CHARACTERISTICS OF PATIENTS WHO RECEIVED BIOLOGICAL TREATMENT AFTER KIDNEY TRANSPLANTATION AND THE INCIDENCE OF SERIOUS INFECTIONS: A MULTICENTER STUDY

BackgroundKidney transplant patients due to both primary kidney involvement of chronic/autoimmune inflammatory diseases and end-stage kidney disease related to amyloidosis are followed up in rheumatology clinics. Biological agents one of the treatment options in kidney transplant recipients with chronic/autoimmune inflammatory disease.ObjectivesHowever, there is insufficient data on the development of infection in kidney transplant recipients who received biological treatment. Herein, we aimed to determine the incidence of serious infections in patients with kidney transplant recipients who are received biological therapy.MethodsKidney transplant recipients who are received biological agents due to rheumatologic disease were included in the study. Patients' demographic features, transplantation data, biological treatment, development of infection and severity of infection were screened retrospectively. Infections that requiring hospitalization were defined as severe infections.ResultsA total of 31 patients were included in the study, 14 (45%) of whom were female and mean age was 41 ±9 years. Twenty-five patients (80%) of them were non-preemptive kidney transplant and mean duration of hemodialysis before the transplantation was 40 ±40 months. Twenty-three patients (74%) had end stage kidney failure due to FMF-amyloidosis(Figure-1-). Seventeen patients (54%) received anakinra, 11 patients (35%) received canakinumab and 3 patients (10%) received etanercept with other immunosuppressive treatment. Mean treatment duration of biological agents was 4.2±2.6 years. Two patients developed solid organ malignancy and one patient developed hematological malignancy after transplantation. Sixteen of the patients (52%) were hospitalized at least once due to infection and 4 patients (13%) died due to infection. The cause of decease in two patients was COVID-19.ConclusionRheumatic diseases are an important cause of end-stage renal disease and definitive treatment is kidney transplantation. Kidney transplant recipients due to rheumatological disease also use biological agents in the post-transplantation period. Kidney transplant recipients have higher risk for the development of infection since they receive immunosuppressive therapy and use of biologic agents may further increase the risk for development infection. Meyer et al reported that infection developed in 54 of 187 solid organ transplant recipients using biological agents.[1] Mean treatment duration of biological agents was 12 months in this study. The incidence of infection was 54% in our study. Mean treatment duration of biological agent was 4.2 year was considered main reason for higher incidence of infection in our study.Reference[1]Meyer F, Weil-Verhoeven D, Prati C, Wendling D, Verhoeven F. Safety of biologic treatments in solid organ transplant recipients: A systematic review. Semin Arthritis Rheum. 2021 Dec;51(6):1263-1273. doi: 10.1016/j.semarthrit.2021.08.013. Epub 2021 Aug 26. Erratum in: Semin Arthritis Rheum. 2022 Aug;55:152015. PMID: 34507811.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Cellular and humoral immune responses after SARS-CoV-2 vaccination in pediatric kidney recipients

Objective: Humoral and cellular immune responses to SARS-CoV-2 vaccination are reduced in adult kidney recipients. After pediatric kidney transplantation there are only few data available - mostly limited to monitoring of SARS-CoV-2 antibodies. Method(s): Cellular and humoral immune responses have been monitored before and after SARS-CoV-2 vaccination in pediatric kidney recipients. After in vitro stimulation with SARS-CoV-2 antigen (spike glycoprotein) virus-specific CD4 and CD8 T cells (SARS-CoV-2-Tvis) have been identified by cytokine flow cytometry. SARS-CoV-2 IgG was measured by CMIA. Result(s): Immune response after SARS-CoV-2 vaccination was analyzed in a total of 30 pediatric kidney recipients (age at 1st vaccine dose 5.2 - 17.8 years, median 14.8 years;43% male;30/30 2 vaccine doses;23/30 3 vaccine doses). At time of vaccination 22 patients (73%) received a tacrolimus (Tac)-based immunosuppression combined with mycophenolate mofetil (MMF;n = 15) or everolimus (n = 6) or neither of them (n = 1);3 patients were exposed to cyclosporine A and 5 patients to a calcineurin inhibitor (CNI)- free immunosuppression. MMF was used in 18/30 patients. After 1st dose of mRNA vaccine SARS-CoV-2 antibodies were detectable in 50% of pediatric kidney recipients, after 2nd dose in 78% and after 3rd dose in 88%. After the 2nd vaccine dose absence of humoral immune response (< 33.8 BAU/ml) was only found in case of MMF use (predominately combined with Tac). Peak IgG values (> 2,080 BAU/ml) were only detected in MMF-free regimens (6/7). Cellmediated response partially differed from humoral response, e. g., in some patients SARS-CoV2-Tvis were found despite lack of virus-specific antibodies. After 1st vaccine dose SARS-CoV-2-Tvis were detectable in 50% of pediatric kidney recipients, after 2nd dose in 92%. After 2nd vaccine dose absence or very low levels of SARS-CoV-2-Tvis (< 0.3 cells/mul) were only found in Tac-based immunosuppressive regimens, whereas higher levels (> 1.3 cells/mul) were exclusively detected in patients with MMFfree medication. Conclusion(s): After pediatric kidney transplantation humoral and cellular immune responses to SARS-CoV-2 vaccination were suboptimal, but more pronounced than in adult kidney recipients. Use of Tac and MMF was associated with impaired immune response to vaccination. SARS-CoV-2-specific humoral response corresponded only partially to cell-mediated response. Additional monitoring of SARS-CoV- 2-Tvis might be recommendable to improve assessment of the individual vaccine response and thereby to personalize the decision on the necessity of further vaccine doses.

Enhance Access to Kidney Transplantation and Living Kidney Donation (EnAKT LKD): Statistical Analysis Plan of a Registry-Based, Cluster-Randomized Clinical Trial.

Background: Enhance Access to Kidney Transplantation and Living Kidney Donation (EnAKT LKD) is a quality improvement intervention designed to enhance access to kidney transplantation and living kidney donation. We conducted a cluster-randomized clinical trial to evaluate the effect of the intervention versus usual care on completing key steps toward receiving a kidney transplant. Objective: To prespecify the statistical analysis plan for the EnAKT LKD trial. Design: The EnAKT LKD trial is a pragmatic, 2-arm, parallel-group, registry-based, open-label, cluster-randomized, superiority, clinical trial. Randomization was performed at the level of the chronic kidney disease (CKD) programs (the "clusters"). Setting: Twenty-six CKD programs in Ontario, Canada. Participants: More than 10 000 patients with advanced CKD (ie, patients approaching the need for dialysis or receiving maintenance dialysis) with no recorded contraindication to receiving a kidney transplant. Methods: The trial data (including patient characteristics and outcomes) will be obtained from linked administrative health care databases (the "registry"). Stratified covariate-constrained randomization was used to allocate the 26 CKD programs (1:1) to provide the intervention or usual care from November 1, 2017, to December 31, 2021 (4.17 years). CKD programs in the intervention arm received the following: (1) support for local quality improvement teams and administrative needs; (2) tailored education and resources for staff, patients, and living kidney donor candidates; (3) support from kidney transplant recipients and living kidney donors; and (4) program-level performance reports and oversight by program leaders. Outcomes: The primary outcome is completing key steps toward receiving a kidney transplant, where up to 4 unique steps per patient will be considered: (1) patient referred to a transplant center for evaluation, (2) a potential living kidney donor begins their evaluation at a transplant center to donate a kidney to the patient, (3) patient added to the deceased donor transplant waitlist, and (4) patient receives a kidney transplant from a living or deceased donor. Analysis plan: Using an intent-to-treat approach, the primary outcome will be analyzed using a patient-level constrained multistate model adjusting for the clustering in CKD programs. Trial Status: The EnAKT LKD trial period is November 1, 2017, to December 31, 2021. We expect to analyze and report the results once the data for the trial period is available in linked administrative health care databases. Trial Registration: The EnAKT LKD trial is registered with the U.S. National Institute of Health at clincaltrials.gov (NCT03329521 available at https://clinicaltrials.gov/ct2/show/NCT03329521). Statistical Analytic Plan: Version 1.0 August 26, 2022.

Contexte: EnAKT LKD est une intervention d'amélioration de la qualité visant à améliorer l'accès à la transplantation rénale et au don vivant de rein. Nous avons mené un essai clinique randomisé par grappes afin d'évaluer l'effet de l'intervention, par rapport aux soins habituels, sur le taux d'étapes clés réalisées dans le processus de réception d'une greffe de rein. Objectif: Exposer les grandes lignes du plan d'analyse statistique de l'essai EAKT LKD. Conception: EAKT LKD est un essai clinique pragmatique ouvert, à deux bras, en groupes parallèles, basé sur un registre, et randomisé en grappes. La randomisation a été réalisée au niveau des programmes d'insuffisance rénale chronique (IRC) (les « grappes ¼). Cadre: 26 programmes d'IRC en Ontario (Canada). Sujets: Plus de 10 000 patients atteints d'IRC de stade avancé (des patients approchant le besoin de dialyse ou recevant une hémodialyse d'entretien) sans contre-indication documentée à la greffe rénale. Méthodologie: Les données de l'essai (y compris les caractéristiques et les résultats des patients) seront obtenues à partir de bases de données administratives en santé (le « registre ¼). La randomisation stratifiée avec contraintes de covariables a servi à répartir les 26 programmes d'IRC (1:1) selon qu'ils allaient fournir l'intervention ou les soins habituels entre le 1er novembre 2017 et le 31 décembre 2021 (4,17 ans). Les programmes d'IRC du bras d'intervention ont eu droit au soutien suivant: (1) des équipes locales d'amélioration de la qualité et du soutien administratif; (2) de l'information et des ressources sur mesure pour le personnel, les patients et les donneurs vivants; (3) du soutien de la part de receveurs et de donneurs vivants; et (4) des rapports sur le rendement au niveau du programme et une surveillance assurée par les chefs de programme. Résultats: Le principal critère d'évaluation est le taux d'étapes clés accomplies vers la réception d'une greffe de rein, où jusqu'à quatre étapes uniques par patient seront comptabilisées: (1) le patient est aiguillé vers un centre de transplantation pour évaluation; (2) un possible donneur vivant de rein contacte un centre de transplantation pour un receveur en particulier et amorce son évaluation; (3) le patient est ajouté à la liste d'attente pour une transplantation d'un donneur décédé, et (4) le patient reçoit une greffe de rein d'un donneur vivant ou décédé. Plan d'analyse: Selon une approche fondée sur l'intention de traiter, le critère d'évaluation principal sera analysé au niveau du patient en utilisant un modèle multiétats contraint, corrigé dans les programmes d'IRC en fonction du regroupement. Statut de l'essai: L'essai EnAKT LKD s'est tenu du 1er novembre 2017 au 31 décembre 2021. Nous analyserons les résultats et en rendrons compte dès que les données seront disponibles dans les bases de données administratives couplées du système de santé.

Dialysis Requirements of Kidney Transplant Recipients During COVID-19

Objective: The complications of Coronavirus Disease 2019 (COVID-19) have increased among kidney transplant recipients (KTR) due to chronic immunosuppression and comorbidities. Additionally, acute kidney injury (AKI) is frequently observed during COVID-19. This study aimed to investigate the impact of COVID-19 on kidney allograft survival. Materials and Methods: The retrospective, single-center investigation study included 88 patients who had a functioning kidney allograft prior to COVID-19 diagnosis. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection was confirmed with a polymerase chain reaction (PCR) test and thoracic computerized tomography. AKI and dialysis require-ments were analyzed using laboratory, demographic, and clinical parameters. Results: The median age of the patients was 44.5 (34.3-53.8) years, and the median allograft survival was 59.0 (20.8-116.5) months. The mean baseline estimated glomerular filtration rate (eGFR) was 58.2 (21.2-92.8) ml/min/1.73 m2 before the COVID-19 diagnosis. The frequency of AKI was 70.4% (62 patients), and dialysis therapy was required in nine patients (10.2%). The clinical features of COVID-19 and inflammatory markers had no statistical significance in predicting dialysis requirements. However, logistic regression analysis indicated that serum protein level (p=0.034), serum albumin level (p=0.048), hemoglobin (p=0.028), baseline eGFR (p=0.033), and age (p=0.041) were significantly predictive for dialysis requirements. Conclusion: Age, anemia, and decreased baseline eGFR are related to severe AKI and dialysis therapy in KTR during COVID-19.

Optimizing COVID-19 Vaccination Strategy in Pediatric Kidney Transplant Recipients: Humoral and Cellular Response to SARS-CoV-2 mRNA Vaccination.

In this retrospective cohort study, we analyze the early humoral and cellular response in 64 adolescents KTx recipients, after two or three doses of mRNA vaccine BNT162b2 against different variants of COVID-19. After 2 doses, 77.8% % of children with no history of infection had a positive humoral response with a median anti-S IgG level of 1107 (IQR, 593-2,658) BAU/mL. All the patients with a history of infection responded with a higher median IgG level (3,265 (IQR, 1,492-8,178) BAU/mL). In non-responders after 2 doses, 75% responded after a third dose with a median Ab titer at 355 (IQR, 140-3,865 BAU/mL). Neutralizing activity was significantly lower against the delta and the omicron variants compared to the wild-type strain and did not improve after a 3rd dose, while infection did provide higher levels of neutralizations against the variants. T cell specific response correlated with humoral response and no patient displayed a cellular response without a humoral response. Adolescent KTx recipients exhibit a high seroconversion rate after only two doses. A third injection, induces a response in the majority of the non-responders patients but did not counterbalance the strong decrease in neutralizing antibody activities against variants highlighting the need for boosters with specific vaccines.

Research highlights on kidney transplantation in 2021: Voices from China

Over the past 70 years, kidney transplantation has become not only the most mature but also the highest-success-rate surgery among all organ transplantation surgeries. However, the long-term survival of kidney transplant recipients is still challenged by such key factors as ischemia-reperfusion injury related to kidney transplantation, rejection, chronic renal allograft dysfunction, renal allograft fibrosis, immunosuppressive therapy, infections and others. Relevant fundamental and clinical studies have emerged endlessly. At the same time, the research related to kidney transplantation also becomes a new hot spot accordingly in the context of the normalization of novel coronavirus pneumonia. This article reviewed the cutting-edge hot spots in relation to the fundamental and clinical aspects of kidney transplantation together with relevant new techniques and new visions. The studies included in this article focused on the reports published by Chinese teams that are more applicable to the current situation of kidney transplantation in China, for the purpose of providing new thoughts and strategies for the diagnosis and treatment of kidney transplantation related issues in China.Copyright © 2022 Organ Transplantation. All rights reserved.

Research highlights of renal transplantation in 2020: voice from China

Renal transplantation is the optimal approach to improve the quality of life and restore normal life for patients with end-stage renal diseases. With the development of medical techniques and immunosuppressants, the short-term survival of renal graft has been significantly prolonged, whereas the long-term survival remains to be urgently solved. Renal ischemia-reperfusion injury (IRI), acute rejection, chronic renal allograft dysfunction, renal fibrosis and other factors are still the major problems affecting the survival of renal graft. Relevant researches have always been hot spots in the field of renal transplantation. Meantime, 2020 is an extraordinary year. The novel coronavirus pneumonia (COVID-19) pandemic severely affects the development of all walks of life. Researches related to renal transplantation have also sprung up. In this article, the frontier hotspots of clinical and basic studies related to renal transplantation and the COVID-19 related researches in the field of renal transplantation in China were reviewed, aiming to provide novel therapeutic ideas and strategies.Copyright © 2021 Journal of Zhongshan University. All Rights Reserved.

Pancreatitis Secondary to Paxlovid-Induced Tacrolimus Toxicity

Introduction: Pancreatitis is a very common gastrointestinal disease that results in hospital admission. Early detection and treatment leads to better outcomes. This is the first reported case of pancreatitis secondary to elevated tacrolimus in a patient with prior renal transplantation after receiving Paxlovid for a COVID-19 infection. Case Description/Methods: A 57-year-old male with past medical history of 4 renal transplants secondary to posterior urethral valves who presented to the emergency room with acute onset epigastric pain for 24 hours. He was on tacrolimus 5 mg every 48 hours monotherapy for his immunosuppression. 10 days prior to his presentation he had developed chills and anxiety. He tested positive for COVID-19 at that time on a home rapid test. His symptoms had not significantly improved and given his immunosuppressed state he was given Paxlovid (Nirmatrelvir/ritonavir). He took 2 days of Paxlovid, however after his second day of treatment he developed severe epigastric pain requiring him to go to the emergency room. On admission his labs were notable for a lipase of 150 U/L (ULN 63 U/L). He underwent a CT scan was notable for an enlarged pancreatic head and neck with peripancreatic fat stranding (Figure). He also had a right upper quadrant ultrasound without any cholelithiasis and only trace sludge noted. His creatinine was noted to be 1.81 mg/dl which was above his baseline of 1.2 mg/dl. His tacrolimus trough level resulted at a level 45.6 ng/ml and later peaked at 82.2 ng/ml. His liver enzymes were normal. He was treated as acute pancreatitis with hydration and his tacrolimus was held with overall clinical improvement. Discussion(s): Tacrolimus is one of the most common medications used in solid organ transplantation. It is a calcineurin inhibitor that inhibits both T-lymphocyte signal transduction and IL-2 transcription. It is metabolized by the protein CYP3A and levels are monitored closely. Paxlovid is currently prescribed as an antiviral therapy for COVID-19 infection. The ritonavir compound in Paxlovid is potent inhibitor of CYP3A. Currently the guidelines do not recommend Paxlvoid as a therapeutic in patients taking tacrolimus as there is concern about increased drug levels. There have been several case reports of pancreatitis in setting of tacrolimus. This case report helps to demonstrate the need for close monitoring of therapeutics levels, especially in medications with high risk of drug to drug interaction to help prevent serious side effects such as tacrolimus induced pancreatitis.

Efficacy and safety of a fourth dose of the COVID-19 vaccine in kidney transplant recipients: A systematic review and meta-analysis.

BACKGROUND: Kidney transplant recipients (KTRs) who become infected with SARS-CoV-2 are at greater risk of serious illness and death than the general population. To date, the efficacy and safety of the fourth dose of the COVID-19 vaccine in KTRs have not been systematically discussed. METHODS: This systematic review and meta-analysis included articles from PubMed, Embase, the Cochrane Library, Web of Science, China National Knowledge Infrastructure, and Wanfang Med Online published before May 15, 2022. Studies evaluating the efficacy and safety of a fourth dose of the COVID-19 vaccine in kidney transplant recipients were selected. RESULTS: Nine studies were included in the meta-analysis, with a total of 727 KTRs. The overall pooled seropositivity rate after the fourth COVID-19 vaccine was 60% (95% CI, 49%-71%, I2 = 87.83%, p > 0.01). The pooled proportion of KTRs seronegative after the third dose that transitioned to seropositivity after the fourth dose was 30% (95% CI, 15%-48%, I2 = 94.98%, p < 0.01). CONCLUSIONS: The fourth dose of the COVID-19 vaccine was well tolerated in KTRs with no serious adverse effects. Some KTRs showed a reduced response even after receiving the fourth vaccine dose. Overall, the fourth vaccine dose effectively improved seropositivity in KTRs, as recommended by the World Health Organization for the general population.

Development and validation of multivariable prediction models of serological response to SARS-CoV-2 vaccination in kidney transplant recipients.

Repeated vaccination against SARS-CoV-2 increases serological response in kidney transplant recipients (KTR) with high interindividual variability. No decision support tool exists to predict SARS-CoV-2 vaccination response to third or fourth vaccination in KTR. We developed, internally and externally validated five different multivariable prediction models of serological response after the third and fourth vaccine dose against SARS-CoV-2 in previously seronegative, COVID-19-naïve KTR. Using 20 candidate predictor variables, we applied statistical and machine learning approaches including logistic regression (LR), least absolute shrinkage and selection operator (LASSO)-regularized LR, random forest, and gradient boosted regression trees. For development and internal validation, data from 590 vaccinations were used. External validation was performed in four independent, international validation cohorts comprising 191, 184, 254, and 323 vaccinations, respectively. LASSO-regularized LR performed on the whole development dataset yielded a 20- and 10-variable model, respectively. External validation showed AUC-ROC of 0.840, 0.741, 0.816, and 0.783 for the sparser 10-variable model, yielding an overall performance 0.812. A 10-variable LASSO-regularized LR model predicts vaccination response in KTR with good overall accuracy. Implemented as an online tool, it can guide decisions whether to modulate immunosuppressive therapy before additional active vaccination, or to perform passive immunization to improve protection against COVID-19 in previously seronegative, COVID-19-naïve KTR.

Influencia de la pandemia por Covid 19 en el trasplante de órganos

En el mes de Diciembre (2019) se diagnosticó la infección viral que tuvo una rápida expansión. En el mes de Junio (2020) solo en 188 países fueron diagnosticados 35 millones de pacientes. Desgraciadamente en nuestro país los resultados de la atención a los enfermos (diagnostico, aislamiento, atención), fue peor que en otros muchos (Alemania, Italia, Corea, Taiwán, Grecia, Portugal, Francia, Japón y otros). 778 pacientes trasplantados sufrieron la infección, de ellos, 249 en la Comunidad de Madrid. La donación de órganos se redujo rápidamente debido a que las áreas de hospitalización, UCI, quirófanos, actividad hospitalaria en general hubo de dedicarse al tratamiento de los enfermos infectados. Hubo de asumir la reducción de trasplantes de riñón, hígado, corazón, pulmón, en casi el 90% de las cifras correspondientes a los dos años anteriores (en el mes de abril 0%), en el periodo marzo-Julio 2020. No se permitió el trasplante con donante vivo,” Split” o "Cluster”. Solo en la Comunidad de Madrid se realizaron 37 trasplantes menos en 2020 que en 2019. Los motivos de este descenso fue la reducción de camas en UCI, de posibilidades de utilización de quirófanos, menor número de facultativos, enfermeras, personal sanitario en general (861.112 infectados, de los cuales 36.000 eran sanitarios, con una mortalidad global de 36.000). Nuevos protocolos, formas de tratamiento, vacunación, hicieron posible volver a la cifra de trasplantes realizados entre 2018-2019.Alternate : On 31 December 2019 COVID-19 Viral infection was diagnoses. On june 2020 only in 188 countries 33 millons of infected people were detected. Unfortunately in Spain the results of the treatment has been worse than in Germany, Italy, Corea, Taiwan., Grece, Portugal, France, Japan, and others. 778 transplanted patients were infected. 249 of them in Madrid area. Organ donation was reduced. National Organization of Organ Trasplantation diminished donation, and transplantation of kidney, liver, heart, lung close to 90% (in april, 0%) from march to july 2020. Living rolated or split, and cluster trasplantation was not permited. In Madrid area, on 2020 were done 37 transplantation less than in 2019 the causes of that were the reduction of UCI beds, time in the OR, reduction of doctors and nurses. 861.112 infected people, 32.992 died and from the total number of patients, 36.000 were included as, doctors, nurses and other related with health care areas new protocols, hospitals, intensive care areas, etc were established along 2020 going back to the previous results obtained during 2018-2019.

COVID-19 outcomes in kidney transplant recipients receiving a combination of sofosbuvir-daclatasvir treatment, a single-center study

Introduction: In the coronavirus disease 2019 (COVID-19) era, kidney transplantation recipients (KTRs) are at high risk due to using immunosuppressive drugs. Considering the lack of definitive cure for COVID-19, repurposing existing pharmaceuticals is a way to find an immediate medication. Objectives: This study aimed to evaluate the COVID-19 outcomes in KTRs, receiving combination of sofosbuvir and daclatasvir (SOF-DAC) treatment. Patients and Methods: This research was an observational study of 12 adult kidney transplant recipients with COVID-19, admitted to Shariati hospital, Tehran, Iran (October to December 2020). All the patients received a once-daily combination pill of SOF-DAC at a dose of 400/60 mg for 10 days. Results: Around October to December 2020, 12 adult KTR patients were recruited;four patients (33.3%) died and eight patients survived (66.7%). Acute kidney injury (AKI) secondary to COVID-19 was seen in 11 patients of the study population (91.7%), including four dead cases. Two of the three patients who underwent dialysis due to kidney complications, died. The laboratory results showed that the mean level of each parameter white blood cells (WBC), international normalized ratio (INR), C-reactive protein (CRP), ferritin, D-dimer on the last day of hospital stay was significantly different between two groups of survived and dead patients at a 95% confidence level (P < 0.05). Conclusion: Sofosbuvir combined with DAC for treatment of KTRs with COVID-19 infection reduced the mortality rate. Further, this medication was safe. Patients tolerated it well, and no serious adverse effects were observed. Larger studies are needed to validate these results.

Two-Hit Kidney Allograft Injury by SARS-CoV-2.

Coronavirus disease 2019 (COVID-19) has been associated with acute kidney injury in kidney transplant recipients by several mechanisms. The authors report a case of acute kidney allograft dysfunction in a 48-year-old patient who presented in the emergency room with anasarca and nephrotic syndrome close after mild COVID-19 and no other clinical condition. Histopathology of the allograft biopsy revealed two distinct and simultaneous kidney lesions, collapsing glomerulopathy and thrombotic microangiopathy. Renal function persistently deteriorated, and definitive dialysis was initiated. After excluding other plausible causes for the findings, this case strengthens the hypothesis that the kidney allograft is also a target of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Impact of COVID-19 on 2020 transplant activity and waiting lists in France

The COVID-19 pandemic strongly affected organ procurement and transplantation in France, despite the intense efforts of all participants in this domain. In 2020, the identification and procurement of deceased donors fell by 12% and 21% respectively, compared with the mean of the preceding 2 years. Similarly, the number of new registrations on the national waiting list declined by 12% and the number of transplants by 24%. The 3-month cumulative incidence of death or drop out for worsening condition of patients awaiting a liver transplant was significantly greater in 2020 compared to the previous 2 years. Continuous monitoring at the national level of early post-transplant outcomes showed no deterioration for any organ in 2020. At the end of 2020, less than 1% of transplant candidates and less than 1% of graft recipients - of any organ - had died of COVID-19.Copyright © 2021 The Author(s)

Protection from successive Omicron variants with SARS-CoV-2 vaccine and monoclonal antibodies in kidney transplant recipients.

Introduction: Kidney transplant recipients (KTRs) are at high risk of severe COVID-19, even when they are fully vaccinated. Additional booster vaccinations or passive immunization with prophylactic monoclonal antibodies are recommended to increase their protection against severe COVID-19. Methods: Here, we describe the neutralization of SARS-CoV-2 Delta, Omicron BA.1, BA.2, BA.4, and BA.5 variants, firstly by 39 serum samples from vaccinated KTRs exhibiting anti-spike antibody concentrations ≥264 binding antibody units (BAU)/mL and, secondly, by tixagevimab/cilgavimab. Results: No neutralization was observed for 18% of the KTRs, while serum from only 46% of patients could neutralize the five variants. Cross-neutralization of the Delta and Omicron variants occurred for 65-87% of sera samples. The anti-spike antibody concentration correlated with neutralization activity for all the variants. The neutralization titers against the Delta variant were higher in vaccinated KTRs who had previously presented with COVID-19, compared to those KTRs who had only been vaccinated. Breakthrough infections occurred in 39% of the KTRs after the study. Tixagevimab/cilgavimab poorly neutralizes Omicron variants, particularly BA.5, and does not neutralize BQ.1, which is currently the most prevalent strain. Discussion: As a result, sera from seropositive vaccinated KTRs had poor neutralization of the successive Omicron variants. Several Omicron variants are able to escape tixagevimab/cilgavimab.

Different antibody responses between liver and kidney transplant recipients elicited by third doses of COVID-19 mRNA vaccines.

Background: Solid organ transplant recipients exhibit decreased antibody responses, mainly due to their weakened immune systems. However, data are limited on antibody responses after the primary series of coronavirus disease 2019 (COVID-19) vaccines among recipients of various solid organ transplant types. Thus, we compared the antibody responses after three COVID-19 vaccine doses between liver transplant (LT) and kidney transplant (KT) recipients. Methods: We prospectively enrolled solid organ transplant recipients who received three COVID-19 vaccine doses from June 2021 to February 2022 and measured S1-specific immunoglobulin G antibodies using an enzyme-linked immunosorbent assay. Results: Seventy-six LT and 17 KT recipients were included in the final analysis. KT recipients showed consistently lower antibody responses even after the third vaccine dose (86.2% vs. 52.9%, P=0.008) and lower antibody titers (median, 423.0 IU/mL [interquartile range, 99.6-2,057 IU/mL] vs. 19.7 IU/mL [interquartile range, 6.9-339.4 IU/mL]; P=0.006) than were observed in LT recipients. Mycophenolic acid was a significant risk factor for a seropositive antibody response after the third vaccine dose in the multivariable analysis (odds ratio, 0.06; 95% confidence interval, 0.00-0.39; P=0.02). Conclusions: We found a weaker antibody response despite the completion of the primary series of COVID-19 vaccines in KT recipients than in LT recipients. Mycophenolic acid use in KT recipients might be the main contributor to this observation.

COVID-19 in Renal Transplant Recipients - A Single Center Experience from India.

Introduction: The information on the clinical outcome of renal transplant recipients getting COVID-19 infection is sparse. The aim of this study is to report a single-center experience of renal transplant recipients with COVID-19 from India. Methods: This was a retrospective study of 23 consecutive renal transplant recipients with COVID-19 infection presenting to our center from May 2020 to August 2020. Clinical parameters, laboratory values, imaging characteristics, and outcome of the patients were collected and analyzed. Results: Median follow-up duration was 36 (range: 10-110) days. Median age of patients was 54 (23-70) years, and 87% were male. Median duration since transplant was 69 (range: 15-132) months. The most common presenting feature was fever (82.6%), followed by breathlessness (43.5%) and cough (30.4%). Hospitalization rate was 52.2%, while 34.8% required ICU care. Severe to critical disease was seen in 39.1% of patients, and 17.4% required mechanical ventilation. Patients with severe disease had a higher incidence of lymphopenia (P = 0.005) when compared to the ones with mild to moderate disease. Acute kidney injury was seen in 39.1% of patients, and 13% required dialysis. Mortality rate was 13% overall, and 25% in those hospitalized. Conclusion: Renal transplant recipients with COVID-19 have a poor outcome. Although not all of them need hospitalization, they should be monitored closely. Immunosuppression minimization is an important part of the treatment strategy.

Nirmatrelvir/ritonavir treatment in SARS-CoV-2 positive kidney transplant recipients - a case series with four patients.

BACKGROUND: Despite vaccination coronavirus disease 2019 (COVID-19)-associated mortality caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains high in kidney transplant recipients. Nirmatrelvir is a protease inhibitor with activity against SARS-CoV-2. Nirmatrelvir reduces the risk for mortality and hospitalization, which is approved for treating adults at risk for severe disease. Nirmatrelvir is metabolized by the cytochrome P-450 (CYP) 3A4 isozyme CYP3A4 and is therefore co-administered with the irreversible CYP3A4 inhibitor ritonavir, which results in a drug interaction with tacrolimus. A limited number of patients with nirmatrelvir/ritonavir and tacrolimus therapy after kidney transplantation have been reported to date. It has been reported that tacrolimus was paused during the five-day nirmatrelvir/ritonavir therapy and subtherapeutic tacrolimus levels were observed after finishing nirmatrelvir/ritonavir in two patients. Therefore, optimization of tacrolimus dosing is urgently needed in transplant recipients receiving nirmatrelvir/ritonavir treatment. CASE PRESENTATION: Here, we present our first-hand experience with four patients receiving tacrolimus therapy following kidney transplantation and nirmatrelvir/ritonavir therapy due to COVID-19. Tacrolimus was paused during nirmatrelvir/ritonavir therapy in all patients, which resulted in stable therapeutic tacrolimus levels. Tacrolimus was continued directly after finishing nirmatrelvir/ritonavir to avoid subtherapeutic levels in the first patient treated. This patient received his usual tacrolimus maintenance dose, which resulted in toxic levels. Based on this observation, tacrolimus therapy was continued 24 h after finishing nirmatrelvir/ritonavir treatment at a reduced dose in the subsequent patients. In these patients, therapeutic to supratherapeutic tacrolimus levels were observed despite the therapeutic break and dose reduction. DISCUSSION AND CONCLUSIONS: Based on altered CYP3A4 metabolism, tacrolimus levels have to be closely monitored after treatment with nirmatrelvir/ritonavir. Our study suggests that tacrolimus treatment should be paused during nirmatrelvir/ritonavir medication and be continued 24 h after completing nirmatrelvir/ritonavir therapy at a reduced dose and under close monitoring. Based on the limited number of patients in this study, results must be interpreted with caution.

The impact of frailty syndrome on humoral response to SARS-CoV-2 mRNA vaccines in older kidney transplant recipients.

PURPOSE: Advanced age is associated with an impaired humoral immune response to SARS-CoV-2 mRNA vaccination in kidney transplant recipients (KTR). The mechanisms are, however, poorly understood. Frailty syndrome assessment may determine the most vulnerable population. METHODS: This study is a secondary analysis of a prospective study (NCT04832841) regarding seroconversion after BNT162b2 vaccination, including 101 SARS-CoV-2 naïve KTR 70 years and older. The Fried frailty components were evaluated, and antibodies against S1 and S2 subunits of SARS-CoV-2 were examined > 14 days after the second dose of BNT162b2 vaccine. RESULTS: Seroconversion was observed in 33 KTR. Male gender, eGFR, MMF-free immunosuppression, and a lower frailty score were associated with higher seroconversion rates in univariable regression. Concerning frailty components, physical inactivity had the most negative effect on seroconversion (OR = 0.36, 95% CI 0.14-0.95, p = 0.039). In a multivariable regression adjusted for eGFR, MMF-free immunosuppression, time from transplant and gender, pre-frail (OR = 0.27, 95% CI 0.07-1.00, p = 0.050), and frail status (OR = 0.14, 95% CI 0.03-0.73, p = 0.019) were associated with an increased risk of unresponsiveness to SARS-CoV-2 vaccines. CONCLUSION: Frailty was associated with an impaired humoral response to SARS-CoV-2 mRNA vaccination in older SARS-CoV-2 naïve KTR. TRAIL REGISTRATION: This study is registered under the identifier NCT04832841 on ClinicalTrials.gov.

Clinical Course and Outcomes of COVID-19 in Kidney Transplant Recipients.

Introduction: Kidney transplant recipients (KTR) are at increased risk of morbidity and mortality due to coronavirus disease 2019 (COVID-19). This study aimed to explore the clinical characteristics and outcomes of COVID-19 in KTR. Methods: We reviewed the clinical profile, outcomes, and immunological responses of recipients admitted with COVID-19. We determined the risk factors for mortality and severe COVID-19. Results: Out of 452 recipients on follow-up, 60 were admitted with COVID-19. Prevalent comorbidities were hypertension (71%), diabetes (40%), lung disease (17%). About 27% had tuberculosis. The median Sequential Organ Failure Assessment score at presentation was 3 (interquartile range [IQR] 1-5). There was a high incidence of diarrhea (52%) and anemia (82%). Treatment strategies included antimetabolite withdrawal (85%), calcineurin inhibitor decrease or withdrawal (64%), increased steroids (53%), hydroxychloroquine (21%), remdesivir (28.3%), and tocilizumab (3.3%). Severe COVID-19 occurred in 34 (56.4%) patients. During a median follow-up of 42.5 days (IQR 21-81 days), 83% developed acute kidney injury (AKI) and eight (13%) died. Mortality was associated with the baseline graft dysfunction, hypoxia at admission, lower hemoglobin and platelets, higher transaminases, higher C reactive protein, diffuse radiological lung involvement, hypotension requiring inotropes, and Kidney Diseases Improving Global Outcomes (KDIGO) stage 3 AKI (univariate analysis). Around 57% of patients remained RT-PCR positive at the time of discharge. By the last follow-up, 66.6% of patients developed IgM (immunoglobulin M) antibodies and 82.3% of patients developed IgG antibodies. Conclusion: COVID-19 in kidney transplant recipients is associated with a high risk of AKI and significant mortality.