Robert Provenzano

Ferumoxytol as an Intravenous Iron Replacement Therapy in Hemodialysis Patients

BACKGROUND AND OBJECTIVES Intravenous iron is a key component of anemia management for chronic kidney disease (CKD). Ferumoxytol is a unique intravenous iron product that can be administered as a rapid injection in doses up to 510 mg. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This was a randomized, open-label, controlled, multicenter Phase 3 trial to evaluate the safety and efficacy of intravenous ferumoxytol compared with oral iron. Anemic patients with CKD stage 5D on hemodialysis and on a stable erythropoiesis-stimulating agent regimen received either two injections of 510 mg of ferumoxytol within 7 d (n = 114) or 200 mg elemental oral iron daily for 21 d (n = 116). The primary efficacy endpoint was the change in hemoglobin from baseline to day 35. Safety was closely monitored. RESULTS Ferumoxytol resulted in a mean increase in hemoglobin of 1.02 +/- 1.13 g/dl at day 35 compared with 0.46 +/- 1.06 g/dl with oral iron (P = 0.0002). Twice as many ferumoxytol-treated patients than oral iron-treated patients achieved a > or =1 g/dl hemoglobin increase at day 35 (P = 0.0002). There was a greater mean increase in transferrin saturation (TSAT) with ferumoxytol compared with oral iron at day 35 (P < 0.0001). The larger hemoglobin increase after ferumoxytol compared with oral iron at day 35 persisted after adjustment for baseline hemoglobin, TSAT, and serum ferritin. Overall adverse event rates were comparable between groups. CONCLUSIONS In patients on hemodialysis, rapid intravenous injection of 510 mg of ferumoxytol led to significantly greater hemoglobin increases compared with oral iron, with comparable tolerability.

C.E.R.A. Corrects Anemia in Patients with Chronic Kidney Disease not on Dialysis: Results of a Randomized Clinical Trial

BACKGROUND AND OBJECTIVES This study examined the efficacy of C.E.R.A., a continuous erythropoietin receptor activator, for correcting anemia in patients who had chronic kidney disease (CKD) and were not on dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In this open-label, randomized, parallel-group, Phase III study, 324 adult patients with CKD not on dialysis nor receiving treatment with erythropoiesis-stimulating agents (ESAs) were randomly assigned (1:1) to receive subcutaneous C.E.R.A. once every 2 wk or darbepoetin alfa once weekly during an 18-wk correction period and a 10-wk evaluation period. Thereafter, patients receiving C.E.R.A. were randomly assigned to C.E.R.A. once every 2 wk or once monthly, and patients receiving darbepoetin alfa could receive darbepoetin alfa once weekly or once every 2 wk for a 24-wk extension period. Dosage was adjusted to achieve a hemoglobin (Hb) response and to maintain Hb +/-1 g/dl of the response level and 11 to 13 g/dl. Primary end points were Hb response rate during correction and evaluation and change in Hb concentration between baseline and evaluation. RESULTS Hb response rates were 97.5% for C.E.R.A. and 96.3% for darbepoetin alfa. Adjusted mean changes in Hb from baseline to evaluation were 2.15 g/dl (C.E.R.A.) and 2.00 g/dl (darbepoetin alfa). Analysis showed that C.E.R.A. once every 2 wk was as effective as darbepoetin alfa once weekly for correcting anemia. Hb levels remained stable in all groups during the extension period. C.E.R.A. and darbepoetin alfa were well tolerated. CONCLUSIONS Subcutaneous C.E.R.A. once every 2 wk corrects anemia in ESA-naïve patients who are not on dialysis.

Chronic Kidney Disease: Common, Harmful, and Treatable—World Kidney Day 2007

Thursday, March 8, 2007, is World Kidney Day! World Kidney Day was proposed by the International Society of Nephrology and International Federation of Kidney Foundations in 2006 to broadcast a message about kidney diseases to the public, government health officials, general physicians, allied health

Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients

Background Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis. This Phase 2a study tested efficacy (Hb response) and safety of roxadustat in anemic nondialysis-dependent chronic kidney disease (NDD-CKD) subjects. Methods NDD-CKD subjects with hemoglobin (Hb) ≤11.0 g/dL were sequentially enrolled into four dose cohorts and randomized to roxadustat or placebo two times weekly (BIW) or three times weekly (TIW) for 4 weeks, in an approximate roxadustat:placebo ratio of 3:1. Efficacy was assessed by (i) mean Hb change (ΔHb) from baseline (BL) and (ii) proportion of Hb responders (ΔHb ≥ 1.0 g/dL). Pharmacodynamic evaluation was performed in a subset of subjects. Safety was evaluated by adverse event frequency/severity. Results Of 116 subjects receiving treatment, 104 completed 4 weeks of dosing and 96 were evaluable for efficacy. BL characteristics for roxadustat and placebo groups were comparable. In roxadustat-treated subjects, Hb levels increased from BL in a dose-related manner in the 0.7, 1.0, 1.5 and 2.0 mg/kg groups. Maximum ΔHb within the first 6 weeks was significantly higher in the 1.5 and 2.0 mg/kg groups than in the placebo subjects. Hb responder rates were dose dependent and ranged from 30% in the 0.7 mg/kg BIW group to 100% in the 2.0 mg/kg BIW and TIW groups versus 13% in placebo. Conclusions Roxadustat transiently and moderately increased endogenous erythropoietin and reduced hepcidin. Adverse events were similar in the roxadustat and placebo groups. Roxadustat produced dose-dependent increases in blood Hb among anemic NDD-CKD patients in a placebo-controlled trial. Clinical Trials Registration Clintrials.gov #NCT00761657.

Peginesatide in patients with anemia undergoing hemodialysis.

BACKGROUND Peginesatide, a synthetic peptide-based erythropoiesis-stimulating agent (ESA), is a potential therapy for anemia in patients with advanced chronic kidney disease. METHODS We conducted two randomized, controlled, open-label studies (EMERALD 1 and EMERALD 2) involving patients undergoing hemodialysis. Cardiovascular safety was evaluated by analysis of an adjudicated composite safety end point--death from any cause, stroke, myocardial infarction, or serious adverse events of congestive heart failure, unstable angina, or arrhythmia--with the use of pooled data from the two EMERALD studies and two studies involving patients not undergoing dialysis. In the EMERALD studies, 1608 patients received peginesatide once monthly or continued to receive epoetin one to three times a week, with the doses adjusted as necessary to maintain a hemoglobin level between 10.0 and 12.0 g per deciliter for 52 weeks or more. The primary efficacy end point was the mean change from the baseline hemoglobin level to the mean level during the evaluation period; noninferiority was established if the lower limit of the two-sided 95% confidence interval was -1.0 g per deciliter or higher in the comparison of peginesatide with epoetin. The aim of evaluating the composite safety end point in the pooled cohort was to exclude a hazard ratio with peginesatide relative to the comparator ESA of more than 1.3. RESULTS In an analysis involving 693 patients from EMERALD 1 and 725 from EMERALD 2, peginesatide was noninferior to epoetin in maintaining hemoglobin levels (mean between-group difference, -0.15 g per deciliter; 95% confidence interval [CI], -0.30 to -0.01 in EMERALD 1; and 0.10 g per deciliter; 95% CI, -0.05 to 0.26 in EMERALD 2). The hazard ratio for the composite safety end point was 1.06 (95% CI, 0.89 to 1.26) with peginesatide relative to the comparator ESA in the four pooled studies (2591 patients) and 0.95 (95% CI, 0.77 to 1.17) in the EMERALD studies. The proportions of patients with adverse and serious adverse events were similar in the treatment groups in the EMERALD studies. The cardiovascular safety of peginesatide was similar to that of the comparator ESA in the pooled cohort. CONCLUSIONS Peginesatide, administered monthly, was as effective as epoetin, administered one to three times per week, in maintaining hemoglobin levels in patients undergoing hemodialysis. (Funded by Affymax and Takeda Pharmaceutical; ClinicalTrials.gov numbers, NCT00597753 [EMERALD 1], NCT00597584 [EMERALD 2], NCT00598273 [PEARL 1], and NCT00598442 [PEARL 2].).

Oral Hypoxia–Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for the Treatment of Anemia in Patients with CKD

BACKGROUND AND OBJECTIVES Roxadustat (FG-4592), an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis, regulates iron metabolism, and reduces hepcidin, was evaluated in this phase 2b study for safety, efficacy, optimal dose, and dose frequency in patients with nondialysis CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The 145 patients with nondialysis CKD and hemoglobin ≤10.5 g/dl were randomized into one of six cohorts of approximately 24 patients each with varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (two and three times weekly) followed by hemoglobin maintenance with roxadustat one to three times weekly. Treatment duration was 16 or 24 weeks. Intravenous iron was prohibited. The primary end point was the proportion of patients achieving hemoglobin increase of ≥1.0 g/dl from baseline and hemoglobin of ≥11.0 g/dl by week 17 (16 weeks of treatment). Secondary analyses included mean hemoglobin change from baseline, iron utilization, and serum lipids. Safety was evaluated by frequency/severity of adverse events. RESULTS Of the 145 patients enrolled, 143 were evaluable for efficacy. Overall, 92% of patients achieved hemoglobin response. Higher compared with lower starting doses led to earlier achievement of hemoglobin response. Roxadustat-induced hemoglobin increases were independent of baseline C-reactive protein levels and iron repletion status. Overall, over the first 16 treatment weeks, hepcidin levels decreased by 16.9% (P=0.004), reticulocyte hemoglobin content was maintained, and hemoglobin increased by a mean (±SD) of 1.83 (±0.09) g/dl (P<0.001). Overall mean total cholesterol level was reduced by a mean (±SD) of 26 (±30) mg/dl (P<0.001) after 8 weeks of therapy, independent of the use of statins or other lipid-lowering agents. No drug-related serious adverse events were reported. CONCLUSIONS In patients with nondialysis CKD who were anemic, various starting dose regimens of roxadustat were well tolerated and achieved anemia correction with reduced serum hepcidin levels. After anemia correction, hemoglobin was maintained by roxadustat at various dose frequencies without intravenous iron supplementation.

Chronic Kidney Disease: Common, Harmful and Treatable – World Kidney Day 2007

T hursday, March 8, 2007, is World Kidney Day! World Kidney Day was proposed by the International Society of Nephrology and International Federation of Kidney Foundations in 2006 to broadcast a message about kidney diseases to the public, government health officials, general physicians, allied health professionals, individuals, and families. It was launched on March 9, 2006, and will be fully inaugurated this year (http://www.worldkidneyday.org/). The message is that kidney disease is common, harmful, and treatable. In this article, we focus on chronic kidney disease (CKD) as a global public health problem and the urgent need for all countries to have a public health policy for CKD. Until recently, decision makers in public health and biomedical science had viewed CKD as uncommon, without consequences, and untreatable until the stage of kidney failure. The care of patients with CKD had been marginalized, relegated to the subspecialty of nephrology, with payment primarily directed at dialysis and transplantation, which are too costly for the vast majority of people who live outside the developed world. At the same time, costs for other chronic diseases have been mounting. In developed countries, hypertension, diabetes, and cardiovascular disease (CVD) consume a large fraction of resources for health care. The epidemic of obesity will magnify these costs, in the young as well as in the elderly. In developing countries, the burden of these noncommunicable diseases is rising even though communicable diseases are not yet under control. We now recognize that CKD is especially common in people with other chronic diseases and multiplies the risk for adverse outcomes and costs. The public health mandate now is clear. No country can afford to overlook the burden of CKD; prevention, early detection, and intervention are the only cost-effective strategies. In the following paragraphs, we outline the rationale for key elements of a public health policy for CKD and for integrating these elements with programs for other chronic diseases. Rationale Figure 1 shows a conceptual model for CKD as the basis for a public health approach, emphasizing stages of CKD, as well as antecedents, outcomes, and risk factors for development and progression of CKD. CKD is defined as either kidney damage, estimated from markers such as albuminuria, or GFR 60 ml/min per 1.73 m for 3 mo or more (1–3). Albuminuria usually is defined as spot urine protein-to-creatinine ratio 30 mg/g, and GFR usually is estimated from serum creatinine, age, gender, and race. In the United States, recent data from the National Health and Nutrition Examination Survey (NHANES) estimate the prevalence of CKD to be 9.6% in noninstitutionalized adults, corresponding to approximately 19 million people (Table 1) (4,5). The elderly, racial and ethnic minorities, and those with lower socioeconomic status are disproportionately affected. Prevalence estimates in other countries are difficult to interpret because of differences in serum and urine creatinine levels as a result of variability among studies in assays, muscle mass, and diet. Nonetheless, in both developed and developing nations, a consistent picture is emerging of increased risk for CKD among people with CVD risk factors or established CVD. The most important adverse outcomes of CKD include not only complications of decreased GFR and progression to kidney failure but also increased risk for CVD. Many studies show that albuminuria and decreased estimated GFR each consistently and in a graded manner increase the risk for CVD (6). Indeed, recent studies showed that patients with CKD are 100 times more likely to die, principally from CVD, than to develop kidney failure (7). There now are convincing data for efficacy of treatment to prevent complications of decreased GFR, to slow progression of kidney disease, and to reduce CVD risk. Testing for CKD is feasible in clinical practice, and the same methods can be applied in large-scale screening of people who are at increased risk. Therefore, the tools to improve outcomes for CKD are already available. It now is time to establish policies to translate these advances to public health.

Effect of biocompatibility of hemodialysis membranes on serum albumin levels

Hypoalbuminemia in end-stage renal disease is a marker of high morbidity and mortality. In some patients, the cause of low serum albumin levels is easily identified and therefore treatable, but in many patients, the cause is not clear. We studied the effect of changing the dialysis membrane from a bioincompatible to a biocompatible membrane on serum albumin level. Stable hemodialysis patients dialyzed with cuprammonium membranes who had serum albumin levels less than 3.5 g/dL were switched to the more biocompatible membrane, polysulfone. Serum albumin levels increased from 3.22 +/- 0.037 to 3.35 +/- 0.038 g/dL (mean +/- SE; P < 0.002). The increase was seen in patients both with and without diabetes. Thus, dialyzer membrane may affect serum albumin levels and should be considered in the differential diagnosis of hypoalbuminemia in patients undergoing hemodialysis with bioincompatible membranes. Membrane choice may have an important effect on the outcome of morbidity and mortality of hemodialysis patients.

Pulmonary mucormycosis in diabetic renal allograft recipients

Renal allograft recipients are prone to opportunistic infections due to their need of immunosuppression to prevent rejection. Mucormycosis is a rare opportunistic infection caused by a fungi of the order Mucorales. Risk factors predisposing to this disease include prolonged neutropenia, chelation therapy for iron or aluminum overdose, diabetes, and patients who are immunosuppressed. Life-threatening infections can occur, as this fungi has the propensity to invade blood vessel endothelium, resulting in hematologic dissemination. Early diagnosis and prompt aggressive therapy is imperative to achieve an improved outcome. We present two cases of pulmonary mucormycosis in diabetic renal allograft recipients who were treated successfully with amphotericin B and surgical resection of the lesions with preservation of their allograft function. In this era of intensified immunosuppression, we may see an increased incidence of mucormycosis in our transplant population.

Role of Aldosterone in Left Ventricular Hypertrophy among African-American Patients with End-Stage Renal Disease on Hemodialysis

Aims: Recently, serum aldosterone levels have been reported to play a significant role in cardiac hypertrophy. One study of Japanese patients correlated aldosterone levels with the degree of left ventricular hypertrophy (LVH) in those undergoing hemodialysis. However, the role of aldosterone in LVH in non-Japanese patients with end-stage renal disease (ESRD) has not been established. Materials and Methods: Researchers evaluated 42 [29 African-Americans (69%), 11 Caucasians (26%), and 2 other (5%)] male ESRD patients on dialysis for more than 6 months. Pre- and postdialysis, blood pressures and aldosterone and renin concentrations were measured. Transthoracic echocardiography was performed and left ventricular mass (LVM) index was calculated using the Devereaux formula. Medications were reviewed. Results: There were no differences noted in medications prescribed for African-Americans and for Caucasians. Additionally, data from diabetic patients showed no statistically significant correlation between LVM index and any of the variables, including pre- and postdialysis blood pressure, serum potassium, renin, and aldosterone levels, for African-Americans compared to Caucasians. Data from nondiabetic patients showed a positive correlation between LVM and plasma aldosterone concentration in African-Americans (n = 10). Data from nondiabetic Caucasians were disregarded because only one was studied. Conclusion: LVM and aldosterone correlate in African-American males with ESRD on hemodialysis without diabetes. This has important implications for the etiology of, and therapy for LVH in this population. Larger studies are needed to determine whether the same associations exist in females and Caucasians.