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Kullaya Takkavatakarn,1 Jeerath Phannajit,1 Suwasin Udomkarnjananun,1 Suri Tangchitthavorngul,1 Pajaree Chariyavilaskul,2,3 Patita Sitticharoenchai,4 Kearkiat Praditpornsilpa,1 Somchai Eiam-Ong,1 Paweena Susantitaphong1,5 1Division of Nephrology, Department of Medicine, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand; 2Clinical Pharmacokinetics and Pharmacogenomics Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; 3Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; 4Division of Cardiology, Department of Medicine, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok, Thailand; 5Research Unit for Metabolic Bone Disease in CKD Patients, Faculty of Medicine, Chulalongkorn University, Bangkok, ThailandCorrespondence: Paweena Susantitaphong, Division of Nephrology, Department of Medicine, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, 1873 RAMA IV, Bangkok, 10330, Thailand, Tel +662 256-4251, Fax +662 256-4560, Email paweena.s@chula.ac.thIntroduction: Indoxyl sulfate, a protein-bound uremic toxin, has been reported as an atherosclerosis and fibrosis accelerator. This study aimed to determine whether serum indoxyl sulfate is associated with cardiac abnormalities, cardiovascular events, and renal progression to dialysis in patients with chronic kidney disease (CKD).Methods: The prospective study enrolled 89 patients with CKD stage 3 to 5 patients. Serum biochemistry data and indoxyl sulfate were measured. All patients underwent echocardiographic examination. Global longitudinal strain (GLS) was calculated using two-dimensional speckle tracking. The clinical outcomes including cardiovascular event and dialysis initiation were recorded during a 2-year follow-up.Results: Patients were divided into 2 groups based on the median value of serum indoxyl sulfate (low and high indoxyl sulfate groups). Kaplan–Meier analysis revealed that patients with higher indoxyl sulfate (≥ 6.124 mg/L) were significantly associated with renal progression to dialysis (p < 0.001). There was no significant difference in cardiovascular events between 2 groups (p = 0.082). In addition, serum indoxyl sulfate level was independently associated with GLS (r = 0.62; p = 0.01). The risk of cardiovascular events was significantly higher in patients with impaired GLS (>− 16%) (p = 0.015).Conclusion: Serum indoxyl sulfate level was a significant predictor for CKD progression to dialysis and was correlated with GLS, a speckle tracking echocardiography parameter representing early LV systolic dysfunction. Furthermore, GLS was associated with cardiovascular events in CKD patients. Serum indoxyl sulfate measurement may help to identify the high dialysis and cardiovascular risk CKD patients beyond traditional risk factors.Graphical Abstract: Keywords: indoxyl sulfate, chronic kidney disease, echocardiographic parameters, renal outcomes, cardiovascular events

Purpose: Intravenous fluids are mainstay of management of acute kidney injury (AKI) after sepsis but can cause fluid overload. Recent literature shows that restrictive fluid strategy may be beneficial in some patients with AKI, however, identifying these patients is challenging. We aimed to develop and validate a machine learning algorithm to identify patients who would benefit from a restrictive fluid strategy., Methods: We included patients with sepsis who developed AKI within 48 hours of ICU admission and defined restrictive fluid strategy as receiving <500mL fluids within 24 hours after AKI. Our primary outcome was early AKI reversal within 48 hours of AKI onset, and secondary outcomes included sustained AKI reversal and major adverse kidney events (MAKE) at discharge. We used a causal forest, a machine learning algorithm to estimate individual treatment effects and policy tree algorithm to identify patients who would benefit by restrictive fluid strategy. We developed the algorithm in MIMIC-IV and validated it in eICU database., Results: Among 2,091 patients in the external validation cohort, policy tree recommended restrictive fluids for 88.2%. Among these, patients who received restrictive fluids demonstrated significantly higher rate of early AKI reversal (48.2% vs 39.6%, p<0.001), sustained AKI reversal (36.7% vs 27.4%, p<0.001) and lower rates of MAKE by discharge (29.3% vs 35.1%, p=0.019). These results were consistent in adjusted analysis., Conclusion: Policy tree based on causal machine learning can identify septic patients with AKI who benefit from a restrictive fluid strategy. This approach needs to be validated in prospective trials., Competing Interests: Competing Interests GNN is a founder of Renalytix, Pensieve, Verici and provides consultancy services to AstraZeneca, Reata, Renalytix, Siemens Healthineer and Variant Bio, serves a scientific advisory board member for Renalytix and Pensieve. He also has equity in Renalytix, Pensieve and Verici. LC is a consultant for Vifor Pharma INC and has received honorarium from Fresenius Medical Care. JAK reports receiving consulting fees from Astute Medical/bioMerieux, Astellas, Alexion, Chugai Pharma, Novartis, Mitsubishi Tenabe and GE Healthcare and is a Full-time employee of Spectral Medical. All remaining authors have declared no conflicts of interest.

Background: Current classification for acute kidney injury (AKI) in critically ill patients with sepsis relies only on its severity-measured by maximum creatinine which overlooks inherent complexities and longitudinal evaluation of this heterogenous syndrome. The role of classification of AKI based on early creatinine trajectories is unclear., Methods: This retrospective study identified patients with Sepsis-3 who developed AKI within 48-h of intensive care unit admission using Medical Information Mart for Intensive Care-IV database. We used latent class mixed modelling to identify early creatinine trajectory-based classes of AKI in critically ill patients with sepsis. Our primary outcome was development of acute kidney disease (AKD). Secondary outcomes were composite of AKD or all-cause in-hospital mortality by day 7, and AKD or all-cause in-hospital mortality by hospital discharge. We used multivariable regression to assess impact of creatinine trajectory-based classification on outcomes, and eICU database for external validation., Results: Among 4197 patients with AKI in critically ill patients with sepsis, we identified eight creatinine trajectory-based classes with distinct characteristics. Compared to the class with transient AKI, the class that showed severe AKI with mild improvement but persistence had highest adjusted risks for developing AKD (OR 5.16; 95% CI 2.87-9.24) and composite 7-day outcome (HR 4.51; 95% CI 2.69-7.56). The class that demonstrated late mild AKI with persistence and worsening had highest risks for developing composite hospital discharge outcome (HR 2.04; 95% CI 1.41-2.94). These associations were similar on external validation., Conclusions: These 8 classes of AKI in critically ill patients with sepsis, stratified by early creatinine trajectories, were good predictors for key outcomes in patients with AKI in critically ill patients with sepsis independent of their AKI staging., (© 2024. The Author(s).)

Background: Area-level social determinants of health (SDOH) based on patients' ZIP codes or census tracts have been commonly used in research instead of individual SDOHs. To our knowledge, whether machine learning (ML) could be used to derive individual SDOH measures, specifically individual educational attainment, is unknown., Methods: This is a retrospective study using data from the Mount Sinai BioMe Biobank. We included participants that completed a validated questionnaire on educational attainment and had home addresses in New York City. ZIP code-level education was derived from the American Community Survey matched for the participant's gender and race/ethnicity. We tested several algorithms to predict individual educational attainment from routinely collected clinical and demographic data. To evaluate how using different measures of educational attainment will impact model performance, we developed three distinct models for predicting cardiovascular (CVD) hospitalization. Educational attainment was imputed into models as either survey-derived, ZIP code-derived, or ML-predicted educational attainment., Results: A total of 20,805 participants met inclusion criteria. Concordance between survey and ZIP code-derived education was 47%, while the concordance between survey and ML model-predicted education was 67%. A total of 13,715 patients from the cohort were included into our CVD hospitalization prediction models, of which 1,538 (11.2%) had a history of CVD hospitalization. The AUROC of the model predicting CVD hospitalization using survey-derived education was significantly higher than the model using ZIP code-level education (0.77 versus 0.72; p < 0.001) and the model using ML model-predicted education (0.77 versus 0.75; p < 0.001). The AUROC for the model using ML model-predicted education was also significantly higher than that using ZIP code-level education (p = 0.003)., Conclusion: The concordance of survey and ZIP code-level educational attainment in NYC was low. As expected, the model utilizing survey-derived education achieved the highest performance. The model incorporating our ML model-predicted education outperformed the model relying on ZIP code-derived education. Implementing ML techniques can improve the accuracy of SDOH data and consequently increase the predictive performance of outcome models., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: S.G.C. has salary support from NIH grants R01DK115562, UO1DK106962, R01HL085757, R01DK112258, R01DK115562, R01DK126477 and UH3DK114920. SGC reports personal income and equity and stock options from Renalytix and pulse Data; he also reports personal income from Axon Therapeutics, Bayer, Boehringer-Ingelheim, CHF Solutions, ProKidney, Vifor, and Takeda. G.N.N. has received consulting fees from AstraZeneca, Reata, BioVie, and GLG Consulting; has received financial compensation as a scientific board member and advisor to RenalytixAI; and owns equity in RenalytixAI and Pensieve Health as a cofounder. D.M.C has received financial compensation for consulting or service on clinical trials comitess from Eli Lilly/Boehringer Ingelheim, Janssen,Astra Zeneca, Allena Pharmaceuticals, Fresenius, Amgen, Gilead, Novo Nordisk, GSK, Medtronic, Merck, Amgen and CSL Behring and receives research funding from Medtronic for clinical trial support, Gilead, NovoNordisk, and Amgen, as well as expert witness fees related to proton pump inhibitors. He also serves as an editor for CJASN. L.C. has received consulting fees from Vifor Pharma, honorarium from Fresenius Medical Care, and is supported in part by K23DK124645. All remaining authors have declared no conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials, (Copyright: © 2024 Takkavatakarn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: End-stage kidney disease (ESKD) is associated with increased morbidity and mortality. Identifying patients with stage 4 CKD (CKD4) at risk of rapid progression to ESKD remains challenging. Accurate prediction of CKD4 progression can improve patient outcomes by improving advanced care planning and optimizing healthcare resource allocation., Methods: We obtained electronic health record data from patients with CKD4 in a large health system between January 1, 2006, and December 31, 2016. We developed and validated four models, including Least Absolute Shrinkage and Selection Operator (LASSO) regression, random forest, eXtreme Gradient Boosting (XGBoost), and artificial neural network (ANN), to predict ESKD at 3 years. We utilized area under the receiver operating characteristic curve (AUROC) to evaluate model performances and utilized Shapley additive explanation (SHAP) values and plots to define feature dependence of the best performance model., Results: We included 3,160 patients with CKD4. ESKD was observed in 538 patients (21%). All approaches had similar AUROCs; ANN yielded the highest AUROC (0.77; 95%CI 0.75 to 0.79) and LASSO regression (0.77; 95%CI 0.75 to 0.79), followed by random forest (0.76; 95% CI 0.74 to 0.79), and XGBoost (0.76; 95% CI 0.74 to 0.78)., Conclusions: We developed and validated several models for near-term prediction of kidney failure in CKD4. ANN, random forest, and XGBoost demonstrated similar predictive performances. Using this suite of models, interventions can be customized based on risk, and population health and resources appropriately allocated., (© 2023. The Author(s).)

Background: Appropriate dialysis prescription in the transitional setting from chronic kidney disease to end-stage kidney disease is still challenging. Conventional thrice-weekly haemodialysis (HD) might be associated with rapid loss of residual kidney function (RKF) and high mortality. The benefits and risks of incremental HD compared with conventional HD were explored in this systematic review and meta-analysis., Methods: We searched MEDLINE, Scopus and Cochrane Central Register of Controlled Trials up to April 2023 for studies that compared the impacts of incremental (once- or twice-weekly HD) and conventional thrice-weekly HD on cardiovascular events, RKF, vascular access complications, quality of life, hospitalization and mortality., Results: A total of 36 articles (138 939 participants) were included in this meta-analysis. The mortality rate and cardiovascular events were similar between incremental and conventional HD {odds ratio [OR] 0.87 [95% confidence interval (CI)] 0.72-1.04 and OR 0.67 [95% CI 0.43-1.05], respectively}. However, hospitalization and loss of RKF were significantly lower in patients treated with incremental HD [OR 0.44 (95% CI 0.27-0.72) and OR 0.31 (95% CI 0.25-0.39), respectively]. In a sensitivity analysis that included studies restricted to those with RKF or urine output criteria, incremental HD had significantly lower cardiovascular events [OR 0.22 (95% CI 0.08-0.63)] and mortality [OR 0.54 (95% CI 0.37-0.79)]. Vascular access complications, hyperkalaemia and volume overload were not statistically different between groups., Conclusions: Incremental HD has been shown to be safe and may provide superior benefits in clinical outcomes, particularly in appropriately selected patients. Large-scale randomized controlled trials are required to confirm these potential advantages., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Purpose: To perform a systematic review of case reports and case series to investigate risk factors, treatment modalities, and the outcome of penile calciphylaxis., Method: We performed a systematic search of the MEDLINE and Scopus databases to identify case reports or case series of penile calciphylaxis. The patient characteristics, laboratory investigations, diagnostic modalities, treatment modalities, and outcomes were extracted. We compared clinical characteristics and treatment between patients who survived or demised and between patients with clinical improvement and those without to identify the poor prognostic risk factors., Results: Ninety-four articles were included from 86 case reports and 8 case series with 121 patients. Most of the patients were on hemodialysis (78.9%). The median time since starting dialysis was 48 months (24-96 months). Sodium thiosulfate was used to treat penile calciphylaxis in 23.6%. For surgical management, partial or total penectomy was performed in 45.5% of the patients. There was no association between sodium thiosulfate use, partial or total penectomy, and improvement in clinical outcomes. The mortality rate in patients with penile calciphylaxis was 47.8% and the median time to death was 3 months (0.75-9 months). The presence of extragenital involvement was significantly related to mortality (p = 0.03)., Conclusion: A calcified penile artery results in penile calciphylaxis, a rare vascular phenomenon associated with high morbidity and mortality. Management of penile calciphylaxis includes the medical management of risk factors, surgical debridement, or penectomy. Therefore, early prevention and diagnosis as well as immediate appropriate treatment are needed., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Sodium-glucose co-transporter 2 inhibitor (SGLT2i) has been shown to improve renal outcomes in both diabetic and non-diabetic kidney disease. However, the effect of SGLT2i on renal outcomes in patients with non-diabetic obesity is still not established., Materials and Methods: In this double-blind, randomized controlled trial, we assigned non-diabetic patients with body mass index (BMI) ≥ 25 kg/m 2 , persistent 24-hour urine albumin-creatinine ratio (UACR) ≥ 10 mg/gCr, and estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m 2 , who had been treated with renin-angiotensin system blockade, to canagliflozin 100 mg daily or placebo for 24 weeks. The reduction in UACR and eGFR at 12 and 24 weeks were explored. (Thai Clinical Trials Registry 20190203003)., Results: Of 247 non-diabetic obese patients screened, 32 patients met inclusion criteria and underwent randomization. The median baseline of UACR was 69.1 mg/gCr. There were no statistically significant differences in albuminuria reduction between the groups at 12 weeks and 24 weeks. The estimated GFR in the canagliflozin group decreased significantly from baseline at 12 weeks (-5.39 mL/min/1.73m 2 ; 95% CI -9.81 to -0.97; p = 0.017) but not at 24 weeks (-1.16 mL/min/1.73m 2 ; 95% CI -5.58 to 3.26; p = 0.66), and there was no significant change from baseline in the placebo group at both 12 and 24 weeks., Conclusion: Canagliflozin 100 mg daily was well tolerated but did not significantly reduce UACR in non-diabetic obese patients with microalbuminuria. However, a significant temporary decline in eGFR might reflect a subtle reduction in glomerular hyperfiltration.

Background: The excretion of trimethylamine N-oxide (TMAO) (uremic toxin) into the intestine might be enhanced, due to the limited renal elimination in chronic kidney disease (CKD), possibly induced TMAO reductase (a TMAO-neutralizing enzyme) in gut bacteria. Detection of TMAO reductase in serum could be used as a biomarker of gut permeability defect., Objective: To explore the correlation between serum TMAO reductase, gut leakage, and systemic inflammation in CKD., Methods: Mouse models of gut leakage; including 5/6 nephrectomy-induced chronic kidney disease (CKD), a model without colitis, and 1.5% dextran sulfate solution (DSS), a colitis model, were performed. In parallel, serum samples from patients with chronic hemodialysis (n = 48) and the healthy control (n = 20) were analyzed., Results: Gut-leakage (FITC-dextran, endotoxemia, and reduced intestinal tight junction protein) was detected in both CKD and DSS models. While TMAO reductase and TMAO were elevated in the serum of both mouse models and patients, TMAO reductase correlated with TMAO, gut- leakage, and serum IL-6 only in mice but not in patients. Notably, endotoxemia was used as a surrogate marker of gut leakage in patients. In patients, TMAO reductase and TMAO did not correlate with serum IL-6 and vascular complications using the ankle-brachial index and cardio-ankle vascular index., Conclusions: Serum TMAO reductase was elevated in CKD mice and patients with CKD. Serum TMAO reductase was correlated with TMAO and gut-leakage only in mice but not in patients. Further studies in patients are needed to determine the benefit of serum TMAO reductase in patients with CKD.

Renal anemia in chronic kidney disease (CKD) is associated with poor outcomes. Hypoxia-inducible factor (HIF) stabilizer, which induces endogenous erythropoietin synthesis and enhances iron mobilization, is a novel treatment for anemia in CKD. We conducted a systematic review and meta-analysis to analyze the effect of HIF stabilizers in anemic CKD patients. This meta-analysis included 43 officially published articles and 3 unpublished studies (27 338 patients). HIF stabilizer treatment significantly increased hemoglobin (Hb) level when compared with placebo (mean difference 1.19 g/dL; 95% confidence interval 0.94 to 1.44 g/dL; P  < .001). There was no significant difference in Hb level when compared with erythropoiesis-stimulating agents (ESAs). Significant reductions of ferritin and transferrin saturation (TSAT) were observed, while total iron-binding capacity was increased in the HIF stabilizer group compared with placebo or ESAs. HIF stabilizers significantly reduced hepcidin, high-density lipoprotein, low-density lipoprotein and triglyceride levels. Acute kidney injury and thrombotic events were significantly observed in patients receiving HIF stabilizers. There were no significant differences in myocardial infarction, stroke, dialysis initiation, pulmonary hypertension and mortality between HIF stabilizer and control groups. The present meta-analysis provided evidence that HIF stabilizers increased Hb and TIBC levels and reduced hepcidin, ferritin and TSAT in CKD patients with renal anemia. Long-term follow-up studies on clinical outcomes of HIF stabilizers are still needed., Competing Interests: All authors declare that there is no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Acute kidney injury (AKI) is a common complication after a surgery, especially in cardiac and aortic procedures, and has a significant impact on morbidity and mortality. Early identification of high-risk patients and providing effective prevention and therapeutic approach are the main strategies for reducing the possibility of perioperative AKI. Consequently, several risk-prediction models and risk assessment scores have been developed for the prediction of perioperative AKI. However, a majority of these risk scores are only derived from preoperative data while the intraoperative time-series monitoring data such as heart rate and blood pressure were not included. Moreover, the complexity of the pathophysiology of AKI, as well as its nonlinear and heterogeneous nature, imposes limitations on the use of linear statistical techniques. The development of clinical medicine's digitization, the widespread availability of electronic medical records, and the increase in the use of continuous monitoring have generated vast quantities of data. Machine learning has recently shown promise as a method for automatically integrating large amounts of data in predicting the risk of perioperative outcomes. In this article, we discussed the development, limitations of existing work, and the potential future direction of models using machine learning techniques to predict AKI after a surgery., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The worldwide burden of HCV infection among hemodialysis patients has not been systematically examined., Methods: A systematic literature search was conducted in MEDLINE and Scopus to determine the worldwide prevalence of HCV infection, risk factors, and clinical outcomes among hemodialysis patients. Random-effect models and meta-regressions were used to generate pooled estimates and assess heterogeneity., Results: Four hundred and seven studies with 1,302,167 participants were analyzed. The pooled prevalence of HCV infection was 21%. The highest prevalence was observed in Africa (28%) and low-income countries (48.5%). A significant prevalence decline was observed following the publication year and was also inversely related to GDP and total population of each country. Factors associated with HCV positivity included younger age, longer dialysis duration, more blood transfusions, and dialyzer reuse. The pooled unadjusted hazard ratio for all-cause mortality was 1.12 (95% CI 1.03-1.22), and the adjusted hazard ratio was 1.21 (95% CI 1.12-1.30) in HCV-infected compared to non-HCV infected patients., Conclusions: HCV infection among hemodialysis patients is a worldwide shared burden and is associated with a higher risk of death. Avoiding unnecessary blood transfusion and dialyzer reuse should be encouraged to prevent HCV transmission in hemodialysis units., (© 2022. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Twice daily TAC (BID TAC) and prolonged released once daily dose tacrolimus (OD TAC) have different pharmacokinetic (PK) profiles in kidney transplant (KT) recipients. Precise dose adjustment recommendations when converting from BID TAC to OD TAC remain inconclusive. A single center, PK study was conducted in stable KT recipients taking constant doses of TAC, mycophenolic acid, and prednisolone. The area under the concentration-time curve (AUC) 0-24 and C trough were measured before and 4 weeks after 1:1 conversion from BID TAC to OD TAC without subsequent dose adjustment. A 90% confidence interval (CI) of geometric mean ratio (GMR) of OD TAC/BID TAC within the range of 0.9-1.11 was utilized to indicate equivalence of the narrow therapeutic index drugs. The roles of CYP3A5 genotypic polymorphism on PK parameters were also assessed. There were 20 patients with median time since transplantation of 18 months. The mean of CKD-EPI eGFR was 60.7 ± 16.43 mL/min/1.73 m 2 . The median total daily TAC dose of 0.058 mg/kg/day. The geometric means (%CV) of AUC 0-24 of OD and BID TAC were 205.16 (36.4%) and 210.3 (32.5%) ng/mL × h, respectively, with a GMR of 0.98 (90%CI 0.91-1.04). The geometric means (%CV) of C trough of OD TAC and BID TAC were 5.43 (33.1%) and 6.09 (34.6%) ng/mL, respectively. The GMR of C trough was 0.89 (90%CI 0.82-0.98), which was below 0.9. The newly calculated target C trough level of OD TAC was 4.8-6.2 ng/mL. The best abbreviated AUC 0-24 was AUC = 0.97(C0) + 5.79(C6) + 18.97(C12) - 4.26. The GMR AUC 0-24 was within the range of 0.9-1.11 irrespective of CYP3A5 genotypic polymorphism while the GMR of C trough was below 0.9 only in the CYP3A5 expressor patients. The 1:1 conversion from BID TAC to OD TAC without subsequent dose adjustment provided similar AUC 0-24 regardless of CYP3A5 genotypic polymorphism. However, the C trough was lower in the CYP3A5 expressor group. Therefore, it is not necessary to routinely increase the OD TAC dose after conversion.Trial registration: Thai Clinical Trials Registry (TCTR20210715002)., (© 2022. The Author(s).)

Background: Hemodialysis (HD) using super high-flux dialyzer (HD + SHF) comparably removed uremic toxins to high-volume postdilution online hemodiafiltration (olHDF). Integration of hemoperfusion (HP) to HD + SHF (HD + SHF + HP) might provide superior uremic toxin removing capability to high-volume postdilution olHDF., Method: The present study was conducted in thrice-a-week HD patients to compare the efficacy in removing indoxyl sulfate (IS), beta-2 microglobulin (β 2 M), and urea between high-volume postdilution ol-HDF and HD + SHF + HP, comprising HD + SHF as the main treatment plus HD + SHF + HP 1/week in the first 4 weeks and 1/2 weeks in the second 4 weeks., Results: Ten prevalent HD patients with blood flow rate (BFR) above 400 ml/min were randomized into two sequences of 8-week treatment periods of HD + SHF + HP and later high-volume postdilution olHDF or vice versa. When compared with high-volume postdilution olHDF (convective volume of 26.02 ± 1.8 L/session), HD + SHF + HP provided comparable values of percentage reduction ratio of IS (52.0 ± 11.7 vs. 56.3 ± 7.5%, p = 0.14) and β 2 M (83.7 ± 4.9 vs. 84.0 ± 4.3%, p = 0.37) and slightly lower urea reduction ratio. Despite greater dialysate albumin loss (p = 0.008), there was no significant change in serum albumin level in HD + SHF + HP group., Conclusions: HD + SHF + HP could not provide superior efficacy in removing uremic toxins to high-volume postdilution olHDF. The use of low BFR of 200 ml/min during the first 2 h of HD + SHF + HP session, according to the instruction of manufacturer, might impair the efficacy of the HD + SHF part in removing uremic toxins., (© 2022 International Center for Artificial Organs and Transplantation and Wiley Periodicals LLC.)

Aim: The incidences of osteoporosis, fracture and vascular calcification increase concordantly with the progression of chronic kidney disease (CKD). CKD-mineral bone disease (CKD-MBD) induced by hyperphosphatemia is a major pathophysiologic mechanism. The effects of phosphate binders on bone turnover biomarkers and bone mineral density (BMD) in haemodialysis patients are still inconclusive. Our aim is to demonstrate the effects of these phosphate binders on different aspects of CKD-MBD., Methods: We conducted a prospective cohort of 65 haemodialysis patients to investigate the effect of 12-month monotherapy of phosphate binders composing calcium-based phosphate binders (CPB) or non-calcium-based phosphate binders (NCPB), including sevelamer and lanthanum, on bone turnover biomarkers and BMD changes. The performance of bone turnover biomarkers to predict low BMD was attentively determined., Results: When compared with CPB, NCPB use was associated with higher levels of bone turnover biomarkers. NCPB was also associated with lower BMD at lumbar and distal radius. Total procollagen type 1N-terminal propeptide (P1NP), bone-specific alkaline phosphatase (BALP), and tartrate-resistant acid phosphatase 5b (TRAP5b) provided the best performance for diagnosing low BMD in haemodialysis patients., Conclusion: Switching from CPB to NCPB might increase bone biomarkers and prevent the development of adynamic bone disease. On the contrary, NCPB should be cautiously used in haemodialysis patients who already had low BMD. P1NP, BALP and TRAP5b could be used to guide the appropriate management, including anti-resorptive and anabolic medications, and predict low BMD in haemodialysis patients treated with phosphate binders., (© 2022 Asian Pacific Society of Nephrology.)

Background: Besides reducing hyperphosphatemia in chronic kidney disease (CKD) patients, phosphate lowering agents might provide beneficial effects on clinical and laboratory parameters. This meta-analysis was conducted to comprehensively examine the impact of all phosphate lowering agents on various aspects of clinical and laboratory outcomes in CKD patients., Method: A systematic literature search was performed in MEDLINE, Scopus, and the Cochrane Register of Controlled Trials until July 2020 to identify randomized controlled trials (RCTs) which compared the effects of each phosphate lowering agent with controls, comprising placebo and all other phosphate lowering agents. Various clinical and laboratory outcomes were analyzed. Random effects model was used to compute the standardized mean difference for continuous variables and the risk ratio (RR) for binary variables., Results: This meta-analysis included 127 RCTs with 20,215 patients. Sevelamer and lanthanum significantly reduced all-cause mortality (RR 0.610, 95% CI 0.401-0.929 and 0.467, 95% CI 0.337-0.647, respectively) but not cardiovascular (CV) mortality or CV events. Hospitalization rates were significantly diminished by sevelamer (RR 0.527; 95% CI 0.308-0.902). Certain phosphate lowering agents improved biochemical parameters including serum phosphate, calcium, coronary artery calcium scores, fibroblast growth factor-23, bone biomarkers, and lipid profiles. Intact parathyroid hormone and bone mineral density were not significantly changed., Conclusions: In addition to decreasing serum phosphate levels, various beneficial effects on clinical and laboratory parameters of phosphate lowering agents might play potential roles in diminishing morbidity and mortality in CKD patients., (© 2021. Italian Society of Nephrology.)

Introduction: The heightened fibroblast growth factor 23 (FGF23) level in patients with chronic kidney disease (CKD) is associated with increased cardiovascular disease and mortality. We performed a systematic review and meta-analysis to synthesize the available strategies to reduce FGF23 in CKD patients., Methods: We conducted a meta-analysis by searching the databases of MEDLINE, Scopus, and Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) and single-arm studies that examined the effects of dietary phosphate restriction, phosphate binders, iron supplements, calcimimetics, parathyroidectomy, dialysis techniques, and the outcome of preservation of residual renal function (RRF) on FGF23 levels in CKD patients. Random-effects model meta-analyses were used to compute changes in the outcome of interests., Results: A total of 41 articles (7590 patients), comprising 36 RCTs, 5 prospective studies were included in this meta-analysis. Dietary phosphate restriction less than 800 mg per day yielded insignificant effect on FGF23 reduction. Interestingly sevelamer, lanthanum, iron-based phosphate binders, and iron supplement significantly lowered FGF23 levels. In CKD patients with secondary hyperparathyroidism, calcimimetics prescription could significantly reduce FGF23 levels, while surgical parathyroidectomy had no significant effect. In dialysis patients, preservation of RRF and hemoperfusion as well as hemodiafiltration provided a significant decrease in FGF23 levels., Conclusions: The present meta-analysis demonstrated that non-calcium-based phosphate binders including sevelamer, lanthanum, and iron-based phosphate binders, iron supplements, calcimimetics, hemoperfusion, and preservation of RRF could effectively reduce FGF23 in CKD patients., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction: Expanded hemodialysis (HD using a medium cut-off dialyzer [HD + MCO]) provides comparable or better removal of various uremic toxins, particularly large middle-molecule uremic toxins, than post-dilution online hemodiafiltration (olHDF). Uremic toxin-removing effectiveness between HD + MCO and mixed-dilution olHDF, one of the currently most efficient olHDF modalities, has not been assessed., Method: This randomized controlled trial was conducted in 14 prevalent thrice-a-week HD patients with blood flow rate above 400 mL/min. The patients were randomized into two sequences of 2-week treatment periods of HD + MCO and later mixed-dilution olHDF or vice versa. The reduction ratio (RR) values of small-molecule as well as middle-molecule uremic toxins and protein-bound uremic toxins were measured at baseline and at the end of the treatment., Results: When compared with mixed-dilution olHDF, HD + MCO provided slightly lower β2M RR, but the value was still higher than 75%; showed similar κFLC RR, IS RR, and URR; and yielded significantly higher RR values of α1M (p &lt; 0.001) and λFLC (p &lt; 0.001). Despite higher albumin loss in HD + MCO, the serum albumin levels at the end of the study were comparable between both groups., Conclusion: Expanded HD (HD + MCO) provided similar effectiveness in removing various uremic toxins and could exhibit greater removal of large middle-molecule uremic toxins, such as α1M and λFLC. Expanded HD can be used as an effective alternative option for mixed-dilution olHDF., (© 2022 S. Karger AG, Basel.)

Introduction: Accumulation of protein-bound uremic toxins, including indoxyl sulfate and p-cresyl sulfate, are associated with increased cardiovascular disease and mortality in chronic kidney disease (CKD). We performed a systematic review and meta-analysis to synthesize the available strategies for lowering protein-bound uremic toxin levels in CKD patients., Methods: We conducted a meta-analysis by searching the databases of MEDLINE, Scopus, and the Cochrane Central Register of Controlled Trials for observational studies and randomized controlled trials (RCTs) that examined the effect of dietary protein restrictions, biotic supplements (including prebiotics, probiotics, and synbiotics), AST-120, dialysis techniques, and the outcome of preservation of residual renal function (RRF) on indoxyl sulfate and p-cresyl sulfate levels. Random-effect model meta-analyses were used to compute changes in the outcomes of interest., Results: A total of 38 articles (2,492 patients), comprising 28 RCTs, 8 single-arm or prospective cohort studies, and 2 cross-sectional studies were included in this meta-analysis. When compared with placebo, prebiotics, synbiotics, and AST-120 provided significantly lower levels of both serum indoxyl sulfate and p-cresyl sulfate. There were no significant reductions in serum indoxyl sulfate and p-cresyl sulfate levels in patients receiving probiotics. Preservation of RRF in dialysis patients resulted in lower levels of both of the protein-bound uremic toxins. When compared with conventional hemodialysis, hemodiafiltration significantly decreased serum p-cresyl sulfate alone, whereas a significant change in serum indoxyl sulfate levels was observed only in studies with long-term observation periods. Very low protein diet (VLPD) and other oral medications yielded insignificant differences in protein-bound uremic toxins., Conclusions: The present meta-analysis demonstrated that prebiotics, synbiotics, and AST-120 can effectively reduce both serum indoxyl sulfate and p-cresyl sulfate in CKD patients when compared with placebo. Preservation of RRF was associated with lower serum indoxyl sulfate and p-cresyl sulfate levels. The effect of biotic supplements was detected only in dialysis patients. For non-dialysis CKD patients, the results were limited due to the small number of studies. Further studies are needed to determine the efficacy in these populations., (© 2021. Italian Society of Nephrology.)

Incremental hemodialysis (HD) has become an exciting approach according to the recognition of the importance of preserving residual kidney function (RKF). However, not all incident HD patients are suitable for this approach, particularly once-weekly HD. This is the first study which reported the effectiveness of once-weekly online-hemodiafiltration (OL-HDF) plus low protein diet (LPD) in incident HD patients. All stage 5 CKD patients who had chosen HD as their treatment modality at the HD center of King Chulalongkorn Memorial Hospital, Bangkok, Thailand, with RKF ⩾ 3 mL/min calculated by renal clearance of urea and urine output ⩾ 800 mL/day, started the treatment with once-weekly OL-HDF. Dietitians advised patients to consume LPD (0.6-0.8 g/kg/day) on non-dialysis days and a regular protein diet on the dialysis day (1.2 g/kg/day). Eleven incident HD patients were enrolled in the study. The mean RKF and urine volume at baseline were 4.56 ± 2.21 mL/min and 2,019.54 ± 743.73 mL/day, respectively. After 6 and 12 months of follow-up, the mean RKF of the patients who remained in the once-weekly OL-HDF protocol were 3.82 ± 1.68 mL/min and 3.28 ± 0.95 mL/min, respectively. The median duration of once-weekly OL-HDF before transitioning to twice- or thrice-weekly OL-HDF was 7 months (3-24 months). The most common indication for stepping prescription was too low RKF. We reported that dialysis initiation in the university-based center with once-weekly OL-HDF in carefully selected incident HD patients combined with LPD under serial monitoring is practical. Further studies on the clinical benefits of once-weekly OL-HDF are still required.

Background: Sodium bicarbonate (NaHCO 3 ) is one of the promising solutions that has good safety profile and theoretical advantages regarding antimicrobial and antithrombotic properties but there are still limited reports., Objective: To compare the efficacy in lowering rate of catheter loss due to catheter-related thrombosis (CRT) or catheter-related blood stream infection (CRBSI) between sodium bicarbonate and heparin lock in prevalent chronic hemodialysis (HD) patients., Design: A multicenter, randomized, open-label study., Setting: In a developing country, Thailand., Patients: Chronic HD patients with tunneled central venous catheter., Measurements: Catheter loss rate, rate of catheter-related blood stream infection, catheter-related thrombosis, and exit site or tunnel infection., Methods: The prospective multicenter randomized controlled trial was conducted, we randomly assigned 118 patients undergoing HD with tunneled central venous catheter to receive a catheter locking solution of sodium bicarbonate or heparin. The primary outcome was a catheter loss rate due to CRT or CRBSI, while the secondary outcome was a composite outcome of CRT, CRBSI, or exit site/tunnel infection (ESI/TI)., Results: The present study was stopped early due to an excess of catheter-related thrombosis in the sodium bicarbonate group. From the first 6 weeks of follow-up, there were no catheter losses due to CRT or CRBSI in both groups. The sodium bicarbonate group had a significantly higher rate of the secondary composite outcomes and this was entirely caused by CRT with the median time to thrombosis of 23.6 days. Every CRT event could be successfully rescued by using a single dose of recombinant tissue plasminogen activator (rt-PA)., Limitations: Short follow-up period., Conclusions: In prevalent HD patients with tunneled CVCs, use of a sodium bicarbonate locking solution for prevention of CRT is inferior to heparin and is associated with a high rate of catheter-related thrombosis., Trial Registration: The study was registered with the Thai Clinical Trials Registry TCTR 20200610003., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: All authors have completed the ICMJE uniform disclosure form for Disclosure of Potential Conflicts of Interest and none were reported., (© The Author(s) 2021.)

P-cresyl sulfate and indoxyl sulfate are strongly associated with cardiovascular events and all-cause mortality in chronic kidney disease (CKD). This randomized controlled trial was conducted to compare the effects between sevelamer and calcium carbonate on protein-bound uremic toxins in pre-dialysis CKD patients with hyperphosphatemia. Forty pre-dialysis CKD patients with persistent hyperphosphatemia were randomly assigned to receive either 2400 mg of sevelamer daily or 1500 mg of calcium carbonate daily for 24 weeks. A significant decrease of total serum p-cresyl sulfate was observed in sevelamer therapy compared to calcium carbonate therapy (mean difference between two groups -5.61 mg/L; 95% CI -11.01 to -0.27 mg/L; p = 0.04). There was no significant difference in serum indoxyl sulfate levels ( p = 0.36). Sevelamer had effects in terms of lowering fibroblast growth factor 23 ( p = 0.01) and low-density lipoprotein cholesterol levels ( p = 0.04). Sevelamer showed benefits in terms of retarding CKD progression. Changes in vascular stiffness were not found in this study.

The objective of this study was to determine the impact of calcium sensing receptor (CASR) A990G genetic polymorphism on parathyroid hormone (PTH) lowering response to cinacalcet treatment when controlling for significant influencing clinical factors. This retrospective study was conducted on 135 Thai hemodialysis (HD) patients with secondary hyperparathyroidism (SHPT). CASR A990G genotypes were determined. The patients were identified as either G carriers (heterozygous or homozygous CASR 990G allele carriers) or noncarriers (homozygous CASR 990A carriers). Tested covariates were baseline PTH level (bPTH), baseline serum phosphate (bPhos), baseline serum calcium (bCa), baseline calcitriol equivalent dose (bCtriol), baseline ergocalciferol dose (bErgo), and age. The ANCOVA showed that intact PTH levels after 12 weeks of cinacalcet treatment (PTHw12) was significantly lower among G carriers compared with noncarriers after controlling for bPTH, bPhos, bCtriol, and bErgo (F(1, 127) = 15.472, p < 0.001), with the adjusted mean difference of 253.7 pg/mL. The logistic regression analysis revealed that the odds of a G carrier achieving 30% PTH reduction after 12-week cinacalcet treatment were 3.968 times greater than the odds for a noncarrier after adjusting for bPhos, bCtriol, and age. In conclusion, the CASR A990G polymorphism significantly influences cinacalcet response in HD patients with SHPT., (© 2021. The Author(s).)

Objectives: This meta-analysis was conducted to investigate the current global incidence and mortality of COVID-19 and also explored the associated factors including geographic variations, transmission scenarios, country economic status, and healthcare performance., Methods: The search was conducted in online databases based on reports from national authorities by March 28, 2021. Random-effects model meta-analyses and meta-regression analyses were used to generate summary estimates and explored sources of heterogeneity., Results: The cumulative number of confirmed COVID-19 cases was 125,704,789 reported by 216 countries. The pooled Daily Cumulative Index (DCI) was 1423.87 cases/day which was highest in South America (2759.15 cases/day) followed by North America (2252.49 cases/day), Europe (1858.44 cases/day), Asia (1484.84 cases/day), Africa (193.09 cases/day), and Australia/Oceania (18.55 cases/day). The overall pooled mortality rate of COVID-19 was 1.53%. Higher income countries and countries with community transmission had higher DCI. By meta-regression, country total health expenditure per capita, percentage of universal health coverage, and total number of tests were associated with higher DCI. On the contrary, country Gross Domestic Product (GDP) per capita were negatively correlated with mortality rate., Conclusion: To date, 216 countries around the world are affected by COVID-19. Higher income, GDP, and countries' investments on heath are associated with higher DCI while higher GDP correlates with lower mortality. Community transmission route have more impact on the incidence and mortality of COVID-19., Competing Interests: The authors declare they have no conflicts of interest., (© 2021 The Authors. Published by Atlantis Press International B.V.)

Background: The novel coronavirus (COVID-19), caused by SARS-CoV-2, showed various prevalence and case-fatality rates (CFR) among patients with different pre-existing chronic conditions. End-stage renal disease (ESRD) patients with renal replacement therapy (RRT) might have a higher prevalence and CFR due to reduced immune function from uremia and kidney tropism of SARS-CoV-2, but there was a lack of systematic study on the infection and mortality of the SARS-CoV-2 infection in ESRD patients with various RRT., Methodology/principal Findings: We searched five electronic databases and performed a systematic review and meta-analysis up to June 30, 2020, to evaluate the prevalence and case fatality rate (CFR) of the COVID-19 infection among ESRD patients with RRT. The global COVID-19 data were retrieved from the international database on June 30, 2020, for estimating the prevalence and CFR of the general population as referencing points. Of 3,272 potential studies, 34 were eligible studies consisted of 1,944 COVID-19 confirmed cases in 21,873 ESRD patients with RRT from 12 countries in four WHO regions. The overall pooled prevalence in ESRD patients with RRT was 3.10% [95% confidence interval (CI) 1.25-5.72] which was higher than referencing 0.14% global average prevalence. The overall estimated CFR of COVID-19 in ESRD patients with RRT was 18.06% (95% CI 14.09-22.32) which was higher than the global average at 4.98%., Conclusions: This meta-analysis suggested high COVID-19 prevalence and CFR in ESRD patients with RRT. ESRD patients with RRT should have their specific protocol of COVID-19 prevention and treatment to mitigate excess cases and deaths., Competing Interests: The authors have declared that no competing interests exist.

Background Non-vitamin K antagonist oral anticoagulants (NOACs) have better pharmacologic properties than warfarin and are recommended in preference to warfarin in most patients with non-valvular atrial fibrillation. Besides lower bleeding complications, other advantages of NOACs over warfarin particularly renal outcomes remain inconclusive. Methods and Results Electronic searches were conducted through Medline, Scopus, Cochrane Library databases, and ClinicalTrial.gov. Randomized controlled trials and observational cohort studies reporting incidence rates and hazard ratio (HR) of renal outcomes (including acute kidney injury, worsening renal function, doubling serum creatinine, and end-stage renal disease) were selected. The random-effects model was used to calculate pooled incidence and HR with 95% CI. Eighteen studies were included. A total of 285 201 patients were enrolled, 118 863 patients with warfarin and 166 338 patients with NOACs. The NOACs group yielded lower incidence rates of all renal outcomes when compared with the warfarin group. Patients treated with NOACs showed significantly lower HR of risk of acute kidney injury (HR, 0.70, 95% CI, 0.64-0.76; P <0.001), worsening renal function (HR, 0.83; 95% CI, 0.73-0.95; P =0.006), doubling serum creatinine (HR, 0.58; 95% CI, 0.41-0.82; P =0.002), and end-stage renal disease (HR, 0.82; 95% CI, 0.78-0.86; P <0.001). Conclusions In non-valvular atrial fibrillation, patients treated with NOACs have a lower risk of both acute kidney injury and end-stage renal disease when compared with warfarin.

Purpose: The mortality of dialysis patients treated with high-volume online hemodiafiltration (OL-HDF) is better than hemodialysis, but is still higher than healthy population. Low daily physical activity increases cardiovascular mortality. Addition of intradialytic exercise (IDX) program might improve physical activity and health status in OL-HDF patients. This pilot open-labeled randomized-controlled trial was conducted to evaluate the effects of IDX on physical activity and other clinical parameters in OL-HDF patients., Methods: Twelve OL-HDF patients were randomized into control (n = 6) or IDX (n = 6) groups. The subjects in IDX group were trained to exercise using a cycle ergometer for 60 min during each OL-HDF session. Physical activity measured as daily step count using a wrist-worn triaxial accelerometer, physical fitness, or cardiorespiratory fitness assessed by VO 2 max and other physical performance tests, lean body mass determined by the Dual-energy X-ray absorptiometry (DXA), quality of life (QOL), and various parameters were compared between baseline and 6 months., Results: The baseline physical activity status was comparable. Following 6-month IDX, the physical activity was significantly improved in IDX group [+ 1048.79 (+ 741.50, + 2792.54) vs. - 362.06 (- 1626.82, - 167.47) steps/day, p = 0.01], while physical fitness and QOL were unchanged. The lean body mass parameters were preserved in the IDX group while seemed to decrease in the control group. Serum albumin was significantly increased in the IDX group (p = 0.01). The hemoglobin changes were significantly better (p = 0.01) and the erythropoietin resistance index was significantly lower in the IDX group (p = 0.03). Phosphate reduction was significantly greater in the IDX group (p = 0.04)., Conclusions: IDX could improve physical activity and other metabolic parameters in OL-HDF patients and these might contribute to further improvement in clinical and survival outcomes., Trial Registration: ClinicalTrials.gov Registration: NCT03353844.

Although high-volume postdilution online hemodiafiltration (ol-HDF) is superior to high-flux HD in removing all kinds of uremic toxins and improving survival, this treatment is not available in most HD centers. The present study was conducted to compare the effectiveness in removals of protein-bound (indoxyl sulfate [IS]), middle-molecule [beta-2 microglobulin (B2M) and alpha-1 microglobulin (A1MG)], and small-molecule uremic toxins between super high-flux HD (SHF-HD), HD with a novel SHF dialyzer and high-volume postdilution ol-HDF in a noninferiority fashion. Fifteen prevalent HD patients were randomly allocated into two sequences of 12-week treatment periods of SHF-HD treatment and later high-volume postdilution ol-HDF period or vice versa. Each treatment period was divided by a wash-out phase of 4-week high-flux HD. Twelve of 15 patients could complete the study. When compared with high-volume postdilution ol-HDF (convective volume of 24.4 ± 3.52 L), SHF-HD provided comparable reduction ratio values of IS, B2M, and A1MG with mean difference of 5.87 (95% confidence interval [CI] -1.63, 13.37), 1.98 (95% CI,-0.21, 4.18), and 22.96 (95% CI, -1.91, 47.83), respectively. The spKt/Vurea was not different. The predialysis levels of all uremic toxins at baseline and after 12-week treatment did not differ between both groups. Although albumin loss in dialysate in SHF-HD was greater than high-volume postdilution ol-HDF, the serum albumin levels after 12-week SHF-HD treatment were significantly higher than baseline. In conclusion, SHF-HD provides noninferior effectiveness to high-volume postdilution ol-HDF in removing various uremic toxins with significantly increased serum albumin levels despite higher albumin loss. SHF-HD might be an effectively alternative treatment when high-volume postdilution ol-HDF is not available., (© 2020 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Background: This meta-analysis was conducted to examine the pleiotropic effects of all available antidiabetic agents except insulin for type 2 diabetes on renal and cardiovascular outcomes., Methods: A systematic literature search was performed in PubMed, EMBASE, and Cochrane database to identify randomized-controlled trials which compared the effectiveness between all antidiabetic agents apart from insulin regarding all aspects of renal and cardiovascular outcomes. Random effect model was utilized to compute for hazard ratio., Results: Nineteen articles with 140,851 participants were included in this meta-analysis. When compared with placebo, SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors exhibited significantly lower hazard ratios of progression of albuminuria. SGLT-2 inhibitors and DPP-4 inhibitors showed a significantly higher hazard ratio of regression of albuminuria. Only SGLT-2 inhibitors illustrated significantly lower hazard ratios of doubling of serum creatinine and incidence of renal replacement therapy (RRT). A significantly lower hazard ratio of composite renal outcome was detected in both SGLT-2 inhibitors and GLP-1 agonists. A significantly lower hazard ratio of all-cause mortality was identified in SGLT-2 inhibitors and GLP-1 agonist. Furthermore, a significantly lower hazard ratio of cardiovascular mortality was found in both SGLT-2 inhibitors and GLP-1 agonists., Conclusion: Comparing across all antidiabetic agents apart from insulin, SGLT-2 inhibitors provided extensively renoprotective effects among diabetic patients as well as reduced hazard ratios of heart failure, cardiovascular mortality, and all-cause mortality. GLP-1 agonists yielded benefits regarding progression of albuminuria, composite renal outcome, and cardiovascular and all-cause mortalities. DPP-4 inhibitors offered only renal protection including progression and regression of albuminuria.

Background: Vitamin D supplement is one of the current possible interventions to reduce fall and fracture. Despite having several studies on vitamin D supplement and fall and fracture reductions, the results are still inconclusive. We conducted a meta-analysis to examine the effect of vitamin D supplement in different forms and patient settings on fall and fracture., Methods: A systematic literature research was conducted in MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials to identify randomized controlled trials (RCTs) to compare the effects of vitamin D supplements on fall and fracture outcomes. Random-effect models were used to compute the weighted mean difference for continuous variables and the risk ratio for binary variables., Results: Forty-seven RCTs with 58,424 participants were identified reporting on fall outcome. Twenty-four of 47 studies with 40,102 subjects also reported fracture outcome. Major populations were elderly women with age less than 80 years. Overall, vitamin D supplement demonstrated a significant effect on fall reduction, RR = 0.948 (95% CI 0.914-0.984; P = .004, I = 41.52). By subgroup analyses, only vitamin D with calcium supplement significantly reduce fall incidence, RR = 0.881 (95% CI 0.821-0.945; P < .001, I = 49.19). Vitamin D3 supplement decreased incidence of fall but this occurred only when vitamin D3 was supplemented with calcium. Regarding fracture outcome, vitamin D supplement failed to show fracture lowering benefit, RR = 0.949 (95% CI 0.846-1.064; P = .37, I = 37.92). Vitamin D along with calcium supplement could significantly lower fracture rates, RR = 0.859 (95% CI 0.741-0.996; P = .045, I = 25.48)., Conclusions: The use of vitamin D supplement, especially vitamin D3 could reduce incidence of fall. Only vitamin D with calcium supplement showed benefit in fracture reduction.

Background: There is no consensus on intravenous (IV) iron supplement dose, schedule, and serum ferritin target in functional iron deficiency anemia to maintain optimum target levels of iron stores by several guidelines., Objective: To examine the effect of IV iron supplementation to different targets of serum ferritin on erythropoietin dose and inflammatory markers in chronic hemodialysis (HD) patients with functional iron deficiency anemia., Design: A multicenter, randomized, open-label study., Setting: In a developing country, Thailand., Patients: Chronic HD patients with functional iron deficiency anemia., Measurements: Erythropoietin resistance index, high-sensitivity C-reactive protein, and fibroblast growth factor 23., Methods: Two hundred adult chronic HD patients with transferrin saturation less than 30% and serum ferritin of 200 to 400 ng/mL were randomized 1:1 to maintain serum ferritin 200 to 400 ng/mL (low-serum ferritin group, N = 100) or 600 to 700 ng/mL (high-serum ferritin group, N = 100). During a 6-week titration period, participants randomized to the high-serum ferritin group initially received 600 mg IV iron (100 mg every week), while the participants in the low-serum ferritin group did not receive IV iron. During the 6-month follow-up period, the dose of IV iron was adjusted by protocol., Results: The mean dose of IV iron was 108.3 ± 28.2 mg/month in the low-serum ferritin group and 192.3 ± 36.2 mg/month in the high-serum ferritin group. The mean serum ferritin was 367.0 ± 224.9 ng/mL in the low ferritin group and 619.6 ± 265.2 ng/mL in the high ferritin group. The erythropoietin resistance index was significantly decreased in the high-serum ferritin group compared to the low-serum ferritin group after receiving IV iron in the 6-week titration period (mean difference: -113.43 ± 189.14 vs 41.08 ± 207.38 unit/week/g/dL; P < .001) and 3-month follow-up period (mean differences: -88.88 ± 234.43 vs -10.48 ± 217.75 unit/week/g/dL; P = .02)., Limitations: Short follow-up period., Conclusion: Maintaining a serum ferritin level of 600 to 700 ng/mL by IV iron administration of approximately 200 mg per month as a maintenance protocol can decrease erythropoietin dose requirements in chronic HD patients with functional iron deficiency anemia., Trials Registration: The study was registered with the Thai Clinical Trials Registry TCTR20180903003., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Objective: To systemically review the meta-analysis exploring the effectiveness and safety of restricted protein diet supplemented with ketoanalogues (KAs) when compared with regular diet or low protein diet (LPD) without KAs in chronic kidney disease (CKD) patients., Study Design and Methods: We conducted electronic searches in PubMed, Scopus, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from January 1960 to May 2018 to identify randomized controlled clinical trials that explored the effects of restricted protein diet including vegetarian and mixed type of protein with KAs on kidney endpoints including the changes in estimated glomerular filtration rate (eGFR) and proteinuria, nutritional status, and CKD-mineral bone disorder., Results: Seventeen RCTs with 1,459 participants were included in our meta-analysis. Restricted protein diet with KAs significantly preserved eGFR and reduced proteinuria, serum phosphate, parathyroid hormone (PTH) level, systolic blood pressure, diastolic blood pressure, and serum cholesterol. By subgroup analysis, very low protein diet (VLPD) with KAs was plausibly superior to LPD with KAs in slowing the decline in eGFR. Only VLPD with KAs significantly improved serum PTH, systolic blood pressure, and diastolic blood pressure while both regimens significantly decreased serum phosphate. Only LPD with KAs significantly raised serum albumin and serum calcium., Conclusion: Restricted protein diet supplemented with KAs could effectively improve kidney endpoints including preserving eGFR and diminishing proteinuria, blood pressure levels, and CKD-mineral bone disorder parameters without causing malnutrition. VLPD with KAs appears to provide more effectiveness in slowing the decline in eGFR, lowering blood pressure, reducing serum PTH, and less increasing serum calcium level., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors have nothing to disclose.

Background: We performed a systematic review and meta-analysis to examine factors associated with HBV immune response in dialysis patients, and the association between the immune response to the HBV vaccine and mortality., Methods: Electronic databases were searched for studies of dialysis patients that compared the characteristics of HBV vaccine responders and non-responders. Mortality was also analyzed according to the vaccine immune response (defined by hepatitis B surface antibody titer > 10 mIU/mL). Random-effects model meta-analyses were performed to compute a weighted mean difference (WMD), a pooled odds ratio (OR), and a pooled risk ratio (RR) between groups., Results: We identified 61 studies with a total of 6628 dialysis patients who completed the course of HBV vaccination, 4582 responders (69%) and 2046 non-responders (31%). By meta-analysis, relative to non-responders, HBV vaccine responders had a higher dialysis adequacy as measured by Kt/V (WMD 0.08, P < 0.001), a higher serum albumin (WMD 0.12 gm/dL, P < 0.001), a higher normalized protein catabolic rate (WMD 0.12 gm/kg/day, P = 0.001), a higher hemoglobin (WMD 0.15 gm/L, P = 0.03), and a higher parathyroid hormone level (WMD 44 pg/mL, P = 0.004). HBV vaccine responders were younger (WMD - 4.68 years, P < 0.001), had been on dialysis for longer (WMD 2.60 months, P < 0.001), were less likely to have diabetes mellitus (pooled OR 0.65, P < 0.001), and were less likely to carry the human leukocyte antigen (HLA) DR3 (pooled OR 0.38, P = 0.01). Compared to non-responders, HBV vaccine responders had lower risk for all-cause mortality (pooled RR 0.64, P < 0.001), and lower risk for cardiovascular-related mortality (pooled RR 0.74, P = 0.02)., Conclusion: In dialysis patients, the lack of immune response to the HBV vaccine is associated with older age, diabetes mellitus, HLA-DR3 status, shorter time on dialysis, lower nutritional status, lower hemoglobin, lower PTH level, and lower dialysis adequacy. Tackling some of these modifiable factors might improve the HBV vaccine immune response.