Chronic kidney disease associated cardiomyopathy: recent advances and future perspectives.

PURPOSE OF REVIEW: Cardiomyopathy in chronic kidney disease (CKD) is a complex condition with multiple triggers and poor prognosis. This review provides an overview of recent advances in CKD-associated cardiomyopathy, with a focus on pathophysiology, newly discovered biomarkers and potential therapeutic targets. RECENT FINDINGS: CKD is associated with a specific pattern of myocardial hypertrophy and fibrosis, resulting in diastolic and systolic dysfunction, and often triggered by nonatherosclerotic processes. Novel biomarkers, including amino-terminal type III procollagen peptide (PIIINP), carboxy-terminal type I procollagen peptide (PICP), FGF23, marinobufagenin, and several miRNAs, show promise for early detection and risk stratification. Treatment options for CKD-associated cardiomyopathy are limited. Sodium glucose cotransporter-2 inhibitors have been shown to reduce left ventricle hypertrophy and improve ejection fraction in individuals with diabetes and mild CKD, and are currently under investigation for more advanced stages of CKD. In hemodialysis patients calcimimetic etelcalcetide resulted in a significant reduction in left ventricular mass. SUMMARY: CKD-associated cardiomyopathy is a common and severe complication in CKD. The identification of novel biomarkers may lead to future therapeutic targets. Randomized clinical trials in individuals with more advanced CKD would be well posed to expand treatment options for this debilitating condition.

Adherence to Plant-Based Diets and Risk of CKD Progression and All-Cause Mortality: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Studies have shown that generally healthy individuals who consume diets rich in plant foods have a lower risk of incident chronic kidney disease (CKD) and cardiovascular disease. This study investigated the prospective associations of plant-based diets with the risk of CKD progression and all-cause mortality in individuals with CKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 2,539 participants with CKD recruited between 2003-2008 into the Chronic Renal Insufficiency Cohort (CRIC) Study. EXPOSURE: Responses on the Diet History Questionnaire were used to calculate scores for the overall plant-based diet index, healthy plant-based diet index, and unhealthy plant-based diet index. OUTCOME: (1) CKD progression defined as≥50% estimated glomerular filtration rate decline from baseline or kidney replacement therapy (dialysis, transplant) and (2) all-cause mortality. ANALYTICAL APPROACH: Cox proportional hazards models to compute hazard ratios and 95% confidence intervals adjusting for lifestyle, socioeconomic, and clinical covariates. RESULTS: There were 977 CKD progression events and 836 deaths during a median follow-up period of 7 and 12 years, respectively. Participants with the highest versus lowest adherence to overall plant-based diets and healthy plant-based diets had 26% (HR, 0.74 [95% CI, 0.62-0.88], P trend<0.001) and 21% (HR, 0.79 [95% CI, 0.66-0.95], P trend=0.03) lower risks of all-cause mortality, respectively. Each 10-point higher score of unhealthy plant-based diets was modestly associated with a higher risk of CKD progression (HR, 1.14 [95% CI, 1.03-1.25) and all-cause mortality (HR, 1.11 [95% CI, 1.00-1.23). LIMITATIONS: Self-reported diet may be subject to measurement error. CONCLUSIONS: Adherence to an overall plant-based diet and a healthy plant-based diet is associated with a reduced risk of all-cause mortality among individuals with CKD. An unhealthy plant-based was associated with an elevated risk of CKD progression and all-cause mortality. PLAIN-LANGUAGE SUMMARY: Plant-based diets are healthful dietary patterns that have been linked to a lower risk of chronic diseases. However, the impact of plant-based diets on clinical outcomes in patients with chronic kidney disease (CKD) is not well established. In 2,539 individuals with CKD, we examined the associations of adherence to 3 different types of plant-based diets with the risks of CKD progression and all-cause mortality. We found that following an overall plant-based diet and a healthy plant-based diet was associated with a lower risk of all-cause mortality. By contrast, following an unhealthy plant-based diet was associated with a higher risk of CKD progression and all-cause mortality. These results suggest that the quality of plant-based diets may be important for CKD management.

Isolated Diastolic Hypertension and Kidney and Cardiovascular Outcomes in CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study.

Rationale & Objective: The clinical significance of isolated diastolic hypertension in patients with chronic kidney disease (CKD) is unclear. We assessed the prevalence of isolated diastolic hypertension and its association with adverse kidney and cardiovascular outcomes in participants in the Chronic Renal Insufficiency Cohort (CRIC) study. Study Design: Prospective cohort study. Setting & Population: CRIC study participants with complete baseline data on systolic blood pressure (SBP) and diastolic BP (DBP) (N=5,621). Exposure: Isolated diastolic hypertension defined as SBP ≤ 130 mm Hg and DBP >80 mm Hg. Reference Group: Normotension, defined as SBP ≤ 130 mm Hg and DBP ≤ 80 mm Hg. Outcomes: Composite kidney events (50% decline in estimated glomerular filtration rate or onset of kidney failure), composite cardiovascular events (myocardial infarction, heart failure, stroke, or peripheral arterial disease), and all-cause mortality. Analytical Approach: Cox proportional hazards models adjusted for demographic, health behavior, and clinical covariates. Results: Of the 5,621 participants, 347 (6.2%) had isolated diastolic hypertension. Among the 347 participants with isolated diastolic hypertension, there was no association between isolated diastolic hypertension and the composite kidney outcome (HR, 1.17; 95% CI, 0.93-1.47; P = 0.18), composite cardiovascular events (HR, 0.91; 95% CI, 0.65-1.27; P = 0.58), or all-cause mortality (HR, 0.82; 95% CI, 0.57-1.19; P = 0.30). Limitations: Older age of cohort and low number of participants of Asian ethnicity limit generalizability of findings. A relatively small sample size is inadequate to detect modest associations with outcomes. Conclusions: Isolated diastolic hypertension was not associated with the risk of adverse kidney and cardiovascular events in participants with CKD. Plain Language Summary: Clinicians frequently encounter patients with kidney disease who have controlled systolic blood pressure (BP) but high diastolic BP and do not know whether they should intensify BP treatment in an attempt to control the diastolic BP. We examined whether having controlled systolic BP but uncontrolled diastolic BP leads to worse heart and kidney outcomes in patients with chronic kidney disease. We did not find any such association. However, our study was relatively small and had a number of limitations. Till larger studies confirm or refute this finding, we recommend not increasing blood pressure medications to improve the diastolic BP control if the systolic BP is already well controlled in patients with chronic kidney disease.

Evaluation of a large-scale aptamer proteomics platform among patients with kidney failure on dialysis.

BACKGROUND: Patients with kidney failure suffer high mortality, and we currently lack markers for risk stratification for these patients. We carried out a quality control study of a modified aptamer assay (SomaScan v.4.0) that measures ~ 5000 proteins, in preparation for a larger study using this platform in cohorts with kidney failure. METHODS: Forty participants from the Cardiac, Endothelial Function and Arterial Stiffness in End-Stage Renal Disease (CERES study) were selected to analyze technical and short-term biological variability, orthogonal correlations and differential protein expression in plasma from patients who died during 2.5 year follow-up. Long-term (one year) variability was studied in 421 participants in the Chronic Renal Insufficiency Cohort. We evaluated 4849 aptamers (4607 unique proteins) using data formats including raw data and data formatted using Adaptive Normalization by Maximum Likelihood (ANML), an algorithm developed for SomaScan data in individuals with normal kidney function. RESULTS: In ANML format, median[IQR] intra-assay coefficient of variation (CV) was 2.38%[1.76, 3.40] and inter-assay CV was 7.38%[4.61, 13.12]. Short-term within-subject CV was 5.76% [3.35, 9.72]; long-term CV was 8.71%[5.91, 13.37]. Spearman correlations between aptamer and traditional assays for PTH, NT-proBNP, FGF-23 and CRP were all > 0.7. Fold-change (FC) in protein levels among non-survivors, significant after Bonferroni correction, included SVEP1 (FC[95% CI] 2.14 [1.62, 2.82]), keratocan (1.74 [1.40, 2.15]) and LanC-like protein 1 (0.56 [0.45, 0.70]). Compared to raw aptamer data, technical and short-term biological variability in paired samples was lower in ANML-formatted data. ANML formatting had minimal impact on orthogonal correlations with traditional assays or the associations of proteins with the phenotype of mortality. CONCLUSIONS: SomaScan had excellent technical variability and low within-subject short-term variability. ANML formatting could facilitate comparison of biomarker results with other studies that utilize this format. We expect SomaScan to provide novel and reproducible information in patients with kidney failure on dialysis.

Emerging Preventive Strategies in Chronic Kidney Disease: Recent Evidence and Gaps in Knowledge.

PURPOSE OF REVIEW: Chronic kidney disease (CKD) is increasingly prevalent worldwide and is associated with increased cardiovascular risk. New therapeutic options to slow CKD progression and reduce cardiovascular morbidity and mortality have recently emerged. This review highlights recent evidence and gaps in knowledge in emerging CKD preventive strategies. RECENT FINDINGS: EMPA-Kidney trial found that empagliflozin, a sodium-glucose co-transporter 2 inhibitor (SGLT2i) led to 28% lower risk of progression of kidney disease or death from cardiovascular causes, compared to placebo. This reinforced the previous findings from DAPA-CKD and CREDENCE trials and led to inclusion of SGLT2i as the cornerstone of CKD preventive therapy in both diabetic and non-diabetic CKD. Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, slowed diabetic kidney disease progression by 23% compared to placebo in a pool analysis of FIDELIO-DKD and FIGARO-DKD trials. Non-pharmacological interventions, including low protein diet, and early CKD detection and risk stratification strategies based on novel biomarkers have also gained momentum. Ongoing efforts to explore the wealth of molecular mechanisms in CKD, added to integrative omics modeling are well posed to lead to novel therapeutic targets in kidney care. While breakthrough pharmacological interventions continue to improve outcomes in CKD, the heterogeneity of kidney diseases warrants additional investigation. Further research into specific kidney disease mechanisms will facilitate the identification of patient populations most likely to benefit from targeted interventions.

Effect of Intensive Blood Pressure Control on Kidney Outcomes: Long-Term Electronic Health Record-Based Post-Trial Follow-Up of SPRINT.

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.

Depression and incident cardiovascular disease among patients with chronic kidney disease.

Background: Depression 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. Methods: We 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. Results: Among 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). Conclusions: Among patients with CKD stages 2-4 enrolled in CRIC without preexisting CVD, depression was associated with a 29% increased risk of incident CVD.

Low concentrations of medium-sized HDL particles predict incident CVD in chronic kidney disease patients.

Patients with chronic kidney disease (CKD) are at high risk for CVD. However, traditional CVD risk factors cannot completely explain the increased risk. Altered HDL proteome is linked with incident CVD in CKD patients, but it is unclear whether other HDL metrics are associated with incident CVD in this population. In the current study, we analyzed samples from two independent prospective case-control cohorts of CKD patients, the Clinical Phenotyping and Resource Biobank Core (CPROBE) and the Chronic Renal Insufficiency Cohort (CRIC). We measured HDL particle sizes and concentrations (HDL-P) by calibrated ion mobility analysis and HDL cholesterol efflux capacity (CEC) by cAMP-stimulated J774 macrophages in 92 subjects from the CPROBE cohort (46 CVD and 46 controls) and in 91 subjects from the CRIC cohort (34 CVD and 57 controls). We tested associations of HDL metrics with incident CVD using logistic regression analysis. No significant associations were found for HDL-C or HDL-CEC in either cohort. Total HDL-P was only negatively associated with incident CVD in the CRIC cohort in unadjusted analysis. Among the six sized HDL subspecies, only medium-sized HDL-P was significantly and negatively associated with incident CVD in both cohorts after adjusting for clinical confounders and lipid risk factors with odds ratios (per 1-SD) of 0.45 (0.22-0.93, P = 0.032) and 0.42 (0.20-0.87, P = 0.019) for CPROBE and CRIC cohorts, respectively. Our observations indicate that medium-sized HDL-P-but not other-sized HDL-P or total HDL-P, HDL-C, or HDL-CEC-may be a prognostic cardiovascular risk marker in CKD.

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

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/1.73m2; 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 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.

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

RATIONALE & OBJECTIVE: 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. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 3,027 participants from the Chronic Renal Insufficiency Cohort Study. EXPOSURE: 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. OUTCOME: Incident KFRT (primary outcome), and annual estimated glomerular filtration rate (eGFR) slope (secondary outcome). ANALYTICAL APPROACH: Multivariable Cox models and mixed-effects models. RESULTS: 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). LIMITATIONS: The possibility of residual confounding. CONCLUSIONS: 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. PLAIN-LANGUAGE SUMMARY: 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.

Metabolic acidosis post kidney transplantation.

Metabolic acidosis, a common complication in patients with chronic kidney disease (CKD), results in a multitude of deleterious effects. Though the restoration of kidney function following transplantation is generally accompanied by a correction of metabolic acidosis, a subset of transplant recipients remains afflicted by this ailment and its subsequent morbidities. The vulnerability of kidney allografts to metabolic acidosis can be attributed to reasons similar to pathogenesis of acidosis in non-transplant CKD, and to transplant specific causes, including donor related, recipient related, immune mediated factors, and immunosuppressive medications. Correction of metabolic acidosis in kidney transplantation either with alkali therapy or through dietary manipulations may have potential benefits and the results of such clinical trials are eagerly awaited. This review summarizes the published evidence on the pathogenesis and clinical consequences of chronic metabolic acidosis in kidney transplant recipients.

Effect of Intensive versus Standard BP Control on AKI and Subsequent Cardiovascular Outcomes and Mortality: Findings from the SPRINT EHR Study.

Background: Adjudication of inpatient AKI in the Systolic Blood Pressure Intervention Trial (SPRINT) was based on billing codes and admission and discharge notes. The purpose of this study was to evaluate the effect of intensive versus standard BP control on creatinine-based inpatient and outpatient AKI, and whether AKI was associated with cardiovascular disease (CVD) and mortality. Methods: We linked electronic health record (EHR) data from 47 clinic sites with trial data to enable creatinine-based adjudication of AKI. Cox regression was used to evaluate the effect of intensive BP control on the incidence of AKI, and the relationship between incident AKI and CVD and all-cause mortality. Results: A total of 3644 participants had linked EHR data. A greater number of inpatient AKI events were identified using EHR data (187 on intensive versus 155 on standard treatment) as compared with serious adverse event (SAE) adjudication in the trial (95 on intensive versus 61 on standard treatment). Intensive treatment increased risk for SPRINT-adjudicated inpatient AKI (HR, 1.51; 95% CI, 1.09 to 2.08) and for creatinine-based outpatient AKI (HR, 1.40; 95% CI, 1.15 to 1.70), but not for creatinine-based inpatient AKI (HR, 1.20; 95% CI, 0.97 to 1.48). Irrespective of the definition (SAE or creatinine based), AKI was associated with increased risk for all-cause mortality, but only creatinine-based inpatient AKI was associated with increased risk for CVD. Conclusions: Creatinine-based ascertainment of AKI, enabled by EHR data, may be more sensitive and less biased than traditional SAE adjudication. Identifying ways to prevent AKI may reduce mortality further in the setting of intensive BP control.

Association of Proximal Tubular Secretory Clearance with Long-Term Decline in Cognitive Function.

BACKGROUND: People with chronic kidney disease (CKD) are at high risk for cognitive impairment and progressive cognitive decline. Retention of protein-bound organic solutes that are normally removed by tubular secretion is hypothesized to contribute to cognitive impairment in CKD. METHODS: We followed 2362 participants who were initially free of cognitive impairment and stroke in the prospective Chronic Renal Insufficiency Cohort (CRIC) Study. We estimated tubular secretory clearance by the 24-hour kidney clearances of eight endogenous solutes that are primarily eliminated by tubular secretion. CRIC study investigators assessed participants' cognitive function annually using the Modified Mini-Mental State (3MS) Examination. Cognitive decline was defined as a sustained decrease of more than five points in the 3MS score from baseline. Using Cox regression models adjusted for potential confounders, we analyzed associations between secretory solute clearances, serum solute concentrations, and cognitive decline. RESULTS: The median number of follow-up 3MS examinations was six per participant. There were 247 incident cognitive decline events over a median of 9.1 years of follow-up. Lower kidney clearances of five of the eight secretory solutes (cinnamoylglycine, isovalerylglycine, kynurenic acid, pyridoxic acid, and tiglylglycine) were associated with cognitive decline after adjustment for baseline eGFR, proteinuria, and other confounding variables. Effect sizes ranged from a 17% to a 34% higher risk of cognitive decline per 50% lower clearance. In contrast, serum concentrations of the solutes were not associated with cognitive decline. CONCLUSIONS: Lower kidney clearances of secreted solutes are associated with incident global cognitive decline in a prospective study of CKD, independent of eGFR. Further work is needed to determine the domains of cognition most affected by decreased secretory clearance and the mechanisms of these associations.

Deoxycholic Acid and Coronary Artery Calcification in the Chronic Renal Insufficiency Cohort.

Background Deoxycholic acid (DCA) is a secondary bile acid that may promote vascular calcification in experimental settings. Higher DCA levels were associated with prevalent coronary artery calcification (CAC) in a small group of individuals with advanced chronic kidney disease. Whether DCA levels are associated with CAC prevalence, incidence, and progression in a large and diverse population of individuals with chronic kidney disease stages 2 to 4 is unknown. Methods and Results In the CRIC (Chronic Renal Insufficiency Cohort) study, we evaluated cross-sectional (n=1057) and longitudinal (n=672) associations between fasting serum DCA levels and computed tomographic CAC using multivariable-adjusted regression models. The mean age was 57±12 years, 47% were women, and 41% were Black. At baseline, 64% had CAC (CAC score >0 Agatston units). In cross-sectional analyses, models adjusted for demographics and clinical factors showed no association between DCA levels and CAC >0 compared with no CAC (prevalence ratio per 1-SD higher log DCA, 1.08 [95% CI, 0.91-1.26). DCA was not associated with incident CAC (incidence per 1-SD greater log DCA, 1.08 [95% CI, 0.85-1.39]) or CAC progression (risk for increase in ≥100 and ≥200 Agatston units per year per 1-SD greater log DCA, 1.05 [95% CI, 0.84-1.31] and 1.26 [95% CI, 0.77-2.06], respectively). Conclusions Among CRIC study participants, DCA was not associated with prevalent, incident, or progression of CAC.

Gut-derived bacterial toxins impair memory CD4+ T cell mitochondrial function in HIV-1 infection.

People living with HIV (PLWH) who are immune nonresponders (INRs) are at greater risk of comorbidity and mortality than are immune responders (IRs) who restore their CD4+ T cell count after antiretroviral therapy (ART). INRs have low CD4+ T cell counts (<350 c/µL), heightened systemic inflammation, and increased CD4+ T cell cycling (Ki67+). Here, we report the findings that memory CD4+ T cells and plasma samples of INRs from several cohorts are enriched in gut-derived bacterial solutes p-cresol sulfate (PCS) and indoxyl sulfate (IS) that both negatively correlated with CD4+ T cell counts. In vitro PCS or IS blocked CD4+ T cell proliferation, induced apoptosis, and diminished the expression of mitochondrial proteins. Electron microscopy imaging revealed perturbations of mitochondrial networks similar to those found in INRs following incubation of healthy memory CD4+ T cells with PCS. Using bacterial 16S rDNA, INR stool samples were found enriched in proteolytic bacterial genera that metabolize tyrosine and phenylalanine to produce PCS. We propose that toxic solutes from the gut bacterial flora may impair CD4+ T cell recovery during ART and may contribute to CD4+ T cell lymphopenia characteristic of INRs.

Risk Prediction Models for Atherosclerotic Cardiovascular Disease in Patients with Chronic Kidney Disease: The CRIC Study.

BACKGROUND: Individuals with CKD may be at high risk for atherosclerotic cardiovascular disease (ASCVD). However, there are no ASCVD risk prediction models developed in CKD populations to inform clinical care and prevention. METHODS: We developed and validated 10-year ASCVD risk prediction models in patients with CKD that included participants without self-reported cardiovascular disease from the Chronic Renal Insufficiency Cohort (CRIC) study. ASCVD was defined as the first occurrence of adjudicated fatal and nonfatal stroke or myocardial infarction. Our models used clinically available variables and novel biomarkers. Model performance was evaluated based on discrimination, calibration, and net reclassification improvement. RESULTS: Of 2604 participants (mean age 55.8 years; 52.0% male) included in the analyses, 252 had incident ASCVD within 10 years of baseline. Compared with the American College of Cardiology/American Heart Association pooled cohort equations (area under the receiver operating characteristic curve [AUC]=0.730), a model with coefficients estimated within the CRIC sample had higher discrimination (P=0.03), achieving an AUC of 0.736 (95% confidence interval [CI], 0.649 to 0.826). The CRIC model developed using clinically available variables had an AUC of 0.760 (95% CI, 0.678 to 0.851). The CRIC biomarker-enriched model had an AUC of 0.771 (95% CI, 0.674 to 0.853), which was significantly higher than the clinical model (P=0.001). Both the clinical and biomarker-enriched models were well-calibrated and improved reclassification of nonevents compared with the pooled cohort equations (6.6%; 95% CI, 3.7% to 9.6% and 10.0%; 95% CI, 6.8% to 13.3%, respectively). CONCLUSIONS: The 10-year ASCVD risk prediction models developed in patients with CKD, including novel kidney and cardiac biomarkers, performed better than equations developed for the general population using only traditional risk factors.