Solid-organ Transplants From Living Donors: Cumulative United States Experience on 140,156 Living Donor Transplants Over 28 Years.

BACKGROUND: Transplantation of organs from living donors helps to decrease the organ shortage and shortens waiting times. Living donor (LD) transplantation is also generally associated with better outcomes. Unfortunately, there has been no comprehensive analysis and comparison of all types of solid-organ transplantation from living donors since the inception of the United Network for Organ Sharing (UNOS). METHODS: Using the UNOS/Organ Procurement and Transplantation Network (OPTN) database, all LD transplants from October 1, 1987, to December 31, 2015, were studied with univariate and multivariate analyses. RESULTS: A total of 140,090 organs were transplanted from LDs, accounting for 21% of all transplants in the United States. Over 95% were kidney; 4% were liver; and <1% intestine, lung, and pancreas LDs. Only LD kidney transplant patient and graft survival rates were significantly higher compared deceased donor transplants over the period of analysis. The best long-term LD transplant results were achieved in pediatric liver recipients. Significantly more women than men donated organs and significantly more men than women received solid-organ transplants. A regional disparity was observed for LD kidney as well as for LD liver transplants. Despite improvements in outcomes and increased use of nonbiologic donors, the number of LD transplants in the United States has declined. This decline was greater in children than adults and was noted for all types of organ transplants. CONCLUSION: Further efforts are needed to educate the public, health professionals, and transplant candidates on the advantages of living vs deceased donor organ transplantation. Compared with other countries, LD transplantation has yet to reach its full potential in the United States.

Pancreas Transplantation: An Alarming Crisis in Confidence.

In the past decade, the annual number of pancreas transplantations performed in the United States has steadily declined. From 2004 to 2011, the overall number of simultaneous pancreas-kidney (SPK) transplantations in the United States declined by 10%, whereas the decreases in pancreas after kidney (PAK) and pancreas transplant alone (PTA) procedures were 55% and 34%, respectively. Paradoxically, this has occurred in the setting of improvements in graft and patient survival outcomes and transplanting higher-risk patients. Only 11 centers in the United States currently perform ≥20 pancreas transplantations per year, and most centers perform <5 pancreas transplantations annually; many do not perform PAKs or PTAs. This national trend in decreasing numbers of pancreas transplantations is related to a number of factors including lack of a primary referral source, improvements in diabetes care and management, changing donor and recipient considerations, inadequate training opportunities, and increasing risk aversion because of regulatory scrutiny. A national initiative is needed to "reinvigorate" SPK and PAK procedures as preferred transplantation options for appropriately selected uremic patients taking insulin regardless of C-peptide levels or "type" of diabetes. Moreover, many patients may benefit from PTAs because all categories of pancreas transplantation are not only life enhancing but also life extending procedures.

Pancreas After Islet Transplantation: A First Report of the International Pancreas Transplant Registry.

Pancreas after islet (PAI) transplantation is a treatment option for patients seeking insulin independence through a whole-organ transplant after a failed cellular transplant. This report from the International Pancreas Transplant Registry (IPTR) and the United Network for Organ Sharing (UNOS) studied PAI transplant outcomes over a 10-year time period. Forty recipients of a failed alloislet transplant subsequently underwent pancreas transplant alone (50%), pancreas after previous kidney transplant (22.5%), or simultaneous pancreas and kidney (SPK) transplant (27.5%). Graft and patient survival rates were not statistically significantly different compared with matched primary pancreas transplants. Regardless of the recipient category, overall 1- and 5-year PAI patient survival rates for all 40 cases were 97% and 83%, respectively; graft survival rates were 84% and 65%, respectively. A failed previous islet transplant had no negative impact on kidney graft survival in the SPK category: It was the same as for primary SPK transplants. According to this IPTR/UNOS analysis, a PAI transplant is a safe procedure with low recipient mortality, high graft-function rates in both the short and long term and excellent kidney graft outcomes. Patients with a failed islet transplant should know about this alternative in their quest for insulin independence through transplantation.

What defines success in pancreas and islet transplantation-insulin independence or prevention of hypoglycemia? A review.

Pancreas transplantation is considered to be the treatment of choice for selected uremic and diabetic patients, and insurance coverage is widely provided. In the USA, islet transplantation is considered to be an experimental procedure that awaits formal results of ongoing phase III trials to justify biologic licensure and transition to standard of care. Pancreas and islet registry analyses focus on different functional endpoints: insulin independence (pancreas transplants) versus avoidance of hypoglycemia (islet transplants). Although the results of islet transplants have significantly improved, the frequent use of multiple donor organs, suboptimal islet yields, and difficulties in monitoring successful engraftment or in diagnosing rejection remain major barriers that need to be overcome. Although pancreas and islet transplantations are frequently considered to be competing procedures, they are actually complementary treatment options for patients with type 1 diabetes mellitus. Because the results of pancreas transplants are superior to those for islet transplants, diabetic patients with a low surgical risk should undergo a pancreas transplantation. Type 1 diabetics with a high surgical risk (eg, serious comorbidities) should undergo an islet transplantation. Only an integrated approach to pancreas and islet transplantation, tailored to the need of the individual patient, will maximize the benefit of a scarce resource. Both procedures, if successful, have in common that they represent the only biologic treatment option to date for type 1 diabetic patients that prevents hypoglycemia long term.

Excellent outcomes can be achieved in young pancreas transplant alone recipients by addition of sirolimus to maintenance immunosuppression regimen.

BACKGROUND: Pancreas transplant alone (PTA) has evolved into a viable treatment option for nonuremic patients with labile diabetes mellitus. Historically, PTA outcomes were inferior to simultaneous pancreas-kidney transplant outcomes, because of the higher rate of graft loss due to rejection in PTA recipients. But with advances in immunosuppression, PTA outcomes have improved significantly--except in young PTA recipients. The more potent immune system in young recipients appears to play a key role. In this study, our objective was to investigate outcomes of PTA, by recipient age, with the use of different immunosuppressive maintenance regimens. METHODS: Using information from the International Pancreas Transplant Registry and from the United Network for Organ Sharing, we analyzed outcomes of 393 technically successful enteric-drained transplants in the PTA category that were performed from January 2003 through December 2012. All PTA recipients underwent induction immunosuppression with thymoglobulin and pulse steroids and were then maintained on long-term low-dose prednisone. Excluded from our study group were patients who experienced surgical graft loss. We divided the 393 recipients into 2 age groups: <42 years (187 patients) versus ≥42 years (206 patients). For both the younger group and the older group, we compared 2 maintenance immunosuppressive regimens: (1) tacrolimus (Tac) and mycophenolate mofetil (MMF) versus (2) Tac/MMF and sirolimus (Srl). We refer to immunosuppression with Tac and MMF as the non-Srl regimen. RESULTS: The overall 3-year graft survival rate, across both age groups, was significantly better with the Srl regimen (P = .03). Regardless of the immunosuppressive regimen used, outcomes were significantly better in the older group than in the younger group (P = .05). In the older group, with both regimens, outcomes were similar (P = .55). But in the younger group, outcomes with the Srl regimen were significantly better (P = .009) than with the non-Srl regimen and, in fact, were similar to outcomes in the older group. CONCLUSIONS: Our study shows that adding Srl to the standard maintenance immunosuppressive regimen of Tac and MMF provides the best outcomes in young PTA recipients, the most immunologically robust and therefore the most immunologically challenging age group. To achieve excellent outcomes, more potent immunosuppression is required in this cohort. We think that PTA should be offered to young patients with labile diabetes before secondary complications develop.

Declining numbers of pancreas transplantations but significant improvements in outcome.

In the United States, over the past 8 years, the number of pancreas transplantations has steadily declined. This decline comes as a surprise, because patient and graft outcomes have substantially improved during the same period of time. Patient survival rates at 1 year in all 3 recipient categories are >96%; graft survival rates are 82%-89%. Changes in immunosuppressive therapy have had a positive impact on outcome, as have better pancreas donor and recipient selection criteria and refined post-transplantation patient care. Although different factors may have contributed to the declining pancreas transplantation numbers, a more effective process of publicly promoting and widely communicating the improved results of pancreas transplantation is warranted.

Metabolic profile of pancreatic acinar and islet tissue in culture.

BACKGROUND: The amount and condition of exocrine impurities may affect the quality of islet preparations, especially during culture. In this study, the objective was to determine the oxygen demand and viability of islet and acinar tissue post-isolation and whether they change disproportionately while in culture. METHOD: We compared the oxygen consumption rate (OCR) normalized to DNA (OCR/DNA, a measure of fractional viability in units of nmol/min/mg DNA), and the percent change in OCR and DNA recoveries between adult porcine islet and acinar tissue from the same preparation (paired) over 6-9 days of standard culture. Paired comparisons were done to quantify differences in OCR/DNA between islet and acinar tissue from the same preparation, at specified time points during culture. RESULTS: The mean (±SE) OCR/DNA was 74.0 ± 11.7 units higher for acinar (vs islet) tissue on the day of isolation (n = 16, P < .0001), but 25.7 ± 9.4 units lower after 1 day (n = 8, P = .03), 56.6 ± 11.5 units lower after 2 days (n = 12, P = .0004), and 65.9 ± 28.7 units lower after 8 days (n = 4, P = .2) in culture. DNA and OCR recoveries decreased at different rates for acinar versus islet tissue over 6-9 days in culture (n = 6). DNA recovery decreased to 24 ± 7% for acinar and 75 ± 8% for islets (P = .002). Similarly, OCR recovery decreased to 16 ± 3% for acinar and remained virtually constant for islets (P = .005). CONCLUSION: Differences in the metabolic profile of acinar and islet tissue should be considered when culturing impure islet preparations. OCR-based measurements may help optimize pre-islet transplantation culture protocols.

Islet preparation purity is overestimated, and less pure fractions have lower post-culture viability before clinical allotransplantation.

BACKGROUND: Replacement of ß-cells with the use of isolated islet allotransplantation (IT) is an emerging therapy for type 1 diabetics with hypoglycemia unawareness. The current standard protocol calls for a 36-72-hour culture period before IT. We examined 13 clinical islet preparations with ≥2 purity fractions to determine the effect of culture on viability. METHODS: After standard islet isolation and purification, pure islet fractions were placed at 37°C with 5% CO2 for 12-24 hours and subsequently moved to 22°C, whereas less pure fractions were cultured at 22°C for the entire duration. Culture density was targeted at a range of 100-200 islet equivalents (IEQ)/cm(2) adjusted for purity. Islets were assessed for purity (dithizone staining), quantity (pellet volume and DNA), and viability (oxygen consumption rate normalized to DNA content [OCR/DNA] and membrane integrity). RESULTS: Results indicated that purity was overestimated, especially in less pure fractions. This was evidenced by significantly larger observed pellet sizes than expected and tissue amount as quantified with the use of a dsDNA assay when available. Less pure fractions showed significantly lower OCR/DNA and membrane integrity compared with pure. The difference in viability between the 2 purity fractions may be due to a variety of reasons, including hypoxia, nutrient deficiency, toxic metabolite accumulation, and/or proteolytic enzymes released by acinar tissue impurities that are not neutralized by human serum albumin in the culture media. CONCLUSIONS: Current clinical islet culture protocols should be examined further, especially for less pure fractions, to ensure the maintenance of viability before transplantation. Even though relatively small, the difference in viability is important because the amount of dead or dying tissue introduced into recipients may be dramatically increased, especially with less pure preparations.

Results of open and robot-assisted pancreatectomies with autologous islet transplantations: treating chronic pancreatitis and preventing surgically induced diabetes.

For patients with chronic pancreatitis (CP), standard surgical procedures (eg, partial or total resections, drainage procedures) are inadequate treatment options, because they do not confer pain relief and they leave patients prone to brittle diabetes and hypoglycemia. The combination of total pancreatectomy and islet autotransplantation (TP-IAT), however, can create insulin-independent and pain-free states. At our center, from August 2009 through August 2013, 61 patients with CP underwent either open or robot-assisted TP-IAT. The 30-day mortality rate was 0%. The transplanted islet equivalents per body weight ranged from 10,000 to 17,770. In all, 19% of the patients became insulin independent (after a range of 1-24 months); 27% of patients required <10 units of insulin. Moreover, at 12 months after surgery, 71% of the patients were pain free and no longer required analgesics. Our metabolic outcomes could have been even better if most patients had been referred at an earlier disease stage; instead, ∼80% had already undergone surgical procedures, and 91% had abnormal results on preoperative continuous glucose monitoring tests. Only if patients with CP are referred early for a TP-IAT-rather than being subjected to additional inadequate endoscopic and surgical procedures-can insulin-independent and pain-free states be accomplished in most.

Islet oxygen consumption rate dose predicts insulin independence for first clinical islet allotransplants.

BACKGROUND: Human islet allotransplantation for the treatment of type 1 diabetes is in phase III clinical trials in the U.S. and is the standard of care in several other countries. Current islet product release criteria include viability based on cell membrane integrity stains, glucose-stimulated insulin release, and islet equivalent (IE) dose based on counts. However, only a fraction of patients transplanted with islets that meet or exceed these release criteria become insulin independent following 1 transplant. Measurements of islet oxygen consumption rate (OCR) have been reported as highly predictive of transplant outcome in many models. METHOD: In this article we report on the assessment of clinical islet allograft preparations using OCR dose (or viable IE dose) and current product release assays in a series of 13 first transplant recipients. The predictive capability of each assay was examined and successful graft function was defined as 100% insulin independence within 45 days post-transplant. RESULTS: OCR dose was most predictive of CTO. IE dose was also highly predictive, while glucoses stimulated insulin release and membrane integrity stains were not. CONCLUSION: OCR dose can predict CTO with high specificity and sensitivity and is a useful tool for evaluating islet preparations prior to clinical human islet allotransplantation.

Human islet viability and function is maintained during high-density shipment in silicone rubber membrane vessels.

BACKGROUND: The shipment of human islets (IE) from processing centers to distant laboratories is beneficial for both research and clinical applications. The maintenance of islet viability and function in transit is critically important. Gas-permeable silicone rubber membrane (SRM) vessels reduce the risk of hypoxia-induced death or dysfunction during high-density islet culture or shipment. SRM vessels may offer additional advantages: they are cost-effective (fewer flasks, less labor needed), safer (lower contamination risk), and simpler (culture vessel can also be used for shipment). METHOD: IE were isolated from two manufacturing centers and shipped in 10-cm(2) surface area SRM vessels in temperature- and pressure-controlled containers to a distant center after at least 2 days of culture (n = 6). Three conditions were examined: low density (LD), high density (HD), and a microcentrifuge tube negative control (NC). LD was designed to mimic the standard culture density for IE preparations (200 IE/cm(2)), while HD was designed to have a 20-fold higher tissue density, which would enable the culture of an entire human isolation in 1-3 vessels. Upon receipt, islets were assessed for viability (measured by oxygen consumption rate normalized to DNA content [OCR/DNA)]), quantity (measured by DNA), and, when possible, potency and function (measured by dynamic glucose-stimulated insulin secretion measurements and transplants in immunodeficient B6 Rag(+/-) mice). Postshipment OCR/DNA was not reduced in HD vs LD and was substantially reduced in the NC condition. HD islets exhibited normal function postshipment. Based on the data, we conclude that entire islet isolations (up to 400,000 IE) may be shipped using a single, larger SRM vessel with no negative effect on viability and ex vivo and in vivo function.

Three types of simultaneous pancreas and kidney transplantation.

PURPOSE: The purposes of this study were to study and compare clinical and functional outcomes after simultaneous deceased donor pancreas and kidney transplantation (SPK DD), simultaneous deceased donor pancreas and living donor kidney transplantation (SPK DL), and simultaneous living donor pancreas and kidney transplantation (SPK LL). METHODS: From January 1, 1996 to September 1, 2005, 8918 primary, simultaneous pancreas and kidney transplantation (SPK) procedures were reported to the International Pancreas Transplant Registry. Of these, 8764 (98.3%) were SPK DD, 115 (1.3%) were SPK DL, and 39 (0.4%) were SPK LL. We compared these 3 groups with regard to several endpoints including patient and pancreas and kidney graft survival rates. RESULTS: The 1-year and 3-year patient survival rates for SPK DD were 95% and 90%, 97% and 95% for SPK DL, and 100% and 100% for SPK LL recipients, respectively (P ≥ .07). The 1-year and 3-year pancreas graft survival rates for SPK DD were 84% and 77%, 83% and 71% for SPK DL, and 90% and 84% for SPK LL recipients, respectively (P ≥ .16). The 1-year and 3-year kidney graft survival rates for SPK DD were 92% and 84%, 94% and 86% for SPK DL, and 100% and 89% for SPK LL recipients, respectively (P ≥ .37). CONCLUSIONS: Patient survival rates and graft survival rates for pancreas and kidney were similar among the 3 groups evaluated in this study.

Age-based disparity in outcomes of intestinal transplants in pediatric patients.

Outcomes of intestinal transplants (ITx; n = 977) for pediatric patients are examined using the United Network for Organ Sharing data from 1987 to 2009. Recipients were divided into four age groups: (1) <2 years of age (n = 569), (2) 2-6 years (n = 219), (3) 6-12 years (n = 121) and (4) 12-18 years (n = 68). Of 977 ITx, 287 (29.4%) were isolated ITx and 690 (70.6%) were liver and ITx (L-ITx). Patient survival for isolated ITx at 1, 3 and 5 years, 85.3%, 71.3% and 65.0%, respectively, was significantly better than L-ITx, 68.4%, 57.0% and 51.4%, respectively, (p = 0.0001); this was true for all age groups, except for patients <2 years of age. The difference in graft survival between isolated ITx and L-ITx was significant at 1 and 3 years (Wilcoxon test, p = 0.0012). After attrition analysis of graft survival of patients who survived past first year, 3 and 5 years, graft survival for L-ITx patient was significantly better than those for isolated ITx. Isolated ITx should be considered early before the onset of liver disease in children >2 with intestinal failure but is not advantageous in patients <2 years.

Long-term results after pancreas transplantation.

With the advances in technique and immunosupression, not only the short- but the long-term outcomes of pancreas transplantation have improved significantly. This retrospective study describes the long-term outcomes of simultaneous pancreas and kidney (SPK) transplants, pancreas after kidney (PAK), and pancreas transplants alone (PTA). An overall analysis was performed for all deceased donor (DD) primary pancreas transplants performed in the United States between 1988 and 1999. In addition, the long-term outcome for pancreas transplants performed at the University of Minnesota (UM) was analyzed. For SPK transplants performed in the United States between 1998 and 1999, the half-life of the pancreas was almost 12 years, and was 12.5 years for kidneys. For SPK cases where the pancreas was functioning at 1 year, the half-lives of both the pancreas and the kidney grafts extended more than 14 years. The half-lives of solitary pancreas transplants were between 7 years for PAK and 9 years for PTA cases. For US solitary transplants with at least 1 year of graft function, the half-lives extended to almost 9 years. Pancreas transplants performed at the UM showed the same significant improvements over time. Of special interest is the excellent long-term graft function of pancreas transplants from a living donor, which in the early years clearly surpassed that of solitary DD pancreas transplants. A multivariate analysis showed that the factor with the highest impact on long-term graft function in all three transplant categories was the use of a young donor. In SPK cases, the most frequent reason for late graft loss was death with a functioning graft. In solitary pancreas transplants, most late graft losses were still due to immunological reasons.

Intestinal graft versus native liver cytokine expression in a rat model of intestinal transplantation: effect of donor-specific cell augmentation.

INTRODUCTION: Immunomodulation by portal vein delivery of donor antigen reduces intestinal graft rejection. We investigated the impact of portal venous donor-specific cell augmentation (blood versus bone marrow) on cytokine expression in intestinal grafts versus native livers. METHODS: Ten groups of intestinal transplants (brown Norway male to Lewis female rats) varied by (1). the type of donor-specific cell augmentation and (2). the use and dose of tacrolimus-based immunosuppression. Tissue samples for histologic analysis and cytokine mRNA analysis were obtained at designated time points. RESULTS: Without immunosuppression, no type of cell augmentation reduced the rate of rejection. With immunosuppression, outcome was significantly better after portal donor-specific blood transfusion (versus bone marrow infusion). Irrespective of the type of cell augmentation, severe rejection caused strong intragraft expression of IL-1alpha, IL-1beta, IFN-gamma, and TNF-alpha; liver expression mainly involved TNF-alpha. Of note, nonimmunosuppressed, cell-augmented rats showed hardly any differences in cytokine expression in their grafts versus significant increases in their native livers. With immunosuppression, bone marrow infusion (versus blood transfusion) increased intragraft cytokine expression of IL-1alpha, IL-1beta, IFN-gamma, as well as TNF-alpha, and liver expression of IL-1beta. CONCLUSIONS: (1). Rejection and donor-specific cell augmentation independently caused differences in intragraft versus native liver cytokine expression after intestinal transplants. (2). Portal donor-specific blood transfusion (versus bone marrow infusion) lowered the incidence of rejection and diminished intragraft cytokine up-regulation. (3). In our study, TNF-alpha appeared to be the cytokine most strongly associated with rejection.

Pancreas after kidney transplants.

BACKGROUND: For certain uremic diabetic patients, a sequential transplant of a kidney (usually from a living donor) followed by a cadaver pancreas has become an attractive alternative to a simultaneous transplant of both organs. The purpose of this study was to compare outcomes with simultaneous pancreas-kidney (SPK) versus pancreas after kidney (PAK) transplants to determine advantages and disadvantages of the two procedures. METHODS: Between January 1, 1994, and June 30, 2000, we performed 398 cadaver pancreas transplants at our center. Of these, 193 were SPK transplants and 205 were PAK transplants. We compared these two groups with regard to several endpoints, including patient and graft survival rates, surgical complications, acute rejection rates, waiting times, length of hospital stay, and quality of life. RESULTS: Overall, surgical complications were more common for SPK recipients. The total relaparotomy rate was 25.9% for SPK recipients versus 15.1% for PAK recipients (P = 0.006). Leaks, intraabdominal infections, and wound infections were all significantly more common in SPK recipients (P = 0.009, P = 0.05, and P = 0.01, respectively, versus PAK recipients). Short-term pancreas graft survival rates were similar between the two groups: at 1 year posttransplant, 78.0% for SPK recipients and 77.9% for PAK recipients (P = not significant). By 3 years, however, pancreas graft survival differed between the two groups (74.1% for SPK and 61.7% for PAK recipients), although this did not quite reach statistical significance (P = 0.15). This difference in graft survival seemed to be due to increased immunologic losses for PAK recipients: at 3 years posttransplant, the incidence of immunologic graft loss was 16.2% for PAK versus 5.2% for SPK recipients (P = 0.01). Kidney graft survival rates were, however, better for PAK recipients. At 3 years after their kidney transplant, kidney graft survival rates were 83.6% for SPK and 94.6% for PAK recipients (P = 0.001). The mean waiting time to receive the pancreas transplant was 244 days for SPK and 167 days for PAK recipients (P = 0.001). CONCLUSIONS: PAK transplants are a viable option for uremic diabetics. While long-term pancreas graft results are slightly inferior to SPK transplants, the advantages of PAK transplants include the possibility of a preemptive living donor kidney transplant, better long-term kidney graft survival, significantly decreased waiting times, and decreased surgical complication rates. Use of a living donor for the kidney transplant expands the donor pool. Improvements in immunosuppressive regimens will hopefully eliminate some of the difference in long-term pancreas graft survival between SPK and PAK transplants.

Bone marrow augmentation in kidney transplantation: a large animal study.

Specific immunomodulatory strategies are required to eliminate the need for lifelong dependence on debilitating immunosuppressants. One proposed strategy is to simultaneously transplant the kidney and infuse donor-specific bone marrow cells. We prospectively studied the effect of unmodified donor-specific bone marrow infusion (DSBMI) on rejection, infection, graft-versus-host disease (GvHD), and graft survival. We performed 57 kidney transplants in mixed lymphocyte culture (MLC)-reactive, outbred pigs. The groups of recipient pigs differed according to the use of (1) indefinite versus short-term tacrolimus-based immunosuppression, (2) DSBMI, and (3) recipient preconditioning (RPC: whole body irradiation with 400 rads on day 0 and horse anti-pig thymocyte globulin (ATG) on days -2, -1, and 0). In all, we studied eight groups: group 1, nonimmunosuppressed control pigs (n = 8); group 2, nonimmunosuppressed DSBMI pigs (n = 7); group 3, nonimmunosuppressed RPC + DSBMI pigs (n = 5); group 4, tacrolimus (indefinite) pigs (n = 11); group 5, tacrolimus (10 days only) pigs (n = 5); group 6, DSBMI + tacrolimus (indefinite) pigs (n = 8); group 7, DSBMI + tacrolimus (10 days only) pigs (n = 6); and group 8, RPC + DSBMI + tacrolimus (indefinite) pigs (n = 7). DSBMI alone (group 2) or in combination with RPC (group 3) did not prolong graft survival, as compared with nonimmunosuppressed controls (group 1). In groups 1, 2, and 3, all but one pig died from rejection; in group 3 only, 45% of the pigs died from concurrent infection or GvHD, indicating that RPC in combination with DSBMI aggravated the risk of generalized infection and GvHD. Post-transplant immunosuppression--irrespective of indefinite or short-term administration--was required for prolonged graft survival. With indefinite use of immunosuppression, graft survival rates and death rates from rejection were not different for pigs with (group 6) versus without (group 4) DSBMI; however, the death rate from infection was higher in group 6, suggesting that the bone marrow inoculum increased the risk of systemic infection. With short-term use of immunosuppression, graft survival rates were higher and death rates from rejection lower for pigs with (group 7) versus without (group 5) DSBMI. But DSBMI and short-term immunosuppression (group 7) failed to prolong survival beyond that achieved with indefinite immunosuppression (groups 4 and 6). Although the combination of DSBMI and short-term immunosuppression (group 7) reduced the risk of infection, it did not avert severe rejection. The addition of RPC to DSBMI and indefinite immunosup- pression (group 8) significantly decreased graft survival, as compared with groups 4, 6, and 7. It also increased the incidence of death from rejection, GvHD, and infection, or a combination thereof. Unmodified DSBMI did not prolong graft survival after kidney transplantation, nor did it decrease the incidence of rejection. But it aggravated the risk of GvHD and infection. Short-term immunosuppression with DSBMI reduced the incidence of death from infection or GvHD, but it resulted in a higher incidence of death from rejection (as compared with indefinite use of immunosuppression). RPC, combined with DSBMI and indefinite immunosuppression, increased the death rate from rejection, GvHD, infection, or a combination thereof. In this large animal study, the effect of unmodified DSBMI has been disappointing. The search continues for the optimal way to successfully perform bone marrow augmentation in solid organ transplants.

Experimental short-term immunosuppression after bowel transplantation and donor-specific bone marrow infusion.

HYPOTHESIS: We previously showed in a large animal pig model that unmodified donor-specific bone marrow infusion (DSBMI) did not facilitate total bowel engraftment; in contrast, it increased the risks of rejection, infection, and graft-vs-host disease (GVHD) posttransplant. We hypothesize that continuous immunosuppression, in combination with DSBMI, might contribute to-or even trigger-these unwarranted immune responses by both host and graft; therefore, discontinuing immunosuppression might decrease these risks and prolong survival. METHODS: Six groups of outbred, mixed lymphocyte culture-reactive pigs underwent a total (small and large) bowel transplant: group 1, nonimmunosuppressed control pigs (n = 5); group 2, nonimmunosuppressed DSBMI pigs (n = 6); group 3, tacrolimus (indefinite) pigs (n = 7); group 4, tacrolimus (indefinite) plus DSBMI pigs (n = 7); group 5, tacrolimus (10 days only) pigs (n = 5); and group 6, tacrolimus (10 days only) plus DSBMI pigs (n = 6). RESULTS: The combination of short-term immunosuppression and DSBMI (group 6) significantly prolonged survival, compared with short-term immunosuppression only (group 5) or DSBMI only (group 2). Short-term immunosuppression and DSBMI (group 6) did not prolong overall survival, compared with indefinite immunosuppression with (group 4) or without (group 3) DSBMI: survival rates at 7, 14, and 28 days posttransplant were 100%, 100%, and 67% in group 6; 100%, 100%, and 71% in group 3; and 100%, 67%, and 47% in group 4 (P =.14). Short-term immunosuppression and DSBMI (group 6) increased the incidence of rejection, infection, and GVHD, compared with indefinite immunosuppression without (but not with) DSBMI. CONCLUSIONS: Short-term immunosuppression and DSBMI did not prolong survival and did not reduce the incidence of death from rejection, infection, or GVHD, compared with indefinite immunosuppression without DSBMI. But short-term immunosuppression and DSBMI resulted in a lower incidence of death from infection and GVHD, compared with indefinite immunosuppression and DSBMI. When immunosuppression was discontinued 10 days posttransplant, the effect of DSBMI was insufficient to avert death from rejection. CLINICAL RELEVANCE: The clinical results of bowel transplantation trail those of other solid organ transplants. It reduced the rates of infection and GVHD. Our study shows that systemically infused donor-specific bone marrow with short-term or indefinite immunosuppression does not improve outcome after bowel transplantation. It seems necessary to modify the time, dosing, routing, and/or composition of donor-specific bone marrow before it can be successfully used in clinical bowel transplantation.

Pancreas transplantation for treatment of diabetes mellitus.

Pancreas transplantation is the only treatment for type I diabetes mellitus that can induce an insulin-independent normoglycemic state. Because of the need for immunosuppression, it has been most widely applied in uremic diabetic recipients of kidney transplant with a high success rate, particularly when done as a simultaneous (SPK) procedure (insulin independence > 80% at 1 year) with patient and kidney graft survival rates equivalent to or higher than in those who receive a kidney transplant alone. The results of solitary pancreas transplants (PAK in nephropathic diabetic recipients or PTA in nonuremic recipients) have also dramatically improved; 1-year graft survival rates are more than 80% and 70%, respectively, with the new immunosuppressants tacrolimus and mycophenolate mofetil. Multiple factors are important for successful application of pancreas transplantation, as summarized in this review.