Reversal Of Rejection Research Articles

Clinical profile and outcomes of rejection after deep anterior lamellar keratoplasty in keratoconus.

To report the clinical features and management outcomes of rejection after deep anterior lamellar keratoplasty (DALK). The clinical features, indications, predisposing risk factors, management, and outcome of six eyes of six patients with rejection after DALK were analyzed retrospectively. The median time of rejection from the day of surgery was 12 (range 3-36) months. Median duration of symptoms was 4 (range 2-28) days. The indication for DALK was keratoconus in all eyes. The clinical features at presentation included graft haze, vascularization, and melt at the graft-host junction. The risk factors noted were noncompliance to steroids in all eyes, vernal conjunctivitis (four eyes), and eccentric graft (one eye). The rejection episode reversed with topical steroids in all eyes and intravenous methylprednisolone in one eye. One eye developed secondary fungal keratitis after initial recovery and one eye had a second episode of rejection 3 months later, which resulted in progressive vessels and lipid keratopathy in the visual axis. The median best corrected visual acuity was 20/40 (range 20/30-20/200). Severe stromal rejection can present with graft melt. Repeat episodes of rejection can occur on sudden cessation of topical steroids. Prompt recognition of clinical signs and symptoms with timely management helps in quick reversal of the rejection episode. Reversal of graft rejection results in good visual outcomes.

Low Fouling Polyelectrolyte Layer-by-Layer Self-Assembled Membrane for High Performance Dye/Salt Fractionation: Sequence Effect of Self-Assembly.

Layer-by-layer (LbL) self-assembly of oppositely charged polyelectrolytes (PEs) is usually performed on a conventional ultrafiltration base substrate (negative zeta potential) by depositing a cationic PE as a first layer. Herein, we report the facile and fast formation of high performance molecular selective membrane by the nonelectrostatic adsorption of anionic PE on the polyvinylidene fluoride (PVDF, zeta potential -17 mV) substrate followed by the electrostatic LbL assembly. Loose nanofiltration membranes have been prepared via both concentration-polarization (CP-LbL, under applied pressure) driven and conventional (C-LbL, dipping) LbL self-assembly. When the first layer is poly(styrene sodium) sulfonic acid, the LbL assembled membrane contains free -SO3- groups and exhibits higher rejection of Na2SO4 and lower rejection of MgCl2. The reversal of salt rejection occurs when the first layer is quaternized polyvinyl imidazole (PVIm-Me). The membrane (five layers) prepared by first depositing PStSO3Na shows higher rejection of several dyes (97.9 to >99.9%), higher NaCl to dye separation factor (52-1800), and higher dye antifouling performance as compared to the membrane prepared by first depositing PVIm-Me (97.5-99.5% dye rejection, separation factor ∼40-200). However, the C-LbL membrane requires a longer time of self-assembly or higher PE concentration to reach a performance close to the CP-LbL membranes. The membranes exhibit excellent pressure, pH (3-12), and salt (60 g L-1) stability. This work provides an insight for the construction of low fouling and high-performance membranes for the fractionation of dye and salt based on the LbL self-assembly sequence.

#4610 LACK OF EFFICACY AND SAFETY OF ECULIZUMAB FOR TREATMENT OF ANTIBODY-MEDIATED REJECTION FOLLOWING RENAL TRANSPLANTATION

Abstract Background and Aims We evaluated the efficacy and safety of eculizumab in comparison with plasmapheresis and intravenous immunoglobulin therapy in renal transplant recipients diagnosed with antibody-mediated rejection (AMR). Method This was a multicenter, open-label, prospective, randomized analysis. The patients were randomized by therapy type (eg, eculizumab infusions or standard of care [SOC]: plasmapheresis/intravenous immunoglobulin). The patients (ie, eculizumab arm: 7 patients, SOC arm: 4 patients) were evaluated for the continued presence of donor-specific antibodies (DSAs) and C4d (staining on biopsy), as well as histologic evidence, using repeat renal biopsy after treatment. Results The allograft biopsies revealed that eculizumab did not prevent the progression to transplant glomerulopathy. Cases of AMR were diagnosed in the early post-transplantation period in 2 patients (eculizumab arm: 1 patient, SOC arm: 1 patient) and in the late period in 9 patients. Most of the reports show that eculizumab, in combination with other therapeutic measures such as PP and/or IVIG, effectively reversed rejection. However, eculizumab alone could not treat AMR effectively. Only 2 patients in the SOC arm experienced rejection reversal, and no graft losses occurred in either group. After AMR treatment, the DSA titers generally decreased compared to titers taken at the time of AMR diagnosis. There were no serious adverse effects in the eculizumab arm. Conclusion Eculizumab alone cannot treat AMR effectively and does not prevent acute AMR from progressing to chronic AMR or transplant glomerulopathy. However, it should be considered as a potential alternative therapy because it may be associated with decreased DSA levels.

Extracorporeal photopheresis in the treatment of cardiac allograft rejection: A single-centre experience

Despite novel immunosuppressive (IS) protocols, adverse effects of IS drugs continue to have notable negative impact on patient and cardiac allograft survival after heart transplantation (HTx). Therefore, IS regimens with less toxic side effects are sorely needed. We aimed to evaluate the efficacy of extracorporeal photopheresis (ECP) in combination with tacrolimus-based maintenance IS therapy in the treatment of allograft rejection in adult HTx recipients. Indications for ECP included acute moderate-to-severe or persistent mild cellular rejection, or mixed rejection. Twenty-two patients underwent a median of 22(2–44) ECP treatments after HTx. Median duration of ECP course was 173.5(2–466) days. No relevant adverse effects of ECP were noted. Reduction of methylprednisolone doses was safe throughout the ECP course. ECP, used in conjunction with pharmacological anti-rejection therapy, had a successful reversal of cardiac allograft rejection, decreased the rates of subsequential rejection episodes and normalized the allograft function in patients completing the ECP course. Short- and long-term survivals were excellent (91% at 1 and 5 years post-ECP) and comparable to International Society for Heart and Lung Transplantation registry data on HTx recipient overall survival. In conclusion, ECP can be safely used for the treatment and prevention of cardiac allograft rejection in conjunction with traditional IS regimen.

Impact of pandemic COVID-19 lockdown on penetrating keratoplasty patients.

To study the impact of the COVID-19 lockdown on the regular follow-up of keratoplasty patients. This retrospective interventional case series included 30 patients who had immunological corneal endothelial rejection out of 190 patients who came for post-PKP follow-up between September 15, 2019, and September 30, 2020. The demographics, primary diagnosis, surgical technique, time of presentation, recovery of graft, associated ocular problems, and visual acuity at 1 month were analyzed. Forward stepwise (likelihood ratio) binary logistic regression was used to find significant variables. The study population had 19 males (63.33%) and 11 females (36.67%). The mean age of the study group was 42.83 ± 18.89 (8-80) years. Of 30 patients, 19 (63.3%) presented before and 11 (36.7%) after the COVID-19 lockdown. Overall, 23 (77%) showed a reversal of graft rejection. Logistic regression showed that preoperative indications, large-sized grafts, and deep corneal vascularization were significant risk factors for non-resolution of graft rejection. It was noted that patients who presented to the hospital late had poor recovery (P = 0.002). The delay in the presentation was a significant risk factor for non-resolution of graft rejection (P < 0.01). Z-test for proportions revealed that the difference in the non-resolution of rejection on immediate or delayed treatment in patients presenting during lockdown (P = 0.002) was significant. This article is to highlight the impact of the COVID-19 lockdown on graft rejection recovery of PKP patients due to delays in follow-up. Early treatment helps in the recovery of graft transparency and the reversal of immunological graft rejection. Also, primary diagnosis, deep vascularization, and large-sized grafts were significant risk factors for non-resolution of graft rejection.

Lack of Efficacy and Safety of Eculizumab for Treatment of Antibody-Mediated Rejection Following Renal Transplantation

We evaluated the efficacy and safety of eculizumab in comparison with plasmapheresis and intravenous immunoglobulin therapy in renal transplant recipients diagnosed with antibody-mediated rejection (AMR). This was a multicenter, open-label, prospective, randomized analysis. The patients were randomized by therapy type (eg, eculizumab infusions or standard of care [SOC]: plasmapheresis/intravenous immunoglobulin). The patients (ie, eculizumab arm: 7 patients, SOC arm: 4 patients) were evaluated for the continued presence of donor-specific antibodies (DSAs) and C4d (staining on biopsy), as well as histologic evidence, using repeat renal biopsy after treatment. The allograft biopsies revealed that eculizumab did not prevent the progression to transplant glomerulopathy. Only 2 patients in the SOC arm experienced rejection reversal, and no graft losses occurred in either group. After AMR treatment, the DSA titers generally decreased compared to titers taken at the time of AMR diagnosis. There were no serious adverse effects in the eculizumab arm. Eculizumab alone cannot treat AMR effectively and does not prevent acute AMR from progressing to chronic AMR or transplant glomerulopathy. However, it should be considered as a potential alternative therapy because it may be associated with decreased DSA levels.

Role of PD-L1 in heart transplant rejection

Abstract Background Acute cellular rejection remains a major cause of morbidity after heart transplantation with up to 30% of patients experiencing at least one rejection episode during the first year. Unfortunately, the mechanism underling rejection remains poorly understood and the gold standard for diagnosing rejection remains frequent cardiac biopsy for rejection surveillance – a process that is both invasive and costly. Purpose PD-L1 is a co-inhibitory transmembrane protein that interacts with PD-1 on T cells to inhibit T cell activation. Endothelial PD-L1 expression in the heart has been shown in mouse models to play a key role in attenuating immune-mediated cardiac disease like myocarditis. Recent data that anti-PD-1 and anti-PD-L1 therapy can lead to myocarditis further supports a role for PD-1/PD-L1 signaling in cardiovascular homeostasis. We hypothesize that PD-L1 expression correlates with rejection severity. Methods Endomyocardial biopsy from a cohort of 19 heart transplant patients were analyzed for PD-L1 expression using immunohistochemistry and image analysis with HALO software. Each patient had biopsies corresponding to 0R, 1R, and 2R grades of rejection (n=57) and thus each patient served as their own internal control. Detailed clinical data was also collected on these patients from the electronic medical record. Results Average PD-L1 levels associated with 0R (n=19), 1R (n=21), and 2R (n=17) rejection were 1.54, 9.15, and 18.90 respectively (P&amp;lt;0.001). In patients who were treated for 2R rejection with increased immunosuppression (n=9), PD-L1 levels decreased from an average of 21.72 before treatment to an average of 5.64 after treatment (P&amp;lt;0.05). A multiple regression was run to see if PD-L1 level was associated with right heart pressures, EKG intervals, echo data, or common lab values. Accounting for age, race, and sex, it was found that PD-L1 was significantly associated with PA pressure (P&amp;lt;0.01, beta = 0.45), PCW pressure (P&amp;lt;0.01, beta = 0.42), and BNP (P&amp;lt;0.01, beta = 0.55). Conclusions Upregulation of PD-L1 in the heart is strongly associated with severity of cellular rejection after heart transplantation. Successful treatment of rejection with immunosuppression decreases PD-L1 levels. These data suggest that PD-L1 is a potential biomarker for heart transplant rejection. Further correlation of PD-L1 levels with signs of right heart strain (increased PA and PCW pressure) and systolic dysfunction (BNP) supports a clinical picture of PD-L1 as a useful biomarker for detecting both cellular rejection and reversal of rejection after treatment. Cohort identification and results Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health grants R56 HL141466 and R01 HL141466

Outcome of Recipient Surgery and 6-Month Follow-Up of the Swedish Live Donor Robotic Uterus Transplantation Trial.

Uterus transplantation has proved to be a feasible treatment for uterine factor infertility. Herein, we report on recipient outcome in the robotic uterus transplantation trial of 2017–2019. The eight recipients had congenital uterine aplasia. The donors were six mothers, one sister, and one family friend. Donor surgery was by robotic-assisted laparoscopy. Recipient surgery was by laparotomy and vascular anastomoses to the external iliacs. The duration (median (ranges)) of recipient surgery, blood loss, measured (left/right) uterine artery blood flow after reperfusion, and length of hospital stay were 5.15 h (4.5–6.6), 300 mL (150–600), 43.5 mL/min (20–125)/37.5 mL/min (10–98), and 6 days (5–9), respectively. Postoperative uterine perfusion evaluated by color Doppler showed open anastomoses but restricted blood distribution in two cases. Repeated cervical biopsies in these two cases initially showed ischemia and, later, necrosis. Endometrial growth was not seen, and hysterectomy was later performed, with pathology showing partly viable myometrium and fibrosis but necrosis towards the cavity. The other six patients acquired regular menstrual cyclicity. Surgery was performed in two patients to correct vaginal stenosis. Reversible rejection episodes were seen in two patients. In conclusion, the rate of viable uterine grafts during the initial 6-months of the present study (75%) leaves room for improvement in the inclusion/exclusion criteria of donors and in surgical techniques. Initial low blood flow may indicate subsequent graft failure.

P1755EFFICACY AND SAFETY ECULIZUMAB FOR THE TREATMENT OF ANTIBODY MEDIATED REJECTION FOLLOWING RENAL TRANSPLANTATION

Abstract Background and Aims : We evaluated the efficacy and safety of eculizumab in comparison with plasmapheresis (PP) and intravenous immunoglobulin (IVIG) therapy in renal transplant recipients diagnosed with antibody-mediated rejection (AMR). Methods This was a multi-center, open-label, prospective, randomized analysis. The patients were randomized as to therapy type (eculizumab infusions or standard of care, SOC: PP/IVIG). The patients (eculizumab arm: 7 patients, SOC arm: 4 patient) were evaluated for the continuing presence of donor-specific antibodies (DSAs) and C4d (staining on biopsy), as well as histological evidence, using repeat renal biopsies after treatment. Results The allograft biopsies revealed that eculizumab did not prevent the progression to transplant glomerulopathy. Only 2 patients in the SOC arm experienced rejection reversal, and no graft losses occurred in either group. Following AMR treatment, the DSA titers generally decreased compared to titers taken at the time of AMR diagnosis. There were no serious adverse effects in the eculizumab arm. Conclusion Eculizumab alone is not sufficient to treat AMR and does not prevent acute AMR from progressing to chronic AMR or to transplant glomerulopathy. However, it should be considered as a potential alternative therapy because it may be associated with decreased DSA levels.

MENAHAN ATAU MENEKAN KEKEBALAN (IMUNOSUPRESI) UNTUK PENCANGKOKAN GINJAL (Bagian II)

Renal transplantation is the treatment of choice for most patients with end stage renal disease. Most of the time, transplantationrejection is immunological mediated. Both T cells and circulating antibodies are induced against allograft. Successful organtransplantation requires the use of immunosuppressive drugs to prevent the host's immune system from rejecting the transplanted organ.The development of immunosuppressive drugs is the key to successful allograft function Immunosuppressive agents are used for induction(intense immunosuppressant in the initial days after transplantation), maintenance and reversal of established rejection. This reviewfocuses on agents that are either approved or in phase 2 or phase 3 trials in kidney transplantation.

IMUNOSUPRESI UNTUK PENCANGKOKAN GINJAL (Bagian I)

Renal transplantation is the treatment of choice for most patients with end stage renal disease. Most of the time, transplantationrejection is immunological mediated. Both T cells and circulating antibodies are induced against allograft. Successful organtransplantation requires the use of immunosuppressive drugs to prevent the host's immune system from rejecting the transplanted organ.The development of immunosuppressive drugs is the key to successful allograft function Immunosuppressive agents are used for induction(intense immunosuppressant in the initial days after transplantation), maintenance and reversal of established rejection. This reviewfocuses on agents that are either approved or in phase 2 or phase 3 trials in kidney transplantation.

Topical Tacrolimus as Adjuvant Therapy to Corticosteroids in Acute Endothelial Graft Rejection After Penetrating Keratoplasty: A Randomized Controlled Trial.

To evaluate the efficacy of topical tacrolimus 0.05% as adjuvant therapy to corticosteroids in the treatment of acute endothelial rejection of a penetrating keratoplasty (PKP) graft. Patients with the clinical diagnosis of acute endothelial rejection of a PKP graft were randomized into 2 groups-group 1: receiving topical tacrolimus 0.05% as adjuvant therapy to corticosteroid treatment and group 2: receiving only corticosteroid treatment. Main outcome measures were rejection reversal, time to rejection reversal, and recurrence of rejection. Thirty-one eyes of 31 patients (17 and 14 eyes in group 1 and 2, respectively) were included in the study. The rejection episode completely resolved in 88.2% of patients in group 1 and 85.7% of patients in group 2 [hazard ratio = 0.60, 95% confidence interval (CI) = 0.28-1.29, P = 0.191]. After adjusting for preoperative factors using the inverse-probability weighting method, the time to resolution of rejection was significantly shorter in group 1 than group 2 (average treatment effect = 16, 95% CI, 3.7-28.7, P = 0.013). The recurrence rate of rejection was significantly higher in group 2 (39.7, 95% CI, 12.8-92.6 per 1000 months of follow-up) than in group 1 (3.6, 95% CI, 0.05-19.9 likewise); risk ratio: 11.1, 95% CI, 1.3-95.0, P = 0.028. Topical tacrolimus 0.05% as an adjunct to steroids can hasten the resolution of endothelial rejection of a PKP graft and potentially decreases the recurrence of rejection. However, it may not improve rejection reversal success.

Tacrolimus Eye Drops as Adjunct Therapy in Severe Corneal Endothelial Rejection Refractory to Corticosteroids.

To evaluate the safety and efficacy of tacrolimus eye drops as adjunctive therapy in the treatment of severe corneal endothelial rejection after penetrating keratoplasty refractory to corticosteroids. In this prospective interventional case series, 11 eyes of 11 patients assessed for severe corneal endothelial rejection, with an inadequate response to topical, local, and systemic corticosteroids, were treated with either 0.01% or 0.05% tacrolimus eye drops 4 times daily. Improvement in signs of rejection, visual function, and development of complications were monitored. The duration of steroid treatment before intervention was 8.1 ± 1.4 days (range = 7-11). Patients were subsequently administered topical tacrolimus 0.01% or 0.05% qid. The time to clinical improvement was 10.3 ± 3.4 days (range = 3-17). The time to rejection reversal was 27.8 ± 16.3 days (range = 7-52). After 3 months, 10 patients (90.8%) demonstrated clinical improvement, and complete restoration of graft clarity was achieved in 5 patients (45.4%). In responsive cases, steroid therapy was successfully tapered off after 60.2 ± 19.7 days (range = 36-93). The best spectacle-corrected visual acuity improved from 1.7 ± 0.9 to 0.8 ± 0.5 logMAR (P = 0.0016). Reported side effects included stinging on drop instillation and punctate epithelial keratopathy. Tacrolimus eye drops may be able to play an adjunctive therapeutic role in patients with severe corneal endothelial rejection refractory to conventional steroid treatment. Controlled studies are needed to further investigate the role of tacrolimus in this setting.

Polyclonal and monoclonal antibodies for treating acute rejection episodes in kidney transplant recipients.

Registry data shows that between 15-35% kidney recipients will undergo treatment for at least one episode of acute rejection within the first post transplant year. Treatment options include pulsed steroid therapy, the use of an antibody preparation, the alteration of background immunosuppression, or combinations of these options. In 2002, in the US, 61.4% patients with an acute rejection episode received steroids, 20.4% received an antibody preparation and 18.2% received both.To determine the benefits and harms of mono- or polyclonal antibodies (Ab) used to treat acute rejection in kidney transplant recipients.We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (in The Cochrane Library, issue 2, 2005), MEDLINE (1966-June 2005), EMBASE (1980-June 2005), and the specialised register of the Cochrane Renal Group (June 2005).Randomised controlled trials (RCTs) in all languages comparing all mono- and polyclonal antibody preparations, given in combination with any other immunosuppressive agents, for the treatment of acute graft rejection, when compared to any other treatment for acute rejection.Two reviewers independently assessed trials for eligibility and quality, and extracted data. Results are expressed as relative risk (RR) with 95% confidence intervals (CI).Twenty one trials (49 reports, 1387 patients) were identified. Trials were generally small, incompletely reported, especially for potential harms, and did not define outcome measures adequately. Fourteen trials (965 patients) compared therapies for first rejection episodes. Ab was better than steroid in reversing rejection (RR 0.57, 95% CI 0.38 to 0.87) and preventing graft loss (death censored RR 0.74, CI 0.58 to 0.95) but there was no difference in preventing subsequent rejection or death at one year. Seven trials (422 patients) investigated Ab treatment of steroid-resistant rejection. There was no benefit of muromonab-CD3 over ATG or ALG in either reversing rejection, preventing subsequent rejection, preventing graft loss or death.In reversing first rejection, any antibody is better than steroid and also prevents graft loss, but subsequent rejection and patient survival are not significantly different. In reversing steroid-resistant rejection the effects of different antibodies are also not significantly different. Given the clinical problem caused by acute rejection, data are very sparse, and clinically important differences in outcomes between widely used interventions have not been excluded. Standardised reproducible outcome criteria are needed.

Donor Endothelial Cell Count Does Not Correlate With Descemet Stripping Automated Endothelial Keratoplasty Transplant Survival After 2 Years of Follow-up

To analyze the influence of low endothelial cell density (ECD) of donor cornea tissue, donor age, and sex on the transplant survival rate after Descemet stripping automated endothelial keratoplasty (DSAEK). Graft ECD, age, and sex of donors used for DSAEK (n = 1789) during 7 years (2007-2014) in 4 Scandinavian hospitals were assessed for potential association with transplant survival at 2 years of follow-up using a Cox regression model correcting for confounding factors. The data were obtained from The Swedish Cornea Transplant Registry. Transplant failure occurred in 196 patients, with 69 early failures during the first 3 postoperative months, and 127 late secondary failures. Twenty-five of the late secondary failures were due to rejection. Reversible rejections occurred in 67 patients. There was no significant impact of donor age [hazard ratio (HR) 1.0, 95% confidence interval (CI), 0.99-1.02, P = 0.32] or endothelial cell count (HR 1.00, 95% CI, 0.99-1.01, P = 0.3) on the survival rate of DSAEK transplants at 2 years of follow-up. The use of donor grafts with low ECD (<2300 cells/mm) did not influence the survival rate (HR 1.3, 95% CI, 0.76-2.35, P = 0.31). Male donor sex was associated with lower 2-year graft survival (HR 1.5, 95% CI, 1.04-2.28, P = 0.03), but not with rejection events (P = 0.26). Based on data from The Swedish Cornea Transplant Registry, low donor ECD was not detrimental to graft survival, whereas donor sex seemed to influence the outcome at the end of the 2-year follow-up.

Bortezomib in the treatment of antibody-mediated rejection in pediatric kidney transplant recipients: A multicenter Midwest Pediatric Nephrology Consortium study.

Antibody-mediated rejection leads to allograft loss after kidney transplantation. Bortezomib has been used in adults for the reversal of antibody-mediated rejection; however, pediatric data are limited. This retrospective study was conducted in collaboration with the Midwest Pediatric Nephrology Consortium. Pediatric kidney transplant recipients who received bortezomib for biopsy-proven antibody-mediated rejection between 2008 and 2015 were included. The objective was to characterize the use of bortezomib in pediatric kidney transplant recipients. Thirty-three patients received bortezomib for antibody-mediated rejection at nine pediatric kidney transplant centers. Ninety percent of patients received intravenous immunoglobulin, 78% received plasmapheresis, and 78% received rituximab. After a median follow-up of 15months, 65% of patients had a functioning graft. The estimated glomerular filtration rate improved or stabilized in 61% and 36% of patients at 3 and 12months post-bortezomib, respectively. The estimated glomerular filtration rate at diagnosis significantly predicted estimated glomerular filtration rate at 12months after adjusting for chronic histologic changes (P .001). Fifty-six percent of patients showed an at least 25% reduction in the mean fluorescence intensity of the immune-dominant donor-specific antibody, 1-3months after the first dose of bortezomib. Non-life-threatening side effects were documented in 21 of 33 patients. Pediatric kidney transplant recipients tolerated bortezomib without life-threatening side effects. Bortezomib may stabilize estimated glomerular filtration rate for 3-6months in pediatric kidney transplant recipients with antibody-mediated rejection.

The impact of donor age and endothelial cell density on graft survival following penetrating keratoplasty

PurposeTo determine if donor age and preoperative endothelial cell density (ECD) affect corneal endothelial failure following penetrating keratoplasty (PK).MethodsPreoperative and postoperative data for PKs performed in the UK between April...

Th-17 Alloimmune Responses in Renal Allograft Biopsies From Recipients of Kidney Transplants Using Extended Criteria Donors During Acute T Cell–Mediated Rejection

Although renal transplantation using expanded criteria donors has become a common practice, immune responses related to immunosenescence in those kidney allografts have not been studied yet in humans. We performed a retrospective molecular analysis of the T cell immune response in 43 kidney biopsies from patients with acute T cell-mediated rejection including 25 from recipients engrafted with a kidney from expanded criteria donor and 18 from recipients grafted with optimal kidney allograft. The clinical, transplant and acute T cell-mediated rejection characteristics of both groups were similar at baseline. The expression of RORγt, Il-17 and T-bet mRNA was significantly higher in the elderly than in the optimal group (p = 0.02, p = 0.036, and p = 0.01, respectively). Foxp3 mRNA levels were significantly higher in elderly patients experiencing successful acute T cell-mediated rejection reversal (p = 0.03). The presence of IL-17 mRNA was strongly associated with nonsuccessful reversal in elderly patients (p = 0.008). Patients with mRNA IL17 expression detection and low mRNA Foxp3 expression experienced significantly more treatment failure (87.5%) than patients with no mRNA IL17 expression and/or high mRNA Foxp3 expression (26.7%; p = 0.017). Our study suggests that the Th17 pathway is involved in pathogenesis and prognosis of acute T cell-mediated rejection in recipients of expanded criteria allograft.

OR19 Successful reversal of severe kidney allograft rejection mediated by angiotensin II type 1-receptor antibodies

Case Study The patient is a non-sensitized 64 year-old African American male who received a split en bloc deceased donor kidney transplant with standard induction using solumedrol and basiliximab. Post-discharge his renal function remained stable with a baseline creatinine between 1.0 and 1.2 mg/dL. During this time he experienced severe GI side effects related to MMF which led to its temporary discontinuation for 2 weeks, followed by resumption at reduced dosage (250 mg BID). One week later, his creatinine acutely worsened from 1.0 to 3.1 mg/dL. The patient’s allograft pathology showed mixed acute C4d+ antibody-mediated rejection (AMR) and cell-mediated rejection with transmural arteritis (Banff scores g1, t3, i3, v3, ptc1). Surprisingly, neither anti-HLA nor MICA antibodies were identified in any of his post-transplant sera. Further investigation uncovered anti-angiotensin II type-1 receptor antibodies (AT1R ab) and endothelial cell crossmatch (ECXM) positivity which correlated with the timing of his acute rejection. Fig. 1 illustrates the kinetics of the patient’s AT1R ab level in relationship to his clinical course. Pre-transplant, high AT1R ab binding was detected at 18 U/ml (positive cutoff >17 U/ml) – this reactivity increased to 27 U/ml on the day of his allograft biopsy. In parallel with this surge, the patient’s creatinine deteriorated to a peak of 5.7 mg/dL necessitating temporary dialysis. Of note, his blood pressure which had been previously well-controlled converted to a state of hypertensive urgency requiring IV nicardipine infusion. He was treated aggressively with ATG, plasmapheresis, IVIG, and losartan. After one week of treatment his AT1R ab level became undetectable; remarkably, the patient also showed rapid clinical recovery and control of his blood pressure. Post-discharge his renal function returned to his previous baseline. He continues to take losartan for AT1R blockade and is treated with short courses of plasmapheresis and IVIG to reduce his anti-AT1R level as necessary. Download full-size image

The complement interference phenomenon as a cause of underestimation of high titer anti-HLA antibodies in a renal transplant recipient

Single antigen bead assay is the most sensitive laboratory tool for the anti-HLA antibody (Ab) identification in renal transplant recipients. However, this assay was shown to be prone to the prozone effect (PrE), giving false negative results in sera with high titer anti-HLA Ab. The ethylenediaminetetraacetic acid-EDTA’s Ca++ chelating effect on the C1 complement was described to eliminate the PrE allowing the anti-HLA Ab identification. A mean fluorescence intensity (MFI) ⩾ 2 fold increase in neat versus EDTA treated sera was considered relevant to PrE. We report a case of chronic Ab mediated rejection in a renal transplant recipient with anti-HLA-DQA1∗05:05,DQB1∗03:01 donor specific Ab (DSA), revealed after treatment of the sera with EDTA. Female patient, 36 years old, diagnosed with juvenile nephronophthisis, received a first graft from a living related donor in 1991. During the first year post transplantation the patient experienced two biopsy proven reversible rejection episodes and until 2010 she had no other evidence of graft malfunction. De novo DSA were detected in 2010, as shown on the table. In 2015, due to inconsistency between the sudden elevation of serum creatinine levels and absence of DSA, the patient’s sera were further analyzed after EDTA treatment. DSA with high MFI were detected post-EDTA treatment. The presence of DSA was confirmed with positive B-Flow crossmatch with the donor. Also, a kidney biopsy on 03/26/2015 showed chronic antibody mediated rejection with C4d deposition. Taking into account that the follow up post-transplantation is based on HLA Ab detection and identification, these results highlight the importance of using patients’ sera with EDTA treatment to abolish the PrE before the performance of single antigen bead assay, in order to detect the presence of HLA antibodies. Download : Download full-size image