Impact of ureteral stricture and treatment choice on long-term graft survival in kidney transplantation.

We aimed to evaluate the influence of urological complications occurring within the first year after kidney transplantation on long-term patient and graft outcomes, and sought to examine the impact of the management approach of ureteral strictures on long-term graft function. We collected data on urological complications occurring within the first year posttransplant. Graft survivals, patient survival, and rejection rates were compared between recipients with and without urological complications. Male gender of the recipient, delayed graft function, and donor age were found to be significant risk factors for urological complications after kidney transplantation (P < .05). Death censored graft survival analysis showed that only ureteral strictures had a negative impact on long-term graft survival (P = .0009) compared to other complications. Death censored graft survival was significantly shorter in kidney recipients managed initially with minimally invasive approach when compared to the recipients with no stricture (P = .001). However, graft survival was not statistically different in patients managed initially with open surgery (P = .47). Ureteral strictures following kidney transplantation appear to be strongly negatively correlated with long-term graft survival. Our analysis suggests that kidney recipients with ureteral stricture should be managed initially with open surgery, with better long-term graft survival.

Acute cellular and antibody-mediated rejection of the pancreas allograft: incidence, risk factors and outcomes.

Antibody-mediated rejection (AMR) after pancreas transplantation is a recently identified entity. We describe the incidence of, risk factors for, and outcomes after AMR, and the correlation of C4d immunostaining and donor-specific antibody (DSA) in the diagnosis of AMR. We retrospectively analyzed 162 pancreas transplants in 159 patients who underwent 94 pancreas allograft biopsies between 2006 and 2009. Univariate and multivariate analyses were performed to evaluate risk factors for pancreas graft AMR. One-year rejection rates and survival after rejection were calculated by Kaplan-Meier methods. AMR occurred in 10% of patients by 1-year posttransplant. Multivariate risk factors identified for AMR include nonprimary simultaneous pancreas-kidney (SPK) transplant, primary solitary pancreas (PAN) transplant and race mismatch. After pancreas rejection, patient survival was 100% but 20% (8 of 41) of pancreas grafts failed within 1 year. Graft survival after acute cellular rejection (ACR), AMR and mixed rejection was similar. Of biopsies that stained >5% C4d, 80% were associated with increased Class I DSA. In summary, AMR occurs at a measurable rate after pancreas transplantation, and the diagnosis should be actively sought using C4d staining and DSA levels in patients with graft dysfunction, especially after nonprimary SPK and primary PAN transplantation.

Long-term pancreatic allograft survival after renal retransplantation in prior simultaneous pancreas-kidney recipients.

Over a 23-year period, our center performed 82 renal retransplants in prior simultaneous pancreas-kidney recipients with functioning pancreatic allografts. All patients were insulin-independent at retransplantation. We aimed to quantify the risk of returning to insulin therapy and to identify factors that predispose patients to pancreatic allograft failure after renal retransplantation. Among these 82 patients, pancreatic allograft survival after renal retransplantation was 78%, 49% and 40% at 1, 5 and 10 years. When analyzing risk factors, we unexpectedly found no clear relationship between the cause of primary renal allograft failure, hemoglobin A1c (HbA1c) or fasting C-peptide level at retransplant and subsequent pancreatic allograft failure. An elevated HbA1c in the month after renal retransplant correlated with subsequent pancreatic graft loss and patients experiencing pancreatic graft loss were more likely to subsequently lose their renal retransplant. Although it is difficult to prospectively identify those patients who will return to insulin therapy after repeat renal transplantation, the relatively high frequency of this event mandates that this risk be conveyed to patients. Nonetheless, the survival benefit associated with renal retransplantation justifies pursuing retransplantation in this population.

Is there any role for antithymocyte induction in renal transplantation?

The use of an antibody induction agent in kidney transplantation lowers the risk of an acute rejection episode and may improve graft outcomes. Antithymocyte globulin (ATG) is the most commonly used antibody induction agent for kidney transplantation in the United States, despite its significant side effect profile and cost compared to the interleukin-2 receptor antagonists (IL2-RA). Our review suggests the IL2-RA are safe and well tolerated, and provide equal clinical benefit to ATG at a lower cost. We propose that there is insufficient evidence to justify the use of ATG induction in kidney transplantation.

Incidence of and risk factors for posttransplant diabetes mellitus after pancreas transplantation.

Posttransplant diabetes mellitus (PTDM) after pancreas transplantation (PTX) has not been extensively examined. This single center, retrospective analysis of 674 recipients from 1994 to 2005 examines the incidence of and risk factors for PTDM after PTX. PTDM was defined by fasting plasma glucose level > or =126 mg/dL, confirmed on a subsequent measurement or treatment with insulin or oral hypoglycemic agent for > or =30 days. The incidence of PTDM was 14%, 17% and 25% at 3, 5 and 10 years after PTX, respectively and was higher (p = 0.01) in solitary pancreas (PAN) versus simultaneous kidney pancreas (SPK) recipients (mean follow-up 6.5 years). In multivariate analysis, factors associated with PTDM were: older donor age (hazard ratio [HR] 1.04, 95% confidence interval [CI] 1.03-1.06, p < 0.001), higher recipient body mass index (HR 1.07,CI 1.01-1.13, p = 0.01), donor positive/recipient negative CMV status (HR 1.65,CI 1.03-2.6, p = 0.04), posttransplant weight gain (HR 4.7,CI 1.95-11.1, p < 0.001), pancreas rejection (HR 1.94.CI 1.3-2.9, p < 0.001) and 6 month fasting glucose (HR 1.01,CI 1.01-1.02, p < 0.001), hemoglobin A(1)c, (HR 1.12,CI 1.05-1.22, p = 0.002) and triglyceride to high-density lipoprotein (TG/HDL) ratio (HR 0.94,CI 0.91-0.96, p < 0.001). This study delineates the incidence and identifies risk factors for PTDM after PTX.

FTY720 and everolimus in de novo renal transplant patients at risk for delayed graft function: results of an exploratory one-yr multicenter study.

This exploratory, multicenter, open-label study evaluated the efficacy and safety of FTY720, as a part of an immunosuppressive regimen, in combination with everolimus and steroids in de novo renal transplant recipients at increased risk of delayed graft function (DGF). Patients received FTY720 (5 mg) and everolimus (4 mg) 2-12 h pre-transplantation, followed by 2.5 mg/d FTY720 and concentration-controlled everolimus (4-8 ng/mL) post-transplant for 12 months. Induction therapy was prohibited. After enrollment of 56 of the planned 200 patients between 2000 and 2002, the recruitment was terminated. The primary endpoint, rate of graft loss, or death at three months was 15.4% and the biopsy-confirmed acute rejection was 42.3%. Death or graft loss at 12 months in the DGF and non-DGF arms was 36.0% and 25.9%, respectively. The mean estimated creatinine clearance at three months was 63 and 55 mL/min in the non-DGF and DGF groups, respectively, while at 12 months it was 56 mL/min in both the groups. Although there was no comparator arm, the results from this exploratory study (compared with data from other phases II and III trials) indicated no apparent benefits of FTY720-based regimens for prevention of acute rejection and preservation of renal function in renal transplant recipients at high risk of DGF.

Early and limited use of tacrolimus to avoid rejection in an alemtuzumab and sirolimus regimen for kidney transplantation: clinical results and immune monitoring.

Alemtuzumab induction with 60 days of tacrolimus treatment and continuous sirolimus treatment prevented acute rejection in nine of 10 consecutive renal allograft recipients. All patients are alive with a functioning kidney graft at 27-39 months of follow-up. Extensive immune monitoring was performed in all patients. Alloantibody detection, cytokine kinetics assay (CKA), and trans vivo delayed-type hypersensitivity (DTH) assay were performed every 6 months showing correlation with clinical evolution. Despite alloantibody presence in five patients, eight patients remain without the need for specific treatment and only sirolimus monotherapy in decreasing dosage. Four patients take only 1 mg sirolimus daily with levels of 3-4 ng/mL. One patient showed clinical signs of rejection at month 9 post-transplant, with slow increase in serum creatinine and histological signs of mixed cellular (endarteritis) and humoral rejection (C4d positivity in peritubular capillaries and donor-specific antibody (DSA)). In summary, the addition of tacrolimus therapy for 2 months to a steroid-free, alemtuzumab induction and sirolimus maintenance protocol limited the previously shown acute rejection development. Nevertheless, alloantibody was present in serum and/or C4d present on 1-year biopsy in half the patients. The combination of CKA and DSA monitoring or the performance of transvivo DTH correlated with immune status of the patients.

A comparison of alemtuzumab with basiliximab induction in simultaneous pancreas-kidney transplantation.

Alemtuzumab is a humanized, rat monoclonal antibody directed against the CD52 antigen. After binding, alemtuzumab causes profound and durable depletion and has been successfully used as immune induction therapy for organ transplantation. This was a single center, retrospective review of patients who underwent simultaneous pancreas-kidney transplantation at the University of Wisconsin using alemtuzumab induction therapy compared with historical controls that received induction with basiliximab. There were no differences in donor or recipient demographics, rates of patient survival, renal or pancreas allograft survival, renal allograft delayed graft function, EBV infection, BKV infection, PTLD or sepsis. There was a statistically significant increase in the incidence of cytomegalovirus (CMV) infection in the alemtuzumab-treated group. Given the significantly higher incidence of CMV infections, we have since altered our induction protocol to consist of a single 30 mg dose of alemtuzumab instead of two doses. The long-term effects of this change remain to be seen. Due to the results seen in this study, the low initial cost of the drug and the absence of any severe, short-term side effects, alemtuzumab has been selected as the induction drug of choice at our center for patients undergoing SPK.

Calcineurin inhibitor withdrawal after renal transplantation with alemtuzumab: clinical outcomes and effect on T-regulatory cells.

To address the results of calcineurin inhibitor (CNI) withdrawal after alemtuzumab induction relative to CNI continuation, we performed a pilot randomized clinical trial in renal allograft recipients on CNI, a mycophenolic acid derivative and steroids after the first 2 months posttransplantation. Forty patients were randomized to taper off CNI or to maintain it, and followed for at least 1 year. Four patients in the withdrawal group were treated for acute rejection while no patient received antirejection treatment in the control group. Two control patients withdrew CNI due to nephrotoxicity. Estimated GFR was similar in both groups after 1 year. Flow cytometry of CD4(+)CD25(+)CTLA-4(+)FoxP3(+) regulatory T cells (Treg) demonstrated a significant increase in Treg percentages in the peripheral blood of alemtuzumab-treated patients on CNI early postransplant. Furthermore, the increased Treg percentages in the withdrawal cohort were unchanged at month 6 postenrollment, whereas they decreased significantly in those patients maintained on CNI. Patients withdrawn from CNI after alemtuzumab trend toward a higher rejection rate, but most patients can be weaned from a CNI using this regimen. With the exception of maintaining increased Treg levels, the benefits are not appreciable in this short follow-up, and a larger randomized trial is justified.

Kidney function after solitary pancreas transplantation.

Preserving kidney function in patients after solitary pancreas transplantation (SPTx) is an important consideration, yet various factors may negatively impact long-term function of the native kidneys or kidney allograft. To determine changes in kidney function over time in a series of patients receiving SPTx, we conducted a retrospective analysis and tracked changes in serum creatinine (SCr) and calculated glomerular filtration rate (GFR) from baseline to 6 months, 1 year, or 3 years after SPTx in a series of pancreas after kidney transplants PAK; (n = 61) and pancreas transplants alone PTA; (n = 27) performed at our institution. The mean follow-up for the PAK and PTA groups was 3.4 and 2.7 years, respectively. In this series, 8% of patients after SPTx developed significant kidney failure, defined by either initiation of dialysis or receiving a kidney transplant (PAK-6, PTA-1). Twenty seven percent of SPTx patients with a baseline GFR < 60 suffered either an elevated SCr > 2.2, dialysis, or kidney transplant, whereas no patients with a baseline GFR > 60 developed significant kidney dysfunction. In the PAK group, the GFR did not show significant deterioration over time. In contrast to relatively stable kidney function in PAK patients, PTA patients experienced overall significantly greater rates of decline over time. GFR in PTA patients decreased from 78 +/- 19 (40 to 114) mL/min/1.73 m2 at baseline to 65 +/- 20 at 1 year (P = .006), while SCr increased from 1.03 +/- 0.25 mg/dL to 1.28 +/- 0.43 over the same time period (P = .012). These data show that kidney function may deteriorate after SPTx and proper patient selection may reduce the frequency of this complication.

Long-term administration of enteric-coated mycophenolate sodium (EC-MPS; myfortic) is safe in kidney transplant patients.

BACKGROUND: To date, there are no data on long-term use of enteric-coated mycophenolate sodium (EC-MPS; myfortic) from time of renal transplantation. We report the first long-term safety and efficacy data on EC-MPS when administered for up to 3 years post transplant. METHODS: De novo renal transplant recipients completing 1 year of treatment in a multicenter, randomized, double-blind trial of EC-MPS versus mycophenolate mofetil (MMF) were invited to take part in an open-label extension during which all patients received EC-MPS 720 mg b.i.d. Results from the period 12 - 36 months post transplant were compared to comparable data from MMF-treated patients taking part in two studies of everolimus versus MMF (RAD 201 and RAD 251). RESULTS: Of 367 patients completing the blinded core study, 247(62%) entered the open-label extension phase. During the first 24 months of the extension, the incidence, type and severity of adverse events were comparable between the newly-exposed and long-term EC-MPS patients. There were 2 deaths in the newly-exposed group and 4 among long-term EC-MPS patients, with 1 and 2 graft losses, respectively. Six patients (5%) in the newly-exposed group and 4 (3%) in the long-term EC-MPS group experienced biopsy-proven acute rejection. Cross-study comparisons indicated that the tolerability profile of EC-MPS was similar to MMF, including the incidence of adverse events, infections and malignancies, as was the incidence of efficacy events. CONCLUSION: These results demonstrate that EC-MPS with cyclosporine and steroids provides good long-term efficacy and tolerability, and confirm the safety of converting renal transplant patients from MMF to EC-MPS.

Recovery and utilization of deceased donor kidneys from small pediatric donors.

The optimal use of kidneys from small pediatric deceased donors remains undetermined. Using data from the Scientific Registry of Transplant Recipients, 2886 small (< 21 kg) pediatric donors between 1993 and 2002 were identified. Donor factors predictive of kidney recovery and transplantation (1343 en bloc; 1600 single) were identified by logistic regression. Multivariable Cox regression was used to assess the risk of graft loss. The rate of kidney recovery from small pediatric donors was significantly higher with increasing age, weight and height. The odds of transplant of recovered small donor kidneys were significantly higher with increasing age, weight, height and en bloc recovery (adjusted odds ratio = 65.8 vs. single; p < 0.0001), and significantly lower with increasing creatinine. Compared to en bloc, solitary transplants had a 78% higher risk of graft loss (p < 0.0001). En bloc transplants had a similar graft survival to ideal donors (p = 0.45) while solitary transplants had an increased risk of graft loss (p < 0.0001). En bloc recovery of kidneys from small pediatric donors may result in the highest probability of transplantation. Although limited by the retrospective nature of the study, kidneys transplanted en bloc had a similar graft survival to ideal donors but may not maximize the number of successfully transplanted recipients.

A new modified technique of ureteroureterostomy in rat kidney transplantation.

Different strain combinations of rat are available to study immunological and transplant-related problems in kidney transplant models. Although numerous modifications of surgical techniques for ureteric reconstruction have been evaluated in order to reduce complications and to extend long-term survival, ureteric complications still occur frequently, especially when there is a disproportion in the diameter of donor and host ureters. Instead of using the current nonsplinted ureteroureterostomy, a versatile and rapid technical modification was developed to perform reconstruct the ureters of disproportionate diameter. The overall incidence of ureteric complications was 80% (8/10) using the former method, whereas this rate was significantly reduced to 15% (3/20) using the new method (P < .001). Our modification shows the feasibility of a nonsplinted ureteroureterostomy for the technical, highly demanding rat model of kidney transplantation with an acceptable rate of ureteric complications considering disproportionate differences in diameter between the host and the donor ureter.

Enteric-coated mycophenolate sodium: therapeutic equivalence to mycophenolate mofetil in de novo renal transplant patients.

The introduction of mycophenolate mofetil (MMF)--the morpholino ester prodrug of mycophenolic acid (MPA)--has improved graft and patient survival, but its use has been linked with the occurrence of adverse events, particularly gastrointestinal (GI) side effects. These can be sufficiently severe to require dose reductions or discontinuation, which may lead to acute rejection episodes or graft failure. An enteric-coated formulation delivering mycophenolic acid-enteric-coated mycophenolate sodium (EC-MPS)-has been developed with the aim of improving upper GI tolerability. Therapeutic equivalence of EC-MPS 720 mg b.i.d. vs MMF 1000 mg b.i.d. has been established in a pivotal phase III, 12-month, international, randomized, double-blind, parallel group study, involving patients undergoing de novo renal transplantation. The incidence of efficacy failure (composite variable of biopsy-proven acute rejection [BPAR], graft loss, death or loss to follow-up) was similar between the two groups at 6 months (EC-MPS 25.8% vs MMF 26.2%; 95% CI [-8.7, +8.0]), demonstrating therapeutic equivalence. Efficacy failure remained similar between the two treatment groups at 12 months. The overall incidence of adverse events and GI side effects were also comparable between treatment groups throughout the 12-month study period, although fewer patients in the EC-MPS group experienced study drug discontinuations, interruptions, or dose reductions (12 months: EC-MPS 15.0% vs MMF 19.5%). Subgroup analysis revealed similar safety profiles for EC-MPS and MMF in elderly patients and patients with diabetes at baseline. The EC-MPS 720 mg b.i.d. and MMF 1000 mg b.i.d. show therapeutic equivalence in de novo renal transplant patients. Therefore, EC-MPS offers transplant physicians and their patients an alternative MPA therapy that is as effective and safe as MMF.

Decreased immunogenicity of human fetal pancreas allografts following hyperbaric oxygen culture.

Human fetal pancreas (HFP) is a potential source of transplantable islets for the treatment of type 1 insulin-dependent diabetes mellitus (IDDM). Pretransplant culture techniques such as long-term culture, high-oxygen culture, UVB irradiation, and low-temperature culture have previously been used to reduce the immunogenicity of tissue for transplantation. In this study, we use hyperbaric oxygen culture (HOC) to modify MHC Class I expression on HFP and to reduce the immunological response of human peripheral blood mononuclear cells (PBMC) to HFP using a sponge matrix allograft model. To study the interaction of naïve PBMC with HOC-treated or untreated HFP allografts, sponges embedded with HFP tissue were implanted into the peritoneal cavity of NOD-SCID mice and injected with 1 x 10(7) freshly isolated human PBMC at the time of transplant. By day 14, human CD45 cells represented less than 2% of the cells recovered from the sponges implanted with HOC-treated HFP. In contrast, human CD45(+) cells represented nearly 15% (P =.0018) of the cells isolated from sponges implanted with conventionally cultured HFP grafts. Approximately 75% of the human CD45(+) cells from conventionally cultured HFP allografts were producing IFNgamma as determined by intracellular cytokine analysis. These data suggest that HOC treatment of HFP abrogates the activation and proliferation of PBMC. Pretransplant HOC treatment of islets is a simple technique that could be used to reduce immunogenicity and increase allograft survival while decreasing the requirement for immunosuppressive drugs.

Removal of CD45+ cells from human fetal pancreas alters immunogenicity in vitro.

Human fetal pancreas (HFP) is a potential source of islets for the treatment of diabetes mellitus with the potential for growth and differentiation after transplantation. However, because of the small mass of a given HFP, multiple donors would be required for transplantation, thereby increasing the immunological challenge to the recipient. In this study, we investigate the contribution of hematopoietic cells to the immunogenicity of HFP. Single cell suspensions of HFP were depleted of CD45(+) cells using antibody-conjugated magnetic beads. In vitro mixed lymphocyte islet cultures were established using with CD45-depleted or nondepleted HFP. Depletion of CD45(+) cells resulted in the low levels of IFNgamma production at early time points (day 4), which increased to near normal levels by day 7. The development of donor-specific CTL was not consistently inhibited by CD45 cell depletion. The data suggests that CD45(+) cells within HFP are capable of stimulating immune responses by the direct pathway of antigen presentation, but that the indirect pathway is also involved in the development of CTL. The inhibition of early IFNgamma release, however, may be beneficial for the survival of transplanted islets. Therefore, the combination of CD45 depletion strategies with standard immunosuppressive drug therapies could result in better long-term survival of transplanted islets.

Simultaneous pancreas-kidney and pancreas transplantation.

The best available method currently for achieving steady normoglycemia in individuals with type 1 diabetes mellitus (DM) is replacing the pancreas, e.g. whole pancreas transplantation. Pancreatic transplantation, as either simultaneous pancreas-kidney (SPK) or solitary pancreas transplantation alone (PTA), has moved beyond simple metabolic or quality-of-life goals. It is now an effective treatment to reverse or minimize metabolic abnormalities and complications of type 1 DM as well as potentially extend the life span of those afflicted by type 1 DM and its many co-morbid complications. Candidates for SPK and PTA transplantation need to meet various criteria even to undergo the transplant procedure and receive a pancreatic allograft that is deemed suitable. SPK and PTA recipients, though free from insulin use, still may encounter common post-transplant medical complications, e.g. cardiovascular disease, high blood pressure, as well as complications unique to SPK and PTA transplantation. The advantages of PTA and SPK transplantation are frankly now more obvious as improvements in surgical technique and new immunosuppression have made an increasing number of PTA and SPK transplants viable and functional long-term. The idea of pancreas transplantation can be touted as a therapeutic advance for type 1 DM. It can improve survival and limit many diabetic-related complications, while improving quality of life, especially in those individuals also afflicted with diabetic-related kidney disease.