Associations of vitamin D receptor activators and calcimimetics with falls and effect modifications by physical activity: A prospective cohort study on the Japan Dialysis Outcomes and Practice Patterns Study.

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.

Effectiveness of calcimimetics on fractures in dialysis patients with secondary hyperparathyroidism: meta-analysis of randomized trials.

INTRODUCTION: This study aimed to assess the effectiveness of calcimimetics in reducing the risk of fractures in dialysis patients with secondary hyperparathyroidism (SHPT). MATERIAL AND METHODS: A comprehensive literature search was conducted using PubMed, Embase, and Cochrane Library for articles published through December 9, 2023. The quality of each trial was evaluated using the Cochrane Collaboration tool. Meta-analysis was performed using a random-effects model, and effect measures across studies were synthesized. The risk ratio (RR) and 95% confidence interval (CI) were used to quantify the risk of fracture. RESULTS: We identified seven studies involving 6481 dialysis patients with SHPT. The administration of calcimimetics reduced fracture incidence compared to placebo or conventional treatment (RR: 0.50, 95% CI 0.29-0.88, p = 0.02). Calcimimetics demonstrated a low number needed to treat (NNT) to prevent an incident fracture (NNT: 47). CONCLUSION: The use of calcimimetics offers a significant benefit in reducing the risk of fractures in patients undergoing dialysis with SHPT.

Calcimimetics treatment strategy for serum calcium and phosphate management in patients with secondary hyperparathyroidism undergoing dialysis: A systematic review and meta-analysis of randomized studies.

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.

The impact of low and high dialysate calcium concentrations on cardiovascular disease and death in patients undergoing maintenance hemodialysis: a systematic review and meta-analysis.

BACKGROUND: The optimal dialysate calcium (Ca) concentration for patients undergoing hemodialysis remains inconclusive, particularly concerning cardiovascular protection. METHODS: We conducted a systematic review of 19 randomized controlled trials (RCTs) and a meta-analysis of eight RCTs to determine the optimal dialysate Ca concentration for cardiovascular protection. We compared outcomes in patients receiving maintenance hemodialysis treated with either a low-Ca dialysate (LCD) (1.125 or 1.25 mmol/L) or a high-Ca dialysate (HCD) (1.5 or 1.75 mmol/L). The outcomes were coronary artery calcification score (CACS), all-cause and cardiovascular death, cardiovascular function and structure, and serum biochemical parameters. RESULTS: There was no significant difference between LCD and HCD concerning CACS (standardized mean difference [SMD] = -0.16, 95% confidence interval [CI]: [-0.38, 0.07]), the risk of all-cause death, and cardiovascular death in patients treated with chronic maintenance hemodialysis. Conversely, LCD was associated with a significantly lower intima-media thickness (SMD = -0.49, 95% CI [-0.94, -0.05]) and pulse wave velocity than HCD (SMD = -0.86, 95% CI [-1.21, -0.51]). Furthermore, LCD significantly decreased serum Ca levels (mean difference [MD] = 0.52 mg/dL, 95% CI [0.19, 0.85]) and increased serum parathyroid hormone levels (MD = 44.8 pg/mL, 95% CI [16.2, 73.3]) compared with HCD. Notably, most RCTs examined in our analysis did not include patients receiving calcimimetics. CONCLUSIONS: Our meta-analysis showed no significant differences in cardiovascular calcification and death between LCD and HCD and revealed a paucity of RCTs on dialysate Ca concentrations, including those involving patients on calcimimetics, indicating the urgent need for further studies.

Risk Factors for Thromboembolic Events in Patients With Dialysis-Dependent CKD: Pooled Analysis of Phase 3 Roxadustat Trials in Japan.

INTRODUCTION: Thromboembolic events have occurred in clinical trials of roxadustat. This post hoc analysis explored potential factors related to thromboembolic events in dialysis-dependent patients treated with roxadustat in four phase 3 clinical trials in Japan. METHODS: Thromboembolic events with onset before and after week 12 were evaluated. Baseline risk factors for thromboembolic events were investigated by Cox regression analyses. Nested case-control analyses using conditional logistic models with matched pairs of case-control data explored relationships between thromboembolic events and laboratory parameters. RESULTS: Of the 444 patients, 56 thromboembolic events were observed in 44 patients during ≤ 52 weeks of treatment. The proportion of venous and arterial thromboembolic events gradually increased after week 12. Baseline risk factors included hemodialysis (vs peritoneal dialysis), advanced age (≥ 65 years), shorter dialysis vintage (< 4 months), and history of thromboembolism. The absence of concomitant intravenous or oral iron therapy (including ferric citrate) was associated with thromboembolic events before week 12 (hazard ratio 11.25; 95% confidence interval [CI] 3.36-37.71; vs presence). Case-control analysis revealed that low average transferrin saturation (< 10%; unadjusted odds ratio [OR] 6.25; 95% CI 1.52-25.62; vs ≥ 20%), high average transferrin level (≥ 2.5 g/L; unadjusted OR 4.36; 95% CI 1.23-15.39; vs < 2.0 g/L), and high average roxadustat dose (≥ 150 mg; unadjusted OR 5.95; 95% CI 1.07-33.16; vs < 50 mg) over the previous 8 weeks before the event onset were associated with thromboembolic events after week 12. However, adjustment for iron status extinguished the significant relationship between roxadustat dose and events. Multivariate case-control analysis showed that increased transferrin from baseline (≥ 1.0 g/L; adjusted OR 7.85; 95% CI 1.82-33.90; vs < 0.5 g/dL) and decreased mean corpuscular volume (< - 2 fL; adjusted OR 5.55; 95% CI 1.73-17.83; vs ≥ 0 fL) were associated with increased risk of thromboembolic events. CONCLUSION: In addition to established risk factors, iron deficiency may be related to thromboembolic events. Graphical Abstract available for this article. TRIAL REGISTRATION: NCT02780726, NCT02952092, NCT02780141, NCT02779764.

Roxadustat is an oral medicine that treats anemia in patients with chronic kidney disease (CKD). Thromboembolic events, or blood vessels blocked by a blood clot, have occurred in clinical trials of roxadustat. This study explored potential factors that may be related to thromboembolic events in roxadustat-treated patients with anemia of CKD on dialysis before and after week 12. This study found that hemodialysis (vs peritoneal dialysis), advanced age (older than 65 years), short amount of time on dialysis (less than 4 months), previous history of thromboembolic events, and not receiving iron therapy were risk factors for thromboembolic events before week 12. Iron deficiency and high roxadustat dose were risk factors for thromboembolic events after week 12. When iron status was also considered, we did not find that roxadustat dose was related to thromboembolic events. A different model found that increased levels of transferrin, a protein that transports iron, from baseline and decreased mean corpuscular volume, or smaller red blood cells, increased the risk of thromboembolic events. Patients with anemia of CKD on dialysis may benefit from more intentional monitoring and management of iron while receiving roxadustat.

Risk Factors for Thromboembolic Events in Patients With Dialysis-Dependent CKD: Pooled Analysis of Four Global Roxadustat Phase 3 Trials.

INTRODUCTION: Risk factors for thromboembolic events in patients with dialysis-dependent chronic kidney disease (CKD) receiving roxadustat are unknown. Iron deficiency has been reported as a risk factor for thrombosis in the general population. METHODS: Thromboembolic events with onset before and after week 12 in patients receiving roxadustat were evaluated in this pooled analysis of four global phase 3 trials, PYRENEES, SIERRAS, HIMALAYAS, and ROCKIES. Baseline risk factors for thromboembolic events were investigated by Cox regression analyses. Nested case-control analyses with matched pairs of case-control data explored the relationship between thromboembolic events and last known laboratory parameters before event onset. RESULTS: Of 2354 patients, 1026 thromboembolic events were observed in 568 patients. Baseline risk factors found included hemodialysis (vs peritoneal dialysis), advanced age (≥ 65 years), Black race, high high-sensitivity C-reactive protein, and history of thromboembolism, cardiovascular disease, or diabetes. Univariate case-control analyses revealed that high hemoglobin rate of rise (≥ 0.5 g/dL/week; odds ratio [OR] 2.09; 95% confidence interval [CI] 0.98-4.46) showed a trend towards increased risk of thromboembolic events before week 12, and high rate of hemoglobin decline was associated with events after week 12 (< - 0.5 g/dL/week; OR 3.73; 95% CI 1.68-8.27) as compared to stable hemoglobin levels (≥ - 0.1 to < 0.1 g/dL/week). Multivariate case-control analyses showed that low last known hemoglobin level (< 10 g/dL: adjusted OR 1.91; 95% CI 1.04-3.50; vs ≥ 12 g/dL) and low last known transferrin saturation (TSAT < 10%: adjusted OR 3.78; 95% CI 1.71-8.39; vs ≥ 30%) before event onset were associated with events after week 12. In patients with last known TSAT < 30%, higher roxadustat dose was associated with thromboembolic events; however, no association was observed in those with TSAT ≥ 30%. CONCLUSIONS: Among various risk factors for thromboembolic events, it is reasonable to avoid a rapid increase and decline in hemoglobin levels as well as ensure TSAT ≥ 30%, rather than increasing the roxadustat dose. Graphical Abstract available for this article. TRIAL REGISTRATION: NCT02278341, NCT02273726, NCT02052310, NCT02174731.

Roxadustat is an oral treatment for patients with anemia, or low hemoglobin levels, due to chronic kidney disease. Thromboembolic events are caused by a blood clot blocking blood vessels, and they have occurred in clinical trials of roxadustat. This analysis evaluated risk factors for thromboembolic events in patients receiving roxadustat to treat anemia of chronic kidney disease who are on dialysis. Two different statistical approaches were used to investigate risk factors for thromboembolic events that occurred before and after 12 weeks of roxadustat treatment. We found that rapid improvement of anemia after starting roxadustat treatment may be associated with an increased risk of thromboembolic events occurring in the first 12 weeks of treatment. In contrast, severe anemia or worsening of anemia was associated with an increased risk of thromboembolic events after week 12. Low iron levels in the blood or greater decline of available iron in the blood from baseline were also detected as risk factors for the events after week 12, suggesting that iron supplementation is important in patients who are iron-deficient. Moreover, thromboembolic events were also associated with older age (≥ 65 years), Black race, high levels of inflammation, and having had a previous thromboembolic event or having a history of cardiovascular disease or diabetes. Some risk factors, such as iron status and hemoglobin levels, can be changed after beginning roxadustat treatment and should be monitored and modified, as needed.

Body fluid volume calculated using the uric acid kinetic model relates to the vascular event.

PURPOSE: We developed a method to measure the extracellular and intracellular fluid volumes using the kinetics of uric acid in the bodies of Japanese patients undergoing dialysis. In this research, we aimed to assess the prognosis of vascular events using this uric acid kinetic model method. METHODS: We conducted a retrospective cohort study of 1,298 patients who were undergoing hemodialysis or predilution online hemodiafiltration at the end of December 2019 at 13 institutions in Japan. Information on vascular events was acquired in 2020. Vascular event prognosis was defined as the new incidence of one or more of the following four types of vascular events: myocardial infarction, cerebral infarction, cerebral hemorrhage, or limb amputation. We measured the extracellular fluid volume and intracellular fluid volume after dialysis using the uric acid kinetic model method and determined the association between ECV, ICV, and vascular event risk. RESULTS: A high extracellular volume was substantially linked to an increased risk of vascular events. In addition, while a crude analysis revealed that a high intracellular volume was associated with a low risk of vascular events, this was not statistically significant after multifactorial adjustment. This result was partly affected by the low measurement accuracy of the serum urea nitrogen level used for the intracellular volume calculation. CONCLUSIONS: Extracellular volume calculated using the uric acid kinetic model method is a prognostic factor for vascular events in patients undergoing hemodialysis.

Associations of calcium, phosphate and intact parathyroid hormone levels with mortality, residual kidney function and technical failure among patients on peritoneal dialysis.

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.

Epidemiology and predictors of hyponatremia in a contemporary cohort of patients with malignancy: a retrospective cohort study.

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.

Hypocalcemia and cardiovascular mortality in cinacalcet users.

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-average) 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 mean annual dropout rate of 2.9%. Hypocalcemia was not associated with cardiovascular mortality in the baseline or time-average 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.

Mediators between canagliflozin and renoprotection vary depending on patient characteristics: Insights from the CREDENCE trial.

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.

Association between serum iron markers, iron supplementation and cardiovascular morbidity in pre-dialysis chronic kidney disease.

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.

Possible contribution of phosphate to the pathogenesis of chronic kidney disease in dolphins.

This study aimed to investigate whether phosphate contributes to the pathogenesis of chronic kidney disease (CKD) in dolphins. Renal necropsy tissue of an aged captive dolphin was analyzed and in vitro experiments using cultured immortalized dolphin proximal tubular (DolKT-1) cells were performed. An older dolphin in captivity died of myocarditis, but its renal function was within the normal range until shortly before death. In renal necropsy tissue, obvious glomerular and tubulointerstitial changes were not observed except for renal infarction resulting from myocarditis. However, a computed tomography scan showed medullary calcification in reniculi. Micro area X-ray diffractometry and infrared absorption spectrometry showed that the calcified areas were primarily composed of hydroxyapatite. In vitro experiments showed that treatment with both phosphate and calciprotein particles (CPPs) resulted in cell viability loss and lactate dehydrogenase release in DolKT-1 cells. However, treatment with magnesium markedly attenuated this cellular injury induced by phosphate, but not by CPPs. Magnesium dose-dependently decreased CPP formation. These data support the hypothesis that continuous exposure to high phosphate contributes to the progression of CKD in captive-aged dolphins. Our data also suggest that phosphate-induced renal injury is mediated by CPP formation in dolphins, and it is attenuated by magnesium administration.

The cisplatin-induced acute kidney injury is a novel risk factor for postoperative complications in patients with esophageal cancer: a retrospective cohort study.

BACKGROUND: Cisplatin-induced acute kidney injury (AKI) is common during preoperative chemotherapy for esophageal cancer. The purpose of this study was to investigate the association between AKI after preoperative chemotherapy and postoperative complications in patients with esophageal cancer. METHODS: In this retrospective cohort study, we included patients who had received preoperative chemotherapy with cisplatin and underwent surgical resection for esophageal cancer under general anesthesia from January 2017 to February 2022 at an education hospital. A predictor was stage 2 or higher cisplatin-induced AKI (c-AKI) defined by the KDIGO criteria within 10 days after chemotherapy. Outcomes were postoperative complications and length of hospital stays. Associations between c-AKI and outcomes including postoperative complications and length of hospital stays were examined with logistic regression models. RESULTS: Among 101 subjects, 22 developed c-AKI with full recovery of the estimated glomerular filtration (eGFR) before surgery. Demographics were not significantly different between patients with and without c-AKI. Patients with c-AKI had significantly longer hospital stays than those without c-AKI [mean (95% confidence interval (95%CI)) 27.6 days (23.3-31.9) and 43.8 days (26.5-61.2), respectively, mean difference (95%CI) 16.2 days (4.4-28.1)]. Those with c-AKI had higher C-reactive protein (CRP) levels and prolonged weight gain after surgery and before the events of interest despite having comparable eGFR trajectories after surgery. c-AKI was significantly associated with anastomotic leakage and postoperative pneumonia [odds ratios (95%CI) 4.14 (1.30-13.18) and 3.87 (1.35-11.0), respectively]. Propensity score adjustment and inverse probability weighing yielded similar results. Mediation analysis showed that a higher incidence of anastomotic leakage in patients with c-AKI was primarily mediated by CRP levels (mediation percentage 48%). CONCLUSION: c-AKI after preoperative chemotherapy in esophageal cancer patients was significantly associated with the development of postoperative complications and led to a resultant longer hospital stay. Increased vascular permeability and tissue edema due to prolonged inflammation might explain the mechanisms for the higher incidence of postoperative complications.

Association of Four Types of Vascular Access Including Arterial Superficialization with Mortality in Maintenance Hemodialysis Patients: A Nationwide Cohort Study in Japan.

INTRODUCTION: Vascular access usage varies widely across countries. Previous studies have evaluated the association of clinical outcomes with the three types of vascular access, namely, arteriovenous fistula (AVF), arteriovenous graft (AVG), and tunneled and cuffed central venous catheter (TC-CVC). However, little is known regarding the association between arterial superficialization (AS) and the mortality of patients. METHODS: A nationwide cohort study was conducted using data from the Japanese Society for Dialysis Therapy Renal Data Registry (2006-2007). We included patients aged ≥20 years undergoing hemodialysis with a dialysis vintage ≥6 months. The exposures of interest were the four types of vascular access: AVF, AVG, AS, and TC-CVC. Cox proportional hazard models were used to evaluate the associations of vascular access types with 1-year all-cause and cause-specific mortality. RESULTS: A total of 183,490 maintenance hemodialysis patients were included: 90.7% with AVF, 6.9% with AVG, 2.0% with AS, and 0.4% with TC-CVC. During the 1-year follow-up period, 13,798 patients died. Compared to patients with AVF, those with AVG, AS, and TC-CVC had a significantly higher risk of all-cause mortality after adjustment for confounding factors: adjusted hazard ratios (95% confidence intervals) - 1.30 (1.20-1.41), 1.56 (1.39-1.76), and 2.15 (1.77-2.61), respectively. Similar results were obtained for infection-related and cardiovascular mortality. CONCLUSION: This nationwide cohort study conducted in Japan suggested that AVF usage may have the lowest risk of all-cause mortality. The study also suggested that the usage of AS may be associated with better survival rates compared to those of TC-CVC in patients who are not suitable for AVF or AVG.

Excess risk of cardiovascular events in patients in the United States vs. Japan with chronic kidney disease is mediated mainly by left ventricular structure and function.

While patients receiving dialysis therapy in the United States are more likely to develop cardiovascular disease (CVD) than those in Japan, direct comparisons of patients with predialysis chronic kidney disease (CKD) are rare. To study this, we compared various outcomes in patients with predialysis CKD using data from the Chronic Renal Insufficiency Cohort (CRIC) and CKD Japan Cohort (CKD-JAC) studies and determined mediators of any differences. Candidate mediators included left ventricular (LV) indices assessed by echocardiography. Among 3125 CRIC and 1097 CKD-JAC participants, the mean LV mass index (LVMI) and ejection fraction (EF) were 55.7 and 46.6 g/m2 and 54% and 65%, respectively (both significant). The difference in body mass index (32 and 24 kg/m2, respectively) largely accounted for the differences in LVMI and C-reactive protein levels across cohorts. Low EF and high LVMI were significantly associated with subsequent CVD in both cohorts. During a median follow-up of five years, CRIC participants were at higher risk for CVD (adjusted hazard ratio [95% confidence interval]: 3.66 [2.74-4.89]) and death (4.69 [3.05-7.19]). A three-fold higher C-reactive protein concentration and higher phosphate levels in the United States cohort were moderately strong mediators of the differences in CVD. However, echocardiographic parameters were stronger mediators than these laboratory measures. LVMI, EF and their combination mediated the observed difference in CVD (27%, 50%, and 57%, respectively) and congestive heart failure (33%, 62%, and 70%, respectively). Thus, higher LV mass and lower EF, even in the normal range, were found to be predictive of CVD in CKD.

TFEB-mediated lysosomal exocytosis alleviates high-fat diet-induced lipotoxicity in the kidney.

Obesity is a major risk factor for end-stage kidney disease. We previously found that lysosomal dysfunction and impaired autophagic flux contribute to lipotoxicity in obesity-related kidney disease, in both humans and experimental animal models. However, the regulatory factors involved in countering renal lipotoxicity are largely unknown. Here, we found that palmitic acid strongly promoted dephosphorylation and nuclear translocation of transcription factor EB (TFEB) by inhibiting the mechanistic target of rapamycin kinase complex 1 pathway in a Rag GTPase-dependent manner, though these effects gradually diminished after extended treatment. We then investigated the role of TFEB in the pathogenesis of obesity-related kidney disease. Proximal tubular epithelial cell-specific (PTEC-specific) Tfeb-deficient mice fed a high-fat diet (HFD) exhibited greater phospholipid accumulation in enlarged lysosomes, which manifested as multilamellar bodies (MLBs). Activated TFEB mediated lysosomal exocytosis of phospholipids, which helped reduce MLB accumulation in PTECs. Furthermore, HFD-fed, PTEC-specific Tfeb-deficient mice showed autophagic stagnation and exacerbated injury upon renal ischemia/reperfusion. Finally, higher body mass index was associated with increased vacuolation and decreased nuclear TFEB in the proximal tubules of patients with chronic kidney disease. These results indicate a critical role of TFEB-mediated lysosomal exocytosis in counteracting renal lipotoxicity.

Not baseline but time-dependent erythropoiesis-stimulating agent responsiveness predicts cardiovascular disease in hemodialysis patients receiving epoetin beta pegol: A multicenter prospective PARAMOUNT-HD Study.

BACKGROUND: Responsiveness to erythropoiesis-stimulating agents (ESAs) has been reported to be associated with increased cardiovascular disease (CVD) and mortality in patients undergoing hemodialysis (HD). However, the association between hyporesponsiveness to the long-acting ESA, epoetin beta pegol (CERA), and CVD remains unknown. METHODS: This multicenter prospective study included 4034 patients undergoing maintenance HD. After shifting from prior ESA to CERA, we studied the association between erythropoietin resistance index (ERI) at six months and outcomes, including cardiac events, major adverse cardiovascular events (MACE), and all-cause mortality, using Cox proportional hazards models (Landmark analyses) and marginal structural models to adjust for time-dependent confounding factors, including iron-containing medications and hemodiafiltration (HDF). RESULTS: The median dialysis vintage and the observational period were 5.0 years and 22.1 months, respectively. The landmark analyses revealed that the highest tertile of baseline ERI (T3) was associated with a significantly higher all-cause mortality than the lowest tertile (T1) (hazard ratio [HR]: 1.48, 95% CI: 1.03-2.13). Furthermore, marginal structural models revealed that time-dependent ERI T3 was significantly associated with increased cardiac events (HR: 1.59, 95% CI: 1.14-2.23), MACE (HR: 1.60, 95% CI: 1.19-2.15), all-cause mortality (HR: 1.97, 95% CI: 1.40-2.77), and heart failure (HF) (HR: 2.05, 95% CI: 1.23-3.40) compared to T1. A linear mixed effects model showed that iron-containing medications and HDF are negatively associated with time-dependent ERI. CONCLUSIONS: Baseline ERI at six months predicted only all-cause mortality; however, time-dependent ERI was a predictor of cardiac events, all-cause mortality, MACE, and HF. The widespread use of iron-containing medications and HDF would ameliorate ESA hyporesponsiveness.