during normoglycemia and moderate hyperglycemia in diabetics. Scand J Clin Lab Invest 32:311–316, 1973 [PubMed: 4203766]

48.

Hostetter TH, Troy JL, Brenner BM: Glomerular hemodynamics in experimental diabetes mellitus. Kidney Int 19:410–415, 1981 [PubMed: 7241881]

49.

Mogensen CE: Kidney function and glomerular permeability to macromolecules in early juvenile diabetes. Scand J Clin Lab Invest 28:79–90, 1971 [PubMed: 5093522]

50.

Christiansen JS, Gammelgaard J, Frandsen M, Parving HH: Increased kidney size, glomerular filtration rate and renal plasma flow in short-term insulin-dependent diabetics. Diabetologia 20:451–456, 1981 [PubMed: 7016638]

51.

Vora JP, Dolben J, Dean JD, Thomas D, Williams JD, Owens DR, Peters JR: Renal hemodynamics in newly presenting non-insulin dependent diabetes mellitus. Kidney Int 41:829–835, 1992 [PubMed: 1513105]

52.

Cherney DZ, Scholey JW, Miller JA: Insights into the regulation of renal hemodynamic function in diabetic mellitus. Curr Diabetes Rev 4:280–290, 2008 [PubMed: 18991597]

53.

Vervoort G, Veldman B, Berden JH, Smits P, Wetzels JF: Glomerular hyperfiltration in type 1 diabetes mellitus results from primary changes in proximal tubular sodium handling without changes in volume expansion. Eur J Clin Invest 35:330–336, 2005 [PubMed: 15860045]

54.

Persson P, Hansell P, Palm F: Tubular reabsorption and diabetes-induced glomerular hyperfiltration. Acta Physiol (Oxf) 200:3–10, 2010 [PMC free article: PMC2919631] [PubMed: 20518753]

55.

Keller CK, Bergis KH, Fliser D, Ritz E: Renal findings in patients with short-term type 2 diabetes. J Am Soc Nephrol 7:2627–2635, 1996 [PubMed: 8989741]

56.

Myers BD, Nelson RG, Williams GW, Bennett PH, Hardy SA, Berg RL, Loon N, Knowler WC, Mitch WE: Glomerular function in Pima Indians with noninsulin-dependent diabetes mellitus of recent onset. J Clin Invest 88:524–530, 1991 [PMC free article: PMC295379] [PubMed: 1864963]

57.

Mauer M, Drummond K; International Diabetic Nephropathy Study Group: The early natural history of nephropathy in type 1 diabetes: I. Study design and baseline characteristics of the study participants. Diabetes 51:1572–1579, 2002 [PubMed: 11978658]

58.

Caramori ML, Gross JL, Pecis M, de Azevedo MJ: Glomerular filtration rate, urinary albumin excretion rate, and blood pressure changes in normoalbuminuric normotensive type 1 diabetic patients: an 8-year follow-up study. Diabetes Care 22:1512–1516, 1999 [PubMed: 10480518]

59.

Jerums G, Premaratne E, Panagiotopoulos S, MacIsaac RJ: The clinical significance of hyperfiltration in diabetes. Diabetologia 53:2093–2104, 2010 [PubMed: 20496053]

60.

Magee GM, Bilous RW, Cardwell CR, Hunter SJ, Kee F, Fogarty DG: Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis. Diabetologia 52:691–697, 2009 [PubMed: 19198800]

61.

Wesson DE: Moving closer to an understanding of the hyperfiltration of type 2 diabetes mellitus. Am J Physiol Regul Integr Comp Physiol 290:R973–R974, 2006 [PubMed: 16537822]

62.

Levine DZ, Iacovitti M, Robertson SJ, Mokhtar GA: Modulation of single-nephron GFR in the db/db mouse model of type 2 diabetes mellitus. Am J Physiol Regul Integr Comp Physiol 290:R975–R981, 2006 [PubMed: 16339386]

63.

Lervang HH, Jensen S, Brochner-Mortensen J, Ditzel J: Early glomerular hyperfiltration and the development of late nephropathy in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 31:723–729, 1988 [PubMed: 3071482]

64.

Sasson AN, Cherney DZ: Renal hyperfiltration related to diabetes mellitus and obesity in human disease. World J Diabetes 3:1–6, 2012 [PMC free article: PMC3258534] [PubMed: 22253940]

65.

Melsom T, Mathisen UD, Ingebretsen OC, Jenssen TG, Njolstad I, Solbu MD, Toft I, Eriksen BO: Impaired fasting glucose is associated with renal hyperfiltration in the general population. Diabetes Care 34:1546–1551, 2011 [PMC free article: PMC3120190] [PubMed: 21593291]

66.

Mogensen CE, Andersen MJ: Increased kidney size and glomerular filtration rate in untreated juvenile diabetes: normalization by insulin-treatment. Diabetologia 11:221–224, 1975 [PubMed: 1149954]

67.

Christiansen JS, Gammelgaard J, Tronier B, Svendsen PA, Parving HH: Kidney function and size in diabetics before and during initial insulin treatment. Kidney Int 21:683–688, 1982 [PubMed: 7050506]

68.

Schmitz A, Hansen HH, Christensen T: Kidney function in newly diagnosed type 2 (non-insulin-dependent) diabetic patients, before and during treatment. Diabetologia 32:434–439, 1989 [PubMed: 2806767]

69.

Garcia Puig J, Mateos Anton F, Grande C, Pallardo LF, Arnalich F, Gil A, Vasquez JJ, Montero Garcia A: Relation of kidney size to kidney function in early insulin-dependent diabetes. Diabetologia 21:363–367, 1981 [PubMed: 7286496]

70.

Vora JP, Dolben J, Williams JD, Peters JR, Owens DR: Impact of initial treatment on renal function in newly-diagnosed type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 36:734–740, 1993 [PubMed: 8405740]

71.

Mogensen CE, Andersen MJ: Increased kidney size and glomerular filtration rate in early juvenile diabetes. Diabetes 22:706–712, 1973 [PubMed: 4728209]

72.

Lemley KV, Abdullah I, Myers BD, Meyer TW, Blouch K, Smith WE, Bennett PH, Nelson RG: Evolution of incipient nephropathy in type 2 diabetes mellitus. Kidney Int 58:1228–1237, 2000 [PubMed: 10972685]

73.

Lemley KV, Boothroyd DB, Blouch KL, Nelson RG, Jones LI, Olshen RA, Myers BD: Modeling GFR trajectories in diabetic nephropathy. Am J Physiol Renal Physiol 289:F863–F870, 2005 [PubMed: 15900022]

74.

Christensen CK, Mogensen CE: The course of incipient diabetic nephropathy: studies of albumin excretion and blood pressure. Diabet Med 2:97–102, 1985 [PubMed: 2952409]

75.

Nelson RG, Bennett PH, Williams GW, Berg RL, Hardy SA, Knowler WC, Mitch WE, Myers BD; Diabetic Renal Disease Study: Glomerular function in Pima Indians with type 2 (non-insulin-dependent) diabetes. Diabetologia 33(Suppl):A48, 1990

76.

Schmitz A, Christensen T, Moller A, Mogensen CE: Kidney function and cardiovascular risk factors in non-insulin-dependent diabetics (NIDDM) with microalbuminuria. J Intern Med 228:347–352, 1990 [PubMed: 2266344]

77.

Nelson RG, Beck GJ, Myers BD: Course of glomerular injury in Pima Indians with early diabetic nephropathy. J Am Soc Nephrol 4:306, 1993

78.

Pavkov ME, Knowler WC, Mason CC, Lemley KV, Myers BD, Nelson RG: Early renal function decline in type 2 diabetes. Clin J Am Soc Nephrol 7:78–84, 2012 [PMC free article: PMC3265342] [PubMed: 22076874]

79.

Skupien J, Warram JH, Smiles AM, Niewczas MA, Gohda T, Pezzolesi MG, Cantarovich D, Stanton R, Krolewski AS: The early decline in renal function in patients with type 1 diabetes and proteinuria predicts the risk of end-stage renal disease. Kidney Int 82:589–597, 2012 [PMC free article: PMC3425658] [PubMed: 22622493]

80.

Perkins BA, Ficociello LH, Roshan B, Warram JH, Krolewski AS: In patients with type 1 diabetes and new-onset microalbuminuria the development of advanced chronic kidney disease may not require progression to proteinuria. Kidney Int 77:57–64, 2010 [PMC free article: PMC3725722] [PubMed: 19847154]

81.

Mauer SM, Steffes MW, Chern M, Brown DM: Mesangial uptake and processing of macromolecules in rats with diabetes mellitus. Lab Invest 41:401–406, 1979 [PubMed: 502472]

82.

Viberti GC, Macintosh D, Bilous RW, Pickup JC, Keen H: Proteinuria in diabetes mellitus: role of spontaneous and experimental variation of glycemia. Kidney Int 21:714–720, 1982 [PubMed: 7050509]

83.

Kaysen GA, Myers BD, Couser WG, Rabkin R, Felts JM: Mechanisms and consequences of proteinuria. Lab Invest 54:479–498, 1986 [PubMed: 3517485]

84.

Brenner BM, Hostetter TH, Humes HD: Glomerular permselectivity: barrier function based on discrimination of molecular size and charge. Am J Physiol 234:F455–F460, 1978 [PubMed: 665772]

85.

Mauer MS, Steffes MW, Ellis EN, Sutherland DE, Brown DM, Goetz FC: Structural-functional relationships in diabetic nephropathy. J Clin Invest 74:1143–1155, 1984 [PMC free article: PMC425280] [PubMed: 6480821]

86.

Qian Y, Feldman E, Pennathur S, Kretzler M, Brosius FC, 3rd: From fibrosis to sclerosis: mechanisms of glomerulosclerosis in diabetic nephropathy. Diabetes 57:1439–1445, 2008 [PMC free article: PMC4239998] [PubMed: 18511444]

87.

Anderson S, Vora JP: Current concepts of renal hemodynamics in diabetes. J Diabetes Complications 9:304–307, 1995 [PubMed: 8573753]

88.

Kanwar YS, Wada J, Sun L, Xie P, Wallner EI, Chen S, Chugh S, Danesh FR: Diabetic nephropathy: mechanisms of renal disease progression. Exp Biol Med (Maywood) 233:4–11, 2008 [PubMed: 18156300]

89.

Steinke JM, Sinaiko AR, Kramer MS, Suissa S, Chavers BM, Mauer M; International Diabetic Nephropathy Study Group: The early natural history of nephropathy in type 1 diabetes: III. Predicators of 5-year urinary albumin excretion rate patterns in initially normoalbuminuric patients. Diabetes 54:2164–2171, 2005 [PubMed: 15983218]

90.

Perrin NE, Torbjornsdotter T, Jaremko GA, Berg UB: Risk markers of future microalbuminuria and hypertension based on clinical and morphological parameters in young type 1 diabetes patients. Pediatr Diabetes 11:305–313, 2010 [PubMed: 19761528]

91.

Caramori ML, Parks A, Mauer M: Renal lesions predict progression of diabetic nephropathy in type 1 diabetes. J Am Soc Nephrol 24:1175–1181, 2013 [PMC free article: PMC3699823] [PubMed: 23687360]

92.

Fioretto P, Mauer M, Brocco E, Velussi M, Frigato F, Muollo B, Sambataro M, Abaterusso C, Baggio B, Crepaldi G, Nosadini R: Patterns of renal injury in NIDDM patients with microalbuminuria. Diabetologia 39:1569–1576, 1996 [PubMed: 8960844]

93.

Osterby R, Gall MA, Schmitz A, Nielsen FS, Nyberg G, Parving HH: Glomerular structure and function in proteinuric type 2 (non-insulin-dependent) diabetic patients. Diabetologia 36:1064–1070, 1993 [PubMed: 8243856]

94.

Nosadini R, Velussi M, Brocco E, Bruseghin M, Abaterusso C, Saller A, Dalla Vestra M, Carraro A, Bortoloso E, Sambataro M, Barzon I, Frigato F, Muollo B, Chiesura-Corona M, Pacini G, Baggio B, Piarulli F, Sfriso A, Fioretto P: Course of renal function in type 2 diabetic patients with abnormalities of albumin excretion rate. Diabetes 49:476–484, 2000 [PubMed: 10868971]

95.

Moriya T, Suzuki Y, Inomata S, Iwano M, Kanauchi M, Haneda M: Renal histological heterogeneity and functional progress in normoalbuminuric and microalbuminuric Japanese patients with type 2 diabetes. BMJ Open Diabetes Res Care 2:e000029, 2014 [PMC free article: PMC4212561] [PubMed: 25452869]

96.

Dane MJ, Khairoun M, Lee DH, van den Berg BM, Eskens BJ, Boels MG, van Teeffelen JW, Rops AL, van der Vlag J, van Zonneveld AJ, Reinders ME, Vink H, Rabelink TJ: Association of kidney function with changes in the endothelial surface layer. Clin J Am Soc Nephrol 9:698–704, 2014 [PMC free article: PMC3974363] [PubMed: 24458084]

97.

Satchell S: The role of the glomerular endothelium in albumin handling. Nat Rev Nephrol 9:717–725, 2013 [PubMed: 24080802]

98.

Garsen M, Rops AL, Rabelink TJ, Berden JH, van der Vlag J: The role of heparanase and the endothelial glycocalyx in the development of proteinuria. Nephrol Dial Transplant 29:49–55, 2014 [PubMed: 24166469]

99.

Zhang C, Meng Y, Liu Q, Xuan M, Zhang L, Deng B, Zhang K, Liu Z, Lei T: Injury to the endothelial surface layer induces glomerular hyperfiltration rats with early-stage diabetes. J Diabetes Res 2014 Apr 9 [Epub] doi: 10.1155/2014/953740 [PMC free article: PMC4000657] [PubMed: 24812636] [CrossRef]

100.

Satchell SC, Braet F: Glomerular endothelial cell fenestrations: an integral component of the glomerular filtration barrier. Am J Physiol Renal Physiol 296:F947–F956, 2009 [PMC free article: PMC2681366] [PubMed: 19129259]

101.

Ballermann BJ: Contribution of the endothelium to the glomerular permselectivity barrier in health and disease. Nephron Physiol 106:19–25, 2007 [PubMed: 17570944]

102.

Weil EJ, Lemley KV, Mason CC, Yee B, Jones LI, Blouch K, Lovato T, Richardson M, Myers BD, Nelson RG: Podocyte detachment and reduced glomerular capillary endothelial fenestration promote kidney disease in type 2 diabetic nephropathy. Kidney Int 82:1010–1017, 2012 [PMC free article: PMC3472108] [PubMed: 22718189]

103.

Fioretto P, Mauer M: Histopathology of diabetic nephropathy. Semin Nephrol 27:195–207, 2007 [PMC free article: PMC2746982] [PubMed: 17418688]

104.

Tervaert TW, Mooyaart AL, Amann K, Cohen AH, Cook HT, Drachenberg CB, Ferrario F, Fogo AB, Haas M, de Heer E, Joh K, Noel LH, Radhakrishnan J, Seshan SV, Bajema IM, Bruijn JA; Renal Pathology Society: Pathologic classification of diabetic nephropathy. J Am Soc Nephrol 21:556–563, 2010 [PubMed: 20167701]

105.

Steffes MW, Bilous RW, Sutherland DE, Mauer SM: Cell and matrix components of the glomerular mesangium in type I diabetes. Diabetes 41:679–684, 1992 [PubMed: 1587395]

106.

White KE, Bilous RW; The Collaborative Study Group: Type 2 diabetic patients with nephropathy show structural-functional relationships that are similar to type 1 disease. J Am Soc Nephrol 11:1667–1673, 2000 [PubMed: 10966491]

107.

Caramori ML, Kim Y, Huang C, Fish AJ, Rich SS, Miller ME, Russell G, Mauer M: Cellular basis of diabetic nephropathy: 1. Study design and renal structural-functional relationships in patients with long-standing type 1 diabetes. Diabetes 51:506–513, 2002 [PubMed: 11812762]

108.

Poole G: Intercapillary glomerulosclerosis and the Kimmelstiel-Wilson syndrome. Postgrad Med J 29:137–146, 1953 [PMC free article: PMC2500335] [PubMed: 13055534]

109.

Najafian B, Alpers CE, Fogo AB: Pathology of human diabetic nephropathy. Contrib Nephrol 170:36–47, 2011 [PubMed: 21659756]

110.

Schwartz MM, Lewis EJ, Leonard-Martin T, Lewis JB, Batlle D: Renal pathology patterns in type II diabetes mellitus: relationship with retinopathy. The Collaborative Study Group. Nephrol Dial Transplant 13:2547–2552, 1998 [PubMed: 9794557]

111.

Osterby R, Parving HH, Hommel E, Jorgensen HE, Lokkegaard H: Glomerular structure and function in diabetic nephropathy. Early to advanced stages. Diabetes 39:1057–1063, 1990 [PubMed: 2384188]

112.

Salmon AH, Toma I, Sipos A, Muston PR, Harper SJ, Bates DO, Neal CR, Peti-Peterdi J: Evidence for restriction of fluid and solute movement across the glomerular capillary wall by the subpodocyte space. Am J Physiol Renal Physiol 293:F1777–F1786, 2007 [PubMed: 17804486]

113.

Kriz W: Progressive renal failure—inability of podocytes to replicate and the consequences for development of glomerulosclerosis. Nephrol Dial Transplant 11:1738–1742, 1996 [PubMed: 8918614]

114.

Becker JU, Hoerning A, Schmid KW, Hoyer PF: Immigrating progenitor cells contribute to human podocyte turnover. Kidney Int 72:1468–1473, 2007 [PubMed: 17898701]

115.

Ohse T, Pippin JW, Chang AM, Krofft RD, Miner JH, Vaughan MR, Shankland SJ: The enigmatic parietal epithelial cell is finally getting noticed: a review. Kidney Int 76:1225–1238, 2009 [PMC free article: PMC3708665] [PubMed: 19847153]

116.

Shankland SJ, Wolf G: Cell cycle regulatory proteins in renal disease: role in hypertrophy, proliferation, and apoptosis. Am J Physiol Renal Physiol 278:F515–F529, 2000 [PubMed: 10751212]

117.

Pagtalunan ME, Miller PL, Jumping-Eagle S, Nelson RG, Myers BD, Rennke HG, Coplon NS, Sun L, Meyer TW: Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest 99:342–348, 1997 [PMC free article: PMC507802] [PubMed: 9006003]

118.

Sun YB, Qu X, Zhang X, Caruana G, Bertram JF, Li J: Glomerular endothelial cell injury and damage precedes that of podocytes in adriamycin-induced nephropathy. PLOS ONE 8:e55027, 2013 [PMC free article: PMC3554670] [PubMed: 23359116]

119.

Nakagawa T, Sato W, Glushakova O, Heinig M, Clarke T, Campbell-Thompson M, Yuzawa Y, Atkinson MA, Johnson RJ, Croker B: Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy. J Am Soc Nephrol 18:539–550, 2007 [PubMed: 17202420]

120.

Yuen DA, Stead BE, Zhang Y, White KE, Kabir MG, Thai K, Advani SL, Connelly KA, Takano T, Zhu L, Cox AJ, Kelly DJ, Gibson IW, Takahashi T, Harris RC, Advani A: eNOS deficiency predisposes podocytes to injury in diabetes. J Am Soc Nephrol 23:1810–1823, 2012 [PMC free article: PMC3482727] [PubMed: 22997257]

121.

Dane MJ, van den Berg BM, Avramut MC, Faas FG, van der Vlag J, Rops AL, Ravelli RB, Koster BJ, van Zonneveld AJ, Vink H, Rabelink TJ: Glomerular endothelial surface layer acts as a barrier against albumin filtration. Am J Pathol 182:1532–1540, 2013 [PubMed: 23518410]

122.

Morigi M, Buelli S, Angioletti S, Zanchi C, Longaretti L, Zoja C, Galbusera M, Gastoldi S, Mundel P, Remuzzi G, Benigni A: In response to protein load podocytes reorganize cytoskeleton and modulate endothelin-1 gene: implication for permselective dysfunction of chronic nephropathies. Am J Pathol 166:1309–1320, 2005 [PMC free article: PMC1606387] [PubMed: 15855633]

123.

Torbjornsdotter TB, Perrin NE, Jaremko GA, Berg UB: Widening of foot processes in normoalbuminuric adolescents with type 1 diabetes. Pediatr Nephrol 20:750–758, 2005 [PubMed: 15827743]

124.

Dalla Vestra M, Masiero A, Roiter AM, Saller A, Crepaldi G, Fioretto P: Is podocyte injury relevant in diabetic nephropathy? Studies in patients with type 2 diabetes. Diabetes 52:1031–1035, 2003 [PubMed: 12663476]

125.

Nakamura T, Ushiyama C, Suzuki S, Hara M, Shimada N, Ebihara I, Koide H: Urinary excretion of podocytes in patients with diabetic nephropathy. Nephrol Dial Transplant 15:1379–1383, 2000 [PubMed: 10978394]

126.

Siu B, Saha J, Smoyer WE, Sullivan KA, Brosius FC, 3rd: Reduction in podocyte density as a pathologic feature in early diabetic nephropathy in rodents: prevention by lipoic acid treatment. BMC Nephrol 7:6, 2006 [PMC free article: PMC1435876] [PubMed: 16539708]

127.

Ronconi E, Sagrinati C, Angelotti ML, Lazzeri E, Mazzinghi B, Ballerini L, Parente E, Becherucci F, Gacci M, Carini M, Maggi E, Serio M, Vannelli GB, Lasagni L, Romagnani S, Romagnani P: Regeneration of glomerular podocytes by human renal progenitors. J Am Soc Nephrol 20:322–332, 2009 [PMC free article: PMC2637058] [PubMed: 19092120]

128.

Shankland SJ, Anders HJ, Romagnani P: Glomerular parietal epithelial cells in kidney physiology, pathology, and repair. Curr Opin Nephrol Hypertens 22:302–309, 2013 [PubMed: 23518463]

129.

Bohle A, Wehrmann M, Bogenschutz O, Batz C, Muller CA, Muller GA: The pathogenesis of chronic renal failure in diabetic nephropathy. Investigation of 488 cases of diabetic glomerulosclerosis. Pathol Res Pract 187:251–259, 1991 [PubMed: 2068008]

130.

Najafian B, Mauer M: Progression of diabetic nephropathy in type 1 diabetic patients. Diabetes Res Clin Pract 83:1–8, 2009 [PubMed: 19070384]

131.

Stout LC, Kumar S, Whorton EB: Insudative lesions—their pathogenesis and association with glomerular obsolescence in diabetes: a dynamic hypothesis based on single views of advancing human diabetic nephropathy. Hum Pathol 25:1213–1227, 1994 [PubMed: 7959667]

132.

Mauer SM, Lane P, Zhu D, Fioretto P, Steffes MW: Renal structure and function in insulin-dependent diabetes mellitus in man. J Hypertens Suppl 10:S17–S20, 1992 [PubMed: 1619499]

133.

Horsfield GI, Lannigan R: Exudative lesions in diabetes mellitus. J Clin Pathol 18:47–53, 1965 [PMC free article: PMC472832] [PubMed: 14247704]

134.

Alsaad KO, Herzenberg AM: Distinguishing diabetic nephropathy from other causes of glomerulosclerosis: an update. J Clin Pathol 60:18–26, 2007 [PMC free article: PMC1860608] [PubMed: 17213346]

135.

Najafian B, Crosson JT, Kim Y, Mauer M: Glomerulotubular junction abnormalities are associated with proteinuria in type 1 diabetes. J Am Soc Nephrol 17(4 Suppl 2):S53–S60, 2006 [PubMed: 16565248]

136.

Garg AX, Kiberd BA, Clark WF, Haynes RB, Clase CM: Albuminuria and renal insufficiency prevalence guides population screening: results from the NHANES III. Kidney Int 61:2165–2175, 2002 [PubMed: 12028457]

137.

Kramer HJ, Nguyen QD, Curhan G, Hsu CY: Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus. JAMA 289:3273–3277, 2003 [PubMed: 12824208]

138.

MacIsaac RJ, Tsalamandris C, Panagiotopoulos S, Smith TJ, McNeil KJ, Jerums G: Nonalbuminuric renal insufficiency in type 2 diabetes. Diabetes Care 27:195–200, 2004 [PubMed: 14693989]

139.

Caramori ML, Fioretto P, Mauer M: Low glomerular filtration rate in normoalbuminuric type 1 diabetic patients: an indicator of more advanced glomerular lesions. Diabetes 52:1036–1040, 2003 [PubMed: 12663477]

140.

Rigalleau V, Lasseur C, Raffaitin C, Beauvieux MC, Barthe N, Chauveau P, Combe C, Gin H: Normoalbuminuric renal-insufficient diabetic patients: a lower-risk group. Diabetes Care 30:2034–2039, 2007 [PubMed: 17485574]

141.

Kramer CK, Leitao CB, Pinto LC, Silveiro SP, Gross JL, Canani LH: Clinical and laboratory profile of patients with type 2 diabetes with low glomerular filtration rate and normoalbuminuria. Diabetes Care 30:1998–2000, 2007 [PubMed: 17468344]

142.

Rychlik I, Fliser D, Ritz E: Non-diabetic renal disease in type 2 diabetes mellitus. In Nephropathy in Type 2 Diabetes. Ritz E, Rychlik I, Eds. Oxford, U.K., Oxford University Press, 1999, p. 7–88

143.

MacIsaac RJ, Panagiotopoulos S, McNeil KJ, Smith TJ, Tsalamandris C, Hao H, Matthews PG, Thomas MC, Power DA, Jerums G: Is nonalbuminuric renal insufficiency in type 2 diabetes related to an increase in intrarenal vascular disease? Diabetes Care 29:1560–1566, 2006 [PubMed: 16801579]

144.

Pavkov ME, Mason CC, Bennett PH, Curtis JM, Knowler WC, Nelson RG: Change in the distribution of albuminuria according to estimated glomerular filtration rate in Pima Indians with type 2 diabetes. Diabetes Care 32:1845–1850, 2009 [PMC free article: PMC2752932] [PubMed: 19592626]

145.

Bolignano D, Lacquaniti A, Coppolino G, Donato V, Campo S, Fazio MR, Nicocia G, Buemi M: Neutrophil gelatinase-associated lipocalin (NGAL) and progression of chronic kidney disease. Clin J Am Soc Nephrol 4:337–344, 2009 [PMC free article: PMC2637601] [PubMed: 19176795]

146.

Nielsen SE, Sugaya T, Hovind P, Baba T, Parving HH, Rossing P: Urinary liver-type fatty acid-binding protein predicts progression to nephropathy in type 1 diabetic patients. Diabetes Care 33:1320–1324, 2010 [PMC free article: PMC2875447] [PubMed: 20185732]

147.

Nielsen SE, Andersen S, Zdunek D, Hess G, Parving HH, Rossing P: Tubular markers do not predict the decline in glomerular filtration rate in type 1 diabetic patients with overt nephropathy. Kidney Int 79:1113–1118, 2011 [PubMed: 21270761]

148.

von Eynatten M, Baumann M, Heemann U, Zdunek D, Hess G, Nawroth PP, Bierhaus A, Humpert PM: Urinary L-FABP and anaemia: distinct roles of urinary markers in type 2 diabetes. Eur J Clin Invest 40:95–102, 2010 [PubMed: 19912308]

149.

Nielsen SE, Hansen HP, Jensen BR, Parving HH, Rossing P: Urinary neutrophil gelatinase-associated lipocalin and progression of diabetic nephropathy in type 1 diabetic patients in a four-year follow-up study. Nephron Clin Pract 118:c130–c135, 2011 [PubMed: 21160226]

150.

Vaidya VS, Niewczas MA, Ficociello LH, Johnson AC, Collings FB, Warram JH, Krolewski AS, Bonventre JV: Regression of microalbuminuria in type 1 diabetes is associated with lower levels of urinary tubular injury biomarkers, kidney injury molecule-1, and N-acetyl-β-D-glucosaminidase. Kidney Int 79:464–470, 2011 [PMC free article: PMC3033751] [PubMed: 20980978]

151.

Nielsen SE, Reinhard H, Zdunek D, Hess G, Gutierrez OM, Wolf M, Parving HH, Jacobsen PK, Rossing P: Tubular markers are associated with decline in kidney function in proteinuric type 2 diabetic patients. Diabetes Res Clin Pract 97:71–76, 2012 [PubMed: 22402306]

152.

Kim SS, Song SH, Kim IJ, Yang JY, Lee JG, Kwak IS, Kim YK: Clinical implication of urinary tubular markers in the early stage of nephropathy with type 2 diabetic patients. Diabetes Res Clin Pract 97:251–257, 2012 [PubMed: 22440044]

153.

Fu WJ, Li BL, Wang SB, Chen ML, Deng RT, Ye CQ, Liu L, Fang AJ, Xiong SL, Wen S, Tang HH, Chen ZX, Huang ZH, Peng LF, Zheng L, Wang Q: Changes of the tubular markers in type 2 diabetes mellitus with glomerular hyperfiltration. Diabetes Res Clin Pract 95:105–109, 2012 [PubMed: 22015481]

154.

Conway BR, Manoharan D, Manoharan D, Jenks S, Dear JW, McLachlan S, Strachan MW, Price JF: Measuring urinary tubular biomarkers in type 2 diabetes does not add prognostic value beyond established risk factors. Kidney Int 82:812–818, 2012 [PubMed: 22718188]

155.

Liu KD, Yang W, Anderson AH, Feldman HI, Demirjian S, Hamano T, He J, Lash J, Lustigova E, Rosas SE, Simonson MS, Tao K, Hsu CY; Chronic Renal Insufficiency Cohort (CRIC) study investigators: Urine neutrophil gelatinase-associated lipocalin levels do not improve risk prediction of progressive chronic kidney disease. Kidney Int 83:909–914, 2013 [PMC free article: PMC3642209] [PubMed: 23344473]

156.

Araki S, Haneda M, Koya D, Sugaya T, Isshiki K, Kume S, Kashiwagi A, Uzu T, Maegawa H: Predictive effects of urinary liver-type fatty acid-binding protein for deteriorating renal function and incidence of cardiovascular disease in type 2 diabetic patients without advanced nephropathy. Diabetes Care 36:1248–1253, 2013 [PMC free article: PMC3631864] [PubMed: 23223350]

157.

O’Seaghdha CM, Hwang SJ, Larson MG, Meigs JB, Vasan RS, Fox CS: Analysis of a urinary biomarker panel for incident kidney disease and clinical outcomes. J Am Soc Nephrol 24:1880–1888, 2013 [PMC free article: PMC3810081] [PubMed: 23990678]

158.

Chou KM, Lee CC, Chen CH, Sun CY: Clinical value of NGAL, L-FABP and albuminuria in predicting GFR decline in type 2 diabetes mellitus patients. PLOS ONE 8:e54863, 2013 [PMC free article: PMC3551928] [PubMed: 23349979]

159.

Panduru NM, Forsblom C, Saraheimo M, Thorn L, Bierhaus A, Humpert PM, Groop PH; FinnDiane Study Group: Urinary liver-type fatty acid-binding protein and progression of diabetic nephropathy in type 1 diabetes. Diabetes Care 36:2077–2083, 2013 [PMC free article: PMC3687279] [PubMed: 23378622]

160.

Kamijo-Ikemori A, Sugaya T, Yasuda T, Kawata T, Ota A, Tatsunami S, Kaise R, Ishimitsu T, Tanaka Y, Kimura K: Clinical significance of urinary liver-type fatty acid-binding protein in diabetic nephropathy of type 2 diabetic patients. Diabetes Care 34:691–696, 2011 [PMC free article: PMC3041209] [PubMed: 21273494]

161.

Fufaa GD, Weil EJ, Nelson RG, Hanson RL, Bonventre JV, Sabbisetti V, Waikar SS, Mifflin TE, Zhang X, Xie D, Hsu CY, Feldman HI, Coresh J, Vasan RS, Kimmel PL, Liu KD; Chronic Kidney Disease Biomarkers Consortium Investigators: Association of urinary KIM-1, L-FABP, NAG and NGAL with incident end-stage renal disease and mortality in American Indians with type 2 diabetes mellitus. Diabetologia 58:188–198, 2015 [PMC free article: PMC4258130] [PubMed: 25316431]

162.

Aksun SA, Ozmen D, Ozmen B, Parildar Z, Mutaf I, Turgan N, Habif S, Kumanliogluc K, Bayindir O: Beta2-microglobulin and cystatin C in type 2 diabetes: assessment of diabetic nephropathy. Exp Clin Endocrinol Diabetes 112:195–200, 2004 [PubMed: 15127324]

163.

Viberti GC, Keen H, Mackintosh D: Beta 2-microglobulinaemia: a sensitive index of diminishing renal function in diabetics. Br Med J (Clin Res Ed) 282:95–98, 1981 [PMC free article: PMC1503840] [PubMed: 6161671]

164.

Astor BC, Shafi T, Hoogeveen RC, Matsushita K, Ballantyne CM, Inker LA, Coresh J: Novel markers of kidney function as predictors of ESRD, cardiovascular disease, and mortality in the general population. Am J Kidney Dis 59:653–662, 2012 [PMC free article: PMC3880682] [PubMed: 22305758]

165.

Miyazawa I, Araki S, Obata T, Yoshizaki T, Morino K, Kadota A, Ugi S, Kawai H, Uzu T, Nishio Y, Koya D, Haneda M, Kashiwagi A, Maegawa H: Association between serum soluble TNFα receptors and renal dysfunction in type 2 diabetic patients without proteinuria. Diabetes Res Clin Pract 92:174–180, 2011 [PubMed: 21288590]

166.

Lopes-Virella MF, Baker NL, Hunt KJ, Cleary PA, Klein R, Virella G; DCCT/EDIC Research Group: Baseline markers of inflammation are associated with progression to macroalbuminuria in type 1 diabetic subjects. Diabetes Care 36:2317–2323, 2013 [PMC free article: PMC3714479] [PubMed: 23514730]

167.

Niewczas MA, Ficociello LH, Johnson AC, Walker W, Rosolowsky ET, Roshan B, Warram JH, Krolewski AS: Serum concentrations of markers of TNFalpha and Fas-mediated pathways and renal function in nonproteinuric patients with type 1 diabetes. Clin J Am Soc Nephrol 4:62–70, 2009 [PMC free article: PMC2615709] [PubMed: 19073786]

168.

Niewczas MA, Gohda T, Skupien J, Smiles AM, Walker WH, Rosetti F, Cullere X, Eckfeldt JH, Doria A, Mayadas TN, Warram JH, Krolewski AS: Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes. J Am Soc Nephrol 23:507–515, 2012 [PMC free article: PMC3294310] [PubMed: 22266663]

169.

Gohda T, Niewczas MA, Ficociello LH, Walker WH, Skupien J, Rosetti F, Cullere X, Johnson AC, Crabtree G, Smiles AM, Mayadas TN, Warram JH, Krolewski AS: Circulating TNF receptors 1 and 2 predict stage 3 CKD in type 1 diabetes. J Am Soc Nephrol 23:516–524, 2012 [PMC free article: PMC3294299] [PubMed: 22266664]

170.

Forsblom C, Moran J, Harjutsalo V, Loughman T, Waden J, Tolonen N, Thorn L, Saraheimo M, Gordin D, Groop PH, Thomas MC; FinnDiane Study Group: Added value of soluble tumor necrosis factor-α receptor 1 as a biomarker of ESRD risk in patients with type 1 diabetes. Diabetes Care 37:2334–2342, 2014 [PubMed: 24879837]

171.

Saulnier PJ, Gand E, Ragot S, Ducrocq G, Halimi JM, Hulin-Delmotte C, Llaty P, Montaigne D, Rigalleau V, Roussel R, Velho G, Sosner P, Zaoui P, Hadjadj S; SURDIAGENE Study Group: Association of serum concentration of TNFR1 with all-cause mortality in patients with type 2 diabetes and chronic kidney disease: follow-up of the SURDIAGENE Cohort. Diabetes Care 37:1425–1431, 2014 [PubMed: 24623026]

172.

Pavkov ME, Nelson RG, Knowler WC, Cheng Y, Krolewski AS, Niewczas MA: Elevation of circulating TNF receptors 1 and 2 increases the risk of end-stage renal disease in American Indians with type 2 diabetes. Kidney Int 87:812–819, 2015 [PMC free article: PMC4382420] [PubMed: 25272234]

173.

Yao Y, Rabodzey A, Dewey CF, Jr.: Glycocalyx modulates the motility and proliferative response of vascular endothelium to fluid shear stress. Am J Physiol Heart Circ Physiol 293:H1023–H1030, 2007 [PubMed: 17468337]

174.

Jeansson M, Bjorck K, Tenstad O, Haraldsson B: Adriamycin alters glomerular endothelium to induce proteinuria. J Am Soc Nephrol 20:114–122, 2009 [PMC free article: PMC2615716] [PubMed: 19073829]

175.

Wahl P, Deppermann D, Hasslacher C: Biochemistry of glomerular basement membrane of the normal and diabetic human. Kidney Int 21:744–749, 1982 [PubMed: 7109461]

176.

Vernier RL, Steffes MW, Sisson-Ross S, Mauer SM: Heparan sulfate proteoglycan in the glomerular basement membrane in type 1 diabetes mellitus. Kidney Int 41:1070–1080, 1992 [PubMed: 1513088]

177.

Alfino PA, Neugarten J, Schacht RG, Dworkin LD, Baldwin DS: Glomerular size-selective barrier dysfunction in nephrotoxic serum nephritis. Kidney Int 34:151–155, 1988 [PubMed: 2460659]

178.

Andersson M, Nilsson U, Hjalmarsson C, Haraldsson B, Nystrom JS: Mild renal ischemia-reperfusion reduces charge and size selectivity of the glomerular barrier. Am J Physiol Renal Physiol 292:F1802–F1809, 2007 [PubMed: 17376766]

179.

Bennett CM, Glassock RJ, Chang RL, Deen WM, Robertson CR, Brenner BM, Troy JL, Ueki IR, Rasmussen B: Permselectivity of the glomerular capillary wall. Studies of experimental glomerulonephritis in the rat using dextran sulfate. J Clin Invest 57:1287–1294, 1976 [PMC free article: PMC436781] [PubMed: 1262472]

180.

Blouch K, Deen WM, Fauvel JP, Bialek J, Derby G, Myers BD: Molecular configuration and glomerular size selectivity in healthy and nephrotic humans. Am J Physiol 273:F430–F437, 1997 [PubMed: 9321916]

181.

Fox JG, Quin JD, Paterson KR, O’Reilly DS, Smith MP, Boulton-Jones JM: Glomerular charge selectivity in type 1 (insulin-dependent) diabetes mellitus. Diabet Med 12:387–391, 1995 [PubMed: 7648799]

182.

Groggel GC, Stevenson J, Hovingh P, Linker A, Border WA: Changes in heparan sulfate correlate with increased glomerular permeability. Kidney Int 33:517–523, 1988 [PubMed: 2452273]

183.

Guasch A, Myers BD: Determinants of glomerular hypofiltration in nephrotic patients with minimal change nephropathy. J Am Soc Nephrol 4:1571–1581, 1994 [PubMed: 8025231]

184.

Myers BD, Winetz JA, Chui F, Michaels AS: Mechanisms of proteinuria in diabetic nephropathy: a study of glomerular barrier function. Kidney Int 21:633–641, 1982 [PubMed: 6178872]

185.

Oliver JD, 3rd, Anderson S, Troy JL, Brenner BM, Deen WM: Determination of glomerular size-selectivity in the normal rat with Ficoll. J Am Soc Nephrol 3:214–228, 1992 [PubMed: 1382654]

186.

Olson JL, Hostetter TH, Rennke HG, Brenner BM, Venkatachalam MA: Altered glomerular permselectivity and progressive sclerosis following extreme ablation of renal mass. Kidney Int 22:112–126, 1982 [PubMed: 6182335]

187.

Olson JL, Rennke HG, Venkatachalam MA: Alterations in the charge and size selectivity barrier of the glomerular filter in aminonucleoside nephrosis in rats. Lab Invest 44:271–279, 1981 [PubMed: 7464051]

188.

Ruggenenti P, Mosconi L, Sangalli F, Casiraghi F, Gambara V, Remuzzi G, Remuzzi A: Glomerular size selective dysfunction in NIDDM is not ameliorated by ACE inhibition or by calcium channel blockade. Kidney Int 55:984–994, 1999 [PubMed: 10027935]

189.

Scandling JD, Black VM, Deen WM, Myers BD: Glomerular permselectivity in healthy and nephrotic humans. Adv Nephrol Necker Hosp 21:159–176, 1992 [PubMed: 1566645]

190.

Scandling JD, Myers BD: Glomerular size-selectivity and microalbuminuria in early diabetic glomerular disease. Kidney Int 41:840–846, 1992 [PubMed: 1381005]

191.

Haraldsson B, Sorensson J: Why do we not all have proteinuria? An update of our current understanding of the glomerular barrier. News Physiol Sci 19:7–10, 2004 [PubMed: 14739395]

192.

Singh A, Satchell SC, Neal CR, McKenzie EA, Tooke JE, Mathieson PW: Glomerular endothelial glycocalyx constitutes a barrier to protein permeability. J Am Soc Nephrol 18:2885–2893, 2007 [PubMed: 17942961]

193.

Singh A, Friden V, Dasgupta I, Foster RR, Welsh GI, Tooke JE, Haraldsson B, Mathieson PW, Satchell SC: High glucose causes dysfunction of the human glomerular endothelial glycocalyx. Am J Physiol Renal Physiol 300:F40–F48, 2011 [PMC free article: PMC3023224] [PubMed: 20980411]

194.

Lemley KV, Blouch K, Abdullah I, Boothroyd DB, Bennett PH, Myers BD, Nelson RG: Glomerular permselectivity at the onset of nephropathy in type 2 diabetes mellitus. J Am Soc Nephrol 11:2095–2105, 2000 [PubMed: 11053486]

195.

Deckert T, Kofoed-Enevoldsen A, Vidal P, Norgaard K, Andreasen HB, Feldt-Rasmussen B: Size- and charge selectivity of glomerular filtration in type 1 (insulin-dependent) diabetic patients with and without albuminuria. Diabetologia 36:244–251, 1993 [PubMed: 8462774]

196.

Friedman S, Jones HW, III, Golbetz HV, Lee JA, Little HL, Myers BD: Mechanisms of proteinuria in diabetic nephropathy II: a study of the size-selective glomerular filtration barrier. Diabetes 32(Suppl 2):40–46, 1983 [PubMed: 6086024]

197.

Myers BD, Nelson RG, Bennett PH, Mitch WE; Diabetic Renal Disease Study: Glomerular function at onset of nephropathy in NIDDM (Abstract). J Am Soc Nephrol 2:A295, 1991

198.

Tomlanovich S, Deen WM, Jones HW, 3rd, Schwartz HC, Myers BD: Functional nature of glomerular injury in progressive diabetic glomerulopathy. Diabetes 36:556–565, 1987 [PubMed: 2436961]

199.

Pavenstadt H, Kriz W, Kretzler M: Cell biology of the glomerular podocyte. Physiol Rev 83:253–307, 2003 [PubMed: 12506131]

200.

Peti-Peterdi J: Independent two-photon measurements of albumin GSC give low values. Am J Physiol Renal Physiol 296:F1255–F1257, 2009 [PMC free article: PMC2692442] [PubMed: 19297453]

201.

Russo LM, Sandoval RM, Campos SB, Molitoris BA, Comper WD, Brown D: Impaired tubular uptake explains albumin-uria in early diabetic nephropathy. J Am Soc Nephrol 20:489–494, 2009 [PMC free article: PMC2653682] [PubMed: 19118149]

202.

Comper WD, Hilliard LM, Nikolic-Paterson DJ, Russo LM: Disease-dependent mechanisms of albuminuria. Am J Physiol Renal Physiol 295:F1589–F1600, 2008 [PubMed: 18579704]

203.

Peti-Peterdi J, Burford JL, Hackl MJ: The first decade of using multiphoton microscopy for high-power kidney imaging. Am J Physiol Renal Physiol 302:F227–F233, 2012 [PMC free article: PMC3340919] [PubMed: 22031850]

204.

Tanner GA, Rippe C, Shao Y, Evan AP, Williams JC, Jr.: Glomerular permeability to macromolecules in the Necturus kidney. Am J Physiol Renal Physiol 296:F1269–F1278, 2009 [PubMed: 19339627]

205.

Tanner GA: Glomerular sieving coefficient of serum albumin in the rat: a two-photon microscopy study. Am J Physiol Renal Physiol 296:F1258–F1265, 2009 [PubMed: 19211688]

206.

Keen H, Chlouverakis C, Fuller J, Jarrett RJ: The concomitants of raised blood sugar: studies in newly detected hyper-glycemics. II. Urinary albumin excretion, blood pressure and their relation to blood sugar levels. Guys Hosp Rep 118:247–254, 1969 [PubMed: 5804067]

207.

Nelson RG, Kunzelman CL, Pettitt DJ, Saad MF, Bennett PH, Knowler WC: Albuminuria in type 2 (non-insulin-dependent) diabetes mellitus and impaired glucose tolerance in Pima Indians. Diabetologia 32:870–876, 1989 [PubMed: 2612758]

208.

Collins VR, Dowse GK, Finch CF, Zimmet PZ, Linnane AW: Prevalence and risk factors for micro- and macroalbuminuria in diabetic subjects and entire population of Nauru. Diabetes 38:1602–1610, 1989 [PubMed: 2583379]

209.

Saydah SH, Pavkov ME, Zhang C, Lacher DA, Eberhardt MS, Burrows NR, Narva AS, Eggers PW, Williams DE: Albuminuria prevalence in first morning void compared with previous random urine from adults in the National Health and Nutrition Examination Survey, 2009–2010. Clin Chem 59:675–683, 2013 [PMC free article: PMC4562457] [PubMed: 23315482]

210.

Claudi T, Cooper JG: Comparison of urinary albumin excretion rate in overnight urine and albumin creatinine ratio in spot urine in diabetic patients in general practice. Scand J Prim Health Care 19:247–248, 2001 [PubMed: 11822649]

211.

Gansevoort RT, Verhave JC, Hillege HL, Burgerhof JG, Bakker SJ, de Zeeuw D, de Jong PE; PREVEND Study Group: The validity of screening based on spot morning urine samples to detect subjects with microalbuminuria in the general population. Kidney Int Suppl 94:S28–S35, 2005 [PubMed: 15752236]

212.

Howey JE, Browning MC, Fraser CG: Biologic variation of urinary albumin: consequences for analysis, specimen collection, interpretation of results, and screening programs. Am J Kidney Dis 13:35–37, 1989 [PubMed: 2912063]

213.

Afkarian M, Zelnick LR, Hall YN, Heagerty PJ, Tuttle K, Weiss NS, de Boer IH: Clinical manifestations of kidney disease among US adults with diabetes, 1988–2014. JAMA 316:602–610, 2016 [PMC free article: PMC5444809] [PubMed: 27532915]

214.

Menke A, Orchard TJ, Imperatore G, Bullard KM, Mayer-Davis E, Cowie CC: The prevalence of type 1 diabetes in the United States. Epidemiology 24:773–774, 2013 [PMC free article: PMC4562437] [PubMed: 23903880]

215.

Costacou T, Fried L, Ellis D, Orchard TJ: Sex differences in the development of kidney disease in individuals with type 1 diabetes mellitus: a contemporary analysis. Am J Kidney Dis 58:565–573, 2011 [PMC free article: PMC3183221] [PubMed: 21840097]

216.

Klein R, Klein BE, Linton KL, Moss SE: Microalbuminuria in a population-based study of diabetes. Arch Intern Med 152:153–158, 1992 [PubMed: 1728911]

217.

Groop PH, Thomas MC, Moran JL, Waden J, Thorn LM, Makinen VP, Rosengard-Barlund M, Saraheimo M, Hietala K, Heikkila O, Forsblom C; FinnDiane Study Group: The presence and severity of chronic kidney disease predicts all-cause mortality in type 1 diabetes. Diabetes 58:1651–1658, 2009 [PMC free article: PMC2699848] [PubMed: 19401416]

218.

Parving HH, Hommel E, Mathiesen E, Skott P, Edsberg B, Bahnsen M, Lauritzen M, Hougaard P, Lauritzen E: Prevalence of microalbuminuria, arterial hypertension, retinopathy and neuropathy in patients with insulin dependent diabetes. Br Med J (Clin Res Ed) 296:156–160, 1988 [PMC free article: PMC2544895] [PubMed: 3122980]

219.

Skrivarhaug T, Bangstad HJ, Stene LC, Sandvik L, Hanssen KF, Joner G: Low risk of overt nephropathy after 24 yr of childhood-onset type 1 diabetes mellitus (T1DM) in Norway. Pediatr Diabetes 7:239–246, 2006 [PubMed: 17054444]

220.

Eeg-Olofsson K, Cederholm J, Nilsson PM, Zethelius B, Svensson AM, Gudbjornsdottir S, Eliasson B: Glycemic control and cardiovascular disease in 7,454 patients with type 1 diabetes: an observational study from the Swedish National Diabetes Register (NDR). Diabetes Care 33:1640–1646, 2010 [PMC free article: PMC2890374] [PubMed: 20424222]

221.

Raile K, Galler A, Hofer S, Herbst A, Dunstheimer D, Busch P, Holl RW: Diabetic nephropathy in 27,805 children, adolescents, and adults with type 1 diabetes: effect of diabetes duration, A1C, hypertension, dyslipidemia, diabetes onset, and sex. Diabetes Care 30:2523–2528, 2007 [PubMed: 17630266]

222.

Parving HH, Lewis JB, Ravid M, Remuzzi G, Hunsicker LG; DEMAND investigators: Prevalence and risk factors for microalbuminuria in a referred cohort of type II diabetic patients: a global perspective. Kidney Int 69:2057–2063, 2006 [PubMed: 16612330]

223.

Mogensen CE, Christensen CK: Predicting diabetic nephropathy in insulin-dependent patients. N Engl J Med 311:89–93, 1984 [PubMed: 6738599]

224.

Viberti GC, Jarrett RJ, Mahmud U, Hill RD, Argyropoulos A, Keen H: Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet 1:1430–1432, 1982 [PubMed: 6123720]

225.

Parving HH, Oxenboll B, Svendsen PA, Christiansen JS, Andersen AR: Early detection of patients at risk of developing diabetic nephropathy. A longitudinal study of urinary albumin excretion. Acta Endocrinol (Copenh) 100:550–555, 1982 [PubMed: 6812342]

226.

Mathiesen ER, Oxenboll B, Johansen K, Svendsen PA, Deckert T: Incipient nephropathy in type 1 (insulin-dependent) diabetes. Diabetologia 26:406–410, 1984 [PubMed: 6468791]

227.

Messent JW, Elliott TG, Hill RD, Jarrett RJ, Keen H, Viberti GC: Prognostic significance of microalbuminuria in insulin-dependent diabetes mellitus: a twenty-three year follow-up study. Kidney Int 41:836–839, 1992 [PubMed: 1513106]

228.

Mogensen CE: Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 310:356–360, 1984 [PubMed: 6690964]

229.

Jerums G, Cooper ME, Seeman E, Murray RM, McNeil JJ: Spectrum of proteinuria in type I and type II diabetes. Diabetes Care 10:419–427, 1987 [PubMed: 3622199]

230.

Nelson RG, Knowler WC, Pettitt DJ, Saad MF, Charles MA, Bennett PH: Assessment of risk of overt nephropathy in diabetic patients from albumin excretion in untimed urine specimens. Arch Intern Med 151:1761–1765, 1991 [PubMed: 1888242]

231.

Johns L, Rao PS, Kanagasabapathy AS: Rate of progression of albuminuria in type II diabetes. Five-year prospective study from South India. Diabetes Care 17:888–890, 1994 [PubMed: 7956637]

232.

Andersen AR, Christiansen JS, Andersen JK, Kreiner S, Deckert T: Diabetic nephropathy in type 1 (insulin-dependent) diabetes: an epidemiological study. Diabetologia 25:496–501, 1983 [PubMed: 6363177]

233.

Klein R, Klein BE, Moss SE: The incidence of gross proteinuria in people with insulin-dependent diabetes mellitus. Arch Intern Med 151:1344–1348, 1991 [PubMed: 2064485]

234.

Noth RH, Krolewski AS, Kaysen GA, Meyer TW, Schambelan M: Diabetic nephropathy: hemodynamic basis and implications for disease management. Ann Intern Med 110:795–813, 1989 [PubMed: 2653154]

235.

Rossing P, Hougaard P, Parving HH: Progression of microalbuminuria in type 1 diabetes: ten-year prospective observational study. Kidney Int 68:1446–1450, 2005 [PubMed: 16164620]

236.

Ballard DJ, Humphrey LL, Melton LJ, 3rd, Frohnert PP, Chu PC, O’Fallon WM, Palumbo PJ: Epidemiology of persistent proteinuria in type II diabetes mellitus. Population-based study in Rochester, Minnesota. Diabetes 37:405–412, 1988 [PubMed: 3378684]

237.

Klein R, Klein BE, Moss SE: Incidence of gross proteinuria in older-onset diabetes. A population-based perspective. Diabetes 42:381–389, 1993 [PubMed: 8432408]

238.

Kunzelman CL, Knowler WC, Pettitt DJ, Bennett PH: Incidence of proteinuria in type 2 diabetes mellitus in the Pima Indians. Kidney Int 35:681–687, 1989 [PubMed: 2785225]

239.

Krolewski AS, Warram JH, Christlieb AR, Busick EJ, Kahn CR: The changing natural history of nephropathy in type I diabetes. Am J Med 78:785–794, 1985 [PubMed: 3993659]

240.

Kofoed-Enevoldsen A, Borch-Johnsen K, Kreiner S, Nerup J, Deckert T: Declining incidence of persistent proteinuria in type I (insulin-dependent) diabetic patients in Denmark. Diabetes 36:205–209, 1987 [PubMed: 3803732]

241.

Pambianco G, Costacou T, Ellis D, Becker DJ, Klein R, Orchard TJ: The 30-year natural history of type 1 diabetes complications: the Pittsburgh Epidemiology of Diabetes Complications Study experience. Diabetes 55:1463–1469, 2006 [PubMed: 16644706]

242.

Bojestig M, Arnqvist HJ, Hermansson G, Karlberg BE, Ludvigsson J: Declining incidence of nephropathy in insulin-dependent diabetes mellitus. N Engl J Med 330:15–18, 1994 [PubMed: 8259139]

243.

Rossing P: The changing epidemiology of diabetic microangiopathy in type 1 diabetes. Diabetologia 48:1439–1444, 2005 [PubMed: 15986235]

244.

Hovind P, Tarnow L, Rossing K, Rossing P, Eising S, Larsen N, Binder C, Parving HH: Decreasing incidence of severe diabetic microangiopathy in type 1 diabetes. Diabetes Care 26:1258–1264, 2003 [PubMed: 12663607]

245.

The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 329:977–986, 1993 [PubMed: 8366922]

246.

Larson TS, Santanello N, Shahinfar S, O’Brien PC, Palumbo PJ, Melton LJ, 3rd, Leibson CL: Trends in persistent proteinuria in adult-onset diabetes: a population-based study. Diabetes Care 23:51–56, 2000 [PubMed: 10857968]

247.

Pavkov ME, Knowler WC, Bennett PH, Looker HC, Krakoff J, Nelson RG: Increasing incidence of proteinuria and declining incidence of end-stage renal disease in diabetic Pima Indians. Kidney Int 70:1840–1846, 2006 [PubMed: 17003816]

248.

Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR; UKPDS Group: Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 63:225–232, 2003 [PubMed: 12472787]

249.

Bilous R: Microvascular disease: what does the UKPDS tell us about diabetic nephropathy? Diabet Med 25(Suppl 2):25–29, 2008 [PubMed: 18717975]

250.

Kussman MJ, Goldstein HH, Gleason RE: The clinical course of diabetic nephropathy. JAMA 236:1861–1863, 1976 [PubMed: 989537]

251.

Rossing P, Hommel E, Smidt UM, Parving HH: Impact of arterial blood pressure and albuminuria on the progression of diabetic nephropathy in IDDM patients. Diabetes 42:715–719, 1993 [PubMed: 8482428]

252.

Roy MS, Affouf M, Roy A: Six-year incidence of proteinuria in type 1 diabetic African Americans. Diabetes Care 30:1807–1812, 2007 [PubMed: 17475942]

253.

Roy MS, Affouf M: Six-year progression of retinopathy and associated risk factors in African American patients with type 1 diabetes mellitus: the New Jersey 725. Arch Ophthalmol 124:1297–1306, 2006 [PubMed: 16966625]

254.

Araki S, Haneda M, Sugimoto T, Isono M, Isshiki K, Kashiwagi A, Koya D: Factors associated with frequent remission of microalbuminuria in patients with type 2 diabetes. Diabetes 54:2983–2987, 2005 [PubMed: 16186402]

255.

Gaede P, Tarnow L, Vedel P, Parving HH, Pedersen O: Remission to normoalbuminuria during multifactorial treatment preserves kidney function in patients with type 2 diabetes and microalbuminuria. Nephrol Dial Transplant 19:2784–2788, 2004 [PubMed: 15328385]

256.

Pavkov ME, Knowler WC, Hanson RL, Bennett PH, Nelson RG: Predictive power of sequential measures of albuminuria for progression to ESRD or death in Pima Indians with type 2 diabetes. Am J Kidney Dis 51:759–766, 2008 [PMC free article: PMC2386511] [PubMed: 18436086]

257.

Vupputuri S, Nichols GA, Lau H, Joski P, Thorp ML: Risk of progression of nephropathy in a population-based sample with type 2 diabetes. Diabetes Res Clin Pract 91:246–252, 2011 [PubMed: 21156326]

258.

Xu J, Lee ET, Devereux RB, Umans JG, Bella JN, Shara NM, Yeh J, Fabsitz RR, Howard BV: A longitudinal study of risk factors for incident albuminuria in diabetic American Indians: the Strong Heart Study. Am J Kidney Dis 51:415–424, 2008 [PMC free article: PMC2776644] [PubMed: 18295057]

259.

Xu J, Knowler WC, Devereux RB, Yeh J, Umans JG, Begum M, Fabsitz RR, Lee ET: Albuminuria within the “normal” range and risk of cardiovascular disease and death in American Indians: the Strong Heart Study. Am J Kidney Dis 49:208−216, 2007 [PubMed: 17261423]

260.

Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf B, Halle JP, Young J, Rashkow A, Joyce C, Nawaz S, Yusuf S; HOPE Study Investigators: Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA 286:421–426, 2001 [PubMed: 11466120]

261.

Yuyun MF, Adler AI, Wareham NJ: What is the evidence that microalbuminuria is a predictor of cardiovascular disease events? Curr Opin Nephrol Hypertens 14:271–276, 2005 [PubMed: 15821422]

262.

Hillege HL, Fidler V, Diercks GF, van Gilst WH, de Zeeuw D, van Veldhuisen DJ, Gans RO, Janssen WM, Grobbee DE, de Jong PE; Prevention of Renal and Vascular End Stage Disease (PREVEND) Study Group: Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation 106:1777–1782, 2002 [PubMed: 12356629]

263.

Astor BC, Hallan SI, Miller ER, 3rd, Yeung E, Coresh J: Glomerular filtration rate, albuminuria, and risk of cardiovascular and all-cause mortality in the US population. Am J Epidemiol 167:1226–1234, 2008 [PubMed: 18385206]

264.

Borch-Johnsen K, Andersen PK, Deckert T: The effect of proteinuria on relative mortality in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 28:590–596, 1985 [PubMed: 4054448]

265.

Nelson RG, Pettitt DJ, Carraher MJ, Baird HR, Knowler WC: Effect of proteinuria on mortality in NIDDM. Diabetes 37:1499–1504, 1988 [PubMed: 3181642]

266.

Jensen T, Borch-Johnsen K, Kofoed-Enevoldsen A, Deckert T: Coronary heart disease in young type 1 (insulin-dependent) diabetic patients with and without diabetic nephropathy: incidence and risk factors. Diabetologia 30:144–148, 1987 [PubMed: 3582820]

267.

Jarrett RJ: The epidemiology of coronary heart disease and related factors in the context of diabetes mellitus and impaired glucose tolerance. In Diabetes and Heart Disease. Jarrett RJ, Ed. Amsterdam, Elsevier, 1984, p. 1–23

268.

Pavkov ME, Bennett PH, Sievers ML, Krakoff J, Williams DE, Knowler WC, Nelson RG: Predominant effect of kidney disease on mortality in Pima Indians with or without type 2 diabetes. Kidney Int 68:1267–1274, 2005 [PMC free article: PMC1800940] [PubMed: 16105060]

269.

Orchard TJ, Secrest AM, Miller RG, Costacou T: In the absence of renal disease, 20 year mortality risk in type 1 diabetes is comparable to that of the general population: a report from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetologia 53:2312–2319, 2010 [PMC free article: PMC3057031] [PubMed: 20665208]

270.

Arun CS, Stoddart J, Mackin P, Macleod JM, New JP, Marshall SM: Significance of microalbuminuria in long-duration type 1 diabetes. Diabetes Care 26:2144–2149, 2003 [PubMed: 12832327]

271.

Allen KV, Walker JD: Microalbuminuria and mortality in long-duration type 1 diabetes. Diabetes Care 26:2389–2391, 2003 [PubMed: 12882867]

272.

Rosolowsky ET, Skupien J, Smiles AM, Niewczas M, Roshan B, Stanton R, Eckfeldt JH, Warram JH, Krolewski AS: Risk for ESRD in type 1 diabetes remains high despite renoprotection. J Am Soc Nephrol 22:545–553, 2011 [PMC free article: PMC3060448] [PubMed: 21355053]

273.

Nelson RG: Is treatment of nephropathy in type 1 diabetes efficacious but ineffective? J Am Soc Nephrol 22:402–404, 2011 [PubMed: 21355059]

274.

Perrone RD, Madias NE, Levey AS: Serum creatinine as an index of renal function: new insights into old concepts. Clin Chem 38:1933–1953, 1992 [PubMed: 1394976]

275.

Jarrett RJ, Viberti GC, Argyropoulos A, Hill RD, Mahmud U, Murrells TJ: Microalbuminuria predicts mortality in non-insulin-dependent diabetes. Diabet Med 1:17–19, 1984 [PubMed: 6242771]

276.

Schmitz A, Vaeth M: Microalbuminuria: a major risk factor in non-insulin-dependent diabetes. A 10-year follow-up study of 503 patients. Diabet Med 5:126–134, 1988 [PubMed: 2964977]

277.

Mattock MB, Morrish NJ, Viberti GC, Keen H, Fitzgerald AP, Jackson G: Prospective study of microalbuminuria as predictor of mortality in NIDDM. Diabetes 41:736–741, 1992 [PubMed: 1587400]

278.

Niel A, Hawkins M, Potok M, Thorogood M, Cohen D, Mann J: A prospective population-based study of microalbuminuria as a predictor of mortality in NIDDM. Diabetes Care 16:996–1003, 1993 [PubMed: 8359108]

279.

Liu JE, Robbins DC, Palmieri V, Bella JN, Roman MJ, Fabsitz R, Howard BV, Welty TK, Lee ET, Devereux RB: Association of albuminuria with systolic and diastolic left ventricular dysfunction in type 2 diabetes: the Strong Heart Study. J Am Coll Cardiol 41:2022–2028, 2003 [PubMed: 12798576]

280.

Shara NM, Wang H, Mete M, Al-Balha YR, Azalddin N, Lee ET, Franceschini N, Jolly SE, Howard BV, Umans JG: Estimated GFR and incident cardiovascular disease events in American Indians: the Strong Heart Study. Am J Kidney Dis 60:795–803, 2012 [PMC free article: PMC3473098] [PubMed: 22841159]

281.

Naqvi SB, Collins AJ: Infectious complications in chronic kidney disease. Adv Chronic Kidney Dis 13:199–204, 2006 [PubMed: 16815225]

282.

McDonald HI, Thomas SL, Millett ER, Nitsch D: CKD and the risk of acute, community-acquired infections among older people with diabetes mellitus: a retrospective cohort study using electronic health records. Am J Kidney Dis 66:60–68, 2015 [PMC free article: PMC4510204] [PubMed: 25641062]

283.

Dalrymple LS, Katz R, Kestenbaum B, de Boer IH, Fried L, Sarnak MJ, Shlipak MG: The risk of infection-related hospitalization with decreased kidney function. Am J Kidney Dis 59:356–363, 2012 [PMC free article: PMC3288732] [PubMed: 21906862]

284.

Burrows NR, Cho P, McKeever Bullard K, Narva AS, Eggers PW: Survival on dialysis among American Indians and Alaska Natives with diabetes in the United States, 1995–2010. Am J Public Health 104(Suppl 3):S490–S495, 2014 [PMC free article: PMC4035878] [PubMed: 24754656]

285.

Ishikawa I: [Renal cell carcinoma in chronic hemodialysis patients. A 1998 questionnaire study.] [Article in Japanese] J Jpn Soc Dial Ther 33:181–188, 2000

286.

Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, Feyzi JM, Ivanovich P, Kewalramani R, Levey AS, Lewis EF, McGill JB, McMurray JJ, Parfrey P, Parving HH, Remuzzi G, Singh AK, Solomon SD, Toto R; TREAT Investigators: A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 361:2019–2032, 2009 [PubMed: 19880844]

287.

Wong G, Hayen A, Chapman JR, Webster AC, Wang JJ, Mitchell P, Craig JC: Association of CKD and cancer risk in older people. J Am Soc Nephrol 20:1341–1350, 2009 [PMC free article: PMC2689896] [PubMed: 19406977]

288.

Shebl FM, Warren JL, Eggers PW, Engels EA: Cancer risk among elderly persons with end-stage renal disease: a population-based case-control study. BMC Nephrol 13:65, 2012 [PMC free article: PMC3441292] [PubMed: 22834953]

289.

Larsson SC, Wolk A: Diabetes mellitus and incidence of kidney cancer: a meta-analysis of cohort studies. Diabetologia 54:1013–1018, 2011 [PubMed: 21274512]

290.

Habib SL, Rojna M: Diabetes and risk of cancer. ISRN Oncol 2013 Feb 7 [Epub] doi: 10.1155/2013/583786 [PMC free article: PMC3582053] [PubMed: 23476808] [CrossRef]

291.

Izzedine H, Perazella MA: Onconephrology: an appraisal of the cancer and chronic kidney disease links. Nephrol Dial Transplant 30:1979–1988, 2015 [PMC free article: PMC4832985] [PubMed: 25648910]

292.

Berhane AM, Weil EJ, Knowler WC, Nelson RG, Hanson RL: Albuminuria and estimated glomerular filtration rate as predictors of diabetic end-stage renal disease and death. Clin J Am Soc Nephrol 6:2444–2451, 2011 [PMC free article: PMC3186453] [PubMed: 21852671]

293.

Ninomiya T, Perkovic V, de Galan BE, Zoungas S, Pillai A, Jardine M, Patel A, Cass A, Neal B, Poulter N, Mogensen CE, Cooper M, Marre M, Williams B, Hamet P, Mancia G, Woodward M, MacMahon S, Chalmers J; ADVANCE Collaborative Group: Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol 20:1813–1821, 2009 [PMC free article: PMC2723977] [PubMed: 19443635]

294.

Shara NM, Wang H, Valaitis E, Pehlivanova M, Carter EA, Resnick HE, Wang W, Umans JG, Lee ET, Howard BV, Devereux RB, Wilson PW: Comparison of estimated glomerular filtration rates and albuminuria in predicting risk of coronary heart disease in a population with high prevalence of diabetes mellitus and renal disease. Am J Cardiol 107:399–405, 2011 [PMC free article: PMC3035999] [PubMed: 21257005]

295.

Rosenson RS, Fioretto P, Dodson PM: Does microvascular disease predict macrovascular events in type 2 diabetes? Atherosclerosis 218:13–18, 2011 [PubMed: 21763654]

296.

Yokoyama H, Oishi M, Kawai K, Sone H; Japan Diabetes Clinical Data Management Study Group: Reduced GFR and microalbuminuria are independently associated with prevalent cardiovascular disease in type 2 diabetes: JDDM study 16. Diabet Med 25:1426–1432, 2008 [PubMed: 19046241]

297.

Tong PC, Kong AP, So WY, Yang X, Ng MC, Ho CS, Ma RC, Ozaki R, Ng V, Chow CC, Lam CW, Chan JC, Cockram CS: Interactive effect of retinopathy and macroalbuminuria on all-cause mortality, cardiovascular and renal end points in Chinese patients with type 2 diabetes mellitus. Diabet Med 24:741–746, 2007 [PubMed: 17403120]

298.

So WY, Kong AP, Ma RC, Ozaki R, Szeto CC, Chan NN, Ng V, Ho HS, Lam CW, Chow CC, Cockram CS, Chan JC, Tong PC: Glomerular filtration rate, cardiorenal end points and all-cause mortality in type 2 diabetic patients. Diabetes Care 29:2046–2052, 2006 [PubMed: 16936151]

299.

Gimeno-Orna JA, Lou-Arnal LM, Boned-Juliani B, Molinero-Herguedas E: Mild renal insufficiency as a cardiovascular risk factor in non-proteinuric type II diabetes. Diabetes Res Clin Pract 64:191–199, 2004 [PubMed: 15126007]

300.

Yang X, Ma RC, So WY, Ko GT, Kong AP, Lam CW, Ho CS, Cockram CS, Wong VC, Tong PC, Chan JC: Impacts of chronic kidney disease and albuminuria on associations between coronary heart disease and its traditional risk factors in type 2 diabetic patients—the Hong Kong diabetes registry. Cardiovasc Diabetol 6:37, 2007 [PMC free article: PMC2219954] [PubMed: 18053157]

301.

Leelawattana R, Rattarasarn C, Lim A, Soonthornpun S, Setasuban W: Causes of death, incidence and risk factors of cardiovascular diseases in Thai type 2 diabetic patients: a 5 year follow-up study. Diabetes Res Clin Pract 60:183–189, 2003 [PubMed: 12822563]

302.

Juutilainen A, Lehto S, Ronnemaa T, Pyorala K, Laakso M: Proteinuria and metabolic syndrome as predictors of cardiovascular death in non-diabetic and type 2 diabetic men and women. Diabetologia 49:56–65, 2006 [PubMed: 16365726]

303.

Bruno G, Merletti F, Bargero G, Novelli G, Melis D, Soddu A, Perotto M, Pagano G, Cavallo-Perin P: Estimated glomerular filtration rate, albuminuria and mortality in type 2 diabetes: the Casale Monferrato study. Diabetologia 50:941–948, 2007 [PubMed: 17333106]

304.

Casiglia E, Zanette G, Mazza A, Donadon V, Donada C, Pizziol A, Tikhonoff V, Palatini P, Pessina AC: Cardiovascular mortality in non-insulin-dependent diabetes mellitus. A controlled study among 683 diabetics and 683 age- and sex-matched normal subjects. Eur J Epidemiol 16:677–684, 2000 [PubMed: 11078126]

305.

Valmadrid CT, Klein R, Mos SE, Klein BE: The risk of cardiovascular disease mortality associated with microalbuminuria and gross proteinuria in persons with older-onset diabetes mellitus. Arch Intern Med 160:1093–1100, 2000 [PubMed: 10789601]

306.

Yang X, So WY, Kong AP, Ho CS, Lam CW, Stevens RJ, Lyu RR, Yin DD, Cockram CS, Tong PC, Wong V, Chan JC: Development and validation of stroke risk equation for Hong Kong Chinese patients with type 2 diabetes: the Hong Kong Diabetes Registry. Diabetes Care 30:65–70, 2007 [PubMed: 17192335]

307.

Davis TM, Millns H, Stratton IM, Holman RR, Turner RC: Risk factors for stroke in type 2 diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS) 29. Arch Intern Med 159:1097–1103, 1999 [PubMed: 10335687]

308.

Knobler H, Zornitzki T, Vered S, Oettinger M, Levy R, Caspi A, Faraggi D, Livschitz S: Reduced glomerular filtration rate in asymptomatic diabetic patients: predictor of increased risk for cardiac events independent of albuminuria. J Am Coll Cardiol 44:2142–2148, 2004 [PubMed: 15582311]

309.

Fox CS, Matsushita K, Woodward M, Bilo HJ, Chalmers J, Heerspink HJ, Lee BJ, Perkins RM, Rossing P, Sairenchi T, Tonelli M, Vassalotti JA, Yamagishi K, Coresh J, de Jong PE, Wen CP, Nelson RG; Chronic Kidney Disease Prognosis Consortium: Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet 380:1662–1673, 2012 [PMC free article: PMC3771350] [PubMed: 23013602]

310.

Muntner P, Coresh J, Powe NR, Klag MJ: The contribution of increased diabetes prevalence and improved myocardial infarction and stroke survival to the increase in treated end-stage renal disease. J Am Soc Nephrol 14:1568–1577, 2003 [PubMed: 12761257]

311.

Cowie CC, Port FK, Wolfe RA, Savage PJ, Moll PP, Hawthorne VM: Disparities in incidence of diabetic end-stage renal disease according to race and type of diabetes. N Engl J Med 321:1074–1079, 1989 [PubMed: 2797067]

312.

Nelson RG, Newman JM, Knowler WC, Sievers ML, Kunzelman CL, Pettitt DJ, Moffett CD, Teutsch SM, Bennett PH: Incidence of end-stage renal disease in type 2 (non-insulin dependent) diabetes mellitus in Pima Indians. Diabetologia 31:730–736, 1988 [PubMed: 3240833]

313.

Rostand SG, Kirk KA, Rutsky EA, Pate BA: Racial differences in the incidence of treatment for end-stage renal disease. N Engl J Med 306:1276–1279, 1982 [PubMed: 7040967]

314.

Lopes AA, Port FK, James SA, Agodoa L: The excess risk of treated end-stage renal disease in blacks in the United States. J Am Soc Nephrol 3:1961–1971, 1993 [PubMed: 8338929]

315.

Stephens GW, Gillaspy JA, Clyne D, Mejia A, Pollak VE: Racial differences in the incidence of end-stage renal disease in types I and II diabetes mellitus. Am J Kidney Dis 15:562–567, 1990 [PubMed: 2368696]

316.

Pugh JA, Stern MP, Haffner SM, Eifler CW, Zapata M: Excess incidence of treatment of end-stage renal disease in Mexican Americans. Am J Epidemiol 127:135–144, 1988 [PubMed: 3276155]

317.

Burden AC, McNally PG, Feehally J, Walls J: Increased incidence of end-stage renal failure secondary to diabetes mellitus in Asian ethnic groups in the United Kingdom. Diabet Med 9:641–645, 1992 [PubMed: 1511571]

318.

Newman JM, Marfin AA, Eggers PW, Helgerson SD: End state renal disease among Native Americans, 1983–86. Am J Public Health 80:318–319, 1990 [PMC free article: PMC1404694] [PubMed: 2305914]

319.

Pavkov ME, Bennett PH, Knowler WC, Krakoff J, Sievers ML, Nelson RG: Effect of youth-onset type 2 diabetes on incidence of end-stage renal disease and mortality in young and middle-aged Pima Indians. JAMA 296:421–426, 2006 [PubMed: 16868300]

320.

Pavkov ME, Hanson RL, Knowler WC, Sievers ML, Bennett PH, Nelson RG: Effect of intrauterine diabetes exposure on the incidence of end-stage renal disease in young adults with type 2 diabetes. Diabetes Care 33:2396–2398, 2010 [PMC free article: PMC2963501] [PubMed: 20693350]

321.

McMillan MA, Briggs JD, Junor BJ: Outcome of renal replacement treatment in patients with diabetes mellitus. BMJ 301:540–544, 1990 [PMC free article: PMC1663846] [PubMed: 2207427]

322.

Hirschl MM, Heinz G, Sunder-Plassmann G, Derfler K: Renal replacement therapy in type 2 diabetic patients: 10 years’ experience. Am J Kidney Dis 20:564–568, 1992 [PubMed: 1462983]

323.

Rischen-Vos J, van der Woude FJ, Tegzess AM, Zwinderman AH, Gooszen HC, van den Akker PJ, van Es LA: Increased morbidity and mortality in patients with diabetes mellitus after kidney transplantation as compared with non-diabetic patients. Nephrol Dial Transplant 7:433–437, 1992 [PubMed: 1321380]

324.

Koch M, Thomas B, Tschope W, Ritz E: Survival and predictors of death in dialysed diabetic patients. Diabetologia 36:1113–1117, 1993 [PubMed: 8243864]

325.

Cowie CC, Port FK, Rust KF, Harris MI: Differences in survival between black and white patients with diabetic end-stage renal disease. Diabetes Care 17:681–687, 1994 [PubMed: 7924777]

326.

Yan G, Norris KC, Yu AJ, Ma JZ, Greene T, Yu W, Cheung AK: The relationship of age, race, and ethnicity with survival in dialysis patients. Clin J Am Soc Nephrol 8:953–961, 2013 [PMC free article: PMC3675850] [PubMed: 23539227]

327.

Murthy BV, Molony DA, Stack AG: Survival advantage of Hispanic patients initiating dialysis in the United States is modified by race. J Am Soc Nephrol 16:782–790, 2005 [PubMed: 15677309]

328.

Nelson RG, Hanson RL, Pettitt DJ, Knowler WC, Bennett PH: Survival during renal replacement therapy for diabetic end-stage renal disease in Pima Indians. Diabetes Care 19:1333–1337, 1996 [PubMed: 8941459]

329.

Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, Held PJ, Port FK: Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 341:1725–1730, 1999 [PubMed: 10580071]

330.

McFarlane PA: Should patients remain on intensive hemodialysis rather than choosing to receive a kidney transplant? Semin Dial 23:516–519, 2010 [PubMed: 21039877]

331.

Port FK, Wolfe RA, Mauger EA, Berling DP, Jiang K: Comparison of survival probabilities for dialysis patients vs cadaveric renal transplant recipients. JAMA 270:1339–1343, 1993 [PubMed: 8360969]

332.

Humphrey LL, Ballard DJ, Frohnert PP, Chu CP, O’Fallon WM, Palumbo PJ: Chronic renal failure in non-insulin-dependent diabetes mellitus. A population-based study in Rochester, Minnesota. Ann Intern Med 111:788–796, 1989 [PubMed: 2817626]

333.

Hasslacher C, Ritz E, Wahl P, Michael C: Similar risks of nephropathy in patients with type I or type II diabetes mellitus. Nephrol Dial Transplant 4:859–863, 1989 [PubMed: 2515489]

334.

Pugh JA, Medina R, Ramirez M: Comparison of the course to end-stage renal disease of type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetic nephropathy. Diabetologia 36:1094–1098, 1993 [PubMed: 8243860]

335.

Norris K, Nissenson AR: Race, gender, and socioeconomic disparities in CKD in the United States. J Am Soc Nephrol 19:1261–1270, 2008 [PubMed: 18525000]

336.

Barbour SJ, Schachter M, Er L, Djurdjev O, Levin A: A systematic review of ethnic differences in the rate of renal progression in CKD patients. Nephrol Dial Transplant 25:2422–2430, 2010 [PubMed: 20519230]

337.

Ward MM: Socioeconomic status and the incidence of ESRD. Am J Kidney Dis 51:563–572, 2008 [PubMed: 18371532]

338.

Painter RC, Osmond C, Gluckman P, Hanson M, Phillips DI, Roseboom TJ: Transgenerational effects of prenatal exposure to the Dutch famine on neonatal adiposity and health in later life. BJOG 115:1243–1249, 2008 [PubMed: 18715409]

339.

Klein R, Klein BE, Moss SE: Prevalence of microalbuminuria in older-onset diabetes. Diabetes Care 16:1325–1330, 1993 [PubMed: 8269789]

340.

Coonrod BA, Ellis D, Becker DJ, Bunker CH, Kelsey SF, Lloyd CE, Drash AL, Kuller LH, Orchard TJ: Predictors of microalbuminuria in individuals with IDDM. Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Care 16:1376–1383, 1993 [PubMed: 8269796]

341.

Hasslacher C, Stech W, Wahl P, Ritz E: Blood pressure and metabolic control as risk factors for nephropathy in type 1 (insulin-dependent) diabetes. Diabetologia 28:6–11, 1985 [PubMed: 3979689]

342.

Nelson RG, Knowler WC, Pettitt DJ, Hanson RL, Bennett PH: Incidence and determinants of elevated urinary albumin excretion in Pima Indians with NIDDM. Diabetes Care 18:182–187, 1995 [PubMed: 7729295]

343.

Cooper ME, Frauman A, O’Brien RC, Seeman E, Murray RM, Jerums G: Progression of proteinuria in type 1 and type 2 diabetes. Diabet Med 5:361–368, 1988 [PubMed: 2968887]

344.

Fabre J, Balant LP, Dayer PG, Fox HM, Vernet AT: The kidney in maturity onset diabetes mellitus: a clinical study of 510 patients. Kidney Int 21:730–738, 1982 [PubMed: 7109459]

345.

Niskanen L, Voutilainen R, Terasvirta M, Lehtinen J, Teppo AM, Groop L, Uusitupa M: A prospective study of clinical and metabolic associates of proteinuria in patients with type 2 diabetes mellitus. Diabet Med 10:543–549, 1993 [PubMed: 8365091]

346.

Larkins RG, Dunlop ME: The link between hyperglycemia and diabetic nephropathy. Diabetologia 35:499–504, 1992 [PubMed: 1612221]

347.

Mauer SM, Goetz FC, McHugh LE, Sutherland DE, Barbosa J, Najarian JS, Steffes MW: Long-term study of normal kidneys transplanted into patients with type I diabetes. Diabetes 38:516–523, 1989 [PubMed: 2647558]

348.

Scott LJ, Warram JH, Hanna LS, Laffel LM, Ryan L, Krolewski AS: A nonlinear effect of hyperglycemia and current cigarette smoking are major determinants of the onset of microalbuminuria in type 1 diabetes. Diabetes 50:2842–2849, 2001 [PubMed: 11723069]

349.

Romero P, Salvat M, Fernandez J, Baget M, Martinez I: Renal and retinal microangiopathy after 15 years of follow-up study in a sample of type 1 diabetes mellitus patients. J Diabetes Complications 21:93–100, 2007 [PubMed: 17331857]

350.

Selvin E, Francis LM, Ballantyne CM, Hoogeveen RC, Coresh J, Brancati FL, Steffes MW: Nontraditional markers of glycemia: associations with microvascular conditions. Diabetes Care 34:960–967, 2011 [PMC free article: PMC3064058] [PubMed: 21335368]

351.

Fioretto P, Bruseghin M, Berto I, Gallina P, Manzato E, Mussap M: Renal protection in diabetes: role of glycemic control. J Am Soc Nephrol 17(4 Suppl 2):S86–S89, 2006 [PubMed: 16565255]

352.

Keane WF, Brenner BM, de Zeeuw D, Grunfeld JP, McGill J, Mitch WE, Ribeiro AB, Shahinfar S, Simpson RL, Snapinn SM, Toto R; RENAAL Study Investigators: The risk of developing end-stage renal disease in patients with type 2 diabetes and nephropathy: the RENAAL study. Kidney Int 63:1499–1507, 2003 [PubMed: 12631367]

353.

Wiseman MJ, Saunders AJ, Keen H, Viberti G: Effect of blood glucose control on increased glomerular filtration rate and kidney size in insulin-dependent diabetes. N Engl J Med 312:617–621, 1985 [PubMed: 3883162]

354.

Christiansen JS, Frandsen M, Parving HH: Effects of intravenous glucose infusion on renal function in normal man and in insulin-dependent diabetics. Diabetologia 21:368–373, 1981 [PubMed: 7286497]

355.

Stackhouse S, Miller PL, Park SK, Meyer TW: Reversal of glomerular hyperfiltration and renal hypertrophy by blood glucose normalization in diabetic rats. Diabetes 39:989–995, 1990 [PubMed: 2373266]

356.

Helal I, Fick-Brosnahan GM, Reed-Gitomer B, Schrier RW: Glomerular hyperfiltration: definitions, mechanisms and clinical implications. Nat Rev Nephrol 8:293–300, 2012 [PubMed: 22349487]

357.

Cooper ME: Pathogenesis, prevention, and treatment of diabetic nephropathy. Lancet 352:213–219, 1998 [PubMed: 9683226]

358.

Miller JA: Impact of hyperglycemia on the renin angiotensin system in early human type 1 diabetes mellitus. J Am Soc Nephrol 10:1778–1785, 1999 [PubMed: 10446946]

359.

Satchell SC, Tooke JE: What is the mechanism of microalbuminuria in diabetes: a role for the glomerular endothelium? Diabetologia 51:714–725, 2008 [PMC free article: PMC2292427] [PubMed: 18347777]

360.

Steffes MW, Sutherland DE, Goetz FC, Rich SS, Mauer SM: Studies of kidney and muscle biopsy specimens from identical twins discordant for type I diabetes mellitus. N Engl J Med 312:1282–1287, 1985 [PubMed: 4039409]

361.

Fioretto P, Mauer M: Reversal of diabetic nephropathy: lessons from pancreas transplantation. J Nephrol 25:13–18, 2012 [PubMed: 22241641]

362.

Mathiesen ER, Ronn B, Jensen T, Storm B, Deckert T: Relationship between blood pressure and urinary albumin excretion in development of microalbuminuria. Diabetes 39:245–249, 1990 [PubMed: 2227133]

363.

Raal FJ, Kalk WJ, Taylor DR, Osler CE, Panz VR: The relationship between the development and progression of microalbuminuria and arterial blood pressure in type 1 (insulin-dependent) diabetes mellitus. Diabetes Res Clin Pract 16:221–227, 1992 [PubMed: 1425143]

364.

Steinke JM: The natural progression of kidney injury in young type 1 diabetic patients. Curr Diab Rep 9:473–479, 2009 [PubMed: 19954694]

365.

Schultz CJ, Neil HA, Dalton RN, Konopelska Bahu T, Dunger DB; Oxford Regional Prospective Study Group: Blood pressure does not rise before the onset of microalbuminuria in children followed from diagnosis of type 1 diabetes. Diabetes Care 24:555–560, 2001 [PubMed: 11289484]

366.

Viberti GC, Keen H, Wiseman MJ: Raised arterial pressure in parents of proteinuric insulin dependent diabetics. Br Med J (Clin Res Ed) 295:515–517, 1987 [PMC free article: PMC1247425] [PubMed: 3117203]

367.

Barzilay J, Warram JH, Bak M, Laffel LM, Canessa M, Krolewski AS: Predisposition to hypertension: risk factor for nephropathy and hypertension in IDDM. Kidney Int 41:723–730, 1992 [PubMed: 1513093]

368.

Lurbe E, Redon J, Kesani A, Pascual JM, Tacons J, Alvarez V, Batlle D: Increase in nocturnal blood pressure and progression to microalbuminuria in type 1 diabetes. N Engl J Med 347:797–805, 2002 [PubMed: 12226150]

369.

Nelson RG, Pettitt DJ, de Courten MP, Hanson RL, Knowler WC, Bennett PH: Parental hypertension and proteinuria in Pima Indians with NIDDM. Diabetologia 39:433–438, 1996 [PubMed: 8777992]

370.

Nelson RG, Pettitt DJ, Baird HR, Charles MA, Liu QZ, Bennett PH, Knowler WC: Pre-diabetic blood pressure predicts urinary albumin excretion after the onset of type 2 (non-insulin-dependent) diabetes mellitus in Pima Indians. Diabetologia 36:998–1001, 1993 [PubMed: 8243885]

371.

Canessa M, Adragna N, Solomon HS, Connolly TM, Tosteson DC: Increased sodium-lithium countertransport in red cells of patients with essential hypertension. N Engl J Med 302:772–776, 1980 [PubMed: 7354809]

372.

Woods JW, Falk RJ, Pittman AW, Klemmer PJ, Watson BS, Namboodiri K: Increased red-cell sodium-lithium countertransport in normotensive sons of hypertensive parents. N Engl J Med 306:593–595, 1982 [PubMed: 6949036]

373.

Clegg G, Morgan DB, Davidson C: The heterogeneity of essential hypertension. Relation between lithium efflux and sodium content of erythrocytes and a family history of hypertension. Lancet 2:891–894, 1982 [PubMed: 6126750]

374.

Cooper R, LeGrady D, Nanas S, Trevisan M, Mansour M, Histand P, Ostrow D, Stamler J: Increased sodium-lithium countertransport in college students with elevated blood pressure. JAMA 249:1030–1034, 1983 [PubMed: 6823057]

375.

Zerbini G, Gabellini D, Ruggieri D, Maestroni A: Increased sodium-lithium countertransport activity: a cellular dysfunction common to essential hypertension and diabetic nephropathy. J Am Soc Nephrol 15(Suppl 1):S81–S84, 2004 [PubMed: 14684679]

376.

Mangili R, Bending JJ, Scott G, Li LK, Gupta A, Viberti G: Increased sodium-lithium countertransport activity in red cells of patients with insulin-dependent diabetes and nephropathy. N Engl J Med 318:146–150, 1988 [PubMed: 3336402]

377.

Jones SL, Trevisan R, Tariq T, Semplicini A, Mattock M, Walker JD, Nosadini R, Viberti GC: Sodium-lithium countertransport in microalbuminuric insulin-dependent diabetic patients. Hypertension 15:570–575, 1990 [PubMed: 2347619]

378.

Jensen JS, Mathiesen ER, Norgaard K, Hommel E, Borch-Johnsen K, Funder J, Brahm J, Parving HH, Deckert T: Increased blood pressure and erythrocyte sodium/lithium countertransport activity are not inherited in diabetic nephropathy. Diabetologia 33:619–624, 1990 [PubMed: 2257999]

379.

Carr S, Mbanya JC, Thomas T, Keavey P, Taylor R, Alberti KG, Wilkinson R: Increase in glomerular filtration rate in patients with insulin-dependent diabetes and elevated erythrocyte sodium-lithium countertransport. N Engl J Med 322:500–505, 1990 [PubMed: 2300121]

380.

Lopes de Faria JM, Silveira LA, Morgano M, Pavin EJ, Lopes de Faria JB: Erythrocyte sodium-lithium countertransport and proliferative diabetic retinopathy. Invest Ophthalmol Vis Sci 41:1482–1485, 2000 [PubMed: 10798666]

381.

Elving LD, Wetzels JF, de Nobel E, Berden JH: Erythrocyte sodium-lithium countertransport is not different in type 1 (insulin-dependent) diabetic patients with and without diabetic nephropathy. Diabetologia 34:126–128, 1991 [PubMed: 2065847]

382.

Gall MA, Rossing P, Jensen JS, Funder J, Parving HH: Red cell Na+/Li+ countertransport in non-insulin-dependent diabetics with diabetic nephropathy. Kidney Int 39:135–140, 1991 [PubMed: 2002627]

383.

Giordano M, Castellino P, Solini A, Canessa ML, DeFronzo RA: Na+/Li+ and Na+/H+ countertransport activity in hypertensive non-insulin-dependent diabetic patients: role of insulin resistance and antihypertensive treatment. Metabolism 46:1316–1323, 1997 [PubMed: 9361692]

384.

Fujita J, Tsuda K, Seno M, Obayashi H, Fukui I, Seino Y: Erythrocyte sodium-lithium countertransport activity as a marker of predisposition to hypertension and diabetic nephropathy in NIDDM. Diabetes Care 17:977–982, 1994 [PubMed: 7988318]

385.

Herman WH, Prior DE, Yassine MD, Weder AB: Nephropathy in NIDDM is associated with cellular markers for hypertension. Diabetes Care 16:815–818, 1993 [PubMed: 8388330]

386.

Volzke H, Gruska S, Vogelgesang D, Kerner W, Kraatz G, Rettig R: Intracellular calcium and sodium-lithium countertransport in type 2 diabetic patients with and without albuminuria. Endocr J 53:773–781, 2006 [PubMed: 16983181]

387.

Van Norren K, Thien T, Berden JH, Elving LD, De Pont JJ: Relevance of erythrocyte Na+/Li+ countertransport measurement in essential hypertension, hyperlipidaemia and diabetic nephropathy: a critical review. Eur J Clin Invest 28:339–352, 1998 [PubMed: 9650006]

388.

Diamond JR, Karnovsky MJ: Focal and segmental glomerulosclerosis: analogies to atherosclerosis. Kidney Int 33:917–924, 1988 [PubMed: 3292816]

389.

Moorhead JF, El-Nahas M, Chan MK, Varghese Z: Lipid nephrotoxicity in chronic progressive glomerular and tubulo-inter-stitial disease. Lancet 2:1309–1311, 1982 [PubMed: 6128601]

390.

Cases A, Coll E: Dyslipidemia and the progression of renal disease in chronic renal failure patients. Kidney Int Suppl 99:S87–S93, 2005 [PubMed: 16336584]

391.

Marcovecchio ML, Dalton RN, Prevost AT, Acerini CL, Barrett TG, Cooper JD, Edge J, Neil A, Shield J, Widmer B, Todd JA, Dunger DB: Prevalence of abnormal lipid profiles and the relationship with the development of microalbuminuria in adolescents with type 1 diabetes. Diabetes Care 32:658–663, 2009 [PMC free article: PMC2660471] [PubMed: 19171721]

392.

Ku E, Campese V: Is lipid management effective for all stages of CKD? Blood Purif 35:26–30, 2013 [PubMed: 23343543]

393.

Jenkins AJ, Lyons TJ, Zheng D, Otvos JD, Lackland DT, McGee D, Garvey WT, Klein RL; DCCT/EDIC Research Group: Lipoproteins in the DCCT/EDIC cohort: associations with diabetic nephropathy. Kidney Int 64:817–828, 2003 [PubMed: 12911531]

394.

Kwan BC, Kronenberg F, Beddhu S, Cheung AK: Lipoprotein metabolism and lipid management in chronic kidney disease. J Am Soc Nephrol 18:1246–1261, 2007 [PubMed: 17360943]

395.

Krentz AJ: Lipoprotein abnormalities and their consequences for patients with type 2 diabetes. Diabetes Obes Metab 5(Suppl 1):S19–S27, 2003 [PubMed: 14984018]

396.

Thomas MC, Rosengard-Barlund M, Mills V, Ronnback M, Thomas S, Forsblom C, Cooper ME, Taskinen MR, Viberti G, Groop PH: Serum lipids and the progression of nephropathy in type 1 diabetes. Diabetes Care 29:317–322, 2006 [PubMed: 16443880]

397.

Thorn LM, Forsblom C, Fagerudd J, Thomas MC, Pettersson-Fernholm K, Saraheimo M, Waden J, Ronnback M, Rosengard-Barlund M, Bjorkesten CG, Taskinen MR, Groop PH FinnDiane Study Group: Metabolic syndrome in type 1 diabetes: association with diabetic nephropathy and glycemic control (the FinnDiane study). Diabetes Care 28:2019–2024, 2005 [PubMed: 16043748]

398.

Kamanna VS: Low density lipoproteins and mitogenic signal transduction processes: role in the pathogenesis of renal disease. Histol Histopathol 17:497–505, 2002 [PubMed: 11962755]

399.

Sibley SD, Hokanson JE, Steffes MW, Purnell JQ, Marcovina SM, Cleary PA, Brunzell JD: Increased small dense LDL and intermediate-density lipoprotein with albuminuria in type 1 diabetes. Diabetes Care 22:1165–1170, 1999 [PMC free article: PMC2635089] [PubMed: 10388983]

400.

Retnakaran R, Cull CA, Thorne KI, Adler AI, Holman RR; UKPDS Study Group: Risk factors for renal dysfunction in type 2 diabetes: U.K. Prospective Diabetes Study 74. Diabetes 55:1832–1839, 2006 [PubMed: 16731850]

401.

Tershakovec AM, Keane WF, Zhang Z, Lyle PA, Appel GB, McGill JB, Parving HH, Cooper ME, Shahinfar S, Brenner BM: Effect of LDL cholesterol and treatment with losartan on end-stage renal disease in the RENAAL study. Diabetes Care 31:445–447, 2008 [PubMed: 18070995]

402.

Colhoun HM, Lee ET, Bennett PH, Lu M, Keen H, Wang SL, Stevens LK, Fuller JH: Risk factors for renal failure: the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia 44(Suppl 2):S46–S53, 2001 [PubMed: 11587050]

403.

Rossi MC, Nicolucci A, Pellegrini F, Comaschi M, Ceriello A, Cucinotta D, Giorda C, Valentini U, Vespasiani G, De Cosmo S: Identifying patients with type 2 diabetes at high risk of microalbuminuria: results of the DEMAND (Developing Education on Microalbuminuria for Awareness of reNal and cardiovascular risk in Diabetes) Study. Nephrol Dial Transplant 23:1278–1284, 2008 [PubMed: 18039647]

404.

Smulders YM, Rakic M, Stehouwer CD, Weijers RN, Slaats EH, Silberbusch J: Determinants of progression of microalbuminuria in patients with NIDDM. A prospective study. Diabetes Care 20:999–1005, 1997 [PubMed: 9167114]

405.

Fagot-Campagna A, Nelson RG, Knowler WC, Pettitt DJ, Robbins DC, Go O, Welty TK, Lee ET, Howard BV: Plasma lipoproteins and the incidence of abnormal excretion of albumin in diabetic American Indians: the Strong Heart Study. Diabetologia 41:1002–1009, 1998 [PubMed: 9754817]

406.

Cooper ME, Jandeleit-Dahm KA: Lipids and diabetic renal disease. Curr Diab Rep 5:445–448, 2005 [PubMed: 16316596]

407.

Gyebi L, Soltani Z, Reisin E: Lipid nephrotoxicity: new concept for an old disease. Curr Hypertens Rep 14:177–181, 2012 [PubMed: 22290079]

408.

Attia DM, Feron O, Goldschmeding R, Radermakers LH, Vaziri ND, Boer P, Balligand JL, Koomans HA, Joles JA: Hypercholesterolemia in rats induces podocyte stress and decreases renal cortical nitric oxide synthesis via an angiotensin II type 1 receptor-sensitive mechanism. J Am Soc Nephrol 15:949–957, 2004 [PubMed: 15034097]

409.

Attia DM, Ni ZN, Boer P, Attia MA, Goldschmeding R, Koomans HA, Vaziri ND, Joles JA: Proteinuria is preceded by decreased nitric oxide synthesis and prevented by a NO donor in cholesterol-fed rats. Kidney Int 61:1776–1787, 2002 [PubMed: 11967027]

410.

Chade AR, Zhu XY, Grande JP, Krier JD, Lerman A, Lerman LO: Simvastatin abates development of renal fibrosis in experimental renovascular disease. J Hypertens 26:1651–1660, 2008 [PubMed: 18622245]

411.

Feron O, Dessy C, Moniotte S, Desager JP, Balligand JL: Hypercholesterolemia decreases nitric oxide production by promoting the interaction of caveolin and endothelial nitric oxide synthase. J Clin Invest 103:897–905, 1999 [PMC free article: PMC408139] [PubMed: 10079111]

412.

Romero JC, Reckelhoff JF: State-of-the-Art lecture. Role of angiotensin and oxidative stress in essential hypertension. Hypertension 34:943–949, 1999 [PubMed: 10523389]

413.

Kopkan L, Khan MA, Lis A, Awayda MS, Majid DS: Cholesterol induces renal vasoconstriction and anti-natriuresis by inhibiting nitric oxide production in anesthetized rats. Am J Physiol Renal Physiol 297:F1606–F1613, 2009 [PMC free article: PMC2801331] [PubMed: 19776170]

414.

Nosadini R, Tonolo G: Role of oxidized low density lipoproteins and free fatty acids in the pathogenesis of glomerulopathy and tubulointerstitial lesions in type 2 diabetes. Nutr Metab Cardiovasc Dis 21:79–85, 2011 [PubMed: 21186102]

415.

Tang C, Kanter JE, Bornfeldt KE, Leboeuf RC, Oram JF: Diabetes reduces the cholesterol exporter ABCA1 in mouse macrophages and kidneys. J Lipid Res 51:1719–1728, 2010 [PMC free article: PMC2882721] [PubMed: 19965614]

416.

Proctor G, Jiang T, Iwahashi M, Wang Z, Li J, Levi M: Regulation of renal fatty acid and cholesterol metabolism, inflammation, and fibrosis in Akita and OVE26 mice with type 1 diabetes. Diabetes 55:2502–2509, 2006 [PubMed: 16936198]

417.

Merscher-Gomez S, Guzman J, Pedigo CE, Lehto M, Aguillon-Prada R, Mendez A, Lassenius MI, Forsblom C, Yoo T, Villarreal R, Maiguel D, Johnson K, Goldberg R, Nair V, Randolph A, Kretzler M, Nelson RG, Burke GW, 3rd, Groop PH, Fornoni A; FinnDiane Study Group: Cyclodextrin protects podocytes in diabetic kidney disease. Diabetes 62:3817–3827, 2013 [PMC free article: PMC3806621] [PubMed: 23835338]

418.

Herman-Edelstein M, Scherzer P, Tobar A, Levi M, Gafter U: Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy. J Lipid Res 55:561–572, 2014 [PMC free article: PMC3934740] [PubMed: 24371263]

419.

van Nielen M, Feskens EJ, Mensink M, Sluijs I, Molina E, Amiano P, Ardanaz E, Balkau B, Beulens JW, Boeing H, Clavel-Chapelon F, Fagherazzi G, Franks PW, Halkjaer J, Huerta JM, Katzke V, Key TJ, Khaw KT, Krogh V, Kuhn T, Menendez VV, Nilsson P, Overvad K, Palli D, Panico S, Rolandsson O, Romieu I, Sacerdote C, Sanchez MJ, Schulze MB, Spijkerman AM, Tjonneland A, Tumino R, van der A DL, Wurtz AM, Zamora-Ros R, Langenberg C, Sharp SJ, Forouhi NG, Riboli E, Wareham NJ; InterAct Consortium: Dietary protein intake and incidence of type 2 diabetes in Europe: the EPIC-InterAct Case-Cohort Study. Diabetes Care 37:1854–1862, 2014 [PubMed: 24722499]

420.

Hoogeveen EK, Kostense PJ, Jager A, Heine RJ, Jakobs C, Bouter LM, Donker AJ, Stehouwer CD: Serum homocysteine level and protein intake are related to risk of microalbuminuria: the Hoorn Study. Kidney Int 54:203–209, 1998 [PubMed: 9648080]

421.

Brenner BM, Meyer TW, Hostetter TH: Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N Engl J Med 307:652–659, 1982 [PubMed: 7050706]

422.

Brenner BM: Hemodynamically mediated glomerular injury and the progressive nature of kidney disease. Kidney Int 23:647–655, 1983 [PubMed: 6336299]

423.

Farr LE, Smadel JE: The effect of dietary protein on the course of nephrotoxic nephritis in rats. J Exp Med 70:615–627, 1939 [PMC free article: PMC2133771] [PubMed: 19870934]

424.

Friend PS, Fernandes G, Good RA, Michael AF, Yunis EJ: Dietary restrictions early and late: effects on the nephropathy of the NZB x NZW mouse. Lab Invest 38:629–632, 1978 [PubMed: 96299]

425.

Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BM: Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. Am J Physiol 241:F85–F93, 1981 [PubMed: 7246778]

426.

Hostetter TH, Meyer TW, Rennke HG, Brenner BM: Chronic effects of dietary protein in the rat with intact and reduced renal mass. Kidney Int 30:509–517, 1986 [PubMed: 3784291]

427.

Zatz R, Meyer TW, Rennke HG, Brenner BM: Predominance of hemodynamic rather than metabolic factors in the pathogenesis of diabetic glomerulopathy. Proc Natl Acad Sci U S A 82:5963–5967, 1985 [PMC free article: PMC390674] [PubMed: 3862110]

428.

Meek RL, LeBoeuf RC, Saha SA, Alpers CE, Hudkins KL, Cooney SK, Anderberg RJ, Tuttle KR: Glomerular cell death and inflammation with high-protein diet and diabetes. Nephrol Dial Transplant 28:1711–1720, 2013 [PMC free article: PMC3707525] [PubMed: 23314315]

429.

Tuttle KR, Bruton JL, Perusek MC, Lancaster JL, Kopp DT, DeFronzo RA: Effect of strict glycemic control on renal hemodynamic response to amino acids and renal enlargement in insulin-dependent diabetes mellitus. N Engl J Med 324:1626–1632, 1991 [PubMed: 2030719]

430.

Tuttle KR, Bruton JL: Effect of insulin therapy on renal hemodynamic response to amino acids and renal hypertrophy in non-insulin-dependent diabetes. Kidney Int 42:167–173, 1992 [PubMed: 1635346]

431.

Uribarri J, Tuttle KR: Advanced glycation end products and nephrotoxicity of high-protein diets. Clin J Am Soc Nephrol 1:1293–1299, 2006 [PubMed: 17699361]

432.

Banerjee T, Crews DC, Wesson DE, Tilea A, Saran R, Rios Burrows N, Williams DE, Powe NR; Centers for Disease Control and Prevention Chronic Kidney Disease Surveillance Team: Dietary acid load and chronic kidney disease among adults in the United States. BMC Nephrol 15:137, 2014 [PMC free article: PMC4151375] [PubMed: 25151260]

433.

Shah SN, Abramowitz M, Hostetter TH, Melamed ML: Serum bicarbonate levels and the progression of kidney disease: a cohort study. Am J Kidney Dis 54:270–277, 2009 [PMC free article: PMC4354889] [PubMed: 19394734]

434.

Whaley-Connell AT, Sowers JR, Stevens LA, McFarlane SI, Shlipak MG, Norris KC, Chen SC, Qiu Y, Wang C, Li S, Vassalotti JA, Collins AJ; Kidney Early Evaluation Program Investigators: CKD in the United States: Kidney Early Evaluation Program (KEEP) and National Health and Nutrition Examination Survey (NHANES) 1999–2004. Am J Kidney Dis 51(4 Suppl 2):S13–S20, 2008 [PubMed: 18359403]

435.

Rudberg S, Stattin EL, Dahlquist G: Familial and perinatal risk factors for micro-and macroalbuminuria in young IDDM patients. Diabetes 47:1121–1126, 1998 [PubMed: 9648837]

436.

Chase HP, Garg SK, Marshall G, Berg CL, Harris S, Jackson WE, Hamman RE: Cigarette smoking increases the risk of albuminuria among subjects with type 1 diabetes. JAMA 265:614–617, 1991 [PubMed: 1987411]

437.

Muhlhauser I, Sawicki P, Berger M: Cigarette-smoking as a risk factor for macroproteinuria and proliferative retinopathy in type 1 (insulin-dependent) diabetes. Diabetologia 29:500–502, 1986 [PubMed: 3758532]

438.

Hovind P, Rossing P, Tarnow L, Parving HH: Smoking and progression of diabetic nephropathy in type 1 diabetes. Diabetes Care 26:911–916, 2003 [PubMed: 12610058]

439.

Muhlhauser I, Bender R, Bott U, Jorgens V, Grusser M, Wagener W, Overmann H, Berger M: Cigarette smoking and progression of retinopathy and nephropathy in type 1 diabetes. Diabet Med 13:536–543, 1996 [PubMed: 8799657]

440.

Biesenbach G, Janko O, Zazgornik J: Similar rate of progression in the predialysis phase in type I and type II diabetes mellitus. Nephrol Dial Transplant 9:1097–1102, 1994 [PubMed: 7800207]

441.

Sawicki PT, Didjurgeit U, Muhlhauser I, Bender R, Heinemann L, Berger M: Smoking is associated with progression of diabetic nephropathy. Diabetes Care 17:126–131, 1994 [PubMed: 8137682]

442.

Hsu CC, Hwang SJ, Tai TY, Chen T, Huang MC, Shin SJ, Wen CP, Shih YT, Yang HJ, Chang CT, Chang CJ, Loh CH, Fuh MT, Li YS, Chang HY: Cigarette smoking and proteinuria in Taiwanese men with type 2 diabetes mellitus. Diabet Med 27:295–302, 2010 [PubMed: 20536492]

443.

Chuahirun T, Khanna A, Kimball K, Wesson DE: Cigarette smoking and increased urine albumin excretion are interrelated predictors of nephropathy progression in type 2 diabetes. Am J Kidney Dis 41:13–21, 2003 [PubMed: 12500217]

444.

Gambaro G, Bax G, Fusaro M, Normanno M, Manani SM, Zanella M, Dangelo A, Fedele D, Favaro S: Cigarette smoking is a risk factor for nephropathy and its progression in type 2 diabetes mellitus. Diabetes Nutr Metab 14:337–342, 2001 [PubMed: 11853366]

445.

Afghahi H, Cederholm J, Eliasson B, Zethelius B, Gudbjornsdottir S, Hadimeri H, Svensson MK: Risk factors for the development of albuminuria and renal impairment in type 2 diabetes—the Swedish National Diabetes Register (NDR). Nephrol Dial Transplant 26:1236–1243, 2011 [PubMed: 20817668]

446.

Jaimes EA, Tian RX, Raij L: Nicotine: the link between cigarette smoking and the progression of renal injury? Am J Physiol Heart Circ Physiol 292:H76–H82, 2007 [PubMed: 16920799]

447.

Obert DM, Hua P, Pilkerton ME, Feng W, Jaimes EA: Environmental tobacco smoke furthers progression of diabetic nephropathy. Am J Med Sci 341:126–130, 2011 [PMC free article: PMC3022961] [PubMed: 20924282]

448.

Czekaj P, Palasz A, Lebda-Wyborny T, Nowaczyk-Dura G, Karczewska W, Florek E, Kaminski M: Morphological changes in lungs, placenta, liver and kidneys of pregnant rats exposed to cigarette smoke. Int Arch Occup Environ Health 75(Suppl):S27–S35, 2002 [PubMed: 12397408]

449.

Huang MF, Lin WL, Ma YC: A study of reactive oxygen species in mainstream of cigarette. Indoor Air 15:135–140, 2005 [PubMed: 15737156]

450.

Wilkes HC, Kelleher C, Meade TW: Smoking and plasma fibrinogen. Lancet 1:307–308, 1988 [PubMed: 2893128]

451.

Paterson AM, Mancia G, FitzGerald GA: Proceedings of the symposium on smoking: a risk factor for cardiovascular disease. Am Heart J 115(Suppl 2):S240–S294, 1988

452.

Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen A: Albuminuria reflects widespread vascular damage. The Steno hypothesis. Diabetologia 32:219–226, 1989 [PubMed: 2668076]

453.

Ogden CL, Flegal KM, Carroll MD, Johnson CL: Prevalence and trends in overweight among US children and adolescents, 1999–2000. JAMA 288:1728–1732, 2002 [PubMed: 12365956]

454.

Nelson RG, Pavkov ME, Hanson RL, Knowler WC: Changing course of diabetic nephropathy in the Pima Indians. Diabetes Res Clin Pract 82(Suppl 1):S10–S14, 2008 [PMC free article: PMC2603306] [PubMed: 18842316]

455.

Pavkov ME, Hanson RL, Knowler WC, Bennett PH, Krakoff J, Nelson RG: Changing patterns of type 2 diabetes incidence among Pima Indians. Diabetes Care 30:1758–1763, 2007 [PubMed: 17468358]

456.

Wang Y, Chen X, Song Y, Caballero B, Cheskin LJ: Association between obesity and kidney disease: a systematic review and meta-analysis. Kidney Int 73:19–33, 2008 [PubMed: 17928825]

457.

Kambham N, Markowitz GS, Valeri AM, Lin J, D’Agati VD: Obesity-related glomerulopathy: an emerging epidemic. Kidney Int 59:1498–1509, 2001 [PubMed: 11260414]

458.

Zoccali C, Mallamaci F: Adiponectin and leptin in chronic kidney disease: causal factors or mere risk markers? J Ren Nutr 21:87–91, 2011 [PubMed: 21195927]

459.

Alejandre Alcazar MA, Boehler E, Amann K, Klaffenbach D, Hartner A, Allabauer I, Wagner L, von Horsten S, Plank C, Dotsch J: Persistent changes within the intrinsic kidney-associated NPY system and tubular function by litter size reduction. Nephrol Dial Transplant 26:2453–2465, 2011 [PubMed: 21367848]

460.

Straub RH, Schaller T, Miller LE, von Horsten S, Jessop DS, Falk W, Scholmerich J: Neuropeptide Y cotrans-mission with norepinephrine in the sympathetic nerve-macrophage interplay. J Neurochem 75:2464–2471, 2000 [PubMed: 11080198]

461.

Alejandre Alcazar MA, Boehler E, Rother E, Amann K, Vohlen C, von Horsten S, Plank C, Dotsch J: Early postnatal hyperalimentation impairs renal function via SOCS-3 mediated renal postreceptor leptin resistance. Endocrinology 153:1397–1410, 2012 [PubMed: 22253420]

462.

Taylor GW, Borgnakke WS: Periodontal disease: associations with diabetes, glycemic control and complications. Oral Dis 14:191–203, 2008 [PubMed: 18336370]

463.

Akar H, Akar GC, Carrero JJ, Stenvinkel P, Lindholm B: Systemic consequences of poor oral health in chronic kidney disease patients. Clin J Am Soc Nephrol 6:218–226, 2011 [PubMed: 21115624]

464.

Xiong X, Buekens P, Vastardis S, Pridjian G: Periodontal disease and gestational diabetes mellitus. Am J Obstet Gynecol 195:1086–1089, 2006 [PubMed: 16846573]

465.

Kshirsagar AV, Craig RG, Moss KL, Beck JD, Offenbacher S, Kotanko P, Klemmer PJ, Yoshino M, Levin NW, Yip JK, Almas K, Lupovici EM, Usvyat LA, Falk RJ: Periodontal disease adversely affects the survival of patients with end-stage renal disease. Kidney Int 75:746–751, 2009 [PubMed: 19165177]

466.

Shultis WA, Weil EJ, Looker HC, Curtis JM, Shlossman M, Genco RJ, Knowler WC, Nelson RG: Effect of periodontitis on overt nephropathy and end-stage renal disease in type 2 diabetes. Diabetes Care 30:306–311, 2007 [PubMed: 17259499]

467.

Fisher MA, Taylor GW, West BT, McCarthy ET: Bidirectional relationship between chronic kidney disease and periodontal disease: structural equation modeling. Kidney Int 79:347–355, 2011 [PMC free article: PMC3045269] [PubMed: 20927035]

468.

Sanz M, D’Aiuto F, Deanfield J, Fernandez-Aviles F: European workshop in periodontal health and cardiovascular disease—scientific evidence on the association between periodontal and cardiovascular diseases: a review of the literature. Eur Heart J 12(Suppl B):B3–B12, 2010

469.

Tonetti MS, D’Aiuto F, Nibali L, Donald A, Storry C, Parkar M, Suvan J, Hingorani AD, Vallance P, Deanfield J: Treatment of periodontitis and endothelial function. N Engl J Med 356:911–920, 2007 [PubMed: 17329698]

470.

Agodoa LY, Francis ME, Eggers PW: Association of analgesic use with prevalence of albuminuria and reduced GFR in US adults. Am J Kidney Dis 51:573–583, 2008 [PubMed: 18371533]

471.

Harirforoosh S, Jamali F: Renal adverse effects of nonsteroidal anti-inflammatory drugs. Expert Opin Drug Saf 8:669–681, 2009 [PubMed: 19832117]

472.

Evans M, Fored CM, Bellocco R, Fitzmaurice G, Fryzek JP, McLaughlin JK, Nyren O, Elinder CG: Acetaminophen, aspirin and progression of advanced chronic kidney disease. Nephrol Dial Transplant 24:1908–1918, 2009 [PubMed: 19155536]

473.

Musu M, Finco G, Antonucci R, Polati E, Sanna D, Evangelista M, Ribuffo D, Schweiger V, Fanos V: Acute nephrotoxicity of NSAID from the foetus to the adult. Eur Rev Med Pharmacol Sci 15:1461–1472, 2011 [PubMed: 22288307]

474.

Adams DH, Michael J, Bacon PA, Howie AJ, McConkey B, Abu D: Non-steroidal anti-inflammatory drugs and renal failure. Lancet 1:57–60, 1986 [PubMed: 2867313]

475.

Perneger TV, Whelton PK, Klag MJ: Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs. N Engl J Med 331:1675–1679, 1994 [PubMed: 7969358]

476.

Clive DM, Stoff JS: Renal syndromes associated with nonsteroidal antiinflammatory drugs. N Engl J Med 310:563–572, 1984 [PubMed: 6363936]

477.

Brater DC: Clinical aspects of renal prostaglandins and NSAID therapy. Semin Arthritis Rheum 17(3 Suppl 2):17–22, 1988 [PubMed: 3334106]

478.

Stillman MT, Schlesinger PA: Nonsteroidal anti-inflammatory drug nephrotoxicity. Should we be concerned? Arch Intern Med 150:268–270, 1990 [PubMed: 2405799]

479.

Patel NS, Cuzzocrea S, Collino M, Chaterjee PK, Mazzon E, Britti D, Yaqoob MM, Thiemermann C: The role of cycloxygenase-2 in the rodent kidney following ischaemia/reperfusion injury in vivo. Eur J Pharmacol 562:148–154, 2007 [PubMed: 17343844]

480.

Cherney DZ, Miller JA, Scholey JW, Bradley TJ, Slorach C, Curtis JR, Dekker MG, Nasrallah R, Hebert RL, Sochett EB: The effect of cyclooxygenase-2 inhibition on renal hemodynamic function in humans with type 1 diabetes. Diabetes 57:688–695, 2008 [PubMed: 18083781]

481.

Nath KA: Tubulointerstitial changes as a major determinant in the progression of renal damage. Am J Kidney Dis 20:1–17, 1992 [PubMed: 1621674]

482.

Segal R, Lubart E, Leibovitz A, Iaina A, Caspi D: Renal effects of low dose aspirin in elderly patients. Isr Med Assoc J 8:679–682, 2006 [PubMed: 17125112]

483.

Goldszer RC, Coodley EL, Rosner MI, Simons WM, Schwartz AB: Hyperkalemia associated with indomethacin. Arch Intern Med 141:802–804, 1981 [PubMed: 7016059]

484.

Winkelmayer WC, Waikar SS, Mogun H, Solomon DH: Nonselective and cyclooxygenase-2-selective NSAIDs and acute kidney injury. Am J Med 121:1092–1098, 2008 [PubMed: 19028206]

485.

Whelton A, Hamilton CW: Nonsteroidal anti-inflammatory drugs: effects on kidney function. J Clin Pharmacol 31:588–598, 1991 [PubMed: 1894754]

486.

Curhan GC, Knight EL, Rosner B, Hankinson SE, Stampfer MJ: Lifetime nonnarcotic analgesic use and decline in renal function in women. Arch Intern Med 164:1519–1524, 2004 [PubMed: 15277282]

487.

Rexrode KM, Buring JE, Glynn RJ, Stampfer MJ, Youngman LD, Gaziano JM: Analgesic use and renal function in men. JAMA 286:315–321, 2001 [PubMed: 11466097]

488.

Wei L, MacDonald TM, Jennings C, Sheng X, Flynn RW, Murphy MJ: Estimated GFR reporting is associated with decreased nonsteroidal anti-inflammatory drug prescribing and increased renal function. Kidney Int 84:174–178, 2013 [PMC free article: PMC3697045] [PubMed: 23486517]

489.

Radhakrishnan J, Perazella MA: Drug-induced glomerular disease: attention required! Clin J Am Soc Nephrol 10:1287–1290, 2015 [PMC free article: PMC4491281] [PubMed: 25876771]

490.

Markowitz GS, Bomback AS, Perazella MA: Drug-induced glomerular disease: direct cellular injury. Clin J Am Soc Nephrol 10:1291–1299, 2015 [PMC free article: PMC4491280] [PubMed: 25862776]

491.

McCullough PA, Adam A, Becker CR, Davidson C, Lameire N, Stacul F, Tumlin J; CIN Consensus Working Panel: Risk prediction of contrast-induced nephropathy. Am J Cardiol 98:27K–36K, 2006 [PubMed: 16949378]

492.

Koopman RJ, Mainous AG, 3rd, Liszka HA, Colwell JA, Slate EH, Carnemolla MA, Everett CJ: Evidence of nephropathy and peripheral neuropathy in US adults with undiagnosed diabetes. Ann Fam Med 4:427–432, 2006 [PMC free article: PMC1578655] [PubMed: 17003143]

493.

Sundkvist G, Lilja B: Autonomic neuropathy predicts deterioration in glomerular filtration rate in patients with IDDM. Diabetes Care 16:773–779, 1993 [PubMed: 8495619]

494.

Lilja B, Nosslin B, Bergstrom B, Sundkvist G: Glomerular filtration rate, autonomic nerve function, and orthostatic blood pressure in patients with diabetes mellitus. Diabetes Res 2:179–181, 1985 [PubMed: 4085171]

495.

Kim YK, Lee JE, Kim YG, Kim DJ, Oh HY, Yang CW, Kim KW, Huh W: Cardiac autonomic neuropathy as a predictor of deterioration of the renal function in normoalbuminuric, normotensive patients with type 2 diabetes mellitus. J Korean Med Sci 24(Suppl):S69–S74, 2009 [PMC free article: PMC2633204] [PubMed: 19194565]

496.

Ewing DJ, Campbell IW, Clarke BF: The natural history of diabetic autonomic neuropathy. Q J Med 49:95–108, 1980 [PubMed: 7433630]

497.

Bramham K, Rajasingham D: Pregnancy in diabetes and kidney disease. J Renal Care 38(Suppl 1):78–89, 2012 [PubMed: 22348367]

498.

Biesenbach G, Stoger W, Zazgornik J: [Changes in renal protein excretion and kidney function in type I diabetics during and following pregnancy in relation to the stage of preexistent diabetic nephropathy]. [Article in German] Klin Wochenschr 65:1048–1053, 1987 [PubMed: 3431031]

499.

Powe CE, Thadhani R: Diabetes and the kidney in pregnancy. Semin Nephrol 31:59–69, 2011 [PubMed: 21266265]

500.

Diabetes Control and Complications Trial Research Group: Effect of pregnancy on microvascular complications in the Diabetes Control and Complications Trial. Diabetes Care 23:1084–1091, 2000 [PMC free article: PMC2631985] [PubMed: 10937502]

501.

Gordon M, Landon MB, Samuels P, Hissrich S, Gabbe SG: Perinatal outcome and long-term follow-up associated with modern management of diabetic nephropathy. Obstet Gynecol 87:401–409, 1996 [PubMed: 8598963]

502.

Rossing K, Jacobsen P, Hommel E, Mathiesen E, Svenningsen A, Rossing P, Parving HH: Pregnancy and progression of diabetic nephropathy. Diabetologia 45:36–41, 2002 [PubMed: 11845221]

503.

Gordin D, Hiilesmaa V, Fagerudd J, Ronnback M, Forsblom C, Kaaja R, Teramo K, Groop PH; FinnDiane Study Group: Pre-eclampsia but not pregnancy-induced hypertension is a risk factor for diabetic nephropathy in type 1 diabetic women. Diabetologia 50:516–522, 2007 [PubMed: 17216281]

504.

Rocco L, Gil FZ, da Fonseca Pletiskaitz TM, de Fatima Cavanal M, Gomes GN: Effect of sodium overload on renal function of offspring from diabetic mothers. Pediatr Nephrol 23:2053–2060, 2008 [PubMed: 18574600]

505.

Nelson RG: Intrauterine determinants of diabetic kidney disease in disadvantaged populations. Kidney Int Suppl 83:S13–S16, 2003 [PubMed: 12864868]

506.

Luyckx VA, Bertram JF, Brenner BM, Fall C, Hoy WE, Ozanne SE, Vikse BE: Effect of fetal and child health on kidney development and long-term risk of hypertension and kidney disease. Lancet 382:273–283, 2013 [PubMed: 23727166]

507.

Ruta LA, Dickinson H, Thomas MC, Denton KM, Anderson WP, Kett MM: High-salt diet reveals the hypertensive and renal effects of reduced nephron endowment. Am J Physiol Renal Physiol 298:F1384–F1392, 2010 [PubMed: 20335316]

508.

Pinheiro AR, Salvucci ID, Aguila MB, Mandarim-de-Lacerda CA: Protein restriction during gestation and/or lactation causes adverse transgenerational effects on biometry and glucose metabolism in F1 and F2 progenies of rats. Clin Sci (Lond) 114:381–392, 2008 [PubMed: 17927565]

509.

Harrison M, Langley-Evans SC: Intergenerational programming of impaired nephrogenesis and hypertension in rats following maternal protein restriction during pregnancy. Br J Nutr 101:1020–1030, 2009 [PMC free article: PMC2665257] [PubMed: 18778527]

510.

Reddy MA, Natarajan R: Epigenetics in diabetic kidney disease. J Am Soc Nephrol 22:2182–2185, 2011 [PMC free article: PMC3250203] [PubMed: 22021712]

511.

Dabelea D, Hanson RL, Bennett PH, Roumain J, Knowler WC, Pettitt DJ: Increasing prevalence of type II diabetes in American Indian children. Diabetologia 41:904–910, 1998 [PubMed: 9726592]

512.

Abi Khalil C, Travert F, Fetita S, Rouzet F, Porcher R, Riveline JP, Hadjadj S, Larger E, Roussel R, Vexiau P, Le Guludec D, Gautier JF, Marre M: Fetal exposure to maternal type 1 diabetes is associated with renal dysfunction at adult age. Diabetes 59:2631–2636, 2010 [PMC free article: PMC3279566] [PubMed: 20622173]

513.

Abrahamson DR, Steenhard BM: Perinatal nephron programming is not so sweet in maternal diabetes. J Am Soc Nephrol 19:837–839, 2008 [PubMed: 18385416]

514.

Tran S, Chen YW, Chenier I, Chan JS, Quaggin S, Hebert MJ, Ingelfinger JR, Zhang SL: Maternal diabetes modulates renal morphogenesis in offspring. J Am Soc Nephrol 19:943–952, 2008 [PMC free article: PMC2386724] [PubMed: 18305124]

515.

White SL, Perkovic V, Cass A, Chang CL, Poulter NR, Spector T, Haysom L, Craig JC, Salmi IA, Chadban SJ, Huxley RR: Is low birth weight an antecedent of CKD in later life? A systematic review of observational studies. Am J Kidney Dis 54:248–261, 2009 [PubMed: 19339091]

516.

Li S, Chen SC, Shlipak M, Bakris G, McCullough PA, Sowers J, Stevens L, Jurkovitz C, McFarlane S, Norris K, Vassalotti J, Klag MJ, Brown WW, Narva A, Calhoun D, Johnson B, Obialo C, Whaley-Connell A, Becker B, Collins AJ; Kidney Early Evaluation Program Investigators: Low birth weight is associated with chronic kidney disease only in men. Kidney Int 73:637–642, 2008 [PubMed: 18094674]

517.

Hsu CW, Yamamoto KT, Henry RK, De Roos AJ, Flynn JT: Prenatal risk factors for childhood CKD. J Am Soc Nephrol 25:2105–2111, 2014 [PMC free article: PMC4147970] [PubMed: 24744441]

518.

Seaquist ER, Goetz FC, Rich S, Barbosa J: Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 320:1161–1165, 1989 [PubMed: 2710189]

519.

Borch-Johnsen K, Norgaard K, Hommel E, Mathiesen ER, Jensen JS, Deckert T, Parving HH: Is diabetic nephropathy an inherited complication? Kidney Int 41:719–722, 1992 [PubMed: 1513092]

520.

Pettitt DJ, Saad MF, Bennett PH, Nelson RG, Knowler WC: Familial predisposition to renal disease in two generations of Pima Indians with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 33:438–443, 1990 [PubMed: 2401399]

521.

Hanson RL, Craig DW, Millis MP, Yeatts KA, Kobes S, Pearson JV, Lee AM, Knowler WC, Nelson RG, Wolford JK: Identification of PVT1 as a candidate gene for end-stage renal disease in type 2 diabetes using a pooling-based genome-wide single nucleotide polymorphism association study. Diabetes 56:975–983, 2007 [PubMed: 17395743]

522.

Millis MP, Bowen D, Kingsley C, Watanabe RM, Wolford JK: Variants in the plasma-cytoma variant translocation gene (PVT1) are associated with end-stage renal disease attributed to type 1 diabetes. Diabetes 56:3027–3032, 2007 [PubMed: 17881614]

523.

Pezzolesi MG, Poznik GD, Mychaleckyj JC, Paterson AD, Barati MT, Klein JB, Ng DP, Placha G, Canani LH, Bochenski J, Waggott D, Merchant ML, Krolewski B, Mirea L, Wanic K, Katavetin P, Kure M, Wolkow P, Dunn JS, Smiles A, Walker WH, Boright AP, Bull SB; DCCT/EDIC Research Group, Doria A, Rogus JJ, Rich SS, Warram JH, Krolewski AS: Genome-wide association scan for diabetic nephropathy susceptibility genes in type 1 diabetes. Diabetes 58:1403–1410, 2009 [PMC free article: PMC2682673] [PubMed: 19252134]

524.

Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group: Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA 290:2159–2167, 2003 [PMC free article: PMC2622725] [PubMed: 14570951]

525.

Pezzolesi MG, Poznik GD, Skupien J, Smiles AM, Mychaleckyj JC, Rich SS, Warram JH, Krolewski AS: An intergenic region on chromosome 13q33.3 is associated with the susceptibility to kidney disease in type 1 and 2 diabetes. Kidney Int 80:105–111, 2011 [PMC free article: PMC3774030] [PubMed: 21412220]

526.

Craig DW, Millis MP, DiStefano JK: Genome-wide SNP genotyping study using pooled DNA to identify candidate markers mediating susceptibility to end-stage renal disease attributed to type 1 diabetes. Diabet Med 26:1090–1098, 2009 [PubMed: 19929986]

527.

Shimazaki A, Kawamura Y, Kanazawa A, Sekine A, Saito S, Tsunoda T, Koya D, Babazono T, Tanaka Y, Matsuda M, Kawai K, Iiizumi T, Imanishi M, Shinosaki T, Yanagimoto T, Ikeda M, Omachi S, Kashiwagi A, Kaku K, Iwamoto Y, Kawamori R, Kikkawa R, Nakajima M, Nakamura Y, Maeda S: Genetic variations in the gene encoding ELMO1 are associated with susceptibility to diabetic nephropathy. Diabetes 54:1171–1178, 2005 [PubMed: 15793258]

528.

Leak TS, Perlegas PS, Smith SG, Keene KL, Hicks PJ, Langefeld CD, Mychaleckyj JC, Rich SS, Kirk JK, Freedman BI, Bowden DW, Sale MM: Variants in intron 13 of the ELMO1 gene are associated with diabetic nephropathy in African Americans. Ann Hum Genet 73:152–159, 2009 [PMC free article: PMC2778056] [PubMed: 19183347]

529.

Knowler WC, Coresh J, Elston RC, Freedman BI, Iyengar SK, Kimmel PL, Olson JM, Plaetke R, Sedor JR, Seldin MF; Family Investigation of Nephropathy and Diabetes Research Group: The Family Investigation of Nephropathy and Diabetes (FIND): design and methods. J Diabetes Complications 19:1–9, 2005 [PubMed: 15642484]

530.

Iyengar SK, Abboud HE, Goddard KA, Saad MF, Adler SG, Arar NH, Bowden DW, Duggirala R, Elston RC, Hanson RL, Ipp E, Kao WH, Kimmel PL, Klag MJ, Knowler WC, Meoni LA, Nelson RG, Nicholas SB, Pahl MV, Parekh RS, Quade SR, Rich SS, Rotter JI, Scavini M, Schelling JR, Sedor JR, Sehgal AR, Shah VO, Smith MW, Taylor KD, Winkler CA, Zager PG, Freedman BI; Family Investigation of Nephropathy and Diabetes Research Group: Genome-wide scans for diabetic nephropathy and albuminuria in multiethnic populations: the Family Investigation of Nephropathy and Diabetes (FIND). Diabetes 56:1577–1585, 2007 [PubMed: 17363742]

531.

Schelling JR, Abboud HE, Nicholas SB, Pahl MV, Sedor JR, Adler SG, Arar NH, Bowden DW, Elston RC, Freedman BI, Goddard KA, Guo X, Hanson RL, Ipp E, Iyengar SK, Jun G, Kao WH, Kasinath BS, Kimmel PL, Klag MJ, Knowler WC, Nelson RG, Parekh RS, Quade SR, Rich SS, Saad MF, Scavini M, Smith MW, Taylor K, Winkler CA, Zager PG, Shah VO; Family Investigation of Nephropathy and Diabetes Research Group: Genome-wide scan for estimated glomerular filtration rate in multi-ethnic diabetic populations: the Family Investigation of Nephropathy and Diabetes (FIND). Diabetes 57:235–243, 2008 [PubMed: 18003762]

532.

Mooyaart AL, Valk EJ, van Es LA, Bruijn JA, de Heer E, Freedman BI, Dekkers OM, Baelde HJ: Genetic associations in diabetic nephropathy: a meta-analysis. Diabetologia 54:544–553, 2011 [PMC free article: PMC3034040] [PubMed: 21127830]

533.

Langefeld CD, Beck SR, Bowden DW, Rich SS, Wagenknecht LE, Freedman BI: Heritability of GFR and albuminuria in Caucasians with type 2 diabetes mellitus. Am J Kidney Dis 43:796–800, 2004 [PubMed: 15112169]

534.

Reddy MA, Zhang E, Natarajan R: Epigenetic mechanisms in diabetic complications and metabolic memory. Diabetologia 58:443–455, 2015 [PMC free article: PMC4324095] [PubMed: 25481708]

535.

Alvarez ML, DiStefano JK: The role of non-coding RNAs in diabetic nephropathy: potential applications as biomarkers for disease development and progression. Diabetes Res Clin Pract 99:1–11, 2013 [PubMed: 23102915]

536.

Dwivedi RS, Herman JG, McCaffrey TA, Raj DS: Beyond genetics: epigenetic code in chronic kidney disease. Kidney Int 79:23–32, 2011 [PMC free article: PMC3867804] [PubMed: 20881938]

537.

Blood glucose control and the evolution of diabetic retinopathy and albuminuria. A preliminary multicenter trial. The Kroc Collaborative Study Group. N Engl J Med 311:365–372, 1984 [PubMed: 6377076]

538.

Bending JJ, Viberti GC, Watkins PJ, Keen H: Intermittent clinical proteinuria and renal function in diabetes: evolution and effect of glycaemic control. Br Med J (Clin Res Ed) 292:83–86, 1986 [PMC free article: PMC1339106] [PubMed: 3080101]

539.

Feldt-Rasmussen B, Mathiesen E, Deckert T: Effect of two years of strict metabolic control on progression of incipient nephropathy in insulin-dependent diabetes. Lancet 2:1300–1304, 1986 [PubMed: 2878175]

540.

Dahl-Jorgensen K, Bjoro T, Kierulf P, Sandvik L, Bangstad HJ, Hanssen KF: Long-term glycemic control and kidney function in insulin-dependent diabetes mellitus. Kidney Int 41:920–923, 1992 [PubMed: 1513113]

541.

Reichard P, Nilsson BY, Rosenqvist U: The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med 329:304–309, 1993 [PubMed: 8147960]

542.

DCCT/EDIC Research Group; de Boer IH, Sun W, Cleary PA, Lachin JM, Molitch ME, Steffes MW, Zinman B: Intensive diabetes therapy and glomerular filtration rate in type 1 diabetes. N Engl J Med 365:2366–2376, 2011 [PMC free article: PMC3270008] [PubMed: 22077236]

543.

Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group: Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 353:2643–2653, 2005 [PMC free article: PMC2637991] [PubMed: 16371630]

544.

Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA: 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359:1577–1589, 2008 [PubMed: 18784090]

545.

Del Prato S: Megatrials in type 2 diabetes. From excitement to frustration? Diabetologia 52:1219–1226, 2009 [PubMed: 19373446]

546.

Duckworth WC, Abraira C, Moritz TE, Davis SN, Emanuele N, Goldman S, Hayward R, Huang GD, Marks JB, Reaven PD, Reda DJ, Warren SR, Zieve FJ; Investigators of the VADT: The duration of diabetes affects the response to intensive glucose control in type 2 subjects: the VA Diabetes Trial. J Diabetes Complications 25:355–361, 2011 [PubMed: 22055259]

547.

Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, Lafont S, Bergeonneau C, Kassai B, Erpeldinger S, Wright JM, Gueyffier F, Cornu C: Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials. BMJ 343:d4169, 2011 [PMC free article: PMC3144314] [PubMed: 21791495]

548.

Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 28:103–117, 1995 [PubMed: 7587918]

549.

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes, UKPDS 33. UK Prospective Diabetes Study (UKPDS) Group. Lancet 352:837–853, 1998 [PubMed: 9742976]

550.

Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352:854–865, 1998 [PubMed: 9742977]

551.

Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT: Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 358:2545–2559, 2008 [PMC free article: PMC4551392] [PubMed: 18539917]

552.

ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F: Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 358:2560–2572, 2008 [PubMed: 18539916]

553.

Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD; VADT Investigators: Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 360:129–139, 2009 [PubMed: 19092145]

554.

National Kidney Foundation: KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 update. Am J Kidney Dis 60:850–886, 2012 [PubMed: 23067652]

555.

Gerich JE, Meyer C, Woerle HJ, Stumvoll M: Renal gluconeogenesis: its importance in human glucose homeostasis. Diabetes Care 24:382−391, 2001 [PubMed: 11213896]

556.

Williams ME: Management of diabetes in dialysis patients. Curr Diab Rep 9:466–472, 2009 [PubMed: 19954693]

557.

Ix JH: Hemoglobin A1c in hemodialysis patients: should one size fit all? Clin J Am Soc Nephrol 5:1539–1541, 2010 [PubMed: 20671219]

558.

Morgan L, Marenah CB, Jeffcoate WJ, Morgan AG: Glycated proteins as indices of glycaemic control in diabetic patients with chronic renal failure. Diabet Med 13:514–519, 1996 [PubMed: 8799653]

559.

Joy MS, Cefalu WT, Hogan SL, Nachman PH: Long-term glycemic control measurements in diabetic patients receiving hemodialysis. Am J Kidney Dis 39:297–307, 2002 [PubMed: 11840370]

560.

Inaba M, Okuno S, Kumeda Y, Yamada S, Imanishi Y, Tabata T, Okamura M, Okada S, Yamakawa T, Ishimura E, Nishizawa Y; Osaka CKD Expert Research Group: Glycated albumin is a better glycemic indicator than glycated hemoglobin values in hemodialysis patients with diabetes: effect of anemia and erythropoietin injection. J Am Soc Nephrol 18:896–903, 2007 [PubMed: 17267743]

561.

Riveline JP, Teynie J, Belmouaz S, Franc S, Dardari D, Bauwens M, Caudwell V, Ragot S, Bridoux F, Charpentier G, Marechaud R, Hadjadj S: Glycaemic control in type 2 diabetic patients on chronic haemodialysis: use of a continuous glucose monitoring system. Nephrol Dial Transplant 24:2866–2871, 2009 [PubMed: 19389864]

562.

Freedman BI, Shihabi ZK, Andries L, Cardona CY, Peacock TP, Byers JR, Russell GB, Stratta RJ, Bleyer AJ: Relationship between assays of glycemia in diabetic subjects with advanced chronic kidney disease. Am J Nephrol 31:375–379, 2010 [PubMed: 20299782]

563.

Ng JM, Cooke M, Bhandari S, Atkin SL, Kilpatrick ES: The effect of iron and erythropoietin treatment on the A1C of patients with diabetes and chronic kidney disease. Diabetes Care 33:2310–2313, 2010 [PMC free article: PMC2963485] [PubMed: 20798337]

564.

Ramirez SP, McCullough KP, Thumma JR, Nelson RG, Morgenstern H, Gillespie BW, Inaba M, Jacobson SH, Vanholder R, Pisoni RL, Port FK, Robinson BM: Hemoglobin A(1c) levels and mortality in the diabetic hemodialysis population: findings from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Diabetes Care 35:2527–2532, 2012 [PMC free article: PMC3507600] [PubMed: 22912431]

565.

Shurraw S, Hemmelgarn B, Lin M, Majumdar SR, Klarenbach S, Manns B, Bello A, James M, Turin TC, Tonelli M; Alberta Kidney Disease Network: Association between glycemic control and adverse outcomes in people with diabetes mellitus and chronic kidney disease. Arch Intern Med 171:1920–1927, 2011 [PubMed: 22123800]

566.

Sturm G, Lamina C, Zitt E, Lhotta K, Haider F, Neyer U, Kronenberg F: Association of HbA1c values with mortality and cardiovascular events in diabetic dialysis patients. The INVOR study and review of the literature. PLOS ONE 6:e20093, 2011 [PMC free article: PMC3097236] [PubMed: 21625600]

567.

Balamuthusamy S, Srinivasan L, Verma M, Adigopula S, Jalandara N, Hathiwala S, Smith E: Renin angiotensin system blockade and cardiovascular outcomes in patients with chronic kidney disease and proteinuria: a metaanalysis. Am Heart J 155:791–805, 2008 [PubMed: 18440325]

568.

ACE Inhibitors in Diabetic Nephropathy Trialist Group: Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensin-converting enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med 134:370–379, 2001 [PubMed: 11242497]

569.

Lemley KV: When to initiate ACEI/ARB therapy in patients with type 1 and 2 diabetes. Pediatr Nephrol 25:2021–2034, 2010 [PubMed: 20352458]

570.

Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 329:1456–1462, 1993 [PubMed: 8413456]

571.

Mauer M, Zinman B, Gardiner R, Suissa S, Sinaiko A, Strand T, Drummond K, Donnelly S, Goodyer P, Gubler MC, Klein R: Renal and retinal effects of enalapril and losartan in type 1 diabetes. N Engl J Med 361:40–51, 2009 [PMC free article: PMC2978030] [PubMed: 19571282]

572.

Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. The EUCLID Study Group. Lancet 349:1787–1792, 1997 [PubMed: 9269212]

573.

Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 355:253–259, 2000 [PubMed: 10675071]

574.

Ruggenenti P, Fassi A, Ilieva AP, Bruno S, Iliev IP, Brusegan V, Rubis N, Gherardi G, Arnoldi F, Ganeva M, Ene-Iordache B, Gaspari F, Perna A, Bossi A, Trevisan R, Dodesini AR, Remuzzi G; Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) Investigators: Preventing microalbuminuria in type 2 diabetes. N Engl J Med 351:1941–1951, 2004 [PubMed: 15516697]

575.

Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R: Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med 128:982–988, 1998 [PubMed: 9625684]

576.

Bilous R, Chaturvedi N, Sjolie AK, Fuller J, Klein R, Orchard T, Porta M, Parving HH: Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials. Ann Intern Med 151:11–20, 2009 [PubMed: 19451554]

577.

Mann JF, Schmieder RE, Dyal L, McQueen MJ, Schumacher H, Pogue J, Wang X, Probstfield JL, Avezum A, Cardona-Munoz E, Dagenais GR, Diaz R, Fodor G, Maillon JM, Ryden L, Yu CM, Teo KK, Yusuf S; TRANSCEND (Telmisartan Randomised Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease) Investigators: Effect of telmisartan on renal outcomes a randomized trial. Ann Intern Med 151:1–10, 2009 [PubMed: 19451556]

578.

Haller H, Ito S, Izzo JL, Jr., Januszewicz A, Katayama S, Menne J, Mimran A, Rabelink TJ, Ritz E, Ruilope LM, Rump LC, Viberti G; ROADMAP Trial Investigators: Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 364:907–917, 2011 [PubMed: 21388309]

579.

Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P; Irbesartan in Patients With Type 2 Diabetes and Microalbuminuria Study Group: The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 345:870–878, 2001 [PubMed: 11565519]

580.

Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S; RENAAL Study Investigators: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345:861–869, 2001 [PubMed: 11565518]

581.

Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I; Collaborative Study Group: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345:851–860, 2001 [PubMed: 11565517]

582.

ONTARGET Investigators; Yusuf D, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P, Anderson C: Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 358:1547–1559, 2008 [PubMed: 18378520]

583.

Barnett AH, Bain SC, Bouter P, Karlberg B, Madsbad S, Jervell J, Mustonen J; Diabetics Exposed to Telmisartan and Enalapril Study Group: Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med 351:1952–1961, 2004 [PubMed: 15516696]

584.

Vejakama P, Thakkinstian A, Lertrattananon D, Ingsathit A, Ngarmukos C, Attia J: Reno-protective effects of renin-angiotensin system blockade in type 2 diabetic patients: a systematic review and network meta-analysis. Diabetologia 55:566–578, 2012 [PMC free article: PMC3268972] [PubMed: 22189484]

585.

Lv J, Perkovic V, Foote CV, Craig ME, Craig JC, Strippoli GF: Antihypertensive agents for preventing diabetic kidney disease. Cochrane Database Syst Rev 12:CD004136, 2012 [PubMed: 23235603]

586.

Strippoli GF, Craig M, Deeks JJ, Schena FP, Craig JC: Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review. BMJ 329:828, 2004 [PMC free article: PMC521570] [PubMed: 15459003]

587.

Mann JF, Anderson C, Gao P, Gerstein HC, Boehm M, Ryden L, Sleight P, Teo KK, Yusuf S; ONTARGET Investigators: Dual inhibition of the renin-angiotensin system in high-risk diabetes and risk for stroke and other outcomes: results of the ONTARGET trial. J Hypertens 31:414–421, 2013 [PubMed: 23249829]

588.

Croom KF, Curran MP, Goa KL, Perry CM: Irbesartan: a review of its use in hypertension and in the management of diabetic nephropathy. Drugs 64:999–1028, 2004 [PubMed: 15101793]

589.

Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW, Cooper ME: Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ 321:1440–1444, 2000 [PMC free article: PMC27545] [PubMed: 11110735]

590.

Bakris GL, Ruilope L, Locatelli F, Ptaszynska A, Pieske B, de Champlain J, Weber MA, Raz I: Treatment of microalbuminuria in hypertensive subjects with elevated cardiovascular risk: results of the IMPROVE trial. Kidney Int 72:879–885, 2007 [PubMed: 17667984]

591.

Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W, Leehey DJ, McCullough PA, O’Connor T, Palevsky PM, Reilly RF, Seliger SL, Warren SR, Watnick S, Peduzzi P, Guarino P; VA NEPHRON-D Investigators: Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 369:1892–1903, 2013 [PubMed: 24206457]

592.

Parving HH, Persson F, Lewis JB, Lewis EJ, Hollenberg NK; AVOID Study Investigators: Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 358:2433–2446, 2008 [PubMed: 18525041]

593.

Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, Chaturvedi N, Persson F, Desai AS, Nicolaides M, Richard A, Xiang Z, Brunel P, Pfeffer MA; ALTITUDE Investigators: Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 367:2204–2213, 2012 [PubMed: 23121378]

594.

Bangalore S, Kumar S, Lobach I, Messerli FH: Blood pressure targets in subjects with type 2 diabetes mellitus/impaired fasting glucose observations from traditional and bayesian random-effects meta-analyses of randomized trials. Circulation 123:2799–2810, 2011 [PubMed: 21632497]

595.

Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW, Striker G: The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med 330:877–884, 1994 [PubMed: 8114857]

596.

Walker WG, Hermann J, Anderson J: Racial differences in renal protective effect of enalapril vs hydrochlorothiazide in randomized doubly blinded trial in hypertensive NIDDM (Abstract). J Am Soc Nephrol 4:A310, 1993

597.

McClellan WM, Warnock DG, Judd S, Muntner P, Kewalramani R, Cushman M, McClure LA, Newsome BB, Howard G: Albuminuria and racial disparities in the risk for ESRD. J Am Soc Nephrol 22:1721–1728, 2011 [PMC free article: PMC3171942] [PubMed: 21868498]

598.

Murea M, Freedman BI: Essential hypertension and risk of nephropathy: a reappraisal. Curr Opin Nephrol Hypertens 19:235–241, 2010 [PMC free article: PMC2904692] [PubMed: 20051853]

599.

Weir MR, Bakris GL, Weber MA, Dahlof B, Devereux RB, Kjeldsen SE, Pitt B, Wright JT, Kelly RY, Hua TA, Hester RA, Velazquez E, Jamerson KA: Renal outcomes in hypertensive black patients at high cardiovascular risk. Kidney Int 81:568–576, 2012 [PubMed: 22189843]

600.

James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC, Jr., Svetkey LP, Taler SJ, Townsend RR, Wright JT, Jr., Narva AS, Ortiz E: 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 311:507–520, 2014 [PubMed: 24352797]

601.

American Diabetes Association: Cardiovascular disease and risk management. Sec. 8. In “Standards of Medical Care in Diabetes—2015.” Diabetes Care 38(Suppl 1):S49–S57, 2015

602.

Dasgupta K, Quinn RR, Zarnke KB, Rabi DM, Ravani P, Daskalopoulou SS, Rabkin SW, Trudeau L, Feldman RD, Cloutier L, Prebtani A, Herman RJ, Bacon SL, Gilbert RE, Ruzicka M, McKay DW, Campbell TS, Grover S, Honos G, Schiffrin EL, Bolli P, Wilson TW, Lindsay P, Hill MD, Coutts SB, Gubitz G, Gelfer M, Vallee M, Prasad GV, Lebel M, McLean D, Arnold JM, Moe GW, Howlett JG, Boulanger JM, Larochelle P, Leiter LA, Jones C, Ogilvie RI, Woo V, Kaczorowski J, Burns KD, Petrella RJ, Hiremath S, Milot A, Stone JA, Drouin D, Lavoie KL, Lamarre-Cliche M, Tremblay G, Hamet P, Fodor G, Carruthers SG, Pylypchuk GB, Burgess E, Lewanczuk R, Dresser GK, Penner SB, Hegele RA, McFarlane PA, Khara M, Pipe A, Oh P, Selby P, Sharma M, Reid DJ, Tobe SW, Padwal RS, Poirier L; Canadian Hypertension Education Program: The 2014 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension. Can J Cardiol 30:485–501, 2014 [PubMed: 24786438]

603.

Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, Christiaens T, Cifkova R, De Backer G, Dominiczak A, Galderisi M, Grobbee DE, Jaarsma T, Kirchhof P, Kjeldsen SE, Laurent S, Manolis AJ, Nilsson PM, Ruilope LM, Schmieder RE, Sirnes PA, Sleight P, Viigimaa M, Waeber B, Zannad F, Redon J, Dominiczak A, Narkiewicz K, Nilsson PM, Burnier M, Viigimaa M, Ambrosioni E, Caufield M, Coca A, Olsen MH, Schmieder RE, Tsioufis C, van de Borne P, Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S, Clement DL, Coca A, Gillebert TC, Tendera M, Rosei EA, Ambrosioni E, Anker SD, Bauersachs J, Hitij JB, Caulfield M, De Buyzere M, De Geest S, Derumeaux GA, Erdine S, Farsang C, Funck-Brentano C, Gerc V, Germano G, Gielen S, Haller H, Hoes AW, Jordan J, Kahan T, Komajda M, Lovic D, Mahrholdt H, Olsen MH, Ostergren J, Parati G, Perk J, Polonia J, Popescu BA, Reiner Z, Ryden L, Sirenko Y, Stanton A, Struijker-Boudier H, Tsioufis C, van de Borne P, Vlachopoulos C, Volpe M, Wood DA: 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 34:2159–2219, 2013 [PubMed: 23771844]

604.

Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group: KDIGO clinical practice guideline for the management of blood pressure in chronic kidney disease. Kidney Int Suppl 2:337–414, 2012

605.

Barrett-Connor E, Grundy SM, Holdbrook MJ: Plasma lipids and diabetes mellitus in an adult community. Am J Epidemiol 115:657–663, 1982 [PubMed: 7081197]

606.

Feingold KR, Grunfeld C, Pang M, Doerrler W, Krauss RM: LDL subclass phenotypes and triglyceride metabolism in non-insulin-dependent diabetes. Arterioscler Thromb 12:1496–1502, 1992 [PubMed: 1450181]

607.

Quaschning T, Schomig M, Keller M, Thiery J, Nauck M, Schollmeyer P, Wanner C, Kramer-Guth A: Non-insulin-dependent diabetes mellitus and hypertriglyceridemia impair lipoprotein metabolism in chronic hemodialysis patients. J Am Soc Nephrol 10:332–341, 1999 [PubMed: 10215333]

608.

Chonchol M, Cook T, Kjekshus J, Pedersen TR, Lindenfeld J: Simvastatin for secondary prevention of all-cause mortality and major coronary events in patients with mild chronic renal insufficiency. Am J Kidney Dis 49:373–382, 2007 [PubMed: 17336698]

609.

Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Charlton-Menys V, DeMicco DA, Fuller JH; CARDS Investigators: Effects of atorvastatin on kidney outcomes and cardiovascular disease in patients with diabetes: an analysis from the Collaborative Atorvastatin Diabetes Study (CARDS). Am J Kidney Dis 54:810–819, 2009 [PubMed: 19540640]

610.

Collins R, Armitage J, Parish S, Sleigh P, Peto R; Heart Protection Study Collaborative Group: MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 361:2005–2016, 2003 [PubMed: 12814710]

611.

Tonelli M, Keech A, Shepherd J, Sacks F, Tonkin A, Packard C, Pfeffer M, Simes J, Isles C, Furberg C, West M, Craven T, Curhan G: Effect of pravastatin in people with diabetes and chronic kidney disease. J Am Soc Nephrol 16:3748–3754, 2005 [PubMed: 16251235]

612.

Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, Wanner C, Krane V, Cass A, Craig J, Neal B, Jiang L, Hooi LS, Levin A, Agodoa L, Gaziano M, Kasiske B, Walker R, Massy ZA, Feldt-Rasmussen B, Krairittichai U, Ophascharoensuk V, Fellstrom B, Holdaas H, Tesar V, Wiecek A, Grobbee D, de Zeeuw D, Gronhagen-Riska C, Dasgupta T, Lewis D, Herrington W, Mafham M, Majoni W, Wallendszus K, Grimm R, Pedersen T, Tobert J, Armitage J, Baxter A, Bray C, Chen Y, Chen Z, Hill M, Knott C, Parish S, Simpson D, Sleight P, Young A, Collins R; SHARP Investigators: The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 377:2181–2192, 2011 [PMC free article: PMC3145073] [PubMed: 21663949]

613.

Wanner C, Krane V, Marz W, Olschewski M, Mann JF, Ruf G, Ritz E; German Diabetes and Dialysis Study Investigators: Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med 353:238–248, 2005 [PubMed: 16034009]

614.

Fellstrom BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J, Chae DW, Chevaile A, Cobbe SM, Gronhagen-Riska C, De Lima JJ, Lins R, Mayer G, McMahon AW, Parving HH, Remuzzi G, Samuelsson O, Sonkodi S, Sci D, Suleymanlar G, Tsakiris D, Tesar V, Todorov V, Wiecek A, Wuthrich RP, Gottlow M, Johnsson E, Zannad F; AURORA Study Group: Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 360:1395–1407, 2009 [PubMed: 19332456]

615.

Holdaas H, Holme I, Schmieder RE, Jardine AG, Zannad F, Norby GE, Fellstrom BC; AURORA study group: Rosuvastatin in diabetic hemodialysis patients. J Am Soc Nephrol 22:1335–1341, 2011 [PMC free article: PMC3137581] [PubMed: 21566054]

616.

Jardine AG, Holdaas H, Fellstrom B, Cole E, Nyberg G, Gronhagen-Riska C, Madsen S, Neumayer HH, Maes B, Ambuhl P, Olsson AG, Holme I, Fauchald P, Gimpelwicz C, Pedersen TR; ALERT Study Investigators: Fluvastatin prevents cardiac death and myocardial infarction in renal transplant recipients: post-hoc subgroup analyses of the ALERT Study. Am J Transplant 4:988–995, 2004 [PubMed: 15147434]

617.

Tonelli M, Collins D, Robins S, Bloomfield H, Curhan GC; Veterans’ Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) Investigators: Gemfibrozil for secondary prevention of cardiovascular events in mild to moderate chronic renal insufficiency. Kidney Int 66:1123–1130, 2004 [PubMed: 15327407]

618.

Ansquer JC, Foucher C, Rattier S, Taskinen MR, Steiner G; DAIS Investigators: Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: results from the Diabetes Atherosclerosis Intervention Study (DAIS). Am J Kidney Dis 45:485–493, 2005 [PubMed: 15754270]

619.

Davis TM, Ting R, Best JD, Donoghoe MW, Drury PL, Sullivan DR, Jenkins AJ, O’Connell RL, Whiting MJ, Glasziou PP, Simes RJ, Kesaniemi YA, Gebski VJ, Scott RS, Keech AC; Fenofibrate Intervention and Event Lower in Diabetes Study investigators: Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia 54:280–290, 2011 [PubMed: 21052978]

620.

Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P, Drury P, Kesaniemi YA, Sullivan D, Hunt D, Colman P, d’Emden M, Whiting M, Ehnholm C, Laakso M; FIELD study investigators: Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): a randomized controlled trial. Lancet 366:1849–1861, 2005 [PubMed: 16310551]

621.

Wen SF, Huang TP, Moorthy AV: Effects of low-protein diet on experimental diabetic nephropathy in the rat. J Lab Clin Med 106:589–597, 1985 [PubMed: 3903011]

622.

Sallstrom J, Carlström M, Olerud J, Fredholm BB, Kouzmine M, Sandler S, Persson AE: High-protein-induced glomerular hyperfiltration is independent of the tubuloglomerular feedback mechanism and nitric oxide synthases. Am J Physiol Regul Integr Comp Physiol 299:R1263–R1268, 2010 [PubMed: 20739607]

623.

Wiseman MJ, Bognetti E, Dodds R, Keen H, Viberti GC: Changes in renal function in response to protein restricted diet in type 1 (insulin-dependent) diabetic patients. Diabetologia 30:154–159, 1987 [PubMed: 3582821]

624.

Cohen D, Dodds R, Viberti GC: Effect of protein restriction in insulin dependent diabetics at risk of nephropathy. Br Med J (Clin Res Ed) 294:795–798, 1987 [PMC free article: PMC1245861] [PubMed: 3105747]

625.

Pedersen MM, Mogensen CE, Jorgensen FS, Moller B, Lykke G, Pedersen O: Renal effects from limitation of high dietary protein in normoalbuminuric diabetic patients. Kidney Int Suppl 27:S115–S121, 1989 [PubMed: 2636645]

626.

Dullaart RP, Beusekamp B, Meijer S, van Doormaal JJ, Sluiter WJ: Long-term effects of protein-restricted diet on albuminuria and renal function in IDDM patients without clinical nephropathy and hypertension. Diabetes Care 16:483–492, 1993 [PubMed: 8432221]

627.

Tuttle KR, Puhlman ME, Cooney SK, Short RA: Effects of amino acids and glucagon on renal hemodynamics in type 1 diabetes. Am J Physiol Renal Physiol 282:F103–F112, 2002 [PubMed: 11739118]

628.

Ciavarella A, Di Mizio G, Stefoni S, Borgnino LC, Vannini P: Reduced albuminuria after dietary protein restriction in insulin-dependent diabetic patients with clinical nephropathy. Diabetes Care 10:407–413, 1987 [PubMed: 3622197]

629.

Evanoff G, Thompson C, Brown J, Weinman E: Prolonged dietary protein restriction in diabetic nephropathy. Arch Intern Med 149:1129–1133, 1989 [PubMed: 2719506]

630.

Walker JD, Dodds RA, Murrells TJ, Bending JJ, Mattock MB, Keen H, Viberti GC: Restriction of dietary protein and progression of renal failure in diabetic nephropathy. Lancet 2:1411–1415, 1989 [PubMed: 2574360]

631.

Zeller K, Whittaker E, Sullivan L, Raskin P, Jacobson HR: Effect of restricting dietary protein on the progression of renal failure in patients with insulin-dependent diabetes mellitus. N Engl J Med 324:78–84, 1991 [PubMed: 1984187]

632.

Hansen HP, Tauber-Lassen E, Jensen BR, Parving HH: Effect of dietary protein restriction on prognosis in patients with diabetic nephropathy. Kidney Int 62:220–228, 2002 [PubMed: 12081581]

633.

Pijls LT, de Vries H, van Eijk JT, Donker AJ: Protein restriction, glomerular filtration rate and albuminuria in patients with type 2 diabetes mellitus: a randomized trial. Eur J Clin Nutr 56:1200–1207, 2002 [PubMed: 12494305]

634.

Pan Y, Guo LL, Jin HM: Low-protein diet for diabetic nephropathy: a meta-analysis of randomized controlled trials. Am J Clin Nutr 88:660–666, 2008 [PubMed: 18779281]

635.

Meloni C, Tatangelo P, Cipriani S, Rossi V, Suraci C, Tozzo C, Rossini B, Cecilia A, Di Franco D, Straccialano E, Casciani CU: Adequate protein dietary restriction in diabetic and nondiabetic patients with chronic renal failure. J Ren Nutr 14:208–213, 2004 [PubMed: 15483780]

636.

McGuire S: Institute of Medicine. 2010. Strategies to reduce sodium intake in the United States. Washington, DC: The National Academies Press. Adv Nutr 1:49–50, 2010 [PMC free article: PMC3042781] [PubMed: 22043452]

637.

U.S. Department of Agriculture and U.S. Department of Health and Human Services: Dietary Guidelines for Americans, 2010. 7th Edition. Washington, DC: U.S. Government Printing Office, 2010 [PMC free article: PMC3090168] [PubMed: 22332062]

638.

Centers for Disease Control and Prevention: Usual sodium intakes compared with current dietary guidelines—United States, 2005–2008. MMWR Morb Mortal Wkly Rep 60:1413–1417, 2011 [PubMed: 22012113]

639.

Suckling RJ, He FJ, MacGregor GA: Altered dietary salt intake for preventing and treating diabetic kidney disease. Cochrane Database Syst Rev 12:CD006763, 2010 [PubMed: 21154374]

640.

Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, Obarzanek E, Conlin PR, Miller ER, 3rd, Simons-Morton DG, Karanja N, Lin PH; DASH-Sodium Collaborative Research Group: Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. N Engl J Med 344:3–10, 2001 [PubMed: 11136953]

641.

Lin J, Fung TT, Hu FB, Curhan GC: Association of dietary patterns with albuminuria and kidney function decline in older white women: a subgroup analysis from the Nurses’ Health Study. Am J Kidney Dis 57:245–254, 2011 [PMC free article: PMC3026604] [PubMed: 21251540]

642.

Perkins BA, Rabbani N, Weston A, Ficociello LH, Adaikalakoteswari A, Niewczas M, Warram J, Krolewski AS, Thornalley P: Serum levels of advanced glycation endproducts and other markers of protein damage in early diabetic nephropathy in type 1 diabetes. PLOS ONE 7:e35655, 2012 [PMC free article: PMC3338454] [PubMed: 22558190]

643.

RamachandraRao SP, Zhu Y, Ravasi T, McGowan TA, Toh I, Dunn SR, Okada S, Shaw MA, Sharma K: Pirfenidone is renoprotective in diabetic kidney disease. J Am Soc Nephrol 20:1765–1775, 2009 [PMC free article: PMC2723978] [PubMed: 19578007]

644.

Shimizu T, Fukagawa M, Kuroda T, Hata S, Iwasaki Y, Nemoto M, Shirai K, Yamauchi S, Margolin SB, Shimizu F, Kurokawa K: Pirfenidone prevents collagen accumulation in the remnant kidney in rats with partial nephrectomy. Kidney Int Suppl 63:S239–S243, 1997 [PubMed: 9407470]

645.

Cho ME, Smith DC, Branton MH, Penzak SR, Kopp JB: Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis. Clin J Am Soc Nephrol 2:906–913, 2007 [PubMed: 17702727]

646.

Sharma K, Ix JH, Mathew AV, Cho M, Pflueger A, Dunn SR, Francos B, Sharma S, Falkner B, McGowan TA, Donohue M, RamachandraRao S, Xu R, Fervenza FC, Kopp JB: Pirfenidone for diabetic nephropathy. J Am Soc Nephrol 22:1144–1151, 2011 [PMC free article: PMC3103734] [PubMed: 21511828]

647.

Hagiwara S, Kantharidis P, Cooper ME: What are new avenues for renal protection, in addition to RAAS inhibition? Curr Hypertens Rep 14:100–110, 2012 [PubMed: 22298106]

648.

Zieman SJ, Melenovsky V, Clattenburg L, Corretti MC, Capriotti A, Gerstenblith G, Kass DA: Advanced glycation endproduct crosslink breaker (alagebrium) improves endothelial function in patients with isolated systolic hypertension. J Hypertens 25:577–583, 2007 [PubMed: 17278974]

649.

Kass DA, Shapiro EP, Kawaguchi M, Capriotti AR, Scuteri A, deGroof RC, Lakatta EG: Improved arterial compliance by a novel advanced glycation end-product crosslink breaker. Circulation 104:1464–1470, 2001 [PubMed: 11571237]

650.

Shan D, Wu HM, Yuan QY, Li J, Zhou RL, Liu GJ: Pentoxifylline for diabetic kidney disease. Cochrane Database Syst Rev 2:CD006800, 2012 [PubMed: 22336824]

651.

Goicoechea M, Garcia de Vinuesa S, Quiroga B, Verdalles U, Barraca D, Yuste C, Panizo N, Verde E, Munoz MA, Luno J: Effects of pentoxifylline on inflammatory parameters in chronic kidney disease patients: a randomized trial. J Nephrol 25:969–975, 2012 [PubMed: 22241639]

652.

Komers R: Rho kinase inhibition in diabetic kidney disease. Curr Opin Nephrol Hypertens 20:77–83, 2011 [PubMed: 21076299]

653.

Gaede P, Lund-Andersen H, Parving HH, Pedersen O: Effect of multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 358:580–591, 2008 [PubMed: 18256393]

654.

Sharkey TP, Root HF: Infection of the urinary tract in diabetes. JAMA 104:2231–2235, 1935

655.

Baldwin AD, Root HF: Infections of the upper urinary tract in the diabetic patient. N Engl J Med 223:244–250, 1940

656.

Robbins SL, Tucker AW, Jr.: Causes of death in diabetes. A report of 307 autopsied cases. N Engl J Med 231:865–868, 1944

657.

Edmondson HA, Martin HE, Evans N: Necrosis of renal papillae and acute pyelonephritis in diabetes mellitus. Arch Intern Med 79:148–175, 1947 [PubMed: 20285219]

658.

Aye RC: Renal papillary necrosis. Diabetes 3:124–128, 1954 [PubMed: 13161733]

659.

Zhanel GG, Harding GK, Nicolle LE: Asymptomatic bacteriuria in patients with diabetes mellitus. Rev Infect Dis 13:150–154, 1991 [PubMed: 2017615]

660.

Renko M, Tapanainen P, Tossavainen P, Pokka T, Uhari M: Meta-analysis of the significance of asymptomatic bacteriuria in diabetes. Diabetes Care 34:230–235, 2011 [PMC free article: PMC3005460] [PubMed: 20937688]

661.

Ishay A, Lavi I, Luboshitzky R: Prevalence and risk factors for asymptomatic bacteriuria in women with type 2 diabetes mellitus. Diabet Med 23:185–188, 2006 [PubMed: 16433717]

662.

Bonadio M, Boldrini E, Forotti G, Matteucci E, Vigna A, Mori S, Giampietro O: Asymptomatic bacteriuria in women with diabetes: influence of metabolic control. Clin Infect Dis 38:e41–e45, 2004 [PubMed: 14999644]

663.

Makuyana D, Mhlabi D, Chipfupa M, Munyombwe T, Gwanzura L: Asymptomatic bacteriuria among outpatients with diabetes mellitus in an urban black population. Cent Afr J Med 48:78–82, 2002 [PubMed: 14562524]

664.

Kelestimur F, Unal A, Pasaoglu H, Basar E, Kilic H, Doganay M: [Asymptomatic bacteriuria in patients with diabetes mellitus]. [Article in Turkish] Mikrobiyol Bul 24:126–132, 1990 [PubMed: 2089231]

665.

Schmitt JK, Fawcett CJ, Gullickson G: Asymptomatic bacteriuria and hemoglobin A1. Diabetes Care 9:518–520, 1986 [PubMed: 3769720]

666.

Abu-Bakare A, Oyaide SM: Asymptomatic bacteriuria in Nigerian diabetics. J Trop Med Hyg 89:29–32, 1986 [PubMed: 3528518]

667.

Rozsai B, Lanyi E, Berki T, Soltesz G: Urinary cytokine response to asymptomatic bacteriuria in type 1 diabetic children and young adults. Pediatr Diabetes 7:153–158, 2006 [PubMed: 16787522]

668.

Mendoza T, García de los Ríos M, Lafourcade M, Soto C, Durruty P, Alvo M: [Asymptomatic bacteriuria in type 2 diabetics women]. [Article in Spanish] Rev Med Chil 130:1001–1007, 2002 [PubMed: 12434647]

669.

Vigg B, Rai V: Asymptomatic bacteriuria in diabetics. J Assoc Physicians India 25:57–61, 1977 [PubMed: 924956]

670.

Joffe BI, Seftel HC, Distiller LA: Asymptomatic bacteriuria in diabetes mellitus. S Afr Med J 48:1306–1308, 1974 [PubMed: 4604134]

671.

Rozsai B, Lanyi E, Soltesz G: Asymptomatic bacteriuria and leukocyturia in type 1 diabetic children and young adults. Diabetes Care 26:2209–2210, 2003 [PubMed: 12832338]

672.

Boroumand MA, Sam L, Abbasi SH, Salarifar M, Kassaian E, Forghani S: Asymptomatic bacteriuria in type 2 Iranian diabetic women: a cross sectional study. BMC Womens Health 6:4, 2006 [PMC free article: PMC1402268] [PubMed: 16504076]

673.

Zhanel GG, Nicolle LE, Harding GK: Prevalence of asymptomatic bacteriuria and associated host factors in women with diabetes mellitus. The Manitoba Diabetic Urinary Infection Study Group. Clin Infect Dis 21:316–322, 1995 [PubMed: 8562738]

674.

Boyko EJ, Fihn SD, Scholes D, Abraham L, Monsey B: Risk of urinary tract infection and asymptomatic bacteriuria among diabetic and nondiabetic postmenopausal women. Am J Epidemiol 161:557–564, 2005 [PubMed: 15746472]

675.

Sotiropoulos A, Skourtis S, Merkouris P, Peppas T, Apostolou O, Kontela E, Skliros E, Pappas S: Incidence and outcome of asymptomatic bacteriuria in females with type 2 diabetes mellitus over a 1-year follow-up period and association with risk factors. Diabet Med 22:1625–1626, 2005 [PubMed: 16241934]

676.

Geerlings SE, Stolk RP, Camps MJ, Netten PM, Hoekstra JB, Bouter KP, Bravenboer B, Collet JT, Jansz AR, Hoepelman AI: Asymptomatic bacteriuria may be considered a complication in women with diabetes. Diabetes Mellitus Women Asymptomatic Bacteriuria Utrecht Study Group. Diabetes Care 23:744–749, 2000 [PubMed: 10840989]

677.

Geerlings SE, Stolk RP, Camps MJ, Netten PM, Collet JT, Schneeberger PM, Hoepelman AI: Consequences of asymptomatic bacteriuria in women with diabetes mellitus. Arch Intern Med 161:1421–1427, 2001 [PubMed: 11386891]

678.

Sawers JS, Todd WA, Kellett HA, Miles RS, Allan PL, Ewing DJ, Clarke BF: Bacteriuria and autonomic nerve function in diabetic women. Diabetes Care 9:460–464, 1986 [PubMed: 3533474]

679.

Brauner A, Flodin U, Hylander B, Ostenson CG: Bacteriuria, bacterial virulence and host factors in diabetic patients. Diabet Med 10:550–554, 1993 [PubMed: 8365092]

680.

Hansen RO: Bacteriuria in diabetic and non-diabetic out-patients. Acta Med Scand 176:721–730, 1964 [PubMed: 14259911]

681.

Vejlsgaard R: Studies on urinary infection in diabetics. I. Bacteriuria in patients with diabetes mellitus and in control subjects. Acta Med Scand 179:173–182, 1966 [PubMed: 5325464]

682.

Ooi BS, Chen BT, Yu M: Prevalence and site of bacteriuria in diabetes mellitus. Postgrad Med J 50:497–499, 1974 [PMC free article: PMC2495655] [PubMed: 4464512]

683.

Jaspan JB, Mangera C, Krut LH: Bacteriuria in black diabetics. S Afr Med J 51:374–376, 1977 [PubMed: 847559]

684.

Forland M, Thomas V, Shelokov A: Urinary tract infections in patients with diabetes mellitus. Studies on antibody coating of bacteria. JAMA 238:1924–1926, 1977 [PubMed: 333137]

685.

Huvos A, Rocha H: Frequency of bacteriuria in patients with diabetes mellitus. A controlled study. N Engl J Med 261:1213–1216, 1959 [PubMed: 14405661]

686.

O’Sullivan DJ, FitzGerald MG, Meynell MJ, Malins JM: Urinary tract infection. A comparative study in the diabetic and general populations. Br Med J 1:786–788, 1961 [PMC free article: PMC1953843] [PubMed: 13730121]

687.

Karunajeewa H, McGechie D, Stuccio G, Stingemore N, Davis WA, Davis TM: Asymptomatic bacteriuria as a predictor of subsequent hospitalisation with urinary tract infection in diabetic adults: the Fremantle Diabetes Study. Diabetologia 48:1288–1291, 2005 [PubMed: 15918016]

688.

Harding GK, Zhanel GG, Nicolle LE, Cheang M; Manitoba Diabetes Urinary Tract Infection Study Group: Antimicrobial treatment in diabetic women with asymptomatic bacteriuria. N Engl J Med 347:1576–1583, 2002 [PubMed: 12432044]

689.

Ribera MC, Pascual R, Orozco D, Perez BC, Pedrera V, Gil V: Incidence and risk factors associated with urinary tract infection in diabetic patients with and without asymptomatic bacteriuria. Eur J Clin Microbiol Infect Dis 25:389–393, 2006 [PubMed: 16767487]

690.

Semetkowska-Jurkiewicz E, Horoszek-Maziarz S, Galinski J, Manitius A, Krupa-Wojciechowska B: The clinical course of untreated asymptomatic bacteriuria in diabetic patients—14-year follow-up. Mater Med Pol 27:91–95, 1995 [PubMed: 8935144]

691.

Czaja CA, Rutledge BN, Cleary PA, Chan K, Stapleton AE, Stamm WE; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group: Urinary tract infections in women with type 1 diabetes mellitus: survey of female participants in the Epidemiology of Diabetes Interventions and Complications study cohort. J Urol 181:1129–1134, 2009 [PMC free article: PMC2699609] [PubMed: 19152925]

692.

Foy MC, Estrella MM, Lucas GM, Tahir F, Fine DM, Moore RD, Atta MG: Comparison of risk factors and outcomes in HIV immune complex kidney disease and HIV-associated nephropathy. Clin J Am Soc Nephrol 8:1524–1532, 2013 [PMC free article: PMC3805081] [PubMed: 23685946]

693.

Flandre P, Pugliese P, Cuzin L, Bagnis CI, Tack I, Cabie A, Poizot-Martin I, Katlama C, Brunet-Francois C, Yazdanpanah Y, Dellamonica P; New AIDS Data Group: Risk factors of chronic kidney disease in HIV-infected patients. Clin J Am Soc Nephrol 6:1700–1707, 2011 [PubMed: 21566114]

694.

Fernando SK, Finkelstein FO, Moore BA, Weissman S: Prevalence of chronic kidney disease in an urban HIV infected population. Am J Med Sci 335:89–94, 2008 [PubMed: 18277114]

695.

Nasr SH, Markowitz GS, Stokes MB, Said SM, Valeri AM, D’Agati VD: Acute postinfectious glomerulonephritis in the modern era: experience with 86 adults and review of the literature. Medicine (Baltimore) 87:21–32, 2008 [PubMed: 18204367]

696.

Kim PS, Woods C, Dutcher L, Georgoff P, Rosenberg A, Mican JA, Kopp JB, Smith MA, Hadigan C: Increased prevalence of albuminuria in HIV-infected adults with diabetes. PLOS ONE 6:e24610, 2011 [PMC free article: PMC3172239] [PubMed: 21931772]

697.

Zaidan M, Lescure FX, Brocheriou I, Dettwiler S, Guiard-Schmid JB, Pacanowski J, Rondeau E, Pialoux G, Girard PM, Ronco P, Plaisier E: Tubulointerstitial nephropathies in HIV-infected patients over the past 15 years: a clinico-pathological study. Clin J Am Soc Nephrol 8:930–938, 2013 [PMC free article: PMC3675854] [PubMed: 23430209]

698.

Eknoyan G, Qunibi WY, Grissom RT, Tuma SN, Ayus JC: Renal papillary necrosis: an update. Medicine (Baltimore) 61:55–73, 1982 [PubMed: 7038374]

699.

Abdulhayoglu S, Marble A: Necrotizing renal papillitis (papillary necrosis) in diabetes. Am J Med Sci 248:623–632, 1964 [PubMed: 14251899]

700.

Griffin MD, Bergstralhn EJ, Larson TS: Renal papillary necrosis—a sixteen-year clinical experience. J Am Soc Nephrol 6:248–256, 1995 [PubMed: 7579092]

Appendices

APPENDIX 22.1. Crude and Adjusted 1-Year Survival Probabilities Among Incident End-Stage Renal Disease Persons, by Age, Sex, Race/Ethnicity, and Primary Diagnosis, U.S., 1980–2011

APPENDIX 22.2. Crude and Adjusted 5-Year Survival Probabilities Among Incident End-Stage Renal Disease Persons, by Age, Sex, Race/Ethnicity, and Primary Diagnosis, U.S., 1980–2007

APPENDIX 22.3. Adjusted Survival Probabilities Among Persons Initiating End-Stage Renal Disease Treatment in 2007, U.S.

APPENDIX 22.4. Crude Mortality Rates Among Prevalent End-Stage Renal Disease Persons With Diabetes, by Age, Sex, and Race/Ethnicity, U.S., 2012

APPENDIX 22.5. Crude and Adjusted Annual Mortality Rates Among End-Stage Renal Disease Persons, by Age, Sex, Race, Primary Diagnosis, and Patient Vintage, U.S., 1985–2012

CONVERSIONS

Conversions for A1c, cholesterol, and triglyceride values are provided in Diabetes in America Appendix 1 Conversions.

DUALITY OF INTEREST

Drs. Pavkov, Collins, Coresh, and Nelson reported no conflicts of interest, with the following potential exceptions. Dr. Coresh received grant support from the National Kidney Foundation. Dr. Coresh possesses rights to the following intellectual property: PCT/US2015/044567 Provisional patent (Coresh, Inker, and Levey) filed August 15, 2014—Precise estimation of glomerular filtration rate from multiple biomarkers. The technology is not licensed in whole or in part to any company. Tufts Medical Center, Johns Hopkins University, and Metabolon, Inc. have a collaboration agreement to develop a product to estimate glomerular filtration rate from a panel of markers (June 25, 2016). Dr. Coresh is a member of the Global Hyperkalemia Council (sponsored by Relypsa, no personal compensation).

ACKNOWLEDGMENTS/FUNDING Dr. Nelson’s work was supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the National Institutes of Health nor the Centers for Disease Control and Prevention.