Abstract:
Background: Chronic kidney disease (CKD) is globally one of the leading causes of disease burden. Risk of death from cardiovascular disease was twice as high in CKD as non-CKD patients. Thus, knowing its risk and prognostic factors should help to identify patients at risk, and establish effective strategies for prevention of CKD occurrence. Therefore, CKD progression can be properly managed. A series of three studies were conducted to address these issues. Objectives: 1) To compare efficacy of renin angiotensin system (RAS) blockers with other active drugs or placebo with respect to end-stage renal disease (ESRD), doubling of serum creatinine, macro-albuminuria, micro-albuminuria, and promotion of albuminuria regression in type 2 diabetic subjects. 2) To determine the median time of changing glomerular filtration rate (GFR) categories and probability of kidney failure (KF)/death separately in diabetic and non-diabetic subjects. 3) To assess the role of small solute clearance index (rKt/V, tKt/V, and tCrcl) on death in continuous ambulatory peritoneal dialysis (CAPD) patients. Methods: For the first objective, a systematic review and network meta-analysis of randomized controlled trials was performed to evaluate the reno-protective effects of RAS blockers. Randomized controlled trials were identified from Medline and Embase up to April 2011. Data were independently extracted by two reviewers. A random effect model was applied to pool treatment effects. For the second objective, a population-based retrospective cohort of CKD progression was conducted using community-health screening, hospitals, and death registry data in Ubon Ratchathani province from 1997-2011. A competing risk model was applied to estimate the probability of KF and median time for CKD progression. For the last objective, a retrospective cohort study of patients receiving CAPD was conducted during 2008 and 2011. A receiver operating characteristic curve was applied to calibrate the cutoffs of rKt/V, tKt/V, and tCrcl. Kaplan-Meier and time-varying covariate cox-regression were applied to estimate overall death and prognosis. Results: For efficacy of RAS blockers, a network meta-analysis detected significant treatment effects across all outcomes, i.e., 62% significantly lower risk of ESRD (pooled risk ratio (RR)=0.38, 95% CI: 0.31, 0.47); 77% significantly lower risk of serum creatinine doubling (pooled RR=0.23, 95% CI: 0.09, 0.57); 39% significantly lower risk of macro-albuminuria (pooled RR=0.61, 95% CI: 0.47, 0.77); 39% significantly lower risk of micro-albuminuria (pooled RR=0.61, 95% CI: 0.45, 0.83) when compared to other anti-hypertensive drugs; and 16% more likely to promote regression of albuminuria when compared to dihydropyridine calcium channel blockers (d-CCB). For CKD progression, diabetic subjects progressed more rapidly through GFR categories with the median times for CKD progression from GFR categories G1 to G2, G2 to G3a, G3a to G3b, G3b to G4, and G4 to G5 of 4.4, 6.1, 4.9, 6.3, and 9.0 years, respectively. Non-diabetic subjects had the corresponding median time of 9.4, 14.0, 11.0, 13.8, and >14.3 years. Diabetic subjects were 49% (case-specific hazard ratio (HR)=1.49, 95% CI: 1.37, 1.42) more likely to develop KF than non-diabetic subjects. For CAPD, the rKt/V and tKt/V cutoffs were 0.25 and 1.75, respectively. The risks of death for those above these cutoffs were 57% (HR=0.43, 95% CI: 0.31, 0.60), and 29% (HR=0.71, 95% CI: 0.52, 0.98) lower for rKt/V and tKt/V, respectively. Conclusion: We have demonstrated the specific reno-protective effects of RAS blockers in real clinical outcomes, i.e., ESRD & doubling of serum creatinine in type 2 diabetic subjects compared with other anti-hypertensive drugs and placebo using a network meta-analysis. CKD progression from less advanced GFR categories to KF was twice as rapid in diabetic as non-diabetic subjects. We have calibrated the cutoffs of rKt/V and tKt/V which could be used to predict prognosis in CAPD patients.