Nephrology Dialysis Transplantation 27 (Supplement 2): ii28–ii30, 2012 doi:10.1093/ndt/gfs189
ANAEMIA FO059
CROSS-SPECIES EVALUATION OF PEGINESATIDE PHARMACOKINETICS, ERYTHROPOIETIC ACTIVITY, AND ERYTHROPOIETIN RECEPTOR (EPOR) BINDING
FO060 Table 2 Effect estimates of the association between various predictors and the log EPO resistance index (ERI) in univariate and multivariate analysis. Effect estimates represent change in the log ERI per unit change in the predictor. For all models, EPO resistance index was calculated as units of EPO used per week/ patient weight in Kg/ hemoglobin in g/dl at basel ine. %C-alb is carbamylated albumin level/ total serum albumin level. High %C-Alb is >= 0.01.
Jennifer M. Green1, Richard B. Mortensen2, K-L Fong3, Qing Fan2, Karen Leu2, Peter J. Schatz2 and Kathryn Woodburn4 1 Affymax, Inc., Palo Alto, USA, 2Affymax, Inc., 3Accellient Partners LLC, 4Affymax Inc, Palo Alto, USA Introduction and Aims: Peginesatide is a PEGylated, investigational, peptide-based erythropoiesis stimulating agent that is designed to specifically stimulate the EPOR and is currently being developed for the treatment of anemia of chronic kidney disease in dialysis patients. The peginesatide peptide has a unique structure with no sequence similarity to erythropoietin. This study was conducted across species to evaluate the pharmacokinetics (PK), to define the extent of systemic exposure, to characterize erythropoietic activity in vivo, and to examine a possible mechanism of clearance. Methods: Mouse, rat, rabbit, dog, and monkey were given a single IV dose of 0.05-2 mg/kg peginesatide. Blood samples were obtained for PK analysis and to evaluate erythropoietic response. Binding of peginesatide to the EPOR of each species was quantified using a radioligand competition binding assay. Results: Elimination of peginesatide from the plasma exhibited a biphasic pattern characterized by a rapid initial phase and a prolonged terminal phase. The dose-dependent half-lives ranged from 19.9 hours in the rat to 73.7 hours in dog. The volume of distribution approximated the plasma volume in each species, suggesting that peginesatide is confined primarily to the vascular compartment. Peginesatide was pharmacologically active in mice, rats, rabbits, and monkeys. Administration resulted in consistent dose-dependent increases in BFU-E, reticulocytes, hemoglobin, and red blood cells. Surprisingly, peginesatide was not active in the dog despite higher per-dose exposure than other species. Quantification of EPOR binding demonstrated that peginesatide binds to the mouse and rat EPOR with high affinity (IC50s of 101 and 38 pM, respectively). Although the dog EPOR is highly homologous with the EPOR from other species, peginesatide did not bind. A comparison of sequences revealed that methionine 150 of the EPOR, an amino acid previously shown to be involved in binding of peginesatide-related peptides, is conserved in all tested species except the dog. Mutation of the valine at this position in the dog EPOR to methionine allowed peginesatide to bind the mutant dog EPOR with high affinity (IC50 97 pM). Conclusions: A similar PK and erythropoietic response profile for peginesatide was observed across all species tested, except the dog. Peginesatide has a longer half-life and greater systemic exposure in the dog. This observation, taken together with the lack of peginesatide binding to the dog EPOR, suggests that clearance of peginesatide may be mediated in part by EPOR. FO060
PROTEIN CARBAMYLATION AND ERYTHROPOIETIN RESISTANCE IN END STAGE KIDNEY DISEASE
Sahir Kalim1, Hector Tamez2, Julia Wenger2, Elizabeth Ankers2, Anders Berg3, Ananth Karumanchi3 and Ravi Thadhani2 1 Massachusettes General Hosptial, Boston USA, 2Massachusetts General Hospital, Boston, USA, 3Beth Israel Deaconess Medical Center, Boston, USA Introduction and Aims: Erythropoeitin (EPO) is a growth factor commonly used to manage anemia in patients with chronic kidney disease (CKD). A significant clinical challenge is relative resistance to EPO, which leads to higher EPO doses, FO060 Table 1 The mean EPO resistance index score (natural log) for high and low carbamylated albumin groups. EPO resistance index is presented as units of EPO used per week/ patient weight in Kg/ hemoglobin in g/dl. %C-alb is carbamylated albumin level/ total serum albumin level. High %C-Alb is >= 0.01.
failure to achieve target hemoglobin levels, and increased risk of adverse outcomes. The etiology of EPO resistance is multi-factorial and likely relates to iron stores, inflammation, and other novel causes. Carbamylation-induced protein modifications have been shown to occur through both uremic and inflammatory pathways, and increase as kidney function declines. The post translational protein alterations of carbamylation may be involved in the progression of various diseases by changing the structure, charge, and function of enzymes, hormones, receptors, and amino acids. In this study we characterize the relationship between protein carbamylation and EPO resistance in incident hemodialysis patients, testing the hypothesis that carbamylation burden is independently associated with EPO resistance. Methods: One-hundred and seventy-nine subjects from the ArMORR (Accelerated Mortality in Renal Replacement) cohort, a prospective study with 10,044 incident hemodialysis patients, were selected based on the availability of carbamyaltion data. Carbamylated albumin level at day 90 from initation of dialysis was used as the surrogate of overall baseline carbamylation level. Prior work showing that elevated percent carbamylated albumin (%C-Alb > = 0.01) is significantly associated with all-cause mortality prompted us to dichotomize subjects into clinically meaningful high (> = 0.01) and low (< 0.01) %C-Alb groups. The primary outcome, EPO resistance index (ERI), was calculated as the weekly weight-adjusted dose of EPO (U/kg/week) divided by hemoglobin (Hgb) concentration (g/dL). ERI calculation utilized day 180 measures, reflecting 90 days of EPO treatment after the carbamylation measure. Univariate analysis measured the relationship between %C-Alb groups and ERI. Multiple linear regression adjusted for age, sex, race, baseline Hgb, parathyroid hormone level, body mass index (BMI), serum albumin, ferritin, and transferrin saturation level. Results: The mean %C-Alb was 0.0087 (median 0.0080, interquartile range 0.0038). The mean ERI score was 28.1 (median 18.7, interquartile range 27.5). Data was highly right skewed but fufilled model assumptions after log transformation. In univariate analysis, carbamylation level showed a significant positive association with ERI score ( p value < 0.001, Table 1). The multivariate model also showed %C-Alb groups were significantly associated with ERI after adjusting for covariates ( p value = 0.02, Table 2). Other variables significantly associated with ERI in univariate analysis were Hgb ( p value < 0.001), BMI ( p value < 0.001), albumin ( p value < 0.001), and ferritin ( p value = 0.004) (Table 2). In addition to %C-Alb, only Hgb ( p value < 0.001) and BMI ( p value < 0.001) retained statistical significance in the multivariate model (Table 2). While %C-Alb showed a positive relation with ERI, Hgb and BMI showed negative associations. Conclusions: Carbamylated albumin is associated with EPO resistance index at three months. The link between carbamylation and EPO resistance warrants further study to better understand the pathophysiology of anemia in CKD and how best to treat patients affected by it.
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Abstracts
Nephrology Dialysis Transplantation
FO061
HEMOSIDEROSIS DURING HEMODIALYSIS: AN MRI STUDY BASES ON 119 PATIENTS
Rostoker Guy1, Griuncelli Mireille1, Loridon Christelle1, Roy Myriam1, Exception: Index and length must refer to a location within the string. Parameter name: length1, Cohen Yves1 and Janklewicz Philipppe11Hôpital Privé Claude Galien Introduction and Aims: Most dialysis patients receiving erythropoesis-stimulating agents (ESA) also receive parenteral iron supplementation. There are few data on the risk of hemosiderosis in this setting. Methods: We prospectively measured liver iron concentration (LIC) by means of T1 and T2* contrast magnetic resonance imaging (MRI) without gadolinium, in a cohort of 119 fit hemodialysis patients receiving both parenteral iron and ESA in keeping with current guidelines. Results: Mild to severe hepatic iron overload was observed in 100 patients (84%; CI: 76%-90%), of whom 36% (CI: 27%-46%) had severe hepatic iron overload (LIC > 201 μmol/g of dry weight). In the cross-sectional study, infused iron, hepcidin and C-reactive protein values correlated with hepatic iron stores in both univariate analysis ( p
