Candesartan cilexetil reduces chronic renal allograft injury in Fisher→Lewis rats

Objectives To determine the effects of the angiotensin II receptor antagonist, candesartan cilexetil, on glomerular and systemic blood pressures and the development of renal injury in Lewis rat recipients of a single Fisher kidney (F334 --> LEW transplantation), an established rat model of chronic renal allograft failure. Design Recent studies have shown that chronic injury of renal allografts in F334 --> LEW rats may be virtually abrogated by supplying the Lewis recipients with two Fisher kidneys or, alternatively, by retaining a native kidney. These findings imply a major contribution from processes associated with nephron loss to the pathogenesis of chronic renal allograft failure, a notion supported by the observation that transplanting two kidneys also normalizes glomerular capillary pressure (P-GC) in F344 --> LEW rats. Thus, a pharmacological reduction in P-GC, by blocking the effects of angiotensin II, should also lessen renal injury in F344 --> LEW rats. Materials and methods Bilaterally nephrectomized F344 --> LEW rats were treated with the angiotensin II receptor blocker candesartan cilexetil (TCV-116) at 40 mg/l or with vehicle, administered in drinking water. Proteinuria and systolic blood pressure were assessed monthly, and histological studies were carried out after 24 weeks. The glomerular filtration rate and glomerular pressures were determined after 10 weeks in additional rats by clearance and micropuncture studies. Results Treatment with candesartan cilexetil lowered systemic blood pressure, normalized P-GC at 10 weeks and greatly reduced proteinuria and allograft glomerulosclerosis at 24 weeks. Conclusions These data indicate that the development of renal injury in F344 --> LEW renal allografts can be prevented by the pharmacological blockade of angiotensin II receptors using candesartan cilexetil. This suggests that angiotensin-dependent processes contribute significantly to chronic injury in this model of late renal allograft failure. (C) Rapid Science Publishers.