Immunosuppression In Kidney Transplantation Research Articles

#99 Clinical characteristics and outcomes of PTLD after kidney transplant: a single center experience

Abstract Background and Aims Post-Transplant Lymphoproliferative Disorder (PTLD) is a serious and potentially fatal complication of immunosuppression in kidney transplantation. Given the rarity of this entity, a high index of suspicion is necessary. We aimed to review the incidence, clinical presentation, histological subtypes, treatment, patient and graft survival of PTLD in kidney transplant patients in our unit. Methods Observational retrospective study, including adults diagnosed with PTLD between 1998 and 2023 in a Kidney Transplantation Center. Results Of 1390 kidney transplant recipients, 4 (0.3%) developed PTLD with a mean age of 52 ± 12.5 years. All cases were late-onset, occurring one year after transplantation with a median time from transplantation to diagnosis of 16.7 ± 7.3 years (range: 5-22 years). Of these, none had EBV donor/recipient mismatch. Two patients had prior rejection episodes (one patient, acute T cell-mediated rejection and the other patient, acute T cell-mediated rejection and active antibody mediated rejection). Clinical presentation was variable. Non-specific constitutional symptoms such as fever, fatigue and night sweats were present in all patients. Organ-specific symptoms were also present: lumbar pain in one patient with bone involvement, and delirium and lethargy in two patients with central nervous system involvement. Laboratory analyses revealed an increase in serum LDH in all patients. The primary sites of involvement were central nervous system (50%), lymph nodes (25%) and bone (25%). At PTLD diagnosis, immunosuppression included: tacrolimus (100%), mycophenolate mofetil (75%), low-dose of steroids (50%) and everolimus (25%). Regarding histologic classification, 75% were monomorphic and 25% polymorphic. In the monomorphic group, all patients had Diffuse Large B Cell Lymphoma (CD20 positive). In the polymorphic group, the patient had a Mixed Cellularity Classic Hodgkin Lymphoma (CD20 negative). Immunosuppression therapy was reduced in all patients with discontinuation of mycophenolate mofetil and tacrolimus. In the patient who was taking everolimus, the dose was increased due to the potential clinical antitumor effects of mTOR inhibition. Additional therapies included, rituximab in monotherapy or in combination with chemotherapy (R-CHOP) in the monomorphic group. Palliative measures were selected for one patient of this group due to advanced disease. The patient with Mixed Cellularity Classic Hodgkin Lymphoma (CD20 negative) did chemotherapy with ABVD. None of the patients underwent surgery or radiation therapy. Two patients needed dialysis. Three patients died in the first four weeks after PTLD diagnosis, all due to infectious complications. Patient survival was 25% one year after diagnosis. Conclusions Although the incidence of PTLD was low following kidney transplantation, its impact was significant in kidney graft and overall patient survival. Given the poor prognosis, new therapies combining high efficacy and low toxicity are an urgent unmet medical need in this field.

Evaluation of Tacrolimus Concentrations and Clinical Outcomes Between Extended and Immediate Release Formulations in Kidney Transplant.

Objectives: Tacrolimus remains the mainstay of immunosuppression in kidney transplantation. Understanding the relationship between therapeutic tacrolimus levels and outcomes of acute rejection, patient/graft survival, and tolerability are important. The relationship between time to therapeutic tacrolimus levels and outcomes has not been well established, specifically with the use of extended release tacrolimus formulation (LCP-Tac). This study investigated time to therapeutic tacrolimus levels of 2 tacrolimus formulations, LCP-Tac and immediate release tacrolimus (IR-Tac), as a predictor of clinical outcomes. Methods: This was a single-center, retrospective, cohort study of kidney transplant recipients at Duke Hospital between 2013-2021. The primary objective evaluated the difference in time to therapeutic tacrolimus levels with LCP-Tac vs IR-Tac regimens. Secondary endpoints included time within therapeutic range during the first 3months post-transplant, incidence of biopsy-proven rejection, development of de novo donor specific antibodies, and patient and allograft survival at 12months post-transplant. Results: 128 patients were included (63 in LCP-Tac group and 65 in IR-Tac group). The time to therapeutic tacrolimus level was similar between formulations (7.2 days with LCP-Tac compared to 6.7days with IR-Tac, P = .63). The time within therapeutic range during the first 3months post-transplant, via modified Rosendaal, was similar with LCP-Tac and IR-Tac (56.1% vs 64.8%, respectively). Rates of biopsy-proven acute rejection at 12months were similar (7/63 (11.1%) compared to 4/65 (6.2%)). There was no difference in patient/graft survival between groups. Conclusions: The time to therapeutic tacrolimus levels did not differ based on tacrolimus formulation and was not correlated with clinical outcomes.

Beyond Human Limits: Harnessing Artificial Intelligence to Optimize Immunosuppression in Kidney Transplantation.

The field of kidney transplantation is being revolutionized by the integration of artificial intelligence (AI) and machine learning (ML) techniques. AI equips machines with human-like cognitive abilities, while ML enables computers to learn from data. Challenges in transplantation, such as organ allocation and prediction of allograft function or rejection, can be addressed through AI-powered algorithms. These algorithms can optimize immunosuppression protocols and improve patient care. This comprehensive literature review provides an overview of all the recent studies on the utilization of AI and ML techniques in the optimization of immunosuppression in kidney transplantation. By developing personalized and data-driven immunosuppression protocols, clinicians can make informed decisions and enhance patient care. However, there are limitations, such as data quality, small sample sizes, validation, computational complexity, and interpretability of ML models. Future research should validate and refine AI models for different populations and treatment durations. AI and ML have the potential to revolutionize kidney transplantation by optimizing immunosuppression and improving outcomes. AI-powered algorithms enable personalized and data-driven immunosuppression protocols, enhancing patient care and decision-making. Limitations include data quality, small sample sizes, validation, computational complexity, and interpretability of ML models. Further research is needed to validate and enhance AI models for different populations and longer-term dosing decisions.

Immune tolerance via FCR001 cell therapy compared with maintenance immunosuppression for kidney transplantation: Real-world evidence analysis of safety and efficacy.

While kidney transplantation (KTx) has traditionally required lifelong immunosuppression, an investigational stem cell therapy, FCR001, has been demonstrated to induce tolerance and eliminate the need for immunosuppression through the establishment of persistent mixed chimerism in a phase 2 clinical study. Real-world evidence (RWE) methods were employed to compare the safety and efficacy of non-myeloablative conditioning with FCR001 with standard of care [SOC] immunosuppression in a retrospective single-center analysis of outcomes among propensity score matched living-donor KTx receiving SOC (n=144) or FCR001 (n=36). Among the FCR001 recipients, 26 (72%) developed persistent chimerism allowing durable elimination of all immunosuppression. There was no significant difference in the composite primary endpoint (biopsy-proven acute rejection [BPAR], graft loss, or death) at 60 months (FCR001 27.8%, n=10 and SOC 28.5%, n=41; p=.9). FCR001 recipients demonstrated superior kidney function at 5 years (estimated glomerular filtration rate [eGFR] [mean±standard deviation]: 64.1±15.3) compared to SOC (51.7±18.8; p=.02). At 5 years, FCR001 recipients experienced fewer complications including new-onset diabetes post-transplant, although two patients developed graft versus host disease. In conclusion, RWE demonstrated that KTx combined with non-myeloablative conditioning and FCR001 resulting in superior kidney function without increasing the risk of rejection, graft loss, or death among patients off immunosuppression.

#6915 IMMUNOLOGIC EFFECTS OF THE DECREASE OF IMMUNOSUPPRESSION AFTER SARS-COV-2 INFECTION IN KIDNEY TRASPLANT RECIPIENTS

Abstract Background and Aims The decrease of immunosuppression (IS) in kidney transplant (KT) recipients with SARS-CoV-2 infection was proposed during the first years of the pandemic due to the lack of knowledge of the course of the infection and the absence of vaccines and specific treatment. The effects of this decrease are being assessed in a medium-long term. Method Unicentric retrospective study that included 19 patients with a kidney biopsy after a SARS-CoV-2 infection (120 days). We measured acute kidney injury (AKI) after de infection, decrease in the IS during the infection, rejection episodes and renal function evolution during 24 months after the infection. Results The studied group was constituted by 19 patients from which 57.9% (11/19) men, age 56 (51, 70), being the first KT in 78.9% (15/19) of them. The IS induction was in a 57.9% (11/19) Basilximab and in a 42.1% (8/19) thymoglobulin, and the usual IS of all of them was done with prednisone, tacrolimus and mycophenolic acid. There was a graft loss in 26.3% (5/19), being all of immunologic cause, and 10.5% (2/19) of patients died. The severity of the SARS-CoV-2 infection was different between patients (21.1% (4/11) asymptomatic, 47.1% (9/19) mild respiratory symptoms, 5.3% (1/19) severe pneumonia not requiring critical care unit and 26.3% (5/19) severe pneumonia requiring critical care unit, with a decrease in IS in a 42% (8/19) of patients (steroids in monotherapy in a 31.6% (6/19) and bitherapy with steroids and tacrolimus in a 10,5% (2/19), to achieve 5-7ng/mL blood levels). AKI was found after the first month after the infection in a 57.9% (11/19) of patients, being in a 42% (8/19) AKI KDIGO1 and in a 16% (3/19) AKI KDIGO3. Renal function kept worsening until the sixth month after the infection [CKDEPI before SARS-CoV-2 37mL/min (32, 45) vs CKDEPI 6months after 34mL/min (22, 48.3); p = 0.3]. There was an improvement in renal function in 12 months after the infection (38mL/min (25, 48)). Acute graft rejection was detected in renal biopsies after the infection in 31.6% (6/19) being cellular in 15.8% (3/19), humoral in 10.5% (2/19) and mixed in 5.3% (1/19), de novo DSA were found in 15.8% (3/19). Conclusion The decrease in IS after SARS-CoV-2 in KT recipient has an elevated immunologic price. Glomerular filtrate rate decreases after 6 months from infection with a recovery at 1 year.

A systematic review and meta-analysis comparing everolimus and calcineurin inhibitors (CNIs) to mycophenolate and CNIs in kidney transplant patients.

This study compared everolimus and mycophenolate mofetil, each paired with calcineurin inhibitors (CNIs) and used with or without steroids, for maintaining immunosuppression in kidney transplant (KT) patients. Relevant studies published before August 21, 2022 were retrieved from PubMed, the Cochrane Central Register of Controlled Trials, and the gray literature. The risk of bias was assessed independently using the revised Cochrane risk of bias assessment tool (RoB 2). RevMan ver. 5.4 was used to calculate the risk ratios (RRs) with corresponding 95% confidence intervals (CIs) for biopsy-proven acute rejection, death, and infection. The mean difference (MD) was used to compare the estimated glomerular filtration rate (eGFR) between the groups. Sixteen randomized controlled trials with a total of 5,403 patients were synthesized to compare everolimus (n=2,763) with mycophenolate (n=2,542) for maintaining post-KT immunosuppression. The meta-analysis showed no significant difference in the risk for biopsy-proven acute rejection (RR=1.12; 95% CI, 0.92-1.35; I2=29%) and death (RR=0.85; 95% CI, 0.63-1.16; I2=0%). The eGFR had no significant difference between the two groups (MD=0.93; 95% CI, -2.25 to 4.1; I2=84%). The risk for any infection was significantly higher in the mycophenolate group than in the everolimus group (RR=0.83; 95% CI, 0.73-0.93; I2=66%). Our meta-analysis showed that when paired with a CNI, everolimus and mycophenolate had no difference in risk for biopsy-proven acute rejection, death, or increase in eGFR. However, the mycophenolate group exhibited a significantly higher risk of infection.

TIGIT agonism alleviates costimulation blockade-resistant rejection in a regulatory T cell-dependent manner.

Belatacept-based immunosuppression in kidney transplantation confers fewer off-target toxicities than calcineurin inhibitors but comes at a cost of increased incidence and severity of acute rejection, potentially due to its deleterious effect on both the number and function of Foxp3+ regulatory T cells (Tregs). TIGIT is a CD28 family coinhibitory receptor expressed on several subsets of immune cells including Tregs. We hypothesized that coinhibition through TIGIT signaling could function to ameliorate costimulation blockade-resistant rejection. The results demonstrate that treatment with an agonistic anti-TIGIT antibody, when combined with costimulation blockade by CTLA-4Ig, can prolong allograft survival in a murine skin graft model compared with CTLA-4Ig alone. Further, this prolongation of graft survival is accompanied by an increase in the frequency and number of graft-infiltrating Tregs and a concomitant reduction in the number of CD8+ T cells in the graft. Through the use of Treg-specific TIGIT conditional knockout animals, we demonstrated that the TIGIT-mediated reduction in the graft-infiltrating CD8+ T cell response is dependent on signaling of TIGIT on Foxp3+ Tregs. Our results highlight both the key functional role of TIGIT on Foxp3+ Tregs under conditions in which CTLA-4 is blocked and the therapeutic potential of TIGIT agonism to optimize costimulation blockade-based immunosuppression.

Sirolimus-Induced Rash in a Kidney Transplant Patient.

Sirolimus is an inhibitor of the mammalian target of rapamycin, which is used in kidney transplant immunosuppression. The clinical spectrum of cutaneous adverse events associated with sirolimus use varies, with maculopapular rash being an uncommon side effect very rarely reported in the literature. We present the case of a 78-year-old male renal transplant recipient who developed a diffuse maculopapular pruritic rash after starting sirolimus. This case report demonstrates that maculopapular rash is an uncommon sirolimus-related side effect that must be identified promptly so the medication can be discontinued and rash progression prevented.LEARNING POINTSAcneiform dermatitis, folliculitis, onychopathy, oral ulcers, rash and stomatitis are all common dermatological side effects of sirolimus.The occurrence of a diffuse pruritic maculopapular rash associated with sirolimus use is rare, but an important differential to keep in mind.Sirolimus cessation is required in case of diffuse pruritic maculopapular rash.

MO948: Impact of DE Novo Immunosuppression in The Covid-19 Serological Status at Kidney Transplantation

BACKGROUND AND AIMSCOVID-19 infection has heavily impacted our national health system since March-2020. Although the kidney transplant (KT) activity was strongly reduced initially, nowadays it is partially recovered by using ‘COVID-clean’ pathways and vaccination of KT candidates since February-2021. However, scarce information is available regarding how de novo KT immunosuppression influences the serological status of vaccinated recipients.METHODWe reviewed the course of 38 de novo KT recipients transplanted between March-September 2021 fully vaccinated before KT. SARS-CoV-2 IgG antibodies against Spike (IgG-S) before and after KT (median: 32 days) were quantified with a serological assay (positive ≥13.0 AU/mL).RESULTSOf 38 recipients, 35 showed positive IgG-S at KT (92%). We exclude from the analysis, 4 recipients with COVID infection which interfered the analysis and 5 with inappropriate samples. The remaining 26 recipients had received the second dose of the mRNA vaccine a median time of 48 days before the pre-KT IgG determination. All patients maintained IgG-S over the cut-off after KT, but we observed that half de novo recipients (53.8%) showed a 50% reduction in the level of IgG-S at 1 month: 12/20 (60%) of those who received induction with basiliximab and 2/6 (33%) who received thymoglobulin. Regarding the impact of maintenance immunosuppression under induction with basiliximab, the IgG-S levels halved in 50% of those with tacrolimus-mycophenolate and 67% with tacrolimus-everolimus.The restricted analysis of IgG-S levels excluding five outliers before KT (>800 AU/mL) showed the most intense reduction in three KT recipients who received thymoglobulin-tacrolimus- mycophenolate (263.8 versus 68.8, 74%) compared with seven basiliximab-tacrolimus-mycophenolate cases (494.4 versus 359.8, 27%) and eleven basiliximab-tacrolimus-everolimus (344.0 versus 306.4, 11%) KT recipients.CONCLUSIONImmunosuppression in de novo KT recipients reduces significantly the seroprotective levels of antibodies anti-Spike induced by COVID m-RNA vaccines in more than half the recipients. In our experience, the combination of thymoglobulin, tacrolimus and mycophenolate produces a more intense reduction than the combination of basiliximab with tacrolimus and mycophenolate or everolimus.

Innovative immunosuppression in kidney transplantation: A challenge for unmet needs.

Due to the optimal results obtained in kidney transplantation and to the lack of interest of the industries, new innovative drugs in kidney transplantation are difficult to be encountered. The best strategy to find the new drugs recently developed or under development is to search in the sections of kidney transplantation still not completely covered by the drugs on the market. These unmet needs are the prevention of delayed graft function (DGF), the protection of the graft over the long time and the desensitization of preformed anti human leukocyte antigen antibodies and the treatment of the acute antibody-mediated rejection. These needs are particularly relevant due to the expansion of some kind of kidney transplantation as transplantation from non-heart beating donor and in the case of antibody-incompatible grafts. The first are particularly exposed to DGF, the latter need a safe desensitization and a safe treatments of the antibody mediated rejections that often occur. Particular caution is needed in treating these drugs. First, they are described in very recent studies and the follow-up of their effect is of course rather short. Second, some of these drugs are still in an early phase of study, even if in well-conducted randomized controlled trials. Particular caution and a careful check need to be used in trials launched 2 or 3 years ago. Indeed, is always necessary to verify whether the study is still going on or whether and why the study itself was abandoned.

Simultaneous Kidney and Parathyroid Transplantation in the Management of Genetic Hypoparathyroidism in a Child.

Background.Genetically determined hypoparathyroidism can lead to life-threatening episodes of hypocalcemia and, more rarely, to end-stage kidney disease at a young age. Parathyroid allotransplantation is the only curative treatment, and in patients already receiving immunosuppression for kidney transplantation, there may be little additional risk involved. We report the first such case in a child.Methods.An 11-y-old girl, known to have hypoparathyroidism secondary to an activating pathogenic variant in the calcium-sensing receptor, developed end-stage kidney disease and was started on intermittent hemodialysis. Since the age of 2.5 y, she had been receiving treatment with exogenous synthetic parathyroid hormone (PTH). In June 2019, at the age of 11.8 y, she received a living-donor kidney and simultaneous parathyroid gland transplant from her father. The kidney was implanted into the right iliac fossa, followed by implantation of the parathyroid gland into the exposed rectus muscle.Results.The kidney graft showed immediate function while the intrinsic serum PTH level remained low at 3 ng/L. Exogenous PTH infusion was reduced on day 6 posttransplantation to stimulate PTH production by the new gland, which resulted in improving intrinsic PTH concentrations of 28 ng/L by day 9. Twelve months after transplantation, PTH levels remain in normal range and the kidney graft function is stable with a serum creatinine of 110 μmol/L.Conclusions.Simultaneous living donation and transplantation of a kidney and a parathyroid gland into a child is safe and feasible and has the potential to cure primary hypoparathyroidism as well as kidney failure.

Lower versus higher starting tacrolimus dosing in kidney transplant recipients.

Achieving therapeutic tacrolimus levels is an essential component of balancing immunosuppression in kidney transplantation. At our institution, the starting tacrolimus dose was reduced from .075 mg/kg BD (higher dose [HD]) to .050 mg/kg BD (lower dose [LD]), to better achieve our target level of 6–10 μg/L in the early posttransplant period. Kidney transplant recipients (KTRs) transplanted 1‐year before (HD: n = 64) and after (LD: n = 63) the starting dose reduction were retrospectively compared. Achieved tacrolimus levels were significantly lower in the LD group during the first 14 days posttransplant, but not at day 21 or day 28. A higher proportion of LD KTRs achieved therapeutic levels (day 1–3: 36.1% vs. 18.8%; day 4–7: 50.8% vs. 40.6%, day 8–14: 83.6% vs. 71.7%), while the HD KTRs were more likely to have supratherapeutic levels. Tacrolimus dose was significantly lower on day 5 compared to day 0 in the HD group but similar in the LD group. Rates of delayed graft function, posttransplant diabetes, and treated rejection at 6 months and graft outcomes at 3 years were all similar. Lowering the starting tacrolimus dose increased the proportion of KTRs achieving therapeutic range and minimized dose changes early posttransplant without an impact on clinical outcomes.

POS-815 An Exploratory Study on Tacrolimus Time-in-Therapeutic Range (TTR) among Kidney Allograft Recipients in a Malaysian Tertiary Care Hospital

Tacrolimus is the cornerstone of immunosuppression in kidney transplantation (KT). Time-in-therapeutic range (TTR) and time-to-therapeutic level has been highlighted as a potential method of tacrolimus monitoring. We evaluated the tacrolimus TTR, time-to therapeutic level and adverse outcomes present in the Malaysian population in the 1-year post-KT.

POS-794 Conversion to sirolimus in kidney transplant patients: the main indications

The mTOR inhibitors (Sirolimus) has been used in kidney transplantation for very specific indications, essentially in case of neoplastic complications after transplantation secondary to calcineurin inhibitors.Then, the indications have been extended.To describe the different indications of sirolimus conversion in renal transplant patients in Tunisia, we carried out a multicenter study. This is a retrospective multicentric cross-sectional and analytical study performed over a period of 30 years (from 1986 to 2017), which collected all kidney transplant patients who received mTOR inhibitors during any time of their follow-up for a minimum period of 6 months. During study period, 89 patients were collected from the different Tunisian renal transplantation units. The majority of patients came from the SAHLOUL and CHARLES NICOLLES hospitals. The average age of patients at the time of transplantation was 34.71 years. Seventy percent were male. Initial nephropathy was indeterminate in 39 % of patients. All patients received sirolimus during their post-transplant follow-up with a mean of 3.13 +/- 4.73 years. The first indication (49% of cases) of Sirolimus initiation in our study was the diagnosis of neoplastic and pre-neoplastic lesions. Neoplastic lesions were noted in 36 patients (40%) and pre-neoplastic lesions in 08 patients. The most frequent neoplasia was Kaposi's sarcoma in diagnosed in 22.5% of patients. The second indication for switching to sirolimus was calcineurin inhibitors toxicity. In fact, 21 patients in our study had received Sirolimus because of calcineurin inhibitors toxicity. Tacrolimus toxicity was noted in 13 patients (15%) and Ciclosporin toxicity was found in 08 patients (9%). On the other hand, seven patients in our study had received Sirolimus after renal transplantation because of BK virus nephritis. Two patients had presented a thrombotic micro angiopathy related to tacrolimus requiring switching to Sirolimus. One patient presented with severe leuko-neutropenia with white blood cell count of 880/mm³ and neutrophils of 150/mm³. The etiological investigation was negative. In front of persistence of this leuko-neutropenia despite decreasing and then withdrawing MMF, a switch to Sirolimus was decided. In addition, Sirolimus was administered to one patient because of a primary CMV infection that occurred after 04 months of renal transplantation and was resistant to treatment with Foscavir and Ganciclovir. Furthermore, 13 patients had been programmed to be converted to Sirolimus. The conversion was decided, in 04 cases, in front of past history of lesions providing degeneration before the transplantation. These antecedents were: villous atrophy, a colloid thyroid nodule, Bourneville's tuberous sclerosis causing degeneration of skin nodules, and a mixed germ cell tumor. In 09 patients, the systematic conversion to Sirolimus was a part of a national protocol. Conversion from calcineurin inhibitor to sirolimus is one of the major thrusts of the current development of immunosuppression in kidney transplantation. The aim is to minimize the side effects of calcineurin inhibitors and ensure better graft and patient survival. According to our study, neoplastic complications and calcineurin inhibitors toxicity are the main indications of conversion to Sirolimus in Tunisia.

Case Study - Candida auris in Skilled Nursing Facility

Candida Auris (C. auris), is a multidrug-resistant organism, first described in Japan 2009, and now a serious, emerging global health threat1. C. auris pathogen can potentiate morbidity and mortality, i.e. lifelong contact precaution isolation, intravenous antifungal treatment, hospitalization and mortality rate of 30-60%1. Los Angeles County (LAC) developed 15 new cases in May 2020, and 73 cases in July 2020, amidst COVID-19 pandemic2. A 88 year old Black female had a positive skin test for C. auris by LAC Department of Public Health (DPH) during skilled nursing facility (SNF) admission for hip fracture in September 2020. Patient’s risk factors for C. auris included: age, kidney transplantation (1998) immunosuppression on tacrolimus, fungal infection on fluconazole, drug-drug interaction between tacrolimus-fluconazole including nephrotoxicity and neurotoxicity, malnutrition, bedbound, Stage 4 sacrococcyx pressure ulcer, osteomyelitis on broad-spectrum antibiotics, chronic indwelling catheter, and healthcare setting. Our multimorbid and frail patient remained asymptomatic with C. auris under an interdisciplinary team approach, including geriatricians, infectious disease, pharmacists, SNF team and local DPH. Our patient’s psychosocial isolation and family distress with local DPH guidelines for COVID-19 SNF visitation restrictions were compounded by multifaceted coordination of patient-centered care between SNF team and specialists via telehealth. Further research in the prevention, detection, and management of C. auris is warranted to protect our vulnerable SNF residents. 1. Centers for Disease Control and Prevention. (2020). Tracking Candida auris. https://www.cdc.gov/fungal/candida-auris/tracking-c-auris.html 2. Los Angeles County Health Alert Network. (2020). CDPH Health Advisory: Resurgence of Candida auris in Healthcare Facilities in the Setting of COVID-19. http://publichealth.lacounty.gov/eprp/lahan/alerts/CAHANCauris082020.pdf

Crossmatch, Donor-specific Antibody Testing, and Immunosuppression in Simultaneous Liver and Kidney Transplantation: A Review.

Since the introduction of simultaneous liver-kidney transplantation (SLKT) in the 1960s, the potential for immunological protection from the liver allograft to a simultaneously transplanted kidney has been recognized. Due to expanded indications and changes in allocation policies, there has been increased utilization of SLKT. Despite growing experience, a lack of consensus exists regarding the extent of the immunological privilege of the liver the role for donor-specific HLA antibody (DSA) and crossmatch testing, and appropriateness of modern immunosuppression protocols in SLKT recipients. This review provides a detailed analysis of SLKT outcomes in the context of these factors, suggesting that although the liver can reduce the incidence of antibody-mediated rejection, attention should be given to liver allograft function, previous failed transplants, and other risk factors in pretransplant risk assessment. Current methods of DSA and crossmatch testing in SLKT are also discussed, and the role of specific DSA (high mean fluorescence intensity antibody, C1q+ binding) and their potential importance in posttransplant risk assessment are examined. Finally, trends in SLKT immunosuppression are discussed, including the use of nondepleting agents for induction and de-escalating use of steroids for maintenance immunosuppression. Ongoing research, including multicenter or randomized trials, will be necessary to optimize immune-related outcomes in SLKT recipients.

Steroid avoidance/withdrawal and maintenance immunosuppression in pediatric kidney transplantation.

Corticosteroids have been an integral part of maintenance immunosuppression for pediatric kidney transplantation. However, prolonged steroid therapy is associated with significant toxicities resulting in several SW/avoidance strategies in recent years. This comprehensive review aims to discuss steroid-related toxicities and the safety, efficacy, and benefit of steroid avoidance/withdrawal immunosuppression in pediatric kidney transplant recipients. Initial studies of SW/avoidance conducted in the setting of CSA and AZA showed an increased incidence of AR but no increase in graft loss or mortality with SW/avoidance maintenance immunosuppression. Studies performed under modern immunosuppression (induction therapy, Tac, and MMF) show no significant increase in AR or graft loss with SW/avoidance immunosuppression. Furthermore, SW/avoidance immunosuppression is associated with significant improvement in growth, BMI, BP control, and lipid profile in pediatric kidney transplant recipients. Despite these data, SW/avoidance remains controversial, and only 40% of pediatric kidney transplant recipients in the United States are currently on SW/avoidance maintenance immunosuppression. SW/avoidance maintenance immunosuppression is safe and associated with fewer side effects compared with steroid-inclusive maintenance immunosuppression in pediatric kidney transplant recipients.

Functional Immune Tolerance Induced By Sequential Hematopoietic Stem Cell-Solid Organ Transplantation

Solid organ transplantation (SOT) treats over 1500 children/year in the US. While short-term outcomes have improved, long-term outcomes still remain poor. With the rare exception of monozygotic twins as donors, recipients require lifelong immunosuppression with its accompanying toxicities, the risk of nonadherence, and chronic rejection. Further, up to half of recipients require a second transplant.We have pioneered translational approaches that abrogate rejection and the need for post-transplant immunosuppression. Previous attempts in adult patients utilizing allogeneic hematopoietic stem cell transplantation (HSCT) to eliminate the need for post-SOT immunosuppression in non-histocompatible kidney transplant (KT) recipients have failed(Lowsky R, BMT 2019). The establishment of mixed lymphoid chimerism has permitted a reduction in the number of immunosuppressive drugs needed, but not their discontinuation, whereas complete donor engraftment after HSCT has resulted in fatal graft-versus-host disease in some patients (Leventhal JR, Eur J Pediatr 2000). The use of HSCT to eliminate the need for immunosuppression following pediatric KT has not been evaluated. We have pioneered sequential haploidentical HSCT followed by KT in three patients with Schimke immuno-osseous dysplasia (SIOD) to abrogate kidney rejection and the need for post-transplant immunosuppression.SIOD is a monogenic disorder with progressive nephropathy correctable by KT and a T-cell immunodeficiency curable by HSCT. All three patients received αβT-cell/CD19 B-cell depleted HSCT (αβhaplo-HSCT) from a parent prior to a KT from the same parental donor. The pre-HSCT reduced intensity preparative regimen consisted of fludarabine (a starting dose of 1 mg/kg x 4 days, which was adjusted based on AUC), total body irradiation (TBI) 200 cGy, cyclophosphamide 1200 mg/m 2, anti-thymocyte globulin (ATG) thymoglobulin® 7.5 mg/kg, and rituximab 200 mg/m 2. Immunosuppressive drugs were not prophylactically administered after HSCT. After confirmation of full donor lymphoid chimerism post-HSCT, the patients received a living donor KT from their parental HSCT donor. Post-KT immunosuppression included intraoperative methylprednisolone and post-operative low-dose oral prednisone (0.5 mg/kg/day with taper) and tacrolimus (target serum level of 3-5 ng/ml) to reduce potential reperfusion inflammation. All immunosuppressive drugs were tapered off by Day +30 post-KT. To demonstrate functional tolerance after KT, Mixed Lymphocyte Cultures (MLC) were performed between peripheral blood mononuclear cells (PBMC) and patient/parent-derived irradiated EBV transformed lymphoblastoid cells lines (EBV-LCL) as stimulators (Figure 1). PBMC were isolated from SIOD patients (n=3) by Ficoll Hypaque separation and were labelled with Invitrogen™ CellTrace Violet Proliferation Kit (CTV). EBV-LCL were established from SIOD patients, parents and healthy donors. The assay was performed in round bottom microtiter plates with 100,000 labelled PBMC as responder cells (R) and 50,000 irradiated (30gy) EBV-LCL in RPMI medium with 10% fetal calf serum. Cells were harvested on Day 6, and T-cell proliferation determined by CTV expression of CD3+ T cells using a Novocyte Penteon flow cytometer (Agilent).Donor-derived T cells isolated from the peripheral blood of all three recipients > 1-year post-HSCT/KT, did not respond to the donor cells, while they did proliferate to the non-donor parental and control cells (Fig. 1). These results demonstrate that post-HSCT/KT the circulating donor-derived T cells are functionally tolerant to the transplanted kidney and, therefore, are unable to mediate graft rejection even in the absence of immune suppression. We have achieved two goals: first, ablating the recipient immune system before HSCT we safely established a new donor-derived immune system - that could also, if required, cure a patient's underlying disease- and, second, functional tolerance to the transplanted kidney.At 12 to 24 months after KT, all patients have full donor lymphoid and myeloid chimerism, normal renal function without immunosuppression, MLC demonstrated tolerance towards donor cells, and normal proliferative responses to non-donor parental cells. These findings suggest that the combination of αβhaplo-HSCT and SOT could be extended to other solid transplantation like liver and small intestine. [Display omitted] DisclosuresBertaina: Cellevolve Bio: Membership on an entity's Board of Directors or advisory committees; Neovii: Membership on an entity's Board of Directors or advisory committees; AdicetBio: Membership on an entity's Board of Directors or advisory committees. Shah: OrchardTherapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Dr. Shah currently serves on the medical advisory board for Orchard Therapeutics . Parkman: Jasper Biotech: Consultancy.

Neuropathological Variability within a Spectrum of NMDAR-Encephalitis.

To describe the neuropathological features of N-methyl-D-aspartate receptor (NMDAR)-encephalitis in an archival autopsy cohort. We examined four autopsies from patients with NMDAR-encephalitis; two patients were untreated, three had comorbidities: small cell lung cancer, brain post-transplant lymphoproliferative disease (PTLD), and overlapping demyelination. The two untreated patients had inflammatory infiltrates predominantly composed of perivascular and parenchymal CD3+ /CD8- T cells and CD79a+ B cells/plasma cells in basal ganglia, amygdala, and hippocampus with surrounding white matter. The hippocampi showed a significant decrease of NMDAR-immunoreactivity that correlated with disease severity. The patient with NMDAR-encephalitis and immunosuppression for kidney transplantation developed a brain monomorphic PTLD. Inflammatory changes were compatible with NMDAR-encephalitis. Additionally, plasma cells accumulated in the vicinity of the necrotic tumor along with macrophages and activated microglia that strongly expressed pro-inflammatory activation markers HLA-DR, CD68, and IL18. The fourth patient developed demyelinating lesions in the setting of a relapse 4 years after NMDAR-encephalitis. These lesions exhibited the hallmarks of classic multiple sclerosis with radially expanding lesions and remyelinated shadow plaques without complement or immunoglobulin deposition, compatible with a pattern I demyelination. The topographic distribution of inflammation in patients with NMDAR-encephalitis reflects the clinical symptoms of movement disorders, abnormal behavior, and memory dysfunction with inflammation dominantly observed in basal ganglia, amygdala, and hippocampus, and loss of NMDAR-immunoreactivity correlates with disease severity. Co-occurring pathologies influence the spatial distribution, composition, and intensity of inflammation, which may modify patients' clinical presentation and outcome. ANN NEUROL 2021;90:725-737.

Immunological Results of Long-Term Use of Mammalian Target of Rapamycin (mTOR) Inhibitors and Its Effects on Renal Graft Functions.

BackgroundCalcineurin inhibitor drugs (CNI), which are the basis of immunosuppression in kidney transplantation, contribute to renal graft loss, with increased morbidity and mortality due to their potentially harmful effects on the renal graft, cardiovascular system, and tumor pathology. For this reason, the mammalian target of rapamycin inhibitors (mTORi) such as sirolimus (SRL) and everolimus (EVE) has been preferred more frequently, as they are associated with fewer complications and longer graft function.Material/MethodsWe enrolled 89 adult renal transplant patients (37 patients on mTORi and 52 on CNI) who had similar age, sex, primary renal disease, dialysis type, post-transplant follow-up period, and donor type. We analyzed and compared the data between patients using mTORi for longer than 5 years and those using CNI regarding pre- and post-transplant panel reactive antibody (PRA), and donor-specific antibody (DSA), as well as post-transplantation and current graft functions.ResultsAlthough those using mTORi for more than 5 years had significantly higher mismatch rates (P=0.024) than those using CNI, there was no significant change in PRA and DSA levels. Transplant time was longer in mTORi users (P=0.025). The switch time to mTORi in patients ranged from 0 to 19 years, but the average was 4 years. As expected, actual spot urine protein/creatinine was significantly higher in those using mTORi (P=0.009). Diabetes mellitus (DM) and BK virus nephropathy (BKVN) rates were significantly higher due to switching the regimen from CNI to mTORi.ConclusionsLong-term use of mTORi does not appear to be an immunological problem.