Optimization of cyclosporine therapy in renal transplantation

Abstract

It is well recognized that CsA is a potentially nephrotixic drug. CsA can induce a dose-dependent intrarenal vasoconstriction with reduced renal plasma flow and glomerular filtration rate. These functional abnormalities are reversible, even after months of CsA. However, CsA can also be responsible of morphologic lesions that are usually dosedependent. The tubular lesions, such as megamythocondria, isometric vacuolization, and calcification, are reversible. More severe is the so-called CsA-arteriolopathy, which affects the afferent arterioles and is characterized by mucinoid thickening of the arteriolar wall or by a nodular hialynosis of the intima. This arteriolopathy may be reversible if CsA is stopped, but in many cases it heralds the appearance of interstitial fibrosis with irreversible progression to renal failure. The nephrotoxicity of CsA has been considered as a main limit for a prolonged renal allograft survival. The retrospective data of the United Network for Organ Sharing seem to support this concern, since the half-life of cadaveric renal transplants was reported to range around 7 years both in the years between 1975 and 1979 when CsA was not available and between 1985 and 1990 when most transplant units used CsA. On the other hand, a number of studies reported that the most common cause of late graft failure in CsA-treated renal transplants was not represented by chronic toxicity but by chronic rejection, which was often triggered by the use of insufficient doses of CsA. To evaluate the long-term impact of CsA on graft survival we retrospectively examined our own series of renal transplants treated with CsA and functioning for at least 6 months. In 632 CsA-treated primary renal allografts followed for 68 6 40.6 months, the graft half-life was 19.9 years (standard error [SE] 22.5), and the pure graft half-life was 24.8 years (SE 30.99). Chronic rejection (83%), recurrence of glomerulonephritis (10%), and vascular thrombosis (5%) accounted for graft losses that occurred after the sixth month. Only one case of well documented CsA nephropathy was responsible for late graft failure. To assess the impact of long-term CsA on renal function, we studied 121 cadaveric renal transplant recipients with their allograft still functioning after 10 years of uninterrupted CsA administration. The mean creatinine clearance was 59 6 14.9 mL/min at 1 year after transplantation and was 57 6 25.3 mL/min at 10 years. Only 11 patients doubled their plasma creatinine from the first to the tenth year. The mean systolic (136 6 20 mmHg) and diastolic (87 6 11 mmHg) blood pressure values were within normal values at the tenth year. At 10 years, 104 patients (86%) versus 96 (80%) at 1 year received antihypertensive therapy. Proteinuria more than 1 g per day was found in 23 patients. All of them received a renal biopsy that showed chronic rejection in 15 cases, de novo membranous glomerulonephritis in 3, and recurrence of primary glomerulonephritis in 5. In conclusion, the prolonged use of CsA does not impede but rather favors a long-term allograft survival. At least in expert hands, the prolonged administration of CsA does not produce progressive attrition of renal function. The main cause of late graft failure remains chronic rejection that can be favored by the use of doses of CsA too low for maintenance.