Showing papers by "Giovanni F.M. Strippoli published in 2018"

Phosphate binders for preventing and treating chronic kidney disease‐mineral and bone disorder (CKD‐MBD)

Abstract: BACKGROUND Phosphate binders are used to reduce positive phosphate balance and to lower serum phosphate levels for people with chronic kidney disease (CKD) with the aim to prevent progression of chronic kidney disease-mineral and bone disorder (CKD-MBD). This is an update of a review first published in 2011. OBJECTIVES The aim of this review was to assess the benefits and harms of phosphate binders for people with CKD with particular reference to relevant biochemical end-points, musculoskeletal and cardiovascular morbidity, hospitalisation, and death. SEARCH METHODS We searched the Cochrane Kidney and Transplant Register of Studies up to 12 July 2018 through contact with the 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 (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA We included randomised controlled trials (RCTs) or quasi-RCTs of adults with CKD of any GFR category comparing a phosphate binder to another phosphate binder, placebo or usual care to lower serum phosphate. Outcomes included all-cause and cardiovascular death, myocardial infarction, stroke, adverse events, vascular calcification and bone fracture, and surrogates for such outcomes including serum phosphate, parathyroid hormone (PTH), and FGF23. DATA COLLECTION AND ANALYSIS Two authors independently selected studies for inclusion and extracted study data. We applied the Cochrane 'Risk of Bias' tool and used the GRADE process to assess evidence certainty. We estimated treatment effects using random-effects meta-analysis. Results were expressed as risk ratios (RR) for dichotomous outcomes together with 95% confidence intervals (CI) or mean differences (MD) or standardised MD (SMD) for continuous outcomes. MAIN RESULTS We included 104 studies involving 13,744 adults. Sixty-nine new studies were added to this 2018 update.Most placebo or usual care controlled studies were among participants with CKD G2 to G5 not requiring dialysis (15/25 studies involving 1467 participants) while most head to head studies involved participants with CKD G5D treated with dialysis (74/81 studies involving 10,364 participants). Overall, seven studies compared sevelamer with placebo or usual care (667 participants), seven compared lanthanum to placebo or usual care (515 participants), three compared iron to placebo or usual care (422 participants), and four compared calcium to placebo or usual care (278 participants). Thirty studies compared sevelamer to calcium (5424 participants), and fourteen studies compared lanthanum to calcium (1690 participants). No study compared iron-based binders to calcium. The remaining studies evaluated comparisons between sevelamer (hydrochloride or carbonate), sevelamer plus calcium, lanthanum, iron (ferric citrate, sucroferric oxyhydroxide, stabilised polynuclear iron(III)-oxyhydroxide), calcium (acetate, ketoglutarate, carbonate), bixalomer, colestilan, magnesium (carbonate), magnesium plus calcium, aluminium hydroxide, sucralfate, the inhibitor of phosphate absorption nicotinamide, placebo, or usual care without binder. In 82 studies, treatment was evaluated among adults with CKD G5D treated with haemodialysis or peritoneal dialysis, while in 22 studies, treatment was evaluated among participants with CKD G2 to G5. The duration of study follow-up ranged from 8 weeks to 36 months (median 3.7 months). The sample size ranged from 8 to 2103 participants (median 69). The mean age ranged between 42.6 and 68.9 years.Random sequence generation and allocation concealment were low risk in 25 and 15 studies, respectively. Twenty-seven studies reported low risk methods for blinding of participants, investigators, and outcome assessors. Thirty-one studies were at low risk of attrition bias and 69 studies were at low risk of selective reporting bias.In CKD G2 to G5, compared with placebo or usual care, sevelamer, lanthanum, iron and calcium-based phosphate binders had uncertain or inestimable effects on death (all causes), cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification. Sevelamer may lead to constipation (RR 6.92, CI 2.24 to 21.4; low certainty) and lanthanum (RR 2.98, CI 1.21 to 7.30, moderate certainty) and iron-based binders (RR 2.66, CI 1.15 to 6.12, moderate certainty) probably increased constipation compared with placebo or usual care. Lanthanum may result in vomiting (RR 3.72, CI 1.36 to 10.18, low certainty). Iron-based binders probably result in diarrhoea (RR 2.81, CI 1.18 to 6.68, high certainty), while the risks of other adverse events for all binders were uncertain.In CKD G5D sevelamer may lead to lower death (all causes) (RR 0.53, CI 0.30 to 0.91, low certainty) and induce less hypercalcaemia (RR 0.30, CI 0.20 to 0.43, low certainty) when compared with calcium-based binders, and has uncertain or inestimable effects on cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification. The finding of lower death with sevelamer compared with calcium was present when the analysis was restricted to studies at low risk of bias (RR 0.50, CI 0.32 to 0.77). In absolute terms, sevelamer may lower risk of death (all causes) from 210 per 1000 to 105 per 1000 over a follow-up of up to 36 months, compared to calcium-based binders. Compared with calcium-based binders, lanthanum had uncertain effects with respect to all-cause or cardiovascular death, myocardial infarction, stroke, fracture, or coronary artery calcification and probably had reduced risks of treatment-related hypercalcaemia (RR 0.16, CI 0.06 to 0.43, low certainty). There were no head-to-head studies of iron-based binders compared with calcium. The paucity of placebo-controlled studies in CKD G5D has led to uncertainty about the effects of phosphate binders on patient-important outcomes compared with placebo.It is uncertain whether the effects of binders on clinically-relevant outcomes were different for patients who were and were not treated with dialysis in subgroup analyses. AUTHORS' CONCLUSIONS In studies of adults with CKD G5D treated with dialysis, sevelamer may lower death (all causes) compared to calcium-based binders and incur less treatment-related hypercalcaemia, while we found no clinically important benefits of any phosphate binder on cardiovascular death, myocardial infarction, stroke, fracture or coronary artery calcification. The effects of binders on patient-important outcomes compared to placebo are uncertain. In patients with CKD G2 to G5, the effects of sevelamer, lanthanum, and iron-based phosphate binders on cardiovascular, vascular calcification, and bone outcomes compared to placebo or usual care, are also uncertain and they may incur constipation, while iron-based binders may lead to diarrhoea.

Neurocognitive and Educational Outcomes in Children and Adolescents with CKD A Systematic Review and Meta-Analysis

Abstract: Background and objectives Poor cognition can affect educational attainment, but the extent of neurocognitive impairment in children with CKD is not well understood. This systematic review assessed global and domain-specific cognition and academic skills in children with CKD and whether these outcomes varied with CKD stage. Design, setting, participants, & measurements Electronic databases were searched for observational studies of children with CKD ages 21 years old or younger that assessed neurocognitive or educational outcomes. Risk of bias was assessed using a modified Newcastle–Ottawa scale. We used random effects models and expressed the estimates as mean differences with 95% confidence intervals stratified by CKD stage. Results Thirty-four studies (25 cross-sectional, n=2095; nine cohort, n=991) were included. The overall risk of bias was high because of selection and measurement biases. The global cognition (full-scale intelligence quotient) of children with CKD was classified as low average. Compared with the general population, the mean differences (95% confidence intervals) in full-scale intelligence quotient were −10.5 (95% confidence interval, −13.2 to −7.72; all CKD stages, n=758), −9.39 (95% confidence interval, −12.6 to −6.18; mild to moderate stage CKD, n=582), −16.2 (95% confidence interval, −33.2 to 0.86; dialysis, n=23), and −11.2 (95% confidence interval, −17.8 to −4.50; transplant, n=153). Direct comparisons showed that children with mild to moderate stage CKD and kidney transplants scored 11.2 (95% confidence interval, 2.98 to 19.4) and 10.1 (95% confidence interval, −1.81 to 22.0) full-scale intelligence quotient points higher than children on dialysis. Children with CKD also had lower scores than the general population in executive function and memory (verbal and visual) domains. Compared with children without CKD, the mean differences in academic skills (n=518) ranged from −15.7 to −1.22 for mathematics, from −9.04 to −0.17 for reading, and from −14.2 to 2.53 for spelling. Conclusions Children with CKD may have low-average cognition compared with the general population, with mild deficits observed across academic skills, executive function, and visual and verbal memory. Limited evidence suggests that children on dialysis may be at greatest risk compared with children with mild to moderate stage CKD and transplant recipients.

Immunosuppressive treatment for proliferative lupus nephritis.

Abstract: Background Cyclophosphamide, in combination with corticosteroids, has been first-line treatment for inducing disease remission for proliferative lupus nephritis, reducing death at five years from over 50% in the 1950s and 1960s to less than 10% in recent years. Several treatment strategies designed to improve remission rates and minimise toxicity have become available. Treatments, including mycophenolate mofetil (MMF) and calcineurin inhibitors, alone and in combination, may have equivalent or improved rates of remission, lower toxicity (less alopecia and ovarian failure) and uncertain effects on death, end-stage kidney disease (ESKD) and infection. This is an update of a Cochrane review first published in 2004 and updated in 2012. Objectives Our objective was to assess the evidence and evaluate the benefits and harms of different immunosuppressive treatments in people with biopsy-proven lupus nephritis. The following questions relating to management of proliferative lupus nephritis were addressed: 1) Are new immunosuppressive agents superior to or as effective as cyclophosphamide plus corticosteroids? 2) Which agents, dosages, routes of administration and duration of therapy should be used? 3) Which toxicities occur with the different treatment regimens? Search methods We searched the Cochrane Kidney and Transplant Specialised Register up to 2 March 2018 with support from the Cochrane 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 (ICTRP) Search Portal and ClinicalTrials.gov. Selection criteria Randomised controlled trials (RCTs) and quasi-RCTs comparing any immunosuppressive treatment for biopsy-proven class III, IV, V+III and V+VI lupus nephritis in adult or paediatric patients were included. Data collection and analysis Data were abstracted and the risks of bias were assessed independently by two authors. Dichotomous outcomes were calculated as risk ratio (RR) and measures on continuous scales calculated as mean differences (MD) with 95% confidence intervals (CI). The primary outcomes were death (all causes) and complete disease remission for induction therapy and disease relapse for maintenance therapy. Evidence certainty was determined using GRADE. Main results In this review update, 26 new studies were identified, to include 74 studies involving 5175 participants overall. Twenty-nine studies included children under the age of 18 years with lupus nephritis, however only two studies exclusively examined the treatment of lupus nephritis in patients less than 18 years of age. Induction therapy Sixty-seven studies (4791 participants; median 12 months duration (range 2.5 to 48 months)) reported induction therapy. The effects of all treatment strategies on death (all causes) and ESKD were uncertain (very low certainty evidence) as this outcome occurred very infrequently. Compared with intravenous (IV) cyclophosphamide, MMF may have increased complete disease remission (RR 1.17, 95% CI 0.97 to 1.42; low certainty evidence), although the range of effects includes the possibility of little or no difference. Compared to IV cyclophosphamide, MMF is probably associated with decreased alopecia (RR 0.29, 95% CI 0.19 to 0.46; 170 less (129 less to 194 less) per 1000 people) (moderate certainty evidence), increased diarrhoea (RR 2.42, 95% CI 1.64 to 3.58; 142 more (64 more to 257 more) per 1000 people) (moderate certainty evidence) and may have made little or no difference to major infection (RR 1.02, 95% CI 0.67 to 1.54; 2 less (38 less to 62 more) per 1000 people) (low certainty evidence). It is uncertain if MMF decreased ovarian failure compared to IV cyclophosphamide because the certainty of the evidence was very low (RR 0.36, 95% CI 0.06 to 2.18; 26 less (39 less to 49 more) per 1000 people). Studies were not generally designed to measure ESKD. MMF combined with tacrolimus may have increased complete disease remission (RR 2.38, 95% CI 1.07 to 5.30; 336 more (17 to 1048 more) per 1000 people (low certainty evidence) compared with IV cyclophosphamide, however the effects on alopecia, diarrhoea, ovarian failure, and major infection remain uncertain. Compared to standard of care, the effects of biologics on most outcomes were uncertain because of low to very low certainty of evidence. Maintenance therapy Nine studies (767 participants; median 30 months duration (range 6 to 63 months)) reported maintenance therapy. In maintenance therapy, disease relapse is probably increased with azathioprine compared with MMF (RR 1.75, 95% CI 1.20 to 2.55; 114 more (30 to 236 more) per 1000 people (moderate certainty evidence). Multiple other interventions were compared as maintenance therapy, but patient-outcome data were sparse leading to imprecise estimates. Authors' conclusions In this review update, studies assessing treatment for proliferative lupus nephritis were not designed to assess death (all causes) or ESKD. MMF may lead to increased complete disease remission compared with IV cyclophosphamide, with an acceptable adverse event profile, although evidence certainty was low and included the possibility of no difference. Calcineurin combined with lower dose MMF may improve induction of disease remission compared with IV cyclophosphamide, but the comparative safety profile of these therapies is uncertain. Azathioprine may increase disease relapse as maintenance therapy compared with MMF.

Prevalence and patterns of cognitive impairment in adult hemodialysis patients: the COGNITIVE-HD study.

Abstract: Background Mounting evidence indicates an increased risk of cognitive impairment in adults with end-stage kidney disease on dialysis, but the extent and pattern of deficits across the spectrum of cognitive domains are uncertain. Methods We conducted a cross-sectional study of 676 adult hemodialysis patients from 20 centers in Italy, aiming to evaluate the prevalence and patterns of cognitive impairment across five domains of learning and memory, complex attention, executive function, language and perceptual-motor function. We assessed cognitive function using a neuropsychological battery of 10 tests and calculated test and domain z-scores using population norms (age or age/education). We defined cognitive impairment as a z-score ≤ -1.5. Results Participants' median age was 70.9 years (range 21.6-94.1) and 262 (38.8%) were women. Proportions of impairment on each domain were as follows: perceptual-motor function 31.5% (150/476), language 41.2% (273/662), executive function 41.7% (281/674), learning and memory 42.2% (269/638), complex attention 48.8% (329/674). Among 474 participants with data for all domains, only 28.9% (n = 137) were not impaired on any domain, with 25.9% impaired on a single domain (n = 123), 17.3% on two (n = 82), 13.9% on three (n = 66), 9.1% on four (n = 43) and 4.9% (n = 23) on all five. Across patients, patterns of impairment combinations were diverse. Conclusions In conclusion, cognitive impairment is extremely common in hemodialysis patients, across numerous domains, and patients often experience multiple deficits simultaneously. Clinical care should be tailored to meet the needs of patients with different types of cognitive impairment and future research should focus on identifying risk factors for cognitive decline.

Person-Centered Integrated Care for Chronic Kidney Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Abstract: Background and objectives The effectiveness of person-centered integrated care strategies for CKD is uncertain We conducted a systematic review and meta-analysis of randomized, controlled trials to assess the effect of person-centered integrated care for CKD Design, setting, participants, & measurements We searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials (from inception to April of 2016), and selected randomized, controlled trials of person-centered integrated care interventions with a minimum follow-up of 3 months Random-effects meta-analysis was used to assess the effect of person-centered integrated care Results We included 14 eligible studies covering 4693 participants with a mean follow-up of 12 months In moderate quality evidence, person-centered integrated care probably had no effect on all-cause mortality (relative risk [RR], 086; 95% confidence interval [95% CI], 068 to 108) or health-related quality of life (standardized mean difference, 002; 95% CI, −005 to 010) The effects on renal replacement therapy (RRT) (RR, 100; 95% CI, 065 to 155), serum creatinine levels (mean difference, 059 mg/dl; 95% CI, −038 to 036), and eGFR (mean difference, 151 ml/min per 173 m2; 95% CI, −325 to 627) were very uncertain Quantitative analysis suggested that person-centered integrated care interventions may reduce all-cause hospitalization (RR, 038; 95% CI, 015 to 095) and improve BP control (RR, 120; 95% CI, 100 to 144), although the certainty of the evidence was very low Conclusions Person-centered integrated care may have little effect on mortality or quality of life The effects on serum creatinine, eGFR, and RRT are uncertain, although person-centered integrated care may lead to fewer hospitalizations and improved BP control

The association of mediterranean and DASH diets with mortality in adults on hemodialysis: The DIET-HD multinational cohort study

Abstract: Background Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diets associate with lower cardiovascular and all-cause mortality in the general population, but the benefits for patients on hemodialysis are uncertain.Methods Mediterranean and DASH diet scores were derived from the GA2LEN Food Frequency Questionnaire within the DIET-HD Study, a multinational cohort study of 9757 adults on hemodialysis. We conducted adjusted Cox regression analyses clustered by country to evaluate the association between diet score tertiles and all-cause and cardiovascular mortality (the lowest tertile was the reference category).Results During the median 2.7-year follow-up, 2087 deaths (829 cardiovascular deaths) occurred. The adjusted hazard ratios (95% confidence intervals) for the middle and highest Mediterranean diet score tertiles were 1.20 (1.01 to 1.41) and 1.14 (0.90 to 1.43), respectively, for cardiovascular mortality and 1.10 (0.99 to 1.22) and 1.01 (0.88 to 1.17), respectively, for all-cause mortality. Corresponding estimates for the same DASH diet score tertiles were 1.01 (0.85 to 1.21) and 1.19 (0.99 to 1.43), respectively, for cardiovascular mortality and 1.03 (0.92 to 1.15) and 1.00 (0.89 to 1.12), respectively, for all-cause mortality. The association between DASH diet score and all-cause death was modified by age (P=0.03); adjusted hazard ratios for the middle and highest DASH diet score tertiles were 1.02 (0.81 to 1.29) and 0.70 (0.53 to 0.94), respectively, for younger patients (≤60 years old) and 1.05 (0.93 to 1.19) and 1.08 (0.95 to 1.23), respectively, for older patients.Conclusions Mediterranean and DASH diets did not associate with cardiovascular or total mortality in hemodialysis.

New fecal test for non-invasive Helicobacter pylori detection: A diagnostic accuracy study.

Abstract: Aim To assess the diagnostic accuracy of a new fecal test for detecting Helicobacter pylori (H. pylori), using13C-urea breath test as the reference standard, and explore bacterial antibiotic resistance. Methods We conducted a prospective two-center diagnostic test accuracy study. We enrolled consecutive people≥ 18 years without previous diagnosis of H. pylori infection, referred for dyspepsia between February and October 2017. At enrollment, all participants underwent 13C-urea breath test. Participants aged over 50 years were scheduled to undergo upper endoscopy with histology. Participants collected stool samples 1-3 d after enrollment for a new fecal investigation (THD fecal test). The detection of bacterial 23S rRNA subunit gene indicated H. pylori infection. We also used the index diagnostic test to examine mutations conferring resistance to clarithromycin and levofloxacin. Independent investigators analyzed index test and reference test standard results blinded to the other test findings. We estimated sensitivity, specificity, positive (PPV) and negative (NPV) predictive value, diagnostic accuracy, positive and negative likelihood ratio (LR), together with 95% confidence intervals (CI). Results We enrolled 294 consecutive participants (age: Median 37.0 years, IQR: 29.0-46.0 years; men: 39.8%). Ninety-five (32.3%) participants had a positive13C-urea breath test. Twenty-three (7.8%) participants underwent upper endoscopy with histology, with a full concordance between 13C-urea breath test and histology in detecting H. pylori infection. Four (1.4%) out of the 294 participants withdrew from the study after the enrollment visit and did not undergo THD fecal testing. In the 290 participants who completed the study, the THD fecal test sensitivity was 90.2% (CI: 84.2%-96.3%), specificity 98.5% (CI:96.8%-100%), PPV 96.5% (CI: 92.6%-100%), NPV 95.6% (CI: 92.8%-98.4%), accuracy 95.9% (CI: 93.6%-98.2%), positive LR 59.5(CI: 19.3-183.4), negative LR 0.10 (CI: 0.05-0.18). Out of 83 infected participants identified with the THD fecal test, 34 (41.0%) had bacterial genotypic changes consistent with antibiotic-resistant H. pylori infection. Of these, 27 (32.5%) had bacterial strains resistant to clarithromycin, 3 (3.6%) to levofloxacin, and 4 (4.8%) to both antibiotics. Conclusion The THD fecal test has high performance for the non-invasive diagnosis of H. pylori infection while additionally enabling the assessment of bacterial antibiotic resistances.

The Long-Term Impact of Renin-Angiotensin System (RAS) Inhibition on Cardiorenal Outcomes (LIRICO): A Randomized, Controlled Trial

Abstract: Background The comparative effectiveness of treatment with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or their combination in people with albuminuria and cardiovascular risk factors is unclear. Methods In a multicenter, randomized, open label, blinded end point trial, we evaluated the effectiveness on cardiovascular events of ACE or ARB monotherapy or combination therapy, targeting BP Results Because of slow enrollment, the trial was modified and stopped 41% short of targeted enrollment of 2100 participants, corresponding to 35% power to detect a 25% reduced risk in the primary outcome. Our analysis included 1243 adults, with median follow-up of 2.7 years. Efficacy outcomes were similar between groups (ACE inhibitor versus ARB, ACE inhibitor versus combination, ARB versus combination) as were rates of serious adverse events. The rate of permanent discontinuation for ARB monotherapy (6.3%) was significantly lower than for ACE inhibitor monotherapy (15.7%) or combined therapy (18.3%). Conclusions Patients may tolerate ARB monotherapy better than ACE inhibitor monotherapy. However, data from this trial and similar trials, although as yet inconclusive, show no trend suggesting differences in mortality and renal outcomes with ACE inhibitors or ARBs as dual or monotherapy in patients with albuminuria and diabetes or other cardiovascular risk factors.

Mesalazine for People with Diverticular Disease: A Systematic Review of Randomized Controlled Trials.

Abstract: Background. Diverticular disease treatment is limited to fibres, antibiotics, and surgery. There is conflicting evidence on mesalazine benefits and harms. Aim. We systematically reviewed current evidence on benefits and harms of mesalazine versus all other treatments in people with diverticular disease. Methods. We searched MEDLINE, EMBASE, CENTRAL, ClinicalTrials.gov for studies published to July 2018. We estimated risk ratios (RR) for dichotomous outcomes (disease remission/recurrence, acute diverticulitis in symptomatic uncomplicated diverticular disease, need for surgery/hospitalization, all-cause/disease-related mortality, adverse events), mean differences (MD) or standardized MD (SMD) for continuous outcomes (quality of life, symptoms score, time to recurrence/remission), and their 95% confidence intervals (CI) using random-effects models. We quantified heterogeneity by Chi2 and I2 tests. We performed subgroup analyses by disease subtype, comparator, follow-up duration, mesalazine dose, and mode of administration. Results. We identified 13 randomized trials (n=3028 participants). There was a higher likelihood of disease remission with mesalazine than controls in acute uncomplicated diverticulitis (1 trial, 81 participants, RR=2.67, 95%CI=1.05-6.79), but not in symptomatic uncomplicated diverticular disease (1 trial, 123 participants, RR=1.04, 95%CI=0.81-1.34). There was a lower likelihood of disease recurrence with mesalazine than controls in symptomatic uncomplicated diverticular disease (2 trials, 216 participants, RR=0.52, 95%CI=0.28-0.97), but not in acute uncomplicated diverticulitis (7 trials, 2196 participants, RR=0.90, 95%CI=0.61-1.33). There was no difference in the likelihood of developing acute diverticulitis in symptomatic uncomplicated diverticular disease between the two groups (3 trials, 484 participants, RR=0.26, 95%CI=0.06-1.20). There was a higher global symptoms score reduction with mesalazine than controls in symptomatic uncomplicated diverticular disease (2 trials, 326 participants, SMD=-1.01, 95%CI=-1.51,-0.52) and acute uncomplicated diverticulitis (2 trials, 153 participants, SMD=-0.56, 95%CI=-0.88,-0.24). Conclusions. Mesalazine may reduce recurrences in symptomatic uncomplicated diverticular disease. There is uncertainty on the effect of mesalazine in achieving diverticular disease remission. Mesalazine may not prevent acute diverticulitis in symptomatic uncomplicated diverticular disease.

Corticosteroid or Nonsteroidal Antiinflammatory Drugs for the Treatment of Acute Gout: A Systematic Review of Randomized Controlled Trials

Abstract: Objective Nonsteroidal antiinflammatory drugs (NSAID) are used as first-line agents to treat acute gout. Recent trials suggest a possible first-line role for corticosteroids. Methods We conducted a metaanalysis of randomized controlled trials (RCT) evaluating corticosteroid versus NSAID therapy (nonselective and selective) as treatment for acute gout. MEDLINE, EMBASE, and CENTRAL were systematically searched through August 2016. Outcomes included pain, bleeding, joint swelling, erythema, tenderness, activity limitation, response to therapy, quality of life, time to resolution, supplementary analgesics, and adverse events. Evidence quality was summarized using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) system. Results Six eligible trials (817 patients) were identified. The mean study followup was 15 days (range 4–30). Risks of bias were generally low. In low- to moderate-quality evidence, corticosteroids did not have different effects on pain score at Conclusion There is no evidence that corticosteroids and NSAID have different efficacy in managing pain in acute gout, but corticosteroids appear to have a more favorable safety profile for selected adverse events analyzed in existing RCT.

Potassium binders for chronic hyperkalaemia in people with chronic kidney disease

Abstract: Background Hyperkalaemia is a common electrolyte abnormality caused by reduced renal potassium excretion in patients with chronic kidney diseases (CKD). Potassium binders, such as sodium polystyrene sulfonate and calcium polystyrene sulfonate, are widely used but may lead to constipation and other adverse gastrointestinal (GI) symptoms, reducing their tolerability. Patiromer and sodium zirconium cyclosilicate are newer ion exchange resins for treatment of hyperkalaemia which may cause fewer GI side-effects. Although more recent studies are focusing on clinically-relevant endpoints such as cardiac complications or death, the evidence on safety is still limited. Given the recent expansion in the available treatment options, it is appropriate to review the evidence of effectiveness and tolerability of all potassium exchange resins among people with CKD, with the aim to provide guidance to consumers, practitioners, and policy-makers. Objectives To assess the benefits and harms of potassium binders for treating chronic hyperkalaemia among adults and children with CKD. Search methods We searched the Cochrane Kidney and Transplant Register of Studies up to 10 March 2020 through contact with the 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 (ICTRP) Search Portal and ClinicalTrials.gov. Selection criteria Randomised controlled trials (RCTs) and quasi-randomised controlled studies (quasi-RCTs) evaluating potassium binders for chronic hyperkalaemia administered in adults and children with CKD. Data collection and analysis Two authors independently assessed risks of bias and extracted data. Treatment estimates were summarised by random effects meta-analysis and expressed as relative risk (RR) or mean difference (MD), with 95% confidence interval (CI). Evidence certainty was assessed using GRADE processes. Main results Fifteen studies, randomising 1849 adult participants were eligible for inclusion. Twelve studies involved participants with CKD (stages 1 to 5) not requiring dialysis and three studies were among participants treated with haemodialysis. Potassium binders included calcium polystyrene sulfonate, sodium polystyrene sulfonate, patiromer, and sodium zirconium cyclosilicate. A range of routes, doses, and timing of drug administration were used. Study duration varied from 12 hours to 52 weeks (median 4 weeks). Three were cross-over studies. The mean study age ranged from 53.1 years to 73 years. No studies evaluated treatment in children. Some studies had methodological domains that were at high or unclear risks of bias, leading to low certainty in the results. Studies were not designed to measure treatment effects on cardiac arrhythmias or major GI symptoms. Ten studies (1367 randomised participants) compared a potassium binder to placebo. The certainty of the evidence was low for all outcomes. We categorised treatments in newer agents (patiromer or sodium zirconium cyclosilicate) and older agents (calcium polystyrene sulfonate and sodium polystyrene sulfonate). Patiromer or sodium zirconium cyclosilicate may make little or no difference to death (any cause) (4 studies, 688 participants: RR 0.69, 95% CI 0.11, 4.32; I2 = 0%; low certainty evidence) in CKD. The treatment effect of older potassium binders on death (any cause) was unknown. One cardiovascular death was reported with potassium binder in one study, showing that there was no difference between patiromer or sodium zirconium cyclosilicate and placebo for cardiovascular death in CKD and HD. There was no evidence of a difference between patiromer or sodium zirconium cyclosilicate and placebo for health-related quality of life (HRQoL) at the end of treatment (one study) in CKD or HD. Potassium binders had uncertain effects on nausea (3 studies, 229 participants: RR 2.10, 95% CI 0.65, 6.78; I2 = 0%; low certainty evidence), diarrhoea (5 studies, 720 participants: RR 0.84, 95% CI 0.47, 1.48; I2 = 0%; low certainty evidence), and vomiting (2 studies, 122 participants: RR 1.72, 95% CI 0.35 to 8.51; I2 = 0%; low certainty evidence) in CKD. Potassium binders may lower serum potassium levels (at the end of treatment) (3 studies, 277 participants: MD -0.62 mEq/L, 95% CI -0.97, -0.27; I2 = 92%; low certainty evidence) in CKD and HD. Potassium binders had uncertain effects on constipation (4 studies, 425 participants: RR 1.58, 95% CI 0.71, 3.52; I2 = 0%; low certainty evidence) in CKD. Potassium binders may decrease systolic blood pressure (BP) (2 studies, 369 participants: MD -3.73 mmHg, 95%CI -6.64 to -0.83; I2 = 79%; low certainty evidence) and diastolic BP (one study) at the end of the treatment. No study reported outcome data for cardiac arrhythmias or major GI events. Calcium polystyrene sulfonate may make little or no difference to serum potassium levels at end of treatment, compared to sodium polystyrene sulfonate (2 studies, 117 participants: MD 0.38 mEq/L, 95% CI -0.03 to 0.79; I2 = 42%, low certainty evidence). There was no evidence of a difference in systolic BP (one study), diastolic BP (one study), or constipation (one study) between calcium polystyrene sulfonate and sodium polystyrene sulfonate. There was no difference between high-dose and low-dose patiromer for death (sudden death) (one study), stroke (one study), myocardial infarction (one study), or constipation (one study). The comparative effects whether potassium binders were administered with or without food, laxatives, or sorbitol, were very uncertain with insufficient data to perform meta-analysis. Authors' conclusions Evidence supporting clinical decision-making for different potassium binders to treat chronic hyperkalaemia in adults with CKD is of low certainty; no studies were identified in children. Available studies have not been designed to measure treatment effects on clinical outcomes such as cardiac arrhythmias or major GI symptoms. This review suggests the need for a large, adequately powered study of potassium binders versus placebo that assesses clinical outcomes of relevance to patients, clinicians and policy-makers. This data could be used to assess cost-effectiveness, given the lack of definitive studies and the clinical importance of potassium binders for chronic hyperkalaemia in people with CKD.

Renal transplant outcomes and de novo donor-specific anti-human leukocyte antigen antibodies: a systematic review.

Abstract: Background Pre-transplant donor-specific anti-human leukocyte antigen antibodies (DSAs) are known risk factors for acute rejection and reduced graft survival after kidney transplantation. DSAs may also develop de novo DSAs (dnDSAs) after transplantation but the clinical implications of these antibodies remain uncertain. Methods We undertook a systematic review of observational studies that examined the association between dnDSAs and graft and patient outcomes (through August 2017) with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system of reporting used to assess the quality of evidence available. Results Thirty-six studies involving 10 535 transplant recipients were eligible. There was moderate quality evidence that transplant recipients who developed dnDSAs had increased risks of acute antibody-mediated rejection (AMR) [relative risk (RR) 9.66; 95% confidence interval (CI) 6.79-13.73, 16 studies, n = 4174]. For all other outcomes, the evidence was low to very low due to moderate-high heterogeneity and low study quality (acute cellular rejection, RR 2.92; 95% CI 2.16-3.94, 22 studies, n = 4991, low-quality evidence; chronic AMR and transplant glomerulopathy RR 6.78; 95% CI 4.31-10.66, 3 studies, n = 1617, very low-quality evidence; and graft loss RR 4.95; 95% CI 3.81-6.43, 19 studies, n = 5473, low-quality evidence). Meta-regression indicated that deceased kidney donation (R2 = 1.00, P < 0.001) and region of study conduction (R2 = 0.50, P = 0.005) modified associations between dnDSAs and outcomes. Conclusions dnDSAs are associated with increased risks of adverse graft and patient outcomes after kidney transplantation, but estimation uncertainty of the augmented risks exist due to limitations such as heterogeneity within the existing literature. Therapeutic interventions targeted to eliminate or prevent these antibodies evaluated in randomized controlled trials are needed to establish whether dnDSAs are causal to transplantation outcomes.