Search

Clinical Trial registry name and registration number: ClinicalTrials.gov Identifiers: NCT02065791 (CREDENCE), NCT03036150 (DAPA-CKD), NCT03594110 (EMPA-KIDNEY)., (Copyright © 2024 by the American Society of Nephrology.)

Background: In the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin improved kidney and cardiovascular outcomes and reduced the rate of estimated glomerular filtration decline (eGFR slope) in patients with type 2 diabetes and CKD. In other clinical trials of patients with CKD or heart failure, the protective effects of SGLT2 inhibitors on eGFR slope were greater in participants with versus participants without type 2 diabetes. This post hoc analysis of the CREDENCE trial assessed whether the effects of canagliflozin on eGFR slope varied according to patient subgroups by baseline glycated hemoglobin A1c (HbA1c)., Methods: CREDENCE ( ClinicalTrials.gov [ NCT02065791 ]) was a randomized controlled trial in adults with type 2 diabetes with an HbA1c of 6.5%-12.0%, an eGFR of 30-90 ml/min per 1.73 m 2 , and a urinary albumin-to-creatinine ratio of 300-5000 mg/g. Participants were randomly assigned to canagliflozin 100 mg once daily or placebo. We studied the effect of canagliflozin on eGFR slope using linear mixed-effects models., Results: The annual difference in total eGFR slope was 1.52 ml/min per 1.73 m 2 (95% confidence interval [CI], 1.11 to 1.93) slower in participants randomized to canagliflozin compared with placebo. The rate of eGFR decline was faster in those with poorer baseline glycemic control. The mean difference in total eGFR slope between canagliflozin and placebo was greater in participants with poorer baseline glycemic control (difference in eGFR slope of 0.39, 1.36, 2.60, 1.63 ml/min per 1.73 m 2 for HbA1c subgroups 6.5%-7.0%, 7.0%-8.0%, 8.0%-10.0%, 10.0%-12.0%, respectively; Pinteraction = 0.010). The mean difference in change from baseline in urinary albumin-to-creatinine ratio between participants randomized to canagliflozin and placebo was smaller in patients with baseline HbA1c 6.5%-7.0% (-17% [95% CI, -28 to -5]) compared with those with an HbA1c of 7.0%-12% (-32% [95% CI, -40 to -28]; Pinteraction = 0.03)., Conclusions: The effect of canagliflozin on eGFR slope in patients with type 2 diabetes and CKD was more pronounced in patients with higher baseline HbA1c, partly because of the more rapid decline in kidney function in these individuals., Clinical Trial Registry Name and Registration Number: Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE), NCT02065791., (Copyright © 2023 by the American Society of Nephrology.)

Background and Objectives: Clinical trials in nephrology are enriched for patients with micro- or macroalbuminuria to enroll patients at risk of kidney failure. However, patients with normoalbuminuria can also progress to kidney failure. TNF receptor-1, TNF receptor-2, and kidney injury marker-1 (KIM-1) are known to be associated with kidney disease progression in patients with micro- or macroalbuminuria. We assessed the value of TNF receptor-1, TNF receptor-2, and KIM-1 as prognostic biomarkers for CKD progression in patients with type 2 diabetes and normoalbuminuria., Design, Setting, Participants, & Measurements: TNF receptor-1, TNF receptor-2, and KIM-1 were measured using immunoassays in plasma samples from patients with type 2 diabetes at high cardiovascular risk participating in the Canagliflozin Cardiovascular Assessment Study trial. We used multivariable adjusted Cox proportional hazards analyses to estimate hazard ratios per doubling of each biomarker for the kidney outcome, stratified the population by the fourth quartile of each biomarker distribution, and assessed the number of events and event rates., Results: In patients with normoalbuminuria ( n =2553), 51 kidney outcomes were recorded during a median follow-up of 6.1 (interquartile range, 5.8-6.4) years (event rate, 3.5; 95% confidence interval, 2.6 to 4.6 per 1000 patient-years). Each doubling of baseline TNF receptor-1 (hazard ratio, 4.2; 95% confidence interval, 1.8 to 9.6) and TNF receptor-2 (hazard ratio, 2.3; 95% confidence interval, 1.5 to 3.6) was associated with a higher risk for the kidney outcome. Baseline KIM-1, urinary albumin-creatinine ratio, and eGFR were not associated with kidney outcomes. The event rates in the highest quartile of TNF receptor-1 (≥2992 ng/ml) and TNF receptor-2 (≥11,394 ng/ml) were 5.6 and 7.0 events per 1000 patient-years, respectively, compared with 2.8 and 2.3, respectively, in the lower three quartiles., Conclusions: TNF receptor-1 and TNF receptor-2 are associated with kidney outcomes in patients with type 2 diabetes and normoalbuminuria., Clinical Trial Registry Name and Registration Number: CANagliflozin cardioVascular Assessment Study (CANVAS), NCT01032629., (Copyright © 2022 by the American Society of Nephrology.)

Background and Objectives: Atrasentan reduces the risk of kidney failure but increases the risk of edema and, possibly, heart failure. Patients with severe CKD may obtain greater absolute kidney benefits from atrasentan but may also be at higher risk of heart failure. We assessed relative and absolute effects of atrasentan on kidney and heart failure events according to baseline eGFR and urinary albumin-creatinine ratio (UACR) in a post hoc analysis of the Study of Diabetic Nephropathy with Atrasentan (SONAR) trial., Design, Setting, Participants, & Measurements: The effect of atrasentan versus placebo in 3668 patients with type 2 diabetes and CKD with elevated albuminuria was examined in the SONAR trial. We used Cox proportional hazards regression analysis to study effects on the primary kidney outcome (composite of doubling of serum creatinine, kidney failure, or kidney death) and heart failure hospitalization across subgroups of eGFR (<30, ≥30-45, and ≥45 ml/min per 1.73 m 2 ) and UACR (<1000, ≥1000-3000, and ≥3000 mg/g)., Results: Atrasentan reduced the relative risk of the primary kidney outcome (hazard ratio, 0.71; 95% confidence interval, 0.58 to 0.88) consistently across all subgroups of baseline eGFR and UACR (all P interaction >0.21). Patients in the highest UACR and lowest eGFR subgroups, in whom rates of the primary kidney outcome were highest, showed the largest absolute benefit (all P interaction <0.01). The risk of heart failure hospitalization was higher in the atrasentan group (hazard ratio, 1.39; 95% confidence interval, 0.97 to 1.99) and was consistent across subgroups, with no evidence that relative or absolute risks differed across eGFR or UACR subgroups (all P interaction >0.09)., Conclusions: Atrasentan reduced the relative risk of the primary kidney outcome consistently across baseline UACR and eGFR subgroups. The absolute risk reduction was greater among patients in the lowest eGFR and highest albuminuria category who were at highest baseline risk. Conversely, the relative and absolute risks of heart failure hospitalization were similar across baseline UACR and eGFR subgroups. Clinical Trial registry name and registration number: Study of Diabetic Nephropathy with Atrasentan (SONAR), NCT01858532., (Copyright © 2021 by the American Society of Nephrology.)

Background and Objectives: Neuropathy is a common complication of kidney disease that lacks proven disease-modifying treatments. Hemodiafiltration improves clearance of uremic toxins and is associated with better nerve function than hemodialysis. We aimed to determine whether hemodiafiltration reduces the progression of neuropathy in people receiving hemodialysis., Design, Setting, Participants, & Measurements: The Filtration in the Neuropathy of End-Stage Kidney Disease Symptom Evolution (FINESSE) study was an open-label, blinded end point assessment, controlled trial that randomized maintenance hemodialysis recipients to hemodiafiltration or high-flux hemodialysis for 48 months or until death or cessation of dialysis at four study centers. The primary outcome was the mean change in the yearly modified total neuropathy score from baseline, with time points weighted equally., Results: A total of 124 participants were randomized and followed for a mean of 41 months. At baseline, neuropathy was present in 91 (73%) participants (modified total neuropathy score greater than or equal to two), and 38 (31%) had moderate to severe neuropathy (modified total neuropathy score 9-28). Convection volume in the hemodiafiltration arm was a median of 24.7 (interquartile range, 22.4-26.5) L. The mean modified total neuropathy score (SEM) worsened by 1.7 (0.4)/28 and 1.2 (0.4)/28 in the hemodiafiltration and hemodialysis groups, respectively, with a mean difference of 0.5 (95% confidence interval, -0.7 to 1.7; P =0.37). There was no difference in survival (hazard ratio, 1.24; 95% confidence interval, 0.61 to 2.51; log rank P =0.55) or any of the prespecified adverse events. There was no difference between groups in the number of participants who suffered an adverse event adjusted by follow-up time (relative risk, 1.05; 95% confidence interval, 0.83 to 1.32; P =0.68)., Conclusions: Neuropathy is still a common complication of kidney disease without disease-altering therapy. Hemodiafiltration did not affect neuropathy progression compared with hemodialysis., Clinical Trial Registry Name and Registration Number: Filtration in the Neuropathy of End-Stage Kidney Disease Symptom Evolution (FINESSE), ACTRN12609000615280., (Copyright © 2021 by the American Society of Nephrology.)

Background and Objectives: The kidney protective effects of renin-angiotensin system inhibitors are greater in people with higher levels of albuminuria at treatment initiation. Whether this applies to sodium-glucose cotransporter 2 (SGLT2) inhibitors is uncertain, particularly in patients with a very high urine albumin-to-creatinine ratio (UACR; ≥3000 mg/g). We examined the association between baseline UACR and the effects of the SGLT2 inhibitor, canagliflozin, on efficacy and safety outcomes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) randomized controlled trial., Design, Setting, Participants, & Measurements: The study enrolled 4401 participants with type 2 diabetes, an eGFR of 30 to <90 ml/min per 1.73 m 2 , and UACR of >300 to 5000 mg/g. Using Cox proportional hazards regression, we examined the relative and absolute effects of canagliflozin on kidney, cardiovascular, and safety outcomes according to a baseline UACR of ≤1000 mg/g ( n =2348), >1000 to <3000 mg/g ( n =1547), and ≥3000 mg/g ( n =506). In addition, we examined the effects of canagliflozin on UACR itself, eGFR slope, and the intermediate outcomes of glycated hemoglobin, body weight, and systolic BP., Results: Overall, higher UACR was associated with higher rates of kidney and cardiovascular events. Canagliflozin reduced efficacy outcomes for all UACR levels, with no evidence that relative benefits varied between levels. For example, canagliflozin reduced the primary composite outcome by 24% (hazard ratio [HR], 0.76; 95% confidence interval [95% CI], 0.56 to 1.04) in the lowest UACR subgroup, 28% (HR, 0.72; 95% CI, 0.56 to 0.93) in the UACR subgroup >1000 to <3000 mg/g, and 37% (HR, 0.63; 95% CI, 0.47 to 0.84) in the highest subgroup ( P heterogeneity =0.55). Absolute risk reductions for kidney outcomes were greater in participants with higher baseline albuminuria; the number of primary composite events prevented across ascending UACR categories were 17 (95% CI, 3 to 38), 45 (95% CI, 9 to 81), and 119 (95% CI, 35 to 202) per 1000 treated participants over 2.6 years ( P heterogeneity =0.02). Rates of kidney-related adverse events were lower with canagliflozin, with a greater relative reduction in higher UACR categories., Conclusions: Canagliflozin safely reduces kidney and cardiovascular events in people with type 2 diabetes and severely increased albuminuria. In this population, the relative kidney benefits were consistent over a range of albuminuria levels, with greatest absolute kidney benefit in those with an UACR ≥3000 mg/g., Clinical Trial Registry Name and Registration Number: ClinicalTrials.gov: CREDENCE, NCT02065791., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021&#95;02&#95;22&#95;CJN15260920&#95;final.mp3., (Copyright © 2021 by the American Society of Nephrology.)

Background and Objectives: The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial demonstrated that the sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin reduced the risk of kidney failure and cardiovascular events in participants with type 2 diabetes mellitus and CKD. Little is known about the use of SGLT2 inhibitors in patients with eGFR <30 ml/min per 1.73 m 2 . The participants in the CREDENCE study had type 2 diabetes mellitus, a urinary albumin-creatinine ratio >300-5000 mg/g, and an eGFR of 30 to <90 ml/min per 1.73 m 2 at screening. This post hoc analysis evaluated participants with eGFR <30 ml/min per 1.73 m 2 at randomization., Design, Setting, Participants, & Measurements: Effects of eGFR slope through week 130 were analyzed using a piecewise, linear, mixed-effects model. Efficacy was analyzed in the intention-to-treat population, on the basis of Cox proportional hazard models, and safety was analyzed in the on-treatment population. At randomization (an average of 29 days after screening), 174 of 4401 (4%) participants had an eGFR <30 ml/min per 1.73 m 2 (mean [SD] eGFR, 26 [3] ml/min per 1.73 m 2 )., Results: From weeks 3 to 130, there was a 66% difference in the mean rate of eGFR decline with canagliflozin versus placebo (mean slopes, -1.30 versus -3.83 ml/min per 1.73 m 2 per year; difference, -2.54 ml/min per 1.73 m 2 per year; 95% confidence interval [CI], 0.90 to 4.17). Effects of canagliflozin on kidney, cardiovascular, and mortality outcomes were consistent for those with eGFR <30 and ≥30 ml/min per 1.73 m 2 (all P interaction >0.20). The estimate for kidney failure in participants with eGFR <30 ml/min per 1.73 m 2 (hazard ratio, 0.67; 95% CI, 0.35 to 1.27) was similar to those with eGFR ≥30 ml/min per 1.73 m 2 (hazard ratio, 0.70; 95% CI, 0.54 to 0.91; P interaction=0.80). There was no imbalance in the rate of kidney-related adverse events or AKI associated with canagliflozin between participants with eGFR <30 and ≥30 ml/min per 1.73 m 2 (all P interaction >0.12)., Conclusions: This post hoc analysis suggests canagliflozin slowed progression of kidney disease, without increasing AKI, even in participants with eGFR <30 ml/min per 1.73 m 2 ., (Copyright © 2020 by the American Society of Nephrology.)

Background and Objectives: Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is commonly prescribed to patients with type 2 diabetes. As this drug is primarily eliminated by the kidney, a reduced dose is recommended for patients with CKD. Some evidence suggests that sitagliptin is associated with a higher risk of congestive heart failure, particularly at higher doses. We compare the 1-year risk of death or hospitalization with congestive heart failure in patients with CKD newly prescribed sitagliptin at >50 versus ≤50 mg/d., Design, Setting, Participants, & Measurements: This population-based cohort study included older adults (>66 years) with type 2 diabetes and an eGFR<45 ml/min per 1.73 m 2 (but not receiving dialysis) who were newly prescribed sitagliptin between 2010 and 2017 in Ontario, Canada. We used inverse probability of treatment weighting on the basis of propensity scores to balance baseline characteristics. The primary composite outcome was death or hospitalization with congestive heart failure. Secondary outcomes included hospitalization with pancreatitis or hypoglycemia, all-cause hospitalization, and glycemic control. Weighted hazard ratios were obtained using Cox proportional hazards regression, and 95% confidence intervals were obtained using bootstrap variance estimators., Results: Of 9215 patients, 6518 started sitagliptin at >50 mg/d, and 2697 started sitagliptin at ≤50 mg/d. The 1-year risk of death or hospitalization with congestive heart failure did not differ significantly between groups (79 versus 126 events per 1000 person-years; weighted hazard ratio, 0.88; 95% confidence interval, 0.67 to 1.14); hospitalization with pancreatitis (weighted hazard ratio, 0.98; 95% confidence interval, 0.32 to 3.03) and hypoglycemia (weighted hazard ratio, 1.10; 95% confidence interval, 0.64 to 1.90) also did not differ significantly between groups. Patients starting sitagliptin at >50 mg/d had lower mean glycated hemoglobin concentrations (weighted between-group difference, -0.12%; 95% confidence interval, -0.19 to -0.06) and a lower risk of all-cause hospitalization (weighted hazard ratio, 0.81; 95% confidence interval, 0.66 to 0.98)., Conclusions: The risk of death or congestive heart failure was not higher in older adults with CKD starting sitagliptin at >50 versus ≤50 mg/d., Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2020&#95;11&#95;25&#95;CJN08310520&#95;final.mp3., (Copyright © 2020 by the American Society of Nephrology.)

Background and Objectives: In the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG Outcome), empagliflozin, in addition to standard of care, significantly reduced risk of cardiovascular death by 38%, hospitalization for heart failure by 35%, and incident or worsening nephropathy by 39% compared with placebo in patients with type 2 diabetes and established cardiovascular disease. Using EMPA-REG Outcome data, we assessed whether the Kidney Disease Improving Global Outcomes (KDIGO) CKD classification had an influence on the treatment effect of empagliflozin., Design, Setting, Participants, & Measurements: Patients with type 2 diabetes, established atherosclerotic cardiovascular disease, and eGFR≥30 ml/min per 1.73 m 2 at screening were randomized to receive empagliflozin 10 mg, empagliflozin 25 mg, or placebo once daily in addition to standard of care. Post hoc , we analyzed cardiovascular and kidney outcomes, and safety, using the two-dimensional KDIGO classification framework., Results: Of 6952 patients with baseline eGFR and urinary albumin-creatinine ratio values, 47%, 29%, 15%, and 8% were classified into low, moderately increased, high, and very high KDIGO risk categories, respectively. Empagliflozin showed consistent risk reductions across KDIGO categories for cardiovascular outcomes ( P values for treatment by subgroup interactions ranged from 0.26 to 0.85) and kidney outcomes ( P values for treatment by subgroup interactions ranged from 0.16 to 0.60). In all KDIGO risk categories, placebo and empagliflozin had similar adverse event rates, the notable exception being genital infection events, which were more common with empagliflozin for each category., Conclusions: The observed effects of empagliflozin versus placebo on cardiovascular and kidney outcomes were consistent across the KDIGO risk categories, indicating that the effect of treatment benefit of empagliflozin was unaffected by baseline CKD status., Clinical Trial Registry Name and Registration Number: EMPA-REG OUTCOME, NCT01131676., (Copyright © 2020 by the American Society of Nephrology.)

Background and Objectives: Elevated BP is an important risk factor for cardiovascular disease, with a prevalence of over 80% in patients undergoing maintenance dialysis. We assessed the comparative BP-lowering efficacy and the safety of BP-lowering drugs in patients undergoing maintenance dialysis., Design, Settings, Participants, & Measurements: We performed a frequentist random effects network meta-analysis of randomized, controlled trials evaluating BP-lowering agents in adult patients undergoing maintenance dialysis. Electronic databases (CENTRAL, MEDLINE, and Embase) were systematically searched (up to August 2018) for relevant trials. The main outcome was systolic BP reduction., Results: Forty trials (4283 participants) met our inclusion criteria. Angiotensin-converting enzyme inhibitors, β -blockers, calcium-channel blockers, and aldosterone antagonists lowered systolic BP to a greater extent than placebo, with effect sizes ranging from -10.8 mm Hg (95% confidence interval, -14.8 to -6.7 mm Hg) for the aldosterone antagonists to -4.3 mm Hg (95% confidence interval, -7.2 to -1.5 mm Hg) for angiotensin-converting enzyme inhibitors. Aldosterone antagonists and β -blockers were superior to angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, calcium-channel blockers, and renin inhibitors at lowering systolic BP. Compared with angiotensin-converting enzyme inhibitors, aldosterone antagonists and β -blockers lowered systolic BP by 6.4 mm Hg (95% confidence interval, -11.4 to -1.4 mm Hg) and 4.4 mm Hg (95% confidence interval, -7.4 to -1.3 mm Hg), respectively. Systolic BP reduction was not different with angiotensin receptor blockers, α -blockers, and calcium-channel blockers compared with angiotensin-converting enzyme inhibitors. Renin inhibitors were less effective. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists incurred risks of drug discontinuation due to adverse events and hypotension., Conclusions: BP-lowering agents significantly reduced systolic BP in patients undergoing maintenance dialysis. β -Blockers and aldosterone antagonists may confer larger reductions, although treatment with aldosterone antagonists may be limited by adverse events., (Copyright © 2020 by the American Society of Nephrology.)

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 ( P adjusted =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; P adjusted =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; P adjusted =0.04), Mental Component Summary (mean difference, 2.5; 95% CI, 0.5 to 4.6; P =0.02; P adjusted =0.05) and Kidney Disease Component Score (mean difference, 3.5; 95% CI, 1.5 to 5.5; P =0.001; P adjusted =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., (Copyright © 2019 by the American Society of Nephrology.)

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., (Copyright © 2019 by the American Society of Nephrology.)

IgA nephropathy (IgAN) is an important cause of ESKD for which there are no approved therapies. A challenge for evaluating treatments for IgAN is the usual long time course for progression to ESKD. The aim of this Kidney Health Initiative project was to identify surrogate end points that could serve as reliable predictors of a treatment's effect on long-term kidney outcomes in IgAN and be used as a basis for approval. Proteinuria was identified as the most widely recognized and well studied risk factor for progression to ESKD in IgAN. The workgroup performed a critical review of the data on proteinuria reduction as a surrogate end point for a treatment's effect on progression to ESKD in IgAN. Epidemiologic data indicate a strong and consistent relationship between the level and duration of proteinuria and loss of kidney function. Trial-level analyses of data from 13 controlled trials also show an association between treatment effects on percent reduction of proteinuria and treatment effects on a composite of time to doubling of serum creatinine, ESKD, or death. We conclude that data support the use of proteinuria reduction as a reasonably likely surrogate end point for a treatment's effect on progression to ESKD in IgAN. In the United States, reasonably likely surrogate end points can be used as a basis for accelerated approval of therapies intended to treat serious or life-threatening conditions, such as IgAN. The clinical benefit of products approved under this program would need to be verified in a postmarketing confirmatory trial., (Copyright © 2019 by the American Society of Nephrology.)

Background and Objectives: Endothelin A receptor antagonists (ERAs) decrease residual albuminuria in patients with diabetic kidney disease; however, their clinical utility may be limited by fluid retention. Consequently, the primary objective of this study was to identify predictors for ERA-induced fluid retention among patients with type 2 diabetes and CKD. A secondary objective was to determine if the degree of fluid retention necessarily correlated with the magnitude of albuminuria reduction in those patients receiving ERAs., Design, Setting, Participants, & Measurements: A post hoc analysis was conducted of the phase IIb atrasentan trials assessing albuminuria reduction in 211 patients with type 2 diabetes, urine albumin/creatinine ratios of 300-3500 mg/g, and eGFRs of 30-75 ml/min per 1.73 m(2) who were randomly assigned to receive placebo (n=50) or atrasentan 0.75 mg/d (n=78) or 1.25 mg/d (n=83) for 12 weeks. Changes in body weight and hemoglobin (Hb) after 2 weeks of treatment were used as surrogate markers of fluid retention., Results: Baseline predictors of weight gain after 2 weeks of atrasentan treatment were higher atrasentan dose, lower eGFR, higher glycated hemoglobin, higher systolic BP, and lower homeostatic metabolic assessment product. Higher atrasentan dose and lower eGFR also predicted decreases in Hb. There were no changes in B-type natriuretic peptide. There was no correlation between reduction in albuminuria after 2 weeks of atrasentan treatment and changes in body weight or Hb., Conclusions: In the Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With Atrasentan/JAPAN trials, atrasentan-associated fluid retention was more likely in patients with diabetes and nephropathy who had lower eGFR or received a higher dose of atrasentan. Finding that albuminuria reduction was not associated with changes in body weight and Hb suggests that the albuminuria-reducing efficacy of atrasentan is not impaired by fluid retention., (Copyright © 2015 by the American Society of Nephrology.)

Background and Objectives: Clinical trials of the intensity of renal replacement therapy (RRT) for people with acute kidney injury (AKI) have produced conflicting results. A systematic review and meta-analysis was undertaken to assess the effect of different intensities of RRT on all-cause mortality and renal recovery in AKI patients., Design, Setting, Participants, & Measurements: MEDLINE, EMBASE, and the Cochrane Library database were systematically searched for trials published between 1950 and 2009. Inclusion criteria were completed, prospective, adult-population, randomized controlled studies. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated. Summary estimates of RR were obtained using a random effects model. Heterogeneity, metaregression, publication bias, and subgroup analyses were conducted., Results: Eight trials were identified that provided data on 3841 patients and 1808 deaths. More intense RRT (35 to 48 ml/kg per h or equivalent) had no overall effect on the risk of death (RR 0.89, 95% CI 0.76 to 1.04, P = 0.143) or recovery of renal function (RR 1.12, 95% CI 0.95 to 1.31, P = 0.181) compared with less-intensive regimens (20 to 25 ml/kg per h or equivalent). Significant heterogeneity was identified with contributing factors including publication year (P = 0.004) and Jadad score (P = 0.048)., Conclusions: Within the intensity ranges studied, higher intensity RRT does not reduce mortality rates or improve renal recovery among patients with AKI. The results do not negate the importance of RRT intensity in the treatment of AKI patients but rather reinforce the need to better understand the effects of treatment modalities, doses, and timing in this varied, high-risk population.