Tacrolimus-based Immunosuppression Research Articles

Risk Factors of Acute Renal Failure After Orthotopic Liver Transplantation: Single-center Experience

BackgroundAcute renal failure (ARF) is one of the most significant complications of orthotopic liver transplantation (OLT), associated with increased mortality rate and the development of chronic renal dysfunction. The aim of the study was to determine the perioperative risk factors for ARF in patients without previous history of renal disease who are undergoing OLT. Materials and methodsForty-six patients who developed ARF after OLT performed in 1 transplant center were included in the study, and 52 consecutive patients without that complication served as a control group. Renal dysfunction was defined as a glomerular filtration rate <60 mL/min/1.73 m2. The data concerning preoperative diseases, perioperative renal function, first-line immunosuppressive therapy, and blood transfusion requirement were retrospectively analyzed and compared among groups. Logistic regression modeling was used to determine risk factors for ARF. ResultsPatients who developed ARF were significantly older (mean age 53.3 vs 46.3 years, P = .057), had higher level of preoperative (0.79 vs 0.71 mg/dL, P = .0062) and intraoperative (0.85 vs 0.74 mg/dL, P = .0045) creatinine. The risk factors for ARF were intraoperative and 24-hour post-transplant creatinine level >0.9 mg/dL and high-dose tacrolimus-based immunosuppression. Transfusion of ≤6 units of red blood cells diminished the risk of ARF. Sex and preoperative diseases were not predictive to ARF in our regression models. ConclusionCareful operative technique with low blood loss and immunosuppressive therapy of low nephrotoxic potential should be recommended in older patients to diminish the risk of renal dysfunction after orthotopic liver transplantation. Patients with higher levels of perioperative creatinine should be considered to have first-line immunosuppression without calcineurin inhibitors or with low-dose immunosuppressants of known nephrotoxic potential.

Early Histopathological Changes in New-Onset Diabetes After Kidney Transplantation

BackgroundNew-onset diabetes after transplantation (NODAT) is one of the most common complications after kidney transplantation. MethodsPatients were randomly assigned to receive cyclosporine A–based or tacrolimus-based immunosuppression. Fasting and oral glucose tolerance tests were performed, and the patients were assigned to one of the following 3 groups, on the basis of the results: normal, impaired fasting glucose/impaired glucose tolerance, or NODAT. NODAT developed in 14% of patients receiving cyclosporine A–based immunosuppression and in 26% of patients taking tacrolimus (P = .0002). ResultsAlbumin levels were similar, but uric acid level (P = .002) and the age of the recipient (P = .003) were significantly different between the diabetic and the normal groups. Evaluation of tissue samples revealed that acute cellular rejection and interstitial fibrosis/tubular atrophy were significantly different in the NODAT group. Changes in the Banff score provided significant difference regarding tubulitis and interstitial inflammation (P = .05). ConclusionsThe pathological effect of new-onset diabetes after kidney transplantation can be detected in the morphology of the renal allograft earlier, before the development of any sign of functional impairment.

Low Incidence of New Onset Diabetes Mellitus After Renal Transplantation Under Low-Dose Tacrolimus-Based Immunosuppression: A Single Center Experience.

Introduction:New onset diabetes mellitus after transplantation (NODAT) is a common metabolic complication after renal transplantation, and its incidence varies depending on definition of diagnosis of NODAT, patient group (ethnicity), and immunosuppressive regimen. NODAT could be a cause of poor graft outcomes including infectious complications and poor graft function. We have employed low-dose tacrolimus immunosuppression with low-levels of tacrolimus trough after transplantation. We assessed the incidence of NODAT under low-dose tacrolimus immunosuppression and examined the association between NODAT and graft function after renal transplantation. Patients and Methods:Eight hundred seventy-four renal transplants were carried out at our institution between 1998 and 2013, and all of them were treated with tacrolimus-based immunosuppression. Out of 874, 115 were excluded from this study because they had diabetes mellitus preoperatively -- so called diabetic nephropathy patients. Eight hundred seventy-four patients were enrolled in this retrospective study. All patients had their FBS and HbA1c examined after renal transplantation every 3-6 months. Induction phase, tacrolimus trough levels were 6-10ng/ml and 3-5ng/ml in the maintenance phase. We started treatment by modification of lifestyle and/or antidiabetic medication once NODAT was diagnosed after transplantation. We analyzed the clinical characteristics of recipients, and long-term patient and graft survival. Results:The overall incidence of NODAT was 4.5% (n = 34). Sixteen patients were treated with insulin injection (2%) and 9 patients were on medical treatment. Nine patients were on diet therapy alone. The 10-year patient survival of NODAT and non-NODAT recipients was 79.8% and 97.9%, respectively, and was not significant between two groups. The 10-year graft survival of NODAT and non-NODAT recipients was 73.7% and 89.4%, respectively, and was significant between two groups (p=0.04). Both the tacrolimus dose and trough levels were not different between the two groups at most time points after kidney transplantation. Conclusions:The incidence of NODAT was 4.5% and was low under low-dose tacrolimus immunosuppression. NODAT did not negatively affect patient survival under low-dose tacrolimus immunosuppression, although the graft survival was slightly poorer in NODAT patients than non-NODAT patients.

Prophylaxis for Hepatitis B Recurrence and Renal Sparing Effects With Telbivudine in Liver Recipients Receiving Hepatitis B Core Positive Donor Grafts.

Background Living donor liver transplantation & use of HBV core positive grafts have been employed to expand the donor pool. Hepatitis B immune globulin(HBIG) & nucleos(t)ide analogues can prevent HBV recurrence post liver transplant (LT). Renal sparing effects of Telbivudine (LdT) have been shown in LT & non-LT patients. We aim to study the efficacy of LdT in liver recipients who received HBV core positive donor grafts in preventing HBV recurrence (defined as HBsAg and/or HBV DNA negativity) and maintaining renal function. Methods Adult liver recipients transplanted for indications other than HBV who received a HBV core positive graft were identified. Patients on LdT for HBV prophylaxis were included. Liver chemistries, renal function & creatinine clearance (MDRD4), creatinine kinase (CK), immunosuppressive trough levels, HBsAg & HBV DNA levels were collected at 3 monthly intervals. Results 4 liver recipients were switched from Lamivudine to LdT for HBV prophylaxis. All patients were HBsAg negative prior to LdT switch, did not receive HBIG post LTx, and were maintained on tacrolimus-based immunosuppression as per center protocol. All patients remain free from HBV recurrence 3 months after conversion. 75% had mild to moderate renal impairment prior to LdT switch; all patients showed improvement in eGFR (1.2 - 28 ml/min/1.73m2) 3 months after conversion from LAM to LdT. Serum tacrolimus trough levels (±1.5ng/ml) were similar at LdT switch and at 3 months. There were no reports of myositis or CK elevation.Table: No Caption available.Conclusions In this novel real life experience among liver recipients transplanted for reasons other than HBV receiving a HBV core positive donor graft, LdT was shown to be effective in preventing HBV recurrence and well tolerated. Improvements in eGFR were seen in all patients. Larger randomized trials with longer follow up are needed.

Expression of Activated LFA-1 in Human Renal Allografts With Rejection.

Leukocyte function-associated antigen-1 (LFA-1) is an attractive therapeutic target in transplantation because of its critical roles in T cell adhesion, trafficking, costimulation, and immunologic synapse formation. However, some pre-clinical and clinical studies have associated anti-LFA-1 therapy with immunosuppression-related complications, indicating that more specific therapies are needed. LFA-1 undergoes an activation-induced conformational change that enhances its binding affinity, and AL-579 is a novel human antibody that exclusively binds the active, high affinity conformation of LFA-1. Specifically targeting activated LFA-1, and thus only activated T cells, may confer adequate rejection prophylaxis while avoiding non-selective immunosuppression. To characterize the presence of activated LFA-1 in human kidney transplant rejection, we identified 24 first time kidney transplant recipients maintained with belatacept- or tacrolimus-based immunosuppression who had a biopsy-confirmed acute cellular rejection (ACR) and had undergone clinically indicated core needle biopsies (18-gauge). 13 had adequate tissue samples for additional analysis. These included 7 patients with Banff 1A or 1B rejection, and 6 patients with Banff 2B rejection. One patient with Banff 2B rejection had concomitant antibody-mediated rejection and chronic rejection and underwent transplant nephrectomy. The nephrectomy specimen was also available for analysis. Immunohistochemical staining was performed with AL-579 to detect activated LFA-1. AL-579+ cells predominantly were found along tubules and vessels, with some AL-579+ cells infiltrated into tubules, arterial walls and areas of endarteritis. There was no difference in the number of AL-579+ cells between samples from patients receiving tacrolimus (n=9) or belatacept (n=4) (3.12 vs 4.58/HPF; P=0.089) or between Banff 1A/1B and Banff 2B rejections (3.95 vs 3.63/HPF; P=0.812), but the distribution suggests a relationship between active LFA-1 and vascular and tubular diapedesis. In the nephrectomy specimen with Banff 2B rejection, there was dense AL-579 staining in tubular walls, glomeruli, and areas of endarteritis. These data show activated LFA-1 is highly present in rejecting kidney allografts and suggest that a highly activated cell phenotype can be targeted by AL-579. These cells may represent a novel target population for therapeutic intervention.

Comparison of New-Onset Diabetes After Kidney Transplant Between Hispanics and Caucasians Treated With Tacrolimus-Based Immunosuppression.

Comparison of New-Onset Diabetes After Kidney Transplant Between Hispanics and Caucasians Treated With Tacrolimus-Based Immunosuppression.

Donor Specific Antibody (DSA) Formation in Tacrolimus-Based, Mycophenolate vs mTOR Immunosuppression Regimens.

The influence of mTOR inhibition upon DSA formation and later clinical events is controversial, with small reports suggesting a higher rate of DSA with mTOR but experimental data suggesting potential inhibitory signaling pathways. Prior clinical studies did not include regimens with tacrolimus (TAC) and/or prednisone (P) with adequate controls. We compared de novo DSA formation (DSA+) rates between two common immunosuppression regimens (TAC/MPA/P vs. lower exposure TAC/mTOR/P) and clinical outcomes Methods: 66 kidney and SPK recipients on TAC (lo)/mTOR/P (36 with everolimus, 30 with sirolimus) from hospital discharge were compared in a case-control study to 132 patients on TAC/MPA/P, matched for age, gender, race, and type/timing of transplant from 2007-2012. DSA assessment was performed prospectively at time of transplant and at 1, 6, 12, and 24 months post-transplant using single antigen beads. We compared de novo DSA formation ( ≥500 MFI), proteinuria, GFR and acute rejection (AR) between the two groups. Results: With a mean follow up of 796 days, TAC (lo)/mTOR had a higher proportion DSA+ at all time points but did not meet statistical significance. By one year, DSA+ rates were 35% with TAC (lo)/mTOR vs 28% with TAC/MPA (OR 1.37; 95% CI 0.69-2.75; p= 0.37) There was no significant difference between the two arms when comparing clinical outcomes, including GFR at 12 months, proteinuria at 12 months and AR at 12 months.Table: No Caption available.When comparing Sirolimus vs Everolimus, there was no significant difference in DSA formation or clinical outcomes. Neither the type of DSA (class I vs class II) nor strength of DSA (MFI) were significantly different among groups. Comparing those that formed DSA vs those that did not, GFR was not different at 1 year but proteinuria was significantly higher in DSA+ vs DSA- (0.35 vs 0.17g/d, p=0.03). Conclusion:In kidney and SPK transplant patients on TAC/prednisone regimens, mTOR inhibition was associated with similar rates of DSA formation compared to MPA. Our study did not demonstrate a difference in GFR, proteinuria or acute rejection at one year between the two arms. mTOR therapy is neither protective nor permissive in DSA formation or downstream clinical surrogates of antibody-mediated injury. DISCLOSURES:Wiseman, A.: Other, Novartis, consultant, Tolera, consultant, Astellas, consultant.

Highly Sensitized Patients: Targeting Alloreactive T-Cells in Renal Re-Transplantation.

Kidney transplant recipients (KTRs) undergoing re-transplantation are at increased risk of poorer graft outcome. Despite undetectable donor-specific antibodies, many KTRs express high frequencies of donor-reactive T-cells pre-transplantation. Current induction strategies, however, fail to target these cells. Here, we studied 40 KTRs with detectable donor-reactive T-cells undergoing re-transplantation. Our immunosuppressive strategy included lymphocyte depletion induction, anti-TNF treatment, IVIG, and a tacrolimus-based triple-drug maintenance immunosuppression. An age, gender, and maintenance immunosuppression matched control group of 40 KTRs undergoing re-transplantation and 120 KTRs undergoing first transplantation receiving standard immunosuppression were used for comparison. Samples were collected before transplantation, at +1, +2, +3 months posttransplantation. CMV-specific and alloreactive T-cells were measured using an IFNg Elispot assay. The extent of immunosuppression was quantified by lymphocyte subpopulations. No differences were observed for 5-year graft survival and eGFR between highly sensitized KTRs and the first transplant control group (p>0.05). However, 5-year graft survival in the highly-sensitized group was significantly better compared to the re-transplant control group (p=0.02). No differences were observed concerning the incidence of acute rejection, septic complications, CMV, BKV, or EBV viremia (p>0.05). Donor-reactive T-cells in highly sensitized KTRs decreased significantly after transplantation (p=0.001). Highly sensitized KTRs show an absolute lymphopenia with significantly decreased CD4+ T-cells posttransplantation with a long-lasting down-regulation of IFNg and TNFa levels (p<0.05). No differences were observed for CMV-specific immune responses (p>0.05). Our data suggest that a combination of lymphocyte depletion and anti-TNF treatment effectively depletes donor-reactive T-cells. Targeting donor-reactive T-cells in highly sensitized KTRs results in graft function, graft survival, and incidence of acute rejection episodes comparable to first transplant KTRs receiving standard immunosuppression.This approach is safe regarding pathogen control, and could improve allograft outcome in re-transplantation.

Direct Correlation Between Tacrolimus Levels and Serum Creatinine Seen Only Early After Transplant.

Calcineurin inhibitors are a known cause of acute and chronic renal toxicity. It's unclear, however, whether tacrolimus trough levels correlate directly with serum creatinine levels, and if so, how long do those correlations persist. METHODS: We reviewed data on 19 liver transplant recipients (mean age, 51.8 yr; median, 50 yr) whose tacrolimus-based immunosuppression began between 1/2009 and 12/2011. We recorded trough tacrolimus levels and serum creatinine levels whenever the two markers were analyzed simultaneously; we also recorded the posttransplant interval at which the simultaneous levels were drawn. The data were non-parametrically distributed, so Spearman's rho was used for statistical analysis. RESULTS: During follow-up for a mean of 857 days (median 995 days), there were 731 simultaneous measurements of trough tacrolimus and creatinine. There were an average of 40 observations per patient (range 16-92). Overall, tacrolimus trough levels and serum creatinine were strongly correlated (R = 0.081, p=0.029). Upon closer analysis, however, the correlation was significant only for measurements obtained within 12 months of transplant (p<0.001). Beyond 12 months, there was no correlation. CONCLUSION: The correlation between tacrolimus trough levels and creatinine is only present early after transplant. After 12 months, renal impairment may be chronic and multifactorial and not as easily corrected by lowering the tacrolimus dose. Minimizing the tacrolimus dose early after transplant may be important in preventing chronic renal effects.

Time-dependent variability in tacrolimus trough blood levels is a risk factor for late kidney transplant failure

Wide variations in tacrolimus levels have been identified as a risk factor for inferior kidney allograft survival but past studies have not properly accounted for the dynamic nature of drug exposure over time. Here we evaluated whether time-varying exposure to tacrolimus increases the risk of long-term adverse outcomes in a retrospective cohort study in adult kidney transplant recipients on tacrolimus-based immunosuppression. Time-dependent Cox proportional hazards models were used to examine the association between the standard deviation of tacrolimus levels (TacSD) starting at 1-year post-transplant and the composite end point of late allograft rejection, transplant glomerulopathy, or total graft loss (including death). Among 356 patients, there was a significant 27% increase in the adjusted hazard of the composite end point for every 1-unit increase in TacSD (hazard ratio 1.27 (95% confidence interval 1.03, 1.56)). There was also a graded increase in the relative hazard for the composite end point by TacSD threshold (hazard ratios 1.33, 1.50, 1.84, and 2.56 for TacSD 1.5, 2, 2.5, and 3, respectively). The results were similar for total graft loss and the composite end point excluding death. Thus, increased time-dependent TacSD may be an independent risk factor for adverse kidney transplant outcomes. TacSD may serve as a monitoring tool to identify high-risk patients. Whether interventions to decrease TacSD will improve outcomes requires further study.

Telaprevir drug monitoring during antiviral therapy of hepatitis C graft infection after liver transplantation

Recurrence of hepatitis C virus (HCV) infection after orthotopical liver transplantation (OLT) is common and associated with reduced graft and patient survival. The protease inhibitor telaprevir may enhance virological response rates in patients after OLT in combination with pegylated interferon-alfa and ribavirin. Pharmacokinetic studies have shown significant drug-drug interactions between telaprevir and immunosuppression (IS), but telaprevir pharmacokinetics in OLT patients with IS are unknown. Aim of the present study was to analyse telaprevir plasma concentrations in patients with HCV genotype 1 infection after OLT in comparison to patients without OLT and IS. Five patients with HCV genotype 1 infection after OLT and 37 HCV genotype 1-infected patients patients without prior OLT were treated with telaprevir 2250 mg daily, ribavirin 1000/1200 mg daily and pegylated interferon-alfa-2a 180 μg once weekly (triple therapy). Telaprevir plasma concentrations were analysed by liquid chromatography-electrospray-ionization-tandem mass spectrometry. HCV RNA was assessed by automatized reverse-transcription polymerase chain-reaction. Median (range) telaprevir plasma concentrations of TW 4, 8 and 12 were 3970 (1980-4430) ng/ml and 2520 (1870-8730) ng/ml in patients after OLT and ciclosporin- or tacrolimus-based IS, respectively, as compared to 2790 (1870-3140) in non-OLT patients (P = 0.3). In one patient with tacrolimus-based IS, telaprevir dose had to be adjusted to achieve virological response. Telaprevir plasma concentrations were steady at treatment weeks 4, 8 and 12 in patients with and without IS. Telaprevir drug monitoring may be necessary in patients with tacrolimus-based IS in patients with HCV graft infection after OLT.

Tuberculosis in Solid-Organ Transplant Recipients: Disease Characteristics and Outcomes in the Current Era

We determined the characteristics of posttransplant tuberculosis and the impact of rifampin-based antituberculosis regimens on outcomes in the current era. Patients comprised 64 transplant recipients with tuberculosis, divided into 2 consecutive cohorts: an earlier cohort (cases occurring from 2003 to 2007) and a later cohort (cases from 2008 to 2011). Patients from the later versus earlier era had tuberculosis develop later after transplant (odds ratio, 1.01; 95% CI, 1.00-1.02; P= .05), were more likely to be liver transplant recipients (odds ratio, 4.52; 95% CI, 1.32-15.53; P= .02), and were more likely to receive tacrolimus-based immunosuppression (odds ratio, 3.24; 95% CI, 1.14-9.19; P= .03). Mortality rate was 10% in the later cohort and 21% in the earlier cohort (P= .20). Rifampin-based treatment was less likely to be used in patients with prior rejection (P= .04). However, neither rejection rate (P= .71) nor mortality (P= .93) after tuberculosis differed between recipients who received rifampin and recipients who did not. Thus, notable changes have occurred in the epidemiological characteristics of tuberculosis in transplant recipients. Overall mortality rate has improved, with about 90% of the patients now surviving after tuberculosis.

Co-administration of ketoconazole and tacrolimus to kidney transplant recipients: cost minimization and potential metabolic benefits.

To evaluate the effects of the co-administration of tacrolimus and ketoconazole to a group of kidney transplant recipients, we studied 30 kidney transplant recipients with stable kidney function who were maintained on tacrolimus-based immunosuppression. They were prescribed ketoconazole (100 mg/day) with a concomitant reduction in daily tacrolimus dose to maintain its level within the therapeutic range. The study included 19 males and 11 females with a mean age of 36 ± 12 years. All patients were at least three months post-transplant and had tacrolimus trough levels within the therapeutic range of 5-7 ng/mL. Desired tacrolimus trough levels could be achieved in 29/30 patients after the addition of ketoconazole. This resulted in a significant reduction of the median tacrolimus dose from 5 mg/day (range 3-20 mg/day) at baseline to 2 mg/day (range 1-4 mg/day) (P = 0.00). The median reduction in the tacrolimus dose was 63% (range 50-83%). The median monthly tacrolimus cost dropped from 375 US$ per patient (range 225-1440 US$) to 150 US$ per patient (range 120-300 US$). There were no reported adverse drug effects during the study period. After one year of follow-up, there was a small but significant improvement in the estimated glomerular filtration rate (72 ± 18 versus 78 ± 20 mL/min, P = 0.01) and a significant reduction in serum uric acid levels (7.7 ± 1.7 versus 5.9 ± 0.8 mg/dL, P = 0.003). The co-administration of ketoconazole and tacrolimus to kidney trans-plant recipients is safe and significantly reduces the cost of immunosuppression. In addition, this combination appears to have a beneficial effect on kidney function.

Clinical management of inflammatory bowel disease in the organ recipient

There was estimated a higher incidence of de novo inflammatory bowel disease (IBD) after solid organ transplantation than in the general population. The onset of IBD in the organ transplant recipient population is an important clinical situation which is associated to higher morbidity and difficulty in the medical therapeutic management because of possible interaction between anti-reject therapy and IBD therapy. IBD course after liver transplantation (LT) is variable, but about one third of patients may worsen, needing an increase in medical therapy or a colectomy. Active IBD at the time of LT, discontinuation of 5-aminosalicylic acid or azathioprine at the time of LT and use of tacrolimus-based immunosuppression may be associated with an unfavorable outcome of IBD after LT. Anti-tumor necrosis factor alpha (TNFα) therapy for refractory IBD may be an effective and safe therapeutic option after LT. The little experience of the use of biological therapy in transplanted patients, with concomitant anti-rejection therapy, suggests there be a higher more careful surveillance regarding the risk of infectious diseases, autoimmune diseases, and neoplasms. An increased risk of colorectal cancer (CRC) is present also after LT in IBD patients with primary sclerosing cholangitis (PSC). An annual program of endoscopic surveillance with serial biopsies for CRC is recommended. A prophylactic colectomy in selected IBD/PSC patients with CRC risk factors could be a good management strategy in the CRC prevention, but it is used infrequently in the majority of LT centers. About 30% of patients develop multiple IBD recurrence and 20% of patients require a colectomy after renal transplantation. Like in the liver transplantation, anti-TNFα therapy could be an effective treatment in IBD patients with conventional refractory therapy after renal or heart transplantation. A large number of patients are needed to confirm the preliminary observations. Regarding the higher clinical complexity of this subgroup of IBD patients, a close multidisciplinary approach between an IBD dedicated gastroenterologist and surgeon and an organ transplantation specialist is necessary in order to have the best clinical management of IBD after transplantation.

Update On Phase 2 Clinical Trial To Induce Tolerance In Mismatched Living Donor Renal Transplant Recipients

Nineteen subjects have been enrolled in a phase 2 protocol (FDA IDE 13947) to induce donor-specific tolerance in HLA-mismatched related and unrelated recipients of living donor renal allografts (KTx). The protocol is based upon tolerogenic CD8+/TCR- facilitating cells (FC) and nonmyeloablative conditioning. Recipients are conditioned with fludarabine (30 mg/kg/dose, days -5, -4, -3), cyclophosphamide (50 mg/kg/dose, day -3 and +3), 200 cGy TBI (day -1) followed by KTx (day 0). A G-CSF mobilized peripheral blood mononuclear cell product is apheresed from the donor &gt; 2 weeks prior to the KTx, processed to remove GVHD-producing cells yet retain CD34+ cells and FC (FCRx), and cryopreserved until infusion on day +1 post-KTx. Subjects ranged in age from 18 to 65 years. All were HLA-disparate from their donors, ranging from 5 of 6 matched related to 0 of 6 unrelated. 18 of 19 subjects exhibited engraftment at 1 month; one highly sensitized subject (PRA &gt; 50%) did not engraft. Subjects were discharged on post-operative day 2 and managed as outpatients. Mycophenolate mofetil and tacrolimus-based immunosuppression were administered for 6 months. At 6 months the MMF was discontinued if the protocol biopsy was normal and stable renal function present. Tacrolimus was weaned at month 9 (trough levels 3-6) and discontinued at 1 year if chimerism, normal renal function, and normal kidney biopsy were noted. No subjects have experienced GVHD or engraftment syndrome. Two early subjects who received a suboptimal cell dose and one other highly sensitized subject were only transiently chimeric (&lt; 6 months); all transiently chimeric subjects resumed endogenous hematopoiesis and are maintained on low-dose tacrolimus monotherapy with stable renal function. The protocol was subsequently modified to exclude subjects with a PRA &gt; 20%. One chimeric subject developed viral sepsis at month 3, thrombosed his kidney, and was successfully re-transplanted off study. A second subject developed CNI-induced hemolytic uremic syndrome (HUS) which resulted in graft loss. He is currently off all immunosuppression and his HUS has resolved. The remaining subjects are either off all immunosuppression (n = 9; 1 to 36 months) or are in the process of tapering. None of the chimeric subjects have developed rejection on protocol biopsy while 3 of the 5 who were not durably chimeric had Banff 1A rejection on protocol biopsy. Recurrence of autoimmune disease has occurred in 2 of 4 non-chimeric subjects, but not in any of the durable chimeric subjects. In summary, high levels of durable chimerism and tolerance without GVHD have been achieved in mismatched related and unrelated recipients of living KTx. Disclosures: Tollerud: Regenerex, LLC: Equity Ownership. Ildstad:Regenerex, LLC: Equity Ownership.

Gender differences in oxidative and nitrosative stress parameters in kidney transplant patients on tacrolimus-based immunosuppression

Cardiovascular (CV) morbidity and mortality rates are still higher after kidney transplantation than in general population. It is known that oxidative and nitrosative stress may contribute to the progress of CV disease in a post-transplant period, but still gender aspect has not been elucidated completely. The aim of this study was to analyze the gender differences in the oxidative and nitrosative stress parameters, as well as asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels among kidney transplant patients on tacrolimus-based immunosuppression. Our research included 35 patients (20 men and 15 women) with renal transplant and 25 healthy volunteers. Patients were on chronic immunosuppressive regimen, which included tacrolimus, mycophenolate mofetil and prednisone. In order to estimate oxidative and nitrosative stress, we determined plasma levels of thiobarbituric acid-reactive substances (TBARS), activity of catalase (CAT), levels of total (protein and non-protein) sulfhydryl (SH) groups, advanced oxidation protein products (AOPP), ADMA and SDMA, as well as nitrite/nitrate (NOx) ratio. TBARS, CAT and SH in plasma were significantly higher in male patients than in female patients (p < 0.05, p < 0.01 and p < 0.05, respectively). There were no gender-dependent differences in AOPP, ADMA, SDMA and NOx in kidney transplant patients. Correlation analysis, Pearson and Spearman, showed significant correlations between tested oxidative and nitrosative stress parameters in male kidney transplant patients. Alternatively, in female patients, there were no significant correlations between tested parameters. Our findings show that men might be more prone to oxidative damage than women. ADMA, the proven marker of CV morbidity and mortality, may be more significant in male kidney transplant patients concerning oxidative stress control of its level and function.

Impact of cyclosporine versus tacrolimus on the incidence ofde novomalignancy following liver transplantation: a single center experience with 609 patients

De novo malignancies are a major cause of late death after liver transplantation. Aim of the present study was to determine whether use of cyclosporine versus tacrolimus affects long-term tumor incidence considering potential confounders. De novo malignancies in 609 liver transplant recipients at Munich Transplant Centre between 1985 and 2007 were registered. In 1996, the standard immunosuppressive regimen was changed from cyclosporine to tacrolimus. Different effects of those drugs on long-term tumor incidence were analyzed in multivariate analysis. During 3765 patient years of follow-up (median 4.78years), 87 de novo malignancies occurred in 71 patients (mean age 47.5±13.3years, mean time after liver transplantation 5.7±3.7years). The cumulative incidence of de novo malignancies was 34.7% for all tumor entities after 15years as compared to 8.9% for a nontransplanted population. The most frequent tumors observed were nonmelanoma skin cancers (44.83%). Moreover, post-transplant lymphoid disease, oropharyngeal cancer (n=6, 6.9%), upper gastrointestinal tract cancer (n=4, 4.6%), lung cancer (n=4, 4.6%), gynecological malignancies (n=4, 4.6%), and kidney cancer (n=3, 3.45%) were detected. Multivariate analysis revealed recipient age [hazards ratio (HR) 1.06], male gender (HR 1.73), and tacrolimus-based immunosuppression (HR 2.06) as significant risk factors. Based on those results, a tacrolimus-based immunosuppression should be discussed especially in older male patients. Whether reducing tacrolimus target levels may reduce the risk for de novo malignancies has yet to be determined in prospective trials.

Inflammatory Bowel Disease after Liver Transplantation for Primary Sclerosing Cholangitis

The course of inflammatory bowel disease (IBD) after liver transplantation (LT) for primary sclerosing cholangitis (PSC) is complex, with several IBD-, PSC-, and transplant-related factors interplaying with each other. Approximately one-third of patients with known IBD improve, and one-third paradoxically worsen, after LT for PSC. Active IBD, discontinuation of 5-aminosalicylates (5-ASA) at time of LT and tacrolimus-based immunosuppression may be associated with an unfavorable course of IBD after LT. Approximately 14-30% patients with PSC may develop de novo IBD 10 years after LT. LT confers a high risk of pouchitis after ileal pouch-anal anastomosis, although it may not be higher than baseline rates for PSC patients. The risk of colorectal cancer continues to be high after LT for PSC, and is higher in this cohort of patients with PSC-IBD, compared with patients undergoing LT for other indications. IBD does not adversely affect patient survival after LT, although the risk of recurrent PSC in the allograft may be higher in patients with IBD and an intact colon at time of LT. Standard therapy with 5-ASA and/or azathioprine may be appropriate for treatment of active IBD after LT and maintenance of remission. Anti-tumor necrosis factor-α agents are effective, but should be used with caution because of high risk of adverse events. The management of IBD after LT requires close coordination between transplant hepatologists and IBD experts.

Conversion to Prolonged-Release Tacrolimus for Pediatric Living Related Donor Liver Transplant Recipients

Prolonged-release tacrolimus allows for once-daily dosing. Although many adult recipients have been switched from standard tacrolimus, prolonged-release tacrolimus has not been popular for pediatric patients despite the potential benefits for medication compliance. We report on prolonged-release tacrolimus for 11 pediatric living related donor liver transplant (LRDLT) recipients. Patients under 18 years of age who were receiving standard tacrolimus-based immunosuppression and steroid taper underwent conversion from standard to prolonged-release tacrolimus. We monitored tacrolimus trough levels and liver function tests (LFTs). We also assessed adverse effects and satisfaction levels for prolonged-release tacrolimus. Mean age at transplantation was 4.3 years. The mean duration of follow-up was 12 months. The ratios of trough levels with prolonged-release vs standard tacrolimus were 0.97, 0.95, and 0.92 at 1, 2, and 4 weeks post conversion, respectively. Two patients discontinued prolonged-release tacrolimus owing to abnormal LFTs and neurological abnormalities, respectively; but symptoms resolved after reconversion. One patient returned to standard tacrolimus and the other was converted to cyclosporine. Once-daily administration satisfied 89% of patients. In the overall assessment, conversion to prolonged-release tacrolimus satisfied all patients. Prolonged-release tacrolimus was useful for pediatric patients after LRDLT. Trough levels after conversion were compatible with those before conversion. Most patients were satisfied with prolonged-release tacrolimus. However, some patients failed conversion because of unexpected responses. Close observation after conversion is required even if patients have previously had an uneventful course on standard tacrolimus.

Screening for BK Viremia Reduces But Does Not Eliminate the Risk of BK Nephropathy

This study reviewed the outcomes of a screening protocol for BK viremia to determine if early diagnosis, followed by immunosuppression minimization, would prevent progression to nephropathy and graft loss. This review included 369 renal transplant recipients tested for BK virus at serial time points after transplantation. Management included immunosuppression minimization plus cidofovir treatment for BK nephropathy. Recipients received tacrolimus-based immunosuppression, with 8% prednisone-free and 6% who received desensitization. With a mean follow-up of 22 ± 10 months, 16% (n = 57) of recipients became BK viremia positive. The median (range) time to diagnosis was 3 (1-17) months. Because renal biopsy was performed selectively, 59% of recipients underwent biopsy, with 47% showing BK nephropathy. Seventy-four percent of recipients cleared the virus at a median (range) time of 9 (3-33) months, with four grafts lost to BK nephropathy. Cidofovir-treated recipients displayed a higher viral load at diagnosis but showed equivalent renal function at last evaluation. In multivariate analysis, recipient age, Asian ethnicity, deceased donor, and prednisone use were factors independently associated with BK viremia. Actuarial survival of BK-positive grafts was worse than that of BK-negative grafts (P<0.01, log-rank test). At 9 and 12 months, the mean estimated glomerular filtration rate of the BK-positive group was lower than that of the BK-negative cohort (P = 0.02). Despite using a screening protocol combined with immunosuppression minimization, BK-positive recipients had a greater risk of graft loss and impaired function than recipients free of infection. Future investigations should focus on practices to prevent BK viremia.