Simultaneous pancreas kidney transplants in diabetic patients with end-stage renal disease: the 20-yr experience.

INTRODUCTION: We are reporting the results over a 20 yr period of simultaneous pancreas-kidney transplants in patients with end-stage renal disease and diabetes mellitus. The outcomes of the transplants, performed between 1989 and 2008, are stratified by pretransplant c-peptide value. METHODS: One hundred and seventy-three patients with end-stage renal disease due to diabetes, and were stratified according to undetectable c-peptide (x < 0.8 ng/mL) and detectable c-peptide (x > 0.8 ng/mL) levels. RESULTS: Patients with detectable c-peptide (x > 0.8 ng/mL) were the oldest at diabetes diagnosis (24.2 vs. 15.4 yr, p < 0.0001), and oldest at transplant (42.8 vs. 38.5, p < 0.0001) had fewer years of insulin use (19.19 vs. 22.57 yr, p = 0.012), and were heavier pre transplant (BMI: 26.09 vs. 23.1, p < 0.0001), and heavier post transplant (29.8 vs. 24.7, p < 0.0001). Those with detectable c-peptide levels (x > 0.8 ng/mL) had better graft survival than those with an undetectable c-peptide level (x < 0.8 ng/mL), p = 0.064; while those with undetectable levels, had better patient survival than those with detectable c-peptide levels (p = 0.019). CONCLUSION: Despite the differences between groups by BMI, age of onset of insulin use, and age at transplant, there was a difference in patient but not graft survival within the 20 yr follow-up period.

Surgical complications in 275 HIV-infected liver and/or kidney transplantation recipients.

BACKGROUND: In this report, we examine the surgical safety and complications (SC) among 125 liver (L) and 150 kidney (K) HIV+ transplantation (TX) recipients in a prospective nonrandomized U.S. multicenter trial. METHODS: Subjects were required to have CD4+ T-cell counts >200/100 cells/mm3 (K/L) and undetectable plasma HIV-1 RNA (Viral Load [VL]) (K) or expected posttransplantation suppression (L). Impact of SCs (N ≥ 7) was evaluated by use of the proportional hazards models. Baseline morbidity predictors for SCs (N ≥ 7) were assessed in univariate proportional hazards models. RESULTS: At median 2.7 (interquartile range 1.9-4.1) and 2.3 (1.0-3.7) years after TX, 3-month and 1-year graft survival were [K] 96% (95% CI 91%-98%) and 91% (95% CI 85%-94%) and [L] 91% (95% CI 85%-95%) and 77% (95% CI 69%-84%), respectively. A total of 14 K and 28 L graft losses occurred in the first year; 6 K and 11 L were in the first 3 months. A total of 26 (17%) K and 43 (34%) L experienced 29 and 62 SCs, respectively. In the liver multivariate model, re-exploration was marginally associated (hazard ratio [HR] 2.8; 95% CI 1.0-8.4; P = .06) with increased risk of graft loss, whereas a greater MELD score before transplantation (HR 1.07 per point increase; 95% CI: 1.01-1.14; P = .02), and detectable viral load before TX (HR 3.6; 95% CI 0.9-14.6; P = .07) was associated with an increased risk of wound infections/dehiscence. CONCLUSION: The rates and outcomes of surgical complications are similar to what has been observed in the non-HIV setting in carefully selected HIV-infected liver and kidney TX recipients.

Paired kidney donor exchanges and antibody reduction therapy: novel methods to ameliorate disparate access to living donor kidney transplantation in ethnic minorities.

BACKGROUND: Currently ethnic minority patients comprise 60% of patients listed for kidney transplantation in the US; however, they receive only 55% of deceased donor renal transplants and 25% of living donor renal transplants. Ethnic disparities in access to kidney transplantation result in increased morbidity and mortality for minority patients with end-stage renal disease. Because these patients remain dialysis dependent for longer durations, they are more prone to the development of HLA antibodies that further delay the possibility of receiving a successful kidney transplant. STUDY DESIGN: Two to 4 pretransplant and post-transplant plasma exchanges and i.v. immunoglobulin were used to lower donor-specific antibody levels to less than 1:16 dilution; cell lytic therapy was used additionally in some cases. Match pairing by virtual cross-matching was performed to identify the maximal exchange benefit. Sixty candidates for renal transplantation were placed into 4 paired kidney exchanges and/or underwent antibody reduction therapy. RESULTS: Sixty living donor renal transplants were performed by paired exchange pools and/or antibody reduction therapy in recipients whose original intended donors had ABO or HLA incompatibilities or both (24 desensitization and 36 paired kidney exchanges). Successful transplants were performed in 38 ethnic minorities, of which 33 were African American. Twenty-two recipients were white. Graft and patient survival was 100% at 6 months; graft function (mean serum creatinine 1.4 g/dL) and acute rejection rates (20%) have been comparable to traditional live donor kidney transplantation. CONCLUSIONS: Paired kidney donor exchange pools with antibody reduction therapy can allow successful transplant in difficult to match recipients. This approach can address kidney transplant disparities.

Pancreas transplantation for type 2 diabetes mellitus.

PURPOSE OF REVIEW: This review will provide evidence that selected patients with type 2 diabetes mellitus (T2DM) may benefit from vascularized pancreas transplantation (PTX). RECENT FINDINGS: Initial experience with simultaneous pancreas-kidney transplantation (SPKT) in patients with T2DM and end-stage renal disease (ESRD) suggested that augmentation of endogenous insulin production by PTX in patients with C-peptide-positive, insulin-requiring diabetes resulted in insulin independence, improved glucose counter-regulation, and enhanced quality of life. A number of single-center retrospective studies have documented equivalent outcomes in patients with either type 1 diabetes mellitus (T1DM) or T2DM undergoing predominantly SPKT, although clearly a selection bias exists for patients in the latter category. Selection criteria for SPKT in T2DM include patients less than 55-60 years of age with a BMI less than 30-32 kg/m², insulin-requiring for a minimum of 5 years with a total daily insulin requirement less than 1 u/kg/day, a fasting C-peptide level less than 10 ng/ml, absence of severe vascular disease or tobacco abuse, adequate cardiac function, and presence of 'complicated' diabetes. Data from the International Pancreas Transplant Registry show that up to 7% of SPKT recipients are classified as having T2DM and that outcomes in these patients are comparable to those undergoing SPKT and classified as having T1DM. SUMMARY: Consequently, characterization of the 'type' of diabetes may be irrelevant and insulin-requiring diabetic patients with ESRD should be evaluated for PTX based exclusively on their predicted ability to tolerate the surgical procedure and requisite immunosuppression as well as comply with a stringent posttransplant follow-up regimen.

Outcomes of kidney transplantation in HIV-infected recipients.

BACKGROUND: The outcomes of kidney transplantation and immunosuppression in people infected with human immunodeficiency virus (HIV) are incompletely understood. METHODS: We undertook a prospective, nonrandomized trial of kidney transplantation in HIV-infected candidates who had CD4+ T-cell counts of at least 200 per cubic millimeter and undetectable plasma HIV type 1 (HIV-1) RNA levels while being treated with a stable antiretroviral regimen. Post-transplantation management was provided in accordance with study protocols that defined prophylaxis against opportunistic infection, indications for biopsy, and acceptable approaches to immunosuppression, management of rejection, and antiretroviral therapy. RESULTS: Between November 2003 and June 2009, a total of 150 patients underwent kidney transplantation; survivors were followed for a median period of 1.7 years. Patient survival rates (±SD) at 1 year and 3 years were 94.6±2.0% and 88.2±3.8%, respectively, and the corresponding mean graft-survival rates were 90.4% and 73.7%. In general, these rates fall somewhere between those reported in the national database for older kidney-transplant recipients (≥65 years) and those reported for all kidney-transplant recipients. A multivariate proportional-hazards analysis showed that the risk of graft loss was increased among patients treated for rejection (hazard ratio, 2.8; 95% confidence interval [CI], 1.2 to 6.6; P=0.02) and those receiving antithymocyte globulin induction therapy (hazard ratio, 2.5; 95% CI, 1.1 to 5.6; P=0.03); living-donor transplants were protective (hazard ratio, 0.2; 95% CI, 0.04 to 0.8; P=0.02). A higher-than-expected rejection rate was observed, with 1-year and 3-year estimates of 31% (95% CI, 24 to 40) and 41% (95% CI, 32 to 52), respectively. HIV infection remained well controlled, with stable CD4+ T-cell counts and few HIV-associated complications. CONCLUSIONS: In this cohort of carefully selected HIV-infected patients, both patient- and graft-survival rates were high at 1 and 3 years, with no increases in complications associated with HIV infection. The unexpectedly high rejection rates are of serious concern and indicate the need for better immunotherapy. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00074386.).

Pancreas transplant and incidental Meckel's diverticulum: not always a straightforward decision.

INTRODUCTION: Unexpected intraoperative findings are not rare in surgical practice. Meckel's diverticulum with a mass is one such example. There are only two previously reported cases of Meckel's in transplantation, and neither involved pancreas transplant. RESULTS AND DISCUSSION: We present a case report of novel surgical technique using a Meckel's diverticulectomy site for the duodeno-enterostomy to managing the exocrine secretions of the transplanted pancreas. We also discuss management of Meckel's diverticulum. The patient tolerated the procedure without complication, and continues to have normal renal and pancreatic function without any gastrointestinal (GI) complaints. The excised Meckel's diverticulum contained both gastric and pancreatic tissue. CONCLUSION: Although uncertainty about the best management practices exists in the general surgery patient population, given the potential complications that may arise from Meckel's diverticulum, in transplant patients the Meckel's should be removed when encountered. The point of excision can safely be incorporated into other intestinal anastomoses.

The Washington, D.C. experience with uncontrolled donation after circulatory determination of death: promises and pitfalls.

The author recounts his experience with an uDCD program that ran for three years at the Washington Hospital I Center in Washington, D.C. in the 1990s. Challenges, I benefits, and lessons learned are considered in depth. A I primary focus is the importance of community education, Organ Procurement Organization support, and the need for immediate in-situ preservation of organs.

Influence of long chain polyunsaturated fatty acids and ornithine concentrations on complications after renal transplant.

OBJECTIVES: The present study, registered at clinicaltrials.gov with the unique registration number NCT00560014, sought to evaluate the relations between fatty acid concentrations in red blood cells or plasma and amino acid concentrations in plasma on rejection, calcineurin inhibitor toxicity, and new-onset diabetes mellitus. MATERIALS AND METHODS: Lipid profiles on plasma or red blood cell samples were performed preoperatively and postoperatively in 54 patients. Plasma amino acid profiles were obtained in 49 of these patients. RESULTS: High concentrations of total omega-3 fatty acids, eicosapentaenoic and docosahexaenoic acids in red blood cells, and ornithine in plasma, all were associated with a significantly lower incidence of rejection, whereas high total omega-6 fatty acids were associated with a high rejection rate. Calcineurin inhibitor toxicity was associated with low levels of docosahexaenoic acid, ornithine, and the omega-3 index, and high total omega-6 and omega-3/omega-6 ratios. Inhibition of new-onset diabetes mellitus was seen only with high levels of ornithine. Peak concentrations of fatty acids in red blood cells were not obtained until after 30 days. High levels of arginine were not associated with reduced complications. CONCLUSIONS: The levels of selected nutrients in plasma and red blood cell membranes appear to have a profound effect on complications after renal transplant. These preliminary results need confirmation in prospective randomized clinical trials.

Clinically significant proteinuria following the administration of sirolimus to renal transplant recipients.

BACKGROUND: Sirolimus is the latest immunosuppressive agent used to prevent rejection, and may have less nephrotoxicity than calcineurin inhibitor (CNI)-based regimens. To date there has been little documentation of clinically significant proteinuria linked with the use of sirolimus. We have encountered several patients who developed substantial proteinuria associated with sirolimus use. In each patient, the close temporal association between the commencement of sirolimus therapy and proteinuria implicated sirolimus as the most likely etiology of the proteinuria. METHODS: We analyzed the clinical and laboratory information available for all 119 patients transplanted at the Washington Hospital Center between 1999-2003 for whom sirolimus was a component of their immunosuppressant regimen. In these patients, the magnitude of proteinuria was assessed on morning urine samples by turbidometric measurement or random urine protein:creatinine ratios, an estimate of grams of proteinuria/day. Laboratory results were compared between prior, during and following sirolimus use. RESULTS: Twenty-eight patients (24%) developed increased proteinuria from baseline during their post-transplantation course. In 21 patients an alternative cause of proteinuria was either obvious or insufficient data was available to be conclusive. In 7 of the 28 patients there was a striking temporal association between the initiation of sirolimus and the development of nephrotic-range proteinuria. Proteinuria correlated most strongly with sirolimus therapy when compared to other demographic and clinical variables. In most patients, discontinuation of sirolimus resulted in a decrease, but not resolution, of proteinuria. CONCLUSIONS: Sirolimus induces or aggravates pre-existing proteinuria in an unpredictable subset of renal allograft recipients. Proteinuria may improve, but does not resolve, when sirolimus is withdrawn.

Cardiac surgery in renal transplant recipients: experience from Washington Hospital Center.

BACKGROUND: The number of renal transplant survivors requiring surgical treatment for cardiovascular diseases is increasing. A retrospective study was conducted to determine the outcomes of renal transplant recipients undergoing cardiac surgery. METHODS: Fifty-seven renal transplant recipients whose cardiac surgery was performed between 1987 and 2004, and whose allograft was functioning at the time of cardiac surgery, were identified. We analyzed postoperative mortality and morbidity as well as late mortality. RESULTS: Among 57 patients, 70.2% had hypertension, 54.4% diabetes, and 28.1% poor left ventricular function (ejection fraction < 0.35). Preoperative renal insufficiency (serum creatinine level > or = 3 mg/dL) was noted in 12.3% of the patients. Coronary artery disease was the dominant indication for the surgery. The median interval from renal transplant to cardiac surgery was 60 months. In-hospital mortality was 5.3%. All deaths were cardiac-related. Infectious complications occurred in 17.5% of the patients. Acute allograft failure requiring hemodialysis occurred in 28.6% of the patients with preoperative renal insufficiency, more frequent than those without preoperative renal insufficiency. Multivariable analysis identified preoperative renal insufficiency, mitral valve disease, and left ventricular dysfunction as independent predictors of in-hospital major adverse events (including death, infection, and renal failure). The 3-year survival was 71% after a median follow-up of 34 months. CONCLUSIONS: Infection control and renal protection should be stressed to ensure the safety of cardiac surgery in this patient group, while preoperative renal insufficiency, mitral valve disease, and left ventricular dysfunction are associated with early adverse outcomes. In the renal transplant recipients undergoing an isolated CABG, avoidance of cardiopulmonary bypass and use of arterial grafts might lead to better outcomes.

Bilateral laparoscopic radical nephrectomy for renal tumors in patients with acquired cystic kidney disease.

PURPOSE: We describe our experience with simultaneous bilateral laparoscopic radical nephrectomy performed in patients with acquired cystic kidney disease (ACKD) and renal tumors. MATERIALS AND METHODS: Between June 2000 and September 2002, 10 patients with ACKD underwent simultaneous bilateral laparoscopic radical nephrectomy for renal lesions suspicious for carcinoma. The lesions were discovered during pretransplant evaluation in 9 patients and incidentally in 1 renal transplant recipient. A 3- or 4-port transperitoneal approach was used for each side to mobilize the kidney and secure the renal hilum. Both specimens were extracted through a midline supraumbilical incision. Operative time, blood loss, analgesic requirements, hospital stay, and convalescence and recurrence rates were determined. RESULTS: The mean age of the patients was 41.6 years (range, 29-47 years). Mean operative time was 6.5 hours (range, 4.5-9.7 hours) and mean estimated blood loss was 164 cc (range, 50-300 cc). There was one intraoperative complication-a clotted arteriovenous (AV) graft; and 2 postoperative complications-1 fluid overload and 1 adrenal insufficiency. The average length of hospital stay was 3.1 days (range, 2-4 days) and mean convalescence was 2.8 weeks (range, 1-6 weeks). All cancers were confined to the kidneys and there has been no recurrence during follow-up ranging from 6 to 26 months. CONCLUSION: Bilateral laparoscopic radical nephrectomy in end-stage renal disease patients is safe and feasible. The advantages of the laparoscopic approach include minimal intraoperative blood loss, shorter hospital stay, minimal postoperative pain, and a rapid return to normal activity. The laparoscopic technique offers an effective, minimally invasive therapeutic alternative to open surgery in high-risk end-stage renal disease patients.

A multicenter, prospective study of C2-monitored cyclosporine microemulsion in a U.S. population of de novo renal transplant recipients.

BACKGROUND: Monitoring cyclosporine microemulsion (CsA-ME; Neoral) exposure 2 hours postdose (C2) has been reported to optimize the efficacy and safety of CsA-ME therapy. The addition of induction therapy to a maintenance regimen including CsA-ME C2 monitoring has not been evaluated. METHODS: In all, 123 adult renal transplant recipients were recruited at 14 U.S. centers for this 6-month study. CsA-ME dose was to be titrated to attain C2 targets of 1700 and 1500 ng/ml during posttransplant months 1 and 2, respectively. After 2 months, patients were randomized to one of two groups with different, decreasing C2 targets. Basiliximab, mycophenolate mofetil, and corticosteroids completed the study immunosuppression. RESULTS: Of the 119 evaluable patients, 76% were male, 22% African American, and 66% deceased donor recipients. Biopsy-proven acute rejection occurred in 10 patients (9.3%); there were two failed grafts and one death. Serum creatinine and calculated GFR values suggest good renal function, with month 6 medians of 1.5 ng/ml and 67 ml/min/1.73 m. Safety and tolerability assessments revealed no unexpected outcomes. Observed C2 levels were generally lower than protocol targets, particularly in the first weeks posttransplantation. CONCLUSIONS: The striking efficacy and outcomes may have been achieved in this study with lower C2 levels of CsA-ME because of the addition of basiliximab induction.

Trends in donation after cardiac death.

The deceased cardiac donor (DCD) can provide organs that are suitable for transplantation. However, in order to increase recovery and utilization of this under-utilized organ donor source, a number of issues remain to be resolved. First, the public understanding is essential for support of this end-of-life option to donate after cardiac death. Extensive education of donor hospitals will be needed to identify potential donors and arrange for their care. Organ procurement organizations will have to commit to the extra effort required to identify and manage these donors and to design recovery techniques to maximize procurement of abdominal and thoracic organs. Pulsatile machine perfusion may be needed for assessing viability of DCD kidneys, although the evidence is lacking that pump preservation improves survival of DCD kidneys that are transplanted. It will also be important to identify transplant centers and suitable patients within those centers that will accept DCD organs. Preselecting recipients will speed allocation as has been the case for expanded criteria donors. Special efforts to minimize reperfusion injury should be made initially to protect what might be more "injury-prone" DCD organs and calcineurin inhibitors should probably be avoided during the early posttransplant period. The graft survival rates for DCD kidneys and pancreata have been comparable to those for conventional deceased donor grafts, whereas graft survival rates for DCD liver recipients have been significantly poorer than with conventional livers. Thus, we need to continue exploring approaches to improve patient and graft survival for DCD liver transplant recipients.

Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the NIH IG02 trial.

Reported are the reduction of anti-HLA antibody levels and improvement of transplant rates by intravenous immunoglobulin (IVIG) in a randomized, double-blind, placebo-controlled clinical trial. Between 1997 and 2000, a total of 101 adult patients with ESRD who were highly sensitized to HLA antigens (panel reactive antibody [PRA] > or =50% monthly for 3 mo) enrolled onto an NIH-sponsored trial (IG02). Patients received IVIG or placebo. Subjects received IVIG 2 g/kg monthly for 4 mo or an equivalent volume of placebo with additional infusions at 12 and 24 mo after entry if not transplanted. If transplanted, additional infusions were given monthly for 4 mo. Baseline PRA levels were similar in both groups. However, IVIG significantly reduced PRA levels in study subjects compared with placebo. Sixteen IVIG patients (35%) and eight placebo patients (17%) were transplanted. Rejection episodes occurred in 9 of 17 IVIG and 1 of 10 placebo subjects. Seven graft failures occurred (four IVIG, three placebo) among adherent patients with similar 2-yr graft survival rates (80% IVIG, 75% placebo). With a median follow-up of 2 yr after transplant, the viable transplants functioned normally with a mean +/- SEM serum creatinine of 1.68 +/- 0.28 for IVIG versus 1.28 +/- 0.13 mg/dl for placebo. Adverse events rates were similar in both groups. We conclude that IVIG is better than placebo in reducing anti-HLA antibody levels and improving transplantation rates in highly sensitized patients with ESRD. Transplant rates for highly sensitized patients with ESRD awaiting kidney transplants are improved with IVIG therapy.

Human renal allograft rejection despite the absence of allogeneic passenger leukocytes.

Passenger leukocytes have been suggested to be both pro-tolerant and immunogenic. The opportunity to evaluate the role of allogeneic passenger leukocytes in humans was presented by a 47-year-old man who donated bone marrow to his HLA-identical leukemic sister. Eleven years later he developed renal failure. The sister's marrow was noted to be 100% XY karyotype and free of malignancy. She donated a kidney to her brother. Immunosuppression was tapered following transplantation. After 6 months, the recipient was on monotherapy sirolimus, 1 mg every third day. A surveillance biopsy was normal and sirolimus was stopped. Eight weeks later, he presented with severe rejection that reversed with Thymoglobulin. Renal function returned to baseline and has been stable on conventional immunosuppression.

Acute renal transplant rejection possibly related to herbal medications.

Use of herbal and alternative medications in the United States is increasing. Many of these medications have unknown mechanisms of actions, and possible metabolic interactions with prescribed medications. We report a case of late acute rejection after exposure to two popular herbal medications.

Randomized trial of tacrolimus + mycophenolate mofetil or azathioprine versus cyclosporine + mycophenolate mofetil after cadaveric kidney transplantation: results at three years.

METHODS: Two hundred twenty-three recipients of first cadaveric kidney allografts were randomized to receive tacrolimus (TAC) + mycophenolate mofetil (MMF), TAC + azathioprine (AZA), or cyclosporine (Neoral; CsA) + MMF. All regimens contained corticosteroids, and antibody induction was used only in patients who experienced delayed graft function (DGF). Patients were followed-up for 3 years. RESULTS: The results at 3 years corroborate and extend the findings of the 2-year results. Patients with DGF treated with TAC+MMF experienced an increase in 3-year allograft survival compared with patients receiving CsA+MMF (84.1% vs. 49.9%, P=0.02). Patients randomized to either treatment arm containing TAC exhibited numerically superior kidney function when compared with CsA. During the 3 years, new-onset insulin dependence occurred in 6, 3, and 11 patients in the TAC+MMF, CsA+MMF, and TAC+AZA treatment arms, respectively. Furthermore, patients randomized to TAC+MMF received significantly lower doses of MMF as compared with those who received CsA+MMF. CONCLUSION: All three immunosuppressive regimens provided excellent safety and efficacy. However, the best results overall were achieved with TAC+MMF. The combination may provide particular benefit to kidney allograft recipients with DGF. In patients who experienced DGF, graft survival was better at 3 years in those patients receiving TAC in combination with either MMF or AZA as compared with the patients receiving CsA with MMF.

Severe acute renal failure after exposure to sirolimus-tacrolimus in two living donor kidney recipients.

BACKGROUND: We began a clinical trial in African Americans comparing sirolimus-tacrolimus to standard immunosuppression. We report two African American male living donor kidney recipients who developed acute renal failure after exposure to sirolimus-tacrolimus. METHODS: Both patients received similar doses of sirolimus and tacrolimus to achieve target levels of 5 to 15 ng/mL and prednisone in tapering doses. Renal function and tacrolimus and sirolimus levels were systematically monitored. RESULTS: Although both kidneys functioned immediately, acute oliguric renal failure developed approximately 2 weeks after transplantation. Transplant kidney biopsy showed acute tubular necrosis in patient 2. Sirolimus-tacrolimus was then stopped in both patients. Both patients required temporary hemodialysis. Renal function returned 2 weeks later and was normal 2 months after transplantation on tacrolimus plus mycophenolate mofetil. CONCLUSION: Combination sirolimus-tacrolimus may cause nephrotoxicity in some patients by mechanisms that are presently unexplained.