International consensus on post-transplantation diabetes mellitus.

Post-transplantation diabetes mellitus (PTDM) remains a leading complication after solid organ transplantation. Previous international PTDM consensus meetings in 2003 and 2013 provided standardized frameworks to reduce heterogeneity in diagnosis, risk stratification and management. However, the last decade has seen significant advancements in our PTDM knowledge complemented by rapidly changing treatment algorithms for management of diabetes in the general population. In view of these developments, and to ensure reduced variation in clinical practice, a 3rd international PTDM Consensus Meeting was planned and held from 6-8 May 2022 in Vienna, Austria involving global delegates with PTDM expertise to update the previous reports. This update includes opinion statements concerning optimal diagnostic tools, recognition of prediabetes (impaired fasting glucose and/or impaired glucose tolerance), new mechanistic insights, immunosuppression modification, evidence-based strategies to prevent PTDM, treatment hierarchy for incorporating novel glucose-lowering agents and suggestions for the future direction of PTDM research to address unmet needs. Due to the paucity of good quality evidence, consensus meeting participants agreed that making GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) recommendations would be flawed. Although kidney-allograft centric, we suggest that these opinion statements can be appraised by the transplantation community for implementation across different solid organ transplant cohorts. Acknowledging the paucity of published literature, this report reflects consensus expert opinion. Attaining evidence is desirable to ensure establishment of optimized care for any solid organ transplant recipient at risk of, or who develops, PTDM as we strive to improve long-term outcomes.

Sex differences in the survival benefit of kidney transplantation: a retrospective cohort study using target trial emulation.

BACKGROUND: Kidney transplantation is the preferred treatment for eligible patients with kidney failure who need renal replacement therapy. However, it remains unclear whether the anticipated survival benefit from kidney transplantation is different for women and men. METHODS: We included all dialysis patients recorded in the Austrian Dialysis and Transplant Registry who were waitlisted for their first kidney transplant between 2000 and 2018. In order to estimate the causal effect of kidney transplantation on 10-year restricted mean survival time, we mimicked a series of controlled clinical trials and applied inverse probability of treatment and censoring weighted sequential Cox models. RESULTS: This study included 4408 patients (33% female) with a mean age of 52 years. Glomerulonephritis was the most common primary renal disease both in women (27%) and men (28%). Kidney transplantation led to a gain of 2.22 years (95% CI 1.88 to 2.49) compared with dialysis over a 10-year follow-up. The effect was smaller in women (1.95 years, 95% CI 1.38 to 2.41) than in men (2.35 years, 95% CI 1.92 to 2.70) due to a better survival on dialysis. Across ages the survival benefit of transplantation over a follow-up of 10 years was smaller in younger women and men and increased with age, showing a peak for both women and men aged about 60 years. CONCLUSIONS: There were few differences in survival benefit by transplantation between females and males. Females had better survival than males on the waitlist receiving dialysis and similar survival to males after transplantation.

Effect of the phosphate binder sucroferric oxyhydroxide in dialysis patients on endogenous calciprotein particles, inflammation, and vascular cells.

BACKGROUND: Calciprotein particles (CPPs), colloidal mineral-protein nanoparticles, have emerged as potential mediators of phosphate toxicity in dialysis patients, with putative links to vascular calcification, endothelial dysfunction and inflammation. We hypothesized that phosphate binder therapy with sucroferric oxyhydroxide (SO) would reduce endogenous CPP levels and attenuate pro-calcific and pro-inflammatory effects of patient serum towards human vascular cells in vitro. METHODS: This secondary analysis of a randomised controlled crossover study compared the effect of 2-week phosphate binder washout with high-dose (2000 mg/day) and low-dose (250 mg/day) SO therapy in 28 haemodialysis patients on serum CPP levels, inflammatory cytokine/chemokine arrays and human aortic smooth muscle cell (HASMC) and coronary artery endothelial cell (HCAEC) bioassays. RESULTS: In our cohort (75% male, 62 ± 12 years) high-dose SO reduced primary (amorphous) and secondary (crystalline) CPP levels {-62% [95% confidence interval (CI) -76 to -44], P < .0001 and -38% [-62 to -0.14], P < .001, respectively} compared with washout. Nine of 14 plasma cytokines/chemokines significantly decreased with high-dose SO, with consistent reductions in interleukin-6 (IL-6) and IL-8. Exposure of HASMC and HCAEC cultures to serum of SO-treated patients reduced calcification and markers of activation (IL-6, IL-8 and vascular cell adhesion protein 1) compared with washout. Serum-induced HASMC calcification and HCAEC activation was ameliorated by removal of the CPP-containing fraction from patient sera. Effects of CPP removal were confirmed in an independent cohort of chronic kidney disease patients. CONCLUSIONS: High-dose SO reduced endogenous CPP formation in dialysis patients and yielded serum with attenuated pro-calcific and inflammatory effects in vitro.

Humoral response after a third and fourth dose of mRNA-based SARS-CoV-2 vaccine in previously seronegative kidney transplant recipients.

Growing evidence shows diminished response to mRNA-based SARS-CoV­2 vaccination in kidney transplant recipients. We aimed to investigate the seroconversion rate after a 3rd and 4th dose of mRNA vaccination in kidney transplant recipients without prior antibody response to two or three vaccination doses.This retrospective study included 324 prevalent kidney transplant recipients of a single tertiary transplantation center of which 157 remained seronegative, defined as anti-spike-RBD-IgG antibody titer < 7.1 BAU/ml, after two doses of mRNA-based SARS-CoV­2 vaccination. Maintenance immunosuppression was not changed. The median patient age was 60.6 years (IQR 51.4-68.1 years), 66.9% were male. Positivity for anti-spike-RBD-IgG (≥ 7.1 BAU/ml) was measured 4-5 weeks after administration of a 3rd and 4th vaccine dose.Seroconversion rates were 63.9% after a 3rd dose and 29.3% after a 4th dose of vaccine. Cumulative prevalence of seropositivity was 51.5% after 2 doses, 80.5% after 3 doses and 84.2% after 4 doses.In conclusion, seroconversion can be achieved in the majority of the kidney transplant recipients by administrating three or four doses of mRNA vaccine without changing maintenance immunosuppression.

Survival Benefit of First Single-Organ Deceased Donor Kidney Transplantation Compared With Long-term Dialysis Across Ages in Transplant-Eligible Patients With Kidney Failure.

Importance: Kidney transplant is considered beneficial in terms of survival compared with continued dialysis for patients with kidney failure. However, randomized clinical trials are infeasible, and available evidence from cohort studies is at high risk of bias. Objective: To compare restricted mean survival times (RMSTs) between patients who underwent transplant and patients continuing dialysis across transplant candidate ages and depending on waiting time, applying target trial emulation methods. Design, Setting, and Participants: In this retrospective cohort study, patients aged 18 years or older appearing on the wait list for their first single-organ deceased donor kidney transplant between January 1, 2000, and December 31, 2018, in Austria were evaluated. Available data were obtained from the Austrian Dialysis and Transplant Registry and Eurotransplant and included repeated updates on wait-listing status and relevant covariates. Data were analyzed between August 1, 2019, and December 23, 2021. Exposures: A target trial was emulated in which patients were randomized to either receive the transplant immediately (treatment group) or to continue dialysis and never receive a transplant (control group) at each time an organ became available. Main Outcomes and Measures: The primary outcome was time from transplant allocation to death. Effect sizes in terms of RMSTs were obtained using a sequential Cox approach. Results: Among the 4445 included patients (2974 men [66.9%]; mean [SD] age, 52.2 [13.2] years), transplant was associated with increased survival time across all considered ages compared with continuing dialysis and remaining on the wait list within a 10-year follow-up. The estimated RMST differences were 0.57 years (95% CI, -0.14 to 1.84 years) at age 20 years, 3.01 years (95% CI, 2.50 to 3.54 years) at age 60 years, and 2.48 years (95% CI, 1.88 to 3.04 years) at age 70 years. The survival benefit for patients who underwent transplant across ages was independent of waiting time. Conclusions and Relevance: The findings of this study suggest that kidney transplant prolongs the survival time of persons with kidney failure across all candidate ages and waiting times.

Modeling pulse wave velocity trajectories-challenges, opportunities, and pitfalls.

In this commentary, we discuss the analysis of trajectories of pulse wave velocity in a longitudinal cohort study of children with chronic kidney disease (the Cardiovascular Comorbidity in Children with Chronic Kidney Disease - Transplantation study). We revisit the analysis made by the study authors and unravel some additional limitations. We also reevaluate the implicit assumptions that were made in the chosen analysis and suggest extensions of the basic linear mixed model to obtain more differentiated answers to research questions in nephrology.

European Renal Best Practice endorsement of guidelines for diagnosis and therapy of thrombotic thrombocytopaenic purpura published by the International Society on Thrombosis and Haemostasis.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease that is caused by severe ADAMTS-13 deficiency. Immune-mediated TTP develops due to autoantibodies against ADAMTS-13, whereas congenital TTP is caused by mutations in the ADAMTS13 gene. Diagnostic possibilities and treatment options in TTP have emerged in recent years, which prompted the International Society on Thrombosis and Haemostasis (ISTH) to publish clinical practice guidelines for the diagnosis and treatment of TTP in 2020. In this article, the European Renal Best Practice Working Group endorsed the ISTH guidelines and emphasizes a number of considerations, including the importance of rapid ADAMTS-13 activity testing, the use of rituximab and anti-von Willebrand factor therapies such as caplacizumab, that enhance the clinical applicability of the guidelines in Europe.

Prediction models for living organ transplantation are poorly developed, reported, and validated: a systematic review.

OBJECTIVE: To identify and critically appraise risk prediction models for living donor solid organ transplant counselling. STUDY DESIGN AND SETTING: We systematically reviewed articles describing the development or validation of prognostic risk prediction models about living donor solid organ (kidney and liver) transplantation indexed in Medline until April 4, 2021. Models were eligible if intended to predict, at transplant counselling, any outcome occurring after transplantation or donation in recipients or donors. Duplicate study selection, data extraction, assessment for risk of bias and quality of reporting was done using the CHARMS checklist, PRISMA recommendations, PROBAST tool, and TRIPOD Statement. RESULTS: We screened 4691 titles and included 49 studies describing 68 models (35 kidney, 33 liver transplantation). We identified 49 new risk prediction models and 19 external validations of existing models. Most models predicted recipients outcomes (n = 38, 75%), e.g., kidney graft loss (29%), or mortality of liver transplant recipients (55%). Many new models (n = 46, 94%) and external validations (n = 17, 89%) had a high risk of bias because of methodological weaknesses. The quality of reporting was generally poor. CONCLUSION: We advise against applying poorly developed, reported, or validated prediction models. Future studies could validate or update the few identified methodologically appropriate models.

The effect of phosphate binder therapy with sucroferric oxyhydroxide on calcification propensity in chronic haemodialysis patients: a randomized, controlled, crossover trial.

BACKGROUND: Calcification propensity is associated with the risk for cardiovascular events and death in end-stage renal disease patients. Here we investigated the effect of lowering serum phosphate with oral phosphate binder therapy on calcification propensity. METHODS: We performed an open-label, randomized, controlled, crossover study in chronic haemodialysis patients with hyperphosphataemia. Patients (n = 39) were randomized in a 1:1 ratio to either low-dose (250 mg/day) sucroferric oxyhydroxide (SO) followed by high-dose (2000 mg/day) SO or vice versa, with washout phases before and after SO treatment. The primary endpoint was changed in calcification propensity as measured by calciprotein particle formation time (T50 test) between washout and high-dose SO treatment in patients with ≥85% adherence to the prescribed SO dose (per-protocol analysis). RESULTS: In the primary per-protocol analysis (n = 28), 2000 mg/day SO treatment resulted in a mean increase in T50 of 66 min (95% CI 49-84 min, P < 0.0001), from 243 ± 63 to 309 ± 74 min compared with phosphate binder washout. Serum phosphate decreased from 2.28 ± 0.5 to 1.63 ± 0.43 mmol/L (P < 0.0001). SO at 250 mg/day did not influence T50 (P = 0.4) or serum phosphate concentrations (P = 0.9) compared with phosphate binder washout. The secondary intention-to-treat analysis (n = 39) showed similar results: an increase in T50 of 52 min (95% CI 31-74 min, P < 0.0001) and a decrease in serum phosphate from 2.18 ± 0.5 to 1.64 ± 0.46 mmol/L. No major adverse cardiovascular event, case of calciphylaxis or death occurred during the study. CONCLUSION: Phosphate binder treatment with SO improves serum calcification propensity of haemodialysis patients and might lead to improved outcomes.

Markers of potassium homeostasis in salt losing tubulopathies- associations with hyperaldosteronism and hypomagnesemia.

BACKGROUND: Renal loss of potassium (K+) and magnesium (Mg2+) in salt losing tubulopathies (SLT) leads to significantly reduced Quality of Life (QoL) and higher risks of cardiac arrhythmia. The normalization of K+ is currently the most widely accepted treatment target, however in even excellently designed RCTs the increase of K+ was only mild and rarely normalized. These findings question the role of K+ as the ideal marker of potassium homeostasis in SLT. Aim of this hypothesis-generating study was to define surrogate endpoints for future treatment trials in SLT in terms of their usefulness to determine QoL and important clinical outcomes. METHODS: Within this prospective cross-sectional study including 11 patients with SLTs we assessed the biochemical, clinical and cardiological parameters and their relationship with QoL (RAND SF-36). The primary hypothesis was that QoL would be more dependent of higher aldosterone concentration, assessed by the transtubular-potassium-gradient (TTKG). Correlations were evaluated using Pearson's correlation coefficient. RESULTS: Included patients were mainly female (82%, mean age 34 ± 12 years). Serum K+ and Mg2+ was 3.3 ± 0.6 mmol/l and 0.7 ± 0.1 mmol/l (mean ± SD). TTKG was 9.5/3.4-20.2 (median/range). While dimensions of mental health mostly correlated with serum Mg2+ (r = 0.68, p = 0.04) and K+ (r = 0.55, p = 0.08), better physical health was associated with lower aldosterone levels (r = -0.61, p = 0.06). TTKG was neither associated with aldosterone levels nor with QoL parameters. No relevant abnormalities were observed in neither 24 h-ECG nor echocardiography. CONCLUSIONS: Hyperaldosteronism, K+ and Mg2+ were the most important parameters of QoL. TTKG was no suitable marker for hyperaldosteronism or QoL. Future confirmatory studies in SLT should assess QoL as well as aldosterone, K+ and Mg2+.

Prediction models for diagnosis and prognosis of covid-19: systematic review and critical appraisal

OBJECTIVE: To review and appraise the validity and usefulness of published and preprint reports of prediction models for diagnosing coronavirus disease 2019 (covid-19) in patients with suspected infection, for prognosis of patients with covid-19, and for detecting people in the general population at increased risk of covid-19 infection or being admitted to hospital with the disease. DESIGN: Living systematic review and critical appraisal by the COVID-PRECISE (Precise Risk Estimation to optimise covid-19 Care for Infected or Suspected patients in diverse sEttings) group. DATA SOURCES: PubMed and Embase through Ovid, up to 1 July 2020, supplemented with arXiv, medRxiv, and bioRxiv up to 5 May 2020. STUDY SELECTION: Studies that developed or validated a multivariable covid-19 related prediction model. DATA EXTRACTION: At least two authors independently extracted data using the CHARMS (critical appraisal and data extraction for systematic reviews of prediction modelling studies) checklist; risk of bias was assessed using PROBAST (prediction model risk of bias assessment tool). RESULTS: 37 421 titles were screened, and 169 studies describing 232 prediction models were included. The review identified seven models for identifying people at risk in the general population; 118 diagnostic models for detecting covid-19 (75 were based on medical imaging, 10 to diagnose disease severity); and 107 prognostic models for predicting mortality risk, progression to severe disease, intensive care unit admission, ventilation, intubation, or length of hospital stay. The most frequent types of predictors included in the covid-19 prediction models are vital signs, age, comorbidities, and image features. Flu-like symptoms are frequently predictive in diagnostic models, while sex, C reactive protein, and lymphocyte counts are frequent prognostic factors. Reported C index estimates from the strongest form of validation available per model ranged from 0.71 to 0.99 in prediction models for the general population, from 0.65 to more than 0.99 in diagnostic models, and from 0.54 to 0.99 in prognostic models. All models were rated at high or unclear risk of bias, mostly because of non-representative selection of control patients, exclusion of patients who had not experienced the event of interest by the end of the study, high risk of model overfitting, and unclear reporting. Many models did not include a description of the target population (n=27, 12%) or care setting (n=75, 32%), and only 11 (5%) were externally validated by a calibration plot. The Jehi diagnostic model and the 4C mortality score were identified as promising models. CONCLUSION: Prediction models for covid-19 are quickly entering the academic literature to support medical decision making at a time when they are urgently needed. This review indicates that almost all pubished prediction models are poorly reported, and at high risk of bias such that their reported predictive performance is probably optimistic. However, we have identified two (one diagnostic and one prognostic) promising models that should soon be validated in multiple cohorts, preferably through collaborative efforts and data sharing to also allow an investigation of the stability and heterogeneity in their performance across populations and settings. Details on all reviewed models are publicly available at https://www.covprecise.org/. Methodological guidance as provided in this paper should be followed because unreliable predictions could cause more harm than benefit in guiding clinical decisions. Finally, prediction model authors should adhere to the TRIPOD (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis) reporting guideline. SYSTEMATIC REVIEW REGISTRATION: Protocol https://osf.io/ehc47/, registration https://osf.io/wy245. READERS' NOTE: This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This version is update 3 of the original article published on 7 April 2020 (BMJ 2020;369:m1328). Previous updates can be found as data supplements (https://www.bmj.com/content/369/bmj.m1328/related#datasupp). When citing this paper please consider adding the update number and date of access for clarity.

Predicting donor, recipient and graft survival in living donor kidney transplantation to inform pretransplant counselling: the donor and recipient linked iPREDICTLIVING tool - a retrospective study.

Although separate prediction models for donors and recipients were previously published, we identified a need to predict outcomes of donor/recipient simultaneously, as they are clearly not independent of each other. We used characteristics from transplantations performed at the Oslo University Hospital from 1854 live donors and from 837 recipients of a live donor kidney transplant to derive Cox models for predicting donor mortality up to 20 years, and recipient death, and graft loss up to 10 years. The models were developed using the multivariable fractional polynomials algorithm optimizing Akaike's information criterion, and optimism-corrected performance was assessed. Age, year of donation, smoking status, cholesterol and creatinine were selected to predict donor mortality (C-statistic of 0.81). Linear predictors for donor mortality served as summary of donor prognosis in recipient models. Age, sex, year of transplantation, dialysis vintage, primary renal disease, cerebrovascular disease, peripheral vascular disease and HLA mismatch were selected to predict recipient mortality (C-statistic of 0.77). Age, dialysis vintage, linear predictor of donor mortality, HLA mismatch, peripheral vascular disease and heart disease were selected to predict graft loss (C-statistic of 0.66). Our prediction models inform decision-making at the time of transplant counselling and are implemented as online calculators.

Remote ischaemic conditioning for myocardial infarction or elective PCI: systematic review and meta-analyses of randomised trials.

BACKGROUND: The efficacy of remote ischaemic conditioning in clinical trials of ST-segment elevation myocardial infarction (STEMI) or elective percutaneous coronary intervention is controversial. We aimed to systematically review and meta-analyse whether remote ischaemic conditioning reduces myocardial damage in those patients. METHODS: We searched PubMed, Embase and Web of Science from inception until December 2017 for randomised clinical trials evaluating remote ischaemic conditioning versus a control group. Two independent reviewers extracted data of 23 trials (2118 patients with STEMI; 2048 patients undergoing elective percutaneous coronary intervention) which were meta-analysed using random-effects models. RESULTS: Remote ischaemic conditioning reduced infarct size in STEMI patients when assessed by imaging (mean difference of infarct size as percentage of left ventricle -2.43, 95% confidence interval (CI) -4.37 to -0.48; P=0.01; I2=44%; n=925) or biomarkers related to myocardial injury (peak values of cardiac biomarker release reported as standardised mean difference -0.19, 95% CI -0.37 to -0.02; P=0.03; I2=58%; n=1483) and increased myocardial salvage index (mean difference 0.07, 95% CI 0.01 to 0.13; P=0.02; I2=49%; n= 636). Left ventricular ejection fraction was increased when assessed during the first days after STEMI (mean difference 1.53, 95% CI 0.23 to 2.83; P=0.02; I2=28%; n=1192). Remote ischaemic conditioning had no influence on biomarker values after elective percutaneous coronary intervention (standardised mean difference 0.06, 95% CI -0.17 to 0.30; P=0.59). CONCLUSIONS: Despite a statistically significant reduction of myocardial damage in STEMI patients, the magnitude of the reduction was small and a significant impact on clinical events is unlikely. With respect to elective percutaneous coronary intervention, remote ischaemic conditioning had no influence on myocardial injury and its use is not supported by our analysis.

Dialysis vintage and outcomes in renal transplantation.

Pre-emptive kidney transplantation is the recommended strategy for patients with end-stage renal failure in all guidelines [Kidney Disease: Improving Global Outcomes (KDIGO), The Australian and New Zealand Dialysis and Transplantation Registry (ANZDATA), European Renal Best Practice Guideline (ERBP), British Transplant Society (BTS)]. This recommendation is intuitive and based on few older studies with considerable limitations. In addition, there is conflicting evidence as to whether the duration of dialysis vintage impacts on graft and patient survival after transplantation. The objective of this structured review was to critically review the published evidence on dialysis vintage and outcomes by including the most recent papers on that topic. We searched Medline using keywords for kidney transplantation, pre-emptive, dialysis vintage and relevant outcomes, and found 14 eligible cohort studies. The best evidence was found for pre-emptive transplantation, which was found to be associated with a lower risk of actual graft loss (including death as event) compared with non-pre-emptive transplantation. When only patients were considered that have been registered pre-emptively but then received or did not receive a pre-emptive transplant, the association with functional graft survival (excluding death as event) was only marginal. Dialysis vintage had a graded association with patient survival in most of the studies, but an unclear estimate with functional graft survival. Older studies also found an association of dialysis vintage with death-censored graft survival, but this association is likely confounded by selection and the competing risk of death and was no longer observed in recent eras, i.e. in transplants performed in the last decade. In summary, the recommendation for pre-emptive kidney transplantation for optimal patient and graft survival remains valid even in recent periods but the association of dialysis vintage after dialysis initiation with death-censored graft survival is less clear. The association of dialysis vintage with mortality after transplantation depends on the median duration of dialysis of the wait-listed population as well as acceptance rates for transplantation, and may thus be country specific. Nevertheless, it is reasonable to advocate pre-emptive kidney transplantation in all age groups. What remains unsolved is the selection issues since the reasons for longer waiting time on dialysis are difficult to capture in retrospective observational studies, and lead time as well as immortal time bias may have confounded the mortality data.

Interventions for chronic non-hypovolaemic hypotonic hyponatraemia.

BACKGROUND: Chronic (present > 48 hours) non-hypovolaemic hyponatraemia occurs frequently, can be caused by various conditions, and is associated with shorter survival and longer hospital stays. Many treatments, such as fluid restriction or vasopressin receptor antagonists can be used to improve the hyponatraemia, but whether that translates into improved patient-important outcomes is less certain. OBJECTIVES: This review aimed to 1) look at the benefits and harms of interventions for chronic non-hypovolaemic hypotonic hyponatraemia when compared with placebo, no treatment or head-to-head; and 2) determine if benefits and harms vary in absolute or relative terms dependent on the specific compound within a drug class, on the dosage used, or the underlying disorder causing the hyponatraemia. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 1 December 2017 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. We also screened the reference lists of potentially relevant studies, contacted authors, and screened the websites of regulatory agencies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs that compared the effects of any intervention with placebo, no treatment, standard care, or any other intervention in patients with chronic non-hypovolaemic hypotonic hyponatraemia. We also included subgroups with hyponatraemia from studies with broader inclusion criteria (e.g. people with chronic heart failure or people with cirrhosis with or without hyponatraemia), provided we could obtain outcomes for participants with hyponatraemia from the report or the study authors. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed risk of bias. We expressed treatment effects as mean difference (MD) for continuous outcomes (health-related quality of life, length of hospital stay, change from baseline in serum sodium concentration, cognitive function), and risk ratio (RR) for dichotomous outcomes (death, response and rapid increase in serum sodium concentration, hypernatraemia, polyuria, hypotension, acute kidney injury, liver function abnormalities) together with 95% confidence intervals (CI). MAIN RESULTS: We identified 35 studies, enrolling 3429 participants. Twenty-eight studies (3189 participants) compared a vasopressin receptor antagonist versus placebo, usual care, no treatment, or fluid restriction. In adults with chronic, non-hypovolaemic hypotonic hyponatraemia, vasopressin receptor antagonists have uncertain effects on death at six months (15 studies, 2330 participants: RR 1.11, 95% CI 0.92 to 1.33) due to risk of selective reporting and serious imprecision; and on health-related quality of life because results are at serious risk of performance, selective reporting and attrition bias, and suffer from indirectness related to the validity of the Short Form Health Survey (SF-12) in the setting of hyponatraemia. Vasopressin receptor antagonists may reduce hospital stay (low certainty evidence due to risk of performance bias and imprecision) (3 studies, 610 participants: MD -1.63 days, 95% CI -2.96 to -0.30), and may make little or no difference to cognitive function (low certainty evidence due to indirectness and imprecision). Vasopressin receptor antagonists probably increase the intermediate outcome of serum sodium concentration (21 studies, 2641 participants: MD 4.17 mmol/L, 95% CI 3.18 to 5.16), corresponding to two and a half as many people having a 5 to 6 mmol/L increase in sodium concentration compared with placebo at 4 to 180 days (moderate certainty evidence due to risk of attrition bias) (18 studies, 2014 participants: RR 2.49, 95% CI 1.95 to 3.18). But they probably also increase the risk of rapid serum sodium correction - most commonly defined as > 12 mmol/L/d (moderate certainty evidence due to indirectness) (14 studies, 2058 participants: RR 1.67, 95% CI 1.16 to 2.40) and commonly cause side-effects such as thirst (13 studies, 1666 participants: OR 2.77, 95% CI 1.80 to 4.27) and polyuria (6 studies, 1272 participants): RR 4.69, 95% CI 1.59 to 13.85) (high certainty evidence). The potential for liver toxicity remains uncertain due to large imprecision. Effects were generally consistent across the different agents, suggesting class effect.Data for other interventions such as fluid restriction, urea, mannitol, loop diuretics, corticosteroids, demeclocycline, lithium and phenytoin were largely absent. AUTHORS' CONCLUSIONS: In people with chronic hyponatraemia, vasopressin receptor antagonists modestly raise serum sodium concentration at the cost of a 3% increased risk of it being rapid. To date there is very low certainty evidence for patient-important outcomes; the effects on mortality and health-related quality of life are unclear and do not rule out appreciable benefit or harm; there does not appear to be an important effect on cognitive function, but hospital stay may be slightly shorter, although available data are limited. Treatment decisions must weigh the value of an increase in serum sodium concentration against its short-term risks and unknown effects on patient-important outcomes. Evidence for other treatments is largely absent.Further studies assessing standard treatments such as fluid restriction or urea against placebo and one-another would inform practice and are warranted. Given the limited available evidence for patient-important outcomes, any study should include these outcomes in a standardised manner.

Risk prediction models for graft failure in kidney transplantation: a systematic review.

Risk prediction models are useful for identifying kidney recipients at high risk of graft failure, thus optimizing clinical care. Our objective was to systematically review the models that have been recently developed and validated to predict graft failure in kidney transplantation recipients. We used PubMed and Scopus to search for English, German and French language articles published in 2005-15. We selected studies that developed and validated a new risk prediction model for graft failure after kidney transplantation, or validated an existing model with or without updating the model. Data on recipient characteristics and predictors, as well as modelling and validation methods were extracted. In total, 39 articles met the inclusion criteria. Of these, 34 developed and validated a new risk prediction model and 5 validated an existing one with or without updating the model. The most frequently predicted outcome was graft failure, defined as dialysis, re-transplantation or death with functioning graft. Most studies used the Cox model. There was substantial variability in predictors used. In total, 25 studies used predictors measured at transplantation only, and 14 studies used predictors also measured after transplantation. Discrimination performance was reported in 87% of studies, while calibration was reported in 56%. Performance indicators were estimated using both internal and external validation in 13 studies, and using external validation only in 6 studies. Several prediction models for kidney graft failure in adults have been published. Our study highlights the need to better account for competing risks when applicable in such studies, and to adequately account for post-transplant measures of predictors in studies aiming at improving monitoring of kidney transplant recipients.

Steroid withdrawal after renal transplantation: a retrospective cohort study.

BACKGROUND: Immunosuppressive regimens in renal transplantation frequently contain corticosteroids, but many centers withdraw steroids as a consequence of unwanted side effects of steroids. The optimal timing to withdraw steroids after transplantation, however, remains unclear. The aim of this study was to determine an optimal time point following kidney transplantation that is associated with reduced mortality without jeopardizing the allograft to allow safe discontinuation of steroids. METHODS: We conducted a retrospective cohort study and computed a concatenated landmark-stratified Cox supermodel to estimate hazard ratios and 95% confidence intervals for mortality and graft loss using dynamic propensity score matching to adjust for confounding by indication. RESULTS: A total of 6070 first kidney transplant recipients in the Austrian Dialysis and Transplant Registry who were transplanted between 1990 and 2012 were evaluated and classified according to steroid treatment status throughout follow-up after kidney transplantation; 2142 patients were withdrawn from steroids during the study period. Overall, 1131 patients lost their graft and 821 patients in the study cohort died. Steroid withdrawal within 18 months after transplantation was associated with an increased rate of graft loss compared to steroid maintenance during that time (6 months after transplantation: HR = 1.8; 95% CI, 1.3 to 2.6; 18 months after transplantation: HR = 1.3; 95% CI, 1.1 to 1.6; 24 months after transplantation: HR = 1.2; 95% CI, 0.9 to 1.5), while mortality was not different between groups. CONCLUSIONS: Our findings suggest that steroid withdrawal after anti-IL-2 induction in the first 18 months after transplantation is associated with an increased risk of allograft loss.

Why creating standardized core outcome sets for chronic kidney disease will improve clinical practice.

Chronic kidney disease (CKD) is common and is associated with increased mortality, morbidity and cost. However, insufficient high-quality trial data are available to answer many relevant clinical questions in this field. In addition, a wide range of variable outcomes are used in studies, and often they are incompletely reported. Furthermore, there is a lack of patient-relevant outcomes, such as mortality, morbidity, quality of life, pain, need for dialysis or costs. Common problems with outcome reporting are as follows: choosing the wrong domains to measure; within domains, choosing the wrong measures (invalid surrogates, composite, non-patient relevant); within measures, choosing the wrong/variable metrics; and within metrics, choosing variable presentation methods. With this article, we aim to underline why standardized outcome reporting is key to achieving evidence-based guidance and improving clinical care for patients; highlight the frameworks available for achieving core outcome sets; and starting from these frameworks, we propose steps needed to develop a core outcome set in the field of CKD. We hope that standardized core outcome sets for nephrology will lead to the most important outcome of guideline production, improving outcomes for our patients.