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Rationale & Objective: Little information exists on the incidence of and risk factors for chronic kidney disease (CKD) in contemporary US cohorts and whether risk factors differ by race, sex, or region in the United States., Study Design: Observational cohort study., Setting & Participants: 4,198 Black and 7,799 White participants aged at least 45 years, recruited from 2003 through 2007 across the continental United States, with baseline estimated glomerular filtration rate (eGFR)>60mL/min/1.73m 2 and eGFR assessed again approximately 9 years later., Exposures: Age, sex, race (Black or White), region ("stroke belt" or other), education, income, systolic blood pressure, body mass index, diabetes, coronary heart disease, hyperlipidemia, smoking, and albuminuria., Outcomes: (1) eGFR change and (2) incident CKD defined as eGFR<60mL/min/1.73m 2 and≥40% decrease from baseline or kidney failure., Analytical Approach: Linear regression and modified Poisson regression were used to determine the association of risk factors with eGFR change and incident CKD overall and stratified by race, sex, and region., Results: Mean age of participants was 63±8 (SD) years, 54% were female, and 35% were Black. After 9.4±1.0 years of follow-up, CKD developed in 9%. In an age-, sex-, and race-adjusted model, Black race (β =-0.13; P<0.001) was associated with higher risk of eGFR change, but this was attenuated in the fully adjusted model (β=0.02; P=0.5). Stroke belt residence was independently associated with eGFR change (β =-0.10; P<0.001) and incident CKD (relative risk, 1.14 [95% CI, 1.01-1.30]). Albuminuria was more strongly associated with eGFR change (β of-0.26 vs-0.17; P=0.01 for interaction) in Black compared with White participants. Results were similar for incident CKD., Limitations: Persons of Hispanic ethnicity were excluded; unknown duration and/or severity of risk factors., Conclusions: Established CKD risk factors accounted for higher risk of incident CKD in Black versus White individuals. Albuminuria was a stronger risk factor for eGFR decrease and incident CKD in Black compared with White individuals. Living in the US stroke belt is a novel risk factor for CKD., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the formation of multiple kidney cysts that leads to growth in total kidney volume (TKV) and progression to kidney failure. Venglustat is a glucosylceramide synthase inhibitor that has been shown to inhibit cyst growth and reduce kidney failure in preclinical models of ADPKD., Study Design: STAGED-PKD was a 2-stage, multicenter, double-blind, randomized, placebo-controlled phase 2/3 study in adults with ADPKD at risk of rapidly progressive disease, who were selected based on Mayo Clinic imaging classification of ADPKD class 1C, 1D, or 1E and an estimated glomerular filtration rate (eGFR) of 30-89.9mL/min/1.73m 2 ., Setting & Participants: Enrollment included 236 and 242 patients in stages 1 and 2, respectively., Interventions: In trial stage 1, the patients were randomized 1:1:1 to venglustat, 8mg; venglustat, 15mg; or placebo. In stage 2, the patients were randomized 1:1 to venglustat, 15mg (highest dose identified as safe and well tolerated in stage 1), or placebo., Outcomes: Primary end points were rate of change in TKV over 18 months in stage 1 and eGFR slope over 24 months in stage 2. Secondary end points were eGFR slope over 18 months (stage 1), rate of change in TKV (stage 2), and safety/tolerability, pain, and fatigue (stages 1 and 2)., Results: A prespecified interim futility analysis showed that venglustat treatment had no effect on the annualized rate of change in TKV over 18 months (stage 1) and had a faster rate of decline in eGFR slope over 24 months (stage 2). Due to this lack of efficacy, the study was terminated early., Limitations: The short follow-up period after the end of treatment and limited generalizability of the findings., Conclusions: In patients with rapidly progressing ADPKD, treatment with venglustat at either 8mg or 15mg showed no change in the rate of change in TKV and a faster rate of eGFR decline in STAGED-PKD despite a dose-dependent decrease in plasma glucosylceramide levels., Funding: This study was funded by Sanofi., Trial Registration: Registered at ClinicalTrials.gov with study number NCT03523728., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Clonal hematopoiesis of indeterminate potential (CHIP), defined by the age-related ontogenesis of expanded leukemogenic variants indicative of a genetically distinct clonal leukocyte population, is associated with risk of hematologic malignancy and cardiovascular disease. In experimental models, recapitulation of CHIP promotes kidney interstitial fibrosis with direct tissue infiltration of donor macrophages. We tested the hypothesis that CHIP is associated with kidney function decline in the general population., Study Design: Cohort study., Setting & Participants: 12,004 individuals from 3 community-based cohorts in the TOPMed Consortium., Exposure: CHIP status from whole-genome sequences obtained from DNA extracted from peripheral blood., Outcome: Risk of 30% decline in estimated glomerular filtration rate (eGFR) and percent eGFR decline per year during the follow-up period., Analytical Approach: Cox proportional hazards models for 30% eGFR decline end point and generalized estimating equations for annualized relative change in eGFR with meta-analysis. Study-specific estimates were combined using fixed-effect meta-analysis., Results: The median baseline eGFR was 84mL/min/1.73m 2 . The prevalence of CHIP was 6.6%, 9.0%, and 12.2% in persons aged 50-60, 60-70, and>70 years, respectively. Over a median follow-up period of 8 years, for the 30% eGFR outcome 205 events occurred among 1,002 CHIP carriers (2.1 events per 100 person-years) and 2,041 events in persons without CHIP (1.7 events per 100 person-years). In meta-analysis, CHIP was associated with greater risk of a 30% eGFR decline (17% [95% CI, 1%-36%] higher; P=0.04). Differences were not observed between those with baseline eGFR above or below 60mL/min/1.73m 2 , of age above or below 60 years, or with or without diabetes., Limitations: Small number of participants with moderate-to-advanced kidney disease and restricted set of CHIP driver variants., Conclusions: We report an association between CHIP and eGFR decline in 3 general population cohorts without known kidney disease. Further studies are needed to investigate this novel condition and its potential impact among individuals with overt kidney disease., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Achievement of decongestion in acute heart failure (AHF) is associated with improved survival and cardiovascular outcomes but can be associated with acute declines in estimated glomerular filtration rate (eGFR). We examined whether the rate of in-hospital decongestion is associated with longer term kidney function decline., Study Design: Post hoc analysis of trial data., Settings & Participants: Patients with ≥2 measures of kidney function (n = 3,500) from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial., Exposure: In-hospital rate of change in assessments of volume overload, including B-type natriuretic peptide (BNP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and clinical congestion score (0-12); and rate of change in hemoconcentration including measures of hematocrit, albumin, and total protein., Outcome: Incident chronic kidney disease GFR category 4 or worse (chronic kidney disease [CKD] categories G4-G5; defined by a new eGFR of <30 mL/min/1.73 m 2 ) and eGFR decline of >40%., Analytical Approach: Multivariable cause-specific hazards models., Results: Over median 10-month follow-up period, faster decreases in volume overload and more rapid increases in hemoconcentration were associated with a decreased risk of incident CKD G4-G5 and eGFR decline of >40%. In adjusted analyses, for every 6% faster decline in BNP per week, there was a 32% lower risk of both incident CKD G4-G5 (HR, 0.68 [95% CI, 0.58-0.79]) and eGFR decline of >40% (HR, 0.68 [95% CI, 0.57-0.80]). For every 1% faster increase per week in absolute hematocrit, there was a lower risk for both incident CKD G4-G5 (HR, 0.73 [95% CI, 0.64-0.84]) and eGFR decline of >40% (HR, 0.82 [95% CI, 0.71-0.95]), with results consistent for other biomarkers., Limitations: Possibility of residual confounding., Conclusions: These results provide reassurance that more rapid decongestion in patients with AHF does not increase the risk of adverse kidney outcomes in patients with heart failure., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Optimal blood pressure (BP) control is a major therapeutic strategy in the management of chronic kidney disease (CKD). We studied the association between BP and adverse kidney outcomes within a diverse cohort of Koreans with CKD., Study Design: Prospective observational cohort study., Setting & Participants: 2,044 participants from the Korean Cohort Study for Outcomes in Patients With CKD (KNOW-CKD)., Exposures: Baseline and time-updated systolic BP (SBP) and diastolic BP (DBP)., Outcome: A composite kidney outcome of a≥50% decline in estimated glomerular filtration rate (eGFR) from the baseline value or incident kidney replacement therapy., Analytical Approach: Multivariate cause-specific hazards models and marginal structural models were fitted for baseline and time-updated BP, respectively., Results: During 7,472 person-years of follow-up, the primary composite kidney outcome occurred in 473 participants (23.1%), an incidence rate of 63.3 per 1,000 patient-years. Compared with baseline SBP<120mm Hg, the hazard ratios (HRs) for 120-129, 130-139, and≥140mm Hg were 1.10 (95% CI, 0.83-1.44), 1.20 (95% CI, 0.93-1.59), and 1.43 (95% CI, 1.07-1.91), respectively. This association was more evident in the model with time-updated SBP, for which the corresponding HRs were 1.31 (95% CI, 0.98-1.75), 1.59 (95% CI, 1.16-2.16), and 2.29 (95% CI, 1.69-3.11), respectively. In the analyses of DBP, we observed that time-updated DBP but not baseline DBP was significantly associated with the composite kidney outcome. Compared to patients with SBP<120mm Hg, patients with higher SBP had steeper slopes of eGFR decline. In the model including both SBP and DBP, only SBP was significantly associated with the composite kidney outcome., Limitations: Observational design, unmeasured confounders, and use of office BPs only., Conclusions: In patients with CKD, higher SBP and DBP levels were associated with a higher risk of a composite kidney outcome reflecting CKD progression. SBP had a greater association with adverse kidney outcomes than DBP., (Copyright © 2021 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Physical activity is associated with lower risk for cardiovascular disease, diabetes, and hypertension, which have shared risk factor profiles with chronic kidney disease (CKD). However, there are conflicting findings regarding the relationship between physical activity and CKD. The objective was to evaluate the association between physical activity and CKD development over long-term follow-up using the Atherosclerosis Risk in Communities (ARIC) Study., Study Design: Prospective cohort study., Setting & Participants: 14,537 participants aged 45 to 64 years., Predictors: Baseline physical activity status was assessed using the modified Baecke Physical Activity Questionnaire at visit 1 (1987-1989) and categorized according to the 2018 Physical Activity Guidelines for Americans to group participants as inactive, insufficiently active, active, and highly active., Outcomes: Incident CKD defined as estimated glomerular filtration rate (eGFR)<60mL/min/1.73m 2 at follow-up and≥25% decline in eGFR relative to baseline, CKD-related hospitalization or death, or initiation of kidney replacement therapy., Analytical Approach: Cox proportional hazards regression., Results: At baseline, 37.8%, 24.2%, 22.7%, and 15.3% of participants were classified as inactive, insufficiently active, active, and highly active, respectively. During a median follow-up of 24 years, 33.2% of participants developed CKD. After adjusting for age, sex, race-center, education, smoking status, diet quality, diabetes, coronary heart disease, hypertension, antihypertensive medication, body mass index, and baseline eGFR, higher categories of physical activity were associated with lower risk for CKD compared with the inactive group (HRs for insufficiently active, 0.95 [95% CI, 0.88-1.02]; active, 0.93 [95% CI, 0.86-1.01]; highly active, 0.89 [95% CI, 0.81-0.97]; P for trend = 0.007)., Limitations: Observational design and self-reported physical activity that was based on leisure time activity only. Due to low numbers, participants who were not Black or White were excluded., Conclusions: Highly active participants had lower risk for developing CKD compared with inactive participants., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Soluble urokinase plasminogen activator receptor (suPAR) is a novel biomarker associated with incident chronic kidney disease (CKD) and has been identified as an independent risk factor for CKD progression in children, although these findings remain preliminary, limited to a single point in time, and unreplicated in pediatric cohorts., Study Design: Prospective longitudinal cohort study., Setting & Participants: 565 participants aged 1 to 16 years enrolled in the Chronic Kidney Disease in Children (CKiD) Study., Exposure: Plasma suPAR levels, categorized by quartiles, measured at study entry and a 6-month follow-up interval., Outcome: CKD progression, defined as the initiation of kidney replacement therapy (dialysis or transplantation) or >50% decline in estimated glomerular filtrate rate (eGFR)., Analytic Approach: Associations between plasma suPAR quartiles and risk for CKD progression were estimated using lognormal survival models, adjusting for potential confounders., Results: Participants in the highest suPAR quartile experienced 54% faster progression compared with the lowest quartile after adjustment for demographic and traditional CKD risk factors (P < 0.001). Addition of eGFR to the model attenuated the risk, although those in the highest quartile experienced 33% faster progression compared with the lowest quartile (P = 0.008). Plasma suPAR levels showed little change over 6 months., Limitations: Potential for residual confounding, reliance on observational data, relatively fewer patients with higher eGFRs for subgroup analysis., Conclusions: Higher suPAR levels are associated with shorter time to kidney replacement therapy or halving of eGFR in children with CKD. This association is attenuated slightly with inclusion of eGFR in regression modeling but remains a significant association for participants with the highest suPAR levels., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: In populations with folic acid fortification or supplementation, the main nutritional determinant of total homocysteine levels is vitamin B 12 (B12) status. We aimed to evaluate the modifying effect of B12 levels on the association between folic acid treatment and chronic kidney disease (CKD) progression., Study Design: A post hoc analysis of an interventional trial., Setting & Participants: This is a post hoc analysis of 1,374 hypertensive adults with mild to moderate CKD and B12 measurements at baseline from the kidney disease substudy of the China Stroke Primary Prevention Trial (CSPPT), conducted in 20 communities in Jiangsu province in China, a region with low folate consumption., Interventions: Assignments to a double-blinded daily treatment of enalapril, 10mg, and folic acid, 0.8mg; or enalapril, 10mg, alone., Outcomes: The primary outcome was progression of CKD (defined as a decrease in estimated glomerular filtration rate [eGFR] ≥ 30% and to a level of<60mL/min/1.73m 2 if baseline eGFR was≥60mL/min/1.73m 2 ; or a decrease in eGFR≥50% if baseline eGFR was<60mL/min/1.73m 2 ; or kidney failure)., Results: Mean baseline eGFR in this study was 86.1±20.5 (SD) mL/min/1.73m 2 . Median treatment duration was 4.4 years. Among participants with higher baseline B12 levels (≥248pmol/L), compared to enalapril alone, enalapril-folic acid treatment was associated with an 83% reduction in the odds of the primary outcome (OR, 0.17; 95% CI, 0.07-0.40). However, among those with baseline B12 levels<248pmol/L (metabolic B12 deficiency), there was no significant group difference in the primary outcome (OR, 1.21; 95% CI, 0.51-2.85). The interaction between B12 level and folic acid treatment was significant (P = 0.001)., Limitations: The analysis is post hoc and event rate is low., Conclusions: Folic acid treatment was associated with a greater reduction in the odds of CKD progression among patients with mild to moderate CKD and higher B12 levels., Funding: Government funding (National Key Research and Development Program of China)., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Data for the association of sex with chronic kidney disease (CKD) progression are conflicting, a relationship this study sought to examine., Study Design: Pooled analysis of 4 Italian observational cohort studies., Setting & Participants: 1,311 older men and 1,024 older women with estimated glomerular filtration rate (eGFR)<45mL/min/1.73m 2 followed up in renal clinics., Predictor: Sex., Outcomes: End-stage kidney disease (ESKD), defined as maintenance dialysis or kidney transplantation, as the primary outcome; all-cause mortality and eGFR decline as secondary outcomes., Analytical Approach: Cox proportional hazard analysis to estimate the relative risk for ESKD and mortality and linear mixed models to estimate the rate of eGFR decline., Results: Age, systolic blood pressure, and use of renin-angiotensin system inhibitors were similar in men and women. Baseline eGFRs were 27.6±10.2 in men and 26.0±10.6mL/min/1.73m 2 in women (P<0.001), while median proteinuria was lower in women (protein excretion, 0.45 [IQR, 0.14-1.10] g/d) compared with men (0.69 [IQR 0.19-1.60] g/d; P<0.001). During a median follow-up of 4.2 years, 757 developed ESKD (59.4% men) and 471 died (58.4% men). The adjusted risks for ESKD and mortality were higher in men (HRs of 1.50 [95% CI, 1.28-1.77] and 1.30 [95% CI, 1.06-1.60], respectively). This finding was consistent across CKD stages. We observed a significant interaction between sex and proteinuria, with the risk for ESKD in men being significantly greater than for women at a level of proteinuria of ∼0.5g/d or greater. The slope of decline in eGFR was steeper in men (-2.09; 95% CI, -2.21 to-1.97mL/min/1.73m 2 per year) than in women (-1.79; 95% CI, -1.92 to-1.66mL/min/1.73m 2 per year; P<0.001). Although sex differences in eGFR decline were not different across CKD stages (P=0.3), the difference in slopes between men and women was progressively larger with proteinuria >0.5g/d (P = 0.04)., Limitations: Residual confounding; only whites were included., Conclusions: Excess renal risk in men may, at least in part, be related to higher levels of proteinuria in men compared with women., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Chronic kidney disease (CKD), defined as estimated glomerular filtration rate (eGFR)<60mL/min/1.73m 2 , is a risk factor for cardiovascular morbidity and mortality. Little is known about low birth weight and risk for CKD in middle-aged adults in the general population. We estimated the causal association between birth weight and eGFR in a Dutch cohort of middle-aged men and women., Study Design: Retrospective cohort study., Setting & Participants: 6,671 participants in the Netherlands Epidemiology of Obesity (NEO) Study. Replication study using data for 133,814 participants studied by the CKDGen consortium., Exposure: Birth weight was self-reported and also based on an instrumental variable, 59 birth weight-associated genetic variants, derived from an independent data source., Outcome: eGFR at the age of 45 to 65 years., Analytical Approach: We assessed the association between self-reported birth weight and eGFR in the NEO Study using multivariable linear regression, adjusted for age, sex, education, smoking, and alcohol use. The effect of the instrument on eGFR was estimated using separate 2-sample Mendelian randomization analyses: one using individual data from the NEO cohort and one using summary data from the CKDGen consortium., Results: At baseline, mean eGFR was 86±12.4 (SD) mL/min/1.73m 2 . After multivariable adjustment, self-reported birth weight was not associated with kidney function in middle age. Two-sample Mendelian randomization analysis showed that in the NEO cohort, for each 500-g lower birth weight defined using genetic variants, there was a 3.7 (95% CI, 0.5-6.9)-mL/min/1.73m 2 lower eGFR at the age of 45 to 65 years. However, using CKDGen summary-level data, there was a smaller nonsignificant relationship between birth weight and eGFR., Limitations: Birth weight was self-reported., Conclusions: Lower birth weight defined using genetic variants was associated with lower eGFRs in Dutch middle-aged adults. However, this finding was not replicated within the CKDGen consortium., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Progression of chronic kidney disease (CKD) in sickle cell disease (SCD) and its risk factors remain poorly defined. We identified characteristics associated with CKD as well as decline in estimated glomerular filtration rate (eGFR) and presence of proteinuria over time in adults with SCD., Study Design: Retrospective observational study., Setting & Participants: Patients with SCD 18 years or older in a single center from 2004 to 2013., Predictors: Baseline clinical and laboratory measures, comorbid conditions, SCD-related complications, relevant treatments, and severity of genotypes defined as severe (homozygous SCD [HbSS]/sickle-β 0 -thalassemia [HbSβ 0 ]) or mild (hemoglobin SC disease [HbSC]/sickle-β + -thalassemia [HbSβ + ]-thalassemia)., Outcomes: Presence at baseline of CKD, defined here as eGFR<90mL/min/1.73m 2 or proteinuria (≥1+) on urinalysis or current kidney transplant or dialysis therapy; change in eGFR; and presence of proteinuria over time., Analytical Approach: Logistic regression for baseline CKD. Linear mixed-effects model for eGFR decline and generalized linear mixed-effects model for proteinuria during the study period evaluating for interaction with time. Stratified by genotype severity., Results: Among 427 patients, 331 had 2 or more measurements of creatinine. During a median follow-up of 4.01 (interquartile range, 1.66-7.19) years, annual eGFR decline was 2.05mL/min/1.73m 2 for severe genotypes (P<0.001) and 1.16mL/min/1.73m 2 (P=0.02) for mild genotypes. At baseline, 21.4% of patients with severe genotypes had CKD versus 17.2% of those with mild genotypes. For severe genotypes, angiotensin-converting enzyme-inhibitor/angiotensin receptor blocker use (OR, 6.10; 95% CI, 2.03-18.29; P=0.001) and avascular necrosis (OR, 0.40; 95% CI, 0.16-0.97; P=0.04) were associated with baseline CKD. Among those with mild genotypes, higher hemoglobin level was associated with lower probability of CKD (OR per 1-g/dL greater hemoglobin level, 0.63; 95% CI, 0.43-0.93; P=0.02). Rate of eGFR decline was inversely related to hemoglobin level (β = 0.46 [SE, 0.23]; P=0.04) within the severe genotype subgroup. No factors were identified to be associated with proteinuria over time., Limitations: Retrospective observational study, limited direct measures of albuminuria., Conclusions: Patients with SCD exhibit rapid decline in eGFR over time. Decline in eGFR is associated with markers of disease severity and associated comorbid conditions., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Although socioeconomic status has been associated with chronic kidney disease (CKD), little is known about its relationship to residential neighborhood context., Study Design: Secondary analysis of the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective cohort study designed to investigate the development and progression of subclinical cardiovascular disease., Setting & Participants: 6,814 men and women who were between 45 and 84 years of age and free of cardiovascular disease were recruited between 2000 and 2002 from Baltimore, MD; Chicago, IL; Forsyth County, NC; Los Angeles, CA; New York, NY; and St. Paul, MN., Exposures: A composite neighborhood problem score (calculated based on 7 participant-reported domains at study entry: adequacy of food sources, availability of parks/playground, noise, sidewalks, traffic, trash and litter, and violence) and a social cohesion score (calculated based on 5 participant-reported attributes of people in their neighborhood: close knit; get along; willing to help neighbors; trustworthy; and share values)., Outcomes: Estimated glomerular filtration rate (eGFR; calculated using the CKD-EPI [CKD Epidemiology Collaboration] creatinine-cystatin C equation) and an indicator of eGFR decline > 30% since study entry using follow-up eGFR quantified at 4 examinations: 2000 to 2002, 2004 to 2005, 2005 to 2007, and 2010 to 2011., Analytical Approach: Associations between each neighborhood measure (in separate models) and eGFR decline > 30% from baseline and annualized eGFR change were estimated using Cox proportional hazards and linear mixed regression models, respectively, adjusting for potential confounders., Results: While neighborhood social context differs by race/ethnicity, neither neighborhood problems nor social cohesion was independently associated with eGFR decline after adjustment for confounders., Limitations: Incomplete capture of the early stages of eGFR decline, reliance on observational data, limited variation in neighborhood measures, and the potential for residual confounding., Conclusions: Although we showed no independent association between neighborhood context and eGFR decline, it is associated with many CKD risk factors and further work is needed to clarify whether it has an independent role in CKD., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Random assignment to the intensive systolic blood pressure (SBP) arm (<120mmHg) in the Systolic Blood Pressure Intervention Trial (SPRINT) resulted in more rapid declines in estimated glomerular filtration rates (eGFRs) than in the standard arm (SBP<140mmHg). Whether this change reflects hemodynamic effects or accelerated intrinsic kidney damage is unknown., Study Design: Longitudinal subgroup analysis of clinical trial participants., Settings & Participants: Random sample of SPRINT participants with prevalent chronic kidney disease (CKD) defined as eGFR<60mL/min/1.73m 2 by the CKD-EPI (CKD Epidemiology Collaboration) creatinine-cystatin C equation at baseline., Outcomes & Measurements: Urine biomarkers of tubule function (β 2 -microglobulin [B2M], α 1 -microglobulin [A1M]), and uromodulin), injury (interleukin 18, kidney injury molecule 1, and neutrophil gelatinase-associated lipocalin), inflammation (monocyte chemoattractant protein 1), and repair (human cartilage glycoprotein 40) at baseline, year 1, and year 4. Biomarkers were indexed to urine creatinine concentration and changes between arms were evaluated using mixed-effects linear models and an intention-to-treat approach., Results: 978 SPRINT participants (519 in the intensive and 459 in the standard arm) with prevalent CKD were included. Mean age was 72±9 years and eGFR was 46.1±9.4mL/min/1.73m 2 at baseline. Clinical characteristics, eGFR, urinary albumin-creatinine ratio, and all 8 biomarker values were similar across arms at baseline. Compared to the standard arm, eGFR was lower by 2.9 and 3.3mL/min/1.73m 2 in the intensive arm at year 1 and year 4. None of the 8 tubule marker levels was higher in the intensive arm compared to the standard arm at year 1 or year 4. Two tubule function markers (B2M and A1M) were 29% (95% CI, 10%-43%) and 24% (95% CI, 10%-36%) lower at year 1 in the intensive versus standard arm, respectively., Limitations: Exclusion of persons with diabetes, and few participants had advanced CKD., Conclusions: Among participants with CKD in SPRINT, random assignment to the intensive SBP arm did not increase any levels of 8 urine biomarkers of tubule cell damage despite loss of eGFR. These findings support the hypothesis that eGFR declines in the intensive arm of SPRINT predominantly reflect hemodynamic changes rather than intrinsic damage to kidney tubule cells., (Published by Elsevier Inc.)

Rationale & Objective: Random assignment to intensive blood pressure (BP) lowering (systolic BP<120mmHg) compared to a less intensive BP target (systolic BP<140mmHg) in the Action to Control Cardiovascular Risk in Diabetes BP (ACCORD-BP) trial resulted in a more rapid decline in estimated glomerular filtration rate (eGFR). Whether this reflects hemodynamic effects or intrinsic kidney damage is unknown., Study Design: Longitudinal analysis of a subgroup of clinical trial participants., Settings & Participants: A subgroup of 529 participants in ACCORD-BP., Exposures: Urine biomarkers of tubular injury (kidney injury molecule 1, interleukin 18 [IL-18]), repair (human cartilage glycoprotein 39 [YKL-40]), and inflammation (monocyte chemoattractant protein 1) at baseline and year 2., Outcomes: Changes in eGFR from baseline to 2 years., Analytical Approach: We compared changes in biomarker levels and eGFRs across participants treated to an intensive versus less intensive BP goal using analysis of covariance., Results: Of 529 participants, 260 had been randomly assigned to the intensive and 269 to the standard BP arm. Mean age was 62±6.5 years and eGFR was 90mL/min/1.73m 2 . Baseline clinical characteristics, eGFRs, urinary albumin-creatinine ratios (ACRs), and urinary biomarker levels were similar across BP treatment groups. Compared to less intensive BP treatment, eGFR was 9.2mL/min/1.73m 2 lower in the intensive BP treatment group at year 2. Despite the eGFR reduction, within this treatment group, ACR was 30% lower and 4 urinary biomarker levels were unchanged or lower at year 2. Also within this group, participants with the largest declines in eGFRs had greater reductions in urinary IL-18 and YKL-40 levels. In a subgroup analysis of participants developing incident chronic kidney disease (sustained 30% decline and eGFR<60mL/min/1.73m 2 ; n=77), neither ACR nor 4 biomarker levels increased in the intensive treatment group, whereas the level of 1 biomarker, IL-18, increased in the less intensive treatment group., Limitations: Few participants with advanced baseline chronic kidney disease. Comparisons across treatment groups do not represent comparisons of treatment arms created solely through randomization., Conclusions: Among a subset of ACCORD-BP trial participants, intensive BP control was associated with reductions in eGFRs, but not with an increase in injury marker levels. These findings support that eGFR decline observed with intensive BP goals in ACCORD participants may predominantly reflect hemodynamic alterations., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Reduced glomerular filtration rate (GFR) in the absence of albuminuria is a common manifestation of chronic kidney disease (CKD) in diabetes. However, the frequency with which it progresses to end-stage kidney disease (ESKD) is unknown., Study Design: Multicenter prospective cohort study., Setting & Participants: We included 1,908 participants with diabetes and reduced GFR enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study in the United States., Predictors: Urinary albumin and protein excretion., Outcomes: Incident ESKD, CKD progression (ESKD or ≥50% reduction in estimated GFR [eGFR] from baseline), and annual rate of decline in kidney function., Measurements: ESKD was ascertained by self-report and by linkage to the US Renal Data System. We used Cox proportional hazards modeling to estimate the association of albuminuria and proteinuria with incident ESKD or CKD progression and linear mixed-effects models to assess differences in eGFR slopes among those with and without albuminuria., Results: Mean eGFR at baseline was 41.2mL/min/1.73m 2 . Normal or mildly increased 24-hour urinary albumin excretion (<30mg/d) at baseline was present in 28% of participants, but in only 5% of those progressing to ESKD. For those with baseline normal or mildly increased albuminuria, moderately increased albuminuria (albumin excretion, 30-299mg/d), and 2 levels of severely increased albuminuria (albumin excretion, 300-999 and ≥1,000mg/d): crude rates of ESKD were 7.4, 34.8, 78.7, and 178.7 per 1,000 person-years, respectively; CKD progression rates were 17.0, 61.4, 130.5, and 295.1 per 1,000 person-years, respectively; and annual rates of eGFR decline were -0.17, -1.35, -2.74, and -4.69mL/min/1.73m 2 , respectively., Limitations: We were unable to compare the results with healthy controls., Conclusions: In people with diabetes with reduced eGFRs, the absence of albuminuria or proteinuria is common and carries a much lower risk for ESKD, CKD progression, or rapid decline in eGFR compared with those with albuminuria or proteinuria. The rate of eGFR decline in normoalbuminuric CKD was similar to that reported for the general diabetic population., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Serum uric acid concentrations increase in chronic kidney disease (CKD) and may lead to tubular injury, endothelial dysfunction, oxidative stress, and intrarenal inflammation. Whether uric acid concentrations are associated with kidney failure and death in CKD is unknown., Study Design: Prospective observational cohort study., Settings & Participants: 3,885 individuals with CKD stages 2 to 4 enrolled in the Chronic Renal Insufficiency Cohort (CRIC) between June 2003 and September 2008 and followed up through March 2013., Predictor: Baseline uric acid concentrations., Outcomes: Kidney failure (initiation of dialysis therapy or transplantation) and all-cause mortality., Results: During a median follow-up of 7.9 years, 885 participants progressed to kidney failure and 789 participants died. After adjustment for demographic, cardiovascular, and kidney-specific covariates, higher uric acid concentrations were independently associated with risk for kidney failure in participants with estimated glomerular filtration rates (eGFRs) ≥ 45mL/min/1.73m 2 (adjusted HR per 1-standard deviation greater baseline uric acid, 1.40; 95% CI, 1.12-1.75), but not in those with eGFRs<30mL/min/1.73m 2 . There was a nominally higher HR in participants with eGFRs of 30 to 44mL/min/1.73m 2 (adjusted HR, 1.13; 95% CI, 0.99-1.29), but this did not reach statistical significance. The relationship between uric acid concentration and all-cause mortality was J-shaped (P=0.007)., Limitations: Potential residual confounding through unavailable confounders; lack of follow-up measurements to adjust for changes in uric acid concentrations over time., Conclusions: Uric acid concentration is an independent risk factor for kidney failure in earlier stages of CKD and has a J-shaped relationship with all-cause mortality in CKD. Adequately powered randomized placebo-controlled trials in CKD are needed to test whether urate lowering may prove to be an effective approach to prevent complications and progression of CKD., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Cardiac structural abnormalities, common in African Americans, are associated with adverse clinical outcomes. Associations between echocardiography-measured subclinical heart failure and kidney function decline are unknown and may identify novel risk factors for kidney disease in this population., Study Design: Prospective cohort study., Setting & Participants: 2,418 Jackson Heart Study participants with baseline echocardiograms and longitudinal measures of estimated glomerular filtration rate (eGFR) calculated from the CKD-EPI creatinine equation. 2,219 participants had baseline eGFRs≥60mL/min/1.73m 2 ., Predictors: Left ventricular mass (LVM) and ejection fraction (LVEF) and pulmonary artery systolic pressure (PASP) quantified from baseline echocardiograms., Outcomes: Primary outcome was >30% eGFR decline or progression to end-stage renal disease (ESRD; need for dialysis therapy) over a mean of 8 years. Secondary outcome, eGFR<60mL/min/1.73m 2 or progression to ESRD and eGFR decline >1mL/min/1.73m 2 per year among those with baseline eGFRs≥60mL/min/1.73m 2 ., Measurements: Logistic regression models, adjusted for demographics, physical characteristics, comorbid conditions, and medication use., Results: Mean age was 52.2±11.9 (SD) years, 37% of participants were men; mean baseline eGFR was 87.3±17.3mL/min/1.73m 2 . The primary and secondary outcomes occurred in 148 (6.1%) and 162 (7.1%) participants, respectively. In unadjusted models, every 25-g greater LVM was significantly associated with greater odds of eGFR decline > 30% or ESRD (OR, 1.38; 95% CI, 1.26-1.51) and incident eGFR<60mL/min/1.73m 2 or ESRD (OR, 1.30; 95% CI, 1.20-1.42); only the former remained statistically significant after adjustment. There was no association of LVEF or PASP with either eGFR decline > 30% or ESRD (LVEF: adjusted OR, 0.95 [95% CI, 0.84-1.07]; PASP: adjusted OR, 0.98 [95% CI, 0.87-1.11]) or incident eGFR<60mL/min/1.73m 2 or ESRD (LVEF: adjusted OR, 0.98 [95% CI, 0.86-1.11]; PASP: adjusted OR, 1.05 [95% CI, 0.94-1.18]) in multivariable models., Limitations: No midstudy creatinine measurement at examination 2., Conclusions: Greater LVM was significantly associated with eGFR decline > 30% or ESRD among African Americans in a community-based cohort. Treating and reversing elevated LVM may reduce the burden and progression of kidney disease in this high-risk population., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: It is not clear whether the pattern of kidney function decline in patients with chronic kidney disease (CKD) may relate to outcomes after reaching end-stage renal disease (ESRD). We hypothesize that an abrupt decline in kidney function prior to ESRD predicts early death after initiating maintenance hemodialysis therapy., Study Design: Prospective cohort study., Setting & Participants: The Chronic Renal Insufficiency Cohort (CRIC) Study enrolled men and women with mild to moderate CKD. For this study, we studied 661 individuals who developed chronic kidney failure that required hemodialysis therapy initiation., Predictors: The primary predictor was the presence of an abrupt decline in kidney function prior to ESRD. We incorporated annual estimated glomerular filtration rates (eGFRs) into a mixed-effects model to estimate patient-specific eGFRs at 3 months prior to initiation of hemodialysis therapy. Abrupt decline was defined as having an extrapolated eGFR≥30mL/min/1.73m(2) at that time point., Outcomes: All-cause mortality within 1 year after initiating hemodialysis therapy., Measurements: Multivariable Cox proportional hazards., Results: Among 661 patients with CKD initiating hemodialysis therapy, 56 (8.5%) had an abrupt predialysis decline in kidney function and 69 died within 1 year after initiating hemodialysis therapy. After adjustment for demographics, cardiovascular disease, diabetes, and cancer, abrupt decline in kidney function was associated with a 3-fold higher risk for death within the first year of ESRD (adjusted HR, 3.09; 95% CI, 1.65-5.76)., Limitations: Relatively small number of outcomes; infrequent (yearly) eGFR determinations; lack of more granular clinical data., Conclusions: Abrupt decline in kidney function prior to ESRD occurred in a significant minority of incident hemodialysis patients and predicted early death in ESRD., (Copyright © 2016 National Kidney Foundation, Inc. All rights reserved.)

Background: Associations between sodium phosphate enemas and nephropathy have raised concerns about the safety of use as part of a bowel-cleansing regimen administered prior to colonoscopies. The objectives of this analysis are to evaluate the impact of sodium phosphate enema versus polyethylene glycol powder for oral solution (PEG) use prior to colonoscopy screening on estimated glomerular filtration rate (eGFR) decline in Veterans Affairs (VA) patients and identify other risk factors contributing to eGFR decline., Study Design: Retrospective cohort study., Setting & Participants: 70,499 VA patients receiving sodium phosphate enemas (with or without PEG) or PEG alone prior to colonoscopy screenings., Predictor: Use of either sodium phosphate or PEG., Outcomes: A 50% increase in serum creatinine level over a 15-month, over a 6-week, and between a 9- and 15-month period was used to define any, acute, or long-term eGFR decline, respectively., Measurements: Multivariable logistic regressions estimated the likelihood of eGFR decline conditional on the use of sodium phosphate enemas versus PEG alone, controlling for potential confounders., Results: A greater proportion of patients using sodium phosphate enemas versus PEG had any (P<0.001) or long-term (P=0.003) eGFR declines, whereas similar proportions had acute eGFR declines (P=0.9). In the adjusted analyses, use of sodium phosphate enemas (± PEG was associated with an increased likelihood of having any (OR, 1.3; 95% CI, 1.2-1.5) or long-term (OR, 1.4; 95% CI, 1.1-1.8) eGFR decline, but not acute eGFR decline (OR, 1.0; 95% CI, 0.6-1.7). Other risk factors for eGFR decline included diabetes and non-iron deficient anemia., Limitations: Unobserved heterogeneity due to volume depletion and potential selection bias due to higher-risk patients preferentially prescribed sodium phosphate enemas., Conclusions: Use of sodium phosphate enemas versus PEG alone prior to colonoscopy screening increases the risk for VA patients having long-term eGFR decline. Patients with non-iron deficient anemia are at particularly high risk for eGFR decline. These findings motivate the need to re-examine prescribing practices for sodium phosphate enemas as part of a bowel-cleansing regimen., (Copyright © 2016 National Kidney Foundation Inc. All rights reserved.)