Why do we reject a graft? Role of indirect allorecognition in graft rejection

Abstract

renal transplant dysfunction, as manifested by a slow, progressive rise in serum creatinine, developed; the decreasing renal function was associated with proteinuria (1 to 2 g/24 hr). The erratic cyclosporine levels and blood pressure readings led to the suspicion that he remained noncompliant with his medications. A renal transplant biopsy one year ago (when his serum creatinine was 4.0 mg/dl and urinary protein-to-creatinine ratio was 1.2) showed evidence of chronic allograft nephropathy (Fig. 1). Specifically, the renal parenchyma was greatly distorted by widespread sclerosis. Most glomeruli were either globally or segmentally obsolescent or appeared hypoperfused. Extensive tubular atrophy was present. The interstitium was expanded by connective tissue and patchy mononuclear cell infiltrates. Isolated tubules showed evidence of tubulitis. Arteries revealed extensive intimal proliferation with near obliteration of the CASE PRESENTATION lumens. Small arteries and arterioles revealed concentric layers A 42-year-old Hispanic man had a history of end-stage renal of connective tissue or prominent hyaline deposition in the wall. disease secondary to malignant hypertension. He had been Several vessels showed signs of active inflammation of the on hemodialysis for two years before receiving a 4-antigen intima (endotheliitis). Results from the renal biopsy along with mismatched, cadaveric renal allograft four years ago. Positive the progressive decline in renal function prompted a change for cytomegalovirus (CMV), he received a CMV-negative kidin his medications from azathioprine to mycophenolic mofetil ney. His serologic hepatitis profile showed positive hepatitis B (Cellcept), but renal transplant dysfunction progressed, necesantibody but negative antigen, and negative hepatitis C antisitating reinstitution of hemodialysis therapy. body. His initial post-transplant course was complicated by delayed graft function and one episode of presumed acute rejection in the first two weeks post transplant, which responded to administration of a steroid pulse. At discharge after transplantation, his serum creatinine level was at its nadir value of 1.1 mg/dl. Cyclosporine, azathioprine, DISCUSSION and steroids were initiated and maintained. He developed postDr. Mohamed H. Sayegh (Research Director, Laboratransplant hypertension, which was managed with an angiotensin-converting-enzyme inhibitor. Approximately four months tory of Immunogenetics and Transplantation, Renal Divipost transplant, he had another acute rejection episode, which sion, Brigham and Women’s Hospital; and Associate Prowas believed to be secondary to noncompliance with his medifessor of Medicine, Harvard Medical School, Boston, cations, as reflected by erratic cyclosporine levels during his Massachusetts, USA): This patient is a typical recipient follow-up clinic visits. Subsequent to that episode, his renal of a cadaveric renal transplant who ultimately developed transplant function had been relatively stable (serum creatinine in the 2.1 to 2.6 mg/dl range). But two years ago, progressive chronic allograft nephropathy that led to a second episode of end-stage renal disease. Although chronic allograft nephropathy has been recognized for years, only