Incidence of Posttransplantation Diabetes Mellitus in De Novo Kidney Transplant Recipients Receiving Prolonged-Release Tacrolimus-Based Immunosuppression With 2 Different Corticosteroid Minimization Strategies: ADVANCE, A Randomized Controlled Trial.

BACKGROUND: ADVANCE (NCT01304836) was a phase 4, multicenter, prospectively randomized, open-label, 24-week study comparing the incidence of posttransplantation diabetes mellitus (PTDM) with 2 prolonged-release tacrolimus corticosteroid minimization regimens. METHODS: All patients received prolonged-release tacrolimus, basiliximab, mycophenolate mofetil and 1 bolus of intraoperative corticosteroids (0-1000 mg) as per center policy. Patients in arm 1 received tapered corticosteroids, stopped after day 10, whereas patients in arm 2 received no steroids after the intraoperative bolus. The primary efficacy variable was the diagnosis of PTDM as per American Diabetes Association criteria (2010) at any point up to 24 weeks postkidney transplantation. Secondary efficacy variables included incidence of composite efficacy failure (graft loss, biopsy-proven acute rejection or severe graft dysfunction: estimated glomerular filtration rate (Modification of Diet in Renal Disease-4) <30 mL/min per 1.73 m), acute rejection and graft and patient survival. RESULTS: The full-analysis set included 1081 patients (arm 1: n = 528, arm 2: n = 553). Baseline characteristics and mean tacrolimus trough levels were comparable between arms. Week 24 Kaplan-Meier estimates of PTDM were similar for arm 1 versus arm 2 (17.4% vs 16.6%; P = 0.579). Incidence of composite efficacy failure, graft and patient survival, and mean estimated glomerular filtration rate were also comparable between arms. Biopsy-proven acute rejection and acute rejection were significantly higher in arm 2 versus arm 1 (13.6% vs 8.7%, P = 0.006 and 25.9% vs 18.2%, P = 0.001, respectively). Tolerability profiles were comparable between arms. CONCLUSIONS: A prolonged-release tacrolimus, basiliximab, and mycophenolate mofetil immunosuppressive regimen is efficacious, with a low incidence of PTDM and a manageable tolerability profile over 24 weeks of treatment. A lower incidence of biopsy-proven acute rejection was seen in patients receiving corticosteroids tapered over 10 days plus an intraoperative corticosteroid bolus versus those receiving an intraoperative bolus only.

A Prospective Randomized Trial on the Effect of Using an Electronic Monitoring Drug Dispensing Device to Improve Adherence and Compliance.

BACKGROUND: Outcome after renal transplantation depends on patient compliance and adherence for early detection of complications and identification of intervention opportunities. Compliance describes the degree to which patients follow medical advice and take their medications. Adherence has been defined as the extent to which a patients' behavior coincides with clinical prescriptions. MATERIALS AND METHODS: Patients were randomized 7 to 14 days after transplantation into groups with (n = 40) and without (n = 40) an electronic medication dispenser (EMD). The EMD, which was used for the 1-year study period, recorded the date and time the patient took their medications and was monitored via a web-based application. Patients were monitored for 1 year regarding outpatient follow-up visits, emergency hospitalizations, renal biopsies, rejection episodes, renal function, and blood concentration of medications. RESULTS: Compliance in the intervention group was 97.8% (the control group was not assessed). Number of missed doses varied significantly by weekday (P = 0.033); patients were most likely to miss doses on Saturdays and Thursdays. Patients missed a total of 11 follow-up visits. During the study, 92 biopsies were performed on 55 patients (intervention group: 32 [17]; control group, 60 [38]). Biopsy-verified rejection was three times more common among controls (13 patients vs. 4; P = 0.054, not significant). Average P-creatinine level was slightly lower in the intervention group than the control group (131 vs. 150 µmol/L, not significant), whereas mean tacrolimus was similar (7.32 vs. 7.22 ng/mL, n.s.). CONCLUSIONS: The EMD is associated with high compliance, and there are also indications of a lower rejection rate.

An observational cohort study of the effect of hypertension on the loss of renal function in pediatric kidney recipients.

BACKGROUND: Post-transplant hypertension impacts negatively on renal graft survival. Our primary objective was to analyze the effect of hypertension on the glomerular filtration rate (GFR) slope. METHODS: All clinical charts of children who underwent renal transplantation since the introduction of the routine use of ambulatory blood pressure monitoring (ABPM) were reviewed. Eligibility criteria for inclusion were measurement of GFR at 3 months, at 1 year post-transplant, and thereafter at yearly intervals; ABPM performed annually after transplantation; and functioning graft for a minimum of 2 years. RESULTS: Sixty-eight (39 males) of 79 patients, aged 9.1±5.3 years, met the inclusion criteria. The mean follow-up was 6.2±2.8 years. Twenty-four patients had normotension or controlled hypertension throughout their follow-up (normotensive group). Forty-four patients had hypertension or noncontrolled hypertension at some point(s) during the follow-up period (hypertensive group). GFR slope was -1.6ml/min/1.73 m(2) per year (95% confidence interval (CI = -3.7 to 0.4) in the normotensive group and -2ml/min/1.73 m(2) per year (95% CI = -3 to -1.1) in the hypertensive group (P = 0.42). There was no difference between groups with regard to the change in GFR values from 3 months to 1 year and to last control (P = 0.87). At most recent control, the overall prevalence of controlled hypertension was 78.2% (95% CI = 63.6-89.1). CONCLUSIONS: Although the results of our study are encouraging, they need to be confirmed in a larger prospective study using the same post-transplant follow-up protocol.

The outcome of the endothelial precursor cell crossmatch test in lymphocyte crossmatch positive and negative patients evaluated for living donor kidney transplantation.

The presence of human leukocyte antigen (HLA) and non-HLA antibodies (Abs) in kidney transplant recipients is associated with graft rejections. This study reports the results of an endothelial precursor cell crossmatch (EPCXM) test for detection of non-HLA Abs and its correlation to lymphocyte crossmatch (LXM) test results, the degree and type of sensitization, and transplantation (Tx) outcome in patients evaluated for living donor (LD) kidney transplantation (KTx). Patients were tested before any pre-transplantation (pre-Tx) treatment and at Tx. Pre-Tx treatments included B cell depletion and Ab removal. Patient records were reviewed for assessment of renal graft function, results of biopsies, and identification of complications affecting the graft. Pre-Tx sera from 32% of the LD patients had IgG and/or IgM-binding donor EPCs. Twenty-five percent of the patients were EPCXM IgM+. Of the patients with negative LXM tests, 25% had EPC Abs mainly of IgM class not reactive with HLA. There was no difference in rejection frequency or serum creatinine levels between the EPCXM+ and EPCXM- groups. The pre-Tx EPCXM+ group had significantly more patients with delayed graft function. Prospective studies with appropriate control groups are needed to establish whether pre-treatments aiming at removing anti-endothelial cell antibodies, as detected by the EPCXM pre-Tx, have a beneficial effect on short-term and long-term graft survival.

Intentional ABO-incompatible heart transplantation: a case report of 2 adult patients.

BACKGROUND: In 2009, we started to screen all patients on the heart transplant waiting list for the presence of blood group anti-A or anti-B antibodies. From our experience with ABO-incompatible kidney transplantation, we know that transplantation can safely be performed if the antibody level is reduced to a titer of immunoglobulin G (IgG) 1:8. METHODS: We decided to accept all patients with anti-A or anti-B antibody titer ≤1:8 for ABO-incompatible heart transplantation without any special pre-treatment and patients with antibody titers of IgG 1:16 and 1:32, provided 1 apheresis session could be performed immediately before transplantation. RESULTS: We found 6 of 13 patients were suitable for this program, and 2 ABO incompatible patients underwent successful transplantation with a follow-up of 1 year. CONCLUSION: In heart transplant candidates where there are problems obtaining a compatible heart and who are not suitable for ventricular assist device support, ABO-incompatible heart transplantations can be considered using our protocol, provided that the levels of anti-A or anti-B antibodies are low.

Renal transplantation in infants and small children.

There are still concerns about renal transplantation in small children. The aim of this study was to identify prenatal data, underlying diseases, patient and graft survival, graft function and growth in young renal transplant recipients at our center. A retrospective analysis was performed on 50 kidney transplants performed during the period 1981-2008 in children weighing <13 kg. Their median age at transplantation was 1.4 (range 0.4-3.7) years and the median weight was 9.5 (3.4-12.1) kg. The underlying diseases were congenital in 88% of the patients and acquired in 12%. Ten-year patient survival was 88% (82% before 1998 and 95% since 1998). Ten-year graft survival was 82% (75 and 95%, respectively). Graft function (glomerular filtration rate) deteriorated from a mean of 75-48 ml/min/1.73 m(2) within 10 years. There was rapid catch-up growth within the first years post-transplant, from a median height of -2.44 standard deviation score (SDS) at transplantation to -0.74 SDS after 3 years. In small children, patient and graft survival were as good as those in older children. Renal function deteriorated during the first years post-transplant but stabilized within a few years. In most children, there was a substantial improvement in growth within the first years after transplantation.

ABO-incompatible kidney transplantation in children.

We designed a new protocol to enable safe ABO-incompatible kidney transplantation. The new protocol utilizes antigen-specific immunoadsorption rather than unspecific plasma exchange to remove existing anti A/B antibodies and rituximab rather than splenectomy to prevent rebound of antibodies. Sixty patients have so far been successfully transplanted with this protocol and 10 of those have been children. When compared with ABO-compatible transplantations, we could not find any differences in success rate, renal function, or adverse events.

The efficacy of antigen-specific immunoadsorption and rebound of anti-A/B antibodies in ABO-incompatible kidney transplantation.

BACKGROUND: As antigen-specific immunoadsorption (IA) using the Glycosorb®-ABO columns is becoming increasingly popular in ABO-incompatible (ABOi) transplantation, in this study, we retrospectively investigated the efficacy of Glycosorb®-ABO IA in vivo and ex vivo. We also assessed the risk of anti-A/B antibody (ABab) rebound before and after ABOi kidney transplantation. METHODS: A protocol for ABOi living donor kidney transplantation was used, combining four preoperative and three preemptive postoperative Glycosorb®-ABO IAs with rituximab and maintenance immunosuppression. ABabs were determined by a haemagglutination titration technique. RESULTS: ABOi kidney transplantation was attempted 45 times and 43 transplantations were performed. Overall patient survival was 93% and graft survival was 91%. Mean follow-up was 4.5 years. Glycosorb®-ABO IA significantly reduced the ABabs in the majority of patients (P < 0.0001). However, in three patients (6.8%), the antibody elimination was incomplete. Inadequate adsorption of core-chain-dependent ABabs may explain this finding, but further studies are needed. In five patients, the preconditioning was interrupted before transplantation, resulting in ABab rebound. Yet, when preconditioning was restarted, the antibodies could be removed as planned. After ABOi transplantation, rebound of ABabs was seen in two patients (5%). CONCLUSIONS: Glycosorb®-ABO IA in combination with rituximab effectively depletes ABabs in most patients, but owing to core-chain-dependent ABabs, Glycosorb®-ABO IA may be less effective than nonspecific techniques for antibody removal in some patients. Rebound before transplantation subsequent to interrupted preconditioning does not hamper a successful ABOi transplantation. Postoperatively, when this protocol for ABOi transplantation is followed, the risk of ABab rebound is small.

Isoagglutinin adsorption in ABO-incompatible transplantation.

As the demand for kidney transplantation is constantly growing methods to expand the donor pool have become increasingly important. ABO-incompatibility has hitherto been regarded as an absolute contraindication to living donor donation. However, as ABO-incompatibility has accounted for the majority of living donor exclusions, efforts have been made to overcome this immunologic barrier. Successful desensitization protocols thus far, have combined plasmapheresis for antibody removal with splenectomy to reduce the antibody producing B-cell pool, in addition to quadruple immunosuppression. Although good graft function has been achieved, the high risks involved have been deterrent. We have developed a protocol for ABO-incompatible kidney transplantation based on antigen-specific immunoadsorption and rituximab, in combination with standard maintenance immunosuppression (tacrolimus, mycophenolate mofetil and corticosteroids). We hypothesized that the anti-A/B antibodies could be effectively eliminated and good graft function achieved, without the complications of coagulopathy and transfusion reactions associated with plasmapheresis. Furthermore, we hypothesized that the substitution of splenectomy with a single dose of the anti-CD20 antibody rituximab would further reduce surgical risk as well as the risk of infectious complications. In 2001 the program for ABO-incompatible kidney transplantation was started at our center. To date 50 ABO-incompatible kidney transplantations have been performed according to the protocol based on antigen-specific immunoadsorption and rituximab. Safety and efficacy of the protocol has been evaluated in several studies, all showing that the antigen-specific immunoadsorption is well tolerated and without any serious side effects. Patient and graft survival as well as kidney function have been comparable to that of ABO-compatible living donor kidney transplantation and the incidence of antibody-mediated rejection 0%. We conclude that AB0-incompatible kidney transplantation using a protocol based on antigen-specific immunoadsorption and rituximab, in combination with triple immunosuppressive therapy is safe and effective. ABO-incompatibility following this protocol does not have a negative impact on graft function. ABO-incompatible kidney transplantation is equivalent to standard ABO-compatible living donor kidney transplantation.

A randomized, doubleblind, placebo-controlled, study of single-dose rituximab as induction in renal transplantation.

UNLABELLED: We performed a prospective, double blind, randomized, placebo-controlled multicenter study on the efficacy and safety of rituximab as induction therapy, together with tacrolimus, mycophenolate mofetil, and steroids. The primary endpoint was defined as acute rejection, graft loss, or death during the first 6 months. Secondary endpoints were creatinine clearance, incidence of infections, and incidence of rituximab-related adverse event. RESULTS: We enrolled 140 patients (44 living donor and 96 deceased donor), and of those, 68 rituximab and 68 placebo patients fulfilled the study. In all the patients receiving rituximab, there was a complete depletion of CD19/CD20 cells, whereas there was no change in the number of CD19/CD20 cells in the placebo group. There were 10 treatment failures in the rituximab group versus 14 in the placebo group (P=0.348). There were eight rejection episodes in the rituximab group versus 12 in the placebo group (P=0.317) Creatinine clearance was 66+/-22 mL/min in the study group and 67+/-23 mL/min in the placebo group. There was no difference in the number of bacterial infections, cytomegalovirus infections, and BK virus infections or fungal infections. CONCLUSION: We performed a placebo-controlled study of rituximab induction in renal transplantation. There was a tendency toward fewer and milder rejections during the first 6 months in the rituximab group. Although induction with one dose of rituximab induced a complete depletion B cells, there was no increase in the incidence of infectious complications or leukopenia and it seems safe, therefore, to conduct further studies on the use of rituximab in transplantation.

Multicenter evaluation of a novel endothelial cell crossmatch test in kidney transplantation.

BACKGROUND: Despite their clinical importance, clinical routine tests to detect anti-endothelial cell antibodies (AECA) in organ transplantation have not been readily available. This multicenter prospective kidney transplantation trial evaluates the efficacy of a novel endothelial cell crossmatch (ECXM) test to detect donor-reactive AECA associated with kidney allograft rejection. METHODS: Pretransplant serum samples from 147 patients were tested for AECA by a novel flow cytometric crossmatch technique (XM-ONE) using peripheral blood endothelial progenitor cells as targets. Patient enrolment was based on acceptance for transplantation determined by donor lymphocyte crossmatch results. RESULTS: Donor-reactive AECA were found in 35 of 147 (24%) patients. A significantly higher proportion of patients with a positive ECXM had rejections (16 of 35, 46%) during the follow-up of at least 3 months compared with those without AECA (13 of 112, 12%; P<0.00005). Both IgG and IgM AECAs were associated with graft rejections. Mean serum creatinine levels were significantly higher in patients with a positive ECXM test at 3 and 6 months posttransplant. CONCLUSIONS: XM-ONE is quick, easy to perform on whole blood samples and identifies patients at risk for rejection and reduced graft function not identified by conventional lymphocyte crossmatches.

Comparing mycophenolate mofetil regimens for de novo renal transplant recipients: the fixed-dose concentration-controlled trial.

BACKGROUND: Fixed-dose mycophenolate mofetil (MMF) reduces the incidence of acute rejection after solid organ transplantation. The Fixed-Dose Concentration Controlled trial assessed the feasibility and potential benefit of therapeutic drug monitoring in patients receiving MMF after de novo renal transplant. METHODS: Patients were randomized to a concentration-controlled (n=452; target exposure 45 mg hr/L) or a fixed-dose (n=449) MMF-containing regimen. The primary endpoint was treatment failure (a composite of biopsy-proven acute rejection [BPAR], graft loss, death, or MMF discontinuation) by 12 months posttransplantation. RESULTS: Mycophenolic acid (MPA) exposures for both groups were similar at most time points and were below 30 mg hr/L in 37.3% of patients at day 3. There was no difference in the incidence of treatment failure (25.6% vs. 25.7%, P=0.81) or BPAR (14.9% vs. 15.5%, P>0.05) between the concentration-controlled and the fixed-dose groups, respectively. We did find a significant relationship between MPA-area under the concentration-time curve on day 3 and the incidence of BPAR in the first month (P=0.009) or in the first year posttransplantation (P=0.006). For later time points (day 10, month 1) there was no significant relationship between area under the concentration-time curve and BPAR (0.2572 and 0.5588, respectively). CONCLUSIONS: There was no difference in the incidence of treatment failure between the concentration-controlled and the fixed-dose groups. The applied protocol of MMF dose adjustments based on target MPA exposure was not successful, partly because physicians seemed reluctant to implement substantial dose changes. Current initial MMF doses underexpose more than 35% of patients early after transplantation, increasing the risk for BPAR.

ABO-incompatible kidney transplantation using antigen-specific immunoadsorption and rituximab: a 3-year follow-up.

BACKGROUND: In 2001 a protocol for ABO-incompatible (ABOi) kidney transplantation based on antigen-specific immunoadsorption and rituximab was introduced at our center, short-term results being comparable with those of ABO-compatible (ABOc) living donor kidney transplantation. Of greater importance, however, is long-term graft function, thus far not evaluated. The aim of this study was therefore to assess long-term results of this protocol. METHODS: Twenty ABOi kidney recipients with more than 12-month follow-up were included in the study: all adult crossmatch negative ABOi kidney recipients (n=15) were compared with an adult ABOc living donor recipient control group (n=30), and all pediatric ABOi kidney recipients (<16 years of age) (n=5) were compared with a group of pediatric ABOc kidney recipients (n=18). RESULTS: Mean follow-up was three years. There was no significant difference in patient survival, nor in graft survival or in the incidence of acute rejection in any of the groups. In the adult kidney recipients mean glomerular filtration rate was equivalent at all time points (79-83 mL/min), as was Deltas-creatinine. In the pediatric groups, Deltas-creatinine was similar but glomerular filtration rate lower among the ABOi kidney recipients. There was a significant reduction (P<0.0001) without rebound in A/B antibody titers after transplantation (median IgG 1:2 and median IgM 1:1>1 year posttransplant) compared with pretransplant levels (median IgG 1:32 and IgM 1:16). CONCLUSION: We conclude that ABOi kidney transplantation using antigen-specific immunoadsorption and rituximab is equivalent to ABOc living donor kidney transplantation. ABOi transplantation after this protocol does not have a negative impact on long-term graft function.

Implementation of a Protocol for ABO-incompatible kidney transplantation--a three-center experience with 60 consecutive transplantations.

BACKGROUND: A new protocol for ABO-incompatible kidney transplantation has recently been introduced. We report here on the joint experience of the implementation in Stockholm and Uppsala, Sweden and Freiburg, Germany. METHODS: The new protocol utilizes antigen-specific immunoadsorption to remove existing ABO-antibodies, rituximab, and intravenous immunoglobulin to prevent the rebound of antibodies, and conventional tacrolimus, mycophenolate-mofetil, and prednisolone immunosuppression. Sixty consecutive ABO-incompatible kidney transplantations were included in the study. The outcome is compared with the results of 274 ABO-compatible live donor transplantations performed during the same period. RESULTS: Two of the ABO-incompatible grafts have been lost (non-compliance and death with functioning graft). All the remaining 58 grafts had good renal function at a follow-up of up to 61 months. We did not observe any late rebound of antibodies and there were no humoral rejections. Graft survival was 97% for the ABO-incompatible compared with 95% for the ABO-compatible. Patient survival was 98% in both groups. There was a significant variation in preoperative A/B-antibody titer between the centers, with a median 1:8 in Uppsala, median 1:32 in Stockholm and median 1:128 in Freiburg. More preoperative antibody adsorptions were therefore needed in Freiburg than in Stockholm and Uppsala. CONCLUSIONS: The new protocol was easily implemented and there were no graft losses that could be related to ABO-incompatibility. A significant inter-institutional variation in the measurement of anti-AB-antibodies was found, having a substantial impact on the number of immunoadsorptions and consequently on the total cost for the procedure. A standardized fluorescence-activated cell sorting technique for antibody quantification is much needed.

Comparing the tube and gel techniques for ABO antibody titration, as performed in three European centers.

Data from 60 consecutive ABO-incompatible kidney transplantations performed in Stockholm, Sweden; Freiburg, Germany; and Uppsala, Sweden, revealed significant variation in preoperative A/B antibody levels, with median titers of 1:32, 1:128, and 1:8, respectively. We wanted to investigate whether these differences were method-related. The same samples from 21 healthy blood donors were analyzed in the three centers using current local methods. Results confirmed method-related differences, with higher A/B titers in Freiburg and lower titers in Uppsala compared with Stockholm. Results for the same sample differed by a median of three (range 0 to 6) titer steps. When the same number of samples were analyzed in the three centers using the same gel method and the same test erythrocytes, results differed by a median of one titer step (range 0 to 4) for the same sample. In conclusion, gel hemagglutination technique significantly decreases intercenter variation compared with tube technique.

The European experience.

A new protocol for ABO-incompatible kidney transplantation was introduced in 2001. In this protocol, antigen-specific immunoadsorption to remove existing AB antibodies is used in addition to rituximab to prevent rebound of antibodies and conventional immunosuppression (tacrolimus, mycophenolate mofetil, and prednisolone). This protocol has successively been implemented in many European centers, primarily in Sweden and Germany but also in the UK, Switzerland, the Netherlands, Norway, Denmark, Greece and Spain, and almost 200 ABO-incompatible transplantations have now been performed. In a recent 3-center pooled analysis of 60 consecutive ABO-incompatible living-donor transplantations, there were no graft losses that could be related to the ABO incompatibility and, when compared with ABO-compatible transplantations, no difference in graft or patient survival was found.