The prognosis for diabetics with renal insufficiency is still unfavourable even today. The five-year survival of dialysis patients with type 2 diabetes is approximately 30% and as such resembles the life expectancy resulting from a malignant gastrointestinal tumour. The poor prognosis is based on the excessively high cardiovascular morbidity and mortality of these patients whose cause cannot be explained merely by a cluster of conventional risk factors for atherosclerosis.1,2 Over the last years the role of anaemia, which can be demonstrated in the majority of patients with terminal renal insufficiency,3,4 has been closely examined as a possible partial cause for cardiovascular complications.
Anaemia can lead to defects in the cardiovascular system through various mechanisms.5,6 Functional adaptations, such as an increase in cardiac output to ensure an adequate supply of oxygen to the tissues, first occur upon falling haemoglobin levels. If this hyperdynamic situation persists, structural modifications of the heart muscle occur that are mediated via various growth factors, cytokines and other mediators: development of a left ventricular hypertrophy (LVH) and enlargement of the heart cavities (eccentric hypertrophy). It is known that LVH is associated with a higher risk for ischaemic events, cardiac insufficiency or even death.3,4 The presence of anaemia represents a pre-disposing factor for the appearance of ischaemias, arrhythmias or formation of fibroses through further reductions in the coronary reserves. Several studies have been able to show an association between anaemia and the appearance of cardiovascular complications in renal-insufficient or cardiac-insufficient patients.7–9 The treatment of anaemia with erythropoietin, for example, led to a partial regeneration of the left ventricular muscular mass, an improvement in performance and an improvement in prognosis.10,11
Up to now it was considered that a renal anaemia appears only with severe renal insufficiency, i.e. creatinine-clearance <30ml/min. However, more recent studies have shown that the haemoglobin concentration starts to decline at a creatinine-clearance of <60ml/min.12 Patients with diabetes in particular seem to have a higher risk of developing anaemia when kidney function is impaired.13,14 While the initially published studies only reported on small collectives without a precise definition of the stage of the renal insufficiency, the DiaNe project recently conducted a broad screening of the prevalence of anaemia in Germany and its relationship to kidney function in undialysed diabetics.
Prevalence of Anaemia in Diabetic Nephropathy – The DiaNe Project
In practices specialised in diabetology, 120,034 patients with known diabetes were screened for the presence of renal insufficiency, defined as a serum creatinine >1.3mg/dl. Three thousand, three hundred and seven patients were identified (2,069 men, average age 67.7 years and 1,438 women, average age 71.2 years). Haemoglobin concentration was determined and creatinine-clearance was calculated according to the Cockgroft-Gault procedure. Details of the study were published elsewhere.15 According to World Health Organization (WHO) criteria, anaemia was diagnosed among men with a haemoglobin level of <13g/dl and among women with a level of <12g/dl. A therapy-obligatory anaemia was defined gender-independently as a haemoglobin level of <11g/dl.
The average haemoglobin level of all patients amounted in women to 12.1±2.11g/dl and in men to 13.07±2.43g/dl. In both sexes the average haemoglobin levels decreased with decreasing kidney function (coefficient of correlation according to Pearson 0.305; p<0.01). According to WHO criteria, 44% of the women and 40% of the men with renal insufficiency revealed anaemia. A severe anaemia, i.e. haemoglobin values <11g/dl, was determined in 26% (female) and 17% (male) of the patients.
Figure 1 shows gender-specificity of the prevalence of anaemia according to stage of renal insufficiency. Already, at a creatinine-clearance of 60–89ml/min, 35% of the women and 25% of the men showed anaemia. The prevalence of a therapy-obligatory anaemia (haemoglobin <11g/dl) in these patients already lay at 18% (female) and 11% (male). With increasing renal insufficiency the anaemia rate increased as expected. With pre-terminal renal insufficiency, about 65% of the female and 83% of the male patients showed anaemia according to WHO criteria; the corresponding prevalence of therapy-obligatory anaemia was 41% and 43%, respectively.
Figure 2 shows the prevalence of anaemia among diabetics of the DiaNe collective compared with a population study from the US (National Health and Nutrition Examination Survey – NHANES III).12 It shows that anaemia occurs 6–10 times more frequently in diabetic patients than in the average population at slight restriction of renal function. When comparing this with patients suffering from renal insufficiency of a non-diabetic origin, a similar result is apparent (see Figure 3). The prevalence of anaemia at a serum creatinine level below 3mg/dl was approximately 2–10-fold higher amongst the diabetics of the DiaNe collective than in patients with a non-diabetic nephropathy.16
The DiaNe project therefore confirms the initial findings13,14 that among diabetic patients with renal dysfunction anaemia occurs earlier than in non-diabetic patients. Similar findings were recently published from 800 diabetic patients with and without nephropathy by Thomas et al.17 in an Australian study. In comparison with NHANES III, these authors found a 3–5-fold higher anaemia prevalence in the creatinine-clearance range of 90–30ml/min. With more severe impairment of renal function, no difference could be found in comparison with non-diabetics with severe renal insufficiency in the DiaNe collective. This corresponds to the findings of the Predialysis Survey of Anaemia Management (PRESAM), which also found no difference in the anaemia prevalence amongst pre-terminal kidney-insufficient patients with and without diabetes.18
Causes Underlying Early Anaemia Development
The causes underlying the frequent occurrence of anaemia among diabetics have not yet been clarified completely. Thomas et al.17 recently showed that about half of their diabetic patients with anaemia had inadequate iron stores. Similar results were obtained from another study in South Korea.19 Transferrinuria, chronic inflammation, an autoimmune gastritis or infections with Helicobacter pylori – with the latter occurring more frequently in diabetics – have been discussed as possible causes of the iron deficiency. Blood loss due to frequent blood withdrawal or blood sugar self-checks might also come into consideration as possible causes for an iron deficit, although Thomas et al. could not find any relationship between the number of blood withdrawals and the degree of the anaemia.17 Changed eating habits, e.g. a decreased protein intake with kidney insufficiency, may also play a role.
Apart from an inadequate iron supply, a disturbed regulation of EPO synthesis represents a significant factor in anaemia development among diabetics with renal dysfunction. It has been shown that EPO synthesis is not increased appropriately when haemoglobin levels fall off.13,14 This leads to a so-called renal anaemia that is both normochromic and normocytic. The pathogenesis of the disturbed erythropoietin response remains to be clarified in detail. Damage of the tubulointerstitial tissue (seen more often in diabetics), an autonomous neuropathy, chronic inflammation and various other factors are discussed.17,20 The authors’ group was able to show recently that renally-insufficient diabetics with poor metabolic control show lower haemoglobin and EPO levels than patients with better adjusted metabolic regulation.21
Clinical Consequences
An early diagnosis of anaemia in proteinuric diabetics is important since a reduction in haemoglobin coincides with the development of cardiovascular complications even before the dialysis stage is reached. Levin et al.22 were able to show in a large prospective study that one-third of patients with a creatinine-clearance of between 75 and 25ml/min show an LVH. After a follow-up period of one year the increase in muscle mass was basically determined by two factors that could both be influenced by therapy: systolic blood pressure and haemoglobin level. The authors showed that within this patient collective a decrease in haemoglobin of 0.5g/dl correlates with a significant increase in LVH.
Early recognition and treatment of anaemia might therefore represent an important component in the cardiovascular protection of renally-insufficient patients. The final results of prospective studies remain to be published. More recent studies assume that the progression of the nephropathy is promoted by the anaemia too. In a follow-up study of type 1 and type 2 diabetics with nephropathy, Hasslacher et al.23 were able to show that patients with anaemia showed a more rapid decline of kidney function than patients without anaemia. Similar findings were also acquired in the Reduction of Endpoints in Non-Insulin- Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) study.24 Kuriyama et al.25 found that an increase in haemoglobin caused by erythropoietin among anaemic patients with renal insufficiency of varying origin was associated with a slower progression of nephropathy.
Amongst diabetics with nephropathy, the appearance of anaemia therefore identifies a group with an excessively high cardiovascular and renal risk. The DiaNe study shows that mild forms of anaemia can often be detected among patients with minor renal insufficiency. Consistent monitoring of the frequently taken blood counts, further characterisation of an (accidentally) detected anaemia and, where necessary, introduction of therapy represent important new tasks in the everyday treatment of diabetic patients.