A Double-Blind, Double-Dummy, Flexible-Design Randomized Multicenter Trial: Early Safety of Single- Versus Divided-Dose Rabbit Anti-Thymocyte Globulin Induction in Renal Transplantation.

A previous nonblinded, randomized, single-center renal transplantation trial of single-dose rabbit anti-thymocyte globulin induction (SD-rATG) showed improved efficacy compared with conventional divided-dose (DD-rATG) administration. The present multicenter, double-blind/double-dummy STAT trial (Single dose vs. Traditional Administration of Thymoglobulin) evaluated SD-rATG versus DD-rATG induction for noninferiority in early (7-day) safety and tolerability. Ninety-five patients (randomized 1:1) received 6 mg/kg SD-rATG or 1.5 mg/kg/dose DD-rATG, with tacrolimus-mycophenolate maintenance immunosuppression. The primary end point was a composite of fever, hypoxia, hypotension, cardiac complications, and delayed graft function. Secondary end points included 12-month patient survival, graft survival, and rejection. Target enrollment was 165 patients with an interim analysis scheduled after 80 patients. Interim analysis showed primary end point noninferiority of SD-rATG induction (p = 0.6), and a conditional probability of <1.73% of continued enrollment producing a significant difference (futility analysis), leading to early trial termination. Final analysis (95 patients) showed no differences in occurrence of primary end point events (p = 0.58) or patients with no, one, or more than one event (p = 0.81), or rejection, graft, or patient survival (p = 0.78, 0.47, and 0.35, respectively). In this rigorously blinded trial in adult renal transplantation, we have shown SD-rATG induction to be noninferior to DD-rATG induction in early tolerability and equivalent in 12-month safety. (Clinical Trials.gov #NCT00906204.).

Successful urgent transplantation of an adult kidney into a child with inferior vena cava thrombosis.

Poor venous drainage options following inferior vena cava (IVC) thrombosis have been considered to complicate or preclude renal transplantation of adult kidneys into pediatric patients. We describe urgent renal transplantation in a 5-year-old (15.3 kg) male with IVC thrombosis using an adult living donor. Preoperative magnetic resonance venography revealed a patent infrahepatic/suprarenal vena cava and portal system. In surgery, the right liver lobe was mobilized sufficiently to anastomose the graft renal vein to the native IVC at the confluence of the native left renal vein and proximal vena cava. Graft function has remained excellent with serum creatinine of 0.5 mg/dL at 36 months. IVC thrombosis need not preclude successful transplantation of adult-sized kidneys into children.

Increased primary non-function in transplanted deceased-donor kidneys flushed with histidine-tryptophan-ketoglutarate solution.

Histidine-Tryptophan-Ketoglutarate (HTK) solution is increasingly used to flush and preserve organ donor kidneys, with efficacy claimed equivalent to University of Wisconsin (UW) solution. We observed and reported increased graft pancreatitis in pancreata flushed with HTK solution, which prompted this review of transplanting HTK-flushed kidneys. We analyzed outcomes of deceased-donor kidneys flushed with HTK and UW solutions with a minimum of 12 months follow-up, excluding pediatric and multi-organ recipients. We evaluated patient and graft survival and rejection rates, variables that might constitute hazards to graft survival and renal function. Two-year patient survival, rejection, renal function and graft survival were not different, but early graft loss (<6 months) was worse in HTK-flushed kidneys (p < 0.03). A Cox analysis of donor grade, cold ischemic time, panel reactive antibodies (PRA), donor race, first vs. repeat transplant, rejection and flush solution showed that only HTK use predicted early graft loss (p < 0.04; relative risk = 3.24), almost exclusively attributable to primary non-function (HTK, n = 5 (6.30%); UW, n = 1 (0.65%); p = 0.02). Delayed graft function and early graft loss with HTK occurred only in lesser grade kidneys, suggesting it should be used with caution in marginal donors.

Hashimoto's encephalopathy after intensive lymphocyte depletion with rabbit anti-thymocyte globulin in a renal transplant patient.

There has been no reported case of Hashimoto's encephalopathy (HE) ('steroid-responsive encephalopathy associated with autoimmune thyroiditis', 'SREAT'), in the renal transplant recipient population. We describe the case of a 55-year-old female with Type-1 diabetes who presented 2 years posttransplantation in a comatose state that had developed over the preceding 24 h. The patient had received a short, intensive course of rATG induction at the time of transplantation and early steroid withdrawal. After 6 months she had been withdrawn from calcineurin inhibitors and was maintained on mycophenolate mofetil and sirolimus. Systematic workup determined the cause of her coma to be HE. High-dose steroid therapy resulted in complete resolution of the patient's symptoms. The literature regarding the diagnosis, course and treatment of HE is reviewed and the possibility that increased use of steroid-free immunosuppression and intensive lymphocyte depletion regimens may increase the prevalence of de novo autoimmune disease is discussed.

University of wisconsin solution with trypsin inhibitor pefabloc improves survival of viable human and primate impure islets during storage.

Background. Recent studies suggest that impure islets (islets which have not been isolated from exocrine tissue and other parts of the pancreas) have great potential for successful transplantation. The evidence that supports this view includes findings that embedded islets (islets surrounded by exocrine tissue) undergo less apoptosis, peripancreatic lymph nodes prevent recurrence of IDDM (insulin dependent diabetes mellitus), and that islet yields and insulin content decrease during the purification process. Improved protocols have also been developed to prevent allorejection of impure islets. Despite these promising results, the storage of impure islets remains difficult, and was a method sought to decrease storage losses.Methods. Storage methods of impure human and non-human primate islets were compared, using either culture media or University of Wisconsin solution (UW). The effects of trypsin inhibition using Pefabloc (Roche Molecular Biochemicals, Indianapolis, IN) during storage period were also examined.Results. Low temperature and inhibition of trypsin activity during storage of impure islets improved both islet yield and viability. It was found that using UW solution and trypsin inhibition allowed perfect preservation of viable impure islets up to 48 h. A functional assay by glucose stimulation test showed these impure islet responded to glucose stimulation after 24 h.Conclusion. The benefits of storing impure islets using UW solution and Pefabloc at low temperature have been established. This improved method of preserving impure islets makes this model of transplantation even more viable.

Effect of storage and preservation methods on viability in transplantable human skin allografts.

This study compared the metabolic activity of fresh skin samples to that of cadaver human skin allografts processed and stored by current tissue banking methods. We chose to use two metabolic assays as surrogate measures for viability in these grafts. Skin allografts stored either in liquid media at 4 degrees C for varying periods of time or stored by cryopreservation were quantitatively assessed for viability by tetrazolium reduction and oxygen consumption assays. These measurements were compared to viability assessments of fresh autograft skin. Human cadaver skin grafts, after procurement and just prior to further tissue bank processing, exhibited approximately 60% of the metabolic activity found in fresh skin samples obtained from living surgical donors. If allowed an overnight (18-24 h) incubation period at 37 degrees C, cadaver samples showed a recovery of their metabolic activity to 95% of that found in the autograft skin samples. When stored in liquid media at 4 degrees C, the cadaver skin declined steadily in cellular metabolic activity, arriving in less than 5 days storage at a measurement below that of cryopreserved skin. The cryopreserved skin was measured both immediately after thawing and dilution of cryoprotectant, as well as after equilibration and overnight incubation. Skin cryopreserved with dimethylsulfoxide Me(2)SO retained higher viability than glycerol cryopreserved skin. Residual concentrations of cryoprotectants were determined following typical recommendations for thawing and diluting skin allografts. The implications of these findings for transplantation and tissue banking are discussed.