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Background: Romosozumab is an antibody that binds and inhibits sclerostin, thereby increasing bone formation and decreasing bone resorption. A double-blinded, randomized, phase-2, dose-finding trial was performed to evaluate the effect of romosozumab on the radiographic and clinical outcomes of surgical fixation of tibial diaphyseal fractures. Methods: Patients (18 to 82 years old) were randomized 3:1:1:1:1:1:1:1:1:1 to a placebo or 1 of 9 romosozumab treatment groups. Patients received subcutaneous injections of romosozumab or the placebo postoperatively on day 1 and weeks 2, 6, and 12. The primary outcome was the time to radiographic evidence of healing ("radiographic healing") analyzed after the week-24 assessments had been completed for all patients. Results: A total of 402 patients were randomized: 299 to the romosozumab group and 103 to the placebo group. The median time to radiographic healing (the primary outcome) ranged from 14.4 to 18.6 weeks in the romosozumab groups and was 16.4 weeks (95% confidence interval [CI]: 14.6 to 18.0 weeks) in the placebo group, which was not a significant difference. There was also no significant difference in the median time to clinical healing, no relationship between romosozumab dose/frequency and unplanned revision surgery, and no apparent treatment benefit in terms of physical function. The safety and tolerability profile of romosozumab was comparable with that of the placebo. Conclusions: Romosozumab did not accelerate tibial fracture-healing in this patient population. Additional studies of patients at higher risk for delayed healing are needed to explore the potential of romosozumab to accelerate tibial fracture-healing. Level of evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

We evaluated the pharmacokinetics, pharmacodynamics, and safety of evolocumab, a fully human monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), in an open‐label, parallel‐design study in participants with normal renal function (n = 6), severe renal impairment (RI; n = 6), or end‐stage renal disease (ESRD) receiving hemodialysis (n = 6) who received a single 140‐mg dose of evolocumab. The effects of evolocumab treatment on low‐density lipoprotein cholesterol (LDL‐C) lowering and unbound PCSK9 concentrations were similar in the normal renal function group and the renally impaired groups. Geometric mean Cmax and AUClast values in the severe RI and ESRD hemodialysis groups compared with the normal renal function group were lower but within 37% of the normal renal function group (Jonckheere‐Terpstra trend test; Cmax, P = .23; AUClast, P = .22) and within 26% after adjusting for body weight (mean body weight was approximately 9% higher in the renally impaired groups compared with the normal renal function group). No correlations were observed between exposure and baseline creatinine clearance. No adverse event was determined by the investigators to be related to evolocumab, and there were no trends indicative of clinically important effects on laboratory variables or vital signs. Overall, there were no meaningful differences in evolocumab exposure, as assessed by Cmax and AUClast, in patients with severe RI and ESRD hemodialysis compared with patients with normal renal function, and LDL‐C‐lowering effects were similar across groups. These results support the use of evolocumab without dose adjustment in patients who have severe RI or ESRD.

Author(s): Schemitsch, Emil H; Miclau, Theodore; Karachalios, Theofilos; Nowak, Lauren L; Sancheti, Parag; Poolman, Rudolf W; Caminis, John; Daizadeh, Nadia; Dent-Acosta, Ricardo E; Egbuna, Ogo; Chines, Arkadi; Maddox, Judy; Grauer, Andreas; Bhandari, Mohit | Abstract: BackgroundRomosozumab is a bone-forming antibody that increases bone formation and decreases bone resorption. We conducted a double-blinded, randomized, phase-2, dose-finding trial to evaluate the effect of romosozumab on the clinical outcomes of open reduction and internal fixation of intertrochanteric or femoral neck hip fractures.MethodsPatients (55 to 94 years old) were randomized 2:3:3:3 to receive 3 subcutaneous injections of romosozumab (70, 140, or 210 mg) or a placebo postoperatively on day 1 and weeks 2, 6, and 12. The primary end point was the difference in the mean timed "Up a Go" (TUG) score over weeks 6 to 20 for romosozumab versus placebo. Additional end points included the time to radiographic evidence of healing and the score on the Radiographic Union Scale for Hip (RUSH).ResultsA total of 332 patients were randomized: 243 to receive romosozumab (70 mg, n = 60; 140 mg, n = 93; and 210 mg, n = 90) and 89 to receive a placebo. Although TUG scores improved during the study, they did not differ significantly between the romosozumab and placebo groups over weeks 6 to 20 (p = 0.198). The median time to radiographic evidence of healing was 16.4 to 16.9 weeks across treatment groups. The RUSH scores improved over time across treatment groups but did not differ significantly between the romosozumab and placebo groups. The overall safety and tolerability profile of romosozumab was comparable with that of the placebo.ConclusionsRomosozumab did not improve the fracture-healing-related clinical and radiographic outcomes in the study population.Level of evidenceTherapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

The pegfilgrastim on-body injector (OBI) is a single-use, disposable, battery-powered injector that is designed to automatically deliver a single subcutaneous dose of pegfilgrastim beginning approximately 27 hours after activation and continuing over approximately 45 minutes. In this open-label study, we assessed performance of the OBI delivering placebo buffer in healthy volunteers.Healthy men and women aged 18-55 years, with a body mass index of 18-35 kg/mThe primary endpoint of the study was successful delivery of placebo buffer based on a composite of the following: no substantial leakage during or after administration, green status light indicator on the injector during and after administration, and fill indicator bar at the empty position after administration. The secondary endpoint was the incidence of treatment-emergent adverse events (AEs).Of the 150 subjects enrolled, 149 (99.3%) completed the study. Study subjects were 48.0% men, and 52.0% women; 47.3% were white, 35.3% black or African American, 12.7% Asian, and 4.7% other. Mean (SD) age was 35.9 (10.8) years. Of the 297 total deliveries, 292 (98.3%) were considered successful: 147/149 (98.7%; 95% confidence interval [CI]: 95.2%-99.6%) to the abdomen and 145/148 (98.0%; 95% CI: 94.2%-99.3%) to the back of the upper arm. Five deliveries were considered unsuccessful: two due to hazard alarms, and three due to substantial leakage. The most common treatment-emergent AEs (in2% of subjects overall) by preferred term were medical device site reaction (20.7%), catheter-site hemorrhage (8.7%), and headache (3.3%). No serious AEs were reported.The pegfilgrastim OBI was well tolerated, and deliveries of placebo buffer were successful 98.3% of the time. The generalizability of these results may be limited by the conduct of this study in healthy subjects in a controlled environment.

Evolocumab binds PCSK9, increasing low-density lipoprotein cholesterol (LDL-C) receptors and lowering LDL-C. Target-mediated evolocumab elimination is attributable to PCSK9 binding. As circulating PCSK9 and LDL-C levels are primarily regulated by the liver, we compared evolocumab pharmacokinetics, pharmacodynamics, and safety in individuals with and without hepatic impairment. Open-label, parallel-group study evaluating the pharmacokinetics of evolocumab in hepatic-impaired (Child–Pugh Class A or B) or healthy adults. Participants were classified as having no, mild, or moderate hepatic impairment (n = 8/group), and received a single 140-mg evolocumab dose. Assessments of unbound evolocumab and PCSK9 were made pre- and post-dose. Adverse events were monitored throughout the study. No significant association was observed between baseline PCSK9 and increasing level of hepatic impairment. No difference in extent and time-course of PCSK9 or LDL-C reduction was observed, despite an apparent decrease in mean unbound evolocumab exposure with increasing hepatic impairment (Jonckheere–Terpstra trend test; maximum serum concentration: P = .18; area under the curve: P = .09). Maximum reductions were observed in moderately impaired subjects versus healthy individuals: mean maximum serum concentration, –34%; mean area under the concentration-time curve (AUC), –47%. On average, unbound PCSK9 serum concentrations fell by >80% at 4 hours after a single evolocumab dose. Mean (95% confidence interval) maximum LDL-C reductions in the healthy, mild, and moderate groups were –57% (–64%, –48%), –70% (–75%, –63%), and –53% (–61%, –43%), respectively. No safety risks were identified. These results support evolocumab use without dose adjustment in patients with active liver disease and mild or moderate hepatic impairment. This article is protected by copyright. All rights reserved

Etelcalcetide (AMG 416) is a novel synthetic peptide calcium-sensing receptor activator in clinical development as an intravenous calcimimetic for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease (CKD) on hemodialysis. Etelcalcetide is composed of seven d-aminoacids with an l-cysteine linked to a d-cysteine by a disulfide bond. A single intravenous dose of [14C]etelcalcetide (10 mg; 26.3 kBq; 710 nCi) was administered to patients with CKD on hemodialysis to elucidate the pharmacokinetics, biotransformation, and excretion of etelcalcetide in this setting. Blood, dialysate, urine, and feces were collected to characterize the pharmacokinetics, biotransformation product profiles, mass balance, and formation of anti-etelcalcetide antibodies. Accelerator mass spectrometry was necessary to measure the microtracer quantities of C-14 excreted in the large volumes of dialysate and other biomatrices. An estimated 67 % of the [14C]etelcalcetide dose was recovered in dialysate, urine, and feces 176 days after dose administration. Etelcalcetide was primarily cleared by hemodialysis, with approximately 60 % of the administered dose eliminated in dialysate. Minor excretion was observed in urine and feces. Biotransformation resulted from disulfide exchange with endogenous thiols, and preserved the etelcalcetide d-amino acid backbone. Drug-related radioactivity circulated primarily as serum albumin peptide conjugate (SAPC). Following removal of plasma etelcalcetide by hemodialysis, re-equilibration occurred between SAPC and l-cysteine present in blood to partially restore the etelcalcetide plasma concentrations between dialysis sessions. No unanticipated safety signals or anti-etelcalcetide or anti-SAPC antibodies were detected. Electronic supplementary material The online version of this article (doi:10.1007/s40262-016-0433-0) contains supplementary material, which is available to authorized users.

The incidences of osteoporosis and chronic kidney disease (CKD) both increase with increasing age, yet there is a paucity of data on treatments for osteoporosis in the setting of impaired kidney function. We examined the efficacy and safety of denosumab (DMAb) among subjects participating in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) Study. We estimated creatinine clearance (eGFR) using Cockcroft-Gault and classified levels of kidney function using the modified National Kidney Foundation classification of CKD. We examined incident fracture rates; changes in bone mineral density (BMD), serum calcium, and creatinine; and the incidence of adverse events after 36 months of follow-up in subjects receiving DMAb or placebo, stratified by level of kidney function. We used a subgroup interaction term to determine if there were differences in treatment effect by eGFR. Most (93%) women were white, and the mean age was 72.3 ± 5.2 years; 73 women had an eGFR of 15 to 29 mL/min; 2817, between 30 to 59 mL/min; 4069, between 60 to 89 mL/min, and 842 had an eGFR of 90 mL/min or greater. None had stage 5 CKD. Fracture risk reduction and changes in BMD at all sites were in favor of DMAb. The test for treatment by subgroup interaction was not statistically significant, indicating that treatment efficacy did not differ by kidney function. Changes in creatinine and calcium and the incidence of adverse events were similar between groups and did not differ by level of kidney function. It is concluded that DMAb is effective at reducing fracture risk and is not associated with an increase in adverse events among patients with impaired kidney function.

The long-term use of calcineurin inhibitors (CNI) leads to renal dysfunction in many liver transplant (LT) recipients. The purpose of this analysis is to evaluate renal function in patients converted from CNI to sirolimus (SRL). From May 2002-November 2006, 137 LT were performed in 125 patients, 72 of which were converted to SRL. Evaluation of SRL conversion was stratified by early conversion (

Background. A number of studies have suggested that conversion from calcineurin inhibitors (CNI) to sirolimus (SRL) can improve graft function in renal transplant patients. None of these studies has converted patients to SRL in the absence of steroids. Methods. We describe our experience with 278 renal transplants of which 153 were converted from CNI to SRL. The majority of patients had steroids withdrawn after 6 days. Almost all patients received antithymocyte globulin induction and were maintained on mycophenolate mofetil. Results. Six months after conversion, patients remaining on SRL therapy had a mean increase in estimated glomerular filtration rate of 6.93 mL/min/1.73 m 2 (P

Denosumab is a fully human monoclonal immunoglobulin G2 antibody that inhibits bone resorption and increases bone mass and strength. The present clinical study assessed serum and seminal fluid pharmacokinetics following a single denosumab dose in healthy men, and evaluated whether denosumab in seminal fluid poses any risk to a fetus in the event of unprotected sexual intercourse with a pregnant partner.An open-label, single-dose study in 12 healthy men was conducted over a 106-day period. Subjects received a single subcutaneous dose of 60-mg denosumab on day 1. Serum and seminal fluid samples were collected at specified time points to assess denosumab pharmacokinetics. Adverse events were recorded.Denosumab was measurable at low concentrations in seminal fluid (~2% of serum concentrations). The mean [standard deviation (SD)] maximum observed drug concentration (Cmax ) was 6170 (2070) ng ml(-1) (serum) and 100 (81.9) ng ml(-1) (seminal fluid). The median time to Cmax (tmax ) was 8 days (serum) and 21 days (seminal fluid). The mean (SD) area under the plasma concentration-time curve (AUC) from time zero to the time of the last quantifiable concentration (AUClast ) was 333 000 (122 000) day•ng ml(-1) (serum) and 5220 (4880) day•ng ml(-1) (seminal fluid). The mean (SD) Cmax and AUC ratios between seminal fluid and serum were 0.0217 (0.0154) and 0.0170 (0.0148), respectively. Using conservative assumptions for ejaculate volume (6 ml), vaginal absorption (100%) and placental transfer (100%), the measured mean denosumab seminal fluid Cmax would result in fetal exposure that was more than 110 times below the preclinically derived 'no effect level' for denosumab.These results indicate a negligible risk to a fetus exposed to denosumab via seminal fluid transfer to a pregnant partner.

Up to 9% of renal transplant recipients have severe multifactorial erythropoietin-resistant anemia. Human parvovirus B19 (PVB19) infection can cause severe anemia and is likely underreported. Sparse information on epidemiology and management in this population exists. To address these issues, after our first index case, we modified our clinical practice to prospectively screen patients with persistent hemoglobin (Hb)

Background. Blacks receive live donor kidney transplant (LDKT) less often than patients of all other races. Weevaluated the effectiveness of educational interventions in removing barriers to LDKT for blacks.Methods. Patients were randomized to three interventions in which health educator(s) delivered an intervention to(a) the patient and his/her guests in the patient’s home (house calls [HC], n=54), (b) clusters of patients and theirguests in the transplant center (group based [GB], n=49), and (c) the individual patient alone in the transplant center(individual counseling [IC], n=49).Results. At the 2-year endpoint, 15% (n=8), 8% (n=4), and 6% (n=3) of HC, GB, and IC patients, respectively,received LDKT (P=0.30). Patients in the HC group were more likely than patients in the GB and IC groups to have atleast one donor inquiry (82% vs. 61% vs. 47%, P=0.001) and evaluation (65% vs. 39% vs. 27%, PG0.001). Patients inthe HC group alsoweremorelikely to have higher knowledge, fewer concerns, and higher willingness to talk to othersabout donation 6 weeks after intervention.Conclusions. These findings underscore the importance of including the patient’s social network in LDKTeducationand the potential of the HC intervention to reduce racial disparity in LDKTrates.Keywords: Live donor kidney transplant, Kidney transplantation, Living donation, Kidney donation, Living donor,Psychosocial, Transplant education, Race.(Transplantation 2014;98: 979Y986)

We show that HIV-infected waitlisted patients (n=33) had significantly lower knowledge (P0.001), more concerns (P=0.01), and lower willingness to pursue live-donor kidney transplantation (LDKT; P=0.02) than matched noninfected patients. The majority (78%) of patients felt that their HIV status reduced their chance of LDKT. Although limited to a single center and a small sample, our data suggest that HIV-infected patients who are waitlisted for kidney transplantation may need more education about the potential benefits of LDKT and may benefit from patient-centered decision support to facilitate a risk-benefit assessment consistent with their preferences and values.

Background: Abnormal mineral metabolism is not uncommon after renal transplant (TXP). In dialysis patients, elevated serum phosphorous (P), calcium (Ca), CaP product, and parathyroid hormone (PTH) are associated with increased morbidity and mortality. The effect of these abnormalities on recipient and graft survival after renal transplantation is unknown. Methods: We retrospectively analyzed 422 kidney-only transplants performed between June 1996 and June 2003. Cases with graft or recipient survival less than three months, pre-TXP parathyroidectomy (PTX), cinacalcet therapy and incomplete records were excluded, leaving 303 cases for analysis using Cox models that included post-TXP PTX, levels of albumin-adjusted Ca(Caadj), P, CaadjP product and PTH. Results: There was an 11–25% prevalence of abnormal serum Caadj, P or CaadjP product within the first year post-TXP. At least 24% of recipients not undergoing PTX with an equation estimated GFR of 40–60 mL/min had PTH levels >130 pg/mL at one yr post-TXP. This is above levels recommended by the U.S National Kidney Foundation kidney disease quality initiative for patients with stages I–IV chronic kidney disease. Adjusted Ca > 10.5 mg/dL at three months post-TXP was an independent risk for recipient death (OR 3.0; 95% CI: 1.2–7.4). A CaadjP product >35 mg2/dL2 at six months (OR 4.0; 95% CI: 1.2–13.1), and Ca >10.5 mg/dL at 12 months post-TXP (OR 4.0; 95% CI: 1.2–14) were independent risks for death-censored graft loss. Twenty-two recipients underwent PTX for severe hyperparathyroidism. Conclusion: Abnormalities of mineral metabolism are common early after renal TXP. An elevated serum Caadj at three months post-TXP increases the risk for recipient death, while an elevated CaadjP and Caadj later in the first post-TXP year increases the risk of long-term death-censored graft loss.

p p a CASE REPORT T patient was a 22-year-old white woman with a history of end-stage renal disease of unknown cause. istory, physical examination, and serological testing at the ime of her initial evaluation were unrevealing, and a native idney biopsy performed months earlier showed only advanced lomerular and tubulointerstitial scarring. She started dialysis herapy in 2002 and received a 6-antigen–mismatch cardiaceath donor kidney transplant in June 2003. Preimplantation iopsy showed only minimal scarring. Her course was compliated by several days of delayed graft function, but she eventully was discharged to home on a maintenance regimen of acrolimus, mycophenolate mofetil, and prednisone. The patient was followed up in the outpatient clinic and eached a nadir creatinine level of 3.7 mg/dL (327.1 mol/L) y day 30 posttransplantation. On posttransplantation day 38, he underwent renal biopsy for a serum creatinine level of 4.7 g/dL (415.5 mol/L). The biopsy specimen showed diffuse nterstitial edema and patchy mononuclear inflammation. Neurophils were inconspicuous, and tubules showed degenerative pithelial changes, with associated mild tubulitis. No endarteriis was seen. There were 13 glomeruli, of which 3 were globally clerotic. Of the remaining glomeruli, 1 tuft showed focal ecrosis with neutrophils, fibrin, and an associated cellular rescent (Fig 1). The focal crescentic process was understood to e suggestive of an immune complex glomerulonephritis or ystemic vasculitic process, but examination was limited by the ack of material for immunofluorescence and electron microsopy. The borderline tubulointerstitial changes were not beieved to suggest an acute cellular rejection. Hepatitis virus, and uman immunodeficiency virus and BK virus polymerase hain reaction testing (blood and urine) results were negative. creening enzyme-linked immunosorbent assay tests for anti– lomerular basement membrane antibodies were negative, and 3 and C4 levels were normal. She subsequently was treated