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Background and Aims Incident heart failure (HF) among individuals with chronic kidney disease (CKD) incurs hospitalizations that burden patients and health care systems. There are few preventative therapies, and the Pooled Cohort equations to Prevent Heart Failure (PCP-HF) perform poorly in the setting of CKD. New drug targets and better risk stratification are urgently needed. Methods In this analysis of incident HF, SomaScan V4.0 (4638 proteins) was analysed in 2906 participants of the Chronic Renal Insufficiency Cohort (CRIC) with validation in the Atherosclerosis Risk in Communities (ARIC) study. The primary outcome was 14-year incident HF (390 events); secondary outcomes included 4-year HF (183 events), HF with reduced ejection fraction (137 events), and HF with preserved ejection fraction (165 events). Mendelian randomization and Gene Ontology were applied to examine causality and pathways. The performance of novel multi-protein risk models was compared to the PCP-HF risk score. Results Over 200 proteins were associated with incident HF after adjustment for estimated glomerular filtration rate at P < 1 × 10−5. After adjustment for covariates including N-terminal pro-B-type natriuretic peptide, 17 proteins remained associated at P < 1 × 10−5. Mendelian randomization associations were found for six proteins, of which four are druggable targets: FCG2B, IGFBP3, CAH6, and ASGR1. For the primary outcome, the C -statistic (95% confidence interval [CI]) for the 48-protein model in CRIC was 0.790 (0.735, 0.844) vs. 0.703 (0.644, 0.762) for the PCP-HF model (P =.001). C -statistic (95% CI) for the protein model in ARIC was 0.747 (0.707, 0.787). Conclusions Large-scale proteomics reveal novel circulating protein biomarkers and potential mediators of HF in CKD. Proteomic risk models improve upon the PCP-HF risk score in this population. [ABSTRACT FROM AUTHOR]

Background: Kidney disease (KD) is an important health equity issue with Black, Hispanic, and socioeconomically disadvantaged individuals experiencing a disproportionate disease burden. Prior to 2021, the commonly used estimated glomerular filtration rate (eGFR) equations incorporated coefficients for Black race that conferred higher GFR estimates for Black individuals compared to non-Black individuals of the same sex, age, and blood creatinine concentration. With a recognition that race does not delineate distinct biological categories, a joint task force of the National Kidney Foundation and the American Society of Nephrology recommended the adoption of the CKD-EPI 2021 race-agnostic equations. Content: This document provides guidance on implementation of the CKD-EPI 2021 equations. It describes recommendations for KD biomarker testing, and opportunities for collaboration between clinical laboratories and providers to improve KD detection in high-risk populations. Further, the document provides guidance on the use of cystatin C, and eGFR reporting and interpretation in gender-diverse populations. Summary: Implementation of the CKD-EPI 2021 eGFR equations represents progress toward health equity in the management of KD. Ongoing efforts by multidisciplinary teams, including clinical laboratorians, should focus on improved disease detection in clinically and socially high-risk populations. Routine use of cystatin C is recommended to improve the accuracy of eGFR, particularly in patients whose blood creatinine concentrations are confounded by processes other than glomerular filtration. When managing gender-diverse individuals, eGFR should be calculated and reported with both male and female coefficients. Gender-diverse individuals can benefit from a more holistic management approach, particularly at important clinical decision points. [ABSTRACT FROM AUTHOR]

Background: Arterial calcification and stiffness are common in people with chronic kidney disease (CKD). Higher vitamin K status has been associated with less arterial calcification and stiffness in CKD in cross-sectional studies. Objectives: To determine the association of vitamin K status with coronary artery calcium (CAC) and arterial stiffness [pulse wave velocity (PWV)] at baseline and over 2-4 follow-up years in adults with mild-to-moderate CKD. Methods: Participants (n = 2722) were drawn from the well-characterized Chronic Renal Insufficiency Cohort. Two vitamin K status biomarkers, plasma phylloquinone and plasma dephospho-uncarboxylated matrix gla protein [(dp)ucMGP], were measured at baseline. CAC and PWV were measured at baseline and over 2-4 y of follow-up. Differences across vitamin K status categories in CAC prevalence, incidence, and progression (defined as ≥100 Agatston units/y increase) and PWV at baseline and over follow-up were evaluated using multivariable-adjusted generalized linear models. Results: CAC prevalence, incidence, and progression did not differ across plasma phylloquinone categories. Moreover, CAC prevalence and incidence did not differ according to plasma (dp)ucMGP concentration. Compared with participants with the highest (dp)ucMGP (≥450 pmol/L), those in the middle category (300-449 pmol/L) had a 49% lower rate of CAC progression (incidence rate ratio: 0.51; 95% CI: 0.33, 0.78). However, CAC progression did not differ between those with the lowest (<300 pmol/L) and those with the highest plasma (dp) ucMGP concentration (incidence rate ratio: 0.82; 95% CI: 0.56, 1.19). Neither vitamin K status biomarker was associated with PWV at baseline or longitudinally. [ABSTRACT FROM AUTHOR]

Background Patients with chronic kidney disease (CKD) have an increased risk of peripheral arterial disease (PAD). The ankle–brachial index (ABI), a noninvasive measure of PAD, is a predictor of adverse events among individuals with CKD. In general populations, changes in ABI have been associated with mortality, but this association is not well understood among patients with CKD. Methods We conducted a prospective study of 2920 participants in the Chronic Renal Insufficiency Cohort Study without lower extremity revascularization or amputation at baseline and with at least one follow-up ABI measurement (taken at annual visits) during the first 4 years of follow-up. The ABI was obtained by the standard protocol. Results In Cox proportional hazard regression analyses, we found a U-shaped association of average annual change in ABI with all-cause mortality. After adjusting for baseline ABI and other covariates, compared with participants with an average annual change in ABI of 0–<0.02, individuals with an average annual change in ABI <−0.04 or ≥0.04 had multivariable-adjusted hazard ratios (HRs) of 1.81 [95% confidence interval (CI) 1.34–2.44) and 1.42 (95% CI 1.12–1.82) for all-cause mortality, respectively. Compared with the cumulative average ABI of 1.0–<1.4, multivariable-adjusted HRs for those with a cumulative average ABI of <0.9, 0.9–<1.0 and ≥1.4 were 1.93 (95% CI 1.42–2.61), 1.20 (0.90–1.62) and 1.31 (0.94–1.82), respectively. Conclusions This study indicates both larger decreases and increases in average annual changes in ABI (>0.04/year) were associated with higher mortality risk. Monitoring changes in ABI over time may facilitate risk stratification for mortality among individuals with CKD. [ABSTRACT FROM AUTHOR]

Background Patients with chronic kidney disease (CKD) face risks of not only end-stage kidney disease (ESKD), cardiovascular disease (CVD) and death, but also decline in kidney function, quality of life (QOL) and mental and physical well-being. This study describes the multidimensional trajectories of CKD using clinical events, kidney function and patient-reported outcome measures (PROMs). We hypothesized that more advanced CKD stages would associate with more rapid decline in each outcome. Methods Among 3939 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study, we evaluated multidimensional disease trajectories by G- and A-stages of enrollment estimated glomerular filtration rate (eGFR) and albuminuria, respectively. These trajectories included clinical events (ESKD, CVD, heart failure and death), eGFR decline and PROMs [kidney disease QOL (KDQOL) burden, effects and symptoms questionnaires, as well as the 12-item short form mental and physical component summaries]. We also evaluated a group-based multitrajectory model to group participants on the basis of longitudinal PROMs and compared group assignments by enrollment G- and A-stage. Results The mean participant age was 58 years, 45% were women, mean baseline eGFR was 44 mL/min/1.73 m2 and median urine albumin:creatinine ratio was 52 mg/g. The incidence of all clinical events was greater and eGFR decline was faster with more advanced G- and A-stages. While baseline KDQOL and physical component measures were lower with more advanced G- and A-stage of CKD, changes in PROMs were inconsistently related to the baseline CKD stage. Groups formed on PROM trajectories were fairly distinct from existing CKD staging (observed agreement 60.6%) and were associated with the risk of ESKD, CVD, heart failure and death. Conclusions More advanced baseline CKD stage was associated with a higher risk of clinical events and faster eGFR decline, and was only weakly related to changes in patient-reported metrics over time. [ABSTRACT FROM AUTHOR]

Background Noninvasive quantitative measurement of fibrosis in chronic kidney disease (CKD) would be desirable diagnostically and therapeutically but standard radiologic imaging is too variable for clinical usage. By applying a vibratory force, tissue shear wave stiffness can be measured by magnetic resonance elastography (MRE) that may correlate with progression of kidney fibrosis. Since decreased kidney perfusion decreases tissue turgor and stiffness, we combined newly available three-dimensional MRE shear stiffness measurements with MR arterial spin labeling (ASL) kidney blood flow rates to evaluate fibrosis in diabetic nephropathy. Methods Thirty individuals with diabetes and Stage 0–5 CKD and 13 control individuals without CKD underwent noncontrast MRE with concurrent ASL blood flow measurements. Results MRE cortical shear stiffness at 90 Hz was decreased significantly below controls in all CKD stages of diabetic nephropathy. Likewise, ASL blood flow decreased progressively from 480 ± 136 mL/min/100 g of cortical tissue in controls to 302 ± 95, 229 ± 7 and 152 ± 32 mL/min/100 g in Stages 3, 4 and 5 CKD, respectively. A magnetic resonance imaging (MRI) surrogate for the measured glomerular filtration fraction [surrogate filtration fraction = estimated glomerular filtration rate (eGFR)/ASL] decreased progressively from 0.21 ± 0.07 in controls to 0.16 ± 0.04 in Stage 3 and 0.10 ± 0.02 in Stage 4–5 CKD. Conclusions In this pilot study, MRI with ASL blood flow rates can noninvasively measure decreasing kidney cortical tissue perfusion and, with eGFR, a decreasing surrogate filtration fraction in worsening diabetic nephropathy that appears to correlate with increasing fibrosis. Differing from the liver, MRE shear stiffness surprisingly decreases with worsening CKD, likely related to decreased tissue turgor from lower blood flow rates. [ABSTRACT FROM AUTHOR]

Background. Intermittent smoking is prevalent amongHispanics, but little is known about whether this smoking pattern associates with increased chronic kidney disease (CKD) risk in this population. The objective of the present study is to identify patterns of exposure associated with CKD in US Hispanics. Methods. We used cross-sectional data on 15 410 participants of the Hispanics Community Health Study/the Study of Latinos, a population-based study of individuals aged 18-74 years, recruited in 2008 to 2011 from four US field centers (Bronx, NY; Chicago, IL; Miami, FL; San Diego, CA). Smoking exposure was obtained through a questionnaire. CKD was defined by an estimated glomerular filtration rate of <60 mL/min/ 1.73 m² or a urine albumin-to-creatinine ratio of ≥30 mg/g. Results. Approximately 14% of individuals were daily and 7% were intermittent smokers, and 16% were past smokers. There was a significant interaction between smoking status and packyears of exposure (P = 0.0003). In adjusted models, therewas an increased odds of CKD among daily, intermittent and past smokers by pack-years compared with never smokers. The association of intermittent smokers was significant at 10 pack-years [odds ratio (OR) = 1.38, 95% confidence intervals (CI) 1.06, 1.81], whereas for daily smokers this association was observed at 40 pack-years (OR = 1.43, 95% CI 1.09, 1.89). Conclusions. Our findings of increased risk of CKD among Hispanics who are intermittent smokers support screening and smoking cessation interventions targeted to this population for the prevention of CKD. It also suggests novel mechanistic pathways for kidney toxicity that should be further explored in future studies. [ABSTRACT FROM AUTHOR]

Background. We conducted single-marker, gene- and pathway- based analyses to examine the association between renin-angiotensin-aldosterone system (RAAS) variants and chronic kidney disease (CKD) progression among Chronic Renal Insufficiency Cohort study participants. Methods. A total of 1523 white and 1490 black subjects were genotyped for 490 single nucleotide polymorphisms (SNPs) in 12 RAAS genes as part of the ITMAT-Broad-CARe array. CKD progression phenotypes included decline in estimated glomerular filtration rate (eGFR) over time and the occurrence of a renal disease event, defined as incident end-stage renal disease or halving of eGFR from baseline. Mixed-effects models were used to examine SNP associations with eGFR decline, while Cox proportional hazards models tested SNP associations with renal events. Geneand pathway-based analyses were conducted using the truncated product method. All analyses were stratified by race, and a Bonferroni correction was applied to adjust for multiple testing. Results. Among white and black participants, eGFR declined an average of 1.2 and 2.3 mL/min/1.73 m²/year, respectively, while renal events occurred in a respective 11.5 and 24.9% of participants. We identified strong gene- and pathway-based associations with CKD progression. The AGT and RENBP genes were consistently associated with risk of renal events in separate analyses of white and black participants (both P < 1.00 × 10-6). Driven by the significant gene-based findings, the entire RAAS pathway was also associated with renal events in both groups (both P < 1.00 × 10-6). No single-marker associations with CKD progression were observed. Conclusions. The current study provides strong evidence for a role of the RAAS in CKD progression. [ABSTRACT FROM AUTHOR]

BackgroundLimited health literacy is prevalent and has been linked to adverse patient outcomes. We examined the relationship between health literacy and cardiovascular disease (CVD) risk factors, including blood pressure (BP) parameters, lipids, waist-to-hip ratio (WHR), body mass index (BMI), and tobacco utilization among dialysis patients.MethodsWe conducted a cross-sectional study of 72 participants in a prospective cohort study of vascular calcification in newly initiated dialysis patients. Health literacy was assessed using the Short Test of Functional Health Literacy (S-TOFHLA) in Adults. The study population was dichotomized into those with and without adequate literacy. Linear and logistic regression analyses were used to predict continuous and dichotomous cardiovascular risk factor variables, respectively.ResultsTwenty-one percent had limited health literacy. Compared to limited health literacy, adequate health literacy was associated with lower BP parameters in multivariable analyses (systolic blood pressure (SBP): β −16.8, s.e. 6.7, P = 0.01; diastolic blood pressure (DBP): β −13.8, s.e. 4.1, P = 0.001; mean arterial pressure (MAP): β −14.8, s.e. 4.6, P = 0.002). Health literacy was not a statistically significant predictor of low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, WHR, BMI, or tobacco utilization.ConclusionsLimited health literacy is common in individuals on dialysis. Individuals with adequate health literacy skills had DBP readings that were on average 13.8 mm Hg lower and MAP that was 14.8 mm Hg lower than those with inadequate health literacy. Prospective studies to elucidate if improvements in health literacy skills will lead to improvement in BP control are needed.American Journal of Hypertension (2012); doi:10.1038/ajh.2011.252 [ABSTRACT FROM AUTHOR]

Background. Acculturation affects health, but it has never been studied with kidney disease.Methods. We studied the association of language spoken at home, generation and birth place with kidney function among Hispanics and Chinese in the Multi-Ethnic Study of Atherosclerosis (n = 2999). Kidney function was determined by cystatin C (eGFRcys) and albumin/creatinine ratio (ACR). We evaluated mediators in models: Model 1 = age, sex, income, education; Model 2 = Model 1 + behaviors; and Model 3 = Model 1 + comorbidities.Results. Among Hispanics, speaking mixed Spanish/English was significantly associated with lower eGFRcys (− 2.83 mL/min/1.73 m2, − 5.69–0.04) and higher ACR (RD 40%, 17–68%) compared with speaking Spanish only; this was mildly attenuated by behaviors (− 2.29, − 5.33–0.75; RD 42%, 18–72%) but not comorbidities (− 3.04, − 5.83 to − 0.23); RD 35%, 14–59%). US-born Hispanics had lower eGFRcys compared with foreign-born Hispanics [1.83 mL/min/1.73 m2 lower (0.97–1.31) for Generation 1; 1.37 mL/min/1.73 m2 lower (0.75–1.57) for Generation ≥ 2].In contrast, Chinese who spoke any English had higher eGFRcys (2.53, 95% CI: − 1.70–6.78), but similar ACR (RD − 5%, 95% CI: − 26–23%) compared with those speaking Chinese only, but associations were not statistically significant.Conclusion. Higher acculturation was associated with worse kidney function in Hispanics, mediated perhaps by behavioral factors but not comorbidities. Associations may be in the opposite direction among Chinese. Future studies are needed to elucidate these mechanisms. [ABSTRACT FROM AUTHOR]

BackgroundPatients with chronic kidney disease (CKD) have a disproportionate risk of cardiovascular disease. This study was designed to assess the association between two noninvasive measures of cardiovascular risk, pulse wave analysis (PWA), and carotid intima-media thickness (IMT), in a cohort of CKD patients enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study.MethodsThree hundred and sixty-seven subjects with CKD enrolled in the CRIC study at the University of Pennsylvania site (mean age 59.9 years, blood pressure 129/74 mm Hg, estimated glomerular filtration rate 48 ml/min/1.73 m2, IMT 0.8 mm) had both carotid IMT and PWA measurements. Carotid ultrasound was also used to determine the presence of plaque. PWA was used to determine augmentation index (AI), amplification ratio (AMPR), aortic pulse pressure (C_PP), and central aortic systolic pressure (C_SP).ResultsIMT was significantly associated with all PWA-derived measures. However, on multivariable linear regression analysis, only AMPR (regression coefficient −0.072, P = 0.006), C_PP (regression coefficient 0.0025, P < 0.001), and C_SP (regression coefficient 0.0017, P < 0.001) remained significantly associated with IMT. The prevalence of carotid plaque in the cohort was 59%. Of the PWA-derived measures, only C_PP was significantly associated with the presence of carotid plaque (P < 0.001).ConclusionsPWA-derived measures are associated with carotid IMT and plaque in the CKD. Of these measures, C_PP was most associated with carotid IMT and plaque.American Journal of Hypertension 2009; doi:10.1038/ajh.2009.156 [ABSTRACT FROM AUTHOR]