Effect of losartan on slowing progression of chronic allograft nephropathy.

OBJECTIVE: To investigate the effects of losartan, a specific angiotensin II receptor blocker, on slowing progression of renal insufficiency in patients with biopsy-proven chronic allograft nephropathy (CAN) and the molecular mechanism of the therapy. METHODS: Twenty-two renal transplant recipients with biopsy-proven CAN (group A) were treated with losartan within two months after renal dysfunction for at least one year. Losartan was administered at a dose of 50 mg/d. Twenty-four recipients in the same fashion (group B) who never received angiotensin II receptor antagonist were studied as control. The investigation time for each patient lasted one year. Renal functions and concentrations of plasma and urine transforming growth factor-beta1 (TGF-beta1) were compared between the two groups at the initiation and end of the study. In group A, expressions of TGF-betal mRNA and immunofluorescence intensity of TGF-betal protein and pathological alterations in renal biopsy specimens were compared between before losartan therapy and after one year of the therapy. RESULTS: At the initiation of the investigation, no significant differences were found between group A and group B in clinical data such as donor age, cold-ischemia time, HLA mismatch, levels of creatinine clearance (Ccr), plasma and urine TGF-beta1 concentrations. One year later, 14 of 22 (63.6%) patients showed stable or improved graft functions in group A, and 4 of 24 (16.7%) in group B. The difference was significant (P < 0.05). At the end of the study, urine TGF-betal concentration was 273.8 +/- 84.1 pg/mg x Cr in group A and 457.2 +/- 78.9 pg/mg x Cr in group B. During one year study period, loss of Ccr was 6.6 +/- 5.4 mL/min in group A and 16.2 +/- 9.1 mL/min in group B. Both of the differences were significant between the two groups (P < 0.01). No significant differences were found in plasma TGF-betal concentrations between the four values determined at the initiation and end of the study in the two groups (F = 2.56, P > 0.05). After one year losartan therapy, group A showed a significant decrease in expressions of TGF-beta1 mRNA and TGF-betal protein in renal biopsy specimens [from 1.59 +/- 0.35 to 0.96 +/- 0.27 and from (10.83 +/- 2.33) x l0(6) to (6.41 +/- 1.53) x 10(6), respectively; both P < 0.01], but in light microscopy the histological changes were similar to the first renal biopsy. Losartan was excellently tolerated in all patients in group A. No cases with losartan therapy showed too low blood pressure and other side effects. CONCLUSION: This study suggests that losartan have an effect on slowing progression of CAN. Reducing production of intrarenal TGF-betal may play a decisive role in the efficacy of losartan.

[TGF-beta1 in allograft and long-term renal function].

OBJECTIVE: To determine the relation between transforming growth factor beta1 (TGF-beta1) in allograft and long-term renal function. METHODS: Urine TGF-beta1 relative concentration (divided by urine creatinine) was tested in 168 recipients whose renal function was normal between August 1, 2000 and March 31, 2001. Twenty patients with higher urine TGF-beta1 relative concentrations formed Group A, and another 20 patients with lower urine TGF-beta1 formed Group B. In both groups biopsies were carried out in 15 cases and 12 cases respectively, and TGF-beta1 in the biopsis was tested by immunofluorescence. Blood TGF-beta1 concentrations in the 2 groups were also tested. Three years later, the renal function was compared between the 2 groups. Biopsies were carried out in renal recipients whose creatinine was higher than that of the normal. RESULTS: Blood TGF-beta1 concentrations in the 2 groups were not different significantly; 3 years after the transplantation, there was more loss of renal function and more chronic allograft nephropathy (CAN) cases in Group A than in Group B. Expression of TGF-beta1 in the allografts was higher in Group A than in Group B. The differences in the 2 groups were significant. CONCLUSION: The findings suggest that the higher expression of TGF-beta1 in the allografts is associated with the lower long-term survival rate of kidney graft. The level of urine TGF-beta1 after the renal transplantation can predict the long-term renal function.