Article

Anaemia in Patients with Diabetic Nephropathy - Prevalence, Causes and Clinical Consequences

Acknowledgements: The study was supported by ORTHO BIOTEC, a division of Janssen Cilag, Neuss, Germany

Open access:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

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.

References

  1. Parfey PS, Foley RN, Harnett JD, et al., Outcome and risk factors of ischemic heart disease in chronic uremia, Kidney Int, 1996;49:1428–34.
    Crossref | PubMed
  2. Locatelli F, Bommer J, London GM, et al., Cardiovascular disease determinants in chronic renal failure: clinical approach and treatment, Nephrol Dial Transplant, 2001;16:459–68.
    Crossref | PubMed
  3. Foley RN, Patrick MB, Parfrey S, et al., The impact of anemia in cardiomyopathy, morbidity, and mortality in end-stage renal disease, Am J Kid Dis, 1996;28:53–61.
    Crossref | PubMed
  4. Parfey PS, Foley RN, Harnett JD, et al., Outcome and risk factors for left ventricular disorders in chronic uraemia, Nephrol Dial Transplant, 1996;11:1277–85.
    Crossref | PubMed
  5. Eckardt KU, Cardiovascular consequences of renal anaemia and erythropoietin therapy, Nephrol Dial Transplant, 1999;14: 1317–23.
    Crossref | PubMed
  6. London GM, Left ventricular alterations and end-stage renal disease, Nephrol Dial Transplant, 2002;17:29–36.
    Crossref | PubMed
  7. Levin A, Anemia and left ventricular hypertrophy in chronic kidney disease populations; a review of the current state of knowledge, Kidney Int, 2002;80:535–8.
    Crossref | PubMed
  8. Anand I, Kuskowski M, Rector T, et al., Anemia and change in hemoglobin over time related to mortality and morbidity in patients with chronic heart failure, Circulation, 2005;112: 1121–7.
    Crossref | PubMed
  9. Tong P, Kong A, Wing-Yee So, et al., Hematocrit, independent of chronic kidney disease, predicts adverse cardiovascular outcomes in Chinese patients with type 2 diabetes, Diabetes Care, 2006;29:2439–44.
    Crossref | PubMed
  10. Fink JC, Biahut SA, Reddy M, Light PD, Use of erythropoietin before the initiation of dialysis and its impact on mortality, Am J Kid Dis, 2001;37:348–55.
    Crossref | PubMed
  11. Rao M, Pereira B, Optimal anemia management reduces cardiovascular morbidity, mortality, and costs in chronic kidney disease, Kidney Int, 2005;68:1432–8.
    Crossref | PubMed
  12. Astor BC, Munter P, Levin A, Association of kidney function with anemia: the Third National Health and Nutrition Examination Survey, Arch Intern Med, 2002;162:1401–8.
    Crossref | PubMed
  13. Ishimura E, Nishizawa Y, Okuno S, Diabetes mellitus increases the severity of anemia in non-dialyzed patients with renal failure, J Nephrol, 1998;11:83–6.
    PubMed
  14. Bosman DR, Winkler AS, Marsden JT, et al., Anemia with erythropoietin deficiency occurs early in diabetic nephropathy, Diabetes Care, 2001;24:495–9.
    Crossref | PubMed
  15. Hasslacher C, Prävalenz und Schweregrad einer Anämie bei Diabetikern mit eingeschränkter Nierenfunktion, Diabetes und Stoffwechsel, 2004;13:181–5.
  16. Jungers PY, Robino C, Choukroun G, et al., Incidence of anaemia, and use of epoetin therapy in pre-dialysis patients: a prospective study in 403 patients, Nephrol Dial Transplant, 2002;17:1621–7.
    Crossref | PubMed
  17. Thomas MC, MacIsaac RJ, Tsalamandris C, et al., Unrecognized Anemia in patients with diabetes, Diabetes Care, 2003;26: 1164–9.
    Crossref | PubMed
  18. Valderrabano F, Anaemia management in chronic kidney disease patients: an overview of current clinical practice, Nephrol Dial Transplant, 2002;17:13–18.
    Crossref | PubMed
  19. Yun YS, Lee HC, Yoo NC, et al., Reduced erythropoietin responsiveness to anemia in diabetic patients before advanced diabetic nephropathy, Diabetes Res Clin Practice, 1999;46: 223–9.
    Crossref | PubMed
  20. Symeonidis A, Kouraklis-Symeonidis A, Psiroyiannis A, Inappropriately low erythropoietin response for the degree of anemia in patients with noninsulin-dependent diabetes mellitus, Ann Hematol, 2006;85:79–85.
    Crossref | PubMed
  21. Hasslacher C, Raupp D, Vogt C, Influence of metabolic control on development of anemia and erythropoietin levels in Type 1 diabetic patients with and without nephropathy, Diabetic Med, 2006;23(Suppl 4):93.
  22. Levin A, Thompson CR, Ethier J, et al., Left ventricular mass index increase in early renal disease: impact of decline in haemoglobin, Am J Kid Dis, 1999;34:250–56.
  23. Hasslacher C, Schlueter V, Ruderich F, Koops S, Influence of anaemia on loss of kidney function of proteinuric Type 1 and Type 2 diabetic patients, Diabetologia, 2002;45(Suppl. 2):A363.
  24. Mohanram A, Zhang Z, Shahinfar SH, Anemia and end-stage renal disease in patients with type 2 diabetes and nephropathy, Kidney Int, 2004;66:1131–8.
    Crossref | PubMed
  25. Kurijama S, Tomonari H, Yoshida H, et al., Reversal of Anemia by Erythropoietin therapy retards the progression of chronic renal failure, especially in nondiabetic patients, Nephron, 1997;77:176–85.
    Crossref | PubMed