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Supplemental digital content is available in the text., Background We conducted a randomized and unblinded 2×2 sequential-factorial trial, composed of an induction arm (part 1) comparing single-dose (SD) versus divided-dose rabbit antithymocyte globulin (rATG), and a maintenance arm (part 2) comparing tacrolimus minimization versus withdrawal. We report the long-term safety and efficacy of SD-rATG induction in the context of early steroid withdrawal and tacrolimus minimization or withdrawal. Methods Patients (n=180) received 6 mg/kg rATG, SD or four alternate-day doses (1.5 mg/kg/dose), with early steroid withdrawal and tacrolimus or sirolimus maintenance. After 6 months targeted maintenance levels were tacrolimus, 2 to 4 ng/mL and sirolimus, 4 to 6 ng/mL or, if calcineurin inhibitor–withdrawn, sirolimus 8 to 12 ng/mL with mycophenolate mofetil 2 g two times per day. Primary endpoints were renal function (abbreviated modification of diet in renal disease) and chronic graft histopathology (Banff). Secondary endpoints included patient survival, graft survival, biopsy-proven rejection, and infectious or noninfectious complications. Results Follow-up averaged longer than 4 years. Tacrolimus or sirolimus and mycophenolate mofetil exposure was identical between groups. The SD-rATG associated with improved renal function (2-36 months; P

Background: We aimed to evaluate and quantify the risk of serious opportunistic infections after induction with polyclonal antibodies versus IL-2 receptor antagonists (IL-2RAs) in randomized clinical trials. Methods: PRISMA guidelines were followed and random-effects models were performed. Results: 70 randomized clinical trials (10,106 patients) were selected: 36 polyclonal antibodies (n = 3377), and 34 IL-2RAs (n = 6729). Compared to controls, polyclonal antibodies showed higher risk of serious opportunistic infections (OR: 1.93, 95% CI: 1.34–2.80; p < 0.0001); IL-2RAs were associated with lower risk of serious opportunistic infections (OR: 0.80, 95% CI: 0.68–0.94; p = 0.009). Polyclonal antibodies were associated with higher risk of bacterial (OR: 1.58, 95% CI: 1.00–2.50; p = 0.049) and viral infections (OR: 2.37, 95% CI: 1.60–3.49; p < 0.0001), while IL-2RAs were associated with lower risk of cytomegalovirus (CMV) disease (OR: 0.73, 95% CI: 0.56–0.97; p = 0.032). Adjusted indirect comparison: compared to polyclonal antibodies, IL-2RAs were associated with lower risk of serious opportunistic infections (OR: 0.41, 95% CI: 0.34–0.49; p < 0.0001), bacterial infections (OR: 0.51, 95% CI: 0.39–0.67; p < 0.0001) and CMV disease (OR: 0.58, 95% CI: 0.34–0.98; p = 0.043). Results remained consistent across allografts. Conclusion: The risk of serious opportunistic infections, bacterial infections and CMV disease were all significantly decreased with IL-2RAs compared to polyclonal antibodies.

Stevens RB, Lane JT, Boerner BP, Miles CD, Rigley TH, Sandoz JP, Nielsen KJ, Skorupa JY, Skorupa AJ, Kaplan B, Wrenshall LE. Single-dose rATG induction at renal transplantation: superior renal function and glucoregulation with less hypomagnesemia. Clin Transplant 2012: 26: 123–132. © 2011 John Wiley & Sons A/S. Abstract: Background: Rabbit anti-thymocyte globulin (rATG) induction reduces reperfusion injury and improves renal function in kidney recipients by means of properties unrelated to T-cell lysis. Here, we analyze intensive rATG induction (single dose, rATGS, vs. divided dose, rATGD) for improved renal function and protection against hyperglycemia. Methods: Patients without diabetes (n = 98 of 180) in a prospective randomized trial of intensive rATG induction were followed for six months for the major secondary composite end point of impaired glucose regulation (hyperglycemia and new-onset diabetes after transplantation, NODAT). Prospectively collected data included fasting blood glucose and HbA1c. Serum Mg++ was routinely collected and retrospectively analyzed. Results: Induction with rATGS produced less impaired glucose regulation (p = 0.05), delayed NODAT development (p = 0.02), less hyperglycemia (p = 0.02), better renal function (p = 0.04), and less hypomagnesemia (p = 0.02), a factor associated with a lower incidence of NODAT. Generalized linear modeling confirmed that rATGS protects against a synergistic interaction between tacrolimus and sirolimus that otherwise increased hypomagnesemia (p = 0.008) and hyperglycemia (p = 0.03). Conclusions: rATGS initiated before renal reperfusion improved early renal function and reduced impaired glucose regulation, an injury by diabetogenic maintenance agents (tacrolimus and sirolimus).

Maintenance immunosuppression with sirolimus (SRL) in renal transplantation has been associated with proteinuria. We report long-term outcomes of kidney transplant recipients maintained on steroid-free regimens, either SRL with low-dose tacrolimus (SRL/L-Tac) or mycophenolate mofetil (MMF) with high-dose tacrolimus (MMF/H-Tac). We conducted a case-matched study of 50 patients receiving MMF/H-Tac, matched 1:2 with 100 patients maintained on SRL/L-Tac. All patients were induced with rabbit antithymocyte globulin followed by early steroid withdrawal. Comparisons were made of patient and graft survival, graft function, acute rejection, and albuminuria. There were no significant differences between the SRL/L-Tac and MMF/H-Tac groups for patient survival, graft survival, occurrence of acute rejection, or graft function. There was no difference in the proportion of patients with albumin/creatinine ratio (ACR) ≥300 μg/mg (19% vs. 20%), but more patients in the SRL group were receiving renin-angiotensin system blocking agents (72% vs. 53%, p = 0.04). Only flushing the donor kidney with histidine-tryptophan-ketoglutarate solution (vs. UW solution) was predictive of albuminuria. Long-term outcomes are similar at our center for kidney transplant patients receiving either SRL/L-Tac or MMF/H-Tac. Although the occurrence of albuminuria was not different, significantly more SRL-treated patients were receiving antiproteinuric medications.

Background. The 2003 International Consensus Guidelines defined new-onset diabetes after transplantation. This study determined the risk of new-onset diabetes following kidney transplantation using these criteria. Methods. Consecutive nondiabetic patients who received kidney transplantation between August 2001 and March 2003 (recent, n=61) and before August 2001 (earlier, n=61) were retrospectively evaluated. Results. In all, 74% in the recent group and 56% in the earlier group developed diabetes by 1 year posttransplant. Median time to diabetes development was 23 days in the recent vs. 134 days in the earlier group (P=0.0304). Most patients developed diabetes within 60 days after transplantation. Immunosuppression was the strongest correlate of diabetes development; tacrolimus and cyclosporine A treatments were associated with increased risk. The rate of development was also greater when rapamycin was added to tacrolimus, compared to when it was not. The risk was double in African-Americans compared to whites. Age, body mass index, family history of diabetes, and etiology of renal failure did not predict diabetes; however, the mean age of patients was greater than previously reported. Conclusions. The majority of patients are at risk of developing new-onset diabetes within a short time after kidney transplantation. The risk may be due to preexisting risk factors, immunosuppressive agents, or older age. The significance of these findings is not clear, but demands appropriate follow-up studies related to glycemia, end-organ complications, and graft function. It remains to be determined whether the 2003 International Consensus Guidelines are adequate to appropriately diagnose diabetes in the posttransplant time period, with special emphasis on the first 3 months.

Iliac arteries in allograft pancreas recipients may be compromised by the patient's underlying disease or previous surgical intervention. We describe a previously unreported arterial reconstruction using an extended segmental common/external iliac artery patch with anastomosis of the pancreatic Y-graft to the patch internal iliac artery, and review the options for arterial reconstruction reported by others. This technique may find application in both pancreas and kidney transplantation to salvage a damaged or diseased iliac artery.

Although West Nile fever is mild in the vast majority of infected persons, there is growing evidence that the disease may be more severe in the immunocompromised population. We describe 3 recipients of kidney or pancreas transplants who developed West Nile fever, 2 of whom had meningoencephalitis. As is the norm when treating serious infections in transplant recipients, a reduction of immunosuppression was pursued for these patients. Despite the severe nature of the disease in 2 patients, all recovered from the disease. The time course of neurologic recovery in the 2 patients with meningoencephalitis is highlighted. We also review the literature on West Nile fever in organ transplant recipients. In areas where West Nile virus is endemic, one must have a high index of suspicion for the illness when dealing with fever in transplant recipients.

Introduction The two most significant impediments to renal allograft survival are rejection and the direct nephrotoxicity of the immunosuppressant drugs required to prevent it. Calcineurin inhibitors (CNI), a mainstay of most immunosuppression regimens, are particularly nephrotoxic. Until less toxic antirejection agents become available, the only option is to optimize our use of those at hand. Aim To determine whether intensive rabbit anti-thymocyte globulin (rATG) induction followed by CNI withdrawal would individually or combined improve graft function and reduce graft chronic histopathology–surrogates for graft and, therefore, patient survival. As previously reported, a single large rATG dose over 24 hours was well-tolerated and associated with better renal function, fewer infections, and improved patient survival. Here we report testing whether complete CNI discontinuation would improve renal function and decrease graft pathology. Methods Between April 20, 2004 and 4-14-2009 we conducted a prospective, randomized, non-blinded renal transplantation trial of two rATG dosing protocols (single dose, 6 mg/kg vs. divided doses, 1.5 mg/kg every other day x 4; target enrollment = 180). Subsequent maintenance immunosuppression consisted of tacrolimus, a CNI, and sirolimus, a mammalian target of rapamycin inhibitor. We report here the outcome of converting patients after six months either to minimized tacrolimus/sirolimus or mycophenolate mofetil/sirolimus. Primary endpoints were graft function and chronic histopathology from protocol kidney biopsies at 12 and 24 months Results CNI withdrawal (on-treatment analysis) associated with better graft function (p

IN BRIEFShapiro and colleagues recently reported a 100% cure rate for type 1 diabetes with their “Edmonton protocol” for islet transplantation. This unprecedented success has caused a groundswell of enthusiasm and an unparalleled effort to replicate their experience. It has also raised questions about the clinical reality of this therapy and sparked a dialog about which patients should benefit from receiving this scarce allocated resource. This article reviews the factors contributing to the Edmonton success and obstacles to immediate and long-term expansion of islet transplantation. The authors argue that use of the two-layered method of pancreas preservation will enable the Edmonton protocol to cure diabetes from single and marginal cadaveric donors. A concerted effort will be required to expedite routing of pancreases to islet processing centers and transplant programs. The long-term success and expansion of islet transplantation will depend on not only safer forms of immunosuppression, but also new sources of islet tissue.

Background. How the localization of antigen to the liver, through means such as oral ingestion, induces tolerance is poorly understood. Methods. To elucidate potential mechanisms we used an adoptive transfer system wherein ova-specific T cells were infused into a syngeneic host, and antigen-specific T-cell responses after delivery of soluble antigen into the liver were monitored. Results. After infusion of antigen into the portal vein, the frequency of antigen-specific T cells in lymph nodes draining the liver was lower than the frequency in peripheral lymph nodes. These findings were the reverse of what is typically observed after subcutaneous injection of antigen with adjuvant. Infusion of antigen with adjuvant into the portal vein did not alter this pattern of antigen-specific T-cell localization; however, an increased frequency of T cells, compared with antigen alone, was observed in peripheral lymph nodes and spleen. After exposure to antigen via the portal vein, T cells isolated from lymph nodes draining the liver and challenged with antigen in vitro exhibited a diminished proliferative response compared with T cells isolated from nondraining lymph nodes. This hyporesponsiveness was not observed when the antigen was administered with adjuvant. Conclusions. Our findings suggest that the influence of the liver on immune responses might reflect two processes: (1) loss of antigen-specific T cells after primary antigen injection, and (2) hyporesponsiveness on reexposure to antigen. These mechanisms may contribute to the prevention of undesirable immune responses to foods and enteric bacteria in the gastrointestinal tract. Furthermore, these results underscore the importance of minimizing inflammation in circumstances such as islet transplantation, if endogenous mechanisms of tolerance induction are to be maximized.

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.

Background: Simultaneous kidney-pancreas transplantation has become a recognized therapy for type I diabetes mellitus patients with diabetic nephropathy, neuropathy, and retinopathy. In the vast majority of these procedures, both grafts are placed intraperitoneally, which reduces posttransplant morbidity. Recently, in some of our recipients, we noted renal dysfunction related to complications of the renal pedicle. Our objectives in this study were to identify the cause of this renal dysfunction and to prevent its occurrence in future recipients. Study Design: We undertook a retrospective chart review of simultaneous kidney-pancreas recipients who experienced renal dysfunction related to renal pedicle complications. Results: We found four recipients with renal dysfunction related to renal pedicle torsion, diagnosed by serial ultrasound scans and kidney graft biopsies. Early diagnosis allowed salvage of three kidney grafts, but one was lost after late diagnosis. Conclusions: A high level of suspicion is needed to diagnose renal pedicle torsion. If simultaneous kidney-pancreas recipients have recurrent renal dysfunction, and rejection has been excluded, serial ultrasound scans with color flow Doppler examinations are needed. Once the diagnosis is made, a nephropexy to the anterior abdominal wall is indicated to prevent further torsion and save the kidney graft. We recommend prophylactic nephropexy of left renal grafts if the renal pedicle is ≥5 cm long and if there is a 2 cm or more discrepancy between the length of the artery and the vein.

Evidence presented in this paper indicates that nitric oxide (NO), generated by a nonspecific "wound"-type of inflammation, is an important mediator of the early dysfunction of transplanted islets in rodents. Although allogeneic islets stimulate NO production to a greater degree than syngeneic islets, the amounts of NO produced after either are significantly elevated above baseline. Inhibition of NO production by N(G)-monomethyl-L-arginine (NMA), markedly decreases the time needed to restore euglycemia after intraportal transplantation of syngeneic islets in diabetic rats. The dose of NMA used was not observably toxic, with no significant changes in blood pressure, hepatic artery blood flow, serum hepatic enzyme levels, or in weight compared with control animals. In rat recipients of intraportal syngeneic transplants, evidence that NO is produced at the site of implantation includes (1) an early and transient increase in posttransplant hepatic vein nitrate levels (pretransplant, 90 microM; 24 hr, 230 microM; 48 hr, 250 microM; 72 hr, 170 microM; and 96 hr, 140 microM), (2) concurrent appearance of inducible NO synthase mRNA in liver extracts, and (3) immunohistochemical localization of inducible NO synthase within the transplanted islets. Suppression of NO production or inhibition of NO activity is a potential strategy to increase the early function and engraftment transplanted islets in the clinical setting.

Atherosclerosis is associated with aging based on numerous epidemiologic studies, whereas arterial wall hypoxia has been associated with other risk factors for atherosclerosis. We studied the effect of age on the transarterial wall oxygen gradient in the rat using an oxygen microelectrode. A decrease in oxygen tension in the outer 35% of the artery wall was noted in 36- to 40-week-old rats when compared to 3- to 4-week-old rats. These findings were noted despite no difference in arterial blood oxygen tension between the two groups and prior to any histologic evidence of atherosclerotic lesion formation. Our observations suggest that aging decreases the delivery of oxygen to the outer artery wall.

Background The Thymoglobulin Antibody Immunosuppression in Living Donor Recipients registry was established to assess clinical experience with rabbit antithymocyte globulin (rATG; Thymoglobulin) in living donor renal transplant recipients. Methods From 2003 to 2008, US transplant centers prospectively entered information on patients who received rATG induction. In addition to standard United Network for Organ Sharing registry data elements, information was collected regarding immunosuppression, viral prophylaxis, acute rejection, and adverse events. Results Data on 2322 patients from 49 transplant centers were enrolled and met inclusion criteria for analysis. Patient and graft survival were 99.3% and 99.0% at 6 months and 98.4% and 98.2% at 12 months as recorded in Thymoglobulin Antibody Immunosuppression in Living Donor Recipients registry and were 91.5% and 83.2% at 5 years by Kaplan-Meier estimates based on linked United Network for Organ Sharing registry records. Freedom from rejection was 93.6% through 5 years. Mean rATG cumulative dose was 5.29 mg/kg. More than one-third of patients (37.6%) were steroid-free at discharge, and nearly half of patients (48%) were steroid-free at 12 months. Before discharge, 3.2% experienced serious adverse events, with 11 events (0.005%) reported as possibly or probably related to rATG. Incidence of cytomegalovirus infection was 4.2% at 12 months, and 99.1% of patients were posttransplant lymphoproliferative disorder-free through 5 years. Conclusions rATG induction in living donor renal transplantation is safe and associated with a low incidence of acute rejection and posttransplantation complications.

Products of inflammation, such as interleukin-1 beta (IL-1 beta) and nitric oxide (NO), may impair early function of pancreatic islet grafts. In in vitro studies, freshly isolated rat islets of Langerhans cultured for 24 hr (10 islets/well) in the presence of 20 IU/ml of IL-1 beta released 57% less insulin (mean +/- S.E. of 151 +/- 61 microU) on the average than control (385 +/- 89 microU) cultures (n = 9, P = 0.08). Nitrite levels in the medium (indirect measure of NO) after islets were cultured for a 24-hr period were nearly 3-fold greater in IL-1 beta-exposed islets than control islet cultures (5.8 +/- 1.0 microM vs. 2.2 +/- 0.3 microM, P = 0.03). Production of nitrite by islet cells in the presence of IL-1 beta was inhibited in cultures also containing 2 mM L-NG-monomethyl-Arginine (L-NMMA) (3.4 +/- 0.4 microM, n = 9, P = 0.09 vs. control). When islets were maintained for 1 hr in 30 mg/dl glucose followed by 300 mg/dl for 1 hr, insulin release (stimulated) increased 6-fold (from 7 +/- 2 to 45 +/- 11 microU) in control cultures but only 3-fold (from 4 +/- 2 to 12 +/- 4 microU) in IL-1 beta-exposed cultures (n = 9, P = .01). Addition of 2 mM L-NMMA to islet cultures in the presence of IL-1 beta (20 IU/ml) (n = 9) restored insulin release to normal (from 6 +/- 2 to 38 +/- 9 microU, P > or = 0.6), suggesting that NO mediates the inhibitory effect of IL-1 beta on beta-cell function. In in vivo studies, rats with streptozotocin-induced diabetes (blood glucose > 400 mg/dl) received minimal (750 hand-picked islets) intraportal beta cell mass isografts with (n = 5) or without (n = 9) treatment with 100 mg/7 days of L-NMMA from 3 days before transplantation to 4 days after transplantation (POD -3 to +4). L-NMMA-treated rats became euglycemic (glucose < 200 mg/dl) earlier than nontreated rats (mean +/- SD of 6.4 +/- 2.5 vs. 16.7 +/- 4.7 days posttransplant, P = 0.001). These findings support the hypothesis that NO is a mediator of beta cell dysfunction after intraportal transplantation of freshly isolated islets of Langerhans.

Interleukin-2 (IL-2) is a multifaceted cytokine with immunostimulatory and immunosuppressive properties. Our laboratory recently demonstrated that the availability of IL-2 is regulated, in part, by association with perlecan, a heparan sulfate proteoglycan. Given the abundance of perlecan in blood vessels, we asked whether IL-2 is present in vessel walls. Our results indicate that IL-2 is associated with endothelial and smooth muscle cells within the human arterial wall. This IL-2 is released by heparanase, and promotes the proliferation of an IL-2-dependent cell line. Given the presence of IL-2 in human arteries, we asked whether the large vessels of IL-2-deficient mice were normal. The aortas of IL-2-deficient mice exhibited a loss of smooth muscle cells, suggesting that IL-2 may contribute to their survival. In their entirety, these results suggest a here-to-fore unrecognized role of IL-2 in vascular biology, and have significant implications for both the immune and cardiovascular systems.

Rabbit anti-thymocyte globulin (rATG) induction reduces reperfusion injury and improves renal function in kidney recipients by means of properties unrelated to T-cell lysis. Here, we analyze intensive rATG induction (single dose, rATG(S) , vs. divided dose, rATG(D) ) for improved renal function and protection against hyperglycemia.Patients without diabetes (n = 98 of 180) in a prospective randomized trial of intensive rATG induction were followed for six months for the major secondary composite end point of impaired glucose regulation (hyperglycemia and new-onset diabetes after transplantation, NODAT). Prospectively collected data included fasting blood glucose and HbA(1c). Serum Mg(++) was routinely collected and retrospectively analyzed.Induction with rATG(S) produced less impaired glucose regulation (p = 0.05), delayed NODAT development (p = 0.02), less hyperglycemia (p = 0.02), better renal function (p = 0.04), and less hypomagnesemia (p = 0.02), a factor associated with a lower incidence of NODAT. Generalized linear modeling confirmed that rATG(S) protects against a synergistic interaction between tacrolimus and sirolimus that otherwise increased hypomagnesemia (p = 0.008) and hyperglycemia (p = 0.03).rATG(S) initiated before renal reperfusion improved early renal function and reduced impaired glucose regulation, an injury by diabetogenic maintenance agents (tacrolimus and sirolimus).

The history of ascorbic acid (AA) and cancer has been marked with controversy. Clinical studies evaluating AA in cancer outcome continue to the present day. However, the wealth of data suggesting that AA may be highly beneficial in addressing cancer-associated inflammation, particularly progression to systemic inflammatory response syndrome (SIRS) and multi organ failure (MOF), has been largely overlooked. Patients with advanced cancer are generally deficient in AA. Once these patients develop septic symptoms, a further decrease in ascorbic acid levels occurs. Given the known role of ascorbate in: a) maintaining endothelial and suppression of inflammatory markers; b) protection from sepsis in animal models; and c) direct antineoplastic effects, we propose the use of ascorbate as an adjuvant to existing modalities in the treatment and prevention of cancer-associated sepsis.

Maintenance immunosuppression with sirolimus (SRL) in renal transplantation has been associated with proteinuria. We report long-term outcomes of kidney transplant recipients maintained on steroid-free regimens, either SRL with low-dose tacrolimus (SRL/L-Tac) or mycophenolate mofetil (MMF) with high-dose tacrolimus (MMF/H-Tac). We conducted a case-matched study of 50 patients receiving MMF/H-Tac, matched 1:2 with 100 patients maintained on SRL/L-Tac. All patients were induced with rabbit antithymocyte globulin followed by early steroid withdrawal. Comparisons were made of patient and graft survival, graft function, acute rejection, and albuminuria. There were no significant differences between the SRL/L-Tac and MMF/H-Tac groups for patient survival, graft survival, occurrence of acute rejection, or graft function. There was no difference in the proportion of patients with albumin/creatinine ratio (ACR) ≥300 μg/mg (19% vs. 20%), but more patients in the SRL group were receiving renin-angiotensin system blocking agents (72% vs. 53%, p = 0.04). Only flushing the donor kidney with histidine-tryptophan-ketoglutarate solution (vs. UW solution) was predictive of albuminuria. Long-term outcomes are similar at our center for kidney transplant patients receiving either SRL/L-Tac or MMF/H-Tac. Although the occurrence of albuminuria was not different, significantly more SRL-treated patients were receiving antiproteinuric medications.

New strategies that modify the coagulation/inflammatory cascades may be applicable to solid organ transplant (SOT) recipients in the treatment of complications. However, data on kinetics of post-SOT cascades are needed before considering these strategies. Prospectively collected pre-transplant serum measurements of inflammatory (high-sensitive C-reactive protein, HS-CRP) and coagulation (d-Dimer, DD; protein C, PC) markers were compared to post-operative (day 1–90) values in deceased-donor liver (DDLT) and renal (DDRT) transplant recipients, living-related renal recipients (LRT) and donors (LRD). A total of 85 SOT were enrolled: 25 DDLT, 32 DDRT/LRT, 28 LRD. HS-CRP increased in all groups, mainly immediate post-SOT and in LRDs. DD had a similar pattern mainly in LRT and LRD. PC increased significantly over time in the DDLT group ( p

Background The optimal dosing protocol for rabbit anti-thymocyte globulin (rATG) induction in renal transplantation has not been determined, but evidence exists that rATG infusion before renal allograft reperfusion improves early graft function. Infusing a large rATG dose over a short interval has not previously been evaluated for its effect on renal function and allograft nephropathy in a prospective, randomized comparison against conventional rATG induction. Methods Between April 20, 2004 and December 26, 2007 we enrolled renal transplant patients into a prospective, randomized, nonblinded trial of two rATG dosing protocols (single dose, 6 mg/kg vs. divided doses, 1.5 mg/kg every other day x 4; target enrollment=160) followed after 6 months by calcineurin-inhibitor withdrawal. Primary endpoints are renal function by calculated glomerular filtration rate (GFR) and chronic allograft nephropathy at protocol biopsy. We now present the early GFR data of all 160 patients and safety and efficacy data of the first 142 patients with 6 months follow up and before calcineurin inhibitor withdrawal (average follow up=23.3+/-11.6 months). Results There were no differences between groups in rATG-related adverse events, patient and graft survival, acute rejection, or chronic allograft nephropathy rate at 6 months. Calculated DeltaGFR (POD 1-4) was significantly better in the single-dose group (P=0.02), with a trend toward improved renal function from months 2 to 6 in recipients of deceased donor kidneys (P=0.08). Conclusions This study demonstrates that administering 6 mg/kg of rATG over 24 hr is safe and is associated with improved early renal function compared with administering rATG in alternate-day doses.

Background. Patients with diabetes have been reported to have greater dyslipidemia after kidney transplant (KTX). Because postKTX management of diabetes has changed markedly since those reports, we hypothesized that lipids can be controlled as well in diabetic as in nondiabetic recipients. Methods. We compared lipid levels up to 2 years after KTX ( n= 192) between diabetic and nondiabetic recipients. The cohort was subdivided into nondiabetic (nonDM-K; n=123), type 2 (DM2-K; n=33), or type 1 diabetes after KTX (DM1-K; n= 14), or type 1 after kidney-pancreas transplant (DM1-KP; n=22). Results. Mean age and body mass index of DM2-K were greater than the others (P

Background: Gender differences in graft survival has been reported after some types of organ transplantation, but not after pancreas transplantation. This study compares graft survival between women and men after simultaneous pancreas–kidney transplantation (SPK). Methods: All first time SPK (n = 163) transplants (109 M/54 F) performed between 1989 and 2000 at University of Nebraska Medical Center, where data was available, were analyzed for overall graft and patient survival. Graft failure was then subdivided into early ( 6 months), and compared between women and men. Results: The 5-yr pancreas and kidney graft survival rates for all SPK recipients was 86% [95% confidence interval (CI) = 81–92%] and 87% (95% CI = 82–93%), respectively. While overall pancreas graft survival in women was similar to men (p = 0.16), early pancreas graft failure was greater in women than men (p = 0.010) with no one cause for failure predominant. There was no gender difference in late pancreas graft failure or in early, or late kidney graft failure in the same recipients. The gender difference was unexplained by differences in age, immunosuppression, body mass index (BMI), or diabetes duration between women and men. Conclusions: This is the first report of a gender difference in pancreas graft survival after SPK with greater early (

Previous reports indicate that the two-layer method (TLM) of human pancreas preservation is superior to University of Wisconsin solution (UW) when pancreata are preserved for extended periods (i.e.,24 h) prior to islet isolation. In this study, the efficacy of using the TLM for preserving pancreata for short periods (i.e.,13 h) was evaluated using both nonhuman primate and human pancreata preserved with a TLM kit precharged with oxygen. An oxygen precharged TLM (static TLM) was established and compared with the original TLM with continuous oxygen supply. For the static TLM, the perfluorochemical was fully oxygenated and the oxygen supply removed prior to pancreas preservation. In the primate model, pancreata were preserved by the static TLM, the original TLM, and UW for 5 h prior to islet isolation. In the human model, pancreata were preserved with the static TLM or the original TLM or UW for 4-13 h. Both primate and human pancreata were processed by intraductal collagenase injection and digestion followed by continuous density gradient purification to isolate islets. Islets were assessed for islet yield, purity, viability, and in vitro functionality. In the primate model, islet yield, viability, and in vitro functionality were significantly improved by both the static TLM and the original TLM with similar results. Postculture islet yields were 23,877 +/- 3619 IE/g in the static TLM, 21,895 +/- 3742 IE/g in the original TLM, and 6773 +/- 735 IE/g in UW. In the human model, both the static TLM and the original TLM significantly increased islet yield compared with UW with postculture islet yields of 2659 +/- 549 IE/g in the static TLM, 2244 +/- 557 IE/g in the original TLM, and 1293 +/- 451 IE/g in UW. Nonhuman primate and human pancreata stored in the static TLM, immediately upon procurement, yield isolated islets of a substantially higher quantity than when pancreata are stored in UW. Thus, the use of the static TLM should replace the use of UW for storage of pancreata during transport prior to islet isolation.

We tested whether two-layer method (TLM) pancreas preservation and trypsin inhibition (Pefabloc) during processing allows longer preservation while retaining or improving viable islet recovery. Non-marginal primate (Macaca nemestrina) and marginal human (ischemic or preservation-injured) pancreata were processed with a research-oriented pan technique (Seattle method). Organs were processed upon arrival (+/- Pefabloc), or after TLM or University of Wisconsin solution (UW) preservation (+ Pefabloc). Islet yield, viability, and function were assessed. Pefabloc increased M. nemestrina islet yields from 9696 +/- 1749 IE/g to 15 822 +/- 1332 IE/g (p0.01). Two-layer method preservation (6 h) further increased yields, to 23 769 +/- 2773 IE/g (vs. + Pefabloc; p0.01). Similarly, Pefabloc increased marginal human islet yields from 2473 +/- 472 IE/g to 4723 +/- 1006 IE/g (p0.04). This increase was maintained after lengthy TLM preservation (30 h; 4801 +/- 1066 IE/g). We also tested the applicability of TLM preservation (23.5 +/- 3.2 h) to the processing of marginal human pancreata by the Edmonton/Immune Tolerance Network clinical protocol. Islet yield and function approached published results of pancreata processed 4.8 +/- 0.8 h after organ recovery (p = 0.06). Pefabloc, and TLM vs. UW preservation, prolonged the tolerable interval between organ recovery and islet isolation. Islet yield, viability, and functionality improved from both marginal and nonmarginal pancreata.

There is increasing evidence that the behavior of antigen-presenting cells may be regulated, in part, by the surrounding microenvironment. Components of the microenvironment of solid tissues that might influence antigen-presenting cell functions include glycosaminoglycans. We previously showed that heparan sulfate glycosaminoglycans activate macrophages, leading to profound alterations in T cell responses. Here we demonstrate the functional changes that occur in murine antigen-presenting cells induced by heparan sulfate and other glycosaminoglycans, and postulate how these functional changes influence the nature of local immune responses. Heparan sulfate triggered up-regulation of ICAM-1 and I-A, caused the release by antigen-presenting cells of interleukin (IL)-1, IL-6, tumor necrosis factor, IL-12, transforming growth factor β, and prostaglandin E2 (PGE2), and (in macrophages) induced cytotoxic capability. Heparin induced IL-12 and interferon-γ production but did not promote the release of other cytokines. Chondroitin sulfate and dermatan sulfate, although not stimulating the production of cytokines or of PGE2, elicited the production by macrophages of nitric oxide. These findings support a model in which the glycosaminoglycan composition of a given tissue, which may be altered by inflammatory processes, helps to regulate the behavior of antigen-presenting cells, which in turn determines the characteristics of the immune response that ensues. J. Leukoc. Biol. 66: 391–400; 1999.

A critical shortage of donor organs has driven many in the transplantation community to consider the use of animals as organ donors for humans, that is, xenotransplantation. While successful xenotransplantation of primate kidneys was achieved 25 years ago, most now advocate use of nonprimates as donors because of the risk of disease transmission and ethical concerns attendant to the use of primates. The major hurdle to xenotransplantation of organs between phylogenetically disparate species is the hyperacute rejection reaction that invariably destroys organ xenografts placed in unmodified recipients. Here we review recent insights concerning the pathogenesis of hyperacute rejection reactions. We focus particular attention on the endothelial cell, which serves not only as the target of xenoreactive antibodies and complement, but also, as a consequence of endothelial cell activation, as an instrument of tissue injury. We discuss a phenomenon called "accommodation" in which an organ graft acquires resistance to humoral-mediated injury.