Chronic Renal Insufficiency Cohort Study Research Articles

A 4-Variable Model to Predict Cardio-Kidney Events and Mortality in Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort (CRIC) Study

Introduction: Current prognostic models for chronic kidney disease (CKD) are complex and were designed to predict a single outcome. We aimed to develop and validate a simple and parsimonious prognostic model to predict cardio-kidney events and mortality. Methods: Patients from the CRIC Study (n = 3,718) were randomly divided into derivation (n = 2,478) and validation (n = 1,240) cohorts. Twenty-nine candidate variables were preselected. Multivariable Cox regression models were developed using stepwise selection for various cardio-kidney endpoints, namely, (i) the primary composite outcome of 50% decline in estimated glomerular filtration rate (eGFR) from baseline, end-stage renal disease, or cardiovascular (CV) mortality; (ii) hospitalization for heart failure (HHF) or CV mortality; (iii) 3-point major CV endpoints (3P-MACE); (iv) all-cause death. Results: During a median follow-up of 9 years, the primary outcome occurred in 977 patients of the derivation cohort and 501 patients of the validation cohort. Log-transformed N-terminal pro-B-type natriuretic peptide (NT-proBNP), log-transformed high-sensitive cardiac troponin T (hs-cTnT), log-transformed albuminuria, and eGFR were the dominant predictors. The primary outcome risk score discriminated well (c-statistic = 0.83) with a proportion of events of 11.4% in the lowest tertile of risk and 91.5% in the highest tertile at 10 years. The risk model presented good discrimination for HHF or CV mortality, 3P-MACE, and all-cause death (c-statistics = 0.80, 0.75, and 0.75, respectively). The 4-variable risk model achieved similar c-statistics for all tested outcomes in the validation cohort. The discrimination of the 4-variable risk model was mostly superior to that of published models. Conclusion: The combination of NT-proBNP, hs-cTnT, albuminuria, and eGFR in a single 4-variable model provides a unique individual prognostic assessment of multiple cardio-kidney outcomes in CKD.

Effect of blood pressure index on clinical outcomes in patients with heart failure and chronic kidney disease.

This study aimed to assess the effect of blood pressure (BP) index, in terms of level and variability, on the progression of cardiovascular and renal diseases in patients with both heart failure (HF) and chronic kidney disease (CKD). The study involved patients with HF and CKD from the database of the Chronic Renal Insufficiency Cohort (CRIC) study. The study endpoint includes the following: (i) primary endpoint, including cardiovascular disease (CVD) events, renal events, and all-cause death; (ii) CVD events; (iii) renal events; and (iv) all-cause death. Among 3939 participants in the CRIC study, a total of 382 patients were included. The duration of the follow-up was 6.3±2.7years, the age was 60.2±8.9years, and 57.6% were male. BP index included 20 indicators in relation to BP level and variability, 4 of which were analysed including baseline systolic BP (SBP), standard deviation of SBP, coefficient of variation of diastolic BP (DBP CV), and average real variability of pulse pressure. In the Cox regression analysis after adjustment, baseline SBP was significant for the risk of primary endpoint [hazard ratio (HR) 1.22, 95% confidence interval (CI) 1.03-1.44, P=0.02] and renal events (HR 1.54, 95% CI 1.22-1.95, P<0.001), and DBP CV was significant for the risk of primary endpoint (HR 1.03, 95% CI 1.01-1.06, P=0.02) and CVD events (HR 1.04, 95% CI 1.02-1.07, P<0.01). The result of the forest plot depicted that baseline SBP had a linear association with the risk of CVD and renal events (P=0.04 and 0.001, respectively) and DBP CV with CVD events (P=0.02). As the restricted cubic spline models displayed, DBP CV featured a J- or L-curved association with the primary endpoint, renal events, and all-cause death (P for nonlinearity=0.01, <0.001, and 0.01, respectively). The baseline SBP and DBP CV may remain significant for clinical outcomes in patients with both HF and CKD. The increase in baseline SBP is associated with a higher risk of primary endpoint, CVD events, and renal events,and the increase in DBP CV with a higher risk of CVD events. Concerning nonlinear association, DBP CV features a J- or L-curved relationship with the primary endpoint, renal events, and all-cause death, with a higher risk at both low and high values. https://www. gov; unique identifier: NCT00304148.

Frailty and Cardiovascular Outcomes in Adults With CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study

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. Prospective cohort study. 2,539 adults in the Chronic Renal Insufficiency Cohort Study. Frailty status assessed using 5 criteria: slow gait speed, muscle weakness, low physical activity, exhaustion, and unintentional weight loss. Atherosclerotic events, incident heart failure, all-cause death, and cardiovascular death. Cause-specific hazards models. At study entry, the participants' mean age was 62 years, 46% were female, the mean estimated glomerular filtration rate was 45.4mL/min/1.73m2, 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). Self-report of aspects of the frailty assessment and comorbidities, which may have led to bias in some estimates. 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. 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.

Factors Associated With Non-vaccination for Influenza Among Patients With CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study

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. Longitudinal observational study. 3,692 Chronic Renal Insufficiency Cohort Study (CRIC) participants. Demographic factors, social determinants of health, clinical conditions, and health behaviors. 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. Mixed-effects Poisson models to estimate adjusted prevalence ratios (APRs). 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/1.73m2), 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. Possible residual confounding. 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. 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.

Plasma Serotonin and Cardiovascular Outcomes in Chronic Kidney Disease.

Background Platelet-poor plasma serotonin levels are associated with adverse cardiovascular outcomes. Although plasma serotonin levels increase in chronic kidney disease, the cardiovascular implications remain unknown. Methods and Results In 1114 participants from the prospective CRIC (Chronic Renal Insufficiency Cohort) Study, we evaluated the association between plasma serotonin, categorized as undetectable, intermediate, and high (≥20 ng/mL) levels, and cross-sectional findings on echocardiography, including left ventricular hypertrophy, left ventricular ejection fraction, and pulmonary hypertension. We also analyzed whether serotonin was associated with time-to-event cardiovascular outcomes, including heart failure hospitalization and atherosclerotic cardiovascular disease (ASCVD) events, in addition to mortality. Because selective serotonin reuptake inhibitors decrease plasma serotonin levels, we specifically evaluated the influence of selective serotonin reuptake inhibitor use in the relationship between serotonin and outcomes. Plasma serotonin level inversely correlated with estimated glomerular filtration rate and directly correlated with blood pressure. High plasma serotonin was associated with left ventricular hypertrophy (adjusted odds ratio, 2.74 [95% CI, 1.11-7.41]). In contrast, undetectable plasma serotonin level was associated with the highest risk of heart failure (adjusted hazard ratio [HR], 2.26 [95% CI, 1.40-3.66]) and ASCVD events (adjusted HR, 1.96 [95% CI, 1.15-3.32]). Conclusions In a large chronic kidney disease cohort, plasma serotonin levels correlated with blood pressure, and elevated serotonin levels were associated with left ventricular hypertrophy. In contrast, undetectable plasma serotonin was associated with the highest risk of heart failure and ASCVD events.

Vitamin D Metabolites and Risk of Cardiovascular Disease in Chronic Kidney Disease: The CRIC Study.

Background The ratio of 24,25-dihydroxyvitamin D3/25-hydroxyvitamin D3 (vitamin D metabolite ratio [VDMR]) may reflect functional vitamin D activity. We examined associations of the VDMR, 25-hydroxyvitamin D (25[OH]D), and 1,25-dihydroxyvitamin D (1,25[OH]2D) with cardiovascular disease (CVD) in patients with chronic kidney disease. Methods and Results This study included longitudinal and cross-sectional analyses of 1786 participants from the CRIC (Chronic Renal Insufficiency Cohort) Study. Serum 24,25-dihydroxyvitamin D3, 25(OH)D, and 1,25(OH)2D were measured by liquid chromatography-tandem mass spectrometry 1 year after enrollment. The primary outcome was composite CVD (heart failure, myocardial infarction, stroke, and peripheral arterial disease). We used Cox regression with regression-calibrated weights to test associations of the VDMR, 25(OH)D, and 1,25(OH)2D with incident CVD. We examined cross-sectional associations of these metabolites with left ventricular mass index using linear regression. Analytic models adjusted for demographics, comorbidity, medications, estimated glomerular filtration rate, and proteinuria. The cohort was 42% non-Hispanic White race and ethnicity, 42% non-Hispanic Black race and ethnicity, and 12% Hispanic ethnicity. Mean age was 59 years, and 43% were women. Among 1066 participants without prevalent CVD, there were 298 composite first CVD events over a mean follow-up of 8.6 years. Lower VDMR and 1,25(OH)2D were associated with incident CVD before, but not after, adjustment for estimated glomerular filtration rate and proteinuria (hazard ratio, 1.11 per 1 SD lower VDMR [95% CI, 0.95-1.31]). Only 25(OH)D was associated with left ventricular mass index after full covariate adjustment (0.6 g/m2.7 per 10 ng/mL lower [95% CI, 0.0-1.3]). Conclusions Despite modest associations of 25(OH)D with left ventricular mass index, 25(OH)D, the VDMR, and 1,25(OH)2D were not associated with incident CVD in chronic kidney disease.

Depression and incident cardiovascular disease among patients with chronic kidney disease

BackgroundDepression is associated with an increased risk of cardiovascular disease (CVD) and is prevalent among patients with chronic kidney disease (CKD). We aimed to identify the association of depression with incident CVD. MethodsWe studied patients with CKD stages 2–4 enrolled in the Chronic Renal Insufficiency Cohort (CRIC) and excluded participants with preexisting CVD. The Cox proportional hazard model was used to examine the association between baseline depression [Beck's Depression Inventory (BDI) score ≥11] and incidence of CVD (cerebrovascular accident, myocardial infarction, heart failure, or peripheral artery disease). Models were adjusted for age, sex, race, estimated glomerular filtration rate (eGFR), urine albumin-creatinine ratio (UACR), systolic and diastolic blood pressure, and 10-year estimated CVD risk. ResultsAmong 2585 CRIC study participants, 640 (25%) patients had depression at study baseline. Compared to patients without depression, patients with depression were more likely to be women (56% vs. 46%), non-White (68% vs. 53%), with household income <$20,000 (53% vs. 26%), without a high school degree (31% vs. 15%), uninsured (13% vs. 7%), with lower eGFR (42 vs. 46 ml/min/1.73 m (Palmer et al., 2013 Jul)22), and with higher UACR (90 vs. 33 mg/g). In multivariate analyses, depression was associated with a 29% increased risk of developing CVD (adjusted hazard ratio 1.29, 95% confidence interval 1.03–1.62, p = 0.03). BDI (as a continuous variable) was associated with CVD (adjusted hazard ratio 1.017, 95% confidence interval 1.004–1.030, p = 0.012). ConclusionsAmong patients with CKD stages 2–4 enrolled in CRIC without preexisting CVD, depression was associated with a 29% increased risk of incident CVD.

Blood Pressure, Incident Cognitive Impairment, and Severity of CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study

Hypertension is a known risk factor for dementia and cognitive impairment. There are limited data on the relation of systolic blood pressure (SBP) and diastolic blood pressure (DBP) with incident cognitive impairment in adults with chronic kidney disease. We sought to identify and characterize the relationship among blood pressure, cognitive impairment, and severity of decreased kidney function in adults with chronic kidney disease. Longitudinal cohort study. 3,768 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study. Baseline SBP and DBP were examined as exposure variables, using continuous (linear, per 10-mm Hg higher), categorical (SBP<120 [reference], 120 to 140,>140mm Hg; DBP<70 (reference), 70 to 80, > 80mm Hg) and nonlinear terms (splines). Incident cognitive impairment defined as a decline in Modified Mini-Mental State Examination (3MS) score to greater than 1 standard deviation below the cohort mean. Cox proportional hazard models adjusted for demographics as well as kidney disease and cardiovascular disease risk factors. The mean age of participants was 58±11 (SD) years, estimated glomerular filtration rate (eGFR) was 44mL/min/1.73m2 ± 15 (SD), and the median follow-up time was 11 (IQR, 7-13) years. In 3,048 participants without cognitive impairment at baseline and with at least 1 follow-up 3MS test, a higher baseline SBP was significantly associated with incident cognitive impairment only in the eGFR>45mL/min/1.73m2 subgroup (adjusted hazard ratio [AHR], 1.13 [95% CI, 1.05-1.22] per 10mm Hg higher SBP]. Spline analyses, aimed at exploring nonlinearity, showed that the relationship between baseline SBP and incident cognitive impairment was J-shaped and significant only in the eGFR>45mL/min/1.73m2 subgroup (P=0.02). Baseline DBP was not associated with incident cognitive impairment in any analyses. 3MS test as the primary measure of cognitive function. Among patients with chronic kidney disease, higher baseline SBP was associated with higher risk of incident cognitive impairment specifically in those individuals with eGFR>45mL/min/1.73m2. High blood pressure is a strong risk factor for dementia and cognitive impairment in studies of adults without kidney disease. High blood pressure and cognitive impairment are common in adults with chronic kidney disease (CKD). The impact of blood pressure on the development of future cognitive impairment in patients with CKD remains unclear. We identified the relationship between blood pressure and cognitive impairment in 3,076 adults with CKD. Baseline blood pressure was measured, after which serial cognitive testing was performed over 11 years. Fourteen percent of participants developed cognitive impairment. We found that a higher baseline systolic blood pressure was associated with an increased risk of cognitive impairment. We found that this association was stronger in adults with mild-to-moderate CKD compared with those with advanced CKD.

Association of urine and plasma ADMA with atherosclerotic risk in DKD cardiovascular disease risk in diabetic kidney disease: findings from the Chronic Renal Insufficiency Cohort (CRIC) study.

Chronic kidney disease (CKD) is associated with atherosclerotic cardiovascular disease (ASCVD) risk, especially among those with diabetes. Altered metabolism of solutes that accumulate in CKD [asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and trimethylamine N-oxide (TMAO)] may reflect pathways linking CKD with ASCVD. This case-cohort study included Chronic Renal Insufficiency Cohort participants with baseline diabetes, estimated glomerular filtration rate <60mL/min/1.73 m2, and without prior history for each outcome. The primary outcome was incident ASCVD (time to first myocardial infarction, stroke or peripheral artery disease event) and secondary outcome was incident heart failure. The subcohort comprised randomly selected participants meeting entry criteria. Plasma and urine ADMA, SDMA and TMAO concentrations were determined by liquid chromatography-tandem mass spectrometry. Associations of uremic solute plasma concentrations and urinary fractional excretions with outcomes were evaluated by weighted multivariable Cox regression models, adjusted for confounding covariables. Higher plasma ADMA concentrations (per standard deviation) were associated with ASCVD risk [hazard ratio (HR) 1.30, 95% confidence interval (CI) 1.01-1.68]. Lower fractional excretion of ADMA (per standard deviation) was associated with ASCVD risk (HR 1.42, 95% CI 1.07-1.89). The lowest quartile of ADMA fractional excretion was associated with greater ASCVD risk (HR 2.25, 95% CI 1.08-4.69) compared with the highest quartile. Plasma SDMA and TMAO concentration and fractional excretion were not associated with ASCVD. Neither plasma nor fractional excretion of ADMA, SDMA and TMAO were associated with incident heart failure. These data suggest that decreased kidney excretion of ADMA leads to increased plasma concentrations and ASCVD risk.

Lipoprotein(a) and the Risk for Recurrent Atherosclerotic Cardiovascular Events Among Adults With CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study

Many adults with chronic kidney disease (CKD) and atherosclerotic cardiovascular disease (ASCVD) have high lipoprotein(a) levels. It is unclear whether high lipoprotein(a) levels confer an increased risk for recurrent ASCVD events in this population. We estimated the risk for recurrent ASCVD events associated with lipoprotein(a) in adults with CKD and prevalent ASCVD. Observational cohort study. We included 1,439 adults with CKD and prevalent ASCVD not on dialysis enrolled in the Chronic Renal Insufficiency Cohort study between 2003 and2008. Baseline lipoprotein(a) mass concentration, measured using a latex-enhanced immunoturbidimetric assay. Recurrent ASCVD events (primary outcome), kidney failure, and death (exploratory outcomes) through2019. We used Cox proportional-hazards regression models to estimate adjusted HR (aHRs) and 95% CIs. Among participants included in the current analysis (mean age 61.6 years, median lipoprotein(a) 29.4 mg/dL [25th-75th percentiles 9.9-70.9 mg/dL]), 641 had a recurrent ASCVD event, 510 developed kidney failure, and 845 died over a median follow-up of 6.6 years. The aHR for ASCVD events associated with 1 standard deviation (SD) higher log-transformed lipoprotein(a) was 1.04 (95% CI, 0.95-1.15). In subgroup analyses, 1 SD higher log-lipoprotein(a) was associated with an increased risk for ASCVD events in participants without diabetes (aHR, 1.23; 95% CI, 1.02-1.48), but there was no evidence of an association among those with diabetes (aHR, 0.99; 95% CI, 0.88-1.10, P comparing aHRs=0.031). The aHR associated with 1 SD higher log-lipoprotein(a) in the overall study population was 1.16 (95% CI, 1.04-1.28) for kidney failure and 1.02 (95% CI, 0.94-1.11) for death. Lipoprotein(a) was not available in molar concentration. Lipoprotein(a) was not associated with the risk for recurrent ASCVD events in adults with CKD, although it was associated with a risk for kidney failure.

Obesity Weight Loss Phenotypes in CKD: Findings From the Chronic Renal Insufficiency Cohort Study

Although people with chronic kidney disease (CKD) and obesity have important motivations to lose weight, weight loss is also associated with health risks. We examined whether patterns of change in systolic blood pressure (SBP), serum albumin level, and fat-free mass (FFM) can help to differentiate between healthy and high-risk weight loss in this population. Using data from the Chronic Renal Insufficiency Cohort Study (CRIC), we estimated a joint multivariate latent class model with 6 classes to identify distinct trajectories of body mass index (BMI), albumin, and SBP among participants with obesity (BMI≥30 kg/m2 at baseline), accounting for informative missingness from death. In a secondary analysis, we fit a 6-class model with BMI and FFM. Among 2831 participants (median baseline BMI 35.6, interquartile range [IQR] 32.4-40.0 kg/m2), median follow-up was 6.8 (IQR 4.8-12.9) years, median age was 61 (IQR 54-67) years, 53% were male, 50% were non-Hispanic Black, and 82% were trying to control or lose weight at baseline. Latent classes were associated with mortality risk (5-year cumulative incidence of mortality 6.8% and 1.5% in class 6 and 3, respectively). Class 6 had the highest mortality rate and was characterized by early, steep BMI loss, early serum albumin decline, and late SBP increase. In the secondary analysis, a class characterized by steep BMI and FFM loss was associated with the highest death risk. Among adults with CKD and obesity, BMI loss with concomitant serum albumin or FFM loss was associated with a high risk of death.

Identification of RhBG Mutations that Impair NH3/NH4+ Transport in Patients with Chronic Kidney Disease

Background: Acid-base disturbances are common in many illnesses, and metabolic acidosis is a major complication in patients with chronic kidney disease (CKD). The kidneys respond to acidosis by increasing urinary excretion of total ammonia (NH 3 /NH 4 + ) and to a lesser extent titratable acids. In the collecting duct, total ammonia is secreted by the NH 3 /NH 4 + transporters, RhBG and RhCG. RhBG transports NH 3 and NH 4 + at the basolateral membrane of intercalated cells. In CKD patients, the increase in ammonium excretion in response to acidosis is markedly impaired. Recent studies suggest that the reduced ability of the kidney to excrete ammonium is likely a cause of detrimental renal outcome in CKD and faster progression towards end-stage renal disease. Hypothesis: This study aims to identify loss of function mutations of RhBG (nsSNPs) that impair NH 3 /NH 4 + transport which may contribute to the deleterious effect of acidosis in CKD. Methods: We used Chronic Renal Insufficiency Cohort (CRIC) study to select SNPs of RhBG that are present in CKD patients but not in controls, or have a significant odds ratio (OR). Transport studies were conducted on Xenopus oocytes expressing Rh proteins or mutants. Wild-type RhBG (RhBG-WT) or RhBG-mutants were expressed by microinjecting oocytes with respective mRNA. H 2 O-injected oocytes served as negative controls. Each oocyte was perfused with solutions containing 5 mM NH 3 /NH 4 + or 5 mM MA/MA + (methylamine/methylammonium, a surrogate of NH 3 /NH 4 + ) to test RhBG function. Using ion-selective microelectrodes, we measured changes in intracellular pH, whole cell currents or surface pH to assess transport of NH 3 or NH 4 + . Results: Two RhBG mutations, G148R and G148W, which are only present in the patient group from CRIC cohort, significantly inhibited transport of NH 3 and NH 4 + (and MA/MA + ) compared with RhBG-WT (p&lt;0.05) in Xenopus oocytes. Two other mutations, G86S and G86C, positively associated with CKD patients (OR=4.65, p&lt;0.05), showed different inhibition patterns: G86S maintained the ability to transport NH 4 + , NH 3 and MA + while G86C inhibited NH 3 and NH 4 + transport but MA + transport was less affected compared with RhBG-WT. Both G86S and G86C showed a 50% decrease in MA transport (p&lt;0.05) that was still significantly higher than negative control. Conclusions: We discovered two RhBG mutations, G148R and G148W, in CKD patients that completely inhibited the transport of NH 3 /NH 4 + . The other two mutations, G86S and G86C, partially inhibited transport, and G86C was more deleterious than G86S in its inhibitory effect on NH 4 + and NH 3 transport. Significance: This study is the first to identify, in a cohort of CKD patients, 4 mutations with functional effects on NH 3 /NH 4 + transport. This work provides the foundation to further investigate whether naturally occurring genetic variations that impair ammonia secretion are associated with fast CKD progression under acidosis conditions. Funding grants: NIH-U54 GM104940, Paul Teschan Research, NIH-R01, Carol Lavin Bernick, Tulane institutional This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Probing the Association between Acute Kidney Injury and Cardiovascular Outcomes.

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. 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). 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. 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.

Ultraprocessed Foods and Kidney Disease Progression, Mortality, and Cardiovascular Disease Risk in the CRIC Study

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). Prospective cohort study. Chronic Renal Insufficiency Cohort Study participants who completed baseline dietary questionnaires. Ultraprocessed food intake (in servings per day) classified according to the NOVA system. 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). Cox proportional hazards models adjusted for demographic, lifestyle, and health covariates. 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/1.73m2; tertile 3 vs tertile 1, HR, 2.61; 95% CI, 1.32-5.18) but not stages 3a-5 (eGFR<60mL/min/1.73m2; P=0.003 forinteraction). 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). Self-reported diet. 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. 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.

Cardiac Structure and Function and Subsequent Kidney Disease Progression in Adults With CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study

Heart-kidney crosstalk is recognized as the cardiorenal syndrome. We examined the association of cardiac function and structure with the risk of kidney failure with replacement therapy (KFRT) in a chronic kidney disease (CKD) population. Prospective observational cohort study. 3,027 participants from the Chronic Renal Insufficiency Cohort Study. Five preselected variables that assess different aspects of cardiac structure and function: left ventricular mass index (LVMI), LV volume, left atrial (LA) area, peak tricuspid regurgitation (TR) velocity, and left ventricular ejection fraction (EF) as assessed by echocardiography. Incident KFRT (primary outcome), and annual estimated glomerular filtration rate (eGFR) slope (secondary outcome). Multivariable Cox models and mixed-effects models. The mean age of the participants was 59±11 SD years, 54% were men, and mean eGFR was 43±17mL/min/1.73m2. Between 2003 and 2018 (median follow-up, 9.9 years), 883 participants developed KFRT. Higher LVMI, LV volume, LA area, peak TR velocity, and lower EF were each statistically significantly associated with an increased risk of KFRT, with corresponding HRs for the highest versus lowest quartiles (lowest vs highest for EF) of 1.70 (95% CI, 1.27-2.26), 1.50 (95% CI, 1.19-1.90), 1.43 (95% CI, 1.11-1.84), 1.45 (95% CI, 1.06-1.96), and 1.26 (95% CI, 1.03-1.56), respectively. For the secondary outcome, participants in the highest versus lowest quartiles (lowest vs highest for EF) had a statistically significantly faster eGFR decline, except for LA area (ΔeGFR slope per year,-0.57 [95% CI,-0.68 to-0.46] mL/min/1.73m2 for LVMI,-0.25 [95% CI,-0.35 to-0.15] mL/min/1.73m2 for LV volume,-0.01 [95% CI,-0.12 to-0.01] mL/min/1.73m2 for LA area,-0.42 [95% CI,-0.56 to-0.28] mL/min/1.73m2 for peak TR velocity, and-0.11 [95% CI,-0.20 to-0.01] mL/min/1.73m2 for EF, respectively). The possibility of residual confounding. Multiple aspects of cardiac structure and function were statistically significantly associated with the risk of KFRT. These findings suggest that cardiac abnormalities and incidence of KFRT are potentially on the same causal pathway related to the interaction between hypertension, heart failure, and coronary artery diseases. Heart disease and kidney disease are known to interact with each other. In this study, we examined whether cardiac abnormalities, as assessed by echocardiography, were linked to the subsequent progression of kidney disease among people living with chronic kidney disease (CKD). We found that people with abnormalities in heart structure and function had a greater risk of progression to advanced CKD that required kidney replacement therapy and had a faster rate of decline in kidney function. Our study indicates the potential role of abnormal heart structure and function in the progression of kidney disease among people living with CKD.

Social Determinants of Health and Their Impact on the Black Race Coefficient in Serum Creatinine-Based Estimation of GFR: Secondary Analysis of MDRD and CRIC Studies.

The cause for differences in serum creatinine between Black and non-Black individuals incorporated into prior GFR-estimating equations is not understood. We explored whether social determinants of health can account for this difference. We conducted a secondary analysis of baseline data of the Modification of Diet in Renal Disease and Chronic Renal Insufficiency Cohort studies ( N =1628 and 1423, respectively). Data in both study cohorts were stratified by race (Black versus non-Black). We first evaluated the extent to which the coefficient of Black race in estimating GFR from creatinine is explained by correlations of race with social determinants of health and non-GFR determinants of creatinine. Second, we evaluated whether the difference between race groups in adjusted mean creatinine can be explained by social determinants of health and non-GFR determinants of creatinine. In models regressing measured GFR on creatinine, age, sex, and race, the coefficient for Black race was 21% (95% confidence interval, 0.176 to 0.245) in Modification of Diet in Renal Disease and 13% (95% confidence interval, 0.097 to 0.155) in the Chronic Renal Insufficiency Cohort and was not attenuated by the addition of social determinants of health, alone or in combination. In both studies, the coefficient for Black race was larger at lower versus higher income levels. In models, regressing creatinine on measured GFR, age, and sex, mean creatinine was higher in Black versus non-Black participants in both studies, with no effect of social determinants of health. Adjustment for selected social determinants of health did not influence the relationship between Black race and creatinine-based estimated GFR.

Abstract P538: Abnormal Serum Potassium is Associated With Risk of Chronic Kidney Disease Progression and All-Cause Mortality in Patients With Chronic Kidney Disease

Introduction: Chronic Kidney Disease (CKD) is a major risk factor for end-stage renal disease (ESRD) and premature death. It remains unclear if abnormal serum potassium is associated with CKD progression. We assessed the prospective relationship between serum potassium with both CKD progression and all-cause mortality among participants with CKD in the Chronic Renal Insufficiency Cohort (CRIC) Study. Methods: The CRIC study is a prospective cohort study of 3,939 participants with CKD from seven locations in the United States. Serum potassium was calculated as the cumulative mean from serum samples collected at baseline and annual follow-up visits prior to developing an event. Clinical cut points were used to group serum potassium: hypokalemia (&lt;3.5 mmol/L), normokalemia (≥3.5 and ≤5.0 mmol/L), and hyperkalemia (&gt;5.0 mmol/L). Kidney disease progression was defined as either incident end-stage renal disease or a 50% decline in estimated glomerular filtration rate (eGFR) from baseline. Cox proportional hazards models were used to examine the associations between serum potassium and CKD progression and all-cause mortality adjusting for baseline age, sex, race/ethnicity, education, clinic site, body mass index, cigarette smoking, alcohol drinking, physical activity, history of diabetes, hypercholesterolemia, and cardiovascular disease, use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, use of diuretics, use of other antihypertensive medications, and eGFR. Results: CRIC patients had a mean age of 57.7 years, were 45.1% female, and 41.9% Non-Hispanic Black. The prevalence of hypokalemia and hyperkalemia was 2.5% and 7.3%, respectively. Over an average 6.5 and 11.0 years of follow-up for CKD progression and all-cause mortality, respectively, 1,784 CKD progression events and 1,621 deaths occurred. Hypokalemia had a hazard ratio (HR) of 1.65 [95% confidence interval (CI): 1.25-2.10; p=.0004] for CKD progression compared with normokalemia. Similarly, hyperkalemia had a HR of 1.76 (95% CI, 1.50-2.06, p&lt;.0001) for CKD progression compared to normokalemia. The HR for all-cause mortality were 1.57 (95% CI, 1.13-2.18; p=.0066) for hypokalemia compared with normokalemia, and 1.43 (95% CI, 1.19-1.72, p=.0001) for hyperkalemia compared with normokalemia, after multivariable adjustment. Conclusions: Our study found that abnormally high and low serum potassium is associated with increased risk of CKD progression and all-cause mortality. These findings suggest that interventions that maintain serum potassium levels in the normal range may reduce the risk of CKD progression and premature death among patients with CKD.

Abstract P537: Abnormal Serum Potassium is Associated With Risk of Cardiovascular Disease in Patients With Chronic Kidney Disease

Introduction: Patients with chronic kidney disease (CKD) are at an increased risk of cardiovascular disease (CVD) compared to the general population. The role that abnormal serum potassium plays in the risk of CVD in patients with CKD is unclear. Our objective is to examine the association of hypokalemia and hyperkalemia with risk for cardiovascular events in patients with CKD. Methods: Data from 3,939 patients from the Chronic Renal Insufficiency Cohort (CRIC) Study, a multicenter cohort study of patients with CKD, were used. Cumulative average serum potassium collected annually prior to CVD events was calculated. Hypokalemia (&lt;3.5 mmol/L) and hypokalemia (&gt;5.0 mmol/L) were compared to normokalemia (3.5 - 5.0 mmol/L). Composite CVD was defined as congestive heart failure (CHF), stroke, myocardial infarction (MI), and atrial fibrillation (afib). Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) and were adjusted for age, gender, race/ethnicity, education, study site, body mass index, cigarette smoking, alcohol use, physical activity, history of diabetes, hypercholesteremia, and CVD, baseline use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, use of diuretics, use of other antihypertensive medication, and baseline eGFR. Results: Participants had a median age of 59.0 years and were 55% male, 42% Non-Hispanic White, and 42% Non-Hispanic Black. The prevalence of hypokalemia and hyperkalemia was 2.5% and 6.4%, respectively. Median follow-up was 9.2 years for composite CVD. Hypokalemia and hyperkalemia are both significantly associated with composite CVD, CHF, MI, and afib when compared to normokalemia (Table). Conclusions: We found significant associations between abnormal serum potassium and CVD in patients with CKD. Interventions to maintain normokalemia in patients with CKD could potentially reduce the risk of CVD in this high-risk population.

Association between Depressive Symptom Trajectory and Chronic Kidney Disease Progression: Findings from the Chronic Renal Insufficiency Cohort Study.

While depression is highly prevalent among individuals with chronic kidney disease (CKD), little is known about the course of depressive symptoms over time. We characterized trajectories of depressive symptoms and CKD progression and evaluated the association between depressive symptoms trajectory and CKD progression. 2361 individuals with mild-to-moderate CKD enrolled in the Chronic Renal Insufficiency Cohort Study. The Beck Depression Inventory (BDI) was used to assess depressive symptoms at baseline and biennially. Higher BDI scores indicate worse depressive symptoms. Estimated glomerular filtration rate (eGFR) was calculated using the 2021 CKD-EPI equation. Group-based trajectory models were used to determine trajectories of BDI score and eGFR change over time. Multinomial logistic regression was used to examine factors associated with BDI trajectories and to evaluate the association of BDI trajectories with eGFR change. Over 8 years of follow-up, three patterns of depressive symptoms were identified: persistently low BDI score (57.7%), persistently moderate BDI score (33.1%), and persistently high BDI score (9.2%). Three eGFR trajectory groups were identified: non-linear, rapid eGFR decline (21.5%); linear, expected eGFR decline (54.8%); and stable eGFR (23.7%). Predictors of persistently moderate and high BDI trajectories included low educational attainment, smoking, and poor quality of life. Compared to those with a persistently low BDI score, the odds for non-linear, rapid eGFR decline were higher for those with persistently moderate BDI scores (OR, 1.45; 95% CI, 1.04-2.03) and persistently high BDI scores (OR, 1.90; 95% CI, 1.02-3.56). No association between moderate BDI score and linear, expected eGFR decline was observed. Depressive symptoms remained largely stable among individuals with mild-to-moderate CKD, and persistently moderate and high BDI scores were associated with non-linear, rapid eGFR decline. Future work is needed to better understand the interplay between depression and CKD progression.

A generalized covariate-adjusted top-scoring pair algorithm with applications to diabetic kidney disease stage classification in the Chronic Renal Insufficiency Cohort (CRIC) Study

BackgroundThe growing amount of high dimensional biomolecular data has spawned new statistical and computational models for risk prediction and disease classification. Yet, many of these methods do not yield biologically interpretable models, despite offering high classification accuracy. An exception, the top-scoring pair (TSP) algorithm derives parameter-free, biologically interpretable single pair decision rules that are accurate and robust in disease classification. However, standard TSP methods do not accommodate covariates that could heavily influence feature selection for the top-scoring pair. Herein, we propose a covariate-adjusted TSP method, which uses residuals from a regression of features on the covariates for identifying top scoring pairs. We conduct simulations and a data application to investigate our method, and compare it to existing classifiers, LASSO and random forests.ResultsOur simulations found that features that were highly correlated with clinical variables had high likelihood of being selected as top scoring pairs in the standard TSP setting. However, through residualization, our covariate-adjusted TSP was able to identify new top scoring pairs, that were largely uncorrelated with clinical variables. In the data application, using patients with diabetes (n = 977) selected for metabolomic profiling in the Chronic Renal Insufficiency Cohort (CRIC) study, the standard TSP algorithm identified (valine-betaine, dimethyl-arg) as the top-scoring metabolite pair for classifying diabetic kidney disease (DKD) severity, whereas the covariate-adjusted TSP method identified the pair (pipazethate, octaethylene glycol) as top-scoring. Valine-betaine and dimethyl-arg had, respectively, ≥ 0.4 absolute correlation with urine albumin and serum creatinine, known prognosticators of DKD. Thus without covariate-adjustment the top-scoring pair largely reflected known markers of disease severity, whereas covariate-adjusted TSP uncovered features liberated from confounding, and identified independent prognostic markers of DKD severity. Furthermore, TSP-based methods achieved competitive classification accuracy in DKD to LASSO and random forests, while providing more parsimonious models.ConclusionsWe extended TSP-based methods to account for covariates, via a simple, easy to implement residualizing process. Our covariate-adjusted TSP method identified metabolite features, uncorrelated from clinical covariates, that discriminate DKD severity stage based on the relative ordering between two features, and thus provide insights into future studies on the order reversals in early vs advanced disease states.