Etelcalcetide controls secondary hyperparathyroidism and raises sclerostin levels in hemodialysis patients previously uncontrolled with cinacalcet.

INTRODUCTION: There is scarce clinical experience with etelcalcetide in patients with secondary hyperparathyroidism uncontrolled with cinacalcet. The effect of etelcalcetide on serum sclerostin levels remains to be clarified. MATERIALS AND METHODS: Prospective cohort study in prevalent hemodialysis patients with uncontrolled sHPT under cinacalcet for at least 3 months, mean parathyroid hormone (PTH)>800pg/mL and calcium (Ca)>8.3mg/dL. Etelcalcetide 5mg IV/HD was initiated after cinacalcet washout. Levels of PTH, Ca, and phosphorus (Pi) followed monthly for 6 months. Plasma sclerostin levels measured before etelcalcetide treatment and after 6 months. RESULTS: Thirty-four patients were enrolled, 19 (55.9%) male gender. Mean age 60.7 (± 12.3) years; median time on HD 82.5 (7-296) months and median cinacalcet dose was 180mg/week (Interquartile Range: 180-270). Serum Ca, Pi and PTH levels showed a significant reduction after etelcalcetide treatment from 8.8mg/dL, 5.4mg/dL and 1005pg/mL to 8.1mg/dL (p=0.08), 4.9mg/dL (p=0.01) and 702pg/mL (p<0.001), respectively. Median etelcalcetide dose remained at 5mg/HD. Plasma sclerostin concentration increased from 35.66pmol/L (IQR11.94-54.58) to 71.05pmol/L (IQR54.43-84.91) (p<0.0001). CONCLUSION: Etelcalcetide improved sHPT control in this group of patients, previously under cinacalcet treatment, and significantly increased plasma sclerostin concentration. The impact of etelcalcetide treatment on sclerostin levels is a novel finding.

Isolating mineralized bone and bone marrow mRNA from transiliac bone biopsies stored in a stabilizing solution: A comparative study.

The molecular mechanisms underlying metabolic bone diseases, including renal osteodystrophy, are poorly understood. Transcriptomics are increasingly used to characterize biological molecular networks and prove promising in identifying therapeutic targets and biomarkers. A reliable method for obtaining sufficient amounts of high quality RNA from human bone biopsies is a prerequisite for the implementation of molecular diagnostics in clinical research and practice. The present study aimed to develop a simple and adequate method for isolating bone and bone marrow mRNA from transiliac bone biopsies. Several storage, separation, and extraction procedures were compared. The procedure was optimized in pig samples and subsequently validated in human samples. Appropriate amounts of mineralized bone and bone marrow mRNA of moderate to high quality were obtained from transiliac bone biopsies that were immersed in the stabilizing solution Allprotect Tissue Reagent at room temperature for up to 3 days prior to freezing. After thawing, bone marrow and mineralized bone were separated by a multistep centrifugation procedure and subsequently disrupted and homogenized by a bead crusher. Appropriate separation of mineralized bone and bone marrow was confirmed by discriminatory gene expression profiles.

Contemporary kidney transplantation has a limited impact on bone microarchitecture.

Bone microarchitecture is an important component of bone quality and disturbances may reduce bone strength and resistance to trauma. Kidney transplant recipients have an excess risk of fractures, and bone loss affecting both trabecular and cortical bone compartments have been demonstrated after kidney transplantation. The primary aim of this study was to investigate the impact of kidney transplantation on trabecular and cortical bone microarchitecture, assessed by histomorphometry and micro computed tomography (µCT). Iliac crest bone biopsies, analyzed by bone histomorphometry and µCT, were performed at time of kidney transplantation and 12 months post-transplantation in an unselected cohort of 30 patients. Biochemical markers of mineral metabolism and bone turnover were measured at both time-points. At 12 months post-transplantation, bone turnover was low in 5 (17%) and normal in 25 (83%) patients. By histomorphometry, bone remodeling normalized, with decreases in eroded perimeters (4.0 to 2.1%, p = 0.02) and number of patients with marrow fibrosis (41 to 0%, p < 0.001). By µCT, trabecular thickness (134 to 125 µM, p = 0.003) decreased slightly. Other parameters of bone volume and microarchitecture, including cortical thickness (729 to 713 µm, p = 0.73) and porosity (10.2 to 9.5%, p = 0.15), remained stable. We conclude that kidney transplantation with current immunosuppressive protocols has a limited impact on bone microarchitecture.

Peritoneal Dialysis Cuff-Shaving-A Salvage Therapy for Refractory Exit-Site Infections.

Introduction:Cuff-shaving has been described as a salvage technique for refractory exit-site infections, with conflicting data regarding infection and catheter outcomes. We describe our experience with cuff-shaving as a rescue therapy for exit-site infections unresponsive to systemic therapy.Methods:We retrospectively reviewed patients who underwent cuff-shaving between January 2012 and June 2017. Refractory exit-site infection was defined as purulent discharge from the exit site with no clinical response after 3 weeks of systemic antibiotic treatment.Results:Fifty-three cuff-shavings were included, mean age was 53.4 ± 13.4 years, 26 patients were male. Median dialysis vintage was 29 months (interquartile range [IQR] 14.3 - 38), and 39 (73.6%) were on continuous ambulatory peritoneal dialysis (CAPD). The exit-site infection rate before cuff-shaving was 1.12 episodes per patient-year and the median time from infection to shaving was 52 days (IQR 35 - 76). The most frequent agents were Staphylococcus aureus (34%), Corynebacterium spp. (17%) and Pseudomonas aeruginosa (15%). Median follow-up was 9 months (IQR 1 - 18.5), during which time 35 catheters were removed, 5 due to non-infectious reasons. Using the Kaplan-Meier survival analysis, median catheter survival was 24 months (95% confidence interval [CI] 4.17 - 43.83). At 12 months, the probability of catheter survival was 54% and was not statistically different between gram-positive and gram-negative agents, although it was significantly shorter for fungal agents.Conclusion:Cuff-shaving is a feasible rescue therapy to treat refractory exit-site infections. In our experience, it allowed resolution of infections in a significant proportion of cases, except for fungal agents, and therefore extended catheter survival time, besides being associated with a small rate of complications.

Bone biopsy: an ally in the management of fragility fractures in chronic kidney disease.

Patients with chronic kidney disease (CKD) have an increased susceptibility to fracture and this risk gradually rises as renal disease progresses. Chronic Kidney Disease-Mineral and Bone Disorder (CKD- MBD) encompasses the mineral, bone, hormonal and calcific cardiovascular abnormalities that develop in these patients. Renal osteodystrophy (ROD) corresponds to the histopathologic description of bone lesions associated with CKD-MBD. Fragility fracture approach in CKD stages 1-3a may be similar to that of the general population. However, in stages 3b-5, osteoporosis cannot be established by the World Health Organization (WHO) criteria based on bone mineral density (BMD) or the presence of fragility fractures, because low BMD and fractures can also occur in the different forms of ROD. The gold standard for the diagnosis and classification of ROD is tetracycline double-labelled transiliac bone biopsy, with bone histology and histomorphometric analysis. By informing on bone turnover, mineralization and volume, it is a valuable tool that may help guide the management of CKD patients with fragility fractures, as therapeutic measures are distinct depending if the patient has osteoporosis or one of the forms of ROD. For patients with stages 1-3 CKD, without biochemical abnormalities suggestive of CKD-MBD, who sustained low-trauma fractures, any therapeutic approved for use in osteoporosis could be used. However, there is little evidence for the efficacy and safety of conventional anti-osteoporotic agents in patients with more advanced CKD stages, so currently the approach is opinion-based and must be patient-tailored depending on the presence or absence of ROD.

Reactivation of Hepatitis B virus in kidney transplant recipients with previous clinically resolved infection: A single-center experience.

BACKGROUND: Hepatitis B virus (HBV) reactivation in kidney transplant recipients (KTR) involves important morbidity and mortality. Despite being more common in patients who are HBsAg-positive, it may occur in patients with clinically resolved infection (HBsAg-negative and anti-HBc-positive), in whom the presence of the protective anti-HB antibody is thought to decrease the risk of reactivation. Data regarding reactivation rates in this population are scarce. OBJECTIVE: To retrospectively evaluate the risk of HBV reactivation in KTR with previously resolved infection. MATERIAL AND METHODS: Retrospective cohort study including patients who underwent a kidney transplant between January 1994 and December 2014 with resolved HBV infection at the time of transplantation (anti-HBc seropositivity without detectable HBsAg, with or without anti-HB-positive antibodies and normal liver enzymes). RESULTS: Out of 966 patients, 95 patients with evidence of resolved HBV infection were analyzed, of which 86 had a titer of anti-HBs >10mIU/ml. Mean follow-up time was 93 months; 12 patients had lost anti-HBs. Two patients showed evidence of reactivation. Risk factors associated with loss of anti-HBs were elderly age (>60) and occurrence of acute graft rejection (p<0.05). CONCLUSION: The risk of HBV reactivation in KTR with previously resolved infection is not negligible at 2%. Elderly age and acute rejection were associated with loss of anti-HBs, and these patients may benefit from closer monitoring of HBV DNA levels. Routine serology and/or HBV viral load monitoring in HBsAg-negative, anti-HBc-positive patients is recommended and should be emphasized in these patients.

Old and new calcimimetics for treatment of secondary hyperparathyroidism: impact on biochemical and relevant clinical outcomes.

Secondary hyperparathyroidism (SHPT) is associated with increased bone turnover, risk of fractures, vascular calcifications, and cardiovascular and all-cause mortality. The classical treatment for SHPT includes active vitamin D compounds and phosphate binders. However, achieving the optimal laboratory targets is often difficult because vitamin D sterols suppress parathyroid hormone (PTH) secretion, while also promoting calcium and phosphate intestinal absorption. Calcimimetics increase the sensitivity of the calcium-sensing receptor, so that even with lower levels of extracellular calcium a signal can still exist, leading to a decrease of the set-point for systemic calcium homeostasis. This enables a decrease in plasma PTH levels and, consequently, of calcium levels. Cinacalcet was the first calcimimetic to be approved for clinical use. More than 10 years since its approval, cinacalcet has been demonstrated to effectively reduce PTH and improve biochemical control of mineral and bone disorders in chronic kidney patients. Three randomized controlled trials have analysed the effects of treatment with cinacalcet on hard clinical outcomes such as vascular calcification, bone histology and cardiovascular mortality and morbidity. However, a final conclusion on the effect of cinacalcet on hard outcomes remains elusive. Etelcalcetide is a new second-generation calcimimetic with a pharmacokinetic profile that allows thrice-weekly dosing at the time of haemodialysis. It was recently approved in Europe, and is regarded as a second opportunity to improve outcomes by optimizing treatment for SHPT. In this review, we summarize the impact of cinacalcet with regard to biochemical and clinical outcomes. We also discuss the possible implications of the new calcimimetic etelcalcetide in the quest to improve outcomes.