Background: Several cardiac biomarkers of cardiac stress, inflammation and fibrosis [N-terminal pro brain-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), growth differentiation factor 15 (GDF-15), and soluble ST2 (sST2)] have been associated with atherosclerotic disease (ASCVD) in the general population. We hypothesized that these cardiac biomarkers may also be associated with the ASCVD in patients with chronic kidney disease (CKD). Methods: We analyzed levels of NT-proBNP, hsTnT, GDF-15 and sST2 in a cohort of 2,732 participants with mild to moderate CKD from the CRIC study. Outcomes included incident ASCVD, defined as the first instance of myocardial infarction, stroke, or peripheral vascular disease. We used Cox proportional hazard models to the test the association of each cardiac biomarker with risk of incident ASCVD, adjusting for multiple possible covariates. Results: When modeled continuously (per SD increase in the log-transformed biomarker), NT-proBNP, hsTnT, GDF-15 and sST2 were significantly associated with incident ASCVD: [NT-proBNP HR 1.51 (95% CI 1.27, 1.81); hsTnT HR 1.61 (95% CI 1.38, 1.89); GDF-15 HR 1.44 (95% CI 1.20, 1.73); sST2 HR 1.19 (95% CI 1.04, 1.36)]. Conclusions: NT-proBNP, hsTnT, GDF-15, and sST2 were significantly associated with incident ASCVD in CKD. These associations may highlight specific mechanisms for the development of ASCVD in CKD.

Background Contemporary guidelines recommend using atherosclerotic cardiovascular disease screening tools to guide primary prevention. The performance of these scores is not well known in patients with moderate to advanced chronic kidney disease, particularly in combination with clinically available cardiac biomarkers including N‐terminal pro–brain‐type natriuretic peptide and high‐sensitivity troponin T (hsTnT). Methods and Results We studied 1027 participants from the Chronic Renal Insufficiency Cohort without self‐reported atherosclerotic cardiovascular disease who were not taking aspirin or statins at enrollment. Framingham Risk Score, Pooled Cohort Equation, N‐terminal pro–brain‐type natriuretic peptide, and hsTnT were measured at baseline. Outcomes included fatal and nonfatal myocardial infarction, stroke, and cardiac death. We calculated 10‐fold cross‐validated Harrell’s C‐indices for each risk score and cardiac biomarker alone and in combination. The C‐index (95% CI) for discrimination of atherosclerotic cardiovascular disease was 0.72 (0.67, 0.77) for the Framingham Risk Score, and 0.72 (0.67, 0.76) for the Pooled Cohort Equation. HsTnT had comparable discrimination to each risk score, and improved the discrimination of each (change in Framingham 0.029, 95% CI 0.003, 0.055; change in Pooled Cohort Equation 0.027, 95% CI 0.002, 0.052). N‐terminal pro–brain‐type natriuretic peptide had poorer discrimination than the risk scores and did not significantly improve their discrimination (change in Framingham 0.009, 95% CI −0.001, 0.018; change in Pooled Cohort Equation 0.011, 95% CI −0.001, 0.024). Conclusions The Framingham Risk Score and Pooled Cohort Equation demonstrated moderate discrimination for atherosclerotic cardiovascular disease in patients with chronic kidney disease. HsTnT, but not N‐terminal pro–brain‐type natriuretic peptide, improved their discrimination overall. Until chronic kidney disease–specific atherosclerotic cardiovascular disease risk scores can be developed, it may be worth considering how to incorporate hsTnT into existing clinical risk scores.

Background Persons 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 >5 point decrease 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 6 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 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.

Background Patients with chronic kidney disease (CKD) have dysfunctional high-density lipoprotein (HDL) particles as compared with the general population. Understanding the lipid composition of HDL may provide mechanistic insight. We tested associations of estimated glomerular filtration rate (eGFR) and albuminuria with relative HDL abundance of ceramides, sphingomyelins, and phosphatidylcholines in participants with CKD. Methods We studied 490 participants with CKD from the Seattle Kidney Study. HDL was isolated from plasma; targeted lipidomics was used to quantify the relative abundance of ceramides, sphingomyelins, and phosphatidylcholines per 10 µg of total HDL protein. We evaluated the associations of eGFR and albuminuria with levels of individual lipids and lipid classes (including 7 ceramides, 6 sphingomyelins, and 24 phosphatidylcholines) using multivariable linear regression, controlling for multiple comparisons via the false discovery rate. Results The mean (SD) eGFR was 45 (24) mL/min/1.73 m2; the median (IQR[interquartile range]) albuminuria was 108 (16, 686) mg/g (12.2 [1.8, 77.6] mg/mmol) urine creatinine. After adjusting for demographics, past medical history, laboratory values, and medication use, eGFR was not associated with higher relative abundance of any class of lipids or individual lipids. Greater albuminuria was significantly associated with a higher relative abundance of total ceramides and moderate–long R-chain sphingomyelins, ceramides 22:0 and 24:1, hexosylceramide 16:0, sphingomyelin 16:0, and phosphatidylcholines 29:0, 30:1, and 38:2; the strongest association was for hexosylceramide 16:0 (increase per doubling of urine albumin to creatinine ratio 0.022 (95% CI, 0.012–0.032). Conclusions Greater albuminuria was significantly associated with specific alterations in the lipid composition of HDL in participants with CKD.

This is an Early Access article. Please select the PDF button, above, to view it. Be sure to also read the PRO: 10.34067/KID.0000022021 and the COMMENTARY: 10.34067/KID.0001372021