losartan-potassium and Diabetic-Nephropathies

Diabetes is one of the leading causes of chronic kidney disease (CKD), and multiple underlying mechanisms involved in pathogenesis of diabetic nephropathy (DN) have been described. Although various treatments and diagnosis applications are available, DN remains a clinical and economic burden, considering that about 40% of type 2 diabetes patients will develop nephropathy. In the past years, some research found that hypoxia response and hypoxia-inducible factors (HIFs) play critical roles in the pathogenesis of DN. Hypoxia-inducible factors (HIFs) HIF-1, HIF-2, and HIF-3 are the main mediators of metabolic responses to the state of hypoxia, which seems to be the one of the earliest events in the occurrence and progression of diabetic kidney disease (DKD). The abnormal activity of HIFs seems to be of crucial importance in the pathogenesis of diseases, including nephropathies. Studies using transcriptome analysis confirmed by metabolome analysis revealed that HIF stabilizers (HIF-prolyl hydroxylase inhibitors) are novel therapeutic agents used to treat anemia in CKD patients that not only increase endogenous erythropoietin production, but also could act by counteracting the metabolic alterations in incipient diabetic kidney disease and relieve oxidative stress in the renal tissue. In this review, we present the newest data regarding hypoxia response and HIF involvement in the pathogenesis of diabetic nephropathy and new therapeutic insights, starting from improving kidney oxygen homeostasis.

Topics: Basic Helix-Loop-Helix Transcription Factors; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Humans; Hypoxia; Oxygen; Prolyl-Hydroxylase Inhibitors; Renal Insufficiency, Chronic

Anaemia is a common finding in diabetes, particularly in those patients with albuminuria or renal dysfunction and is associated with impaired erythropoietin (EPO) secretion. This review focuses on mechanisms involved in the regulation of erythropoiesis in diabetic patients in an effort to elucidate the competing effects of the renin angiotensin system (RAS) blockade and sodium-glucose cotransporter-2 (SGLT2) inhibitors on haemoglobin concentration and hematocrit values.. The RAS shows significant activation in diabetic subjects. Angiotensin II, its active octapeptide, causes renal tubulointerstitial hypoxia, which stimulates hypoxia-inducible factors (HIF) and increases EPO secretion and erythropoiesis. As expected, drugs that inactivate RAS, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB) are associated with a significant hematocrit-lowering effect and/or anaemia in various clinical conditions, including diabetes. Dual blockade by a combination of ACEi and ARB in diabetic patients achieves a better RAS inhibition, but at the same time a worse drop of haemoglobin concentration. Increased glucose reabsorption by SGLTs in diabetic subjects generates a high-glucose environment in renal tubulointerstitium, which may impair HIF-1, damage renal erythropoietin-producing cells (REPs) and decrease EPO secretion and erythropoiesis. SGLT2 inhibitors, which inhibit glucose reabsorption, may attenuate glucotoxicity in renal tubulointerstitium, allowing REPs to resume their function and increase EPO secretion. Indeed, EPO levels increase within a few weeks after initiation of therapy with all known SGLT2 inhibitors, followed by increased reticulocyte count and a gradual elevation of haemoglobin concentration and hematocrit level, which reach zenith values after 2-3 months. Key Messages: The competing effects of RAS blockade and SGLT2 inhibitors on erythropoiesis may have important clinical implications. The rise of hematocrit values by SGLT2 inhibitors given on top of RAS blockade in recent outcome trials may significantly contribute to the cardiorenal protection attained. The relative contribution of each system to erythropoiesis and outcome remains to be revealed in future studies.

Topics: Anemia; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoiesis; Erythropoietin; Hematocrit; Hemoglobins; Humans; Hypertension; Kidney Tubules; Renal Reabsorption; Renin-Angiotensin System; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors

Anemia is the major complication resulting from chronic kidney disease (CKD) and also a risk factor for cardiovascular events and a poor quality of life (QoL). Diabetic kidney disease (DKD) is the major cause of CKD. Initially, insulin resistance has been reported to increase erythropoiesis, but it might be a minor issue. DKD-related anemia developed earlier and was more severe than non-DKD-related anemia based on more complicated mechanisms, including greater bleeding tendency associated with antiplatelet effect, less O2 sensing due to autonomic neuropathy or renin-angiotensin-aldosterone system inhibitor use, inhibitory effect of inflammatory cytokines, urinary loss of erythropoietin (EPO), and poor response to EPO. In DKD patients, prompt correction of anemia allows for a better cardiovascular outcome and QoL, which are similar to the promising effect of anemia correction in CKD patients. However, current evidence recommended that the avoidance of a high or normalized hemoglobin (Hb) level has been suggested in the treatment of anemia in DKD patients. Despite that EPO has a pleotropic effect on renal protection from animal studies, the renal benefit was less evident in CKD and DKD patients. Recently, the antidiabetic agent, sodium glucose cotransporter-2 inhibitors (SGLT2i), has been reported to exhibit the renal benefits due to the tubulo-glomerular feedback in addition to sugar control. It may also be due to less renal ischemic through higher EPO levels, followed by higher Hb levels. More studies are needed to clarify the link between the renal benefit of SGLT2i and EPO production.

Topics: Anemia; Diabetic Nephropathies; Erythropoietin; Humans; Renal Insufficiency, Chronic

Topics: Adenosine Triphosphate; Cell Hypoxia; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diabetic Nephropathies; Disease Progression; Diuresis; Erythropoiesis; Erythropoietin; Gene Expression Regulation; Glucose; Heart; Heart Failure; Hematocrit; Hemoglobins; Humans; Kidney; Kidney Tubules, Proximal; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 2 Inhibitors; Sodium-Potassium-Exchanging ATPase; Sympathetic Nervous System

Foot ulcers affect 15% of patients with diabetes, resulting in a great health burden. The occurrence and development of diabetic foot ulcers is associated with neuropathy, peripheral arterial disease, and infection. Several growth factors are involved in these processes, including epidermal growth factor, vascular endothelial growth factor, transforming growth factor-beta, fibroblast growth factor, and erythropoietin, which could promote wound healing of patients with diabetes. Thus, this review discusses the role of these growth factors in the pathogenesis of diabetic foot ulcers, aiming to achieve novel insights into the management of diabetic foot ulcers.

Topics: Diabetic Foot; Diabetic Nephropathies; Epidermal Growth Factor; Erythropoietin; Humans; Intercellular Signaling Peptides and Proteins; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A; Wound Healing

We describe a hemodialysis (HD) patient who successfully underwent total hip arthroplasty with autologous blood transfusion (ABT). There were several problems with collecting ABT in this setting.. A literature search for HD patients and ABT produced 8 articles describing 29 patients. Higher doses of erythropoietin stimulating agents were used to collect ABT than for a typical HD session. In 75% of the cases autologous blood was collected just after HD to collect better quality blood. The optimal clinical procedures for ABT in HD patients need to be clarified.

Topics: Adolescent; Adult; Aged; Arthroplasty, Replacement, Hip; Blood Transfusion, Autologous; Diabetic Nephropathies; Erythropoietin; Female; Humans; Male; Middle Aged; Renal Dialysis; Treatment Outcome; Young Adult

The multipronged drug approach targeting blood pressure and serum levels of glucose, insulin, and lipids fails to fully prevent diabetic nephropathy (DN). Recently, a broad range of anomalies associated with oxygen biology, such as hypoxia, oxidative stress (OS), and dyserythropoiesis, have been implicated in DN. This review delineates the cellular mechanisms of these anomalies to pinpoint novel therapeutic approaches. The PHD-HIF system mitigates hypoxia: HIF activates a broad range of reactions against hypoxia whereas PHD is an intracellular oxygen sensor negatively regulating HIF. The Keap1-Nrf2 system mitigates OS: Nrf2 activates cellular reactions against OS whereas Keap1 negatively regulates Nrf2. Clinical trials of PHD inhibitors to correct anemia in patients with CKD as well as of a Nrf2 activator, bardoxolone methyl, for DN are under way, even if the latter has been recently interrupted. A specific PHD1 inhibitor, a Keap1 inhibitor, and an allosteric effector of hemoglobin may offer alternative, novel therapies. Erythropoietin (EPO) is critical for the development of erythroid progenitors and thus for tissue oxygen supply. Renal EPO-producing (REP) cells, originating from neural crests, but not fibroblasts from injured tubular epithelial cells, transdifferentiate into myofibroblasts and contribute to renal fibrosis. Agents restoring the initial function of REP cells might retard renal fibrosis. These newer approaches targeting oxygen biology may offer new treatments not only for DN but also for several diseases in which hypoxia and/or OS is a final, common pathway.

Topics: Diabetic Nephropathies; Erythropoietin; Humans; Hypoxia; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor-Proline Dioxygenases; Intracellular Signaling Peptides and Proteins; Kelch-Like ECH-Associated Protein 1; NF-E2-Related Factor 2; Oxidative Stress; Oxygen; Signal Transduction

Hypoxia-inducible factor (HIF) is a transcriptional master regulator that takes control of the gene expressions under hypoxia. Several lines of evidence have shown that chronic hypoxia in tubulointerstitium results in irreversible renal disease. Recently, HIF1 was reported to organize a cluster of histone-modifying enzymes by binding to their promoter regions in various kinds of cell lines. However, its function in renal disease remains largely unknown. We focused on the epigenetic regulation on the progression of chronic kidney disease and have reviewed the latest knowledge in this area with special emphasis on the involvement of HIF. For example, a set of HIF1 downstream target genes also were reported to be regulated by cooperative combination of HIF1 and histone demethylase. We suggest a novel epigenetic pathway that affects the final common pathway to end-stage renal disease in addition to the tubulointerstitial hypoxia. We emphasize the importance of figuring out the epigenetic mechanisms of renal failure to find the novel therapeutic approach of chronic kidney disease.

Topics: Chromatin Assembly and Disassembly; Diabetic Nephropathies; Epigenesis, Genetic; Erythropoietin; Fibrosis; Humans; Hypoxia-Inducible Factor 1; Kidney Failure, Chronic; Kidney Tubules

We formed the GEnetics of Nephropathy-an International Effort (GENIE) consortium to examine previously reported genetic associations with diabetic nephropathy (DN) in type 1 diabetes. GENIE consists of 6,366 similarly ascertained participants of European ancestry with type 1 diabetes, with and without DN, from the All Ireland-Warren 3-Genetics of Kidneys in Diabetes U.K. and Republic of Ireland (U.K.-R.O.I.) collection and the Finnish Diabetic Nephropathy Study (FinnDiane), combined with reanalyzed data from the Genetics of Kidneys in Diabetes U.S. Study (U.S. GoKinD). We found little evidence for the association of the EPO promoter polymorphism, rs161740, with the combined phenotype of proliferative retinopathy and end-stage renal disease in U.K.-R.O.I. (odds ratio [OR] 1.14, P = 0.19) or FinnDiane (OR 1.06, P = 0.60). However, a fixed-effects meta-analysis that included the previously reported cohorts retained a genome-wide significant association with that phenotype (OR 1.31, P = 2 × 10(-9)). An expanded investigation of the ELMO1 locus and genetic regions reported to be associated with DN in the U.S. GoKinD yielded only nominal statistical significance for these loci. Finally, top candidates identified in a recent meta-analysis failed to reach genome-wide significance. In conclusion, we were unable to replicate most of the previously reported genetic associations for DN, and significance for the EPO promoter association was attenuated.

Topics: Adaptor Proteins, Signal Transducing; Adult; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Erythropoietin; Finland; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Ireland; Kidney Failure, Chronic; Phenotype; Promoter Regions, Genetic; United States; White People

This meta-analysis assessed the pooled effect of each genetic variant reproducibly associated with diabetic nephropathy.. PubMed, EMBASE and Web of Science were searched for articles assessing the association between genes and diabetic nephropathy. All genetic variants statistically associated with diabetic nephropathy in an initial study, then independently reproduced in at least one additional study, were selected. Subsequently, all studies assessing these variants were included. The association between these variants and diabetic nephropathy (defined as macroalbuminuria/proteinuria or end-stage renal disease [ESRD]) was calculated at the allele level and the main measure of effect was a pooled odds ratio. Pre-specified subgroup analyses were performed, stratifying for type 1/type 2 diabetes mellitus, proteinuria/ESRD and ethnic group.. The literature search yielded 3,455 citations, of which 671 were genetic association studies investigating diabetic nephropathy. We identified 34 replicated genetic variants. Of these, 21 remained significantly associated with diabetic nephropathy in a random-effects meta-analysis. These variants were in or near the following genes: ACE, AKR1B1 (two variants), APOC1, APOE, EPO, NOS3 (two variants), HSPG2, VEGFA, FRMD3 (two variants), CARS (two variants), UNC13B, CPVL and CHN2, and GREM1, plus four variants not near genes. The odds ratios of associated genetic variants ranged from 0.48 to 1.70. Additional variants were detected in subgroup analyses: ELMO1 (Asians), CCR5 (Asians) and CNDP1 (type 2 diabetes).. This meta-analysis found 24 genetic variants associated with diabetic nephropathy. The relative contribution and relevance of the identified genes in the pathogenesis of diabetic nephropathy should be the focus of future studies.

Topics: Adaptor Proteins, Signal Transducing; Apolipoprotein C-I; Apolipoproteins E; Carboxypeptidases; Diabetic Nephropathies; Dipeptidases; Erythropoietin; Genetic Variation; Heparan Sulfate Proteoglycans; Humans; Intercellular Signaling Peptides and Proteins; Nerve Tissue Proteins; Nitric Oxide Synthase Type III; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptors, CCR5

Heavy chain deposition disease (HCDD) is a comparatively recently described entity characterized by glomerular and tubular basement membrane deposition of monoclonal heavy chains without associated light chains. To our knowledge, review of the literature shows only 24 previously reported cases of HCDD with unequivocal evidence of monoclonal heavy chain deposition in the kidney using immunofluorescence microscopic and electron microscopic studies. The predominant heavy chain subtype was γ. There has been a single case of μ HCDD and 2 previously reported cases of α HCDD. In this report, we describe 3 additional cases of α HCDD, all with a crescentic pattern of injury and one of which was associated with cutis laxa. We compare their clinicopathologic features with all previously reported cases of HCDD.

Topics: Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Cutis Laxa; Dexamethasone; Diabetic Nephropathies; Erythropoietin; Fatal Outcome; Female; Heavy Chain Disease; Hematuria; Humans; Hypertension, Renal; Immunoglobulin alpha-Chains; Immunoglobulin gamma-Chains; Immunoglobulin mu-Chains; Kidney Glomerulus; Male; Multiple Myeloma; Paraproteinemias; Proteinuria; Pyrazines; Thalidomide; Urticaria; Vasculitis, Leukocytoclastic, Cutaneous

Topics: Acidosis; Anemia; Bone Diseases, Metabolic; Chronic Disease; Darbepoetin alfa; Diabetic Nephropathies; Diet, Protein-Restricted; Erythropoietin; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Kidney Diseases; Male; Nephrology; Renin-Angiotensin System

Erythropoiesis-stimulating agents (ESA) are used to treat renal anemia. The TREAT study (Trial to Reduce Cardiovascular Events with Aranesp Ther- apy) of diabetic patients with chronic kidney disease (CKD) found that the risk of stroke was significantly higher than in the control arm. This raises the question as to what causes this phenomenon. Platelets may play a crucial role in this context. Atherogenesis involves complex interactions between platelets and monocytes (platelet-monocyte crosstalk) and with endothelial cells. Platelets are activated in cases of diabetes mellitus, especially. During atherogenesis, partial functions of platelets other than those inhibited by aspirin, as a cyclooxygenase inhibitor, or by adenosine diphosphate receptor P2Y(12)antagonists, such as thienopyridines, are of relevance. During platelet-monocyte crosstalk, specifically, an important role is played by adhesion receptors such as selectins and integrins. In addition, ESA cause platelet activation by direct and indirect mechanisms. Antagonistic thereto is a renal bleeding tendency in cases of severe CKD, due to platelet dysfunction, which can be remedied with appropriate renal replacement therapy and administration of ESA in order to reach a hemoglobin (Hb) level of 10 g/dl. However, if the Hb level exceeds 10 g/dl, the even stronger platelet activation caused by ESA, combined with the activation caused by diabetes, leads to a prothrombotic state, which in patients with severe atherosclerosis can result in acute atherothrombotic complications, in the genesis of which platelets play a key role. This would be one hypothesis for explaining the increased incidence of strokes in the TREAT study.

Topics: Anemia; Atherosclerosis; Blood Platelets; Darbepoetin alfa; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Erythropoietin; Female; Hematinics; Hemoglobinometry; Humans; Integrins; Intracranial Embolism; Male; Monocytes; Platelet Activation; Randomized Controlled Trials as Topic; Receptor Cross-Talk; Renal Replacement Therapy; Selectins

Topics: Acute Kidney Injury; Autoantigens; Darbepoetin alfa; Diabetic Nephropathies; Erythropoietin; Glomerulonephritis, Membranous; Hematinics; Humans; Immunosuppressive Agents; Kidney Diseases; Lupus Nephritis; Randomized Controlled Trials as Topic; Renal Replacement Therapy

Topics: Animals; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Erythropoietin; Humans; Hypoxia; Kidney Failure, Chronic; Models, Biological; Polymorphism, Single Nucleotide; Promoter Regions, Genetic

Anemia is one of the world's most common preventable conditions, yet it is often overlooked, especially in people with diabetes mellitus. Diabetes-related chronic hyperglycemia can lead to a hypoxic environment in the renal interstitium, which results in impaired production of erythropoietin by the peritubular fibroblasts and subsequent anemia. Anemia in patients with diabetes mellitus might contribute to the pathogenesis and progression of cardiovascular disease and aggravate diabetic nephropathy and retinopathy. Anemia occurs earlier in patients with diabetic renal disease than in nondiabetic individuals with chronic kidney disease. Although erythropoietin has been used to treat renal anemia for nearly two decades, debate persists over the optimal target hemoglobin level. Most guidelines recommend that hemoglobin levels be maintained between 105g/l and 125g/l. The suggested role of anemia correction--to prevent the progression of left ventricular hypertrophy in patients with diabetes mellitus--is yet to be established. However, an emphasis on regular screening for anemia, alongside that for other diabetes-related complications, might help to delay the progression of vascular complications in these patients.

Topics: Anemia; Diabetes Mellitus; Diabetic Nephropathies; Erythropoietin; Hemoglobins; Humans; Models, Biological

Topics: Anemia; Animals; Diabetic Nephropathies; Disease Progression; Epoetin Alfa; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Nephrotic Syndrome; Proteinuria; Quality of Life; Randomized Controlled Trials as Topic; Recombinant Proteins

Erythropoietin (EPO) is a haematopoietic cytokine, mainly generated in the renal cortex, and its secretion and action is impaired in chronic kidney disease (CKD). Early renal damage in diabetes mellitus (DM) is usually not detected because diabetes-induced nephron hypertrophy maintains glomerular filtration rate (GFR) and an elevated plasma creatinine concentration is a relatively late manifestation of diabetic nephropathy. However, anaemia occurs more frequently in subjects with DM when compared with those with non-DM renal disease. While reduced production and a blunted response to EPO occurs in DM with early renal damage, other factors including chronic inflammation, autonomic neuropathy and iron deficiency are also important. Although recombinant human erythropoietin (rhEPO) has been an effective therapeutic agent in CKD anaemia, it appears to be more effective in patients with DM, even in earlier stages. Nevertheless, patients with DM are also more likely to be iron deficient, a barrier to effective rhEPO therapy. The effect of treatment on the reliability of haemoglobin A(1c) as an index of glycaemic control must be remembered. It is proposed that anaemia and its causes must be important components of care in subjects with early diabetic renal damage.

Topics: Anemia; Creatinine; Diabetic Nephropathies; Erythropoietin; Female; Humans; Iron; Iron Deficiencies; Kidney Failure, Chronic; Male; Recombinant Proteins

The mortality rate in diabetics with chronic kidney disease (CKD) is seven times higher than end-stage renal disease mainly because of cardiac causes. Anaemia may have a relevant role in the pathogenesis of cardiovascular (CV) disease in CKD. Anaemia occurs at an earlier stage of CKD in diabetic individuals than in those with other causes of CKD. Observational findings support the unfavourable influence of anaemia on mortality in CKD patients, and the combination of anaemia and CKD in diabetics identifies a group with a particularly high mortality risk. While the effect of erythropoietin on these patients' quality of life is known, its impact on mortality and CV risk is uncertain. The recent Anaemia Correction in Diabetes (ACORD) trial in diabetic CKD patients, which targeted haemoglobin levels of 13-15 mg/dl, disclosed no statistically significant favourable or adverse effects on mortality or morbidity over the 2-year follow-up, while other studies endeavouring to nearly normalize haemoglobin have reportedly proved risky. Even if anaemia is causally involved, the pathogenesis of CV disease in diabetics with CKD is so complex that addressing just one factor (anaemia) may not suffice to prevent CV risk, and normalizing haemoglobin levels may even be harmful.

Topics: Anemia; Cardiovascular Diseases; Diabetic Nephropathies; Erythropoietin; Humans; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic; Risk

Diabetic nephropathy is traditionally considered to be a primarily glomerular disease, although this contention has recently been challenged. Early tubular injury has been reported in patients with diabetes mellitus whose glomerular function is intact. Chronic hypoxia of the tubulointerstitium has been recognized as a mechanism of progression that is common to many renal diseases. The hypoxic milieu in early-stage diabetic nephropathy is aggravated by manifestations of chronic hyperglycemia-abnormalities of red blood cells, oxidative stress, sympathetic denervation of the kidney due to autonomic neuropathy, and diabetes-mellitus-induced tubular apoptosis; as such, tubulointerstitial hypoxia in diabetes mellitus might be an important early event. Chronic hypoxia could have a dominant pathogenic role in diabetic nephropathy, not only in promoting progression but also during initiation of the condition. Early loss of tubular and peritubular cells reduces production of 1,25-dihydroxyvitamin D3 and erythropoietin, which, together with dysfunction of their receptors caused by the diabetic state, diminishes the local trophic effects of the hormones. This diminution could further compromise the functional and structural integrity of the parenchyma and contribute to the gradual decline of renal function.

Topics: Animals; Calcitriol; Capillaries; Chronic Disease; Diabetic Nephropathies; Disease Progression; Erythropoietin; Filtration; Humans; Hyperglycemia; Hypoxia; Kidney; Kidney Glomerulus; Kidney Tubules; Oxidative Stress; Proteinuria; Receptors, Calcitriol

Both chronic kidney disease (CKD) and type II diabetes mellitus (DM) are increasing in frequency among Western populations and both are potent risk factors for the development of anaemia. The presence of CKD and diabetes together represent the most important aetiopathogenic combination for the development of anaemia. New evidence has highlighted some of the underlying mechanisms which make diabetic patients more susceptible to dyserythropoiesis, particularly once they have developed concomitant CKD. In addition, recent publications from large-scale epidemiological studies have highlighted the impact of anaemia on diabetic patients. The purpose of this review was to focus on the pathophysiology and impact of anaemia in DM.

Topics: Anemia; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Quality of Life

Anemia is prevalent in patients with chronic kidney disease (CKD) and is a risk factor for poor disease outcome. Anemia acts as a risk multiplier, significantly increasing the risk of death in anemic versus nonanemic CKD patients with similar comorbidities. Erythropoiesis-stimulating agents (ESA) are a mainstay for the treatment of anemia in renal patients on dialysis, but recent data suggests that earlier treatment of anemia in CKD may delay the onset of end-stage renal disease (ESRD) and decrease mortality. Nonetheless, anemia of CKD is under-recognized and undertreated during the period before initiation of dialysis, when anemia correction may have the greatest impact on disease outcome. This report describes anemia in CKD and its association with diabetes, cardiovascular disease, and poor disease outcome, and offers suggestions for the recognition and treatment of anemia of CKD in the primary care setting.

Topics: Algorithms; Anemia; Comorbidity; Diabetic Nephropathies; Disease Progression; Erythropoiesis; Erythropoietin; Ferritins; Humans; Hypertension; Kidney Diseases; Oxidative Stress; Primary Health Care; Quality of Life; Recombinant Proteins; Risk Factors

Anaemia is a common finding in patients with diabetes, particularly in those with overt nephropathy or renal impairment. In tertiary clinics, at least one outpatient in five with diabetes has anaemia, for whom it constitutes a significant additional burden.. Anaemia is associated with an increased risk of diabetic complications including nephropathy, retinopathy and macrovascular disease. Anaemia may also be significant in determining the outcome of heart failure and hypoxia-induced organ damage in diabetes. While several factors contribute to the increased prevalence of anaemia in diabetes, the failure of the kidney to increase erythropoietin in response to falling haemoglobin appears to be the dominant factor. Although there is a clear rationale for correcting anaemia in people with diabetes, it remains to be established whether this will lead to improved outcomes. Moreover, the balance of risks, costs, and benefits remains to be established in patients with diabetes. The Trial to Reduce Cardiovascular Events with Aranesp (darbepoetin alpha) Therapy (TREAT) is a randomised controlled trial designed to determine the impact of anaemia correction on mortality and non-fatal cardiovascular events in patients with type 2 diabetes and stage 3-4 nephropathy.. It is anticipated that TREAT will help to define the optimal approach to the management of anaemia in diabetes.

Topics: Anemia; Diabetes Complications; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; Erythropoietin; Humans

Cardiovascular disease (CVD) is the major cause of morbidity and mortality in people with diabetes and in those with chronic kidney disease (CKD). Diabetes, occurring in epidemic proportions in the United States and worldwide, is also the leading cause of CKD and kidney failure. Identification of modifiable risk factors for CVD in patients with diabetes and CKD is thus of paramount importance. Anemia is increasingly recognized as a potential CVD risk factor in patients with diabetic nephropathy, in whom it is generally more severe and occurs at an earlier stage of CKD. In this review, we discuss the epidemiologic evidence, pathophysiologic mechanisms, and the current research findings, highlighting the role of anemia as a potential modifiable risk factor for CVD in patients with diabetic nephropathy, a particularly vulnerable population for CVD.

Topics: Anemia; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus; Diabetic Nephropathies; Erythropoietin; Humans; Risk Factors

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.

Topics: Anemia; Animals; Diabetic Nephropathies; Erythropoiesis; Erythropoietin; Hemolysis; Humans; Hypoxia-Inducible Factor 1; Inflammation; Iron Deficiencies; Kidney; Kidney Failure, Chronic; Receptors, Erythropoietin; Uremia

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.

Topics: Anemia; Diabetes Complications; Diabetic Angiopathies; Diabetic Nephropathies; Erythropoietin; Heart Diseases; Humans

Anemia has recently been recognized as a frequent complication of diabetic nephropathy, appearing earlier than in nondiabetic renal disease and amplifying the risks of cardiovascular and microvascular complications. A major cause is an inappropriate erythropoietin response to anemia, often accompanied by iron deficiency and therapy with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

Topics: Anemia; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Disease Progression; Erythropoietin; Heart Diseases; Humans

The number of diabetic patients with renal disease increased significantly in the last years worldwide. Anemia is an important and frequent component of diabetic nephropathy that may begin early in the course of the chronic renal disease of diabetics, and is more severe in diabetic patients with renal disease than in non - diabetic renal patients controlled for the same level of renal function. The reason for the anemia is decreased erythropoietin level caused by diminished production and, in a lesser degree, by increased excretion of erythropoietin in the urine. There is a close connection between diabetic nephropathy, anemia and cardiovascular complications. On the basis of small studies correction of anemia may decrease the progression of diabetic nephropathy and cardiovascular complications. However, the result of ongoing large randomised controlled studies are required to get "evidence-based" data to prove that correction of anemia has beneficial effects on microvascular and macrovascular diabetic complications, particularly cardiac disease, and on progression of diabetic nephropathy.

Topics: Anemia, Hypochromic; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Epoetin Alfa; Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins; Time Factors

The combination of diabetes and chronic kidney disease is associated with increased mortality and reduced quality of life. Recent studies have shown that, in general, late referral of patients to the renal unit increases mortality, and that patients with diabetes who are referred late have a particularly poor prognosis. Several co-morbid conditions have been shown to contribute to poor patient outcomes, including both cardiovascular disease and anaemia. In patients with diabetic nephropathy, anaemia is more severe and is seen earlier than in patients with non-diabetic renal disease. Although the treatment of anaemia with recombinant human erythropoietin (rhEPO; epoetin) is well established, the only data currently available concerning the effects of early intervention in patients with diabetic nephropathy are from small-scale studies. Therefore, two large-scale studies have been designed to provide information on the efficacy of epoetin treatment and on how current management strategies might be improved. The Anaemia CORrection in Diabetes (ACORD) study will provide information on the potential cardiac benefits of early anaemia management in patients with early, type 2 diabetic nephropathy. The Individualised Risk-profiling In DIabEtes Mellitus (IRIDIEM) study will provide evidence-based guidance in risk factor management, by assessing the efficacy of individualized interventions.

Topics: Anemia; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Recombinant Proteins; Referral and Consultation; Survival Rate

Anaemia is a frequent complication of diabetic nephropathy. It has only recently been recognised that in diabetic patients anaemia is seen not only in preterminal renal failure, but also frequently in patients with only minor derangement of renal function. At any level of glomerular filtration rate (GFR) anaemia is more frequent and severe in diabetic compared to nondiabetic patients. A major cause of anaemia is an inappropriate response of erythropoietin to anaemia. Additional factors are iron deficiency and iatrogenic factors, e.g. ACE inhibitor treatment. When serum creatinine is still normal, the erythropoietin concentration is predictive of more rapid loss of glomerular function. When serum creatinine is elevated, the haemoglobin values are predictive of the rate of progression. It is currently under investigation whether reversal of anaemia attenuates the rate of progression. Because most of the late complications of diabetes (retinopathy, neuropathy, heart disease, peripheral arterial disease) involve ischaemic tissue damage, it would be intuitively plausible that treatment with human recombinant erythropoietin should be beneficial, but definite evidence for this hypothesis is currently not available.

Topics: Anemia; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Erythrocytes, Abnormal; Erythropoietin; Heart Failure; Humans; Kidney Failure, Chronic; Myocardial Ischemia; Peripheral Vascular Diseases

The rising incidence of type 2 diabetes mellitus and of its complications will make it the most important health care challenge in the first quarter of the 21st Century. Diabetic nephropathy left unchecked will overwhelm the renal resources. Simple methods (proper diet and exercise, prevention of obesity) are successful in preventing type 2 diabetes in the great majority of the persons at risk. In patients with established type 2 diabetes, nephropathy can be prevented or greatly delayed by strict metabolic control, strict control of blood pressure using angiotensin-converting enzyme inhibitors and angiotensin receptor blockers as the first line of drugs, tight control of serum lipids using statins as indicated, low protein diet, avoidance of smoking and other nephrotoxic influences, prevention of abnormalities in calcium/phosphorus metabolism, and prevention of renal anemia by the early use of erythropoietin. Current research offers the promise of definitive prevention of both type 2 diabetes and diabetic nephropathy.

Topics: Albuminuria; Anemia; Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Erythropoietin; Glomerular Filtration Rate; Humans; Hypertension; Mitochondria

Analysis of the biologic effects of erythropoietin and pathophysiology of chronic kidney diseases (CKD) suggests that treatment with erythropoiesis-stimulating agents (ESA) could slow the progression of CKD. By decreasing hypoxia and oxidative stress, it could prevent the development of interstitial fibrosis and the destruction of tubular cells. It could have direct protective effects on tubular cells through its antiapoptotic properties. It could help maintain the integrity of the interstitial capillary network through its effects on endothelial cells. Thus, suggesting that correcting anemia with ESA could slow the progression of CKD is biologically plausible. In patients with CKD, three small prospective studies and a retrospective study have suggested that treatment with ESA may have protective effects. Post-hoc analysis of the Reduction in Endpoints in Noninsulin-dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan study has also shown that anemia was an independent risk factor for progression of nephropathy in patients with type 2 diabetes. In addition, a large clinical trial, which had to be stopped prematurely because of labeling change for subcutaneous administration of epoetin alfa, suggests that complete normalization of hemoglobin levels is safe in CKD patients not on dialysis and without severe cardiovascular disease. Thus, it seems reasonable to advocate starting a large randomized, prospective study to determine if normalization of hemoglobin concentration can effectively slow the progression of CKD.

Topics: Anemia; Apoptosis; Clinical Trials as Topic; Diabetic Nephropathies; Disease Progression; Epoetin Alfa; Erythrocyte Count; Erythropoietin; Hematinics; Hemoglobins; Humans; Kidney Failure, Chronic; Nephrons; Prospective Studies; Protein Binding; Receptors, Erythropoietin; Recombinant Proteins; Retrospective Studies; Risk Factors

Topics: Anemia; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Humans; Kidney Failure, Chronic

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.

Topics: Anemia; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic; Recombinant Proteins

Topics: Anemia; Diabetic Nephropathies; Diabetic Retinopathy; Erythropoietin; Humans; Recombinant Proteins

Topics: Anemia; Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Autonomic Nervous System Diseases; Diabetic Nephropathies; Diabetic Neuropathies; Erythropoietin; Humans; Recombinant Proteins

Anaemia is an important component of diabetic nephropathy but only recently has it attracted the attention of diabetologists and nephrologists. In diabetic patients, anaemia is the result of diminished erythropoietin production and, to a lesser degree, of increased excretion of erythropoietin in the urine, whereas erythropoietin responsiveness remains unchanged. Although erythropoietin concentrations are predictive of the rate of progression of renal disease, epidemiological studies have failed to show lower haemoglobin concentrations in patients with diabetic compared with non-diabetic renal disease with impaired renal function. However, inappropriately low erythropoietin concentrations and anaemia have been reported in subcohorts of diabetic patients. Further studies are required to determine whether reversal of anaemia has beneficial effects on microvascular and macrovascular diabetic complications, particularly cardiac disease, retinopathy and peripheral arterial disease.

Topics: Anemia; Chronic Disease; Diabetes Mellitus; Diabetic Nephropathies; Erythropoietin; Humans; Kidney Diseases; Kidney Failure, Chronic; Prevalence

Topics: Age Factors; Databases, Factual; Diabetic Nephropathies; Diet, Protein-Restricted; Erythropoietin; Female; Glomerulonephritis; Humans; Internet; Japan; Kidney Failure, Chronic; Male; Morbidity; Prognosis; Reference Standards; Renal Dialysis; Sex Factors; Time Factors

Anaemia occurs earlier and is more severe in diabetic patients with end-stage renal disease (ESRD) than in non-diabetic ESRD patients controlled for the same level of renal function. In contrast to non-diabetic patients, diabetic ESRD patients demonstrate an impaired physiological response to anaemia; endogenous serum erythropoietin levels are low in relation to the level of anaemia. The reasons for the anaemia are probably a combination of tubulointerstitial damage and autonomic neuropathy. The use of angiotensin-converting enzyme inhibitors, which has been reported to be associated with an inhibition of erythropoiesis, does not seem to have a clinically significant effect on haemoglobin levels. In order to address all the independent risk factors in diabetic ESRD, optimal management of these patients should involve interdisciplinary care (diabetologist and nephrologist) and consideration of correction of anaemia.

Topics: Anemia; Creatinine; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Erythropoietin; Hemoglobins; Humans; Kidney Failure, Chronic

In patients with cardiovascular disease, partial correction of anaemia with epoetin improves quality of life and exercise capacity, and reduces left ventricular hypertrophy. The currently recommended haemoglobin in these patients is 11-12 g/dl. The optimal haemoglobin in patients with diabetes mellitus does not differ from that in non-diabetic patients; however, haemoglobin should be increased slowly. There is no difference in the recommended haemoglobin between children and adults. However, epoetin sensitivity is lower in children who, therefore, typically need the same absolute dose of epoetin as adults. Epoetin treatment may delay the progression of chronic renal failure (CRF) in paediatric patients. Elderly patients obtain similar benefits from epoetin as younger adults; moreover, there are no differences in the doses of epoetin required or the optimal haemoglobin. There are very few data available on the effects of epoetin in patients with CRF and chronic obstructive pulmonary disease. At present, a haemoglobin of 11 g/dl seems appropriate. In sickle-cell anaemia patients with CRF, a high haemoglobin could precipitate painful crises; consequently, the recommended haemoglobin is the pre-CRF concentration of 6-9 g/dl. There is no convincing evidence of any effect of previous epoetin treatment on the long-term outcome of renal transplantation. In patients with a failing or failed transplant, the required dose of epoetin may be higher than in pre-transplantation patients. In such cases, transplant nephrectomy might be considered.

Topics: Adult; Aged; Anemia; Anemia, Sickle Cell; Child; Diabetic Nephropathies; Erythropoietin; Humans; Kidney Failure, Chronic; Kidney Transplantation; Lung Diseases, Obstructive

Topics: Biomarkers; Diabetic Nephropathies; Disease Progression; Erythropoietin; Humans; Kidney Tubules; Radioimmunoassay; Severity of Illness Index

Topics: Diabetic Nephropathies; Erythropoietin; Glucose Intolerance; Humans; Insulin Resistance; Kidney Failure, Chronic; Renal Dialysis

A case of posttransplant erythrocytosis in a 51-year-old diabetic man is described. This problem, which can occur in 5 to 15% of renal transplant patients, can result from a contracted plasma volume (diuretics, pressure natriuresis, or glycosuria) or from a true elevation in red blood cell mass. Once the diagnosis of true erythrocytosis is made by a radiolabeled red blood cell mass study, secondary causes such as hypoxia, liver disease, polycythemia rubra vera, renal artery stenosis, and cystic kidney disease should be excluded. Posttransplant erythrocytosis has only been observed in renal transplant recipients and appears to be more frequent with cyclosporine compared with azathioprine therapy. An inappropriately high level of erythropoietin has been described in some, but not all patients, suggesting stimulation of erythropoietin production as the mechanism. Posttransplant erythrocytosis can be associated with an increased incidence of thrombotic events. The presence of this potential complication has prompted intervention to maintain the hematocrit below 50 to 55%. Measures such as discontinuation of diuretics as well as better control of blood pressure and plasma glucose should be used to facilitate the correction of extracellular volume contraction. Phlebotomy has been the most accepted intervention to intermittently lower the hematocrit when needed, but this can lead to iron deficiency. Newer therapeutic modalities are now being used to treat the problem medically. Theophylline, which reduces adenosine-mediated erythropoietin synthesis, is effective but may be associated with side effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Blood Volume; Bloodletting; Combined Modality Therapy; Cyclosporine; Diabetic Nephropathies; Diuretics; Erythrocyte Volume; Erythropoietin; Feedback; Humans; Iron Deficiencies; Kidney Transplantation; Male; Middle Aged; Polycythemia; Postoperative Complications; Theophylline

HbA1c is the most accepted laboratory parameter for the long term observation of glucose control. There is still much of a debate about the use of HbA1c as a metabolic indicator in diabetic patients (DM) on haemodialysis (HD) and erythropoiesis-stimulating agent (ESA) therapy because of the altered erythrocyte turn over in patients with chronic kidney disease and haemodialysis (CKD5D). In 102 CKD5 patients with and without diabetes mellitus, we examined the dose dependent variability in HbA1c and fructosamine levels under haemodialysis and treated with epoetin α (n=48) and a new generation agent with continuous stimulation of methoxy polyethylene glycol epoetin beta (C.E.R.A.; n=54). HbA1c levels were affected by therapy with ESA treatments. ESA dose was inversely correlated with HbA1c and an escalation of 10.000 IU per week induced an estimated decrease of HbA1c of 0.6 percent. In addition, the increase of reticulocyte number as a marker for erythropoiesis was significantly inversely correlated with the increase of ΔHbA1c. ESA treatments had no such effect on the alternative metabolic parameter fructosamine. When compared, both therapeutic agents had comparable success in attaining haemoglobin (Hb) target values. C.E.R.A. showed better correlation and was more effective over a longer dose interval. Our results show that HbA1c levels in patients should be carefully interpreted based on interfering factors. Nevertheless, HbA1c is currently the most consistent parameter for use ascertaining metabolic status of patients suffering from diabetes mellitus.

Topics: Adult; Aged; Aged, 80 and over; Diabetic Nephropathies; Epoetin Alfa; Erythropoietin; Female; Fructosamine; Glycated Hemoglobin; Hematinics; Humans; Male; Middle Aged; Polyethylene Glycols; Renal Dialysis; Renal Insufficiency, Chronic

Contrast-induced-nephropathy (CIN) is associated with poor outcomes, thus prevention of CIN may be of clinical value. Erythropoietin (EPO) has been shown to elicit tissue-protective effects in experimental models and in clinical studies of acute kidney injury. We therefore evaluated its effectiveness for prevention of CIN after coronary angiography (CA) ± percutaneous coronary intervention (PCI) in diabetic patients with chronic kidney disease.. A prospective, randomized, controlled trial was carried out in 138 diabetic patients with eGFR <60 mL/min who underwent non-urgent CA ± PCI. Patients received normal saline and n-acetyl cysteine before CA, with or without 50,000 U of EPO administered 30 min prior to CA. CIN was defined as an increase in serum creatinine of at least 0.5 mg/dL during the first 2 days after exposure to contrast media. Primary outcome was the incidence of CIN. Secondary outcomes were the sensitivity and positive predictive value (PPV) of Cystatin C (CC) and Neutrophil-gelatinase-associated-lipocalin (NGAL) for diagnosis of CIN.. The observed incidence of CIN was 8.7%, significantly lower than the expected for such high-risk population. The administration of EPO prior to CA did not reduce the incidence of CIN (9.7% vs. 7.6%, P = 0.65). CC and NGAL demonstrated a low sensitivity (16.6%) and low PPV (6.7 and 33.3%, respectively) for detecting CIN.. The administration of EPO prior to CA did not reduce the incidence of CIN. Additional prospective research with a larger sample size and in other patient categories is essential to further define the potential protective effect of EPO on prevention of CIN.

Topics: Acetylcysteine; Acute Kidney Injury; Aged; Aged, 80 and over; Biomarkers; Contrast Media; Coronary Angiography; Cystatin C; Cytoprotection; Diabetic Nephropathies; Double-Blind Method; Drug Administration Schedule; Erythropoietin; Female; Humans; Infusions, Intravenous; Iohexol; Israel; Lipocalin-2; Male; Middle Aged; Prospective Studies; Protective Agents; Recombinant Proteins; Renal Insufficiency, Chronic; Risk Factors; Time Factors; Treatment Outcome; Triiodobenzoic Acids

The cause of death in patients with chronic kidney disease (CKD) varies with CKD severity, but variation has not been quantified.. Retrospective analysis of prospective randomized clinical trial.. We analyzed 4,038 individuals with anemia and diabetic CKD from TREAT, a randomized trial comparing darbepoetin alfa and placebo.. Baseline estimated glomerular filtration rate (eGFR) and protein-creatinine ratio (PCR).. Cause of death as adjudicated by a blinded committee.. Median eGFR and PCR ranged from 20.6 mL/min/1.73 m(2) and 4.1 g/g in quartile 1 (Q1) to 47.0 mL/min/1.73 m(2) and 0.1 g/g in Q4 (P<0.01). Of 806 deaths, 441, 298, and 67 were due to cardiovascular (CV), non-CV, and unknown causes, respectively. Cumulative CV mortality at 3 years was higher with lower eGFR (Q1, 15.5%; Q2, 11.1%; Q3, 11.2%; Q4, 10.3%; P<0.001) or higher PCR (Q1, 15.2%; Q2, 12.3%; Q3, 11.7%; Q4, 9.0%; P<0.001). Similarly, non-CV mortality was higher with lower eGFR (Q1, 12.7%; Q2, 8.4%; Q3, 6.7%; Q4, 6.1%; P<0.001) or higher PCR (Q1, 10.3%; Q2, 7.9%; Q3, 9.4%; Q4, 6.4%; P=0.01). Sudden death was 1.7-fold higher with lower eGFR (P=0.04) and 2.1-fold higher with higher PCR (P<0.001). Infection-related mortality was 3.3-fold higher in the lowest eGFR quartile (P<0.001) and 2.8-fold higher in the highest PCR quartile (P<0.02). The overall proportion of CV and non-CV deaths was not significantly different across eGFR or PCR quartiles.. Results may not be generalizable to nondiabetic CKD or diabetic CKD in the absence of anemia. Measured GFR was not available.. In diabetic CKD, both lower baseline GFR and higher PCR are associated with higher CV and non-CV mortality rates, particularly from sudden death and infection. Efforts to improve outcomes should focus on CV disease and early diagnosis and treatment of infection.

Topics: Aged; Cardiovascular Diseases; Cause of Death; Cholesterol, HDL; Cholesterol, LDL; Darbepoetin alfa; Diabetic Angiopathies; Diabetic Nephropathies; Erythropoietin; Female; Hematinics; Humans; Male; Middle Aged; Multivariate Analysis; Renal Insufficiency, Chronic; Retrospective Studies; Triglycerides

Short daily hemodialysis (HD) has a protective effect against dialysis-induced hypotension (DIH). We examined whether this effect extends beyond the treatment period.. We analyzed clinical variables in 6 patients (5 with diabetes mellitus) who underwent conventional hemodialysis (CHD) for 4 h three times weekly for 12 weeks; then short daily HD for 2 h six times weekly for 12 weeks, and then 12 more weeks of CHD. All patients had been given vasopressors for severe DIH.. The severe DIH disappeared during the short daily HD. There were significant decreases in body weight (BW), cardiothoracic ratio (CTR), blood pressure (BP), normal saline solution (NSS) amount (62.8 +/- 26.4 vs. 9.8 +/- 7.4 ml/session, p < 0.05), frequency (0.60 +/- 0.26 vs. 0.10 +/- 0.07 infusions/session, p < 0.05) and postdialysis atrial natriuretic peptide (ANP) (176.8 +/- 56.4 vs. 104.8 +/- 42.3 pg/ml, p < 0.05). Weekly ultrafiltration volume (6.3 +/- 0.9 vs. 7.9 +/- 0.7 l, p < 0.05) was significantly higher during the short daily HD period than during the first CHD period. The vasopressor treatment was therefore stopped or reduced in all patients during the short daily HD period. Because DIH recurred in the second CHD period despite a significant increase in BP, the vasopressor treatment was resumed in 5 patients. BW, CTR, NSS infusion amount and frequency, or postdialysis ANP did not differ significantly between the short daily HD and second CHD periods.. The protective effect of short daily HD against DIH lasted more than 12 weeks after the treatment ended. We therefore conclude that temporary short daily HD is useful for preventing DIH.

Topics: Aged; Anemia; Antihypertensive Agents; Appointments and Schedules; Arteriovenous Shunt, Surgical; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Diabetic Nephropathies; Echocardiography; Erythropoietin; Female; Ferritins; Humans; Hypertension, Renal; Hypotension; Iron; Kidney Failure, Chronic; Male; Middle Aged; Natriuretic Peptide, Brain; Quality of Life; Recombinant Proteins; Renal Dialysis; Uremia

Anaemia is a key component of diabetic nephropathy, but its importance has only recently been recognised. Recombinant human erythropoietin (epoetin) is an established treatment for renal anaemia, and may help to reduce complications associated with diabetic nephropathy, such as cardiovascular disease. The limited experience with the use of epoetin in this patient group prompts the urgent need for clinical data on anaemia correction in early diabetic nephropathy, particularly with regard to benefits on cardiovascular risk reduction. The Anaemia CORrection in Diabetes (ACORD) study will investigate the effects of anaemia correction on cardiac structure and function in patients with early diabetic nephropathy. This 15-month multicentre study will recruit 160 adult patients with diabetes, mild or moderate chronic kidney disease (with creatinine clearance >or=30 ml/min at screening) and moderate anaemia (haemoglobin [Hb], 10.5-13.0 g/dl). Patients will be randomised to one of two groups: the early treatment group will receive subcutaneous epoetin beta (NeoRecormon) at study entry to maintain target Hb levels of 13-15 g/dl, while the control group will reflect current practice and will not receive epoetin therapy until Hb levels decline below 10.5 g/dl. The primary efficacy variable, change in left ventricular mass index, will be evaluated at 15 months following randomisation; secondary efficacy variables will include changes in cardiac structure and function over the study period. The ACORD study should provide valuable information on the benefits of anaemia correction in patients with early diabetic nephropathy. The study will also increase awareness of the importance of treating anaemia associated with diabetes.

Topics: Anemia; Clinical Trials as Topic; Diabetic Nephropathies; Epoetin Alfa; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Recombinant Proteins; Survival Analysis; Time Factors

A mild anaemia is often found in patients with congestive heart failure (CHF), but its significance is uncertain. In an open uncontrolled study we investigated the effect of correcting this anaemia [haemoglobin (Hb) 9.5-11.5 g%] with subcutaneous (s.c.) erythropoietin (Epo) and intravenous (i.v.) iron (Fe) in 179 patients, 84 type II diabetics and 95 non-diabetics, with moderate to severe CHF which was resistant to maximally tolerated doses of standard CHF medications.. Epo, s.c., was given every 1-3 weeks to achieve and maintain the Hb at 12.5 g%. Fe (Fe sucrose-Venofer) was added i.v. as necessary to maintain the Fe stores. Duration of treatment was 11.8 + 8.2 months.. With the Epo-Fe treatment the Hb increased from 10.41 +/- 1.0 to 13.1 +/- 1.3 g% in diabetics and from 10.5 +/- 1.0 to 12.9 +/- 1.2 g% in non-diabetics. Comparing the diabetics and non-diabetics, the New York Heart Association functional class improved by 34.8 and 32.4%, respectively. breathlessness and/or fatigue, as measured by a self-administered Visual Analogue Scale, improved by 69.7 and 67.4%, and the left ventricular ejection fraction improved by 7.4 and 11.5%, respectively. The number of hospitalizations fell by 96.4 and 95.3%, respectively, compared with the pre-treatment period. Although the glomerular filtration rate (GFR) was falling at a rate of approximately 1 ml/min/month before the study in both groups, neither the mean serum creatinine nor the GFR changed significantly during the study period. The mean dose of Epo needed, measured in IU/week/kg body weight, was similar in the two groups.. The correction of the mild anaemia that was found in diabetics and non-diabetics with resistant CHF and mild to moderate chronic renal failure improved the cardiac function and patient functional status, stabilized the renal function and markedly reduced the need for hospitalization.

Topics: Aged; Anemia; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Erythropoietin; Female; Heart Failure; Hemoglobins; Humans; Injections, Intravenous; Injections, Subcutaneous; Iron; Kidney Failure, Chronic; Male; Recombinant Proteins; Treatment Outcome

Impaired red blood cell-deformability (RBC-df) is noted in patients with diabetes and may play a role in the pathogenesis of microvasculopathy and nephropathy. We report the effects of erythropoietin (EPO) alone and combined with aminoguanidine (AG) for 1 year on RBC-df in predialysis patients (P-DPs) with renal insufficiency and in end-stage renal disease (ESRD) patients on maintenance hemodialysis (DPs). Nine P-DPs who received EPO 50 U/kg by subcutaneous injection 3 times per week are compared with 5 P-DPs treated without EPO (mean serum creatinine 4.1 +/- 0.1 versus 4.2 +/- 0.6 mg/dL, respectively). Twelve DPs (Kt/V = 1.5 +/- 0.1) were studied. Six DPs received AG 200 mg/every other day by mouth and EPO 50 U/kg by intravenous (IV) injection, and 6 DPs received EPO (50 U/kg) and placebo and served as control. RBC-df improved significantly in 9 P-DPs treated with EPO at 6 months (from 2.7 +/- 0.1 to 1.6 +/- 0.2, P = 0.005). This positive effect was sustained at 12 months (P = 0.005); there was no change in RBC-df in P-DPs receiving usual care without EPO. RBC-df improved significantly and progressively at 6 and 12 months in DPs treated with EPO and AG (from 2.2 +/- 0.2 to 1.8 +/- 0.2; P = 0.01; 1.2 +/- 0.1; P = 0.001, respectively); there was limited improvement in RBC-df in DPs treated with EPO and placebo. We conclude that EPO treatment significantly improved RBC-df in diabetic P-DPs, but EPO alone has no significant effect on RBC-df after 12 months in diabetic DPs. The combination of EPO and AG restores RBC-df to near-normal levels in diabetic DPs. We speculate that the effect of EPO on RBC-df seen in P-DPs and DPs is related to increased synthesis and influx of new and younger RBCs. AG may confer protection of RBCs in DPs by blocking advanced glycosylated end-product (AGE) formation.

Topics: Area Under Curve; Diabetic Nephropathies; Drug Therapy, Combination; Erythrocyte Deformability; Erythropoietin; Female; Guanidines; Hematocrit; Humans; Injections, Subcutaneous; Male; Middle Aged; Renal Dialysis; Uremia

We compared the effect of recombinant human erythropoietin (rhEPO) administration by continuous s.c. infusion (CSI) with that of a weekly bolus s.c. injection (SBI) in five malnourished predialysis anemic patients with diabetic nephropathy. rhEPO was either continuously infused at a flow rate of 6000 IU per week (36 IU/h) (CSI group) or injected s.c. at a dose of 6000 IU once a week (SBI group) for 4 weeks, in a cross-over comparative study with a washout period of 4 weeks. Mean+/-S.D. plasma EPO levels increased from a basal value of 18.0+/-4.9 mIU/ml to a steady state value of 70.5+/-38.9 mIU/ml 2 weeks after the start of CSI of rhEPO (P < 0.05). Increases in reticulocyte count above the basal value were greater in the CSI group than the SBI group at 3 weeks after the start of treatment (0.94+/-0.35% vs -0.03+/-0.46%, P < 0.05). Increases in Hb concentration above the basal value were much greater in the CSI group than the SBI group at 4 weeks after the start of treatment (2.56+/-0.77 g/dl vs 0.28+/-0.62 g/dl, P < 0.05). These findings suggest that rhEPO administration by CSI is more effective than by SBI for improving anemia in malnourished predialysis patients with diabetic nephropathy.

Topics: Aged; Aged, 80 and over; Anemia; Body Mass Index; Cross-Over Studies; Diabetic Nephropathies; Erythropoietin; Female; Hemoglobins; Humans; Infusions, Parenteral; Injections, Subcutaneous; Iron; Male; Middle Aged; Nutrition Disorders; Recombinant Proteins; Renal Dialysis; Reticulocyte Count

Erythropoietin (EPO) is reported to be mainly produced by renal peritubular interstitial cells. Serum levels of EPO may provide new information on the tubulointerstitial lesions in patients with diabetic nephropathy. We determined EPO, hemoglobin (Hb), and Hb x EPO in 63 diabetic patients who showed normo-, micro- or macroalbuminuria with normal or reduced renal function (creatinine clearance, Ccr, > or = 60 ml/min or < 60 ml/min). In addition, we followed up Ccr during a mean of 26 months in 13 patients with overt nephropathy and normal renal function. The following results were obtained: (1) Hb, EPO, and Hb x EPO values gradually decreased along with advancing stages of nephropathy, and (2) 6 patients with rapidly decreasing renal function showed significantly lower initial EPO and Hb x EPO values than 7 patients without it (p < 0.01). We conclude that EPO and Hb x EPO values may be a new marker predicting future chronic renal failure in diabetic overt nephropathy.

Topics: Albuminuria; Biomarkers; Diabetic Nephropathies; Disease Progression; Erythropoietin; Female; Follow-Up Studies; Hemoglobinometry; Humans; Male; Middle Aged

Erythropoietin was administered to five anemic azotemic diabetic subjects for 1 year to assess the effect of increasing red cell mass on clinical well-being and the course of renal functional decline. None of the subjects manifested worsened hypertension or cerebrovascular or cardiovascular complications despite an increase in mean hematocrit from a baseline mean of 29.6% to a mean of 39.5%. The serum creatinine concentration after 1 year of treatment with erythropoietin was 3.7 mg/dL, which was unchanged from the baseline value of 3.5 mg/dL. Plasma viscosity remained constant as red cell mass increased. Although the viscosity of whole blood rose as the hematocrit increased, it was within the range of normal blood viscosity for an equivalent hematocrit. The favorable impact of erythropoietin treatment on three diabetic subjects who had macular edema and anemia is described. One hypothesis to explain the benefit of a raised hematocrit on both diabetic nephropathy and retinopathy is that the metabolic, hormonal, and hemodynamic components of the diabetic syndrome, in concert, produce tissue and cellular hypoxia that is ameliorated in part by the greater oxygen-transporting capacity of a raised red cell mass. The pseudohypoxia of diabetes may be implicated in the pathogenesis of diabetic neuropathy, retinopathy, muscular dysfunction, and nephropathy.

Topics: Blood Viscosity; Creatinine; Diabetic Nephropathies; Diabetic Retinopathy; Erythropoietin; Female; Hematocrit; Humans; Kidney Failure, Chronic; Macular Edema; Middle Aged; Recombinant Proteins

Recombinant human erythropoietin (rHuEPO) was administered to males undergoing hemodialysis, and its effects on penile erection and hypothalamus-pituitary-gonadal hormone levels were studied. The subject consisted of 18 males undergoing hemodialysis ranging in age from 22 to 58 years (mean 45.3 years). Chronic glomerulonephritis was present in 16, and diabetic nephropathy in 2, as underlying disease. rHuEPO was administered intravenously at 1,500 U 3 times a week with a target to increase the Ht value to 25% or above. Penile erection was evaluated subjectively by a questionnaire based on a visual analogue scale and objectively by semi quantitative measurement of nocturnal penile tumescence (NPT) using an erectometer. Of the 18 patients, subjective improvements in penile erection were observed in 13 (72%), and objective improvements in NPT were observed in 10 (56%). The administration of rHuEPO may alleviate hyperprolactinemia but was found to have no effect on the FSH, LH, Zn, or HS-PTH level. rHuEPO was suggested to be fairly effective for the treatment of sexual disorders.

Topics: Adult; Chronic Disease; Diabetic Nephropathies; Erectile Dysfunction; Erythropoietin; Glomerulonephritis; Humans; Hypothalamo-Hypophyseal System; Male; Middle Aged; Penile Erection; Recombinant Proteins; Renal Dialysis; Testis

Topics: Adult; Aged; Clinical Trials as Topic; Combined Modality Therapy; Diabetic Nephropathies; Erythropoietin; Hematocrit; Humans; Kidney; Kidney Failure, Chronic; Middle Aged; Recombinant Proteins; Renal Dialysis

Topics: Anemia; Diabetic Nephropathies; Erythropoietin; Female; Glycated Hemoglobin; Hematocrit; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis

Gliflozins provide a breakthrough in the management of type-2 diabetes. In addition to facilitating normoglycemia, these sodium-glucose cotransporter type 2 (SGLT2) inhibitors attenuate obesity, hypertension, dyslipidemia, and fluid retention, reduce cardiovascular morbidity, retard the progression of renal dysfunction, and improve survival. The administration of gliflozins also triggers erythropoietin (EPO) production, with the consequent induction of reticulocytosis and erythrocytosis. The mechanism(s) by which gliflozins induce erythropoiesis is a matter of debate. Whereas the canonical pathway of triggering EPO synthesis is through renal tissue hypoxia, it has been suggested that improved renal oxygenation may facilitate EPO synthesis via noncanonical trails. The latter proposes that recovery of peritubular interstitial fibroblasts producing erythropoietin (EPO) is responsible for enhanced erythropoiesis. According to this hypothesis, enhanced glucose/sodium reuptake by proximal tubules in uncontrolled diabetes generates cortical hypoxia, with injury to these cells. Once transport workload declines with the use of SGLT2i, they recover and regain their capacity to produce EPO. In this short communication, we argue that this hypothesis is incorrect. First, there is no evidence for interstitial cell injury related to hypoxia in the diabetic kidney. Tubular, rather than interstitial cells are prone to hypoxic injury in the diabetic kidney. Moreover, hypoxia, not normoxia, stimulates EPO synthesis by hypoxia-inducible factors (HIFs). Hypoxia regulates EPO synthesis as it blocks HIF prolyl hydroxylases (that initiate HIF alpha degradation), hence stabilizing HIF signals, inducing HIF-dependent genes, including EPO located in the deep cortex, and its production is initiated by the apocrinic formation of HIF-2, colocalized in these same cells.

Topics: Diabetic Nephropathies; Erythropoietin; Glucose; Humans; Hypoxia; Kidney; Polycythemia; Reticulocytosis; Sodium; Sodium-Glucose Transporter 2 Inhibitors

The oxidative stress response plays an important role in the occurrence and development of diabetic kidney disease (DKD). It has become a new treatment target for DKD. In the current study, the effects of carbamylated erythropoietin (CEPO) on renal oxidative stress and damage in diabetic rats were examined. Thirty Sprague Dawley rats were intraperitoneally administered with 60 mg/kg streptozotocin to establish the diabetes model. The diabetic rats were randomly allocated into 4 groups (n=6 each): diabetes model group (DM group), DM + CEPO treatment group (DC group), DM + CEPO + EPO receptor (EPOR) blocking peptide treatment group (DCEB group), and DM + CEPO + CD131 blocking peptide treatment group (DCCB group). Meanwhile, a normal control group (NC group, n=6) was set up. Kidney tissues and blood samples were obtained for evaluation of oxidative stress and renal function. The results showed that diabetic rats exhibited increased oxidative stress in the kidney and early pathological changes associated with DKD. Treatment with CEPO reduced oxidative stress and attenuated renal dysfunction. However, diabetic rats treated with the combination of CEPO and EPOR blocking peptide or CD131 blocking peptide showed increased oxidative stress and reduced renal function when compared with CEPO treatment alone group. These results suggested that CEPO can protect against kidney damage in DKD by inhibiting oxidative stress injury via EPOR-CD131 heterodimers.

Topics: Animals; Cytokine Receptor Common beta Subunit; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Erythropoietin; Humans; Kidney; Oxidative Stress; Rats; Rats, Sprague-Dawley; Streptozocin

Topics: Acute Kidney Injury; Diabetes Mellitus; Diabetic Nephropathies; Erythropoietin; Humans; Kidney; Nephrology

Adult human kidneys produce erythropoietin (EPO), which regulates red blood cell formation; however, whether EPO also functions directly on kidney development and controls diabetic kidney disease remains unknown. Here we analyzed the role of EPO in kidney development and under hyperglycemic conditions in zebrafish and in humans.. Diabetic patients and respective controls were enrolled in two cohorts. Serum EPO level and urine protein change upon human EPO administration were then analyzed. Transient knockdown and permanent knockout of EPO and EPOR in renal TG(WT1B:EGFP) zebrafish were established using the morpholino technology and CRISPR/Cas9 technology. Zebrafish embryos were phenotypically analyzed using fluorescence microscopy, and functional assays were carried out with the help of TexasRed labeled 70 kDa Dextran. Apoptosis was determined using the TUNEL assay and Annexin V staining, and caspase inhibitor zVADfmk was used for rescue experiments.. In type 2 diabetic patients, serum EPO level decreased with the duration of diabetes, which was linked to reduced kidney function. Human recombinant EPO supplementation ameliorated proteinuria in diabetic nephropathy patients. In zebrafish, loss-of-function studies for EPO and EPOR, showed morphological and functional alterations within the pronephros, adversely affecting pronephric structure, leading to slit diaphragm dysfunction by increasing apoptosis within the pronephros. Induction of hyperglycemia in zebrafish embryos induced pronephros alterations which were further worsened upon silencing of EPO expression.. EPO was identified as a direct renal protective factor, promoting renal embryonic development and protecting kidneys from hyperglycemia induced nephropathy.

Topics: Aged; Animals; Apoptosis; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Female; Humans; Kidney; Male; Middle Aged; Proteinuria; Recombinant Proteins; Zebrafish

Diabetes-triggered apoptosis of Schwann cells (SC) contributes to the degradation of diabetic peripheral neuropathy (DNP). In recent years, mesenchymal stem cells (MSC) were applied to DPN repair and it was demonstrated that paracrine secretion played a key role in neuroprotection exerted by MSC. Erythropoietin (EPO) is a potent cytokine capable of reducing apoptosis of SC. However, the expression of EPO in MSC is limited. In this study, we hypothesized that overexpression of EPO in MSC (EPO-MSC) may significantly improve their neuroprotective potentials. The EPO overexpression in MSC was achieved by lentivirus transduction. SC derived from the periphery nerve of diabetic rats were cocultured with MSC or EPO-MSC in normal or high glucose culture condition, respectively. In normal glucose culture condition, the overexpression of EPO in MSC promoted the MSC-induced restoration of SC from diabetic rats, including increases in GSH level and cell viability, decrease in TUNEL apoptosis, upregulation of antiapoptotic proteins, p-Akt, and Bcl-2, and downregulation of proapoptotic proteins, cleaved caspase-3, and Bax. The subsequent results in high glucose culture condition showed similar promotions achieved by EPO-MSC. Thus, it could be concluded that EPO-MSC possessed a potent potential in hampering apoptosis of SC, and the suppression was probably attributed to attenuating oxidative stress and regulating apoptosis related protein factors.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Caspase 3; Cell Survival; Coculture Techniques; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Erythropoietin; Glutathione; Mesenchymal Stem Cells; Oxidative Stress; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Schwann Cells; Transduction, Genetic; Up-Regulation

This study aimed at investigating the possible protective effect of erythropoietin beta on experimental diabetic nephropathy (DN) model in rats.. Sprague Dawley rats (n = 32) were allocated into 4 equal groups of 8 each, the control (Group C), diabetes (Group D), erythropoietin beta (Group E), and erythropoietin beta treated DN (Group E + D) groups. Streptozocin (65 mg/kg) was used to induce diabetes in 10-week old rats. Erythropoietin beta was given intraperitoneally at a dose of 500 IU/kg/3 days of a week for 12 weeks. Renal function parameters, intrarenal levels and activities of oxidative stress biomarkers, serum inflammatory parameters and kidney histology were determined.. Group E + D had lower mean albumin-to-creatinine ratio (p < 0.001) as well as higher creatinine clearance (p = 0.035) than the diabetic rats (Group D). Intrarenal malondialdehyde levels were significantly lower (p = 0.004); glutathione (GSH) levels (p = 0.003), GSH peroxidase (p = 0.004) and superoxide dismutase (p < 0.005) activities of renal tissue were significantly higher in Group E + D than in Group D. The mean serum levels of interleukin-4 (p < 0.005), interleukin 1 beta (p = 0.012), interferon gamma (p = 0.018) and tumor necrosis factor alpha (p < 0.005) were significantly lower; serum levels of monocyte chemoattractant protein 1 (p = 0.018) was significantly higher in Group E + D when compared to Group D. The mean scores of tubulointerstitial inflammation (p = 0.004), tubular injury (p = 0.013) and interstitial fibrosis (p = 0.003) were also lower in Group E + D when compared to Group D.. Our data seem to suggest a potential role of erythropoietin beta for reducing the progression of DN in an experimental rat model. This protective effect is, in part, attributable to the suppression of the inflammatory response and oxidative damage.

Topics: Animals; Cytokines; Diabetic Nephropathies; Disease Models, Animal; Erythropoietin; Glutathione; Inflammation Mediators; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

C.E.R.A. (continuous erythropoietin receptor activator, pegilated-rHuEPO ß) corrects and maintains stable hemoglobin levels in once-monthly administration in chronic kidney disease (CKD) patients. The aim of this study was to evaluate the management of anemia with C.E.R.A. in CKD patients not on dialysis in the clinical setting.. Two hundred seventy two anemic CKD patients not on dialysis treated with C.E.R.A. were included in this retrospective, observational, multicentric study during 2010. Demographical characteristics, analytical parameters concerning anemia, treatment data and iron status were recorded.. C.E.R.A. achieved a good control of anemia in both naïve patients (mean Hemoglobin 11.6g/dL) and patients converted from a previous ESA (mean Hemoglobin 11.7g/dL). Most naïve patients received C.E.R.A. once monthly during the correction phase and required a low monthly dose (median dose 75 µg/month). The same median dose was required in patients converted from a previous ESA, and it was lower than recommended in the Summary of Product Characteristics (SPC). Iron status was adequate in 75% of anemic CKD patients, but only 50% of anemic patients with iron deficiency received iron supplementation.. C.E.R.A. corrects and maintains stable hemoglobin levels in anemic CKD patients not on dialysis, requiring conversion doses lower than those recommended by the SPC, and achieving target hemoglobin levels with once-monthly dosing frequency both in naïve and converted patients.

Topics: Adolescent; Adult; Aged; Anemia; Anemia, Iron-Deficiency; Diabetic Nephropathies; Drug Administration Schedule; Erythropoietin; Female; Hemoglobins; Humans; Iron; Male; Middle Aged; Polyethylene Glycols; Renal Insufficiency, Chronic; Retrospective Studies; Young Adult

Chronic kidney disease (CKD) patients on dialysis regularly receive erythropoiesis stimulating agent (ESA) for treating renal anaemia during their dialysis unlike those who are not on dialysis. In such patients, the longer acting ESA can be helpful in reducing their frequent visits to the health care facilities and improving their compliance. This study was aimed to examine the efficacy and safety of continuous erythropoietin receptor activator (CERA), a long acting ESA in treating renal anaemia in patients with diabetic CKD not on dialysis.. In this prospective, open-labelled, pilot clinical study, 35 adult type 2 diabetes patients with nephropathy and renal anaemia, who were not on dialysis nor receiving treatment with ESA were administered CERA subcutaneously once in two weeks for a period of 24 weeks. The primary efficacy end point was to evaluate the Hb response (Hb rise of ≥1 g/dl above the baseline or Hb level ≥11 g/dl) during the study period.. All patients showed Hb rise ≥1 g/dl during the study period and 80 per cent patients could achieve Hb value ≥11 g/dl. The maximum median Hb rise of 1.2 g/dl occurred in the initial 6 weeks after starting the treatment. The mean creatinine clearance (CrCl) improved by 2.8 ml/min, with mean Hb rise of 2.6 g/dl from the baseline after administration of CERA. Worsening of blood pressure (BP) control (42.9%) was the most common adverse event.. CERA once in two weeks was found to be efficacious in correcting anaemia in the ESA-naïve patients with diabetic nephropathy who are not on dialysis. However, regular monitoring of blood pressure is required while on treatment with CERA.

Topics: Adult; Anemia; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoiesis; Erythropoietin; Female; Humans; Male; Middle Aged; Polyethylene Glycols; Renal Dialysis; Renal Insufficiency, Chronic

A number of genes have been identified in diabetic nephropathy. Association between diabetes-associated nephropathy and polymorphisms in the erythropoietin (EPO) gene, variants in the superoxide dismutase 1 (SOD1) gene and plasmacytoma variant translocation 1 (PVT1) gene have been identified. The EPO, SOD1:SFRS15 and PVT1 genes were genotyped using the single nucleotide polymorphism (SNP) technique in 38 diabetic nephropathy patients (Group 1) compared with 64 diabetic type 2 subjects without nephropathy (Group 2) at the Mubarak Alkabeer Hospital, Kuwait. The frequency of the risk allele T of the EPO (rs1617640) gene was high in both groups (0.96 in Group 1 and 0.92 in Group 2). Similarly, SNPs of the PVT1 (rs2720709) gene showed a higher frequency of the risk allele G in both groups (0.70 in the Group 1 and 0.68 in Group 2). Although the frequency of the risk allele A was higher than the frequency of the non-risk allele C of the SOD1:SFRS15 gene in both groups, the lowest probability value was observed in those gene SNPs (P = 0.05). We observed that the A allele of the SOD1:SFRS15 gene (rs17880135) was more frequently present in Group 1 (0.75) compared with Group 2 (0.62). Susceptibility to diabetes-associated nephropathy is partially mediated by genetic predisposition, and screening tests may open the gate for new therapeutic approaches.

Topics: Case-Control Studies; Diabetic Nephropathies; Erythropoietin; Gene Frequency; Genetic Predisposition to Disease; Humans; Nuclear Proteins; Phenotype; Polymorphism, Single Nucleotide; Proteins; Risk Factors; RNA-Binding Proteins; RNA, Long Noncoding; Serine-Arginine Splicing Factors; Superoxide Dismutase; Superoxide Dismutase-1

HbA(1c) values are unreliable in patients with diabetes who have chronic kidney disease who receive iron and/or erythropoiesis stimulating agents. The study aimed to evaluate the utility of the complementary glycaemic markers glycated albumin, fructosamine and 1,5 anhydroglucitol in this group of patients.. A prospective study of patients with Type 2 diabetes and chronic kidney disease stage IIIB/IV undergoing intravenous iron or erythropoiesis-stimulating agent therapy. Glycaemic control was monitored using HbA(1c), seven-point daily glucose thrice weekly, continuous glucose monitoring, glycated albumin, fructosamine and 1,5 anhydroglucitol.. Fifteen patients [9 men; median age 72 years (interquartile range 68-74), follow-up period (16.4 ± 3.7 weeks)] received parenteral iron; 15 patients [11 men; 70 years (interquartile range 62-75), (17.3 ± 3.3 weeks)] received erythropoiesis-stimulating agent. HbA(1c) fell following treatment with both iron [57 mmol/mol (7.4%) to 53 mmol/mol (7.0%), P < 0.001] and erythropoiesis-stimulating agent [56 mmol/mol (7.3%) to 49 mmol/mol (6.6%), P = 0.01] despite mean blood glucose remaining unchanged (iron: 9.55 to 9.71 mmol/l, P = 0.07; erythropoiesis-stimulating agent: 8.72 to 8.78 mmol/l, P = 0.89). Unlike HbA1c , the glycated albumin, fructosamine and 1,5 anhydroglucitol levels did not change following iron [glycated albumin (16.8 to 16.3%, P = 0.10); fructosamine (259.5 to 256 μmol/l, P = 0.89); 1,5 anhydroglucitol (54.2 to 50.9 μmol/l, P = 0.89)] or erythropoiesis-stimulating agent [glycated albumin (17.9 to 17.5%, P = 0.29), fructosamine (324.3 to 306.0 μmol/l, P = 0.52), 1,5 anhydroglucitol (58.2 to 46.7 μmol/l, P = 0.35)]. Despite this, HbA(1c) was consistently the marker most closely related to mean blood glucose before and after each treatment (R range 0.7-0.88).. These data indicate that HbA(1c) was statistically most closely related to mean blood glucose, but clinical trends in glycaemia in patients undergoing iron or erythropoiesis-stimulating agent therapy are likely best assessed by including one of these additional glycaemic markers.

Topics: Administration, Intravenous; Aged; Biomarkers; Blood Glucose; Delivery of Health Care; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Fructosamine; Glycated Hemoglobin; Glycated Serum Albumin; Glycation End Products, Advanced; Hematinics; Humans; Iron; Male; Monitoring, Physiologic; Prospective Studies; Recombinant Proteins; Renal Insufficiency, Chronic; Serum Albumin; Severity of Illness Index; Time Factors; Treatment Outcome

Podocyte damage and accumulation of advanced glycation end products (AGEs) are characteristics of diabetic nephropathy (DN). The pathophysiology of AGE-challenged podocytes, such as hypertrophy, apoptosis, and reduced cell migration, is closely related to the induction of the cell cycle inhibitor p27(Kip1) and to the inhibition of neuropilin 1 (NRP1). We have previously demonstrated that treatment with erythropoietin is associated with protective effects for podocytes in vitro. db/db mice with overt DN aged 15-16 wk were treated with either placebo, epoetin-β, or continuous erythropoietin receptor activator (CERA) for 2 wk. db/db mice compared with nondiabetic db/m control mice revealed the expected increases in body weight, blood glucose, albumin-to-creatinine ratio, and AGE accumulation. Whereas there were no differences in body weight, hyperglycemia and AGEs were observed among diabetic mice that received epoetin-β compared with CERA and placebo treatment, indicating that epoetin-β/CERA treatment does not interfere with the development of diabetes in this model. However, the albumin-to-creatinine ratio was significantly lower in db/db mice treated with epoetin-β or CERA. Furthermore, kidney weights in db/db mice were increased compared with db/m control mice, indicating renal hypertrophy, whereas the increase in renal weight in epoetin-β- or CERA-treated db/db mice was significantly lower than in placebo-treated control mice. Induction of p27(Kip1) and suppression of NRP1 were significantly reduced in the epoetin-β treatment group versus the CERA treatment group. Furthermore, erythropoietin treatment diminished the diabetes-induced podocyte loss. Together, independently from hematopoetic effects, epoetin-β or CERA treatment was associated with protective changes in DN, especially that NRP1 and p27(Kip1) expressions as well as numbers of podocytes returned to normal levels. Our data show, for the first time, that medication of overt DN with erythropoietin for a short time can ameliorate albuminuria and podocyte loss.

Topics: Albuminuria; Animals; Cyclin-Dependent Kinase Inhibitor p27; Diabetic Nephropathies; Erythropoietin; Glycation End Products, Advanced; Male; Mice; Neuropilin-1; Podocytes; Polyethylene Glycols; Recombinant Proteins

Anemia is a major complication of end-stage renal disease. Hemodialysis itself is regarded as a stimulus activating inflammation. Pro-inflammatory cytokines are able to suppress erythropoiesis. In this pilot study, we analyzed the changes in methylation status of promoters of immune response genes in cell-free DNA to detect the differences between diabetic subjects (n = 18) with different therapeutic doses of recombinant erythropoietin.. The extent of promoter methylation of 24 genes in plasma cell-free DNA was examined before and after hemodialysis using EpiTect Methyl qPCR Array Inflammatory Response and Autoimmunity (Qiagen).. The patients with higher methylation status of gene sequences IL13RA1, IL15, EDG3 and INHA in interdialytic interval were significantly overrepresented in the group with none or mild anemia therapy.. The results are in agreement with the fact that IL13 and IL15 are known inhibitors of erythropoiesis and with considered immunomodulatory role of cell-free DNA.

Topics: Anemia; Cluster Analysis; Cytokines; Diabetic Nephropathies; DNA Methylation; Erythropoietin; Female; Gene Expression Profiling; Humans; Immunity; Male; Promoter Regions, Genetic; Renal Dialysis

Although thyroid diseases exist in patients with renal failure, thyroid function tests are not routine tests in patients on chronic hemodialysis (HD). Therefore, the impact of thyroid diseases on erythropoietin (EPO) dosage in HD patients is not well defined. This study evaluated the relationship between the dose of EPO and the presence or absence of thyroid dysfunction in HD patients.. This study included 1013 adult patients on HD who did not have a malignancy, liver cirrhosis, thalassemia, iron deficiency, gastrointestinal bleeding, or a major operation within 6 months. Patients were characterized as being euthyroid, or having the sick euthyroid syndrome, primary hypothyroidism, subclinical hypothyroidism, hyperthyroidism, or subclinical hyperthyroidism based on thyroid function tests. Routine biochemistry profiles including an index of the efficiency of HD, along with clinical data over the previous 6-month period, were collected and analyzed. Multiple regression models were employed to assess the relationship between the dose of EPO and the presence or absence of thyroid status.. The mean monthly EPO dosages were 77.7±37.0, 70.2±40.6, 90.8±68.4, 78.5±46.7, and 82.3±41.2 μg, respectively, in the sick euthyroid syndrome, euthyroid patients, hypothyroidism, subclinical hypothyroidism, and subclinical hyperthyroidism groups (p<0.05). After adjustment of all other variables in multiple regression, the mean monthly EPO dosage was 19.00±8.59 μg more in hypothyroid patients compared with euthyroid patients (p=0.027). Further, considering an interaction with the presence of diabetes, the mean monthly EPO dosage in patients with either hypothyroidism or subclinical hypothyroidism and diabetes was 54.66±17.12 μg (p=0.001) and 31.51±10.38 μg more than that of euthyroid patients, respectively (p=0.002).. In HD patients, the EPO dosage required to maintain the target hemoglobin level is significantly higher in patients having both hypothyroidism or subclinical hypothyroidism and diabetes than in euthyroid patients.

Topics: Aged; Anemia, Hemolytic; Cross-Sectional Studies; Diabetic Nephropathies; Drug Monitoring; Erythropoietin; Euthyroid Sick Syndromes; Female; Hematinics; Humans; Hyperthyroidism; Hypothyroidism; Kidney Failure, Chronic; Male; Middle Aged; Prevalence; Recombinant Proteins; Renal Dialysis; Severity of Illness Index; Taiwan; Thyroid Diseases; Thyroid Gland

This study assessed the added effect of 6 months of erythropoietin (EPO) administration in patients suffering from diabetic neuropathy with mild to moderate chronic kidney disease (CKD) managed with gabapentin. Twenty diabetic patients with mild to moderate CKD were included; 12 in gabapentin and 8 in EPO+gabapentin group. The subjects underwent nerve conduction studies (NCS) at the initiation of the investigation and after 6-month treatment. NCS were made in deep and superficial peroneal, tibial, and sural nerves. After 6 months, in both the groups, proximal motor latency (PML) nonsignificantly improved in deep peroneal and tibial nerves; conversely, dorsal motor latency (DML) got slightly impaired in these two nerves. A nonsignificant disruption and improvement was observed in deep peroneal and tibial motor nerve conduction velocity (MNCV), respectively, in gabapentin group. Although the F-wave of tibial and deep peroneal nerves remained stable in gabapentin group, a nonsignificant improvement was observed in EPO+gabapentin group. H-reflex of tibial nerve and all the evaluated parameters of sural and superficial peroneal nerves remained constant in all patients. Thus, it can be concluded that 6-month administration of EPO+gabapentin, or gabapentin alone in mild to moderate CKD patients with diabetic neuropathy could not improve nerve performance.

Topics: Aged; Aged, 80 and over; Amines; Cyclohexanecarboxylic Acids; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Drug Therapy, Combination; Erythropoietin; Excitatory Amino Acid Antagonists; Female; Gabapentin; gamma-Aminobutyric Acid; Humans; Male; Middle Aged; Neural Conduction; Neurologic Examination; Peripheral Nervous System Diseases; Peroneal Nerve; Recombinant Proteins; Renal Insufficiency; Sural Nerve; Surveys and Questionnaires; Tibial Nerve

Anaemia is a common finding in people with diabetes and chronic kidney disease and failure of the kidney to produce erythro-poietin in response to a falling haemoglobin concentration is a key component, correlating with the degree of albuminuria, renal dysfunction and iron deficiency. Anaemia in diabetes is associated with a number of adverse outcomes, including increased risk of all cause and cardiovascular mortality. Whether or not anaemia is a marker or mediator of adverse outcome still remains to be completely resolved. Treatment of anaemia in diabetes has quality of life benefits and reduces transfusion requirements. Correction of anaemia to normal haemoglobin concentrations is associated with significant adverse cardiovascular outcomes and is not recommended, escalating doses of erythropoiesis-stimulating agents should be avoided. The treatment of anaemia in people with diabetes and chronic kidney disease should begin with optimisation of iron stores. An aspirational haemoglobin concentration range of 10-12 g/dl with anaemia management, balances proven benefits of anaemia treatment with potential cardiovascular risk.

Topics: Anemia; Diabetes Complications; Diabetic Nephropathies; Erythropoietin; Hematinics; Humans; Iron; Iron Deficiencies; Renal Insufficiency, Chronic

Since the half-life of red blood cells (RBCs) is shorter in hemodialysis patients, the value of glycated hemoglobin (HbA1c) as a marker of glycemic control in patients with diabetes on hemodialysis has recently been questioned. It is thought that it is not a good marker of mean plasma glucose (MPG) over a 3-month duration. In our current study, we evaluate whether monthly HbA1c values is a better marker of glycemic control than HbA1c every 3 months.. We performed a cross-sectional analysis of a retrospective cohort of 152 patients with diabetes who presented to two hemodialysis units in NYC. Patients had weekly predialysis glucose levels checked over the last 3 months, and HbA1c values were checked every 3 months. Data collection spanned a 6-month time frame from August 2008 to January 2009.. We found no difference in the correlation between HBA1c/mean plasma glucose (MPG) over the last month (MPG1m) and HbA1c/mean plasma glucose (MPG) over the last 3 months (MPG3m; r = 0.57 and r = 0.53, respectively; P = 0.212). Using multivariate analysis, reticulocyte count and weekly erythropoietin dose were found to independently and inversely effect the correlations HbA1c/MPG1m and HbA1c/MPG3m.. The value of HbA1c in hemodialysis for monitoring glycemic control is limited in the setting of a high reticulocyte count (>2%) and a high weekly erythropoietin dose. Checking HbA1c monthly versus every 3 months is not a better approximation of glycemic control in hemodialysis patients.

Topics: Blood Glucose; Cross-Sectional Studies; Diabetic Nephropathies; Erythropoietin; Female; Glycated Hemoglobin; Humans; Kidney Failure, Chronic; Male; Multivariate Analysis; Regression Analysis; Renal Dialysis; Reticulocyte Count; Retrospective Studies

Topics: Aged; Diabetic Nephropathies; Erythropoietin; Female; Glycated Hemoglobin; Glycated Serum Albumin; Glycation End Products, Advanced; Hematinics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Serum Albumin

Endothelial progenitor cells (EPCs) are thought to be important for maintaining normal vascular function. We conducted a prospective study evaluating the effect of the erythropoiesis-stimulating agent darbepoetin alfa on EPCs and vascular function in patients with chronic kidney disease (CKD), with or without diabetes. Thirty subjects with CKD (20 subjects with type II diabetes mellitus and 10 without diabetes mellitus) received weekly subcutaneous administration of darbepoetin alfa for 4 weeks. EPCs were measured at baseline and 2 and 4 weeks after drug administration. Vascular function was measured with brachial ultrasound and cell activity was measured with a cell proliferation assay. Cells expressing CD133, CD34, CD146 and CD146/31 were significantly elevated (all p < 0.05), flow-mediated vasodilatation increased 2.1%, 95% CI: (0.4%, 3.8%) and colony-forming units increased twofold, 95% CI: (1.7, 2.3) after 4 weeks of treatment with darbepoetin alfa. Subjects with diabetes exhibited an increase in a subset of EPCs (CD133( +) and 34(+), p < 0.01 and p = 0.06, respectively), vasodilatation and proliferation. In conclusion, the administration of darbepoetin alfa for 4 weeks increased a subset of EPCs, improved endothelial function and increased cell proliferation, including those with diabetes, which is consistent with a favorable improvement in vascular health.

Topics: AC133 Antigen; Aged; Antigens, CD; Antigens, CD34; Biomarkers; Cell Proliferation; Chronic Disease; Darbepoetin alfa; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Endothelial Cells; Erythropoietin; Female; Glycoproteins; Hematinics; Humans; Kidney Diseases; Linear Models; Male; Middle Aged; Peptides; Philadelphia; Prospective Studies; Stem Cells; Time Factors; Treatment Outcome; Vasodilation

Antibody (Ab)-mediated pure red cell aplasia (PRCA) is a rare but important side effect in patients with chronic kidney disease who receive recombinant human erythropoietin (rhEPO). Ab-mediated PRCA was first reported in the 1990s, and the incidence subsequently increased and reached a peak in 2001. After improvements in rhEPO products and the administration route, the incidence was reduced by 90%, and now Ab-mediated PRCA only develops in a limited number of patients who receive rhEPO subcutaneously for a long period. We describe here the clinical course of one such rare patient with Ab-mediated PRCA. The patient was a 70-year-old man with chronic renal failure secondary to diabetic nephropathy. He had not received rhEPO therapy before the initiation of hemodialysis. He started hemodialysis and began to receive rhEPO therapy intravenously. Three months later, his hemoglobin level started declining and he became transfusion dependent. A diagnosis of Ab-mediated PRCA was made by bone marrow examination and detection of anti-EPO Abs. He was successfully treated with cyclosporine and became independent of blood transfusions. This case is a reminder that vigilance is required regarding the development of Ab-mediated PRCA upon rhEPO therapy, regardless of the administration route.

Topics: Aged; Autoantibodies; Diabetic Nephropathies; Erythropoietin; Humans; Injections, Intravenous; Kidney Failure, Chronic; Male; Recombinant Proteins; Red-Cell Aplasia, Pure

A randomized trial had suggested that high doses of erythropoiesis-stimulating agents (ESAs) might increase the risk of cardiovascular outcomes in predialysis diabetic patients. To evaluate this risk in diabetic patients receiving dialysis, we used data from 35,593 elderly Medicare patients on hemodialysis in the US Renal Data System of whom 19,034 were diabetic. A pooled logistic model was used to estimate the monthly probability of mortality and a composite cardiovascular end point. Inverse probability weighting was used to adjust for measured time-dependent confounding by indication, estimated separately for diabetic and non-diabetic cohorts. The adjusted 9-month mortality risk, significantly different between an ESA dose of 45,000 and 15,000 U/week, was 13% among diabetics and 5% among non-diabetics. In diabetic patients, the hazard ratio (HR) for more than 40,000 U/week was 1.32 for all-cause mortality and 1.26 for a composite end point of death and cardiovascular events compared with patients receiving 20,000 to 30,000 U/week. The corresponding HRs in non-diabetic patients were 1.06 and 1.10, respectively. A smaller effect of dose was found in non-diabetic patients. Thus, higher ESA doses, which are often necessary to achieve high hemoglobin levels, are not beneficial, and possibly harmful, to diabetic patients receiving dialysis. Our findings support a Food and Drug Administration advisory recommending that the lowest possible ESA dose be used to treat hemodialysis patients.

Topics: Aged; Cardiovascular Diseases; Databases, Factual; Diabetic Cardiomyopathies; Diabetic Nephropathies; Erythropoietin; Female; Hematinics; Humans; Male; Medicare; Recombinant Proteins; Renal Dialysis; Risk Factors; United States

Anemia and inflammation are prevalent in diabetic patients with chronic kidney disease (CKD). The role of endogenous erythropoietin (EPO) in the pathophysiology of anemia in chronic diseases and its relationship to clinical outcomes remain uncertain. In this cohort study, we aimed to identify factors associated with endogenous EPO levels and investigate their relation to all-cause mortality.. Between 2004 and 2005, 215 patients with type 2 diabetes were enrolled. Exclusion criteria included stage renal disease ESRD and any form of anemia therapy. The association of EPO levels with clinical and laboratory variables was investigated by linear regression modeling. Predictors of all-cause mortality were evaluated by Cox proportional hazards analyses.. Patients (median age, 67 years; 52% men; median duration of diabetes, 10 years; median estimated GFR, 49 ml/min per 1.73 m²) were followed for up to 7.0 years. Forty-one patients died. Elevated EPO levels were independently associated with elevated C-reactive protein, low ferritin, and hypertension, in a multivariate model that also included age, cardiovascular disease, kidney function, albumin, cholesterol, and hemoglobin. Higher EPO levels were independently predictive for mortality, as were age, low levels of albumin, and cardiovascular disease.. In diabetic patients with CKD, elevated endogenous EPO levels were predictive for mortality and were related mainly to markers of inflammation, independent of kidney function, and despite low hemoglobin levels. Understanding the phenomenon of EPO resistance and iron dysregulation caused by inflammation is crucial for effective and safe treatment of anemia in patients with CKD.

Topics: Aged; Analysis of Variance; Anemia; Biomarkers; C-Reactive Protein; Chronic Disease; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Female; Germany; Humans; Inflammation; Inflammation Mediators; Kaplan-Meier Estimate; Linear Models; Longitudinal Studies; Male; Prognosis; Proportional Hazards Models; Risk Assessment; Risk Factors; Time Factors; Up-Regulation

The use of erythropoiesis-stimulating agents (ESAs) in patients with chronic kidney disease has declined as randomized controlled trials have demonstrated increased risk of cardiovascular complications and mortality without a marked benefit in quality of life. Several studies have suggested that exposure to high dosages of ESA, rather than raising of the hemoglobin concentration, explains this increased risk. Cotter and colleagues report that exposure to high dosages of ESA in patients with diabetes is associated with increased risk.

Topics: Diabetic Nephropathies; Erythropoietin; Female; Hematinics; Humans; Male; Renal Dialysis

Sustained high glucose impairs bone metabolism in patients with type 2 diabetes mellitus (T2DM). In this study, the relationship between glycemic control and bone metabolism was examined in male hemodialysis (HD) patients with T2DM. To avoid the effect of menstruation and the menstrual cycle, obesity, and glycosuria-induced hypercalciuria on bone metabolism, male anuric nonobese HD patients with T2DM (n = 42) were enrolled. Calcaneus stiffness index (SI) was determined using ultrasound after HD session. Casual plasma glucose (PG), glycated hemoglobin (HbA(1c)), and glycated albumin (GA) were measured before the HD session. In simple regression analysis, log PG (r = -0.333, P < .05) and log GA (r = -0.350, P < .05), but not log HbA(1c) (r = -0.134, P = .3985), exhibited significant and negative correlations with calcaneus SI. In multiple regression analysis including log BMI, log cCa x Pi product, and log PG, log PG was associated significantly in a negative manner with calcaneus SI, in addition to log cCa x Pi product. When log PG was replaced with log GA or log HbA(1c), log GA, but not log HbA(1c), emerged as a significant factor associated. The mechanism as to why HbA(1c) failed to associate could be explained by its false reduction by erythropoietin injection. The present study supported the notion of GA as an appropriate indicator for glycemic control in HD patients with T2DM. Furthermore, it is suggested that poor glycemic control might be a significant factor toward decreasing calcaneus SI in T2DM HD patients.

Topics: Aged; Blood Glucose; Bone and Bones; Calcaneus; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Glycated Hemoglobin; Glycoproteins; Humans; Male; Middle Aged; Recombinant Proteins; Regression Analysis; Renal Dialysis; Serum Albumin; Ultrasonography

Decrease of hemoglobin occurs in diabetic patients with nephropathy earlier than in nondiabetic patients, probably due to impaired synthesis of erythropoietin (EPO). Apart from EPO, insulin also stimulates erythropoiesis. We investigate whether there are differences between human insulin and insulin analogs in respect of their erythropoiesis stimulating effect.. Hemoglobin concentration and other factors which may influence hemoglobin levels were analyzed retrospectively in 203 type 1 diabetic patients with various degrees of kidney function. Eighty-six patients were treated with human insulin and 117 patients received an insulin analog.. Hemoglobin concentration did not differ in patients with normal renal function (creatinine clearance (CCL) >90 ml/min) treated with human insulin or insulin analogs. In patients with impaired renal function (CCL<90 ml/min) there was a significant decrease of hemoglobin with declining kidney function in patients treated with human insulin (r=0.463; p<0.003) but not in patients treated with insulin analog (r=-0.12; p=0.4). This result remained significant after adjustment of multiple potential confounders such as age, gender, diabetes duration, BMI, metabolic control, kidney function, chronic inflammation or use of ACE-inhibitors or AT1-blockers.. Insulin analogs mitigate the decline of hemoglobin in diabetic patients with impaired renal function. This might be due to a stimulating effect of insulin analogs on erythropoiesis via IGF receptor or a sustained activation of the insulin receptor.

Topics: Creatinine; Diabetic Nephropathies; Erythropoietin; Female; Hemoglobins; Humans; Hypoglycemic Agents; Insulin; Kidney Function Tests; Male

Topics: Anemia; Clinical Trials as Topic; Darbepoetin alfa; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Evidence-Based Medicine; Hematinics; Hemoglobins; Humans; Renal Insufficiency, Chronic; Safety

Topics: Anemia; Cardiovascular Diseases; Darbepoetin alfa; Diabetic Nephropathies; Double-Blind Method; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Placebos; Prospective Studies; Randomized Controlled Trials as Topic; Research Design; Risk Factors; Treatment Outcome

Anaemia occurs in 25% of people attending hospital diabetes clinics, but this may not be representative of all people with diabetes. We aimed to determine the prevalence of anaemia in a prospective population-based sample stratified by estimated glomerular filtration rate (eGFR) using the 4-point Modification of Diet in Renal Disease (MDRD) formula.. All 7331 patients on our district register were stratified by eGFR. Seven hundred and thirty were approached by letter on two occasions. Two hundred and thirty-four (32%) returned questionnaires and blood samples. Responders (R), non-responders (NR) and the whole cohort (C) were similar: mean +/- sd age R 61.7 +/- 12.7 years; NR 61.3 +/- 15.1 years; C 61.8 +/- 14.2 years; diabetes duration R 8.8 +/- 8.6 years; NR 8.2 +/- 7.9 years; C 7.5 +/- 7.8 years, Type 1 diabetes R 10.1%, NR 10.8%, C 9.4%. Anaemia was defined using World Health Organization criteria: haemoglobin < 13 g/dl for men, < 12 g/dl for women.. Previously undiagnosed anaemia was present in 15% of the whole group, 36% with eGFR < 60 ml/min per 1.73 m(2) and 9% of those with eGFR > 60 ml/min per 1.73 m(2). Anaemia was as a result of erythropoietin deficiency in 34%, abnormal haematinics in 40% and was unexplained in 26% of patients. Five per cent of the patients had anaemia below the treatment threshold of 11 g/dl.. The prevalence of unrecognized anaemia in population-based cohorts is lower than that in hospital-based studies. Current clinical surveillance in the UK is failing to detect anaemia in stage 3-5 chronic kidney disease (eGFR < 60 ml/min per 1.73 m(2)) and current guidelines will not detect 9% of diabetic patients with anaemia and an eGFR > 60 ml/min per 1.73 m(2).

Topics: Aged; Anemia; Diabetes Mellitus; Diabetic Nephropathies; England; Erythropoietin; Female; Glomerular Filtration Rate; Hematinics; Humans; Male; Middle Aged; Population Groups; Prevalence; Prospective Studies; Surveys and Questionnaires

Topics: Anemia; Diabetic Nephropathies; Diabetic Retinopathy; Erythropoietin; Humans

In patients with diabetes mellitus, hemoglobin A(1c) (A1C) is commonly interpreted as a measure of long-term glycemic control, reflecting a mean glucose level over the previous 2-3 months. Although some reports suggest that treatment with recombinant erythropoietin may affect A1C values in patients undergoing hemodialysis, we know of no evidence to support this interaction in patients with chronic renal insufficiency who are not undergoing hemodialysis. In addition, we know of no evidence specific to the treatment effect of epoetin alfa and/or darbepoetin alfa on A1C. We describe a 64-year-old man with diabetes, chronic kidney disease, and anemia who was treated consecutively with epoetin alfa and darbepoetin alfa and experienced a temporal reduction in A1C level to a nadir of 4.4%. Throughout approximately 3 years of treatment with these erythropoietin analogs, the patient's total daily dose of insulin was reduced in response to his decreasing A1C values, despite elevated blood glucose levels and the absence of patient-reported hypoglycemic events. Five months after the patient's erythropoietin therapy was discontinued, his A1C value increased to 8.8%, leading us to conclude that management of the insulin dose may have been different without the falsely lowered A1C levels. Use of the Naranjo adverse drug reaction probability scale indicated a probable association between this patient's reduced A1C levels and erythropoietin therapy. This case demonstrates that both epoetin alfa and darbepoetin alfa may artificially lower A1C levels in a patient with diabetes who is not undergoing dialysis, and therefore this finding can be interpreted as a class effect. Clinicians should be aware of factors that affect A1C values, specifically erythrocyte life span. In patients receiving erythropoietin, therapeutic decisions should be based on A1C and glucose levels, as well as patient symptoms suggestive of hypo- or hyperglycemia, to avoid therapy changes that could complicate disease management.

Topics: Anemia; Darbepoetin alfa; Diabetes Mellitus; Diabetic Nephropathies; Diagnostic Errors; Drug Therapy, Combination; Epoetin Alfa; Erythropoietin; Glycated Hemoglobin; Hematinics; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

Topics: Aged; Aged, 80 and over; Anemia; Arteriovenous Shunt, Surgical; Catheterization; Comorbidity; Diabetic Nephropathies; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Length of Stay; Male; Middle Aged; Obesity; Renal Dialysis; Retrospective Studies

Sialic acids (SA) located in erythrocyte membranes (EM) play an important role in the survival of circulating red blood cells.. The aim of the present study was to evaluate the SA content in EM obtained from patients on chronic hemodialysis (HD) and to examine the relationships between SA and hematological parameters. Moreover, the effects of HD, treatment with human recombinant erythropoetin (epoetin), and some biochemical and hematological parameters were analyzed.. The total protein (TP) and total sialic acids (TSA), together with SA bound with proteins (PBSA) and lipids (LBSA), were determined in EM of 72 HD patients and compared with the control group of healthy individuals (CG; n=25). The adequacy of HD, weekly epoetin doses, mean arterial pressure (MAP), comorbidity score, serum levels of albumin, intact parathyroid hormone (iPTH), low-density lipoprotein cholesterol (LDL-cholesterol) were estimated in patients.. Compared to the CG, HD patients had higher levels of TSA (p < 0.001), PBSA (p < 0.001), LBSA (p <0.001) and decreased TP levels (p < 0.001). The TP (p < 0.045) and PBSA (p < 0.05) levels were higher in patients with diabetic nephropathy than in non-diabetic HD patients. In HD patients there were correlations between TSA, PBSA in EM and some hematologial parameters. There were no relationships between the TSA, PB content in EM and variables such as HD, epoetin treatment, MAP comorbidity score, albumin, iPTH, and LDL-cholesterol.. The results of the current study demonstrated there are significantly higher levels of TSA, PBSA, LBSA and lower TP levels in EM obtained from HD patients compared to healthy subjects. Comorbidity score, epoetin and HD treatment, MAP, iPTH, albumin and LDL cholesterol had no influence on SA levels in EM of patients.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Chronic Disease; Comorbidity; Diabetic Nephropathies; Erythrocyte Membrane; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; N-Acetylneuraminic Acid; Recombinant Proteins; Renal Dialysis; Smoking

To investigate the relationship between Erythropoietin (EPO) and 1,25-dihydroxyvitamin D levels, and tubular damage in patients with diabetes mellitus (DM) without persistent microalbuminuria.. We measured serum EPO and 1,25-dihydroxyvitamin D levels and tubular injury markers such as urinary N-acetyl-beta-d-glucosaminidase (NAG) and retinol binding protein (RBP) levels in 41 non-diabetic controls, 40 patients with Type 1 and 40 with Type 2 DM.. Median serum EPO levels were lower in Type 1 (2.57 mIU/ml: p<0.001) and Type 2 DM (5.69 mIU/ml: p=0.044) than in controls (8.76 mIU/ml), though haemoglobin levels did not differ. Median 1,25-dihydroxyvitamin D levels were lower in Type 1 (41.0 pmol/l: p=0.001) and Type 2 DM (41.8 pmol/l: p=0.035) than in controls (56.1 pmol/l), though serum creatinine, calcium, phosphate and PTH levels did not differ. Median RBP excretion was higher in Type 2 DM (0.35 mg/l vs. 0.23 mg/l: p=0.013) than in controls. Median NAG excretion was higher in Type 1 DM (1,079 micromol/h vs.1,030 micromol/h: p=0.048) compared to controls.. Tubulo-interstitial damage with low levels of EPO and 1,25-dihydroxyvitamin D occurs early in Type 1 and Type 2 DM before persistent microalbuminuria.

Topics: Adult; Albuminuria; Blood Glucose; Blood Pressure; Creatinine; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Female; Glycated Hemoglobin; Humans; Kidney Tubules; Male; Middle Aged; Reference Values; Vitamin D; Young Adult

Topics: Anemia; Cardiovascular Diseases; Darbepoetin alfa; Diabetic Nephropathies; Erythropoiesis; Erythropoietin; Hematinics; Humans; Kidney Failure, Chronic; Treatment Outcome

Our aim was to evaluate red blood cell (RBC) membrane protein composition in chronic kidney disease (CKD) stage 5 patients under haemodialysis (HD) and recombinant human erythropoietin (rhEPO) therapy, and its linkage to rhEPO hyporesponsiveness. We evaluated in 63 CKD stage 5 patients (32 responders and 31 non-responders to rhEPO therapy) and in 26 healthy controls RBC count, haematocrit, haemoglobin concentration, haematimetric indices, reticulocyte count, reticulocyte production index, RBC osmotic fragility test and membrane protein analyses. CKD stage 5 patients presented significant changes in membrane protein composition, namely a reduction in spectrin, associated to altered protein 4.1/spectrin and spectrin/band 3 ratios. Non-responder CKD stage 5 patients were more anaemic, with more microcytic and anisocytic RBCs, than responders; significantly altered ankyrin/band 3 and spectrin/ankyrin ratios were also observed. CKD stage 5 patients under HD are associated with an altered protein membrane structure, which seems to the disease itself and/or to the interaction with HD membranes.

Topics: Aged; Anemia; Anion Exchange Protein 1, Erythrocyte; Ankyrins; Blood Proteins; Darbepoetin alfa; Diabetic Nephropathies; Drug Resistance; Epoetin Alfa; Erythrocyte Membrane; Erythropoietin; Female; Folic Acid; Humans; Iron; Kidney Failure, Chronic; Male; Membrane Proteins; Membranes, Artificial; Middle Aged; Oxidation-Reduction; Recombinant Proteins; Renal Dialysis; Spectrin

Significant morbidity and mortality among patients with diabetes mellitus result largely from a greatly increased incidence of microvascular complications. Proliferative diabetic retinopathy (PDR) and end stage renal disease (ESRD) are two of the most common and severe microvascular complications of diabetes. A high concordance exists in the development of PDR and ESRD in diabetic patients, as well as strong familial aggregation of these complications, suggesting a common underlying genetic mechanism. However, the precise gene(s) and genetic variant(s) involved remain largely unknown. Erythropoietin (EPO) is a potent angiogenic factor observed in the diabetic human and mouse eye. By a combination of case-control association and functional studies, we demonstrate that the T allele of SNP rs1617640 in the promoter of the EPO gene is significantly associated with PDR and ESRD in three European-American cohorts [Utah: P = 1.91 x 10(-3); Genetics of Kidneys in Diabetes (GoKinD) Study: P = 2.66 x 10(-8); and Boston: P = 2.1 x 10(-2)]. The EPO concentration in human vitreous body was 7.5-fold higher in normal subjects with the TT risk genotype than in those with the GG genotype. Computational analysis suggests that the risk allele (T) of rs1617640 creates a matrix match with the EVI1/MEL1 or AP1 binding site, accounting for an observed 25-fold enhancement of luciferase reporter expression as compared with the G allele. These results suggest that rs1617640 in the EPO promoter is significantly associated with PDR and ESRD. This study identifies a disease risk-associated gene and potential pathway mediating severe diabetic microvascular complications.

Topics: Alleles; Animals; Cell Line; Cohort Studies; Diabetic Nephropathies; Diabetic Retinopathy; Erythropoietin; Gene Expression Regulation; Genes, Reporter; Genetic Predisposition to Disease; Haplotypes; Humans; Kidney; Luciferases; Mice; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Retina; RNA, Messenger

Diabetic patients with nephropathy show a decline of hemoglobin even at a moderate degree of kidney dysfunction which may impair cardiovascular prognosis. As main reason a disturbed synthesis of erythropoietin (EPO) has been suggested, the pathogenesis, however, is unclear. The clinical significance of metabolic control for the hemoglobin and EPO levels was investigated.. The following parameters were determined in 185 type 1 diabetic patients: hemoglobin, HbA1c, calculated creatinine clearance, urinary albumin/creatinine ratio, lipids, high-sensitive C-reactive protein (hsCRP). Serum concentration of EPO was determined in 56 consecutive patients with renal dysfunction.. Hemoglobin concentration decreased with declining renal function. Patients were stratified according to median HbA1c level (7.4%) in those with better (HbA1c < 7.4%) and worse metabolic control (HbA1c > 7.4%). In patients with kidney dysfunction, the group with better metabolic control showed higher hemoglobin concentrations than the group with worse metabolic control: 13.6 versus 12.6 g/dl at creatinine clearance < 60 ml/min (p = 0.02). Linear regression analysis revealed metabolic control aside from kidney function, gender, hsCRP and use of ACE inhibitiors as a significant influencing factor of hemoglobin concentration. In patients with renal dysfunction, EPO levels were higher in the group with better than worse metabolic control (13.0 vs. 9.8 U/l).. The decline of hemoglobin in diabetic patients with renal dysfunction is mitigated in case of good metabolic control, possibly due to higher EPO concentrations. The results emphasize the clinical significance of a good metabolic control in diabetic patients with nephropathy.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Body Mass Index; Cholesterol; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Erythropoietin; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Regression Analysis; Triglycerides

Anaemia is a common complication of renal impairment. It has been suggested that renal failure secondary to diabetes is associated with more severe anaemia, but this has not been clearly substantiated in the published literature. To clarify this, we undertook a single centre, retrospective study to identify the impact of diabetes on anaemia associated with renal impairment.. Information on clinical, biochemical and haematological parameters of 2,052 stable ambulatory patients attending a single tertiary referral renal unit was collected. The impact of diabetic kidney disease on haemoglobin levels at all degrees of renal impairment was studied by comparison with patients with non-diabetic kidney disease after correcting for other commonly associated variables that influence anaemia in patients with renal impairment.. Linear regression analysis showed lower haemoglobin in patients with diabetic kidney disease (p < 0.01). At chronic kidney disease (CKD) stages 3, 4 and 5, mean haemoglobin levels in patients with diabetic kidney disease compared with those in patients with non-diabetic kidney disease were 129.5 vs 136.9 g/l (p < 0.001), 120.5 vs 126.9 g/l (p < 0.001) and 107.1 vs 115.9 g/l (p < 0.01), respectively. At CKD stage 4 and 5 the two groups were comparable for ferritin, plasma intact parathyroid hormone levels, ACE inhibitor use and length of follow-up by a nephrologist.. Diabetic kidney disease is associated with lower haemoglobin in comparison with non-diabetic kidney disease, especially at GFR <60 ml/min.

Topics: Anemia; Diabetes Mellitus; Diabetic Nephropathies; Disease Progression; Erythropoietin; Female; Hemoglobins; Humans; Kidney Diseases; Male; Middle Aged; Regression Analysis; Retrospective Studies

The significance of glycated albumin (GA), compared with casual plasma glucose (PG) and glycated hemoglobin (HbA(1c)), was evaluated as an indicator of the glycemic control state in hemodialysis (HD) patients with diabetes. The mean PG, GA, and HbA(1c) levels were 164.5 +/- 55.7 mg/dl, 22.5 +/- 7.5%, and 5.85 +/- 1.26%, respectively, in HD patients with diabetes (n = 538), which were increased by 51.5, 31.6, and 17.7%, respectively, compared with HD patients without diabetes (n = 828). HbA(1c) levels were significantly lower than simultaneous PG and GA values in those patients in comparison with the relationship among the three parameters in patients who had diabetes without renal dysfunction (n = 365), as reflected by the significantly more shallow slope of regression line between HbA(1c) and PG or GA. A significant negative correlation was found between GA and serum albumin (r = -0.131, P = 0.002) in HD patients with diabetes, whereas HbA(1c) correlated positively and negatively with hemoglobin (r = 0.090, P = 0.036) and weekly dose of erythropoietin injection (r = -0.159, P < 0.001), respectively. Although PG and GA did not differ significantly between HD patients with diabetes and with and without erythropoietin injection, HbA(1c) levels were significantly higher in patients without erythropoietin. Categorization of glycemic control into arbitrary quartile by HbA(1c) level led to better glycemic control in a significantly higher proportions of HD patients with diabetes than those assessed by GA. Multiple regression analysis demonstrated that the weekly dose of erythropoietin, in addition to PG, emerged as an independent factor associated with HbA(1c) in HD patients with diabetes, although PG but not albumin was an independent factor associated with GA. In summary, it is suggested that GA provides a significantly better measure to estimate glycemic control in HD patients with diabetes and that the assessment of glycemic control by HbA(1c) in these patients might lead to underestimation likely as a result of the increasing proportion of young erythrocyte by the use of erythropoietin.

Topics: Anemia; Blood Glucose; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Glycated Hemoglobin; Glycated Serum Albumin; Glycation End Products, Advanced; Glycosylation; Humans; Logistic Models; Multivariate Analysis; Regression Analysis; Renal Dialysis; Serum Albumin

Topics: Aged; Anemia; Copper; Diabetic Nephropathies; Drug Resistance; Enteral Nutrition; Erythropoietin; Female; Humans; Neutropenia; Renal Dialysis

The present study investigated the relationship between hemoglobin (Hb) levels and autonomic failure using a sensitive marker, coefficient of variation of R-R intervals in electrocardiogram (CVR-R) in order to clarify a cause of normocytic normochromic anemia in type 1 diabetic patients without overt nephropathy. We recruited 46 patients with type 1 diabetes and measured creatinine clearance (Ccr), HbA1c, albuminuria, Hb levels and CVR-R of all patients. In addition, the status of diabetic retinopathy and neuropathy were also evaluated. Serum erythropoietin (EPO), Fe, total iron binding capacity, lactate dehydrogenase, total bilirubin levels and number of reticulocytes and mean corpuscular volume were also measured to distinguish types of anemia. To survey the statistical correlation existing between Hb and body mass index (BMI), Ccr, HbA1c, albuminuria or retinopathy, multiple regression analysis was performed. Serum EPO, Fe, TIBC, LDH and TB levels and number of reticulocytes and MCV were within normal limits. Multiple regression analysis disclosed that HbA1c, nephropathy evaluated by albuminuria and Ccr, and retinopathy has no concern with Hb level. There is only significant relationship between Hb levels and CVR-R. Similar results were obtained even if we analyzed a group of male and female separately. We conclude that CVR-R has the strong relationship on anemia without overt nephropathy in type 1 diabetes, indicating that autonomic failure contributes on the progression of anemia via a poor response of EPO to anemia.

Topics: Adult; Aged; Albuminuria; Anemia; C-Peptide; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Electrocardiography; Erythropoietin; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Sensitivity and Specificity

This study explored the tissue-protective properties of the continuous erythropoietin receptor activator (CERA) in an experimental model of (nonischemic) diabetic kidney injury (i.e., the db/db mouse). Mice were randomly treated with placebo (n = 25), low-dosage CERA (n = 25), and high-dosage CERA (n = 25). Also studied were 25 nondiabetic db/m mice. Hematocrit was comparable in placebo and low-dosage CERA-treated mice but increased significantly with high-dosage CERA (P < 0.01 versus both). Significantly reduced expression of TGF-beta, vascular endothelial growth factor, and collagen IV was found in glomeruli and the tubulointerstitial area with CERA treatment, and these beneficial molecular effects were clearly dosage dependent (both P < 0.05 versus placebo). Similarly, CERA treatment caused a dosage-dependent increase in p-Akt, nephrin, and perlecan tissue expression (all P < 0.05 versus placebo). However, the accelerated mesangial expansion that was observed in placebo-treated db/db mice (versus db/m controls) was significantly reduced only in low-dosage CERA-treated mice (P < 0.01). Moreover, albuminuria was significantly reduced in low- but not high-dosage CERA-treated mice compared with placebo treatment (P < 0.05). In an ancillary study, phlebotomy was performed in high-dosage CERA-treated db/db mice to keep hematocrit within normal (baseline) levels. This procedure resulted in significantly (P < 0.05) less albuminuria as compared with high-dosage CERA-treated mice without phlebotomy, thus preserving the tissue-protective potential of CERA. Long-term CERA treatment has beneficial dosage-dependent effects on molecular pathways of diabetic kidney damage. Low-dosage CERA does not affect hematocrit and therefore may be a feasible method of tissue protection in this setting.

Topics: Animals; Diabetic Nephropathies; Erythropoietin; Immunohistochemistry; Kidney; Mice; Polyethylene Glycols; Recombinant Proteins

We designed a study to evaluate whether erythropoietin (EPO), given to patients on continuousambulatory peritoneal dialysis (CAPD) both with and without diabetes mellitus (DM), influences tissue factor (TF), tissue factor pathway inhibitor (TFPI) and oxidative stress (SOX).. We assessed TF, TFPI and a marker of SOX, Cu/Zn superoxide dismutase (Cu/Zn SOD) in 16 diabetic CAPD patients (8 with EPO therapy), 39 non-diabetic CAPD patients (23 with EPO therapy) and 18 healthy controls.. Patients on CAPD showed a significant increase in plasma concentrations of TF, TFPI and Cu/Zn SOD as compared to controls. EPO therapy was related to a decrease in these parameters in diabetic patients, whereas in non-diabetic patients EPO did not affect their levels. In diabetics, TF was positively correlated with TFPI and Cu/Zn SOD levels. There was a positive relationship between TFPI and Cu/Zn SOD, whereas inverse relationships existed between TFPI and haemoglobin, haematocrit (Ht), EPO dose and triglycerides. Multivariate analysis showed that independent variables linked to TFPI levels in diabetic patients were Cu/Zn SOD, Ht and EPO dose.. Our data suggest that correction of anaemia with EPO therapy is associated with a significant decrease in TF, TFPI and SOX in diabetic CAPD patients.

Topics: Adult; Aged; Diabetic Nephropathies; Erythropoietin; Female; Humans; Male; Middle Aged; Oxidative Stress; Peritoneal Dialysis; Recombinant Proteins; Signal Transduction; Thromboplastin

Anemia of renal failure is primarily a problem of decreased RBC production due to erythropoietin deficiency. RBC survival is also reduced, perhaps due to decreased RBC deformability. This study measured blood viscosity over a range of shear rates in erythropoietin-treated patients on hemodialysis (HD), and compared the findings to matched patients with chronic renal insufficiency (CRI) and healthy controls.. Four groups (control, CRI, non-diabetic HD, and diabetic HD) of 9 matched subjects were recruited. Blood viscosity was measured using a cone-plate viscometer over a variety of shear rates (11 to 225 s(-1)).. Control subjects had lower viscosity values throughout all shear rates when compared to the 3 renal disease groups (P value=0.039). A trend was observed to higher levels of renal function being associated with decreased blood viscosity in patients with CRI.. Patients with kidney disease have increased blood viscosity at all shear rates. This may be related to changes in RBC shape and decreased deformability in patients with kidney disease, independent of HD- or DM-status. This may have implications for strategies to treat anemia in these patients.

Topics: Aged; Analysis of Variance; Blood Viscosity; Case-Control Studies; Diabetic Nephropathies; Erythrocyte Aging; Erythrocyte Deformability; Erythrocytes; Erythropoietin; Female; Hemorheology; Humans; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Renal Insufficiency, Chronic

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.

Topics: Adult; Aged; Aged, 80 and over; Albuminuria; Anemia; Biological Availability; Blood Pressure; C-Reactive Protein; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Erythropoietin; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Iron; Iron Deficiencies; Kidney; Male; Middle Aged

This case-control study was undertaken in 75 subjects categorized into 3 equal groups (A: diabetic subjects with macroalbuminuria, B: non-diabetic subjects with macroalbuminuria and C; control subjects). Serum erythropoietin (EPO) was estimated and analyzed in relation to hemoglobin levels in the three groups. The Pearson's coefficient (r) for hemoglobin and log natural EPO was significant for groups A (0.01), B (0.05) and C (0.01). Linear regression analysis of hemoglobin and log natural EPO showed significant differences between the study and control groups; however no significant difference could be demonstrated amongst the study groups. Hence, it was concluded that an inadequate EPO production occurs in renal failure, which accounts for the anaemia and diabetes does not confer an additional discrepancy in this mechanism over non-diabetic macroalbuminuria.

Topics: Adult; Aged; Albuminuria; Anemia; Case-Control Studies; Diabetic Nephropathies; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged

Topics: Albuminuria; Anemia; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Europe; Humans; Practice Guidelines as Topic; Prognosis; Quality of Life

The porphyrias are inherited or acquired metabolic disorders caused by a partial deficiency in one of the enzymes of the heme biosynthetic pathway. Eight enzymes are utilized in the synthesis of heme. An enzyme defect in one of the last seven enzymes will result in one of the seven different forms of porphyria, some of which have similar signs and symptoms. This article describes six diabetic, azotemic patients with no prior history of porphyria, who developed a syndrome similar to acute intermittent porphyria after initiation of treatment with erythropoietin. One of the patients developed the syndrome predialysis, whereas the remaining patients were on maintenance hemodialysis. The symptoms varied but all resolved when erythropoietin was discontinued and reappeared in four cases when erythropoietin was restarted. In all of the patients, the enzyme aminolevulinic acid-dehydratase (ALA-D) was low and the uroporphyrinogen synthase was normal. This enzyme abnormality suggests an acquired form of delta-aminolevulinic acid dehydratase porphyria (ADP). Lead toxicity, succinylacetone, and zinc deficiency are known to depress ALA-D, but these conditions were not present. The development of the acute porphyria syndrome while the patients were receiving pharmacological doses of erythropoietin, which resolved when the drug was stopped, suggests that by stimulating heme synthesis, erythropoietin may unmask an enzyme deficiency resulting in the clinical expression of ADP. The patients responded favorably to a regimen that included discontinuation of erythropoietin, tight blood sugar control, maintaining the hematocrit above 30%, and a KT/V, a measure of dialysis adequacy, of 1.5 in the hemodialysis group. Plasmapheresis accelerated the recovery when used in two patients.

Topics: Adult; Aged; Diabetic Nephropathies; Erythropoietin; Female; Humans; Male; Middle Aged; Nephrosclerosis; Plasmapheresis; Porphobilinogen Synthase; Porphyria, Erythropoietic; Renal Dialysis

Recombinant erythropoietin upregulates the expression of the vascular endothelial growth factor (VEGF) receptors, Flt-1 (VEGFR-1) and KDR/Flk-1 (VEGFR-2), in endothelial cells. The integrity of the VEGF system seems to be crucial for the regulation of endothelial permeability and thus for the avoidance of renal protein leakage. As albuminuria/proteinuria is a hallmark of diabetic nephropathy, we examined cross-sectionally in 35 type 1 and 37 type 2 diabetic patients with various degrees of renal dysfunction and albuminuria whether there was an interrelationship between intrinsic erythropoietin (EPO) and VEGF/Flt-1.. In patients with plasma creatinine values < or =1.5 (n = 53) or >1.5 mg/dL (n = 19), the mean serum EPO was 5.6 +/- 4.4 and 10.2 +/- 7.0 mU/mL (P = 0.02), respectively. In the two groups, urinary and serum VEGF(165) concentrations were similarly distributed (mean 94.3 +/- 91.8 vs 108 +/- 72.2 ng/L and 91.7 +/- 76.8 vs 91.9 +/- 74.9 ng/L, respectively; both P = NS). The mean urinary Flt-1 for the two groups amounted to 0.14 +/- 0.35 and 0.51 +/- 0.93 ng/mL (P = 0.045), respectively. No correlation between VEGF or Flt-1 and EPO was apparent.. Our data suggest that in vivo EPO does not affect the functionality and/or production of components of the VEGF/Flt-1 system in diabetics with normal or reduced renal function.

Topics: Adult; Aged; Aged, 80 and over; Albuminuria; Anemia; Cross-Sectional Studies; Diabetic Nephropathies; Erythropoietin; Female; Humans; Kidney; Male; Middle Aged; Renal Insufficiency; Solubility; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1

Diabetes mellitus is associated with an increased prevalence of anemia, particularly in patients with nephropathy. We undertook this survey to determine the relationship between anemia and the renal production of erythropoietin in patients with diabetes mellitus.. The clinical data of 722 patients were obtained, including markers of diabetic complications. Erythropoietin levels were measured in the same samples. Patients with a full blood cell count, iron indexes, and renal function within the normal range (n = 151) were used to define the reference range for this population. Anemic patients who had erythropoietin levels within this range were defined as having an "inappropriate erythropoietin response to anemia.". Of the 722 patients, 168 (23.3%) had anemia, of whom 130 (77.4%) had erythropoietin levels inappropriately within the normal range. Although 55.4% of anemic patients had moderate renal impairment, erythropoietin levels were also inappropriately low in 69.2% of anemic patients with normal renal function. However, most of these patients (17 of 26) had diabetic kidney disease, as denoted by albuminuria.. The failure to produce erythropoietin in response to a declining hemoglobin level is a common contributor to anemia in patients with diabetes mellitus. This seems to be a manifestation of diabetic kidney disease, in the presence or absence of renal impairment.

Topics: Aged; Albuminuria; Anemia; Diabetes Mellitus; Diabetic Nephropathies; Erythropoietin; Female; Follow-Up Studies; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney; Male; Middle Aged; Multivariate Analysis

We previously showed that nutritional protein concentrations were predictive of outcome, whereas variables reflecting body composition and dialysis dose were not, in a 30-month prospective follow-up of 1,610 hemodialysis patients. Information on dialysis membrane and erythropoietin use had to be evaluated in an additional follow-up.. A subset of 650 patients from the initial cohort of 1,610 was analyzed for survival in a 2-year extension of follow-up. Detailed data were collected: demographics; cause of renal failure; time on dialysis therapy; type of membrane; erythropoietin treatment; body mass index (BMI); predialysis albumin, prealbumin, and bicarbonate levels; and outcome. Normalized protein catabolic rate (nPCR), dialysis adequacy, and lean body mass were computed from predialysis and postdialysis urea and creatinine values.. Patient characteristics were age of 61 +/- 16 years, 58% men, BMI of 22.7 +/- 4.4 kg/m2 , time on dialysis therapy of 102 +/- 73 months, and 8.8% had diabetes. Dialysis parameters were duration of 247 +/- 31 minutes, Kt/V of 1.4 +/- 0.3, and nPCR of 1.2 +/- 0.3 g/kg/d. Albumin level was 3.73 +/- 0.53 g/dL (37.3 +/- 5.3 g/L), and prealbumin level was 31 +/- 8 mg/dL. The survival rate was 78.7% after 2 years. Survival was influenced by age, presence of diabetes, use of high-flux membrane, and serum albumin level, but not other variables, including Kt/V and prealbumin level. Two-year variations in values for urea, creatinine, and weight were predictive of survival in univariate, but not multivariate, analyses.. In patients on dialysis therapy for a long period, better survival was observed when high-flux dialysis membranes were used.

Topics: Aged; Bicarbonates; Body Composition; Body Mass Index; Cardiovascular Diseases; Cause of Death; Cholesterol; Comorbidity; Creatinine; Diabetic Nephropathies; Erythropoietin; Female; Follow-Up Studies; Humans; Infections; Kidney Failure, Chronic; Life Tables; Male; Membranes, Artificial; Middle Aged; Neoplasms; Permeability; Prealbumin; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; Protein-Energy Malnutrition; Renal Dialysis; Serum Albumin; Survival Analysis; Time Factors; Urea

Patients with diabetes commonly have a greater degree of anemia for their level of renal impairment than those presenting with other causes of renal failure. To clarify the contribution and differing roles of diabetes and nephropathy in the development of anemia in diabetic patients, we examined the hematologic and hematinic parameters of diabetic patients without nephropathy.. The study group was comprised of 62 patients with type 2 diabetes who had been followed for a median of 7 years. For the study, these patients had additional samples taken during their annual routine blood testing for the measurement of extra parameters, including serum ferritin, serum erythropoietin (Epo) levels, and the percentage of reticulocytes. These measurements were combined with the routine parameters Hb, hematocrit, HbA(1c), and glomerular filtration rate.. In all, 8 of the 45 male patients (17.8%) and 2 of the 17 female patients (11.8%) were classified as anemic (Hb <13g/dl and <11.5g/dl, respectively). Although only a small number of the patients had anemia as defined by normal values, a retrospective analysis of individual patients over time revealed a sustained though small decrease in Hb from initial presentation. A statistically significant difference in Epo levels (P = 0.016 by Kruskal-Wallis test) was observed from the group with the lowest (Hb < or =11.5) to that with the highest (Hb > or =14.5) Hb values, with a median Epo value of 37 (interquartile range 24-42) vs. 13 (9-15) IU/l, respectively. In contrast, there was no evidence of an increased reticulocyte response to higher levels of Epo (r = 0.134 [Pearsons], P = 0.36). Reticulocyte counts ranged from 44 (38-57) to 76.5 (56-83) in the lowest and highest Hb groups, respectively.. Although only a small number of subjects in the group were overtly anemic, all subjects had an ongoing, small but significant decrease in Hb since presentation. This study of diabetic patients without nephropathy shows an expected increase in Epo production in response to lowering levels of Hb but without the expected reticulocyte response.

Topics: Adult; Anemia; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Female; Ferritins; Glomerular Filtration Rate; Glycated Hemoglobin; Hematocrit; Hemoglobins; Humans; Male; Middle Aged; Reticulocyte Count; Retrospective Studies

We describe here four male patients with long-term and poorly controlled type 2 diabetes mellitus. They shared many common characteristic complications, such as severe autonomic neuropathy, proliferative retinopathy and normocytic normochromic anemia without progressive renal failure and macroangiopathy. They also showed normal levels of erythropoietin and reticulocyte, which was considered relatively low. The coefficient of variation of R-R, a useful method to estimate autonomic failure, showed markedly advanced autonomic neuropathy in all four patients. Coronary angiography did not reveal stenosis, anomaly or collateral vessels, but left ventriclography showed diffuse or partial hypokinesis. Massive proteinuria, high urinary levels of N-acetyl-beta-D-glucosamidase (NAG) and beta2-microglobulin (beta2M) were detected, though creatinine clearance (Ccr) was not so deteriorated. Treatment with recombinant erythropoietin increased their hemoglobin and hematocrit levels. These common points have a possibility to be brought about by tubulointerstitial damage and microangiopathy may be involved in it.

Topics: Adult; Anemia; Autonomic Nervous System Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Erythropoietin; Humans; Male; Middle Aged; Reticulocyte Count

Topics: Anemia; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Female; Humans; Renal Insufficiency

The view that hemoglobin levels in peritoneal dialysis patients should be maintained at 11 to 12 g/dL is based largely on the results of studies in hemodialysis patients.. We studied 13,974 erythropoietin-treated Medicare patients who initiated peritoneal dialysis between 1991 and 1998. Mean hemoglobin levels for the first 6 months of the study and, subsequently, time to first hospitalization and death during a 2-year follow-up were determined.. The percentages of patients with hemoglobin levels of <10, 10 to 10.9, 11 to 11.9, and >/=12 g/dL were 24.6%, 40.6%, 27.6%, and 7.2%, respectively. First-hospitalization and death rates, respectively, were 109.5 and 21.6 per 100 patient-years in nondiabetic patients, and 152.9 and 31.5 in diabetic patients. In nondiabetic patients, adjusted hospitalization hazard ratios for hemoglobin levels of <10, 10 to 10.9, 11 to 11.9 (reference category), and >/=12 g/dL were 1.29 (P < 0.0001), 1.15 (P < 0.0001), 1, and 0.98 (NS), respectively. The corresponding adjusted mortality hazard ratios were 1.43 (P < 0.0001), 1.13 (P < 0.05), 1, and 1.14 (NS). In diabetic patients, hazard ratios of 1.26 (P < 0.0001), 1.07 (NS), 1, and 0.82 (P < 0.01) were observed for hospitalization, and 1.34 (P < 0.0001), 1.18 (P < 0.01), 1, and 0.92 (NS) for mortality.. In peritoneal dialysis patients, anemia is associated with hospitalization and mortality in a manner supporting current Kidney Dialysis Outcomes Quality Initiative (K/DOQI) hemoglobin targets. In addition, hemoglobin levels of >/=12 g/dL are associated with lower hospitalization rates in diabetic patients.

Topics: Adult; Aged; Anemia; Cohort Studies; Diabetic Nephropathies; Erythropoietin; Female; Hemoglobins; Hospitalization; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis; Recombinant Proteins; Retrospective Studies; United States

Topics: Aged; Diabetic Nephropathies; Epoetin Alfa; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis

Topics: Anemia; Anemia, Sickle Cell; Arteriovenous Shunt, Surgical; Blood Transfusion; Chronic Disease; Darbepoetin alfa; Diabetic Nephropathies; Disease Progression; Erythropoiesis; Erythropoietin; Europe; Evidence-Based Medicine; Ferritins; Hematocrit; Hematologic Tests; Hemoglobinometry; Hemoglobins; Hemorheology; Humans; Iron; Kidney Failure, Chronic; Nutritional Physiological Phenomena; Oxidative Stress; Quality of Life; Recombinant Proteins; Red-Cell Aplasia, Pure; Renal Dialysis; Review Literature as Topic; Transferrin; Treatment Failure; Vitamin E

Erythropoietin (EPO)-deficient anaemia has been described in Type 1 diabetic patients with both severe autonomic neuropathy (AN) and proteinuria. This study was aimed at distinguishing between the effects of AN and nephropathy on haemoglobin and EPO levels in Type 2 diabetic patients at an early stage of diabetic nephropathy.. In 64 Type 2 diabetic patients (age 52 +/- 10 years, duration 10 +/- 9 years) without overt nephropathy and other causes of anaemia or EPO deficit, we assessed cardiovascular tests of AN, 24-h blood pressure (BP) monitoring, urinary albumin excretion rate (UAE), a full blood count, and serum EPO.. Although the Type 2 diabetic patients with AN did not show differences in haemoglobin and EPO when compared with patients without AN, the presence of haemoglobin < 13 g/dl was associated with the presence of AN (chi(2)= 3.9, P < 0.05) and of postural hypotension (chi(2)= 7.8, P < 0.05). In a multiple regression analysis including as independent variables gender, body mass index, duration of diabetes, smoking, creatinine, 24-h UAE, 24-h diastolic BP, ferritin, erythrocyte sedimentation rate, and autonomic score, we found that the only variables independently related to haematocrit were autonomic score, ferritin and erythrocyte sedimentation rate. Finally, the physiological inverse relationship between EPO and haemoglobin present in a control group of 42 non-diabetic non-anaemic subjects was completely lost in Type 2 diabetic patients. The slopes of the regression lines between EPO and haemoglobin of the control subjects and the Type 2 diabetic patients were significantly different (t = 14.4, P < 0.0001).. This study documents an early abnormality of EPO regulation in Type 2 diabetes before clinical nephropathy and points to a contributory role of AN in EPO dysregulation.

Topics: Adult; Aged; Albuminuria; Autonomic Nervous System Diseases; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Neuropathies; Erythropoietin; Female; Hemoglobins; Humans; Hypotension, Orthostatic; Male; Middle Aged

Diabetes is known to be a risk factor for the severity of anemia in non-dialyzed patients with renal failure. The aim of this study was to evaluate differences in hemoglobin (Hb) response to erythropoietin (EPO) in diabetic and nondiabetic patients on chronic hemodialysis (CHD). Sixty-four patients on CHD were included in the study: 24 type 2 diabetics (mean age, 59+/-11 years; 10 men, 14 women) and 40 nondiabetics (age, 53+/-14 years; 21 men, 19 women). All patients received a fixed dose of 50 mg ferric saccharate and EPO per week, dosed individually to achieve a target Hb level of 12 g/dl. Hb levels, ferritin, transferrin saturation (TSAT), EPO requirement (IU/kg/week), folic acid, vitamin B12 and C-reactive protein (CRP) were measured every two months. Additionally, the incidence of infectious diseases during the observation period of six months was evaluated, and a univariate correlation analysis of CRP and EPO requirements was performed in both groups. Patients with and without diabetes were divided into two groups each: those with normal CRP and those with elevated CRP. The EPO requirements of these groups were compared. Under identical iron substitution the mean Hb level increased more, but not significantly, in non-diabetic patients than in diabetic patients. After 6 months the mean Hb levels were 12.1+/-1.2 versus 11.5+/-1.2 g/dl (NS), although the actual EPO requirement was higher in diabetic than in non-diabetic subjects (244+/-122 versus 183+/-118 IU/kg/week; p<0.05). CRP after 6 months was significantly higher in diabetic than in non-diabetic patients (2.6+/-2.2 versus 1.5+/-1.3 mg/dl; p<0.05), as was the incidence of infectious disease (n/patient/month) (0.24 versus 0.08; p<0.05). The correlation coefficient between CRP and EPO requirements was statistically significant in both diabetic (r=0.547 p<0.01) and non-diabetic subjects (r=0.577; p<0.001). All other laboratory indices were similar in both groups. In the diabetic patients with normal CRP (n=6) the Hb levels achieved after six months were similar to those of non-diabetic patients (n=10) with normal CRP (11.9+/-1.1 versus 12.1+/-1.2%), and the required EPO was comparable. We conclude that the Hb response to EPO is reduced in diabetic patients on CHD. This elevated EPO requirement may be explained by a greater prevalence of infectious diseases, characterized by a significantly higher CRP level, in these patients. Other causes for the elevated EPO requirement could be excluded.

Topics: Adult; Aged; C-Reactive Protein; Chi-Square Distribution; Data Interpretation, Statistical; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Erythropoietin; Female; Ferritins; Follow-Up Studies; Hemoglobins; Humans; Male; Middle Aged; Patient Selection; Prospective Studies; Renal Dialysis; Time Factors; Transferrin

The mean arterial pressure (MAP) usually serves as an expression of blood pressure in patients on chronic haemodialysis (PCHD), instead of using solely systolic or diastolic pressure. Pulse pressure (PP) has been recognized as an important correlate of mortality in PCHD. We conducted this study in order to demonstrate clinical and biochemical determinants and variability of predialysis and postdialysis MAP and PP values. A total of 136 single haemodialysis (HD) treatments in 23 subjects (PCHD, 11 male and 12 female patients) were processed during 15 months. MAP before HD was in negative correlation with haemoglobin (P<0.001) and body mass index (BMI) (P<0.001), and in positive correlation with weekly erythropoietin dosage (P=0.017). MAP after HD was in negative correlation with haemoglobin (P<0.001), ultrafiltration per HD (P=0.015), and BMI (P=0.001), and in positive correlation with weekly erythropoietin dosage (P=0.003). PP before HD was in negative correlation with parathyroid hormone (PTH) level (P=0.020), haemoglobin (P<0.001), ultrafiltration per HD (P=0.001), and years on the chronic HD treatment (P=0.001), and in positive correlation with weekly erythropoietin dosage (P<0.001) and age (P<0.001). PP after HD was in significant negative correlation with PTH (P=0.015), haemoglobin (P=0.005), ultrafiltration per HD (P<0.001), BMI (P=0.003), and in positive correlation with weekly erythropoietin dosage (P<0.001) and age (P=0.004). Multiple regression analyses unveiled the strongest and negative correlations between MAP before HD and BMI (beta=-0.37, P=0.01); MAP after HD and haemoglobin (beta=-0.36, P=0.01); PP after HD and ultrafiltration/body weight ratio (beta=-0.41, P<0.001). The strongest and positive correlation was found between PP before HD and erythropoietin dosage per week (beta=0.51, P&<0.001). In conclusion, our findings support the assumption that PP and MAP are associated with different clinical parameters. PP values have advantages as the method of blood pressure expression.

Topics: Alkaline Phosphatase; Biomarkers; Blood Pressure; Blood Proteins; Body Mass Index; Cholesterol, HDL; Chronic Disease; Diabetic Nephropathies; Erythropoietin; Female; Glomerulonephritis; Humans; Male; Phosphorus; Pyelonephritis; Regression Analysis; Renal Dialysis; Sex Factors; Statistics as Topic; Time Factors; Treatment Outcome; Ultrafiltration

Recent report demonstrates that inadequate iron mobilization and defective iron utilization may cause recombinant erythropoieitin (rEPO) hyporesponsiveness in hemodialysis (HD) patients with iron overload. The effect of intravenous ascorbic acid (IVAA) in HD patients selected on the basis of iron overload and EPO resistance also has been proven. However, it is uncertain whether IVAA still works in diabetic ESRD patients with hyperferritinemia. Therefore, the aim of this study focusing on diabetic ESRD patients was to analyze the potential effect of low dose IVAA on improvement of anemia and erythropoiesis-related parameters when compared with control period.. This study consisted of 22 chronic hemodialysis patients with type II diabetes in a single dialysis unit. In studies of this type, all eligible patients are followed up, but the primary comparison is still between different sequentially treatment including control period and post-IVAA period in same patients. IVAA patients received ascorbic acid, 100 mg each administered intravenously three times per week for eight weeks of treatment and four months of post-treatment follow-up.. The demographic characteristics of 22 diabetic uremic patients show that mean age is 63.6 +/- 10.2 years old. The ratio of sex (M/F) = 10/12. Mean duration of HD is 46.7 +/- 33.2 months. As for the urea kinetic study between these two periods including KT/V, nPCR, and URR, there is no significantly different. As for anemia-related parameters, Hb and Hct increased significantly in post-IVAA period after 3 months compared with control period, while MCV did not increase significantly. Serum ferritin significantly decreased at study completion. The same situation is for iron. As for TS, it significantly increased at one month and further markedly increased at subsequent three months.. This study has demonstrated that short-term low dose IVAA therapy can facilitate iron release from reticuloendothelial system but also increase iron utilization in diabetic hemodialysis patients with iron overload. Therefore, IVAA is a potential adjuvant therapy to treat erythropoeitin-hyporesponsive anemia in iron-overloaded patients.

Topics: Aged; Anemia; Ascorbic Acid; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dose-Response Relationship, Drug; Erythrocyte Indices; Erythropoietin; Female; Ferritins; Follow-Up Studies; Free Radical Scavengers; Hematocrit; Hemoglobins; Humans; Infusions, Intravenous; Iron; Iron Overload; Kidney Failure, Chronic; Male; Middle Aged; Parathyroid Hormone; Phosphates; Prospective Studies; Recombinant Proteins; Renal Dialysis; Serum Albumin; Taiwan; Time Factors; Treatment Outcome

A case of erythrocytosis caused by gastric cancer that produced erythropoietin is described. To the authors' knowledge, no case of erythropoietin-producing gastric cancer has been reported until now. A 73-year-old man with a 4-year history of maintenance hemodialysis for diabetic nephropathy required phlebotomy. Serum erythropoietin level was 181 mU/mL (181 IU/L). Gastroscopy results showed rough mucosa with hemorrhaging caused by gastric cancer. The patient underwent distal gastrectomy, and serum erythropoietin level decreased to 27.1 mU/mL (27.1 IU/L) by postoperative day 8. Existence of erythropoietin in the tumor tissue was confirmed immunohistochemically. The presence of severe acquired cystic disease of the kidney, renal cell carcinoma, and other malignant tumors should be investigated in hemodialysis patients displaying erythrocytosis.

Topics: Adenocarcinoma; Aged; Diabetic Nephropathies; Erythropoietin; Gastrectomy; Gastrointestinal Hemorrhage; Hormones, Ectopic; Humans; Male; Paraneoplastic Endocrine Syndromes; Polycythemia; Renal Dialysis; Stomach Neoplasms

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetic Nephropathies; Diet Therapy; Diuretics; Dogs; Erythropoietin; Hemofiltration; Humans; Japan; Kidney Failure, Chronic; Kidney Transplantation; Kidneys, Artificial; Nephrology; Potassium Acetate; Renal Dialysis; Tissue Engineering

Topics: Anemia; Diabetic Nephropathies; Diabetic Retinopathy; Disease Progression; Erythrocyte Aggregation; Erythropoietin; Humans; Recombinant Proteins; Risk Factors

Coincidental with the pandemic growth of diabetes as the prime cause of end-stage renal disease (ESRD), blindness attributable to diabetic retinopathy has become a major concern for all those involved in the care of diabetic ESRD patients. Vision loss is linked to progression of proliferative retinopathy and macular edema.. Extracted from a study of azotemic anemic pre-ESRD patients treated with erythropoietin, a cohort of five diabetic subjects was reassessed in terms of stability of renal function, changes in blood rheology, and course of diabetic eye disease.. All subjects reported subjective improvement in well-being, including enhanced effort tolerance following an increase in hematocrit from a baseline level of to 29.6 +/- 2.0% to a level of 39.5 +/- 2.4% after one year of treatment with erythropoietin (P = <0.0005). Neither hypertension nor deterioration of renal function was noted in any subject. Three patients with macular edema evinced substantive improvement-based stable vision and documented resolution noted in flourescein angiography.. Erythropoietin treatment of anemic azotemic diabetic patients is well tolerated. In a small observational retrospective study of three patients with macular edema, retention of vision and resolution of exudates was noted.

Topics: Anemia; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Erythropoietin; Female; Humans; Middle Aged; Papilledema; Uremia

Renal anaemia starts earlier in the progression of chronic kidney disease (CKD) than was previously thought and is often inadequately monitored and treated. Current treatment guidelines recommend giving recombinant erythropoietin (rHuEPO) as soon as haemoglobin (Hb) concentration falls below 11 g/dl and alternative causes of anaemia have been ruled out. Recent studies show that, in practice, few patients receive rHuEPO in the pre-dialysis period and Hb concentrations are often <9 g/dl at the start of haemodialysis. This is at odds with best practice since renal anaemia is a major risk factor for left ventricular hypertrophy. Many factors other than provision of rHuEPO therapy can affect the occurrence and severity of renal anaemia. Iron deficiency is the most common cause of resistance to rHuEPO and appropriate use of iron supplementation in patients with CKD is still being debated. The acute-phase immune response has a more significant role in renal anaemia and rHuEPO resistance than previously believed, as demonstrated by the need for higher rHuEPO doses in patients with raised levels of C-reactive protein. Women often need higher doses of rHuEPO than men, which may be related to differences in androgen levels between the sexes. Low erythropoietin concentrations are a major factor in diabetic nephropathy. Correction of anaemia with rHuEPO may slow progression of CKD by reducing oxidative stress. These and other factors need to be considered for the optimal treatment of patients with anaemia of CKD.

Topics: Anemia; Angiotensin-Converting Enzyme Inhibitors; Diabetic Nephropathies; Drug Resistance; Erythropoietin; Female; Humans; Iron; Kidney Failure, Chronic; Male; Oxidative Stress; Recombinant Proteins; Sex Characteristics

Data are submitted of results of treatment of anemia of nephrogenic genesis in 44 patients with diabetes mellitus complicated by diabetic glomerulosclerosis and chronic renal failure (CRF). In the patients, blood count was determined together with the corpuscular volume, blood serum level of creatinine, total protein, trace elements (calcium, sodium, potassium), total cholesterin, and beta-lipoproteins (beta-LP). Two drug regimens were adopted: 21 patient received iron preparations, folic acid, cyanocobalamin, calcium preparations, those preparations to be employed to reduce blood level of creatinine, antihypertensives, and eprex, 1000 u. four times daily for up to 4 weeks; these very preparations were given to 23 patients during the same time range but without eprex in the regimen. Four weeks later, those patients having taken eprex demonstrated significant (though not very high) elevation of the content of hemoglobin, corpuscular volume, erythrocytes and drop in total cholesterin and beta-LP in the blood serum. In those patients having had no eprex in their regimen, there were no changes in the studied parameters. Patients with diabetic glomerulosclerosis concurrent with CRF and nephrogenous anemia should be prescribed eprex and preparations of iron, folic acid, cyanocobalamin combined in correction of the above anemia even in the predialysis period. Iron preparations are not to be administered in those settings where there is no reduction in its level.

Topics: Adult; Anemia; Diabetic Nephropathies; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis; Treatment Outcome

An erythropoietin (EPO)-deficient anaemia is recognized in Type 1 diabetic patients with early nephropathy and symptomatic autonomic neuropathy (DN). The aim of this study was to determine whether the EPO response to hypoxia was deficient in order to clarify the mechanisms involved in this process.. Five Type 1 diabetic patients DN (age 39 (28-48) years (mean (range))) with EPO-deficient anaemia (haemoglobin, Hb 10.6 (9.5-12.0) g/dl, EPO 5.0 (3.2-6.5) IU/l) and early diabetic nephropathy (persistent proteinuria 1161.6 (130-2835) mg/day, serum creatinine 97.6 (63-123) micromol/l)) were compared with nine normal subjects (age 31 (24-39) years, Hb 13.4 (11.8-15.7) g/dl, EPO 7.6 (5.6-10.3) IU/l) and four patients with non-diabetic advanced chronic renal failure RF (proteinuria 2157.5 (571-4578) mg/day, serum creatinine 490.2 (406-659) micromol/l, Hb 10.3 (9.0-11.3) g/dl, EPO 4.6 (2.9-8.5) IU/l). The subjects were exposed to 6 h of hypoxia (inspired oxygen 11.6-12.6%) by breathing a gas mixture via a hood. Hourly serum EPO levels were measured.. All groups showed a rise in EPO production after 2 h. The diabetic DN group achieved a similar maximal response to the normal subjects at 6 h (EPO 17.3 +/-5.4 vs. 17.8 +/-7.9 IU/l). The renal failure patients mounted an EPO response to hypoxia but at lower EPO levels.. Although the DN patients have inappropriately low EPO levels for the severity of their anaemia, they can mount an appropriate EPO response to moderate hypoxia. The mechanism underlying the EPO-deficient anaemia present in some diabetic patients remains unclear.

Topics: Adult; Anemia; Autonomic Nervous System Diseases; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Neuropathies; Erythropoietin; Female; Humans; Hypoxia; Kidney Failure, Chronic; Male; Middle Aged; Proteinuria

The normochromic normocytic anemia of erythropoietin (EPO) deficiency is recognized in advanced renal failure but not in early renal disease. The aim of this study was to determine whether anemia with EPO deficiency is found in type 1 diabetic patients with diabetic nephropathy in the absence of advanced renal failure and to compare them with patients with nondiabetic renal disease of similar severity.. A total of 27 type 1 diabetic patients with diabetic nephropathy (DN), defined as having persistent proteinuria (mean 1,086 mg/day [CI 120-5,1901), a serum creatinine < or = 180 micromol/l, and retinopathy, were compared with 26 nondiabetic patients with glomerulonephritis (GN) and persistent proteinuria (1,874 mg/day [349-5,005]). The Hb concentration, red cell indexes, and serum EPO levels were measured, and other causes for the anemia were excluded. The EPO values were compared with a normal reference range obtained from nondiabetic patients with a microcytic anemia. The DN patients were tested for signs of diabetic peripheral and autonomic neuropathy.. We found that 13 of the 27 DN patients were anemic (Hb 10.6 +/- 0.9 g/dl) in marked contrast to none of the GN patients (Hb 13.7 +/- 1.4 g/dl, P < 0.005). In the DN group, serum EPO concentrations failed to increase in response to anemia compared with the response seen in patients with microcytic anemia. Thus, the anemia of the DN group was associated with EPO deficiency. The anemic DN patients showed evidence of more severe proteinuria and diabetic neuropathy than the nonanemic DN patients.. Anemia associated with EPO deficiency can occur early in DN before the onset of advanced renal failure, but does not normally occur in nondiabetic renal disease of similar severity. The pathogenesis requires elucidation.

Topics: Adult; Anemia; Biomarkers; Blood Pressure; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Erythropoietin; Female; Heart Rate; Hemoglobins; Humans; Male; Middle Aged; Proteinuria; Reference Values; Reproducibility of Results

We report the case of a 52-year-old woman with long-term type 1 diabetes mellitus, complicated with proliferative retinopathy, autonomic neuropathy and microalbuminuria and moderate renal failure. A normochromic, normocytic are generative anaemia had been diagnosed for three years. Clinical and biological investigations for the aetiology of anaemia remained normal or negative. Anaemia was associated with a concentration of erythropoietin (EPO) in the normal range, but inappropriately low regarding anaemia. Treatment with recombinant EPO induced a rapid increase in haemoglobin level and improved the patient's quality of life. The role of diabetic neuropathy in the genesis of anaemia, in conjunction with a modest renal impairment is discussed.

Topics: Albuminuria; Anemia; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Electrocardiography; Erythropoietin; Female; Hemoglobins; Humans; Hypotension, Orthostatic; Kidney Failure, Chronic; Middle Aged; Quality of Life; Recombinant Proteins

Peritoneal dialysis (PD) patients have been shown to require less erythropoietin as compared with hemodialysis (HD) patients to maintain similar hemoglobin values. In our unit, we observed that diabetic PD patients required less erythropoietin treatment than did other PD patients. We therefore compared the amount of erythropoietin needed in diabetic and non diabetic patients on PD to maintain a similar hemoglobin value. All polycystic patients were excluded from the study because they rarely require erythropoietin. We also excluded patients with bone marrow disease, active gastrointestinal bleeding, or patients very resistant (requiring more than 25,000 U per week) to Eprex (recombinant human erythropoietin: Janssen-Cilag, North York, Ontario, Canada). Patients not requiring Eprex were also excluded from the study. We calculated the weekly erythropoietin dose in the two groups. We also compared hemoglobin level, iron transferrin saturation, vitamin?12 level, and serum folate. Diabetic patients required a lower weekly erythropoietin dose. Diabetic PD patients in our unti receive an average 4497 U per week compared with 7593 U per week for non diabetic PD patients. The difference (approximately 3000 U per week) is statistically significant.

Topics: Diabetes Mellitus; Diabetic Nephropathies; Erythropoietin; Folic Acid; Hemoglobins; Humans; Kidney Failure, Chronic; Peritoneal Dialysis; Renal Dialysis; Transferrin; Vitamin B 12

The present study looked for variations in blood morphology between diabetic patients (group I, n = 7) and non diabetic patients (group II, n = 16) treated with continuous ambulatory peritoneal dialysis (CAPD). A subsequent trial sought to find a reason for discrepancies in the results between the two groups. The patients in both groups and similar ages, CAPD durations, and erythropoietin dosages. Nutrition, CAPD adequacy, serum iron and ferritin levels, total iron binding capacity (TIBC), transferrin saturation (TSAT), red blood cells (RBCs), mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), hemoglobin (Hb), hematocrit (Hct), white blood cells (WBCs), total lymphocyte count (TLC), platelets (PLTs), and serum intact parathyroid hormone (PTH) were evaluated every three months. The mean result of each parameter was obtained in every patient as representative for the entire CAPD course. Means and standard deviations for all respective parameters were then calculated for the two groups and compared. In patients with diabetes as compared with patients without diabetes, significantly higher numbers of RBCs, WBCs, and PLTs were seen, as were higher values for Hb and Hct and a lower serum PTH concentration. Values for WBCs, PLTs, and MCH obtained in all patients (n = 23) were correlated with serum intact PTH (r = -0.520, p = 0.011; r = -0.422, p = 0.045; and r = -0.436, p = 0.037 respectively). When data obtained in the patients receiving erythropoietin were excluded and the correlation analysis was repeated for the 10 remaining patients, a correlation between serum PTH and RBCs was found (r = -0.685, p = 0.029). With comparable age, renal function, nutrition, erythropoietin dosage, iron indices, and CAPD adequacy, duration, and outcome, higher parameters of blood morphology in diabetic patients may be related to lower levels of serum intact PTH, indicating no or only mild secondary hyperparathyroidism. Patients with diabetes usually show smaller disturbances in PTH level than do non diabetic uremic patients on CAPD. Better peripheral morphology indices in the group with diabetes can be expected when other factors affecting hematologic status are similar.

Topics: Adult; Blood Cell Count; Diabetes Mellitus; Diabetic Nephropathies; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Male; Middle Aged; Parathyroid Hormone; Peritoneal Dialysis, Continuous Ambulatory; Retrospective Studies

The epidemiology of end-stage renal disease (ESRD) is changing all over the world. Particularly dramatic changes of the epidemiology of ESRD have occurred in central and eastern Europe (CEE). The aim of the present study was (i) to document the further expansion of renal replacement therapy (RRT) noted in recent years in CEE and (ii) to analyse in some detail treatment modalities and underlying renal conditions.. Three independent surveys were performed in 1995, 1997 and 1998. Fifteen CEE countries participated. The data were mainly obtained from national registries which are based on centre and patient questionnaires.. The data collected from 15 CEE countries document further expansion of RRT in this region. The report includes data on the availability of RRT in Byelorussia, Estonia, and Russia which have become available for the first time. The epidemiology of dialysed patients has changed remarkably. In the majority of countries the number of diabetic patients has increased, most dramatically so in the Czech Republic (31% of all dialysed patients), in the majority of the other countries 10-14%. The number of ESRD patients with the diagnosis of hypertensive nephropathy has also increased and this was accompanied by an increase in proportion of elderly (>65 years) patients, i.e. 46% in the Czech Republic and 12-25% in most other countries.. Dramatic changes of the availability of RRT treatment have occurred in central and eastern Europe. The proportion of diabetic nephropathy and elderly patients has risen. Large differences in RRT exist between individual CEE countries and this appears mainly dependent on the level of economic development.

Topics: Age Distribution; Aged; Diabetic Nephropathies; Drug Utilization; Erythropoietin; Europe; Humans; Kidney Failure, Chronic; Kidney Transplantation; Renal Replacement Therapy

Erythropoietin (EPO) deficiency is the main cause of renal anaemia. However, inhibition of erythropoiesis by cytokines such as tumour necrosis factor alpha (TNF-a) may play an important role. The aim of this work was to study the effects of pentoxifylline, an agent with anti-TNF-a properties, on the haematologic status in anaemic patients with advanced renal failure.. In a prospective study, 7 anaemic patients with advanced renal disease (creatinine clearance <30 ml/min) were treated with pentoxifylline (400 mg orally daily) for 6 months. The evolution of haemoglobin, haematocrit, creatinine clearance and serum EPO and TNF-a a concentrations were compared with those obtained from an untreated control group.. Haemoglobin and haematocrit significantly increased in the pentoxifylline-treated patients (9.9+/-0.5 g/dl and 27.9+/-1.6% at baseline; 10.6+/-0.6 g/dl and 31.3+/-1.9% at the 6th month, respectively, p < 0.01), whereas no variation was seen in the control group. Serum EPO levels remained stable in all patients. However, the serum TNF-a concentration decreased significantly in patients receiving pentoxifylline (basal 623+/-366 pg/ml; 6th month 562+/-358 pg/ml, p < 0.01), but not in the control group.. Our findings suggest that the inhibition of erythropoiesis by cytokines may play a significant role in renal anaemia. The administration of agents with anti-cytokine properties, such as pentoxifylline, can improve the haematologic status in anaemic patients with advanced renal failure.

Topics: Aged; Anemia; Diabetic Nephropathies; Erythropoietin; Female; Hematologic Agents; Humans; Kidney Failure, Chronic; Male; Pentoxifylline; Tumor Necrosis Factor-alpha

To discover whether Type 1 diabetic patients with autonomic neuropathy might be anaemic and erythropoietin (EPO)-depleted.. Fifteen Type 1 diabetic patients with serious complications (DM-COMP) were selected because of severe symptomatic autonomic neuropathy, including significant postural hypotension. All had proteinuria from nephropathy (three microalbuminuria and 12 macroalbuminuria), but a normal serum creatinine (< 122 micromol/l). They were compared to age and duration matched Type 1 diabetic controls without autonomic neuropathy (DM-controls) and non-diabetic patients with and without hypochromic, microcytic anaemia.. The DM-COMP patients were anaemic (mean haemoglobin (Hb) 11.1+/-1.2 g/dl), sometimes severely (minimum Hb 9.2 g/dl), compared to non-neuropathic DM-controls (Hb 13.7+/-0.7 g/dl; P < 0.001). Furthermore, EPO failed to increase in association with anaemia in the DM-COMP group compared to the progressive increase in the non-diabetic, anaemic patients (difference of regression lines P < 0.001), indicating EPO depletion in the anaemic, diabetic patients. There was no other demonstrable cause for the anaemia. Treatment with EPO in 5 DM-COMP patients led to a rapid increase in haemoglobin (range 1.7-5.0 g/dl) with improvement in wellbeing.. Some Type 1 diabetic patients with autonomic neuropathy present with an EPO-depleted anaemia, which responds to treatment with EPO. This observation supports the concept of autonomic neuropathy as a cause of anaemia with EPO depletion, although the role of established renal damage cannot be excluded.

Topics: Adult; Albuminuria; Anemia; Autonomic Nervous System Diseases; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Diabetic Neuropathies; Erythropoietin; Female; Hemoglobins; Humans; Middle Aged; Proteinuria

We often encounter diabetic patients with anemia in whom the causes of anemia were not clearly identified despite differential hematologic studies. We therefore studied the clinical and biochemical characteristics of diabetic patients with anemia of uncertain cause and measured erythropoietin (Epo) concentrations in 35 diabetic subjects without significant diabetic renal disease. Among 62 medical records of diabetic patients with anemia, showing no evidence of advanced diabetic nephropathy (creatinine clearance > or = 30 mg/kg/1.73 m2), the causes of the anemia were not able to be identified in 28 cases (45.2%). In addition, we enrolled 35 diabetic patients with uncertain causes of anemia in order to evaluate the serum Epo responsiveness to anemia, and compared levels to a group of non-diabetic subjects also with anemia. The serum Epo concentrations of diabetic patients (17.6 +/- 8.1 mIU/ml) were significantly lower than those of non-diabetic patients with similar degree of decrease in hemoglobin concentrations (144.9 +/- 108.0 mIU/ml, P<0.001). The hemoglobin concentrations of diabetic patients correlated with creatinine clearance (r = 0.34, P = 0.03), serum creatinine (r = -0.49, P = 0.003) and albumin excretion rate (r = -0.44, P = 0.009), but showed no relation to age, duration of diabetes, glycated hemoglobin, presence of retinopathy or neuropathy. We concluded that reduced Epo responsiveness to anemia could explain the anemia present in diabetic patient but without advanced diabetic nephropathy. This may reflect early renal interstitial damage.

Topics: Aged; Anemia; Creatinine; Diabetes Complications; Diabetes Mellitus; Diabetic Nephropathies; Erythropoietin; Female; Hemoglobins; Humans; Male; Middle Aged

Peripheral vascular disease is a serious and frequent problem in diabetic patients. Since the beginning of the widespread use of erythropoietin (EPO), we have noted an increase in peripheral vascular disease in diabetic patients receiving peritoneal dialysis and erythropoietin. This prompted us to study the effects of erythropoietin on peripheral vascular disease in patients receiving peritoneal dialysis. We retrospectively reviewed medical records of all diabetic patients in our program who received peritoneal dialysis from 1990 to 1996. Demographic and laboratory data as well as EPO use data were collected. Hospital days and occurrence of vascular events (defined as peripheral vascular surgery, amputation, or recommendation of vascular surgery or amputation by a vascular surgeon) were determined for diabetic patients receiving peritoneal dialysis. Comparisons were made between those who received EPO and those who did not received EPO, as well as comparing vascular events in 28 patients who received peritoneal dialysis before and after beginning EPO. Patients who received erythropoietin were found to have a significantly shorter time to a first vascular event, a greater number of vascular events, and more hospital days associated with vascular disease than diabetic patients who did not receive erythropoietin. With multivariate analysis, significant risk factors for the development of peripheral vascular disease in these patients were erythropoietin use, erythropoietin dose, and smoking. Twenty-eight patients who initially performed peritoneal dialysis without receiving EPO, and later received EPO, had a significant increase in vascular events, including amputations only while receiving EPO. We found the use of erythropoietin to be associated with peripheral vascular events in diabetic patients who receive peritoneal dialysis. Further investigation is warranted.

Topics: Adult; Aged; Amputation, Surgical; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Dose-Response Relationship, Drug; Erythropoietin; Female; Humans; Ischemia; Kidney Failure, Chronic; Leg; Length of Stay; Male; Middle Aged; Myocardial Infarction; Peritoneal Dialysis; Recombinant Proteins; Retrospective Studies

Topics: Adult; Diabetic Nephropathies; Diastole; Echocardiography; Erythropoietin; Humans; Kidney Transplantation; Male; Systole; Ventricular Dysfunction, Left

The superimposition of human immunodeficiency virus (HIV) infection, associated opportunistic infections, and anti-retroviral therapy further worsens the severity of anemia in patients also suffering from end-stage renal disease. A major cause of anemia in renal failure is a deficiency of erythropoietin. The causes of anemia in HIV disease include direct and indirect stem cell inhibition by the virus, increased peripheral destruction of red blood cells, and bone marrow suppression by various opportunistic infections and therapeutic drugs, particularly zidovudine. We compared the efficacy of recombinant human erythropoietin (rHuEPO) therapy in improving the anemia in HIV-infected end-stage renal disease patients (group I) with that in nondiabetic (group II) and diabetic (group III) hemodialysis patients without HIV infection. All three groups of patients were comparable in dialysis prescription and serum iron studies. Iron supplementation was prescribed to all patients, and none received blood transfusions. After 8 weeks of rHuEPO therapy (administered intravenously in a dose of 100 U/kg body weight thrice weekly), the mean increase in hematocrit was similar in all responders (5.8% increase in hematocrit in 23 of 30 HIV patients and 6.7% increase in 24 of 30 non-HIV patients). Response in hematocrit was noted in HIV patients despite the presence of opportunistic infections in 15 and zidovudine administration in 11. Seven HIV-positive patients and six non-HIV patients failed to respond to rHuEPO. Irrespective of the HIV status, the baseline serum EPO levels in patients responding to rHuEPO were significantly lower than those in nonresponders.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; AIDS-Associated Nephropathy; Anemia; Case-Control Studies; Diabetic Nephropathies; Erythropoietin; Female; Ferrous Compounds; Hematocrit; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Zidovudine

Meticulous glucose control that begins long before conception is fundamental to protecting the fetus and mother. Maternal hypertension, retinopathy, renal disease, and neuropathy may lead to complications, but optimal education, care, and fetal monitoring can reduce the risks.

Topics: Adult; Algorithms; Antihypertensive Agents; Blood Glucose Self-Monitoring; Cesarean Section; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Erythropoietin; Female; Fetal Monitoring; Humans; Hypertension; Infant, Newborn; Insulin; Male; Pre-Eclampsia; Pregnancy; Pregnancy Complications, Cardiovascular; Pregnancy in Diabetics; Pregnancy, High-Risk; Prenatal Care

There has been a gradual increase in the number of diabetic and elderly patients maintained on continuous ambulatory peritoneal dialysis (CAPD) replacement therapy. Eighty randomly selected patients were studied over two years. Weekly normalized urea clearance (KT/Vurea), weekly creatinine clearance/1.73 m2 body surface area (BSA) (Ccr), and protein catabolic rate (PCR) were measured. Selected clinical outcome criteria were assessed. Weekly KT/Vurea was correlated with weekly Ccr (r = 0.538, p < 0.001), and weekly KT/Vurea was correlated with PCR (r = 0.393, p < 0.001). Patients were then stratified according to presence or absence of diabetes mellitus and age > 60 or < or = 60 years. Diabetic and nondiabetic patients had similar weekly KT/Vurea, weekly Ccr, PCR, serum albumin levels, weekly erythropoietin (EPO) requirements, peritonitis rates, and CAPD-related hospitalization rates. The total hospitalization rates, however, were higher in diabetic patients. Elderly and younger patients had similar weekly KT/Vurea, weekly Ccr, PCR, serum albumin levels, and weekly EPO requirements. Elderly patients, however, had higher peritonitis rates and higher total and CAPD-related hospitalization rates.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Body Surface Area; Diabetic Nephropathies; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Proteins; Serum Albumin; Urea

Diabetic retinopathy improved in three patients with renal insufficiency after a rise in hematocrit induced by administration of recombinant erythropoietin. The change involved significant resorption of hard exudates in patients who were not eligible to receive laser treatment.. Three patients with diabetic nephropathy had the associated chronic anemia of renal insufficiency. In each patient, diabetic retinopathy with foveal/parafoveal hard exudates (but no clinically significant macular edema) was initially evaluated ophthalmoscopically. Fluorescein angiography demonstrated a low-grade diffuse leakage pattern. Treatment with subcutaneous recombinant erythropoietin (4000 IU twice weekly) was initiated within 1 to 3 months of initial evaluation. The resolution of hard exudates was observed on ophthalmoscopic examination and graded fundus photography (ETDRS seven standard field).. Within 6 months of initiation of erythropoietin treatment, a substantial reduction of exudate was observed in all three patients, the hematocrit having increased from a mean of 21% to a mean of 33% (a mean increase of 33% in each patient). Visual acuity improved in two patients and stabilized in the other. Follow-up fluorescein angiographic examination demonstrated no change in the leakage pattern.. Although no direct cause and effect relationship can be established, raising the red cell mass by treatment with recombinant erythropoietin may serve as adjunctive treatment of diabetic retinopathy in patients with diabetic renal insufficiency.

Topics: Absorption; Anemia; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diabetic Retinopathy; Erythropoietin; Exudates and Transudates; Female; Fundus Oculi; Humans; Injections, Subcutaneous; Kidney Failure, Chronic; Middle Aged; Recombinant Proteins

Topics: Adult; Anemia; Diabetic Nephropathies; Erythropoietin; Female; Humans; Insulin Resistance; Male; Middle Aged; Renal Dialysis

Topics: Adult; Aged; Anemia; Blood Pressure; Blood Viscosity; Creatinine; Diabetic Nephropathies; Erythropoietin; Female; Humans; Male; Middle Aged; Recombinant Proteins; Uremia

Topics: Anemia; Diabetic Nephropathies; Erythropoietin; Female; Humans; Kidney Failure, Chronic; Middle Aged; Recombinant Proteins

We assessed human recombinant erythropoietin (rHuEPO) as treatment for anemia in azotemic patients who did not require dialytic therapy. The study group consisted of 5 azotemic men and 5 women (mean serum creatinine concentration 5.2 +/- 3.2 mg/dl) whose mean hematocrit was 27.4 + 3.0%. Of these, 5 subjects had diabetic nephropathy. The study was a 12-month rHuEPO maintenance (open label) trial in which a previously established median i.v. dose of 50 U/kg was given three times each week. The rHuEPO was temporarily discontinued when the target hematocrit of 37% was achieved, and after the hematocrit decreased below 35%, it was restarted at half the initial dose. Of the 10 subjects who started the trial, 2 (both nondiabetic) deteriorated early in the study, and before a hematocrit rise was attained commenced maintenance hemodialysis. All subjects completed the year of study and achieved the target hematocrit. Mean hematocrit rose 42% (p less than 0.001) in a mean period of 3.3 +/- 1.3 months. When treatment was interrupted at a hematocrit of 37%, mean absolute reticulocyte count fell from 1.21 +/- 0.59% to 0.38 +/- 0.14% within one week. After rHuEPO was withdrawn, the increase in hematocrit persisted for a mean of 13.0 +/- 6.0 days and patients were able to sustain hematocrits above 35% for a mean of 1.44 +/- 0.6 months. Coincidentally with the rise in hematocrit during rHuEPO treatment, whole-blood viscosity increased significantly (p less than 0.001) but remained within the range for individuals with normal renal function at an equivalent hematocrit (p greater than or equal to 0.5).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Anemia; Blood Viscosity; Diabetic Nephropathies; Erythropoietin; Female; Hematocrit; Humans; Kidney Failure, Chronic; Male; Middle Aged; Recombinant Proteins; Renal Dialysis; Uremia