Risk Factors for Type 1 Diabetes Recurrence in Immunosuppressed Recipients of Simultaneous Pancreas-Kidney Transplants.

Patients with type 1 diabetes (T1D) who are recipients of pancreas transplants are believed to rarely develop T1D recurrence in the allograft if effectively immunosuppressed. We evaluated a cohort of 223 recipients of simultaneous pancreas-kidney allografts for T1D recurrence and its risk factors. With long-term follow-up, recurrence was observed in approximately 7% of patients. Comparing the therapeutic regimens employed in this cohort over time, lack of induction therapy was associated with recurrence, but this occurs even with the current regimen, which includes induction; there was no influence of maintenance regimens. Longitudinal testing for T1D-associated autoantibodies identified autoantibody positivity, number of autoantibodies, and autoantibody conversion after transplantation as critical risk factors. Autoantibodies to the zinc transporter 8 had the strongest and closest temporal association with recurrence, which was not explained by genetically encoded amino acid sequence donor-recipient mismatches for this autoantigen. Genetic risk factors included the presence of the T1D-predisposing HLA-DR3/DR4 genotype in the recipient and donor-recipient sharing of HLA-DR alleles, especially HLA-DR3. Thus, T1D recurrence is not uncommon and is developing in patients treated with current immunosuppression. The risk factors identified in this study can be assessed in the transplant clinic to identify recurrent T1D and may lead to therapeutic advances.

Pretransplant CD4 Count Influences Immune Reconstitution and Risk of Infectious Complications in Human Immunodeficiency Virus-Infected Kidney Allograft Recipients.

In current practice, human immunodeficiency virus-infected (HIV(+) ) candidates with CD4 >200 cells/mm(3) are eligible for kidney transplantation; however, the optimal pretransplant CD4 count above this threshold remains to be defined. We evaluated clinical outcomes in patients with baseline CD4 >350 and <350 cells/mm(3) among 38 anti-thymocyte globulin (ATG)-treated HIV-negative to HIV(+) kidney transplants performed at our center between 2006 and 2013. Median follow-up was 2.6 years. Rates of acute rejection and patient and graft survival were not different between groups. Occurrence of severe CD4 lymphopenia (<200 cells/mm(3) ), however, was more common among patients with a baseline CD4 count 200-349 cells/mm(3) compared with those transplanted at higher counts (75% vs. 30% at 4 weeks [p = 0.04] and 71% vs. 5% at 52 weeks [p = 0.001], respectively, after transplant). After adjusting for age, baseline CD4 count of 200-349 cells/mm(3) was an independent predictor of severe CD4 lymphopenia at 4 weeks (relative risk [RR] 2.6; 95% confidence interval [CI] 1.3-5.1) and 52 weeks (RR 14.3; 95% CI 2-100.4) after transplant. Patients with CD4 <200 cells/mm(3) at 4 weeks had higher probability of serious infections during first 6 months after transplant (19% vs. 50%; log-rank p = 0.05). These findings suggest that ATG must be used with caution in HIV(+) kidney allograft recipients with a pretransplant CD4 count <350 cells/mm(3) .

Kidney allograft survival of African American and Caucasian American recipients with lupus.

BACKGROUND: African Americans with lupus who receive kidney transplants have high prevalence of predictors of allograft failure, which can explain their poor outcomes. METHODS: Of 1223 African Americans and 1029 Caucasian Americans with lupus who received kidney transplants from deceased donors between 1987 and 2006 with complete records in the UNOS program, 741 pairs were matched in 16 predictors employing a predicted probability of group membership. The primary outcome was allograft failure. Main secondary outcomes were rejection, allograft failure due to rejection, and mortality. RESULTS: Matched pairs were predominantly women (82%) with a mean age of 39 years. Twenty-four percent of recipients received kidneys from expanded criteria donors. African Americans and Caucasian Americans matched well (p ≥ 0.05): donor age, gender and race; recipient age, gender, education and insurance; dialysis prior to transplant, kidneys from expanded criteria donors, cold ischemia time, history of prior kidney transplant, panel reactive antibodies, human leukocyte antigens mismatch, blood type compatibility, transplant Era, and follow-up time. Contrary to the unmatched cohort with significantly higher allograft failure rate (events per 100 patient-years) in African Americans compared to Caucasian Americans (10.49 vs 6.18, p<0.001), matched pairs had similar allograft failure rates (8.41 vs 7.81, p=0.418). Matched pairs also had similar rates of rejections (9.82 vs 9.39, p=0.602), allograft failure due to rejection (6.19 vs 5.71, p=0.453), and mortality (2.79 vs 3.52, p=0.097). CONCLUSION: In lupus recipients of kidney transplants from deceased donors, African American and Caucasian Americans have similar allograft failure rates when predictors are matched between groups.

Inhibitors of mTOR and risks of allograft failure and mortality in kidney transplantation.

Data on long-term outcomes of users of inhibitors of the mammalian target of rapamycin (mTORI) are lacking in kidney transplantation. In an analysis of 139 370 US kidney transplant recipients between 1999 through 2010, we compared clinical outcomes among users of mTORIs versus calcineurin inhibitors (CNI) in their primary immunosuppresive regimen. During the first 2 years posttransplantation, primary use of mTORIs without CNIs (N = 3237) was associated with greater risks of allograft failure and death compared with a CNI-based regimen (N = 125 623); the hazard ratio (HR) of the composite outcome ranged from 3.67 (95% confidence interval [CI], 3.12-4.32) after discharge to 1.40 (95% CI 1.26-1.57) by year 2. During years 2-8, primary use of mTORIs without CNIs was independently associated with greater risks of death (HR 1.25; 95% CI, 1.11-1.41) and the composite (HR 1.17; 95%CI, 1.08-1.27) in fully adjusted analyses. The results were qualitatively unchanged in subgroups defined by medical history, immunological risk and clinical course during the index transplant hospitalization. In a propensity-score matched cohort, use of mTORIs was associated with significantly worse outcomes during the first 2 years and greater risks of death (HR 1.21; 95% CI, 1.05-1.39) and the composite (HR 1.18; 95% CI, 1.08-1.30) in years 2-8. Compared with CNI-based regimens, use of an mTORI-based regimen for primary immunosuppression in kidney transplantation was associated with inferior recipient survival.

Advantage of rapamycin over mycophenolate mofetil when used with tacrolimus for simultaneous pancreas kidney transplants: randomized, single-center trial at 10 years.

Simultaneous pancreas kidney transplantation (SPKT) is the treatment of choice for patients with type 1 diabetes and end-stage renal disease. Rapamycin and mycophenolate mofetil (MMF) have been used for maintenance immunosuppression with tacrolimus in SPKT; however, long-term outcomes are lacking. From September 2000 through December 2009, 170 SPKT recipients were enrolled in a randomized, prospective trial receiving Rapamycin (n = 84) or MMF (n = 86). All patients received dual induction therapy with thymoglobulin and daclizumab, and low-dose maintenance tacrolimus and corticosteroids. Compared to MMF, rates of freedom from first biopsy-proven acute kidney or pancreas rejection were superior for Rapamycin at year 1 (kidney: 100% vs. 88%; P = 0.001; pancreas: 99% vs. 92%; P = 0.04) and at year 10 (kidney: 88% vs. 71%, P = 0.01; pancreas: 99% vs. 89%, P = 0.01). The higher rates of rejection were associated with withholding MMF (vs. Rapamycin, p = 0.009), generally for gastrointestinal or bone marrow toxicity. There was no significant difference in creatinine, proteinuria, c-peptide, viral infections, lymphoproliferative disorders or posttransplant diabetes. HbA1C and lipid levels were normal in both groups, although higher in the Rapamycin arm. There were no significant differences in patient or allograft survival. In this 10-year SPKT study, Rapamycin in combination with tacrolimus was better tolerated and more effective than MMF. Overall, the patient and allograft survival were equivalent.

Predisposing factors of diminished survival in simultaneous liver/kidney transplantation.

Since the adoption of the Model for End-Stage Liver Disease, simultaneous liver/kidney transplants (SLKT) have substantially increased. Recently, unfavorable outcomes have been reported yet contributing factors remain unclear. We retrospectively reviewed 74 consecutive adult SLKT performed at our center from 2000 to 2010 and compared with kidney transplant alone (KTA, N = 544). In SLKT, patient and death-censored kidney graft survival rates were 64 ± 6% and 81 ± 5% at 5 years, respectively (median follow-up, 47 months). Multivariable analyses revealed three independent risk factors affecting patient survival: hepatitis C virus positive (HCV+, hazard ratio [HR] 2.9, 95% confidence interval [CI] 1.1-7.9), panel reactive antibody (PRA) > 20% (HR 2.8, 95% CI 1.1-7.2) and female donor gender (HR 2.9, 95% CI 1.1-7.9). For death-censored kidney graft survival, delayed graft function was the strongest negative predictor (HR 8.3, 95% CI 2.5-27.9), followed by HCV+ and PRA > 20%. The adjusted risk of death-censored kidney graft loss in HCV+ SLKT patients was 5.8 (95% CI 1.6-21.6) compared with HCV+ KTA (p = 0.008). Recurrent HCV within 1 year after SLKT correlated with early kidney graft failure (p = 0.004). Careful donor/recipient selection and innovative approaches for HCV+ SLKT patients are critical to further improve long-term outcomes.

Technical modification for laparoscopic donor nephrectomy to minimize testicular pain: a complication with significant morbidity.

The laparoscopic approach to donor nephrectomy is becoming increasingly common. While it is felt that the recovery from laparoscopic nephrectomy is quicker and less painful, a number of complications have been reported. A rarely reported on complication in the literature with significant morbidity is ipsilateral orchalgia. From 1998 to 2008, 257 hand-assisted laparoscopic donor nephrectomies were performed at our institution. Eight of 129 (6.2%) men complained of de novo ipsilateral orchalgia postoperatively. The average duration of pain was 402 days. Patients reported significant morbidity related to this complication. None, however, required further treatment. Three patients reported that they would reconsider organ donation as a result of testicular pain. Our technique originally included dissection and ligation of the gonadal vein en bloc with the ureter at the level of the left common iliac artery. Since recognizing this complication, we have adopted a gonadal vein sparing approach so as not to disturb the vessel below its point of ligation at the renal vein. To date, 50 patients have undergone the modified technique without experiencing orchalgia. In conclusion, ipsilateral testicular pan is a relatively frequent complication of laparoscopic donor nephrectomy and may be a source of significant morbidity. Using a modified surgical technique, this complication can be reduced or eradicated.

Open or laparoscopic nephrectomy and extracoroporeal repair of complicated renal artery aneurysms: techniques for renal salvage.

Renal artery aneurysm is an infrequently seen disease. The most feared symptom is rupture, which is often rapidly fatal. Indications for intervention include size, intractable symptoms and pregnancy. Many cases are managed by endovascular techniques; however, very complex cases often are referred to the urologist. We report our experience with the rarely used technique of renal artery aneurysms repair comprised of nephrectomy, extracorporeal vascular reconstruction with aneurysmectomy, and autotransplant.

Combined pancreas and en bloc kidney transplantation using a bladder patch technique from very small pediatric donors.

Very small pediatric donors are underutilized for pancreas and kidney transplantation for the fear of inadequate islet mass and higher incidence of technical complications, and the lower age limit for such donors is not well defined. We present here two cases of combined pancreas and en bloc kidney transplantation from very small pediatric donors (14 and 18 months old) to adult type 1 diabetic and uremic patients. The conventional surgical procedure for simultaneous pancreas and kidney transplantation with systemic venous and bladder exocrine drainage was successfully applied to very small organs. For both, we utilized the recently described bladder patch technique for ureteral reconstruction. One patient developed venous thrombosis (partial thrombosis of the splenic and mesenteric veins) and the other urine leak (from a midportion of the medial ureter without compromising the bladder patch) after the transplants; both were successfully managed and the patients demonstrated immediate and sustained pancreas and kidney graft functions for 12 and 2 months posttransplantation. These cases illustrate the feasibility of combined pancreas and en bloc kidney transplantation from very small pediatric donors using a bladder patch technique to avoid small ureteral anastomosis.

Mycobacterium abscessus infection in solid organ transplant recipients: report of three cases and review of the literature.

Mycobacterium abscessus is an ubiquitous organism found in the environment. This rapidly growing mycobacterium infrequently causes disease in humans; however, in immunocompromised hosts, disease can range from localized cutaneous lesions to disseminated infection. The organism is resistant to most antimycobacterial drugs and therapy can be limited by drug interactions. The exact incidence of M. abscessus infection among solid organ transplant (SOT) recipients is unknown; data are only available from previously reported cases in the literature. We describe 3 cases of M. abscessus infection in SOT recipients diagnosed within a 5-month period. One of the cases followed multi-visceral transplantation, the first such case to be reported in the literature. An epidemiological investigation did not reveal significant commonalities among the cases, and pulsed-field gel electrophoresis of genomic DNA of the case isolates confirmed their non-identity. All cases improved with antibiotic therapy, most notably with the new glycylcycline, tigecycline, along with surgical intervention in 2 of the cases. In addition, we review features and characteristics of M. abscessus infections in recipients of SOT reported in the literature from 1992 to 2008 and summarize some selected therapeutic concerns and issues related to treatment.

SMPDL3b modulates insulin receptor signaling in diabetic kidney disease.

Sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is a lipid raft enzyme that regulates plasma membrane (PM) fluidity. Here we report that SMPDL3b excess, as observed in podocytes in diabetic kidney disease (DKD), impairs insulin receptor isoform B-dependent pro-survival insulin signaling by interfering with insulin receptor isoforms binding to caveolin-1 in the PM. SMPDL3b excess affects the production of active sphingolipids resulting in decreased ceramide-1-phosphate (C1P) content as observed in human podocytes in vitro and in kidney cortexes of diabetic db/db mice in vivo. Podocyte-specific Smpdl3b deficiency in db/db mice is sufficient to restore kidney cortex C1P content and to protect from DKD. Exogenous administration of C1P restores IR signaling in vitro and prevents established DKD progression in vivo. Taken together, we identify SMPDL3b as a modulator of insulin signaling and demonstrate that supplementation with exogenous C1P may represent a lipid therapeutic strategy to treat diabetic complications such as DKD.

Alemtuzumab (Campath-1H) in kidney transplantation.

Kidney transplantation has become the treatment of choice for both the quality of life and survival in patients with end-stage renal disease (ESRD). However, the immunosuppressive regimen which allows optimal kidney transplant outcome remains elusive. One of the more promising induction agents, Alemtuzumab, was introduced to kidney transplantation by Calne in the late 1990s with low dose cyclosporine A monotherapy, with the hope of establishing 'prope' or near tolerance. Subsequent pilot studies with Alemtuzumab alone or monotherapy (DSG, Rapa) demonstrated high rates of acute rejection (AR) along with occasional humoral components that lead to abandoning the concept of Alemtuzumab as a 'magic bullet' to achieve tolerance, prope or otherwise. A number of programs (including our own) has since modified maintenance immunosuppression using low dose tacrolimus, and shown acceptable rates of AR, with relatively low incidence of viral infection and lymphoproliferative disorders along with cost benefit. However, there are only three prospective, randomized studies which are small with one year or less follow-up, and most published series utilize historical control groups with relatively short follow-up. As extrapolation from short-term data is far from secure, long-term, prospective, randomized studies with Alemtuzumab will be necessary to determine the optimal immunosuppressive regimen.

Surface tension, metabolic activity, and lipid composition of alveolar cells in washings from normal dog lungs and after pulmonary artery ligation. Importance of a highly surface-active acellular layer.

Lung-washings from mammalian species are a rich source of surfactant and of cells, predominantly alveolar macrophages, that could be important in the metabolism of the surfactant. We obtained washings from normal dogs, and from dogs that had had one pulmonary artery (PA) ligated 1 or 2 days earlier. Centrifugation of wash (400 x g for 20 min) separated a sediment, made up of cells at the bottom and a white layer, largely acellular, from the supernatant. The volume of sediment averaged 2.1 +/- 1.4 ml,. 75% of which was white layer. The cells resembled the large alveolar (type II) cells found in the lung; however they differed by at least one major histochemical reaction. The white layer had greater surface activity than the cells or the supernate, and was richest in phospholipids and lecithin. The cells lost their surface activity when rinsed and resuspended. These observations suggest that surfactant is normally present, mainly in an acellular fraction and possibly at the surface of the alveolar cells. The alveolar macrophages may either store surfactant, rather than synthesize it, or simply acquire a coat of surfactant during sedimentation. After PA ligation, the earliest abnormality was a decrease in the white layer; the cells were fewer, smaller, and weaker in metabolic activity.

Bezoar-related pancreatitis in enterically drained pancreas transplant.

Simultaneous kidney and pancreas transplantation is currently the treatment of choice for type 1 diabetes mellitus with end-stage renal disease. As a result of improvements in surgical techniques and the efficacy of immunosuppression, patient and graft survival rates have improved dramatically over the last two decades. Despite this, it remains a challenging surgical procedure with many potential complications and occasional controversies. Causes of pancreatitis after pancreas transplantation with enteric drainage are not well documented in the literature. We report a case of allograft pancreatitis from pancreatic duct outflow obstruction due to formation of a bezoar in a diverticulized transplant duodeno-jejunal anastomosis. To the best of our knowledge, this is the first case of allograft pancreatitis reported in the literature occurring from bezoar formation.

Dual kidney transplantation using midline extraperitoneal approach: description of a technique.

Dual kidney transplantation is performed using organs from marginal donors that are considered unsuitable for single kidney transplantation. In this report, we describe a simple technique of transplanting these organs extraperitoneally through a lower midline incision.

Pilot Randomized Trial of Tacrolimus/Everolimus vs Tacrolimus/Enteric-Coated Mycophenolate Sodium in Adult, Primary Kidney Transplant Recipients at a Single Center.

BACKGROUND: Recent studies suggest that the combination of tacrolimus (TAC) and everolimus (EVL) could become a viable option for use as standard maintenance immunosuppression in non-highly sensitized kidney transplant recipients. METHODS: We conducted a single-center, open-label, randomized pilot trial comparing two maintenance immunosuppression regimens in non-highly sensitized, adult, primary kidney transplant recipients: (TAC/EVL, Group A) vs our standard maintenance regimen of TAC plus enteric-coated mycophenolate mofetil (TAC/EC-MPS, Group B). In both treatment arms, dual induction therapy consisting of anti-thymocyte globulin (Thymoglobulin) and basiliximab was given. Early corticosteroid withdrawal (by 7-10 days posttransplantation) was also planned in both arms. There were 30 study participants, 15 per treatment arm. Results during the first 12 months posttransplantation are reported here. RESULTS: Between 1 month and 12 months posttransplantation, mean TAC trough levels ranged between 5 and 8 ng/mL in both arms. Mean trough EVL level in Group A ranged between 4 and 6 ng/mL, and mean EC-MPS dose in Group B ranged from 1440 mg at 1 month to 945 mg at 12 months. One patient in Group A vs three patients in Group B experienced a first biopsy-proven acute rejection during the first 12 months posttransplantation (P = .32). Four patients in each group experienced biopsy-proven chronic allograft injury (interstitial fibrosis/tubular atrophy) (P = .99). There was a slight trend toward more favorable renal function in Group A at months 1-3 posttransplantation (P = .06, .10, and .18 for estimated glomerular filtration rate, respectively). No graft failures or deaths were observed in either group during the first 12 months posttransplantation. Four patients in each group developed an infection during the first 12 months posttransplantation. Two patients in Group A developed new-onset diabetes after transplant during the 12-month follow-up period, vs no patients in Group B (P = .13). CONCLUSION: TAC/EVL may be a viable alternative to TAC/EC-MPS for use as standard maintenance immunosuppression in non-highly sensitized kidney transplant recipients and should be given further consideration.

Immunosuppressive treatment options in renal transplantation.

An overview of the first 4 decades of clinical kidney transplantation would characterize progress primarily in the development of new immunosuppressive agents designed to reduce the incidence and severity of acute rejection to improve short-term outcomes, but with less marked effects on long-term patient and graft survival. The new trend of immunosuppressive therapy is to facilitate long-term allograft and patient survival, and to help to maintain a good quality of life after renal transplantation. To achieve these goals, transplant physicians need to determine the immunosuppressive protocols that will best minimize risk factors associated with reduced allograft/patient survival and quality of life. Recent protocols and clinical experience with modern immunosuppression strategies, as well as the efficacy and safety of various combination protocols, will be reviewed.

Ten-Year Follow-up of a Reused Kidney Graft for Transplant Using Sirolimus for Maintenance Immunosuppression.

Reused kidney grafts have been transplanted with successful outcomes, though not widely performed in the Unites States. We present the case of a reused kidney graft with 10-year follow-up. The first donation was from a patient who died from a cerebrovascular accident and whose organs were used for a simultaneous pancreas and kidney transplant. After 5 years, the patient died and kidney was considered for donation and reuse. The patient had a virtual crossmatch with the first donor and a complement-dependent and flow-dependent crossmatch with the second donor. Long-term immune suppression was kept with a calcineurin-inhibitor-free regimen with sirolimus to prevent further damage from the first recipient. Control kidney biopsy showed steady progression of previous CNI toxicity without further damage. We describe the immunological basis of reused graft, the technical aspects of procurement and transplantation, as well as the use of Mammalian target of rapamycin for maintenance immunosuppression with good long-term results. Reused kidney grafts can be a good source of kidney grafts when adequate selection between donor and recipients is made and immunosuppression protocol is tailored to the preexisting damage to the original graft.

Use of intravenous FK506 to treat acute rejection in simultaneous pancreas-kidney transplant recipients on maintenance oral FK506.

Most recipients of simultaneous pancreas-kidney transplants experience acute rejection in the early postoperative course. We report our experience with four recipients of simultaneous pancreas-kidney transplants with acute rejection who were effectively treated with the combination of intravenous and oral FK506 therapy. This spared these patients an extra course of monoclonal or polyclonal antibody.