Association of urine and plasma ADMA with atherosclerotic risk in DKD cardiovascular disease risk in diabetic kidney disease: findings from the Chronic Renal Insufficiency Cohort (CRIC) study.

BACKGROUND: Chronic kidney disease (CKD) is associated with atherosclerotic cardiovascular disease (ASCVD) risk, especially among those with diabetes. Altered metabolism of solutes that accumulate in CKD [asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and trimethylamine N-oxide (TMAO)] may reflect pathways linking CKD with ASCVD. METHODS: This case-cohort study included Chronic Renal Insufficiency Cohort participants with baseline diabetes, estimated glomerular filtration rate <60 mL/min/1.73 m2, and without prior history for each outcome. The primary outcome was incident ASCVD (time to first myocardial infarction, stroke or peripheral artery disease event) and secondary outcome was incident heart failure. The subcohort comprised randomly selected participants meeting entry criteria. Plasma and urine ADMA, SDMA and TMAO concentrations were determined by liquid chromatography-tandem mass spectrometry. Associations of uremic solute plasma concentrations and urinary fractional excretions with outcomes were evaluated by weighted multivariable Cox regression models, adjusted for confounding covariables. RESULTS: Higher plasma ADMA concentrations (per standard deviation) were associated with ASCVD risk [hazard ratio (HR) 1.30, 95% confidence interval (CI) 1.01-1.68]. Lower fractional excretion of ADMA (per standard deviation) was associated with ASCVD risk (HR 1.42, 95% CI 1.07-1.89). The lowest quartile of ADMA fractional excretion was associated with greater ASCVD risk (HR 2.25, 95% CI 1.08-4.69) compared with the highest quartile. Plasma SDMA and TMAO concentration and fractional excretion were not associated with ASCVD. Neither plasma nor fractional excretion of ADMA, SDMA and TMAO were associated with incident heart failure. CONCLUSION: These data suggest that decreased kidney excretion of ADMA leads to increased plasma concentrations and ASCVD risk.

Longitudinal Assessment of Vascular Function With Sunitinib in Patients With Metastatic Renal Cell Carcinoma.

BACKGROUND: Sunitinib, used widely in metastatic renal cell carcinoma, can result in hypertension, left ventricular dysfunction, and heart failure. However, the relationships between vascular function and cardiac dysfunction with sunitinib are poorly understood. METHODS AND RESULTS: In a multicenter prospective study of 84 metastatic renal cell carcinoma patients, echocardiography, arterial tonometry, and BNP (B-type natriuretic peptide) measures were performed at baseline and at 3.5, 15, and 33 weeks after sunitinib initiation, correlating with sunitinib cycles 1, 3, and 6. Mean change in vascular function parameters and 95% confidence intervals were calculated. Linear regression models were used to estimate associations between vascular function and left ventricular ejection fraction, longitudinal strain, diastolic function (E/e'), and BNP. After 3.5 weeks of sunitinib, mean systolic blood pressure increased by 9.5 mm Hg (95% confidence interval, 2.0-17.1; P=0.02) and diastolic blood pressure by 7.2 mm Hg (95% confidence interval, 4.3-10.0; P<0.001) across all participants. Sunitinib resulted in increases in large artery stiffness (carotid-femoral pulse wave velocity) and resistive load (total peripheral resistance and arterial elastance; all P<0.05) and changes in pulsatile load (total arterial compliance and wave reflection). There were no statistically significant associations between vascular function and systolic dysfunction (left ventricular ejection fraction and longitudinal strain). However, baseline total peripheral resistance, arterial elastance, and aortic impedance were associated with worsening diastolic function and filling pressures over time. CONCLUSIONS: In patients with metastatic renal cell carcinoma, sunitinib resulted in early, significant increases in blood pressure, arterial stiffness, and resistive and pulsatile load within 3.5 weeks of treatment. Baseline vascular function parameters were associated with worsening diastolic but not systolic function.

Risk factors for coronary artery calcium among patients with chronic kidney disease (from the Chronic Renal Insufficiency Cohort Study).

Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD). We examined the cross-sectional association between novel risk factors and coronary artery calcium (CAC) measured using electron beam computed tomography or multidetector computed tomography among 2,018 patients with CKD. Using the total Agatston scores, the participants were classified as having no (0), moderate (>0-100), or high (>100) CAC. After adjustment for age, gender, race, study sites, cigarette smoking, previous cardiovascular disease, hypertension, and diabetes, the use of lipid-lowering drugs, body mass index, waist circumference, and cystatin C, several novel risk factors were significantly associated with high CAC. For example, the odds ratios of high CAC associated with 1 SD greater level of risk factors were 1.20 (95% confidence interval 1.04 to 1.38) for serum calcium, 1.21 (95% confidence interval 1.04 to 1.41) for serum phosphate, 0.83 (95% confidence interval 0.71 to 0.97) for log (total parathyroid hormone), 1.21 (95% confidence interval 1.03 to 1.43) for log (homeostasis model assessment-insulin resistance), and 1.23 (95% confidence interval 1.04 to 1.45) for hemoglobin A1c. Additionally, the multivariate-adjusted odds ratio for 1 SD greater level of cystatin C was 1.31 (95% confidence interval 1.14 to 1.50). Serum high-sensitive C-reactive protein, interleukin-6, tumor necrosis factor-α, and homocysteine were not statistically significantly associated with high CAC. In conclusion, these data indicate that abnormal calcium and phosphate metabolism, insulin resistance, and declining kidney function are associated with the prevalence of high CAC, independent of the traditional risk factors in patients with CKD. Additional studies are warranted to examine the causal effect of these risk factors on CAC in patients with CKD.