Hypersensitized Patients Research Articles

#3052 mTOR inhibitors in kidney transplant recipients with high immunological risk: practical insights from clinical experience

Abstract Background and Aims The use of mTOR inhibitors (mTORi) is not usually considered in high immunological risk kidney transplant recipients (KTR) for a perceived increased risk of rejection. However, in most of the studies that examined the combination of mTORi with calcineurin inhibitors (CNI), hypersensitized patients have been excluded from enrollment. The aim of the present study is to analyze our clinical experience with the use of mTORi in association with calcineurin inhibitors (CNI) in this subset of patients. Method Analysis of 212 consecutive kidney transplant recipients with a baseline calculated panel reactive antibody (cPRA) ≥50% who received a graft from June 2013 to December 2019. Immunosuppression was based on tacrolimus, steroids and, alternatively, mycophenolic acid (MPA; n = 96) or mTORi (either sirolimus or everolimus, target trough levels 3-8 ng/ml, n = 116) depending on the active Institution's protocol at the time of transplantation. The outcomes chosen included rejection-free, graft and patient survival and were analyzed by means of Cox-regression analysis. Results Demographic and immunological characteristics were similar between groups, apart from the higher number of living donors in the MPA group (42.7% vs 14.7%%, P < 0.001). Baseline cPRA was 92.5 [76-98]% for the MPA and 94 [77.25-98]% for the mTORi group, respectively (P = 0.882). Induction therapy with lymphocyte-depleting agents was employed in the majority of patients (91.7% in the MPA group and 88.8% in the mTORi group, P = 0.898). Median follow-up time was 2.6 [1.45-4.05] years. Biopsy-proven rejection (either cellular or humoral) occurred in 33.3% of the MPA and in 19.8% of the mTORi group, respectively. Cox-regression analysis of rejection-free survival revealed better rejection-free survival with mTORi versus MPA (HR [95% CI], 0.54 [0.32-0.98], P = 0.028). The only other baseline factor associated with rejection was previous transplantation (HR [95% CI] 1.96 [1.07-3.60], P = 0.030). When entered into a bivariable Cox-regression analysis, both mTORi and previous transplantation maintained a statistical significant association with rejection (mTORi versus MPA HR [95% CI] 0.53 [0.31-0.91], P = 0.023, and previous transplantation HR [95% CI] 2.01 [1.09-3.69], P = 0.024). No differences between mTORi and MPA were noted for graft (HR [95% CI] 0.90 [0.40-2.02], P = 0.807) and patient survival (HR [95% CI] 1.23 [0.60-2.50, P = 0.606). Median creatinine 1 year after transplantation was 1.45 [1.11-1.98]mg/dl for the MPA group and 1.51 [1.09-2.06]mg/dl for the mTORi group (P = 0.917). Conclusion This retrospective study suggests that hypersensitized KTRs can receive safely a maintenance immunosuppression based on a combination of CNI with mTORi, without an increased risk of rejection.

#2822 Can KDPI estimate long-term graft survival in a cohort of Portuguese patients?

Abstract Background and Aims The Kidney Donor Profile Index (KDPI) was introduced in the United States in 2014 to support clinicians' decision-making regarding the acceptance or decline of potential donors. In Portugal, there is no valid stratification score to assist physicians in accepting or declining an organ offer. Our study aims to characterize a cohort of Portuguese kidney transplant recipients and donors and evaluate the correlation between KDPI and long-term graft survival. The results are interpreted considering the nuances of the Portuguese allocation system, which favors an age-matched donor-recipient allocation. Method We conducted an observational single-center retrospective cohort study, which included patients who received a deceased donor kidney transplant at our unit between January 2013 and December 2015. We excluded patients for whom the donor KDPI index was unavailable for retrieval. Besides the KDPI index, we collected data regarding the receptor's demographic, clinical, and immunological characteristics, as well as graft and recipient survival. The primary outcome was death-censored survival, and follow-up ended on the 31st of December 2023. The secondary outcome was survival with a functioning graft. Survival estimates were obtained using Kaplan-Meier curves. We performed univariate and multivariate survival analysis with log-rank tests and Cox proportional-hazards regression models. Results We selected 364 deceased-donor kidney recipients and 212 kidney donors. The mean KDPI was 60% and 53.3% of donors were classified as expanded criteria. The kidney recipients were predominantly male (68.4%), with a mean age of 50.16 years and an average of 4 HLA mismatches. Median follow-up was 102 months. Considering recipient characteristics according to pre-defined KDPI strata (≤ 20%, 21-85%, > 85%), recipients from higher KDPI were significantly older, with a mean age of 40.6, 48.8, and 61.1 years, respectively (p < 0.001), and had a higher average body mass index (p = 0.041). There were no significant differences regarding the number of HLA mismatches (p = 0.624) or the proportion of hypersensitized patients (p = 0.253) between classes. During follow-up, 16.8% patients presented graft failure and 9.9% died with a functioning graft. Cumulative death-censored graft survival at 5, 8, and 10 years was 87.7%, 87.1%, and 84.4% respectively. The cumulative percentage of patients living with a functioning graft at 5, 8, and 10 years was 83.6%, 76.7%, and 68.6%. Death-censored graft survival was lower in recipients of donors with higher KDPI (Fig. 1), although it did not reach statistical significance (p-value = 0.166). The number of HLA mismatches (p = 0.592) or the recipient's age (p = 0.513) did not significantly impact death-censored graft survival, whereas delayed graft function (DGF) was the variable with the strongest association in univariate analysis (p < 0.001). In a multivariate Cox regression model, KDPI (HR 1.02, p = 0.005) and DGF (HR 3.2, p < 0.001) correlated with graft loss, while older recipients (HR 0.971, p = 0.019) seemed to have a protective effect over death-censored survival. Patient survival with a functioning graft was significantly associated with KDPI strata (p = 0.008; Fig. 2), the recipient's age (p = 0.006), and DGF (p < 0.001) in univariate analysis. Considering KDPI kidneys ≥ 90%, 10-year cumulative death-censored survival was 67.9%. Conclusion In our sample, despite not reaching statistical significance, there was a trend for improved death-censored graft survival in patients with lower KDPI, which further emulates the results of other European cohorts. Nevertheless, the 10-year cumulative death-censored survival of higher KDPI kidneys (≥ 90%) was remarkable, showing that long-term acceptable outcomes can be achieved. The impact of KDPI on patient survival with a functioning graft is probably overestimated, given the bias introduced by the Portuguese matching system, which rewards an “old-for-old” donor-recipient allocation.

Donación renal pareada: beneficio de este programa en la tasa de trasplantes y sobrevida del injerto.

To demonstrate the experience since the transplant program under paired kidney donation implementation; program that increases the donation rate by 25-30% in hospitals with no inferior graft survival compared to directed living donor kidney transplantation. Observational, analytical, longitudinal and prospective study from December 2018 to July 2021. All G5 KDIGO chronic kidney patients who were HLA or ABO incompatible with their original donors in the pretransplant protocol and who were transplanted under the paired kidney donation program, were included. 22 kidney transplants were performed under this program. Survival of the graft and the patient 1 year after transplantation was 100%. The post-transplant glomerular filtration rate was 72.5 ± 17 ml/min/1.73 m2 body surface. 36.3% of hypersensitized patients were successfully transplanted. The in-hospital donation rate increased by 33.33%. Transplantation under the kidney paired donation program constitutes a real modality of successful transplantation when there is incompatibility with the original donor. The greater use and socialization of this program can increase the country kidney transplantation rate, reducing the waiting list. Our hospital represents the largest experience published in Mexico with this transplant program.

316.10: Kidney Paired Donation in Latin America, From Theory To Practice

Introduction: Between 25-30% of couples will be ABO or HLA incompatible once they finish the transplant protocol. The Kidney Paired Donation (KPD) program is a modality that resolves this incompatibility by allowing donors to be exchanged. Acord to Newsletter transplant 2020, kidney transplant activity in Latin America under the KPD program is null, however there is a Guatemala case report in 2018 where they started this program and another report from 1998 in Mexico with a series of 12 transplant cases renal with exchange of donors. There has been an evolution over time of the KPD at an international level and to date computer algorithms are used based on the blood group of the donor-recipient, sensitization status and the size of the pool of incompatible couples, determining the best probability of matching success within of the program by optimizing the successful matching of donors and recipients according to the principles of fairness, utility and justice. Method: Observational, analytical, longitudinal and prospective study from December 2018 to July 2021. Were included all G5 KDIGO chronic kidney patients who were HLA or ABO incompatible with their original donors in the pretransplant protocol and who were transplanted under the program of paired kidney donation in the Central Military Hospital, Mexico, City. Results: 22 kidney transplants were performed under this program. The most common CKD etiology was not determined (ND) with 31.8%. Survival of the graft and the patient 1 year after transplantation was 100%. The post-transplant glomerular filtration rate receptor (GFR) was 72.5 (± 17) ml/min/1.73 m2SC; the GFR post-donación was 75.04 (± 15.98) ml/min/1.73/m2SC. 36.3% of hypersensitized patients were successfully transplanted whitout plasmapheresis. The mean age of the recipients was 35.67 (± 12.45) years. The waiting time from admission to the paired program to the transplant was 4.9 months.Inter-hospital donor exchanges have already been carried out; the in-hospital donation rate increased by 33.33%. Discussion: The Case reports or case series published in latinoamerica´s countries show an adequate evolution of the patients and grafts without major complications as our Hospital. Conclusion: Transplantation under the paired kidney donation program constitutes a real modality of successful transplantation when there is incompatibility with the original donor. Increased utilization and socialization of this program can increase the country kidney transplantation rate, reducing the waiting list. Our hospital represents the largest published experience in Mexico and latinamerica with this transplant program.

B Cell-Derived Extracellular Vesicles Reveal Residual B Cell Activity in Kidney Graft Recipients Undergoing Pre-Transplant Desensitization.

Background: Living-donor kidney transplant (LDKT) recipients undergoing desensitization for Human Leukocyte Antigen (HLA)-incompatibility have a high risk of developing antibody-mediated rejection (ABMR). The purpose of the study is to evaluate if residual B cell activity after desensitization could be estimated by the presence of circulating B cell-derived extracellular vesicles (BEVs).Methods: BEVs were isolated by Sepharose-based size exclusion chromatography and defined as CD19+ and HLA-II+ extracellular vesicles. We analyzed stored serum samples from positive crossmatch LDKT recipients before and after desensitization at first post-transplant biopsy and at 12-month protocol biopsy (n = 11). Control groups were formed by hypersensitized patients who were not submitted to desensitization (n = 10) and by low-risk recipients (n = 9). A prospective validation cohort of 11 patients also included the analysis of B cells subpopulations in recipients' blood and lymph nodes recovered upon graft implantation, along with BEVs analysis before and after desensitization.Results: We found out that CD19+ and HLA-II+BEVs dropped significantly after desensitization and relapse in patients who later developed ABMR was evident. We validated these findings in a proof-of-concept prospective cohort of 6 patients who received the same desensitization protocol and also in a control group of 5 LDKT recipients. In these patients, B cell subpopulations were also studied in recipients' blood and lymph nodes that were recovered before the graft implantation. We confirmed the significant drop in BEVs after desensitization and that this paralleled the reduction in CD19+cells in lymph nodes, while in peripheral blood B cells, this change was almost undetectable.Conclusions: BEVs reflected B cell residual activity after desensitization and this could be a valid surrogate of humoral alloreactivity in this setting.

Nickel Allergy of the Skin and Beyond.

Hypersensitization to nickel is one of the most common contact allergies in the modern world and it is considered to be a major cause of contact dermatitis, especially for hand eczema. The aim of this paper is to describe many faces of the nickel allergy and to find out different diagnostic, potential strategies for treatment and prevention in hypersensitized patients. A personal clinical experience with practical clinical cases of contact dermatitis to nickel has also been presented. Electronic databases on this topic was carried out using PubMed-Medline. The literature review identified many articles reporting for nickel contact allergy and pointing the metal as number one allergen in the frequency of positive skin patch test reactions in a large population worldwide. Herein, a summary of the current understanding and evidence on nickel allergy with practical approach and proposed recommendations to the dermatologist, general practitioner, and the allergist were prepared. The prevalence of nickel allergy represents an important socio-economical and health issue. Metal is one of the most common sensitizing agents worldwide. The morbidity due to this metal represents the allergic contact dermatitis and it is constantly growing in many countries. There are also cases of systemic allergic contact dermatitis, where they could be easily misdiagnosed as adverse drug reactions, which lead to delay of the correct diagnosis and inappropriate treatment.

Comparison of Single Antigen Bead–Based, Cell-Based, and Solid Phase–Based Crossmatch Methods

AimAntibody assessment during pretransplantation term is important to detect donor specific antibodies. These donor-specific antibodies are determined by various crossmatch methods (flow cytometric [FCXM], complement-dependent cytotoxic [CDCXM], and Luminex [LMXM]). Recently, single antigen bead (SAB) assays have been used for the assessment of hypersensitized patients. The aim of this study was to compare sensitivity and specificity of the 3 crossmatch methods in reference to the SAB method. MethodIn this study, 69 hypersensitized patients with high class I and/or class II panel reactive antibodies were tested using the flow cytometric SAB method. Serum samples were cross-matched by 3 crossmatch methods with the cells of a volunteer healthy individual, and the results were evaluated according to HLA and cross-reactive epitope groups (CREGs). ResultsSensitivity was found to be better with T FCXM (0.91) and class I LMXM (0.87). Specificity of peripheral blood lymphocyte CDCXM method (1.0) was found to be better than the other 2 methods (0.33 and 0.57, respectively). Sensitivity of class II LMXM (0.88) was found to be better than the others (0.42 for B CDCXM and 0.82 for B FCXM, respectively). The specificity of the B CDCXM, B FCXM, and class II LMXM was similar (0.44, 0.44, and 0.33, respectively). CREGs results were similar to HLA results. ConclusionAlthough CDCXM has high specificity for the detection of anti-HLA antibodies, it has low sensitivity. To increase sensitivity, FCXM or LMXM methods may be used with the CDCXM test. These results will be beneficial for laboratories and clinicians during graft survival and patient health assessment.

Anti-perlecan antibodies and acute humoral rejection in hypersensitized patients without forbidden HLA specificities after kidney transplantation

BackgroundThe improvement in the definition of serum anti-HLA antibodies (HLA-Abs) profiles after Luminex-assay implementation in transplant patients follow-up is clear. This success has permitted the development of hypersensitized-recipient allocation and donor-paired exchange programs improving the access to transplantation. However, non-HLA Abs have been described in transplanted patients but their effect in hypersensitized transplanted recipients is unclear. MethodsTwenty-seven HLA hypersensitized patients awaiting for kidney transplantation (KT) were studied and 11 of them were followed after KT. The HLA Abs profile was confirmed in serum by Single Antigen Luminex assay and panel reactive of antigens >98% was achieved in all patients. Subsequently, the ability to fix complement by C1q test was also assessed. Serum non-HLA Abs before and 1 month after transplantation were measured in the 11 hypersensitized recipients. Results95.2% of the hypersensitized on waiting list had concomitant serum anti-HLA and non-HLA Abs. The more frequent specificity in non-HLA Abs were found against Glutathione S-transferase theta-1 (GSST-1) (in 62%) and C-terminal fragment of perlecan (LG3) (in 52%). Four out of 11 transplanted patients presented early antibody-mediated rejection (ABMR) confirmed by biopsy and had serum anti-LG3 antibodies, two of them with concomitant anti-anti-angiotensin II type I receptor. Only one patient developed de novo-donor specific HLA antibodies. ConclusionsThe incidence of non-HLA antibodies in patients in the waiting list is largely underestimated. The concomitance anti-HLA and non-HLA Abs in hypersensitized patients is very common and the detection of non-HLA Abs in this population could allow to identify patients with an increased risk of humoral rejection.

The Spanish Prioritization System for Highly Sensitized Patients

PATHI. A prioritization kidney allocation system, based on virtual crossmatch, was implemented in Spain in June 2015 to broaden access to transplantation for patients with cPRA ≥98%. Participating centers must offer to the program one of the kidneys of every brain-death donor between 18–70 years old. The algorithm for recipient’s selection was based on blood type compatibility and negative crossmatch by using Human leukocyte Antigens class I (A, B, C) and class II (DRB1, DQB1, DQA1). Aim To evaluate the results of a National prioritization system based on virtual crossmatch in very high sensitized patients waiting for a kidney transplant after 18 months. Methods Demographic and clinical characteristics were collected from every patient included in the program between June 2015 and December 2016. The number of brain death donors assigned to the program, and patients transplanted were analyzed as well as number of kidney offered and reasons for either rejecting an offer or non-proceeding with the transplant once the kidney is accepted. Outcomes of patients transplanted between June 2015 and September 2016 were also studied. Results 786 patients with cPRA ≥98% were registered in the program. 408 (51.9%) were men and the mean age was 52.6 (12.3), median time on dialysis was 75.5 (45.7-114) months. 86.2% of patients had been previously transplanted. 879 brain death donors were assigned to the program. Virtual crossmatch was negative for 308 (35%) donors. From them, 243 kidneys were accepted and 159 transplanted (20.2% over patients included. The mean time from the registration to transplant was 158 (76–277) days. The reasons for refusal (N=163) were reasons related to the recipient (non-immunological) in 34 (36%), unacceptable antigen in 12(13%), donor pathology in 23 (24%) cases, ischemia time in 8 (9%) and age difference in 17 (18%) cases (median age difference 26 (21–35) years). After accepting the kidney, the transplant didn’t proceed in 84 cases (37% due to positive real crossmatch). Outcomes were analyzed in 125 patients. Median cold ischemia time was 19 (16–22) hours. Delayed graft function was detected in 12 (9.6%). The median follow-up time was 7.4 (4–10) months. Patient and graft survival were 93.6% and 89.7% respectively. Median Creatinine level (N=109) was1.48 (1.13-1.97) mg/dl. Conclusion The Spanish prioritization system increases transplant options for hypersensitized patients with excellent outcomes in the short term after transplantation. Non-heart beating donors or living altruistic donors could be offered to the priority allocation system to increase donor pool and transplant options.

Corrected Panel-Reactive Antibody Positivity Rates for Hypersensitized Patients in Turkish Population With Calculated Panel-Reactive Antibody Software

IntroductionHigh rates of panel-reactive antibody (PRA) may decrease the chance of kidney transplantation and may result in long waiting periods before transplantation. The calculated PRA (cPRA) is performed based on unacceptable HLA antigens. These antigens are identified by a program that was created based on the antibodies that developed against the HLA antigens circulating in serum and on the risk of binding of these antibodies to antigens. The antigen profile of the population and antigen frequencies can be measured, and more realistic cPRA positivity rates may be obtained using this method. Materials and MethodsWe developed a program based on the HLA antigens of 494 blood donors in 2 European Federation for Immunogenetics–accredited Tissue Typing Laboratories in Turkey. Next-generation sequencing–based tissue typing (HLA-A, -B, -C, -DR, -DQ, 4 digits) of the samples was performed. The PRA screening test was performed on 380 patients who were waiting for organ transplant from a cadaver in Istanbul Faculty of Medicine. The single antigen bead assay testing was performed to identify the antibody profiles on 48 hypersensitized patients. ResultsThe PRA testing results using the current methods were 44.6% ± 18.5%, and the cPRA rate was 86.2% ± 5.1%. The mean PRA positivity of the sensitized patients using the current methods was 44.6%; however, the rate was 86.2% using the cPRA. DiscussioncPRA shows the rate of the rejected donors according to all unacceptable antigens. The need for a list of unacceptable antigens in place of the PRA positivity rate is a real change in the sensitization-dependent calculation as cPRA positivity rate. ConclusionIn principal, implementation of cPRA will encourage many centers and laboratories to adopt a standard measurement of sensitization in Turkey. It will increase the chances of better donor match, particularly for hypersensitized patients, by the creation of an unacceptable mismatch program using cPRA software.

A Pilot Study of Intralymphatic Immunotherapy for House Dust Mite, Cat, and Dog Allergies.

Several recent clinical trials reported that intralymphatic immunotherapy (ILIT) for some allergens, such as cat dander and pollen, induce tolerance more rapidly than conventional subcutaneous or sublingual immunotherapy, have a comparable duration of effect after only 3 injections, and do not provoke serious local or systemic reactions. However, the efficacy and safety of ILIT are using Dermatophagoides farinae (Df), Dermatophagoides pteronyssinus (Dp), and dog, which are indoor allergens that are commonly found globally, need to be evaluated. Furthermore, use of multiple allergens in ILIT should be investigated. We assessed the clinical efficacy and adverse effects of ILIT using aqueous Df, Dp, dog, and cat allergens or mixtures thereof in patients with allergic rhinitis. A total of 11 subjects with AR sensitized to Df, Dp, cat, and/or dog allergens received 3 intralymphatic inguinal injections of sensitized allergen extract (HollisterStier, New Orleans, LA, USA). Clinical parameters were assessed before ILIT, and 4 months and 1 year after the first injection. Rhinitis symptoms were alleviated and quality of life was improved 4 months after ILIT (P=0.012 and P=0.007, respectively), and these improvements lasted for 1 year after ILIT (P=0.047 and P=0.009, respectively). However, we observed 2 cases of anaphylaxis, one case of a moderate-to-severe systemic hypersensitivity reaction and the other case of a severe local reaction at the injection site after ILIT. In conclusion, ILIT can rapidly improve allergy symptoms and quality of life, and this effect lasts for 1 year. In hypersensitized patients, however, ILIT can provoke severe systemic and/or local hypersensitivity reactions when performed using aqueous allergen extracts.

Implementation of a National Priority Allocation System for Hypersensitized Patients in Spain, Based on Virtual Crossmatch: Initial Results

Access to kidney transplantation for patients with high levels of antibodies against HLA is a major challenge. This issue makes it difficult to detect compatible donors for those patients in a certain geographical area. Consequently, hypersensitized patients remain on the waiting list for long periods and their quality of life deteriorates. Our purpose was to increase access to transplantation for highly sensitized patients by developing a national priority allocation system based on virtual crossmatch. Between June 15, 2015, and May 15, 2016, 675 patients on the kidney transplant waiting list with calculated panel-reactive antibodies ≥98% and undergoing dialysis for at least 12 months were included in the study; 86.1% of the patients had previously received at least one transplant. Solid-phase immunoassays were used to identify class I and II HLA antibodies in all patients. Participating hospitals assigned to the program one of the kidneys of every identified brain-dead real donor between 18 and 70 years old. Survival data were collected for the recipients transplanted between June 15, 2015, and December 31, 2015. In all, 475 (290 male and 185 female) brain-dead donors were assigned to the program. Virtual crossmatch was negative for 191 (41%) donors, 149 offers were accepted, and 102 (21.8%) kidneys were transplanted. At the end of the study, patient and graft survival were both 93.4%. The implementation of a national prioritization system based on virtual crossmatch increased access to transplantation for highly sensitized patients, with excellent results in terms of patient and graft survival.

Low transplantability of 0 blood group and highly sensitized candidates in the Portuguese kidney allocation algorithm: quantifying an old problem in search of new solutions.

The impact of patient's biological differences in waiting time for kidney transplantation is well known and has been a subject of extensive debate and struggle in transplantation community. Our purpose was to evaluate patient's access to kidney transplantation in Portugal, regarding their degree of allosensitization and blood type. A retrospective cohort study including 1020 candidates for kidney transplantation between 01 January 2010 and 31 December 2011 in transplant unit Centro Hospitalar do Porto was performed. The deceased donor organ offer by blood type decreased with the calculated panel reactive antibody (cPRA) increase for A and B blood groups candidates, while in 0 blood group candidates, a significant reduction in organ offer was only observable in hypersensitized (HS) ones. As a consequence, the median waiting time was also significantly higher in 0 blood group patients, when compared to the remaining groups. However, waiting time increased extensively with cPRA regardless blood type, especially HS patients with increases of 368%, 632%, 486%, and 140% for blood groups A, B, AB, and 0, respectively, when compared to each blood group global median waiting time. Our study shows that important measures need to be undertaken in order to mitigate the huge disadvantage that HS and 0 blood type patients naturally have.

Single antigen flow beads for identification of human leukocyte antigen antibody specificities in hypersensitized patients with chronic renal failure

Aims of this studyAims of this study were to identify class I and class II antibodies in highly sensitized patients by flow cytometry single antigen bead (FC-SAB) assay and to evaluate according to donor HLA type in order to increase their kidney transplantation chance.Material and methodsWe analyzed 60 hypersensitive patients of 351 individuals, who applied to our laboratory for PRA test in November 2013-December 2014. Flow cytometric PRA screening and single antigen bead commercial kits were used for these analyses.ResultsIn our study group, 19 (31.7%) of these patients were male while 41 (68.3%) patients were female. The most common acceptable antigens were A*02 (10.11%), HLA-A*23 (10.11%), HLA-B*38 (8.79%) and HLA-DRB1*03 (7.83%) in hypersensitive patients. The highest antibody reactivity on SAB was observed against HLA-A*25, HLA-B*45, HLA-DRB1*04 and HLA-DRB1*08 antigens.ConclusionsThe determination of these acceptable and unacceptable antigens may increase their transplantation chance. Pre-transplant HLA antibody identifications provide prognostic information with respect to the determination of patients who are at increased risk of graft loss.

Pre-clinical heterotopic intrathoracic heart xenotransplantation: a possibly useful clinical technique.

As a step towards clinical cardiac xenotransplantation, our experimental heterotopic intrathoracic xenotransplantation model offers a beating and ejecting donor heart while retaining the recipient's native organ as a backup in case of graft failure. Clinically applicable immunosuppressive regimens (IS) were investigated first, then treatments known to be effective in hypersensitized patients or those with recalcitrant rejection reactions. Consecutive experiments were carried out between 2009 and 2013. Twenty-one genetically modified pigs (GGTA1-knockout/hCD46/± thrombomodulin, in one case HLA-E instead) were used as donors. In all experiments, two cycles of immunoabsorption reduced preformed antibodies. Recipient baboons were divided into two groups according to IS regimen: In group one (n = 10), pre-treatment started either one (anti-CD20) or four weeks (anti-CD20 plus the proteasome inhibitor bortezomib) prior to transplantation. The extended conventional (as for allotransplantation) immunosuppressive maintenance regimen included anti-thymocyte globuline, tacrolimus, mycophenolate mofetil, methylprednisolone and weekly anti-CD20. In group two (n = 11), myeloablative pre-treatment as in multiple myeloma patients (long and short regimens) was added to extended conventional IS; postoperative total thoracic and abdominal lymphoid irradiation (TLI; single dose of 600 cGY) was used to further reduce antibody-producing cells. In the perioperative course, the surgical technique was safely applied: 19 baboons were weaned off extracorporeal circulation and 17 extubated. Nine animals were lost in the early postoperative course due to causes unrelated to surgical technique or IS regimen. Excluding these early failures, median graft survival times of group 1 and 2 were 18.5 (12-50) days and 16 (7-35) days. Necropsy examination of group 1 donor organs revealed hypertrophy of the left ventricular wall in the six longer-lasting grafts; myocardial histology confirmed pre-clinical suspicion of humoral rejection, which was not inhibited by the extended conventional IS including intensified treatments, and signs of thrombotic microangiopathy. Grafts of group 2 presented with only mild-to-moderate features of humoral rejection and thrombotic microangiopathy, except in one case of delayed rejection on day 17. The other experiments in this group were terminated because of untreatable pulmonary oedema, recurring ventricular fibrillation, Aspergillus sepsis, as well as a combination of a large donor organ and late toxic side effects due to TLI. Longer-term results were difficult to achieve in this model due to the IS regimens used. However, we conclude that heterotopic intrathoracic heart transplantation may be an option for clinical xenotransplantation.

A successful desensitization protocol for horse-derived antithymocyte globulin in severe aplastic anemia.

Horse antithymocyte globulin (h-ATG) (ATGAM(®) ) is the first choice of treatment in very severe patients with aplastic anemia who do not have any HLA matched sibling donor. h-ATG is a heterologous serum that may cause anaphylaxis. Alternative treatment strategies must be planned in case of hypersensitivity. Desensitization must be considered in patients without an alternative treatment of choice. We aimed to present the h-ATG desensitization protocol and consider its effectiveness in patients with aplastic anemia who are hypersensitized with h-ATG and do not have an alternative treatment of choice. Skin prick tests were performed with non-diluted solution in eight very severe patients with aplastic anemia who are followed up in Ege University Children's Hospital. Although skin prick test was found negative in these eight patients, different dilution h-ATG intradermal tests were performed and found positive in all patients. h-ATG desensitization program was started to these hypersensitized patients. Desensitization program was started to six male and two female very severe patients with aplastic anemia whose ages were between seven and 19yr (median: 12.9yr). All of the patients completed the desensitization program. While local reaction was seen in two patients, systemic reaction was seen in one patient and late reaction was seen in one patient during and after desensitization program. A successful desensitization program with h-ATG in children with aplastic anemia is presented. Even though there is not an exposure before to such high allergy potential heterologous serum, skin tests should be performed and desensitization must be started to patients who are hypersensitized to h-ATG. As the expected effectiveness of the treatment is so much, the desensitization protocol can be carried out safely and effectively with trained stuff although allergic reactions can be seen.

Is It Appropriate to Implant Kidneys From Elderly Donors in Young Recipients?

Kidneys from elderly donors tend to be implanted in recipients who are also elderly. We present the results obtained after 10 years of evolution on transplanting elderly kidneys into young recipients. Ninety-one consecutive transplants are studied, carried out in our center with kidneys from cadaver donors older than 60 years implanted in recipients younger than 60 years. The control group is made up of 91 transplants, matched with those from the study group, whose donor and recipient were younger than 60 years. There were no differences between groups with regard to recipient age, sex, cause of death and renal function of the donor, hepatitis C and cytomegalovirus serologies, cold ischemia time, tubular necrosis, immediate diuresis, need for dialysis, human leukocyte antigen incompatibilities, hypersensitized patients, acute rejection, waiting time on dialysis, and days of admission. Survival in both groups at 1, 5, and 10 years was 97.6%, 87.2%, and 76.6% vs. 98.8%, 87.5%, and 69.5% for the patient (P=0.642), 92.9%, 81.3%, and 64.2% vs. 93.9%, 76.4%, and 69.5% for the graft (P=0.980), and 94.4%, 92.6%, and 77.4% vs. 94.3%, 86.7%, and 84.4% for the graft with death censured (P=0.747), respectively. Creatininaemias at 1, 5, and 10 years were 172, 175, and 210 vs. 139, 134, and 155 (P<0.05). We conclude that patient and graft survival on transplanting kidneys from elderly donors to young recipients is superimposable on that obtained with young donors. However, renal function is better in the group of young donors.

Induction Immunosuppressive Therapy in Renal Transplantation: Does Basiliximab Make the Difference?

The optimal prophylactic induction immunosuppressive therapy to prevent renal transplant rejection remains controversial. Recently, basiliximab efficiency has been reported in several studies. We sought to evaluate the efficiency of induction immunosuppressive therapy with basiliximab in renal transplantation in our unit based upon the acute rejection rate, patient and graft survivals, first hospital admission length, and incidence of infectious or malignant complications during 4 years of follow-up. We retrospectively evaluated the outcome of two groups of renal transplant recipients treated with triple immunosuppressive therapy (cyclosporine, mycophenolate mofetil, and prednisolone) without (group 1, 149 patients) or with (group 2, 104 patients) induction immunosuppression with basiliximab. The two groups did not differ in demographic characteristics, number of hypersensitized patients, cold ischemia time, or donor age. The group receiving basiliximab displayed a significantly lower acute rejection rate (7.6% vs 24%, P = .001) and shorter first hospital admission (14.4 ± 8 vs 19.5 ± 11 days). There was no difference in graft or patient survival, death due to sepsis, or incidence of posttransplant malignancies. Although there was no difference in graft or patient survival, immunosuppressive induction therapy with basiliximab yielded a significant reduction in the acute rejection rate.

Effect of Delayed Graft Function in Hypersensitized Kidney Transplant Recipients

There is increased evidence about the deleterious effect of delayed graft function (DGF) in both short- and long-term kidney graft outcome. Among the mechanisms involved in the production of DGF, immune factors play a role, especially in the level of hypersensitization. From the 1389 patients transplanted at our hospital until November 2004, it has been found that the presence of moderate and high levels of sensitization, as measured by panel-reactive antibodies, is a risk factor for suffering from DGF. Further, DGF was associated with poor graft survival, and the risk was even higher when DGF was combined with moderate/high panel-reactive antibodies. Recent data demonstrate the usefulness of intravenous immunoglobulins in the management of hypersensitized patients in terms of short-term outcome. It remains to be demonstrated whether this therapy is able to ameliorate the higher ischemic injury that kidneys undergo from these immunologically high-risk patients.

HLA-DR2, a marker for class I antigen sensitization.

After analysis of 423 hemodialysis patients in a transfusion program and 461 cadaver-donor renal transplants, we found that HLA-DR2 frequency was significantly higher in the responder (36%) than in the nonresponder patient group (19%), according to the percentage of PRA (panel reactive antibodies). Among DR2+ patients, the percentage of hypersensitized patients was twice that of DR2- patients. Graft survival curves in cadaver-donor renal transplants indicated a significantly lower survival when recipients were DR2+, even in recipient-donor pairs identical for class II antigens but mismatched for class I antigens. The prognostic probability of low response to transfusions by a stepwise logistic regression analysis showed the influence of sex and DR2 phenotype. By multivariant discriminant analysis, we found that the DR2 phenotype was one of the most influential transfusion sensitization risk factors. Our preliminary conclusion is that DR2 can be related to immune responsiveness to class I antigens.