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Introduction Regular physical activity is associated with longevity in adults receiving hemodialysis, but it is uncertain whether this association varies by causal pathways (cardiovascular and noncardiovascular). Methods DIET-HD was a prospective, multinational study of adults undergoing hemodialysis across Europe and Argentina. We classified participants as physically inactive, occasionally active (irregularly to once a week), or frequently active (twice a week or more), using a self-reported questionnaire. Potential confounders were balanced across exposure groups using propensity scores. Weighted Cox proportional hazards models with double robust estimators evaluated the association between physical activity and all-cause, cardiovascular, and noncardiovascular mortality. Results Of 8043 participants in DIET-HD, 6147 (76%) had information on physical activity. A total of 2940 (48%) were physically inactive, 1981 (32%) occasionally active, and 1226 (20%) frequently active. In a median follow-up of 3.8 years (19,677 person-years), 2337 (38%) deaths occurred, including 1050 (45%) from cardiovascular causes. After propensity score weighting, occasional physical activity was associated with lower all-cause (adjusted hazard ratio [aHR] = 0.80, 95% CI = 0.72–0.89), cardiovascular (aHR = 0.82, 95% CI = 0.70–0.96), and noncardiovascular (aHR = 0.81, 95% CI = 0.69–0.94) mortality compared with inactivity. Frequent physical activity was associated with lower all-cause (aHR = 0.82, 95% CI = 0.71–0.95) and cardiovascular (aHR = 0.77, 95% CI = 0.62–0.94) mortality, but not noncardiovascular mortality (aHR = 0.88, 95% CI = 0.72–1.08). A dose-dependent association of physical activity with cardiovascular death was observed (P trend = 0.01). Conclusion Compared with self-reported physical inactivity, occasional and frequent physical activities were associated, dose dependently, with lower cardiovascular mortality in adults receiving hemodialysis., Graphical abstract

Rationale & Objective Comparative benefits and harms of calcimimetic agents used for the treatment of secondary hyperparathyroidism have not been well characterized. We sought to compare the effectiveness of 3 calcimimetic agents using published data. Study Design Systematic review of randomized controlled trials and network meta-analysis. Setting & Study Population Adults with chronic kidney disease enrolled in a clinical trial of a calcimetic agent. Search Strategy & Sources MEDLINE, EMBASE, CENTRAL (from February 7, 2013, to November 21, 2019), and a published meta-analysis. Data Extraction Two reviewers independently extracted the study data, assessed risk of bias, and rated evidence certainty using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. Analytical Approach Frequentist network meta-analysis was conducted. The primary review outcomes were achievement of a target reduction in serum parathyroid hormone (PTH) levels and hypocalcemia. Additional outcomes were nausea, vomiting, serious adverse events, all-cause mortality, cardiovascular mortality, heart failure, and fracture. Results 36 trials (11,247 participants) were included. All except 4 trials involved dialysis patients. Median follow-up was 26 weeks (range, 1 week to 21.2 months). Compared with placebo, calcimimetic agents had higher odds of achieving target PTH levels with high or moderate certainty. Etelcalcetide had the highest odds of achieving a PTH target compared with evocalcet (OR, 4.93; 95% CI, 1.33-18.2) and cinacalcet (OR, 2.78; 95% CI, 1.19-6.67). Etelcalcetide appeared to cause more hypocalcemia than cinacalcet and evocalcet. Cinacalcet and to a lesser extent etelcalcetide appeared to cause more nausea than placebo. Differences in risk for mortality, cardiovascular end points, or fractures across calcimimetic agents could not be discerned with sufficient certainty. Limitations Lack of longer-term data; heterogeneous end point definitions. Conclusions Evidence of the benefits of calcimimetic therapy is limited to short-term assessment of a putative surrogate outcome (serum PTH). Although etelcalcetide was associated with the largest reduction in PTH levels, side-effect profiles differed across the 3 calcimimetic agents, making it not possible to identify 1 preferred agent.

Background & aims: Dietary and supplemental long chain omega-3 polyunsaturated fatty acids (n-3 PUFA) have shown vascular benefits for the general population, but effects among people with chronic kidney disease (CKD) are largely uncertain. We aimed to evaluate the effects of n-3 PUFA intake among patients with CKD. Methods: We searched MEDLINE, Embase, and CENTRAL through January 12, 2018. Eligible studies were randomized controlled trials evaluating n-3 PUFA intake (supplementation or dietary) compared with placebo, standard care, or other treatment, on cardiovascular and all-cause mortality, end stage kidney disease (ESKD), acute transplant rejection, and allograft loss. Risks of bias and evidence certainty were assessed using Cochrane and Grading of Recommendations Assessment, Development and Evaluation processes. Results: Sixty trials (4129 participants) were eligible, all of supplementation, with a median follow-up of 6 months. Low to very low certainty evidence suggested that n-3 PUFA supplementation reduced cardiovascular death for participants on hemodialysis (39 events; relative risk (RR) 0.45, 95% confidence interval (CI) 0.23–0.89), prevented ESKD (29 events; RR 0.30, CI 0.09–0.98) in participants with CKD not receiving renal replacement therapy, and made little or no difference in all-cause mortality (215 events; RR 1.05, CI 0.84–1.33), acute transplant rejection (188 events; RR 0.98, CI 0.80–1.21) or allograft loss (39 events; RR 0.98, CI 0.54–1.81]). Risk of bleeding (44 events; RR 1.40, CI 0.78–2.49) and gastrointestinal side-effects (103 events; RR 1.14, CI 0.79–1.67) were uncertain. Conclusions: n-3 PUFA supplementation may reduce cardiovascular mortality in patients on hemodialysis but it is uncertain whether supplementation prevents mortality or ESKD in patients with CKD.

Rationale & Objective In the general population, cognitive impairment is associated with increased mortality, and higher levels of education are associated with lower risks for cognitive impairment and mortality. These associations are not well studied in patients receiving long-term hemodialysis and were the focus of the current investigation. Study Design Prospective cohort study. Setting & Participants Adult hemodialysis patients treated in 20 Italian dialysis clinics. Exposures Patients’ cognitive function across 5 domains (memory, attention, executive function, language, and perceptual-motor function), measured using a neuropsychological assessment comprising 10 tests; and patients’ self-reported years of education. Outcome All-cause mortality. Analytical Approach Nested multivariable Cox regression models were used to examine associations of cognition (any domain impaired, number of domains impaired, and global function score from principal components analysis of unadjusted test scores) and education with mortality and whether there were interactions between them. Results 676 (70.6%) patients participated, with a median age of 70.9 years and including 38.8% women. Cognitive impairment was present in 79.4% (527/664; 95% CI, 76.3%-82.5%). During a median follow-up of 3.3 years (1,874 person-years), 206 deaths occurred. Compared to no cognitive impairment, adjusted HRs for mortality were 1.77 (95% CI, 1.07-2.93) for any impairment, 1.48 (95% CI, 0.82-2.68) for 1 domain impaired, 1.88 (95% CI, 1.01-3.53) for 2 domains, and 2.01 (95% CI, 1.14-3.55) for 3 to 5 domains. The adjusted HR was 0.68 (95% CI, 0.51-0.92) per standard deviation increase in global cognitive function score. Compared with primary or lower education, adjusted HRs were 0.79 (95% CI, 0.53-1.20) for lower secondary and 1.13 (95% CI, 0.80-1.59) for upper secondary or higher. The cognition-by-education interaction was not significant (P = 0.7). Limitations Potential selection bias from nonparticipation and missing data; no data for cognitive decline; associations with education were not adjusted for other socioeconomic factors. Conclusions Cognitive impairment is associated with premature mortality in hemodialysis patients. Education does not appear to be associated with mortality.

Rationale & Objective A healthy lifestyle promotes cardiovascular health and reduces cardiac-related mortality in the general population but its benefits for people receiving maintenance hemodialysis are uncertain. Study Design Prospective cohort study. Setting & Participants 5,483 of 9,757 consecutive adults receiving maintenance hemodialysis (January 2014 to June 2017, median dialysis vintage: 3.6 yrs) in a multinational private dialysis network and with complete lifestyle data. Exposures Based on the American Heart Association’s recommendations for cardiovascular prevention, a modified healthy lifestyle score was the sum of four components addressing use of smoking tobacco, physical activity, diet, and control of systolic blood pressure. Outcomes Cardiovascular and all-cause mortality. Analytical Approach Adjusted proportional hazards (aHRs) regression analyses with country as a random effect to estimate the associations between lifestyle score (low [0-2 points] as the referent, medium [3-5], and high [6-8]) and mortality. Associations were expressed as aHRs with 95% confidence intervals (CIs). Results During a median of 3.8 years (17,451 person-years in total), there were 2,163 deaths, of which 826 were related to cardiovascular disease. Compared to patients with a low lifestyle score, the aHRs (95% CIs) for all-cause mortality among those with medium and high lifestyle scores were 0.75 (0.65-0.85) and 0.64 (0.54-0.76), respectively. Compared to patients with a low lifestyle score, the aHRs (95% CIs) for cardiovascular mortality among those with medium and high lifestyle scores were 0.73 (0.59-0.91) and 0.65 (0.49-0.85), respectively. Limitations Self-reported lifestyle, data-driven approach. Conclusions A healthier lifestyle is associated with lower all-cause and cardiovascular mortality among patients receiving maintenance hemodialysis.

Background Guidelines preferentially recommend noncalcium phosphate binders in adults with chronic kidney disease (CKD). We compare and rank phosphate-binder strategies for CKD. Study Design Network meta-analysis. Setting & Population Adults with CKD. Selection Criteria for Studies Randomized trials with allocation to phosphate binders. Interventions Sevelamer, lanthanum, iron, calcium, colestilan, bixalomer, nicotinic acid, and magnesium. Outcomes The primary outcome was all-cause mortality. Additional outcomes were cardiovascular mortality, myocardial infarction, stroke, adverse events, serum phosphorus and calcium levels, and coronary artery calcification. Results 77 trials (12,562 participants) were included. Most (62 trials in 11,009 patients) studies were performed in a dialysis population. Trials were generally of short duration (median, 6 months) and had high risks of bias. All-cause mortality was ascertained in 20 studies during 86,744 patient-months of follow-up. There was no evidence that any drug class lowered mortality or cardiovascular events when compared to placebo. Compared to calcium, sevelamer reduced all-cause mortality (OR, 0.39; 95% CI, 0.21-0.74), whereas treatment effects of lanthanum, iron, and colestilan were not significant (ORs of 0.78 [95% CI, 0.16-3.72], 0.37 [95% CI, 0.09-1.60], and 0.55 [95% CI, 0.07-4.43], respectively). Lanthanum caused nausea, whereas sevelamer posed the highest risk for constipation and iron caused diarrhea. All phosphate binders lowered serum phosphorus levels to a greater extent than placebo, with iron ranked as the best treatment. Sevelamer and lanthanum posed substantially lower risks for hypercalcemia than calcium. Limitations Limited testing of consistency; short follow-up. Conclusions There is currently no evidence that phosphate-binder treatment reduces mortality compared to placebo in adults with CKD. It is not clear whether the higher mortality with calcium versus sevelamer reflects whether there is net harm associated with calcium, net benefit with sevelamer, both, or neither. Iron-based binders show evidence of greater phosphate lowering that warrants further examination in randomized trials.

There are an estimated 14,000 randomized trials published in chronic kidney disease. The most frequently reported outcomes are biochemical endpoints, rather than clinical and patient-reported outcomes including cardiovascular disease, mortality, and quality of life. While many trials have focused on optimizing kidney health, the heterogeneity and uncertain relevance of outcomes reported across trials may limit their policy and practice impact. The international Standardized Outcomes in Nephrology (SONG) Initiative was formed to identify core outcomes that are critically important to patients and health professionals, to be reported consistently across trials. We convened a SONG Implementation Workshop to discuss the implementation of core outcomes. Eighty-two patients/caregivers and health professionals participated in plenary and breakout discussions. In this report, we summarize the findings of the workshop in two main themes: socializing the concept of core outcomes, and demonstrating feasibility and usability. We outline implementation strategies and pathways to be established through partnership with stakeholders, which may bolster acceptance and reporting of core outcomes in trials, and encourage their use by end-users such as guideline producers and policymakers to help improve patient-important outcomes. ispartof: pages:1053-1068 ispartof: Kidney Int vol:94 issue:6 pages:1053-1068 ispartof: location:United States status: published

Background: Sexual dysfunction is an under-recognized problem in men and women with chronic kidney disease (CKD). The prevalence, correlates, and predictors of this condition in patients with CKD have not been evaluated comprehensively. Study Design: Systematic review and meta-analysis. Setting & Population: Patients treated using dialysis (dialysis patients), patients treated using transplant (transplant recipients), and patients with CKD not treated using dialysis or transplant (nondialysis nontransplant patients with CKD). Selection Criteria for Studies: Observational studies conducted in patients with CKD only or including a control group without CKD. Predictor: Type of study population. Outcomes: Sexual dysfunction in men and women with CKD using validated tools, such as the International Index of Erectile Function, the Female Sexual Function Index (FSFI), or other measures as reported by study investigators. Results: 50 studies (8,343 patients) of variable size (range, 16-1,023 patients) were included in this review. Almost all studies explored sexual dysfunction in men and specifically erectile dysfunction. The summary estimate of erectile dysfunction in men with CKD was 70% (95% CI, 62%-77%; 21 studies, 4,389 patients). Differences in reported prevalence rates of erectile dysfunction between different studies were attributable primarily to age, study populations, and type of study tool used to assess the presence of erectile dysfunction. In women, the reported prevalence of sexual dysfunction was assessed in only 306 patients from 2 studies and ranged from 30%-80%. Compared with the general population, women with CKD had a significantly lower overall FSFI score (8 studies or subgroups, 407 patients; mean difference, 9.28; 95% CI, 12.92 to 5.64). Increasing age, diabetes mellitus, and depression consistently were found to correlate with sexual dysfunction in 20 individual studies of patients with CKD using different methods. Limitations: Suboptimal and lack of uniform assessment of outcome measures. Conclusions: Sexual dysfunction is highly prevalent in both men and women with CKD, especially among those on dialysis. Larger studies enrolling different ethnic groups, using validated