Intrarenal renin-angiotensin system activity is augmented after initiation of dialysis.

Abstract

Circulating renin-angiotensin system (RAS) activation is maintained after renal function has deteriorated. The activation of the intrarenal RAS plays a critical role in the pathophysiology of chronic kidney disease (CKD), independently of the circulating RAS. However, the activation of intrarenal RAS and the chymase-dependent pathway after initiation of dialysis has not been clarified. We recruited 19 CKD patients (10 without dialysis and 9 with dialysis) who underwent a heminephrectomy. Circulating RAS was investigated before nephrectomy. The levels of intrarenal RAS components and chymase-positive cells were investigated using radioimmunoassay or immunoblot analysis on samples collected from the removed kidney. Renal damage was evaluated by the extent of tubulointerstitial fibrosis. No significant differences in circulating RAS between nondialysis and dialysis patients were found. However, intrarenal angiotensin II (AngII) and the extent of tubulointerstitial fibrosis in dialysis patients were significantly increased when compared with nondialysis patients. Prorenin and angiotensin-converting enzyme (ACE) levels were dramatically decreased in accordance with renal dysfunction. On the other hand, chymase-positive cells and AngII type 1 receptor (AT1R) expression was significantly increased in dialysis patients when compared with nondialysis patients. In multiple linear regression analyses, there were significant positive and negative relationships between the extent of interstitial fibrosis and angiotensinogen (β=0.45, P=0.042) and prorenin levels (β=-0.85, P<0.01), respectively. In summary, a decrease in prorenin and ACE expression and an increase in chymase, angiotensinogen and AT1R expression in the kidney may augment the intrarenal RAS activation and be associated with renal damage, even after initiation of dialysis.