ABSTRACT
BACKGROUND: Marginal donor organs are used increasingly for transplantation. To define the influences of donor hypertension, we compared the behavior of kidney allografts from hypertensive and normotensive donors in an established rat model of chronic rejection. METHODS: Donor hypertension was induced by partial occlusion of the right renal artery with a silver clip. After 10 weeks, the left kidney was removed and transplanted. Normotensive animals served as controls. All recipients were treated with a low dose of cyclosporine for 10 days (1.5 mg/kg). Blood pressure and proteinuria were determined weekly four times after transplantation. To examine the effects of donor hypertension on late events, grafts (n=6/time point) were examined morphologically and by quantitative reverse transcriptase-polymerase chain reaction analysis at serial intervals. RESULTS: Recipients of kidneys from hypertensive donors developed systemic hypertension in contrast with normotensive controls (P<0.05). Allografts from hypertensive animals showed accelerated deterioration in structure and function after transplantation. Proteinuria became significantly elevated as early as 6 weeks (P<0.05) compared with controls and increased progressively thereafter (P<0.005). Grafts from hypertensive donors, histologically normal at the time of engraftment, developed significant morphologic deterioration after 12 weeks (P<0.01). Changes in allografts from normotensive donors remained minor. mRNA of proinflammatory mediators in hypertensive donor grafts (P<0.01) was up-regulated before transplantation and increased progressively over time (P<0.01). CONCLUSIONS: Donor hypertension intensifies the chronic injury associated with allogeneic kidney transplantation in the rat model used. This condition also leads to induction of recipient hypertension and may be a more important risk factor for chronic graft dysfunction than previously appreciated.
Subject(s)
Graft Survival , Hypertension/physiopathology , Kidney Transplantation/immunology , Kidney/pathology , Kidney/physiopathology , Tissue Donors , Animals , Cytokines/genetics , Disease Progression , Hypertension/pathology , Hypertension/urine , Inflammation Mediators/metabolism , Kidney/immunology , Male , Proteinuria/physiopathology , RNA, Messenger/metabolism , Rats , Rats, Inbred F344 , Rats, Inbred Lew , Reverse Transcriptase Polymerase Chain Reaction , Severity of Illness Index , Survival Analysis , Time Factors , Transplantation, Homologous , Up-RegulationABSTRACT
BACKGROUND: The lack of adequate numbers of kidneys for transplantation has stimulated interest in the use of organs from non-heart-beating donors (NHBDs). The short- and long-term effects of this risk factor on kidney isografts and allografts were examined with a rat model. METHODS: NHBDs were killed by ether overdose. Kidney isografts (male Lewis rats [LEW]-->LEW) were transplanted orthotopically into bilaterally nephrectomized recipients 15, 30, 45, and 90 min after asystole to determine short-term survival patterns, which were compared to those of rats bearing kidneys from living donors (LDs, 0 min). Isografts and allografts (Fisher 344 rats-->LEW) from 45-min and 105-min NHBDs and from LD controls were placed in additional recipients in which contralateral native nephrectomy was performed on day 10 to allow the injured graft to recover from its ischemic insult. Serum creatinine, proteinuria, and graft morphology were assessed serially over a 24-week follow-up period. RESULTS: Early survival and renal dysfunction of isografted rats correlated with the interval of donor cardiac arrest before transplantation. Long-term survival of recipients of kidneys from LDs and between 45-min and 105-min NHBDs was also significantly different (100% vs. 87% vs. 37% at 24 weeks, respectively, P<0.03). Proteinuria increased progressively over time, proportionate to the period of donor asystole, and was associated with increasing cellular infiltration, tubular atrophy, and glomerulosclerosis in the grafts. The development of important functional and structural changes was intensified in NHBD allografts. LD allografts showed early changes of chronic rejection. CONCLUSIONS: The results emphasize the continuum between an initial nonspecific, donor-associated renal injury and late functional and morphologic changes associated with the interval of donor cardiac arrest. These events are accelerated in NHBD allografts that experience the added insult of host alloreactivity.