Association of relative telomere length with progression of chronic kidney disease in two cohorts: effect modification by smoking and diabetes.

Chronic kidney disease (CKD) is a highly progressive disease. We studied the association between relative telomere length (RTL) and CKD progression and tested whether this association is modified by smoking and diabetes mellitus. RTL was measured by qPCR in two prospective cohort studies, the MMKD-Study (n = 166) and the CRISIS-Study (n = 889) with a median follow-up of 4.5 and 2.8 years, respectively. Progression was defined as doubling of baseline serum creatinine (MMKD-Study) and/or end stage renal disease (both studies). 59 and 105 of the patients from MMKD and CRISIS experienced a progression of CKD. Mean standardized pooled RTL was 0.74 ± 0.29. In the meta-analysis shorter RTL at baseline showed a borderline association with CKD progression (HR = 1.07 [95%CI 1.00-1.15]; p = 0.06). We observed an effect modification of RTL and CKD progression by smoking and diabetes (p-values of interaction p = 0.02 and p = 0.09, respectively). Each 0.1 unit shorter RTL was significantly associated with an increased hazard for CKD progression in active-smokers by 44% (HR = 1.44 [1.16-1.81]; p = 0.001) and in patients with diabetes mellitus by 16% (HR = 1.16 [1.01-1.34]; p = 0.03). Estimates were adjusted for baseline age, sex, proteinuria and GFR. This study in two independent cohorts reinforces that RTL is a marker and potentially a pathogenetic factor for CKD progression.

Factors associated with kidney disease progression and mortality in a referred CKD population.

BACKGROUND: Knowing how kidney disease progresses is important for decision making in patients with chronic kidney disease (CKD) and for designing clinical services. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: We examined renal function trajectories in CRISIS (Chronic Renal Insufficiency Standards Implementation Study), in which 1,325 patients with CKD stages 3-5 and mean age of 65.1 years were followed up prospectively for a median of 26 months after referral to a regional nephrology center in the United Kingdom. By protocol, estimated glomerular filtration rate was determined every 12 months. PREDICTORS: CKD stage defined as estimated glomerular filtration rate ≥ 45 (stage 3a), 30-44 (3b), 15-29 (4), and < 15 (5) mL/min/1.73 m². OUTCOMES: Onset of renal replacement therapy (RRT), death, the composite end point of RRT or death, or decreasing CKD stage. RESULTS: During a median follow-up of 26 months, 13% reached the end point of RRT (5.1 events/100 patient-years), 20% died (9.6 deaths/100 patient-years), and 33% reached the combined end point of RRT or death (14.7 events/100 patient-years). For stage 3a, baseline prevalence and annual probabilities of decreasing CKD stage, RRT, and death were 18.0%, 0.41, 0.01, and 0.02, respectively. Corresponding values for stage 3b were 32.5%, 0.22, < 0.01, and 0.06; for stage 4, 36.5%, 0.17, 0.03, and 0.10; and for stage 5, 13.2%, zero (by definition), 0.31, and 0.08, respectively. Markov model projections suggested a steady decrease for proportions with stages 3a, 3b, and 4; a steady increase for death and RRT; and a biphasic pattern for (non-RRT) stage 5, with a plateau in the first 2 years followed by a steady decrease. LIMITATIONS: Single-center observational study. CONCLUSION: This study suggests that death and RRT are the dominant outcomes in patients referred for management of CKD and that most patients spend comparatively little time in late stages without RRT.

Serum phosphate and mortality in patients with chronic kidney disease.

BACKGROUND AND OBJECTIVES: Higher phosphate is associated with mortality in dialysis patients but few prospective studies assess this in nondialysis patients managed in an outpatient nephrology clinic. This prospective longitudinal study examined whether phosphate level was associated with death in a referred population. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: Patients (1203) of nondialysis chronic kidney disease (CKD) in the Chronic Renal Insufficiency Standards Implementation Study were assessed. Survival analyses were performed for quartiles of baseline phosphate relative to GFR, 12-month time-averaged phosphate, and baseline phosphate according to published phosphate targets. RESULTS: Mean (SD) eGFR was 32 (15) ml/min per 1.73 m(2), age 64 (14) years, and phosphate 1.2 (0.30) mmol/L. Cox multivariate adjusted regression in CKD stages 3 to 4 patients showed an increased risk of all-cause and cardiovascular mortality in the highest quartile compared with that in the lowest quartile of phosphate. No association was found in CKD stage 5 patients. Patients who had values above recommended targets for phosphate control had increased risk of all-cause and cardiovascular death compared with patients below target. The highest quartile compared with the lowest quartile of 12-month time-averaged phosphate was associated with an increased risk of mortality. CONCLUSIONS: In CKD stages 3 to 4 patients, higher phosphate was associated with a stepwise increase in mortality. As phosphate levels below published targets (as opposed to within them) are associated with better survival, guidelines for phosphate in nondialysis CKD patients should be re-examined. Intervention trials are required to determine whether lowering phosphate will improve survival.

Factors associated with vascular stiffness: cross-sectional analysis from the Chronic Renal Insufficiency Standards Implementation Study.

BACKGROUND: Vascular stiffness is associated with increased cardiovascular risk. This study aimed to identify factors associated with vascular stiffness in a cohort of chronic kidney disease (CKD) patients. METHODS: The Chronic Renal Insufficiency Standards Implementation Study is a prospective epidemiological study of CKD patients not on dialysis, who are managed in a clinic setting. Phenotypic parameters were collected annually, and vascular stiffness was assessed using augmentation index (AI). Cross-sectional analysis was performed across quintiles of AI to evaluate factors associated with vascular stiffness. RESULTS: Mean patient age was 66.1 +/- 14.1 years and estimated glomerular filtration rate (eGFR) was 31.2 +/- 5.7 ml/min. Corrected calcium was 2.26 +/- 0.2 SD mmol/l, phosphate 1.2 +/- 0.4 SD mmol/l and intact parathyroid hormone 94 +/- 96 SD pg/ml; 18.3% of patients had cardiovascular disease. Increased age and systolic blood pressure were associated with increased AI (all p < 0.001). No statistical association was present between AI and eGFR, intact parathyroid hormone, phosphate or protein excretion. CONCLUSION: This study identified blood pressure as a potentially modifiable risk factor associated with AI, whereas eGFR was not associated with increased AI in a population of CKD stage 3-5 patients. Further knowledge of factors which influence progression of vascular stiffness will be important in risk quantification and management.