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ASPECTS OF IV FERUMOXYTOL ADMINISTRATION AND ACUTE ADVERSE EVENTS IN CKD PATIENTS 1Amit Sharma; 2Brigitte Schiller; 3Zhu Li; 3Lynn Milich; 3Annamaria Kausz 1Boise Kidney & Hypertension Institute, Meridian, ID; 2SatelliteHealthcare, Mountain View, CA; 3AMAG Pharmaceuticals, Inc., Lexington, MA

Feraheme™ (ferumoxytol) Injection, a novel IV iron for the treatment of iron deficiency anemia in patients with CKD, is composed of an iron oxide core with a unique carbohydrate coating, is isotonic, and has a neutral pH, with evidence of lower free iron than other IV irons. One of the advantages of ferumoxytol is that it can be administered as a 510 mg rapid (<1 min) injection with a favorable tolerability profile. To investigate aspects of administering a 1.02 g course, we hypothesized that the rate of acute AEs (within 24 hours post dose) would not differ following the first and second injection, or differ by number of days between injections. We pooled data from 3 pivotal studies in 590 adult dialysis and non-dialysis CKD patients who received 2 x 510 mg ferumoxytol within 2-8 days. There was no meaningful difference in AEs following one (7.8%) vs two (4.8%) injections. There was no trend in AEs associated with how soon the second injection was given (2-4 days: range, 4.6% to 16.0%; 5-8 days: 10.5% to 22.2%); in fact, the shortest interval between doses (2 days) was associated with one of the lowest AE rates (6.5%). These results suggest that 510 mg ferumoxytol is well tolerated, irrespective of the number of injection or interval between injections.

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DOSE CONVERSION ANALYSES BETWEEN EPOETIN ALFA (EPO) AND DARBEPEOTIN ALFA IN HOSPITAL-BASED DIALYSIS CENTERS (HBDCs) Amit Sharma, MD;1 Jerry Yee, MD;2 Shravanthi R Gandra, PhD, MBA;3 Irfan Khan, PhD;3 Jeffrey Petersen, MD3

1Boise Kidney and Hypertension Institute, Meridian, ID; 2Henry Ford Hospital, Detroit, MI; 3Amgen Inc., Thousand Oaks, CA The dose conversion relationship between EPO and darbepoetin alfa is non-proportional across the dosing spectrum. This analysis evaluates the maintenance dose conversion ratio (DCR) between the two erythropoiesis-stimulating agents (ESAs) for chronic hemodialysis (HD) patients in HBDCs using pre and post conversion data. This longitudinal analysis is based on retrospective chart review data from HD patients in 23 HBDCs (2004-2005) that underwent conversion from EPO to darbepoetin alfa. Patients were ≥18 years, had three-times-weekly (TIW) EPO dosing frequency before conversion, and a once-weekly darbepoetin alfa dosing frequency after conversion. No more than 4 consecutive missing TIW EPO dose was allowed. The mean EPO dose over an 8-week pre-conversion maintenance period (weeks -9 to -2), and mean darbepoetin alfa dose over an 8-week (weeks 21 to 28) post-conversion maintenance period were used in the analysis. A population-level mean maintenance DCR was calculated using two methods: a regression-based method using ordinary least squares regression analysis, and a ratio-based method where the DCR was calculated for each individual patient and then averaged for the study population to give a population-level DCR. A total of 337 patients were included; 53% male, and 51.9% were 65-89 years of age. Mean (SD) hemoglobin (Hb) levels for the EPO and darbepoetin alfa maintenance periods were comparable, 11.7 (0.9) and 11.6 (0.9) g/dL, respectively. The population-level DCR (95% CI) between EPO and darbepoetin alfa was 320 (298, 344) using the regression-based method, and 350 (319, 381) using the ratio-based method. The results of this analysis indicate that for a HBDC patient population converting from EPO to darbepoetin alfa and treated to comparable Hb levels, a mean DCR of 320 to 350 can be expected using methods that account for the non-proportional dose relationship.

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IGA NEPHRITIS AND AUTO IMMUNE HEPATITIS IN NEWLY DIAGNOSED SLE: A NEW TRIAD? Mukesh Sharma, Steven Turley, Karina Sulaiman Louisiana State University Health Sciences Center, Shreveport, LA Despite IgA nephritis (IgAN) being the most commonly diagnosed primary glomerulonephritis, its occurrence in conjunction with systemic lupus erythematosus (SLE) has been reported rarely. Although IgAN and lupus nephritis share some common pathophysiological characteristics, the exact underlying pathogenic mechanisms involved and their possible association is poorly understood. Also, though hepatic involvement in SLE is known to occur, the coexistence of SLE and autoimmune hepatitis is rare (1.3-1.7%). To our knowledge the concurrence of SLE, auto-immune hepatitis and IgA nephropathy has not been reported in the past. We report a case of a previously healthy 22 year old African American male who presented with generalized malaise, acute hepatitis with severe jaundice, and gross hematuria. Total bilirubin and transaminases were markedly increased. Renal function was normal but urine analysis was significant for macroscopic hematuria with less than a gram of proteinuria. Potential exposure to hepatotoxic and nephrotoxic drugs was ruled out. HIV, viral hepatitis screen and viral PCR were negative. ANA, anti dsDNA, anti smooth antibody were all positive and C3, C4 were low. After an extensive workup, diagnoses of SLE and auto-immune hepatitis were made. Renal biopsy showed increased mesangial deposits but no crescents, fibrosis, inflammatory infiltration or vasculitis. Electron microscopy showed numerous diffuse mesangial deposits and immunofluorescence was positive for IgA but not for IgM, C1q or fibrin. Oral prednisone was initiated and the clinical symptoms resolved within a week. The abnormal lab values returned to normal within three months. To date only five cases of IgA nephritis in SLE patients have been reported but the concurrence of IgA nephritis, autoimmune hepatitis and SLE has not been reported before. This case highlights the importance of renal biopsy in all lupus patients with abnormal findings on urine analysis. The occurrence of IgAN and autoimmune hepatitis in SLE adds to the myriad of clinical presentations of this disorder and thus is of interest.

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PRIMARY CILIA AND FLUID FLOW ESTABLISH THE ORIENTATION OF MITOTIC SPINDLES Neeraj Sharma and Bradley K. Yoder Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL , USA Disruption of renal cilia results in renal failure characterized by tubular dilation and development of cysts. Most of the proteins involved in cystic kidney diseases localize to cilia or basal body (centrosome) at the base of the cilium. However the connection between primary cilia and renal cysts initiation and progression is still unclear. Abnormal mitotic spindle misorientation is a prominent feature of renal cysts. We proposed that cilia and flow coordinately establish the orientation of mitotic spindles and insulting any of these can randomize the spindle orientation that may lead to cyst formation. To test this hypothesis, we have generated conditional cilia mutant collecting duct cell lines from the CAGG-CreERTM, Kif3aflox mice on the ImmortoMouse background. We analyzed mitotic spindle orientation in a series of imaging with parental and cilia mutant cells under linear flow conditions. We show that ciliated control cells orientate the mitotic spindles parallel to direction of flow whereas mutant cells lacking cilia display random orientation of cell divisions. Furthermore, to assess whether cilia loss and cyst development are associated with abnormal mitotic spindle orientation, we analyzed isolated tubules from Hoxb7-Cre IFT88 conditional mutants. We found that mitotic spindle orientation is more random in mutant than control kidneys. Our results suggest that loss of cilia primarily influences mitotic spindle orientation, which appears to be a major cause of cyst development. Intriguingly we found that cilia loss results in stable and posttranslationally modified cytoplasmic microtubules in vitro as well as in vivo. Furthermore, actin fibers appear to be unorganized in mutant cells. Based on these actin and microtubules phenotypes we propose that abnormal mitotic spindle orientations in cilia mutants could be the result of cytoskeleton defects.

NKF 2010 Spring Clinical Meetings Abstracts A101