ABSTRACT

Diabetes is the most common cause of end-stage kidney disease (ESKD) in the US and other developed countries. Diabetic nephropathy is a chronic condition characterized by a gradual increase in urinary albumin excretion, blood pressure levels and cardiovascular risk, and declining glomerular filtration rate (GFR), which can progress to ESKD. Chronic kidney disease (CKD) is common among patients with diabetes, and it develops in approximately 50% of the patients with type 1 diabetes (T1D) and 30% of those with type 2 diabetes (T2D). Patients with diabetes should be screened for CKD annually. Screening should include both albuminuria measurements and estimates of GFR. The kidney structural changes of diabetic nephropathy are unique to this disease, and closely correlate with kidney function. Multiple factors are associated with CKD in diabetes, and patients with diabetes often require multiple therapies aimed at prevention of progressive CKD and its associated co-morbidities and mortality. Management of cardiorenal risk factors, including lifestyle modifications (diet, exercise, and stop smoking), glucose, blood pressure and lipid control, use of agents blocking the renin angiotensin aldosterone system and use of SGLT2 inhibitors in patients with T2D and other agents with proven renal or cardiovascular benefit are the cornerstones of therapy. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION AND EPIDEMIOLOGY

Diabetes and its complications are a substantial public health problem. In 2021, 10% of the global population (about 537 million adults) were living with diabetes (1). It is estimated that by 2045 this will rise to 784 million (1). Moreover, in a large proportion of patients, diabetes is undiagnosed. The estimates for the increased number of adults with diabetes vary largely according to the geographic region, going from a predicted 13% increase in Europe to a predicted 129% increase in Africa in the next 25 years (1), including a 24% increase in North America and Caribbean. It is estimated that over one in ten (37.3 million) Americans have diabetes, and one in three adult Americans (96 million Americans) have prediabetes (https://www.cdc.gov/diabetes/library/features/diabetes-stat-report.html).

While in populations of European origin, nearly all children and adolescents have type 1 diabetes (T1D), in certain populations (e.g., Japan), type 2 diabetes (T2D) is more common than T1D in this age group. Although the incidence of T1D is also increasing around the globe (2, 3), the rapid increase in the incidence of T2D among children and adolescents is alarming, and it has been linked to increased obesity rates and physical inactivity in this group.

Diabetes is associated with increased mortality and morbidity, and it is the main cause of incident end-stage kidney disease (ESKD) in the US and other developed countries (4). In the US alone, diabetes is responsible for more than 47% of the new ESKD cases. This is in large part due to T2D as most patients with diabetes have T2D rather than T1D. However, the proportion of individuals starting kidney replacement therapy due to diabetes varies significantly, ranging from 13% in China to 66% in Singapore (4). The likelihood of a patient with diabetes developing chronic kidney disease (CKD) is about 40% for patients with T1D and 30% for those with T2D, while the likelihood of a patient with diabetes developing ESKD is lower than that, as a large proportion of these die prematurely, especially from cardiovascular causes, before progressing to ESKD. ESKD is devastating to the individual and of enormous financial and social consequences.

PATHOPHYSIOLOGY

Diabetic nephropathy is a chronic condition that develops over many years. It is characterized by a gradual increase in urinary albumin excretion, blood pressure levels, and cardiovascular risk, declining glomerular filtration rate (GFR) and eventual ESKD. Diabetic nephropathy is associated with characteristic histopathological features (5, 6). About 25 to 50% of individuals with T1D (7, 8) and 45-57% of those with T2D (9-12) have progressively declining GFR with no or minimal albuminuria. Non-albuminuric renal impairment was the predominant phenotype among youth with T1D (13) and also among patients with T2D (14) in Italy, and a strong predictor of mortality (15). T1D patients with non-albuminuric CKD were older (8, 16) at evaluation and at T1D onset (16), were more often female (8, 16), had lower HbA1c (8, 16), total cholesterol, LDL-cholesterol, triglyceride levels (8), and serum uric acid levels (8, 16), had higher estimated GFR (eGFR) (8), were less often hypertensive (8, 16) and less likely to have retinopathy (8, 16) or to smoke (8, 16) than patients with albuminuric CKD (14, 15, 17, 18). HbA1c and blood pressure levels were higher and HDL-cholesterol was lower among non-albuminuric youth with type 1 diabetes and CKD as compared to patients with normal renal function (13). T2D patients with non-albuminuric CKD were also older (19), more often female (10, 11, 19), non-smokers (10, 11), Caucasian or Asian (10), had shorter diabetes duration (11), lower HbA1c (11), total cholesterol (12), LDL-cholesterol (12), triglyceride (11, 12), and systolic blood pressure levels (11, 12), higher eGFR (12, 19), and less often had retinopathy (11, 12) or a history of cardiovascular disease (11) than T2D patients with albuminuric CKD.

CKD in people with diabetes can be the result of diabetic nephropathy, other associated conditions such as hypertensive renal disease and obesity-related glomerulopathy, or other renal diseases, such as IgA nephropathy, focal segmental glomerulosclerosis, acute tubular necrosis, membranous nephropathy, among others (13-15). The frequency of other renal diseases depends, among others, on the prevalence of these conditions in the background population (see Excluding Other Causes of Kidney Disease below).

SCREENING, DIAGNOSIS, STAGES, AND MONITORING

Diabetic kidney disease, or CKD in diabetes, is diagnosed by measurements of kidney function. CKD diagnosis and staging in diabetes follows the same criteria as for patients without diabetes. In the clinical setting, CKD is classically diagnosed by estimates of GFR and measurements of urinary albumin. A decreased GFR indicates loss of filtration capacity, while an elevated albuminuria indicates that an abnormal (elevated) proportion of the albumin filtered by the kidneys is being eliminated in the urine, indicating changes in barrier selectivity.

CKD Stages

The 2020 KDIGO Clinical Practice Guideline for the Evaluation and Management of CKD advocates that final screening status should indicate both the GFR and albuminuria status (Tables 1 and 2) (22). The information can then be used as a measure of risk of progression to ESKD, and this classifier is also a good indicator of cardiovascular morbidity and mortality (Figure 1).

Table 1.

Glomerular Filtration Rate (GFR) Categories in Chronic Kidney Disease.

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GFR category	GFR (mL/min/1.73 m2)	Description
G1	≥90	Normal or high
G2	60–89	Mildly decreaseda
G3a	45–59	Mildly to moderately decreased
G3b	30–44	Moderately to severely decreased
G4	15–29	Severely decreased
G5	<15	Kidney failure

^a

Relative to young adult level.

Table 2.

Albuminuria Categories in Chronic Kidney Disease.

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Category	AER (mg/24 h)	ACR (approximate equivalent)		Description	Previous terminology
		mg/mmol	mg/g
A1	<30	<3	<30	Normal to mildly increased	Normal
A2	30–300	3–30	30–300	Moderately increaseda	Microalbuminuria
A3	>300	>30	>300	Severely increasedb	Proteinuria

^a

Relative to young adult level.

^b

Including nephrotic syndrome.

ACR, urine albumin:creatinine ratio; AER, albumin excretion rate.

Figure 1.

Classification and prognosis of chronic kidney disease by estimated glomerular filtration rate and albuminuria. Source: Reprinted by permission from Macmillan Publishers Ltd: Kidney International, Levin A, Stevens PE (21), copyright 2014.

Monitoring Kidney Disease

Once urinary albumin excretion is abnormal, the ACR should be measured every 3 months and eGFR every 3–6 months, depending on the CKD stage (Figure 2).

Figure 2.

Risk of progression by intensity of coloring (green, yellow, orange, red, deep red). The numbers in the boxes are a guide to the frequency of monitoring (number of times per year). These are general parameters only based on expert opinion and must take into account underlying comorbid conditions and disease state, as well as the likelihood of impacting a change in management for any individual patient. CKD, chronic kidney disease; GFR, glomerular filtration rate. Source: Reprinted by permission from American Diabetes (252).

EXCLUDING OTHER TREATABLE CAUSES OF KIDNEY DISEASE

Excluding other causes of kidney disease is especially important among patients who do not follow the classical course of diabetic nephropathy disease progression. Diabetic nephropathy is a chronic disease, thus if acute decline in GFR is present, other causes should be sought. Other causes of kidney dysfunction should also be considered if proteinuria is present before 5 years of T1D duration, in the presence of active urinary sediment (acanthocytes, cellular casts, etc.), and if there are signs or symptoms of other systemic diseases. Retinopathy may or may not be present in patients with T2D and diabetic nephropathy. The frequency of other kidney diseases will also depend on the frequency of specific diseases (IgA nephropathy, for example) in the background (non-diabetic) population. Urinalysis, ultrasound of the kidney tract, measurement of autoantibodies and immunoglobulins, and kidney biopsy may help clarify the diagnosis. Studies evaluating the frequency of other kidney diseases in patients with diabetes indicate that the frequency of other diseases varies depending on the policy and on the reasons for a kidney biopsy (33-35). When kidney biopsies are done for research purposes, the frequency of other kidney disease is extremely low among patients with T1D without CKD (36, 37) and in Pima Indians with T2D (38).

STRUCTURAL KIDNEY LESIONS IN DIABETES

In patients with T1D, glomerular lesions can be demonstrated after diabetes has been present for a few years, while in T2D they can be present at diagnosis, probably reflecting delayed diagnosis. The changes in kidney structure caused by diabetes are specific, creating a pattern not seen in any other kidney disease. The severity of these diabetic lesions correlates with functional abnormalities (decreased GFR and albuminuria) (5, 6, 36) and it is also related to diabetes duration, glycemic control, and genetic factors. These later relationships are not precise and are in line with the marked variability in diabetic nephropathy susceptibility among patients with diabetes (see Relationships between Kidney Structure and Function below).

Light Microscopy

Renal hypertrophy, the earliest renal structural change in T1D, is not reflected in any specific light microscopy findings. In some patients, glomerular structure may remain normal or near normal for many decades, while others develop progressive disease. Early changes often include arteriolar hyalinosis, thickening of the glomerular basement membrane (GBM), and diffuse mesangial expansion (5, 6, 36). In about 40-50% of patients developing proteinuria, areas of extreme mesangial expansion called Kimmelstiel-Wilson nodules, or nodular mesangial expansion can be observed. Although Kimmelstiel-Wilson nodules are diagnostic of diabetic nephropathy, they are not necessary for severe renal dysfunction to develop. Global glomerulosclerosis can also be observed, especially with progressive disease (Figure 3). Atubular glomeruli and glomerulotubular junction abnormalities can also be present in proteinuric patients with T1D (39, 40). Tubular atrophy and interstitial fibrosis, common to most chronic renal disorders, can be present at later stages.

Figure 3.

Light microscopy photographs of glomeruli in sequential kidney biopsies performed at baseline and after 5 and 10 years of follow-up in a long-standing normoalbuminuric type 1 diabetic patient with progressive mesangial expansion and renal function deterioration. A. Note the diffuse and nodular mesangial expansion and arteriolar hyalinosis in this glomerulus from a patient who was normotensive and normoalbuminuric at the time of this baseline biopsy, 21 years after diabetes onset [Periodic Acid Schiff (PAS) X 400]. B. 5-year follow-up biopsy showing worsening of the diffuse and nodular mesangial expansion and arteriolar hyalinosis in this now microalbuminuric patient with declining GFR (PAS X 400). C. 10-year follow-up biopsy showing more advanced diabetic glomerulopathy in this now proteinuric patient with further reduced GFR. Note also the multiple small glomerular probably efferent arterioles in the hilar region of this glomerulus (PAS X 400), and in the glomerulus in Fig. 3A above. Source: Reprinted with permission from National Kidney Foundation. Pathogenesis and Pathophysiology of Diabetic Nephropathy. Caramori ML, Mauer M. Primer on Kidney Diseases, 5th Edition, Greenberg A, et al., Copyright 2009 (253).

Electron Microscopy

Using morphometric techniques, the first measurable diabetic nephropathy change is thickening of the GBM, which can be detected as early as 1 and 1/2 to 2 and 1/2 years after onset of type 1 diabetes (6, 41-44) (Figure 4). Tubular basement membrane thickening can also be detected, and it parallels GBM thickening (45). Increase in the relative area of the mesangium becomes measurable by 4-5 years (6, 36, 42). Immunohistochemical studies indicate that these changes in mesangium, GBM, and tubular basement membrane represent expansion of the intrinsic extracellular matrix components at these sites, likely including types IV and VI collagen, laminin, and fibronectin. Foot processes (podocyte) changes can be observed by electron microscopy, and the severity of these abnormalities has been associated with kidney function (46, 47). Changes in fenestrated endothelium have also been described in diabetes (47). Interstitial expansion is common to many kidney diseases. Early on in diabetes, interstitial expansion is associated with cellular alterations, while later in the disease process, when GFR is already reduced, there is increase in fibrillar collagen in the interstitium (48).

Figure 4.

Electron microscopy photographs of mesangial area in normal control (A) and in type 1 diabetic patient (B) [X 3,900]. Note the increase in mesangial matrix and cell content, the glomerular basement membrane thickening and the decrease in the capillary luminal space in the diabetic patient (B). Source: Reprinted with permission from National Kidney Foundation. Pathogenesis and Pathophysiology of Diabetic Nephropathy. Caramori ML, Mauer M. Primer on Kidney Diseases, 5th Edition, Greenberg A, et al., Copyright 2009 (253).

While about 30% of patients with T2D and microalbuminuria who have had a kidney biopsy performed for research rather than clinical reasons had the classical diabetic nephropathy lesions described above, 41% have disproportionally severe interstitial fibrosis and tubular atrophy while the remaining 29% had minimal lesions with normal or near normal glomerular structure (49) (Figure 5).

Figure 5.

Light microscopy photographs of glomeruli of patients with type 1 (A) and type 2 diabetes (B-D). A. Diffuse and nodular mesangial expansion and arteriolar hyalinosis in this glomerulus from a microalbuminuric type 1 diabetic patient [Periodic Acid Schiff (PAS) X 400]. B. Normal or near normal renal structure in this glomerulus from a microalbuminuric type 2 diabetic patient (PAS X 400). This photograph was kindly provided by Dr. Paola Fioretto. C. Changes "typical" of diabetic nephropathology (glomerular, tubulo-interstitial and arteriolar changes occurring in parallel) in this renal biopsy from a microalbuminuric type 2 diabetic patient (PAS X 400). D. “Atypical" patterns of injury, with absent or only mild diabetic glomerular changes associated with disproportionately severe tubulo-interstitial changes. Note also a glomerulus undergoing glomerular sclerosis (PAS X 400). Source: Reprinted with permission from National Kidney Foundation. Pathogenesis and Pathophysiology of Diabetic Nephropathy. Caramori ML, Mauer M. Primer on Kidney Diseases, 5th Edition, Greenberg A, et al., Copyright 2009 (253).

RELATIONSHIPS BETWEEN KIDNEY STRUCTURE AND FUNCTION

In type 1 diabetes, the relationships between kidney structure and function are strong (5, 50, 51). Mesangial fractional volume and GBM width are inversely correlated with GFR, and directly correlated with albuminuria (5, 51) and blood pressure (51, 52). Importantly, GBM width is a strong independent predictor of progression to clinically advanced kidney disease among normoalbuminuric patients with T1D (53). Among these patients, global glomerular sclerosis (53, 54) and interstitial expansion (53, 55) are present and are additional independent predictors of GFR loss (53). Although increases in podocyte foot process width also correlates with albuminuria increases in T1D (56-58), our studies in patients with T1D who had no clinical manifestations of CKD at time of their research kidney biopsies indicate that podocyte parameters did not predict long-term progression to clinical CKD (59).

RISK FACTORS

Many factors are associated with CKD in diabetes. Associations may be with both albuminuria and GFR or with one measurement only. Factors that influence the initial development of kidney disease may not be the same as factors influencing progression. Duration of diabetes is one of the strongest risk factors for diabetic nephropathy, particularly in T1D.

CO-MORBIDITIES AND ASSOCIATED COMPLICATIONS

The prognosis for people with diabetes and CKD is much poorer than for those without CKD. Both albuminuria and eGFR <60 mL/min/1.73 m² (Figure 6 and 7) contribute independently and synergistically to the increased all-cause and cardiovascular risk (127-131).

Figure 6.

Declining glomerular filtration rate is associated with all-cause and cardiovascular mortality in individuals with and without diabetes. (A, B) All-cause mortality. (C, D) Cardiovascular mortality. Panels A and C use one reference point (diamond, eGFR of 95 mL/min per 1.73 m2 in the no diabetes group) for both individuals with and without diabetes to show the main effect of diabetes on risk. Panels B and D use separate references (diamonds) in the diabetes and no diabetes groups to assess interaction with diabetes specifically. Hazard ratios were adjusted for age, sex, race, smoking, history of cardiovascular disease, serum total cholesterol concentration, body-mass index, and albuminuria (log albumin-to-creatinine ratio, log protein-to-creatinine, or categorical dipstick proteinuria [negative, trace, 1+, ≥2+]). Blue and red circles denote p<0.05 as compared with the reference (diamond). Significant interaction between diabetes and eGFR is shown by x signs. eGFR=estimated glomerular filtration rate. Reproduced from Fox et al. 2012 (254), Copyright 2012, with permission from Elsevier.

Figure 7.

Increasing albuminuria is associated with all-cause and cardiovascular mortality in individuals with and without diabetes. (A, B) All-cause mortality. (C, D) Cardiovascular mortality. Panels A and C use one reference point (diamond, ACR of 5 mg/g in the no diabetes group), for both individuals with and without hypertension to show the main effect of diabetes on risk. Panels B and D use separate references (diamonds) in the diabetes and no diabetes groups to assess interaction with diabetes specifically. Hazard ratios were adjusted for age, sex, race, smoking, history of cardiovascular disease, serum total cholesterol concentration, body-mass index, and estimated glomerular filtration rate. Blue and red circles denote p<0.05 as compared with the reference (diamond). Significant interaction between diabetes and ACR is shown by x signs. ACR=albumin-to-creatinine ratio. Reproduced from Fox et al. 2012 (254), Copyright 2012, with permission from Elsevier.

PREVENTION AND TREATMENT

Although multiple strategies are now available to slow diabetic nephropathy progression, prevention of kidney disease remains crucial. The risk of developing diabetic nephropathy is particularly reduced by achievement and maintenance of good blood glucose and blood pressure control (22).

A guideline on management of diabetes in CKD from Kidney Disease Improving Global Outcomes (KDIGO) emphasize management of cardiorenal risk factors lifestyle factors (diet, exercise, and stop smoking), glucose, blood pressure, and lipids including blockade of the renin angiotensin aldosterone system and in T2D SGLT2 inhibition (Figure 8) (148).

Figure 8.

Putative promoters of progression of diabetic nephropathy. Source: Reproduced from Fox et al. 2012 (254), Copyright 2012, with permission from Elsevier.

Glucose Lowering Medications and Organ Protection

SGLT2 INHIBITORS

For over twenty years renin angiotensin system (RAS) blockade was the only recommended treatment for diabetic nephropathy. After many unsuccessful attempts in developing new therapies the first success has been with SGLT2 inhibitors. When initially tested for safety in cardiovascular outcome trials, empagliflozin showed not only a benefit on the primary endpoint major adverse cardiovascular events (168) but also a significant benefit on hospitalization for heart failure was also observed. In addition, a reduction in incident or worsening nephropathy occurred (HR 0.61; 95% CI, 0.53 to 0.70) (169). These findings were confirmed in cardiovascular outcome trials with canagliflozin, dapagliflozin and ertugliflozin (170). Importantly the benefits on kidney outcomes were independent of baseline eGFR from <45 ml/min/1.73m2 to >90 ml/min/1.73m2 and also independent of urinary albumin creatinine ratio <30mg/g, 30-300 or >300 mg/g (171). The first study with hard renal endpoints (end stage kidney disease, significant loss of renal function) as primary endpoint using a SGLT2 inhibitor was CREDENCE showing a major benefit on renal outcome, but also on heart failure and major adverse cardiovascular events in people with type 2 diabetes, urine albumin creatinine ratio >300 mg/g and eGFR 30-90 ml/min/1.73m² (172). The primary outcome was a composite of end stage kidney disease, a doubling of the serum creatinine level, or death from renal or cardiovascular causes. The study was stopped early showing a benefit of canagliflozin with a HR 0.70; (95% CI, 0.59 to 0.82). These data were confirmed and extended by the DAPA-CKD study including subjects with chronic kidney disease with or without diabetes (173). EMPA-KIDNEY included participants with CKD with and without T2D as DAPA-CKD, but in addition to participants with albuminuria, EMPA-KIDNEY also included a group of study participants with impaired eGFR (20-45 mL/min/1.73m²) and normal albumin excretion (174). This study was recently stopped for positive findings which remain to be disclosed. Whereas SGLT2i’s were introduced to treat hyperglycemia, they also provide organ protection in diabetes with eGFR <45 mL/min/1.73m² where there is no effect on blood glucose. Dapagliflozin and empagliflozin were also able to reduce heart failure hospitalization in people with heart failure with reduced ejection fraction (175), and empagliflozin was the first agent reported to reduce hospitalization for heart failure in people with heart failure with preserved ejection fraction, with similar benefit in those with and without diabetes (86, 176). In the DAPA-CKD study it was also demonstrated that dapagliflozin was able to reduce progression of CKD, hospitalization for heart failure and mortality in people with CKD with type 2 diabetes, but just as well in people with non-diabetic CKD (173) (Table 4).

Table 4.

Summary of SGLT2 Inhibitors on Renal Disease

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	Number	Mean Follow-up (years)	Hazard Ratio* (95% CI)	P value
EMPA-REG Empagliflozin	7,020	3.1	0.54 (0.40-0.75	<0.001
CANVAS Canagliflozin	10,142	3.6	0.60 (0.47-0.77)	--
DECLARE-TIMI 58 Dapagliflozin	17,160	4.2	0.53 (0.43-0.66)	<0.001
VERTIS-CV Ertugliflozin	8,246	3.0	0.81 (0.63-1.04)	0.08
CREDENCE Canagliflozin	4,401	2.6	0.66 (0.53-0.81)	<0.01
DAPA-HF Dapagliflozin	4,774	1.5	0.71 (0.44-1.16)	0.17
EMPEROR Empagliflozin	3,730	1.3	0.52 (0.32-0.77)	0.026
DAPA-CKD Dapagliflozin	4304	2.4	0.56 (0.45-0.68)	<0.001

*

Renal composite outcomes Adapted from (177)

The explanation for the renal and cardiac benefits is not clear but multiple mechanisms have been suggested and probably glucose reduction is not very important. The inhibition of SGLT2 in the proximal tubule leads to blockade of glucose and sodium reabsorption, thus increasing distal tubular sodium delivery, which via macula densa and tubulo-glomerular feedback reduces intraglomerular pressure through constriction of the afferent glomerular arterioles. This is reflected clinically in the small dip in GFR when starting SGLT2i treatment and this mechanism has been suggested as the key mechanism behind the kidney protective effects. Reduction in blood pressure, body weight, increased uric acid excretion, and change in fuel metabolites have also been suggested to contribute (169). Blocking uptake of sodium in the proximal tubule has also been suggested to reduce oxygen consumption, thereby reducing hypoxia, leading to less inflammation and fibrosis in experimental studies and acute studies in humans were able to demonstrate improved renal oxygen availability (178).

In T2D with CKD metformin is recommended as first glucose lowering agent after lifestyle intervention, as in others with T2D, and then SGLT2 inhibitors are recommended independent of HbA1c for their organ protective effect, particularly in patients with albuminuria or heart failure (179, 180)(181) (Figure 9). In Europe the SGLT inhibitors sotagliflozin and dapagliflozin were initially approved for treatment of T1D, however the risk for normoglycemic diabetic ketoacidosis is increased compared to T2D and there are no studies of the kidney benefit in diabetic nephropathy in T1D. Currently, sotagliflozin is not marketed and the indication for dapagliflozin for treatment of T1D was stopped, and additional studies are needed to determine whether these agents can be safely used in patients with T1D to prevent CKD and cardiovascular progression.

Figure 9.

Patients with diabetes and CKD should be treated with a comprehensive strategy to reduce risks of kidney disease progression and cardiovascular disease Source: Reproduced with permission from Kidney Disease: Improving Global Outcomes (KDIGO) (172).

GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONISTS

For some long-acting glucagon-like peptide-1 receptor agonists (GLP1-RA) (liraglutide, semaglutide, and dulaglutide) the cardiovascular outcome trials in type 2 diabetes demonstrated cardiovascular benefits, in subjects with already existing atherosclerotic CVD (180). The benefit on CVD outcomes was also demonstrated in CKD populations and thus GLP1-RA are recommended in the treatment of T2D with diabetic nephropathy when metformin and SGLT2 inhibition cannot control glucose (Figure 10). Studies also demonstrated positive kidney effects as secondary endpoints, mostly driven by reductions in albuminuria, but also some potential effects on eGFR. A kidney benefit was supported by the AWARD 7 study with dulaglutide in T2D with CKD although the primary endpoint was glycemic control (182). Semaglutide is being tested in the FLOW study (ClinicalTrials.gov NCT03819153) to determine whether it will confer benefits on hard renal and cardiovascular outcomes among participants with T2D when compared to placebo.

Figure 10.

Antihyperglycemic Therapies in Patients with Diabetes and CKD Source KDIGO guideline on management of diabetes in CKD Source: Reproduced with permission from Kidney Disease: Improving Global Outcomes (KDIGO) (172).

FURTHER MANAGEMENT OF CHRONIC KIDNEY DISEASE STAGE 3 OR POORER

Organization of Care

Structured care, delivered by trained specialists working with clear protocols with specific, multiple treatment goals for all the variables described above, reduces the incidence of moderately elevated albuminuria (247, 248) and provides greater kidney and cardiovascular benefits than routine care for individuals with T2D and CKD (179, 249, 250). Progression to ESKD or death, need for laser therapy for management of retinopathy, and cardiovascular endpoints including stroke and heart failure are all reduced by such multifactorial interventions (251-254). When structured intensive multifactorial intervention targeting lifestyle factors (diet, exercise, smoking) and heart and kidney risk factors (blood glucose, blood pressure, lipid management) compared to usual care was started already in T2D with moderately elevated albuminuria, long-term follow-up of the Steno-2 study demonstrated that eight years of intervention translated into almost 8 years of extended median survival (Figure 11) (251).

Figure 11.

Steno-2 post-trial: Twenty-one years sustained effect of intensive multifactorial intervention compared to standard of care for 8 years targeting lifestyle and heart and kidney risk factors.

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