Delayed graft function and cast nephropathy associated with tacrolimus plus rapamycin use

Delayed graft function (DGF) occurs in 15 to 25% (range, 10 to 62%) of cadaveric kidney transplant recipients and up to 9% of living donor recipients. In addition to donor, recipient, and procedural factors, the choice of immunosuppression may influence the development of DGF. The impact of immunosuppression on DGF was studied. The frequency of DGF was evaluated in first cadaveric or living donor kidney allograft recipients (n = 144) transplanted at the University of Washington from November 1999 through September 1, 2001. Donor, recipient, and procedural factors, as well as biopsy results, were compared between patients who developed DGF and those who did not. DGF was more common in patients treated with rapamycin than without (25% versus 8.9%, P = 0.02) and positively correlated with rapamycin dose (P = 0.008). In those developing DGF, the duration of posttrans- plant dialysis increased with donor age (P = 0.003) but decreased with mycophenolate mofetil use (P = 0.01). All biopsies during episodes of DGF demonstrated changes of acute tubular injury. Of the patients with tubular injury, 12 treated with rapamycin and tacrolimus developed intratubular cast formation indistinguishable from myeloma cast nephropathy. Histologic, immunohistochemical, and ultrastructural studies indicated that these casts were composed at least in part of degenerating renal tubular epithelial cells. These findings suggest that rapamycin therapy exerts increased toxicity on tubular epithelial cells and/or retards healing, leading to an increased incidence of DGF. Additionally, raparnycin treatment combined with a calcineurin inhibitor may lead to extensive tubular cell injury and death and a unique form of cast nephropathy.