Erythropoietin Deficiency Research Articles

Pathogenesis of Renal Anemia

Anemia is a common complication of chronic kidney disease. Although mechanisms involved in the pathogenesis of renal anemia include chronic inflammation, iron deficiency, and shortened half-life of erythrocytes, the primary cause is deficiency of erythropoietin (EPO). Serum EPO levels in patients with chronic kidney disease are usually within the normal range and thus fail to show an appropriate increase with decreasing hemoglobin levels, as found in nonrenal anemias. Studies elucidating the regulation of EPO expression led to the identification of the hypoxia inducible factor-hypoxia responsive element system. However, despite much progress in understanding the molecular mechanisms through which cells can sense oxygen availability and translate this information into altered gene expression, the reason why EPO production is inappropriately low in diseased kidneys remains incompletely understood. Both alterations in the function of EPO-producing cells and perturbations of the oxygen-sensing mechanism in the kidney may contribute. As with other anemias, the consequences of renal anemia are a moderate decrease in tissue oxygen tensions and counterregulatory mechanisms that maintain total oxygen consumption, including a persistent increase in cardiac output.

Anemia and the Heart in Chronic Kidney Disease

Cardiovascular disease is highly prevalent at all stages of chronic kidney disease (CKD) and is the leading cause of morbidity and mortality. Individuals with CKD commonly have multiple risk factors for the development of cardiovascular disease, including both traditional and nontraditional risk factors. Anemia is a nontraditional cardiovascular risk factor found in CKD that contributes to the development and progression of structural abnormalities of the heart, namely left ventricular hypertrophy and dilation. In addition, a deficiency of erythropoietin per se also may have important pathophysiologic consequences. In this review we summarize the evidence from observational studies showing an association between anemia and adverse cardiac outcomes at all stages of CKD. In addition, we provide an overview of the evidence accumulating from randomized controlled trials conducted in both nondialysis and dialysis CKD populations evaluating the effect of anemia correction on cardiac outcomes such as changes in left ventricular hypertrophy.

The High Prevalence of Anemia in Diabetes Is Linked to Functional Erythropoietin Deficiency

Anemia is a common finding in diabetes, particularly in patients with albuminuria or renal impairment. We recently showed that at least 1 in 5 outpatients with type 1 or type 2 diabetes in tertiary clinics have anemia, in whom it constitutes a significant additional burden. Anemia is associated strongly with an increased risk of diabetic complications including nephropathy, retinopathy, and heart failure. Although a number of factors contribute to an increased prevalence of anemia in diabetes, an uncoupling of hemoglobin concentration and renal erythropoietin synthesis associated with tubular dysfunction appears to be the dominant factor. In our patients with diabetes and anemia, more than three quarters had functional erythropoietin deficiency. This association was most pronounced in patients with renal impairment, in whom nearly half of all patients had anemia. However, 70% of anemic patients without renal impairment also had inappropriately low erythropoietin levels. Consequently, the likelihood of functional erythropoietin deficiency, as a cause of anemia in patients with diabetes, is not dependent on the severity of renal impairment. Although there is a clear rationale for correction of anemia in diabetes, it remains to be established whether this will lead to improved outcomes. Some small studies suggest improvement in cardiac outcomes and hospitalization. It is anticipated that large ongoing studies will help define the optimal approach to the management of anemia in diabetes.

Anemia, Renal Transplantation, and the Anemia Paradox

Anemia is prevalent in renal transplant recipients (RTRs), as it is in all chronic kidney disease (CKD) populations. Mild anemia occurs in up to 40% of RTRs, and more severe anemia (110 g/L) occurs in about 9% to 22% of patients. As in CKD, impaired graft (renal) function is a major predictor of anemia identified in nearly all studies, suggesting a major role for erythropoietin deficiency. Chronic inflammation, malnutrition, iron deficiency, and medications (angiotensin converting enzyme inhibitors, angiotensin receptor blockers, mycophenolate, azathioprine, and sirolimus) are contributory factors seen in some, but not all, studies. Although pathophysiologic and observational data strongly support a causal association between low hemoglobin levels and cardiovascular outcomes in RTRs, no randomized controlled trial to date has been able to show a clear benefit of anemia treatment on cardiovascular outcomes or mortality in either RTR or other CKD populations. This important paradox has led some investigators to question the causal nature of the association between anemia and heart disease. Resolution of this paradox, at least for patients with stage 2/3 CKD, will depend on the outcome of randomized controlled trials currently in progress. Similar trials sorely are needed in renal transplant populations. In the interim, current opinion favors treating persistent anemia in RTRs to achieve targets similar to those recommended for dialysis and CKD patients.

Anemia and the role of erythropoietin in diabetes

Anemia is more common in patients with diabetes than without diabetes, and the problem is magnified in patients with renal impairment. Diabetic patients with anemia may be at increased risk of adverse outcomes from diabetic retinopathy, nephropathy, neuropathy, and cardiovascular disease. The etiology of anemia in diabetes is multifactorial and includes inflammation, nutritional deficiencies, concomitant autoimmune diseases, drugs, and hormonal changes in addition to kidney disease. Anemia that is associated with erythropoietin deficiency may have prognostic significance for persons with nephropathy or heart failure. In early diabetic nephropathy, damage to the peritubular fibroblasts can occur and lead to erythropoietin deficiency and anemia prior to the loss of filtration. Correction of the anemia not only leads to less fatigue, greater exercise tolerance, and an improved quality of life but also to a reduction in mortality and hospital admissions for congestive heart failure (CHF). Data are accumulating that suggest that treatment of anemia will slow the progression of microvascular and macrovascular complications, including postural hypotension from autonomic neuropathy, retinopathy, and loss of renal function from diabetic nephropathy. Promptly diagnosing and treating anemia in patients with diabetes may result in an improved quality of life and decreased morbidity and mortality.

Polyamines as an Inhibitor on Erythropoiesis of Hemodialysis Patients by In Vitro Bioassay Using the Fetal Mouse Liver Assay

The pathogenesis of anemia in patients with chronic renal failure has been greatly attributed to erythropoietin (EPO) deficiency. Recently, however, there has been some thought that uremic inhibitors might suppress the activity of EPO and reduce the maturation of erythropoiesis. Polyamines are well known to be involved in the regulation of cellular proliferation and differentiation. Furthermore, the polyamine levels in the serum or erythrocytes are elevated in chronic hemodialysis patients, and can be lowered immediately by hemodialysis. In the present study, we first measured the polyamines levels (putrescine, spermidine, spermine) by high performance liquid chromatography (HPLC) in 20 chronic hemodialysis patients, and investigated the effects of polyamines on erythropoiesis by in vitro bioassay using fetal mouse liver cells. The direct effects of polyamines in erythroid colony formation in the medium with and without EPO were evaluated. Each polyamine level in chronic hemodialysis patients was higher than in the healthy subjects, and a significant negative correlation was found between polyamines and erythropoiesis. Polyamines inhibited the activity of EPO, but they did not have any direct effect on colony formation of the fetal mouse liver cells. These results suggest that polyamines have inhibitory effects on the proliferation or maturation of erythroid precursor cells and are intimately involved in the pathogenesis of renal anemia in chronic hemodialysis patients.

Functional erythropoietin deficiency in patients with Type 2 diabetes and anaemia

Anaemia is a common finding in patients with diabetic nephropathy. Impaired production of erythropoietin is thought to be the predominant cause, as a result of renal microvascular disease. This study aims to determine the prevalence of functional erythropoietin deficiency in a cross-sectional survey of patients with Type 2 diabetes. Clinical data on 604 patients with Type 2 diabetes were obtained, including a full blood count, iron indices and detailed history of diabetic complications. Erythropoietin levels were correlated with the presence of anaemia, iron deficiency and renal dysfunction. Functional erythropoietin deficiency was defined by erythropoietin levels in the normal range despite the presence of anaemia. Nineteen per cent of patients (n = 112) were anaemic, among whom erythropoietin deficiency (76%) and reduced iron availability (58%) were common findings. Over 90% of patients had erythropoietin deficiency, once those with reduced iron stores or availability were excluded. Most of these patients had moderate renal impairment (60%, n = 67). However, even in the absence of renal impairment, 71% of anaemic patients (n = 32/45) had functional erythropoietin deficiency, although most had other evidence of nephropathy. In addition, two-thirds of patients with reduced iron availability were unable to increase erythropoietin above the normal range. These findings confirm the failure of the kidney to produce erythropoietin in response to a falling haemoglobin is a key component to anaemia in diabetes. The likelihood of functional erythropoietin deficiency as a cause of anaemia is not dependent on the severity of renal impairment or excluded in diabetic patients with reduced iron stores or availability.

Cadmium and cisplatin damage erythropoietin-producing proximal renal tubular cells

The concomitant manifestations of proximal renal tubular dysfunction and anemia with erythropoietin (Epo) deficiency observed in chronic cadmium (Cd) intoxication, such as Itai-itai disease, suggest a close local correlation between the Cd-targeted tubular cells and Epo-producing cells in the kidney. Therefore, we investigated the local relationship between hypoxia-induced Epo production and renal tubular injury in rats injected with Cd at 2 mg/kg twice a week for 8 months. Anemia due to insufficient production of Epo was observed in Cd-intoxicated rats. In situ hybridization detected Epo mRNA expression in the proximal renal tubular cells of hypoxic rats without Cd intoxication, and the Cd-intoxicated rats showed atrophy of Epo-expressing renal tubules and replacement of them with fibrotic tissue. A single dose of cisplatin at 8 mg/kg, which can induce clinical manifestations similar to those of Cd including renal tubular damage along with Epo-deficient anemia, resulted in Epo-expressing renal tubule destruction on day 4. These data indicate that Cd and cisplatin would induce anemia through the direct injury of the proximal renal tubular cells that are responsible for Epo production.

Frequency of Anti-Erythropoietin Antibodies in Patients with End Stage Renal Disease Treated with Recombinant Erythropoietin.

End Stage Renal Disease (ESRD) manifests hematologic, cardiovascular, inflammatory, and immunologic dysfunctions. Erythropoietin deficiency is present in ESRD leading to anemic states. ESRD patients receive regular/repeated administration of commercially available recombinant erythropoietin (r-E) (Epogen® Procrit® Patients treated with r-E have been known to develop thrombotic complications during r-E therapy. Antibodies to erythropoietin are generated in some patients and lead to erythropoietic aplasia. The mechanisms of the anti-erythropoietin antibody induced aplasia and reported hypercoagulability state in patients treated with r-E are not fully understood. Anticoagulant drugs such as heparin are used to reduce the incidence of thrombotic complications during r-E therapy. To understand pathogenesis leading to hypercoagulable state and its potential link with r-E treatment, blood samples taken from a group of 60 patients with ESRD were drawn prior to initiation of antithrombotic therapy. These patients on periodic hemodialysis were administered r-E 6–8 weeks prior to blood drawn. Anti-erythropoietin antibody titer, anti-phospholipid antibody (APA) titer, CRP levels, fibrinopeptide-A (FPA), nitric oxide (NO) levels, asymmetric 1,3-dimethylarginine (ADMA) levels, and thrombin activatable fibrinolytic inhibitor (TAFI) levels were measured. Five of 60 patients (8.3%) showed higher titers of anti-erythropoietin antibodies. Three of 60 patients (5%) exhibited positive titers of anti-phospholipid antibodies. Marked elevation of the CRP, FPA, NO, ADMA, and TAFI levels were noted in comparison to match controls. Patients with positive levels of anti-erythropoietin antibody titer (3 to 5 folds) exhibited a simultaneous elevation of FPA, CRP and TAFI suggesting the potential role of anti-erythropoietin antibody in mediating these responses. These observations indicate that ESRD patients treated with r-E are at a higher risk of developing thrombotic complications. The upregulation of NO and ADMA in these patients is suggestive of ongoing inflammatory processes. Anticoagulants such as low molecular weight heparins may be useful in the management of these patients.

Anaemia after renal transplantation

Anaemia is a frequent complication among long-term renal transplant recipients. A prevalence of approximately 40% has been reported in several studies. If renal function declines to stage 5 kidney disease, the prevalence of anaemia in kidney transplants is even higher. A positive correlation between haemoglobin concentration and creatinine clearance has been reported, which is a function of endogenous erythropoietin production by the functioning graft. Inflammation related to a retained kidney graft may cause hypo-responsiveness to erythropoietic agents once kidney transplant recipients return to dialysis. Furthermore, the use of azathioprine, mycophenolate mofetil and sirolimus may be associated with post-transplant anaemia. Along with erythropoietin deficiency, depletion of iron stores is one of the major reasons for anaemia in the kidney transplant population. The proportion of hypochromic red blood cells appears to be a useful parameter to measure iron supply and utilization as well as to estimate mortality risks in kidney transplant recipients. While anaemia is an important cardiovascular risk-factor after transplantation, our data suggest that anaemia is not associated with mortality and graft loss. Nevertheless, inadequate attention is paid so far to the management of anaemia after renal transplantation. A promising future aspect for risk reduction of cardiovascular disease includes the effect of erythropoietic agents on endothelial progenitor cells.

Hyporesponsiveness to erythropoietic therapy due to chronic inflammation

The anaemia associated with chronic renal failure is multi-factorial. Although a relative erythropoietin deficiency is a major factor, it has also been recognized in recent times that uraemia is a chronic inflammatory state, and thus patients with renal failure also develop anaemia due to mechanisms associated with chronic inflammation. Thus, patients with chronic renal failure have activation of various immune cells, both monocytes and T-cells. These mononuclear cells have also been shown to release pro-inflammatory cytokines such as IL-1, IL-6, TNF-alfa and interferon gamma. These cytokines, particularly TNF-alfa and interferon gamma, are known to cause significant suppression of erythropoiesis. The exact molecular mechanism for this effect is not yet clear, but interferon gamma is an important stimulator of apoptosis in various cell types, including erythroid progenitor cells. This effect may be potentiated by other cytokines such as TNF-alfa, and this might then antagonise the anti-apoptotic action of erythropoietin on erythroid progenitors cells, thus reducing responsiveness to exogenous erythropoietic therapy. Chronic renal failure is also associated with increased hepcidin production which may also exacerbate the anaemia by inducing a functional iron deficiency in such patients.

Anaemia of chronic disease in chronic heart failure: the emerging evidenceThe opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

This editorial refers to ‘Blunted erythropoietin production and defective iron supply for erythropoiesis as major causes of anaemia in patients with chronic heart failure’† by C. Opasich et al., on page 2232 Elucidating disease pathogenesis constitutes an important aim of scientific endeavour, being critical for the identification of novel therapeutic strategies for the alleviation of suffering. Nowhere has this been more apparent than in chronic heart failure (CHF), where impressive survival benefits have been achieved as a long-term consequence of mechanistic studies into the role of neurohormonal activation in disease progression.1 Therefore, given this magnitude of potential benefit, illuminating the mechanisms that drive adverse phenomena in CHF remains an agenda of substantial importance. Anaemia is a prevalent and adverse comorbidity in CHF, but little is known about its origins. Over the past 5 years, a plethora of studies have suggested that not only is anaemia more common in CHF than could be accounted for by age and other demographic characteristics, but that its presence is associated with greater symptoms, exercise intolerance, and an amplified risk of mortality.2–4 Pilot studies indicate that its empirical treatment with recombinant erythropoietin (EPO) and intravenous iron may confer clinical benefits in anaemic CHF patients.5 However, rational anaemia correction involves targeting its underlying cause(s), which have yet to be resolved in CHF. Conceptually, an attenuated erythrocyte mass (‘true anaemia’) may be acquired subsequent to haemolysis or to EPO, iron, folate, and/or vitamin B12 deficiency. Prominent among these factors are EPO and iron. EPO is the principal humoral regulator of erythropoiesis, is elaborated by renal parenchymal cells in response … *Corresponding author. Tel: +44 20 7351 8127; fax: +44 20 7351 8733. E-mail address : d.okonko{at}imperial.ac.uk

Starvation in the Midst of Plenty? The Role of Hypoxia in Progression: Hypoxia in Renal Disease with Proteinuria and/or Glomerular Hypertension. Am J Path 265: 1979-1992, 2004.

Starvation in the Midst of Plenty? The Role of Hypoxia in Progression: Hypoxia in Renal Disease with Proteinuria and/or Glomerular Hypertension. Am J Path 265: 1979-1992, 2004.

Anemia after orthotopic liver transplantation is common and often due to relative erythropoietin deficiency: Alex Befeler, C R Varma, Harvey Solomon, Sanjay Ramrakhiani, Saint Louis University, St Louis, MO

Anemia after orthotopic liver transplantation is common and often due to relative erythropoietin deficiency: Alex Befeler, C R Varma, Harvey Solomon, Sanjay Ramrakhiani, Saint Louis University, St Louis, MO

Anemia in Heart Failure

Despite advances in the treatment of heart failure (HF) over the past decade, the prognosis remains poor. Anemia is a well-recognized comorbidity in many chronic conditions, but its role in HF has only recently been recognized. Anemia is significantly related to symptoms, exercise capacity, and prognosis in HF; it has been identified as an independent risk factor for mortality in those with left ventricular dysfunction. When HF patients have concomitant renal disease, they invariably become anemic owing to erythropoietin deficiency. In chronic HF patients without renal disease, erythropoietin levels may be elevated in response to anemia, but not adequately increased to overcome it. Some degree of erythropoietin resistance may also be present because of elevated plasma levels of cytokines. Several studies in anemic HF patients have shown positive outcomes using erythropoietin and iron supplementation therapy to increase hemoglobin concentrations to more normal levels. This article reviews the current information available regarding anemia in HF and discusses the clinical implications and treatment of this syndrome.

HEREDITARY HEMOCHROMATOSIS IN AN INDIAN MAN TREATED WITH ERYTHROPOIETIN

Mr. R.S., a 62 year old man of Indian descent, was evaluated in 1997 for abnormal liver enzymes (transaminases 1–2 times ULN). He had developed non-insulin dependent diabetes mellitus several years prior. He had coronary artery disease, hypercholesterolemia, hypertension and gout, for which he was on multiple medications, including simvastatin. His father had died of liver disease attributed to alcohol abuse. Mr. R.S. admitted to excessive alcohol consumption until four months prior when he had quit on the advice of his physician. Chronic viral hepatitis was excluded and his transaminitis was thought to be due to medications and fatty liver. In 2001 he was referred for evaluation of anemia and abdominal pain. He had developed chronic renal insufficiency. During colonoscopy, two small adenomatous polyps were excised. Upper endoscopy was normal. His liver profile was still abnormal, however, and he was investigated for chronic hepatitis. Ferritin was 3153 mg/ml (ULN 400 mg/ml). Fatty liver was reported on ultrasound. He was homozygous for His63Asp mutation for hereditary hemochromatosis. Liver biopsy showed inflammation and fibrosis, iron overload and moderate steatosis. The patient had two phlebotomies. His hemoglobin fell from 99 g/l to 64 g/l while his ferritin decreased to 1239 mg/l. Phlebotomies were held and he started erythropoietin. The hemoglobin recovered to 90 g/l and he had a third phlebotomy. He remained on erythropoietin and four months later had another phlebotomy after which his hemoglobin was 102 g/l and ferritin 276 mg/l. Over the subsequent 18 months he continued erythropoietin but had no further phlebotomies. He stopped erythropoietin 9 months ago. His hemoglobin is stable at 123 g/l and ferritin 48 mg/l. This case highlights important issues in the diagnosis and management of hemochromatosis. Features of hemochromatosis were evident at this patient's first presentation in 1997, underscoring the importance of complete investigations into causes of chronic hepatitis. This case also demonstrates that one should not limit the search for hemochromatosis to Caucasians. Lastly, this patient's renal insufficiency caused erythropoietin deficiency and anemia that made replacement of this hormone a key element of therapy. Increased erythropoiesis induced by erythropoietin allowed utilization of the excess iron.

Complications of the nephrotic syndrome and their treatment

The nephrotic syndrome occurs in association with a diverse array of primary and secondary glomerular disorders. Despite the different etiologies, many of the clinical effects are similar. This review focuses on the pathogenesis and treatment of edema formation, hyperlipidemia, and the hypercoagulable state. Major abnormalities of the endocrine system and evidence of erythropoietin deficiency will be reviewed. Finally, non-specific treatments aimed at reducing proteinuria will also be discussed.

Interpretation of erythropoietin levels in patients with various degrees of renal insufficiency and anemia

Chronic renal failure leads to hyporegenerative anemia due to erythropoietin deficiency. The creatinine clearance and hemoglobin levels, at which anemia treatment with recombinant erythropoietin should be started, are unclear. Interpretation of serum erythropoietin levels in the context of renal insufficiency remains controversial and was addressed in this study. Three hundred and ninety-five patients were randomly chosen out of over 5000 consecutive patients investigated by coronary angiography at a single center between 1997 and 2001. Laboratory values and clinical information were prospectively collected in a central registry. Serum samples were frozen before angiography and now used to measure serum erythropoietin levels and evaluate the relationship between erythropoietin and hemoglobin levels in the context of various degrees of renal insufficiency. The patients with the lowest renal function (creatinine clearance <20 mL/min) had significantly lower hemoglobin levels than the group with normal renal function. However, erythropoietin levels were identical indicating a lower set point for erythropoietin regulation. Above a creatinine clearance of 40 mL/min a significant inverse correlation between erythropoietin and hemoglobin levels was observed and described with the formula erythropoietin [U/L]= 2.5 x (140 - hemoglobin [g/L]) or alternatively Deltaerythropoietin (U/L) =-2.5 xDeltahemoglobin (g/L). Below 40 mL/min no significant correlation was found. A cut-off level for an altered set point of erythropoietin regulation was determined at 40 mL/min creatinine clearance. Above this cut-off hemoglobin negatively regulates erythropoietin. Below the cut-off erythropoietin levels remain stable. Pathophysiologic concepts for this finding and clinical implications in patients with moderate renal failure are discussed.

Erythropoietin-induced thrombosis as a result of increased inflammation and thrombin activatable fibrinolytic inhibitor.

Chronic inflammation is a major cause of morbidity and mortality in end-stage renal disease. The associated anemia in these patients due to renal cortical atrophy and erythropoietin deficiency is treated with recombinant erythropoietin. Recent reports suggest a growing incidence of symptomatic venous thrombosis in cancer patients treated with recombinant erythropoietin. Several investigators have reported on different mechanisms of thrombosis in these patients. We hypothesize that thrombosis in patients with end-stage renal disease due to increased expression of C-reactive protein (CRP) as a result of chronic inflammation promotes the release of thrombin activatable fibrinolytic inhibitor causing fibrinolytic deficit and eventually thrombosis. Furthermore, because endothelial nitric oxide is responsible for the maintenance of the normal vascular function, the decreased levels of nitric oxide in chronic inflammation cause endothelial damage and result in thrombosis. To test this hypothesis, blood samples were collected from 106 patients (49 male and 57 female, aged 59.8+/-15.7 years) with end-stage renal disease undergoing hemodialysis and treated with recombinant erythropoietin at a mean dose of 201.8 U/kg/week. Blood samples were drawn in 5-mL tubes containing 3.2% sodium citrate just before the hemodialysis procedure. These blood samples were immediately centrifuged to obtain platelet-poor plasma, which was aliquoted and frozen at -70 degrees C until further analysis. Erytropoietin antibodies were measured using an anti-EPO enzyme-linked immunosorbent assay (ELISA) method developed in our laboratory. Nitric oxide was measured using a NO analyzer (Sievers 280I, Ionics, Boulder, CO). Plasma CRP levels were measured with a highly sensitive ELISA method IMUNOCLONE CRP ELISA (American Diagnostica, Greenwich, CT). TAFI antigen levels in plasma were analyzed with an IMUCLONE TAFI ELISA kit (American Diagnostica, Greenwich, CT). TAFI functional activity was assayed with an ACTICHROME TAFI activity kit. The measured levels of nitric oxide, CRP, TAFI antigen, and TAFI functional were 37.36+/-36.8 (normal value, 37.49+/-18.96; range, 19.3-102 microM), 12.27+/-10.6 (normal value, < 1 microg/mL), 146.9+/-28.4% NHP (normal, 100% NHP), and 102.55+/-37% NHP (normal range, 22.3-165.7; mean, 89.5% NHP), respectively. The erythropoietin antibody was detected in 9.4% of the patient group. While 20% of the erythropoietin antibody-positive and 27.1% of the erythropoietin antibody-negative patients experienced chest pain, thrombotic events developed in 9.4% of the erythropoietin antibody-negative patients. These data provide the rationale for a novel mechanism of thrombosis through increased activity of CRP, nitric oxide, and TAFI, leading to fibrinolytic deficit and thrombosis in patients treated with erythropoietin.

Anaemia in diabetes.

Anaemia is a common complication of chronic kidney disease (CKD). It is often more severe and occurs at an earlier stage in patients with diabetic nephropathy than in patients with CKD of other causes. This anaemia results from erythropoietin deficiency, which seems to develop in patients with type 1 diabetes even at relatively "normal" levels of serum creatinine. Early erythropoietin- deficiency anaemia occurs in both type 1 and type 2 diabetes, although the prevalence may be higher in type 1 diabetes. However, numerically most patients with erythropoietin-deficiency anaemia have type 2 diabetes as it is a much more common disease. There is also a greater prevalence in women than men but this is not related to iron stores. In addition, erythropoietin-deficiency anaemia is associated with the presence of autonomic neuropathy in patients with diabetes. Small studies have suggested that recombinant human erythropoietin (rhEPO; epoetin) treatment is effective in correcting erythropoietin-deficiency anaemia in patients with diabetes. Additionally, rhEPO therapy improves quality of life and well-being in these patients. Studies also suggest that treatment with rhEPO to restore a normal haematocrit ameliorates orthostatic hypotension. Given the high cardiovascular risk in patients with diabetic nephropathy, it is important to determine in prospective clinical trials whether early anaemia correction can also improve cardiovascular outcomes.