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Study Objective. To evaluate the frequency of early posttransplant hemorrhagic complications in patients with kidney and kidney-pancreas transplants who received thromboprophylaxis with enoxaparin and aspirin. Design. Retrospective chart review. Setting. University-based tertiary care center. Patients. Thirteen patients who had received enoxaparin within 10 days of kidney or kidney-pancreas transplantation. Intervention. Medical records were reviewed, and data from patients who had received low-dose aspirin 81 mg once/day and enoxaparin within 10 days of transplantation were collected. Measurements and Main Results. Major bleeding events were defined as intracranial or retroperitoneal bleeding, or a decrease in hemoglobin of greater than 2 g/dl that was confirmed on repeat evaluation. Nine (69%) of the 13 patients had confirmed major bleeding events and required blood transfusions. Six of the nine patients had elevated serum creatinine levels. Conclusion. The combination of enoxaparin and low-dose aspirin early after kidney or kidney-pancreas transplantation was associated with a high frequency of hemorrhagic events. Further evaluation is needed to determine the safety of enoxaparin in combination with aspirin after transplantation.

To investigate the possibility that we have been underestimating the true incidence of acute rejection, we began to perform protocol biopsies after kidney transplantation. This analysis looks at the one-week biopsies. Between March 1 and October 1, 1999, 100 adult patients undergoing cadaveric kidney or kidney/pancreas transplantation, or living donor kidney transplantation, underwent 277 biopsies. We focused on the subset of biopsies in patients without delayed graft function (DGF) and with stable or improving renal function, who underwent a biopsy 8.2 ± 2.6 d (range 3–18 d) after transplantation (n = 28). Six (21 %) patients with no DGF and with stable or improving renal function had borderline histopathology, and 7 (25%) had acute tubulitis on the one-week biopsy. Of the 277 kidney biopsies, there was one (0.4%) serious hemorrhagic complication, in a patient receiving low molecular weight heparin; she ultimately recovered and has normal renal function. Her biopsy showed Banff 1 B tubulitis. In patients with stable or improving renal allograft function early after transplantation, subclinical tubulitis may be present in a substantial number of patients. This suggests that the true incidence of rejection may be higher than is clinically appreciated.

Objective To recommend practice guidelines for transplant physicians, primary care providers, health care planners, and all those who are concerned about the well-being of the live organ donor. Participants An executive group representing the National Kidney Foundation, and the American Societies of Transplantation, Transplant Surgeons, and Nephrology formed a steering committee of 12 members to evaluate current practices of living donor transplantation of the kidney, pancreas, liver, intestine, and lung. The steering committee subsequently assembled more than 100 representatives of the transplant community (physicians, nurses, ethicists, psychologists, lawyers, scientists, social workers, transplant recipients, and living donors) at a national conference held June 1-2, 2000, in Kansas City, Mo. Consensus process Attendees participated in 7 assigned work groups. Three were organ specific (lung, liver, and kidney) and 4 were focused on social and ethical concerns (informed consent, donor source, psychosocial issues, and live organ donor registry). Work groups' deliberations were structured by a series of questions developed by the steering committee. Each work group presented its deliberations to an open plenary session of all attendees. This information was stored and shaped into a statement circulated electronically to all attendees for their comments, and finally approved by the steering committee for publication. The term consensus is not meant to convey universal agreement of the participants. The statement identifies issues of controversy; however, the wording of the entire statement is a consensus by approval of all attendees. Conclusion The person who gives consent to be a live organ donor should be competent, willing to donate, free from coercion, medically and psychosocially suitable, fully informed of the risks and benefits as a donor, and fully informed of the risks, benefits, and alternative treatment available to the recipient. The benefits to both donor and recipient must outweigh the risks associated with the donation and transplantation of the living donor organ.

Background The long-term safety and efficacy of tacrolimus in pancreas transplantation has not yet been demonstrated. The observation of prolonged pancreatic graft function under tacrolimus would indicate that any potential islet toxicity is short-lived and clinically insignificant. We report herein the results of pancreas transplantation in patients receiving primary tacrolimus immunosuppression for a minimum of 2 years. Methods. From July 4, 1994 until April 18, 1996, 60 patients received either simultaneous pancreas-kidney transplant (n=55), pancreas transplant only (n=4), or pancreas after kidney transplantation (n=1). Baseline immunosuppression consisted of tacrolimus and steroids without antilymphocyte induction. Azathioprine was used as a third agent in 51 patients and mycophenolate mofetil in 9. Rejection episodes within the first 6 months occurred in 48 (80%) patients and were treated with high-dose corticosteroids. Antilymphocyte antibody was required in eight (13%) patients with steroid-resistant rejection. Results. With a mean follow-up of 35.1±5.9 months (range: 24.3-45.7 months), 6-month and 1-, 2-, and 33-year graft survival is 88%, 82%, 80%, and 80% (pancreas) and 98%, 96%, 93%, and 91% (kidney), respectively. Six-month and 1-, 2-, and 3-year patient survival is 100%, 98%, 98%, and 96.5%. Mean fasting glucose is 91.6±13.8 mg/dl, and mean glycosylated hemoglobin is 5.1±0.7% (normal range: 4.3-6.1%). Mean tacrolimus dose is 6.5±2.6 mg/day and mean prednisone dose 2.0±2.9 mg/day at follow-up. Complete steroid withdrawal was possible in 31 (65%) of the 48 patients with functioning pancreases. Conclusions. These data show for the first time that tacrolimus is a safe and effective long-term primary agent in pancreas transplantation and provides excellent long-term islet function without evidence of toxicity while permitting steroid withdrawal in the majority of patients.

Background. Our organ procurement organization has been forced to liberalize the donor criteria in order to expand the donor pool for pancreas transplantation. In this report, we describe our experience using whole organ pancreatic grafts from marginal donors, which include grafts obtained from donors over 45 years of age and from donors who were identified to be hemodynamically unstable at the time of organ retrieval. Methods. A prospective study was performed between July 1994 and March 1998, during which time 137 pancreas transplants were performed at our center using organs procured by our own surgeons (organs sent by other teams were excluded). The rapid en bloc technique was used exclusively. The use of pancreatic grafts from marginal donors was analyzed for short-term and overall graft survival, and for delayed graft function and complications. Results. Overall pancreas graft survival for our series was 83%, with a mean follow-up of 23 months. There were 22 pancreas grafts from donors over 45 years of age, 13 of whom were greater than 50 years of age. The actual graft survival rate of the over-45 donor group was 86%. Fifty-one grafts were removed from hemodynamically unstable donors on high-dose vasopressors. The actual graft survival in this group was 86%. There was no significant difference found in graft survival between recipients of pancreatic grafts from marginal and nonmarginal donors. Delayed graft function was exhibited by more recipients of grafts from donors on high-dose vasopressors (P

Advances in the surgical techniques, preservation solutions, and methods for predicting eventual long-term renal function from expanded donors will be critical in allowing precise selection criteria for kidneys for transplantation, resulting in the optimum use of a scarce and precious resource. Until other options such as xenotransplantation or tissue engineering become realistic, the challenge for the millennium will be to identify which donor organs previously considered suboptimal can be safely used to expand the organ donor pool. © 1999 by Elsevier Science Inc.

Summary Background Insight into the mechanisms of organ engraftment and acquired tolerance has made it possible to facilitate these mechanisms, by tailoring the timing and dosage of immunosuppression in accordance with two therapeutic principles: recipient pretreatment, and minimum use of post-transplant immunosuppression. We aimed to apply these principles in recipients of renal and extrarenal organ transplants. Methods 82 patients awaiting kidney, liver, pancreas, or intestinal transplantation were pretreated with about 5 mg/kg of a broadly reacting rabbit antithymocyte globulin during several hours. Post-transplant immunosuppression was restricted to tacrolimus unless additional drugs were needed to treat breakthrough rejection. After 4 months, patients on tacrolimus monotherapy were considered for dose-spacing to every other day or longer intervals. Findings We frequently saw evidence of immune activation in graft biopsy samples, but unless this was associated with graft dysfunction or serious immune destruction, treatment usually was not intensified. Immunosuppression-related morbidity was virtually eliminated. 78 (95%) of 82 patients survived at 1 year and at 13–18 months. Graft survival was 73 (89%) of 82 at 1 year and 72 (88%) of 82 at 13–18 months. Of the 72 recipients with surviving grafts, 43 are on spaced doses of tacrolimus monotherapy: every other day (n=6), three times per week (11), twice per week (15), or once per week (11). Interpretation The striking ability to wean immunosuppression in these recipients indicates variable induction of tolerance. The simple therapeutic principles are neither drug-specific nor organ-specific. Systematic application of these principles should allow improvements in quality of life and long-term survival after organ transplantation.

To assess a technique for simultaneous recovery of the intestine, pancreas, and liver from the same donor.With the more frequent use of pancreatic and intestinal transplantation, a procurement procedure is needed that permits retrieval of both organs as well as the liver from the same cadaveric donor for transplantation to different recipients. It is believed by many procurement officers and surgeons, however, that this objective is not technically feasible.A technique for simultaneous recovery of the intestine, pancreas, and liver was used in 13 multiorgan cadaver donors during a 26-month period, with transplantation of the organs to 33 recipients. The intestine was removed from 11 donors separately and in continuity with the pancreas in the other 2. Six additional pancreases were excised and transplanted separately. Thirteen livers were retrieved, one of which was discarded because of steatorrhea. Ten of the remaining 12 livers were transplanted intact; the other 2 were split in situ and used as reduced-size hepatic allografts in four recipients.None of the 11 intestinal, 6 pancreatic, 2 intestinal-pancreatic, or 14 whole or partial liver allografts sustained serious ischemic injury or were lost as a result of technical complications. One liver recipient died 25 months after surgery of recurrent C virus hepatitis. The other 32 recipients had adequate allograft function with a mean follow-up of 8 months.It was possible using the described technique to retrieve intestine, pancreas, and liver allografts safely from the same donor and to transplant these organs to different recipients.

BACKGROUND Between July 1, 1994 and December 1, 1998, 147 simultaneous kidney/pancreas transplantations were performed at our center. Of 95 patients who experienced at least one acute renal allograft rejection episode after transplantation, 7 (7.4%) developed rejection in the presence of stable and normal or near-normal renal function. METHODS The indication for renal allograft biopsy was a rising serum lipase, i.e., suspected pancreatic rejection. All seven patients were treated with steroids and augmentation of the tacrolimus dose, with a fall in the serum lipase and no change in the serum creatinine. RESULTS The serum creatinine levels just before, at the time of, 1 week after the biopsy, and at most recent follow-up were 1.4+/-0.4, 1.3+/-0.3, 1.2+/-0.2, and 1.2+/-0.2 mg/dl. The serum lipase levels just before, at the time of, 1 week after the biopsy, and at most recent follow-up were 1022+/-1157 mg/dl, 874+/-996 mg/dl, 243+/-260 mg/dl, and 94+/-75 mg/dl. The tacrolimus dosages and levels at the time of the biopsy and 1 week later were 14.9+/-5.0 mg/day and 15.0+/-4.0 ng/ml, and 16.4+/-6.3 mg/day and 15.1+/-6.8 ng/ml. CONCLUSIONS These findings suggest that, in patients undergoing simultaneous kidney/pancreas transplantation, the entity of dissynchronous pancreatic allograft rejection without renal allograft rejection may not really exist. These data also make an additional fundamental point that acute rejection may occur in patients with normal and stable renal function.

To further enhance chimerism, 229 primary allograft recipients have received perioperative intravenous infusion of a single dose of 3 to 6 × 108 unmodified donor bone marrow (BM) cells/kg body weight. In addition, 42 patients have been accrued in a concurrent protocol involving multiple (up to three) sequential perioperative infusions of 2 × 108 BM cells/kg/day from day 0–2 posttransplantation (PTx). Organ recipients (n = 133) for whom BM was not available were monitored as controls. The infusion of BM was safe and except for 50 (18%), all study patients have optimal graft function. Of the control patients, allografts in 30 (23%) have been lost during the course of follow-up. The cumulative risk of acute cellular rejection (ACR) was statistically lower in the study patients compared with that of controls. It is interesting that, 62% of BM-augmented heart recipients were free of ACR (Grade ≥ 3A) in the first 6 months PTx compared to controls. The incidence of obliterative bronchiolitis was also statistically lower in study lung recipients (3.8%) compared with the contemporaneously acquired controls (31%). The levels of donor cell chimerism were at least a log higher in the peripheral blood of majority of the study patients compared with that of controls. The incidence of donor-specific hyporeactivity, as determined by one-way mixed leukocyte reaction, was also higher in those BM-augmented liver, kidney, and lung recipients that could be evaluated compared to controls. J. Leukoc. Biol. 66: 310–314; 1999.

Marked elevation of vascular resistance in the rat pancreas is shown after systemic infusion of cyclosporine. Verapamil administration after cyclosporine reversed this effect and allowed maintenance of baseline vascular resistance and blood flow to the pancreas despite additional infusions of cyclosporine. Cyclosporine toxicity in rat pancreas may be directly related to increased vascular resistance. Verapamil might offer protection from this effect.

After whole organ pancreas transplantation with duodenojejunostomy to drain the exocrine secretions was reintroduced in 1984,1 a few centers adopted this technique to replace transplantation of the body and tail of the pancreas, which had been the procedure of choice in the 1970s and early 1980s. Although in the early clinical trials using cyclosporine in whole organ pancreas transplantation, the incidence of thrombosis appeared to be less than with transplantation of the tail or “pancreatic segment,” it was by no means insignificant, and it was considered that cyclosporine, given its vasoconstrictive properties, might be a contributing factor.2 However, there were other reasons why the pancreas was more prone to thrombosis than either the kidney or the liver, in both of which there is a much higher blood flow by comparison with the pancreas. These factors include twisting or compression of the portal vein, ischemic injury, pancreatitis, and reperfusion injury. In addition, acute rejection played a role in early pancreas allograft loss. Therefore, it was believed that if a lower dose of cyclosporine (or no cyclosporine at all) was used in combination with an anti-T cell antibody administered during the first 10 days following transplantation, the incidence of acute rejection and thrombosis would be reduced. Most pancreas transplant centers in the United States and Europe adopted this immunosuppression regimen with delayed introduction of cyclosporine, the so-called “quadruple sequential immunosuppressive therapy,” introduced by Sollinger.3 In the late 1980s and 1990s, both patient and graft survival improved with this regimen, probably more as a result of technical refinements and a more restrictive policy of donor and recipient selection, than improvement in immunosuppression. In spite of these better results, surgically-related morbidity remained high,4 but this phenomenon was not related to the choice of immunosuppressive regimen. By mid-1995, experience had been gained in a few centers using tacrolimus-based immunosuppression in pancreas transplantation, and a multicenter analysis was presented in a preliminary fashion in 1996 by Gruessner,5 and again, with more complete data and greater patient accrual in 1997 at the annual meeting of the American Society of Transplant Surgeons (ASTS).6 All of the contributing centers but one (Pittsburgh) used tacrolimus in combination with antibody induction. Results of the retrospective multicenter analysis. presented by Gruessner, showed a 1 year patient and graft survival of 97% and 85%, respectively.6 Although the Pittsburgh group, which did not use anti T-cell induction therapy, contributed more patients than each of the other centers, except the University of Minnesota, in the multicenter retrospective analysis, the majority of the patients in the study had received antibody induction. Graft success rates were better with tacrolimus-based immunosuppression than with other drug regimens. In addition, graft survival improved substantially with tacrolimus in patients receiving a pancreas without a kidney, ie, pancreas after kidney transplantation (PAK) and pancreas transplant alone (PTA).6,7 However, these “solitary” graft recipients also received anti T-cell induction therapy in addition to tacrolimus. Although the data clearly showed that tacrolimus was superior to cyclosporine, it was difficult to conclude in a definitive fashion that the addition of an anti-T-cell preparation in combination with tacrolimus was necessary.

We report a successful en bloc pancreas and kidney transplantation on a type I diabetic patient with advanced peripheral arterial calcific disease, who had frequent life-threatening episodes of hypoglycemia. The en bloc double organ, created by joining the graft renal artery to the arterial Y graft of the pancreas, was implanted to the proximal left common iliac artery, which was the only site available for an arterial anastomosis. Under appropriate circumstances, this procedure would be an option for potential combined pancreas-kidney transplant recipients with severe calcific arterial disease.

DESPITE its attended complications, immunosuppression for graft acceptance and the impending threat of chronic rejection are two of the many overwhelming factors that have necessitated the implementation of strategies aimed at inducing donor-specific tolerance (DST). With the postulation that persistence of donor cell chimerism after organ transplantation (Tx) may play a notable role in allograft acceptance and the establishment of DST,1-3 we initiated a prospective clinical trial to deliberately augment this phenomenon by perioperative donor bone marrow (BM) infusion. We report here the outcome in 198 study patients with a follow-up of 5 to 1387 days. Also summarized are the results in 115 allograft recipients who, owing to unavailability of consent to retrieve vertebral bodies (VB) from the cadaveric donors, were monitored as coetaneous controls.

A.S. Rao, P. Fontes, A. Iyengar, R. Shapiro, F. Dodson, R. Corry, S. Pham, M. Jordan, A. Zeevi, C. Rastellini, A. Aitouche, F. Egidi, H.A. Gritsch, J. Reyes, J.J. Fung, and T.E. Starzl Thomas E. Starzl Transplantation Institute and the Departments of Surgery (A.S.R., P.F., A.I., R.S., F.D., R.C., S.P., M.J., C.R., J.R., J.J.F., T.E.S.) and Pathology (A.S.R., A.Z.), University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

The discovery of the presence of previously unsuspected microchimerism in successful longterm liver and kidney transplant recipients prompted us to postulate that these cells are essential for graft acceptance and the induction of donor-specific hyporeactivity.1–3 This observation provided the basis for the initiation of a new therapeutic strategy which involved infusion of donor bone marrow (BM) cells under conventional immunosuppressive treatment with tacrolimus and prednisolone.4 The initial outcome of sequential in vitro immunologic evaluations performed to determine the development of donor-specific hyporeactivity in the first 15 BM-augmented and 16 contemporaneous controls has been described previously.5,6 We report here the immune profile of 102 BM-augmented and 57 control patients who were at least 6 months posttransplantation.

Chronic pancreas transplant rejection with enteric exocrine drainage can lead to significant long-term complications. We report a case of a 47-year-old male insulin-dependent diabetic who survived the complications of peripancreatic abscess, enterocutaneous fistula, and arterioenteric fistula related to pancreas transplantation. To avoid these long-term complications, we now recommend elective removal of nonfunctioning, enterically drained pancreas allografts.

Early observations by Snell and Steinmuller provided unequivocal evidence that non-parenchymal cells, resident within the organ play an important role in allograft rejection1–3.

Design and analysis of the turbine disc cooling and secondary air systems, thermal analysis of the rotor structure and subsequent validation of the temperature levels are described for a 4.9 MW industrial gas turbine. A general purpose air flow network solver specifically developed for GT air systems is used to analyse and optimise the disc cooling air flows and determine the interaction between disc air, rotor blade cooling air and leakage. Analysis of the individual wheelspace cavities is undertaken accounting for windage heating, rim sealing and potential for ingestion, heat transfer levels and cooling air temperature rise. This involves both simple 1D methods based on conservation of angular momentum and CFD analysis to determine flow recirculation mechanisms in the disc wheelspace. The thermal boundary conditions from the above are applied to a finite difference thermal analysis model of the turbine rotor to predict temperature distributions at both steady state and transient conditions. Test validation on the engine provides air system pressures and temperatures to validate the airflow analysis and rotor temperatures from thermal paints to validate the thermal analysis.

On the basis of observations in patients with long-term (28-30 years) renal allograft survival, all of whom had evidence of systemic microchimerism, we began a program of combined simultaneous kidney/bone marrow transplantation. Between 12/14/92, and 10/31/94, 36 kidney transplant recipients received 3-5 x 10(8) unmodified bone marrow cells/kg; 6 patients also received pancreatic islets, and 7 patients also received a pancreas. The mean recipient age was 39.0 +/- 10.8 years, and the mean donor age was 31.8 +/- 16.1 years; the mean cold ischemia time was 23.0 +/- 9.1 hr. Twenty control patients received kidneys alone, mainly because of refusal by the donor family to consent to vertebral body recovery; 3 of these patients also received a pancreas. The mean recipient age was 47.9 +/- 11.7 years, and the mean donor age was 41.5 +/- 17.9 years; the mean cold ischemia time was 28.6 +/- 6.2 hr. All patients received tacrolimus-based therapy, without radiation, cytoreduction, or induction antilymphocyte preparations. Blood was drawn prior to and at regular intervals after transplantation for detection of chimerism and for immunologic studies. With a mean follow-up of 11.1 +/- 5.8 months, all 36 study patients are alive, and 33 (92%) have functioning allografts with a mean serum creatinine of 1.9 +/- 1.2 mg/dl and a BUN of 26 +/- 9 mg/dl. Graft vs. host disease was not seen in any patient. The incidence of rejection was 72%; 11% of the patients required OKT3 or ATG for steroid-resistant rejection. The incidence of CMV was 14%, and that of delayed graft function was 17%. A total of 18 (90%) control patients are alive, and 17 (85%) have functioning allografts, with a mean serum creatinine of 2.1 +/- 1.3 mg/dl, and a BUN of 30 +/- 13 mg/dl. The incidence of rejection was 60%, and 10% required OKT3 or ATG. CMV was seen in 15%, and delayed graft function in 20% (P = NS). In the study patients, chimerism was detected in the peripheral blood of 30 of 31 (97%) evaluable patients by either PCR or flow cytometry. In the control patients, chimerism was seen in 9 of 14 (64%) evaluable patients (P.02). Decreasing donor-specific responsiveness was seen in 6/29 (21%) evaluable study, and 4/14 (29%) evaluable control patients (P = NS). We conclude that combined kidney/bone marrow transplantation is associated with acceptable patient and graft survival, augmentation of chimerism, and no change in the early events after transplantation.

SIMULTANEOUS pancreas and kidney transplantation (SPK) has become a highly successful procedure that routinely allows patients to become insulin free and corrects many of the metabolic complications of long-standing diabetes. Previous studies of lipid metabolism with SPK patients have largely been conducted under cyclosporine immunosuppression. In these studies, SPK patients have enjoyed improvement of the prevailing pretransplant hyperlipidemia. Most studies, however, have been relatively short term and have not demonstrated that the improvement in total cholesterol after SPK can be sustained. Since CYA may cause hyperlipidemia, the advantage due to the SPK could be counteracted by the adverse effects of CYA. Tacrolimus (TAC) has experienced increasing use in pancreatic transplantation. Tacrolimus has a more beneficial effect on serum lipids and therefore would be likely to allow sustained normalization of total cholesterol over the long term. We report our experience with serum lipid metabolism over a 5-year period in SPK patients under TAC.

A problem associated with parenteral cyclosporine has been the increased incidence of renal toxicity. Cremophor-EL, the vehicle for parenteral cyclosporine has been associated with massive histamine release and anaphylaxis in certain animal models. We investigated the effects of Cremophor-EL on the cardiac output (CO); mean arterial pressure (MAP); and hepatic, renal and pancreatic blood flow in the anesthesized canine model. Doppler flow probes were utilized to calculate individual organ blood flow. Profound adverse affects were noted on the CO, MAP, and hepatic blood flow. There were negative trends noted in the renal and splenic arterial flow that did not reach statistical significance. It was noted that the changes in organ blood flow were partially independent on MAP and the total dose of Cremophor-EL. We therefore conclude that it is prudent to consider the possible adverse hemodynamic role of Cremophor-EL in canine allograft dysfunction.

Our group at lowa was the first to show that combined liver-pancreas retrievals could be accomplished with successful implantation of both organs into different individuals (1). We and others have subsequently performed this procedure routinely, and it has been shown that results of liver transplantation are not compromised (2).

In 1973, Gerhard Opelz demonstrated the favorable effect of preoperative blood transfusion in improving renal allograft survival by as much as 20% (1). He further showed that success was linearly related to the number of blood transfusions and graft survival rates of close to 80% could be achieved with ten or more units of transfusions administered prior to the operation (2). In retrospect, these data were even more striking in that it could be achieved in the pre-cyclosporine era using only azathioprine and prednisone. It was further noted that the effect was greater than could be accomplished by simply exclusion of those patients who were sensitized from the blood transfusions. Following this, a rash of papers were written showing a similar effect achieved by blood transfusion in animal models. In addition, a number of large centers looked at data retrospectively and showed the favorable effect by comparing their own patients who were transfused with those who had received no blood. Our own data in the mid-1970s showed a 50% success rate in patients who were not transfused, compared to a 70% rate of success in the transfused patients (3).

The discovery of persistent alloantigen (i.e., chimerism) in the lymphoid and nonlymphoid tissues of successful long-term organ transplant recipients has prompted many to conclude that this phenomenon plays an important role in allograft acceptance.1,2 These findings have been corroborated in experimental models of transplantation (Tx) tolerance.3 Although the precise phenotype of cells involved in the induction of observed donor-specific tolerance (DST) is unclear, there exists overwhelming evidence suggesting that perhaps immature dendritic cells, which are resident within the graft and known to migrate after Tx, modulate host anti-donor effector responses.4 As these cells are of bone marrow (BM) origin, it was rational to propose that perioperative donor BM infusion may augment this phenomenon with resultant salutary effect on patient and graft survivals. In 1992 we initiated a clinical trial involving perioperative infusion of unmodified BM cells obtained from the vertebral bodies of cadaveric donors into abdominal and thoracic organ allograft recipients. An interim analysis of the outcome in these patients is reported at their most recent follow-up.

THE two most common causes of late organ allograft failure are complications associated with the long-term use of nonspecific immunosuppression and chronic rejection. Incidentally, this undesirable outcome could be prevented by timely adoption of clinically applicable strategies that would result in the induction of donor-specific tolerance (DST). We have previously advanced the hypothesis that stable existence of donor cell chimerism in organ allograft recipients may induce DST with ultimate enhancement of patient and graft survival.1,2 To test this hypothesis, we proceeded to augment chimerism in clinical organ transplant recipients by adjuvant perioperative unmodified donor bone marrow (BM) infusion.2,3 Reported herein is the outcome of this prospective trial in which 251 study (BM-augmented) and 129 contemporaneous controls have been accrued since its initiation in June 1992.

Although autotransplantation of islets has been shown to successfully reverse pancreatectomy-induced diabetes, such an outcome is rarely witnessed after islet cell allotransplantation.1,2 To promote acceptance of islets in diabetic patients suffering from end-stage renal disease (ESRD), perioperative infusion of donor bone marrow (BM) to augment chimerism has already been attempted.1,3 A less than desirable outcome of the latter approach has prompted the exploration of alternative strategies which would allow for successful islet cell transplantation (Tx). It has been previously shown that, unlike concomitant Tx, islets implanted subsequent to BM infusion in rodents results in indefinite reversal of streptozotocin-induced diabetes.4 However, despite its uniqueness, the principal limitation for clinical application of this procedure was the unpredictable islet cell recovery encountered using contemporary culture and cryopreservation techniques. Recognizing this predicament, we embarked on developing a novel technique that allowed for prolonged islet cell culture with an acceptable loss of their viability and function.5 This accomplishment motivated the initiation of a clinical trial for delayed islet cell infusion into diabetic kidney transplant recipients, who have exhibited demonstrable immune modulation and are maintained on relatively lower doses of immunosuppression (IS); reported herein is the clinical outcome in these patients.

THE SUCCESSFUL isolation and subsequent auto.1 transplantation of islets into pancreatectomized patients has promulgated the possible use of this procedure for the treatment of insulin-dependent type I diabetes (IDOM).1.2 However, our inability to diagnose and promptly treat islet allograft rejection combined with the deleterious effects of currently used immunosuppressive agents have severely limited the clinical utility of this approach. In an attempt to evolve a universally applicable strategy for the surgical treatment of 100M, we at the Thomas E. Starzl Transplantation Institute have performed, between January 1990 and May 1996. 42 pancreatic islet cell transplantations. We report herein, the results of our 6-year experience with this procedure in humans and discuss some of the approaches that we have evolved that may assist in the successful engraftment of allotransplanted islets.

Purpose. The results of steroid withdrawal in pancreas transplant recipients under tacrolimus immunosuppression were analyzed. Methods. From July 4, 1994 until April 30, 1998, 147 pancreas transplantations were performed in 141 patients, including 126 simultaneous pancreas-kidney transplantations, 13 pancreas after kidney transplantation, and 8 pancreas transplantations alone. Baseline immunosuppression consisted of tacrolimus and steroids without antilymphocyte induction. Twenty-three patients were excluded from analysis because of early graft loss in 17 cases, retransplantation in 5 cases, and simultaneous pancreas-kidney transplantation after heart transplantation in 1 patient. Results. With a mean follow-up of 2.8±1.1 years (range 1.0 to 4.8 years), complete steroid withdrawal was achieved in 58 (47%) patients with a mean time to steroid withdrawal of 15.2±8 months (range 4 to 40 months after transplantation). Of the entire cohort of 141 patients, overall 1-, 2-, and 4-year patient survival rates were 98%, 95.5%, and 86%, respectively. Overall 1-, 2-, and 4-year graft survival rates were 83%, 80%, and 71% (pancreas) and 95%, 91%, and 84% (kidney), respectively. Of the 124 patients analyzed for steroid withdrawal, 1-, 2-, and 4-year patient survival rates were 98%, 97%, and 92%, respectively. Overall 1-, 2-, and 4-year graft survival rates were 98%, 91.5%, 83% (pancreas) and 97%, 95%, and 91% (kidney). Patient, pancreas, and kidney survival rates at 1 year were 100%, 100%, and 98% (off steroids) versus 97%, 91%, and 96% (on steroids, all NS) and at 4 years were 100%, 94%, and 95% (off steroids) versus 78%, 68%, and 85% (on steroids, P=0.01, 0.002, and NS, respectively). The cumulative risk of rejection at the time of follow-up was 76% for patients on steroids versus 74% for patients off steroids (P=NS). Seven patients originally tapered off steroids were treated for subsequent rejection episodes, which were all steroid sensitive, and two of these seven patients are currently off steroids. Thirteen patients received antilymphocyte therapy for steroid-resistant rejection, five of whom are now off steroids. Tacrolimus trough levels were 9.3±2.4 ng/ml (off steroids) and 9.7±4.3 (on steroids, P=NS). Mean fasting glucose levels were 98±34 mg/dl (off steroids) and 110±41 mg/dl (on steroids, P=NS). Mean glycosylated hemoglobin levels were 5.2±0.9% (off steroids) and 6.2±2.1% (on steroids, P=0.02), and mean serum creatinine levels were 1.4±0.8 mg/dl (off steroids) and 1.7±1.0 mg/dl (on steroids, P=0.02). Conclusion. These data show for the first time that steroid withdrawal can be safely accomplished in pancreas transplant recipients maintained on tacrolimus-based immunosuppression. Steroid withdrawal is associated with excellent patient and graft survival with no increase in the cumulative risk of rejection.

Objective The effect of donor bone marrow was evaluated for its potentially favorable effect in the authors' simultaneous pancreas/ kidney transplant program. Methods From July 1994 to January 1999, 177 pancreas transplants were performed, 151 of which were simultaneous pancreas/ kidney transplants. All patients received tacrolimus, mycophenolate mofetil, and steroids for immunosuppression (azathioprine was used in the first year of the program). Fifty-three simultaneous pancreas/kidney transplant recipients received perioperative unmodified donor bone marrow, 3 to 6 x 10 8 cells/kg. Results Overall actuarial survival rates at 1 and 3 years were 98% and 95% (patient), 95% and 87% (kidney), and 86% and 80% (pancreas), respectively. In the adjuvant bone marrow group, 1- and 3-year survival rates were 96% and 91% (patient), 95% and 87% (kidney), and 83% and 83% (pancreas), respectively. For 98 recipients who did not receive bone marrow, survival rates at 1 and 3 years were 100% and 98% (patient), 96% and 86% (kidney), and 87% and 79% (pancreas), respectively. No pancreas allografts were lost after 3 months in bone marrow recipients, and seven in the non-bone marrow recipients were lost to rejection at 0.7, 6.7, 8.8, 14.6, 24.1, 24.3, and 25.5 months. Twenty-two percent of bone marrow patients were steroid-free at 1 year, 45% at 2 years, and 67% at 3 years. Nineteen percent of the non-bone marrow recipients were steroid-free at 1 year, 38% at 2 years, and 45% (p = 0.02) at 3 years. The mean acute cellular rejection rate was 0.94 ± 1. 1 in the bone marrow group and 1.57 ± 1.3 (p = 0.003) in the non-bone marrow group (includes borderline rejection and multiple rejections). The level of donor cell chimerism in the peripheral blood of bone marrow patients was at least two logs higher than in controls. Conclusion In this series, which represents the largest experience with adjuvant bone marrow infusion in pancreas recipients, there was a higher steroid withdrawal rate (p = 0.02), fewer rejection episodes, and no pancreas graft loss after 3 months in bone marrow recipients compared with contemporaneous controls. All pancreas allografts lost to chronic rejection (n = 6) were in the non-bone marrow group. Donor bone marrow administered around the time of surgery may have a protective effect in pancreas transplantation.