Transcontinental shipping of pancreatic islets for autotransplantation after total pancreatectomy.

Islet autotransplantation prevents diabetes in some patients after total pancreatectomy. Pancreatectomy is done at most hospitals but islets are prepared at only a few centers. We report a case in which the pancreas was sent to a laboratory half a continent distant from the operative site, and islets were prepared and returned to the original hospital for autotransplantation 16 h after resection. At 10 months posttransplantation, the patient is normoglycemic and insulin independent, with an appropriate insulin secretion in response to glucose. Endocrine function can be retained after pancreatectomy even if the islets are isolated at a remote laboratory, and autotransplantation could be offered to patients without the need to travel. This outcome implies that the typical handling and processing of a pancreas destined to yield an islet allograft should not prevent the recovery of a sufficient number of viable beta cells to establish insulin independence in type 1 diabetic recipients.

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.

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.

Intra-abdominal fungal infections after pancreatic transplantation: incidence, treatment, and outcome.

BACKGROUND: Intra-abdominal infections account for 15 percent of technical failures after pancreatic transplantation. Although some data are available about intra-abdominal bacterial infections, no study has analyzed the incidence, treatment, and outcome of intra-abdominal fungal infections. STUDY DESIGN: We retrospectively studied 445 consecutive pancreatic transplantations--45 percent were simultaneous pancreatic and renal, 24 percent pancreatic after renal, and 31 percent pancreatic transplantations alone--in patients with Type I diabetes mellitus. Donors were cadavers in 92 percent and living relatives in 8 percent. Primary transplantations were done in 80 percent and retransplantation in 20 percent. Of these 445 pancreatic transplantations, 90 percent were bladder-drained, 9 percent enteric-drained, and 1 percent duct-injected. Only symptomatic patients with documented culture-positive intra-abdominal fungal infections were included. RESULTS: Intra-abdominal fungal infections occurred after pancreatic transplantation in 41 (9.2 percent) of 445 patients. Donor age, but not recipient age, was a significant risk factor. The rate of infections was higher for enteric-drained (21 percent) than for bladder-drained (10 percent) transplantations; for organs donated by living relatives (16 percent) than for those from cadavers (9 percent); and for pancreatic after renal (12 percent) and simultaneous pancreatic-renal (11 percent) than for pancreatic-only (5 percent) recipients. The rate of intra-abdominal fungal infections was 6 percent for recipients who were given antifungal prophylaxis (fluconazole, 400 mg/day for seven days after transplantation) compared with 10 percent for those without prophylaxis. The one-year graft survival rate for recipients with infection was 17 percent compared with 65 percent for those without (p = 0.0001); the survival rate was 70 percent compared with 92 percent for patients with and without infection, respectively (p = 0.0007). In 22 percent of recipients, the infection resolved and graft function persisted; in 58 percent, the infection resolved after transplant pancreatectomy; and in 20 percent, death occurred despite transplant pancreatectomy. Recipients with sole fungal or fungal and bacterial infection (n = 41) were 50 percent less likely to recover with a functioning graft and had a risk of death that was three times higher (p < or = 0.05) than those with sole bacterial infection (n = 48). CONCLUSIONS: Intra-abdominal fungal infections after pancreatic transplants are associated with high morbidity and mortality rates, significantly higher than for sole bacterial infections. In addition to aggressive treatment, including transplant pancreatectomy and reduction of immunosuppression, efforts must be made toward better prevention of intra-abdominal fungal infections.

Long-term peritoneal dialysis before transplantation and intra-abdominal infection after simultaneous pancreas-kidney transplantations.

OBJECTIVE: To investigate whether long-term peritoneal dialysis before transplantation entails a higher risk than hemodialysis for intra-abdominal infection after bladder-drained simultaneous pancreas-kidney transplantations. DESIGN: Large single-center case-control study. SETTING: A large university hospital (referral center). PATIENTS: In all, 189 bladder-drained simultaneous pancreas-kidney transplantations were done from January 1, 1986, to December 31, 1994: before transplantations were performed, 32 recipients (17%) were undergoing peritoneal dialysis, 71 recipients (38%) were undergoing hemodialysis, and 86 recipients (46) were not undergoing dialysis. MAIN OUTCOME MEASURES: The intra-abdominal infection rate after transplantation and the rate of graft loss due to infection. RESULTS: Intra-abdominal infections developed in 33 recipients (18%) after transplantation. Graft and patient survival rates were significantly lower for recipients with vs without an infection (P < .001 for both). Both the dialysis mode and dialysis dependence did not affect the infection rate: of the 33 recipients with an infection, 7 (21%) were undergoing peritoneal dialysis, 15 (46%) were undergoing hemodialysis, and 11 (33%) were not undergoing dialysis before transplantation (P = .3). The rate of graft loss due to infection was not significantly different for recipients who were undergoing peritoneal dialysis vs hemodialysis (P = .1). However, it was higher for recipients who were undergoing dialysis (peritoneal dialysis and hemodialysis) vs those patients who were not undergoing dialysis (P = .04). CONCLUSIONS: Candidates for simultaneous pancreas-kidney transplantation should undergo the transplantation preemptively (ie, before they become dependent on dialysis) because the rate of graft loss due to infection was higher for recipients who were undergoing dialysis (irrespective of the dialysis mode). If dialysis cannot be avoided, the choice of peritoneal dialysis vs hemodialysis can be individualized, since these dialysis modes do not have significantly different rates of infection or of graft loss due to infection.

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.

Vascular graft thrombosis after pancreatic transplantation: univariate and multivariate operative and nonoperative risk factor analysis.

BACKGROUND: Vascular thrombosis is still the leading cause of nonimmunologic, technical pancreatic transplant graft failures. The paucity of published data--coupled with our large institutional experience with pancreatic transplantation in all recipient and transplant categories, using a wide spectrum of surgical techniques--provided the impetus for a retrospective study of graft thrombosis risk factors. STUDY DESIGN: Four hundred thirty-eight patients with pancreatic transplants (45 percent simultaneous pancreas-kidney [SPK], 23 percent pancreas-after-kidney [PAK], and 32 percent pancreatic transplants alone [PTA] and with Type I insulin-dependent diabetes mellitus were studied retrospectively. Of 438 pancreatic transplants, 90 percent were bladder-drained and 10 percent were enteric-drained. Ninety-three percent were from cadaver donors, 90 percent were whole-organ grafts, and 20 percent were retransplantations. Quadruple immunosuppression was given. For bladder-drained, whole-organ transplantations (n=378), we performed Cox regression analyses to study the impact on pancreatic graft thrombosis of donor, recipient, mode of preservation, and surgical variables. RESULTS: The overall thrombosis rate was 12 percent (5 percent arterial, 7 percent venous). For cadaver, bladder-drained, whole-organ pancreatic transplants, the thrombosis incidence was highest in PAK recipients (20 percent). The PAK category was also found to be an independent risk factor for thrombosis by stepwise Cox regression analysis. In separate stepwise Cox regression analyses for each category, other identified risk factors for thrombosis included the following: donor age (PAK, PTA); cardiocerebrovascular cause of donor death (SPK, PAK); the use of an aortic Carrel patch (SPK); arterial pancreatic graft reconstruction using a splenic artery to superior mesenteric artery anastomosis (SPK, PTA) or an interposition graft between the splenic artery and the superior mesenteric artery (PTA); portal vein extension graft (PAK); left-sided implantation into the recipient (PAK); and graft pancreatitis (defined as hyperamylasemia exceeding five days post-transplant [PAK, PTA]). CONCLUSIONS: Older donors or those who died of cardiocerebrovascular disease should not be considered for any recipient category. Preservation time needs to be minimized and strategies need to be developed to decrease graft pancreatitis. Surgically, left-sided implantation and arterial reconstructions other than the Y-graft also increase risk, as do portal vein extensions. Renal transplants alone in prospective PAK recipients with Type I diabetes mellitus should, therefore, always be implanted left-sided to allow for right-sided pancreatic graft placement.

Total lymphoid irradiation, without intrathymic injection of donor cells, induces indefinite acceptance of heart but not islet or skin allografts in rats.

Allograft tolerance occurs in rodents given a dose of antilymphocyte serum (ALS) and intrathymic injection (ITI) of donor splenocytes (SC) 1-3 weeks prior to transplant (TX). The purpose of our study was to test total lymphoid irradiation (TLI) as an alternative to ALS in ITI tolerance induction to heart, islet, and skin allografts. Prepubertal Wistar Furth rats were recipients. ITI of donor (Lewis) SC was done at the end of the TLI course. Rats received either a heterotopic heart, a skin graft, or 2300 islets (diabetic recipients) intraportally from Lewis donors. TLI (without ITI) in a dose of 200 rads/day for 5 consecutive days, followed by TX in 3 weeks resulted in indefinite acceptance of heart (but not islet or skin) grafts in 60% of the recipients. These data indicate that TLI by a dose schedule of 200 rads/day for 5 days should be tested for clinical relevance in large animal recipients of immediately vascularized grafts.

Allograft tolerance by intrathymic donor splenocyte transfer: an age-dependent, species-specific phenomenon?

Protocols that allow allograft survival without immunosuppression remain the ultimate goal in transplantation. Intrathymic injection of donor splenocytes into a transiently immunosuppressed recipient has induced tolerance to a variety of subsequently transplanted allografts in rats. The purpose of this study was to determine if recipient age is critical to intrathymic tolerance in light of age-dependent thymic changes, and if this protocol can be extended to an outbred, large animal model. Prepubertal and postpubertal Wistar-Furth rats underwent intrathymic injection of splenocytes from Lewis rats and antilymphocyte serum (ALS) intraperitoneally. On day 21, a heterotopic Lewis heart was transplanted, with graft survival evaluated by cardiac palpation. Graft tolerance (> 100 days) occurred in four out of five (80%) of the prepubertal rats compared to two out of six (33%) postpubertal rats. Tolerance was not demonstrated in rats receiving intrathymic injection of buffer only. In puppies, groups 1 and 2 underwent splenectomy with intrathymic injection of allo splenocytes. Control puppies (group 3) received intrathymic auto splenocytes. Groups 1 and 3 were given antilymphocyte gamma globulin (ALG) on days 7 to 0 with respect to the intrathymic injection. Group 2 did not receive ALG, but instead received cyclosporin A (CSA) on days 0-2. On day 21, all puppies underwent bilateral nephrectomy and single renal transplantation. No additional immunosuppression was given. Tolerance (creatinine < 7 mg/dl for 100 days) was not obtained by any dog in all three groups. There was no difference in graft survival between control and experimental dogs, with the longest surviving graft seen in a control dog (26 days). Our results suggest that thymic change during maturation may alter the ability to induce tolerance by intrathymic injection of donor cells in rats, and that the protocol is not easily adapted to large animals.

Autologous islet transplantation to prevent diabetes after pancreatic resection.

BACKGROUND: Extensive pancreatic resection for small-duct chronic pancreatitis is often required for pain relief, but the risk of diabetes is a major deterrent. OBJECTIVE: Incidence of pain relief, prevention of diabetes, and identification of factors predictive of success were the goals in this series of 48 patients who underwent pancreatectomy and islet autotransplantation for chronic pancreatitis. PATIENTS AND METHODS: Of the 48 patients, 43 underwent total or near-total (> 95%) pancreatectomy and 5 underwent partial pancreatectomy. The resected pancreas was dispersed by either old (n = 26) or new (n = 22) methods of collagenase digestion. Islets were injected into the portal vein of 46 of the 48 patients and under the kidney capsule in the remaining 2. Postoperative morbidity, mortality, pain relief, and need for exogenous insulin were determined, and actuarial probability of postoperative insulin independence was calculated based on several variables. RESULTS: One perioperative death occurred. Surgical complications occurred in 12 of the 48 patients (25%): of these, 3 had a total (n = 27); 8, a near-total (n = 16); and 1, a partial pancreatectomy (p = 0.02). Most of the 48 patients had a transient increase in portal venous pressure after islet infusion, but no serious sequelae developed. More than 80% of patients experienced significant pain relief after pancreatectomy. Of the 39 patients who underwent total or near-total pancreatectomy, 20 (51%) were initially insulin independent. Between 2 and 10 years after transplantation, 34% were insulin independent, with no grafts failing after 2 years. The main predictor of insulin independence was the number of islets transplanted (of 14 patients who received > 300,000 islets, 74% were insulin independent at > 2 years after transplantation). In turn, the number of islets recovered correlated with the degree of fibrosis (r = -0.52, p = 0.006) and the dispersion method (p = 0.005). CONCLUSION: Pancreatectomy can relieve intractable pain caused by chronic pancreatitis. Islet autotransplantation is safe and can prevent long-term diabetes in more than 33% of patients and should be an adjunct to any pancreatic resection. A given patient's probability of success can be predicted by the morphologic features of the pancreas.

Incidence, complications, treatment, and outcome of ulcers of the upper gastrointestinal tract after renal transplantation during the cyclosporine era.

BACKGROUND: Ulcers of the upper gastrointestinal tract after renal transplantation have been reported as a frequent and often lethal complication. Considering the continuous expansion of renal recipient criteria, we reviewed our experience with post-transplant ulcers after 1,034 renal transplants performed during the cyclosporine era. STUDY DESIGN: Our retrospective study analyzed only endoscopy-proven ulcers of the esophagus, stomach, and duodenum in 439 (42 percent) living related adult recipients and 595 (58 percent) cadaver or living unrelated adult recipients. For ulcer prophylaxis, only oral antacids were routinely given post-transplant. RESULTS: There were 41 ulcers in 33 patients (esophageal: n = 5, 12 percent; gastric: n = 17, 42 percent; duodenal: n = 19, 46 percent). Significant complications (n = 16) included 15 bleeding episodes and one perforation. The pathogenesis was viral in seven cases (gastric: n = 6, 15 percent; duodenal: n = 1, 2 percent). The ulcers occurred significantly earlier post-transplant in cadaver or living unrelated compared with living related recipients (median, 53 compared with 508 days, p = 0.02). Nonoperative treatment was successful for 96 percent of all ulcers. We found no ulcer-related mortality or graft loss. For living related recipients, the actuarial graft survival rate at three years was 69 percent for patients with ulcers compared with 86 percent for those without ulcers (p = 0.02); for cadaver or living unrelated recipients, it was 48 percent for patients with ulcers compared with 77 percent for those without ulcers (p = 0.9). For living related recipients, the actuarial patient survival rate at three years was 92 percent for patients with ulcers compared with 93 percent for those without ulcers (p = 0.8); for cadaver or living unrelated recipients, it was 59 percent for patients with ulcers compared with 88 percent for those without ulcers (p = 0.002). CONCLUSIONS: With more specific immunosuppression and more effective antiviral therapy, the incidence of post-transplant ulcers is low. Considering the excellent results of nonoperative ulcer therapy and a zero percent ulcer-related mortality rate, renal transplantation is safe for patients with specific (e.g., ulcer history) as well as nonspecific (e.g., chronic obstructive pulmonary disease) ulcer risk factors.