Pancreas Allograft Recipients Research Articles

Effect of volatile anesthetics on early and delayed outcomes in pancreas transplantation.

Ischemia-reperfusion injury (IRI) is a common cause of allograft dysfunction and patient morbidity in solid organ transplantation. This study compares the effect of different inhaled anesthetics on early IRI and clinical outcomes in pancreas allograft recipients. Data were extracted retrospectively for pancreas transplants at a single center over a 15-year period. Early postoperative pancreatic amylase and lipase levels were used as a marker for graft injury. Clinical outcomes measured included length of hospital stay, readmission, and graft survival. There were 625 pancreas transplants included in the analysis with 3 primary inhaled anesthetics: sevoflurane (53%), desflurane (35%), and isoflurane (12%). In the first 30days post-transplant, peak amylase was lowest for sevoflurane (147) followed by desflurane (159) and isoflurane (229) (p=.03). Peak lipase levels followed the same trend (peak values 118, 131, and 135, respectively; p=.02). Early graft loss, length of hospital stay, and readmission within 3months were similar among all three anesthetic groups. There was no difference in 10-year graft survival by Cox regression. Sevoflurane and desflurane are associated with lower peak amylase and lipase levels postoperatively in pancreas transplantation. Short- and long-term clinical outcomes were equivalent for the three agents.

What Is the Risk of Transmission From HBcAb Positive Donors To the Recipient in Kidney and Pancreas Transplantation?

Introduction: There is variation of practice amongst UK kidney and pancreas transplant units in implanting grafts from HBcAb +ve donors due to the perceived risk of transmission of hepatitis B (HBV). Centres transplanting such grafts have variable practice of antiviral prophylaxis with lamivudine ranging from no prophylaxis to life-long prophylaxis. The aim of this study was to assess the rate of HBV infection in HBsAg -ve recipients of renal and pancreas allografts receiving organs from HBcAb +ve, HBsAg -ve donors. Methods: We surveyed the UK kidney and pancreas transplant units regarding their practices of accepting HBcAb +ve donor grafts and the subsequent use of antiviral prophylaxis. All patients receiving a kidney (KT) and or pancreas (PT) allograft from HBcAb +ve, HBsAg -ve donors between Jan 2002 and Dec 2011 were identified retrospectively from the UK Transplant Registry. Post transplant virology data were also collected. All patients had a minimum follow-up of 2 years. Results: The survey was incomplete at the time of this analysis and hence is not presented. A total of 277 patients were identified who underwent KT (n=252) or PT (n=25) from HBcAb +ve donors. Of these 2 KT recipients were HBsAg +ve prior to transplantation and were excluded from the analysis. Of the remaining 275, seven recipients (6 KT, 1 PT) had documented evidence of HBV positive virology post transplant (2.5%). At the time of this analysis, 178 patients (159 KT, 19 PT) had documented negative virology (65%) and 98 (93 KT and 5 PT) were recorded as ‘not reported’ (35%). Of the 11 KT in our centre, no HBV transmission recorded. All received 100 day lamivudine prophylaxisConclusions: The risk of HBV transmission following kidney and pancreas transplantation from HBcAb +ve donors remains low. Use of antiviral prophylaxis can help reduce this risk further. We suggest 100-day post-transplant lamivudine prophylaxis in kidney and pancreas transplantation. There is a need for clear guidelines for the safe and effective use of HBcAb +ve grafts

Early findings of prospective anti‐HLA donor specific antibodies monitoring study in pancreas transplantation: Indiana University Health Experience

The significance of donor-specific antibodies (DSA) is not well known in the setting of pancreas transplantation. Since December 2009, we prospectively followed pancreas transplant patients with single-antigen-luminex-bead testing at one, two, three, six, and then every six months for the first two yr. Thirty-five of the 92 patients that underwent pancreas transplantation (13 pancreas-alone [PTA], 20 with a kidney [SPK], and two after a kidney [PAK]) agreed to participate in study. Median age at transplant was 45 yr and follow-up was 23 months. Majority were Caucasian (n = 33) and male (n = 18). Rabbit anti-thymocyte globulin induction was used. Median HLA-mismatch was 4.2 ± 1.1. Eight patients (7SPK, 1PAK) developed post-transplant DSA at median follow-up of 76 d (26-119), 1 SPK had pre-formed DSA. Seven patients had both class I and class II DSA, one with class I and one with class II only. Mean peak class I DSA-MFI was 3529 (±1456); class II DSA-MFI was 5734 (±3204) whereas cumulative DSA MFI (CI + CII) was 9264 (±4233). No difference was observed in the patient and donor demographics among patients with and without DSA. One patient in non-DSA group developed acute cellular rejection of pancreas. From our data it appears that post-transplant DSA in pancreas allograft recipients may not impact the early-pancreatic allograft outcomes. The utility of prospective DSA monitoring in pancreatic transplant patients needs further evaluation and long-term follow-up.

Skin cancer after pancreas transplantation

Skin cancer in patients who have undergone pancreas transplantation (PT) has not been extensively characterized. We sought to describe the incidence, tumor burden, and risk factors for skin cancer in PT recipients at Mayo Clinic from 1998 through 2006. A retrospective study was performed by analyzing outcomes among a cohort of pancreas allograft recipients at Mayo Clinic between 1998 and 2006. Among 216 allogeneic PT recipients at 2, 5, and 10 years posttransplantation, the cumulative incidence of any skin cancer was 4.7%, 12.7%, and 19.6%; the cumulative incidence of squamous cell carcinoma was 2.8%, 10.3%, and 16.7%; and the cumulative incidence of basal cell carcinoma was 2.4%, 7.8%, and 17.4%, respectively. The cumulative incidence of a second squamous cell carcinoma developing was 56% at 2 years; the cumulative incidence of a second basal cell carcinoma developing was 36% at 2 years. Of the risk factors examined, only age and having a skin cancer before transplantation were predictive of skin cancer development. This was a retrospective study. Results from a large tertiary center may not be generalizable. Nonmelanoma skin cancers commonly occur in recipients of PT, and those patients who have a history of nonmelanoma skin cancer have a very high likelihood of further skin cancer development.

Conversion to Sirolimus Allows Preservation of Renal Function in Kidney and Kidney–Pancreas Allograft Recipients

The major causes of graft failure are chronic allograft nephropathy (CAN) and patient mortality. Sirolimus (SRL) is a powerful immunosuppressant with a less nephrotoxic profile as well as a lower incidence of cancer. The aim of this study was to evaluate the impact of conversion to SRL from calcineurin inhibitor (CNI)-based therapy in kidney (KT) and kidney–pancreas (SPK) allograft recipients. We analyzed renal function, allograft and patient survival, and SRL-associated adverse effects in 93 adult patients (86 KT and 7 SPK), who were converted to SRL between January 2001 and November 2008. The main reason for conversion was CAN (76; 9%) and 52 (7%) were receiving tacrolimus. Conversion occurred at a median 26.2 months. There was a significant improvement in creatinine clearance (CCr) at 6 months after conversion (CCr baseline 51.4 vs CCr 6m 60.4 mL/min; P < .0001), without changes at 12 and 24 months. However, proteinuria increased significantly at 6 months compared with the baseline: 150 mg/24 hours (0–453) versus 0 mg/24 hours (range, 0–309), respectively ( P < .0001), but did not progress at 12 or 24 months. At the same time we observed more extensive use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers: 60/5%; 65/3% and 70/2% at 6, 12, and 24 months. There were no changes in blood pressure control. Cholesterol significantly increased at 6 months (218.2 ± 37 vs. 186.6 ± 44 mg/dL; P < .0001). Graft and patient survivals at 4 years were 88% and 95%, respectively. Our experience suggested that conversion to SRL constituted a safe alternative with excellent results in patient and graft survival.

Antibody-Mediated Rejection of the Pancreas Allograft

Antibody-mediated rejection (AMR) is an entity that is being increasingly recognized in the setting of solid organ transplantation. Clinical, pathologic, and serologic criteria are perhaps better defined and understood in kidney and heart transplants (1), but little is known for other solid organs, including lung, pancreas, liver, and small intestine transplantation. In an effort to understand the impact and significance of alloantibodies in the setting of pancreas transplantation, we systematically screen for donor-specific antibodies (DSA) and immunolabel with C4d all pancreas allograft biopsies at our institution. In a study of 136 recipients of simultaneous pancreas and kidney transplants, we initially reported two patients with histologic evidence of both kidney and pancreas acute AMR, with diffusely C4d-positive peritubular and interacinar capillary staining, respectively. Both patients had documented circulating DSA. One patient lost both kidney and pancreas allografts 1 year posttransplant, and the second patient fully recovered kidney and pancreas allografts with normal function 2 years posttransplant (2). More recently, in our study of 18 pancreas allograft recipients and 27 biopsies, we found a significant correlation between circulating DSA and C4d staining of interacinar capillaries, and no correlation of DSA with biopsy staining of larger arteries, veins, islets, or interstitium (3). In this study, half of the patients returned to insulin therapy and half of the patients retained normal allograft function after a mean follow-up period of 316.3 days. Patients with pure acute cellular rejection fully recovered allograft function after a mean follow-up period of 208.4 days. The decreased allograft survival in AMR+pancreas recipients is in agreement with the decreased survival shown in C4d+AMR patients reported by Munivenkatappa (4). We have also looked at the potential role of C3d, another proposed tissue marker of antibody activation and deposition in kidney transplant (5). In a group of 16 pancreas allografts, C3d proved to be less sensitive than C4d in identifying patients with AMR, and there was no correlation with class I or class II DSA (Poster presentation to the 2009 ATC). We agree with the viewpoints of Dr. Munivenkatappa, Dr. Papadimitriou, and Dr. Drachenberg in their letter to the editor of this edition of Transplantation. In pancreas transplantation (as in other solid organ transplant) there is perhaps a spectrum of clinical scenarios, tissue evidence of antibody activation, and serologic patterns that still need to be defined to better understand AMR as an entity in the pancreas allograft. The diagnostic criteria for AMR in the pancreas (6) will be a subject of important discussions in the next Banff meeting in Alberta, Canada, August 2009, and will undoubtedly undergo refinement in the future. Jose R. Torrealba Department of Pathology University of Wisconsin Madison, WI Jon Odorico Department of Surgery University of Wisconsin Madison, WI

Medication Errors in the Outpatient Setting

To understand and classify causal factors linked to medication errors and to define opportunities for systematic changes to improve the safety of prescription medication use. All recipients of liver, kidney, and/or pancreas allografts followed up by an academic medical center and encountered in the acute care facility, outpatient clinic, or by telephone during 12 months (April 1, 2004, through March 31, 2005). Errors were sought by specific review of the expected and actual medication lists. Main Outcome Measure Proportion of medication errors in each of 5 classifications developed through iterative revision. Definitions included failure to provide a correct prescription (prescription error); deliver a prescribed medication to the patient (delivery error); possess enough medication for a 24-hour or greater supply (availability error); accurately use an available, prescribed medication (patient error); and identify the type, dosage, or frequency of a medication (reporting error). We identified 149 errors in 93 patients who were prescribed a mean of 10.9 medications each. Adverse events were associated with 48 errors (32%), including hospitalization (17 patients) or outpatient invasive procedure (3 patients) in 13%. Nine episodes of rejection and 6 failed allografts were identified. The most common error type was patient error in 83 errors (56%) with prescription errors in 20 errors (13%), delivery errors in 20 errors (13%), availability errors in 15 errors (10%), and reporting errors in 12 errors (8%). Root cause analysis identified the patient as the cause in 101 errors (68%) while pharmacies and other sectors of the health care team caused 41 errors (27%). Finances were linked to 7 errors (5%). Error frequency was estimated during 4 weeks of outpatient visits at 15 of 219 visits. Outpatient medication errors are abundant, often occult, and associated with significant adverse events in a complex transplant population. The health care system is associated with nearly one third of errors.

IRS-1 Serine Phosphorylation and Insulin Resistance in Skeletal Muscle From Pancreas Transplant Recipients

Insulin-dependent diabetic recipients of successful pancreas allografts achieve self-regulatory insulin secretion and discontinue exogenous insulin therapy; however, chronic hyperinsulinemia and impaired insulin sensitivity generally develop. To determine whether insulin resistance is accompanied by altered signal transduction, skeletal muscle biopsies were obtained from pancreas-kidney transplant recipients (n = 4), nondiabetic kidney transplant recipients (receiving the same immunosuppressive drugs; n = 5), and healthy subjects (n = 6) before and during a euglycemic-hyperinsulinemic clamp. Basal insulin receptor substrate (IRS)-1 Ser (312) and Ser (616) phosphorylation, IRS-1-associated phosphatidylinositol 3-kinase activity, and extracellular signal-regulated kinase (ERK)-1/2 phosphorylation were elevated in pancreas-kidney transplant recipients, coincident with fasting hyperinsulinemia. Basal IRS-1 Ser (312) and Ser (616) phosphorylation was also increased in nondiabetic kidney transplant recipients. Insulin increased phosphorylation of IRS-1 at Ser (312) but not Ser (616) in healthy subjects, with impairments noted in nondiabetic kidney and pancreas-kidney transplant recipients. Insulin action on ERK-1/2 and Akt phosphorylation was impaired in pancreas-kidney transplant recipients and was preserved in nondiabetic kidney transplant recipients. Importantly, insulin stimulation of the Akt substrate AS160 was impaired in nondiabetic kidney and pancreas-kidney transplant recipients. In conclusion, peripheral insulin resistance in pancreas-kidney transplant recipients may arise from a negative feedback regulation of the canonical insulin-signaling cascade from excessive serine phosphorylation of IRS-1, possibly as a consequence of immunosuppressive therapy and hyperinsulinemia.

Graft Survival and Immune Regulation of Pancreas Allograft Recipients Induced With Thymoglobulin, Sirolimus, and Cyclosporine

Background Our objective was to determine the impact of thymoglobulin–sirolimus–cyclosporine immunosuppression on the alloimune response of pancreas–kidney transplant recipients. Methods Thirty-six pancreas transplant recipients received an induction protocol of thymoglobulin, sirolimus, reduced-dose cyclosporine, and corticosteroids. A subset of 10 recipients were also enrolled in a study to measure immune responsiveness. Flow PRA–determined HLA antibody, donor-specific flow cytometry crossmatching (FCXM), T-cell subset, and suppressor cell assays were performed at various timepoints during the first posttransplant year. Results One-year patient, kidney, and pancreas survivals were 97%, 94%, and 92%, respectively. There was 1 death due to sepsis, and 1 kidney and 2 pancreas graft losses. There were no acute rejection episodes. Recipients in the immune-monitoring study displayed depression of CD3, CD4, and CD8 counts (<80%) until 3 months posttransplant. At transplantation, 9 of 10 patients displayed <10% class I HLA antibody. By 3 months, 7 of 10 showed a transient elevation in class I HLA antibodies, with 2 patients expressing >80% flow PRA. At transplant 1 patient was FCXM-positive, whereas, by 3 months posttransplant, 2 of 10 patients demonstrated a positive FCXM. There were no clinical consequences to either the presence of HLA antibody or the positive FCXMs. By 6 months, 7 of 9 patients expressed immunoregulatory suppressor cell activity. Conclusions The absence of acute rejection events was likely due to inhibition of donor-specific immunity. Seventy percent of patients demonstrated an early non–donor-directed HLA antibody response that had no adverse effect on graft function and 78% of the patients displayed immunoregulatory suppressor cell function, probably contributing to the successful clinical outcome.

Thymoglobulin for induction or rejection therapy in pancreas allograft recipients: a single centre experience.

To review the safety and efficacy of thymoglobulin in pancreas transplant patients receiving tacrolimus and mycophenolate mofetil. Retrospective, single centre analysis of 45 patients transplanted between 1995 and 2000 who received 54 courses of thymoglobulin, including 36 courses in 29 solitary pancreas transplant recipients (16 pancreas alone, 13 pancreas after kidney transplants) and 18 courses in 16 simultaneous kidney-pancreas transplant patients. Thirty-two patients (71%) were primary pancreas transplants, 10 (22%) were second transplants and three (7%) were third transplants. Of the 54 treatment courses, 19 (35%) were for induction, 27 (50%) were for primary rejection and eight (15%) were rescue therapy for rejection. All rejection episodes were biopsy-proven in at least one organ. The median thymoglobulin dose was 1.5 mg/kg/d with a mean of six doses (range 3-10). Dose reduction or interruption was required in 28 courses (52%), most often due to leukopenia (n = 24), fever (n = 2) and thrombocytopenia (n = 2). Thymoglobulin was resumed in all but three patients, two with persistent fever and one with infection. Infectious complications (n = 25) occurred in 17 patients (38%) within 30 days and included bacterial (n = 16), cytomegalovirus (n = 4), polyoma (n = 1), fungal (Candida albicans, n = 1), toxoplasmosis (n = 1) and ehrlichiosis (n = 2). Post-transplant lymphoproliferative disease occurred in two patients (4%) at a mean of 70 d post-thymoglobulin treatment. In the 19 patients that received thymoglobulin induction, one simultaneous kidney-pancreas transplant, two pancreas alone and four pancreas after kidney transplant recipients developed rejection (37% incidence), while all remaining patients followed by surveillance protocol biopsies were rejection-free. In the 35 patients that received thymoglobulin for rejection, reversal occurred in 26 of the patients (74%). Rejection recurred within 30 d in five patients and post-treatment biopsies revealed persistent rejection in three of 20 pancreas and two of eight renal biopsies. After a mean follow-up of 6 months, the actual patient and pancreas graft survival rates were 93% and 71%, respectively. Thymoglobulin was effective as induction therapy in high-risk pancreas transplant recipients, and resulted in initial reversal of rejection in 74% of patients. Dose adjustments were required in over half the cases and were usually due to leukopenia. Infections occurring subsequent to thymoglobulin were not uncommon and reflected the immunosuppressive burden of the patient population.

Safety, efficacy, and cost analysis of thymoglobulin induction therapy with intermittent dosing based on CD3+ lymphocyte counts in kidney and kidney-pancreas transplant recipients.

In view of the superior T-cell depletion and prolonged half-life of thymoglobulin, we initiated a protocol to administer thymoglobulin intermittently based on peripheral blood CD3+ lymphocyte counts. In this prospective study, 41 consecutive high-risk cadaver transplant recipients (panel reactive antibody level >30%, repeat transplant recipients, simultaneous pancreas and kidney or pancreas after kidney recipients, prolonged cold-ischemia time, prolonged donor hypotension, non-heart-beating donors) who received thymoglobulin induction therapy were included. The first dose (1.5 mg/kg) of thymoglobulin was administered intraoperatively. CD3+ lymphocyte count in the peripheral blood was determined daily and repeat doses were administered when the CD3+ count was >20 cells/mm3. Calcineurin inhibitors (CI) in low doses were introduced when the allograft function recovered and the serum creatinine level dropped by at least 25% from the pretransplant level. Thymoglobulin treatment was discontinued once therapeutic CI drug levels were achieved. Concomitant immunosuppression consisted of mycophenolate mofetil and prednisone. The mean individual thymoglobulin dose was 104 mg (1.4 mg/kg), and the total cumulative dose per patient was 318 mg (4.2 mg/kg). Patients received an average of three doses and a mean of six CD3 counts were obtained per patient. Introduction of CI was delayed for an average of 6 days posttransplantation. At a mean follow-up of 340 days, two (4.9%) patients died; three (7.3%) renal allografts and two (18.2%) pancreas allografts were lost. Five (12.2%) patients developed a total of six acute rejection episodes. The mean serum creatinine in the 38 patients with a functioning kidney was 1.47 mg/dl, and the mean blood glucose in the 9 pancreas allograft recipients was 89 mg/dl. Cytomegalovirus (CMV) infection occurred in one (2.4%) patient. No posttransplant lymphoproliferative disorders were seen in this patient cohort. The hospital pharmacy charge for a 100-mg dose of thymoglobulin at this center was $2,165, and the laboratory charge for a single CD3 determination was $70. In this study, the average charges per patient for the total dose of thymoglobulin and six CD3 determinations were $7305. In comparison, the charge for daily administration of 104 mg of thymoglobulin (which was the mean dose) for 6 days (mean time to CI therapy initiation) would be $13,510 and for 10 days (mean time to therapeutic CI levels) would be $22,516. This represents a savings of 46% and 68%, respectively. Intermittent thymoglobulin therapy, based on peripheral blood CD3+ lymphocyte counts, is safe and associated with low acute rejection rate in high-risk kidney and kidney-pancreas transplant recipients. A mean of three doses resulted in adequate suppression of CD3+ lymphocytes permitting delayed introduction of CI in low doses until recovery of renal function occurred. When compared to traditional daily administration, intermittent therapy results in significant cost savings and reduces the total cumulative dose of this potent immunosuppressive agent.

Technical and immunosuppressive advances in transplantation for insulin-dependent diabetes mellitus.

Pancreas transplantation has emerged as the single most effective way to achieve normal glucose homeostasis inpatients with type I insulin-dependent diabetes mellitus. Optimal immunosuppressive strategies for pancreas transplantation continue to evolve with the use of newer, more potent immunosuppressive agents,particularly tacrolimus, mycophenolate mofetil, and rapamycin. These agents have contributed to substantially lower rates of allograft rejection and improved graft survival. Regimens designed to avoid nephrotoxicity or spare corticosteroid therapy are emerging as the variety of drug options grows. Also contributing to progressively better results for solitary pancreas transplants are reductions in early graft loss rates and the development of safe, effective biopsy techniques, permitting accurate diagnosis of rejection. Collectively,these factors have allowed solitary pancreas allograft recipients, a group of patients with historically poor long-term graft survival, to enjoy successes nearly equivalent to those of combined kidney-pancreas transplants. Consequently, the American Diabetes Association strongly endorses pancreas transplantation in diabetic patients who have received prior kidney transplants and who have life-threatening metabolic lability.

Peripheral vascular disease in pancreas allograft recipients

Peripheral vascular disease in pancreas allograft recipients

Post-transplantation hypoglycaemia in type 1 diabetic pancreas allograft recipients

Physiologic replacement of insulin in patients with type 1 (insulin-dependent) diabetes following pancreas allograft transplantation results in normoglycaemia during fasting and postprandial states. However, this is achieved at the expense of peripheral hyperinsulinaemia in the heterotopic pancreas allograft recipients with systemic insulin drainage. In addition, the pancreas allograft is denervated and thus devoid of autonomic nervous regulation of pancreatic beta-cell secretion. Recent reports of hypoglycaemia (symptomatic and asymptomatic), which can be fatal, have raised serious concerns regarding the aetiology of the hypoglycaemic epiphenomenon in type 1 diabetic pancreas allograft recipients. Although the prevalence of significant hypoglycaemia following pancreas transplantation remains unknown, it is important to conduct studies to determine the mechanisms, the natural history, predictors and treatment as well as the long-term prognosis (graft and patient survival rates) of type 1 diabetic patients who develop pancreas-allograft-associated hypoglycaemia. Indeed, predictors of hypoglycaemia following pancreas allograft could significantly impact on the selection of appropriate therapeutic options for pancreas allograft transplantation. Finally, whether postpancreas allograft transplantation-associated hypoglycaemia in type 1 diabetic patients carries greater morbidity and mortality when compared to those without hypoglycaemia deserves to be investigated.

Differing Effects of Pancreas-kidney Transplantation With Systemic Versus Portal Venous Drainage on Cholesteryl Ester Transfer in IDDM Subjects

Cholesteryl ester transfer (CET) is accelerated in patients with IDDM treated with conventional (subcutaneous) insulin therapy (CIT) and a number of other disorders associated with premature cardiovascular disease. We have shown that in IDDM this disturbance is closely linked to iatrogenic hyperinsulinemia (HI), because it was reversed when insulin was administered by the intraportal (i.p.) route. In this study, we sought to determine whether HI after successful pancreas-kidney transplantation (PKT) has the same adverse effect on CET. CET was measured by both mass and isotopic assays and compared in two groups of euglycemic non-insulin-requiring IDDM PKT patients with either systemically draining allografts and persistent HI or grafts with portal vein anastomoses that were normoinsulinemic (PK-P). A third group of eight nondiabetic kidney transplant (KT) patients receiving the same immunosuppressive drugs served as control subjects. CET in pancreas-kidney transplantation subjects with systemic venous drainage (PK-S) was increased (P < 0.001) to the same level we have reported previously in IDDM patients receiving CIT and was significantly higher (P < 0.001) than in those subjects with PK-P. CET in the PK-P group did not differ from that of the KT control patients. CET is affected by variations in systemic insulin levels in pancreas transplant patients with allografts that have differing venous drainage. Because high systemic insulin levels are linked to the activation of (ET, euglycemic HI IDDM pancreas allograft recipients may continue to be at high risk for macrovascular complications.

Use of FK506 Immunosuppressive Therapy in Pancreas Transplantation

The purpose of this study was to evaluate the safety, efficacy, and transplant outcomes associated with FK506 rescue and maintenance therapy in pancreas transplant recipients. A chart review was conducted on 10 patients receiving FK506 after pancreas transplantation. Transplant outcomes were compared with an equivalent group of patients receiving cyclosporine. Medication dose, side effects, infections, rejection episodes, glycemic control, and graft survival were recorded from 2 to 28 weeks after transplant. Rescue therapy was successful in the patients who were converted to FK506 prior to a significant decline in glycemic control, whereas those patients who were converted after a decline in glycemic control were required to return to exogenous insulin administration. Neurological complications, nephrotoxicity, incidence of infection, hypertension, rejection, and graft survival were similar for both groups. Use of FK506 is comparable to cyclosporine in pancreas allograft recipients and successful conversion from cyclosporine to FK506 can be undertaken for rescue therapy.

Experimental hyperacute rejection in pancreas allotransplants.

A model of sensitization by intraperitoneal lymph node inoculation was developed to test the hypothesis that hyperacute rejection (HAR) could occur in sensitized recipients of vascularized pancreas allografts. Ten pairs of outbred mongrel dogs that were lymphocytotoxic cross-match assay negative were inoculated with homogenized lymph nodes on either three or four occasions at fortnightly intervals before renal transplantation. A renal allograft from the same donor was used to test the HAR response and to further enhance sensitization by rejection of a vascularized organ. Pancreas transplants were performed 2 weeks later, with biopsies of the graft and blood samples taken at 0, 10, 20, and 30 min and then at 30-min intervals until the grafts were no longer viable. All renal and pancreas grafts were rejected in a classical hyperacute pattern. Within 4 min of revascularization of the pancreas, central lobular hemorrhage and vascular congestion appeared, followed by general edema. Histology demonstrated parallel changes of edema, vascular congestion, necrosis, hemorrhage, and leukocytic infiltrate, which all preceded graft infarction. A sharp decline in both arterial and venous white blood cell count and platelets occurred within 10 min of revascularization with initial sequestration and subsequent release of platelets from the graft (P=0.02). In summary, HAR of the allografted pancreas can be observed by the surgeon within minutes of revascularization, with predictable macroscopic and microscopic changes. This study supports the use of routine lymphocytotoxic cross-match tests for all recipients of pancreas transplants and implies that particular care is warranted in regraft pancreas allograft recipients.

Pancreas Transplantation in Diabetic Humans Normalizes Hepatic Glucose Production During Hypoglycemia

Although successful pancreas transplantation in humans with type I diabetes mellitus restores glucose-induced insulin secretion, provides freedom from insulin treatment, and normalizes fasting glucose levels, much less is known about its effects on counterregulation of hypoglycemia. To determine whether pancreas transplantation normalizes glucagon secretion and hepatic glucose production (HGP) during hypoglycemia, we performed hyperinsulinemic hypoglycemic clamps in successful recipients of pancreas allografts. Recipients were found to have glucagon secretory responses during hypoglycemia that were similar to those of control subjects (incremental glucagon response: recipients, 147 +/- 34 ng/L; control subjects, 161 +/- 43 ng/L, NS) but were significantly higher than those of matched subjects with type I diabetes (23 +/- 9 ng/L, P < 0.01). HGP rates at the end of 120 min of hypoglycemia were also significantly higher in recipients and control subjects than in subjects with diabetes (pancreas recipients, 1.92 +/- 0.33 mg.kg-1.min-1; control subjects, 2.05 +/- 0.18 mg.kg-1.min-1; subjects with type I diabetes, 0.58 +/- 0.12 mg.kg-1.min-1). A comparison with a third group of nondiabetic kidney transplant recipients demonstrated that the beneficial effects on glucose counterregulation were a result of pancreas transplantation and not the associated immunosuppressive therapy. We conclude that pancreas transplantation restores hypoglycemia-induced glucagon secretion and HGP, thereby allowing for normalization of glucose recovery from hypoglycemia.

Variation of haemorheological parameters in renal and pancreatic rejection.

Abnormalities of haemorheology were found in animal and human recipients of kidney and/or pancreas allografts during rejection episodes. Thirteen diabetic canines received solitary pancreatic transplantation and another 13 diabetic and uremic canines underwent combined pancreas and kidney transplantation. Determination of haemorheological parameters was performed before and after operation respectively. During rejection episodes of kidney or pancreas allografts, the values of plasma viscosity, blood reductive viscosity and fibrinogen were significantly higher than those without rejection. On the basis of animal experiments, the determination of haemorheological parameters had been performed on 33 patients (30 receiving renal transplant, 2 pancreatic transplant alone and the remaining 1 combined renal and pancreatic transplant). Consecutive monitoring on these patients showed that a rise in the values of plasma viscosity, blood reductive viscosity and fibrinogen could be demonstrated during rejection episodes. The changes appeared one to three days prior to clinical manifestations and were in accordance with the termination of rejection. Our studies suggest that variation of haemorheological parameters are associated with rejection and the abnormal haemorheology may be an essential factor contributing to graft dysfunction. Moreover, the use of these assays will be beneficial to early diagnosis and better management of rejection in the future.

Minimal model analysis of insulin sensitivity and glucose-mediated glucose disposal in Type 1 (insulin-dependent) diabetic pancreas allograft recipients

Decreased insulin sensitivity and glucose-dependent glucose disposal (glucose effectiveness) have been demonstrated in poorly-controlled Type 1 (insulin-dependent) diabetic patients. We have therefore examined the effects of successful pancreas transplantation that results in long-term physiologic normoglycaemia as measured by insulin sensitivity index and glucose effectiveness in 14 Type 1 diabetic recipients (Group 1) using the Bergman minimal model method. Their results were compared with those of five non-diabetic patients with kidney transplant alone (Group 2) and 10 healthy control subjects (Group 3). Mean plasma glucose levels were indistinguishable in Group 1 when compared to Groups 2 and 3. However, mean basal plasma insulin levels were two- and eight-fold greater in Group 1 (36 +/- 6 microU/ml) than in Group 2 (17 +/- 7 microU/ml) and Group 3 (4.5 +/- 0.6 microU/ml), respectively. Following intravenous glucose (t = 0 min) and tolbutamide (t = 20), peak incremental insulin levels were significantly (p less than 0.001) greater in Group 1 vs Groups 2 and 3. Mean insulin sensitivity index was 65% and 50% lower in Group 1 (2.89 +/- 0.45) and Group 2 (4.11 +/- 1.30), respectively, when compared to Group 3 (8.40 +/- 1.24 x 10(-1) min-1 (microU/ml)-1. In contrast, glucose effectiveness was similar in the three groups (Group 1, 2.48 +/- 0.26; Group 2, 2.05 +/- 0.21; and Group 3, 2.10 +/- 0.17 x 10(-2).min-1). We conclude that, despite prednisone-induced insulin resistance, normal glucose tolerance is achieved by hyperinsulinaemia and normalisation of glucose-dependent glucose disposal following pancreas-kidney transplantation in Type 1 diabetic patients.