SP268
DETRIMENTAL EFFECT OF RENIN ANGIOTENSIN BLOCKADE ON PROGRESSION OF CHRONIC KIDNEY DISEASE AT LATER STAGES: A MATTER OF DOSAGE ADJUSTMENT?

INTRODUCTION AND AIMS: The renoprotective effect of renin-angiotensin (RAS) blockers (angiotensin converting enzyme inhibitors and angiotensin receptor blockers) has been questioned in patients with advanced chronic kidney disease (CKD). Moreover, combination therapy (dual RAS blockade) can further accelerate renal function decline in some populations at risk. However, it is unknown whether this adverse outcome is due to a dose-dependent effect or it can be attributed more specifically to a drug interaction.This study aims to investigate if the rate of renal function decline in advanced CKD patients is associated to the doses of RAS blockers, and, if dual RAS blockade worsens renal function independently of major confounding factors.

METHODS: Retrospective, observational study in an incident cohort of adult patients with CKD stage 4 or 5 not on dialysis, treated with RAS blockers for at least 6 months prior to the study inclusion. Inclusion criteria were: having at least three consecutive measurements of estimated glomerular filtration rate (eGFR) in a follow-up period > 3 months. Decline in renal function was estimated as the slope of the individual linear regression line of eGFR over follow-up time. Equipotent doses of RAS blockers were normalized for a body weight of 70 kg or a body surface area of 1.73 m2 (END-RAS). For example, the END-RAS in a patient with a body weight of 70 kg receiving a daily dose of enalapril 20 mg or valsartan 160 mg was counted as 1, whereas if he/she received dual RAS blockade with both drugs the END-RAS was then of 2, and so on.Associations of END-RAS or dual RAS blockade with the rate of renal function decline were analysed by uni- or multivariate linear regression models, accounting for major confounding variables (demographic, co-morbidity, blood pressure, baseline eGFR, serum bicarbonate, proteinuria, and concurrent medication).

RESULTS: The study group consisted of 813 patients (mean age 64±14 years, 430 males) with a mean eGFR 14.9±4.2 ml/min/1,73 m2. 729 patients were on RAS blockade monotherapy and 84 on dual RAS blockade. Median END-RAS in the whole group was 0.91 (I.Q. ranges 0.69 - 1.20). Patients on dual RAS blockade had significantly higher END-RAS than the rest of study patients (1.52±0.49 vs. 0.93±0.44; p<0.0001). In univariate linear regression, END-RAS blockers were significantly correlated with eGFR decline (beta = -0.149; p<0.0001). Patients on dual RAS blockade showed a significantly faster decline of renal function than the rest of the study patients (-6.19±5.57 vs. -3.04±5.37 ml/min/1,73 m2/year, p<0.0001). By multivariate linear regression, while dual RAS blockade remained independent and significantly associated with faster renal function decline (beta = -0.099; p=0.003), END-RAS (normalized either for body weight or surface area) did not reach statistical significance.

CONCLUSIONS: END-RAS are significantly associated with the rate of renal function decline in advanced CKD patients. However, the detrimental effect of dual RAS blockade on CKD progression seems to be independent of END-RAS and other major confounding factors.