The combination of donor and recipient age is critical in determining host immunoresponsiveness and renal transplant outcome.

OBJECTIVE: To evaluate the interaction of donor and recipient age on transplant outcome and immune response. SUMMARY BACKGROUND DATA: The age of donor and recipient is becoming increasingly important in organ transplantation. We tested the relevance and consequences of recipient and donor age on immunoresponsiveness and transplant outcome in a uni- and multilateral cohort analysis. METHODS: We obtained and analyzed data from 108,188 recipients of deceased donor kidneys of the United Network for Organ Sharing database transplanted between 1995 and 2008. Univariate analysis of allograft and patient survival was calculated by Kaplan Meyer. Multivariate analyses were performed using the Cox Proportional Hazards method. Data were assessed and compared by decades of increasing donor and recipient age with and without censoring transplant loss for death with a functioning graft. This approach allowed a detailed analysis of interacting factors. RESULTS: Transplant survival was lowest in elderly recipients. However, when the analysis was censored for patient's death with a functioning kidney transplant, survival improved incrementally with each decade of increasing recipient age. This was even more surprising as older recipients had received less well-matched organs of poorer quality. The frequency of acute rejection decreased dramatically with increasing age, emphasizing the effect of age on the vigor of the recipient's immune responses. In contrast, increasing donor age was associated with more frequent acute rejection rates. The effects of donor and recipient age in combination demonstrated that grafts of older donors fared significantly better in older recipients. CONCLUSIONS: Our results show that increasing recipient age is associated with an improved transplant survival, lower rates of rejection, and superior outcome of older donor organs. Physiological and/or immunologic aspects of organ and recipient age seem to determine, at least in part, the success of renal transplantation.

Risk factors and outcomes of pancreatitis after open heart surgery.

BACKGROUND: We sought to analyze the risk factors and natural history associated with post-cardiac surgery acute pancreatitis. METHODS: Retrospective analysis of all patients having undergone cardiac surgery at our hospital between January 1, 1992, and October 1, 2001. RESULTS: A total of 10,249 cardiac operations were performed. Thirty-nine (0.4%) patients developed postoperative pancreatitis. There was a higher incidence during the period spanning 1992 through 1996 than 1997 through 2001 (0.6% versus 0.2%, P< .05). Patients with pancreatitis had longer postoperative length of stay (51+/-5 days versus 10+/-1 days, P<.05) and a greater in-hospital mortality rate (28% versus 4%, P<.05) than patients who did not develop pancreatitis. A history of alcohol abuse, cardiac surgery performed during 1992 to 1996, increased cardiopulmonary bypass time, and increased cross-clamp time were independent risk factors for the development of pancreatitis. Multiple-organ failure was an independent predictor for death among patients with pancreatitis. CONCLUSIONS: Although the frequency of post-cardiac surgery pancreatitis is diminishing, it is still associated with significant mortality.

Selectin blockade plus therapy with low-dose sirolimus and cyclosporin a prevent brain death-induced renal allograft dysfunction.

Both antigen-dependent and -independent factors influence long-term organ allograft function and survival. Brain death (BD), a significant antigen-independent, donor-related injury upregulates a variety of inflammatory mediators in peripheral organs. One of the earliest responses to such an insult is the expression of selectins by endothelial cells of the transplanted tissues; these in turn trigger a cascade of nonspecific events, that enhance host alloresponses and which may be worsened by toxic effects of long-term immunosuppression. Using a rat model in which donor BD accentuates subsequent renal allograft injury, we have tested the effects of therapy with recombinant P-selectin glycoprotein ligand (rPSGL-Ig) alone, or in combination with sirolimus (SRL) and cyclosporin A. We found that in contrast to the effects of standard doses of SRL or cyclosporine, rPSGL-Ig decreased inflammation in the early posttransplant period such that lower doses of maintenance immunosuppression were sufficient to maintain long-term graft function.

Donor hypertension increases graft immunogenicity and intensifies chronic changes in long-surviving renal allografts.

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.

Recipient hypertension potentiates chronic functional and structural injury of rat renal allografts.

BACKGROUND: Systemic hypertension affects many allograft recipients, is an important risk factor for chronic graft dysfunction, and is linked to reduced graft survival. The condition may up-regulate the expression of inflammatory host cells and their products. These, in turn, may significantly injure vascular endothelium and other components of allografted kidneys. METHODS: Lewis rats received orthotopic F344 renal allografts, a standard model of chronic rejection. Renovascular hypertension was produced by placing a silver clip (0.25 mm) on the renal artery of the retained contralateral native kidney 4 weeks after transplantation. Sham-clipped rats served as normotensive controls. Four recipient groups (Gp) were studied: Gp 1, rats with an allograft plus a clipped native kidney; Gp 2, those with an allograft and a sham-clipped native kidney; Gp 3, isografted animals with a clipped native kidney; and Gp 4, those bearing an isograft and a sham-clipped native kidney. Systolic blood pressure and proteinuria were measured every 2 weeks for 24 weeks. Grafts were assessed serially for morphologic and immunohistologic changes. RESULTS: Systemic blood pressure rose to hypertensive levels in Gps 1 and 3 within a week of clipping but never increased in Gps 2 and 4. Proteinuria developed in hypertensive animals but remained at baseline in normotensive controls. Intimal thickening of allograft arteries progressed to luminal obliteration with extensive perivascular and interstitial fibrosis by 24 weeks. In contrast, vascular changes in isografts of hypertensive hosts were restricted to medial hypertrophy. Tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, platelet derived growth factor (PDGF), endothelin, Il-6, major histocompatibility complex (MHC) class II, and B7 were up-regulated in allografts in hypertensive hosts. Vascular deposition of immunoglobulin (IgG) was increased. These changes were markedly less pronounced in Gp 3 isografts and minimal in the kidneys of the normotensive animals of Gps 2 and 4. CONCLUSIONS: An experimental model is presented that examines the influence of recipient hypertension in the pathogenesis of chronic dysfunction and injury developing in rat renal allografts over time.

Normalization of brain death-induced injury to rat renal allografts by recombinant soluble P-selectin glycoprotein ligand.

Donor brain death has been considered a significant risk factor for both early and late organ allograft dysfunction. This central injury not only evokes an upsurge of catecholamines with resultant peripheral tissue vasoconstriction and ischemia but also promotes release of hormones and inflammatory mediators that may also affect the organs directly. One of the resultant influences of these events is the rapid upregulation of the acute-phase adhesion molecules, the selectins. These initiate leukocyte adhesion to vascular endothelium and trigger subsequent cellular and molecular changes in the compromised tissues. An established F344 --> LEW rat model of chronic rejection was used to examine (1) whether the initial inflammatory events that develop within kidney allografts from brain-dead donors could be normalized using a recombinant soluble form of P-selectin glycoprotein ligand and (2) whether amelioration of these early changes would alter the inexorable progression of chronic allograft rejection. Untreated living donor controls experienced unrelenting chronic rejection over time. This complex process was accelerated in brain-dead donor kidneys. Treatment with P-selectin glycoprotein ligand prevented the early inflammatory changes in the transplanted organs and their subsequent (200 d) functional and morphologic manifestations, particularly when the soluble ligand was administered both to the donor before organ removal and to the recipient after engraftment. This strategy of using a naturally occurring selectin ligand to prevent donor-associated chronic graft dysfunction may be of special clinical interest in cadaver donor transplantation.

Early and late injury to renal transplants from non-heart-beating donors.

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.

Anti-CD28 monoclonal antibody therapy prevents chronic rejection of renal allografts in rats.

The effects of a signaling anti-CD28 mAb (JJ319), which interferes with the CD28-B7 T cell costimulation pathway thought to be involved in the development of chronic rejection of organ transplants, was investigated. Functional, morphologic, and molecular changes in rat renal allografts were examined up to 24 wk after placement. Control Lewis rats, recipients of F344 kidneys, received a single dose of a nonspecific mouse mAb intravenously on the day of transplantation (group 1). Group 2 animals were given anti-CD28 mAb in similar fashion. Group 3 animals were treated with a short course of cyclosporin A (CsA), and group 4 received both anti-CD 28 mAb and CsA. The majority (>95%) of animals in groups 2, 3, and 4 survived throughout the follow-up, compared with 28% in group 1 (P < 0.001). Group 2 and 4 recipients produced negligible proteinuria, whereas group 1 controls developed progressively increasing proteinuria after 4 wk and group 3 animals developed proteinuria by 24 wk. Allografts in groups 2 and 4 were morphologically unremarkable at 24 wk. Kidneys of group 1 animals rapidly developed changes of acute rejection, and those that survived long-term showed extensive glomerulosclerosis and interstitial fibrosis. Changes of early chronic rejection were noted in group 3 grafts. By reverse transcriptase-PCR, expression of representative inflammatory factors interferon-gamma and interleukin-10 were significantly elevated at 24 wk only in the surviving group 1 animals. A single dose of a signaling anti-CD28 mAb administered at transplantation or in combination with a short course of CsA significantly prolonged recipient survival, normalized function, and preserved the morphology of renal allografts in an established model of chronic rejection. These data support an important role for T cell costimulation in the evolution of the chronic process.

Influence of donor brain death on chronic rejection of renal transplants in rats.

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 transplants 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 determined 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 progressively 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 explain in part the clinically noted difference in long-term function between organs from cadaver and living sources.

Ciclosporina: estudios experimentales y aplicación clínica en trasplante de organos / Cyclosporin: experimental studies and clinical applications in organ transplantation

La ciclosporina es un agente inmunosupresor muy potente cuya eficacia ha sido ampliamente demostrada en animales de laboratorio y en la prática clínica. El medicamento actúa bloqueando las fases tempranas de la activación celular que despiertan los antígenos o mitógenos. La ciclosporina, a través de su efecto sobre mediadores humorales llamados linfocinas, inhibe la aparición de linfocitos T-citotóxicos, permitiendo la emergencia del mecanismo supresor de la respuesta inmune. Esta acción selectiva resulta en un estado tolerante de los receptores de alotrasplantes. El uso clínico de la ciclosporina combinado con esteroides, ha mejorado la sobrevida de trasplante de riñón, corazón e hígado, cuando se comparan los resultados obtenidos con los esquemas de inmunosupresión previa. La ciclosporina es un arma efectiva para el tratamiento de los enfermos que reciben trasplantes de órganos