Heart Failure-Type Symptom Score Trajectories in CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study

RATIONALE & OBJECTIVE: Quality of life in chronic kidney disease (CKD) is impaired by a large burden of symptoms including some that overlap with the symptoms of heart failure (HF). We studied a group of individuals with CKD to understand the patterns and trajectories of HF-type symptoms in this setting. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 3,044 participants in the Chronic Renal Insufficiency Cohort (CRIC) without prior diagnosis of HF. PREDICTORS: Sociodemographics, medical history, medications, vital signs, laboratory values, echocardiographic and electrocardiographic parameters. OUTCOME: Trajectory over 5.5 years of a HF-type symptom score (modified Kansas City Cardiomyopathy Questionnaire [KCCQ] Overall Summary Score with a range of 0-100 wheresymptoms). ANALYTICAL APPROACH: Latent class mixed models were used to model trajectories. Multinomial logistic regression was used to model relationships of predictors with trajectory group membership. RESULTS: Five trajectories of KCCQ score were identified in the cohort of 3,044 adults, 45% of whom were female, and whose median age was 61 years. Group 1 (41.7%) had a stable high score (minimal symptoms, average score of 96); groups 2 (35.6%) and 3 (15.6%) had stable but lower scores (mild symptoms [average of 81] and clinically significant symptoms [average of 52], respectively). Group 4 (4.9%) had a substantial worsening in symptoms over time (mean 31-point decline), and group 5 (2.2%) had a substantial improvement (mean 33-point increase) in KCCQ score. A majority of group 1 was male, without diabetes or obesity, and this group had higher baseline kidney function. A majority of groups 2 and 3 had diabetes and obesity. A majority of group 4 was male and had substantial proteinuria. Group 5 had the highest proportion of baseline cardiovascular disease (CVD). LIMITATIONS: No validation cohort available, CKD management changes in recent years may alter trajectories, and latent class models depend on the missing at random assumption. CONCLUSIONS: Distinct HF-type symptom burden trajectories were identified in the setting of CKD, corresponding to different baseline characteristics. These results highlight the diversity of HF-type symptom experiences in individuals with CKD

Clonal Hematopoiesis of Indeterminate Potential Is Associated With Reduced Risk of Cognitive Impairment in Patients With Chronic Kidney Disease

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

Glycolytic lactate in diabetic kidney disease.

Lactate elevation is a well-characterized biomarker of mitochondrial dysfunction, but its role in diabetic kidney disease (DKD) is not well defined. Urine lactate was measured in patients with type 2 diabetes (T2D) in 3 cohorts (HUNT3, SMART2D, CRIC). Urine and plasma lactate were measured during euglycemic and hyperglycemic clamps in participants with type 1 diabetes (T1D). Patients in the HUNT3 cohort with DKD had elevated urine lactate levels compared with age- and sex-matched controls. In patients in the SMART2D and CRIC cohorts, the third tertile of urine lactate/creatinine was associated with more rapid estimated glomerular filtration rate decline, relative to first tertile. Patients with T1D demonstrated a strong association between glucose and lactate in both plasma and urine. Glucose-stimulated lactate likely derives in part from proximal tubular cells, since lactate production was attenuated with sodium-glucose cotransporter-2 (SGLT2) inhibition in kidney sections and in SGLT2-deficient mice. Several glycolytic genes were elevated in human diabetic proximal tubules. Lactate levels above 2.5 mM potently inhibited mitochondrial oxidative phosphorylation in human proximal tubule (HK2) cells. We conclude that increased lactate production under diabetic conditions can contribute to mitochondrial dysfunction and become a feed-forward component to DKD pathogenesis

Whole-exome sequencing study identifies four novel gene loci associated with diabetic kidney disease

Diabetic kidney disease (DKD) is recognized as an important public health challenge. However, its genomic mechanisms are poorly understood. To identify rare variants for DKD, we conducted a whole-exome sequencing (WES) study leveraging large cohorts well-phenotyped for chronic kidney disease and diabetes. Our two-stage WES study included 4372 European and African ancestry participants from the Chronic Renal Insufficiency Cohort and Atherosclerosis Risk in Communities studies (stage 1) and 11 487 multi-ancestry Trans-Omics for Precision Medicine participants (stage 2). Generalized linear mixed models, which accounted for genetic relatedness and adjusted for age, sex and ancestry, were used to test associations between single variants and DKD. Gene-based aggregate rare variant analyses were conducted using an optimized sequence kernel association test implemented within our mixed model framework. We identified four novel exome-wide significant DKD-related loci through initiating diabetes. In single-variant analyses, participants carrying a rare, in-frame insertion in the DIS3L2 gene (rs141560952) exhibited a 193-fold increased odds [95% confidence interval (CI): 33.6, 1105] of DKD compared with noncarriers (P = 3.59 × 10-9). Likewise, each copy of a low-frequency KRT6B splice-site variant (rs425827) conferred a 5.31-fold higher odds (95% CI: 3.06, 9.21) of DKD (P = 2.72 × 10-9). Aggregate gene-based analyses further identified ERAP2 (P = 4.03 × 10-8) and NPEPPS (P = 1.51 × 10-7), which are both expressed in the kidney and implicated in renin-angiotensin-aldosterone system modulated immune response. In the largest WES study of DKD, we identified novel rare variant loci attaining exome-wide significance. These findings provide new insights into the molecular mechanisms underlying DKD

Prevalence and correlates of mitral annular calcification in adults with chronic kidney disease: Results from CRIC study.

BackgroundRisk factors for mitral annular calcification (MAC) and cardiovascular disease (CVD) demonstrate significant overlap in the general population. The aim of this paper is to determine whether there are independent relationships between MAC and demographics, traditional and novel CVD risk factors using cardiac CT in the Chronic Renal Insufficiency Cohort (CRIC) in a cross-sectional study.MethodsA sample of 2070 subjects underwent coronary calcium scanning during the CRIC study. Data were obtained for each participant at time of scan.Subjectswere dichotomized into the presence and absence of MAC. Differences in baseline demographic and transitional risk factor data were evaluated across groups. Covariates used in multivariable adjustment were age, gender, BMI, HDL, LDL, lipid lowering medications, smoking status, family history of heart attack, hypertension, diabetes mellitus, phosphate, PTH, albuminuria, and calcium.ResultsOur study consisted of 2070 subjects, of which 331 had MAC (prevalence of 16.0%). The mean MAC score was 511.98 (SD 1368.76). Age and white race remained independently associated with presence of MAC. Decreased GFR was also a risk factor. African American and Hispanic race, as well as former smoking status were protective against MAC. In multivariable adjusted analyses, the remaining covariates were not significantly associated with MAC. Among renal covariates, elevated phosphate was significant.ConclusionIn the CRIC population, presence of MAC was independently associated with age, Caucasian race, decreased GFR, and elevated phosphate. These results are suggested by mechanisms of dysregulation of inflammation, hormones, and electrolytes in subjects with renal disease

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

BackgroundPatients 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.MethodsForty 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.ResultsIn 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.ConclusionsSomaScan 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

The association between changes in echocardiography and risk of heart failure hospitalizations and death in adults with chronic kidney disease

Abstract Adults with chronic kidney disease (CKD) are at increased risk for developing heart failure (HF). However, longitudinal cardiac remodeling in CKD has not been well-characterized and its association with HF outcomes remains unknown. We evaluated the association between change in echocardiographic parameters between baseline and year 4 with the subsequent risk of HF hospitalization and death using Cox proportional hazard models in a landmark analysis of a prospective multicenter CKD cohort. Among 2673 participants, mean ± SD age was 61 ± 11 years, with 45% women, and 56% non-white. A total of 472 hospitalizations for HF and 776 deaths occurred during a median (interquartile range) follow-up duration of 8.0 (6.3–9.1) years. Patients hospitalized for HF experienced larger preceding absolute increases in left ventricular (LV) volumes and decreases in LV ejection fraction. Adverse changes in LV ejection fraction, LV cavity volume, LV mass index, and LV geometry were independently associated with an increased risk of HF hospitalization and death. Among adults with CKD, deleterious cardiac remodeling occurs over a relatively short timeframe and adverse remodeling is associated with increased risk of HF-related morbidity and mortality