Search

Secretion of solutes by the proximal tubules represents an intrinsic kidney function not directly reflected by the glomerular filtration rate (GFR). The early loss of secretory clearance may reflect unrecognized kidney dysfunction, portending future disease progression.We designed a nested case-control study within the Jackson Heart Study (JHS), a prospective study of African American adults in Mississippi, to associate baseline differences in proximal tubular secretion of 5 endogenously produced solutes with future estimated glomerular rate (eGFR) decline. We matched 127 pairs by creatinine-eGFR, age, diabetes, and sex among the patients who provided a 24-hour urine collection; cases had a ≥25% decline in eGFR compared to 10% in controls over 10 years of follow-up. We measured baseline plasma and urine concentrations of secretory solutes using liquid chromatography-mass spectrometry to determine the odds ratio of kidney disease progression.Mean age was 60 years; 76% were women; 30% had diabetes; mean baseline eGFR was 94±20 ml/min per 1.73 mWe found that in this community-based study of adults without significant kidney disease, lower proximal tubular secretory solute clearance is associated with future eGFR decline.

BACKGROUND: Ceramides exhibit multiple biological activities that may influence the pathophysiology of heart failure. These activities may be influenced by the saturated fatty acid carried by the ceramide (Cer). However, the associations of different circulating Cer species, and their sphingomyelins (SM) precursors, with heart failure have received limited attention. METHODS AND RESULTS: We studied the associations of plasma Cer and SM species with incident heart failure in the Cardiovascular Health Study. We examined 8 species: Cer and SM with palmitic acid (Cer-16 and SM-16), species with arachidic acid (Cer-20 and SM-20), species with behenic acid (Cer-22 and SM-22) and species with lignoceric acid (Cer-24 and SM-24). During a median follow-up of 9.4 years, we identified 1179 cases of incident heart failure among 4249 study participants. In Cox regression analyses adjusted for risk factors, higher levels of Cer-16 and SM-16 were associated with higher risk of incident heart failure (Hazard ratio [HR] for one SD increase:1.25 [95% CI: 1.16–1.36] and 1.28 [1.18–1.40], respectively). In contrast, higher levels of Cer-22 were associated with lower risk of heart failure in multivariable analyses further adjusted for Cer-16 (HR: 0.85 [0.78–0.92]); and higher levels of SM-20, SM-22 and SM-24 were associated with lower risk of heart failure in analyses further adjusted for SM-16 (HRs: 0.83 [0.77–0.90], 0.81 [0.75–0.88], and 0.83 [0.77–0.90] respectively). No statistically significant interactions with age, sex, African American race, BMI or baseline coronary heart disease were detected. Similar associations were observed for heart failure with preserved (n=529) or reduced (n=348) ejection fraction. CONCLUSIONS: This study shows associations of higher plasma levels of Cer-16 and SM-16 with increased risk of heart failure and higher levels of Cer-22, SM-20, SM-22, and SM-24 with decreased risk of heart failure. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov; unique identifier: NCT00005133.

Context.— The goal of the College of American Pathologists Accuracy-Based Proficiency Testing Program is to promote the quality, standardization, and harmonization of clinical laboratory results through proficiency testing specimens that are free from matrix effects, have target values that are traceable to reference methods, and that probe the limitations of current methods. Objective.— To summarize the first 6 years of the Accuracy-Based Vitamin D Survey and highlight key insights from the data generated as it relates to assay performance. Design.— Accuracy-based challenges were created by using pooled human serum samples. Certain samples were derived from participants in an institutional review board–approved protocol in which vitamin D–deficient participants were treated with ergocalciferol (vitamin D2). Reference targets for the survey were set by the Centers for Disease Control and Prevention using isotope-dilution liquid chromatography–tandem mass spectrometry. Each method was compared with the reference method procedure over the course of the program (n = 43 proficiency testing samples). Results.— Linear regression versus the reference method procedure revealed proportional biases across the methods, ranging from 0.0% to 16.7%. Pearson correlation coefficients (r2) ranged from 0.902 to 0.996. Results were influenced by the concentration of 25-hydroxyvitamin D2 as well as the C-3 epimer of 25-hydroxyvitamin D3. During the 6 years, 2 manufacturers altered their assays to match the reference method procedure more closely. Conclusions.— There is considerable bias, both proportional bias and sample-specific matrix effects, affecting many assays. This ongoing accuracy-based proficiency testing program for vitamin D will provide the data needed for laboratories and manufacturers to improve their assays and thereby patient care.

High levels of fasting plasma insulin, reflecting insulin resistance, are an early event in the progression to type 2 diabetes. Experimental studies implicate ceramides in insulin resistance; however, whether circulating ceramides and related sphingolipids are associated with plasma insulin in humans is uncertain. We measured 15 ceramide and sphingomyelin species with different saturated fatty acids in baseline fasting plasma samples from the Strong Heart Family Study, a prospective cohort of American Indians. We examined associations of sphingolipids with plasma insulin, HOMA-IR and HOMA-B at baseline and follow-up (median 5 years later) using linear mixed models adjusted for family structure. Among 2086 participants without diabetes, higher levels of plasma ceramides carrying the fatty acids 16:0, 18:0, 20:0 or 22:0 were associated with higher plasma insulin and higher HOMA-IR at baseline and follow-up (Table). BMI modified associations of sphingomyelin species carrying 18:0, 20:0, 22:0 or 24:0 with insulin (p Table. Plasma Ceramides, Insulin and HOMAIR.SpeciesFold change in geometric mean with 2 fold higher ceramide (95% CI), p-valueBaseline insulinFollow-up insulinBaseline HOMAIRFollow-up HOMAIRCer-16:01.13 (1.07-1.20) 1.9x10-51.10 (1.01-1.21) 0.031.15 (1.08-1.22) 4.7x10-61.11 (1.01-1.22) 0.03Cer-18:01.11 (1.06-1.15) 1.0x10-61.12 (1.06-1.19) 1.0x10-51.12 (1.08-1.17) 6.3x10-81.13 (1.06-1.20) 2.0x10-4Cer-20:01.12 (1.07-1.17) 1.5x10-71.10 (1.03-1.18) 0.0031.13 (1.08-1.18) 1.3x10-71.11 (1.04-1.19) 0.002Cer-22:01.13 (1.08-1.19) 3.9x10-71.12 (1.04-1.20) 0.0041.15 (1.09-1.21) 1.0x10-71.13 (1.04-1.22) 0.004Cer-24:01.(0.99-1.11) 0.081.09 (1.01-1.19) 0.041.(1.00-1.13) 0.041.11 (1.01-1.21) 0.03Covariates: age, sex, site, education, smoking, log(BMI), waist, physical activity. Disclosure R.N. Lemaitre: None. C. Yu: None. A. Hoofnagle: Research Support; Self; Waters Corporation. H. Nair: None. P.N. Jensen: None. A.M. Fretts: None. J.G. Umans: None. C. Sitlani: None. D. Siscovick: None. I. King: None. N. Sotoodehnia: None. B. McKnight: None.

Introduction: Ceramides and sphingomyelins (sphingolipids) are circulating lipids involved in multiple physiological pathways relevant to heart failure (HF) and atrial fibrillation (AF), including apoptosis, oxidative stress, and inflammation. Experimental studies suggest that sphingolipids with different saturated fatty acids exhibit different biological activities, but their relationships with HF and AF are unknown. Hypothesis: Higher levels of plasma ceramide and sphingomyelin that contain the fatty acid 16:0 are associated with higher risks of HF and AF; and higher levels of ceramides and sphingomyelins that contain the fatty acid 20:0, 22:0 or 24:0 are associated with lower risks. Methods: We measured sphingolipids in the Cardiovascular Health Study (CHS) in plasma samples from 1994-95 (N=4026) or from 1992-93 (N=586). We assessed the separate associations of the levels of 8 sphingolipids with risks of incident HF and incident AF using Cox regression. A p-value threshold of 0.006 was used to account for multiple testing. Results: Among 4,612 participants, 1179 incident HF and 1198 incident AF occurred during >40,000 person-years of follow-up. In adjusted analyses, higher levels of Cer-16 (ceramide with 16:0) and SM-16 (sphingomyelin with 16:0) were associated with higher risk of incident HF, but not with risk of incident AF (Table). In contrast, higher levels of Cer-20, Cer-22 and Cer-24 were each associated with lower risk of AF, but not with risk of HF. Higher levels of SM-20, SM-22, and SM-24 tended to be associated with lower risks of AF and HF, with only the association of SM-20 with AF significant. Conclusions: Plasma levels of ceramide and sphingomyelin with 16:0 show different associations with HF and AF than species with 20:0, 22:0 or 24:0. Associations of Cer-16 and SM-16 specifically with higher risk of HF may be due to a role of apoptosis in HF. The novel findings that Cer-20, Cer-22, and Cer-24 are associated with lower risk of AF warrant further examination of the role of these sphingolipids in protecting from AF.