Influence of Donor Brain Death on Chronic Rejection of Renal Transplants in Rats JOHANN PRATSCHKE,* † MARKUS J. WILHELM,* IGOR LASKOWSKI,* MAMORU KUSAKA,* FRANCISCA BEATO,* STEFAN G. TULLIUS, ¶ PETER NEUHAUS, ¶ WAYNE W. HANCOCK, †§ and NICHOLAS L. TILNEY* ‡ *Surgical Research Laboratory and † Department of Pathology, Harvard Medical School, Boston, Massachusetts; ‡ Department of Surgery, Brigham and Women’s Hospital, Boston, Massachusetts; § Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts; and ¶ Department of Surgery, Humboldt University, Charite ´-Virchow Clinic, Berlin, Germany. Abstract. The clinical observation that the results of kidney grafts from living donors (LD), regardless of relationship with the host, are consistently superior to those of cadavers suggests an effect of brain death (BD) on organ quality and function. This condition triggers a series of nonspecific inflammatory events that increase the intensity of the acute immunologic host responses after transplantation (Tx). Herein are examined the influences of this central injury on late changes in renal trans- plants in rats. A standardized model of BD was used. Groups included both allografts and isografts from normotensive brain- dead donors and anesthetized LD. Renal function was deter- mined every 4 wk after Tx, at which time representative grafts were examined by morphology and by reverse transcriptase– PCR. Long-term survival of brain-dead donor transplants was significantly less than LD grafts. Proteinuria was significantly elevated in recipients of grafts from BD donors versus LD controls as early as 6 wk postoperatively and increased pro- gressively through the 52-wk follow up. These kidneys also showed consistently more intense and progressive deterioration in renal morphology. Changes in isografts from brain-dead donors were less marked and developed at a slower tempo than in allografts but were always greater than those in controls. The transcription of cytokines was significantly increased in all brain-dead donor grafts. Donor BD accelerates the progression of long-term changes associated with kidney Tx and is an important risk factor for chronic rejection. These results ex- plain in part the clinically noted difference in long-term func- tion between organs from cadaver and living sources. The observation that kidneys from living, related donors con- sistently perform over time in a manner superior to those from cadaver sources has persisted throughout the entire clinical transplant experience, although the rate of attrition has im- proved relatively little (1). Although the most obvious expla- nation involves histocompatibility differences between donor and host that evoke immune injury to the graft, a clue that antigen-independent injury may also be important has been the unexpected finding that the survival rates of kidneys from living, unrelated donors that have no genetic advantage with the recipient are virtually identical to those of one haplotype– matched living, related sources and are consistently greater than those of mismatched cadaver organs (2). That this dis- crepancy may be based on physiologic and not genetic vari- ables has led investigators to focus on functional and structural changes related to nonspecific injury. It has been suggested that allografted organs, particularly those from less than opti- mal sources, may not be biologically inert at the time of placement but are already programmed to initiate or amplify subsequent host activity and are able to provoke a continuum between the inflammatory changes from initial nonspecific insults and the onset of alloresponsiveness (3,4). Several donor-associated factors implicated in long-term graft dysfunction alone or in combination include age, hyper- tension, diabetes, ischemia/reperfusion, and the systemic ef- fects of brain death (BD) (5). This central catastrophe is an antigen-independent event that is uniquely relevant to the ca- daver donor, the primary source of solid organs for transplan- tation. Such individuals have suffered sudden, extensive, and irreversible central nervous system damage secondary to trauma, hemorrhage, or infarction. Although human data that demonstrate the influence of the risk factor of BD on long-term function of transplanted grafts are not available, BD has been shown in animal models to perturb significantly the function and structure of somatic organs in situ (3). Furthermore, the tempo of acute rejection of both heart and kidney allografts from such donors after transplantation is accelerated because the inflamed organs increase host alloresponsivness (6,7). The etiology of the central injury also seems to be important, because an explosive type of BD perturbs peripheral organs more intensely than a gradual-onset injury (8). In this study, a gradual-onset model of BD was used to keep the donor animal consistently normotensive before organ re- moval and engraftment. This technique reduces as much as Received February 23, 2001. Accepted April 28, 2001. Correspondence to Dr. Nicholas L. Tilney, Brigham and Women’s Hospital, 75 Francis St., Boston, MA 02115. Phone: 617-732-6817; Fax: 617-232-9576; E-mail: bhayslett@rics.bwh.harvard.edu 1046-6673/1211-2474 Journal of the American Society of Nephrology Copyright © 2001 by the American Society of Nephrology J Am Soc Nephrol 12: 2474–2481, 2001