Interventions for preventing the progression of autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the leading inherited cause of kidney disease. Clinical management has historically focused on symptom control and reducing associated complications. Improved understanding of the molecular and cellular mechanisms involved in kidney cyst growth and disease progression has resulted in new pharmaceutical agents targeting disease pathogenesis and preventing disease progression. However, the role of disease-modifying agents for all people with ADPKD is unclear. This is an update of a review first published in 2015. OBJECTIVES: We aimed to evaluate the benefits and harms of interventions to prevent the progression of ADPKD and the safety based on patient-important endpoints, defined by the Standardised Outcomes in NephroloGy-Polycystic Kidney Disease (SONG-PKD) core outcome set, and general and specific adverse effects. SEARCH METHODS: We searched the Cochrane Kidney and Transplants Register of Studies up to 13 August 2024 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 Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing any interventions for preventing the progression of ADPKD with other interventions, placebo, or standard care were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study risks of bias and extracted data. Summary estimates of effects were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) or standardised mean difference (SMD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: We included 57 studies (8016 participants) that investigated 18 pharmacological interventions (vasopressin 2 receptor (V2R) antagonists, antihypertensive therapy, mammalian target of rapamycin (mTOR) inhibitors, somatostatin analogues, antiplatelet agents, eicosapentaenoic acids, statins, kinase inhibitors, diuretics, anti-diabetic agents, water intake, dietary intervention, and supplements) in this review. Compared to placebo, the V2R antagonist tolvaptan probably preserves eGFR (3 studies, 2758 participants: MD 1.26 mL/min/1.73 m2, 95% CI 0.73 to 1.78; I2 = 0%) and probably slows total kidney volume (TKV) growth in adults (1 study, 1307 participants: MD -2.70 mL/cm, 95% CI -3.24 to -2.16) (moderate certainty evidence). However, there was insufficient evidence to determine tolvaptan's impact on kidney failure and death. There may be no difference in serious adverse events; however, treatment probably increases nocturia, fatigue and liver enzymes, may increase dry mouth and thirst, and may decrease hypertension and urinary and upper respiratory tract infections. Data on the impact of other therapeutic interventions were largely inconclusive. Compared to placebo, somatostatin analogues probably decrease TKV (6 studies, 500 participants: SMD -0.33, 95% CI -0.51 to -0.16; I2 = 11%), probably have little or no effect on eGFR (4 studies, 180 participants: MD 4.11 mL/min/1.73 m3, 95% CI -3.19 to 11.41; I2 = 0%) (moderate certainty evidence), and may have little or no effect on kidney failure (2 studies, 405 participants: RR 0.64, 95% CI 0.16 to 2.49; I2 = 39%; low certainty evidence). Serious adverse events may increase (2 studies, 405 participants: RR 1.81, 95% CI 1.01 to 3.25; low certainty evidence). Somatostatin analogues probably increase alopecia, diarrhoea or abnormal faeces, dizziness and fatigue but may have little or no effect on anaemia or infection. The effect on death is unclear. Targeted low blood pressure probably results in a smaller per cent annual increase in TKV (1 study, 558 participants: MD -1.00, 95% CI -1.67 to -0.33; moderate certainty evidence) compared to standard blood pressure targets, had uncertain effects on death, but probably do not impact other outcomes such as change in eGFR or adverse events. Kidney failure was not reported. Data comparing antihypertensive agents, mTOR inhibitors, eicosapentaenoic acids, statins, vitamin D compounds, metformin, trichlormethiazide, spironolactone, bosutinib, curcumin, niacinamide, prescribed water intake and antiplatelet agents were sparse and inconclusive. An additional 23 ongoing studies were also identified, including larger phase III RCTs, which will be assessed in a future update of this review. AUTHORS' CONCLUSIONS: Although many interventions have been investigated in patients with ADPKD, at present, there is little evidence that they improve patient outcomes. Tolvaptan is the only therapeutic intervention that has demonstrated the ability to slow disease progression, as assessed by eGFR and TKV change. However, it has not demonstrated benefits for death or kidney failure. In order to confirm the role of other therapeutic interventions in ADPKD management, large RCTs focused on patient-centred outcomes are needed. The search identified 23 ongoing studies, which may provide more insight into the role of specific interventions.

Antihypertensive treatment for kidney transplant recipients.

BACKGROUND: The comparative effects of specific blood pressure (BP) lowering treatments on patient-important outcomes following kidney transplantation are uncertain. Our 2009 Cochrane review found that calcium channel blockers (CCBs) improved graft function and prevented graft loss, while the evidence for other BP-lowering treatments was limited. This is an update of the 2009 Cochrane review. OBJECTIVES: To compare the benefits and harms of different classes and combinations of antihypertensive drugs in kidney transplant recipients. SEARCH METHODS: We contacted the Information Specialist and searched the Cochrane Kidney and Transplant Register of Studies up to 3 July 2024 using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs evaluating any BP-lowering agent in recipients of a functioning kidney transplant for at least two weeks were eligible. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risks of bias and extracted data. Treatment estimates were summarised using the random-effects model and expressed as relative risk (RR) or mean difference (MD) with 95% confidence intervals (CI). Evidence certainty was assessed using Grades of Recommendation, Assessment, Development and Evaluation (GRADE) processes. The primary outcomes included all-cause death, graft loss, and kidney function. MAIN RESULTS: Ninety-seven studies (8706 participants) were included. One study evaluated treatment in children. The overall risk of bias was unclear to high across all domains. Compared to placebo or standard care alone, CCBs probably reduce all-cause death (23 studies, 3327 participants: RR 0.83, 95% CI 0.72 to 0.95; I2 = 0%; moderate certainty evidence) and graft loss (24 studies, 3577 participants: RR 0.84, 95% CI 0.75 to 0.95; I2 = 0%; moderate certainty evidence). CCBs may make little or no difference to estimated glomerular filtration rate (eGFR) (11 studies, 2250 participants: MD 1.89 mL/min/1.73 m2, 95% CI -0.70 to 4.48; I2 = 48%; low certainty evidence) and acute rejection (13 studies, 906 participants: RR 10.8, 95% CI 0.85 to 1.35; I2 = 0%; moderate certainty evidence). CCBs may reduce systolic BP (SBP) (3 studies, 329 participants: MD -5.83 mm Hg, 95% CI -10.24 to -1.42; I2 = 13%; low certainty evidence) and diastolic BP (DBP) (3 studies, 329 participants: MD -3.98 mm Hg, 95% CI -5.98 to -1.99; I2 = 0%; low certainty evidence). CCBs have uncertain effects on proteinuria. Compared to placebo or standard care alone, angiotensin-converting-enzyme inhibitors (ACEi) may make little or no difference to all-cause death (7 studies, 702 participants: RR 1.13, 95% CI 0.58 to 2.21; I2 = 0%; low certainty evidence), graft loss (6 studies, 718 participants: RR 0.75, 95% CI 0.49 to 1.13; I2 = 0%; low certainty evidence), eGFR (4 studies, 509 participants: MD -2.46 mL/min/1.73 m2, 95% CI -7.66 to 2.73; I2 = 64%; low certainty evidence) and acute rejection (4 studies, 388 participants: RR 1.75, 95% CI 0.76 to 4.04; I2 = 0%; low certainty evidence). ACEi may reduce proteinuria (5 studies, 441 participants: MD -0.33 g/24 hours, 95% CI -0.64 to -0.01; I2 = 67%; low certainty evidence) but had uncertain effects on SBP and DBP. Compared to placebo or standard care alone, angiotensin receptor blockers (ARB) may make little or no difference to all-cause death (6 studies, 1041 participants: RR 0.69, 95% CI 0.36 to 1.31; I2 = 0%; low certainty evidence), eGRF (5 studies, 300 participants: MD -1.91 mL/min/1.73 m2, 95% CI -6.20 to 2.38; I2 = 57%; low certainty evidence), and acute rejection (4 studies, 323 participants: RR 1.00, 95% CI 0.44 to 2.29; I2 = 0%; low certainty evidence). ARBs may reduce graft loss (6 studies, 892 participants: RR 0.35, 95% CI 0.15 to 0.84; I2 = 0%; low certainty evidence), SBP (10 studies, 1239 participants: MD -3.73 mm Hg, 95% CI -7.02 to -0.44; I2 = 63%; moderate certainty evidence) and DBP (9 studies, 1086 participants: MD -2.75 mm Hg, 95% CI -4.32 to -1.18; I2 = 47%; moderate certainty evidence), but has uncertain effects on proteinuria. The effects of CCBs, ACEi or ARB compared to placebo or standard care alone on cardiovascular outcomes (including fatal or nonfatal myocardial infarction, fatal or nonfatal stroke) or other adverse events were uncertain. The comparative effects of ACEi plus ARB dual therapy, alpha-blockers, and mineralocorticoid receptor antagonists compared to placebo or standard care alone were rarely evaluated. Head-to-head comparisons of ACEi, ARB or thiazide versus CCB, ACEi versus ARB, CCB or ACEi versus alpha- or beta-blockers, or ACEi plus CCB dual therapy versus ACEi or CCB monotherapy were scarce. No studies reported outcome data for cancer or life participation. AUTHORS' CONCLUSIONS: For kidney transplant recipients, the use of CCB therapy to reduce BP probably reduces death and graft loss compared to placebo or standard care alone, while ARB may reduce graft loss. The effects of ACEi and ARB compared to placebo or standard care on other patient-centred outcomes were uncertain. The effects of dual therapy, alpha-blockers, and mineralocorticoid receptor antagonists compared to placebo or standard care alone and the comparative effects of different treatments were uncertain.

Causal Relationship Between Kidney Function and Cancer Risk: A Mendelian Randomization Study.

RATIONALE & OBJECTIVE: Patients treated with kidney replacement therapy experience a 1.5- to 2-fold increased risk of cancer and cancer mortality compared with the general population. Whether this excess risk extends to people with earlier stage chronic kidney disease and whether reduced kidney function is causally related to cancer is unclear. STUDY DESIGN: Two-sample Mendelian randomization (MR). SETTING & PARTICIPANTS: Genome-wide association study (GWAS) summary statistics for estimated glomerular filtration rate (eGFR) (n=567,460) and urinary albumin-creatine ratio (UACR) (n=127,865) from the CKDGen consortium and cancer outcomes from the UK Biobank (n = 407,329). EXPOSURE: eGFR and UACR. OUTCOME: Overall cancer incidence, cancer-related mortality and site-specific colorectal, lung, and urinary tract cancer incidence. ANALYTICAL APPROACH: Univariable and multivariable MR conducted for all outcomes. RESULTS: The mean eGFR and median UACR were 91.4mL/min/1.73m2 and 9.32mg/g, respectively, in the CKDGen, and 90.4mL/min/1.73m2 and 9.29mg/g, respectively, in the UK Biobank. There were 98,093 cases of cancer, 15,850 cases of cancer-related death, 6,664 colorectal, 3584 lung, and 3,271 urinary tract cancer cases, respectively. The genetic instruments for eGFR and UACR comprised 34 and 38 variants, respectively. Genetically predicted kidney function (eGFR and UACR) was not associated with overall cancer risk or cancer death. The association between genetically predicted eGFR and UACR and overall cancer incidence had an odds ratio of 0.88 ([95% CI, 0.40-1.97], P=0.8) and 0.90 ([95% CI, 0.78-1.04], P=0.2) respectively, using the inverse-variance weighted method. An adjusted generalized additive model for eGFR and cancer demonstrated evidence of nonlinearity. However, there was no evidence of a causal association between eGFR and cancer in a stratified MR. LIMITATIONS: To avoid overlapping samples a smaller GWAS for UACR was used, which reduced the strength of the instrument and may introduce population stratification. CONCLUSIONS: Our study did not show a causal association between kidney function, overall cancer incidence, and cancer-related death. PLAIN-LANGUAGE SUMMARY: Does reduced kidney function cause cancer? Patients with chronic kidney disease have been shown to have an increased risk of cancer and cancer-related death. However, it is not clear whether kidney disease is causally related to cancer or the association is due to other factors such as immune suppression and inflammation or a result of distortion of the analyses from unidentified variables (confounding). We used large, published genetic studies as well a database including 407,329 people in the United Kingdom in a series of Mendelian randomization analysis. Mendelian randomization uses the random assignment of genetic variants at birth to investigate causal relationships without confounding from measured and unmeasured confounders. We found that there is no evidence of a causal relationship between reduced kidney function and cancer.

Non-immunosuppressive treatment for IgA nephropathy.

BACKGROUND: IgA nephropathy (IgAN) is the most common primary glomerular disease, with approximately 20% to 40% of patients progressing to kidney failure within 25 years. Non-immunosuppressive treatment has become a mainstay in the management of IgAN by improving blood pressure (BP) management, decreasing proteinuria, and avoiding the risks of long-term immunosuppressive management. Due to the slowly progressive nature of the disease, clinical trials are often underpowered, and conflicting information about management with non-immunosuppressive treatment is common. This is an update of a Cochrane review, first published in 2011. OBJECTIVES: To assess the benefits and harms of non-immunosuppressive treatment for treating IgAN in adults and children. We aimed to examine all non-immunosuppressive therapies (e.g. anticoagulants, antihypertensives, dietary restriction and supplementation, tonsillectomy, and herbal medicines) in the management of IgAN. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to December 2023 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs of non-immunosuppressive agents in adults and children with biopsy-proven IgAN were included. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed search results, extracted data and assessed study quality. Results were expressed as mean differences (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes with 95% confidence intervals (CI) using random-effects meta-analysis. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: This review includes 80 studies (4856 participants), of which 24 new studies (2018 participants) were included in this review update. The risk of bias within the included studies was mostly high or unclear for many of the assessed methodological domains, with poor reporting of important key clinical trial methods in most studies. Antihypertensive therapies were the most examined non-immunosuppressive therapy (37 studies, 1799 participants). Compared to placebo or no treatment, renin-angiotensin system (RAS) inhibition probably decreases proteinuria (3 studies, 199 participants: MD - 0.71 g/24 h, 95% CI -1.04 to -0.39; moderate certainty evidence) but may result in little or no difference to kidney failure or doubling of serum creatinine (SCr), or complete remission of proteinuria (low certainty evidence). Death, remission of haematuria, relapse of proteinuria or > 50% increase in SCr were not reported. Compared to symptomatic treatment, RAS inhibition (3 studies, 168 participants) probably decreases proteinuria (MD -1.16 g/24 h, 95% CI -1.52 to -0.81) and SCr (MD -9.37 µmol/L, 95% CI -71.95 to -6.80) and probably increases creatinine clearance (2 studies, 127 participants: MD 23.26 mL/min, 95% CI 10.40 to 36.12) (all moderate certainty evidence); however, the risk of kidney failure is uncertain (1 study, 34 participants: RR 0.20, 95% CI 0.01 to 3.88; very low certainty evidence). Death, remission of proteinuria or haematuria, or relapse of proteinuria were not reported. The risk of adverse events may be no different with RAS inhibition compared to either placebo or symptomatic treatment (low certainty evidence). In low certainty evidence, tonsillectomy in people with IgAN in addition to standard care may increase remission of proteinuria compared to standard care alone (2 studies, 143 participants: RR 1.90, 95% CI 1.45 to 2.47) and remission of microscopic haematuria (2 studies, 143 participants: RR 1.93, 95% CI 1.47 to 2.53) and may decrease relapse of proteinuria (1 study, 73 participants: RR 0.70, 95% CI 0.57 to 0.85) and relapse of haematuria (1 study, 72 participants: RR 0.70, 95% CI 0.51 to 0.98). Death, kidney failure and a > 50% increase in SCr were not reported. These trials have only been conducted in Japanese people with IgAN, and the findings' generalisability is unclear. Anticoagulant therapy, fish oil, and traditional Chinese medicines exhibited small benefits to kidney function in patients with IgAN when compared to placebo or no treatment. However, compared to standard care, the kidney function benefits are no longer evident. Antimalarial therapy compared to placebo in one study reported an increase in a > 50% reduction of proteinuria (53 participants: RR 3.13 g/24 h, 95% CI 1.17 to 8.36; low certainty evidence). Although, there was uncertainty regarding adverse events from this study due to very few events. AUTHORS' CONCLUSIONS: Available RCTs focused on a diverse range of interventions. They were few, small, and of insufficient duration to determine potential long-term benefits on important kidney and cardiovascular outcomes and harms of treatment. Antihypertensive agents appear to be the most beneficial non-immunosuppressive intervention for IgAN. The antihypertensives examined were predominantly angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The benefits of RAS inhibition appear to outweigh the harms in patients with IgAN. The certainty of the evidence of RCTs demonstrating a benefit of tonsillectomy to patients with Japanese patients with IgAN was low. In addition, these findings are inconsistent across observational studies in people with IgAN of other ethnicities; hence, tonsillectomy is not widely recommended, given the potential harm of therapy. The RCT evidence is insufficiently robust to demonstrate efficacy for the other non-immunosuppressive treatments evaluated here.

HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis.

BACKGROUND: Cardiovascular disease is the most frequent cause of death in people with early stages of chronic kidney disease (CKD), and the absolute risk of cardiovascular events is similar to people with coronary artery disease. This is an update of a review first published in 2009 and updated in 2014, which included 50 studies (45,285 participants). OBJECTIVES: To evaluate the benefits and harms of statins compared with placebo, no treatment, standard care or another statin in adults with CKD not requiring dialysis. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 4 October 2023. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. An updated search will be undertaken every three months. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs that compared the effects of statins with placebo, no treatment, standard care, or other statins, on death, cardiovascular events, kidney function, toxicity, and lipid levels in adults with CKD (estimated glomerular filtration rate (eGFR) 90 to 15 mL/min/1.73 m2) were included. DATA COLLECTION AND ANALYSIS: Two or more authors independently extracted data and assessed the study risk of bias. Treatment effects were expressed as mean difference (MD) for continuous outcomes and risk ratios (RR) for dichotomous benefits and harms with 95% confidence intervals (CI). The risk of bias was assessed using the Cochrane risk of bias tool, and the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: We included 63 studies (50,725 randomised participants); of these, 53 studies (42,752 participants) compared statins with placebo or no treatment. The median duration of follow-up was 12 months (range 2 to 64.8 months), the median dosage of statin was equivalent to 20 mg/day of simvastatin, and participants had a median eGFR of 55 mL/min/1.73 m2. Ten studies (7973 participants) compared two different statin regimens. We were able to meta-analyse 43 studies (41,273 participants). Most studies had limited reporting and hence exhibited unclear risk of bias in most domains. Compared with placebo or standard of care, statins prevent major cardiovascular events (14 studies, 36,156 participants: RR 0.72, 95% CI 0.66 to 0.79; I2 = 39%; high certainty evidence), death (13 studies, 34,978 participants: RR 0.83, 95% CI 0.73 to 0.96; I² = 53%; high certainty evidence), cardiovascular death (8 studies, 19,112 participants: RR 0.77, 95% CI 0.69 to 0.87; I² = 0%; high certainty evidence) and myocardial infarction (10 studies, 9475 participants: RR 0.55, 95% CI 0.42 to 0.73; I² = 0%; moderate certainty evidence). There were too few events to determine if statins made a difference in hospitalisation due to heart failure. Statins probably make little or no difference to stroke (7 studies, 9115 participants: RR 0.64, 95% CI 0.37 to 1.08; I² = 39%; moderate certainty evidence) and kidney failure (3 studies, 6704 participants: RR 0.98, 95% CI 0.91 to 1.05; I² = 0%; moderate certainty evidence) in people with CKD not requiring dialysis. Potential harms from statins were limited by a lack of systematic reporting. Statins compared to placebo may have little or no effect on elevated liver enzymes (7 studies, 7991 participants: RR 0.76, 95% CI 0.39 to 1.50; I² = 0%; low certainty evidence), withdrawal due to adverse events (13 studies, 4219 participants: RR 1.16, 95% CI 0.84 to 1.60; I² = 37%; low certainty evidence), and cancer (2 studies, 5581 participants: RR 1.03, 95% CI 0.82 to 1.30; I² = 0%; low certainty evidence). However, few studies reported rhabdomyolysis or elevated creatinine kinase; hence, we are unable to determine the effect due to very low certainty evidence. Statins reduce the risk of death, major cardiovascular events, and myocardial infarction in people with CKD who did not have cardiovascular disease at baseline (primary prevention). There was insufficient data to determine the benefits and harms of the type of statin therapy. AUTHORS' CONCLUSIONS: Statins reduce death and major cardiovascular events by about 20% and probably make no difference to stroke or kidney failure in people with CKD not requiring dialysis. However, due to limited reporting, the effect of statins on elevated creatinine kinase or rhabdomyolysis is unclear. Statins have an important role in the primary prevention of cardiovascular events and death in people who have CKD and do not require dialysis. Editorial note: This is a living systematic review. We will search for new evidence every three months and update the review when we identify relevant new evidence. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Synbiotics, prebiotics and probiotics for people with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is a major public health problem affecting 13% of the global population. Prior research has indicated that CKD is associated with gut dysbiosis. Gut dysbiosis may lead to the development and/or progression of CKD, which in turn may in turn lead to gut dysbiosis as a result of uraemic toxins, intestinal wall oedema, metabolic acidosis, prolonged intestinal transit times, polypharmacy (frequent antibiotic exposures) and dietary restrictions used to treat CKD. Interventions such as synbiotics, prebiotics, and probiotics may improve the balance of the gut flora by altering intestinal pH, improving gut microbiota balance and enhancing gut barrier function (i.e. reducing gut permeability). OBJECTIVES: This review aimed to evaluate the benefits and harms of synbiotics, prebiotics, and probiotics for people with CKD. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 9 October 2023 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 Registry Platform (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) measuring and reporting the effects of synbiotics, prebiotics, or probiotics in any combination and any formulation given to people with CKD (CKD stages 1 to 5, including dialysis and kidney transplant). Two authors independently assessed the retrieved titles and abstracts and, where necessary, the full text to determine which satisfied the inclusion criteria. DATA COLLECTION AND ANALYSIS: Data extraction was independently carried out by two authors using a standard data extraction form. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) or standardised mean difference (SMD) and 95% CI for continuous outcomes. The methodological quality of the included studies was assessed using the Cochrane risk of bias tool. Data entry was carried out by one author and cross-checked by another. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Forty-five studies (2266 randomised participants) were included in this review. Study participants were adults (two studies in children) with CKD ranging from stages 1 to 5, with patients receiving and not receiving dialysis, of whom half also had diabetes and hypertension. No studies investigated the same synbiotic, prebiotic or probiotic of similar strains, doses, or frequencies. Most studies were judged to be low risk for selection bias, performance bias and reporting bias, unclear risk for detection bias and for control of confounding factors, and high risk for attrition and other biases. Compared to prebiotics, it is uncertain whether synbiotics improve estimated glomerular filtration rate (eGFR) at four weeks (1 study, 34 participants: MD -3.80 mL/min/1.73 m², 95% CI -17.98 to 10.38), indoxyl sulfate at four weeks (1 study, 42 participants: MD 128.30 ng/mL, 95% CI -242.77 to 499.37), change in gastrointestinal (GI) upset (borborymgi) at four weeks (1 study, 34 participants: RR 15.26, 95% CI 0.99 to 236.23), or change in GI upset (Gastrointestinal Symptom Rating Scale) at 12 months (1 study, 56 participants: MD 0.00, 95% CI -0.27 to 0.27), because the certainty of the evidence was very low. Compared to certain strains of prebiotics, it is uncertain whether a different strain of prebiotics improves eGFR at 12 weeks (1 study, 50 participants: MD 0.00 mL/min, 95% CI -1.73 to 1.73), indoxyl sulfate at six weeks (2 studies, 64 participants: MD -0.20 µg/mL, 95% CI -1.01 to 0.61; I² = 0%) or change in any GI upset, intolerance or microbiota composition, because the certainty of the evidence was very low. Compared to certain strains of probiotics, it is uncertain whether a different strain of probiotic improves eGFR at eight weeks (1 study, 30 participants: MD -0.64 mL/min, 95% CI -9.51 to 8.23; very low certainty evidence). Compared to placebo or no treatment, it is uncertain whether synbiotics improve eGFR at six or 12 weeks (2 studies, 98 participants: MD 1.42 mL/min, 95% CI 0.65 to 2.2) or change in any GI upset or intolerance at 12 weeks because the certainty of the evidence was very low. Compared to placebo or no treatment, it is uncertain whether prebiotics improves indoxyl sulfate at eight weeks (2 studies, 75 participants: SMD -0.14 mg/L, 95% CI -0.60 to 0.31; very low certainty evidence) or microbiota composition because the certainty of the evidence is very low. Compared to placebo or no treatment, it is uncertain whether probiotics improve eGFR at eight, 12 or 15 weeks (3 studies, 128 participants: MD 2.73 mL/min, 95% CI -2.28 to 7.75; I² = 78%), proteinuria at 12 or 24 weeks (1 study, 60 participants: MD -15.60 mg/dL, 95% CI -34.30 to 3.10), indoxyl sulfate at 12 or 24 weeks (2 studies, 83 participants: MD -4.42 mg/dL, 95% CI -9.83 to 1.35; I² = 0%), or any change in GI upset or intolerance because the certainty of the evidence was very low. Probiotics may have little or no effect on albuminuria at 12 or 24 weeks compared to placebo or no treatment (4 studies, 193 participants: MD 0.02 g/dL, 95% CI -0.08 to 0.13; I² = 0%; low certainty evidence). For all comparisons, adverse events were poorly reported and were minimal (flatulence, nausea, diarrhoea, abdominal pain) and non-serious, and withdrawals were not related to the study treatment. AUTHORS' CONCLUSIONS: We found very few studies that adequately test biotic supplementation as alternative treatments for improving kidney function, GI symptoms, dialysis outcomes, allograft function, patient-reported outcomes, CVD, cancer, reducing uraemic toxins, and adverse effects. We are not certain whether synbiotics, prebiotics, or probiotics are more or less effective compared to one another, antibiotics, or standard care for improving patient outcomes in people with CKD. Adverse events were uncommon and mild.

Scope and Consistency of Cancer Outcomes Reported in Randomized Trials in Kidney Transplant Recipients.

Introduction: Cancer is an important outcome in kidney transplantation, but the scope and consistency of how cancer is defined and reported in trials involving kidney transplant recipients has not been evaluated. This study aimed to assess the range and variability of cancer outcomes in trials involving kidney transplant recipients. Methods: The ClinicalTrials.gov database was searched from February 2000 to July 2021 to identify all randomized controlled trials (RCTs) in adult kidney transplant recipients, and which included cancer as a specified outcome. The definition of cancer, types of cancer (if any), timepoint(s) of measurement and method of aggregation were extracted for each cancer outcome. Results: Of the 819 trials in kidney transplantation, only 84 (10%) included 1 or more cancer outcomes. Of these, 72 of 84 (86%) trials included cancer as a secondary outcome and 12 of 84 (14%) considered cancer as a primary outcome. The most frequent description of cancer was "malignancy" (n = 44, 43%), without reference to diagnostic criteria, histology, grade, or stage. The 2 most common cancer types were posttransplant lymphoproliferative disorder (PTLD) (n = 20, 20%) and nonmelanoma skin cancer (n = 10, 10%). Several methods of aggregation were identified, including incidence or rate (n = 47, 46%), frequency or proportion (n = 30, 29%), and time to event (n = 5, 5%). Approximately half the cancer outcomes were measured at a single time point (n = 44, 52%). Conclusion: Cancer is an infrequently reported outcome and is inconsistently defined in trials of kidney transplant recipients. Consistent reporting of cancer outcomes using standardized definitions would provide important information on the impact of cancer in patients after kidney transplantation.

Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis.

BACKGROUND: Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anaemia in people with chronic kidney disease (CKD). However, their use has been associated with cardiovascular events. This is an update of a Cochrane review first published in 2014. OBJECTIVES: To compare the efficacy and safety of ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, and biosimilar ESAs against each other, placebo, or no treatment) to treat anaemia in adults with CKD. SEARCH METHODS: In this update, we searched the Cochrane Kidney and Transplant Register of Studies up to 29 April 2022 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) that included a comparison of an ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, a biosimilar epoetin or a biosimilar darbepoetin alfa) with another ESA, placebo or no treatment in adults with CKD were considered for inclusion. DATA COLLECTION AND ANALYSIS: Two independent authors screened the search results and extracted data. Data synthesis was performed using random-effects pairwise meta-analysis (expressed as odds ratios (OR) and their 95% confidence intervals (CI)) and network meta-analysis. We assessed for heterogeneity and inconsistency within meta-analyses using standard techniques and planned subgroup and meta-regression to explore sources of heterogeneity or inconsistency. We assessed certainty in treatment estimates for the primary outcomes (preventing blood transfusions and death (any cause)) using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Sixty-two new studies (9237 participants) were included in this update, so the review now includes 117 studies with 25,237 participants. Most studies were at high or unclear risk of bias in most methodological domains. Overall, results remain similar in this update compared to our previous review in 2014. For preventing blood transfusion, epoetin alfa (OR 0.28, 95% CI 0.13 to 0.61; low certainty evidence) and epoetin beta (OR 0.19, 95% CI 0.08 to 0.47; low certainty evidence) may be superior to placebo, and darbepoetin alfa was probably superior to placebo (OR 0.27, 95% CI 0.11 to 0.67; moderate certainty evidence). Methoxy polyethylene glycol-epoetin beta (OR 0.33, 95% CI 0.11 to 1.02; very low certainty evidence), a biosimilar epoetin (OR 0.34, 95% CI 0.11 to 1.03; very low certainty evidence) and a biosimilar darbepoetin alfa (OR 0.37, 95% CI 0.07 to 1.91; very low certainty evidence) had uncertain effects on preventing blood transfusion compared to placebo. The comparative effects of ESAs compared with another ESA on preventing blood transfusions were uncertain, in low to very low certainty evidence. Effects on death (any cause) were uncertain for epoetin alfa (OR 0.79, 95% CI 0.51 to 1.22; low certainty evidence), epoetin beta (OR 0.69, 95% CI 0.40 to 1.20; low certainty evidence), methoxy polyethylene glycol-epoetin beta (OR 1.07, 95% CI 0.67 to 1.71; very low certainty evidence), a biosimilar epoetin (OR 0.80, 95% CI 0.47 to 1.36; low certainty evidence) and a biosimilar darbepoetin alfa (OR 1.63, 95% CI 0.51 to 5.23; very low certainty evidence) compared to placebo. There was probably no difference between darbepoetin alfa and placebo on the odds of death (any cause) (OR 0.99, 95% CI 0.81 to 1.21; moderate certainty evidence). The comparative effects of ESAs compared with another ESA on death (any cause) were uncertain in low to very low certainty evidence. Epoetin beta probably increased the odds of hypertension when compared to placebo (OR 2.17, 95% CI 1.17 to 4.00; moderate certainty evidence). Compared to placebo, epoetin alfa (OR 2.10, 95% CI 1.22 to 3.59; very low certainty evidence), darbepoetin alfa (OR 1.88, 95% CI 1.12 to 3.14; low certainty evidence) and methoxy polyethylene glycol-epoetin beta (OR 1.98, 95% CI 1.05 to 3.74; low certainty evidence) may increase the odds of hypertension, but a biosimilar epoetin (OR 1.88, 95% CI 0.96 to 3.67; low certainty evidence) and biosimilar darbepoetin alfa (OR 1.98, 95% CI 0.84 to 4.66; low certainty evidence) had uncertain effects on hypertension. The comparative effects of all ESAs compared with another ESA, placebo or no treatment on cardiovascular death, myocardial infarction, stroke, vascular access thrombosis, kidney failure, and breathlessness were uncertain. Network analysis for fatigue was not possible due to sparse data.  AUTHORS' CONCLUSIONS: The comparative effects of different ESAs on blood transfusions, death (any cause and cardiovascular), major cardiovascular events, myocardial infarction, stroke, vascular access thrombosis, kidney failure, fatigue and breathlessness were uncertain.

ANTECEDENTES: Los fármacos estimulantes de la eritropoyesis (FEE) se suelen utilizar para tratar la anemia en personas con nefropatía crónica. Sin embargo, su uso se ha asociado a eventos cardiovasculares. Esta es una actualización de una revisión Cochrane publicada por primera vez en 2014. OBJETIVOS: Comparar la eficacia y la seguridad de los FEE (epoetina alfa, epoetina beta, darbepoetina alfa o metoxi­polietilenglicol epoetina beta y FEE biosimilares) entre sí, con placebo, o ningún tratamiento, para el tratamiento de la anemia en adultos con nefropatía crónica. MÉTODOS DE BÚSQUEDA: En esta actualización, a través del contacto con el documentalista, y con el uso de términos de búsqueda pertinentes para esta revisión, se realizaron búsquedas en el Registro de estudios del Grupo Cochrane de Riñón y trasplante (Cochrane Kidney and Transplant) hasta el 29 de abril de 2022. Los estudios en el registro se identifican mediante búsquedas en CENTRAL, MEDLINE y EMBASE, en resúmenes de congresos, en el portal de búsqueda de la Plataforma de registros internacionales de ensayos clínicos (ICTRP) y en ClinicalTrials.gov. CRITERIOS DE SELECCIÓN: Se consideraron para la inclusión los ensayos controlados aleatorizados (ECA) que incluían una comparación de un FEE (epoetina alfa, epoetina beta, darbepoetina alfa o metoxi­polietilenglicol epoetina beta, una epoetina biosimilar o una darbepoetina alfa biosimilar) con otro FEE, placebo o ningún tratamiento en adultos con NC. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores independientes examinaron los resultados de la búsqueda y extrajeron los datos. La síntesis de los datos se realizó mediante un metanálisis pareado de efectos aleatorios (expresada como odds ratio [OR] y sus intervalos de confianza [IC] del 95%) y un metanálisis en red. Se evaluó la heterogeneidad y la inconsistencia dentro de los metanálisis con técnicas estándares y se planeó crear subgrupos y una metarregresión para explorar las fuentes de heterogeneidad o la inconsistencia. Se evaluó la certeza en las estimaciones del tratamiento para los desenlaces principales (prevención de transfusiones de sangre y muerte [por cualquier causa]) mediante el método Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTADOS PRINCIPALES: En esta actualización se incluyeron 62 nuevos estudios (9237 participantes), por lo que la revisión incluye ahora 117 estudios con 25 237 participantes. La mayoría de los estudios tuvieron riesgo alto o incierto de sesgo en la mayoría de los dominios metodológicos. En general, los resultados siguen siendo similares en esta actualización en comparación con la revisión anterior de 2014. Para prevenir la transfusión de sangre, la epoetina alfa (OR 0,28; IC del 95%: 0,13 a 0,61; evidencia de certeza baja) y la epoetina beta (OR 0,19; IC del 95%: 0,08 a 0,47; evidencia de certeza baja) podrían ser superiores al placebo, y la darbepoetina alfa fue probablemente superior al placebo (OR 0,27; IC del 95%: 0,11 a 0,67; evidencia de certeza moderada). La metoxi­polietilenglicol epoetina beta (OR 0,33; IC del 95%: 0,11 a 1,02; evidencia de certeza muy baja), una epoetina biosimilar (OR 0,34; IC del 95%: 0,11 a 1,03; evidencia de certeza muy baja) y una darbepoetina alfa biosimilar (OR 0,37; IC del 95%: 0,07 a 1,91; evidencia de certeza muy baja) tuvieron efectos inciertos sobre la prevención de la transfusión de sangre en comparación con el placebo. Los efectos comparativos de los FEE comparados con otro FEE sobre la prevención de las transfusiones de sangre fueron inciertos, en evidencia de certeza baja a muy baja. Los efectos sobre la mortalidad (por cualquier causa) fueron inciertos para la epoetina alfa (OR 0,79; IC del 95%: 0,51 a 1,22; evidencia de certeza baja), la epoetina beta (OR 0,69; IC del 95%: 0,40 a 1,20; evidencia de certeza baja), la metoxi­polietilenglicol epoetina beta (OR 1,07; IC del 95%: 0,67 a 1,71; evidencia de certeza muy baja), una epoetina biosimilar (OR 0,80; IC del 95%: 0,47 a 1,36; evidencia de certeza baja) y una darbepoetina alfa biosimilar (OR 1,63; IC del 95%: 0,51 a 5,23; evidencia de certeza muy baja) en comparación con el placebo. Es probable que no hubiera diferencias entre la darbepoetina alfa y el placebo en las probabilidades de muerte (por cualquier causa) (OR 0,99; IC del 95%: 0,81 a 1,21; evidencia de certeza moderada). Los efectos comparativos de los FEE comparados con otro FEE sobre la mortalidad (por cualquier causa) fueron inciertos en evidencia de certeza baja a muy baja. Es probable que la epoetina beta aumentara el riesgo de hipertensión en comparación con el placebo (OR 2,17; IC del 95%: 1,17 a 4,00; evidencia de certeza moderada). En comparación con el placebo, la epoetina alfa (OR 2,10; IC del 95%: 1,22 a 3,59; evidencia de certeza muy baja), la epoetina beta (OR 1,88; IC del 95%: 1,12 a 3,14; evidencia de certeza baja) y la metoxi­polietilenglicol epoetina beta (OR 1,98; IC del 95%: 1,05 a 3,74; evidencia de certeza baja) podrían aumentar las probabilidades de hipertensión, pero una epoetina biosimilar (OR 1,88; IC del 95%: 0,96 a 3,67; evidencia de certeza baja) y una darbepoetina alfa biosimilar (OR 1,98; IC del 95%: 0,84 a 4,66; evidencia de certeza baja) tuvieron efectos inciertos sobre la hipertensión. Los efectos comparativos de todos los FEE comparados con otro FEE, placebo o ningún tratamiento sobre la mortalidad cardiovascular, el infarto de miocardio, el accidente cerebrovascular, la trombosis de acceso vascular, la insuficiencia renal y la disnea fueron inciertos. El análisis en red para el cansancio no fue posible debido a los pocos datos disponibles. CONCLUSIONES DE LOS AUTORES: Los efectos comparativos de los diferentes FEE sobre las transfusiones de sangre, la mortalidad (por cualquier causa y cardiovascular), los eventos cardiovasculares mayores, el infarto de miocardio, el accidente cerebrovascular, la trombosis de acceso vascular, la insuficiencia renal, el cansancio y la disnea fueron inciertos.

Variations in Risk of Cancer and Death From Cancer According to Kidney Allograft Function, Graft Loss, and Return to Dialysis.

BACKGROUND: Cancer incidence and mortality may change with varying kidney allograft function and after graft loss. We aimed to quantify cancer incidence and mortality during periods with a functioning graft and after graft loss. METHODS: We included all adult Australians aged 20 and above who commenced kidney replacement therapy between 1982 and 2014 using data from Australia and New Zealand Dialysis and Transplant Registry. We calculated the standardized incidence ratios and standardized mortality ratios (standardized against the Australian general population) for dialysis patients and transplant recipients during periods with a functioning graft and after graft loss. RESULTS: A total of 44 765 dialysis patients without transplants, 13 443 with first kidney transplants, 2951 after first graft loss, 1010 with second transplants, and 279 after second graft loss were followed for 274 660 patient-years. Cancer incidence and mortality (per 100 000 patient-years) were 1564 and 760 in dialysis patients, 1564 and 689 in recipients of first transplants, 1188 and 390 after first graft loss, 1525 and 693 after second transplants, and 1645 and 779 after second graft loss. Cancer standardized incidence ratios and standardized mortality ratios (95% confidence intervals) were 1.15 (1.11-1.20) and 1.29 (1.21-1.36) for dialysis patients, 2.03 (1.94-2.13) and 2.50 (2.33-2.69) for recipients following their first transplant, 1.55 (1.29-1.85) and 1.40 (1.00-1.90) after first graft loss, 2.18 (1.79-2.63) and 3.00 (2.23-3.96) for second transplants, 2.59 (1.56-4.04) and 3.82 (1.75-7.25) after second graft loss. CONCLUSIONS: In kidney transplant recipients, cancer incidence and mortality are highest during periods with a functioning graft and remained higher than in the general population even after graft loss.

Synbiotics, prebiotics and probiotics for solid organ transplant recipients.

BACKGROUND: Solid organ transplantation has seen improvements in both surgical techniques and immunosuppression, achieving prolonged survival. Essential to graft acceptance and post-transplant recovery, immunosuppressive medications are often accompanied by a high prevalence of gastrointestinal (GI) symptoms and side effects. Apart from GI side effects, long-term exposure to immunosuppressive medications has seen an increase in drug-related morbidities such as diabetes mellitus, hyperlipidaemia, hypertension, and malignancy. Non-adherence to immunosuppression can lead to an increased risk of graft failure. Recent research has indicated that any microbial imbalances (otherwise known as gut dysbiosis or leaky gut) may be associated with cardiometabolic diseases in the long term. Current evidence suggests a link between the gut microbiome and the production of putative uraemic toxins, increased gut permeability, and transmural movement of bacteria and endotoxins and inflammation. Early observational and intervention studies have been investigating food-intake patterns, various synbiotic interventions (antibiotics, prebiotics, or probiotics), and faecal transplants to measure their effects on microbiota in treating cardiometabolic diseases. It is believed high doses of synbiotics, prebiotics and probiotics are able to modify and improve dysbiosis of gut micro-organisms by altering the population of the micro-organisms. With the right balance in the gut flora, a primary benefit is believed to be the suppression of pathogens through immunostimulation and gut barrier enhancement (less permeability of the gut). OBJECTIVES: To assess the benefits and harms of synbiotics, prebiotics, and probiotics for recipients of solid organ transplantation. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register up to 9 March 2022 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 measuring and reporting the effects of synbiotics, prebiotics, or probiotics, in any combination and any formulation given to solid organ transplant recipients (any age and setting). Two authors independently assessed the retrieved titles and abstracts and, where necessary, the full text to determine which satisfied the inclusion criteria. DATA COLLECTION AND ANALYSIS: Data extraction was independently carried out by two authors using a standard data extraction form. The methodological quality of included studies was assessed using the Cochrane risk of bias tool. Data entry was carried out by one author and cross-checked by another. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Five studies (250 participants) were included in this review. Study participants were adults with a kidney (one study) or liver (four studies) transplant. One study compared a synbiotic to placebo, two studies compared a probiotic to placebo, and two studies compared a synbiotic to a prebiotic. Overall, the quality of the evidence is poor. Most studies were judged to have unclear (or high) risk of bias across most domains. Of the available evidence, meta-analyses undertaken were of limited data from small studies. Across all comparisons, GRADE evaluations for all outcomes were judged to be very low certainty evidence. Very low certainty evidence implies that we are very uncertain about results (not estimable due to lack of data or poor quality). Synbiotics had uncertain effects on the change in microbiota composition (total plasma p-cresol), faecal characteristics, adverse events, kidney function or albumin concentration (1 study, 34 participants) compared to placebo. Probiotics had uncertain effects on GI side effects, infection rates immediately post-transplant, liver function, blood pressure, change in fatty liver, and lipids (1 study, 30 participants) compared to placebo. Synbiotics had uncertain effects on graft health (acute liver rejection) (2 studies, 129 participants: RR 0.73, 95% CI 0.43 to 1.25; 2 studies, 129 participants; I² = 0%), the use of immunosuppression, infection (2 studies, 129 participants: RR 0.18, 95% CI 0.03 to 1.17; I² = 66%), GI function (time to first bowel movement), adverse events (2 studies, 129 participants: RR 0.79, 95% CI 0.40 to 1.59; I² = 20%), serious adverse events (2 studies, 129 participants: RR 1.49, 95% CI 0.42 to 5.36; I² = 81%), death (2 studies, 129 participants), and organ function measures (2 studies; 129 participants) compared to prebiotics. AUTHORS' CONCLUSIONS: This review highlights the severe lack of high-quality RCTs testing the efficacy of synbiotics, prebiotics or probiotics in solid organ transplant recipients. We have identified significant gaps in the evidence. Despite GI symptoms and postoperative infection being the most common reasons for high antibiotic use in this patient population, along with increased morbidity and the growing antimicrobial resistance, we found very few studies that adequately tested these as alternative treatments. There is currently no evidence to support or refute the use of synbiotics, prebiotics, or probiotics in solid organ transplant recipients, and findings should be viewed with caution. We have identified an area of significant uncertainty about the efficacy of synbiotics, prebiotics, or probiotics in solid organ transplant recipients. Future research in this field requires adequately powered RCTs comparing synbiotics, prebiotics, and probiotics separately and with placebo measuring a standard set of core transplant outcomes. Six studies are currently ongoing (822 proposed participants); therefore, it is possible that findings may change with their inclusion in future updates.

Hypoxia-inducible factor stabilisers for the anaemia of chronic kidney disease.

BACKGROUND: Anaemia occurs in chronic kidney disease (CKD) and is more prevalent with lower levels of kidney function. Anaemia in CKD is associated with death related to cardiovascular (CV) disease and infection. Established treatments include erythropoiesis-stimulating agents (ESAs), iron supplementation and blood transfusions. Oral hypoxia-inducible factors (HIF) stabilisers are now available to manage anaemia in people with CKD. OBJECTIVES: We aimed to assess the benefits and potential harms of HIF stabilisers for the management of anaemia in people with CKD. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 22 November 2021 through contact with the Information Specialist using search terms relevant to our review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: Randomised and quasi-randomised studies evaluating hypoxia-inducible factors stabilisers compared to placebo, standard care, ESAs or iron supplementation in people with CKD were included. DATA COLLECTION AND ANALYSIS: Five authors independently extracted data and assessed the risk of bias. Treatment estimates were summarised using random effects pair-wise meta-analysis and expressed as a relative risk (RR) or mean difference (MD), with a corresponding 95% confidence interval (CI). Evidence certainty was assessed using GRADE. MAIN RESULTS: We included 51 studies randomising 30,994 adults. These studies compared HIF stabilisers to either placebo or an ESA. Compared to placebo, HIF stabiliser therapy had uncertain effects on CV death (10 studies, 1114 participants): RR 3.68, 95% CI 0.19 to 70.21; very low certainty evidence), and nonfatal myocardial infarction (MI) (3 studies, 822 participants): RR 1.29, 95% CI 0.31 to 5.36; I² = 0%; very low certainty evidence), probably decreases the proportion of patients requiring blood transfusion (8 studies, 4329 participants): RR 0.51, 95% CI 0.44 to 0.60; I² = 0%; moderate certainty evidence), and increases the proportion of patients reaching the target haemoglobin (Hb) (10 studies, 5102 participants): RR 8.36, 95% CI 6.42 to 10.89; I² = 37%; moderate certainty evidence). Compared to ESAs, HIF stabiliser therapy may make little or no difference to CV death (17 studies, 10,340 participants): RR 1.05, 95% CI 0.88 to 1.26; I² = 0%; low certainty evidence), nonfatal MI (7 studies, 7765 participants): RR 0.91, 95% CI 0.76 to 1.10; I² = 0%; low certainty evidence), and nonfatal stroke (5 studies, 7285 participants): RR 1.06, 95% CI 0.71 to 1.56; I² = 8%; low certainty evidence), and had uncertain effects on fatigue (2 studies, 3471 participants): RR 0.80, 95% CI 0.56 to 1.16; I² = 0%; very low certainty evidence). HIF stabiliser therapy probably decreased the proportion of patients requiring blood transfusion (11 studies, 10,786 participants): RR 0.87, 95% CI 0.76 to 1.00; I² = 25%; moderate certainty evidence), but may make little or no difference on the proportion of patients reaching the target Hb (14 studies, 4601 participants): RR 1.00, 95% CI 0.93 to 1.07; I² = 70%; low certainty evidence), compared to ESA. The effect of HIF stabilisers on hospitalisation for heart failure, peripheral arterial events, loss of unassisted dialysis vascular access patency, access intervention, cancer, infection, pulmonary hypertension and diabetic nephropathy was uncertain. None of the included studies reported life participation. Adverse events were rarely and inconsistently reported. AUTHORS' CONCLUSIONS: HIF stabiliser management of anaemia had uncertain effects on CV death, fatigue, death (any cause), CV outcomes, and kidney failure compared to placebo or ESAs. Compared to placebo or ESAs, HIF stabiliser management of anaemia probably decreased the proportion of patients requiring blood transfusions, and probably increased the proportion of patients reaching the target Hb when compared to placebo.

Economic Evaluation of Screening for Polyomavirus Infection in Kidney Transplant Recipients: A Cost-Utility Analysis.

Screening for polyomavirus infection after kidney transplantation is recommended by clinical practice guidelines, but cost-effectiveness of this strategy is uncertain. The aim of this study was to estimate the incremental costs and benefits of routine screening for polyomavirus infection compared with no screening in kidney transplant recipients. Methods: Probabilistic Markov models were constructed to compare the health and economic benefits of routine screening for polyomavirus infection using real-time polymerase chain reaction assay. A series of 1-way and probabilistic sensitivity analyses were conducted to define the most influential variables in the model. Results: Monthly screening for 6 mo followed by 3 monthly screenings until 12 mo after transplant was dominant (lower costs and improved outcomes). Compared with no screening, the incremental benefits of screening were 0.294 life-years saved and 0.232 quality-adjusted life-years saved. Total savings from screening were $6986 Australian dollars ($5057 US dollars). The cost-effectiveness ratios were most sensitive to the costs of transplantation and dialysis, age of transplantation, prevalence of viremia, and probability of death in patients with a history of polyomavirus-associated nephropathy. Probabilistic sensitivity analysis indicated that screening (compared with no screening) was the dominant strategy across all plausible ranges of transition probabilities. Conclusions: Screening for polyomavirus infections 1 year following transplantation appears to save money, improves survival, and improves quality of life in kidney transplant recipients.

Patient preferences for cancer screening in chronic kidney disease: a best-worst scaling survey.

BACKGROUND: Despite an increased cancer risk for patients with chronic kidney disease (CKD), uptake of cancer screening varies due to competing priorities and complex health-related issues. This study aimed to elicit the preferences and important attributes of cancer screening in patients with CKD. METHODS: An on-line best-worst scaling survey was used to ascertain the relative importance of 22 screening attributes among CKD patients using an incomplete block design. Preference scores (0-1) were calculated by multinomial logistic regression. Preference heterogeneity was evaluated. RESULTS: The survey was completed by 83 patients: 26 not requiring kidney replacement therapy, 20 receiving dialysis and 37 transplant recipients (mean age 59 years, 53% men, 75% prior to cancer screening). The five most important attributes were early detection {preference score 1.0 [95% confidence interval (CI) 0.90-1.10]}, decreased risk of cancer death [0.85 (0.75-0.94)], false negatives [0.71 (0.61-0.80)], reduction in immunosuppression if detected [0.68 (0.59-0.78)] and non-invasive interventions after positive results [0.68 (0.59-0.78)]. Preference heterogeneity reflected the stage of CKD. Immunosuppression reduction [mean difference 0.11 (95% CI 0.02-0.19)] and views of family/friends [0.10 (reference attribute)] were important for transplant recipients. Screening frequency [-0.18 (95% CI -0.26 to -0.10)] and overdiagnosis of harmless cancers [-0.14 (95% CI -0.22 to -0.10)] were important for dialysis patients. CONCLUSION: Early detection, risk of cancer-related death, false negatives, immunosuppression reduction and non-invasive interventions following detection are important cancer screening considerations among CKD patients. Patient preferences are key to shared decision-making and individualized cancer screening.

Healthy Lifestyle and Mortality Among Adults Receiving Hemodialysis: The DIET-HD Study.

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 years) in a multinational private dialysis network and with complete lifestyle data. EXPOSURE: Based on the American Heart Association's recommendations for cardiovascular prevention, a modified healthy lifestyle score was the sum of 4 components addressing use of smoking tobacco, physical activity, diet, and control of systolic blood pressure. OUTCOME: Cardiovascular and all-cause mortality. ANALYTICAL APPROACH: Adjusted proportional hazards 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 adjusted hazard ratio (AHR) with 95% CI. 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 with patients who had a low lifestyle score, the AHRs for all-cause mortality among those with medium and high lifestyle scores were 0.75 (95% CI, 0.65-0.85) and 0.64 (95% CI, 0.54-0.76), respectively. Compared with patients who had a low lifestyle score, the AHRs for cardiovascular mortality among those with medium and high lifestyle scores were 0.73 (95% CI, 0.59-0.91) and 0.65 (95% CI, 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.

Patients' Perspectives on Shared Decision-Making About Medications in Psoriatic Arthritis: An Interview Study.

OBJECTIVE: Decision-making regarding medications to manage psoriatic arthritis (PsA) is complex because of multiple disease manifestations and comorbidities. Fear of side effects from systemic medications and misalignment in priorities between patients with PsA and rheumatologists makes shared decision-making challenging. We aimed to describe the perspectives of patients with PsA on shared decision-making regarding medication taking. METHODS: Face-to-face semistructured interviews were conducted with 25 adult patients with PsA in Australia. Transcripts were thematically analyzed. RESULTS: Five themes were identified: lacking agency in decision-making (denied choice, knowledge asymmetry, desperation and necessity, restricted by unfair eligibility criteria, automated approach); overwhelmed by potential harms (daunted by aggressive therapy, anticipating lifestyle disruption from side effects, jeopardizing fertility and pregnancy, avoiding relapse); gaining confidence (discernible benefit in function and mental health, sharpening knowledge over time, expertise of family and peers, empowered by information); opting for alternatives (pursuing normality, suspicion of over-medicalization, seeking comprehensive solutions); and developing trust and fortifying collaboration (assurance through a personable approach, seeking consistency, supported in decisional power, resolution through respectful negotiation). CONCLUSION: Patients with PsA lack agency in making treatment decisions and are overwhelmed by the potential harms of systemic medication. Improving knowledge and trust with medical teams in a supportive and collaborative environment, and strategies for managing risks and side effects may improve decision-making about pharmacologic management of PsA.

Factors Associated With Advanced Colorectal Neoplasia in Patients With CKD.

RATIONALE & OBJECTIVE: The risk of developing colorectal cancer in patients with chronic kidney disease (CKD) is twice that of the general population, but the factors associated with colorectal cancer are poorly understood. The aim of this study was to identify factors associated with advanced colorectal neoplasia in patients with CKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Patients with CKD stages 3-5, including those treated with maintenance dialysis or transplantation across 11 sites in Australia, New Zealand, Canada, and Spain, were screened for colorectal neoplasia using a fecal immunochemical test (FIT) as part of the Detecting Bowel Cancer in CKD (DETECT) Study. EXPOSURE: Baseline characteristics for patients at the time of study enrollment were ascertained, including duration of CKD, comorbidities, and medications. OUTCOME: Advanced colorectal neoplasia was identified through a 2-step verification process with colonoscopy following positive FIT and 2-year clinical follow-up for all patients. ANALYTICAL APPROACH: Potential factors associated with advanced colorectal neoplasia were explored using multivariable logistic regression. Sensitivity analyses were performed using grouped LASSO (least absolute shrinkage and selection operator) logistic regression. RESULTS: Among 1,706 patients who received FIT-based screening-791 with CKD stages 3-5 not receiving kidney replacement therapy (KRT), 418 receiving dialysis, and 497 patients with a functioning kidney transplant-117 patients (6.9%) were detected to have advanced colorectal neoplasia (54 with CKD stages 3-5 without KRT, 34 receiving dialysis, and 29 transplant recipients), including 9 colorectal cancers. The factors found to be associated with advanced colorectal neoplasia included older age (OR per year older, 1.05 [95% CI, 1.03-1.07], P<0.001), male sex (OR, 2.27 [95% CI, 1.45-3.54], P<0.001), azathioprine use (OR, 2.99 [95% CI, 1.40-6.37], P=0.005), and erythropoiesis-stimulating agent use (OR, 1.92 [95% CI, 1.22-3.03], P=0.005). Grouped LASSO logistic regression revealed similar associations between these factors and advanced colorectal neoplasia. LIMITATIONS: Unmeasured confounding factors. CONCLUSIONS: Older age, male sex, erythropoiesis-stimulating agents, and azathioprine were found to be significantly associated with advanced colorectal neoplasia in patients with CKD.

Chronic disease prevention programs offered by Aboriginal Community Controlled Health Services in New South Wales, Australia.

OBJECTIVES: To identify and describe chronic disease prevention programs offered by Aboriginal Community Controlled Health Services (ACCHSs) in New South Wales (NSW), Australia. METHODS: ACCHSs were identified through the Aboriginal Health and Medical Research Council of NSW website. Chronic disease programs were identified from the Facebook page and website of each ACCHS. Characteristics, including regions, target population, condition, health behaviour, modality and program frequency were extracted and summarised. RESULTS: We identified 128 chronic disease programs across 32 ACCHSs. Of these, 87 (68%) programs were broad in their scope, 20 (16%) targeted youth, three (2%) targeted Elders, 16 (12%) were for females only and five (4%) were for males only. Interventions included physical activity (77, 60%), diet and nutrition (74, 58%), smoking (70, 55%), and the Aboriginal and Torres Strait Islander Health Check (44, 34%), with 93 programs (73%) of ongoing duration. CONCLUSIONS: Chronic disease prevention programs address chronic conditions by promoting physical activity, diet and nutrition, smoking cessation and health screening. Most target the general Aboriginal community, a few target specific groups based on gender and age, and more than one-quarter are time-limited. Implications for public health: Chronic disease programs that are co-produced with specific groups, based on age and gender, may be needed.

Executive summary of the KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease.

The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease for patients not receiving dialysis represents an update to the KDIGO 2012 guideline on this topic. Development of this guideline update followed a rigorous process of evidence review and appraisal. Guideline recommendations are based on systematic reviews of relevant studies and appraisal of the quality of the evidence. The strength of recommendations is based on the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) approach. The scope includes topics covered in the original guideline, such as optimal blood pressure targets, lifestyle interventions, antihypertensive medications, and specific management in kidney transplant recipients and children. Some aspects of general and cardiovascular health, such as lipid and smoking management, are excluded. This guideline also introduces a chapter dedicated to proper blood pressure measurement since all large randomized trials targeting blood pressure with pivotal outcomes used standardized preparation and measurement protocols adhered to by patients and clinicians. Based on previous and new evidence, in particular the Systolic Blood Pressure Intervention Trial (SPRINT) results, we propose a systolic blood pressure target of less than 120 mm Hg using standardized office reading for most people with chronic kidney disease (CKD) not receiving dialysis, the exception being children and kidney transplant recipients. The goal of this guideline is to provide clinicians and patients a useful resource with actionable recommendations supplemented with practice points. The burden of the recommendations on patients and resources, public policy implications, and limitations of the evidence are taken into consideration. Lastly, knowledge gaps and recommendations for future research are provided.

A Text Messaging Intervention for Dietary Behaviors for People Receiving Maintenance Hemodialysis: A Feasibility Study of KIDNEYTEXT.

RATIONALE & OBJECTIVE: An important component of hemodialysis management involves delivery of complex dietary recommendations. The aim of this study was to determine the feasibility of a mobile phone text-message intervention to improve dietary behavior in people undergoing hemodialysis. STUDY DESIGN: Six-month randomized feasibility study. SETTING & PARTICIPANTS: Patients receiving maintenance hemodialysis across 2 health districts in Sydney, Australia. INTERVENTIONS: Participants randomized to the intervention received 3 text messages per week in addition to standard dietary care for 6 months. The usual care group received standard dietary care. OUTCOMES: The primary outcomes were feasibility measured using recruitment and retention rates, acceptability of the intervention, and adherence to dietary recommendations. Secondary exploratory outcomes included information on certain clinical parameters related to dietary management of patients receiving maintenance hemodialysis. RESULTS: 130 people were recruited; 48% of eligible patients (130 of 272) consented to participate, and 88% (115 of 130) completed the study. Semistructured interviews evaluating acceptability identified 5 themes: clear and comprehensive, engaging with consistent and relevant content, maintaining attention with timely reminders, sustaining interest through ongoing care, and generic messages inadequate to prompt dietary change. There was no difference in adherence to dietary recommendations across treatment groups (odds ratio, 1.21 [95% CI, 0.55-2.72]; P = 0.6). Secondary exploratory analyses suggested reductions in dietary intake of single nutrients (potassium, phosphorus, sodium, protein), interdialytic weight gain, and phosphate binder use among intervention participants compared with participants assigned to standard care. LIMITATIONS: Our feasibility study was of short duration. Adherence was based on self-reported data. Generalizability to populations receiving maintenance hemodialysis outside of an urban, Australian setting is unknown. CONCLUSIONS: A simple mobile phone text-messaging intervention was feasible and acceptable to patients. Further investigation of the impact on patient-reported and clinical outcomes is warranted. FUNDING: Funding for the study was provided by a Sydney Medical School Foundation Grant and the Centre for Transplant and Renal Research at Westmead Hospital. TRIAL REGISTRATION: Registered at Australian New Zealand Clinical Trials Registry with study number ACTRN12617001084370.