Clinical Trials Register Search Portal Research Articles

The efficacy and safety of cyclosporine in children with systemic lupus erythematosus: A protocol for systematic review and meta-analysis

Childhood-onset systemic lupus erythematosus (SLE) is a rare but severe multisystem autoimmune/inflammatory disease with marked heterogeneity between patients, causing anything from mild to life-threatening disease. We performed a protocol for systematic review and meta-analysis to evaluate the efficacy and safety of cyclosporine in childhood-onset SLE. This systematic review has been registered in PROSPERO (CRD42022377450), which will be conducted in accordance with Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 statement. Only randomized controlled trials will be included.We searched the following databases including PubMed, EMBASE, the Cochrane Library, SinoMed, CNKI, VIP, Wanfang Data and International Clinical Trials Register Search Portal, and Clinical Trials.gov. Two researchers will use the Cochrane systematic evaluation tool to assess the risk of bias independently. Data synthesis will be performed using RevMan V.5.4. This study will comprehensively summarize the high-quality trials to determine the efficacy and safety of cyclosporine in the treatment of childhood-onset SLE. This study may be beneficial to health policymakers, clinicians, and patients with regard to the use of cyclosporine in childhood-onset SLE.

MO817ALDOSTERONE ANTAGONISTS FOR PATIENTS WITH CHRONIC KIDNEY DISEASE REQUIRING DIALYSIS

Abstract Background and Aims Patients with chronic kidney disease (CKD) undergoing dialysis are at a particularly high risk of cardiovascular mortality and morbidity. This systematic review and meta-analysis aimed to evaluate the benefits and harms of aldosterone antagonists, both non-selective (spironolactone) and selective (eplerenone), in comparison to control (placebo or standard care) in patients with CKD requiring haemodialysis or peritoneal dialysis. Method We searched the Cochrane Kidney and Transplant Register of Studies up to 29 July 2019 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register Search Portal and ClinicalTrials.gov. We included individual and cluster randomised controlled trials (RCTs), cross-over trials, and quasi-RCTs that compared aldosterone antagonists with placebo or standard care in patients with CKD requiring dialysis. We used a random-effects model meta-analysis to perform a quantitative synthesis of the data. We used the I2 statistic to measure heterogeneity among the trials in each analysis. We indicated summary estimates as a risk ratio (RR) for dichotomous outcomes with their 95% confidence interval (CI). We assessed the certainty of the evidence for each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach. Results We included 16 trials (14 parallel RCTs and two cross-over trials) involving a total of 1,446 patients. Among included studies, 13 trials compared spironolactone to placebo or standard care and one trial compared eplerenone to a placebo. Most studies had an unclear or high risk of bias. Compared to control, aldosterone antagonists reduced the risk of all-cause death for patients with CKD requiring dialysis (9 trials, 1,119 patients: RR 0.45, 95% CI 0.30 to 0.67; moderate certainty of evidence). Aldosterone antagonist also decreased the risk of death due to cardiovascular disease (6 trials, 908 patients: RR 0.37, 95% CI 0.22 to 0.64; moderate certainty of evidence) and cardiovascular and cerebrovascular morbidity (3 trials, 328 patients: RR 0.38, 95% CI 0.18 to 0.76; moderate certainty of evidence). While aldosterone antagonists had an apparent increased risk of gynaecomastia compared with control (4 trials, 768 patients: RR 5.95, 95% CI 1.93 to 18.3; moderate certainty of evidence), the elevated risk of hyperkalaemia due to aldosterone antagonists was uncertain (9 trials, 981 patients: RR 1.41, 95% CI 0.72 to 2.78; low certainty of evidence). Conclusion Based on moderate certainty of the evidence, aldosterone antagonists could reduce the risk of all-cause and cardiovascular death and morbidity due to cardiovascular and cerebrovascular disease but increase the risk of gynaecomastia in patients with CKD requiring dialysis.

Interventions for increasing solid organ donor registration.

A solution for increasing the number of available organs for transplantation is to encourage more individuals to register a commitment for deceased organ donation. However, the percentage of the population registered for organ donation remains low in many countries.To evaluate the benefits and harms of various interventions used to increase deceased organ donor registration.We searched the Cochrane Kidney and Transplant Register of Studies up to 11 August 2020 through contact with an Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register Search Portal and ClinicalTrials.gov.We included all randomised controlled trials (RCTs), cluster RCTs and quasi-RCTs of interventions to promote deceased organ donor registration. We included studies if they measured self-reported or verified donor registration, intention to donate, intention to register a decision or number of individuals signing donor cards as outcomes.Two authors independently assessed retrieved studies and extracted data from included studies. We assessed studies for risk of bias. We obtained summary estimates of effect using a random-effects model and expressed results as risk ratios (RR) (95% confidence intervals; CI) for dichotomous outcomes and mean difference (MD; 95% CI) or standardised mean difference (SMD; 95% CI) for continuous outcomes. In multi-arm trials, data were pooled to create single pair-wise comparisons. Analyses were stratified by specific intervention setting where available.Our search strategy identified 46 studies (47 primary articles, including one abstract) comprising 24 parallel RCTs, 19 cluster RCTs and 3 quasi-RCTs. Sample sizes ranged from 138 to 1,085,292 (median = 514). A total of 16 studies measured registration behaviour, 27 measured intention to register/donate and three studies measured both registration behaviour and intention to register. Interventions were delivered in a variety of different settings: schools (14 studies), driver's motor vehicle (DMV) centres (5), mail-outs (4), primary care centres (3), workplaces (1), community settings (7) and general public (12). Interventions were highly varied in terms of their content and included strategies such as educational sessions and videos, leveraging peer leaders, staff training, message framing, and priming. Most studies were rated as having high or unclear risk of bias for random sequence generation and allocation concealment and low risk for the remainder of the domains. Data from 34/46 studies (74%) were available for meta-analysis. Low certainty evidence showed organ donation registration interventions had a small overall effect on improving registration behaviour (16 studies, 1,294,065 participants: RR 1.30, 95% CI 1.19 to 1.43, I2 = 84%), intention to register/donate (dichotomous) (10 studies, 10,838 participants: RR 1.21, 95% CI 1.03 to 1.42, I2 = 91%) and intention to register/donate (continuous) (9 studies, 3572 participants: SMD 0.23, 95% CI 0.11 to 0.36, I2 = 67%). Classroom-based interventions delivered in a lecture format by individuals from the transplant community may be effective at increasing intention to register/donate (3 studies, 675 participants: RR 1.33, 95% CI 1.15 to 1.55, I² = 0%). Community interventions targeting specific ethnic groups were generally effective at increasing registration rates (k = 5, n = 4186; RR 2.14, 95% CI 1.35 to 3.40, I² = 85%), although heterogeneity was high. In particular, interventions delivered in the community by trained peer-leaders appear to be effective (3 studies, 3819 participant: RR 2.09, 95% CI 1.08 to 4.06, I² = 87%), although again, the data lacked robustness. There was some evidence that framing messages (e.g. anticipated regret) and priming individuals (e.g. reciprocity) in a certain way may increase intention to register/donate, however, few studies measured this effect on actual registration. Overall, the studies varied significantly in terms of design, setting, content and delivery. Selection bias was evident and a quarter of the studies could not be included in the meta-analysis due to incomplete outcome data reporting. No adverse events were reported.In our review, we identified a variety of approaches used to increase organ donor registration including school-based educational sessions and videos, leveraging peer leaders in the community, DMV staff training, targeted messaging and priming. The variability in outcome measures used and incompleteness in reporting meant that most data could not be combined for analysis. When data were combined, overall effect sizes were small in favour of intervention groups over controls, however, there was significant variability in the data. There was some evidence that leveraging peer-leaders in the community to deliver organ donation education may improve registration rates and classroom-based education from credible individuals (i.e. members of the transplant community) may improve intention to register/donate, however, there is no clear evidence favouring any particular approach. There was mixed evidence for simple, low-intensity interventions utilising message framing and priming. However, it is likely that interest in these strategies will persist due to their reach and scalability. Further research is therefore required to adequately address the question of the most effective interventions for increasing deceased organ donor registration.

P1434ALDOSTERONE ANTAGONISTS FOR PATIENTS UNDERGOING DIALYSIS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Background and Aims Patients with chronic kidney disease (CKD) requiring dialysis are at a particularly high risk of cardiovascular mortality and morbidity. Several clinical trials suggested that aldosterone antagonists would be a promising treatment option for patients undergoing dialysis. However, the clinical efficacy and potential harm of aldosterone antagonists for patients with CKD on dialysis have yet to be determined. This review aimed to evaluate the benefits and harms of aldosterone antagonists, both non-selective (spironolactone) and selective (eplerenone), in comparison to control (placebo or standard care) in patients with CKD requiring haemodialysis or peritoneal dialysis. Method We searched the Cochrane Kidney and Transplant Register of Studies up to 29 July 2019 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register Search Portal and ClinicalTrials.gov. We included individual and cluster randomised controlled trials (RCTs), cross-over trials, and quasi-RCTs that compared aldosterone antagonists with placebo or standard care in patients with CKD requiring dialysis. Two review authors independently extracted data and assessed risk of bias for included studies. We used a random-effects model meta-analysis to perform a quantitative synthesis of the data. We used the I statistic to measure heterogeneity among the trials in each analysis. We indicated summary estimates as a risk ratio (RR) for dichotomous outcomes, mean difference (MD) for continuous outcomes, or standardised mean differences (SMD) if different scales were used, with their 95% confidence interval (CI). We assessed the certainty of the evidence for each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach. Results We included 14 trials (12 parallel RCTs and two cross-over trials) involving a total of 1,375 participants. Most included studies had an unclear or high risk of bias. Compared to control, aldosterone antagonists reduced the risk of all-cause death for patients with CKD requiring dialysis (9 trials, 1,119 participants: RR 0.45, 95% CI 0.30 to 0.67; I=0%; moderate certainty of evidence). Aldosterone antagonist also decreased the risk of death due to cardiovascular disease (6 trials, 908 participants: RR 0.37, 95% CI 0.22 to 0.64; I=0%; moderate certainty of evidence) and cardiovascular and cerebrovascular morbidity (3 trials, 328 participants: RR 0.38, 95% CI 0.18 to 0.76; I=0%; moderate certainty of evidence). While aldosterone antagonists had an apparent increased risk of gynaecomastia compared with control (4 trials, 768 participants: RR 5.95, 95% CI 1.93 to 18.3; I=0%; moderate certainty of evidence), the elevated risk of hyperkalaemia (9 trials, 981 participants: RR 1.41, 95% CI 0.72 to 2.78; I=47%; low certainty of evidence) and increase in serum potassium (7 trials, 519 participants: MD 0.21, 95% CI -0.06 to 0.47; I2=84%) due to aldosterone antagonists was uncertain. Aldosterone antagonists had a marginal effect on left ventricular mass among participants undergoing dialysis (7 trials, 562 participants: SMD -0.33, 95% CI -0.72 to 0.05; I2=76%). Conclusion Based on moderate certainty of the evidence, aldosterone antagonists could reduce the risk of all-cause and cardiovascular death and morbidity due to cardiovascular and cerebrovascular disease but increase the risk of gynaecomastia in patients with CKD requiring dialysis. Two ongoing studies will provide better certainty of evidence in the future.

Biocompatible dialysis fluids for peritoneal dialysis.

Biocompatible peritoneal dialysis (PD) solutions, including neutral pH, low glucose degradation product (GDP) solutions and icodextrin, have previously been shown to favourably influence some patient-level outcomes, albeit based on generally sub-optimal quality studies. Several additional randomised controlled trials (RCT) evaluating biocompatible solutions in PD patients have been published recently. This is an update of a review first published in 2014. This review aimed to look at the benefits and harms of biocompatible PD solutions in comparison to standard PD solutions in patients receiving PD. The Cochrane Kidney and Transplant Specialised Register was searched up to 12 February 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register Search Portal and ClinicalTrials.gov. All RCTs and quasi-RCTs in adults and children comparing the effects of biocompatible PD solutions (neutral pH, lactate-buffered, low GDP; neutral pH, bicarbonate(± lactate)-buffered, low GDP; glucose polymer (icodextrin)) in PD were included. Studies of amino acid-based solutions were excluded. Two authors extracted data on study quality and outcomes. Summary effect estimates were obtained using a random-effects model, and results were expressed as risk ratios and 95% confidence intervals (CI) for categorical variables, and mean differences (MD) or standardised mean differences (SMD) and 95% CI for continuous variables. This review update included 42 eligible studies (3262 participants), including six new studies (543 participants). Overall, 29 studies (1971 participants) compared neutral pH, low GDP PD solution with conventional PD solution, and 13 studies (1291 participants) compared icodextrin with conventional PD solution. Risk of bias was assessed as high for sequence generation in three studies, allocation concealment in three studies, attrition bias in 21 studies, and selective outcome reporting bias in 16 studies.Neutral pH, low GDP versus conventional glucose PD solutionUse of neutral pH, low GDP PD solutions improved residual renal function (RRF) preservation (15 studies, 835 participants: SMD 0.19, 95% CI 0.05 to 0.33; high certainty evidence). This approximated to a mean difference in glomerular filtration rate of 0.54 mL/min/1.73 m2 (95% CI 0.14 to 0.93). Better preservation of RRF was evident at all follow-up durations with progressively greater preservation observed with increasing follow up duration. Neutral pH, low GDP PD solution use also improved residual urine volume preservation (11 studies, 791 participants: MD 114.37 mL/day, 95% CI 47.09 to 181.65; high certainty evidence). In low certainty evidence, neutral pH, low GDP solutions may make little or no difference to 4-hour peritoneal ultrafiltration (9 studies, 414 participants: SMD -0.42, 95% CI -0.74 to -0.10) which approximated to a mean difference in peritoneal ultrafiltration of 69.72 mL (16.60 to 122.00 mL) lower, and may increase dialysate:plasma creatinine ratio (10 studies, 746 participants: MD 0.01, 95% CI 0.00 to 0.03), technique failure or death compared with conventional PD solutions. It is uncertain whether neutral pH, low GDP PD solution use led to any differences in peritonitis occurrence, hospitalisation, adverse events (6 studies, 519 participants) or inflow pain (1 study, 58 participants: RR 0.51, 95% CI 0.24 to 1.08).Glucose polymer (icodextrin) versus conventional glucose PD solutionIn moderate certainty evidence, icodextrin probably reduced episodes of uncontrolled fluid overload (2 studies, 100 participants: RR 0.30, 95% CI 0.15 to 0.59) and augmented peritoneal ultrafiltration (4 studies, 102 participants: MD 448.54 mL/d, 95% CI 289.28 to 607.80) without compromising RRF (4 studies, 114 participants: SMD 0.12, 95% CI -0.26 to 0.49; low certainty evidence) which approximated to a mean creatinine clearance of 0.30 mL/min/1.73m2 higher (0.65 lower to 1.23 higher) or urine output (3 studies, 69 participants: MD -88.88 mL/d, 95% CI -356.88 to 179.12; low certainty evidence). It is uncertain whether icodextrin use led to any differences in adverse events (5 studies, 816 participants) technique failure or death. This updated review strengthens evidence that neutral pH, low GDP PD solution improves RRF and urine volume preservation with high certainty. These effects may be related to increased peritoneal solute transport and reduced peritoneal ultrafiltration, although the evidence for these outcomes is of low certainty due to significant heterogeneity and suboptimal methodological quality. Icodextrin prescription increased peritoneal ultrafiltration and mitigated uncontrolled fluid overload with moderate certainty. The effects of either neutral pH, low GDP solution or icodextrin on peritonitis, technique survival and patient survival remain uncertain and require further high quality, adequately powered RCTs.

Prebiotic, Probiotic, and Synbiotic Supplementation in Chronic Kidney Disease: A Systematic Review and Meta-analysis

Gut dysbiosis has been implicated in the pathogenesis of chronic kidney disease (CKD). Restoring gut microbiota with prebiotic, probiotic, and synbiotic supplementation has emerged as a potential therapeutic intervention but has not been systematically evaluated in the CKD population. This is a systematic review. A structured search of MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and the International Clinical Trials Register Search Portal was conducted for articles published since inception until July 2017. Included studies were randomized controlled trials investigating the effects of prebiotic, probiotic, and/or synbiotic supplementation (>1week) on uremic toxins, microbiota profile, and clinical and patient-centered outcomes in adults and children with CKD. Sixteen studies investigating 645 adults met the inclusion criteria; 5 investigated prebiotics, 6 probiotics, and 5 synbiotics. The quality of the studies (Grades of Recommendation, Assessment, Development and Evaluation) ranged from moderate to very low. Prebiotic, probiotic, and synbiotic supplementation may have led to little or no difference in serum urea (9 studies, 345 participants: mean difference [MD] -0.30mmol/L, 95% confidence interval [CI] -2.20 to 1.61, P=.76, I2=53%), indoxyl sulfate (4 studies, 144 participants: MD -0.02mg/dL, 95% CI -0.09 to 0.05, P=.61, I2=0%), and p-cresyl sulfate (4 studies, 144 participants: MD -0.13mg/dL, 95% CI -0.41 to 0.15, P=.35, I2=0%). Prebiotic supplementation may have slightly reduced serum urea concentration (4 studies, 105 participants: MD -2.23mmol/L, 95% CI -3.83 to -0.64, P=.006, I2=11). Of the 2 studies investigating microbiota changes, synbiotic interventions significantly increased Bifidobacterium. Supplement effects on clinical outcomes were uncertain. There is limited evidence to support the use of prebiotics, probiotics, and/or synbiotics in CKD management.

Early versus late ureteric stent removal after kidney transplantation.

Kidney transplantation is the treatment of choice for patients with end-stage kidney disease. In a previous review we concluded that the routine use of ureteric stents in kidney transplantation reduces the incidence of major urological complications (MUC). Unfortunately, this reduction appears to lead to a concomitant rise in urinary tract infections (UTI). For kidney recipients UTI is now the commonest post-transplant complication. This represents a considerable risk to the immunosuppressed transplant recipient, particularly in the era of increased immunologically challenging transplants. There are a number of different approaches taken when considering ureteric stenting and these are associated with differing degrees of morbidity and hospital cost. This review aimed to look at the benefits and harms of early versus late removal of the ureteric stent in kidney transplant recipients. We searched the Cochrane Kidney and Transplant Specialised Register up to 27 March 2017 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 Search Portal and ClinicalTrials.gov. All RCTs and quasi-RCTs were included in our meta-analysis. We included recipients of kidney transplants regardless of demography (adults or children) or the type of stent used. Two authors reviewed the identified studies to ascertain if they met inclusion criteria. We designated removal of a ureteric stent before the third postoperative week (< day 15) or during the index transplant admission as "early" removal. The studies were assessed for quality using the risk of bias tool. The primary outcome of interest was the incidence of MUC. Further outcomes of interest were the incidence of UTI, idiosyncratic stent-related complications, hospital-related costs and adverse events. A subgroup analysis was performed examining the difference in complications reported depending on the type of ureteric stent used; bladder indwelling (BI) versus per-urethral (PU). Statistical analyses were performed using the random effects model and results expressed as relative risk (RR) with 95% confidence intervals (CI). Five studies (1127 patients) were included in our analysis. Generally the risk of bias of the included studies was judged low or unclear; they addressed the research question and utilised a prospective randomised design. It is uncertain whether early stent removal verus late stent removal improved the incidence of MUC (5 studies, 1127 participants: RR 1.87, 95% CI 0.61 to 5.71; I2 = 21%; low certainty evidence). The incidence of UTI may be reduced in the early stent removal group (5 studies, 1127 participants: RR 0.49 95% CI 0.30 to 0.81; I2 = 59%; moderate certainty evidence). This possible reduction in the UTI incidence was only apparent if a BI stent was used, (3 studies, 539 participants, RR 0.45 95% CI 0.29 to 0.70; I2 = 13%; moderate certainty evidence). However, if an externalised PU stent was used there was no discernible difference in UTI incidence between the early and late group (2 studies, 588 participants: RR 0.60 95% CI 0.17, 2.03; I2 = 83%; low certainty evidence). Data on health economics and quality of life outcomes were lacking. Early removal of ureteric stents following kidney transplantation may reduce the incidence of UTI while it uncertain if there is a higher risk of MUC. BI stents are the optimum method for achieving this benefit.