Elevated fibroblast growth factor 23 (FGF23) is associated with cardiovascular disease in patients with chronic kidney disease. As a potential mediating mechanism, FGF23 induces left ventricular hypertrophy; however, its role in arterial calcification is less clear. In order to study this we quantified coronary artery and thoracic aorta calcium by computed tomography in 1501 patients from the Chronic Renal Insufficiency Cohort (CRIC) study within a median of 376 days (interquartile range 331 to 420 days) of baseline. Baseline plasma FGF23 was not associated with prevalence or severity of coronary artery calcium after multivariable adjustment. In contrast, higher serum phosphate levels were associated with prevalence and severity of coronary artery calcium, even after adjustment for FGF23. Neither FGF23 nor serum phosphate were consistently associated with thoracic aorta calcium. We could not detect mRNA expression of FGF23 or its co-receptor, klotho, in human or mouse vascular smooth muscle cells, or normal or calcified mouse aorta. Whereas elevated phosphate concentrations induced calcification in vitro, FGF23 had no effect on phosphate uptake or phosphate-induced calcification regardless of phosphate concentration or even in the presence of soluble klotho. Thus, in contrast to serum phosphate, FGF23 is not associated with arterial calcification and does not promote calcification experimentally. Hence, phosphate and FGF23 promote cardiovascular disease through distinct mechanisms.

Studies of hemodialysis patients have shown a U-shaped association between systolic blood pressure (SBP) and mortality. These studies have largely relied on dialysis-unit SBP measures and have not evaluated whether this U-shape also exists in advanced chronic kidney disease (CKD), prior to starting hemodialysis. We determined the association between SBP and mortality at advanced CKD and again after initiation of hemodialysis. This was a prospective study of Chronic Renal Insufficiency Cohort (CRIC) participants with advanced CKD followed through initiation of hemodialysis. We studied the association between SBP and mortality when participants: 1) had an estimated glomerular filtration rate <30 ml/min/1.73m2 (N=1,705); 2) initiated hemodialysis and had dialysis-unit SBP measures (N=403) and; 3) initiated hemodialysis and had out-of-dialysis-unit SBP measured at a CRIC study visit (N=326). Cox models adjusted for demographics, cardiovascular risk factors and dialysis parameters. A quadratic term for SBP was included to test for a U-shaped association. At advanced CKD, there was no association between SBP and mortality (HR 1.02 [95% CI: 0.98–1.07] per every 10 mm Hg increase). Among participants who started hemodialysis, a U-shaped association between dialysis-unit SBP and mortality was observed. In contrast, there was a linear association between out-of-dialysis-unit SBP and mortality (HR 1.26 [95% CI: 1.14–1.40] per every 10 mm Hg increase). In conclusion, more efforts should be made to obtain out-of-dialysis-unit SBP which may merit more consideration as a target for clinical management and in interventional trials.

BackgroundCardiac troponin T is independently associated with cardiovascular events and mortality in patients with chronic kidney disease (CKD). Serum levels of high sensitivity cardiac troponin T (hs-TnT) reflect subclinical myocardial injury in ambulatory patients. We sought to determine the distribution and predictors of hs-TnT in CKD patients without overt cardiovascular disease (CVD).MethodsWe studied 2464 participants within the multi-ethnic Chronic Renal Insufficiency Cohort (CRIC) who did not have self-reported CVD. We considered renal and non-renal factors as potential determinants of hs-TnT, including demographics, comorbidities, left ventricular (LV) mass, serologic factors, estimated glomerular filtration rate (eGFR) and albumin to creatinine ratio.ResultsHs-TnT was detectable in 81% of subjects, and the median (IQR) hs-TnT was 9.4 pg/ml (4.3-18.3). Analysis was performed using Tobit regression, adjusting for renal and non-renal factors. After adjustment, lower eGFR was associated with higher expected hs-TnT; participants with eGFR < 30 ml/min/1.73 m2 had 3-fold higher expected hs-TnT compared to subjects with eGFR > 60. Older age, male gender, black race, LV mass, diabetes and higher blood pressure all had strong, independent associations with higher expected hs-TnT.ConclusionsKnowledge of the determinants of hs-TnT in this cohort may guide further research on the pathology of heart disease in patients with CKD and help to stratify sub-groups of CKD patients at higher cardiovascular risk.

Background Blood pressure (BP) is often inadequately controlled in patients with chronic kidney disease (CKD). Previous reports of the longitudinal association between achieved level of BP and end-stage renal disease (ESRD) have not incorporated time-updated BP with appropriate adjustment for known confounders. Objective To assess the association between baseline and time-updated systolic BP (SBP) with the progression of CKD. Design Observational, prospective cohort study (ClinicalTrials.gov identifier: NCT00304148) Setting Seven US clinical centers Patients Participants of the Chronic Renal Insufficiency Cohort (CRIC) Study (N=3,708) followed for a median (25th, 75th percentiles) of 5.7 (4.6, 6.7) years Measurements The mean of three seated SBP measurements were used as the visit-specific SBP. SBP was time-updated as the mean of that visit and all prior visits. Outcomes were ESRD and the composite renal endpoint of ESRD (dialysis or transplantation) or halving of the estimated glomerular filtration rate (eGFR). Analyses investigating baseline and time-updated SBP utilized traditional Cox proportional hazards models and marginal structural models, respectively. Results SBP was ≥130 mmHg at all study visits in 19.2% of participants, and ≥140 mmHg in 10.6%. The hazard ratio (95% confidence interval) for ESRD among participants with SBP 130–139 mmHg, compared to SBP <120 mmHg, was 1.46 (1.13–1.88) using only baseline data, and was 2.37 (1.48–3.80) using all available time-updated data. Among those with SBP ≥140 mmHg, corresponding hazard ratios were 1.46 (1.18–1.88) and 3.37 (2.26–5.03), respectively. Limitations SBP was measured once annually, and the CRIC Study cohort is not a random sample. Conclusions Among participants in the CRIC Study, time-updated SBP over 130 mmHg was more strongly associated with progression of CKD than analyses based on baseline SBP. Funding The CRIC Study is funded under cooperative agreements from the National Institute of Diabetes and Digestive and Kidney Diseases, Clinical Translational Science Awards, and other NIH grants.