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We aimed to evaluate the influence of urological complications occurring within the first year after kidney transplantation on long‐term patient and graft outcomes, and sought to examine the impact of the management approach of ureteral strictures on long‐term graft function. We collected data on urological complications occurring within the first year posttransplant. Graft survivals, patient survival, and rejection rates were compared between recipients with and without urological complications. Male gender of the recipient, delayed graft function, and donor age were found to be significant risk factors for urological complications after kidney transplantation (P< .05). Death censored graft survival analysis showed that only ureteral strictures had a negative impact on long‐term graft survival (P= .0009) compared to other complications. Death censored graft survival was significantly shorter in kidney recipients managed initially with minimally invasive approach when compared to the recipients with no stricture (P= .001). However, graft survival was not statistically different in patients managed initially with open surgery (P= .47). Ureteral strictures following kidney transplantation appear to be strongly negatively correlated with long‐term graft survival. Our analysis suggests that kidney recipients with ureteral stricture should be managed initially with open surgery, with better long‐term graft survival. Retrospective analyses show that ureteral strictures following kidney transplantation are negatively correlated with long‐term graft survival and that open surgical management seems to be a better approach to treat these strictures.

This study of “for‐cause” pancreas allograft biopsies in transplant recipients demonstrates that antibodymediated rejection occurs in approximately 10% of patients in the first year with associated risk factors including retransplantation, solitary pancreas transplantation and donor‐recipient race mismatch.

Alemtuzumab induction with 60 days of tacrolimus treatment and continuous sirolimus treatment prevented acute rejection in nine of 10 consecutive renal allograft recipients. All patients are alive with a functioning kidney graft at 27-39 months of follow-up. Extensive immune monitoring was performed in all patients. Alloantibody detection, cytokine kinetics assay (CKA), and trans vivo delayed-type hypersensitivity (DTH) assay were performed every 6 months showing correlation with clinical evolution. Despite alloantibody presence in five patients, eight patients remain without the need for specific treatment and only sirolimus monotherapy in decreasing dosage. Four patients take only 1 mg sirolimus daily with levels of 3-4 ngmL. One patient showed clinical signs of rejection at month 9 post-transplant, with slow increase in serum creatinine and histological signs of mixed cellular (endarteritis) and humoral rejection (C4d positivity in peritubular capillaries and donor-specific antibody (DSA)). In summary, the addition of tacrolimus therapy for 2 months to a steroid-free, alemtuzumab induction and sirolimus maintenance protocol limited the previously shown acute rejection development. Nevertheless, alloantibody was present in serum andor C4d present on 1-year biopsy in half the patients. The combination of CKA and DSA monitoring or the performance of transvivo DTH correlated with immune status of the patients.

Alemtuzumab is a humanized, rat monoclonal antibody directed against the CD52 antigen. After binding, alemtuzumab causes profound and durable depletion and has been successfully used as immune induction therapy for organ transplantation.

To address the results of calcineurin inhibitor (CNI) withdrawal after alemtuzumab induction relative to CNI continuation, we performed a pilot randomized clinical trial in renal allograft recipients on CNI, a mycophenolic acid derivative and steroids after the first 2 months posttransplantation. Forty patients were randomized to taper off CNI or to maintain it, and followed for at least 1 year. Four patients in the withdrawal group were treated for acute rejection while no patient received antirejection treatment in the control group. Two control patients withdrew CNI due to nephrotoxicity. Estimated GFR was similar in both groups after 1 year. Flow cytometry of CD4CD25CTLA-4FoxP3regulatory T cells (Treg) demonstrated a significant increase in Treg percentages in the peripheral blood of alemtuzumab-treated patients on CNI early postransplant. Furthermore, the increased Treg percentages in the withdrawal cohort were unchanged at month 6 postenrollment, whereas they decreased significantly in those patients maintained on CNI. Patients withdrawn from CNI after alemtuzumab trend toward a higher rejection rate, but most patients can be weaned from a CNI using this regimen. With the exception of maintaining increased Treg levels, the benefits are not appreciable in this short follow-up, and a larger randomized trial is justified.

The optimal use of kidneys from small pediatric deceased donors remains undetermined. Using data from the Scientific Registry of Transplant Recipients, 2886 small (<21 kg) pediatric donors between 1993 and 2002 were identified. Donor factors predictive of kidney recovery and transplantation (1343 en bloc; 1600 single) were identified by logistic regression. Multivariable Cox regression was used to assess the risk of graft loss. The rate of kidney recovery from small pediatric donors was significantly higher with increasing age, weight and height. The odds of transplant of recovered small donor kidneys were significantly higher with increasing age, weight, height and en bloc recovery (adjusted odds ratio = 65.8 vs. single; p < 0.0001), and significantly lower with increasing creatinine. Compared to en bloc, solitary transplants had a 78% higher risk of graft loss (p < 0.0001). En bloc transplants had a similar graft survival to ideal donors (p = 0.45) while solitary transplants had an increased risk of graft loss (p < 0.0001). En bloc recovery of kidneys from small pediatric donors may result in the highest probability of transplantation. Although limited by the retrospective nature of the study, kidneys transplanted en bloc had a similar graft survival to ideal donors but may not maximize the number of successfully transplanted recipients.

Hypoalbuminemia is associated with poorer outcomes in renal transplantation. Diabetes can compound hypoalbuminemia's detrimental effects. Kidney-pancreas transplantation alters the diabetic milieu; yet, some patients continue to be hypoalbuminemic.

Organ culture of murine thyroid allografts in hyperbaric oxygen (95 O2at 25 psi, 37°C) for 48 hr, results in prolonged allograft survival. Endocrine tissues can be cultured at 37°C—however, this method may not be applicable to vascularized organs at normothermia. The aim of this study was to apply hyperbaric oxygen culture (HOC) under organ preservation conditions (hypothermia, UW solution) that have been shown to be successful in clinical organ transplantation. B10BR/SGSNJ murine thyroid lobes were transplanted beneath the kidney capsule of C57BL/10J recipients. Thyroids were cultured in Eagle's MEM at 37°C (controls) and at 5°C, under hyperbaric conditions (95 O2:5 CO2, 25 psi). Alternatively, thyroids were cultured in UW solution (± allopurinol/GSH) at 5°C, for up to 7 days. Graft survival was determined 21 days posttransplant by 125I uptake and by histology. In Eagle's MEM, HOC at 37°C/48 hr and 5°C/7 days, resulted in 93 and 20 allograft survivals, respectively. In UW solution (- allopurinol/glutathione [GSH]), HOC at 5°C/7 days resulted in 83 allograft survival: immunoperoxidase staining showed a decrease of MHC class I alloantigen expression. Oxygen free radical scavenger (allopurinol/GSH) addition to the UW solution diminished this effect and suggested an oxygen free radical—mediated mechanism in immunoalteration. These results demonstrate that HOC for 7 days reduced the antigenicity and immunogenicity of murine thyroid grafts under conditions that simulate organ preservation. Hypothermic hyperbaric oxygen culture conditions require testing in a higher animal species and in vascularized grafts to determine if this method can be applied to whole-organ transplantation.

Fox kidney and skin grafts were transplanted into dog recipients. Fox kidneys, transplanted en bloc into untreated dogs, survived 6.2 ± 0.4 days. The skin transplants survived 5.9 ± 1.4 days. The grafted kidneys showed almost normal function before rejection. Both skin and kidney rejection were mediated through a cellular mechanism. Preformed natural antibodies against donor tissue were not present in the serum of the recipients. These results combined with absorption studies suggested a close relationship between fox and dog, but different number and morphology of chromosomes, immunoelectrophoretic patterns of serum proteins, and disparities of the transplantation antigens proved that the fox is a species quite separate from the dog. It was concluded that the fox-dog system, with its similarity to the chimpanzeeman relationship, offers a unique model to study clinically applicable methods of managing xenografts between closely related species.

Canine thyroid tissue (CTy) was subjected to hyperbaric oxygen culture (HOC) under conditions that affect immunoalteration in murine thyroid tissue (MTy). Survival of autografts and allografts implanted under the kidney capsule was determined after 21 days by 125I uptake and histology. Unlike MTy, autograft CTy subjected to normothermic HOC (95% O2, 5% CO2; 1.76kg/cm2) for 48 h did not survive (0/8) whereas decrease of culture duration to 24 h resulted in autograft CTy survival (3/3). Under hypothermia (5°C), HOC could be extended to 7 days with autograft CTy survival (3/3 after 4 days and 3/3 after 7 days). Allograft CTy after 24 h of normothermic HOC and 7 days of hypothermic HOC was rejected. Indicators of oxygen free radical injury were determined: catalase activity was comparable in MTy and CTy (means 14.82 and 6.3–10.8 mm/mg protein, respectively) but superoxide dismutase activity was low in CTy (means 0.01–0.29 and 4.75 U/mg protein, respectively). Malondialdehyde content after 48 h of normothermic HOC was higher in CTy than in MTy (means 2215 and 1275 nmol/g, respectively). The results show that CTy is injured by HOC under conditions tolerated by MTy, and that this difference is related to the greater sensitivity of CTy to oxygen free radical injury.

Early graft rejection crises in renal transplant patients pretreated with donor-specific transfusions (DST) have been attributed to an antibody-mediated reaction, or an in situ primed lymphocyte test (PLT) reaction in the grafted kidney resulting from priming of recipient T cells. To test these hypotheses, we analyzed the mixed lymphocyte culture (MLC) response to donor stimulator cells in 18 DST + azathioprine (AZA)-treated patients, including 7 with living-nonrelated donors (2 HLA-hap-lotype mismatch) and 11 with living-related donors (1 HLA-haplotype mismatch). Studies of the kinetics of anti-donor MLC responses of PBL obtained from patients before and after DST + AZA treatment revealed shifts in the magnitude and timing of antidonor MLC response. We found an increased peak MLC response to donor and/or third-party in 6/18 patients, 4 of whom had early rejection crises; the other 2 patients had blocking factors in their post-DST plasma that strongly (57− 71) inhibited their MLC response. Plasma factors were implicated in the mechanism of early graft crisis, in that patients with an enhanced MLC response in the presence of post-DST plasma showed a significantly (P<.02) shorter time to first rejection episodes as compared with patients with plasma blocking factors. Finally, we confirmed the findings of others that a significant proportion (7/18) of DST + AZA-treated patients had a decreased MLC response. Although such patients experienced classic (2nd week or later) rejection episodes, none had a DST-type (<3 day) crisis. Our data supports the concept of T cell priming by DST, and suggests that patients who fail to develop concomitant suppressor cells or humoral blocking factors will develop a rapid onset cellular rejection crisis in the transplanted kidney.

Human fetal pancreas (HFP) represents an ideal tissue source for transplantation into diabetic patients. Transplantation of HFP lacks many of the technical problems associated with whole organ transplantation and HFP is readily available. In order to proceed with clinical HFP transplantation it must be demonstrated that HFP can reverse experimentally induced diabetes, that HFP can respond to glucose challenge in a manner similar to adult tissue, and that the immunogenicity of HFP can be reduced. We transplanted HFP (13–17 weeks gestational age) beneath the kidney capsule of streptozotocin-induced diabetic BALB/c nu/nu mice. Within 6 to 8 weeks following transplantation, 6 out of 7 (88) animals became normoglycemic. Oral glucose tolerance tests were performed to determine in vivo graft function. Results in cured animals 'were identical to those of normal BALB/c nu/nu mice. In vitro insulin response to glucose challenge demonstrated that grafted HFP was capable of insulin secretion in the presence of high glucose while fresh fetal tissue was not. Human passenger leukocytes, identified immunohistologically at various times after transplantation with monoclonal antibodies to HLA-DR and Leu 10, were greatly reduced by 32 weeks posttransplant. Our data demonstrate that HFP will differentiate and mature in the diabetic nude mouse and that human passenger leukocyte content can be reduced. These findings suggest that HFP is functionally suitable for transplantation into diabetic patients.

Mycophenolate mofetil (MMF), a new immunosup-pressant that selectively inhibits proliferation of T and B lymphocytes, may reduce the frequency and severity of acute graft rejection. Acute graft rejection is the leading cause of graft loss in cadaveric renal transplantation. The purpose of this randomized, double-blind, multicenter study was to evaluate the efficacy and safety of MMF for the prevention of acute rejection episodes in adult patients during the first 6 months after renal transplantation. A total of 499 patients who were to receive a primary cadaveric renal allograft as their first transplant were randomized to receive MMF 1.0 g b.i.d. (MMF 2 g treatment group), MMF 1.5 g b.i.d. (MMF 3 g treatment group), or azathioprine 1–2 mg/kg/day. CsA, corticosteroids, and antithymocyte globulin (ATGAM) were administered as part of a quadruple sequential induction protocol. The primary efficacy endpoint was biopsy-proven rejection or treatment failure (defined as graft loss, death, or premature withdrawal from the study for any reason) during the first 6 months after transplant. All enrolled patients were included in the primary analyses of efficacy on the basis of intent to treat. The 495 patients who received study drug were included in the safety and secondary efficacy analyses. Biopsy-proven acute rejection episodes or treatment failure occurred in 47.6 of patients in the azathioprine group compared with 31.1 (P=0.0015) and 31.3 (P=0.0021) of patients in the MMF 2 g and 3 g treatment groups, respectively. Time to first biopsy-proven rejection episode or treatment failure was significantly longer for MMF 2 g versus azathioprine (P=0.0036) and MMF 3 g versus azathioprine (P=0.0006). First biopsy-proven rejection alone occurred in 38.0 of patients who received azathioprine compared with 19.8 and 17.5 of patients who received MMF 2 g and 3 g, respectively. Patients in the azathioprine group received a greater number of full courses of antirejection treatment as compared with the MMF 2 g and MMF 3 g groups (44.5, 24.8, and 21.1, respectively). The use of antilymphocyte agents to treat rejection was greater in the azathioprine group (20.1) compared with the MMF 2 g group (10.3) and the MMF 3 g group (5.4). At 6 months after transplant, graft and patient survival were similar in all 3 treatment groups. The incidence and types of adverse events were similar among treatment groups, with the exception of a higher incidence of diarrhea, certain other infrequent gastrointestinal adverse events, clinically important leukopenia, and tissue-invasive CMV disease in the MMF groups, particularly in the MMF 3 g group. Three patients who received MMF developed lymphoma/lymphoproliferative disorder. This study demonstrated that MMF administered at a dosage of 2 g or 3 g daily, in combination with maintenance CsA and corticosteroids as triple therapy following ATGAM induction therapy, is more effective than an otherwise identical regimen that includes azathioprine instead of MMF in preventing acute allograft rejection in first cadaveric renal transplant patients. This regimen also has an acceptable adverse event profile. The MMF 3 g dosage was considered to be somewhat less well tolerated than the MMF 2 g dosage.

We have done a comparative analysis of two consecutive clinical trials at our center the first in 56 patients who received blood transfusions from their prospective donors DST group, and the second in 36 patients who received such transfusions while they were taking Imuran in an attempt to reduce the incidence of sensitization against the donor IM DST group. The major findings of our study are 1 Imuran significantly P< .05 reduced the rate of sensitization from 27 to 11 2 Patients who had prolonged dialysis before entering one of these protocols were significantly more likely to become sensitized against their living donors, and had significantly higher sensitization against the leukocyte panel, although panelreactive antibodies were not significantly changed by transfusions from the live donor 3 MLC reactivity against the living donor was not significantly altered by donor transfusions, and was also not different for sensitized and transplanted patients 4 Results of transplantation were excellent in both patient groups, with only two grafts and two patients lost in 68 transplants actuarial oneyear survival of 97 and 93 of patients alive and with functional grafts at one year in the DST and IM DST groups, respectively 5 Rejection episodes occurred in about 50 of each group, but were of a special type DSTtype rejection in about 30 of the DST patients and 10 of the IM DST patients P.07 6 The probability of transplantation, and the results of transplantation after unsuccessful entry into one of these protocols was not adversely affected.

Organ culture facilitates successful transplantation of endocrine tissue in allogenic and xenogenic rodent systems. The major obstacle in applying this approach to human tissue is the difficulty in keeping adult human tissue alive in organ culture for a prolonged period. For this reason we have used an in vivo culture system that allows preservation of endocrine tissue for weeks or months. C57BL6 H2bthyroid grafts transplanted beneath the kidney capsule of Balbc H2dnude mice and retransplanted 15 days later to CBA H2kmice survive indefinitely without immunosuppression. We report here the use of the “interim host system” for allogenic parathyoid tissue in two patients with longstanding hypoparathyroidism after total thyroidectomy.

The donor-specific transfusion protocol (DST) with (DSTI) or without Imuran has resulted in improved graft survival in one-haplotype-mismatched high-MLC-reactive donor-recipient combinations. In this study we have extended the use of donor-specific transfusions to unrelated individuals (group 1), distant relatives (group 2), and two-haplotype-mismatched siblings (group 3). All grafts in group 1 and group 2 are functioning. In group 3, one patient was lost from a myocardial infarct and one kidney was lost due to rejection. In vitro testing was performed using cryopreserved cells obtained prior to transfusion (to), after the third transfusion (tt), and after transplantation (tx). We observed patient-specific suppression in ttplasma and nonspecific suppression by txplasma. We also found ADCC-like activity in tx, but not in toor ttplasma in 2 out of 3 patients. The suppressor effect of ttplasma is mediated by IgG antibody and possibly reflects an antiidiotypic antibody.

A total of 205 patients who underwent donor-specific transfusions with azathioprine (DSTAZA) treatment from 1982 to 1987 included 25 patients (12) who developed antibodies cytotoxic to donor T cells (T warm crossmatch). When we examined a series of 14 variables in relation to the risk of sensitization using a univariate analysis, panel-reactive antibody (PRA) pre-DST of >40, pregnancy, female sex, male-to-female DST, and HLA antigen match all were significant (P<.05) risk factors. Of these variables, only PRA pre-DST >40 proved to be statistically significant (P<.002) in a multivariate logistic regression model (overall P<.001).

In spite of acknowledged advantages for accomplishing early closure of large wounds using mesh grafts, the value of this method is limited by various disadvantages, such as continued loss of biological fluids, the lack of control of infection, and the eventual cosmetic disfigurement—which includes hypertrophic scarring. This paper discusses the use of sheets of foetal calf skin pretreated with nucleic acid to act as an immuno-suppressive agent.

RS‐61443 is a noncompetitive allosteric inhibitor of inosine monophosphate dehydrogenase. At blocks the proliferative response of T and B lymphocytes, prevents the generation of cytotoxic T cells, and inhibits antibody formation. This study was conducted to see whether or not RS‐61443 can reverse acute renal allograft rejection in dogs. At was possible to reverse this process.

Summary In very extensive third-dregee burns, cutting the available healthy skin in the form of a mesh produces a much greater number of areas of epithelization. However, such grafts are exposed to lysis, infection and desiccation during the healing phase, and this conventional technique does not prevent infection and protein-loss on the wound surfaces. This led us to consider whether these disadvantages could be overcome by covering the area of the graft with a suitable material.

One hundred and seventy-nine patients who received transplants between January 1975 and May 1980 have been studied retrospectively in order to elucidate the effect of pre- and perioperative random third-party blood transfusions on first cadaveric renal allograft survival. The 179 patients were approximately evenly divided into four groups; those who received blood transfusions preoperatively only (group 1, n= 45), received blood both pre- and perioperatively (group 2, n= 48), received blood perioperatively only (group 3, n= 37), or were never transfused before transplantation or perioperatively (group 4, n= 49). Actuarial graft survival for group 1 was 73 at 1 to 4 years, which was significantly better (P≥ 0.02) than each of the other three groups at all four intervals. Groups 2, 3, and 4 were statistically identical to each other and had graft survivals of 52 or less at 1 to 4 years.

Summary The combination of autogenous mesh grafts with fetal calf skin xenografts as a temporary coverage markedly stimulates the growth of healthy granulation tissue and accelerates epithelialization, thus resulting in wound closure in the shortest possible time. The final cosmetic result is better and the functional result noticeably better than that obtained with the usual mesh graft method. This is well documented in figures showing various stages of healing after burns.