Epoetin Treatment Research Articles

EPOETIN TREATMENT IMPROVES RED BLOOD CELL AND PLASMA ANTIOXIDANT CAPACITY IN HEMODIALYSIS PATIENTS

The efficiency of human recombinant epoetin in alleviating anemia in hemodialyzed patients has been well documented. However, the effects of rhEPO therapy in correction of antioxidant capacity are not completely explained. In this study we examined both extracellular (plasma) and intracellular (red blood cells) antioxidant potential in hemodialyzed patients before and after three and six months of epoetin treatment by evaluating markers of oxidative stress (malondialdehyde) and antioxidant capacity (thiol groups, superoxide dismutase, and glutathione peroxidase). Six months of treatment with epoetin was followed by significant increases in thiol groups, superoxide dismutase and glutathione peroxidase activities in both plasma and red blood cells of hemodialyzed patients. Hence, during accelerated erythropoiesis, an increase in the number of young hematopoietic cells may replenish erythrocyte superoxide dismutase and glutathione peroxidase activity. However, the consequences of an imbalance between enzymatic antioxidant system (higher superoxide dismutase and lower glutathione peroxidase activity) that exists in these patients are the very high red blood cell and plasma malondialdehyde levels. These results suggest that, in spite of epoetin treatment and improvement in red blood cells and plasma antioxidant capacity, the production of reactive oxygen species overwhelms the intracellular and extracellular antioxidant capacity.

Anaemia management in chronic kidney disease patients: an overview of current clinical practice.

This paper describes three recent, related surveys of anaemia management practice in patients with chronic kidney disease, with particular emphasis on initiation of epoetin therapy. It also compares current practice with the European Best Practice Guidelines (EBPG) for anaemia management. The European Survey of Anaemia Management (ESAM) was a 6 month, longitudinal prospective survey of anaemia management in dialysis patients. Although most survey data concerned patients already on dialysis, some retrospective data concerned initiation of dialysis and epoetin therapy. These findings led to the Predialysis Survey of Anaemia Management (PRESAM), a cross-sectional, retrospective survey of patients beginning dialysis, focusing on referral to renal centres and anaemia management in the year preceding dialysis. The Early Renal Insufficiency Referral Survey (ERIRS) is a further cross-sectional survey currently in progress, investigating referral practices during pre-dialysis care. Collectively, these three surveys provide a wealth of data about pre-dialysis anaemia management. ESAM included data from 14527 patients, PRESAM from 4333 patients, and data from 724 patients enrolled in ERIRS have been analysed. The evidence indicates that, at the time of referral to a renal centre, most patients have haemoglobin concentrations well below the levels recommended by the EBPG. Haemoglobin concentrations are lowest in patients referred within the month prior to the initiation of dialysis. Most patients do not start epoetin treatment until dialysis is initiated, despite having haemoglobin concentrations below the level recommended by the EBPG for the initiation of epoetin. Patients who are referred earlier (i.e. those under the care of the renal centre nephrologist for more than a month before the initiation of dialysis) tend to have higher haemoglobin concentrations and are more likely to be receiving epoetin therapy. Such patients are in the minority, however, indicating that pre-dialysis anaemia management practices continue to fall short of the recommendations of the EBPG.

Anaemia in end-stage renal disease: pathophysiological considerations

Anaemia is a frequent complication of many diseases but the mechanisms that link reduced blood oxygen content to the long-term consequences of anaemia are incompletely understood. The maintenance of oxygen supply to the tissues during anaemia involves complex cardiovascular adaptations, including an increase in cardiac output, reduced peripheral resistance and increased oxygen extraction from haemoglobin (Hb). In addition, hypoxia-inducible factors are associated with the transcriptional activation of genes involved in adaptive mechanisms that increase oxygen delivery and provide alternative metabolic pathways. The complex pathophysiology of chronic kidney disease alters the adaptations to anaemia in uraemic patients. The increased cardiac output induced by anaemia is associated with left ventricular hypertrophy and cardiac disease in renal patients. Alterations in endothelial cell function, common in renal disease, may diminish endothelium-induced vasodilatation, increase the risk of atherosclerosis and impair angiogenesis. Many potential reasons for erythropoietin-induced hypertension in uraemic patients have been postulated, including increased blood viscosity as haematocrit rises, a reversal of hypoxic vasodilatation, increased blood volume that is not compensated by haemodialysis, ultrafiltration and impaired nitric oxide synthesis, preventing vascular relaxation in response to increased blood viscosity. In view of this impaired vascular reactivity, rapid increases in haematocrit should be avoided during epoetin treatment. As the interaction between anaemia and uraemia is very complex, it is not possible to derive the optimal Hb concentration for individual patients by using simple physiological or pathophysiological models and there is a need for good randomized controlled clinical trials to address this issue.

Dialysis: its role in optimizing recombinant erythropoietin treatment.

Although iron deficiency is probably the most important factor affecting response to recombinant erythropoietin (Epo, epoetin), other factors are of significance, including dialysis adequacy. Additionally, water treatment and distribution, sterilizants and the quality of the dialysate in terms of trace elements (particularly chloramine) are of importance in relation to erythropoiesis inhibition. Microbiological or pyrogenic contamination can cause or aggravate anaemia in haemodialysis patients, and the impact of enhanced production of cytokines should be taken into consideration. By removing small and (possibly) medium/large molecules, adequate dialysis is of paramount importance in correcting anaemia and optimizing epoetin therapy. The biocompatibility of dialysis membranes and flux are other important factors. As yet unknown uraemic toxins may suppress erythropoiesis and contribute towards the development of anaemia. It is reasonable to hypothesize that, because anaemia improves after the start of dialysis with cellulose membranes, low molecular weight erythropoiesis inhibitors are involved, as well as medium/large molecular weight inhibitors, which are removed by more permeable membranes. However, in highly selected, adequately dialysed patients without iron or vitamin depletion, the effects of dialysis membrane type on haematological parameters and epoetin efficacy are smaller than might be expected from the results of uncontrolled studies. Improvement in anaemia has been observed using on-line haemofiltration, haemodiafiltration, and sterile dialysate. The results of prospective, randomized trials examining the impact of these factors on anaemia and the effectiveness of epoetin treatment are eagerly awaited.

Identification of patients and risk factors in chronic kidney disease--evaluating risk factors and therapeutic strategies

Three strategies can help delay chronic kidney disease (CKD) progression: early identification of patients, modification of risk factors, and implementation of the best interventions. Early identification of patients requires accurate screening tools. As serum creatinine is an unreliable marker of kidney dysfunction, clinicians should focus on the glomerular filtration rate or other markers of true kidney function. Clinicians should also be aware of other indicators of abnormal kidney function, such as anaemia, acidosis, and increases in parathyroid hormone level. Additionally, both clinicians and patients should be aware of the "non-modifiable" and "modifiable" risk factors for CKD. Non-modifiable risk factors include age, gender, race, diabetes, and genetic make-up, while modifiable risk factors include elevated blood pressure and blood glucose, proteinuria, anaemia, metabolic disturbances, and dyslipidaemia. Patients should be particularly aware of the risk factors common to both cardiac and kidney disease, such as hypertension, proteinuria, anaemia, and (possibly) dyslipidaemia and diabetes. A single centre study demonstrated that inclusion in a multidisciplinary CKD clinic programme produced the greatest increases in time to renal replacement therapy, haemoglobin levels, and epoetin treatment usage at initiation of dialysis in comparison with standard nephrology care or no care. Two years after starting dialysis, the number of deaths was lowest, and the number of patients who had received a transplant or were still on dialysis was highest, in the CKD clinic-treated group. These results confirm those of previous studies, which showed that timely referral to a multidisciplinary team for management prior to dialysis decreases the risk of adverse patient outcomes. This suggests that a multidisciplinary, collaborative, proactive approach increases the likelihood of early identification of CKD patients and risk factor modification. However, further evidence-based demonstrations of success are required, showing benefit to both patients and health care systems.

Epoetin treatment of anemia associated with cancer therapy: a systematic review and meta-analysis of controlled clinical trials.

Epoetin treatment offers an attractive but costly alternative to red blood cell transfusion for managing anemia associated with cancer therapy. The goal of this review is to facilitate more efficient use of epoetin by 1) quantifying the effects of epoetin on the likelihood of transfusion and on quality of life in patients with cancer treatment-related anemia and 2) evaluating whether outcomes are superior when epoetin treatment is initiated at higher hemoglobin thresholds. Two independent reviewers followed a prospective protocol for identifying studies. Outcomes data were combined with the use of a random-effects meta-analysis model. Double-blind, randomized, controlled trials that minimized patient exclusions were defined as higher quality for sensitivity analysis; randomized but unblinded trials and trials with excessive exclusions were included in the meta-analysis but were defined as lower quality. Twenty-two trials (n = 1927) met inclusion criteria, and 12 (n = 1390) could be combined for estimation of odds of transfusion. Epoetin decreased the percentage of patients transfused by 9%-45% in adults with mean baseline hemoglobin concentrations of 10 g/dL or less (seven trials; n = 1080), by 7%-47% in those with hemoglobin concentrations greater than 10 g/dL but less than 12 g/dL (seven trials; n = 431), and by 7%-39% in those with hemoglobin concentrations of 12 g/dL or higher (five trials; n = 308). In sensitivity analysis, the combined odds ratio for transfusion in epoetin-treated patients as compared with controls was 0.45 (95% confidence interval [CI] = 0.33 to 0.62) in higher quality studies and 0.14 (95% CI = 0.06 to 0.31) in lower quality studies. The number of patients needed to treat to prevent one transfusion is 4.4 for all studies, 5.2 for higher quality studies, and 2.6 for lower quality studies. Only studies with mean baseline hemoglobin concentrations of 10 g/dL or less reported statistically significant effects of epoetin treatment on quality of life; quality-of-life data were insufficient for meta-analysis. No studies addressed epoetin's effects on anemia-related symptoms. We conclude that epoetin reduces the odds of transfusion for cancer patients undergoing therapy. Evidence is insufficient to determine whether initiating epoetin earlier spares more patients from transfusion or results in better quality of life than waiting until hemoglobin concentrations decline to nearly 10 g/dL.

The beneficial effects of intervention in early renal disease.

In renal disease, anaemia is a risk factor for cardiovascular disease (CVD), such as left ventricular hypertrophy (LVH), in both dialysis patients and patients with early renal disease. During the past decade, many studies have showed that partial correction of anaemia leads to partial regression of LVH in hypertensive and normotensive dialysis patients. Several reports support the pre-dialysis use of epoetin. Evidence of cardiovascular risk reduction with epoetin treatment in pre-dialysis patients is growing. For example, in an open, prospective study of epoetin in pre-dialysis patients, an increase in mean haemoglobin of 2.7 g/dl was accompanied by a decrease in left ventricular mass index in almost all patients. This regression, obtained in the absence of improved blood pressure (BP) control, confirms the role of anaemia in the genesis of LVH. These results have been confirmed in two recent studies. Risk reduction strategies (i.e. BP control, lipid lowering, smoking cessation, anaemia correction) from the earliest stages of renal disease may facilitate the prevention of cardiovascular conditions such as LVH in chronic renal failure (CRF) patients. Indeed, if all the well recognized risk factors (including anaemia) are aggressively identified and treated, then long-term reductions in cardiovascular morbidity and mortality should be achieved. In conclusion, preliminary studies show reversal of hypertrophy after correction of renal anaemia with epoetin. Extrapolation of results from studies in CRF suggests the use of earlier treatment of anaemia to maximize cardiovascular benefits. Further studies of the cardiovascular benefits of earlier epoetin intervention in early renal disease are indicated.

An association of pre-end-stage renal disease epoetin treatment with post-ESRD mortality: Jay L. Xue, James Ebben, Wendy St. Peter, Allan J. Collins. Minneapolis Medical Research Foundation and University of Minnesota, Minneapolis, Minnesota.

An association of pre-end-stage renal disease epoetin treatment with post-ESRD mortality: Jay L. Xue, James Ebben, Wendy St. Peter, Allan J. Collins. Minneapolis Medical Research Foundation and University of Minnesota, Minneapolis, Minnesota.

European Best Practice Guidelines 1–4 Evaluating anaemia and initiating treatment

and 26.4% of peritoneal dialysis patients. Table 11 Results summarizes the results by country, and some betweencountry variation is observed. Figure 3 presents aggregKey points from the EBPG ate findings for both cohorts of patients. In 35.1% of patients, the start of dialysis and initiation of epoetin $ Evaluate anaemia in chronic renal failure therapy were simultaneous. Only 7.9% of patients were (CRF ) patients when haemoglobin (Hb) is started on epoetin in the 6 months preceding dialysis, 6 months before’ and ‘>6 months Hb is consistently 25% of haemodialysis patients and >30% of peritoneal dialysis patients started epoetin therapy with haeAs EBPG 1–3 are narrative guidelines for which no moglobin levels between 8 and 8.9 g/dl, and >25% of empirical support is available, the data reported here dialysis patients started treatment below 8 g/dl. These pertain mainly to EBPG 4 [1]. They are complemented starting haemoglobin levels were consistent regardless with additional results that support the main issues in of the relationship between start of dialysis and initithis cluster of guidelines. ation of epoetin therapy for both haemodialysis and The relationship between the start of dialysis and peritoneal dialysis patients (Figure 5). Some variability initiation of epoetin treatment was examined. As shown between Western European countries was observed in Figure 2, the patterns are different for haemodialysis

Quality of life benefits of early anaemia treatment

In evaluating outcomes in end-stage renal disease (ESRD), quality of life has become as important as morbidity and mortality. Various instruments are available to analyse patients' perceptions of the physical, psychological and social domains of health. Non-specific instruments, such as the Sickness Impact Profile, the Karnofsky Scale, and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36), have been widely used in evaluating quality of life in various chronic diseases including ESRD. The Kidney Disease Quality of Life (KDQOL) questionnaire and other scales have also have been developed specifically for ESRD patients. Several studies have demonstrated a significant improvement in quality of life after initiation of epoetin treatment in both dialysis patients and those with early renal failure. Quality-of-life scores show a strong positive correlation with haemoglobin concentration. Other factors associated with better quality of life are higher socio-economic level and level of education. However, older age, comorbidity, diabetes, female sex, and unemployment have a negative influence on quality of life. In patients not yet on dialysis, quality of life deteriorates as the glomerular filtration rate decreases. The later the patient is referred to a nephrologist, the worse the quality of life. Recent studies show that quality of life is a prognostic factor for survival. Early and effective treatment of anaemia in ESRD patients is essential in maintaining quality of life both before and after initiation of dialysis.

Early epoetin treatment in patients with renal insufficiency

Historically, epoetin has been used to treat anaemia in patients already receiving renal replacement therapy. For many years, however, the results of early animal experiments raised considerable concern among nephrologists that disease progression would be accelerated if epoetin therapy were initiated in the predialysis phase of renal failure. In retrospect, it has become clear that the results of these early animal experiments were confounded by a concomitant and uncontrolled rise in blood pressure. In subsequent studies in rat models, antihypertensive treatment effectively prevented the adverse effect on disease progression. In addition, the results of several small observational studies and one large controlled study suggest that the glomerular filtration rate is not adversely affected in pre-dialysis patients treated with epoetin as long as blood pressure is well controlled. There are several observations, though not definitive, which suggest that disease progression may even be slower when anaemia is reversed. The benefits of early anaemia treatment with epoetin include increased exercise capacity and improved quality of life, cognitive function, and sexual function. Anaemia has also been identified as an important aetiological factor in the development of left ventricular hypertrophy. Whether pre-emptive treatment of anaemia is indicated in all pre-dialysis patients, or at least in those who develop progressive left ventricular hypertrophy, is currently under investigation.

Increasing the hematocrit has a beneficial effect on quality of life and is safe in selected hemodialysis patients. Spanish Cooperative Renal Patients Quality of Life Study Group of the Spanish Society of Nephrology.

Target hematocrit/hemoglobin values in dialysis patients are still controversial. The Spanish Cooperative Renal Patients Quality of Life Study Group (including 34 hemodialysis units) conducted a prospective, 6-mo study of the effect on patient functional status and quality of life of using epoetin to achieve normal hematocrit in hemodialysis patients with anemia. The possible adverse effects of increased hematocrit, patient hospitalization, and epoetin requirements were also studied. The study included 156 patients (age range, 18 to 65 yr). Given the minimal experience in the safety of increasing hematocrit in dialysis patients to normal levels with epoetin, stable patients on hemodialysis who had received epoetin treatment for at least 3 mo and had a stable hemoglobin level of > or = 9 g/dl were included in the study. Patients with antecedents of congestive cardiac failure, ischemic cardiopathy, diabetes mellitus, uncontrolled hypertension, cerebrovascular accident or seizures, malfunction of the vascular access or severe comorbidity (defined by a comorbidity index), and those over 65 yr of age were excluded from the study. Quality of life was measured with the Sickness Impact Profile (SIP) and Karnofsky scale. Patients completed questionnaires at home at onset and conclusion of the 6-mo study. Mean hematocrit increased from 30.9 to 38.4% and hemoglobin from 10.2 to 12.5 g/dl during the study. Health indicator scores improved significantly: mean Physical Dimension (SIP) from 5.38 to 4.1 (P < 0.005); mean Psychosocial Dimension from 9.2 to 7 (P < 0.001); mean global SIP from 8.9 to 7.25 (P < 0.001); mean Karnofsky scale score from 75.6 to 78.4 (P < 0.01). (SIP is scaled so that lower scores represent better functional status, and vice versa for the Karnofsky scale). Therefore, functional status and quality of life improved with increased hematocrit. No deaths occurred. Three patients (2%) were censored for hypertension and nine (5.7%) for thrombosis of the vascular access. The cumulative probability of thrombosis of the vascular access was 0.067. The average epoetin dose rose from 93 +/- 62 U/kg per wk at onset to 141 +/- 80 U/kg per wk at conclusion, a 51% increase. The number of patients hospitalized decreased and hospital lengths of stay were shorter during the study period than in the same patients in the 6-mo period preceding the study (P < 0.05). Nine patients (5.7%) had thrombosis of the vascular access. There were no changes in the prevalence of arterial hypertension, but three patients (2%) showed hypertension that was difficult to control. It is concluded that normalization of hematocrit in selected hemodialysis patients, i.e., nondiabetic patients without severe cardiovascular or cerebrovascular comorbidities, improves quality of life and decreases morbidity without significant adverse effects.

Guideline 11: Monitoring of haemoglobin concentration during epoetin treatment

Guideline 11: Monitoring of haemoglobin concentration during epoetin treatment

Guideline 17: Possible adverse effects of epoetin treatment: hypertension

Guideline 17: Possible adverse effects of epoetin treatment: hypertension

Guideline 18: Possible adverse effects of epoetin treatment: access thrombosis

Guideline 18: Possible adverse effects of epoetin treatment: access thrombosis

Guideline 14: Causes of an inadequate response to epoetin treatment

Guideline 14: Causes of an inadequate response to epoetin treatment

What are the short-term and long-term consequences of anaemia in CRF patients?

There is a clear relationship between anaemia and cardiovascular risk in chronic renal failure (CRF) patients. Left ventricular hypertrophy (LVH) is present in about three-quarters of patients starting dialysis, and is a strong predictor of mortality. Anaemia contributes to the development of LVH, mainly via increased cardiac output. In some patients, anaemia results in an increase in LV mass, while in others it also results in LV end-diastolic volume dilatation. These changes increase the risk of arrhythmias, myocardial infarction and myocardial fibrosis. The lower the haemoglobin, the more likely it is that LVH and heart failure will develop. Furthermore, a haemoglobin of < 11 g/dl is associated with increased morbidity and mortality. Partial correction of anaemia with epoetin leads to a partial, but not complete, reversal of LVH. One large prospective study (Lombardy Registry) found that epoetin treatment was accompanied by a 30% reduction in crude relative risk of mortality. A progressive reduction in the relative risk of general and cardiovascular mortality was found with increasing haematocrit, with and without adjustment for co-morbid conditions. Mean hospitalizations also decreased with increasing haematocrit. The long-term effects of normalized haematocrit/haemoglobin values in uraemic patients have not yet been evaluated exhaustively in prospective, randomized, multicentre studies. Epoetin treatment has been shown to induce lasting improvements in patients' sense of well-being, reduce fatigue, increase appetite and work capacity, and improve exercise tolerance, libido and work performance. Further studies are needed to demonstrate whether greater haemoglobin concentrations are associated with greater improvements in quality of life during epoetin treatment.

Should anaemia in subtypes of CRF patients be managed differently?

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.

European best practice guidelines for the management of anaemia in patients with chronic renal failure.

Best practice guidelines recommend management strategies and attempt to set standards for optimal patient care. The momentum towards formulating guidelines comes not only from health care professionals, but also from health care management organizations, who need some way of measuring the quality of the services they purchase. The European Best Practice Guidelines for the Management of Anaemia in Patients with Chronic Renal Failure have been drawn up by a Working Party including representatives of the European Renal Association/European Dialysis and Transplantation Association (ERA-EDTA) and the national nephrology societies of a cross-section of European countries. The guidelines draw on the National Kidney Foundation-Dialysis Outcomes Quality Initiative (NKF-DOQI) Clinical Best Practice Guidelines for the Treatment of Anemia in Chronic Renal Failure, but reflect European clinical practice and experience. They include additional publications, and new analysis and interpretation of the evidence base. Topics covered in the European guidelines include diagnosis of the anaemia of chronic renal failure, indications for starting treatment with epoetin, recommended minimum target haemoglobin concentrations, epoetin dosage and route of administration, assessing and optimizing iron stores, causes and management of epoetin resistance, and possible adverse effects of epoetin treatment. The guidelines are not intended to be prescriptive but rather to provide clinical guidance based on the best available evidence. The evidence supporting each guideline is graded, so that physicians may judge its reliability.

Endocrinology and Pd: Optimal Treatment of Anemia in Peritoneal Dialysis Patients

The optimal treatment of anemia in peritoneal dialysis is given by subcutaneous administration of epoetin. The optimal dosing frequency is in most patients 2 -3 injections per week, but in responsive patients once a week may be enough during the maintenance phase. Both before starting and during epoetin treatment it is necessary to monitor for factors causing hyporesponsiveness. The epoetin dose is adjusted monthly aiming at an increase in Hb concentration of 10 g/L per month. Further studies are required to define the optimal target Hb concentration. Iron supplements should be administered routinely. Parenteral iron may be used liberally when oral supplements are ineffective or inconvenient.In the initial three-month period of peritoneal dialysis a marked increase in Hb concentration is common, and if epoetin treatment is necessary low starting doses will be sufficient. In patients with moderate anemia, adequate iron stores and iron availability, and no significant comorbidity, low starting doses are recommended (50 75 U kg-1 week-1). Patients with severe anemia or with comorbidity usually require higher doses and may be started with 75 150 kg-1 week-1. Hypertension is the principal adverse effect of epoetin treatment in patients with chronic renal failure, but it is usually easily controlled by fluid control and/or increased antihypertensive medication.