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AimsGenome-wide association studies revealed an association between a locus at 10q11, downstream from CXCL12, and myocardial infarction (MI). However, the relationship among plasma CXCL12, cardiovascular disease (CVD) risk factors, incident MI, and death is unknown.Methods and resultsWe analysed study-entry plasma CXCL12 levels in 3687 participants of the Chronic Renal Insufficiency Cohort (CRIC) Study, a prospective study of cardiovascular and kidney outcomes in chronic kidney disease (CKD) patients. Mean follow-up was 6 years for incident MI or death. Plasma CXCL12 levels were positively associated with several cardiovascular risk factors (age, hypertension, diabetes, hypercholesterolaemia), lower estimated glomerular filtration rate (eGFR), and higher inflammatory cytokine levels (P < 0.05). In fully adjusted models, higher study-entry CXCL12 was associated with increased odds of prevalent CVD (OR 1.23; 95% confidence interval 1.14, 1.33, P < 0.001) for one standard deviation (SD) increase in CXCL12. Similarly, one SD higher CXCL12 increased the hazard of incident MI (1.26; 1.09,1.45, P < 0.001), death (1.20; 1.09,1.33, P < 0.001), and combined MI/death (1.23; 1.13-1.34, P < 0.001) adjusting for demographic factors, known CVD risk factors, and inflammatory markers and remained significant for MI (1.19; 1.03,1.39, P = 0.01) and the combined MI/death (1.13; 1.03,1.24, P = 0.01) after further controlling for eGFR and urinary albumin:creatinine ratio.ConclusionsIn CKD, higher plasma CXCL12 was associated with CVD risk factors and prevalent CVD as well as the hazard of incident MI and death. Further studies are required to establish if plasma CXCL12 reflect causal actions at the vessel wall and is a tool for genomic and therapeutic trials.

Background: Cardiac troponin T is independently associated with cardiovascular events and mortality in patients with chronic kidney disease (CKD). Serum levels of high sensitivity cardiac troponin T (hs-TnT) reflect subclinical myocardial injury in ambulat

Hispanics are the fastest growing minority group in the United States. The incidence of end-stage renal disease (ESRD) in Hispanics is higher than non-Hispanic Whites and Hispanics with chronic kidney disease (CKD) are at increased risk for kidney failure. Likely contributing factors to this burden of disease include diabetes and metabolic syndrome, both are common among Hispanics. Access to health care, quality of care, and barriers due to language, health literacy and acculturation may also play a role. Despite the importance of this public health problem, only limited data exist about Hispanics with CKD. We review the epidemiology of CKD in US Hispanics, identify the factors that may be responsible for this growing health problem, and suggest gaps in our understanding which are suitable for future investigation. [ABSTRACT FROM AUTHOR]

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) and dementia disproportionately burden patients with chronic kidney disease (CKD). The association between CHIP and cognitive impairment in CKD patients is unknown., Methods: We conducted time-to-event analyses in up to 1452 older adults with CKD from the Chronic Renal Insufficiency Cohort who underwent CHIP gene sequencing. Cognition was assessed using four validated tests in up to 6 years mean follow-up time. Incident cognitive impairment was defined as a test score one standard deviation below the baseline mean., Results: Compared to non-carriers, CHIP carriers were markedly less likely to experience impairment in attention (adjusted hazard ratio [HR] [95% confidence interval {CI}] = 0.44 [0.26, 0.76], p = 0.003) and executive function (adjusted HR [95% CI] = 0.60 [0.37, 0.97], p = 0.04). There were no significant associations between CHIP and impairment in global cognition or verbal memory., Discussion: CHIP was associated with lower risks of impairment in attention and executive function among CKD patients., Highlights: Our study is the first to examine the role of CHIP in cognitive decline in CKD. CHIP markedly decreased the risk of impairment in attention and executive function. CHIP was not associated with impairment in global cognition or verbal memory., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Rationale & Objective: Hemoglobin A 1c (HbA 1c ) is widely used to estimate glycemia, yet it is less reliable in patients with chronic kidney disease (CKD). There is growing interest in the complementary use of glycated albumin (GA) to improve glycemic monitoring and risk stratification. However, whether GA associates with clinical outcomes in a non-dialysis-dependent CKD population remains unknown., Study Design: Prospective cohort study., Setting & Participants: 3,110 participants with CKD from the Chronic Renal Insufficiency Cohort study., Exposure: Baseline GA levels., Outcome: Incident end-stage kidney disease (ESKD), cardiovascular disease (CVD) events, and all-cause mortality., Analytical Approach: Cox proportional hazards regression., Results: Participant characteristics included mean age 59.0±10.8 SD years; 1,357 (43.6%) female; and 1,550 (49.8%) with diabetes. The median GA was 18.7% (IQR, 15.8%-23.3%). During an average 7.9-year follow-up, there were 980 ESKD events, 968 CVD events, and 1,084 deaths. Higher GA levels were associated with greater risks of all outcomes, regardless of diabetes status: hazard ratios for ESKD, CVD, and death among participants with the highest quartile compared with quartile 2 (reference) were 1.42 (95% CI, 1.19-1.69), 1.67 (95% CI, 1.39-2.01), and 1.63 (95% CI, 1.37-1.94), respectively. The associations with CVD and death appeared J-shaped, with increased risk also seen at the lowest GA levels. Among patients with coexisting CKD and diabetes, the associations of GA with outcomes remained significant even after adjusting for HbA 1c . For each outcome, we observed a significant increase in the fraction of new prognostic information when both GA and HbA 1c were added to models., Limitations: Lack of longitudinal GA measurements; and HbA 1c measurements were largely unavailable in participants without diabetes., Conclusions: Among patients with CKD, GA levels were independently associated with risks of ESKD, CVD, and mortality, regardless of diabetes status. GA added prognostic value to HbA 1c among patients with coexisting CKD and diabetes., Plain-Language Summary: Hemoglobin A 1c (HbA 1c ) is widely used to estimate glycemia, yet it is less reliable in patients with chronic kidney disease (CKD). There is growing interest in the complementary use of glycated albumin (GA) to improve glycemic monitoring and risk stratification. However, whether GA associates with clinical outcomes in a non-dialysis-dependent CKD population remains unknown. In this cohort study of 3,110 individuals with non-dialysis-dependent CKD, GA levels were independently associated with risks of end-stage kidney disease, cardiovascular disease (CVD), and mortality. The associations with CVD and mortality appeared to be J-shaped. Among patients with coexisting CKD and diabetes, GA added prognostic value to HbA 1c. Thus, GA may be a valuable complementary test to HbA 1c in patients with CKD., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Coronary artery calcification (CAC) progresses rapidly in people with chronic kidney disease (CKD) compared with the general population. We studied the association between CAC progression and higher risks of atherosclerotic cardiovascular disease (CVD), congestive heart failure, and all-cause mortality among adults with CKD., Study Design: Prospective cohort study., Setting & Participants: 1,310 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study who had at least 1 CAC scan with no prior history of CVD and with observed or imputed data on changes in CAC over time., Exposure: Observed or imputed CAC progression, categorized as incident CAC among participants with 0 CAC on the baseline scan or progressive CAC when the baseline scan demonstrated CAC and there was an increase in CAC≥50 Agatston units per year., Outcome: Atherosclerotic CVD (myocardial infarction or stroke), congestive heart failure, and all-cause mortality., Analytical Approach: Cause-specific Cox proportional hazards regression, stratified by presence of CAC at baseline., Results: A total of 545 participants without and 765 with prevalent CAC at baseline were included. During a mean 3.3 years between CAC assessments, 177 participants (32.5%) without baseline CAC developed incident CAC while 270 participants (35.3%) with baseline CAC developed a≥50 Agatston units per year increase in CAC. After multivariable adjustment, incident CAC was associated with 2.42-fold higher rate of atherosclerotic CVD (95% CI, 1.23-4.79) and 1.82-fold higher rate of all-cause mortality (95% CI, 1.03-3.22). Progressive CAC (≥50 units per year) was not associated with atherosclerotic CVD (HR, 1.42 [95% CI, 0.85-2.35]) but was associated with a 1.73-fold higher rate of all-cause mortality (95% CI, 1.31-2.28). Progressive CAC was not associated with incident heart failure., Limitations: Residual confounding and limited statistical power for some outcomes., Conclusions: Among adults with CKD stages 2-4, CAC progression over a mean 3.3 years was associated with higher risk of atherosclerotic CVD and all-cause mortality. The associations were strongest among participants without CAC at baseline., Plain-Language Summary: Prior research has shown that coronary artery calcification (CAC) is a marker of higher risk of heart disease and death. Less is known about how changes in CAC over time might affect risk, particularly among patients with kidney disease. In this study, participants with chronic kidney disease who developed CAC or had worsening CAC over time showed higher rates of heart attack, stroke, and death than those who did not develop CAC. These findings support the need for further research on longitudinal changes in CAC as a possible aid to establishing prognosis among patients with kidney disease and to inform treatment., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Chronic kidney disease (CKD) is highly prevalent in Central America, and genetic factors may contribute to CKD risk. To understand the influences of genetic admixture on CKD susceptibility, we conducted an admixture mapping screening of CKD traits and risk factors in US Hispanic and Latino individuals from Central America country of origin., Methods: We analyzed 1023 participants of HCHS/SOL (Hispanic Community Health Study/Study of Latinos) who reported 4 grandparents originating from the same Central America country. Ancestry admixture findings were validated on 8191 African Americans from WHI (Women's Health Initiative), 3141 American Indians from SHS (Strong Heart Study), and over 1.1 million European individuals from a multistudy meta-analysis., Results: We identified 3 novel genomic regions for albuminuria (chromosome 14q24.2), CKD (chromosome 6q25.3), and type 2 diabetes (chromosome 3q22.2). The 14q24.2 locus driven by a Native American ancestry had a protective effect on albuminuria and consisted of 2 nearby regions spanning the RGS6 gene. Variants at this locus were validated in American Indians. The 6q25.3 African ancestry-derived locus, encompassing the ARID1B gene, was associated with increased risk for CKD and replicated in African Americans through admixture mapping. The European ancestry type 2 diabetes locus at 3q22.2, encompassing the EPHB1 and KY genes, was validated in European individuals through variant association., Conclusions: US Hispanic/Latino populations are culturally and genetically diverse. This study focusing on Central America grandparent country of origin provides new loci discovery and insights into the ancestry-of-origin influences on CKD and risk factors in US Hispanic and Latino individuals., Competing Interests: None.

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a common inflammatory condition of aging that causes myriad end-organ damage. We have recently shown associations for CHIP with acute kidney injury and with kidney function decline in the general population, with stronger associations for CHIP driven by mutations in genes other than DNMT3A (non- DNMT3A CHIP). Longitudinal kidney function endpoints in individuals with pre-existing chronic kidney disease (CKD) and CHIP have been examined in two previous studies, which reported conflicting findings and were limited by small sample sizes., Methods: In this study, we examined the prospective associations between CHIP and CKD progression events in four cohorts of CKD patients (total N = 5,772). The primary outcome was a composite of 50% kidney function decline or kidney failure. The slope of eGFR decline was examined as a secondary outcome. Mendelian randomization techniques were then used to investigate potential causal effects of CHIP on eGFR decline. Finally, kidney function was assessed in adenine-fed CKD model mice having received a bone marrow transplant recapitulating Tet2 -CHIP compared to controls transplanted wild-type bone marrow., Results: Across all cohorts, the average age was 66.4 years, the average baseline eGFR was 42.6 ml/min/1.73m 2 , and 24% had CHIP. Upon meta-analysis, non- DNMT3A CHIP was associated with a 59% higher relative risk of incident CKD progression (HR 1.59, 95% CI: 1.02-2.47). This association was more pronounced among individuals with diabetes (HR 1.29, 95% CI: 1.03-1.62) and with baseline eGFR ≥ 30 ml/min/1.73m (HR 1.80, 95% CI: 1.11-2.90). Additionally, the annualized slope of eGFR decline was steeper among non- DNMT3A CHIP carriers, relative to non-carriers (β -0.61 ± 0.31 ml/min/1.73m 2 , p = 0.04). Mendelian randomization analyses suggested a causal role for CHIP in eGFR decline among individuals with diabetes. In a dietary adenine mouse model of CKD, Tet2 -CHIP was associated with lower GFR as well as greater kidney inflammation, tubular injury, and tubulointerstitial fibrosis., Conclusion: Non- DNMT3A CHIP is a potentially targetable novel risk factor for CKD progression.

Rationale & Objective: The risk implications of the Kidney Disease: Improving Global Outcomes (KDIGO) chronic kidney disease classification in older adults are controversial. We evaluated the risk of adverse outcomes in this population across categories of estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR)., Study Design: Prospective cohort., Settings & Participants: In total, 2,509 participants aged ≥75 years in the Systolic Blood Pressure Intervention Trial (SPRINT)., Exposure: KDIGO eGFR and UACR categories. We combined KDIGO categories G1 and G2, G3b and G4, as well as A2 and A3., Outcomes: Primary SPRINT outcome (composite of myocardial infarction, other acute coronary syndromes, stroke, heart failure, or death from cardiovascular causes), and all-cause death., Analytical Approach: Multivariable Cox proportional hazard models., Results: Mean age was 79.8 years, and 37.4% were female. The mean eGFR was 64.0 mL/min/1.73 m 2 , and the median UACR was 13.1 mg/g. In multivariable Cox proportional hazard analysis, compared with participants with eGFR ≥ 60 mL/min/1.73 m 2 and UACR < 30 mg/g, there was no statistically significant difference in the risk of the primary outcome among participants with eGFR 45-59 or 15-44 mL/min/1.73 m 2 and UACR < 30 mg/g. However, those with eGFR 45-59 or 15-44 mL/min/1.73 m 2 and UACR ≥ 30 mg/g had higher risk of the primary outcome (HR [95% CI], 1.97 [1.27-3.04] and 3.32 [2.23-4.93], respectively). The risk for all-cause death was higher for each category of abnormal eGFR and UACR, with the highest risk observed among those with eGFR 15-44 mL/min/1.73 m 2 and UACR ≥ 30 mg/g (3.34 [2.05-5.44])., Limitations: Individuals with diabetes and urine protein >1 g/day were excluded from SPRINT., Conclusion: Among older adults SPRINT participants, low eGFR without albuminuria was associated with higher mortality but not with increased risk of cardiovascular events. Additional studies are needed to evaluate an adapted chronic kidney disease stage-based risk stratification for older adults., (© 2024 The Authors.)

Background: Illness perceptions are the unique perspective individuals have on their illness, based on their context and experiences, and are associated with patient outcomes including coping and adherence. The purpose of this study was to explore characteristics that may be driving membership in illness perceptions cluster groups for adults with chronic kidney disease (CKD)., Methods: This study was conducted within the multicenter longitudinal Chronic Renal Insufficiency Cohort (CRIC) Study. Cross-sectional data were collected and combined with CRIC data. Illness perceptions were measured using the Revised Illness Perception Questionnaire. Clustering analysis was conducted in R, and bivariate analysis including linear regression was performed in STATA 16., Results: The sample (n = 197) had a mean age of 68, was 52% women, 53% non-White, and mean estimated glomerular filtration rate (eGFR) 56 ml/min/1.73 m 2 . Three cluster groups were identified, labeled as "Disengaged" (n = 20), "Well-Resourced" (n = 108), and "Distressed" (n = 69). The "Disengaged" group was characterized by low CKD knowledge, many recent hospitalization days, and the lowest perceived CKD burden. The "Well-Resourced" group was characterized by the highest levels of education, CKD knowledge, optimism, and medication adherence. The "Distressed" group was characterized by the highest levels of depression scores, comorbidity burden, CKD burden, CKD symptoms, and lowest optimism. Group membership significantly predicted the number of hospitalization days in adjusted analyses., Conclusions: Illness perceptions groups are associated with number of hospitalization days but are independent of many patient characteristics. Illness perceptions data could be used to tailor care for specific patients at risk for poor health outcomes., (© 2024. The Author(s) under exclusive licence to Italian Society of Nephrology.)

Adults with chronic kidney disease (CKD) tend to be extremely sedentary. We investigated the feasibility and acceptability of a sedentary-reducing intervention for adults with CKD. The intervention utilized telephone-delivered coaching and a consumer wearable device to support participants to reduce their sedentary time. The mean age of participants in the sample was 60.5 years; 72% were women, and 83% had CKD Stage 3. At baseline, participants spent 73% of their waking time sedentary. Inter vention phone call attendance was 100%, study retention was 82%, and the intervention was rated as enjoyable (9.1/10). A telephone-delivered, sedentary-reducing intervention is feasible and acceptable in adults with CKD. Future work is needed investigating the efficacy of sedentary-reducing interventions for adults with CKD., Competing Interests: The authors reported no actual or potential conflict of interest in relation to this nursing continuing professional development (NCPD) activity., (Copyright© by the American Nephrology Nurses Association.)

Background: All-cause mortality among diverse Hispanic/Latino groups in the United States and factors underlying mortality differences have not been examined prospectively., Objective: To describe cumulative all-cause mortality (and factors underlying differences) by Hispanic/Latino background, before and during the COVID-19 pandemic., Design: Prospective, multicenter cohort study., Setting: Hispanic Community Health Study/Study of Latinos., Participants: 15 568 adults aged 18 to 74 years at baseline (2008 to 2011) of Central American, Cuban, Dominican, Mexican, Puerto Rican, South American, and other backgrounds from the Bronx, New York; Chicago, Illinois; Miami, Florida; and San Diego, California., Measurements: Sociodemographic, acculturation-related, lifestyle, and clinical factors were assessed at baseline, and vital status was ascertained through December 2021 (969 deaths; 173 444 person-years of follow-up). Marginally adjusted cumulative all-cause mortality risks (11-year before the pandemic and 2-year during the pandemic) were examined using progressively adjusted Cox regression., Results: Before the pandemic, 11-year cumulative mortality risks adjusted for age and sex were higher in the Puerto Rican and Cuban groups (6.3% [95% CI, 5.2% to 7.6%] and 5.7% [CI, 5.0% to 6.6%], respectively) and lowest in the South American group (2.4% [CI, 1.7% to 3.5%]). Differences were attenuated with adjustment for lifestyle and clinical factors. During the pandemic, 2-year cumulative mortality risks adjusted for age and sex ranged from 1.1% (CI, 0.6% to 2.0%; South American) to 2.0% (CI, 1.4% to 3.0%; Central American); CIs overlapped across groups. With adjustment for lifestyle factors, 2-year cumulative mortality risks were highest in persons of Central American and Mexican backgrounds and lowest among those of Puerto Rican and Cuban backgrounds., Limitation: Lack of data on race and baseline citizenship status; correlation between Hispanic/Latino background and site., Conclusion: Differences in prepandemic mortality risks across Hispanic/Latino groups were explained by lifestyle and clinical factors. Mortality patterns changed during the pandemic, with higher risks in persons of Central American and Mexican backgrounds than in those of Puerto Rican and Cuban backgrounds., Primary Funding Source: National Institutes of Health., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-1990.

Rationale & Objective: The extent to which depression affects the progression of chronic kidney disease (CKD) and leads to adverse clinical outcomes remains inadequately understood. We examined the association of depressive symptoms (DS) and antidepressant medication use on clinical outcomes in 4,839 adults with nondialysis CKD., Study Design: Observational cohort study., Setting and Participants: Adults with mild to moderate CKD who participated in the multicenter Chronic Renal Insufficiency Cohort Study (CRIC)., Exposure: The Beck Depression Inventory (BDI) was used to quantify DS. Antidepressant use was identified from medication bottles and prescription lists. Individual effects of DS and antidepressants were examined along with categorization as follows: (1) BDI <11 and no antidepressant use, (2) BDI <11 with antidepressant use, (3) BDI ≥11 and no antidepressant use, and (4) BDI ≥11 with antidepressant use., Outcomes: CKD progression, incident cardiovascular disease composite, all-cause hospitalizations, and mortality., Analytic Approach: Cox regression models were fitted for outcomes of CKD progression, incident cardiovascular disease, and all-cause mortality, whereas hospitalizations used Poisson regression., Results: At baseline, 27.3% of participants had elevated DS, and 19.7% used antidepressants. Elevated DS at baseline were associated with significantly greater risk for an incident cardiovascular disease event, hospitalization, and all-cause mortality, but not CKD progression, adjusted for antidepressants. Antidepressant use was associated with higher risk for all-cause mortality and hospitalizations, after adjusting for DS. Compared to participants without elevated DS and not using antidepressants, the remaining groups (BDI <11 with antidepressants; BDI ≥11 and no antidepressants; BDI ≥11 with antidepressants) showed higher risks of hospitalization and all-cause mortality., Limitations: Inability to infer causality among depressive symptoms, antidepressants, and outcomes. Additionally, the absence of nonpharmacological data, and required exploration of generalizability and alternative analytical approaches., Conclusions: Elevated DS increased adverse outcome risk in nondialysis CKD, unattenuated by antidepressants. Additionally, investigation into the utilization and counterproductivity of antidepressants in this population is warranted., (© 2024 The Authors.)

Rationale & Objective: Vaccination for influenza is strongly recommended for people with chronic kidney disease (CKD) due to their immunocompromised state. Identifying risk factors for not receiving an influenza vaccine (non-vaccination) could inform strategies for improving vaccine uptake in this high-risk population., Study Design: Longitudinal observational study., Setting & Participants: 3,692 Chronic Renal Insufficiency Cohort Study (CRIC) participants., Exposure: Demographic factors, social determinants of health, clinical conditions, and health behaviors., Outcome: Influenza non-vaccination, which was assessed based on a receipt of influenza vaccine ascertained during annual clinic visits in a subset of participants who were under nephrology care., Analytical Approach: Mixed-effects Poisson models to estimate adjusted prevalence ratios (APRs)., Results: Between 2009 and 2020, the pooled mean vaccine uptake was 72% (mean age, 66 years; 44% female; 44% Black race). In multivariable models, factors significantly associated with influenza non-vaccination were younger age (APR, 2.16 [95% CI, 1.85-2.52] for<50 vs≥75 years), Black race (APR, 1.58 [95% CI, 1.43-1.75] vs White race), lower education (APR, 1.20 [95% CI, 1.04-1.39 for less than high school vs college graduate]), lower annual household income (APR, 1.26 [95% CI, 1.06-1.49] for <$20,000 vs >$100,000), formerly married status (APR, 1.22 [95% CI, 1.09-1.35] vs currently married), and nonemployed status (APR, 1.13 [95% CI, 1.02-1.24] vs employed). In contrast, participants with diabetes (APR, 0.80 [95% CI, 0.73-0.87] vs no diabetes), chronic obstructive pulmonary disease (COPD) (APR, 0.80 [95% CI, 0.70-0.92] vs no COPD), end-stage kidney disease (APR, 0.64 [0.56 to 0.76] vs estimated glomerular filtration rate≥60mL/min/1.73m 2 ), frailty (APR, 0.86 [95% CI, 0.74-0.99] vs no frailty), and ideal physical activity (APR, 0.90 [95% CI, 0.82-0.99] vs. physically inactive) were less likely to have non-vaccination status., Limitations: Possible residual confounding., Conclusions: Among adults with CKD receiving nephrology care, younger adults, Black individuals, and those with adverse social determinants of health were more likely to have the influenza non-vaccination status. Strategies are needed to address these disparities and reduce barriers to vaccination., Plain-Language Summary: Identifying risk factors for not receiving an influenza vaccine ("non-vaccination") in people living with kidney disease, who are at risk of influenza and its complications, could inform strategies for improving vaccine uptake. In this study, we examined whether demographic factors, social determinants of health, and clinical conditions were linked to the status of not receiving an influenza vaccine among people living with kidney disease and receiving nephrology care. We found that younger adults, Black individuals, and those with adverse social determinants of health were more likely to not receive the influenza vaccine. These findings suggest the need for strategies to address these disparities and reduce barriers to vaccination in people living with kidney disease., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Intensive BP lowering in the Systolic Blood Pressure Intervention Trial (SPRINT) produced acute decreases in kidney function and higher risk for AKI. We evaluated the effect of intensive BP lowering on long-term changes in kidney function using trial and outpatient electronic health record (EHR) creatinine values., Methods: SPRINT data were linked with EHR data from 49 (of 102) study sites. The primary outcome was the total slope of decline in eGFR for the intervention phase and the post-trial slope of decline during the observation phase using trial and outpatient EHR values. Secondary outcomes included a ≥30% decline in eGFR to <60 ml/min per 1.73 m 2 and a ≥50% decline in eGFR or kidney failure among participants with baseline eGFR ≥60 and <60 ml/min per 1.73 m 2 , respectively., Results: EHR creatinine values were available for a median of 8.3 years for 3041 participants. The total slope of decline in eGFR during the intervention phase was -0.67 ml/min per 1.73 m 2 per year (95% confidence interval [CI], -0.79 to -0.56) in the standard treatment group and -0.96 ml/min per 1.73 m 2 per year (95% CI, -1.08 to -0.85) in the intensive treatment group ( P < 0.001). The slopes were not significantly different during the observation phase: -1.02 ml/min per 1.73 m 2 per year (95% CI, -1.24 to -0.81) in the standard group and -0.85 ml/min per 1.73 m 2 per year (95% CI, -1.07 to -0.64) in the intensive group. Among participants without CKD at baseline, intensive treatment was associated with higher risk of a ≥30% decline in eGFR during the intervention (hazard ratio, 3.27; 95% CI, 2.43 to 4.40), but not during the postintervention observation phase. In those with CKD at baseline, intensive treatment was associated with a higher hazard of eGFR decline only during the intervention phase (hazard ratio, 1.95; 95% CI, 1.03 to 3.70)., Conclusions: Intensive BP lowering was associated with a steeper total slope of decline in eGFR and higher risk for kidney events during the intervention phase of the trial, but not during the postintervention observation phase., (Copyright © 2023 by the American Society of Nephrology.)

Rationale & Objective: Frailty is common in individuals with chronic kidney disease (CKD) and increases the risk of adverse outcomes in adults with kidney failure requiring dialysis. However, this relationship has not been thoroughly evaluated among those with non-dialysis-dependent CKD., Study Design: Prospective cohort study., Setting & Participants: 2,539 adults in the Chronic Renal Insufficiency Cohort Study., Exposure: Frailty status assessed using 5 criteria: slow gait speed, muscle weakness, low physical activity, exhaustion, and unintentional weight loss., Outcome: Atherosclerotic events, incident heart failure, all-cause death, and cardiovascular death., Analytical Approach: Cause-specific hazards models., Results: At study entry, the participants' mean age was 62 years, 46% were female, the mean estimated glomerular filtration rate was 45.4mL/min/1.73m 2 , and the median urine protein was 0.2mg/day. Frailty status was as follows: 12% frail, 51% prefrail, and 37% nonfrail. Over a median follow-up of 11.4 years, there were 393 atherosclerotic events, 413 heart failure events, 497 deaths, and 132 cardiovascular deaths. In multivariable regression analyses, compared with nonfrailty, both frailty and prefrailty status were each associated with higher risk of an atherosclerotic event (HR, 2.03 [95% CI, 1.41-2.91] and 1.77 [95% CI, 1.35-2.31], respectively) and incident heart failure (HR, 2.22 [95% CI, 1.59-3.10] and 1.39 [95% CI, 1.07-1.82], respectively), as well as higher risk of all-cause death (HR, 2.52 [95% CI, 1.84-3.45] and 1.76 [95% CI, 1.37-2.24], respectively) and cardiovascular death (HR, 3.01 [95% CI, 1.62-5.62] and 1.78 [95% 1.06-2.99], respectively)., Limitations: Self-report of aspects of the frailty assessment and comorbidities, which may have led to bias in some estimates., Conclusions: In adults with CKD, frailty status was associated with higher risk of cardiovascular events and mortality. Future studies are needed to evaluate the impact of interventions to reduce frailty on cardiovascular outcomes in this population., Plain-Language Summary: Frailty is common in individuals with chronic kidney disease (CKD) and increases the risk of adverse outcomes. We sought to evaluate the association of frailty status with cardiovascular events and death in adults with CKD. Frailty was assessed according to the 5 phenotypic criteria detailed by Fried and colleagues. Among 2,539 participants in the CRIC Study, we found that 12% were frail, 51% were prefrail, and 37% were nonfrail. Frailty status was associated with an increased risk of atherosclerotic events, incident heart failure, and death., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research., (© 2024. The Author(s).)

Chronic kidney disease is a leading cause of death and disability globally and impacts individuals of African ancestry (AFR) or with ancestry in the Americas (AMS) who are under-represented in genome-wide association studies (GWASs) of kidney function. To address this bias, we conducted a large meta-analysis of GWASs of estimated glomerular filtration rate (eGFR) in 145,732 AFR and AMS individuals. We identified 41 loci at genome-wide significance (p < 5 × 10 -8 ), of which two have not been previously reported in any ancestry group. We integrated fine-mapped loci with epigenomic and transcriptomic resources to highlight potential effector genes relevant to kidney physiology and disease, and reveal key regulatory elements and pathways involved in renal function and development. We demonstrate the varying but increased predictive power offered by a multi-ancestry polygenic score for eGFR and highlight the importance of population diversity in GWASs and multi-omics resources to enhance opportunities for clinical translation for all., Competing Interests: Declaration of interests P.N. reports investigator-initiated research grants from Allelica, Apple, Amgen, Boston Scientific, Genentech/Roche, and Novartis, personal fees from Allelica, Apple, AstraZeneca, Blackstone Life Sciences, Eli Lilly & Co, Foresite Labs, Genentech/Roche, GV, HeartFlow, Magnet Biomedicine, and Novartis, scientific advisory board membership of Esperion Therapeutics, Preciseli, and TenSixteen Bio, scientific co-founder of TenSixteen Bio, equity in MyOme, Preciseli, and TenSixteen Bio, and spousal employment at Vertex Pharmaceuticals, all unrelated to the present work. M.B.L. has received speaker and advisory fees from Otsuka, Reata, Bayer, and Sanofi Genzyme. G.P. has received speaker and advisory fees from Amgen, Bayer, Novartis, and Sanofi, and has received research grants from Bayer and Sanofi. L.M.R. is a consultant for the TOPMed Administrative Coordinating Center (through Westat)., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hispanic/Latino individuals are less likely to receive optimal treatment for chronic kidney disease than non-Hispanic whites. This may be particularly detrimental for women of reproductive age as chronic kidney disease increases risk for infertility, menstrual irregularities, and pregnancy loss. While these maternal outcomes have been associated with advanced chronic kidney disease, their occurrence in early chronic kidney disease is unclear., Objectives/design: Using baseline (2008-2011) and second study visit (2014-2017) data from the Hispanic Community Health Study/Study of Latinos, we retrospectively assessed the prevalence of chronic kidney disease as well as the association between chronic kidney disease and self-reported infertility, cessation of menses, hysterectomy, and nonviable pregnancy loss (experienced at less than 24 weeks gestation) in women of reproductive age (18-45 years)., Methods: Multivariable survey logistic regression analyses determined the unadjusted and multivariable-adjusted prevalence odds ratios with 95% confidence intervals between chronic kidney disease and the separate outcomes., Results: Among 2589 Hispanic/Latino women included (mean age = 31.4 years), 4.6% were considered to have chronic kidney disease. In adjusted analyses, women with chronic kidney disease did not have a significantly increased odds of infertility (odds ratio = 1.02, 95% confidence interval = 0.42-2.49), cessation of menses (odds ratio = 1.25, 95% confidence interval = 0.52-3.04), or hysterectomy (odds ratio = 1.17, 95% confidence interval = 0.61-2.25) compared to those without chronic kidney disease. In those with chronic kidney disease, the adjusted odds of a nonviable pregnancy loss occurring after baseline visit were increased (odds ratio = 2.11, 95% confidence interval = 0.63-7.02) but not statistically significance., Conclusion: The presence of early stage chronic kidney disease did not confer a significant risk of infertility, cessation of menses, or nonviable pregnancy loss.

Evidence suggests that Mexican adults living in Mexico have a more favorable cardiovascular risk profile than Mexican adults living in the U.S. However, this relationship has not been evaluated among patients with chronic kidney disease (CKD), which is a question of importance given the high risk for cardiovascular disease among patients with CKD. Using data from two ongoing observational cohort studies, we compared the prevalence of ideal cardiovascular health metrics (assessed by the American Heart Association "Life's Simple 7" criteria) in 309 Mexican adults with CKD living in Mexico City to 343 Mexican adults with CKD living in Chicago. Mexican adults with CKD living in Mexico City had a significantly higher prevalence of ideal body mass index (25 vs. 10%), diet (17 vs. 8%), total cholesterol (80 vs. 63%), blood pressure (43 vs. 25%), and fasting glucose (54 vs. 42%). Mexican adults with CKD living in both Mexico City and Chicago had low levels of cardiovascular health scores. Future work is needed to better understand the lower prevalence of ideal cardiovascular health metrics in Chicago as compared to Mexico City., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Progression of chronic kidney disease (CKD) portends myriad complications, including kidney failure. In this study, we analyze associations of 4638 plasma proteins among 3235 participants of the Chronic Renal Insufficiency Cohort Study with the primary outcome of 50% decline in estimated glomerular filtration rate or kidney failure over 10 years. We validate key findings in the Atherosclerosis Risk in the Communities study. We identify 100 circulating proteins that are associated with the primary outcome after multivariable adjustment, using a Bonferroni statistical threshold of significance. Individual protein associations and biological pathway analyses highlight the roles of bone morphogenetic proteins, ephrin signaling, and prothrombin activation. A 65-protein risk model for the primary outcome has excellent discrimination (C-statistic[95%CI] 0.862 [0.835, 0.889]), and 14/65 proteins are druggable targets. Potentially causal associations for five proteins, to our knowledge not previously reported, are supported by Mendelian randomization: EGFL9, LRP-11, MXRA7, IL-1 sRII and ILT-2. Modifiable protein risk markers can guide therapeutic drug development aimed at slowing CKD progression., (© 2023. Springer Nature Limited.)

Rationale & Objective: Heart failure (HF) is an important cause of morbidity and mortality among individuals with chronic kidney disease (CKD). A large body of evidence from preclinical and clinical studies implicates excess levels of fibroblast growth factor 23 (FGF23) in HF pathogenesis in CKD. It remains unclear whether the relationship between elevated FGF23 levels and HF risk among individuals with CKD varies by HF subtype., Study Design: Prospective cohort study., Settings & Participants: A total of 3,502 participants were selected in the Chronic Renal Insufficiency Cohort study., Exposure: Baseline plasma FGF23., Outcomes: Incident HF by subtype and total rate of HF hospitalization. HF was categorized as HF with preserved ejection fraction (HFpEF, ejection fraction [EF] ≥ 50%), HF with reduced EF (HFrEF, EF < 50%) and HF with unknown EF (HFuEF)., Analytical Approach: Multivariable-adjusted cause-specific Cox proportional hazards models were used to investigate associations between FGF23 and incident hospitalizations for HF by subtype. The Lunn-McNeil method was used to compare hazard ratios across HF subtypes. Poisson regression models were used to evaluate the total rate of HF., Results: During a median follow-up time of 10.8 years, 295 HFpEF, 242 HFrEF, and 156 HFuEF hospitalizations occurred. In multivariable-adjusted cause-specific Cox proportional hazards models, FGF23 was significantly associated with the incidence of HFpEF (HR, 1.41; 95% CI, 1.21-1.64), HFrEF (HR, 1.27; 95% CI, 1.05-1.53), and HFuEF (HR, 1.40; 95% CI, 1.13-1.73) per 1 standard deviation (SD) increase in the natural log of FGF23. The Lunn-McNeil method determined that the risk association was consistent across all subtypes. The rate ratio of total HF events increased with FGF23 quartile. In multivariable-adjusted models, compared with quartile 1, FGF23 quartile 4 had a rate ratio of 1.81 (95% CI, 1.28-2.57) for total HF events., Limitations: Self-report of HF hospitalizations and possible lack of an echocardiogram at time of hospitalization., Conclusions: In this large multicenter prospective cohort study, elevated FGF23 levels were associated with increased risks for all HF subtypes., Plain-Language Summary: Heart failure (HF) is a prominent cause of morbidity and mortality in individuals with chronic kidney disease (CKD). Identifying potential pathways in the development of HF is essential in developing therapies to prevent and treat HF. In a large cohort of individuals with CKD, the Chronic Renal Insufficiency Cohort (N = 3,502), baseline fibroblast growth factor-23 (FGF23), a hormone that regulates phosphorous, was evaluated in relation to the development of incident and recurrent HF with reduced, preserved, and unknown ejection fraction. In this large multicenter prospective cohort study, elevated FGF23 levels were associated with increased risk of all HF subtypes. These findings demonstrate the need for further research into FGF23 as a target in preventing the development of HF in individuals with CKD.

Rationale & Objective: Ultraprocessed foods are widely consumed in the United States and are associated with cardiovascular disease (CVD), mortality, and kidney function decline in the general population. We investigated associations between ultraprocessed food intake and chronic kidney disease (CKD) progression, all-cause mortality, and incident CVD in adults with chronic kidney disease (CKD)., Study Design: Prospective cohort study., Setting & Participants: Chronic Renal Insufficiency Cohort Study participants who completed baseline dietary questionnaires., Exposure: Ultraprocessed food intake (in servings per day) classified according to the NOVA system., Outcomes: CKD progression (≥50% decrease in estimated glomerular filtration rate [eGFR] or initiation of kidney replacement therapy), all-cause mortality, and incident CVD (myocardial infarction, congestive heart failure, or stroke)., Analytical Approach: Cox proportional hazards models adjusted for demographic, lifestyle, and health covariates., Results: There were 1,047 CKD progression events observed during a median follow-up of 7 years. Greater ultraprocessed food intake was associated with higher risk of CKD progression (tertile 3 vs tertile 1, HR, 1.22; 95% CI, 1.04-1.42; P=0.01 for trend). The association differed by baseline kidney function, such that greater intake was associated with higher risk among people with CKD stages 1/2 (eGFR≥60mL/min/1.73m 2 ; tertile 3 vs tertile 1, HR, 2.61; 95% CI, 1.32-5.18) but not stages 3a-5 (eGFR<60mL/min/1.73m 2 ; P=0.003 for interaction). There were 1,104 deaths observed during a median follow-up of 14 years. Greater ultraprocessed food intake was associated with higher risk of mortality (tertile 3 vs tertile 1, HR, 1.21; 95% CI, 1.04-1.40; P=0.004 for trend)., Limitations: Self-reported diet., Conclusions: Greater ultraprocessed food intake may be associated with CKD progression in earlier stages of CKD and is associated with higher risk of all-cause mortality in adults with CKD., Plain Language Summary: Ultraprocessed foods are industrial formulations produced using ingredients and processes that are not commonly used in culinary preparations and contain few, if any, intact unprocessed foods. Ultraprocessed foods are widely consumed in the United States, and high intakes of such foods have been linked to cardiovascular disease, kidney disease, and mortality in the general population. In this study, we found that greater intake of ultraprocessed foods was associated with higher risk of kidney disease progression and mortality in adults with chronic kidney disease. Our findings suggest that patients with kidney disease may benefit from greater consumption of fresh, whole, and homemade or hand-prepared foods and fewer highly processed foods., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Patients hospitalized with AKI have higher subsequent risks of heart failure, atherosclerotic cardiovascular events, and mortality than their counterparts without AKI, but these higher risks may be due to differences in prehospitalization patient characteristics, including the baseline level of estimated glomerular filtration rate (eGFR), the rate of prior eGFR decline, and the proteinuria level, rather than AKI itself., Methods: Among 2177 adult participants in the Chronic Renal Insufficiency Cohort study who were hospitalized in 2013-2019, we compared subsequent risks of heart failure, atherosclerotic cardiovascular events, and mortality between those with serum creatinine-based AKI (495 patients) and those without AKI (1682 patients). We report both crude associations and associations sequentially adjusted for prehospitalization characteristics including eGFR, eGFR slope, and urine protein-creatinine ratio (UPCR)., Results: Compared with patients hospitalized without AKI, those with hospitalized AKI had lower eGFR prehospitalization (42 versus 49 ml/min per 1.73 m 2 ), faster chronic loss of eGFR prehospitalization (-0.84 versus -0.51 ml/min per 1.73 m 2 per year), and more proteinuria prehospitalization (UPCR 0.28 versus 0.16 g/g); they also had higher prehospitalization systolic BP (130 versus 127 mm Hg; P < 0.01 for all comparisons). Adjustment for prehospitalization patient characteristics attenuated associations between AKI and all three outcomes, but AKI remained an independent risk factor. Attenuation of risk was similar after adjustment for absolute eGFR, eGFR slope, or proteinuria, individually or in combination., Conclusions: Prehospitalization variables including eGFR, eGFR slope, and proteinuria confounded associations between AKI and adverse cardiovascular outcomes, but these associations remained significant after adjusting for prehospitalization variables., (Copyright © 2023 by the American Society of Nephrology.)

Older adults with chronic kidney disease (CKD) are at risk for cognitive impairment and sleep disturbances. The purpose of the current study was to investigate the relationship between sleep and brain structure/function in older adults with CKD and self-identified cognitive impairment. The sample ( N = 37) had a mean age of 68 years ( SD = 4.9 years), estimated glomerular filtration rate of 43.7 mL/min/1.73m 2 ( SD = 10.98), median sleep time of 7.4 hours, and was 70% female. Sleeping <7.4 hours, compared to ≥7.4 hours, was associated with better attention/information processing (β = 11.46, 95% confidence interval [CI] [3.85, 19.06]) and better learning/memory (β = 2.06, 95% CI [0.37, 3.75]). Better sleep efficiency was associated with better global cerebral blood flow (β = 3.30, 95% CI [0.65, 5.95]). Longer awake length after sleep onset was associated with worse fractional anisotropy of the cingulum (β = -0.01, 95% CI [-0.02, -0.003]). Sleep duration and continuity may be related to brain function in older adults with CKD and self-identified cognitive impairment. [ Journal of Gerontological Nursing, 49 (7), 31-39.].

Background: Prior studies associating acute kidney injury (AKI) with more rapid subsequent loss of kidney function had methodological limitations, including inadequate control for differences between patients who had AKI and those who did not., Objective: To determine whether AKI is independently associated with subsequent kidney function trajectory among patients with chronic kidney disease (CKD)., Design: Multicenter prospective cohort study., Setting: United States., Participants: Patients with CKD ( n  = 3150)., Measurements: Hospitalized AKI was defined by a 50% or greater increase in inpatient serum creatinine (SCr) level from nadir to peak. Kidney function trajectory was assessed using estimated glomerular filtration rate (eGFR) based on SCr level (eGFRcr) or cystatin C level (eGFRcys) measured at annual study visits., Results: During a median follow-up of 3.9 years, 433 participants had at least 1 AKI episode. Most episodes (92%) had stage 1 or 2 severity. There were decreases in eGFRcr (-2.30 [95% CI, -3.70 to -0.86] mL/min/1.73 m 2 ) and eGFRcys (-3.61 [CI, -6.39 to -0.82] mL/min/1.73 m 2 ) after AKI. However, in fully adjusted models, the decreases were attenuated to -0.38 (CI, -1.35 to 0.59) mL/min/1.73 m 2 for eGFRcr and -0.15 (CI, -2.16 to 1.86) mL/min/1.73 m 2 for eGFRcys, and the CI bounds included the possibility of no effect. Estimates of changes in eGFR slope after AKI determined by either SCr level (0.04 [CI, -0.30 to 0.38] mL/min/1.73 m 2 per year) or cystatin C level (-0.56 [CI, -1.28 to 0.17] mL/min/1.73 m 2 per year) also had CI bounds that included the possibility of no effect., Limitations: Few cases of severe AKI, no adjudication of AKI cause, and lack of information about nephrotoxic exposures after hospital discharge., Conclusion: After pre-AKI eGFR, proteinuria, and other covariables were accounted for, the association between mild to moderate AKI and worsening subsequent kidney function in patients with CKD was small., Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M22-3617.

Background: Depression is highly prevalent in individuals on hemodialysis, but it is infrequently identified and remains undertreated. In this paper, we present details of the methodology of a randomized controlled trial (RCT) aimed at testing the feasibility and preliminary efficacy of a 5-week positive psychological intervention in individuals on hemodialysis with comorbid depression delivered using immersive virtual reality (VR) technology., Objective: We aim to describe the protocol and design of the Joviality trial whose main objectives are 2-fold: determine the feasibility of the Joviality VR software through metrics capturing rates of recruitment, refusal, retention, noncompliance, and adherence, as well as end-user feedback; and assess preliminary efficacy for outcomes measures of depressive symptoms, psychological well-being and distress, quality of life, treatment adherence, clinical biomarkers, and all-cause hospitalizations., Methods: This 2-arm RCT is scheduled to enroll 84 individuals on hemodialysis with comorbid depression from multiple outpatient centers in Chicago, Illinois, United States. Enrollees will be randomized to the following groups: VR-based Joviality positive psychological intervention or sham VR (2D wildlife footage and nature-based settings with inert music presented using a head-mounted display). To be eligible, individuals must be on hemodialysis for at least 3 months, have Beck Depression Inventory-II scores of ≥11 (ie, indicative of mild-to-severe depressive symptoms), be aged ≥21 years, and be fluent in English or Spanish. The Joviality VR software was built using agile design principles and incorporates fully immersive content, digital avatars, and multiplex features of interactability. Targeted skills of the intervention include noticing positive events, positive reappraisal, gratitude, acts of kindness, and mindful or nonjudgmental awareness. The primary outcomes include metrics of feasibility and acceptability, along with preliminary efficacy focused on decreasing symptoms of depression. The secondary and tertiary outcomes include quality of life, treatment adherence, clinical biomarkers, and all-cause hospitalization rates. There are 4 assessment time points: baseline, immediately after the intervention, 3 months after the intervention, and 6 months after the intervention. We hypothesize that depressive symptoms and hemodialysis-related markers of disease will substantially improve in participants randomized to the VR-based Joviality positive psychology treatment arm compared with those in the attention control condition., Results: This RCT is funded by the National Institute of Diabetes and Digestive and Kidney Diseases and is scheduled to commence participant recruitment in June 2023., Conclusions: This trial will be the first to test custom-built VR software to deliver a positive psychological intervention, chairside, in individuals on hemodialysis to reduce symptoms of depression. Within the context of an RCT using an active control arm, if proven effective, VR technology may become a potent tool to deliver mental health programming in clinical populations during their outpatient treatment sessions., Trial Registration: ClinicalTrials.gov NCT05642364; https://clinicaltrials.gov/ct2/show/NCT05642364., International Registered Report Identifier (irrid): PRR1-10.2196/45100., (©Rosalba Hernandez, Ken Wilund, Killivalavan Solai, David Tamayo, Drew Fast, Prasakthi Venkatesan, James P Lash, Claudia M Lora, Lizet Martinez, Geovana Martin Alemañy, Angela Martinez, Soonhyung Kwon, Dana Romero, Matthew H E M Browning, Judith T Moskowitz. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 16.06.2023.)

Chronic kidney disease (CKD) was responsible for 1.2 million deaths globally in 2016. Despite the large and growing burden of CKD, treatment options are limited and generally only preserve kidney function. Characterizing molecular precursors to incident and progressive CKD could point to critically needed prevention and treatment strategies. Clonal hematopoiesis of indeterminate potential (CHIP) is typically characterized by the clonal expansion of blood cells carrying somatic mutations in specific driver genes. An age-related disorder, CHIP is rare in the young but common in older adults. Recent studies have identified causal associations between CHIP and atherosclerotic cardiovascular disease which are most likely mediated by inflammation, a hallmark of CKD. Animal evidence has supported causal effects of CHIP on kidney injury, inflammation, and fibrosis, providing impetus for human research. Although prospective epidemiologic studies investigating associations of CHIP with development and progression of CKD are few, intriguing findings have been reported. CHIP was significantly associated with kidney function decline and end stage kidney disease in the general population, although effect sizes were modest. Recent work suggests larger associations of CHIP with kidney disease progression in CKD patients, but further investigations in this area are needed. In addition, the accumulating literature has identified some heterogeneity in associations between CHIP and kidney endpoints across study populations, but reasons for these differences remain unclear. The current review provides an in-depth exploration into this nascent area of research, develops a conceptual framework linking CHIP to CKD, and discusses the clinical and public health implications of this work., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Randomized trials are the gold standard for generating clinical practice evidence, but follow-up and outcome ascertainment are resource-intensive. Electronic health record (EHR) data from routine care can be a cost-effective means of follow-up, but concordance with trial-ascertained outcomes is less well-studied., Methods: We linked EHR and trial data for participants of the Systolic Blood Pressure Intervention Trial (SPRINT), a randomized trial comparing intensive and standard blood pressure targets. Among participants with available EHR data concurrent to trial-ascertained outcomes, we calculated sensitivity, specificity, positive predictive value, and negative predictive value for EHR-recorded cardiovascular disease (CVD) events, using the gold standard of SPRINT-adjudicated outcomes (myocardial infarction (MI)/acute coronary syndrome (ACS), heart failure, stroke, and composite CVD events). We additionally compared the incidence of non-CVD adverse events (hyponatremia, hypernatremia, hypokalemia, hyperkalemia, bradycardia, and hypotension) in trial versus EHR data., Results: 2468 SPRINT participants were included (mean age 68 (SD 9) years; 26% female). EHR data demonstrated ≥80% sensitivity and specificity, and ≥ 99% negative predictive value for MI/ACS, heart failure, stroke, and composite CVD events. Positive predictive value ranged from 26% (95% CI; 16%, 38%) for heart failure to 52% (95% CI; 37%, 67%) for MI/ACS. EHR data uniformly identified more non-CVD adverse events and higher incidence rates compared with trial ascertainment., Conclusions: These results support a role for EHR data collection in clinical trials, particularly for capturing laboratory-based adverse events. EHR data may be an efficient source for CVD outcome ascertainment, though there is clear benefit from adjudication to avoid false positives., Competing Interests: Declaration of Competing Interest CDC receives research support from Bayer Healthcare, Inc. outside the submitted work. AM reports ownership interest in iEnroll, LLC. The remaining authors have nothing to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Significance Statement: Protein carbamylation, a nonenzymatic post-translational protein modification partially driven by elevated blood urea levels, associates with mortality and adverse outcomes in patients with ESKD on dialysis. However, little is known about carbamylation's relationship to clinical outcomes in the much larger population of patients with earlier stages of CKD. In this prospective observational cohort study of 3111 individuals with CKD stages 2-4, higher levels of carbamylated albumin (a marker of protein carbamylation burden) were associated with a greater risk of developing ESKD and other significant adverse clinical outcomes. These findings indicate that protein carbamylation is an independent risk factor for CKD progression. They suggest that further study of therapeutic interventions to prevent or reduce carbamylation is warranted., Background: Protein carbamylation, a post-translational protein modification partially driven by elevated blood urea levels, associates with adverse outcomes in ESKD. However, little is known about protein carbamylation's relationship to clinical outcomes in the much larger population of patients with earlier stages of CKD., Methods: To test associations between protein carbamylation and the primary outcome of progression to ESKD, we measured baseline serum carbamylated albumin (C-Alb) in 3111 patients with CKD stages 2-4 enrolled in the prospective observational Chronic Renal Insufficiency Cohort study., Results: The mean age of study participants was 59 years (SD 10.8); 1358 (43.7%) were female, and 1334 (42.9%) were White. The mean eGFR at the time of C-Alb assessment was 41.8 (16.4) ml/minute per 1.73 m 2 , and the median C-Alb value was 7.8 mmol/mol (interquartile range, 5.8-10.7). During an average of 7.9 (4.1) years of follow-up, 981 (31.5%) individuals developed ESKD. In multivariable adjusted Cox models, higher C-Alb (continuous or quartiles) independently associated with an increased risk of ESKD. For example, compared with quartile 1 (C-Alb ≤5.80 mmol/mol), those in quartile 4 (C-Alb >10.71 mmol/mol) had a greater risk for ESKD (adjusted hazard ratio, 2.29; 95% confidence interval, 1.75 to 2.99), and the ESKD incidence rate per 1000 patient-years increased from 15.7 to 88.5 from quartile 1 to quartile 4. The results remained significant across numerous subgroup analyses, when treating death as a competing event, and using different assessments of eGFR., Conclusions: Having a higher level of protein carbamylation as measured by circulating C-Alb is an independent risk factor for ESKD in individuals with CKD stages 2-4., Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023&#95;04&#95;24&#95;JSN&#95;URE&#95;EP22&#95;042423.mp3., (Copyright © 2023 by the American Society of Nephrology.)

The landmark, multicenter HCHS/SOL (Hispanic Community Health Study/Study of Latinos) is the largest, most comprehensive, longitudinal community-based cohort study to date of diverse Hispanic/Latino persons in the United States. The HCHS/SOL aimed to address the dearth of comprehensive data on risk factors for cardiovascular disease (CVD) and other chronic diseases in this population and has expanded considerably in scope since its inception. This paper describes the aims/objectives and data collection of the HCHS/SOL and its ancillary studies to date and highlights the critical and sizable contributions made by the study to understanding the prevalence of and changes in CVD risk/protective factors and the burden of CVD and related chronic conditions among adults of diverse Hispanic/Latino backgrounds. The continued follow-up of this cohort will allow in-depth investigations on cardiovascular and pulmonary outcomes in this population, and data from the ongoing ancillary studies will facilitate generation of new hypotheses and study questions., Competing Interests: Funding Support and Author Disclosures The HCHS/SOL is a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute to the University of North Carolina (HHSN268201300001I/N01-HC-65233), University of Miami (HHSN268201300004I/N01-HC-65234), Albert Einstein College of Medicine (HHSN268201300002I/N01-HC-65235), University of Illinois Chicago (HHSN268201300003I/N01-HC-65236, Northwestern University), and San Diego State University (HHSN268201300005I/N01-HC-65237). The following institutes/centers/offices have contributed to the HCHS/SOL through a transfer of funds to the National Heart, Lung, and Blood Institute: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Institutes of Health Institution-Office of Dietary Supplements, and UC San Diego, National Institute on Aging: R01AG075758, R56 2-AG048642, RF1AG054548, RF1AG061022, RF1NS127266, R01AG061088, RF1AG077639. The funding agency had a role in the design and conduct of the HCHS/SOL; in the collection, analysis, and interpretation of HCHS/SOL data; and in the review and approval of this manuscript. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. All rights reserved.)

Background: Previous studies have reported cross-sectional associations between measures of epigenetic age acceleration (EAA) and kidney function phenotypes. However, the temporal and potentially causal relationships between these variables remain unclear. We conducted a bidirectional two-sample Mendelian randomization study of EAA and kidney function. Genetic instruments for EAA and estimate glomerular filtration rate (eGFR) were identified from previous genome-wide association study (GWAS) meta-analyses of European-ancestry participants. Causal effects of EAA on kidney function and kidney function on EAA were assessed through summary-based Mendelian randomization utilizing data from the CKDGen GWAS meta-analysis of log-transformed estimated glomerular filtration rate (log-eGFR; n = 5,67,460) and GWAS meta-analyses of EAA (n = 34,710). An allele score-based Mendelian randomization leveraging individual-level data from UK Biobank participants (n = 4,33,462) further examined the effects of EAA on kidney function., Results: Using summary-based Mendelian randomization, we found that each 5 year increase in intrinsic EAA (IEAA) and GrimAge acceleration (GrimAA) was associated with - 0.01 and - 0.02 unit decreases in log-eGFR, respectively (P = 0.02 and P = 0.09, respectively), findings which were strongly supported by allele-based Mendelian randomization study (both P < 0.001). Summary-based Mendelian randomization identified 24% increased odds of CKD with each 5-unit increase in IEAA (P = 0.05), with consistent findings observed in allele score-based analysis (P = 0.07). Reverse-direction Mendelian randomization identified potentially causal effects of decreased kidney function on HannumAge acceleration (HannumAA), GrimAA, and PhenoAge acceleration (PhenoAA), conferring 3.14, 1.99, and 2.88 year decreases in HanumAA, GrimAA, and PhenoAA, respectively (P = 0.003, 0.05, and 0.002, respectively) with each 1-unit increase in log-eGFR., Conclusion: This study supports bidirectional causal relationships between EAA and kidney function, pointing to potential prevention and therapeutic strategies., (© 2023. The Author(s).)

Background: Limited health literacy is associated with significant morbidity and mortality in the general population but the relation of health literacy with long-term clinical outcomes among adults with chronic kidney disease (CKD) is less clear., Methods: Prospective data from the Chronic Renal Insufficiency Cohort (CRIC) Study (n = 3715) were used. Health literacy was assessed with the Short Test of Functional Health Literacy in Adults (dichotomized as limited/adequate). Cox proportional hazards models were used to separately examine the relations of health literacy with CKD progression, cardiovascular event (any of the following: myocardial infarction, congestive heart failure, stroke or peripheral artery disease), and all-cause, cardiovascular and non-cardiovascular mortality. Poisson regression was used to assess the health literacy-hospitalization association. Models were sequentially adjusted: Model 1 adjusted for potential confounders (sociodemographic factors), while Model 2 additionally adjusted for potential mediators (clinical and lifestyle factors) of the associations of interest., Results: In confounder-adjusted models, participants with limited (vs adequate) health literacy [555 (15%)] had an increased risk of CKD progression [hazard ratio (HR) 1.34; 95% confidence interval (CI) 1.06-1.71], cardiovascular event (HR 1.67; 95% CI 1.39-2.00), hospitalization (rate ratio 1.33; 95% CI 1.26-1.40), and all-cause (HR 1.54; 95% CI 1.27-1.86), cardiovascular (HR 2.39; 95% CI 1.69-3.38) and non-cardiovascular (HR 1.27; 95% CI 1.01-1.60) mortality. Additional adjustments for potential mediators (Model 2) showed similar results except that the relations of health literacy with CKD progression and non-cardiovascular mortality were no longer statistically significant., Conclusions: In the CRIC Study, adults with limited (vs adequate) health literacy had a higher risk for CKD progression, cardiovascular event, hospitalization and mortality-regardless of adjustment for potential confounders., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Sickle cell anemia (SCA) negatively impacts the ability to achieve educational and occupational goals increasing vulnerability to socioeconomic challenges. In a cross-sectional analysis of 332 SCA adults, we investigated whether the distressed community index (DCI) was associated with SCA-related complications and nutritional status. More patients with higher DCI had Medicaid insurance. A higher DCI was independently associated with tobacco use and lower body mass index, serum albumin, and vitamin D 25-OH levels after adjusting for insurance status but was not associated with SCA-related complications. Future studies investigating access to healthy foods may help improve health equity in patients with SCA., Competing Interests: The authors disclose no relevant conflict of interest to this study., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Albuminuria is associated with metabolic abnormalities, but these relationships are not well understood. We studied the association of metabolites with albuminuria in Hispanic/Latino people, a population with high risk for metabolic disease., Methods: We used data from 3736 participants from the Hispanic Community Health Study/Study of Latinos, of which 16% had diabetes and 9% had an increased urine albumin-to-creatinine ratio (UACR). Metabolites were quantified in fasting serum through nontargeted mass spectrometry (MS) analysis using ultra-performance liquid chromatography-MS/MS. Spot UACR was inverse normally transformed and tested for the association with each metabolite or combined, correlated metabolites, in covariate-adjusted models that accounted for the study design. In total, 132 metabolites were available for replication in the Hypertension Genetic Epidemiology Network study ( n =300), and 29 metabolites were available for replication in the Malmö Offspring Study ( n =999)., Results: Among 640 named metabolites, we identified 148 metabolites significantly associated with UACR, including 18 novel associations that replicated in independent samples. These metabolites showed enrichment for D-glutamine and D-glutamate metabolism and arginine biosynthesis, pathways previously reported for diabetes and insulin resistance. In correlated metabolite analyses, we identified two modules significantly associated with UACR, including a module composed of lipid metabolites related to the biosynthesis of unsaturated fatty acids and alpha linolenic acid and linoleic acid metabolism., Conclusions: Our study identified associations of albuminuria with metabolites involved in glucose dysregulation, and essential fatty acids and precursors of arachidonic acid in Hispanic/Latino population., Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023&#95;02&#95;08&#95;CJN09070822.mp3., (Copyright © 2022 by the American Society of Nephrology.)

Estimated glomerular filtration rate (eGFR) is used to evaluate kidney function and determine the presence of chronic kidney disease (CKD), a highly prevalent disease in the US 1 , 2 , 3 that varies among subgroups of Hispanic/Latino individuals. 4 , 5 The polygenic risk score (PRS) is a popular method that uses large genome-wide association studies (GWASs) to provide a strong estimate of disease risk. 7 However, due to the limited availability of summary statistics from GWAS meta-analyses based on Hispanic/Latino populations, PRSs can only be computed using different ancestry GWASs. The performance of eGFR PRSs derived from other GWAS reference populations for Hispanic/Latino population has not been examined. We compared PRS constructions for eGFR prediction in Hispanic/Latino individuals using GWAS-significant variants, clumping and thresholding (C&T), 8 and PRS-CS, 22 as well as a combination of PRSs calculated with different reference GWAS meta-analyses from European and multi-ethnic studies in Hispanic/Latino individuals from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). All eGFR PRSs were highly associated with eGFR (p < 1E-20). Additionally, eGFR PRSs were significantly associated with lower risk of prevalent CKD at visit 1 or 2 and incident CKD at visit 2, with the combined PRSs having the best performance. These PRS findings were replicated in an additional dataset of Hispanic/Latino individuals using data from the Women's Health Initiative SNP Health Association Resource (WHI-SHARe). 17 ., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Background: The gut microbiome is altered in chronic kidney disease (CKD), potentially contributing to CKD progression and co-morbidities, but population-based studies of the gut microbiome across a wide range of kidney function and damage are lacking., Methods: In the Hispanic Community Health Study/Study of Latinos, gut microbiome was assessed by shotgun sequencing of stool ( n  = 2,438; 292 with suspected CKD). We examined cross-sectional associations of estimated glomerular filtration rate (eGFR), urinary albumin:creatinine (UAC) ratio, and CKD with gut microbiome features. Kidney trait-related microbiome features were interrogated for correlation with serum metabolites ( n  = 700), and associations of microbiome-related serum metabolites with kidney trait progression were examined in a prospective analysis ( n  = 3,635)., Results: Higher eGFR was associated with overall gut microbiome composition, greater abundance of species from Prevotella, Faecalibacterium, Roseburia, and Eubacterium, and microbial functions related to synthesis of long-chain fatty acids and carbamoyl-phosphate. Higher UAC ratio and CKD were related to lower gut microbiome diversity and altered overall microbiome composition only in participants without diabetes. Microbiome features related to better kidney health were associated with many serum metabolites (e.g., higher indolepropionate, beta-cryptoxanthin; lower imidazole propionate, deoxycholic acids, p-cresol glucuronide). Imidazole propionate, deoxycholic acid metabolites, and p-cresol glucuronide were associated with prospective reductions in eGFR and/or increases in UAC ratio over ~6 y., Conclusions: Kidney function is a significant correlate of the gut microbiome, while the relationship of kidney damage with the gut microbiome depends on diabetes status. Gut microbiome metabolites may contribute to CKD progression.

Objective: Glycated hemoglobin (HbA1c) can predict risk for microvascular complications in patients with diabetes. However, HbA1c's reliability in chronic kidney disease (CKD) has been questioned, with concerns including competition from another posttranslational protein modification, carbamylation, acting on the same amino groups as glycation, and anemia with reduced erythrocyte lifespans leading to altered glycation accumulation. We investigated whether carbamylation and anemia modify the impact of HbA1c on renal outcomes in patients with diabetes and CKD., Research Design and Methods: In 1,516 participants from the Chronic Renal Insufficiency Cohort study with diabetes and CKD, Cox regression models were applied to evaluate the association between HbA1c and CKD progression (composite of end-stage kidney disease or 50% decline in estimated glomerular filtration rate [eGFR]), stratified by carbamylated albumin (C-Alb) quartiles and anemia., Results: The mean eGFR was 38.1 mL/min/1.73 m2, mean HbA1c was 7.5% (58 mmol/mol), and median C-Alb was 8.4 mmol/mol. HbA1c was lower in the higher C-Alb quartiles. During a median follow-up of 6.9 years, 763 participants experienced CKD progression. Overall, higher HbA1c was associated with an increased risk of CKD progression (adjusted hazard ratio 1.07 [95% CI 1.02-1.13]). However, using stratified analyses, HbA1c was no longer associated with CKD progression in the highest C-Alb quartile, but did show a monotonic increase in CKD progression risk across each lower C-Alb quartile (P-interaction = 0.022). Anemia also modified the association between HbA1c and CKD progression (P-interaction = 0.025)., Conclusions: In patients with coexisting diabetes and CKD, the association between HbA1c and CKD progression is modified by carbamylation and anemia., (© 2022 by the American Diabetes Association.)

Rationale & Objective: In the general population, there is an association between higher levels of physical activity and lower risk for cardiovascular events and mortality, but this relationship has not been well evaluated in chronic kidney disease (CKD). We investigated the association between self-reported physical activity and outcomes in a CKD cohort., Study Design: Prospective cohort study., Setting & Participants: 3,926 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study., Exposure: Time-updated self-reported physical activity assessed by (1) quartile of moderate-to-vigorous physical activity (MVPA) and (2) meeting guideline-recommended level of physical activity (categorized as active, meeting guidelines; active, not meeting guidelines; or inactive)., Outcome: Atherosclerotic events (myocardial infarction, stroke, or peripheral artery disease), incident heart failure, and all-cause and cardiovascular death., Analytical Approach: Cox proportional hazards regression., Results: At baseline, compared with the lowest MVPA quartile, those in the highest quartile were more likely to be younger, male, not have prevalent cardiovascular disease, and have higher estimated glomerular filtration rate. Overall, 51% met the physical activity guidelines; of those who did not, 30% were inactive. During the median follow-up period of 13.4 years, there were 772 atherosclerotic events, 848 heart failure events, and 1,553 deaths, and 420 cardiovascular deaths. Compared with the participants in the lowest MVPA quartile, the highest quartile had a lower risk of atherosclerotic events (HR, 0.64 [95% CI, 0.51-0.79]), incident heart failure (HR, 0.71 [95% CI, 0.58-0.87]), and all-cause and cardiovascular death (HRs of 0.54 [95% CI, 0.46-0.63] and 0.47 [95% CI, 0.35-0.64], respectively). The findings were similar for analyses evaluating recommended level of physical activity., Limitations: Self-reported physical activity may result in some degree of misclassification., Conclusions: Higher self-reported physical activity was associated with lower risk of cardiovascular events and mortality in CKD patients, which may have important implications for clinical practice and the design of interventional studies., Plain-Language Summary: In this long-term study of 3,926 adults with chronic kidney disease, we found that individuals with higher levels of physical activity were less likely to experience an atherosclerotic event (for example, a heart attack, stroke, or peripheral arterial disease), new-onset heart failure, and death as compared with those with lower levels of physical activity. The findings were similar for the analyses evaluating adherence to guideline-recommended level of physical activity (that is, for more than 150 minutes per week), and they strengthen the evidence supporting the current guideline recommendations., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: Adherence to recommended medical treatment is critical in chronic kidney disease (CKD) to prevent complications and progression to kidney failure. Overall adherence to treatment is low in CKD, and as few as 40% of patients with kidney failure receive any documented CKD-related care. The purpose of this study was to explore the experiences of patients with CKD and their adherence to CKD treatment plans, and the role their health care providers played in supporting their adherence., Study Design: One-on-one interviews were conducted in 2019-2020 using a semi-structured interview guide. Participants described experiences with adherence to treatment plans and what they did when experiencing difficulty., Setting & Participants: Participants were recruited from the Chronic Renal Insufficiency Cohort (CRIC) study. All CRIC participants were older than 21 years with CKD stages 2-4; this sample consisted of participants from the University of Pennsylvania CRIC site., Analytical Approach: Interviews were recorded, transcribed, and coded using conventional content analysis. Data were organized into themes using NVivo 12., Results: The sample (n = 32) had a mean age of 67 years, 53% were women, 59% were non-White, with a mean estimated glomerular filtration rate of 56.6 mL/min/1.73 m 2 . From analysis of factors relevant to treatment planning and adherence, following 4 major themes emerged: patient factors (multiple chronic conditions, motivation, outlook), provider factors (attentiveness, availability/accessibility, communication), treatment planning factors (lack of plan, proactive research, provider-focused treatment goals, and shared decision making), and treatment plan responses (disagreeing with treatment, perceived capability deficit, lack of information, and positive feedback)., Limitations: The sample was drawn from the CRIC study, which may not be representative of the general population with CKD., Conclusions: These themes align with Behavioral Learning Theory, which includes concepts of internal antecedents (patient factors), external antecedents (provider factors), behavior (treatment planning factors), and consequences (treatment plan responses). In particular, the treatment plan responses point to innovative potential intervention approaches to support treatment adherence in CKD., (© 2022 The Authors.)