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Introduction: Chronic kidney disease (CKD) is only partly caused by traditional risk factors. Endothelial dysfunction is common in CKD and may contribute to CKD incidence. We studied the association of circulating biomarkers reflecting endothelial dysfunction with incident CKD., Methods: The Reasons for Geographical and Racial Differences in Stroke (REGARDS) study is a prospective cohort of 30,239 Black or White adults aged ≥45 years. Baseline levels of intercellular cellular adhesion molecule 1 (ICAM-1), vascular cellular adhesion molecule 1 (VCAM-1), factor VIII (FVIII), and E-selectin were measured in 3300 participants without baseline CKD or albuminuria who attended a second visit 9.4 years later. Kidney outcomes were incident CKD (estimated glomerular filtration rate [eGFR] <60 ml/min per 1.73 m 2 and ≥40% decline or onset of new end-stage kidney disease), incident ≥30% eGFR decline, and incident albuminuria (albumin-to-creatinine ratio [ACR] ≥30 mg/g). Sequentially adjusted logistic regression models assessed the association of biomarkers with kidney outcomes., Results: Median age of participants was 62 years, 49% were women, and 46% identified as Black. Of the participants, 228 (6.9%) developed CKD, 613 (18.9%) experienced ≥30% decline in eGFR, and 356 (11.4%) developed albuminuria. The adjusted odds ratios (ORs) for incident CKD per 1 SD increment biomarker was 1.12 for ICAM-1 (95% confidence interval [CI]: 1.02-1.22), 1.10 for VCAM-1 (95% CI: 1.01-1.20), 1.15 for FVIII (95% CI: 1.06-1.24), and 1.10 for E-selectin (95% CI: 1.01-1.20). Results were similar for incident ≥30% eGFR decline but not albuminuria, where only higher FVIII was positively associated., Conclusion: Higher concentration of ICAM-1, VCAM-1, FVIII, and E-selectin were associated with incident CKD and ≥30% eGFR decline in a large cohort study. Higher FVIII was also associated with incident albuminuria., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Introduction: Tubulointerstitial damage in diabetes and chronic kidney disease (CKD) is poorly captured by estimated glomerular filtration rate (eGFR) and albuminuria. Urine biomarkers of kidney health may better elucidate disease progression in persons with diabetes and CKD., Methods: Per case-cohort design, we randomly selected a subcohort of 560 study participants of the REasons for Geographic And Racial Differences in Stroke (REGARDS) study from 1092 adults with diabetes and baseline eGFR <60 ml/min per 1.73 m 2 and registered a total of 161 end-stage kidney disease (ESKD) cases ( n  = 93 from the subcohort; n  = 68 from outside the subcohort) during 4.3 ± 2.7 years mean follow-up. We measured urine biomarkers of kidney tubule injury (kidney injury molecule-1 [KIM-1]), inflammation and fibrosis (monocyte chemoattractant protein-1 [MCP-1]), repair (chitinase-3-like protein 1 [YKL-40]), and tubule function, including reabsorption (alpha-1-microglobulin [α1m]) and synthetic capacity (epidermal growth factor [EGF] and uromodulin [UMOD]). Weighted Cox regression models estimated ESKD risk adjusting for demographics, ESKD risk factors, and baseline eGFR and urine albumin. Least absolute shrinkage and selection operator (LASSO) regression identified a subset of biomarkers most strongly associated with ESKD., Results: At baseline, subcohort participants had mean age of 70 ± 9 years, mean eGFR of 40 ±13 ml/min per 1.73 m 2 , and median urine albumin-to-creatinine ratio of 33 (interquartile range 10-213) mg/g. Adjusting for baseline eGFR and albuminuria, each 2-fold higher urine KIM-1 (hazard ratio = 1.43 [95% CI: 1.17-1.75]), α1m (hazard ratio = 1.47 [1.19-1.82]), and MCP-1 (hazard ratio = 1.27 [1.06-1.53]) were independently associated with ESKD. LASSO retained KIM-1 and α1m for associations with ESKD., Conclusion: Among adults with diabetes and eGFR <60 ml/min per 1.73 m 2 , higher urine KIM-1, α1m, and MCP-1 are independently associated with incident ESKD, providing insight into kidney disease progression in persons with diabetes and CKD., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Introduction: Earlier identification of individuals at high risk of chronic kidney disease (CKD) may facilitate improved risk factor mitigation., Methods: We evaluated the association of novel plasma biomarkers with incident CKD using a case-cohort design in participants without diabetes and with baseline estimated glomerular filtration rate (eGFR) ≥ 60 ml/min per 1.73 m 2 in the Multi-Ethnic Study of Atherosclerosis (MESA) and Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohorts. Incident CKD was defined as development of eGFR < 60 ml/min per 1.73 m 2 and ≥40% decline in eGFR from baseline. We measured plasma markers of inflammation/fibrosis-soluble tumor necrosis factor receptors (TNFRs) 1 and 2 (TNFR-1 and TNFR-2), monocyte chemotactic protein-1 (MCP-1), chitinase 3-like protein 1 (YKL-40), and soluble urokinase-type plasminogen activator receptor (suPAR)-and tubular injury (kidney injury molecule 1 [KIM-1]). Cox regression models weighted for the case-cohort design were used to estimate hazard ratios (HRs) of incident CKD after adjustment for CKD risk factors, eGFR, and albuminuria., Results: In MESA (median follow-up of 9.2 years), there were 497 individuals in the random subcohort and 163 incident CKD cases. In REGARDS (median follow-up of 9.4 years), there were 497 individuals in the random subcohort and 497 incident CKD cases. Each 2-fold higher plasma KIM-1 (adjusted HR 1.38 [95% CI 1.05-1.81]), suPAR (1.96 [1.10-3.49]), TNFR-1 (1.65 [1.04-2.62]), TNFR-2 (2.02 [1.21-3.38]), and YKL-40 (1.38 [1.09-1.75]) concentrations were associated with incident CKD in MESA. In REGARDS, TNFR-1 (1.99 [1.43-2.76]) and TNFR-2 (1.76 [1.22-2.54]) were associated with incident CKD., Conclusion: Plasma concentrations of soluble TNFR-1 and TNFR-2 are consistently associated with incident CKD in nondiabetic community-living individuals in MESA and REGARDS., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Introduction: Chronic kidney disease (CKD) is greatly affected by social determinants of health. Whether low educational attainment is associated with incident CKD in young adults is unclear., Methods: We evaluated the association of education with incident CKD in 3139 Coronary Artery Risk Development in Young Adults participants. We categorized education into low (high school and less), medium (college), and high (master's and professional studies) groups. Incident CKD was defined as new development of estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m 2 or urine albumin to creatinine ratio (ACR) ≥30 mg/g. Change in eGFR over 20 years was a secondary outcome., Results: At baseline, mean age was 35.0 ± 3.6 years, 47% were Black, and 55% were women. Participants with lower educational attainment were less likely to have high income and health insurance and to engage in a healthy lifestyle. Over 20 years, 407 participants developed CKD (13%). Compared with individuals with low educational attainment, those with medium and high educational attainment had an unadjusted hazard ratios for CKD of 0.79 (95% confidence interval [CI] 0.65-0.97) and 0.44 (95% CI, 0.30-0.63), respectively. This association was no longer significant after adjusting for income, health insurance, lifestyle, and health status. Low educational attainment was significantly associated with a change in eGFR in crude and adjusted analyses, although the association was attenuated in the multivariable models (low: -0.83 [95% CI, -0.91 to -0.75], medium: -0.80 (95% CI, -0.95 to -0.64), and high: -0.70 (95% CI, -0.89 to -0.52) ml/min per 1.73 m 2 per yr)., Conclusions: Health care access, lifestyle, and comorbid conditions likely help explain the association between low educational attainment and incident CKD in young adults., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

Whether APOL1 polymorphisms contribute to the excess risk of hypertension among blacks is unknown. To assess this we evaluated whether self-reported race and, in blacks, APOL1 risk variants (high-risk [2 risk alleles] versus low-risk [0-1 risk allele]) were associated with longitudinal blood pressure. Blood pressure trajectories were determined using linear mixed-effects (slope) and latent class models (5 distinct groups) during 25 years of follow-up in the Coronary Artery Risk Development in Young Adults Study. Associations of race and APOL1 genotypes with blood pressure change, separately, using linear mixed-effects and multinomial logistic regression models, adjusting for demographic, socioeconomic, and traditional hypertension risk factors, anti-hypertensive medication use, and kidney function were evaluated. Among 1700 whites and 1330 blacks (13% APOL1 high-risk, mean age 25 years; 46% male) mean mid-, ([systolic + diastolic blood pressure]/2), systolic, and diastolic blood pressures were 89, 110, and 69 mm Hg, respectively. One percent of participants used anti-hypertensive medications at baseline. Compared to whites, blacks, regardless of APOL1 genotype, had significantly greater increases in mid-blood pressure and were more likely to experience significantly increasing mid-blood pressure trajectories with adjusted relative risk ratios of 5.21 and 7.27 for moderate-increasing and elevated-increasing versus low-stable blood pressure, respectively. Among blacks, longitudinal mid-blood pressure changes and mid-blood pressure trajectory classification were similar by APOL1 risk status. Modeling systolic and diastolic blood pressure as outcomes yielded similar findings. From young adulthood to mid-life, blacks have greater blood pressure increases versus whites that are not fully explained by traditional risk factors. Thus APOL1 variants are not associated with longitudinal blood pressure in blacks., (Copyright © 2017 International Society of Nephrology. All rights reserved.)