1.1. Definition of anaemia
Internationally anaemia is defined as a state in which the quality and/or quantity of circulating red blood cells are below normal. Blood haemoglobin (Hb) concentration serves as the key indicator for anaemia because it can be measured directly, has an international standard, and is not influenced by differences in technology. However, because haemoglobin values in healthy individuals within a population show a normal distribution, a certain number of healthy individuals will fall below a given cut-off point.
Conventionally anaemia is defined as a haemoglobin concentration lower than the established cut off defined by the World Health Organization (WHO)341, and different biological groups have different cut-off haemoglobin values below which anaemia is said to be present. This cutoff figure ranges from 11 grams per decilitre (g/dl) for pregnant women and for children between 6 months and 5 years of age, to 12 g/dl for non-pregnant women, and to 13 g/dl for men (). No downward adjustment for the elderly is made for age. Although there is a theoretical basis for a fall in male haemoglobin levels with age, because of reduced testosterone production, this is clearly not the case for women. Furthermore there is accumulating evidence that anaemia reflects illness and is associated with adverse outcomes in the elderly125.
Haemoglobin cut offs to define anaemia in people living at sea level.
In the Cardiovascular Health Study 8.5% of participants were anaemic by WHO criteria. Those who were anaemic had a greater prevalence of associated comorbidity and significantly higher 11-year death rates than those without anaemia (57% and 39% respectively, p≤0.001). The strongest correlates of anaemia were low body mass index, low activity level, fair or poor self-reported health, frailty, congestive heart failure, and stroke or transient ischemic attack. Anaemia was also associated with higher concentrations of creatinine, C-reactive protein, and fibrinogen, and lower levels of albumin and white blood cell count345.
In addition to gender, age, and pregnancy status, other factors influence the cut-off values for haemoglobin concentration. These include altitude, race, and whether the individual smokes. Although altitude is not a factor in patients in England, ethnicity may influence the cut-off values for haemoglobin concentration.
Data from the USA show that healthy people of African extraction of all age groups at all times, except during the perinatal period, have haemoglobin concentrations 0.5–1.0 g/dl below those of white people, a difference independent of iron-deficiency and socioeconomic factors70,116,142,243,250 Haemoglobin concentration increases in smokers because of the formation of carboxyhaemoglobin, which has no oxygen transport capacity320.
The US Centers for Disease Control and Prevention have developed a smoking-specific haemoglobin adjustment to define anaemia in smokers () and suggest that these values should be subtracted from observed haemoglobin values287.
Haemoglobin adjustment for smokers.
1.2. Chronic kidney disease: definition and prevalence
The Renal National Service Framework79,80 has adopted the US National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) classification of chronic kidney disease (CKD)299. This classification divides CKD into five stages () defined by evidence of kidney damage and level of renal function as measured by glomerular filtration rate (GFR).
Stages of chronic kidney disease.
Stage 5 CKD may be described as established renal failure (also called end stage renal failure), and is CKD which has progressed so far that renal replacement therapy (regular dialysis treatment or kidney transplantation) will be required to maintain life. Established renal failure is an irreversible, long-term condition. A small number of people with established renal failure may choose conservative management only.
Conventionally, the total number of people receiving renal replacement therapy has been taken as a proxy measure for the prevalence of established renal failure. The National Service Framework (NSF) for renal services estimates that more than 27,000 people were receiving renal replacement therapy in England in 2001. Approximately one-half of these had a functioning transplant and the remainder were on dialysis. It is predicted that numbers will rise to around 45,000 over the next 10 years. However, the most recently published Renal Registry Report (2004) highlights that in the UK there were over 37,000 patients receiving renal replacement therapy during 2003, a prevalence of 632 per million population. Of these, 46% had a functioning transplant and the remainder were receiving dialysis treatment265.
Data from the third US National Health and Nutrition Examination Survey (NHANES III) suggests that overall 11% of the population have some degree of kidney disease: 3.3% of the population are in stage 1 CKD, 3.0% in stage 2 CKD, 4.3% in stage 3 CKD, 0.2% in stage 4 CKD and 0.2% in stage 5 CKD320. A similar population prevalence of stage 3–5 CKD has recently been described for England from data derived from primary care records73. It is estimated that 4.9% of the population are in stage 3–5 CKD (estimated GFR less than 60 ml/min/1.73m2), although for methodological reasons this is probably an underestimate.
1.2.1. Is chronic kidney disease a natural consequence of ageing?
For many years glomerular filtration rate has been shown to decline with age. However, is is unclear to what extent these changes are a result of ‘normal ageing’ or a result of disease processes. The cumulative exposure of the kidney to common causes of chronic kidney disease (atherosclerosis, hypertension, diabetes, heart failure, infection and nephrotoxins) increases with age and it is difficult to separate these from the ageing process.
Only one significant longitudinal study to date has addressed the issue of decreasing GFR with increasing age. In the Baltimore Longitudinal Study of Ageing182, 446 community-dwelling participants were followed over a period of up to 24 years. Their data suggests that the decline in GFR with increasing age is largely attributable to hypertension, possibly as a consequence of microvascular disease182. In the absence of hypertension or other identifiable causes of renal disease, one-third of older participants were noted to have stable GFR over a period of 20 years. In a small percentage of participants, GFR actually increased with ageing.
Similarly, Fliser et al101 in a cross-sectional study using inulin clearance found heart failure to be a significant factor in the decline of GFR with increasing age. Additionally, both heart failure and hypertension contributed to reductions in renal plasma flow and increases in the filtration fraction and renal vascular resistance.
In a post-mortem study, Kasiske150 has demonstrated a relationship between the prevalence of sclerotic glomeruli and atherosclerotic vascular disease. Although twice as many patients with significant atherosclerosis had a history of hypertension as those with milder atherosclerosis, hypertension was not found to be independently predictive of glomerulosclerosis.
Further evidence102 suggests that cumulative dietary protein intake is an important determinant of the fall in GFR. Studies such as the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) have shown that the prevalence of reduced GFR is high in older hypertensive patients. Patients with moderate or severe reduction in GFR in the ALLHAT trial were more likely to have a history of cardiovascular disease and left ventricular hypertrophy compared with those with higher levels of GFR. Even modest reductions in GFR were independently associated with a higher prevalence of cardiovascular disease and left ventricular hypertrophy261.
The implications are that disease processes for renal disease in older people are similar to those of younger people and that a decline in renal function is not an inevitable consequence of ageing.
1.2.2. Prevalence of anaemia in patients with chronic kidney disease
The importance of anaemia in CKD has become increasingly apparent since the introduction of erythropoietin treatment into clinical practice in the late 1980s. However, until recently it has not been fully appreciated that anaemia begins to develop early in the course of CKD. NHANES III found lower levels of kidney function to be associated with lower haemoglobin levels and a higher prevalence and severity of anaemia63.
The UK information concerning the prevalence of anaemia in patients with CKD comes from two studies. The prevalence of diagnosed CKD, predicated by serum creatinine levels of ≥130 μmol/l in women and ≥180 μmol/l in men, was 5,554 per million population (pmp), median age was 82 years (range, 18 to 103 years), and median calculated GFR was 28.0 ml/min/1.73m2 (range, 3.6 to 42.8 ml/min/1.73 m2)138. Data for haemoglobin levels were available for 85.6% of patients. Mean haemoglobin concentration was 12.1±1.9 g/dl: 49.6% of men had haemoglobin levels less than 12 g/dl and 51.2% of women had levels less than 11 g/dl. Furthermore, in 27.5% of patients identified, the haemoglobin level was less than 11 g/dl, equivalent to nearly 90,000 of the population based on 2001 Census population figures.
In a larger cross-sectional study abstracting data from 112,215 unselected patients with an age and sex profile representative of the general population, haemoglobin level was weakly correlated with eGFR (r=0.057, p <0.001)73. The population prevalence of stage 3–5 CKD in this study was estimated to be 4.9%. In those patients with stage 3–5 CKD the prevalence of anaemia, defined as a haemoglobin level less than 12 g/dl in men and post-menopausal women and less than 11 g/dl in pre-menopausal women, was 12.0%, haemoglobin level was less than 11 g/dl in 3.8%, equivalent to over 108,000 of the population based on 2001 Census population figures.
1.2.3. Diabetes, CKD and anaemia
It has been known for some years that anaemia exists in patients with diabetes and CKD, and that this anaemia occurs early in the course of diabetic kidney disease and is associated with inappropriately low erythropoietin concentrations134,160. Ishimura et al134 demonstrated that when those with Type 2 diabetes and CKD are compared with those with non-diabetic CKD, despite similarly advanced CKD and similar serum erythropoietin levels, those with Type 2 diabetes were significantly more anaemic.
Similar findings have also been demonstrated in people with Type 1 diabetes and CKD compared with those without diabetes43. More recently, in a series of articles based on cross-sectional surveys of patients with diabetes, Thomas and colleagues demonstrated that at all levels of GFR, anaemia was more prevalent in those with diabetes compared with the general population317, that with increasing albuminuria the prevalence of anaemia was higher at each level of renal function316, and that levels of erythropoietin were inappropriately low in those with anaemia315.
Finally, in a report from the Kidney Early Evaluation Programme (KEEP)88, the prevalence of anaemia in those with diabetes was significantly higher than in those without diabetes in stage 2 and 3 CKD (7.5% vs 5%, p=0.015 and 22.2% vs 7.9%, p<0.001 respectively). Although the prevalence of anaemia was also higher in those with diabetes in stages 1 and 4 CKD the differences were not significant (8.7% vs 6.9% and 52.4% vs 50% respectively).
1.2.4. Causes of anaemia other than chronic kidney disease
Not all anaemia in patients with CKD will be ‘renal anaemia’ and causes of anaemia other than CKD should be actively looked for and excluded before a diagnosis of anaemia associated with CKD can be made ()
Other causes of anaemia in CKD.
Iron deficiency anaemia is the most common cause of anaemia worldwide, either due to negative iron balance through blood loss (commonly gastrointestinal or menstrual), or to inadequate intake which may be nutritional or related to poor gastrointestinal absorption. Studies in elderly patients (aged over 65 years) show that the ‘anaemia of chronic disorders’ predominates, accounting for 34% to 44% of causes126,146,249.
Iron-deficiency is the cause in 15% to 36% of cases and recent bleeding in 7.3%. Vitamin B12 or folate deficiency is the cause in 5.6% to 8.1%, myelodysplastic syndrome and acute leukaemia in 5.6% and chronic leukaemia and lymphoma-related disorders in 5.1%. Other haematological disorders (myelofibrosis, aplastic anaemia, haemolytic anaemia) are the cause in 2.8%, and multiple myeloma in 1.5%.
1.2.5. Pathogenesis of anaemia associated with chronic kidney disease
Although anaemia in patients with CKD may develop in response to a wide variety of causes, erythropoietin deficiency is the primary cause of anaemia associated with CKD. Erythropoietin is predominantly produced by peritubular cells in the kidney and is the hormone responsible for maintaining the proliferation and differentiation of erythroid progenitor cells in the bone marrow. Loss of peritubular cells leads to an inappropriately low level of circulating erythropoietin in the face of anaemia.
Other factors in the genesis of renal anaemia include functional or absolute iron deficiency, blood loss (either occult or overt), the presence of uraemic inhibitors (for example, parathyroid hormone, inflammatory cytokines), reduced half-life of circulating blood cells, and deficiencies of folate or Vitamin B12.
