Sitagliptin Treatment After Total Pancreatectomy With Islet Autotransplantation: A Randomized, Placebo-Controlled Study.

Insulin independence after total pancreatectomy and islet autotransplant (TPIAT) for chronic pancreatitis is limited by a high rate of postprocedure beta cell apoptosis. Endogenous glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are increased by dipeptidyl peptidase 4 inhibitor therapy (sitagliptin) may protect against beta cell apoptosis. To determine the effect of sitagliptin after TPIAT, 83 adult TPIAT recipients were randomized to receive sitagliptin (n = 54) or placebo (n = 29) for 12 months after TPIAT. At 12 and 18 months after TPIAT, participants were assessed for insulin independence; metabolic testing was performed with mixed meal tolerance testing and frequent sample intravenous glucose tolerance testing. Insulin independence did not differ between the sitagliptin and placebo groups at 12 months (42% vs. 45%, p = 0.82) or 18 months (36% vs. 44%, p = 0.48). At 12 months, insulin dose was 9.0 (standard error 1.7) units/day and 7.9 (2.2) units/day in the sitagliptin and placebo groups, respectively (p = 0.67) and at 18 months 10.3 (1.9) and 7.1 (2.6) units/day, respectively (p = 0.32). Hemoglobin A1c levels and insulin secretory measures were similar in the two groups, as were adverse events. In conclusion, sitagliptin could be safely administered but did not improve metabolic outcomes after TPIAT.

HLA-A, -B, -C, -DR, and -DQ Matching in Pancreas Transplantation: Effect on Graft Rejection and Survival.

To enhance selection of appropriate deceased donors for pancreas transplants, we sought to determine whether HLA matching improved posttransplantation outcomes. In this single-center study of 1219 pancreas transplants, we correlated posttransplantation outcomes with HLA-A, -B, -C, -DR, and -DQ matches and mismatches. Rejection was linearly correlated with the number of mismatches. The individual number of HLA mismatches reached significance at four or more with a 2.3- to 2.9-fold increase in rejection. The effect was most predominant with HLA-B (1.8-fold with one mismatch and 2.0-fold with two mismatches) and -DR (1.9-fold with two mismatches) loci, whereas HLA-A, -C, and -DQ matches or mismatches did not independently predict acute rejection. The affect was strongest in solitary pancreas transplants, with little impact for simultaneous pancreas and kidney (SPK). In contrast, HLA matching did not affect graft or patient survival rates but was associated with a reduced risk of opportunistic infection. Avoidance of acute rejection saved an estimated $32 000 for solitary pancreas recipients and $52 000 for SPK recipients in hospital costs. Our data do not support the use of HLA matching for predicting pancreas graft survival but do support its significance for the reduction of acute rejection, particularly for solitary pancreas recipients.

Controversies in pancreas transplantation.

Pancreas transplants are now highly effective for patients with diabetes mellitus. Improvements in outcomes have primarily been due to significant reductions in technical failures and immunological graft loss. In this short review we discuss three areas of controversy in the field of pancreas transplantation. Notwithstanding the controversies we have highlighted, in line with the American Diabetic Association position statement, simultaneous pancreas-kidney transplants and pancreas after kidney transplants should be routine for diabetic kidney recipients, and a pancreas transplant alone is appropriate for non-uremic labile diabetic patients.

Defective glucagon secretion during hypoglycemia after intrahepatic but not nonhepatic islet autotransplantation.

Defective glucagon secretion during hypoglycemia after islet transplantation has been reported in animals and humans with type 1 diabetes. To ascertain whether this is true of islets from nondiabetic humans, subjects with autoislet transplantation in the intrahepatic site only (TP/IAT-H) or in intrahepatic plus nonhepatic (TP/IAT-H+NH) sites were studied. Glucagon responses were examined during stepped hypoglycemic clamps. Glucagon and symptom responses during hypoglycemia were virtually absent in subjects who received islets in the hepatic site only (glucagon increment over baseline = 1 ± 6, pg/mL, mean ± SE, n = 9, p = ns; symptom score = 1 ± 1, p = ns). When islets were transplanted in both intrahepatic + nonhepatic sites, glucagon and symptom responses were not significantly different than Control Subjects (TP/IAT-H + NH: glucagon increment = 54 ± 14, n = 5; symptom score = 7 ± 3; control glucagon increment = 67 ± 15, n = 5; symptom score = 8 ± 1). In contrast, glucagon responses to intravenous arginine were present in TP/IAT-H recipients (TP/IAT: glucagon response = 37 ± 8, n = 7). Transplantation of a portion of the islets into a nonhepatic site should be seriously considered in TP/IAT to avoid posttransplant abnormalities in glucagon and symptom responses to hypoglycemia.

A composite risk model for predicting technical failure in pancreas transplantation.

Technical failure (TF) continues to have a significant impact on the success of pancreas transplantation. We assessed risk factors for TF in 1115 pancreas transplants performed at a single center between 1998 and 2011. The overall TF rate was 10.2%. In a multivariable model, donor BMI ≥ 30 (HR 1.87, p = 0.005), donor Cr ≥ 2.5 (HR 3.16, p = 0.007), donor age >50 (HR 1.73, p = 0.082) and preservation time >20 h (HR 2.17, p < 0.001) were associated with TF. Bladder drainage of exocrine secretions was protective (HR 0.54, p = 0.002). We incorporated these factors in a Composite Risk Model. In this model the presence of one risk factor did not significantly increase risk of TF (HR 1.35, p = 0.346). Two risk factors in combination increased risk greater than threefold (HR 3.65, p < 0.001) and three risk factors increased risk greater than sevenfold (HR 7.66, p = <0.001). The analysis also identified many factors that were not predictive of TF, including previous transplants, immunosuppressive agent selection, and almost all recipient demographic parameters. While the model suggests that two or more risk factors predict TF, strategies to reduce preservation time may mitigate some of this risk.

Proposed thresholds for pancreatic tissue volume for safe intraportal islet autotransplantation after total pancreatectomy.

The simple question of how much tissue volume (TV) is really safe to infuse in total pancreatectomy-islet autotransplantation (TP-IAT) for chronic pancreatitis (CP) precipitated this analysis. We examined a large cohort of CP patients (n = 233) to determine major risk factors for elevated portal pressure (PP) during islet infusion, using bivariate and multivariate regression modeling. Rates of bleeding requiring operative intervention and portal venous thrombosis (PVT) were evaluated. The total TV per kilogram body weight infused intraportally was the best independent predictor of change in PP (ΔPP) (p < 0.0001; R(2) = 0.566). Rates of bleeding and PVT were 7.73% and 3.43%, respectively. Both TV/kg and ΔPP are associated with increased complication rates, although ΔPP appears to be more directly relevant. Receiver operating characteristic analysis identified an increased risk of PVT above a suggested cut-point of 26 cmH2O (area under the curve = 0.759), which was also dependent on age. This ΔPP threshold was more likely to be exceeded in cases where the total TV was >0.25 cm(3)/kg. Based on this analysis, we have recommended targeting a TV of <0.25 cm(3)/kg during islet manufacturing and to halt intraportal infusion, at least temporarily, if the ΔPP exceeds 25 cmH2O. These models can be used to guide islet manufacturing and clinical decision making to minimize risks in TP-IAT recipients.

Prospective randomized trial of maintenance immunosuppression with rapid discontinuation of prednisone in adult kidney transplantation.

Rapid discontinuation of prednisone (RDP) has minimized steroid-related complications following kidney transplant (KT). This trial compares long-term (10-year) outcomes with three different maintenance immunosuppressive protocols following RDP in adult KT. Recipients (n=440; 73% living donor) from March 2001 to April 2006 were randomized into one of three arms: cyclosporine (CSA) and mycophenolate mofetil (MMF) (CSA/MMF, n=151); high-level tacrolimus (TAC, 8-12 µg/L) and low-level sirolimus (SIR, 3-7 µg/L) (TACH/SIRL, n=149) or low-level TAC (3-7 µg/L) and high-level SIR (8-12 µg/L) (TACL/SIR(H) , n=140). Median follow-up was ∼7 years. There were no differences between arms in 10-year actuarial patient, graft and death-censored graft survival or in allograft function. There were no differences in the 10-year actuarial rates of biopsy-proven acute rejection (30%, 26% and 20% in CSA/MMF, TACH/SIRL and TACL/SIRH) and chronic rejection (38%, 35% and 31% in CSA/MMF, TACH/SIRL and TACL/SIRH). Rates of new-onset diabetes mellitus were higher with TACH/SIRL (p=0.04), and rates of anemia were higher with TACH/SIRL and TACL/SIRH (p=0.04). No differences were found in the overall rates of 16 other post-KT complications. These data indicate that RDP-based protocol yield acceptable 10-year outcomes, but side effects differ based on the maintenance regimen used and should be considered when optimizing immunosuppression following RDP.

Metabolic assessment prior to total pancreatectomy and islet autotransplant: utility, limitations and potential.

Islet autotransplant (IAT) may ameliorate postsurgical diabetes following total pancreatectomy (TP), but outcomes are dependent upon islet mass, which is unknown prior to pancreatectomy. We evaluated whether preoperative metabolic testing could predict islet isolation outcomes and thus improve assessment of TPIAT candidates. We examined the relationship between measures from frequent sample IV glucose tolerance tests (FSIVGTT) and mixed meal tolerance tests (MMTT) and islet mass in 60 adult patients, with multivariate logistic regression modeling to identify predictors of islet mass ≥2500 IEQ/kg. The acute C-peptide response to glucose (ACRglu) and disposition index from FSIVGTT correlated modestly with the islet equivalents per kilogram body weight (IEQ/kg). Fasting and MMTT glucose levels and HbA1c correlated inversely with IEQ/kg (r values -0.33 to -0.40, p ≤ 0.05). In multivariate logistic regression modeling, normal fasting glucose (<100 mg/dL) and stimulated C-peptide on MMTT ≥4 ng/mL were associated with greater odds of receiving an islet mass ≥2500 IEQ/kg (OR 0.93 for fasting glucose, CI 0.87-1.0; OR 7.9 for C-peptide, CI 1.75-35.6). In conclusion, parameters obtained from FSIVGTT correlate modestly with islet isolation outcomes. Stimulated C-peptide ≥4 ng/mL on MMTT conveyed eight times the odds of receiving ≥2500 IEQ/kg, a threshold associated with reasonable metabolic control postoperatively.

Comprehensive health assessment and five-yr follow-up of allogeneic islet transplant recipients.

In patients with type 1 diabetes mellitus (T1DM) complicated by severe hypoglycemic episodes, fear of hypoglycemia can significantly impact daily life. We evaluated whether restoration of glycemic awareness and prevention of hypoglycemia by islet allotransplant could reduce fear and improve health status. We conducted a comprehensive evaluation of patient-based outcomes in 48 T1DM subjects screened for allogeneic islet transplant alone (ITA) and 27 subjects who received an ITA. A battery of generic health status and diabetes-specific measures were used to assess ITA at evaluation, six months, and then annually after ITA. Allogeneic islet transplant was associated with a reduction in behaviors adopted in avoiding hypoglycemia (p Value < 0.001) and attenuation in concerns about hypoglycemic episodes (p Value < 0.001). Changes in hypoglycemia fear tracked most closely with insulin use. While there was a trend toward global improvement in health as measured by the EQ-5D (p Value = 0.002) and in depression symptoms as measured by the Beck (p Value = 0.003), physical health remained unchanged following ITA. Our findings support the socioemotional benefits of ITA during the five years after ITA, which to some extent remains dependent on preservation of islet graft function.

Comparison of recipient outcomes following transplant from local versus imported pancreas donors.

The shortage of deceased donor organs for solid organ transplantation continues to be an ongoing dilemma. One approach to increase the number of pancreas transplants is to share organs between procurement regions. To assess for the effects of organ importation, we reviewed the outcomes of 1014 patients undergoing deceased donor pancreas transplant at a single center. We performed univariate and multivariate analyses of the association of donor, recipient and surgical characteristics with patient outcomes. Organ importation had no effect on graft or recipient survival for recipients of solitary pancreas transplants. Similarly, there was no effect on technical failure rate, graft survival or long-term patient survival for simultaneous kidney-pancreas (SPK) recipients. In contrast, there was a significant and independent increased risk of death in the first year in SPK recipients of imported organs. SPK recipients had longer hospitalizations and increased hospital costs. This increased medical complexity may make these patients more susceptible to short-term complications resulting from the longer preservation times of import transplants. These findings support the continued use of organ sharing to reduce transplant wait times but highlight the importance of strategies to reduce organ preservation times.

Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes.

The seemingly inexorable decline in insulin independence after islet transplant alone (ITA) has raised concern about its clinical utility. We hypothesized that induction immunosuppression therapy determines durability of insulin independence. We analyzed the proportion of insulin-independent patients following final islet infusion in four groups of ITA recipients according to induction immunotherapy: University of Minnesota recipients given FcR nonbinding anti-CD3 antibody alone or T cell depleting antibodies (TCDAb) and TNF-α inhibition (TNF-α-i) (group 1; n = 29); recipients reported to the Collaborative Islet Transplant Registry (CITR) given TCDAb+TNF-α-i (group 2; n = 20); CITR recipients given TCDAb without TNF-α-i (group 3; n = 43); and CITR recipients given IL-2 receptor antibodies (IL-2RAb) alone (group 4; n = 177). Results were compared with outcomes in pancreas transplant alone (PTA) recipients reported to the Scientific Registry of Transplant Recipients (group 5; n = 677). The 5-year insulin independence rates in group 1 (50%) and group 2 (50%) were comparable to outcomes in PTA (group 5: 52%; p>>0.05) but significantly higher than in group 3 (0%; p = 0.001) and group 4 (20%; p = 0.02). Induction immunosuppression was significantly associated with 5-year insulin independence (p = 0.03), regardless of maintenance immunosuppression or other factors. These findings support potential for long-term insulin independence after ITA using potent induction therapy, with anti-CD3 Ab or TCDAb+TNF-α-i.

Guidelines for the diagnosis of antibody-mediated rejection in pancreas allografts-updated Banff grading schema.

The first Banff proposal for the diagnosis of pancreas rejection (Am J Transplant 2008; 8: 237) dealt primarily with the diagnosis of acute T-cell-mediated rejection (ACMR), while only tentatively addressing issues pertaining to antibody-mediated rejection (AMR). This document presents comprehensive guidelines for the diagnosis of AMR, first proposed at the 10th Banff Conference on Allograft Pathology and refined by a broad-based multidisciplinary panel. Pancreatic AMR is best identified by a combination of serological and immunohistopathological findings consisting of (i) identification of circulating donor-specific antibodies, and histopathological data including (ii) morphological evidence of microvascular tissue injury and (iii) C4d staining in interacinar capillaries. Acute AMR is diagnosed conclusively if these three elements are present, whereas a diagnosis of suspicious for AMR is rendered if only two elements are identified. The identification of only one diagnostic element is not sufficient for the diagnosis of AMR but should prompt heightened clinical vigilance. AMR and ACMR may coexist, and should be recognized and graded independently. This proposal is based on our current knowledge of the pathogenesis of pancreas rejection and currently available tools for diagnosis. A systematized clinicopathological approach to AMR is essential for the development and assessment of much needed therapeutic interventions.

Differential roles of Mac-1+ cells, and CD4+ and CD8+ T lymphocytes in primary nonfunction and classic rejection of islet allografts.

The high rate of persistent hyperglycemia, termed primary nonfunction, after islet allotransplantation in C57BL/6 mice recipients of B10.BR strain islets, as compared with B10.BR recipients of C57BL/6 islets, led to a series of experiments to determine whether islet allograft primary nonfunction was attributable to technical aspects of the transplant procedure or whether it was a consequence of alloimmunity. Primary nonfunction was prevented by systemic pharmacologic immunosuppression of the host with cyclosporine. Selective immunodepletion of host CD4+ and CD8+ T lymphocytes significantly extended the time of classic rejection but did not significantly affect the rate of primary nonfunction. However, modulation of macrophages by administration to the host of silica completely abolished primary nonfunction. These observations, in conjunction with the immunohistological findings of intense macrophage infiltration in islet allografts from recipients exhibiting persistent post-transplant hyperglycemia, support the hypothesis that primary nonfunction results from a cell-mediated host-immune response of rapid onset that is dependent on macrophages or macrophage byproducts as the main effectors.

Renal transplantation in diabetes mellitus in rats.

Immunoglobulins and complement are deposited in the glomerular mesangium of rats with progressive glomerulosclerosis secondary to chemically induced diabetes mellitus. Isotransplantation of a kidney from a rat diabetic for 6 mo into a normal recipient results within 2 mo in the disappearance of IgG, IgM, and beta(1)C from the mesangium and arrest or reversal of the light microscopic glomerular lesions. Kidneys isotransplanted from normal donors into diabetic rats developed mesangial matrix thickening and deposition of IgG, IgM) and beta(1)C in the mesangium. No glomerular changes occur upon transplantation of a normal kidney into a normal rat. These findings indicate that diabetic glomerular changes in the rat are reversible and are secondary to the diabetic state rather than to the inducing agent.

The glomerular mesangium. 3. Acute immune mesangial injury: a new model of glomerulonephritis.

A mechanism of immune glomerular injury is described based on the fixation of antibody (Ab) to an antigen (Ag) that has localized in the glomerular mesangium. Rabbits were given, intravenously (i.v.), aggregated human IgG (AHIgG) or albumin (AHSA) and 10 h later, when the Ag by immunofluorescent microscopy was present in the mesangium, a kidney was removed and transplanted into a normal rabbit. The recipient then received, i.v., rabbit anti-HIgG or anti-HSA. Within minutes of Ab infusion, glomeruli of the donor kidney had polymorphonuclear (PMN) infiltration that over the next few hours became marked and was associated with glomerular cell swelling. At 24 h a decrease in PMN's and early mesangial proliferation was seen. By 3 days there was marked mesangial hypercellularity and increased mesangial matrix. Within minutes after Ab administration rabbit IgG, C3, and fibrin were seen in the glomerular mesangium. There was a fall in complement titer by 1 min after Ab infusion that was due to complement consumption by the donor kidney. Complement then returned to normal levels by 48 h. Significant glomerular injury did not occur (a) in the recipient's own kidney, (b) from Ag administration and transplantation without recipient Ab administration, or (c) from transplantation and Ab administration without prior Ag administration. These studies demonstrated that Ag localized in the glomerular mesangium can react with circulating Ab and complement resulting in severe glomerular injury.

Human islet isolation for autologous transplantation: comparison of yield and function using SERVA/Nordmark versus Roche enzymes.

Islet autotransplantation (IAT) is used to preserve as much insulin-secretory capacity as possible in patients undergoing total pancreatectomy for painful chronic pancreatitis. The enzyme used to dissociate the pancreas is a critical determinant of islet yield, which is correlated with posttransplant function. Here, we present our experience with IAT procedures to compare islet product data using the new enzyme SERVA/Nordmark (SN group; n = 46) with the standard enzyme Liberase-HI (LH group; n = 40). Total islet yields (mean +/- standard deviation; 216,417 +/- 79,278 islet equivalent [IEQ] in the LH group; 227,958 +/- 58,544 IEQ in the SN group; p = 0.67) were similar. However, the percentage of embedded islets is higher in the SN group compared to the LH group. Significant differences were found in pancreas digestion time, dilution time, and digested pancreas weight between the two groups. Multivariate linear regression analysis showed the two groups differed in portal venous pressure changes. The incidence of graft function and insulin independence was not different between the two groups. The SN and LH enzymes are associated with similar outcomes for IAT. Further optimization of the collagenase/neutral protease ratio is necessary to reduce the number of embedded islets obtained when using the SN enzyme.

Selective retransplant after graft loss to nonadherence: success with a second chance.

Nonadherence (NA) is a difficult posttransplant problem that can lead to graft loss. A retransplant is controversial because of a fear of recurrent NA. We reviewed our center's data base and identified 114 kidney recipients who lost their graft to overt NA; of this group, 35 (31%) underwent a retransplant after a thorough reevaluation. We compared this NA retransplant group to a control group of second transplant recipients who did not lose their first graft to overt NA (non-NA) (n = 552). After 8 years of follow-up, we found no significant differences between the groups in actuarial graft or patient survival rates, renal function, or the incidence of biopsy-proven chronic rejection. However, 5 of 35 (14%) NA recipients versus 10 of 552 (2%) non-NA recipients lost their retransplant to NA (p = 0.0001). Twenty of 35 (57%) of the NA group exhibited repeat NA behavior after retransplant. We conclude that prior graft loss to NA is associated with increased graft loss to NA after retransplant. However, the majority of NA retransplant recipients did well-with overall long-term outcomes similar to those of the non-NA group. With careful patient selection and aggressive intervention, prior overt NA should not be an absolute contraindication to retransplantation.

H-2 antigen class: effect on mouse islet allograft rejection.

Rejection of mouse pancreatic islet allografts occurred in a high percentage of donor recipient combinations identical for H-21-region antigens and differing at H-2K and H-2K + H-2D without I-region disparities. The results suggest that disparities in major histocompatibility complex antigens of class I (H-2K and H-2D) alone are capable of eliciting islet allograft rejection, and that lack of a stimulus from class II (I-region) alloantigens does not ensure permanent islet allograft survival.

Hepatocellular transplantation for metabolic deficiencies: decrease of plasms bilirubin in Gunn rats.

A sustained decrease of plasma bilirubin concentrations occurred in homozygous recessive Gunn rats lacking the enzyme uridine diphosphate glucuronyltransferase following infusion into the portal vein of hepatocytes from heterozygous nonjaundiced Gunn rats possessing the enzyme. Transplantation of cells capable of continuous enzyme production could be an effective mode of therapy for congenital enzyme deficiency diseases.

2202 kidney transplant recipients with 10 years of graft function: what happens next?

The ultimate goal of clinical transplantation is for the recipients to achieve long-term survival, with continuing graft function, that is equivalent to that of the age-matched general population. We studied subsequent outcome in kidney transplant recipients with 10 years of graft function. In all, 2202 kidney transplant recipients survived with graft function >10 years. For 10-year survivors, the actuarial 25-year patient survival rate for primary transplant living donor (LD) recipients was 57%; graft survival, 43%. For primary transplant deceased donor (DD) recipients, the actuarial 25-year patient survival rate was 39%; graft survival, 27%. The two major causes of late graft loss were death (with graft function) and chronic allograft nephropathy (tubular atrophy and interstitial fibrosis). The two major causes of death with function were cardiovascular disease (CVD) and malignancy. For nondiabetic recipients, the mean age at death with function from CVD was 54 +/- 13 years; for diabetic recipients, 53 +/- 7 years. By 20 years posttransplant, morbidity was common: >40% recipients had skin cancer (mean age for nondiabetic recipients, 53 +/- 13 years; for diabetics, 49 +/- 8 years), >10% had non-skin cancer (mean age for nondiabetic recipients, 53 +/- 16 years; for diabetics, 46 +/- 9 years), and >30% had CVD (mean age for nondiabetic recipients, 53 +/- 15 years; for diabetics, 47 +/- 9 years). We conclude that long-term transplant recipients have a high rate of morbidity and early mortality. As short-term results have improved, more focus is needed on long-term outcome.