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Kidney transplant patients are prone to a variety of complications, even for the most experienced surgical teams. Our busy transplant center recently performed its 5,000th solid organ transplant. We present the case of an 18-year-old male with end-stage renal disease who underwent a deceased donor kidney transplant. He developed a urine leak from the necrotic lower pole of his graft kidney and subsequently developed urosepsis and was admitted. Clinicians must have a high suspicion for complications in the immediate post-operative period in kidney transplant patients. In this report, we will highlight our diagnostic and treatment steps to preserve the patient's graft while addressing his rare complications.

The glucagon-like peptide-1 receptor agonist exenatide improves glycemic control by several and not completely understood mechanisms. Herein, we examined the effects of chronic intravenous exenatide infusion on insulin sensitivity, β cell and α cell function and relative volumes, and islet cell apoptosis and replication in nondiabetic nonhuman primates (baboons). At baseline, baboons received a 2-step hyperglycemic clamp followed by an l-arginine bolus (HC/A). After HC/A, baboons underwent a partial pancreatectomy (tail removal) and received a continuous exenatide (n = 12) or saline (n = 12) infusion for 13 weeks. At the end of treatment, HC/A was repeated, and the remnant pancreas (head-body) was harvested. Insulin sensitivity increased dramatically after exenatide treatment and was accompanied by a decrease in insulin and C-peptide secretion, while the insulin secretion/insulin resistance (disposition) index increased by about 2-fold. β, α, and δ cell relative volumes in exenatide-treated baboons were significantly increased compared with saline-treated controls, primarily as the result of increased islet cell replication. Features of cellular stress and secretory dysfunction were present in islets of saline-treated baboons and absent in islets of exenatide-treated baboons. In conclusion, chronic administration of exenatide exerts proliferative and cytoprotective effects on β, α, and δ cells and produces a robust increase in insulin sensitivity in nonhuman primates.

Post-transplant lymphoproliferative disorder (PTLD) is a serious complication after organ transplantation with a cumulative incidence of 1.1% at 18 months and 4.7% at 15 years. It has been reported in patients with or without concomitant Epstein-Barr virus infection. Therapy ranges from a reduction of immunosuppression to administration of conventional cytotoxic chemotherapy. Rituximab, a recombinant chimeric anti-CD20 monoclonal antibody has been used for the treatment of PTLD with promising results and a reduction in treatment-associated mortality. However, the use of rituximab has been associated with spontaneous gastrointestinal perforation. We describe a case of recurrent intestinal perforations after a single dose of rituximab.

A 69-year-old man who underwent a kidney transplantation developed a large pseudoaneurysm at the anastomosis between the right external iliac artery and renal transplant artery. After an unsuccessful attempt using percutaneous thrombin injection, the patient underwent open exploratory laparotomy and surgical ligation of the pseudoaneurysm with preservation of renal graft function.

In this study, we aimed to evaluate the effects of exenatide (EXE) treatment on exocrine pancreas of nonhuman primates. To this end, 52 baboons (Papio hamadryas) underwent partial pancreatectomy, followed by continuous infusion of EXE or saline (SAL) for 14 weeks. Histological analysis, immunohistochemistry, Computer Assisted Stereology Toolbox morphometry, and immunofluorescence staining were performed at baseline and after treatment. The EXE treatment did not induce pancreatitis, parenchymal or periductal inflammatory cell accumulation, ductal hyperplasia, or dysplastic lesions/pancreatic intraepithelial neoplasia. At study end, Ki-67–positive (proliferating) acinar cell number did not change, compared with baseline, in either group. Ki-67–positive ductal cells increased after EXE treatment (P = 0.04). However, the change in Ki-67–positive ductal cell number did not differ significantly between the EXE and SAL groups (P = 0.13). M-30–positive (apoptotic) acinar and ductal cell number did not change after SAL or EXE treatment. No changes in ductal density and volume were observed after EXE or SAL. Interestingly, by triple-immunofluorescence staining, we detected c-kit (a marker of cell transdifferentiation) positive ductal cells co-expressing insulin in ducts only in the EXE group at study end, suggesting that EXE may promote the differentiation of ductal cells toward a β-cell phenotype. In conclusion, 14 weeks of EXE treatment did not exert any negative effect on exocrine pancreas, by inducing either pancreatic inflammation or hyperplasia/dysplasia in nonhuman primates.

Background We have previously reported the successful induction of mixed chimerism and long-term acceptance of renal allografts in MHC-mismatched nonhuman primates after nonmyeloablative conditioning and donor bone marrow transplantation. In this study, we extended our regimen to cardiac allotransplantation and compared the immunological responses of heart and kidney allograft recipients. Methods Five cynomolgus monkeys were conditioned with low-dose total body irradiation (1.5 Gy on days -6 and -5), supplemental thymic irradiation (7 Gy on day -1), antithymocyte globulin (50 mg/kg on days -2, -1, and 0), splenectomy (day 0), donor bone marrow transplantation (day 0), and a 4-week posttransplant course of cyclosporine. Heart allografts from MHC-mismatched donors were transplanted heterotopically on day 0. Results Two monkeys failed to develop multilineage chimerism and rejected their allografts soon after cyclosporine was stopped (postoperative days [PODs] 43 and 56). Three monkeys developed multilineage chimerism, which persisted 20 to 43 days posttransplant by flow cytometric analysis and to POD 124 by polymerase chain reaction analysis. Allograft survival in these recipients was prolonged to 138, 428, and 509 days, and in vitro mixed leukocyte reaction and cell-mediated lympholysis (CML) assays demonstrated donor-specific hyporesponsiveness. However, in contrast to kidney allograft recipients, long-term heart allograft recipients eventually developed humoral and cellular immunity against the donor and rejected the grafts. At the time of rejection, 1.3% to 9.5% of donor coronary arteries exhibited intimal proliferation. Conclusions The induction of transient mixed hematopoietic chimerism leads to long-term heart allograft survival in MHC disparate monkeys without chronic immunosuppression. However, unlike kidney allografts, full tolerance to cardiac allografts was not achieved. Organ-specific modifications of the preparative regimen may be necessary to prevent the chronic cellular and humoral immune responses elicited by cardiac allografts.

Background. Nonmyeloablative T cell depletion followed by donor bone marrow infusion has proved to be an effective approach to induction of mixed chimerism and tolerance of organ allografts in non-human primates. To help define the mechanisms involved we have compared T cell depletion with ATG versus anti-CD2 monoclonal antibody with respect to establishment of mixed chimerism and induction of tolerance. Background. Method. Background. Both nonmyeloablative regimens included low dose total body irradiation (1.5 Gy x 2), thymic irradiation (7 Gy), splenectomy and kidney plus donor bone marrow transplantation, followed by a 4-week posttransplant course of cyclosporine. In addition, the ATG group (13 recipients) received antithymocyte globulin, although the LOCD2b group (10 recipients) were treated with an anti-CD2 monoclonal antibody (LOCD2b). Results. In the ATG group, 11 of 13 monkeys developed multilineage chimerism and 9 survived for more than 100 days without kidney allograft rejection. In contrast, 0/10 monkeys in the LOCD2b group developed chimerism, 5 died of infection and 5 suffered progressive rejection; only 1 recipient survived beyond 100 days. Sequential monitoring of peripheral blood mononuclear cells revealed greater T cell (CD3+) depletion in the LOCD2b-treated animals compared to those receiving ATG. However, NK cells (CD16+CD8+) were significantly more depleted in the ATG group and NK function remained abrogated longer after ATG than LOCD2b treatment (3 weeks vs. Conclusion. Despite excellent T cell depletion by LoCD2b, ATG was more effective in inducing chimerism and tolerance. This difference correlated with anti-NK activity of the two reagents. These data suggest that NK cells may also resist engraftment of allogeneic bone marrow cells in this model.

Hepatitis C virus (HCV) infection is associated with mixed cryoglobulinemia and membranoproliferative glomerulonephritis. After orthotopic liver transplantation (OLT), isolated cases of HCV-associated mixed cryoglobulinemia have been reported. We determined the prevalence and clinical characteristics of mixed cryoglobulinemia in HCV-infected liver transplant recipients at our institution. Between January 1991 and February 1998, a total of 191 OLTs were performed in 178 patients. Among these transplant recipients, 53 patients (29.8%) had positive serological test results for HCV infection by second-generation enzyme-linked immunosorbent assay. We studied 31 HCV-positive (HCV+) and 21 HCV-negative (HCV-) transplant recipients (control group). Renal and liver function studies were performed, and cryoglobulin, rheumatoid factor, C3, C4, and serum HCV RNA levels and genotype were determined. Results were compared using unpaired Student's t-test for continuous variables and Fisher's exact test for categorical variables. Baseline characteristics were similar between the groups. Six patients in the HCV+ group (19%) had mixed cryoglobulins present at the time of evaluation compared with none in the HCV- group (P =. 036). The only parameter associated with cryoglobulins in the HCV+ group was rheumatoid factor (P.01). In 3 HCV+ patients with cryoglobulins, extrarenal signs of cryoglobulinemia were present. Glomerulonephritis was found in 4 HCV+ patients. Two patients with purpura and cryoglobulinemia had reduced clinical manifestations after antiviral therapy. In conclusion, mixed cryoglobulinemia was found in approximately 20% of the HCV+ liver transplant recipients. The presence of purpura or glomerulonephritis suggests HCV-associated mixed cryoglobulinemia, a clinical syndrome that may respond favorably to antiviral therapy.

Background Multilineage chimerism and long-term acceptance of renal allografts has been produced in non-human primates conditioned with a nonmyeloablative regimen. Our study was undertaken to evaluate the immunological and pathological status of long-term survivors and to define the role of splenectomy and of the primarily vascularized kidney in the regimen. Method Monkeys were treated with the basic regimen, including: total body irradiation, thymic irradiation, antithymocyte globulin, donor bone marrow transplantation, and a 4-week course of cyclosporine after which no further immunosuppression was given. They were divided into four groups according to the timing of kidney transplantation (KTx) and splenectomy as follows; group A (n=13): KTx and splenectomy on the day of donor bone marrow transplantation (day 0); group B (n=3): KTx on day 0 without splenectomy; group C (n=7): splenectomy on day 0 but delayed KTx until 3 to 16 weeks post-donor bone marrow transplantation; group D (n=3): both splenectomy and KTx delayed until day 120 post-donor bone marrow transplantation. Results In group A, 11 of 13 monkeys developed chimerism and 9 monkeys achieved long-term survival of 4 to 70 months without evidence of chronic vascular rejection. Alloantibodies were detected in only one long-term survivor. In contrast, all three monkeys in group B developed alloantibodies and rejected their allografts. In group C, long-term survival without alloantibody production was observed in two of three monkeys that had developed chimerism. In group D, all three recipients were sensitized and rejected the kidney allografts rapidly after transplantation. Conclusions 1) Production of anti-donor antibody was prevented in most recipients that developed mixed chimerism in the regimens with splenectomy at the time of donor bone marrow transplantation. 2) If splenectomy is not included in the initial conditioning regimen, induction of B cell tolerance is less likely and the result is late onset of alloantibody production and allograft rejection. 3) Immediate transplantation of the kidney at the time of recipient conditioning is not essential for induction of donor specific hyporesponsiveness by bone marrow transplantation.

Many centers advocate close patient follow-up and a multidisciplinary approach as necessary ingredients for the success of a bariatric surgery program. The military medical environment is not suitable for these conditions. Many patients are referred from great distances to the large regional medical centers, thereby preventing such close follow-up and the ability to create active support groups. A review of the 4-year experience with bariatric surgery at a major military medical center was conducted to determine if the program could be successful, considering that 60% of its patients came from out of state. Hospital records of all 92 patients and the bariatric registry were reviewed. A comprehensive survey to update weight data and assess patient satisfaction was sent to the first 72 patients to undergo surgery. There were no deaths and a perioperative complication rate of 18%. By I year after surgery, 67% of patients lost greater than 50% of their excess weight (mean = 56.6%). Sixty-eight percent of patients responded to the survey; 87% felt they were better off and satisfied with their quality of life since surgery, and 75% reported improved energy levels. If given a chance to rethink their decision, 86% of responders would choose surgery again. A total of 91% were satisfied with their follow-up. Patient proximity to the medical center did not influence weight loss or patient satisfaction. These results suggest that a bariatric surgery program can succeed in a medical environment such as the military where patients are likely to live at great distances from the hospital.

Non-Alcoholic fatty liver disease (NAFLD) is characterized by accumulation of triglycerides (TG) in hepatocytes, which may also trigger cirrhosis. The mechanisms of NAFLD are not fully understood, but insulin resistance has been proposed as a key determinant. Aims To determine the TG content and long chain fatty acyl CoA composition profile in liver from obese non-diabetic insulin resistant (IR) and lean insulin sensitive (IS) baboons in relation with hepatic and peripheral insulin sensitivity. Methods Twenty baboons with varying grades of adiposity were studied. Hepatic (liver) and peripheral (mainly muscle) insulin sensitivity was measured with a euglycemic clamp and QUICKI. Liver biopsies were performed at baseline for TG content and LCFA profile by mass spectrometry, and histological analysis. Findings were correlated with clinical and biochemical markers of adiposity and insulin resistance. Results Obese IR baboons had elevated liver TG content compared to IS. Furthermore, the concentration of unsaturated (LC-UFA) was greater than saturated (LC-SFA) fatty acyl CoA in the liver. Interestingly, LC-FA UFA and SFA correlated with waist, BMI, insulin, NEFA, TG, QUICKI, but not M/I. Histological findings of NAFLD ranging from focal to diffuse hepatic steatosis were found in obese IR baboons. Conclusion Liver TG content is closely related with both hepatic and peripheral IR, whereas liver LC-UFA and LC-SFA are closely related only with hepatic IR in non-human primates. Mechanisms leading to the accumulation of TG, LC-UFA and an altered UFA: LC-SFA ratio may play an important role in the pathophysiology of fatty liver disease in humans.

We have previously observed that donor bone marrow hematopoietic stem cells successfully induce transient mixed chimerism and renal allograft tolerance following non-myeloablative conditioning of the recipient. Stem cells isolated from the peripheral blood (PBSC) may provide similar benefits. We sought to determine the most effective method of mobilizing PBSC for this approach and the effects of differing conditioning regimens on their engraftment.A standard dose (10 μg/kg) or high dose (100 μg/kg) of granulocyte colony-stimulating factor (GCSF) with or without stem cell factor (SCF) was administered to the donor, and PBSC were collected by leukapheresis. Cynomolgus monkey recipients underwent a nonmyeloablative conditioning regimen (total body irradiation, thymic irradiation, and ATG) with splenectomy (splenectomy group) or a short course of anti-CD154 antibody (aCD154) (aCD154 group). Recipients then received combined kidney and PBSC transplantation and a 1-mo post-transplant course of cyclosporine.Treatments with either two cytokines (GCSF+SCF) or high dose GCSF provided significantly more hematopoietic progenitor cells than standard dose GCSF alone. Recipients in the aCD154 group developed significantly higher myeloid and lymphoid chimerism (P0.0001 and P = 0.0002, respectively) than those in the splenectomy group. Longer term renal allograft survival without immunosuppression was also observed in the aCD154 group, while two of three recipients in the splenectomy group rejected their allografts soon after discontinuation of immunosuppression.Protocols including administration of two cytokines (GCSF + SCF) or high dose GCSF alone significantly mobilized more PBSC than standard dose GCSF alone. The recipients of PBSC consistently developed excellent chimerism and survived long-term without immunosuppression, when treated with CD154 blockade.

Although numerous protocols for the induction of allograft tolerance have been successfully applied in rodent studies, only a limited number of these have been translated to nonhuman primates. We have previously reported a nonyeloablative treatment regimen for the induction of mixed chimerism and renal allograft tolerance in nonhuman primates (1–3). The regimen included total body irradiation (TBI), local thymic irradiation (TI), antithymocyte globulin (ATG), either splenectomy or a short course of CD154 blockade (4) and a 1-month postoperative course of cyclosporine. With this protocol, the recipients of MHC mismatched kidney allografts developed transient multilineage mixed chimerism and approximately 50% to 60% of them acquired renal allograft tolerance. More recently, we extended this approach to HLA matched (5–7) or mismatched (8) human kidney transplant recipients. In the clinical trials, we have substituted cyclophosphamide (CP), in place of TBI, because of concern for secondary malignancy after TBI. In our HLA-mismatched kidney transplant recipients, all developed transient mixed chimerism, and four of the five have been off all immnosuppression with a follow-up of 2 to 5 years (8). Encouraged by these clinical studies and prompted by the desire to develop a more similar preclinical model, we evaluated CP in place of TBI in our monkey conditioning regimen. As reported here, we found that cynomolgus monkeys were significantly more resistant to the modulatory effects of CP, requiring larger and more toxic doses to induce chimerism than what was observed in humans. The TBI-based regimen therefore has continued to be essential for the induction of multilineage chimerism and renal allograft tolerance in our nonhuman primate studies.

Costimulatory blockade with anti-CD154 monoclonal antibody (aCD154) prolongs allograft survival in nonhuman primates, but has not reliably induced tolerance when used alone. In the current studies, we evaluated the effect of adding CD154 blockade to a chimerism inducing nonmyeloablative regimen in primates. We observed a significant improvement of donor bone marrow (DBM) engraftment, which has been associated with a lower incidence of acute rejection and long-term survival of renal allografts without the need for previously required splenectomy. Among the long-term survivors, four never showed evidence of rejection, with the longest survival exceeding 1700 days following discontinuation of immunosuppression. Nevertheless, late chronic rejection was observed in three of eight recipients, indicating the necessity of further modifications of the regimen. Control recipients receiving no DBM or donor splenocytes in place of DBM rejected their allografts. Thus, DBM engraftment with, at least, transient mixed chimerism appears essential for induction of allograft tolerance using this conditioning regimen. Modification of the original mixed chimerism approach, by the addition of costimulatory blockade, has been shown to enhance mixed chimerism and induce renal allograft tolerance with less morbidity in nonhuman primates.

A 52-year-old liver transplant recipient presented 8 months after transplantation with oral thrush, then 3 days later with oral ulcers and a diffuse rash, and 5 days later with an acutely reduced white blood cell count, rash, fever, and diarrhea. Bone marrow biopsy revealed severe aplasia. Although graft-versus-host disease (GVHD) was considered, the late onset of these symptoms was felt to render this etiology unlikely because GVHD usually occurs 2 to 6 weeks after transplantation. All potentially myelosuppressive medications were discontinued, and the patient was treated with high doses of hematopoietic growth factors. Because his symptoms continued, chimerism analysis was performed, which indicated that 96% of the peripheral blood mononuclear cells were of liver-donor origin. Ultimately, the patient underwent an allogeneic peripheral blood hematopoietic progenitor cell transplant from a human leukocyte antigen-identical brother, but he died 5 days after transplantation of overwhelming Candida kruseii infection. To our knowledge, this is the first chimerism-analysis-documented case of severe acute GVHD presenting so late after liver transplantation. It is of note that the patient had no known risks for GVHD in that he was relatively young and shared only one major human leukocyte antigen with his donor. Consideration should be given to GVHD as a cause of bone marrow aplasia at any time after organ transplantation. Storage of cell pellets from all transplant recipients and donors is highly recommended to facilitate the diagnostic evaluation.

Presented is the successful management of a difficult abdominal wall closure after pediatric liver transplantation. A 5-week-old boy with biliary atresia underwent urgent cadaveric split liver transplantation. The left lateral segment of an adult donor was utilized. Postoperatively, abdominal skin and fascia could not be closed. A SILASTIC® (Dow Corning, Midland, MI) silo was applied, and complete closure was possible 6 days later.

Presented is a report on the first female hand allotransplantation performed in the USA. The patient sustained a dominant hand amputation at the level of the wrist as a result of a bomb explosion while on active duty in the United States Air Force. A hand allotransplantation was performed at a military treatment facility by a team of physicians composed of representatives from private practice, academia, and military medical institutions.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for many conditions including arthritis. A rare complication of their use is diaphragm-like strictures of the small and large intestines. A 65-year-old woman with a 12-year history of arthritis came to us with a 35-pound weight loss and anorexia. She had been taking piroxicam for 3 years. Evaluation including enteroclysis revealed multiple mid-ileal diaphragm-like strictures and proximal small bowel dilatation. The symptoms persisted despite discontinuance of the drug. Abdominal exploration with intraoperative enteroscopy revealed five ileal strictures within a short segment of bowel. Resection was done and completion enteroscopy showed no other strictures. The patient recovered uneventfully and had full resolution of the symptoms. We discuss the difficulties in diagnosis and management of this drug complication and briefly review the literature.