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ObjectiveThis single-center retrospective study evaluated the use of tixagevimab-cilgavimab as an early treatment for COVID-19 in kidney transplant recipients (KTRs) during the omicron wave.MethodsKTRs were deemed at high risk for moderate-to-severe COVID-19 in presence of at least one comorbidity (age >60 years, diabetes, obesity, or cardiovascular disease) associated with a weak humoral response (ResultsOf the 61 KTRs at high risk, 26 received tixagevimab-cilgavimab. COVID-19-related hospitalizations (3.8% versus 34%, p=0.006) and oxygen need (3.8% versus 23%, p=0.04) were significantly less frequent in patients who received tixagevimab-cilgavimab. In addition, non-significant trends towards a lower number of ICU admissions (3.8% versus 14.3% p=0.17) and deaths (0 versus 3, p=0.13) were observed after administration of tixagevimab-cilgavimab. Ten of the 73 low-risk KTRs received tixagevimab-cilgavimab, and no significant clinical benefit was observed in this subgroup.ConclusionEarly administration of tixagevimab-cilgavimab may be clinically useful in high-risk KTRs with COVID-19; however, no major benefit was observed for low-risk patients.

BackgroundRepeated 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 in KTR.MethodsWe 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 KTR. Using 27 candidate predictor variables, we applied statistical and machine learning approaches including logistic regression (LR), LASSO-regularized LR, random forest, and gradient boosted regression trees. For development and internal validation, data from 585 vaccinations were used. External validation was performed in four independent, international validation datasets comprising 191, 184, 254, and 323 vaccinations, respectively.FindingsLASSO-regularized LR performed on the whole development dataset yielded a 23- and 11- variable model, respectively. External validation showed AUC-ROC of 0.855, 0.749, 0.828, and 0.787 for the sparser 11-variable model, yielding an overall performance 0.819.InterpretationAn 11-variable LASSO-regularized LR model predicts vaccination response in KTR with good overall accuracy. Implemented as an online tool, it can guide decisions when choosing between different immunization strategies to improve protection against COVID-19 in KTR.

The combination of cilgavimab-tixagevimab (Evusheld™, Astra Zeneca) became the mainstay for protecting transplant recipients with poor response to vaccination against the omicron variant. Serum neutralizing capacity against SARS-CoV-2 is positively associated with protection against severe forms of Covid-19.Both anti-RBD IgG titers and neutralizing antibody titers against the omicron BA.1 variant were measured in serum samples collected from 63 adult kidney transplant recipients who received prophylactic injections of Evusheld™. Patients who received prophylactic Ronapreve™ (casirivimab-imdevimab, n = 39) and those who were infected with SARS-CoV-2 during the fifth wave of the pandemic (n = 14) served as negative and positive controls, respectively.After a median interval from injection of 29 days (interquartile range 29-33 days), only 9.5% of patients who received Evusheld™ were able to neutralize the omicron variant compared to 71% of patients who were infected with SARS-CoV-2 and 2.6% of those who received Ronapreve™. Interestingly, convalescent patients displayed higher levels of neutralizing antibodies than those who received EvusheldTM (median: 2.3 log IC50, IQR: 1.5-2.7 versus 0.00 log IC50, IQR: 0&[ndash] 0.05; pThese findings suggest that Evusheld™ given at a dose of 300 mg is not sufficient to elicit an anti-RDB titer that confers in vivo neutralizing activity and support recent FDA recommendations, derived from in vitro models, regarding the need to increase the dose of Evusheld™

While the combination of casirivimab-imdevimab (Ronapreve™ Roche Regeneron) has been shown to confer satisfactory protection against the delta variant kidney transplant recipients (KTRs) with COVID-19, it has limited neutralizing activity against the current variants of concern (Omicron BA.1, BA.1.1 and BA.2). In contrast, cilgavimab-tixagevimab combination (Evusheld™, Astra Zeneca) retains a partial neutralizing activity against omicron in vitro. We examined whether preexposure prophylaxis with Evusheld™ can effectively protect kidney transplant recipients (KTRs) against the Omicron variant.Of the 416 KTRs who received intramuscular prophylactic injections of Evusheld™ (150 mg tixagevimab and 150 mg cilgavimab), 39 (9.4%) developed COVID-19. With the exception of one patient, all KTRs were symptomatic. Hospitalization and admission to an intensive care unit were required for 14 (35.9%) and three patients, respectively. Two KTRs died of COVID-19-related acute respiratory distress syndrome. SARS-CoV-2 sequencing was carried out in 15 cases (BA.1, n = 5; BA.1.1, n = 9; BA.2, n=1). Viral neutralizing activity of the serum against BA.1 variant was negative in the 12 tested patients, suggesting that this prophylaxis strategy provides insufficient protection against this variant of concern.Preexposure prophylaxis with Evusheld™ does not adequately protect KTRs against Omicron. Further clarification of the optimal dosing can assist in our understanding of how best to harness its protective potential.

Kidney transplant recipients (KTR) are at increased risk of fractures. Total urinary hydroxyproline excretion used to be a marker for bone resorption (BR) but faded into the background when more specific markers like Beta-CrossLaps (CTX) became available. Proteomic studies identified numerous hydroxyproline-containing urinary collagen peptides but their origin remains unknown. We followed the hypothesis that some of the urinary collagen peptides are associated with BR and are markers for pathophysiological changes in bone metabolism of KTR. Clinical and laboratory data including serum levels of CTX in 96 KTR from two French centers (Strasbourg, n=38; Paris-Necker, n=58) were correlated with the signal intensity of urinary peptides identified by capillary electrophoresis (CE) coupled to mass spectrometry (MS) and tandem-MS. The effect of oral bisphosphonates on urinary peptides was studied in an independent group of 11 KTR. Eighty-two urinary peptides were identified to be significantly correlated with serum CTX levels in both cohorts. Statistical association with parameters other than BR markers were not significant. Collagen α-1(I) chain (COL1A1) was the most frequently identified peptide source. COL1A1 peptides associated with BR were significantly more hydroxylated than those showing no association (55.9% versus 45,2%, p2-test). From the 82 urinary peptides correlated to CTX, 17 were significantly associated with bisphosphonate treatment. All of these 17 peptides showed a marked reduction in their excretion levels after 410 ± 344 days of bisphosphonate treatment compared to baseline levels. We studied the cleavage sites of these COL1A1 peptides and observed a signature of Cathepsin K and Matrix Metallopeptidase 9. This study provides strong evidence for the occurrence of collagen peptides in the urine of KTR that are associated with BR and that are sensitive to bisphosphonate treatment. Their assessment might become a valuable tool to monitor bone status in KTR.

SARS-CoV-2 pandemic evolved in two consecutive waves over 2020 (for France: 1st wave from March 1 to July 31; and 2nd wave from August 1 to December 31). Improvements in the management of COVID-19 led to a reduction of mortality rates in hospitalized patients during the second wave. Whether this progress also benefited to kidney transplant recipients (KTR), a population particularly vulnerable to severe COVID-19, remained unclear.In France, 957 KTR were hospitalized for COVID-19 in 2020 and their data were prospectively collected in the French SOT COVID registry. The presentation, management, and outcomes of the 359 KTR diagnosed during the 1st wave were compared to those of the 598 of the 2nd wave. Baseline comorbidities were largely similar between KTR of the 2 waves. Maintenance immunosuppression was reduced in most patients but withdrawal of antimetabolite (73.7% vs 58.4%, pWe conclude that changing of therapeutic trends during 2020 did not reduce COVID-19 related mortality in KTR. Our data indirectly support the importance of vaccination and monoclonal neutralizing anti-SARS-CoV-2 antibodies to protect KTR from severe COVID-19.

The US FDA has recently authorized immunocompromised people to receive a third dose of mRNA Covid-19 vaccine following the two-doses regimen to further boost protection. Unfortunately, a non-negligible proportion of people treated with immunosuppressive drugs either do not respond or show only a weak response after a third boost and should, therefore, still be considered at risk of severe Covid-19. As of June 2021, we were granted the opportunity to offer a fourth vaccine dose to French solid organ transplant recipients who still showed a weak antibody response after the third dose. In this multicenter study, we demonstrate that that the protection conferred by a fourth dose is adequate for the majority of kidney transplant recipients.

Data concerning the anti-SARS-CoV-2 antibody response after mRNA COVID-19 vaccine in kidney transplant recipients (KTRs) are currently lacking. Here, we sought to examine this issue by analyzing the serological response observed in 241 KTRs after a first vaccine injection. Our results indicate that KTRs have a weak anti-SARS-CoV-2 antibody response, ultimately resulting in a low seroconversion rate (26/241, 10.8%). This phenomenon likely stems from a high immunosuppression burden in this clinical population.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread widely, causing coronavirus disease 2019 (COVID-19) and significant mortality. However, data on viral loads and antibody kinetics in immunocompromised populations are lacking. We aimed to determine nasopharyngeal and plasma viral loads via RT-PCR and SARS-CoV-2 serology via ELISA and study their association with severe forms of COVID-19 and death in kidney transplant recipients. In this study we examined hospitalized kidney transplant recipients with non-severe (n = 21) and severe (n =19) COVID-19. SARS-CoV-2 nasopharyngeal and plasma viral load and serological response were evaluated based on outcomes and disease severity. Ten recipients (25%) displayed persistent viral shedding 30 days after symptom onset. The SARS-CoV-2 viral load of the upper respiratory tract was not associated with severe COVID-19, whereas the plasma viral load was associated with COVID-19 severity (p=0.0087) and mortality (p=0.024). All patients harbored antibodies the second week after symptom onset that persisted for two months. We conclude that plasma viral load is associated with COVID-19 morbidity and mortality, whereas nasopharyngeal viral load is not. SARS-CoV-2 shedding is prolonged in kidney transplant recipients and the humoral response to SARS-CoV-2 does not show significant impairment in this series of transplant recipients.

BackgroundAlthough cardiovascular disease has been associated with an increased risk of coronavirus disease 2019 (COVID-19), no studies have reported its clinical course in patients with aortic stenosis who had undergone transcatheter aortic valve replacement (TAVR).Several observational studies have found an association between the A blood group and an increased susceptibility to SARS-CoV-2 infection, whereas the O blood group appears to be protective.ObjectiveTo investigate the frequency and clinical course of COVID-19 in a large sample of patients who had undergone TAVR and to determine the associations of the ABO blood group with disease occurrence and outcomes.MethodsPatients who had undergone TAVR between 2010 and 2019 were included in this study and followed-up through the recent COVID-19 outbreak. The main outcomes were the occurrence and severity (hospitalization and/or death) of COVID-19 and their association with the ABO blood group.ResultsOf the 1125 patients who had undergone TAVR, 403 (36%) died before January 1, 2020, and 20 (1.8%) were lost to follow-up. The study sample therefore consisted of 702 patients. Among them, we identified 22 cases (3.1%) with COVID-19. Fourteen patients (63.6%) were hospitalized or died of disease. Multivariate analysis identified the A blood group (versus others) as the only independent predictor of COVID-19 in patients who had undergone TAVR (odds ratio [OR] = 6.32; 95% confidence interval [CI] = 2.11-18.92; p=0.001). The A blood group (versus others; OR = 8.27; 95% CI = 1.83-37.43, p=0.006) and a history of cancer (OR = 4.99; 95% CI = 1.64-15.27, p = 0.005) were significantly and independently associated with disease severity (hospitalization and/or death).ConclusionsPatients who had undergone TAVR are vulnerable to COVID-19. The subgroup with the A blood group was especially prone to develop the disease and showed unfavorable outcomes.Condensed abstractAmong 702 patients who had undergone TAVR between 2010 and 2019 and who were alive on January 1, 2020, 22 patients developed COVID-19. Fourteen patients (63.6%) were hospitalized or died of disease. The A blood group (versus others) was the only independent predictor of COVID-19. The A blood group and a history of cancer were significantly and independently associated with disease severity (hospitalization and/or death). Altogether these findings suggest that patients who had undergone TAVR are vulnerable to COVID-19. The subgroup with the A blood group was especially prone to develop the disease and showed unfavorable outcomes.