Proteomic Assessment of the Risk of Secondary Cardiovascular Events among Individuals with CKD.

BACKGROUND: Cardiovascular risk models have been developed primarily for incident events. Well-performing models are lacking to predict secondary cardiovascular events among people with a history of coronary heart disease, stroke, or heart failure who also have chronic kidney disease (CKD). We sought to develop a proteomics-based risk score for cardiovascular events in individuals with CKD and a history of cardiovascular disease. METHODS: We measured 4638 plasma proteins among 1067 participants from the Chronic Renal Insufficiency Cohort (CRIC) and 536 individuals from the Atherosclerosis Risk in Communities Cohort (ARIC). All had non-dialysis-dependent CKD and coronary heart disease, heart failure, or stroke at study baseline. A proteomic risk model for secondary cardiovascular events was derived by elastic net regression in CRIC, validated in ARIC, and compared to clinical models. Biologic mechanisms of secondary events were characterized through proteomic pathway analysis. RESULTS: A 16-protein risk model was superior to the Framingham risk score for secondary events, including a modified score that included estimated glomerular filtration rate (eGFR). In CRIC, the annualized area under the receiver operating characteristic (AUC) within 1 to 5 years ranged between 0.77 and 0.80 for the protein model and 0.57 and 0.72 for the clinical models. These findings were replicated in the ARIC validation cohort. Biologic pathway analysis identified pathways and proteins for cardiac remodeling and fibrosis, vascular disease, and thrombosis. CONCLUSIONS: The proteomic risk model for secondary cardiovascular events outperformed clinical models based on traditional risk factors and eGFR.

Final Report of a Trial of Intensive versus Standard Blood-Pressure Control.

BACKGROUND: In a previously reported randomized trial of standard and intensive systolic blood-pressure control, data on some outcome events had yet to be adjudicated and post-trial follow-up data had not yet been collected. METHODS: We randomly assigned 9361 participants who were at increased risk for cardiovascular disease but did not have diabetes or previous stroke to adhere to an intensive treatment target (systolic blood pressure, <120 mm Hg) or a standard treatment target (systolic blood pressure, <140 mm Hg). The primary outcome was a composite of myocardial infarction, other acute coronary syndromes, stroke, acute decompensated heart failure, or death from cardiovascular causes. Additional primary outcome events occurring through the end of the intervention period (August 20, 2015) were adjudicated after data lock for the primary analysis. We also analyzed post-trial observational follow-up data through July 29, 2016. RESULTS: At a median of 3.33 years of follow-up, the rate of the primary outcome and all-cause mortality during the trial were significantly lower in the intensive-treatment group than in the standard-treatment group (rate of the primary outcome, 1.77% per year vs. 2.40% per year; hazard ratio, 0.73; 95% confidence interval [CI], 0.63 to 0.86; all-cause mortality, 1.06% per year vs. 1.41% per year; hazard ratio, 0.75; 95% CI, 0.61 to 0.92). Serious adverse events of hypotension, electrolyte abnormalities, acute kidney injury or failure, and syncope were significantly more frequent in the intensive-treatment group. When trial and post-trial follow-up data were combined (3.88 years in total), similar patterns were found for treatment benefit and adverse events; however, rates of heart failure no longer differed between the groups. CONCLUSIONS: Among patients who were at increased cardiovascular risk, targeting a systolic blood pressure of less than 120 mm Hg resulted in lower rates of major adverse cardiovascular events and lower all-cause mortality than targeting a systolic blood pressure of less than 140 mm Hg, both during receipt of the randomly assigned therapy and after the trial. Rates of some adverse events were higher in the intensive-treatment group. (Funded by the National Institutes of Health; SPRINT ClinicalTrials.gov number, NCT01206062.).

Arterial Stiffness and Diabetes Risk in Framingham Heart Study and UK Biobank.

BACKGROUND: Microvascular damage from large artery stiffness (LAS) in pancreatic, hepatic, and skeletal muscles may affect glucose homeostasis. Our goal was to evaluate the association between LAS and the risk of type 2 diabetes using prospectively collected, carefully phenotyped measurements of LAS as well as Mendelian randomization analyses. METHODS: Carotid-femoral pulse wave velocity (CF-PWV) and brachial and central pulse pressure were measured in 5676 participants of the FHS (Framingham Heart Study) without diabetes. We used Cox proportional hazards regression to evaluate the association of CF-PWV and pulse pressure with incident diabetes. We subsequently performed 2-sample Mendelian randomization analyses evaluating the associations of genetically predicted brachial pulse pressure with type 2 diabetes in the UKBB (United Kingdom Biobank). RESULTS: In FHS, individuals with higher CF-PWV were older, more often male, and had higher body mass index and mean arterial pressure compared to those with lower CF-PWV. After a median follow-up of 7 years, CF-PWV and central pulse pressure were associated with an increased risk of new-onset diabetes (per SD increase, multivariable-adjusted CF-PWV hazard ratio, 1.36 [95% CI, 1.03-1.76]; P=0.030; central pulse pressure multivariable-adjusted CF-PWV hazard ratio, 1.26 [95% CI, 1.08-1.48]; P=0.004). In United Kingdom Biobank, genetically predicted brachial pulse pressure was associated with type 2 diabetes, independent of mean arterial pressure (adjusted odds ratio, 1.16 [95% CI, 1.00-1.35]; P=0.049). CONCLUSIONS: Using prospective cohort data coupled with Mendelian randomization analyses, we found evidence supporting that greater LAS is associated with increased risk of developing diabetes. LAS may play an important role in glucose homeostasis and may serve as a useful marker of future diabetes risk.

Dietary Fiber Intake and Clinical Outcomes in Chronic Kidney Disease: A Report From the Chronic Renal Insufficiency Cohort Study.

OBJECTIVE: Dietary interventions are the mainstay of chronic diseases prevention in general population, but the evidence to support such therapeutic approaches in patients with chronic kidney disease (CKD) is less robust. The objective of this study is to examine the association between dietary fiber intake and adverse cardiovascular and kidney outcomes and all-cause mortality in participants with CKD enrolled in the Chronic Renal Insufficiency Cohort study. DESIGN AND METHODS: A total of 3791 Chronic Renal Insufficiency Cohort participants with self-reported dietary fiber intake were included in the analyses stratified by tertiles of dietary fiber at study baseline. Hazard ratios for occurrence of all-cause mortality, composite cardiovascular events and composite kidney events were calculated using Cox Proportional Hazards models adjusted for demographic, clinical, and laboratory characteristics, including levels of inflammatory markers, C-reactive protein and interleukin-6. RESULTS: Mean daily dietary fiber intake was 15.2 g/day. During a median (standard deviation) follow up of 14.6 (4.4) years, 1074 deaths from any cause occurred. In multivariable adjusted models, participants in the middle and low dietary fiber tertiles had a 19% (hazard ratio [95% CI]), 1.19 [1.02, 1.39]) and 11% (1.11 [0.95, 1.31]) greater risk of death respectively, compared to those in the highest fiber intake tertile. No statistically significant associations were observed between dietary fiber intake and adverse cardiovascular and kidney outcomes. Higher dietary fiber intake was not significantly associated with lower levels of C-reactive protein and interleukin-6. CONCLUSION: A lower intake of dietary fiber was not associated with all-cause mortality in participants with CKD after adjustments for kidney function and inflammatory biomarkers. There was no significant association between dietary fiber intake and adverse kidney and cardiovascular outcomes. Future randomized intervention trials are needed to identify whether a high dietary fiber intake translates into improved clinical outcomes in CKD.

Proteomic cardiovascular risk assessment in chronic kidney disease.

AIMS: Chronic kidney disease (CKD) is widely prevalent and independently increases cardiovascular risk. Cardiovascular risk prediction tools derived in the general population perform poorly in CKD. Through large-scale proteomics discovery, this study aimed to create more accurate cardiovascular risk models. METHODS AND RESULTS: Elastic net regression was used to derive a proteomic risk model for incident cardiovascular risk in 2182 participants from the Chronic Renal Insufficiency Cohort. The model was then validated in 485 participants from the Atherosclerosis Risk in Communities cohort. All participants had CKD and no history of cardiovascular disease at study baseline when ∼5000 proteins were measured. The proteomic risk model, which consisted of 32 proteins, was superior to both the 2013 ACC/AHA Pooled Cohort Equation and a modified Pooled Cohort Equation that included estimated glomerular filtrate rate. The Chronic Renal Insufficiency Cohort internal validation set demonstrated annualized receiver operating characteristic area under the curve values from 1 to 10 years ranging between 0.84 and 0.89 for the protein and 0.70 and 0.73 for the clinical models. Similar findings were observed in the Atherosclerosis Risk in Communities validation cohort. For nearly half of the individual proteins independently associated with cardiovascular risk, Mendelian randomization suggested a causal link to cardiovascular events or risk factors. Pathway analyses revealed enrichment of proteins involved in immunologic function, vascular and neuronal development, and hepatic fibrosis. CONCLUSION: In two sizeable populations with CKD, a proteomic risk model for incident cardiovascular disease surpassed clinical risk models recommended in clinical practice, even after including estimated glomerular filtration rate. New biological insights may prioritize the development of therapeutic strategies for cardiovascular risk reduction in the CKD population.

Major cardiovascular events and subsequent risk of kidney failure with replacement therapy: a CKD Prognosis Consortium study.

AIMS: Chronic kidney disease (CKD) increases risk of cardiovascular disease (CVD). Less is known about how CVD associates with future risk of kidney failure with replacement therapy (KFRT). METHODS AND RESULTS: The study included 25 903 761 individuals from the CKD Prognosis Consortium with known baseline estimated glomerular filtration rate (eGFR) and evaluated the impact of prevalent and incident coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) events as time-varying exposures on KFRT outcomes. Mean age was 53 (standard deviation 17) years and mean eGFR was 89 mL/min/1.73 m2, 15% had diabetes and 8.4% had urinary albumin-to-creatinine ratio (ACR) available (median 13 mg/g); 9.5% had prevalent CHD, 3.2% prior stroke, 3.3% HF, and 4.4% prior AF. During follow-up, there were 269 142 CHD, 311 021 stroke, 712 556 HF, and 605 596 AF incident events and 101 044 (0.4%) patients experienced KFRT. Both prevalent and incident CVD were associated with subsequent KFRT with adjusted hazard ratios (HRs) of 3.1 [95% confidence interval (CI): 2.9-3.3], 2.0 (1.9-2.1), 4.5 (4.2-4.9), 2.8 (2.7-3.1) after incident CHD, stroke, HF and AF, respectively. HRs were highest in first 3 months post-CVD incidence declining to baseline after 3 years. Incident HF hospitalizations showed the strongest association with KFRT [HR 46 (95% CI: 43-50) within 3 months] after adjustment for other CVD subtype incidence. CONCLUSION: Incident CVD events strongly and independently associate with future KFRT risk, most notably after HF, then CHD, stroke, and AF. Optimal strategies for addressing the dramatic risk of KFRT following CVD events are needed.

Clinical correlates of medication adherence in individuals with bipolar disorder and comorbid hypertension.

OBJECTIVE: Individuals with bipolar disorder (BD) have high rates of suboptimal medication adherence, medical illness, and premature mortality, largely from cardiovascular causes. This analysis examined the association between adherence to antihypertensive and BD medications and clinical symptoms in patients with BD and comorbid hypertension (HTN) from an ongoing trial to optimize adherence. METHOD: Inclusion criteria were a BD diagnosis, treatment with antihypertensives, adherence challenges, and poorly controlled HTN. Adherence was measured via self-report using the Tablets Routine Questionnaire and using eCAP, an electronic pillcap which captures openings. Average systolic blood pressure (SBP) was calculated from 12 readings over 1 week. The Montgomery-Asberg Depression Rating Scale (MADRS) and the Brief Psychiatric Rating Scale (BPRS) assessed BD symptoms. RESULTS: A total of 83 participants with BD and HTN were included. Adherence to BD and antihypertensive medications were positively correlated. eCAP openings showed more missed doses than self-reported antihypertensive adherence. BD medication adherence was positively correlated with BPRS at baseline; antihypertensive adherence was negatively correlated with SBP at screening. Antihypertensive adherence improved and SBP decreased between screening and baseline. CONCLUSIONS: Adherence levels fluctuated over time and differed based on measurement method in people with comorbid BD and HTN. Self-reported BD adherence was positively related to global psychiatric symptoms and antihypertensive adherence was related to better SBP control. Monitoring both medication and blood pressure led to change in self-reported adherence. BD symptom severity may indicate poor adherence in patients with BD and should be considered in treatment planning.

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

RATIONALE & OBJECTIVE: 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. STUDY DESIGN: Longitudinal cohort study. SETTING & PARTICIPANTS: 3,768 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study. EXPOSURE: 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). OUTCOME: 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. ANALYTICAL APPROACH: Cox proportional hazard models adjusted for demographics as well as kidney disease and cardiovascular disease risk factors. RESULTS: 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. LIMITATIONS: 3MS test as the primary measure of cognitive function. CONCLUSIONS: 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. PLAIN-LANGUAGE SUMMARY: 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.

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.

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.

KDOQI US Commentary on the 2021 KDIGO Clinical Practice Guideline for the Management of Blood Pressure in CKD.

The Kidney Disease Outcomes Quality Initiative (KDOQI) convened a work group to review the 2021 KDIGO (Kidney Disease: Improving Global Outcomes) guideline for the management of blood pressure in chronic kidney disease (CKD). This commentary is the product of that work group and presents the recommendations and practice points from the KDIGO guideline in the context of US clinical practice. A critical addition to the KDIGO guideline is the recommendation for accurate assessment of blood pressure using standardized office blood pressure measurement. In the general adult population with CKD, KDIGO recommends a goal systolic blood pressure less than 120 mm Hg on the basis of results from the Systolic Blood Pressure Intervention Trial (SPRINT) and secondary analyses of the Action to Control Cardiovascular Risk in Diabetes-Blood Pressure (ACCORD-BP) trial. The KDOQI work group agreed with most of the recommendations while highlighting the weak evidence base especially for patients with diabetes and advanced CKD.

Time-Updated Changes in Estimated GFR and Proteinuria and Major Adverse Cardiac Events: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Evaluating repeated measures of estimated glomerular filtration rate (eGFR) and urinary protein-creatinine ratio (UPCR) over time may enhance our ability to understand the association between changes in kidney parameters and cardiovascular disease risk. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Annual visit data from 2,438 participants in the Chronic Renal Insufficiency Cohort (CRIC). EXPOSURES: Average and slope of eGFR and UPCR in time-updated, 1-year exposure windows. OUTCOMES: Incident heart failure, atherosclerotic cardiovascular disease events, death, and a composite of incident heart failure, atherosclerotic cardiovascular disease events, and death. ANALYTICAL APPROACH: A landmark analysis, a dynamic approach to survival modeling that leverages longitudinal, iterative profiles of laboratory and clinical information to assess the time-updated 3-year risk of adverse cardiovascular outcomes. RESULTS: Adjusting for baseline and time-updated covariates, every standard deviation lower mean eGFR (19mL/min/1.73m2) and declining slope of eGFR (8mL/min/1.73m2 per year) were independently associated with higher risks of heart failure (hazard ratios [HRs] of 1.82 [95% CI, 1.39-2.44] and 1.28 [95% CI, 1.12-1.45], respectively) and the composite outcome (HRs of 1.32 [95% CI, 1.11-1.54] and 1.11 [95% CI, 1.03-1.20], respectively). Every standard deviation higher mean UPCR (136mg/g) and increasing UPCR (240mg/g per year) were also independently associated with higher risks of heart failure (HRs of 1.58 [95% CI, 1.28-1.97] and 1.20 [95% CI, 1.10-1.29], respectively) and the composite outcome (HRs of 1.33 [95% CI, 1.17-1.50] and 1.12 [95% CI, 1.06-1.18], respectively). LIMITATIONS: Limited generalizability of annual eGFR and UPCR assessments; several biomarkers for cardiovascular disease risk were not available annually. CONCLUSIONS: Using the landmark approach to account for time-updated patterns of kidney function, average and slope of eGFR and proteinuria were independently associated with 3-year cardiovascular risk. Short-term changes in kidney function provide information about cardiovascular risk incremental to level of kidney function, representing possible opportunities for more effective management of patients with chronic kidney disease.

Ten-Year Risk-Prediction Equations for Incident Heart Failure Hospitalizations in Chronic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort Study and the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Heart failure (HF) is a leading contributor to cardiovascular morbidity and mortality in the population with chronic kidney disease (CKD). HF risk prediction tools that use readily available clinical parameters to risk-stratify individuals with CKD are needed. METHODS: We included Black and White participants aged 30-79 years with CKD stages 2-4 who were enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study and were without self-reported cardiovascular disease. We assessed model performance of the Pooled Cohort Equations to Prevent Heart Failure (PCP-HF) to predict incident hospitalizations due to HF and refit the PCP-HF in the population with CKD by using CRIC data-derived coefficients and survival from CRIC study participants in the CKD population (PCP-HFCKD). We investigated the improvement in HF prediction with inclusion of estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) into the PCP-HFCKD equations by change in C-statistic, net reclassification improvement (NRI), and integrated discrimination improvement index (IDI). We validated the PCP-HFCKD with and without eGFR and UACR in Multi-Ethnic Study of Atherosclerosis (MESA) participants with CKD. RESULTS: Among 2328 CRIC Study participants, 340 incident HF hospitalizations occurred over a mean follow-up of 9.5 years. The PCP-HF equations did not perform well in most participants with CKD and had inadequate discrimination and insufficient calibration (C-statistic 0.64-0.71, Greenwood-Nam-D'Agostino (GND) chi-square statistic P value < 0.05), with modest improvement and good calibration after being refit (PCP-HFCKD: C-statistic 0.61-0.78), GND chi-square statistic P value > 0.05). Addition of UACR, but not eGFR, to the refit PCP-HFCKD improved model performance in all race-sex groups (C-statistic [0.73-0.81], GND chi-square statistic P value > 0.05, delta C-statistic ranging from 0.03-0.11 and NRI and IDI P values < 0.01). External validation of the PCP-HFCKD in MESA demonstrated good discrimination and calibration. CONCLUSIONS: Routinely available clinical data that include UACR in patients with CKD can reliably identify individuals at risk of HF hospitalizations.

Sex Differences in Cardiovascular Outcomes in CKD: Findings From the CRIC Study.

RATIONALE & OBJECTIVE: Cardiovascular events are less common in women than men in general populations; however, studies in chronic kidney disease (CKD) are less conclusive. We evaluated sex-related differences in cardiovascular events and death in adults with CKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 1,778 women and 2,161 men enrolled in the Chronic Renal Insufficiency Cohort (CRIC). EXPOSURE: Sex (women vs men). OUTCOME: Atherosclerotic composite outcome (myocardial infarction, stroke, or peripheral artery disease), incident heart failure, cardiovascular death, and all-cause death. ANALYTICAL APPROACH: Cox proportional hazards regression. RESULTS: During a median follow-up period of 9.6 years, we observed 698 atherosclerotic events (women, 264; men, 434), 762 heart failure events (women, 331; men, 431), 435 cardiovascular deaths (women, 163; men, 274), and 1,158 deaths from any cause (women, 449; men, 709). In analyses adjusted for sociodemographic, clinical, and metabolic parameters, women had a lower risk of atherosclerotic events (HR, 0.71 [95% CI, 0.57-0.88]), heart failure (HR, 0.76 [95% CI, 0.62-0.93]), cardiovascular death (HR, 0.55 [95% CI, 0.42-0.72]), and death from any cause (HR, 0.58 [95% CI, 0.49-0.69]) compared with men. These associations remained statistically significant after adjusting for cardiac and inflammation biomarkers. LIMITATIONS: Assessment of sex hormones, which may play a role in cardiovascular risk, was not included. CONCLUSIONS: In a large, diverse cohort of adults with CKD, compared with men, women had lower risks of cardiovascular events, cardiovascular mortality, and mortality from any cause. These differences were not explained by measured cardiovascular risk factors.

Adiposity, Physical Function, and Their Associations With Insulin Resistance, Inflammation, and Adipokines in CKD.

RATIONALE & OBJECTIVES: Adiposity and physical fitness levels are major drivers of cardiometabolic risk, but these relationships have not been well-characterized in chronic kidney disease (CKD). We examined the associations of visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), intrahepatic fat, and physical function with inflammation, insulin resistance, and adipokine levels in patients with CKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Participants with stages 3-5 CKD not receiving maintenance dialysis, followed up at one of 8 clinical sites in the Chronic Renal Insufficiency Cohort (CRIC) Study, and who underwent magnetic resonance imaging of the abdomen at an annual CRIC Study visit (n = 419). PREDICTORS: VAT volume, SAT volume, intrahepatic fat, body mass index, waist circumference, and time taken to complete the 400-m walk test (physical function). OUTCOMES: Markers of inflammation (interleukin 1ß [IL-1ß], IL-6, tumor necrosis factor receptor 1 [TNFR1], and TNFR2), insulin resistance (homeostasis model assessment of insulin resistance), and adipokine levels (adiponectin, total and high molecular weight, resistin, and leptin). ANALYTICAL APPROACH: Multivariable linear regression of VAT and SAT volume, intrahepatic fat, and physical function with individual markers (log-transformed values), adjusting for relevant covariates. RESULTS: Mean age of the study population was 64.3 years; 41% were women, and mean estimated glomerular filtration rate was 53.2±14.6 (SD) mL/min/1.73m2. More than 85% were overweight or obese, and 40% had diabetes. Higher VAT volume, SAT volume, and liver proton density fat fraction were associated with lower levels of total and high-molecular-weight adiponectin, higher levels of leptin and insulin resistance, and lower high-density lipoprotein cholesterol and higher serum triglyceride levels. A slower 400-m walk time was associated only with higher levels of leptin, total adiponectin, plasma IL-6, and TNFR1 and did not modify the associations between fat measures and cardiometabolic risk factors. LIMITATIONS: Lack of longitudinal data and dietary details. CONCLUSIONS: Various measures of adiposity are associated with cardiometabolic risk factors. Physical function was also associated with the cardiometabolic risk factors studied and does not modify associations between fat measures and cardiometabolic risk factors. Longitudinal studies of the relationship between body fat and aerobic fitness with cardiovascular and kidney disease progression are warranted.

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

RATIONALE & OBJECTIVE: Current dietary guidelines recommend that patients with chronic kidney disease (CKD) restrict individual nutrients, such as sodium, potassium, phosphorus, and protein. This approach can be difficult for patients to implement and ignores important nutrient interactions. Dietary patterns are an alternative method to intervene on diet. Our objective was to define the associations of 4 healthy dietary patterns with risk for CKD progression and all-cause mortality among people with CKD. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 2,403 participants aged 21 to 74 years with estimated glomerular filtration rates of 20 to 70mL/min/1.73m2 and dietary data in the Chronic Renal Insufficiency Cohort (CRIC) Study. EXPOSURES: Healthy Eating Index-2015, Alternative Healthy Eating Index-2010, alternate Mediterranean diet (aMed), and Dietary Approaches to Stop Hypertension (DASH) diet scores were calculated from food frequency questionnaires. OUTCOMES: (1) CKD progression defined as≥50% estimated glomerular filtration rate decline, kidney transplantation, or dialysis and (2) all-cause mortality. ANALYTICAL APPROACH: Cox proportional hazards regression models adjusted for demographic, lifestyle, and clinical covariates to estimate hazard ratios (HRs) and 95% CIs. RESULTS: There were 855 cases of CKD progression and 773 deaths during a maximum of 14 years. Compared with participants with the lowest adherence, the most highly adherent tertile of Alternative Healthy Eating Index-2010, aMed, and DASH had lower adjusted risk for CKD progression, with the strongest results for aMed (HR, 0.75; 95% CI, 0.62-0.90). Compared with participants with the lowest adherence, the highest adherence tertiles for all scores had lower adjusted risk for all-cause mortality for each index (24%-31% lower risk). LIMITATIONS: Self-reported dietary intake. CONCLUSIONS: Greater adherence to several healthy dietary patterns is associated with lower risk for CKD progression and all-cause mortality among people with CKD. Guidance to adopt healthy dietary patterns can be considered as a strategy for managing CKD.

Novel Risk Factors for Progression of Diabetic and Nondiabetic CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: Identification of novel risk factors for chronic kidney disease (CKD) progression may inform mechanistic investigations and improve identification of high-risk subgroups. The current study aimed to characterize CKD progression across levels of numerous risk factors and identify independent risk factors for CKD progression among those with and without diabetes. STUDY DESIGN: The Chronic Renal Insufficiency Cohort (CRIC) Study is a prospective cohort study of adults with CKD conducted at 7 US clinical centers. SETTING & PARTICIPANTS: Participants (N=3,379) had up to 12.3 years of follow-up; 47% had diabetes. PREDICTORS: 30 risk factors for CKD progression across sociodemographic, behavioral, clinical, and biochemical domains at baseline. OUTCOMES: Study outcomes were estimated glomerular filtration rate (eGFR) slope and the composite of halving of eGFR or initiation of kidney replacement therapy. ANALYTICAL APPROACH: Stepwise selection of independent risk factors was performed stratified by diabetes status using linear mixed-effects and Cox proportional hazards models. RESULTS: Among those without and with diabetes, respectively, mean eGFR slope was-1.4±3.3 and-2.7±4.7mL/min/1.73m2 per year. Among participants with diabetes, multivariable-adjusted hazard of the composite outcome was approximately 2-fold or greater with higher levels of the inflammatory chemokine CXCL12, the cardiac marker N-terminal pro-B-type natriuretic peptide (NT-proBNP), and the kidney injury marker urinary neutrophil gelatinase-associated lipocalin (NGAL). Among those without diabetes, low serum bicarbonate and higher high-sensitivity troponin T, NT-proBNP, and urinary NGAL levels were all significantly associated with a 1.5-fold or greater rate of the composite outcome. LIMITATIONS: The observational study design precludes causal inference. CONCLUSIONS: Strong associations for cardiac markers, plasma CXCL12, and urinary NGAL are comparable to that of systolic blood pressure≥140mm Hg, a well-established risk factor for CKD progression. This warrants further investigation into the potential mechanisms that these markers indicate and opportunities to use them to improve risk stratification.

Change in ankle-brachial index and mortality among individuals with chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort Study.

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

Prognostic Significance of Ambulatory BP Monitoring in CKD: A Report from the Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: Whether ambulatory BP monitoring is of value in evaluating risk for outcomes in patients with CKD is not clear. METHODS: We followed 1502 participants of the Chronic Renal Insufficiency Cohort (CRIC) Study for a mean of 6.72 years. We evaluated, as exposures, ambulatory BP monitoring profiles (masked uncontrolled hypertension, white-coat effect, sustained hypertension, and controlled BP), mean ambulatory BP monitoring and clinic BPs, and diurnal variation in BP-reverse dipper (higher at nighttime), nondipper, and dipper (lower at nighttime). Outcomes included cardiovascular disease (a composite of myocardial infarction, cerebrovascular accident, heart failure, and peripheral arterial disease), kidney disease (a composite of ESKD or halving of the eGFR), and mortality. RESULTS: Compared with having controlled BP, the presence of masked uncontrolled hypertension independently associated with higher risk of the cardiovascular outcome and the kidney outcome, but not with all-cause mortality. Higher mean 24-hour systolic BP associated with higher risk of cardiovascular outcome, kidney outcome, and mortality, independent of clinic BP. Participants with the reverse-dipper profile of diurnal BP variation were at higher risk of the kidney outcome. CONCLUSIONS: In this cohort of participants with CKD, BP metrics derived from ambulatory BP monitoring are associated with cardiovascular outcomes, kidney outcomes, and mortality, independent of clinic BP. Masked uncontrolled hypertension and mean 24-hour BP associated with high risk of cardiovascular disease and progression of kidney disease. Alterations of diurnal variation in BP are associated with high risk of progression of kidney disease, stroke, and peripheral arterial disease. These data support the wider use of ambulatory BP monitoring in the evaluation of hypertension in patients with CKD. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/JASN/2020_09_24_JASN2020030236.mp3.

Kidney Clearance of Secretory Solutes Is Associated with Progression of CKD: The CRIC Study.

BACKGROUND: The secretion of organic solutes by the proximal tubules is an essential intrinsic kidney function. However, the clinical significance of the kidney's clearance of tubular secretory solutes is uncertain. METHODS: In this prospective cohort study, we evaluated 3416 participants with CKD from the Chronic Renal Insufficiency Cohort (CRIC) study. We measured plasma and 24-hour urine concentrations of endogenous candidate secretory solutes at baseline, using targeted liquid chromatography-tandem mass spectrometry. The study defined CKD progression by a ≥50% decline in the eGFR, initiation of maintenance dialysis, or kidney transplantation. We used Cox proportional hazards regression to test associations of secretory-solute clearances with CKD progression and mortality, adjusting for eGFR, albuminuria, and other confounding characteristics. RESULTS: Participants in this ancillary study had a mean age of 58 years and 41% were black; the median eGFR was 43 ml/min per 1.73 m2. After adjustment, lower kidney clearances of six solutes-kynurenic acid, pyridoxic acid, indoxyl sulfate, xanthosine, isovalerylglycine, and cinnamoylglycine-were associated with significantly greater risks of CKD progression, with clearance of kynurenic acid, a highly protein-bound solute, having the strongest association. Lower clearances of isovalerylglycine, tiglylglycine, hippurate, and trimethyluric acid were significantly associated with all-cause mortality after adjustment. CONCLUSIONS: We found lower kidney clearances of endogenous secretory solutes to be associated with CKD progression and all-cause mortality, independent of eGFR and albuminuria. This suggests that tubular clearance of secretory solutes provides additional information about kidney health beyond measurements of glomerular function alone.