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Chao Liu,1 Hong Lu,2 Fei Yuan,1 Wei-Li Chen,1 Hong-Rong Xu,1 Hui Li,1 Cheng-Pang Hsu,3 Ogo Egbuna,3 Jihua Wu,2 Clapton Dias,3 Bassam Abosaleem,3 Jitesh Rana,3 Maria Laura Monsalvo,3 Xue-Ning Li,1 Zhigang Yu4 1Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Clinical Pharmacology and Early Development, Amgen China R & D Center, Shanghai, People’s Republic of China; 3Research & Development, Amgen Inc., Thousand Oaks, CA, USA; 4Clinical Development, Amgen China R & D Center, Shanghai, People’s Republic of ChinaCorrespondence: Xue-Ning LiDepartment of Clinical Pharmacology, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, People’s Republic of ChinaTel +86 21 6026 7666Email li.xuening@zs-hospital.sh.cnZhigang YuResearch & Development, Amgen Inc., Thousand Oaks, CA 91320, USATel +1 805 447-9384Email zhigangy@amgen.comPurpose: Evolocumab is a human monoclonal antibody that reduces circulating low-density lipoprotein cholesterol (LDL-C) by inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9). Data on evolocumab pharmacokinetics and pharmacodynamics are derived mostly from Caucasian populations. The objectives of this study were to characterize the single-dose pharmacokinetic and pharmacodynamic parameters, safety, and tolerability of evolocumab in healthy Chinese subjects.Subjects and methods: This was a phase 1, randomized, double-blind, placebo-controlled study (CTR20150465). Two parallel cohorts were randomized 5:1 to receive single subcutaneous injections of either evolocumab (140 mg or 420 mg) or placebo. Pharmacokinetics, pharmacodynamics, and safety were evaluated through day 85. The primary endpoints were maximum concentration (Cmax) and area under the drug concentration–time curve from time 0 to time of last quantifiable concentration (AUClast).Results: Thirty-six men (median age 26) were enrolled to receive evolocumab 140 mg (n=15), evolocumab 420 mg (n=15), or placebo (n=6). After 140 mg and 420 mg evolocumab, mean (SD) Cmax was 13.8 (3.6 μg/mL and 67.6 (15.2) μg/mL, respectively, and mean (SD) AUClast was 166 (55) day·μg/mL and 1110 (274) day·μg/mL, respectively. LDL-C declined reversibly, with reductions of 70% at 140 mg and 71% at 420 mg. Maximum effects on LDL-C and PCSK9 levels were reached by day 15 and 24 hrs, respectively, at 140 mg, and by day 22 and 4 hrs, respectively, at 420 mg. No serious adverse events occurred and the overall incidence of treatment-emergent adverse events was similar for evolocumab and placebo: 26.7% (140 mg) and 33.3% (placebo); 66.7% (420 mg) and 66.7% (placebo).Conclusion: In this population of healthy Chinese subjects, single 140 mg and 420 mg doses of evolocumab exhibited nonlinear kinetics and more than dose-proportional increases in exposure, were associated with up to 71% reduction in LDL-C, and demonstrated a safety profile similar to placebo.Keywords: cardiovascular disease, homozygous familial hypercholesterolemia, PCSK9 inhibitors, monoclonal antibodies, ethnic sensitivity

Objective Evolocumab, a human monoclonal antibody that binds to proprotein convertase subtilisin/kexin type 9 (PCSK9), markedly reduces low-density lipoprotein cholesterol (LDL-C). Here we characterize the pharmacokinetics, pharmacodynamics, safety, and tolerability of evolocumab manufactured at a new site administered in healthy Chinese subjects. Materials and methods This phase 1 study of a single subcutaneous 140-mg dose of evolocumab was conducted in healthy subjects of Chinese descent residing in Hong Kong. Subjects were followed through day 85. Results 20 subjects (all men) were enrolled. Mean (SD) age was 26.6 (8.5) years; baseline LDL-C was 2.4 (0.7) mmol/L. Mean (SD) evolocumab maximum serum concentration (Cmax) was 14.1 (5.0) μg/mL; area under the serum drug concentration-time curve from time 0 to time of last quantifiable concentration (AUClast) was 178 (80) day×μg/mL; AUC from time 0 to infinity (AUCinf) was 187 (80) day×μg/mL; terminal half-life was 5.95 (1.76) days; median time to reach Cmax (tmax) was 4.0 days. Maximum LDL-C decrease (-57.5%) was observed on day 15 and recovered to baseline by day 57. The most common adverse events (AEs) were nasal congestion (20%), oropharyngeal pain (15%), sneezing (15%), cough (10%), upper respiratory tract infection (10%), and diarrhea (10%). Most AEs were isolated incidences of mild severity, with no serious or treatment-related events. No anti-evolocumab antibodies were detected. Conclusion A single 140-mg dose of evolocumab manufactured at the new site and administered in healthy Chinese subjects was associated with typical antibody pharmacokinetics, rapid and reversible decreases in LDL-C, and no new safety events.

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.

Aims 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. Methods 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. Results 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. Conclusions These results indicate a negligible risk to a fetus exposed to denosumab via seminal fluid transfer to a pregnant partner.

Atherosclerosis and osteoporosis are chronic diseases that progress with age, and studies suggest aortic calcification, an indicator of atherosclerosis, is inversely associated with BMD. The OPG/RANK/RANKL system has been proposed as a shared regulatory system for bone and vasculature. Denosumab (DMAb), a monoclonal antibody against RANKL, improved BMD and reduced fracture risk in the FREEDOM trial. We evaluated whether or not treatment with DMAb influenced progression of aortic calcification (AC) and incidence of cardiovascular (CV) adverse events. We included 2,363 postmenopausal women with osteoporosis (1,142 placebo, 1,221 DMAb), selected from 7,808 participants in the FREEDOM trial (3,906 placebo, 3,902 DMAb), at high risk of CV events according to modified Raloxifene Use for the Heart (RUTH) criteria. CV adverse events were reported by participants. AC scores were assessed using a semi-quantitative method from lateral spine x-rays. Change in AC score from baseline to 12 (N = 1,377), 24 (N = 1,231) and 36 months (N = 1,045) was calculated as AC score at follow-up minus AC score at baseline. AC progression was defined as change in AC score > 0. Baseline characteristics, CV risk factors, and AC scores were similar between treatment groups. Mean age of participants was 74 years (range, 60–90), 88% were white, and 77% had AC score > 0 at baseline. Frequency of AC progression over 3 years did not differ between women in placebo (22%) and DMAb (22%) groups (p = 0.98). AC progression did not differ between treatment groups when analyzed by baseline estimated glomerular filtration rate or by baseline AC scores. Frequency of CV adverse events did not differ between placebo (40%) and DMAb (38%) groups (p = 0.26). In conclusion, DMAb treatment had no effect on progression of AC or incidence of CV adverse events compared to placebo.

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)

Drug-disease interactions involving therapeutic proteins that target cytokines and potentially impact cytochrome P450 (CYP) enzymes have been of increased interest to drug regulatory agencies and industry sponsors in recent years. This parallel-group open-label study evaluated the effects of the monoclonal antibody denosumab, an inhibitor of the cytokine RANKL, on the pharmacokinetics of the probe CYP3A4 substrate midazolam in postmenopausal women with osteoporosis. The pharmacokinetics of a 2 mg oral dose of midazolam was evaluated on days 1 and 16. Subjects in Group A received a 60 mg subcutaneous dose of denosumab on day 2, 2 weeks before the second midazolam dose, while subjects in Group B did not. For Group A (n = 17), point estimates for the ratio of least square means for midazolam exposures based on maximum observed plasma concentration (C max) and areas under the plasma concentration-time curve (AUCs) on day 16 versus day 1 ranged from 1.02 to 1.04 and 90% confidence intervals were within 0.80-1.25. No period effect was observed for Group B (n = 8). Midazolam and denosumab coadministration was safe and well tolerated. Inhibition of the cytokine RANKL by denosumab does not affect CYP3A4 in postmenopausal women with osteoporosis and will not alter the pharmacokinetics of drugs metabolized by this enzyme. These results are consistent with data suggesting that RANKL does not impact markers of inflammation and represent the first clinical data demonstrating a lack of effect on CYP3A4 of a therapeutic protein that is a cytokine modulator.

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.

Calcium (Ca) and magnesium (Mg) homeostasis are interrelated and share common regulatory hormones, including parathyroid hormone (PTH) and vitamin D. However, the role of the calcium-sensing receptor (CaSR) in Mg homeostasis in vivo is not well understood. We sought to investigate the interactions between Mg and Ca homeostasis using genetic mouse models with targeted inactivation of PTH (PTH KO) or both PTH and the calcium-sensing receptor (CaSR) (double knockout, DKO). Serum Mg is lower in PTH KO and DKO mice than in WT mice on standard chow, whereas supplemental dietary Ca leads to equivalent Mg levels for all three genotypes. Mg loading increases serum Mg in all genotypes; however, the increase in serum Mg is most pronounced in the DKO mice. Serum Ca is increased with Mg loading in the PTH KO and DKO mice but not in the WT mice. Here, too, the hypercalcemia is much greater in the DKO mice. Serum and especially urinary phosphate are reduced during Mg loading, which is likely due to intestinal chelation of phosphate by Mg. Mg loading decreases serum PTH in WT mice and increases serum calcitonin in both WT and PTH KO mice but not DKO mice. Furthermore, Mg loading elevates serum 1,25-dihydroxyvitamin D in all genotypes, with greater effects in PTH KO and DKO mice, possibly due to reduced levels of serum phosphorus and FGF23. These hormonal responses to Mg loading and the CaSR's role in regulating renal function may help to explain changes in serum Mg and Ca found during Mg loading.

The extracellular calcium (Ca 2+ o )-sensing receptor (CaSR) plays a key role in maintaining Ca 2+ o homeostasis by regulating the functions of parathyroid and kidney in response to perturbations in Ca 2+ o so as to maintain a nearly constant level of blood calcium. The cloning of the CaSR made it feasible to identify several disorders arising from inactivating or activating mutations of the receptor. Heterozygous and homozygous inactivating mutations produce familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT), respectively. The former is typically a benign, autosomal dominant form of parathyroid hormone (PTH)-dependent hypercalcemia, while the latter produces severe, sometimes life-threatening hyperparathyroidism. Patients with FHH generally do not need parathyroid surgery, while total parathyroidectomy is sometimes necessary to control hyperparathyroidism in NSHPT. Activating mutations of the receptor produce autosomal dominant hypocalcemia (ADH), rarely with features of Bartter’s syndrome, because the CaSR is too sensitive to its ligand, Ca 2+ o . As additional hyper- and hypocalcemic patients for CaSR mutations, the clinical presentations of FHH and NSHPT have broadened to the point where their biochemical findings overlap, leading to new diagnostic and therapeutic challenges for the clinician and patient.

Previously referred to as “familial benign hypercalcemia (FBH),” familial hypocalciuric hypercalcemia (FHH) is a benign autosomal dominant disorder of mineral metabolism most often caused by a mutation in the gene encoding the extracellular calcium-sensing receptor (CaSR).

Despite a substantially lower rate of live donor kidney transplantation among Black Americans compared to White Americans, there are few systematic efforts to reduce this racial disparity. This paper describes the rationale and design of a randomized controlled trial aims evaluating the comparative effectiveness of three different educational interventions for increasing live donor kidney transplantation in Black Americans. This trial is a single-site, urn-randomized controlled trial with a planned enrollment of 180 Black Americans awaiting kidney transplantation. Patients are randomized to receive transplant education in one of three education conditions: through group education at their homes (e.g., House Calls), or through group (Group-Based) or individual education (Individual Counseling) in the transplant.. The primary outcome of the trial is the occurrence of a live donor kidney transplant, with secondary outcomes including living donor inquiries and evaluations as well as changes in patient live donor kidney transplantation readiness, willingness, knowledge, and concerns. Sex, gender, dialysis status, and quality of life are evaluated as moderating factors. Findings from this clinical trial have the potential to inform strategies for reducing racial disparities in live donor kidney transplantation. Similar trials have been developed recently to broaden the evaluation of House Calls as an innovative disparity-reducing intervention in kidney transplantation.

The calcium-sensing receptor (CaSR) controls parathyroid hormone (PTH) secretion, which, in turn, via direct and indirect actions on kidney, bone, and intestine, maintains a normal extracellular ionized calcium concentration (Ca2+o). There is less understanding of the CaSR's homeostatic importance outside of the parathyroid gland. We have employed single and double knockout mouse models, namely mice lacking PTH alone (CaSR+/+ PTH−/−, referred to as C+P−), lacking both CaSR and PTH (CaSR−/− PTH−/−, C−P−) or wild-type (CaSR+/+ PTH+/+, C+P+) mice to study CaSR-specific functions without confounding CaSR-mediated changes in PTH. The mice received three hypercalcemic challenges: an oral Ca2+ load, injection or constant infusion of PTH via osmotic pump, or a phosphate-deficient diet. C−P− mice show increased susceptibility to developing hypercalcemia with all three challenges compared with the other two genotypes, whereas C+P− mice defend against hypercalcemia similarly to C+P+ mice. Reduced renal Ca2+ clearance contributes to the intolerance of the C−P− mice to Ca2+ loads, as they excrete less Ca2+ at any given Ca2+o than the other two genotypes, confirming the CaSR's direct role in regulating renal Ca2+ handling. In addition, C+P+ and C+P−, but not C−P−, mice showed increases in serum calcitonin (CT) levels during hypercalcemia. The level of 1,25(OH)2D3 in C−P− mice, in contrast, was similar to those in C+P− and C+P+ mice during an oral Ca2+ load, indicating that increased 1,25(OH)2D3 production cannot account for the oral Ca2+-induced hypercalcemia in the C−P− mice. Thus, CaSR-stimulated PTH release serves as a “floor” to defend against hypocalcemia. In contrast, high-Ca2+o-induced inhibition of PTH is not required for a robust defense against hypercalcemia, at least in mice, whereas high-Ca2+o-stimulated, CaSR-mediated CT secretion and renal Ca2+ excretion, and perhaps other factors, serve as a “ceiling” to limit hypercalcemia resulting from various types of hypercalcemic challenges.

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

Polycystic liver disease is the most common extrarenal manifestation of autosomal dominant polycystic kidney disease. Hepatic cysts often are multiple, and in renal transplant recipients, occult infection with or without concurrent kidney cyst infection is a frequent cause of abdominal pain and fever and may require long-term antibiotic use and hospitalization. Rupture and bleeding of hepatic cysts into the peritoneum or viscera are infrequent complications that have been reported. Identification of a single culprit lesion that could be targeted for surgical intervention often is difficult because such imaging studies as computed tomographic scans, magnetic resonance images, or radionuclide-tagged white cell scans often show several inflamed cysts that can persist over several subsequent scans. Treatment may require surgical intervention. Eradication of infection and wound healing also is made difficult by concomitant immunosuppression in renal transplant recipients. We present the case of a renal transplant recipient with an infected dominant polycystic liver cyst that ruptured into the pericardium, leading to tamponade.

Aim: DMAB is a human monoclonal antibody that binds to RANK ligand to inhibit osteoclast-mediated resorption and is approved to prevent skeletal-related events in pts with bone metastases from solid tumors. DMAB-induced inhibition of bone resorption may impact calcium (Ca) homeostasis, affecting serum Ca levels. This study evaluated the incidence of hypocalcemia and safety parameters of pts with stage 4 or 5D CKD who were administered two subcutaneous (SC) doses of DMAB. Methods: Patients received two 120 mg doses of SC DMAB 28 days apart and were followed until day 113. All pts were required to have controlled secondary hyperparathyroidism and receive oral supplementation of ≥500 mg Ca and 400 IU vitamin D daily. The primary endpoint was the incidence of clinically significant, albumin-adjusted, serum Ca levels Results: 31/32 enrolled pts received 2 DMAB doses (15 stage 4; 16 stage 5D); 1 stage 4 CKD pt received 1 dose before withdrawing consent. 50% of pts were men, 78% white, and the median age was 76 years. The incidence of clinically significant hypocalcemia and adverse events at any point in the study are shown (Table). The majority (∼97%) of hypocalcemic events were mild to moderate in severity. The mean maximal serum DMAB concentrations were similar between the stage 4 and 5D CKD groups, 10.5 vs 8.17 µg/mL after dose 1 and 16.1 vs 14.5 µg/mL after dose 2. Patients (%) Stage 4 N=16 Stage 5D N=16 All N=32 Clinically significant hypocalcemiaa 1 (6.3) 2 (12.5) 3 (9.4) All AEs 10 (62.5) 15 (93.8) 25 (78.1) Hypocalcemia 3 (18.8) 10 (62.5) 13 (40.6) Hypomagnesmia 0 (0.0) 0 (0.0) 0 (0.0) Hypophosphatemia 0 (0.0) 1 (6.3) 1 (3.1) aSerum Ca levels Conclusions: While the use of DMAB was generally well tolerated in pts with stage 4 or 5D CKD, hypocalcemia events occurred despite oral Ca and vitamin D supplementation. This suggests an important role of bone resorption for the maintenance of serum Ca levels in this pt population, even among those with controlled secondary hyperparathyroidism. Stage 5D CKD pts were more likely to experience clinically significant or symptomatic hypocalcemia than stage 4 CKD pts. Use of DMAB in patients with stage 4 or 5D CKD requires careful monitoring for hypocalcemia. Disclosure: G. Block: Advisor for Amgen National Advisory committee (paid) and Steering Committee. Research grants and travel reimbursement from Amgen Inc.; O. Egbuna: Employed by Amgen Inc and owns shares of Amgen stocks. No other disclosures.; S. Zeig: Research funding from Amgen Inc. No other disclosures.; P. Pergola: Have an advisory relationship with Amgen, Keryx, ZS Pharma. Received research support from Amgen. No other disclosures; A. Braun: I was employed by Amgen Inc and own Amgen Inc stocks; Y. Yu: I am employed by Amgen Inc and own Amgen Inc stocks; W. Sohn: I am employed by Amgen Inc and own Amgen stocks; D. Padhi: I am employed by Amgen Inc and own Amgen Inc stocks. All other authors have declared no conflicts of interest.

e20649 Background: Denosumab (Dmab) is approved for patients (pts) with bone metastases from solid tumors to prevent skeletal-related events. Impaired renal function can alter calcium homeostasis a...