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The use of calcineurin inhibitors is generally guided by drug blood levels. However, those levels are chosen based on clinical experience, lacking adequate titration studies.In these analyses, we compared clinical and histologic endpoints in two groups of kidney transplant recipients: in the first (HiTAC, January 2000 to June 2002, n=245) tacrolimus levels were significantly higher than in the second (LoTAC, July 2002 to September 2004, n=330). This change in drug levels (15% reduction) was made in an attempt to reduce the incidence of polyoma virus nephropathy (PVAN). Other immunosuppressive medications were unchanged during these two time periods.The recipient and donor demographics were not statistically different between the two groups. Compared to HiTAC, at one year posttransplant LoTAC had: 1) lower incidence of PVAN (10.5% vs. 2.5%, P<0.0001); 2) lower fasting glucose levels; 3) higher iothalamate glomerular filtration rate (52±19 vs. 59±17 ml/min/m2, P<0.0001); and 4) on protocol one-year biopsies, lower incidence and severity of interstitial fibrosis (67% vs. 45%, P=0.003) and tubular atrophy (82% vs., 66%, P=0.01). The incidence and severity of acute rejection episodes was similar between both groups (7.8% versus 7.6%).Modest reductions in tacrolimus exposure early posttransplant are associated with significant beneficial effects for the patient and the allograft without an increased immunologic risk.