A randomized, double-blind trial of basiliximab immunoprophylaxis plus triple therapy in kidney transplant recipients.

BACKGROUND: A double-blind, placebo-controlled, randomized study was performed to assess whether immunoprophylaxis with basiliximab (Simulect) could reduce the incidence of acute rejection in kidney transplant recipients treated with cyclosporine (Neoral), steroids, and azathioprine. METHODS: Three hundred forty patients received either placebo or basiliximab at a dose of 20 mg, given intravenously on days 0 and 4. All patients received cyclosporine, steroids, and azathioprine. The primary endpoint was the incidence of acute rejection at 6 months. Secondary endpoints included the safety and tolerability of basiliximab and placebo, 1-year patient and graft survival, and significant medical events up to 12 months. RESULTS: During the first 6 months posttransplantation, acute rejection occurred in 20.8% of patients given basiliximab versus 34.9% of patients administered placebo (P=0.005). Similarly, there was a reduction in biopsy-proven acute rejection at 6 months in the patients receiving basiliximab (P=0.023). One-year patient survival was 97.6% with basiliximab and 97.1% with placebo, graft survival was 91.5% versus 88.4%, respectively (NS). The adverse-events profile of patients treated with basiliximab was indistinguishable from that of patients treated with placebo. The number of patients with infections was similar (65.5% for basiliximab vs. 65.7% for placebo), including cytomegalovirus infections (17.3% vs. 14.5%, P=0.245). Nine neoplasms (three in the basiliximab group, six in the placebo arm) were recorded up to 1 year from transplantation. CONCLUSIONS: Basiliximab in combination with cyclosporine, steroids, and azathioprine triple therapy was highly effective in reducing the incidence of acute renal allograft rejection without increasing the incidence of infections and other side effects.

Replicative senescence in organ transplantation-mechanisms and significance.

In the past two decades, transplantation has become a preferred modality of treatment of end-stage failure of vital organs. Currently, with the significant improvement in short-term graft survival rates, the main effort is concentrated on prolonging the functional life span of transplanted organs. One of the theories which were put forward to explain the progressive deterioration of transplant function was that of replicative senescence. Senescence of an organ or tissue results from age and/or environmental stress-dependant modification of cellular function. With time, the accumulation of cellular alterations may lead to deleterious effects in various organs and tissues and adversely affect transplants. In this article we are reviewing the candidate mechanisms of senescence such as telomere shortening, genetic regulation and environmental-'toxic' factors and are examining the implications of the theory of replicative senescence for organ allograft. We are also presenting our experiments with renal ischemia/reperfusion in rat serving as a model of kidney transplantation, where baseline kidney telomere length and novel marker of cellular senescence--senescence associated beta-Galactosidase (SA-Gal) expression in tissue served as markers. For the first time in vivo, we were able to show that with aging of the animals the amount of senescent cells in kidney tissue was increasing, while the average renal tissue telomere length was decreasing. The degree of tissue senescence, as determined by amount of SA-Gal positively stained cells, was inversely correlated with the recovery of the kidney function after ischemia/reperfusion injury. These results confirm the theory of replicative senescence in organ ischemia for the first time in vivo, and quantitatively validate the direct correlation between the amount of senescent cells in the organ and its susceptibility to ischemic injury. We conclude that recent advances in study of the cellular basis of senescence, in vitro and especially in vivo, may hold clues to the understanding of events which could be implicated in the damage or protection of organ allografts.

Page kidney phenomenon in kidney allograft following peritransplant lymphocele.

A case of kidney allograft dysfunction in a recipient with a prior lymphocele is described. We attribute it to a Page kidney phenomenon caused by a constrictive pericapsular fibrosis. Surgical exploration and excision of the fibrotic tissue were followed by the recovery of renal transplant function. To our knowledge, only 1 case of Page kidney in renal allograft due to peritransplant hematoma has been described in the literature.

New immunosuppressive agents for maintenance therapy in organ transplantation.

Traditional cyclosporin-based immunosuppressive protocols are associated with relatively high incidences of early acute rejection and late graft loss due to chronic rejection. In addition, long-term immunosuppression with cyclosporin and corticosteroids has been associated with significant metabolic, infectious, malignant and cosmetic adverse effects. In the last decade, the goals of immunosuppression strategies have included not only short-term survival but also graft acceptance, with a low incidence of early acute rejection and minimal long-term toxicity. Tacrolimus and mycophenolate mofetil are 2 new immunosuppressive agents that have recently been approved for use. The mechanism of action and toxicity profile of tacrolimus are similar to that of cyclosporin. Tacrolimus reduces early acute rejection and is also effective in salvage of allografts with refractory rejection. A wide spectrum of adverse effects, including nephrotoxic, neurotoxic, gastrointestinal, metabolic and hematological effects, has been reported in association with tacrolimus but, unlike cyclosporin, this agent is not associated with hirsutism or gingival hyperplasia. Mycophenolate mofetil, an antimetabolite, has been effective in reducing early acute rejection and in treatment of refractory rejection when used in combination with cyclosporin instead of azathioprine. Its myelosuppressive and gastrointestinal toxicities are mild and reversible, but it may be associated with an increased risk of infections. Both agents permit early corticosteroid withdrawal. Other new immunosuppressive agents that act on different stages of the cell cycle but that have not yet been introduced for wide clinical use, including sirolimus (rapamycin), brequinar, mizoribine and gusperimus, are also discussed in this review.

Herpes simplex keratitis in renal transplant patients.

Five out of 430 patients (1.16%) undergoing kidney transplantation developed an atypical clinical picture of herpetic dendritic keratitis within four weeks after surgery. It was manifested by multiple dendrites, located mainly in the corneal periphery or the limbus, developing in relatively uninflamed eyes. The response to acyclovir therapy was prolonged and took at least three weeks. Additionally, subepithelial infiltrates with ultimate scarring developed in all patients. Disciform keratopathy was not found. This clinical course is ascribed to the patients' immunosuppressed state.

Pancreas transplantation.

Although intensified insulin therapy regimens enable normalization of blood glucose levels and related metabolic parameters, these regimens are associated with an increased incidence of hypoglycemic episodes. Pancreas transplantation has achieved the goal of providing insulin independence with stable and continuous normoglycemia. But because of the associated morbidity and mortality and the need for life-long immunosuppression after transplant, it is difficult to justify pancreas transplantation in diabetic patients at a pre-uremic stage. Pancreas transplantation is therefore performed in conjugation with renal transplantation. The majority of renal transplant centers, however, have been reluctant to perform simultaneous kidney-pancreas transplantation in insulin-dependent uremic patients because of the additional risks associated with pancreas transplantation. More recently, refinements in surgical technique, introduction of new immunosuppressive agents, and better selection of transplant candidates have contributed to improved survival. Today, combined pancreas-kidney transplantation is an accepted treatment for carefully selected patients with insulin dependent diabetes and end-stage renal disease and in a small group of patients with uncontrolled severe metabolic problems. The effect of a euglycemic state after pancreas transplantation on the progression of micro- and macroangiopathy remains to be proved, although recently there is evidence to suggest that some end-organ lesions may be halted or even ameliorated. Further improvement in anti-rejection strategies may achieve better long-term graft survival and provide the incentive to perform pancreas transplantation at an earlier stage, before severe secondary complications of diabetes develop.

The use of the portal system for the transplantation of a neonate kidney graft in a child with Wilms' tumor.

A single an-encephalus neonate kidney graft was transplanted into the portal system of a 6-year-old recipient who had previously undergone removal of the right kidney and inferior vena cava because of Wilms tumor. The left kidney ceased to function shortly thereafter. The child was supported very poorly on hemodialysis, and showed repeated very high levels of cytotoxic antibodies in her serum. The first cross-negative kidney graft that was available harbored two main arteries and duplicate collecting system with two very thin ureters. These vascular anatomic and pathologic variations of both donor graft and recipient necessitated the use of the portal system for renal graft venous drainage and the aorta for the graft revascularization. The ureters that had pinpoint-like lumen were inserted together into the lumen of the native ureter stump and fixated. One year after the transplantation the serum creatinine level is 1.8 mg/dL.

[Liver allografts from donors older than 60: benefits and risks].

With limited organ resources and an increasing number of candidates for liver transplantation, the world-wide trend is towards using liver allografts from donors older than 60 years. This strategy, however, may be hazardous because of the known correlation between advanced donor age and graft dysfunction. Since January 1996, each of 5 patients received a liver allograft from a donor older than 60 years. Preservation time in these cases was shortened as much as possible and liver allografts were used only if there were no other potential risk factors for primary nonfunction. Mean cold ischemic time was significantly shorter in this donor group (7.8 hrs) than for livers from 28 younger donors (10.2 hour; p < 0.01). 3 of the 5 grafts from older donors had normal function immediately. The other 2 initially had biochemical features of preservation injury, but graft function returned to normal within the first week after transplantation. All 5 patients currently have normal graft function, with follow-up ranging from 3-8 months. There was no difference between the 5 recipients of grafts from older donors and 28 adult recipients of grafts from younger donors in extent of preservation injury and in immediate graft function. We conclude that in countries with limited organ resources, such as Israel, liver allografts from older donors can be used within defined limits and minimal preservation time.

[Living-related liver transplantation--first experiences at Rabin Medical Center].

Our experience with living-related liver transplantation is described. In 2 boys and 1 girl, aged 4-4.5 years with acute, fulminating hepatitis A, the presence of very severe jaundice (bilirubin levels > 18 mg%) associated with severe coagulopathy (INR > 10) and encephalopathy indicated the need for urgent liver transplantation. In all 3 cases the left lateral hepatic segment of a matched blood type parent was transplanted. None of the donors suffered a serious complication postoperatively and all returned to full activity in 6-16 weeks. The post-transplantation course was uneventful in 1 child, but in the other 2 there was hepatic arterial thrombosis in 1 at 1 day and in the other at 8 days post-transplantation. Early detection of arterial thrombosis by Doppler sonography permitted salvage of the 2 hepatic grafts after thrombectomy and re-anastomosis. In 1 of these 2 children an anastomotic biliary stricture was found 2 months after transplantation. It was corrected at surgery and a percutaneous stent was inserted. All 3 children are alive with normal graft function at 2, 7 and 8 months post-transplantation, respectively. This initial experience indicates that living-related liver transplantation is feasible in Israel. The technique might help to solve our severe organ shortage for children awaiting liver transplantation.