Management of chronic renal allograft dysfunction in cyclosporine-prednisone treated renal allograft recipients remains problematic. We therefore initiated a protocol of azathioprine addition (1.0-1.5 mg/kg/day) to ongoing CsA/Pred therapy. Three groups were treated. Group A (n = 21) had chronic progressive renal dysfunction (serum creatinine greater than or equal to 2.5 mg/dl or more than 15% above baseline) four or more months after transplantation. Group B (n = 8) had frequent or severe rejection episodes occurring despite adequate CsA levels. Group C (n = 7) had constitutional side effects of CsA with or without renal dysfunction persisting despite drug taper or financial difficulty in affording CsA. Aza was initiated 17.8 +/- 2.8 months after transplantation in group A, the mean serum creatinine having risen from 2.55 +/- 27 mg/dl to 3.04 +/- .20 mg/dl (P = .07) over the six months preceding Aza initiation, despite stable and low therapeutic range HPLC whole-blood CsA levels (118 +/- 10 ng/ml vs. 133 +/- 11 ng/ml, P = NS). Renal function declined at a rate of -0.20 +/- .06 Cr1/year in the six-month period before addition of Aza, and then improved at a rate of 0.09 +/- .04 Cr-1/year after addition of Aza (P = .002). These changes in renal function occurred without a decrease in CsA levels (118 +/- 10 six months before Aza vs. 126 +/- 26 six months after Aza, P = NS). In group B Aza was initiated at 58 +/- 8 days after transplantation when mean sCr was 3.56 +/- .29 mg/dl and mean CsA level was 222 +/- 17 ng/ml. At least follow-up 12.7 +/- 2.0 months after addition of Aza, all group B grafts were functioning, mean sCr was 2.69 +/- .31 mg/dl (P = .09 compared with baseline), and mean CsA level was 128 +/- 34 ng/ml (P = .07 compared with baseline). Group C patients had addition of Aza at 43 +/- 19 months after transplantation when mean sCr was 2.97 +/- .60 and mean CsA level was 125 +/- 30 ng/ml; addition of Aza had no influence on the rate of decline in renal function in this group. Of these 36 patients, 6 received therapy for acute rejection over the entire follow-up period of 12.3 +/- 1.4 months after addition of Aza; 4 of these retain graft function. Infectious complications consisted of 2 urinary tract infections, 1 bacterial pneumonia, and one case of otitis media.(ABSTRACT TRUNCATED AT 400 WORDS)