Effect of early cyclosporine levels on kidney allograft rejection

Acute rejection is the greatest risk factor for development of biopsy-proven chronic rejection and late kidney allograft loss. We previously noted that low cyclosporine (CsA) levels were a risk factor for early acute rejection in pediatric recipients (1). In our current study, we used logistic regression to identify risk factors for acute rejection in 726 adult kidney transplant recipients on triple therapy (prednisone, azathioprine, CsA). Variables considered for logistic regression analysis were donor organ source (cadaver vs. living), degree of HLA mismatch (1 to 6 vs. 0 antigen mismatch), transplant number (primary vs. retransplant), CsA levels (< 125 vs. ≤ 125 ng/ml, < 150 ng/ml vs. ≤ 150 ng/ml, and < 175 vs. ≤ 175 ng/ml), and acute rejection episodes (0 vs. ≤ 1). Of 726 recipients, 401 (55%) received cadaver kidneys; 325 (45%), living related. Overall, 572 (79%) had a primary transplant; 154 (21%), a retransplant. The vast majority of acute rejection episodes occurred within the first 2 months posttransplant; 68% of recipients had no acute rejection episodes by 2 months and 58% had none by 60 months posttransplant. Logistic regression analysis revealed that a cadaver donor kidney (vs. living) (p = 0.004), a 1 to 6 antigen mismatch (vs. 0 mismatch) (p = 0.001), and CsA levels < 150 ng/ml (vs. ≤ 150 ng/ml) correlated with biopsy-proven acute rejection. The correlation for CsA levels < 150 ng/ml (vs. ≤ 150 ng/ml) held true for levels at 1 wk (p < 0.05), 1 month (p = 0.0001), 2 months (p = 0.01), and 3 months (p = 0.02) posttransplant. Similar correlation was found for CsA levels < 125 ng/ml (vs. ≤ 125 ng/ml) and < 175 ng/ml (vs. ≤ 175 ng/ml). Comparative analyses were made (by Chi-square) of acute and chronic rejection rates when recipients were divided into 3 groups by CsA level (< 125 ng/ml, ≤ 125 to < 150 ng/ml, and ≤ 150 ng/ml). At each time point (1 wk, 2 wk, 1 month, 2 months, 3 months), CsA levels < 125 ng/ml (vs. ≤ 125 to < 150 ng/ml and ≤ 150 ng/ml) were associated with the greatest increased risk of acute rejection - for both cadaver and living related recipients (all p < 0.05). CsA levels < 125 ng/ml at each time point (1 wk, 2 wk, 1 month, 2 months, 3 months) were also associated with a significantly increased risk of chronic rejection (all p < 0.001). The incidence of both acute and chronic rejection was reduced in the group with CsA levels ≤ 125 to < 150 ng/ml and further reduced in the ≤ 150 ng/ml group. Our data indicate that maintaining CsA levels ≤ 150 ng/ml as part of triple therapy reduces the incidence of both acute and chronic rejection. Because chronic rejection is the leading cause of late allograft loss, maintaining adequate CsA levels should improve long-term graft survival. Based on this analysis, we have modified our own immunosuppressive regimens to achieve higher CsA levels earlier posttransplant.