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The FDA first licensed erythropoiesis stimulating agents (ESA) for use in patients with ESRD in 1989. Hemoglobin targets for treatment with ESAs were established at the outset on the basis of descriptive pre-ESA literature and Phase I-III data in patients with ESRD. Postrelease literature in ESA-treated patients accumulating over time initially supported improvement in indices of both cardiovascular and other organ function as well as quality of life with therapy. Recommended treatment targets for hemoglobin would evolve further in the United States from four iterations of evidence- and opinion-based practice guidelines appearing between 1997 and 2007. Several randomized, controlled trials published from 1998 to 2009 examined normalization and near-normalization of hemoglobin in patients with both ESRD and CKD; they raised fundamental questions as to the safety of robust correction of anemia. These findings, taken together with subsequent actions of the FDA in ESA labeling and CMS's quality expectations for hemoglobin in payment for dialysis treatments, would result in a comprehensive reassessment of the hemoglobin targets in ESA therapy. A marked decrease in both national ESA utilization and hemoglobin attainment has ensued as a result. This discussion addresses the history of the striking changes in enthusiasm for hemoglobin-targeted anemia therapy from 1989 to the present, and similarly examines the evolution of ferritin-targeted iron administration, which has followed different-and markedly slower-historical development.

Risk factors and mortality associated with calciphylaxis in end-stage renal disease. Background We conducted a case control study to determine risk factors and mortality associated with calciphylaxis in end-stage renal disease. Methods Cases of calciphylaxis diagnosed between December 1989 and January 2000 were identified. Three controls were identified for each hemodialysis patient, with calciphylaxis matched to the date of initiation of hemodialysis. Laboratory data and medication doses were recorded during the 12 months prior to the date of diagnosis and at the time of diagnosis of calciphylaxis. Conditional logistic regression was used to identify risk factors for calciphylaxis. Cox proportional hazards models were used to estimate the risk of death associated with calciphylaxis. Results Nineteen cases and 54 controls were identified. Eighteen patients were hemodialysis patients, and one had a functioning renal allograft. Diagnosis was confirmed by skin biopsy in 16 cases. Women were at a sixfold higher risk of developing calciphylaxis (OR = 6.04, 95% CI 1.62 to 22.6, P = 0.007). There was a 21% lower risk of calciphylaxis associated with each 0.1 g/dL increase in the mean serum albumin during the year prior to diagnosis and at the time of diagnosis of calciphylaxis (OR = 0.79, 95% CI, 0.64 to 0.99, P = 0.037, and OR=0.80, 95% CI, 0.67 to 0.96, P = 0.019, respectively). There was a 3.51-fold increase in the risk of calciphylaxis associated with each mg/dL increase in the mean serum phosphate during the year prior to diagnosis (95% CI, 0.99 to 12.5, P = 0.052). At the time of diagnosis of calciphylaxis, for each 10 IU/L increment in alkaline phosphatase, the risk of calciphylaxis increased by 19% (OR = 1.19, 95% CI, 1.00 to 1.40, P = 0.045). Body mass index, diabetes, blood pressure, aluminum, and higher dosage of erythropoietin and iron dextran were not independent predictors of calciphylaxis. Calciphylaxis independently increased the risk of death by eightfold (OR = 8.58, 95% CI, 3.26 to 22.6, P Conclusions Female gender, hyperphosphatemia, high alkaline phosphatase, and low serum albumin are risk factors for calciphylaxis. Calciphylaxis is associated with a very high mortality.

The role of anaemia in the pathogenesis of abnormal cognitive function in haemodialysis patients is only partly understood. Several contemporary studies have assessed cognitive function in haemodialysis patients using neuropsychological and neurophysiological tests, comparing the results obtained over a wide range of haematocrits before and after treatment with epoetin. Of the neurophysiological tests, which measure electrical impulses from the brain in the presence or absence of specific stimuli, the cognitive event-related potential (ERP) has been particularly useful in evaluating this issue. Changes in amplitude (increase) and latency (decrease) of a specific wave form (P300) seen in the ERP correlate with improved cognitive function in haemodialysis patients following initiation of dialysis therapy. Similar effects are also evident when haematocrit is increased. Marsh et al. (Kidney Int 1991; 39: 155- 163) examined the effect of increasing haematocrit with epoetin therapy on the P300 amplitude and latency, and noted that after increasing haematocrit to 23.7-36% over 12 months with epoetin, P300 amplitude increased (P

Anemia in hemodialysis patients is effectively treated by intravenous (IV) injections of recombinant human erythropoietin (rHuEPO) at each dialysis session. Because the hormone is effective by subcutaneous (SC) administration, it was decided that this study would evaluate low-dose weekly SC rHuEPO therapy. To determine the safety and efficacy of weekly SC rHuEPO administration to hemodialysis patients, only one third the weekly IV dose was given and the effects were compared with those from an age-, gender-, and nephrologic disease-matched control group treated in the standard fashion. Forty-four patients entered the trial and 27 completed the protocol along with 27 control subjects. During Phase 1, experimental and control subjects received standard IV rHuEPO at dialysis for 6 months. During Phase 2, experimental patients received weekly SC rHuEPO at one third the weekly IV dose for 10 months; control subjects continued to receive IV therapy. In Phase 3, both groups were treated for 6 more months with IV rHuEPO. In Phase 2, there was no significant reduction in hematocrit value, reticulocyte count, transferrin saturation, or ferritin level in the experimental group, even with only one third the weekly rHuEPO IV dose over the 10-month period. There were no significant differences between IV and SC rHuEPO administration or between experimental and control subjects in blood pressure, serum chemistries, or parameters of "dialysis adequacy." It was concluded that low-dose weekly SC rHuEPO administration is a safe and effective method for maintaining the hematocrit level of stable hemodialysis patients. This therapy could enhance the efficacy of rHuEPO and substantially reduce costs while preserving patient care outcomes.

Impoverished patients may represent a high-risk population with poor survival. With 1993 U.S. Renal Data System survival tables (to adjust the risk of death for differences in age, race, and ESRD diagnosis), the mortality rates of patients over 3 yr in a large inner-city dialysis facility using high-flux technique were compared with national averages. At least 93.7% of patients were African-American, 50% had incomes below $7,000 per year, and employment was 5% or less. Observed and expected deaths (the latter derived from the U.S. Renal Data System tables) were used to calculate a standardized mortality ratio (observed deaths/expected deaths); the U.S. average is 1.0. The standardized mortality ratio at this facility for each year was < 0.600 and was significantly lower than the U.S. average in 1991, in 1992 (P < 0.05), and for all 3 yr (P < .001). Over all 3 yr, it was lower for females (0.540, P < 0.05), males (0.620, P < 0.05), patients with diabetes (0.593, P < 0.05), and glomerulonephritis (0.318, P < 0.05). For the 3 yr, a Cox regression analysis revealed independent associations between mortality and age (P = 0.004), serum albumin (P = 0.02), Kt/V (P = 0.02), and dialysis for more than 2 yr (P = 0.01). Patients with economic hardship can attain survival significantly better than the national average with the provision of adequate dialysis, nutrition, and support services.

Hypogonadism and anemia are common comorbid conditions in dialysis patients. Testosterone replacement may improve such clinical parameters as anemia, sarcopenia, and low libido. Additionally, by increasing hemoglobin levels, testosterone replacement may allow for a dose reduction in recombinant human erythropoietin (rHuEPO), thereby reducing cost.This phase IV, single-center, placebo-controlled, double-blind study assessed the effect of transdermal testosterone on serum testosterone levels, rHuEPO dose required to maintain hemoglobin level, bone mineral content, lean body mass and fat content, cholesterol level, sexual function, and mood. Forty hypogonadal male hemodialysis patients who were administered rHuEPO were randomly assigned to 100 mg of topical 1% testosterone gel (Testim; Auxilium Pharmaceuticals, Norristown, PA) or placebo, applied daily for 6 months.Forty men with a mean age of 56 years and baseline serum testosterone level less than 300 ng/dL (10.4 nmol/L) participated in this trial. In men assigned to administration of transdermal testosterone, there was an increase beyond that in the placebo group in mean serum testosterone (77.1 ng/dL [2.7 nmol/L]), dihydrotestosterone (DHT; 0.8 nmol/L), and estradiol levels (6.3 pg/mL [23.0 pmol/L]) and a decrease in mean serum luteinizing hormone levels (-3.1 IU/L). Compared with subjects administered placebo, participants on testosterone replacement therapy did not show an appreciable change in rHuEPO dose (mean difference adjusted for baseline values, 12.6 U/kg/wk; P = 0.73), bone mineral density, lean body mass or fat content, cholesterol level, sexual function, or mood.Daily administration of 100 mg of topical 1% testosterone gel for 6 months failed to significantly increase serum testosterone or DHT levels in hypogonadal men with end-stage renal disease. Treatment with transdermal testosterone did not impact on rHuEPO requirement or clinical parameters in this small placebo-controlled study. Greater serum testosterone levels may be required to show clinical benefit in men with end-stage renal disease.

An increasing number of reports documenting resistance to human recombinant erythropoietin (rHuEPO) therapy are challenging the concept that erythropoietin deficiency is the main cause of the anaemia of chronic kidney disease (CKD). In an attempt to establish whether other factors play a more predominant role in the anaemia of CKD, 988 patients receiving dialysis were assessed for a wide range of variables. Data were collected on haematocrit (Hct) levels, rHuEPO dose, dry weight, serum ferritin, transferrin saturation, serum albumin, serum aluminium, serum parathyroid hormone intact, eKt/V for urea, gender, dose of i.v. iron administered, time in hospital, and use of i.v. vancomycin. Hyporesponsiveness to rHuEPO was defined as patients requiring500 IU/kg/week or failing to achieve Hct levels of30%. Ninety-two (9.2%) of the 988 patients met the above criteria for hyporesponsiveness to rHuEPO. In 21 of these patients, Hct concentrations remained30% at 6-month follow-up. There were known haematological causes of refractoriness to rHuEPO in nine of these patients. During extended follow-up, probable causes of hyporesponsiveness were discovered in all but two of the remaining 13 patients. Of 62 dialysis patients who received rHuEPO at doses500 IU/kg/week, 45 (73%) had Hct concentrations of 33-42%. These patients were responding to the higher doses of rHuEPO with no obvious adverse effects. Lower values of serum ferritin, transferrin saturation, and eKt/V, or higher levels of parathyroid hormone or serum aluminium were not associated with higher rHuEPO dose requirements. These results suggest that erythropoietin deficiency is still the main cause of the anaemia of CKD. Erythropoietin replacement therapy can correct the anaemia in almost all iron replete patients providing enough hormone is given, functional iron deficiency is avoided, aluminium levels and parathyroid toxicities are controlled and that no de novo haematological condition that affects erythropoiesis or red blood cell survival develops. Consideration should be given to modifying the definition of rHuEPO hyporesponsiveness. The US Hct target of 33-36% for haemodialysis patients is narrow and the European target of Hct33% may be significantly more practical and physiologically relevant.

Increasing use of medications designed specifically for intravenous administration during hemodialysis has dramatically improved the treatment of many comorbid conditions accompanying end-stage renal disease. Recombinant human erythropoietin has resulted in definitive treatment of the hypoproliferative anemia of uremia, while sustained response to this hormone has been facilitated by treatment with intravenous iron dextran. Simple and effective therapies for many gram-positive infections in end-stage renal disease patients have been realized through the favorable pharmacokinetics and low toxicity of vancomycin when administered during hemodialysis. Major improvements in the therapy of high-turnover bone disease have resulted from the increasing use of intravenous calcitriol during dialysis as well. The contributions of these four medications in improving patient care and the benefits of their administration during the dialysis procedure are reviewed.

Iron overload from repeated transfusions of RBCs in long-term hemodialysis patients is a problem of increasing clinical significance. We report on the prevalence of and diagnostic criteria for identification of hemodialysis patients with iron overload. In 150 unselected hemodialysis patients, 62 (41%) had ferritin levels greater than 2,000 ng/mL (normal = 10 to 360 ng/mL). In 16 of these patients, accurate transfusion histories were obtained and ferritin levels correlated with calculated transfusional iron burden (r = 0.553, P less than .05). These patients could be divided into two distinct groups on the basis of their response to a single dose (2 g, IV) of deferoxamine: "high" responders had twice the level of feroxamine (the chelated product of deferoxamine and iron) of the "low" responders (P less than .001). High responders also had significantly higher prevalence of the "hemochromatosis" alleles A3, B7, and B14 than a large group of dialysis patients awaiting transplantation (71% v 37%, P less than .001). In two patients with iron overload and clinically significant bone disease, bone histology revealed prominent iron staining at the calcification front. We conclude that transfusional iron overload is a significant clinical problem in long-term hemodialysis patients, that may also be associated with bone pathology.