**2. Case description**

LAR, a 20-year-old woman with chronic renal failure due to focal and segmental glomerulosclerosis (FSGS) was admitted at the Clinical Hospital of Faculdade de Medicina de Botucatu (UNESP) to receive a renal transplant. She underwent an HLA—haploidentical living donor transplant from a 50-year-old woman in 17 March 1993. Panel reactivity (PRA) against HLA class I and II antibodies was negative. Induction therapy has not been done. Maintenance therapy was performed with a triple immune suppressive regimen with prednisone (1 mg/ kg/day), azathioprine (4 mg/kg/day) and cyclosporin (8 mg/kg/day). In the early follow-up, without a significant ischemic exposure, the patient had an episode of acute cellular rejection that was adequately treated. At hospital discharge her serum creatinine level was 1.2 mg/dl (eGFR = 60 ml/min) which remained up to 1 year post transplant. The patient started presenting mild proteinuria (0.28 g/24 h) and progressive deterioration of renal function over the years reaching creatinine of 1.8 mg/dl (eGFR = 39 mL/min) after 14 years of transplant (**Figure 1**). Immunosuppression at that time consisted of azathioprine (1.5 mg/kg/day), prednisone (10 mg) and cyclosporin in order to reach a serum level of 100–150 ng/ml. The renal biopsy diagnosis at this time (February 2007) was "chronic allograft nephropathy (CAN)" characterized by mild interstitial fibrosis and tubular atrophy, and intense arteriolar hyalin deposits observed in more than one arteriole, some with circumferential involvement (Banff grade I). A mild mononuclear inflammatory infiltrate was observed in scarred areas. The glomeruli and the small arteries were unremarkable (**Figures 2** and **3**). Tests for C1q, C3, IgG, IgA, IgM and C4d were all negative by immunofluorescence. Losartan was introduced (50 mg/day) and there was a gradual improvement of renal function over time (**Figures 1** and **4**).

All components of the RAS, including the receptors, are present very early in the human development (24–35 days of gestation), suggesting a role for angiotensin II in the organogenesis [3]. The RAS components are present in many tissues, and there are evidences for a tecidual angiotensin II biosynthesis with high concentrations in the kidneys (intrarenal RAS) [4, 5]. They are synthesized by different cells and interact locally with autocrine and paracrine effects. It has been suggested that the plasma RAS is important for acute regulatory mechanisms, whereas the tissue RAS may be more involved in chronic cardiovascular and renal regulation [6, 7].

Therefore, RAS maintains hemodynamic homeostasis and controls tecidual growth.

tion of mononuclear cells and fibrogenesis were observed [8].

plant has been limited [12, 13].

202 Renin-Angiotensin System - Past, Present and Future

the chronic allograft dysfunction.

**2. Case description**

Pathologic consequences can result in overactivity of this cascade with an involvement of the RAS in several renal diseases. Regardless of the initial type of injury, all chronic renal diseases develop glomerular and vascular sclerosis, tubular atrophy and interstitial fibrosis, with progressive nephron loss and chronic renal failure. Adaptative changes in the remaining nephrons after initial injury cause more scarring and nephron loss, thus perpetuating a vicious cycle that results in the end-stage kidney. Chronic RAS activation is involved in these maladaptive mechanisms of progressive renal damage. Angiotensin II-mediated effects such as haemodynamics changes, glomerular and tubular hypertrophy and hyperplasia, infiltra-

The system hyperactivity leads to progressive lesions presenting an important role in the pathophysiology of chronic cardiovascular and renal diseases. The RAS activation has been demonstrated in various kidney diseases, in both experimental and clinical studies [9, 10]. The system blockade, with inhibitors of angiotensin converting enzyme (ACE) of angiotensin II and angiotensin II-receptor blockers, shows large benefits in the treatment of chronic kidney diseases [11]. Thus, the classical approach of Angiotensin II as a vasoactive agent that participates in the systemic hemodynamic changes was expanded to recognize its role as a growth factor that

A significant complication on renal transplantation is the chronic and progressive allograft dysfunction that develops months or years after transplantation. Recent advances with new immunosuppressive drugs did not improve the long-term allograft survival. Despite the well established knowledge of the ability of renin-angiotensin system blockade to control blood pressure and urinary protein excretion, the use of RAS inhibitors and blockers in renal trans-

We review our own observations and recent reports from the literature about the important role of RAS in the pathogenesis of chronic inflammatory process and local tecidual growth, in

LAR, a 20-year-old woman with chronic renal failure due to focal and segmental glomerulosclerosis (FSGS) was admitted at the Clinical Hospital of Faculdade de Medicina de Botucatu

modulates cell proliferation, synthesis and degradation of extracellular matrix.

**Figure 1.** Serum creatinine levels after transplantation. Renal biopsy with chronic allograft nephropathy (CAN) and introduction of losartan 14 years after transplant.

**Figure 2.** Renal allograft biopsy with arteriolar hyalin deposits. PAS-200×.

**Figure 3.** Renal allograft biopsy with focal area with tubulointerstitial fibrosis, tubular atrophy and mononuclear infiltrate. Arteriolar hyalinosis. Masson Trichrome-200×.

**Figure 4.** Proteinuria after transplantation. Renal biopsy with chronic allograft nephropathy (CAN) and introduction of losartan 14 years after transplant.
