key: cord-0836405-zbwoo8oo
authors: Masset, Christophe; Gautier-Vargas, Gabriela; Cantarovich, Diego; Dantal, Jacques; Delbos, Florent; Walencik, Alexandre; Kerleau, Clarisse; Hourmant, Maryvonne; Garandeau, Claire; Meurette, Aurélie; Giral, Magali; Benotmane, Ilies; Caillard, Sophie; Blancho, Gilles
title: Occurrence of de novo Donor Specific Antibodies after Covid-19 in kidney transplant recipients is low despite immunosuppression modulation
date: 2022-02-07
journal: Kidney Int Rep
DOI: 10.1016/j.ekir.2022.01.1072
sha: 8eb049abbd4fa38be03b476300edee4e682d4ee7
doc_id: 836405
cord_uid: zbwoo8oo

INTRODUCTION: Decreased immunosuppression has been proposed for kidney transplant recipients infected with Covid-19 but the impact on the alloreactive immune response during and after infection has been poorly investigated. We assessed the occurrence of anti HLA donor specific antibodies (post-Covid DSA) and rejection episodes following Covid-19 with particular focus on immunosuppression modulation. METHODS: Kidney transplant recipients from two French institutions had anti-HLA antibody screening before and after Covid-19. Management of immunosuppression, rejection episodes, Covid-19 severity, inflammatory markers and antiviral therapies were recorded. RESULTS: From 251 recruited patients, 72 were excluded because of Covid-19 related death (n= 25) and incomplete immunological follow-up (n= 47). Among the remaining 179 included patients, almost half were hospitalized (49.2%). Antimetabolites were interrupted in 47% of patients (82% in hospitalized, median time of resumption of 23 days and in 15% non-hospitalized, median time of resumption of 7 days). Calcineurin inhibitors were interrupted in 12% of patients (all hospitalized, median time of resumption of 11 days). The incidence of post-Covid DSA was 4% (8% and 0% in hospitalized and non-hospitalized, respectively). Allograft rejection occurred in 3 patients (1.7%) and all were hospitalized. Younger age, transplantation less than one year and preexisting DSA were more frequently observed in post-Covid DSA positive patients, whereas inflammatory markers, lymphopenia and use of antiviral therapies were not. CONCLUSION: The incidence of post-Covid DSA among Covid-19 positive kidney transplant recipients was low (4%) despite a significant decrease in immunosuppression and was mainly restricted to high-risk immunological patient’s status. Covid-19 severity was not associated with post-Covid DSA and/or rejection.

Coronavirus-19 infection/disease (Covid-19) is a worldwide pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2) with more than five million deaths attributable so far (end 2021). Greater severity of Covid-19 has been reported in kidney transplant recipients and is most likely due to comorbidities and immunosuppressive therapy [1] [2] [3] . The management of immunosuppression in kidney transplant recipients with Covid-19 varies between centers 4,5 . For non-hospitalized patients with non-symptomatic forms, immunosuppression can be slightly decreased or even maintained 6 . For hospitalized patients, antimetabolite drugs such as Mycophenolate mofetil (MMF) and mycophenolic acid (MPA) are often reduced or stopped whereas calcineurin inhibitors (CNI) such as Tacrolimus or Cyclosporine are continued in order to avoid the occurrence of acute rejection, but also possibly because of potential anti SARS-Cov properties in-vitro 7 

Intensive Care Unit (ICU) with severe forms, no consensus exists and immunosuppression may be completely discontinued. During SARS-Cov-2 infection, viral antigenic stimulation causes a cytokine storm involving high IL-6 levels, potentially leading to an alloreactive reaction against the graft 8, 9 . However, adjunction of immunosuppressive therapies such as high-dose steroids or Tocilizumab may prevent this alloimmune response 10 

We conducted a retrospective cohort analysis of kidney transplant recipients and assessed occurrence of new DSAs (post-Covid DSA) and allograft rejection following Covid-19. As part of their standard follow-up, all included patients had regular anti-HLA screening. Deceased patients were excluded from the final analysis, as were patients with incomplete immunological follow-up (defined as anti-HLA screening more than 24 months prior to and/ We defined DSA according to the time of appearance as follows:

-Pre-existing DSA: presence of a DSA with MFI ≥ 1000 before transplantation.

-Post-transplant DSA: occurrence of a de novo DSA with MFI ≥ 1000 after transplantation but before SARS-Cov-2 infection.

-Post-Covid DSA: occurrence of a de novo DSA with MFI ≥ 1000 after SARS-Cov-2 infection with no description in patient history at any MFI level.

Class I and II anti-HLA antibodies were measured by Luminex® screening (Immucor® or LABScreen -One lambda®). Single antigen screening was then performed for positive cases, and the DSA's MFI was assessed (LABScreen -One lambda®). All MFI above 1000 were included and noted. All sera were treated with EDTA to mitigate interference and the prozone effect. Patients with DSA prior to Covid-19 (pre-existing or post-transplant), were described based on the evolution of MFI values, and were considered significant when the MFI's varied ≥ 25% 11 .

Global management of patients in both institutions was based on current guidelines, suggesting antimetabolite withdrawal for cases of Covid-19 requiring hospitalization, CNI withdrawal for patients admitted to ICU. However, management of immunosuppressive therapies during and after Covid-19 was left to the physicians' discretion, balancing their patients risk for severe Covid-19 and immunological complication. Treatment reduction, withdrawal, and resumption were recorded. If treatment had not been reintroduced yet, we Table 1 summarizes the characteristics of the patients included in the study.

Among the deceased patients, CNI was interrupted in 54% and antimetabolites in 80% of cases. Among patients with incomplete immunological follow-up, CNI was never interrupted in non-hospitalized patients and in 25% of hospitalized ones (median resumption time was 8 days). Antimetabolites were interrupted in 5% of non-hospitalized patients and 73% of hospitalized ones (median resumption time was 27 days).

Among patients with complete immunological follow-up, CNI interruption occurred in 12% (all All patients with post-Covid DSA were hospitalized (2 were admitted in ICU) resulting in an 8% incidence in this specific population. These were younger (45 vs 58 years old, p = 0.17) and

were considered at higher immunological risk (shorter time from transplantation, 2.6 vs 6.8 years, p = 0.06 and with a higher prevalence of previously formed DSA, 29% vs 7%, p = 0.09).

Inflammatory markers (CRP and IL-6 levels), total lymphocyte count and Covid-19 severity (i.e. admission to ICU) did not seem to differ between patients with or without post-Covid DSA. The comparison between hospitalized patients with occurrence of post-Covid DSA and those without is summarized in Table 2 .

Among the seven patients with post-Covid DSA, MMF or MPA were interrupted for all cases (average time of resumption was 27 days), and CNI was interrupted for 3 of 6 (average time of resumption was 13 days). One patient did not receive conventional maintenance therapy (neither Tacrolimus nor antimetabolites) due to a recent life threating acute VZV infection, 

Covid-19 infection/disease after kidney transplantation. Whether this attitude results in a HLA alloreactive response and graft rejection is not known. We report here the outcomes of a large cohort of kidney transplant recipients with Covid-19, with special reference to post-Covid DSA occurrence, graft rejection, graft loss, and immunosuppression reduction. The global incidence of post-Covid DSA was 4% (7 from 179 patients). No post-Covid DSA was observed in patients that were monitored by videoconference or by phone (non-hospitalized), whereas the incidence was 8% in patients who were hospitalized. In fact, the criteria for hospitalization were not defined and were mostly based on patient's demand, not always reflecting the severity of the disease. Therefore, this difference should be interpreted with caution and may be just a result of hazard. In non-Covid-19 kidney transplant recipients, the average occurrence of de novo DSA was 5%, and this varied according to individual immune status (HLA mismatches, previous anti-HLA sensitization, history of rejection) 13 Since the beginning of the Covid-19 era, we took the decision to interrupt antimetabolite immunosuppressants for Covid-19 infected kidney transplant recipients. This was done according to clinical disease severity and after evaluating the risk and benefit balance in each case. Concerning CNI, no changes were made except for ICU admissions, where immunosuppression was almost always totally stopped. It is well demonstrated that early occurrence of dnDSA and acute rejection follows CNI withdrawal 17 or CNI reduction 18 in stable, low-immunological risk kidney transplant recipients. In cases of BKV-induced nephropathy 19, 20 and/or post-transplant lymphoproliferative disorders 21-23 , the reduction of immunosuppression was also followed by an increased risk of dnDSA and ABMR. Therefore, any change in immunosuppressive therapy during Covid-19 could also be associated with an immune response against the graft. A major limitation of our study is the absence of a control group without Covid-19 infection.

However, such a control cohort is somewhat counterintuitive, as reducing or interrupting immunosuppression is not routinely done in the absence of a major reason. In addition, 

An initial report from the French SOT COVID Registry suggests high mortality due to Covid-19 in recipients of kidney transplants

Is Covid-19 infection more severe in kidney transplant recipients?

IMPact of the COVID-19 epidemic on the moRTAlity of kidney transplant recipients and candidates in a French Nationwide registry sTudy (IMPORTANT)

The COVID-19 nephrology compendium: AKI, CKD, ESKD and transplantation

How should I manage immunosuppression in a kidney transplant patient with COVID-19? An ERA-EDTA DESCARTES expert opinion

Kidney allograft recipients, immunosuppression, and coronavirus disease-2019: a report of consecutive cases from a New York City transplant center

Replication of human coronaviruses SARS-CoV, HCoV-NL63 and HCoV-229E is inhibited by the drug FK506

The Impact of Cytomegalovirus Infection and Disease on Rejection Episodes in Renal Allograft Recipients: CMV Infection and Renal Transplant Rejection

Interleukin-6, A Cytokine Critical to Mediation of Inflammation, Autoimmunity and Allograft Rejection: Therapeutic Implications of IL-6 Receptor Blockade

Dexamethasone in Hospitalized Patients with Covid-19

Sensitization in Transplantation: Assessment of Risk (STAR) 2017 Working Group Meeting Report

Special Issue: KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients

Frequency and Clinical Implications of Development of Donor-Specific and Non-Donor-Specific HLA Antibodies after Kidney Transplantation

Eplet Mismatch Load and De Novo Occurrence of Donor-Specific Anti-HLA Antibodies, Rejection, and Graft Failure after Kidney Transplantation: An Observational Cohort Study

Assessment of Tocilizumab (Anti-Interleukin-6 Receptor Monoclonal) as a Potential Treatment for Chronic Antibody-Mediated Rejection and Transplant Glomerulopathy in HLA-Sensitized Renal Allograft Recipients

Failure of Calcineurin Inhibitor (Tacrolimus) Weaning Randomized Trial in Long-Term Stable Kidney Transplant Recipients

Reduction of Extended-Release Tacrolimus Dose in Low-Immunological-Risk Kidney Transplant Recipients Increases Risk of Rejection and Appearance of Donor-Specific Antibodies: A Randomized Study

Onset and progression of de novo donor-specific anti-human leukocyte antigen antibodies after BK polyomavirus and preemptive immunosuppression reduction

De novo donor-specific antibody following BK nephropathy: The incidence and association with antibody-mediated rejection

Post-Transplantation Lymphoproliferative Disorders in Adults

Reduction of Immunosuppression as Initial Therapy for Posttransplantation Lymphoproliferative Disorder★: Reduction of Immunosuppression for PTLD

Prospective Study of Sequential Reduction in Immunosuppression, Interferon Alpha-2B, and Chemotherapy for Posttransplantation Lymphoproliferative Disorder

Randomized Trial Comparing Late Concentration-Controlled Calcineurin Inhibitor or Mycophenolate Mofetil Withdrawal

COVID-19 and kidney transplantation: Results from the TANGO International Transplant Consortium

Protective Role of Tacrolimus, Deleterious Role of Age and Comorbidities in Liver Transplant Recipients With Covid-19: Results From the ELITA/ELTR Multi-center European Study

Influence of patient characteristics and immunosuppressant management on mortality in kidney transplant recipients hospitalized with coronavirus disease 2019 (COVID-19)

Clinical Profile and Outcome of COVID-19 in 250 Kidney Transplant Recipients: A Multicenter Cohort Study From India

COVID-19 and Calcineurin Inhibitors: Should They Get Left Out in the Storm?

The Critically Ill Kidney Transplant Recipient

SARS-CoV-2 and Tacrolimus Blood Concentration in Kidney Transplant Recipients

Immunosuppression minimization in kidney transplant recipients hospitalized for COVID-19

The authors would like to thank all medical staff that took care of patients during the current Covid-19 pandemic. We also thank the clinical research associates who participated in the data collection. The analysis and interpretation of these data are the responsibility of the authors. The authors do not declare any conflict of interest.

The authors declare no funding was received for this study. Table S1 . Description of main histological diagnosis in biopsies after Covid-19 in patients without DSA post-Covid (note that one patient could have several histological diagnoses), "(PDF)"

J o u r n a l P r e -p r o o f

 CKD I  CKD IV  CKD III  CKD II  CKD II  CKD I  CKD III