High-Density Lipoprotein Lipidomics in Chronic Kidney Disease.

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.

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.

Circulating Sphingolipids and All-Cause Mortality: The Strong Heart Family Study.

BACKGROUND: A growing body of research indicates that associations of ceramides and sphingomyelins with mortality depend on the chain length of the fatty acid acylated to the backbone sphingoid base. We examined associations of 8 ceramide and sphingomyelin species with mortality among an American Indian population. METHODS AND RESULTS: The analysis comprised 2688 participants from the SHFS (Strong Heart Family Study). Plasma ceramide and sphingomyelin species carrying long-chain (ie, 16:0) and very-long-chain (ie, 20:0, 22:0, 24:0) saturated fatty acids were measured by sequential liquid chromatography and mass spectroscopy using samples from 2001 to 2003. Participants were followed for 18.8 years (2001-2020). Associations of ceramides and sphingomyelins with mortality were assessed using Cox models. The mean age of participants was 40.8 years. There were 574 deaths during a median 17.4-year follow-up. Ceramides and sphingomyelins carrying fatty acid 16:0 were positively associated with mortality. Ceramides and sphingomyelins carrying longer fatty acids were inversely associated with mortality. Per SD difference in each ceramide and sphingomyelin species, hazard ratios for death were: 1.68 (95% CI, 1.44-1.96) for ceramide-16 (Cer-16), 0.82 (95% CI, 0.71-0.95) for Cer-20, 0.60 (95% CI, 0.51-0.70) for Cer-22, 0.67 (95% CI, 0.56-0.79) for Cer-24, 1.80 (95% CI-1.57, 2.05) for sphingomyelin-16 (SM-16), 0.54 (95% CI, 0.47-0.62) for SM-20, 0.50 (95% CI, 0.44-0.57) for SM-22, and 0.59 (95% CI, 0.52-0.67) for SM-24. CONCLUSIONS: The direction/magnitude of associations of ceramides and sphingomyelins with mortality differs according to the length of the fatty acid acylated to the backbone sphingoid base. REGISTRATION: URL: https://www.clinicatrials.gov; Unique identifier: NCT00005134.

Evaluation of plasma sphingolipids as mediators of the relationship between kidney disease and cardiovascular events.

BACKGROUND: Sphingolipids are a family of circulating lipids with regulatory and signaling roles that are strongly associated with both eGFR and cardiovascular disease. Patients with chronic kidney disease (CKD) are at high risk for cardiovascular events, and have different plasma concentrations of certain plasma sphingolipids compared to patients with normal kidney function. We hypothesize that circulating sphingolipids partially mediate the associations between eGFR and cardiovascular events. METHODS: We measured the circulating concentrations of 8 sphingolipids, including 4 ceramides and 4 sphingomyelins with the fatty acids 16:0, 20:0, 22:0, and 24:0, in plasma from 3,463 participants in a population-based cohort (Cardiovascular Health Study) without prevalent cardiovascular disease. We tested the adjusted mediation effects by these sphingolipids of the associations between eGFR and incident cardiovascular disease via quasi-Bayesian Monte Carlo method with 2,000 simulations, using a Bonferroni correction for significance. FINDINGS: The mean (±SD) eGFR was 70 (±16) mL/min/1.73 m2; 62% of participants were women. Lower eGFR was associated with higher plasma ceramide-16:0 and sphingomyelin-16:0, and lower ceramides and sphingomyelins-20:0 and -22:0. Lower eGFR was associated with risk of incident heart failure and ischemic stroke, but not myocardial infarction. Five of eight sphingolipids partially mediated the association between eGFR and heart failure. The sphingolipids associated with the greatest proportion mediated were ceramide-16:0 (proportion mediated 13%, 95% CI 8-22%) and sphingomyelin-16:0 (proportion mediated 10%, 95% CI 5-17%). No sphingolipids mediated the association between eGFR and ischemic stroke. INTERPRETATION: Plasma sphingolipids partially mediated the association between lower eGFR and incident heart failure. Altered sphingolipids metabolism may be a novel mechanism for heart failure in patients with CKD. FUNDING: This study was supported by T32 DK007467 and a KidneyCure Ben J. Lipps Research Fellowship (Dr. Lidgard). Sphingolipid measurements were supported by R01 HL128575 (Dr. Lemaitre) and R01 HL111375 (Dr. Hoofnagle) from the National Heart, Lung, and Blood Institute (NHLBI).

High-Density Lipoprotein Lipidomics and Mortality in CKD.

Rationale & Objective: Patients with chronic kidney disease (CKD) have dysfunctional high-density lipoprotein (HDL) particles that lack cardioprotective properties; altered lipid composition may be associated with these changes. To investigate HDL lipids as potential cardiovascular risk factors in CKD, we tested the associations of HDL ceramides, sphingomyelins, and phosphatidylcholines with mortality. Study Design: We leveraged data from a longitudinal prospective cohort of participants with CKD. Setting & Participants: We included participants aged greater than 21 years with CKD, excluding those on maintenance dialysis or with prior kidney transplant. Exposure: HDL particles were isolated using density gradient ultracentrifugation. We quantified the relative abundance of HDL ceramides, sphingomyelins, and phosphatidylcholines via liquid chromatography tandem mass spectrometry (LC-MS/MS). Outcomes: Our primary outcome was all-cause mortality. Analytical Approach: We tested associations using Cox regressions adjusted for demographics, comorbid conditions, laboratory values, medication use, and highly correlated lipids with opposed effects, controlling for multiple comparisons with false discovery rates (FDR). Results: There were 168 deaths over a median follow-up of 6.12 years (interquartile range, 3.71-9.32). After adjustment, relative abundance of HDL ceramides (HR, 1.22 per standard deviation; 95% CI, 1.06-1.39), sphingomyelins with long fatty acids (HR, 1.44; 95% CI, 1.05-1.98), and saturated and monounsaturated phosphatidylcholines (HR, 1.22; 95% CI, 1.06-1.41) were significantly associated with increased risk of all-cause mortality (FDR < 5%). Limitations: We were unable to test associations with cardiovascular disease given limited power. HDL lipidomics may not reflect plasma lipidomics. LC-MS/MS is unable to differentiate between glucosylceramides and galactosylceramides. The cohort was comprised of research volunteers in the Seattle area with CKD. Conclusions: Greater relative HDL abundance of 3 classes of lipids was associated with higher risk of all-cause mortality in CKD; sphingomyelins with very long fatty acids were associated with a lower risk. Altered lipid composition of HDL particles may be a novel cardiovascular risk factor in CKD. Plain-Language Summary: Patients with chronic kidney disease have abnormal high-density lipoprotein (HDL) particles that lack the beneficial properties associated with these particles in patients with normal kidney function. To investigate if small lipid molecules found on the surface of HDL might be associated with these changes, we tested the associations of lipid molecules found on HDL with death among patients with chronic kidney disease. We found that several lipid molecules found on the surface of HDL were associated with increased risk of death among these patients. These findings suggest that lipid molecules may be risk factors for death among patients with chronic kidney disease.

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

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

Randomized crossover clinical trial of coenzyme Q10 and nicotinamide riboside in chronic kidney disease.

BackgroundCurrent studies suggest mitochondrial dysfunction is a major contributor to impaired physical performance and exercise intolerance in chronic kidney disease (CKD). We conducted a clinical trial of coenzyme Q10 (CoQ10) and nicotinamide riboside (NR) to determine their impact on exercise tolerance and metabolic profile in patients with CKD.MethodsWe conducted a randomized, placebo-controlled, double-blind, crossover trial comparing CoQ10, NR, and placebo in 25 patients with an estimated glomerular filtration rate (eGFR) of less than 60mL/min/1.73 m2. Participants received NR (1,000 mg/day), CoQ10 (1,200 mg/day), or placebo for 6 weeks each. The primary outcomes were aerobic capacity measured by peak rate of oxygen consumption (VO2 peak) and work efficiency measured using graded cycle ergometry testing. We performed semitargeted plasma metabolomics and lipidomics.ResultsParticipant mean age was 61.0 ± 11.6 years and mean eGFR was 36.9 ± 9.2 mL/min/1.73 m2. Compared with placebo, we found no differences in VO2 peak (P = 0.30, 0.17), total work (P = 0.47, 0.77), and total work efficiency (P = 0.46, 0.55) after NR or CoQ10 supplementation. NR decreased submaximal VO2 at 30 W (P = 0.03) and VO2 at 60 W (P = 0.07) compared with placebo. No changes in eGFR were observed after NR or CoQ10 treatment (P = 0.14, 0.88). CoQ10 increased free fatty acids and decreased complex medium- and long-chain triglycerides. NR supplementation significantly altered TCA cycle intermediates and glutamate that were involved in reactions that exclusively use NAD+ and NADP+ as cofactors. NR decreased a broad range of lipid groups including triglycerides and ceramides.ConclusionsSix weeks of treatment with NR or CoQ10 improved markers of systemic mitochondrial metabolism and lipid profiles but did not improve VO2 peak or total work efficiency.Trial registrationClinicalTrials.gov NCT03579693.FundingNational Institutes of Diabetes and Digestive and Kidney Diseases (grants R01 DK101509, R03 DK114502, R01 DK125794, and R01 DK101509).

Patient-Reported Symptoms and Subsequent Risk of Myocardial Infarction in Chronic Kidney Disease.

BACKGROUND AND OBJECTIVES: Although patient-reported symptoms often precede acute presentations of cardiovascular disease, patients with nondialysis-requiring CKD are less likely to have typical symptoms of atherosclerotic disease when presenting with acute myocardial infarction. However, the associations between typical atherosclerotic symptoms and subsequent risk of myocardial infarction are unknown in ambulatory patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: To determine whether typical atherosclerotic symptoms are associated with risk for subsequent myocardial infarction in people with CKD, we examined participants from the Chronic Renal Insufficiency Cohort Study. Chest pain, shortness of breath, and inability to climb stairs were evaluated annually using the Kidney Disease Quality of Life Instrument. Associations between categorical time-updated symptoms and physician-adjudicated incident myocardial infarction were assessed using Cox regression models. RESULTS: Among 3910 participants (mean age of 58±11 years; mean eGFR =44±15 ml/min per 1.73 m2), there were 476 incident myocardial infarctions over a median follow-up period of 10.4 years (interquartile range, 5.36-12.6 years). Median time from symptom assessment to incident myocardial infarction was 213 days (interquartile range, 111-333 days). Compared with no symptoms, mild, and moderate or worse, symptoms of chest pain (hazard ratio, 1.30; 95% confidence interval, 1.01 to 1.67; and hazard ratio, 1.70; 95% confidence interval, 1.27 to 2.27, respectively) and shortness of breath (hazard ratio, 1.37; 95% confidence interval, 1.10 to 1.70; and hazard ratio, 1.33; 95% confidence interval, 1.05 to 1.69, respectively) were significantly associated with greater risks for subsequent myocardial infarction. Participants reporting mild and severe limitations in climbing stairs (versus no limitation) had significantly higher adjusted risk of myocardial infarction (hazard ratio, 1.44; 95% confidence interval, 1.10 to 1.89; and hazard ratio, 1.89; 95% confidence interval, 1.44 to 2.49, respectively). CONCLUSIONS: In a large ambulatory cohort of adults with CKD, symptoms of atherosclerotic cardiovascular disease were strongly associated with a higher risk for subsequent myocardial infarction. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_03_17_CJN12080921.mp3.

Framingham and American College of Cardiology/American Heart Association Pooled Cohort Equations, High-Sensitivity Troponin T, and N-Terminal Pro-Brain-Type Natriuretic Peptide for Predicting Atherosclerotic Cardiovascular Events Across the Spectrum of Kidney Dysfunction.

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.

Cardiac Biomarkers and Risk of Atherosclerotic Cardiovascular Disease in Patients with CKD.

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 in the general population. We hypothesized that these cardiac biomarkers may also be associated with the atherosclerotic cardiovascular disease in patients with CKD. Methods: We analyzed levels of NT-proBNP, hsTnT, GDF-15, and sST2 in a cohort of 2732 participants with mild to moderate CKD from the Chronic Renal Insufficiency Cohort (CRIC) study. Outcomes included incident atherosclerotic disease, 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 atherosclerotic disease, adjusting for multiple possible confounders. Results: When modeled continuously (per SD increase in the log-transformed biomarker), NT-proBNP, hsTnT, GDF-15, and sST2 were significantly associated with incident atherosclerotic disease after adjustment for multiple potential confounders: (NT-proBNP HR, 1.51; 95% CI, 1.27 to 1.81; hsTnT HR, 1.61; 95% CI, 1.38 to 1.89; GDF-15 HR, 1.44; 95% CI, 1.19 to 1.73; and sST2 HR, 1.19; 95% CI, 1.04 to 1.36). Conclusions: NT-proBNP, hsTnT, GDF-15, and sST2 were significantly associated with incident atherosclerotic cardiovascular disease in patients with CKD. These associations may highlight important mechanisms for the development of atherosclerotic disease in CKD.