the validity of drug effects on proteinuria albuminuria serum creatinine and estimated gfr as surrogate end points for eskd a systematic review

Rationale & Objective Proteinuria, albuminuria, and serum creatinine level are widely used as surrogate end point measures of end-stage kidney disease (ESKD). We evaluated the correlation between antihypertensive drug effects on surrogate renal end points and ESKD. Study Design Systematic review. Setting & Participants Randomized controlled trials of blood pressure–lowering therapy. Selection Criteria for Studies Trials of pharmacological blood pressure–lowering strategies reporting drug effects on albuminuria, proteinuria, or serum creatinine level and ESKD through March 26, 2018. Analytical Approach Bayesian bivariate meta-analysis to calculate correlations between drug effects on surrogate end points and drug effects on ESKD. Risks of bias were adjudicated using the Cochrane tool. Results 22 randomized controlled trials involving 69,642 participants were eligible. Risks of bias in the included trials were frequently unclear due to incomplete reporting. Relative risk for ESKD was statistically significant in 1 of 29 (3.4%) treatment comparisons. There appeared to be little or no correlation between antihypertensive drug effects on serum creatinine level, albuminuria, proteinuria, and the corresponding effects on ESKD. All correlations had wide 95% credible intervals that included the null effect. Limitations Low power due to infrequent outcomes of ESKD and incomplete data reporting in primary trials. Conclusions The association between antihypertensive drug effects on doubling of serum creatinine level and albuminuria or proteinuria with ESKD in treatment trials is not sufficiently certain to enable the confident use of these markers to guide clinical or regulatory decision making

Antimicrobial agents for preventing peritonitis in peritoneal dialysis patients

Background: Peritoneal dialysis (PD) is an important therapy for patients with end-stage kidney disease and is used in more than 200,000 such patients globally. However, its value is often limited by the development of infections such as peritonitis and exit-site and tunnel infections. Multiple strategies have been developed to reduce the risk of peritonitis including antibiotics, topical disinfectants to the exit site and antifungal agents. However, the effectiveness of these strategies has been variable and are based on a small number of randomised controlled trials (RCTs). The optimal preventive strategies to reduce the occurrence of peritonitis remain unclear. This is an update of a Cochrane review first published in 2004. Objectives: To evaluate the benefits and harms of antimicrobial strategies used to prevent peritonitis in PD patients. Search methods: We searched the Cochrane Kidney and Transplant's Specialised Register to 4 October 2016 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Selection criteria: RCTs or quasi-RCTs in patients receiving chronic PD, which evaluated any antimicrobial agents used systemically or locally to prevent peritonitis or exit-site/tunnel infection were included. Data collection and analysis: Two authors independently assessed risk of bias and extracted data. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratio (RR) with 95% confidence intervals (CI). Main results: Thirty-nine studies, randomising 4435 patients, were included. Twenty additional studies have been included in this update. The risk of bias domains were often unclear or high; risk of bias was judged to be low in 19 (49%) studies for random sequence generation, 12 (31%) studies for allocation concealment, 22 (56%) studies for incomplete outcome reporting, and in 12 (31%) studies for selective outcome reporting. Blinding of participants and personnel was considered to be at low risk of bias in 8 (21%) and 10 studies (26%) for blinding of outcome assessors. It should be noted that blinding of participants and personnel was not possible in many of the studies because of the nature of the intervention or control treatment. The use of oral or topical antibiotic compared with placebo/no treatment, had uncertain effects on the risk of exit-site/tunnel infection (3 studies, 191 patients, low quality evidence: RR 0.45, 95% CI 0.19 to 1.04) and the risk of peritonitis (5 studies, 395 patients, low quality evidence: RR 0.82, 95% CI 0.57 to 1.19). The use of nasal antibiotic compared with placebo/no treatment had uncertain effects on the risk of exit-site/tunnel infection (3 studies, 338 patients, low quality evidence: RR 1.34, 95% CI 0.62 to 2.87) and the risk of peritonitis (3 studies, 338 patients, low quality evidence: RR 0.94, 95% CI 0.67 to 1.31). Pre/perioperative intravenous vancomycin compared with no treatment may reduce the risk of early peritonitis (1 study, 177 patients, low quality evidence: RR 0.08, 95% CI 0.01 to 0.61) but has an uncertain effect on the risk of exit-site/tunnel infection (1 study, 177 patients, low quality evidence: RR 0.36, 95% CI 0.10 to 1.32). The use of topical disinfectant compared with standard care or other active treatment (antibiotic or other disinfectant) had uncertain effects on the risk of exit-site/tunnel infection (8 studies, 973 patients, low quality evidence, RR 1.00, 95% CI 0.75 to 1.33) and the risk of peritonitis (6 studies, 853 patients, low quality evidence: RR 0.83, 95% CI 0.65 to 1.06). Antifungal prophylaxis with oral nystatin/fluconazole compared with placebo/no treatment may reduce the risk of fungal peritonitis occurring after a patient has had an antibiotic course (2 studies, 817 patients, low quality evidence: RR 0.28, 95% CI 0.12 to 0.63). No intervention reduced the risk of catheter removal or replacement. Most of the available studies were small and of suboptimal quality. Only six studies enrolled 200 or more patients. Authors' conclusions: In this update, we identified limited data from RCTs and quasi-RCTs which evaluated strategies to prevent peritonitis and exit-site/tunnel infections. This review demonstrates that pre/peri-operative intravenous vancomycin may reduce the risk of early peritonitis and that antifungal prophylaxis with oral nystatin or fluconazole reduces the risk of fungal peritonitis following an antibiotic course. However, no other antimicrobial interventions have proven efficacy. In particular, the use of nasal antibiotic to eradicate Staphylococcus aureus, had an uncertain effect on the risk of peritonitis and raises questions about the usefulness of this approach. Given the large number of patients on PD and the importance of peritonitis, the lack of adequately powered and high quality RCTs to inform decision making about strategies to prevent peritonitis is striking

Association of Drug Effects on Serum Parathyroid Hormone, Phosphorus, and Calcium Levels With Mortality in CKD: A Meta-analysis

Background Serum parathyroid hormone (PTH), phosphorus, and calcium levels are surrogate outcomes that are central to the evaluation of drug treatments in chronic kidney disease (CKD). This systematic review evaluates the evidence for the correlation between drug effects on biochemical (PTH, phosphorus, and calcium) and all-cause and cardiovascular mortality end points in adults with CKD. Study Design Systematic review and meta-analysis. Setting & Population Adults with CKD. Selection Criteria for Studies Randomized trials reporting drug effects on biochemical and mortality end points. Intervention Drug interventions with effects on serum PTH, phosphorus, and calcium levels, including vitamin D compounds, phosphate binders, cinacalcet, bisphosphonates, and calcitonin. Outcomes Correlation between drug effects on biochemical and all-cause and cardiovascular mortality. Results 28 studies (6,999 participants) reported both biochemical and mortality outcomes and were eligible for analysis. Associations between drug effects on surrogate biochemical end points and corresponding effects on mortality were weak and imprecise. All correlation coefficients were less than 0.70, and 95% credible intervals were generally wide and overlapped with zero, consistent with the possibility of no association. The exception was an inverse correlation between drug effects on serum PTH levels and all-cause mortality, which was nominally significant (−0.64; 95% credible interval, −0.85 to −0.15), but the strength of this association was very imprecise. Risk of bias within available trials was generally high, further reducing confidence in the summary correlations. Findings were robust to adjustment for age, baseline serum PTH level, allocation concealment, CKD stage, and drug class. Limitations Low power in analyses and combining evidence from many different drug comparisons with incomplete data across studies. Conclusions Drug effects on serum PTH, phosphorus, and calcium levels are weakly and imprecisely correlated with all-cause and cardiovascular death in the setting of CKD. Risks of mortality (patient-level outcome) cannot be inferred from treatment-induced changes in biochemical outcomes in people with CKD. Similarly, existing data do not exclude a mortality benefit with treatment. Trials need to address patient-centered outcomes to evaluate drug effectiveness in this setting

Research Priorities in CKD: Report of a National Workshop Conducted in Australia

Research aims to improve health outcomes for patients. However, the setting of research priorities is usually performed by clinicians, academics, and funders, with little involvement of patients or caregivers and using processes that lack transparency. A national workshop was convened in Australia to generate and prioritize research questions in chronic kidney disease (CKD) among diverse stakeholder groups. Patients with CKD (n = 23), nephrologists/surgeons (n = 16), nurses (n = 8), caregivers (n = 7), and allied health professionals and researchers (n = 4) generated and voted on intervention questions across 4 treatment categories: CKD stages 1 to 5 (non–dialysis dependent), peritoneal dialysis, hemodialysis, and kidney transplantation. The 5 highest ranking questions (in descending order) were as follows: How effective are lifestyle programs for preventing deteriorating kidney function in early CKD? What strategies will improve family consent for deceased donor kidney donation, taking different cultural groups into account? What interventions can improve long-term post-transplant outcomes? What are effective interventions for post hemodialysis fatigue? How can we improve and individualize drug therapy to control post-transplant side effects? Priority questions were focused on prevention, lifestyle, quality of life, and long-term impact. These prioritized research questions can inform funding agencies, patient/consumer organizations, policy makers, and researchers in developing a CKD research agenda that is relevant to key stakeholders

Dental Health and Mortality in People With End-Stage Kidney Disease Treated With Hemodialysis: A Multinational Cohort Study

Background Dental disease is more extensive in adults with chronic kidney disease, but whether dental health and behaviors are associated with survival in the setting of hemodialysis is unknown. Study Design Prospective multinational cohort. Setting & Participants 4,205 adults treated with long-term hemodialysis, 2010 to 2012 (Oral Diseases in Hemodialysis [ORAL-D] Study). Predictors Dental health as assessed by a standardized dental examination using World Health Organization guidelines and personal oral care, including edentulousness; decayed, missing, and filled teeth index; teeth brushing and flossing; and dental health consultation. Outcomes All-cause and cardiovascular mortality at 12 months after dental assessment. Measurements Multivariable-adjusted Cox proportional hazards regression models fitted with shared frailty to account for clustering of mortality risk within countries. Results During a mean follow-up of 22.1 months, 942 deaths occurred, including 477 cardiovascular deaths. Edentulousness (adjusted HR, 1.29; 95% CI, 1.10-1.51) and decayed, missing, or filled teeth score ≥ 14 (adjusted HR, 1.70; 95% CI, 1.33-2.17) were associated with early all-cause mortality, while dental flossing, using mouthwash, brushing teeth daily, spending at least 2 minutes on oral hygiene daily, changing a toothbrush at least every 3 months, and visiting a dentist within the past 6 months (adjusted HRs of 0.52 [95% CI, 0.32-0.85], 0.79 [95% CI, 0.64-0.97], 0.76 [95% CI, 0.58-0.99], 0.84 [95% CI, 0.71-0.99], 0.79 [95% CI, 0.65-0.95], and 0.79 [95% CI, 0.65-0.96], respectively) were associated with better survival. Results for cardiovascular mortality were similar. Limitations Convenience sample of clinics. Conclusions In adults treated with hemodialysis, poorer dental health was associated with early death, whereas preventive dental health practices were associated with longer survival

Antimicrobial agents to prevent peritonitis in peritoneal dialysis: A systematic review of randomized controlled trials

Background: A large proportion (15% to 50%) of the end-stage renal disease population are on peritoneal dialysis (PD). The major limitation is peritonitis, which leads to technique failure, hospitalization, and increased mortality. Oral, nasal, and topical antibiotic prophylaxis; exit-site disinfectants; and other antimicrobial interventions are used to prevent it. This study was conducted to assess what evidence supports these approaches. Methods: The Cochrane CENTRAL Registry, MEDLINE, EMBASE, and reference lists were searched for randomized trials of antimicrobial agents in patients on PD. Two reviewers extracted data on the number of patients with 1 or more episodes and rates of peritonitis and exit-site and tunnel infection, catheter removal and/or replacement, technique failure, antibiotic toxicity, and all-cause mortality. Analysis was by means of a random-effects model, and results are expressed as relative risk (RR) and 95% confidence intervals (CI). Results: Nineteen eligible trials (1,949 patients) were identified. Nasal mupirocin compared with placebo significantly reduced the exit-site and tunnel infection rate (1 trial; 2,716 patient-months; RR, 0.58; 95% CI, 0.40 to 0.85), but not peritonitis rate (1 trial; 2,716 patient-months; RR, 0.84; 95% CI, 0.44 to 1.60). Perioperative intravenous antibiotic therapy compared with no treatment significantly reduced the risk for early peritonitis (4 trials; 335 patients; RR, 0.35; 95% CI, 0.15 to 0.80), but not exit-site and tunnel infection (3 trials; 114 patients; RR, 0.32; 95% CI, 0.02 to 4.81). Conclusion: Based on 1 study, nasal mupirocin reduces exit-site and tunnel infection, but not peritonitis. Based on 4 studies, preoperative intravenous prophylaxis reduces early peritonitis, but not exit-site and tunnel infection. No other antimicrobial intervention has proven efficacy. Given the large number of patients on PD therapy and the importance of peritonitis, the lack of adequately powered randomized trials to inform decision making about strategies to prevent peritonitis is striking

Catheter-related interventions to prevent peritonitis in peritoneal dialysis: A systematic review of randomized, controlled trials

As many as 15 to 50% of end-stage kidney disease patients are on peritoneal dialysis (PD), but peritonitis limits its more widespread use. Several PD catheter-related interventions (catheter designs, surgical insertion approaches, and connection methods) have been purported to reduce the risk of peritonitis in PD. The goal was to assess the trial evidence supporting their use. The Cochrane CENTRAL Registry, MEDLINE, EMBASE, and reference lists were searched for randomized trials of catheter types and related interventions in PD. Two reviewers extracted data on the rates of peritonitis and exit-site/tunnel infection, catheter removal/replacement, technique failure, and all-cause mortality. Analysis was by a random effects model, and results are expressed as relative risk and 95% confidence intervals. Thirty-seven eligible trials (2822 patients) were identified: eight of surgical strategies of catheter insertion, eight of straight versus coiled catheters, 10 of Y-set versus conventional spike systems, four of Y-set versus double-bag systems, and seven of other interventions. Despite the large total number of patients, few trials covered the same interventions, small numbers of patients were enrolled in each trial, and the methodologic quality was suboptimal. Y-set and twin-bag systems were superior to conventional spike systems (seven trials, 485 patients; relative risk, 0.64; 95% confidence intervals 0.53 to 0.77), and no other catheter-related intervention was demonstrated to prevent peritonitis in PD. This systematic review demonstrates that of all catheter-related interventions designed to prevent peritonitis in PD, only disconnect (twin-bag and Y-set) systems have been proved to be effective (compared with conventional spike systems). Despite the importance of PD as a renal replacement therapy modality and the large number of patients who receive it, it is still not known whether any particular PD catheter designs, implantation techniques, or modalities are effective, given the limitations of available trials

Aldosterone Antagonists for Preventing the Progression of Chronic Kidney Disease: A Systematic Review and Meta-analysis

Background and objectives: Addition of aldosterone antagonists (AA) might provide renal benefits to proteinuric chronic kidney disease (CKD) patients over and above the inhibition of renin-angiotensin system blockers (RAS). We evaluated the benefits and harms of adding selective and nonselective AA in CKD patients already on RAS

Comparative effectiveness of calcimimetic agents for secondary hyperparathyroidism in adults: a systematic review and network meta-analysis

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