Reduction Of Immunosuppression Research Articles

#3090 Parvovirus infection in renal transplant recipients: a systematic review of clinical profile and treatment strategies

Abstract Background and Aims Parvovirus B 19 (PVB-19) virus infection can cause severe, persistent and/or refractory anaemia in kidney transplant recipients (KTR). There is paucity of data on the clinical manifestations, diagnosis and management of this infection and limited to case reports and case series. Method We performed a literature search of kidney transplant recipients infected with PVB-19 in MEDLINE, EMBASE and Cochrane databases and 93 articles were identified as suitable for assessment. The review was conducted in accordance with PRISMA statement. Results A total of two hundred and eighty-two patients were included from the studies assessed in the review. The mean age of the cohort was 37.05 years. The infection was more common in males when compared to females. The median onset of PVB-19 infection post transplantation was at 5 weeks (2, 15 weeks). One fourth of the recipients had at least one episode of rejection prior to PVB-19 infection. Majority of the patients were on Tacrolimus, MMF and corticosteroids maintenance. One third of the patients had co-infections with other organisms (EBV, CMV, etc.). Anemia and fever were the most common manifestations among all the kidney transplant patients infected with PVB-19 while CNS manifestations and rash were least reported. Hemoglobin was low (<10 mg/dl) in ninety eight percent of the patients (n=151). The lowest hemoglobin reported in the due course of illness was 6 mg/dl (5, 7.2 mg/dl) and with corrected reticulocyte count being only 0.2% (0.1%, 0.6%). The most consistent finding on peripheral smear was normocytic, normochromic anemia while a few reported helmet cells too. Pure Erythroid hypoplasia alone (45.3%) combined with giant pronormoblasts and inclusion bodies (49%) were the most common findings on bone marrow aspirate. Majority of PVB-19 diagnosis was made with the help of multiple methods of detection like IgM assay, PCR—qualitative and quantitative (42.2%). The average PCR copies detected were 1.3*107 (4.28*105, 2.53*109). IVIG only (47.2%) and combined IVIG + immunosuppression reduction (41.2%) was the mainstay of the treatment in majority. The median time to recover was 8 weeks (3, 16 weeks). One fourth of the patients had recurrence after recovery. A majority of the patients (96.7%) recovered from reactivation of PVB-19. Conclusion Parvovirus infection is not uncommon in the early post-transplant period. Though data is insufficient, immunosuppression reduction with IVIG remains the treatment of choice for affected patients. Prospective studies to assess the hemoglobin cutoffs and dose of IVIG are needed to frame screening and treatment protocols.

#1274 Post kidney transplant parvovirus disease presenting as refractory anemia—case series of 21 patients

Abstract Background and Aims Kidney transplant recipients (KTRs) are susceptible to a wide range of infections, one of which includes Parvovirus B19 (PVB19). It usually presents in the first year after transplant, with anemia and causes increased morbidity and risk of graft dysfunction. Method Charts of patients undergoing kidney transplant between May 2013 and March 2022 were reviewed. 21 patients had PVB19. Their clinical presentation, laboratory parameters and outcome was studied. The diagnosis of PVB19 was established by PVB19 polymerase chain reaction (PCR) and by bone marrow examination(BME) in 6 patients. Results Prevalence of PVB19 disease was 1.9% (21/1164) with a median time to onset was 39 days post-transplantation. Clinical presentation included fever, generalized weakness, dyspnea, and myalgia in 47%, 76%, 23%, and 33% of patients respectively. Anemia, leukopenia, and thrombocytopenia were present in 100%, 14%, and 9.5% of patients respectively. Graft dysfunction was observed in 61.9% (13/21) patients. 20/21 (95%) patients had a positive PVB19 PCR and one patient had a typical viral inclusion on BME. Immunosuppression especially antiproliferative was reduced in all patients. 8 patients received IVIG, 8 received packed cell blood transfusion and 7 received Erythropoietin therapy. All patients recovered with median time to normalization of hemoglobin was 30 days. One patient had graft loss secondary to non-responsive graft rejection. Conclusion PVB19 is a rare but clinically significant cause of refractory anemia during the early post-transplantation. Any kidney transplant patient in first 4 months who has unexplained normocytic normochromic refractory anemia with or without graft dysfunction should be screened for PVB19 by DNA PCR or BME to rule out PVB19 infection. The use of PCR for diagnosis and reduction in immunosuppressants particularly antiproliferative drugs is the mainstay of treatment.

#2825 BK virus in transplant patients: an enemy to fear or a challenge to accept? The 17-year experience of our transplant center

Abstract Background and Aims Reactivation of the BK virus in immunosuppressed patients is a risk factor for the development of BKV nephropathy. Ten percent of transplant patients are affected by BKV nephropathy, and 50% of them experience graft loss. The purpose of this study is to assess the medium to long-term effects of an early immunosuppression reduction strategy in the presence of urinary and/or serum BKV replication in a large population of kidney transplant recipients from our center. Method A retrospective observational study was conducted on 681 patients from immediate post-transplant with at least 6 months of observation. 91.5% of them were on the same immunosuppressive therapy (MMF, Steroid, tacrolimus). A total of 16200 samples were collected from blood and urine simultaneously for PCR quantification of BKV over a post-transplant period of 54.4 ± 34.2 months. Immunosuppression reduction began after two repeated biweekly detections of viruria >105 copies/ml and/or viremia >103 copies/ml. Results 35% of cases tested positive for viruria, with 19% also positive for viremia. Onset and peak viruria and viremia were observed at 4.1 ± 3.3 months and 4.2 ± 3.5 months, and 5.3 ± 4.6 and 5.4 ± 4.1 months, respectively. Viruria negativization occurred in 79.4% of patients after 13.2 ± 9.7 months, while viremia disappeared in 94.6% after 9.2 ± 7.5 months. In 5 patients with persistent viruria and viremia, therapy with Cidofovir or Leflunomide was initiated following biopsy. 14.3% of patients with persistent viruria maintained low replication and stable renal function. No episodes of acute rejection occurred. Only one case of irreversible BKV nephropathy was observed. Conclusion Timely reduction of immunosuppression allows excellent control of BKV replication, stability of renal function in the medium to long term, and makes the occurrence of irreversible chronic BKV nephropathy rare.

Intravenous Human Immunoglobulin in the Treatment of BK Virus Nephropathy in Kidney Transplant: A Case Report

The BK virus infection is common in the immunocompetent population and is asymptomatic in the majority of cases. However, in renal transplant patients, reactivation and replication can occur, leading to the development of BK virus-associated nephropathy (BKVN), which is associated with renal injury and graft loss. The objective of this case report was to demonstrate a case of BKVN that showed a good response to the use of human immunoglobulin. A 37-year-old man who underwent a second transplant received rabbit-derived anti-thymocyte human immunoglobulin at a dose of 6mg/kg intravenously as induction immunosuppressive therapy, and maintenance therapy with tacrolimus, prednisone, and mycophenolate sodium (MFS). At 3 months post-transplant, he presented sustained BK virus viremia (70,000-100,000 copies/mL), leading to a reduction in the dose of MFS and tacrolimus. A biopsy diagnosed BKVN class 2/B2, and viremia increased to over 1 million copies/mL at 22 months, prompting the discontinuation of tacrolimus without response. Intravenous human immunoglobulin (IVIG) was administered at 2g/kg at 22 months and again at 33 months, with viremia peaking at 2 million copies three months later. However, it steadily declined to 5,500 copies/mL at 52 months post-transplant. Currently, the only proven therapy for BKVN is the reduction of immunosuppression. However, in patients who do not respond, IVIG is considered as an option, with good results demonstrated in case reports, as shown here. Nevertheless, the data are based on case reports or case series, and the development of controlled clinical trials is necessary for confirmation of the efficacy.

Management of paediatric monomorphic post-transplant lymphoproliferative disorders with low-intensity treatment: A multicentre international experience.

Monomorphic post-transplant lymphoproliferative disorder (mPTLD) is a major cause of morbidity/mortality following solid organ transplant (SOT), with infection, mPTLD progression and organ rejection presenting equal risks. Balancing these risks is challenging, and the intensity of therapy required by individual patients is not defined. Although an increasing body of evidence supports the use of a stepwise escalation of therapy through reduction in immunosuppression (RIS) to rituximab monotherapy and low-dose chemo-immunotherapy, many centres still use B-cell non-Hodgkin lymphoma (B-NHL) protocols, especially when managing Burkitt/Burkitt-like (BL) PTLD. This study sought to define outcomes for children managed in the UK or Spanish centres using low-intensity first-line treatments. Retrospective data were anonymously collected on patients younger than 18years of age, with post-SOT mPTLD diagnosed between 2000 and 2020. Only patients given low-intensity treatment at initial diagnosis were included. Fifty-six patients were identified. Age range was 0.9-18years (median 10.7). Most (62.5%) had early-onset PTLD. Haematopathological analysis showed 75% were diffuse large B-cell like, 14.3% were BL and nine of 33 (27%) harboured a MYC-rearrangement. Stage III-IV disease was present in 78.6%. All but one had RIS, 26 received rituximab monotherapy and 24 low-dose chemo-immunotherapy, mostly R-COP. Intensified B-NHL chemotherapy was required in 10/56 (17.9%). There were a total of 13 deaths in this cohort, three related to PTLD progression. The 1-year overall survival (OS), event-free survival (EFS) and progression-free survival (PFS) were 92.8%, 78.6% and 80.2%, respectively. R-COP provides an effective low-dose chemotherapy option. Escalation to more intensive therapies in the minority of inadequately controlled patients is an effective strategy.

Nephrotransplantectomy Using Radiosurgical Techniques

Introduction. Aſter the loss of kidney transplant function, patient curation can be a difficult task. Nephrotransplantectomy (NTE) is the method of choice between reduction of immunosuppression with the abandonment of a non-functioning kidney transplant and embolization. This is an operation with potentially significant indicators of blood loss, complications and mortality. Along with traditional NTE, we began to use endovascular isolation of the allograſt as a method of preoperative preparation before its removal.The aim of the work is to investigate the effect of the use of radiosurgical minimally invasive techniques on the surgical tactics of nephrotransplantectomy, the degree of blood loss, the frequency of complications and blood transfusion.Materials and methods. A retrospective analysis of the data of 52 patients aſter NTE was performed. Depending on the method, patients are divided into two groups. In group 1 (main, n = 22), the operation was performed with pre-performed endovascular embolization of the graſt arteries (EEAT), in group 2 (control, n = 30) — without EEAT. The analysis of the results of the examination, intra- and postoperative indicators in patients by groups was carried out.Results. In group 1, intraoperative blood loss was 10–80 ml, on average (35.4±19.9) ml; in group 2 — from 100 to 600 ml, on average (289.7±138.4) ml (p < 0.001). In group 2, damage to the main vessels occurred more oſten (n = 4) (13.3 % vs. 0 %), hemotransfusion was performed in 53.3 % of cases (n = 16) to correct posthemorrhagic anemia. Postoperative complications in the control group were recorded in 8 patients (26.7 %).Discussion. Preventive endovascular embolization of the arteries of a kidney transplant significantly reduces the frequency ofintra- and postoperative complications, allows nephrectomy to be performed on a planned basis andin a delayed manner.

Association of BKV viremia and nephropathy with adverse alloimmune outcomes in kidney transplant recipients.

Immunosuppression reduction for BK polyoma virus (BKV) must be balanced against risk of adverse alloimmune outcomes. We sought to characterize risk of alloimmune events after BKV within context of HLA-DR/DQ molecular mismatch (mMM) risk score. This single-center study evaluated 460 kidney transplant patients on tacrolimus-mycophenolate-prednisone from 2010-2021. BKV status was classified at 6-months post-transplant as "BKV" or "no BKV" in landmark analysis. Primary outcome was T-cell mediated rejection (TCMR). Secondary outcomes included all-cause graft failure (ACGF), death-censored graft failure (DCGF), de novo donor specific antibody (dnDSA), and antibody-mediated rejection (ABMR). Predictors of outcomes were assessed in Cox proportional hazards models including BKV status and alloimmune risk defined by recipient age and molecular mismatch (RAMM) groups. At 6-months post-transplant, 72 patients had BKV and 388 had no BKV. TCMR occurred in 86 recipients, including 27.8% with BKV and 17% with no BKV (p=.05). TCMR risk was increased in recipients with BKV (HR 1.90, (95% CI 1.14, 3.17); p=.01) and high vs. low-risk RAMM group risk (HR 2.26 (95% CI 1.02, 4.98); p=.02) in multivariable analyses; but not HLA serological MM in sensitivity analysis. Recipients with BKV experienced increased dnDSA in univariable analysis, and there was no association with ABMR, DCGF, or ACGF. Recipients with BKV had increased risk of TCMR independent of induction immunosuppression and conventional alloimmune risk measures. Recipients with high-risk RAMM experienced increased TCMR risk. Future studies on optimizing immunosuppression for BKV should explore nuanced risk stratification and may consider novel measures of alloimmune risk.

Adalimumab for the Treatment of Non-Infectious Uveitis: A Real Life Experience

ABSTRACT Objective To describe the efficacy and safety of adalimumab for the treatment of non-infectious uveitis (NIU) in four Uveitis Units from tertiary Spanish hospitals. Methods Multicenter and retrospective clinical cohort study including all patients with NIU treated with adalimumab from January 2012 to October 2022 in four uveitis units was performed. Efficacy was measured with the number of relapses, ocular inflammation and reduction in immunosuppression and corticosteroid dosage before and after adalimumab use. We collected data regarding adverse effects and examined the immunogenicity of adalimumab. Results One hundred and twenty-two patients (59% females), with a mean age of 48.6 years (SD = 14.8) accounting for 217 eyes were included. The majority (92.6%) were Caucasian. Uveitis analyzed were predominantly panuveitis (34.7%), bilateral (77.9%), acute (41.5%), and non-granulomatous (90%). Most of them were immune mediated (42.6%), and the main reason to initiate adalimumab was refractory disease (96.7%). The analysis was statistically significant due to the reduction in the number of immunosuppressive drugs as well as the dose of oral corticosteroids and the number of relapses during follow-up (p < 0.001). The decrease in ocular inflammation parameters and the improvement in visual acuity (p < 0.05) were also significant. There were no deaths due to the drug and only one reported case of serious infection. In total, 10.9% of 73 patients tested developed anti-adalimumab antibodies and 4.1% lupus-like. Conclusions We consider adalimumab as a leading drug in the treatment of NIU with high safety and efficacy.

Effect of steroid pulses in severe BK virus allograft nephropathy with extensive interstitial inflammation.

As there is no specific antiviral treatment currently available for BK polyomavirus associated nephropathy (BKVAN), its management relies on immunosuppression reduction in kidney transplant patients. Data on efficacy of steroid pulses in this indication are lacking. We performed a retrospective monocenter study on 64 patients diagnosed with biopsy-proven BKVAN. Patients within the "pulse group" (n = 37) received IV methylprednisolone 10mg/kg 3 days consecutively. In the "low dose" steroid group (n = 27), patients were continued oral prednisone 5mg daily. Mean follow up was 78 months in the steroid pulse group and 56 months in the low dose group (p=0.15). Mean eGFR values at diagnosis were comparable, as well as other demographic characteristics. Mean BK plasma viral load was higher in "pulse" than in "low dose" steroid group. Pulse group had higher inflammation and tubulitis (p <0.05). Graft loss reached 57% in the "pulse" group versus 41% in the "low dose" group, p=0.20. Rejection events were similar. No major adverse event was statistically associated with steroid pulse, including infections, cancer, and de novo diabetes. No significant differences were found in the evolution of both groups of patients, despite patients receiving "pulse" steroids were identified as the most severe sharing higher BK viral load and more frequent active lesions on histology.

Abstract 1187: Sensitization to chemo-immunotherapy by targeting TGF-β in preclinical triple negative breast cancer models

Abstract Metastatic triple-negative breast cancer (mTNBC) is refractory to anti-PD-(L)1 immunotherapy. In order to sensitize it, preclinical data show the value of adding chemotherapy treatment for its ability to induce immunogenic cancer cell death (Kroemer et al, 2013). This would enable the recruitment of cytotoxic T-CD8+ lymphocytes (CTL) and thus initiate an antitumor immune response to sensitize tumors to immunotherapy. Nevertheless, the results of clinical trials using chemo-immunotherapy combinations are divergent (IMpassion 130 and 131). The IMpassion 130 trial demonstrated the efficacy of nab-paclitaxel and atezolizumab (anti-PD-L1) in PD-L1+ patients, but unfortunately, IMpassion 131 with paclitaxel did not replicate these results. The choice of chemotherapy to combine with immunotherapy appears to be crucial for inducing an antitumor immune response. Optimizing chemo-immunotherapy combinations is a major challenge in the management of TNBC. The initial aim of this project was to evaluate the immune effects of an experimental chemotherapy doublet, based on two drugs used in mTNBC: cisplatin (CDDP) and eribulin. The idea was to find an alternative to the use of taxanes in combination with anti-PD-(L)1.The effect of the two molecules, alone or in combination, was evaluated on immunogenic death stigmata, modulation of effector or immunosuppressive immune populations and stromal populations, and sensitization to anti-PD-L1 immunotherapy in the immunologically "cold" model: 4T1. The in vivo studies has been realized by generation of orthotopic 4T1 tumors, the analysis of the immune infiltration was performed by RT-qPCR, IHC and flow cytometry. In vitro, our results indicate that CDDP, and more intensely in combination with eribulin, significantly induces the various immunogenic death stigmas. In vivo, the therapeutic effect of chemotherapies is limited, with a superior effect of CDDP and the combination. Nevertheless, CTL recruitment and functionality induced by CDDP are significantly enhanced by eribulin. Despite these data pointing to a potential therapeutic synergy with anti PD-L1 immunotherapy, chemo-immunotherapy treatment fails to induce a superior treatment effect. The significant increase in a TGF-β signature induced by the combination in parallel with CTL recruitment explains this resistance. The results show that inhibition of TGF-β, combined with chemo-immunotherapy in the 4T1 model, leads to a reduction in tumor immunosuppression and intratumoral fibrosis, as well as an increase in CTL infiltration and cytotoxicity, enabling tumor sensitization. Overall, this project highlights the benefits of using an experimental doublet of CDDP and eribulin-based chemotherapies. This project demonstrates that management of chemo-induced immunosuppression mechanisms is necessary to overcome tumor resistance to immunotherapy. Citation Format: Laura Kalfeist, Fanny Ledys, Stacy Petit, Samia Kada-Mohammed, Mickael Rialland, François Ghiringhelli, Emeric Limagne, Sylvain Ladoire. Sensitization to chemo-immunotherapy by targeting TGF-β in preclinical triple negative breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1187.

Leflunomide as adjunct therapy for BK viremia management in pediatric kidney transplant recipients.

BK viremia after kidney transplantation (KT) poses significant risk for BK virus-associated nephropathy and impacts graft survival. Conventional treatment involves reduction of immunosuppression, which in turn may increase risk for rejection. To address this dilemma, use of anti-viral therapy with immunosuppressive properties such as leflunomide is an attractive option. We performed a multi-center, retrospective chart review to report tolerability and effectiveness of leflunomide use for the eradication of BK viremia and prevention of BK virus-associated nephropathy in pediatric KT recipients. Seventy patients prescribed leflunomide were included and were followed up from initiation until 1 year following leflunomide completion. BK viremia was eradicated in 64 (91.4%) patients including 8 of 11 with nephropathy (BKVN) on initial biopsy. Reduced anti-proliferative medication (AP) dosing was not associated with increase in biopsy proven rejection (BPAR). However, complete discontinuation of AP during leflunomide therapy was associated with increase in BPAR in uni- and multivariate logistic regression, as was targeted reduction in calcineurin inhibitor (CNI) trough goals. One graft was lost to BKVN. There was no significant association found between time to BK eradication and leflunomide trough concentration, mycophenolate dose reduction, or steroid use (univariate logistic regression). Few leflunomide adverse drug reactions (ADR) were reported (most commonly: gastrointestinal, hematologic). Leflunomide is a promising adjunctive treatment to immunosuppression reduction for BK virus eradication with minimal ADR. AP reduction, not discontinuation, and judicious reduction in CNI trough goals with close monitoring, is a promising strategy for treatment of BK viremia with concomitant use of leflunomide therapy.

Impact of Immunosenescence in Older Kidney Transplant Recipients: Associated Clinical Outcomes and Possible Risk Stratification for Immunosuppression Reduction.

The number of older individuals receiving a kidney transplant as replacement therapy has significantly increased in the past decades and this increase is expected to continue. Older patients have a lower rate of acute rejection but an increased incidence of death with a functioning graft. Several factors, including an increased incidence of infections, post-transplant malignancy and cardiovascular comorbidity and mortality, contribute to this increased risk. Notwithstanding, kidney transplantation is still the best form of kidney replacement therapy in all patients with chronic kidney disease, including in older individuals. The best form of immunosuppression and the optimal dose of these medications in older recipients remains a topic of discussion. Pharmacological studies have usually excluded older patients and when included, patients were highly selected and their numbers insignificant to draw a reasonable conclusion. The reduced incidence of acute rejection in older recipients has largely been attributed to immunosenescence. Immunosenescence refers to the aging of the innate and adaptive immunity, accumulating in phenotypic and functional changes. These changes influences the response of the immune system to new challenges. In older individuals, immunosenescence is associated with increased susceptibility to infectious pathogens, a decreased response after vaccinations, increased risk of malignancies and cardiovascular morbidity and mortality. Chronic kidney disease is associated with premature immunosenescent changes, and these are independent of aging. The immunosenescent state is associated with low-grade sterile inflammation termed inflammaging. This chronic low-grade inflammation triggers a compensatory immunosuppressive state to avoid further tissue damage, leaving olderindividuals with chronic kidney disease in an immune-impaired state before kidney transplantation. Immunosuppression after transplantation may further enhance progression of this immunosenescent state. This review covers the role of immunosenescence in older kidney transplant recipients and it details present knowledge of the changes in chronic kidney disease and after transplantation. The impact of immunosuppression on the progression and complications of an immunosenescent state are discussed, and the future direction of a possible clinical implementation of immunosenescence to individualize/reduce immunosuppression in older recipients is laid out.

Elevated Plasma CXCL8 Concentrations in Significant Fibrosis but Not in Subclinical Rejection After Adult Liver Transplantation

Background. The noninvasive detection of subclinical graft injury including subclinical T cell–mediated rejection (subTCMR) is one of the unresolved challenges after liver transplantation. Recently, serum C-X-C motif chemokine ligand 8 (CXCL8) was proposed as a highly accurate marker of subTCMR in pediatric liver transplant recipients. We aimed to evaluate the accuracy of the quantification of this chemokine for predicting subTCMR in adult liver transplant recipients, as well as its capacity to classify patients who could benefit from immunosuppression reduction. Methods. Plasma CXCL8 concentrations were measured retrospectively in a prospectively collected cohort of adult liver transplant recipients with well-characterized histologic phenotypes. Results. In total, 78 patients were included. Median plasma CXCL8 concentrations did not differ (P = 0.24) between patients without histological evidence of rejection (3.6 [0.4–22.0] pg/mL), subTCMR (11.5 [0.4–41.0] pg/mL), clinical TCMR (9.4 [0.4–40.5] pg/mL), and other etiologies of graft injury (8.7 [0.4–31.2] pg/mL). Likewise, plasma CXCL8 concentrations did not discriminate between patients within and outside histologic criteria for immunosuppression reduction that were proposed by the 2016 Banff Working Group on Liver Allograft Pathology (cutoff: 10.9 pg/mL, sensitivity: 0.48, and specificity: 0.79). Furthermore, weak correlation was found between plasma CXCL8 and alanine aminotransferase and aspartate aminotransferase (Spearman ρ = 0.18 and 0.25). Patients with significant fibrosis (17.8 [0.4–40.5] pg/mL) showed higher plasma CXCL8 concentrations than patients without fibrosis (8.2 [0.4–41.0] pg/mL; P = 0.05). Conclusions. Plasma CXCL8 concentrations are not predictive of subclinical graft injury or of histological criteria for the minimization of immunosuppression in adult liver transplant recipients.

A multicenter prospective study to define the natural history of BK viral infections in kidney transplantation.

BK polyomavirus (BKV) can cause permanent loss of allograft function due to BKV-associated nephropathy (BKVN) in kidney transplant recipients. Besides immunosuppression reduction, there are no consistently effective interventions for BKV infection. Study purpose was to define natural history of BKV infection, identify risk factors for BKV reactivation and BKVN in kidney transplant recipients, and inform the design/conduct of future clinical trials of BKV-targeted therapeutics. We conducted a multicenter prospective observational study of incident kidney transplant recipients at six U.S. transplant centers. Participants were monitored every 4 weeks for BKV reactivation and followed for up to 24 months post-transplant. We used regression models (logistic, survival, mixed models) to study relationships between BK viremia/BKVN, clinical characteristics, and allograft function. We enrolled 335 participants. Fifty-eight (17%) developed BK viremia, 6 (2%) developed biopsy-proven BKVN, and 29 (9%) developed suspected/presumed BKVN (defined as BKV viral load > 10,000 copies/mL without biopsy). Male donor sex was associated with lower odds for BK viremia, whereas recipient Black race was associated with two-fold increased odds for BK viremia. Recipient female sex was associated with more rapid clearance of BK viremia. Persistent BK viremia/BKVN was associated with poorer allograft function by 24 months post-transplant. We identified multiple donor and recipient demographic factors associated with risk for BKV infection and poorer allograft function by 24 months post-transplant. This may help design future clinical trials of therapies to prevent or mitigate the deleterious impact of BKV reactivation on kidney transplant outcomes.

BK polyomavirus infection: more than 50 years and still a threat to kidney transplant recipients

BK polyomavirus (BKPyV) is a ubiquitous human polyomavirus and a major infection after kidney transplantation, primarily due to immunosuppression. BKPyV reactivation can manifest as viruria in 30%–40%, viremia in 10%–20%, and BK polyomavirus-associated nephropathy (BKPyVAN) in 1%–10% of recipients. BKPyVAN is an important cause of kidney graft failure. Although the first case of BKPyV was identified in 1971, progress in its management has been limited. Specifically, there is no safe and effective antiviral agent or vaccine to treat or prevent the infection. Even in the current era, the mainstay approach to BKPyV is a reduction in immunosuppression, which is also limited by safety (risk of de novo donor specific antibody and rejection) and efficacy (graft failure). However, recently BKPyV has been getting more attention in the field, and some new treatment strategies including the utilization of viral-specific T-cell therapy are emerging. Given all these challenges, the primary focus of this article is complications associated with BKPyV, as well as strategies to mitigate negative outcomes.

Single-Center Outcomes of Epstein-Barr Virus DNAemia in Adult Solid Organ Transplant Recipients.

Immunosuppression in solid organ transplantation (SOT) increases the risk of Epstein-Barr virus (EBV) DNAemia, which may herald development of posttransplant lymphoproliferative disease (PTLD). Few studies have characterized the incidence, risk factors, and clinical impact of EBV DNAemia in adult SOT recipients (SOTR). A single-center, retrospective review of adult (≥18 years) SOTR between 01 January 2015 and 31 December 2019 was conducted. Patients were stratified by the primary study endpoint of development of EBV DNAemia (whole blood EBV DNA PCR > 200 copies/mL). Secondary endpoints included development of PTLD, reduction in immunosuppression (RIS), use of pre-emptive therapy, and all-cause mortality. Among 442 adult SOTR, the predominant transplant organs were the kidney (258, 58%) and liver (141, 31.9%). EBV serostatus in most subjects (430, 97%) was classified as intermediate risk (R+). Eight subjects (2%) were high risk (donor (D+/R-), and 4 (1%) were low risk (D-/R-). The overall incidence of EBV DNAemia was 4.1% (18/442) with a median time to detection of 14 months (range 3-60). The highest proportion of DNAemia was observed in D+/R- subjects (37.5%; p < 0.001). Development of PTLD was significantly associated with EBV DNAemia and occurred in 3/18 patients with DNAemia (16.7%) vs. 3/424 (0.7%) without DNAemia (p < 0.001). All patients with PTLD were managed with RIS and rituximab. We observed that EBV D+/R- serostatus and development of sustained EBV DNAemia were high risk features associated with subsequent development of PTLD in our cohort of adult SOTR.

Evaluating Kaposi Sarcoma in Kidney Transplant Patients: A Systematic Review and Meta-Analysis.

Kaposi's sarcoma (KS) is a malignancy that commonly appears as lesions on the skin or mucosal surfaces but can also develop in other organs. This cancer is usually caused by the human herpesvirus 8 (HHV-8), recently known as Kaposi's sarcoma-associated herpesvirus (KSHV). KS is rare in the general population but can develop in kidney transplant recipients with varying incidence due to immunocompromised status from immunosuppression. The main aim of the present systematic review was to identify the prevalence and treatment of KS in kidney transplant patients. PubMed, Cochrane Library, and Google Scholar databases were searched for studies until October 2023. Full-text studies with similar research objectives were included, while non-English articles, reviews, case reports, ongoing clinical trials, and studies evaluating KS in HIV patients or after other solid organ transplants were excluded. All studies were observational; therefore, methodological quality was assessed using the Newcastle-Ottawa Scale. The statistical analyses were performed with the Comprehensive Meta-Analysis (CMA) software (Biostat, Inc.Englewood, NJ). The pooled analysis from the 15 studies includedshowed that KS develops in 1.5% of kidney transplant recipients and is more prevalent in African (1.7%) and Middle Eastern (1.7%) recipients than in Western recipients (0.07%). KS was also significantly more prevalent among male recipients than female recipients (OR: 2.36; p < 0.0001). Additionally, cyclosporine-based immunosuppression accounts for most KS incidences (79.6%) compared to azathioprine-based immunosuppression (28.2%). Furthermore, reduction or withdrawal of immunosuppression alone resulted in 47.8% KS complete remissions. Post-kidney transplantation KS is more frequent among males and patients of Middle Eastern and African origin. However, the gender difference may be attributed to most patients undergoing kidney transplants being male. Therefore, if gender balance is considered in future studies, then the difference might be insignificant. Based on our results, we can concur that the mainstay treatment for post-transplant KS is reduction or withdrawal of immunosuppression. However, the patients should be closely monitored to avoid KS recurrence and kidney rejection. Furthermore, there is an increased risk for KS with the use of cyclosporine-based immunosuppression. However, this does not mean that the withdrawal of this immunosuppression agent might result in improved KS outcomes because the withdrawal of azathioprine with or without cyclosporine reduction has also led to improved outcomes.

Seizure in the Immediate Postrenal Transplant Period – A Diagnostic and Therapeutic Challenge

ABSTRACT Seizures postkidney transplant occur in 11.4% of recipients and major causes include immunosuppressive drugs, metabolic derangements, central nervous system infections, and posterior reversible encephalopathy syndrome (PRES). PRES is described as an acute clinical-radiological phenomenon commonly associated with hypertensive emergencies, preeclampsia, and neurotoxic effects of immunosuppressive medications. Herein, we describe a young male presenting with seizures 14 h after a successful live-related kidney transplant with magnetic resonance imaging (MRI) of the brain (MRI-T2/FLAIR) showing hyperintense bilateral parietal-occipital and parietal-temporal region suggestive of PRES. The patient was managed without switching or reduction of immunosuppression and the patient recovered with resolution of MRI changes 6 weeks posttransplant with blood pressure control.

Efficacy of mTOR Inhibitors and Intravenous Immunoglobulin for Treatment of Polyoma BK Nephropathy in Kidney Transplant Recipients: A Biopsy-Proven Study.

We investigated the efficacy of a predetermined protocol that consisted of immunosuppressive drug reduction/withdrawal and intravenous immunoglobulin administration for the treatment of polyoma BK virus nephropathy. Patients with biopsy-proven polyoma BK virus nephropathy received a treatment regimen based on discontinuation of both calcineurin inhibitors and antiproliferative agents and switching to mTOR inhibitors accompanied by intravenous immunoglobulin administration. Our study included 508 patients, with polyoma BK viremia detected in 80 patients. The mean age was 45.3 ± 9.5 years (range, 18-71 y), 64% were male, and mean follow-up was 37 ± 21 months (6-94 mo). All 16 patients who developed polyoma BK virus nephropathy and 9 patients who had highgrade polyoma BK viremia without nephropathy received intravenous immunoglobulin treatment. Compared with patients with viremia, patients with polyoma BK virus nephropathy had significantly higher rates of graft loss due to rejection (18.8% vs 1.6%; P = .024) and all-cause graft loss (31.2% vs 6.3%; P = .014). Histopathologically, viral inclusion bodies disappeared and SV40 became negative after treatment in all 13 patients who underwent protocol biopsies. Unfortunately, histopathologically complete recovery without chronic tubular and interstitial tissue damage was achieved in only 4 patients after treatment. In addition, 3 patients lost their grafts due to acute antibody-mediated or mixed-type rejection (18.8%). In patients with polyoma BK virus nephropathy, clearance of viremia and SV40 should not be the sole outcomes to obtain. Aggressive reductions in maintenance immunosuppression and switching to double-drug therapy combined with high-dose intravenous immunoglobulin leads to high rates of graft loss/rejection and sequalae of chronic histological changes.

Clinical characteristics and outcomes of Epstein-Barr virus viral load after allogeneic hematopoietic stem cell transplantation

Epstein-Barr virus (EBV) reactivation can occur following allogenic hematopoietic stem cell transplantation (allo-HSCT). However, the clinical characteristics and outcomes of EBV-viral load are not well known. Thus, we retrospectively analyzed the clinical features and prognostic impact of the EBV viral load in 121 allo-HSCT recipients from our hospital. EBV DNA quantification was performed in whole blood after transplantation. Patients were grouped based on whether EBV DNA quantification reached > 1000 copies/mL during follow-up (N = 50) or not (N = 71). Patients with EBV > 1000 EBV copies/mL were relatively more common in the groups with graft versus host disease (GVHD) prophylaxis including ATG, haploidentical donor type, peripheral blood as a donor source, and acute GVHD II–IV. The 20-month OS and DFS were not significantly different between patients with < 1000 EBV copies/mL and patients with > 1000 EBV copies/mL (20-month OS, 56.0% vs. 60.6%; p = 0.503, 20-month DFS, 50.0% vs. 57.7%; p = 0.179). Immunosuppressant (ISS) dose reduction was achieved after the maximum increase in EBV in 41/50 (82%) patients. Additionally, 30/50 (60%) patients achieved a 50% dose reduction or no restarting of ISS within 3 months of the maximum EBV increase. Among cases wherein EBV DNA quantification reached > 1000 copies/mL, those that achieved rapid dose reduction of ISS tended to have longer overall survival (“not reached” vs 5.4 months, p < 0.001) and disease-free survival (88.4 months vs 5.3 months, p < 0.001) than those in patients who did not. Our data highlight the importance of rapid ISS reduction in post-transplant EBV reactivation.