Effect of denosumab on the incidence of fractures and mortality in patients undergoing hemodialysis: A retrospective cohort study.

BACKGROUND: Patients undergoing hemodialysis are at an elevated risk of fractures; however, substantial evidence for osteoporosis treatment in this population is lacking. We explored the efficacy of denosumab, an anti-IgG2 antibody that targets the receptor activator of nuclear factor-kappa B ligand, in reducing fracture incidence and all-cause mortality in patients undergoing hemodialysis. METHODS: This retrospective cohort study-conducted from December 2013 to December 2022-evaluated the effects of denosumab on fracture incidence and all-cause mortality. Patients who initiated denosumab treatment during the study period were defined as the denosumab group, while those without a history of denosumab administration were defined as the non-denosumab group. Kaplan-Meier curves and log-rank tests were used to assess survival and fracture/mortality risks, respectively. Cox proportional hazards models were used to analyze both fractures and all-cause mortality. RESULTS: Among 214 patients undergoing hemodialysis, 52 (24.3%) received denosumab. The median age was 73.0 ± 11.5 years, with 92 (43.0%) females, and the median dialysis duration was 59 months (interquartile range, 6-126). During the study, thirty-seven non-denosumab-treated patients had fractures compared to eight in the denosumab group. No significant differences were observed in the unadjusted model (HR, 0.53; 95% confidence interval (CI), 0.24-1.14). Adjusting for competing mortality and clinical factors, the HR remained at 0.64 (95% CI, 0.27-1.51). Regarding all-cause mortality, we found a statistically significant difference in the unadjusted model (HR, 0.61 [95% CI, 0.38-0.98]). A significant reduction in mortality was observed in the adjusted model (HR, 0.46 [95% CI, 0.26-0.80]). Notably, the denosumab group showed a significant decrease in mortality, particularly in cardiovascular disease-related cases (HR, 0.33 [95% CI, 0.14-0.78]). CONCLUSIONS: Denosumab may reduce all-cause mortality in patients undergoing hemodialysis, particularly in those with cardiovascular complications. This finding offers a promising direction for osteoporosis treatment in patients undergoing hemodialysis.

Active vitamin D analog and SARS-CoV-2 IgG after BNT162b2 vaccination in patients with hemodialysis.

INTRODUCTION: Vaccination is the effective strategy for coronavirus disease 2019 (COVID-19). However, few studies have investigated the association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin (Ig)G and vitamin D. METHODS: This study aimed to investigate the association between SARS-CoV-2 IgG and active vitamin D analogs in hemodialysis patients. Blood samples were collected four times: before vaccination and 30, 60, and 90 days after vaccination, BNT162b2 (Pfizer©). RESULTS: A total of 418 patients were enrolled. The mean age was 71.1 ± 12 years. Almost two thirds of the patients were prescribed active vitamin D analogs. The distribution of SARS-CoV-2 IgG before vaccination was 235 (93-454) AU/mL. After multiple regression analyses, active vitamin D analog use was found to be associated with higher SARS-CoV-2 IgG levels from prevaccination to 90 days postvaccination. CONCLUSION: This study demonstrated an association between higher SARS-CoV-2 IgG and active vitamin D analog use in hemodialysis patients. CLINICAL TRIAL REGISTRATION: The study information was registered in the UMIN-CTR (UMIN 000046906).

Long-term effects of denosumab on bone mineral density and turnover markers in patients undergoing hemodialysis.

INTRODUCTION: Denosumab, a fully human anti-RANKL monoclonal antibody, is a widely used osteoporosis treatment that is increasingly being used in patients undergoing dialysis; however, its long-term efficacy and safety in these patients remain unknown. MATERIALS AND METHODS: This observational study comprised individuals aged ≥ 20 years undergoing hemodialysis and receiving denosumab. After denosumab administration, we analyzed the long-term changes in bone mineral density (BMD) and levels of bone turnover markers (BTMs) and calcium. RESULTS: The study included 45 patients who have been receiving denosumab for a median duration of 3.8 (interquartile range, 2.5-6.7) years. Tartrate-resistant acid phosphatase 5b (TRACP-5b) levels decreased from a median of 595 (434-778) mU/dL at baseline to 200 (141-430) mU/dL after 6 months of denosumab administration (P < 0.001) and remained low thereafter. Similarly, bone-specific alkaline phosphatase (BAP) levels decreased from a median of 18.2 (15.9-25.8) µg/L at baseline to 12.4 (9.9-15.6) µg/L after 6 months (P < 0.001) and remained low thereafter. Meanwhile, BMD, as assessed with dual energy X-ray absorptiometry and measured at the distal 1/3 of the radius, did not decrease (0.465 ± 0.112 g/cm2 at baseline vs. 0.464 ± 0.112 g/cm2 after administration; P = 0.616). Regarding hypocalcemia, corrected calcium levels reached were the lowest at 7 days after administration and normalized within 30 days. CONCLUSION: The study showed long-term suppression of TRACP-5b and BAP levels and sustaining BMD after denosumab administration over an extended period in patients undergoing hemodialysis.

Increased lymphatic vessels in patients with encapsulating peritoneal sclerosis.

BACKGROUND: The angiogenic response is partly involved in the progression of encapsulating peritoneal sclerosis (EPS). However, the details of the angiogenic response, especially for lymphatic vessels in patients with EPS, remain unclear. In addition, because of technical limitations, morphology studies reported to date have examined only the parietal peritoneum. The morphologies of parietal and visceral lymphatic vessels in patients with EPS both need to be analyzed. METHODS: We examined peritoneal samples from 18 patients with EPS who underwent enterolysis of the visceral peritoneum and compared them with samples from 17 autopsy cases (controls). To examine the angiogenic response, we performed immunohistochemistry for the endothelial markers CD34 (blood vessels) and podoplanin (lymphatic vessels) and for the cell proliferation marker Ki-67. Immunogold electron microscopy analysis for podoplanin was also performed. In 7 of 18 cases, we compared differences in the angiogenic response of the parietal and visceral peritoneal membranes. RESULTS: Angiogenic responses were more frequent in the compact zone than in regenerated layers. The number of capillaries positive for anti-CD34 and anti-podoplanin monoclonal antibodies per unit area of visceral peritoneal tissue was, respectively, 41.1 ± 29.3/mm(2) in EPS patients and 2.7 ± 4.4/mm(2) in controls (p ≤ 0.01) and 48.1 ± 43.9/mm(2) in EPS patients and 4.1 ± 5.4/mm(2) in controls (p ≤ 0.01). The percentage of capillaries positive for anti-Ki-67, CD34, and podoplanin was 4.6% in EPS patients (p ≤ 0.01) and 0.8% in controls (p = 0.09). The immunogold electron microscopy analysis revealed that podoplanin was localized to endothelial cells with anchoring filaments, a specific feature of lymphatic vessels. Furthermore, compared with parietal peritoneal membrane, visceral peritoneal membrane had a more prominent podoplanin-positive capillary profile, but not a prominent CD34-positive capillary profile. In addition, fibroblast-like cells double-positive for podoplanin and smooth muscle actin were markedly increased in the degenerated layer, as previously reported. CONCLUSIONS: Our study demonstrated that lymphatic vessels are increased in the visceral peritoneum of patients with EPS.

Successful treatment of nephrotic syndrome caused by recurrent IgA nephropathy with chronic active antibody-mediated rejection three years after kidney transplantation.

Here, we report the successful treatment of a 38-yr-old Japanese man diagnosed with recurrent immunoglobulin A nephropathy (IgAN) with chronic active antibody-mediated rejection (CAAMR), three yr after undergoing living-related donor kidney transplantation. Immediately after transplantation, the allograft function was well maintained with a serum creatinine (S-Cr) level of <1.8 mg/dL. About three yr after transplantation, urine protein excretion had reached 4.59 g/d, and the S-Cr level had increased to more than 2.0 mg/dL. Based on the allograft biopsy, we diagnosed nephrotic syndrome because of recurrence of IgAN with CAAMR. Subsequently, we performed a tonsillectomy, administered three sessions of steroid pulse therapy, and added losartan for the recurrence of IgAN. We also changed his immunosuppressant from mizoribine to mycophenolate mofetil to treat the CAAMR. The nephrotic syndrome improved with the multiple therapeutic approaches; however, the S-Cr level did not decrease below 2.0 mg/dL. We possibly could have performed additional treatments such as rituximab and intravenous immunoglobulin for the CAAMR, but therapeutic strategies for CAAMR have not yet been established.

Successful treatment of recurrent focal segmental glomerulosclerosis combined with calcineurin inhibitor nephrotoxicity four yr after kidney transplantation.

A 31-yr-old Japanese man with end-stage kidney disease caused by primary focal segmental glomerulosclerosis (FSGS) underwent living related kidney transplantation at the age of 26 yr. The allograft functioned well immediately after surgery, and we did not observe histological findings of rejection and recurrent FSGS in protocol biopsies at two months and one yr after transplantation. Four years after transplantation, the urine protein excretion reached 11 g/d, and the serum creatinine increased over 2.5 mg/dL. We diagnosed nephrotic syndrome due to recurrent FSGS with graft dysfunction and confirmed FSGS lesions with severe endothelial injury with an allograft biopsy, associated with calcineurin inhibitor (CNI) nephrotoxicity. Thereafter, we performed plasmapheresis and steroid therapy with subsequent low-density lipoprotein adsorption, combined with the reduction of tacrolimus. The nephrotic syndrome improved dramatically with the multiple therapeutic approaches. Primary FSGS recurs frequently in patients immediately after kidney transplantation. Post-transplant FSGS has various causes, such as recurrent primary disease, obesity, hyperfiltration, donor-related nephrosclerosis, and CNI-induced arteriolopathy. In the case of nephrotic syndrome after kidney transplantation, we should consider not only recurrent FSGS, but also CNI-induced nephrotoxicity to determine the optimal treatment.

[Chronic kidney disease (CKD) and bone. Management of chronic kidney disease-mineral and bone disorder in peritoneal dialysis patients].

The peritoneal dialysate calcium concentration is an important factor in chronic kidney disease-mineral and bone disorder (CKD-MBD), because dialysate calcium concentrations strongly influence the serum calcium, phosphate, and parathyroid hormone (PTH) levels and the dosage of phosphate binders/vitamin D analogs. High-calcium dialysate has been used to correct hypocalcemia in end-stage renal disease (ESRD). Subsequently, a low-calcium dialysate was produced to increase the dosage of calcium-containing phosphate binders and vitamin D analogs without causing hypercalcemia. However, not enough is known about the effect of low-calcium dialysate in peritoneal dialysis. When we choose low-calcium dialysate, we should keep the risks of deteriorating secondary hyperparathyroidism in mind.