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.

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.

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.

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.

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.

Optimal timing for a pancreas transplant after a successful kidney transplant.

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 option. But how long to wait after the kidney transplant before proceeding with a pancreas transplant is unclear. We studied outcomes in recipients of a pancreas at varying times after a kidney to determine the optimal timing for the second transplant. METHODS: We compared pancreas after kidney (PAK) transplants performed early (< or =4 months) and late (>4 months) after the kidney transplant to determine any significant differences in surgical complications or outcomes between the two groups. RESULTS: Between January 1, 1994, and September 30, 1998, we performed 123 cadaver PAK transplants. Of these, 25 (20%) were early and 98 (80%) were late. Characteristics of the two recipient groups were similar. We found no significant differences in outcome between the two groups. The incidence of surgical complications (bleeding, leaks, thrombosis, infections) and of opportunistic infections (such as cytomegalovirus) did not significantly differ between the two groups. Graft and patient survival rates were also equivalent (P=NS). The incidence of acute rejection by 3 months posttransplant was 20% in both groups. CONCLUSION: The timing of the pancreas transplant for PAK recipients does not seem to influence outcome. As long as an acceptable organ is available and the recipient is clinically stable, a PAK transplant can be performed relatively soon after the kidney transplant.

Pregnancy after pancreas transplantation in the cyclosporine era: report from the International Pancreas Transplant Registry.

BACKGROUND: As of December 31, 1996, a total of 9012 pancreas transplants have been reported to the International Pancreas Transplant Registry (IPTR). Over 75% of these recipients were < or = 40 years of age at the time of their transplant. With continued improvement in short- and long-term outcome after transplant, an increasing number of female recipients have become pregnant. However, outcome after pregnancy in pancreas transplant recipients has not been studied in detail. METHODS: To evaluate the risks of pregnancy after pancreas transplantation in the cyclosporine era, we surveyed the institutions reporting to the IPTR. RESULTS: Nineteen cases of pregnancy in 17 female recipients of simultaneous pancreas-kidney transplants resulted in 19 live births. Metabolic control during pregnancy was good in all cases. Mean duration of gestation was 35.2-2.2 weeks. Mean birth weight was 2150+/-680 g. Two congenital malformations were reported (one bilateral cataract and one double aortic arch). One child developed type I diabetes at age 3 years. Only one pancreas graft and one kidney graft were lost (in two different recipients). The pancreas graft was lost after delivery (because of acute rejection). The kidney graft was lost 3 months after delivery (impaired function due to previous amphotericin B treatment). One case of a worsened secondary complication (retinopathy) was reported. One recipient died of myocardial infarction 7 years after transplant and 5 years after delivery, in spite of a normal pretransplant coronary angiogram and good pancreas function. CONCLUSION: This study shows that simultaneous pancreas-kidney transplantation can restore fertility in uremic type I diabetic female recipients. Thus, both posttransplant contraception and fertility counseling are options for female recipients. However, our analysis demonstrates that, when discussing the possibility of pregnancy with female pancreas recipients, these potential risks must be considered: (1) graft loss, (2) progressive maternal morbidity and mortality even with good glycemic control, and (3) diabetes transmission to offspring.

Donor-specific portal blood transfusion in intestinal transplantation: a prospective, preclinical large animal study.

BACKGROUND: Unlike in kidney and heart transplantation, the role of pretransplant donor-specific blood transfusion (DST) has not been studied prospectively in a large animal model of bowel transplantation. We investigated the impact of portal versus systemic DST on overall survival, rejection, graft-versus-host disease (GVHD), and infection after total (small and large) bowel transplantation in pigs. METHODS: Mixed lymphocyte culture-reactive, outbred pigs underwent total enterectomy and orthotopic total bowel transplantation with portal vein graft drainage. One unit of donor blood was transfused via the portal or systemic circulation (according to a randomization protocol) before graft implantation was begun. We studied six groups, all of which underwent at least a total bowel transplant: group 1 (n=5) comprised nonimmunosuppressed control pigs with portal DST; group 2 (n=6), nonimmunosuppressed control pigs with systemic DST; group 3 (n=5), cyclosporine (CsA)-treated pigs with portal DST; group 4 (n=5), CsA-treated pigs with systemic DST; group 5 (n=5), tacrolimus-treated pigs with portal DST; and group 6 (n=5), tacrolimus-treated pigs with systemic DST. All immunosuppressed pigs received prednisone (2 mg/kg/day) and either CsA (to maintain levels between 250 and 350 ng/ml) or tacrolimus (to maintain levels between 10 and 30 ng/ml). Stomal biopsies and autopsies were obtained to study the incidence of rejection, GVHD, and infection. RESULTS: Portal DST and tacrolimus-based immunosuppression resulted in the highest survival rates. At 7, 14, and 28 days after transplantation, survival rates in group 5 were 100%, 100%, and 80%; in group 6, 100%, 60%, and 40%; and in group 3, 100%, 0%, and 0%, respectively. Only the combination of portal DST and tacrolimus prevented the occurrence of, and death from, rejection. Death from rejection at 7, 14, and 28 days in group 5 was 0%, 0%, and 0%; in group 6, 0%, 33%, and 67%; and in group 3, 0%, 100%, and 100%, respectively. Of note, if immunosuppression was used, the groups with portal (versus systemic) DST had a higher risk of death from infection but a lower risk of death from GVHD. Simultaneous immunologic events were noted more frequently in groups with systemic (versus portal) DST. Long-term survival was noted only in groups with tacrolimus-based immunosuppression and was more common for those with portal (versus systemic) DST. CONCLUSIONS: Portal DST at the time of total bowel transplantation and posttransplant immunosuppression with tacrolimus prevent rejection and significantly increase graft survival. The combination of portal antigen presentation and tacrolimus needs to be studied in clinical bowel transplantation.

Mycophenolate mofetil in pancreas transplantation.

BACKGROUND: Mycophenolate mofetil (MMF) has been shown to decrease the incidence of acute rejection episodes after kidney transplantation. The use of MMF along with tacrolimus for > or =1 year after pancreas transplantation has not been studied in a large single-center analysis. METHODS: Between July 1, 1995 and June 30, 1997, both MMF and tacrolimus were given to 120 pancreas transplant recipients. By category, 61 underwent simultaneous pancreas-kidney transplantation (SPK); 44 underwent pancreas transplantation after previous kidney transplantation (PAK); and 15 underwent pancreas transplantation alone (PTA). By donor source, 86% of the grafts were from a cadaver, and 14% were from a living-related donor. Induction therapy was with MMF, tacrolimus, prednisone, and antithymocyte globulin (n=109) or OKT3 (n=2). Until oral intake was resumed, recipients initially received intravenous azathioprine. Side effects were as follows: gastrointestinal (GI) toxicity in 53% of recipients receiving combined MMF and tacrolimus therapy; bone marrow toxicity in 24% of recipients receiving MMF alone; nephrotoxicity in 18% and neurotoxicity in 11% of recipients receiving tacrolimus alone. We did a matched-pair analysis to compare outcome in MMF versus azathioprine recipients, using the database of the International Pancreas Transplant Registry. Matching criteria included transplantation category, transplantation number, recipient and donor age, duct management, HLA typing, and transplantation year. RESULTS: One-year patient survival rates were 98% for SPK, 98% for PAK, and 100% for PTA (P=NS). For SPK recipients, 1-year pancreas graft survival rates were 86% with MMF versus 79% with azathioprine (P=NS); kidney graft survival rates were 96% with MMF versus 86% with azathioprine (P=NS). The incidence of first rejection episodes at 1 year was significantly lower for MMF recipients (15% with MMF versus 43% with azathioprine) (P = 0.0003). For recipients of solitary pancreas transplants (PTA and PAK), we found no difference in graft survival rates between MMF and azathioprine. The conversion rate from MMF to azathioprine at 1 year was 14% for SPK recipients, 26% for PAK, and 39% for PTA (P < 0.007). The most common reason for conversion was GI toxicity, in particular for nonuremic (PTA) or posturemic (PAK) recipients. The rates of posttransplant infection and lymphoproliferative disease were low for recipients on MMF and tacrolimus. CONCLUSIONS: The combination of MMF and tacrolimus after pancreas transplantation is highly effective and safe. For SPK recipients, the incidence of acute reversible rejection episodes was significantly lower with MMF than with azathioprine. The conversion rate from MMF to azathioprine because of GI toxicity was lowest for SPK and highest for PTA recipients.

Solitary pancreas transplantation for nonuremic patients with labile insulin-dependent diabetes mellitus.

BACKGROUND: Simultaneous pancreas-kidney transplantation has become a widely accepted treatment option for selected uremic patients with insulin-dependent diabetes mellitus (IDDM). Patient survival rates at 1 year exceed 90%, and rates of pancreas graft survival, 70%. However, solitary pancreas transplantation for nonuremic patients with IDDM has been controversial because of the less favorable outcome and the need for long-term immunosuppression with its associated morbidity and mortality. METHODS: We studied the outcome of 225 solitary pancreas transplants during three immunosuppressive eras: the precyclosporine (CsA) era (n=83), the CsA era (n=118), and the tacrolimus era (n=24). Only patients with labile IDDM (e.g., hypoglycemic unawareness, insulin reactions, > or = 2 failed attempts at intensified insulin therapy for metabolic control) underwent solitary pancreas transplantation. Using univariate and multivariate analyses, we looked at patient and graft survival, the risk of surgical complications, and native kidney function during these three eras. RESULTS: Pancreas graft survival improved significantly over time: 34% at 1 year after transplantation in the pre-CsA era, 52% in the CsA era, and 80% in the tacrolimus era (P=0.002). Pancreas graft loss due to rejection decreased from 50% at 1 year in the pre-CsA era, to 34% in the CsA era, to 9% in the tacrolimus era (P=0.008). The rate of technical failures (i.e., the risk of surgical complications) decreased from 30% in the pre-CsA era, to 14% in the CsA era, to 0% in the tacrolimus era (P=0.001). Patient survival rates at 1 year have ranged between 88% and 95% in the three eras (P=NS). Matching for at least one antigen on each HLA locus and avoiding HLA-B mismatches significantly decreased the incidence of rejection. The incidence of native kidney failure due to drug-induced toxicity decreased significantly over time, in part because only recipients with pretransplant creatinine clearance > or = 80 ml/min received transplants. CONCLUSIONS: Solitary pancreas transplantation has become a viable alternative for nonuremic patients with labile IDDM. The risks of surgical complications and drug-induced nephrotoxicity have significantly decreased over time. Using tacrolimus as the mainstay immunosuppressant, patient and graft survival rates now no longer trail those of simultaneous pancreas-kidney transplantation.

Delayed endocrine pancreas graft function after simultaneous pancreas-kidney transplantation. Incidence, risk factors, and impact on long-term outcome.

BACKGROUND: The incidence of delayed endocrine pancreas graft function and its impact on long-term outcome after simultaneous pancreas-kidney transplantation are unknown. METHODS: We studied 54 technically successful adult type I insulin-dependent diabetic recipients of cadaver, whole organ, bladder-drained simultaneous pancreas-kidney transplants (mean age, 37.6 years; 65% male, 35% female; 9% pancreas retransplants; 63% on chronic pretransplant dialysis; mean duration of diabetes, 25.1 years). Insulin was administered during the first 2 weeks after transplantation, as needed, to keep blood glucose < 150 mg/dl. Delayed endocrine pancreas graft function was defined as total, cumulative insulin requirement of > 30 U between day 5 and day 10, and/or > 15 U between day 11 and 15. Quadruple immunosuppression was used for all recipients. RESULTS: The incidence of delayed endocrine pancreas graft function was 69%. By univariate analysis, delayed endocrine graft function was associated with pretransplant recipient weight > 80 kg (P = 0.04), donor age > 45 years (P = 0.02), and cardiocerebrovascular (P = 0.06) and nontraumatic causes of donor death (P = 0.02). The incidence of acute pancreas rejection episodes was similar for recipients without and with delayed endocrine pancreas graft function. Pancreas graft survival at 1 and 3 years was 94% and 82% without versus 76% and 59% with delayed endocrine graft function (P = 0.03). CONCLUSIONS: Increased pancreas graft failure after delayed endocrine function was a consequence of insufficient functional reserve (e.g., older donors) rather than increased immunogenicity. Pretransplant reduction of recipient weight and careful donor selection are therefore crucial in order to decrease the incidence of delayed endocrine pancreas graft function and its negative impact on long-term outcome.

Recipient risk factors have an impact on technical failure and patient and graft survival rates in bladder-drained pancreas transplants.

Recipient selection criteria for pancreas (Px) transplantation differ among centers, based on perceived recipient risk factors, and their validity has not been determined. At the University of Minnesota we have been very liberal in accepting patients for Tx, some of whom have risk factors cited as exclusion criteria by other centers, giving us the opportunity to determine, retrospectively, the impact of their presence on outcome. Between July 1986 and March 1993, we performed 319 bladder-drained cadaver Px Txs at the University of Minnesota, 166 simultaneous with a kidney (SPK), 68 after a kidney (PAK), and 85 alone (PTA). To determine which putative "risk factors" influence patient and graft survival, we used uni- and multivariate (Cox regression) analyses to assess the impact of recipient category, duration of diabetes, and age at onset and at Tx; presence of pre-Tx cardiac (CD) disease (myocardial infarction, bypass, angioplasty), peripheral vascular disease (PVD) (stroke, bypass, angioplasty, amputation); blindness, hypertension, and excess weight; and of Px re-Txs. The incidences of all risk factors except re-Tx were significantly higher in SPK than PTA recipients. Px re-Txs comprised 40% of PAK, 26% of PTA, and 10% of SPK cases (P < 0.0001). Duration of diabetes correlated (P < or = 0.01) with all risk factors but one (hypertension). Recipient age correlated (P < or = 0.01) with CD, blindness, duration of diabetes, and age at onset of diabetes; CD risk factors correlated (P < 0.015) with hypertension and PVD. Recipient age (> or = 45) influenced the technical failure rate only in SPK recipients, with a relative risk (RR) of 2.13 (P = 0.08). Recipient age influenced Px graft and patient survival rates in both SPK and PAK recipients; for those > or = 45, the RR of graft loss was 1.73 and 1.76, respectively (P < or = 0.25), and the RR for ultimately dying was 3.07 in PAK (P = 0.02) and 5.86 in SPK (P = 0.17) recipients. SPK recipients with CD factors were at higher risk to ultimately die (RR = 3.78, P = 0.009), independent of age. Px re-Txs were not at higher risk to fail in PTA, but were in PAK recipients (RR = 1.86, P = 0.09); the risk for technical failure was higher for re-Txs only in SPK recipients (RR = 2.11, P = 0.24). Blindness, hypertension, PVD, and duration of diabetes did not negatively influence patient and graft outcome in any recipient category.(ABSTRACT TRUNCATED AT 400 WORDS)

A prospective study of FK506 versus CsA and pig ATG in a porcine model of small bowel transplantation.

Rejection remains a major barrier to successful bowel transplantation, and immunosuppressive protocols are far from standardized. In 88 nonrelated outbred pigs, we compared the effects of two immunosuppressive regimens--one with FK506, the other with cyclosporine (CsA) and pig antithymocyte globulin (ATG)--on incidence and severity of rejection in the early, critical posttransplant period. Group A (n = 14) was nonimmunosuppressed (controls). Group B (n = 17) received pig ATG (10 mg/kg/day x 10 days), CsA (3 mg/kg/day), prednisolone (2 mg/kg/day), and azathioprine (2.5 mg/kg/day); prednisolone and azathioprine were each reduced by 50% at 8 and 15 days posttransplant. Trough CsA whole-blood concentrations were > or = 400 ng/ml for the first 7 days, > or = 200 ng/ml thereafter. Group C (n = 13) received FK506 (0.2 mg/kg/day) and prednisolone (2 mg/kg/day); prednisolone was reduced by 50% at 8 and 15 days. FK506 whole-blood concentrations were > or = 20 ng/ml. All immunosuppression in groups B and C was given intravenously. We performed orthotopic small bowel transplants with systemic venous drainage. Recipient bowel was resected distal to the second portion of the duodenum and proximal to the rectum at transplant; bowel continuity was restored by duodenojejunostomy; ileostomy was created distally to allow access for daily biopsies. We graded interstitial and vascular rejection separately, according to a scoring system (no, mild, moderate, and severe rejection). Rejection-free graft survivals at 7, 14, and 21 days posttransplant were 38%, 19%, and 0% in group A; 93%, 93%, and 62% in group B; and 100%, 91%, and 82% in group C (P < 0.001). Comparing rejection in the immunosuppressed groups, group C (FK506) had a stronger tendency toward rejection than group B (CsA-ATG); significant differences between groups B and C were, however, noted only on individual days posttransplant, not over time. The death rate due to irreversible rejection was not significantly different in groups B and C (P = 0.8), but was significantly better in both of these immunosuppressed groups than in group A (P < 0.001). Pig survival was significantly longer in group C than in B (P = 0.001) due to a lower infection rate in group C. Posttransplant serum interleukin 2 and 7 levels did not correlate with rejection grades. Graft-versus-host reaction was noted only in the skin in 29% of group A, 73% of group B, and 77% of group C pigs; liver and native bowel were not involved.(ABSTRACT TRUNCATED AT 400 WORDS)

Recipient preconditioning and donor-specific bone marrow infusion in a pig model of total bowel transplantation.

BACKGROUND: In an outbred pig model of total bowel transplantation, we previously showed that simultaneous donor-specific bone marrow infusion (DSBMI), rather than promoting engraftment, sensitizes recipients and causes rejection; it also aggravates the risk of generalized graft-versus-host disease (GVHD) and infection, and tends to reduce recipient and graft survival. Small and large animal models of bone marrow-induced transplant tolerance suggest that some form of recipient preconditioning (RPC) may facilitate engraftment of co-transplanted bone marrow cells and fully expose their tolerogenic potential. METHODS: In a preclinical model, we prospectively studied the effect of RPC on simultaneous DSBMI and total (i.e., small and large) bowel transplantation. RPC consisted of whole body irradiation with 400 R (day 0); some recipients additionally received horse anti-pig antithymocyte globulin (days -2, -1, and 0). We studied six groups of outbred pigs, all of which underwent at least a total bowel transplant: group 1, nonimmunosuppressed control pigs (n=5); group 2, nonimmunosuppressed DSBMI pigs (n=13); group 3, tacrolimus pigs (n=7); group 4, DSBMI+tacrolimus pigs (n=15); group 5, RPC+nonimmunosuppressed DSBMI pigs (n=11); and group 6, RPC+DSBMI+tacrolimus pigs (n=14). RESULTS: RPC did not prolong overall survival at 7, 14, 21, and 28 days after transplant. Survival rates were 100%, 100%, 86%, and 71% in group 3; 71%, 43%, 29%, and 29% in group 6; 55%, 9%, 0%, and 0% in group 5; and 60%, 0%, 0%, and 0% in Group 1. Moreover, RPC (groups 5 and 6) increased the incidence of death from rejection, GVHD, and infection when compared with group 3. Survival was significantly higher for RPC+DSBMI+tacrolimus pigs (group 6), compared with RPC+nonimmunosuppressed DSBMI pigs (group 5). Survival greater than 28 days was noted only in pigs that received tacrolimus after transplant: 71% in group 3 versus 29% in group 6. With both RPC and DSBMI (groups 5 and 6), rejection, GVHD, and infection were not mutually exclusive events. In groups 5 and 6, at autopsy, the incidence of rejection and GVHD was 17%; rejection and infection, 17%; and GVHD and infection, 45%. A combination of all three immunologic events was noted in 14%. CONCLUSIONS: RPC, combined with DSBMI, and with or without posttransplant immunosuppression, does not prolong survival after total bowel transplantation. Rather, it increases the incidence of death from rejection, GVHD, infection, or a combination of these three immunologic events. According to this preclinical study, RPC and unmodified DSBMI do not improve patient and graft outcome after total bowel transplantation and need to be refined before being applied clinically.

Diagnosis of pancreas rejection: cystoscopic transduodenal versus percutaneous computed tomography scan-guided biopsy.

BACKGROUND: The most common cause of graft failure after technically successful pancreas transplants is rejection. Laboratory parameters for detecting pancreas graft rejection are not consistently reliable and can lead to unnecessary antirejection treatment. Histopathologic evaluation is the gold standard in the differential diagnosis of pancreas graft dysfunction. Four biopsy techniques have been described: cystoscopic transduodenal (CB), percutaneous computed tomography scan-guided (PB), open, and laparoscopic biopsy. METHODS: We studied the two most common techniques, CB and PB, in pancreas transplant recipients with presumed rejection. Group 1 comprised 103 attempts at CB in 82 recipients (53 men, 29 women) with bladder-drained (BD) pancreas transplants, at 1 to 80 (median, 14) months after transplant. Group 2 comprised 93 attempts at PB in 68 recipients (41 men, 27 women), at 0.5 to 64 (median, 14) months after transplant. RESULTS: In group 1, of 103 attempts at CB, adequate tissue was obtained in 90 (87%): pancreas alone in 23 (22%), pancreas + duodenum in 35 (34%), duodenum alone in 32 (31%). Of the 58 pancreas biopsies, 23 (40%) showed acute rejection. Of the 67 duodenal biopsies, 16 (24%) showed acute rejection. Complications of CB included macrohematuria in 4 recipients (4%) and microhematuria in 32 (31%). We noted no biopsy-related pancreatitis. The mean cost of CB was $2561+/-246. In group 2, of 93 attempts at PB, adequate tissue (all pancreas) was obtained in 67 (72%); of these, 29 (43%) showed acute rejection. Of 23 inaccessible pancreases, 9 (39%) underwent CB; pancreatic tissue was obtained in four (45%), and results were consistent with rejection in all four. Complications of PB included biopsy-related pancreatitis (serum amylase > or = 25%) in five (7%) recipients, macrohematuria in one (1%), and abdominal hemorrhage in two (3%). The mean cost of PB was $1038+/-78. (1) CB and PB prevented unnecessary antirejection treatment in 44% of our recipients with successful biopsies; (2) CB had a higher success rate for obtaining tissue (including duodenal specimens) and a lower rate of major complications; (3) PB was easier and cheaper, did not require general anesthesia, and was performed as an outpatient procedure. CONCLUSIONS: We conclude that PB should become the biopsy technique of choice in recipients with presumed pancreas graft rejection. If PB fails, recipients with bladder-drained pancreas transplants should undergo CB. If CB fails, or in recipients with enteric-drained or duct-injected pancreas transplants, a laparoscopic or open biopsy should be considered.

Discordant xenoislets from a large animal donor undergo accelerated graft failure rather than hyperacute rejection: impact of immunosuppression, islet mass, and transplant site on early outcome.

BACKGROUND: It is not known whether discordant, free, nonvascularized xenoislets-akin to discordant, vascularized, solid xenoorgans-are hyperacutely rejected. Quantitative xenoislet requirements and the optimal transplant site also remain to be defined. METHODS: We studied these questions with a discordant dog-to-diabetic Lewis rat xenoislet model, using (1) functional (cure of streptozotocin-induced diabetes) and (2) histologic (biopsies of intraportal grafts) parameters. WF-to-Lewis alloislet recipients served as histologic controls. RESULTS: (1) We found that 5000 xenoislet equivalents (IEs) transplanted into the portal veins of nonimmunosuppressed rats never functioned. Peritransplant combination therapy (rapamycin, cyclosporin A, anti-rat lymphocyte serum) significantly prolonged graft survival of 5000 intraportal IEs (median, 3 days) but not of 2500 intraportal or of 5000 intraperitoneal or renal subcapsular IEs. (2) By means of immunofluorescence (at 1 hour after transplantation), we noted immunoglobulin M (IgM) and IgG binding to islets in xenografts but not allografts; we noted complement and fibrinogen binding in both xenografts and allografts. Insulin-positive islet cells within intact xenoislets were demonstrated in nonimmunosuppressed rats up to 48 hours after transplantation. Cellular xenograft infiltration and inflammation, beginning at 6 hours, were observed even in immunosuppressed rats. (3) Thus, in spite of IgM and IgG binding, intraportal discordant xenoislets were not hyperacutely rejected and destroyed. Nevertheless, universal xenoislet nonfunction in nonimmunosuppressed rats was immune mediated. A large xenoislet mass (more than 10,000 IEs/kg), the intraportal site, and combination therapy were absolute prerequisites for immediate function. But even if the prerequisites were all fulfilled, accelerated xenoislet graft failure occurred. CONCLUSIONS: This outcome suggests that the specific binding of IgM and IgG to xenoislets, in conjunction with the binding of complement and fibrinogen, contributed to accelerated graft failure. Thus distinction between discordant and concordant species combinations is important for free, nonvascularized xenoislet transplants. These findings and the steroid-free combination protocol (rapamycin, cyclosporin A, anti-T-cell therapy) warrant further testing in preclinical discordant xenoislet studies.

Conversion from bladder to enteric drainage after pancreaticoduodenal transplantations.

BACKGROUND: Bladder drainage is the most common technique for managing the exocrine secretions of pancreaticoduodenal grafts. However, bladder drainage can cause urinary, pancreatic, and metabolic complications that may require conversion to enteric drainage. With enteric drainage, urinary amylase levels cannot be monitored as a marker for rejection. After enteric conversion, rejection is the major cause of graft loss. Timing the conversion to reduce immunologic graft loss would greatly improve patient and graft survival rates. Our study was designed to assess the incidence of, indications for, and complications of converting from bladder to enteric drainage after pancreaticoduodenal transplantations. METHODS: We retrospectively reviewed our experience with 80 recipients who underwent enteric conversion. We studied the recipient category, the interval from transplantation to conversion, the interval from the last rejection episode to conversion, the indications for conversion, the type of enteric drainage at conversion (loop versus Roux-en-Y), the results of the conversion, and postconversion complications. RESULTS: The major indications for conversion were metabolic acidosis (n = 26, 33%), recurrent urinary tract infections (UTIs) (n = 16, 20%), reflux pancreatitis (n = 15, 19%), and hematuria (n = 12, 15%). For most recipients, their symptoms resolved after conversion (n = 76, 95%). The cumulative probability of undergoing conversion was 13% at 12 months, 21% at 36 months, and 25% at 60 months. Of the recipients with surgical complications after conversion (n = 12, 15%), one lost his graft as a result of pancreatitis. Overall, of the 80 recipients who underwent conversion, 12 (15%) lost their graft, most due to rejection (n = 8, 75%). Immunologic graft loss was highest for recipients of pancreas transplants alone who underwent conversion < or = 6 months after transplantation or < or = 1 year after their last rejection episode. CONCLUSIONS: Enteric conversion is safe and therapeutic in recipients with complications related to the exocrine secretions of bladder-drained pancreas grafts. After conversion, rejection accounted for 75% of the grafts lost. However, waiting at least 1 year after the last rejection episode significantly reduced immunologic graft loss.

Laparoscopic drainage of lymphoceles after kidney transplantation: indications and limitations.

BACKGROUND: Symptomatic lymphoceles are not uncommon after kidney transplantations. Surgical marsupialization with internal drainage is the treatment of choice. However, laparoscopic drainage is reportedly as effective, with only minimal trauma. METHODS: We attempted 14 laparoscopic lymphocele drainages during a 3-year period and studied the indications and limitations, using intraoperative ultrasonography in all cases. RESULTS: Laparoscopic drainage was successful in only 9 (64%) of 14 patients. A conversion to open laparotomy was necessary in five patients; their lymphoceles were lateral and either posterior or inferior to the kidney. Two patients with initially successful laparoscopic drainage required conversion to open laparotomy 21 and 83 days later; their lymphoceles were inferior to the kidney. Laparoscopic drainage shortened the median hospital stay by 4 days versus open surgical drainage and by 7 days versus conversion. Hospital costs for laparoscopic drainage averaged $7400 less versus open drainage and $10,300 less versus conversion. CONCLUSIONS: In patients with symptomatic lymphoceles medial and either superior or anterior to the kidney, laparoscopic drainage under intraoperative ultrasonographic guidance is easy, safe, and effective. It decreases hospitalization, convalescence, and costs. In patients with symptomatic lymphoceles lateral and either posterior or inferior to the kidney, laparoscopic drainage may fail because of anatomic inaccessibility and technical impracticability.

Duodenal complications in bladder-drained pancreas transplantation.

BACKGROUND: The most common type of pancreas transplantation is whole pancreaticoduodenal (with bladder drainage) from a cadaver donor. Complications can arise not only from the pancreas itself but also from the simultaneously transplanted duodenum. The purpose of this study was to analyze the incidence, diagnosis, and treatment of duodenal complications and their impact on patient and pancreas graft survival rates. METHODS: Our retrospective study is based on 425 pancreaticoduodenal transplantations performed between July 1, 1986, and June 30, 1994. Complications pertaining to the duodenal segment were labeled early if they occurred within the first postoperative month and late otherwise. Mean follow-up was 55 months (range, 13 to 108 months). RESULTS: We noted 85 (20%) duodenal complications: duodenal leaks (n = 42), hematuria (n = 26), recurrent urinary tract infections (n = 9), duodenal ulceration or necrosis (n = 6), and bladder stones (n = 2). Of these complications, 40 (48%) required surgical intervention. In all, duodenal complications resulted in 14 (16%) enteric conversions and eight (9%) pancreas graft losses (six because of duodenal leak and 2 because of hematuria). The mortality rate from duodenal complications was 0%. CONCLUSIONS: Duodenal complications were common, but they were not associated with a high rate of pancreas graft loss (only 9%). With early diagnosis and treatment, morbidity can be reduced and death avoided in pancreas transplant recipients.