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Background: The Kidney Disease Improving Global Outcomes guidelines recommend nephrology referral for patients with chronic kidney disease (CKD) stages 4 to 5, significant proteinuria and persistent microscopic haematuria. However, the recommendations are opinion‐based and which patients with CKD benefit more from nephrology referral has not been elucidated. Methods: In this retrospective cohort study, patients referred to our nephrology outpatient clinic from April 2017 to March 2019 were included. We excluded patients considered to have an acute decline in kidney function (annual decline in estimated glomerular filtration rate [eGFR] >10 mL/min/1.73 m2). The slopes of eGFR before and after nephrology referral were estimated and compared by linear mixed effects models. Interaction between time and referral status (before or after referral) was assessed and effect modifications by the presence of diabetes, proteinuria (defined by urine dipstick protein 2+ or more), urine occult blood, hypoalbuminemia (defined by albumin levels less than 3.5 g/dL) and anaemia (defined by haemoglobin levels less than 11.0 g/dL) were evaluated. Results: The eGFR slope significantly improved from −2.05 (−2.39 to −1.72) to −0.96 (−1.36 to −0.56) mL/min/1.73 m2/year after nephrology referral (p <.001). The improvement in eGFR slope was more prominent among those with diabetes mellitus, anaemia, and hypoalbuminemia (all p‐values for three‐way interaction <.001 after adjustment for covariates). Further adjustments for time‐dependent haemoglobin levels, the use of erythropoiesis‐stimulating agents, iron supplementation, anti‐hypertensives and anti‐diabetic medications did not change the significance of the interactions. Conclusions: Nephrology referral slows CKD progression, especially among those with hypoalbuminemia, diabetes or anaemia. Patients with hypoalbuminemia, diabetes or anaemia might benefit more from specialized care and lifestyle modifications by nephrologists. The inclusion of anaemia and hypoalbuminemia in nephrology referral criteria should be considered. [ABSTRACT FROM AUTHOR]

Introduction: Several calcimimetics, other than cinacalcet, are commercially available; however, their effects on calcium and phosphate levels have not yet been fully studied. We conducted a systematic review and meta‐analysis of randomized controlled trials to evaluate the impact of calcimimetics on the management of serum calcium and phosphate levels in patients with secondary hyperparathyroidism undergoing dialysis. Methods: A systematic literature search through October 2023 and a meta‐analysis were conducted on the effects of upacicalcet, etelcalcetide, evocalcet, and cinacalcet on serum calcium and phosphate levels in patients with secondary hyperparathyroidism undergoing dialysis; we searched PubMed, Ovid MEDLINE, and the Cochrane Central Register of Controlled Trials, and 21 studies comprising 6371 patients undergoing dialysis were included. Results: Participants treated with calcimimetics had lower serum calcium and phosphate levels than placebo. Conclusion: Calcimimetics significantly reduced serum calcium and phosphate levels compared to placebo in patients with secondary hyperparathyroidism undergoing dialysis, independent of therapeutic strategy or concomitant vitamin D treatment. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to examine the associations of vitamin D receptor activators (VDRA) and calcimimetics use with falls. Methods: This is a prospective cohort study on hemodialysis patients in the Japan Dialysis Outcomes and Practice Patterns Study. We excluded those who were unable to walk. The associations of VDRA or calcimimetics use with falls and effect modifications by physical activity were analyzed using marginal structural models. Results: In total, 1875 patients were included. VDRA and calcimimetics use was not associated with falls (risk ratio [95% CI]: 1.13 [0.84–1.51] and 1.02 [0.72–1.44]). The risk ratio for falls associated with VDRA use was lower among those with poor physical activity (p for interaction <0.1). Conclusions: Although vitamin D receptor activators and calcimimetics use was not associated with falls, the lower risk ratio for falls with vitamin D receptor activators use among those with poor physical activity suggests that vitamin D receptor activators use might be beneficial among these patients. [ABSTRACT FROM AUTHOR]

Background Calcimimetics are widely used in hemodialysis patients and influence serum calcium levels. Although the Kidney Disease: Improving Global Outcomes guidelines argued that low calcium levels induced by calcimimetics may be harmless, large observational studies investigating the association between hypocalcemia and mortality are scarce. We investigated the association between serum calcium levels and cardiovascular mortality in calcimimetics users using the nationwide Japanese registry for dialysis patients. Methods In this 9-year prospective cohort study, the baseline data were collected at the end of 2009. We enrolled patients on maintenance hemodialysis or hemodiafiltration. We employed three models (baseline, time-dependent and time-averaged) to conduct Cox proportional hazard regression analyses. Results Cinacalcet was prescribed to 12.7% (N  = 22 853) at baseline. The median observation period was 98 (interquartile range 40–108) months and 108 (interquartile range 59–108) months in the whole cohort (N  = 180 136) and in cinacalcet users, respectively. Three-quarters of survivors at the end of 2019 had continued calcimimetic therapy for 10 years, corresponding to a mean annual dropout rate of 2.9%. Hypocalcemia was not associated with cardiovascular mortality in the baseline or time-averaged model. In the time-dependent model, however, the lowest calcium decile (corrected calcium <8.4 mg/dL) was significantly associated with higher cardiovascular mortality than the reference (corrected calcium 8.7–8.9 mg/dL) in both cinacalcet users and all patients [hazard ratio (95% confidence interval) 1.32 (1.00, 1.75) and 1.15 (1.05, 1.26), respectively]. Hypocalcemia was especially associated with sudden death and death due to hemorrhagic stroke, heart failure and ischemic heart disease. Higher rate of fatal and non-fatal cardiovascular events was observed in hypocalcemic patients regardless of cinacalcet usage. Conclusions Our findings suggest that transient hypocalcemia was associated with an increased risk of cardiovascular death independent of cinacalcet usage. We should pay attention to hypocalcemia transiently induced by cinacalcet. [ABSTRACT FROM AUTHOR]

Background The optimal range of serum iron markers and usefulness of iron supplementation are uncertain in patients with pre-dialysis chronic kidney disease (CKD). We investigated the association between serum iron indices and risk of cardiovascular disease (CVD) events and the effectiveness of iron supplementation using Chronic Kidney Disease Japan Cohort data. Methods We included 1416 patients ages 20–75 years with pre-dialysis CKD. The tested exposures were serum transferrin saturation and serum ferritin levels and the outcome measures were any cardiovascular event. Fine–Gray subdistribution hazard models were used to examine the association between serum iron indices and time to events. The multivariable fractional polynomial interaction approach was used to evaluate whether serum iron indices were effect modifiers of the association between iron supplementation and cardiovascular events. Results The overall incidence rate of CVD events for a median of 4.12 years was 26.7 events/1000 person-years. Patients with serum transferrin saturation <20% demonstrated an increased risk of CVD [subdistribution hazard ratio (HR) 2.13] and congestive heart failure (subdistribution HR 2.42). The magnitude of reduction in CVD risk with iron supplementation was greater in patients with lower transferrin saturations (P  = .042). Conclusions Maintaining transferrin saturation >20% and adequate iron supplementation may effectively reduce the risk of CVD events in patients with pre-dialysis CKD. [ABSTRACT FROM AUTHOR]

Background Associations of calcium, phosphate and intact parathyroid hormone (iPTH) levels with outcomes may be different between patients on peritoneal dialysis (PD) and hemodialysis (HD). The aim of the study is to evaluate these associations among PD patients. Methods In this prospective cohort study on the Japan Renal Data Registry, adults on PD at the end of 2009 were included. The observation period was until the end of 2018 and the data were censored at the time of transplantation or transition to HD. Exposures were time-averaged or time-dependent albumin-corrected calcium (cCa), phosphate and iPTH levels. Outcomes were all-cause and cardiovascular mortality, transition to HD and urine output. Data were analyzed using Cox regression models or linear mixed-effects models and the results were shown as cubic spline curves. Results Among 7393 patients, 590 deaths and 211 cardiovascular deaths were observed during a median follow-up of 3.0 years. Higher cCa and phosphate levels were associated with higher mortality. Lower cCa levels were associated with a faster decline, whereas lower phosphate was associated with a slower decline in urine output. Lower phosphate and iPTH levels were associated with a lower incidence of transition to HD. Conclusions Among PD patients, the observed associations of cCa, phosphate and iPTH with mortality, residual kidney function and technical failure suggest that avoiding high cCa, phosphate and iPTH levels might improve outcomes. [ABSTRACT FROM AUTHOR]

Background Hyponatremia is associated with worse outcomes among patients with malignancy. However, contemporary cohort data on epidemiology and risk factors are lacking. Methods In this single-centre, retrospective cohort study, patients who received intravenous antineoplastic agents from 2018 to 2020 at Nagoya City University Hospital were enrolled. Associations of demographics, antineoplastic agents, types of malignancy and concomitant medications with hyponatremia, defined as serum sodium concentration ≤130 mmol/l, were analysed by mixed-effects logistic regression and the machine learning–based LightGBM model artificial intelligence technology. Results Among 2644 patients, 657 (24.8%) developed at least one episode of hyponatremia. Approximately 80% of hyponatremia was due to sodium wasting from the kidneys. Variables associated with hyponatremia both by mixed-effects logistic regression and the LightGBM model were older age, hypoalbuminemia and higher estimated glomerular filtration rate. Among antineoplastic agents, cisplatin {odds ratio [OR] 1.52 [95% confidence interval (CI) 1.18–1.96]}, pembrolizumab [OR 1.42 (95% CI 1.02–1.97)] and bortezomib [OR 3.04 (95% CI 1.96–4.71)] were associated with hyponatremia and these variables also had a positive impact on predicted hyponatremia in the LightGBM model. Conclusions Hyponatremia was common among patients with malignancy. In addition to older age and poor nutritional status, novel antineoplastic agents, including immune checkpoint inhibitors and bortezomib, should be recognized as risk factors for hyponatremia. [ABSTRACT FROM AUTHOR]

Aim: To identify the mediators between canagliflozin and renoprotection in patients with type 2 diabetes at a high risk of end‐stage kidney disease (ESKD). Methods: In this post hoc analysis of the CREDENCE trial, the effect of canagliflozin on potential mediators (42 biomarkers) at 52 weeks and the association between changes in mediators and renal outcomes were evaluated using mixed‐effects and Cox models, respectively. The renal outcome was a composite of ESKD, serum creatinine doubling or renal death. The percentage of the mediating effect of each significant mediator was calculated based on changes in the hazard ratios of canagliflozin after additional adjustment of the mediator. Results: Changes in haematocrit, haemoglobin, red blood cell (RBC) count and urinary albumin‐to‐creatinine ratio (UACR) at 52 weeks significantly mediated 47%, 41%, 40% and 29% risk reduction with canagliflozin, respectively. Further, 85% mediation was attributed to the combined effect of haematocrit and UACR. A large variation in mediating effects by haematocrit change existed among the subgroups, ranging from 17% in those patients with a UACR of more than 3000 mg/g to 63% in patients with a UACR of 3000 mg/g or less. In the subgroups with a UACR of more than 3000 mg/g, UACR change was the highest mediating factor (37%), driven by the strong association between UACR decline and renal risk reduction. Conclusions: The renoprotective effects of canagliflozin in patients at a high risk of ESKD can be significantly explained by changes in RBC variables and UACR. The complementary mediating effects of RBC variables and UACR may support the renoprotective effect of canagliflozin in different patient groups. [ABSTRACT FROM AUTHOR]

Background Outcomes of a combination of peritoneal dialysis (PD) and once-weekly haemodialysis (PD + HD) have not been extensively studied. Methods This prospective cohort study using the Japanese Society for Dialysis Therapy Renal Data Registry included those who transitioned from PD to PD + HD therapy or thrice-weekly HD from 2011 to 2018. Exposure was PD + HD therapy compared with thrice-weekly HD. The outcome was time to all-cause or cause-specific death. Associations between PD + HD therapy and outcomes were examined by Cox regression. Sensitivity analyses were performed by propensity score (PS) matching, PS matching with a shared frailty model in which dialysis facilities were treated as a random effect, inverse probability weighting (IPW), PS adjustment, PS stratification, competing risk regression and on-treatment analyses in which data were censored at the transition to thrice-weekly HD for those on PD + HD therapy. Results During the study period, 1001 subjects transitioned to PD + HD therapy and 2031 to thrice-weekly HD. During a median follow-up of 3.5 years, 575 subjects died. All-cause, cardiovascular, congestive heart failure–related or infection-related mortality were not significantly different between those on PD + HD and those on thrice-weekly HD [hazard ratio 0.95 (95% confidence interval 0.78–1.16), 1.26 (0.92–1.72), 1.24 (0.77–1.99) and 0.89 (0.57–1.39), respectively]. Sensitivity analyses yielded similar results except that PD + HD therapy was associated with significantly lower all-cause mortality by PS adjustment and PS matching with the shared frailty model and lower infection-related mortality by PS adjustment and IPW. Conclusions PD + HD therapy was associated with similar or potentially lower mortality compared with thrice-weekly HD. Considering a flexible lifestyle, PD + HD therapy could be a great option. [ABSTRACT FROM AUTHOR]