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1.
BMJ ; 367: l5873, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31672760

RESUMO

OBJECTIVE: To determine the global capacity (availability, accessibility, quality, and affordability) to deliver kidney replacement therapy (dialysis and transplantation) and conservative kidney management. DESIGN: International cross sectional survey. SETTING: International Society of Nephrology (ISN) survey of 182 countries from July to September 2018. PARTICIPANTS: Key stakeholders identified by ISN's national and regional leaders. MAIN OUTCOME MEASURES: Markers of national capacity to deliver core components of kidney replacement therapy and conservative kidney management. RESULTS: Responses were received from 160 (87.9%) of 182 countries, comprising 97.8% (7338.5 million of 7501.3 million) of the world's population. A wide variation was found in capacity and structures for kidney replacement therapy and conservative kidney management-namely, funding mechanisms, health workforce, service delivery, and available technologies. Information on the prevalence of treated end stage kidney disease was available in 91 (42%) of 218 countries worldwide. Estimates varied more than 800-fold from 4 to 3392 per million population. Rwanda was the only low income country to report data on the prevalence of treated disease; 5 (<10%) of 53 African countries reported these data. Of 159 countries, 102 (64%) provided public funding for kidney replacement therapy. Sixty eight (43%) of 159 countries charged no fees at the point of care delivery and 34 (21%) made some charge. Haemodialysis was reported as available in 156 (100%) of 156 countries, peritoneal dialysis in 119 (76%) of 156 countries, and kidney transplantation in 114 (74%) of 155 countries. Dialysis and kidney transplantation were available to more than 50% of patients in only 108 (70%) and 45 (29%) of 154 countries that offered these services, respectively. Conservative kidney management was available in 124 (81%) of 154 countries. Worldwide, the median number of nephrologists was 9.96 per million population, which varied with income level. CONCLUSIONS: These comprehensive data show the capacity of countries (including low income countries) to provide optimal care for patients with end stage kidney disease. They demonstrate substantial variability in the burden of such disease and capacity for kidney replacement therapy and conservative kidney management, which have implications for policy.


Assuntos
Saúde Global/estatística & dados numéricos , Acesso aos Serviços de Saúde/estatística & dados numéricos , Falência Renal Crônica/terapia , Nefrologia/estatística & dados numéricos , Terapia de Substituição Renal/estatística & dados numéricos , Estudos Transversais , Países em Desenvolvimento/estatística & dados numéricos , Humanos
2.
Artigo em Inglês | MEDLINE | ID: mdl-31672793

RESUMO

BACKGROUND AND OBJECTIVES: Little is known about the effect of changes in dialysis hours on patient-reported outcome measures. We report the effect of doubling dialysis hours on a range of patient-reported outcome measures in a randomized trial, overall and separately for important subgroups. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The A Clinical Trial of IntensiVE Dialysis trial randomized 200 participants to extended or standard weekly hours hemodialysis for 12 months. Patient-reported outcome measures included two health utility scores (EuroQOL-5 Dimensions-3 Level, Short Form-6 Dimension) and their derived quality-adjusted life year estimates, two generic health scores (Short Form-36 Physical Component Summary, Mental Component Summary), and a disease-specific score (Kidney Disease Component Score). Outcomes were assessed as the mean difference from baseline using linear mixed effects models adjusted for time point and baseline score, with interaction terms added for subgroup analyses. Prespecified subgroups were dialysis location (home- versus institution-based), dialysis vintage (≤6 months versus >6 months), region (China versus Australia, New Zealand, Canada), and baseline score (lowest, middle, highest tertile). Multiplicity-adjusted P values (Holm-Bonferroni) were calculated for the main analyses. RESULTS: Extended dialysis hours was associated with improvement in Short Form-6 Dimension (mean difference, 0.027; 95% confidence interval [95% CI], 0.00 to 0.05; P=0.03) which was not significant after adjustment for multiple comparisons (Padjusted =0.05). There were no significant differences in EuroQOL-5 Dimensions-3 Level health utility (mean difference, 0.036; 95% CI, -0.02 to 0.09; P=0.2; Padjusted =0.2) or in quality-adjusted life years. There were small positive differences in generic and disease-specific quality of life: Physical Component Summary (mean difference, 2.3; 95% CI, 0.6 to 4.1; P=0.01; Padjusted =0.04), Mental Component Summary (mean difference, 2.5; 95% CI, 0.5 to 4.6; P=0.02; Padjusted =0.05) and Kidney Disease Component Score (mean difference, 3.5; 95% CI, 1.5 to 5.5; P=0.001; Padjusted =0.005). The results did not differ among predefined subgroups or by baseline score. CONCLUSIONS: The effect of extended hours hemodialysis on patient-reported outcome measures reached statistical significance in some but not all measures. Within each measure the effect was consistent across predefined subgroups. The clinical importance of these differences is unclear.

3.
JACC Heart Fail ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31676303

RESUMO

OBJECTIVES: The purpose of this study was to explore potential mediators of the effects of canagliflozin on heart failure in the CANVAS Program (CANagliflozin cardioVascular Assessment Study; NCT01032629 and CANagliflozin cardioVascular Assessment Study-Renal; NCT01989754). BACKGROUND: Canagliflozin reduced the risk of heart failure among patients with type 2 diabetes in the CANVAS Program. The mechanism of protection is uncertain. METHODS: The percentages of mediating effects of 19 biomarkers were determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the biomarker of interest. Multivariable analyses were used to assess the joint effects of biomarkers that mediated most strongly in univariable analyses. RESULTS: Early changes after randomization in levels of 3 biomarkers (urinary albumin:creatinine ratio, serum bicarbonate, and serum urate) were identified as mediating the effect of canagliflozin on heart failure. Average post-randomization levels of 14 biomarkers (systolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol, total cholesterol, urinary albumin:creatinine ratio, weight, body mass index, gamma glutamyltransferase, hematocrit, hemoglobin concentration, serum albumin, erythrocyte concentration, serum bicarbonate, and serum urate) were identified as significant mediators. Individually, the 3 biomarkers with the largest mediating effect were erythrocyte concentration (45%), hemoglobin concentration (43%), and serum urate (40%). In a parsimonious multivariable model, erythrocyte concentration, serum urate, and urinary albumin:creatinine ratio were the 3 biomarkers that maximized cumulative mediation (102%). CONCLUSIONS: A diverse set of potential mediators of the effect of canagliflozin on heart failure were identified. Some mediating effects were anticipated, whereas others were not. The mediators that were identified support existing and novel hypothesized mechanisms for the prevention of heart failure with sodium glucose cotransporter 2 inhibitors.

4.
Diabetes Obes Metab ; 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31729107

RESUMO

AIMS: Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce several cardiovascular risk factors including plasma glucose, blood pressure, albuminuria and body weight. Long-term treatment lowers risks of cardiovascular and renal events. The objective of this post hoc analysis was to determine the effects of canagliflozin treatment versus placebo on clinical outcomes in relation to body mass index (BMI). MATERIALS AND METHODS: The CANVAS Program randomized 10,142 participants with type 2 diabetes to canagliflozin or placebo. These analyses tested the consistency of canagliflozin treatment effects across BMI levels for cardiovascular, renal, safety, and body weight outcomes in 3 groups defined by baseline BMI: <25, 25-<30, and ≥30 kg/m2 . RESULTS: A total of 10,128 participants with baseline BMI measurements were included. There were 966 participants with BMI <25 kg/m2 , 3153 with BMI 25-<30 kg/m2 , and 6009 with BMI ≥30 kg/m2 . Mean body weight reduction with canagliflozin compared to placebo was greater at 12 months (-2.47 kg [95% CI: -2.64, -2.30]) than at 3 months (-1.53 kg [95% CI: -1.63, -1.44]). The HRs (95% CI) for canagliflozin compared with placebo control for the composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke were HR 1.03 (95% CI: 0.66, 1.59) in participants with BMI <25 kg/m2 , 0.97 (0.76, 1.23) with BMI 25-<30 kg/m2 , and 0.79 (0.67, 0.93) with BMI ≥30 kg/m2 (P for heterogeneity = 0.55). The effects of canagliflozin on each component of the composite were also similar across BMI subgroups, as were effects on heart failure, renal, and safety outcomes (all P for heterogeneity ≥0.15). CONCLUSIONS: Canagliflozin improved cardiovascular and renal outcomes consistently across patients with a broad range of BMI levels. This article is protected by copyright. All rights reserved.

5.
Circulation ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31707795

RESUMO

Traditional management of diabetes mellitus has focused on glycemic control, beginning with lifestyle changes, followed by metformin, and then other classes of antiglycemic agents.1 Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce cardiovascular (CV) events, including CV death, myocardial infarction (MI) and heart failure, and slow progression of renal dysfunction, including prevention of end-stage kidney disease (ESKD).2-3 Because initial clinical trials included mostly patients with baseline HbA1c >7%, current guidelines have recommended this class as add-on therapy for patients whose HbA1c is not at goal, typically ≥7%.1 We hypothesized that there would be similar benefits on CV and renal endpoints regardless of baseline HbA1c, including those with HbA1c <7%.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31495881

RESUMO

BACKGROUND: Doubling of serum creatinine [equivalent to 57% reduction in estimated glomerular filtration rate (eGFR)] is an established surrogate for end-stage kidney disease (ESKD); however, this endpoint necessitates lengthy follow-up and large sample sizes in clinical trials. We explored whether alternative eGFR decline thresholds provide more feasible surrogate kidney endpoints. METHODS: The study involved post hoc analysis of the EMPA-REG OUTCOME® trial. Adults with type 2 diabetes, high cardiovascular risk and eGFR ≥30 mL/min/1.73 m2 were assigned empagliflozin 10 mg or 25 mg (n = 4687) or placebo (n = 2333), on top of standard of care. We assessed composite endpoints incorporating different eGFR decline thresholds (≥30, ≥40, ≥50 or ≥57%) combined with initiation of renal replacement therapy (RRT) or renal death. This trial is registered with ClinicalTrials.gov (NCT01131676). RESULTS: Empagliflozin versus placebo significantly lowered the risk of decline in eGFR for each threshold listed above, combined with initiation of RRT or renal death, ranging from a hazard ratio (HR) of 0.81 [95% confidence interval (CI) 0.72-0.91] for endpoints based on 30% eGFR decline to an HR of 0.37 (0.23-0.61) for endpoints based on 57% eGFR decline. Lower thresholds (e.g. 30%) were associated with higher event rates but weaker treatment effects. The time to the 95% CI of the HR falling to <1.0 decreased with increasing eGFR threshold. CONCLUSIONS: The composite of 40% decline in eGFR, ESKD or renal death appears to provide reliable results similar to the traditional 57% decline in eGFR.

8.
Am J Kidney Dis ; 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31473020

RESUMO

The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) are currently willing to consider a 30% to 40% glomerular filtration rate (GFR) decline as a surrogate end point for kidney failure for clinical trials of kidney disease progression under appropriate conditions. However, these end points may not be practical for early stages of kidney disease. In March 2018, the National Kidney Foundation sponsored a scientific workshop in collaboration with the FDA and EMA to evaluate changes in albuminuria or GFR as candidate surrogate end points. Three parallel efforts were presented: meta-analyses of observational studies (cohorts), meta-analyses of clinical trials, and simulations of trial design. In cohorts, after accounting for measurement error, relationships between change in urinary albumin-creatinine ratio (UACR) or estimated GFR (eGFR) slope and the clinical outcome of kidney disease progression were strong and consistent. In trials, the posterior median R2 of treatment effects on the candidate surrogates with the clinical outcome was 0.47 (95% Bayesian credible interval [BCI], 0.02-0.96) for early change in UACR and 0.72 (95% BCI, 0.05-0.99) when restricted to baseline UACR>30mg/g, and 0.97 (95% BCI, 0.78-1.00) for total eGFR slope at 3 years and 0.96 (95% BCI, 0.63-1.00) for chronic eGFR slope (ie, the slope excluding the first 3 months from baseline, when there might be acute changes in eGFR). The magnitude of the relationships of changes in the candidate surrogates with risk for clinical outcome was consistent across cohorts and trials: a UACR reduction of 30% or eGFR slope reduction by 0.5 to 1.0mL/min/1.73m2 per year were associated with an HR of ∼0.7 for the clinical outcome in cohorts and trials. In simulations, using GFR slope as an end point substantially reduced the required sample size and duration of follow-up compared with the clinical end point when baseline eGFR was high, treatment effects were uniform, and there was no acute effect of the treatment. We conclude that both early change in albuminuria and GFR slope fulfill criteria for surrogacy for use as end points in clinical trials for chronic kidney disease progression under certain conditions, with stronger support for change in GFR than albuminuria. Implementation requires understanding conditions under which each surrogate is likely to perform well and restricting its use to those settings.

10.
Lancet Diabetes Endocrinol ; 7(11): 845-854, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31495651

RESUMO

BACKGROUND: The effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors on kidney failure, particularly the need for dialysis or transplantation or death due to kidney disease, is uncertain. Additionally, previous studies have been underpowered to robustly assess heterogeneity of effects on kidney outcomes by different levels of estimated glomerular filtration rate (eGFR) and albuminuria. We aimed to do a systematic review and meta-analysis to assess the effects of SGLT2 inhibitors on major kidney outcomes in patients with type 2 diabetes and to determine the consistency of effect size across trials and different levels of eGFR and albuminuria. METHODS: We did a systematic review and meta-analysis of randomised, controlled, cardiovascular or kidney outcome trials of SGLT2 inhibitors that reported effects on major kidney outcomes in people with type 2 diabetes. We searched MEDLINE and Embase from database inception to June 14, 2019, to identify eligible trials. The primary outcome was a composite of dialysis, transplantation, or death due to kidney disease. We used random-effects models to obtain summary relative risks (RRs) with 95% CIs and random-effects meta-regression to explore effect modification by subgroups of baseline eGFR, albuminuria, and use of renin-angiotensin system (RAS) blockade. This review is registered with PROSPERO (CRD42019131774). FINDINGS: From 2085 records identified, four studies met our inclusion criteria, assessing three SGLT2 inhibitors: empagliflozin (EMPA-REG OUTCOME), canagliflozin (CANVAS Program and CREDENCE), and dapagliflozin (DECLARE-TIMI 58). From a total of 38 723 participants, 252 required dialysis or transplantation or died of kidney disease, 335 developed end-stage kidney disease, and 943 had acute kidney injury. SGLT2 inhibitors substantially reduced the risk of dialysis, transplantation, or death due to kidney disease (RR 0·67, 95% CI 0·52-0·86, p=0·0019), an effect consistent across studies (I2=0%, pheterogeneity=0·53). SGLT2 inhibitors also reduced end-stage kidney disease (0·65, 0·53-0·81, p<0·0001), and acute kidney injury (0·75, 0·66-0·85, p<0·0001), with consistent benefits across studies. Although we identified some evidence that the proportional effect of SGLT2 inhibitors might attenuate with declining kidney function (ptrend=0·073), there was clear, separate evidence of benefit for all eGFR subgroups, including for participants with a baseline eGFR 30-45 mL/min per 1·73 m2 (RR 0·70, 95% CI 0·54-0·91, p=0·0080). Renoprotection was also consistent across studies irrespective of baseline albuminuria (ptrend=0·66) and use of RAS blockade (pheterogeneity=0·31). INTERPRETATION: SGLT2 inhibitors reduced the risk of dialysis, transplantation, or death due to kidney disease in individuals with type 2 diabetes and provided protection against acute kidney injury. These data provide substantive evidence supporting the use of SGLT2 inhibitors to prevent major kidney outcomes in people with type 2 diabetes. FUNDING: None.

11.
J Am Soc Nephrol ; 30(11): 2229-2242, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31530577

RESUMO

BACKGROUND: If SGLT2 inhibitors protect the kidneys by reducing albuminuria as hypothesized, people with type 2 diabetes mellitus (T2DM) with higher albuminuria should benefit more. METHODS: We conducted a post-hoc analysis of data from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, which randomized 10,142 participants with T2DM and high cardiovascular risk to canagliflozin or placebo. We assessed effects of canagliflozin on renal, cardiovascular, and safety outcomes by baseline albuminuria. The trial included 2266 participants (22.3%) with moderately increased albuminuria (urinary albumin/creatinine ratio [UACR] 30-300 mg/g) and 760 (7.5%) with severely increased albuminuria (UACR >300 mg/g) at baseline. RESULTS: Canagliflozin lowered albuminuria with greater proportional reductions in those with moderately and severely increased albuminuria (P heterogeneity<0.001). After week 13, canagliflozin slowed the annual loss of kidney function across albuminuria subgroups, with greater absolute reductions in participants with severely increased albuminuria (placebo-subtracted difference 3.01 ml/min per 1.73 m2 per year; P heterogeneity<0.001). Heterogeneity for the renal composite outcome of 40% reduction in eGFR, ESKD, or renal-related death was driven by lesser effects in participants with moderately increased albuminuria (P heterogeneity=0.03), but no effect modification was observed when albuminuria was fitted as a continuous variable (P heterogeneity=0.94). Cardiovascular and safety outcomes were mostly consistent across albuminuria levels including increased risks for amputation across albuminuria subgroups (P heterogeneity=0.66). Greater absolute risk reductions in the renal composite outcome were observed in participants with severely increased albuminuria (P heterogeneity=0.004). CONCLUSIONS: The proportional effects of canagliflozin on renal and cardiovascular outcomes are mostly consistent across patients with different levels of albuminuria, but absolute benefits are greatest among those with severely increased albuminuria.

12.
Diabetologia ; 62(10): 1854-1867, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31399845

RESUMO

AIMS/HYPOTHESIS: An increased risk of fracture with canagliflozin vs placebo was reported from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, with heterogeneity of findings identified between the two trials that comprise the CANVAS Program, CANVAS and CANVAS-R. The objective of these analyses was to identify reasons for the possibly different effects on fracture observed between CANVAS and CANVAS-R. METHODS: This study was an analysis of two highly similar trials, CANVAS and CANVAS-R, conducted in 10,142 individuals with type 2 diabetes and history or high risk of cardiovascular disease who received canagliflozin (pooled 100/300 mg once daily) or placebo. Outcomes assessed in this analysis were effects on adjudicated fractures overall and by type, location, association with a fall, dose and follow-up time. RESULTS: A total of 496 participants recorded ≥1 fracture event during follow-up (15.40 vs 11.93 per 1000 patient-years with canagliflozin vs placebo; HR 1.26 [95% CI 1.04, 1.52]). There was significant heterogeneity in the effects on fracture (p = 0.005) between CANVAS (n = 4330: HR 1.55 [95% CI 1.21, 1.97]) and CANVAS-R (n = 5812: HR 0.86 [95% CI 0.62, 1.19]). The between-study heterogeneity in fracture risk was not clearly explained by differences in baseline characteristics, interactions of randomised treatment with participant characteristics, dose effects, duration of follow-up, metabolic effects, adverse events related to falls or adverse events possibly causing falls. CONCLUSIONS/INTERPRETATION: There was no evidence to explain clearly the fracture risk observed in the CANVAS Program or the heterogeneity in fracture risk between the two studies. The recently reported null result for fracture in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial suggests that the observed association in CANVAS is likely to be a chance finding, although an unidentified fall-related mechanism remains a possibility. TRIAL REGISTRATION: ClinicalTrials.gov NCT01032629, NCT01989754.

13.
Ann Intern Med ; 171(3): 181-189, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31307056

RESUMO

Background: Effects of oral anticoagulation in chronic kidney disease (CKD) are uncertain. Purpose: To evaluate the benefits and harms of vitamin K antagonists (VKAs) and non-vitamin K oral anticoagulants (NOACs) in adults with CKD stages 3 to 5, including those with dialysis-dependent end-stage kidney disease (ESKD). Data Sources: English-language searches of MEDLINE, EMBASE, and Cochrane databases (inception to February 2019); review bibliographies; and ClinicalTrials.gov (25 February 2019). Study Selection: Randomized controlled trials evaluating VKAs or NOACs for any indication in patients with CKD that reported efficacy or bleeding outcomes. Data Extraction: Two authors independently extracted data, assessed risk of bias, and rated certainty of evidence. Data Synthesis: Forty-five trials involving 34 082 participants who received anticoagulation for atrial fibrillation (AF) (11 trials), venous thromboembolism (VTE) (11 trials), thromboprophylaxis (6 trials), prevention of dialysis access thrombosis (8 trials), and cardiovascular disease other than AF (9 trials) were included. All but the 8 trials involving patients with ESKD excluded participants with creatinine clearance less than 20 mL/min or estimated glomerular filtration rate less than 15 mL/min/1.73 m2. In AF, compared with VKAs, NOACs reduced risks for stroke or systemic embolism (risk ratio [RR], 0.79 [95% CI, 0.66 to 0.93]; high-certainty evidence) and hemorrhagic stroke (RR, 0.48 [CI, 0.30 to 0.76]; moderate-certainty evidence). Compared with VKAs, the effects of NOACs on recurrent VTE or VTE-related death were uncertain (RR, 0.72 [CI, 0.44 to 1.17]; low-certainty evidence). In all trials combined, NOACs seemingly reduced major bleeding risk compared with VKAs (RR, 0.75 [CI, 0.56 to 1.01]; low-certainty evidence). Limitation: Scant evidence for advanced CKD or ESKD; data mostly from subgroups of large trials. Conclusion: In early-stage CKD, NOACs had a benefit-risk profile superior to that of VKAs. For advanced CKD or ESKD, there was insufficient evidence to establish benefits or harms of VKAs or NOACs. Primary Funding Source: None. (PROSPERO: CRD42017079709).

14.
Diabetologia ; 62(11): 1988-1997, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31302707

RESUMO

AIMS/HYPOTHESIS: Some studies have reported that annual change in eGFR (eGFR slope) is associated with the future risk of end-stage kidney disease, cardiovascular disease and death in general or chronic kidney disease cohorts. However, the benefits of using eGFR slopes for prediction of major clinical outcomes in diabetes are unclear. METHODS: We used data from the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial and the ADVANCE Post-Trial Observational Study (ADVANCE-ON). After excluding the first 4 months during which an acute fall in eGFR was induced by the initiation of an ACE inhibitor and diuretic combination agent, eGFR slopes were estimated by linear mixed models, using three measurements of eGFR at 4, 12 and 24 months after randomisation over 20 months, and categorised according to quartiles. Cox regression models were used to evaluate adjusted HRs for the study's primary outcome, a composite of major renal events, major macrovascular events and all-cause mortality during the subsequent follow-up from 24 months after randomisation. RESULTS: A total of 8,879 participants (80%) were included in this cohort. The mean age was 65.6 years (SD 6.3), the mean eGFR was 75 ml min-1 (1.73 m)-2 (SD 17) and the median urinary albumin/creatinine ratio was 14 µg/mg (interquartile range 7-38). The mean eGFR slope was -0.63 ml min-1 (1.73 m)-2 year-1 (SD 1.75). Over a median follow-up of 7.6 years following the 20-month eGFR slope ascertainment period, 2,221 participants (25%) met the primary outcome. An annual substantial decrease in eGFR (lowest 25%, <-1.63 ml min-1 [1.73 m]-2 year-1) was significantly associated with the subsequent risk of the primary outcome (HR 1.30 [95% CI 1.17, 1.43]) compared with a stable change in eGFR (middle 50%, -1.63 to 0.33). An annual substantial increase in eGFR (highest 25%, >0.33) had no significant association with the risk of the primary outcome (HR 0.96 [95% CI 0.86, 1.07]). CONCLUSIONS/INTERPRETATION: Our study supports the utility of eGFR slope in type 2 diabetes as a surrogate endpoint for renal outcomes, as well as a prognostic factor for identifying individuals at high risk of cardiovascular disease and all-cause mortality. TRIAL REGISTRY NUMBER: ClinicalTrials.gov registration no. NCT00145925 and no. NCT00949286.

15.
J Am Soc Nephrol ; 30(9): 1735-1745, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31292197

RESUMO

BACKGROUND: Surrogate end points are needed to assess whether treatments are effective in the early stages of CKD. GFR decline leads to kidney failure, but regulators have not approved using differences in the change in GFR from the beginning to the end of a randomized, controlled trial as an end point in CKD because it is not clear whether small changes in the GFR slope will translate to clinical benefits. METHODS: To assess the use of GFR slope as a surrogate end point for CKD progression, we performed a meta-analysis of 47 RCTs that tested 12 interventions in 60,620 subjects. We estimated treatment effects on GFR slope (mean difference in GFR slope between the randomized groups), for the total slope starting at baseline, chronic slope starting at 3 months after randomization, and on the clinical end point (doubling of serum creatinine, GFR<15 ml/min per 1.73 m2, or ESKD) for each study. We used Bayesian mixed-effects analyses to describe the association of treatment effects on GFR slope with the clinical end point and to test how well the GFR slope predicts a treatment's effect on the clinical end point. RESULTS: Across all studies, the treatment effect on 3-year total GFR slope (median R 2=0.97; 95% Bayesian credible interval [BCI], 0.78 to 1.00) and on the chronic slope (R 2 0.96; 95% BCI, 0.63 to 1.00) accurately predicted treatment effects on the clinical end point. With a sufficient sample size, a treatment effect of 0.75 ml/min per 1.73 m2/yr or greater on total slope over 3 years or chronic slope predicts a clinical benefit on CKD progress with at least 96% probability. CONCLUSIONS: With large enough sample sizes, GFR slope may be a viable surrogate for clinical end points in CKD RCTs.

16.
Circulation ; 140(9): 739-750, 2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31291786

RESUMO

BACKGROUND: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without previous cardiovascular disease (primary prevention). METHODS: In CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation), 4401 participants with type 2 diabetes mellitus and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care. RESULTS: Primary prevention participants (n=2181, 49.6%) were younger (61 versus 65 years), were more often female (37% versus 31%), and had shorter duration of diabetes mellitus (15 years versus 16 years) compared with secondary prevention participants (n=2220, 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80 [95% CI, 0.67-0.95]; P=0.01), with consistent reductions in both the primary (HR, 0.68 [95% CI, 0.49-0.94]) and secondary (HR, 0.85 [95% CI, 0.69-1.06]) prevention groups (P for interaction=0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78 [95% CI, 0.61-1.00]), nonfatal myocardial infarction (HR, 0.81 [95% CI, 0.59-1.10]), and nonfatal stroke (HR, 0.80 [95% CI, 0.56-1.15]). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P for interaction >0.5 for each outcome). CONCLUSIONS: Canagliflozin significantly reduced major cardiovascular events and kidney failure in patients with type 2 diabetes mellitus and chronic kidney disease, including in participants who did not have previous cardiovascular disease. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02065791.

17.
BMC Nephrol ; 20(1): 258, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31299919

RESUMO

BACKGROUND: Chronic Kidney Disease - Mineral and Bone Disorder (CKD-MBD) is a significant cause of morbidity among haemodialysis patients and is associated with pathological changes in phosphate, calcium and parathyroid hormone (PTH). In the ACTIVE Dialysis study, extended hours dialysis reduced serum phosphate but did not cause important changes in PTH or serum calcium. This secondary analysis aimed to determine if changes in associated therapies may have influenced these findings and to identify differences between patient subgroups. METHODS: The ACTIVE Dialysis study randomised 200 participants to extended hours haemodialysis (≥24 h/week) or conventional haemodialysis (≤18 h/week) for 12 months. Mean differences between treatment arms in serum phosphate, calcium and PTH; and among key subgroups (high vs. low baseline phosphate/PTH, region, time on dialysis, dialysis setting and frequency) were examined using mixed linear regression. RESULTS: Phosphate binder use was reduced with extended hours (- 0.83 tablets per day [95% CI -1.61, - 0.04; p = 0.04]), but no differences in type of phosphate binder, use of vitamin D, dose of cinacalcet or dialysate calcium were observed. In adjusted analysis, extended hours were associated with lower phosphate (- 0.219 mmol/L [- 0.314, - 0.124; P < 0.001]), higher calcium (0.046 mmol/L [0.007, 0.086; P = 0.021]) and no change in PTH (0.025 pmol/L [- 0.107, 0.157; P = 0.713]). The reduction in phosphate with extended hours was greater in those with higher baseline PTH and dialysing at home. CONCLUSION: Extended hours haemodialysis independently reduced serum phosphate levels with minimal change in serum calcium and PTH levels. With a few exceptions, these results were consistent across patient subgroups. TRIAL REGISTRATION: Clinicaltrials.gov NCT00649298 . Registered 1 April 2008.

18.
JAMA Intern Med ; 2019 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-31282924

RESUMO

Importance: Systematic differences between patients included in randomized clinical trials (RCTs) and the general patient population may influence the generalizability of RCT findings. Comprehensive national registries of patients with end-stage kidney disease who are undergoing dialysis provide a unique opportunity to compare trial and real-world patient cohorts. Objective: To determine if participants in large, multicenter dialysis trials were similar to the general population undergoing dialysis in terms of age, comorbidities, and mortality rate. Data Sources: MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials were systematically searched on January 6, 2017, for studies published from January 1, 2007, to December 31, 2016. Data sources were published manuscripts, supplementary material, and trial registration information. Data on the general population undergoing dialysis were derived from the US Renal Data System (USRDS). Data were analyzed from March 17 to July 22, 2018. Study Selection: Randomized clinical trials enrolling only participants undergoing dialysis for end-stage kidney disease with 100 or more adult participants from 2 or more sites. Data Extraction and Synthesis: Abstract screening and data extraction were performed independently by 2 researchers. Data were pooled using a random-effects model. Main Outcomes and Measures: The primary outcome was difference in mean age between the RCT and USRDS populations. Secondary outcomes included differences in mortality rate and comorbidities. Results: The search identified 189 RCTs, enrolling 80 104 participants. Compared with the 2011 USRDS population, RCT participants were younger (mean age, 58.9 years; 95% CI, 58.3-59.5 years vs 61.2 years; P < .001), more likely to be male (58.8%; 95% CI, 57.5%-60.0% vs 55.7%; P < .001), and have coronary artery disease (26.7%; 95% CI, 22.1%-31.4% vs 17.7%; P < .001) and less likely to have diabetes (40.4%; 95% CI, 36.9%-43.8% vs 44.2%; P = .04) or heart failure (19.9%; 95% CI, 15.6%-24.3% vs 29.8%; P < .001). The mortality rate per 100 patient-years during trial participation was less than half that of the USRDS population (8.9; 95% CI, 7.9-10.0 vs 18.6; P < .001). The differences in age, mortality, and coronary artery disease remained when studies recruiting only from the United States were considered. Diabetes was more common in RCT participants from the United States than in the registry population. Conclusions and Relevance: Participants in large, multicenter RCTs of patients with end-stage kidney disease undergoing dialysis are younger, have a different pattern of comorbidities, and have a lower mortality rate than the general population of patients undergoing dialysis. This finding has implications for the generalization of trial results to the broader patient population and for future trial design.

19.
Clin J Am Soc Nephrol ; 14(6): 862-872, 2019 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-31160317

RESUMO

BACKGROUND AND OBJECTIVES: Whether combining changes in eGFR and urine albumin-to-creatinine ratio (UACR) is more strongly associated with outcomes compared with either change alone is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We analyzed 8766 patients with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation Observational (ADVANCE-ON) study. Changes in eGFR and UACR (baseline to 2 years) were defined as ≥40% decrease, minor change, and ≥40% increase. The primary outcome was the composite of major macrovascular (nonfatal or fatal myocardial infarction, nonfatal or fatal stroke, or cardiovascular death), major kidney events (requirement for kidney replacement therapy or kidney death), and all-cause mortality. RESULTS: Over a median of 7.7 years of follow-up, 2191 primary outcomes were recorded. Strong linear associations between eGFR and UACR changes and subsequent risk of the outcome were observed. For eGFR, the hazard ratios were 1.58 (95% confidence interval [95% CI], 1.27 to 1.95) for a decrease ≥40% and 0.82 for an increase ≥40% (95% CI, 0.64 to 1.04) compared with minor change. For UACR, the hazard ratios were 0.96 (95% CI, 0.85 to 1.07) for a decrease ≥40% and 1.32 (95% CI, 1.19 to 1.46) for ≥40% increase compared with minor change. Compared with dual minor changes, both an eGFR decrease ≥40% and a UACR increase ≥40% had 2.31 (95% CI, 1.67 to 3.18) times the risk of the outcome, with evidence of interaction between the two markers. CONCLUSIONS: Clinically meaningful decreases in eGFR and increases in UACR over 2 years, independently and in combination, were significantly associated with higher risk of major clinical outcomes.

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