Cyclosporine reduction causes decreasing of angiotensin II and transforming growth factor-beta expression in chronic allograft nephropathy

Background

High cyclosporine (CsA) levels might lead to nephrotoxicity due to increasing angiotensin II (AII) and transforming growth factor-beta (TGF-β) production. We hypothesized that a chronic reduction in CsA levels would decrease local renal AII and TGF-β expression and result in improvement of renal function and renal pathological changes in renal transplant recipients.

Methods

We determined the AII and TGF-β expression by immunohistochemical staining (IHCS) in sequential human renal biopsy specimens in patients with chronic allograft nephropathies (time between biopsies: 15.9 ± 0.8 months) after they had their CsA levels reduced by 50%. Pathological evaluation included percentage expression (%) of interstitial fibrosis and tubular atrophy (FIB), vascular sclerosis (VS), transplant glomerulopathy (TG), and vascular hyalinosis (VH). Serum creatinine (CR, mg/dl) and BUN (mg/dl) levels were also investigated.

Results

Renal pathological score significantly improved with chronic reduction in CsA blood levels (FIB: from 52 to 26%, p < 0.05; VS: from 22 to 5%, p < 0.05; TG: from 40 to 13%, p < 0.05; VH: from 17 to 1.8%, p < 0.05, respectively). Renal function also significantly improved with chronic reduction of CsA blood level (BUN: from 84 ± 14 to 40 ± 3 mg/dl, p < 0.05; CR: from 3.4 ± 0.4 to 2.2 ± 0.1 mg/dl, p < 0.05, respectively). AII and TGF-β IHCS score (0–4) and positive staining area (%) were significantly decreased in patients with chronic reduction in CsA levels.

Conclusion

These data indicate that chronic reduction in CsA diminishes production of renal tissue AII and AT1 receptor expression, and results in decreased fibrosis and improvement of renal function in patients with chronic allograft nephropathy.