Renal Function Evaluation After Reduction of Cyclosporine A Dose in Renal Transplant Patients
Renal Function Evaluation After Reduction of Cyclosporine A Dose in Renal Transplant Patients
The purpose of the study is to show the efficacy of reduction of cyclosporine A exposure
 measured by the area under the curve by Bayesian estimator on the primary prevention of
 degradation of the renal function in renal transplant recipients
Study population Eligible patients were 18 to 75 years of age and primary or secondary renal
 transplant recipients in their second year posttransplant with stable serum creatinine levels
 (i.e., < 20% variation for the previous 3 months). All patients must have received induction
 therapy, been corticosteroid-free for at least 3 months, and receiving combination
 maintenance therapy consisting of cyclosporine (trough level, 125 to 175 ng/mL) and
 mycophenolate mofetil (CellCept, F. Hoffmann- La Roche AG, Basel, Switzerland) 2 g daily.

 Patients at either low or high risk of graft dysfunction were ineligible; a majority of the
 participating centers maintained low immunological risk patients on cyclosporine alone and
 those with a high risk of graft dysfunction were usually maintained on corticosteroids. For
 this study, low risk was defined as the presence of the following: zero or one acute
 rejection episode with a return of renal function to previous levels after corticosteroid
 treatment, panel-reactive antibody titer <25%, serum creatinine level <125 µmol/L, age >25
 years, and donor age <40 years. High risk was defined as the presence of at least one of the
 following: a serum creatinine level >250 µmol/L, proteinuria >1 g/day, panel-reactive
 antibody titer >80%, >1 episode of T-cell-mediated rejection or at least one episode of
 antibody-mediated rejection posttransplant, or the presence of vasculitis or systemic lupus
 erythematosus which usually were treated with corticosteroids.

 Other exclusion criteria were evidence of systemic infection or malignancy within the
 previous 5 years (except adequately treated nonmetastatic basal or squamous cell carcinoma of
 the skin), leukocyte count <2.5x103/µL, hemoglobin <80 g/dL, platelet count <100x103/µL,
 severe intestinal disorders, pregnancy, breast feeding, current immunosuppressive treatment
 with drugs other than cyclosporine and mycophenolate mofetil. Women of childbearing age were
 required to use adequate contraception during treatment with mycophenolate mofetil and for
 six weeks after its discontinuation.

 Study Endpoints The primary endpoint was the proportion of patients with treatment failure
 (failure to prevent kidney dysfunction) at 24 months, which was a composite of graft loss,
 histologically confirmed acute rejection or cyclosporine toxicity, or a > 15% increase in the
 mean serum creatinine level from the baseline assessment. The mean of the current and two
 previous serum creatinine levels was used to determine the level at baseline, the level at
 the nadir (the time of the lowest serum creatinine measurement),and the level at 2 years.

 The secondary endpoints included the change in estimated glomerular filtration rate (eGFR)
 from baseline calculated using the four-variable equation from the Modification of Diet in
 Renal Disease (MDRD) Study; blood pressure, urinary protein, and lipid levels; severe adverse
 events such as infection requiring hospitalization, neoplasia, or lymphoma; and graft and
 patient survival.

 Study Follow-up and Procedures Weight, blood pressure after a 10-minute rest, serum
 creatinine and glucose levels, a complete blood cell count, and urinary protein levels were
 measured, and the use of immunosuppressive, antihypertensive, and lipid-lowering drugs was
 recorded at baseline and every 2 months. Serum lipid levels were measured at baseline and
 every 6 months. Gynecologic and dermatologic examinations were performed at baseline and
 yearly. Adverse events were recorded.

 Renal biopsies were performed when creatinine levels increased > 20% relative to the nadir or
 when proteinuria was >1 g/day. The nadir level was used as a reference point to obviate the
 risk of missing the diagnosis of rejection in the low-exposure arm; serum creatinine levels
 usually fell after the initiation of a low exposure regimen. Biopsies were classified using
 Banff 1997 criteria by four senior pathologists blinded to the clinical information.
 CNI-associated nephrotoxicity was graded mild, moderate, or severe according to the Banff
 1997 chronicity rejection scores.
Inclusion Criteria:

 -  first or second renal graft

 -  cadaveric renal graft

 -  second year of renal transplantation

 -  stable renal function

 -  moderate renal dysfunction risk

 -  bitherapy with cyclosporine A and mycophenolate mofetil

 -  corticosteroid withdrawal since 3 months at less

 Exclusion Criteria:

 -  2 or more acute rejection episodes

 -  PRA> 80%

 -  serum creatinine> 250µmol/L

 -  24-hour proteinuria > 1g

 -  humoral rejection

 -  vasculitis