anti-IL2 Receptor Research Articles

Impact of GAD65 and IA2 autoantibodies on islet allograft survival.

Islet transplantation (ITx) shows promise in treating T1D, but the role of islet autoantibodies on graft survival has not been clearly elucidated. We aimed to analyze the effect of GAD65 and IA2 autoantibody status on graft survival and attainment of insulin independence in subjects with T1D who underwent ITx. We conducted a retrospective cohort study on 47 ITx recipients from 2000 to 2018. Islet infusion was performed via intrahepatic portal (n=44) or onto the omentum via laparoscopic approach (n=3). Immunosuppression involved anti-IL2 receptor antibody, anti-TNF, and dual combinations of sirolimus, tacrolimus, or mycophenolate mofetil (Edmonton-like) in 38 subjects (80.9%). T-cell depletion induction with Edmonton-like maintenance was used in 9 subjects (19%). GAD65 and IA2 autoantibodies were assessed pre-transplant and post-transplant (monthly) until graft failure, and categorized as persistently negative, persistently positive, or seroconverters. Graft survival was analyzed using U-Mann-Whitney test, and Quade's nonparametric ANCOVA adjusted for confounders. Kaplan-Meier and Log-Rank tests were employed to analyze attainment of insulin independence. P value <0.05 indicated statistical significance. ITx recipients with persistent autoantibody negativity (n = 21) showed longer graft function (98 [61 - 182] months) than those with persistent autoantibody positivity (n = 18; 38 [13 - 163] months), even after adjusting for immunosuppressive induction protocol (P = 0.027). Seroconverters (n=8) had a median graft survival time of 73 (7.7 - 167) months, which did not significantly differ from the other 2 groups. Subjects with persistently single antibody positivity to GAD65 (n = 8) had shorter graft survival compared to negative islet autoantibody (GAD65/IA2) subjects (n = 21; P = 0.016). Time of graft survival did not differ in subjects with single antibody positivity to IA2. The proportion of insulin independence attainment was similar irrespective of autoantibody status. The persistence of islet autoantibodies, as markers of islet autoimmunity, may represent an underappreciated contributing factor to the failure of transplanted β cells. Whether induction with T-cell depletion may lead to improved graft survival, independent of islet autoantibody status, could not be evaluated in our cohort. Larger prospective studies are needed to further address the role of islet autoantibody status on islet graft survival.

The impact of induction therapy in low-immunological risk kidney transplant recipients regardless of HLA matching

BackgroundInduction agents have proved to reduce the rate of acute rejection (AR) in kidney transplant recipients (KTRs) without improving long-term graft and patient survival (PS). ObjectiveThis study evaluates the utility of induction therapy in low immunological risk KTRs regardless of donor-to-recipient HLA matching. MethodsWe retrospectively reviewed the records of 218 patients undergoing kidney transplantation (KT). These patients were divided into two groups according to the usage of induction therapy: 82 did not receive any induction therapy (Group I), and 136 patients received either Anti-IL2 receptor antibodies or anti-thymocyte globulin (Group II). All patients had panel reactive antibody (PRA) < 20% and absence of donor-specific antibodies (DSA). The difference in outcomes were assessed at different intervals following KT. ResultsThe rate of bacterial infections at one year (p-value = 0.032) and the frequency of CMV disease (p-value = 0.044) were significantly higher in Group II (with induction therapy). The duration of hospital stay, the rate and severity of acute rejection, the occurrence of delayed graft function, the rate and type of surgical complications at one year, and the graft function and survival at one and three years were similar between the two groups (p-value = NS). In addition, the financial burden is much less in Group I (without induction therapy), reducing the total cost of the transplant procedure. ConclusionWe conclude that induction therapy in low-immunological risk kidney transplant patients is not a must regardless of donor-to-recipient HLA matching. Therefore, induction therapy did not yield significant health results, but had negative financial consequences.

316.5: Long Term Outcomes of Low Dose Anti-thymocyte Globulin And Anti-interleukin-2 Receptor Antibody Induction in Kidney Transplantation From Expanded Criteria Donors

Background: Using kidneys from expanded criteria donors (ECD) has been increased due to the shortage of donor organs but seemed to have poorer prognosis. The aim of this study was to evaluate the safety and efficacy of rabbit anti-thymocyte globulin (rATG) induction in kidney transplantation (KT) from ECD compared to anti IL-2 receptor antibody (basiliximab). Methods: We retrospectively analyzed 182 patients who underwent KT from ECDs between April 2004 and December 2020. The patients were categorized into two groups according to induction therapy modality. The basiliximab group (n=43) received basiliximab 20mg/kg on day 0 and 4, while low dose rATG group (n=139) received rATG 1.5mg/kg on day 0, 1, and 2. Both groups received tacrolimus, mycopheonolate, and steroids as maintenance immunosuppressive agents. Results: The mean donor age (60.6 vs 64.3, p = 0.007) and KDPI score (84.4 vs 90.0, p = 0.005) were higher in rATG group. Patients in rATG group showed more delayed graft function (11.6% vs 30.9%, p = 0.021) but no significant difference in biopsy proven acute rejection (41.9% vs 35.3%, p =0.546). However, graft survival rates (p = 0.88) and overall survival rates (p = 0.846) were not significantly different between the two groups. CMV infection rate seemed higher in rATG group, but graft survival rate was not influenced by CMV infection (p =0.677). Conclusion: Low dose rATG induction in KT from ECD resulted in comparable patient and graft survival despite the worse donor and recipient profile comparing to basiliximab induction. Therefore, low dose rATG can be considered as an effective and safe induction therapy in KT from ECD.

Living Donor Kidney Transplantation in Patients With Donor-Specific HLA Antibodies After Desensitization With Immunoadsorption.

Due to the current organ shortage, living donor kidney transplantation is increasingly performed across HLA (human leukocyte antigen) or ABO antibody barriers. There is still uncertainty about the risk of antibody-mediated rejection (AMR) episodes, which may limit long-term graft survival. From March 2007 to December 2016, 58 sensitized living donor kidney transplant candidates were identified and 38 patients eventually included in the study: 36 patients (95%) had pre-transplant and pre-desensitization Luminex-detected donor-specific HLA antibodies (DSA), and 17/36 patients (47%) in addition had a positive crossmatch result. Two patients had no detectable DSA but a positive CDC B-cell crossmatch result. Patients were treated with pre- and post-transplant apheresis and powerful immunosuppression including the anti-CD20 antibody rituximab (N = 36) in combination with thymoglobulin (N = 20) or anti-IL2 receptor antibody (N = 18). The results of the 38 successfully desensitized and transplanted patients were retrospectively compared to the results of 76 matched standard-risk recipients. Desensitized patients showed patient and graft survival rates similar to that of standard-risk recipients (P = 0.55 and P = 0.16, respectively). There was a trend toward reduced death-censored graft survival in desensitized patients (P = 0.053) which, however, disappeared when the 34 patients who were transplanted after introduction of sensitive Luminex testing were analyzed (P = 0.43). The incidence of rejection episodes without borderline changes were in desensitized patients with 21% similar to the 18% in standard-risk patients (P = 0.74). Thirty-six patients had pre-transplant HLA class I and/or II DSA that were reduced by 85 and 81%, respectively, during pre-transplant desensitization (P < 0.001 for both). On day 360 after transplantation, 20 of 36 (56%) patients had lost their DSA. The overall AMR rate was 6% in these patients, but as high as 60% in 5 (14%) patients with persistent and de novo DSA during year 1; 2 (40%) of whom lost their graft due to AMR. Eleven (31%) patients with persistent DSA but without de novo DSA had an AMR rate of 18% without graft loss while one patient lost her graft without signs of AMR. Our desensitization protocol for pre-sensitized living donor kidney transplant recipients with DSA resulted in good graft outcomes with side effects and rejection rates similar to that of standard-risk recipients. Adequate patient selection prior to transplantation and frequent immunological monitoring thereafter is critical to minimize rejection episodes and subsequent graft loss.

MO950SIMULTANEOUS LIVER-KIDNEY TRANSPLANT. SIXTEEN YEARS OF MONOCENTRIC EXPERIENCE

Abstract Background and Aims Combined liver-kidney transplant is the best treatment for patients with hepatic and renal failure, even though some studies reported a poor patient survival. The aim of our study is to summarize the clinical characteristics of subjects who undergo simultaneous combined liver-kidney transplantation (SLKT) for advanced liver and kidney disease. Furthermore, we evaluated patient and kidney survival of SLKT recipients compared to solitary kidney transplant (KT) recipients. Method We performed a retrospective analysis of all SLKT recipients performed in a single transplant Center (University Hospital of Modena, Italy) from 01/01/2004 to 12/31/2016. All patients were aged more than 18 years. Results 34 SLKT were performed over 16 years of transplant activity. Mean age of recipients was 51.3 ±9.1years. Males accounted for 65% of the population. All patients were of Caucasians origin except one of African origin. Mean BMI was 69.5 ± 13.9 Kg. Hepatitis C Virus (HCV)-related cirrhosis was the main cause (38.1%) of hepatic failure. Other causes of hepatic disease were ADPKD (26.5%), hepatitis B Virus (HBV) (11.8%), alcohol (8.8%), combined HCV-HBV infection (5.9%), Von Gierke Disease (2.9%), primary biliary cirrhosis (2.9%), and autoimmune cirrhosis (2.9%). Six patients developed hepatocellular carcinoma before undergoing SLKT. Renal disease was caused by ADPKD (26.5%), diabetic nephropathy (14.7%), glomerulonephrites (29.4%), hepatorenal syndrome (8.8%) and other renal diseases (20.6%). Overall, 14.7% of patients was affected by Human Immunodeficiency Virus (HIV), 50% by hypertension and 41% by diabetes. Mean MELD at transplantation was 42 (39.2-46.5) and mean serum creatinine value in pre-emptive patients was 3.09 ±1.4 mg/dl. Mean of donors was 46.7±15.3 years and main cause of death was cranial trauma (47.1%), followed by cerebral haemorrhage (41.2%). Mean KDPI was 52% (22-63) and KDRI 1 (0.73-1.1). Mean time on waiting list was 2.8±1.2 years and half of patients was on dialysis maintenance before SLKT. Mean ischemia time were 6.5 ±1.3 and 12.3 ±2.1 hours for liver and kidney, respectively. Only one patient (2.9%) received double kidney transplantation. Primary induction agent was anti-IL2 receptor monoclonal antibodies (82.6%), thymoglobulin (13%) and with methylprednisolone (4.1%). Post SLKT, kidney early complication consisted of 3 delayed graft functions and 1 transplanctectomy in the only double kidney transplant recipient. At the end of the follow-up (8±4.1 years), mean creatinine was 1.44 ± 0.5 mg/dl and kidney survival accounted for 87.9%. Cox regression analysis showed recipient’ age as a protective factor (HR, 0.03; CI95%, 0.8-0.9) for kidney rejection and donor age as a risk factor (HR, 1.13,CI95% 1-1.1) for renal graft loss. Patient survival at 10 years was 91.2%. Two deaths were caused by infections (50%) and 2 by digestive haemorrhages (50%). SLKT recipients were confronted with 304 cadaveric donor KT recipients performed in the same transplant Center from 01/01/2006 to 12/31/2016. Statistical analysis showed that SLKT recipients had shorter waiting list, dialysis vintage and ischemia times. SLKT recipients had a major prevalence of diabetes and HCV infection but a lower prevalence of hypertension. DGF were less common in SLKT. Patient and graft survival a 1, 5 and 10 years did not show statistically significant differences between SLKT and KT. Conclusion Our analysis shows excellent kidney and patient survival in SLKT. SLKT and KT recipients had similar 1, 5 and 10-years patient and graft survival.

“Simulect” as a model compound for assessing placental transfer of monoclonal antibodies in minipigs

The aim of this study was to directly test and measure in vivo, if placental transfer of monoclonal antibodies takes place in pregnant Göttingen Minipigs to assess their suitability for reproductive assessment of therapeutic monoclonal antibodies.Simulect®, an approved anti CD25 (anti IL-2 receptor alpha) chimeric monoclonal IgG1 antibody, was used as a model monoclonal antibody. Maternal systemic exposure and potential placental transfer of Simulect® to fetuses were investigated following 4 weekly bolus intravenous administration of 5.0 mg/kg from gestation day (GD) 79 or 80 (e.g GD 79, 86, 93 and 100) and with terminal Caesarean section on GD 108 or GD 109 respectively. Results clearly showed exposure in maternal animals, detectable compound in the amniotic fluid from one out of 9 maternal animals, but no exposure in fetuses confirming absence of placental transfer of the selected model antibody Simulect® in minipigs. The absence of Simulect® in the fetuses further supports that the presence of Simulect® in the amniotic fluid in one maternal animal was likely due to contamination with maternal blood during sampling. The demonstrated absence of fetal exposure clearly indicates that, the minipig is not a suitable species for conduct of reproductive toxicity studies with monoclonal antibodies.

331.5: Induction therapy in kidney transplantation using kidney from expanded criteria donor: long term results comparing anti-IL2 receptor antibody and anti-thymocyte globulin.

331.5: Induction therapy in kidney transplantation using kidney from expanded criteria donor: long term results comparing anti-IL2 receptor antibody and anti-thymocyte globulin.

Longitudinal profile of circulating T follicular helper lymphocytes parallels anti-HLA sensitization in renal transplant recipients.

Antibody-mediated rejection is responsible for 30%-50% of renal graft failures. Differentiation of B cells into antibody-producing plasmablasts depends on the collaboration of follicular helper T cells (Tfh). We analyzed circulating Tfh (cTfh) in kidney recipients and studied cTfh relationship with anti-HLA antibody production and graft outcome. cTfh were longitudinally analyzed in a prospective cohort of patients (n=206), pre- and posttransplantation. Clinical data, HLA sensitization, and cTfh function were recorded. Both pretransplant and 6-month posttransplant cTfh were able to derive IgG-producing plasmablasts. Pretransplant cTfh was decreased in patients, especially in those who received dialysis. However, these cells were increased in patients with previous allograft or transfusions and in HLA-sensitized recipients. After transplantation cTfh expanded, significantly more in patients who developed de novo anti-HLA antibodies than in patients who remained unsensitized. Augmented pretransplant cTfh positively correlated with higher intensity of pretransplant anti-HLA class I and with de novo anti-HLA class I and anti-HLA class II antibodies. Consistently, pretransplantation cTfh were higher in patients who experienced acute rejection (HR=1.14 [1.04-1.25]). Thus, we show a role for Tfh in anti-HLA sensitization and rejection. Multicenter studies with additional patient cohorts are needed to validate these results. Immunosuppressive drugs targeting Tfh could be useful to improve outcomes.

Induction Therapy for Kidney Transplant Recipients: Do We Still Need Anti-IL2 Receptor Monoclonal Antibodies?

Induction therapy with antilymphocyte biological agents is widely used after kidney transplantation, most commonly T lymphocyte‐depleting rabbit‐derived antithymocyte globulin (rATG) or an IL‐2 receptor antagonist (IL2RA). Early randomized trials showed that rATG or IL2RA induction reduces early acute rejection, prompting recommendations by Kidney Disease Improving Global Outcomes that IL2RA induction be used routinely in first‐line therapy after kidney transplantation, with lymphocyte‐depleting induction reserved for high‐risk cases. These studies, however, mainly used outdated maintenance regimens. No large randomized trial has examined the effect of IL2RA or rATG induction versus no induction in patients receiving tacrolimus, mycophenolic acid and steroids. With this triple maintenance therapy, the addition of induction may achieve an absolute risk reduction for acute rejection of only 1–4% in standard‐risk patients without improving graft or patient survival. In contrast, rATG induction lowers the relative risk of acute rejection by almost 50% versus IL2RA in patients with high immunological risk. These recent data raise questions about the need for IL2RA in kidney transplantation, as it may no longer be beneficial in standard‐risk transplantation and may be inferior to rATG in high‐risk situations. Updated evidence‐based guidelines are necessary to support clinicians deciding whether and what induction therapy is required for their transplant patients today.

Risk Factors of Cytomegalovirus Disease in Kidney Transplant Recipients: A Single-Center Study in Thailand

BackgroundCytomegalovirus (CMV) infection significantly causes morbidity in kidney transplant (KT) recipients. This study aims to investigate the incidence, timing, and risk factors of CMV infection in KT recipients. MethodsThis is a single-center retrospective study at a tertiary referral hospital. Patients who underwent KT from January 2012 to September 2014 were included. CMV infection was defined as the presence of CMV measured by polymerase chain reaction. Logistic regression analysis was performed to assess independent risk factors of CMV infection after KT. ResultsOf 121 KT patients enrolled, 120 patients had CMV D+/R+ serostatus, and 1 had D-/R+. CMV infection occurred in 33 (27.2%) of patients with a median follow-up time of 16 (IQR 4–25) months. Of those, 25 had CMV viremia and 8 had CMV disease mainly involving the gastrointestinal system. In total, 86% of CMV cases occurred within 3 months. All recipients received anti–IL-2 receptor antibody (IL-2 RA), low-dose rabbit antithymocyte globulin (rATG; total of 1.5 mg/kg), or standard-dose rATG (1.5 mg/kg/day for 3–5 days) for induction. Of those, the incidences of CMV infection were 19.6%, 50%, and 67%, respectively. Preemptive strategy was used in all but 1 patient in the IL-2 RA and low-dose rATG group, whereas universal prophylaxis was given in 67% of patients in the standard-dose rATG group. Independent risk factors of CMV infection were older recipient age (per 10-year increase, OR 1.5; 95% CI 1.04–2.23), and induction with standard (OR 8.19; 95% CI 2.29–34) and low-dose rATG (OR 3.87; 95% CI 1.06–12.23). ConclusionsMore than 25% of KT recipients developed CMV infection within 6 months after KT. The risk is increased in older recipients and induction with rATG. The level of CMV risk in low-dose rATG is 52% lower than in standard-dose rATG. In a limited-resource setting such as Thailand, deferred or preemptive strategy may be acceptable in patients who received IL-2 RA and low-dose rATG, while prophylactic therapy should be given to patients who received standard-dose rATG.

Sa1255 The Comparative Efficacy of Induction of Remission for Mesalamine, Sulfasalazine, and Budesonide for the Treatment of Mild to Moderate Crohn's Disease: A Bayesian Network Meta-Analysis

BACKGROUND & AIMS: There has been a paradigm shift from the traditional approach of treating ulcerative colitis (UC) to simply achieve symptomatic control (clinical remission). Instead, we now aim to treat to ‘deep remission', that is to achieve mucosal healing (MH). It has been demonstrated that patients who achieve MH have lower rates of relapses, steroid use, hospitalization and surgery. We performed a systematic review and meta-analysis on the efficacy of biologic therapies in inducing and maintaining mucosal healing in UC. METHODS: Randomized controlled trials of a biologic therapy compared to a control arm with participants receiving placebo that met predetermined selection criteria were included. Citations were identified through EMBASE, MEDLINE, the Cochrane Central Register of Controlled Trials, proceedings of gastroenterology meetings, manual search of reference lists of trials and review articles, and ongoing trials identified from the registry http:// ClinicalTrials.gov. Data were pooled and we performed a random-effects meta-analysis. As a measure of effect we calculated risk ratio (RR) with corresponding 95% confidence interval (CI) for dichotomous outcomes. Data were analyzed using Review Manager version 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). RESULTS: Thirty-five trials were identified and 13 met the inclusion criteria. Of trials using an antiTNFα, 6 were induction trials totalling over 2000 patients and 3 were maintenance trials totalling over 1500 patients. Anti-TNFα versus placebo increased both induction and maintenance of MH (RR=1.26; 95% CI, 1.07-1.50, and RR=1.68; 95% CI, 1.43-1.97, respectively). The use of an anti-adhesion molecule was evaluated in 3 induction trials, totalling over 1000 patients, and a maintenance trial with over 350 patients. Anti-adhesion molecule versus placebo also increased both induction and maintenance of MH (RR=1.57; 95% CI, 1.19-2.07, and RR=2.71; 95% CI, 1.88-3.93, respectively). Induction of remission was evaluated using an anti-CD20, anti-CD3, and anti-IL2 receptor antibody in 1 trial each. The use of biologic therapy was associated with a decreased risk of study withdrawal due to adverse events for both anti-TNF α (RR=0.65; 95% CI, 0.48-0.86) as well anti-adhesion molecule biologic therapies (RR=0.33; 95% CI, 0.10-1.16). CONCLUSIONS: Biologic therapies are more effective in inducing and maintaining MH than placebo in patients with UC. The effect is seen using both anti-TNFα and anti-adhesion molecule biologic therapies. Both classes of therapies were well tolerated with minimal adverse effects.

Sa1254 Biologic Therapies Are Effective in Inducing and Maintaining Mucosal Healing in Ulcerative Colitis: A Systematic Review & Meta-Analysis

BACKGROUND & AIMS: There has been a paradigm shift from the traditional approach of treating ulcerative colitis (UC) to simply achieve symptomatic control (clinical remission). Instead, we now aim to treat to ‘deep remission', that is to achieve mucosal healing (MH). It has been demonstrated that patients who achieve MH have lower rates of relapses, steroid use, hospitalization and surgery. We performed a systematic review and meta-analysis on the efficacy of biologic therapies in inducing and maintaining mucosal healing in UC. METHODS: Randomized controlled trials of a biologic therapy compared to a control arm with participants receiving placebo that met predetermined selection criteria were included. Citations were identified through EMBASE, MEDLINE, the Cochrane Central Register of Controlled Trials, proceedings of gastroenterology meetings, manual search of reference lists of trials and review articles, and ongoing trials identified from the registry http:// ClinicalTrials.gov. Data were pooled and we performed a random-effects meta-analysis. As a measure of effect we calculated risk ratio (RR) with corresponding 95% confidence interval (CI) for dichotomous outcomes. Data were analyzed using Review Manager version 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). RESULTS: Thirty-five trials were identified and 13 met the inclusion criteria. Of trials using an antiTNFα, 6 were induction trials totalling over 2000 patients and 3 were maintenance trials totalling over 1500 patients. Anti-TNFα versus placebo increased both induction and maintenance of MH (RR=1.26; 95% CI, 1.07-1.50, and RR=1.68; 95% CI, 1.43-1.97, respectively). The use of an anti-adhesion molecule was evaluated in 3 induction trials, totalling over 1000 patients, and a maintenance trial with over 350 patients. Anti-adhesion molecule versus placebo also increased both induction and maintenance of MH (RR=1.57; 95% CI, 1.19-2.07, and RR=2.71; 95% CI, 1.88-3.93, respectively). Induction of remission was evaluated using an anti-CD20, anti-CD3, and anti-IL2 receptor antibody in 1 trial each. The use of biologic therapy was associated with a decreased risk of study withdrawal due to adverse events for both anti-TNF α (RR=0.65; 95% CI, 0.48-0.86) as well anti-adhesion molecule biologic therapies (RR=0.33; 95% CI, 0.10-1.16). CONCLUSIONS: Biologic therapies are more effective in inducing and maintaining MH than placebo in patients with UC. The effect is seen using both anti-TNFα and anti-adhesion molecule biologic therapies. Both classes of therapies were well tolerated with minimal adverse effects.

Lack of clinical association and effect of peripheral WBC counts on immune cell function test in kidney transplant recipients with T-cell depleting induction and steroid-sparing maintenance therapy

The Cylex ImmuKnow assay measures the amount of stimulated ATP production by CD4+ T-cells, and has been used clinically, trying to predict rejection and infection episodes. However, predictive values of this assay after induction therapy with steroid-sparing maintenance protocols are unclear. In this single-center cohort study, we analyzed renal transplant recipients who received T-cell depleting+/−anti-IL2 receptor antibodies and tacrolimus/mycophenolate maintenance without steroids. A total of 4224 ImmuKnow levels in 306 patients were available for analysis. ImmuKnow levels (Mean±SE) changed over time after induction therapy with a paradoxical initial increase: 419±23, 461±32, 519±14, 411±10, 344±6, and 405±3 for pre-transplant, 0–1wk, 1wk–1mo, 1–3mos, 3mos–1yr, and thereafter. This change was parallel to the evolution of peripheral WBC counts and ImmuKnow levels had weak but significant correlation with WBC counts (R2=0.264, P<0.0001). The levels for biopsy-proven rejection (389±56) and borderline/clinical rejection (254±41) were not significantly higher than the levels of quiescent patients. The levels for opportunistic infection (349±48) and other infections (345±27) were not significantly lower than the levels of quiescent patients. The longitudinal changes in ImmuKnow levels were not predictive of rejection or infection. In conclusion, ImmuKnow levels can vary after T-cell depleting induction therapies at various time points, even without significant clinical events. Since ImmuKnow levels seem to be affected by WBC counts, ImmuKnow results need to be interpreted with caution. The effects of leukocytosis or leukopenia caused by immunosuppressive medication on the ImmuKnow assay need further investigation.

Long-Term Kidney Allograft Function and Survival in Prednisone-Free Regimens

The optimal maintenance immunosuppressive regimen to improve long-term renal allograft function and graft survival is yet to be determined. This observational study prospectively compared tacrolimus/sirolimus with tacrolimus/mycophenolate mofetil in renal transplant recipients using a prednisone-free regimen with over 8.5 years of follow-up. Patients received methylprednisonlone and anti-IL2 receptor antagonist (Basiliximab) induction and were blindly randomized to either the tacrolimus/mycophenolate mofetil (n=45) or tacrolimus/sirolimus (n=37) groups. Outcome measures included patient and renal allograft survival, incidence of acute rejection, and estimated GFR. The tacrolimus/mycophenolate mofetil group compared with the tacrolimus/sirolimus group had overall better renal allograft survival (91% versus 70%, P=0.02); 13 patients (35.1%) in the tacrolimus/sirolimus group and 8 patients (17.8%) in the tacrolimus/mycophenolate mofetil group experienced biopsy-proven acute cellular rejection (P=0.07). By 3 months post-transplant, estimated GFR was significantly lower in the tacrolimus/sirolimus group compared with the tacrolimus/mycophenolate mofetil group (47.7 versus 59.6 ml/min per 1.73 m(2), P=0.0002), and this trend persisted throughout the follow-up period. Also, the slope of decline in the tacrolimus/sirolimus group was significantly steeper than in the tacrolimus/mycophenolate mofetil group. This study shows that, in a prednisone-free immunosuppressive regimen, long-term renal graft survival and function are significantly worse in the tacrolimus/sirolimus group than the tacrolimus/mycophenolate mofetil group. The synergistic nephrotoxic effect and higher acute rejection rates in the tacrolimus/sirolimus compared with the tacrolimus/mycophenolate mofetil group adversely affect graft survival.

Steroid avoidance or withdrawal in kidney transplantation

Steroid avoidance or early withdrawal in kidney transplantation is supported by recent guidelines, but late steroid withdrawal after the first posttransplant months has been recently discouraged in those guidelines. We have assessed the recent data trying to confirm whether or not these different steroid-sparing strategies are well tolerated. Reversible, mild acute rejection rates are increased after steroid avoidance or withdrawal. However, steroid avoidance or early withdrawal is well tolerated in low immunological risk kidney transplant recipients receiving induction with anti-IL2 receptor antibodies or thymoglobulin and a drug regimen based on calcineurin inhibitor and mycophenolate mofetil, at least during 5 years, the longest follow-up reported. In addition, steroid withdrawal after 3-6 months is associated with stable graft function and survival stable up to 3 years after transplantation, the longest follow-up reported. Although clear benefits (cardiovascular and others) are obvious in some observational studies, true benefits in randomized controlled trials remain unclear. Both early and late steroid withdrawals are well tolerated in selected low-risk renal allograft recipients treated with modern potent immunosuppression. More trials with carefully designed outcome measures are needed, especially with other modern combinations, including mTOR inhibitors and/or belatacept.

Combined introduction of anti-IL2 receptor antibodies, mycophenolic acid and tacrolimus: effect on malignancies after renal transplantation in a single-centre retrospective cohort study

Several studies suggest that the introduction of tacrolimus (TRL), mycophenolic acid (MPA) and interleukin 2 receptor antibodies (IL2Ra) as single drugs more than a decade ago has not increased the risk of malignancy after renal transplantation. However, only limited data are available on their carcinogenic effects when used in combination as a potent immunosuppressive regimen. A retrospective single-centre cohort study on 929 adult renal transplant recipients. Investigation of the effect of two consecutive immunosuppressive regimens [1993-98, N = 405, anti-lymphocyte antibodies, cyclosporine and azathioprine (AZA); 1999-2007, N = 524, predominantly IL2Ra, TRL and MPA] on the incidence rate of skin cancer, solid tumours and post-transplant lymphoproliferative disease (PTLD). In total, 365 malignancies developed among 113 patients. As compared to the previous cyclosporine and AZA-based immunosuppression, the introduction of the new immunosuppressive regimen did not increase the incidence rate of skin cancer [rate ratio 0.84; 95% confidence interval (CI) 0.48-1.46], solid tumours (0.89; 95% CI 0.46-1.67) and PTLD (0.82; 95% CI 0.28-2.21). Patients treated with the more recent regimens less frequently developed multiple skin cancers and invasive squamous cell cancer. Skin cancer after transplantation was strongly associated with the development of solid tumours (odds ratio 5.2; P < 0.0001). The introduction of the new immunosuppressive drugs reduced the incidence of first year acute rejection from 34.8 to 13.2% (P < 0.0001). Although significantly more efficient in the prevention of acute rejection, the introduction of TRL, MPA and IL2Ra-based immunosuppression after kidney transplantation was not associated with an increased incidence of skin cancer, solid tumours or PTLD.

Traitement immunosuppresseur

Immunosuppressive treatment following renal transplantation includes induction therapy during the initial period when the risk of rejection is higher. Depleting anti-lymphocyte antibodies are indicated mostly in patients who developped anti-HLA antibodies and following a second graft. Anti-IL2 receptor antibodies may be used in non-responders. After the first month, maintenance therapy mostly consists in the association of several immunosuppressants, mainly corticosteroids, an antimetabolic agent (azathioprine or mycophenolate mofetil) and a calcineurin inhibitor (cyclosporine or tacrolimus). Side effects associated with these treatments led to the development of new immunosuppressive protocols, with the reduction or withdrawal of corticosteroids treatment due to its deleterious effects on statural growth, and decreased doses of anti-calcineurin agents to reduce their nephrotoxic effect. These therapeutic options are possible in patients at low immunological risk.

Focal pseudohypertrophy of the left hemi-tongue

A 72 year-old man with a history of diabetes mellitus noticed that his tongue deviated to the left when it was stuck out. He consulted our hospital since this feature persisted for 9 months. The diabetes mellitus was well controlled by voglibose (0.6 mg/day) and gliclazide (80 mg/day), and serum levels of glucose and glycated hemoglobin were 104 mg/dl and 6.1%, respectively. The patient had no signs of neurologic involvement attributable to diabetes mellitus. The left side of the tongue was hypertrophic and the tongue deviated to left (Fig. 1). Left hemi-tongue weakness was evident. There was no fasciculation, and deep tendon reflexes were normal, with no pathological reflexes. The results of other neurological examinations including swallowing, speaking and tasting were negative. Electromyography of the left side of the tongue showed neuropathic motor unit action potentials, polyphasic motor unit potentials, positive sharp wave and fibrillation potentials. The number of motor units per second was decreased. The right side of the tongue showed none of these findings. All other muscles examined (deltoid, biceps, triceps, adductor of thumb, quadriceps, gastrocnemius, and tibialis anterior) showed no evidence of neuropathic or myopathic motor unit action potentials. Magnetic resonance imaging (MRI) of the tongue revealed markedly increased signal intensity in the left side of the tongue on T1-weighted images (Fig. 1a, c) and T2weighted images (Fig. 1b). The left side of the tongue was enlarged. Contrast-enhanced, T1-weighted MRI images obtained with the use of a bolus of gadoliniumdiethylenetriamine pentaacetic acid showed a circular lesion with ringed enhancement in the root of the left side of the tongue (Fig. 1d, white arrow). Intracranial abnormal signals including the brainstem were not evident on MRI. Anti-IL2 receptor antibody (303 U/ml), antinuclear antibody, and M-protein on immunoelectrophoresis were negative. Hypertrophy of the root of the left side of the tongue was evident on laryngoscopy. A biopsy of the root of the tongue showed lymphocyte infiltration with no malignant cells. Monoclonality was absent on immunohistochemical studies. One year later, short inversion time inversion recovery (STIR) images on repeated MRI showed the decreased signal intensity in the left hemitongue with increased signal intensity on T1-weighted images and T2-weighted images. The size of the circular lesion with ringed enhancement was unchanged. On the basis of the ringed enhancement on MRI and the presence of lymphocyte infiltration with no malignancy on histopathological examination, the lesion was diagnosed to be an inflammatory cystic lesion ‘‘abscess’’. On 20 months after consultation to our hospital, the left hemi-tongue weakness was static. These findings could be explained by denervation and reinnervation or by increasing frequencies of motor unit firing from the left hypoglossal nerve and adjacent motor fibers, which were impaired by the cystic lesion in the left side of the tongue. Neuralgic muscle hypertrophy of the limbs has been reported in several types of lower motor neuron disease, such as multifocal motor neuropathy [1], Guillain-Barre syndrome [1], and radiculopathy [3, 4], but such hypertrophy involving cranial nerves has not been reported previously to our knowledge. Prior studies suggest that continuous, spontaneous electrical activity of a muscle associated with disease conditions can cause neuralgic H. Kataoka (&) S. Ueno Department of Neurology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan e-mail: hk55@naramed-u.ac.jp

Induction antibody therapy in renal transplantation using early steroid withdrawal: Long-term results comparing anti-IL2 receptor and anti-thymocyte globulin

BackgroundThe present study intends to investigate the effects of anti-IL2 receptors (anti-IL2R) vs. lymphocyte-depleting agents in the early steroid withdrawal (ESW) scheme. MethodsThis is a retrospective cohort of 167 consecutive adult renal transplant recipients. Immunosuppression was based on tacrolimus and mycophenolate mofetil. Antibody induction therapy was carried out with lymphocyte-depleting agent (thymoglobulin) or anti-IL2R (Basiliximab or Daclizumab). ESW protocol was performed by administering intravenous methlyprednisolone as follows: 500mg on day 0, 250mg on day 1, 125mg on day 2, 60mg on day 3, and then stopped. ResultsAmong the 167 studied patients, 79 (47.3%) received anti-IL2R and 88 (52.7%) received thymoglobulin induction. Significantly fewer episodes of acute rejection were seen at one year in patients treated with thymoglobulin as compared to anti-IL2R (25.6% vs. 11.4%, p=0.01). At five years, a significant difference in graft survival was observed in anti-IL2R-treated patients compared with thymoglobulin (83.5% vs. 95.5%, p=0.01). Multivariate analysis disclosed that female sex, antibody induction therapy using thymoglobulin and a trough tacrolimus level higher than 10 were protective factors against acute rejection, while there was a trend to increased risk of acute rejection at first year post-transplantation in patients presenting delayed graft function (DGF). Antibody induction was independently associated with patient and graft survival at five years (OR 0.213, 95% CI 0.046–0.991, p=0.04). ConclusionESW scheme seems to be safe and its use is beneficial since there are fewer adverse effects. Thymoglobulin induction therapy is associated with fewer rejection episodes. Induction therapy with thymoglobulin is associated with higher patient and allograft survival when comparing with anti-IL2R.

Up-regulation of the sHLA-G5 level by human-mouse chimeric anti-IL-2R monoclonal antibody treatment in kidney transplantation

To find whether the up-regulation of soluble human leucocyte antigen-G5 (sHLA-G5) levels is a new function mechanism of anti-interleukin-2 receptors (anti-IL-2R) monoclonal antibody treatment in kidney transplantation. A total of 215 recipients at our centre from January 2006 to December 2007 were divided into antibody use group (n = 141) and antibody non-use group (n = 74) and another healthy group (n = 69). The sHLA-G5 level in peripheral blood was detected by enzyme-linked immunosorbent assay (ELISA). And the expression of HLA-G5 was confirmed by Western blot and Real-time polymerase chain reaction (PCR). sHLA-G5 levels was (56 ± 30) µg/L in using anti-IL-2 receptor monoclonal antibody before transplantation, It was higher than that before use antibody [(34 ± 20) µg/L], also higher than healthy group [(35 ± 17) µg/L] and antibody non-use group [(36 ± 19) µg/L, P < 0.05, respectively]. At Day 1, Day 4, Week 1, Week 2 post-transplantation, the level of sHLA-G5 of recipients with antibody use was significantly higher than that of those with antibody non-use. The values were as follows: (95 ± 35) µg/L vs (54 ± 16) µg/L, (131 ± 24) µg/L vs (75 ± 22) µg/L, (167 ± 44) µg/L vs (62 ± 17) µg/L, (172 ± 35) µg/L vs (45 ± 16) µg/L (all P < 0.01). And the results of Western blot and RT-PCR corresponded to those of ELISA. The preoperative use of first dose of anti-IL-2R monoclonal antibodies results in the up-regulated level of sHLA-G5. Thus it is beneficial for protecting the kidney survival and reducing the risks of acute rejection.