The immunogenicity of a two-dose mRNA COVID-19 vaccine regimen is low in kidney transplant (KT) recipients. Here, we provide a thorough assessment of the immunogenicity of a three-dose COVID-19 vaccine regimen in this population. We performed a prospective longitudinal study in sixty-one KT recipients given three doses of the BNT162b2 COVID-19 vaccine. We performed semi-structured pharmacovigilance interviews and monitored donor-specific antibodies and kidney function. We compared levels of anti-spike IgG, pseudo-neutralization activity against vaccine homologous and heterologous variants, frequency of spike-specific interferon (IFN)-γ-secreting cells, and antigen-induced cytokine production 28 days after the second and third doses. Reactions to vaccine were mild. One patient developed donor-specific anti-HLA antibodies after the second dose which could be explained by non-adherence to immunosuppressive therapy. Spike-specific IgG seroconversion raised from 44·3% (n=27) after the second dose to 62·3% (n=38) after the third dose (p<0·05). The mean level of spike-specific IgG increased from 1620 (SD, 3460) to 8772 (SD, 16733) AU/ml (p<0·0001). Serum neutralizing activity increased after the third dose for all variants of concern tested including the Delta variant (p<0·0001). The frequency of spike-specific IFN-γ-secreting cells increased from 19·9 (SD, 56·0) to 64·0 (SD, 76·8) cells/million PBMCs after the third dose (p<0·0001). A significant increase in IFN-γ responses was also observed in patients who remained seronegative after three doses (p<0·0001). A third dose of the BNT162b2 vaccine increases both cross-variant neutralizing antibody and cellular responses in KT recipients with an acceptable tolerability profile. Nice University Hospital, University Cote d'Azur.

Background.: Solid organ transplant recipients are at high risk for fatal forms of coronavirus disease 2019 (COVID-19). We conducted a cohort study among kidney transplant (KT) recipients from the French Solid Organ Transplant COVID-19 Registry to investigate the association between maintenance immunosuppressive drugs and 60-d mortality. Methods.: Data from all KT recipients with COVID-19 included in the French Solid Organ Transplant COVID-19 Registry between February 28, 2020, and December 30, 2020, were retrieved. We evaluated associations between immunosuppressive drugs and death within 60 d using logistic regression, with all baseline characteristics considered to influence outcome or immunosuppressive regimen. The Benjamini-Hochberg correction was used for controlling false positive rate; 40 multiple imputations were performed. Adjusted P value <0.05 was considered statistically significant. Results.: There were 1451 KT recipients included. Median age was 58 y, and 66.4% were men. Most frequent comorbidities were hypertension (81.9%), diabetes (34.5%), and cardiovascular disease (29.5%). Median time since transplant was 71 mo. Maintenance immunosuppression regimens included calcineurin inhibitors (1295, 89.2%), antimetabolites (1205, 83%), corticosteroids (1094, 75.4%), mammalian target of rapamycin inhibitors (144, 9.9%), and belatacept (58, 4.0%). Among 1451 transplant recipients, 201 (13.9%) died within 60 d. Older age and higher baseline serum creatinine were associated with mortality (odds ratios, 1.09 [1.07-1.11] and 1.01 [1.005-1.009], P < 0.001). Corticosteroid-free regimens were associated with a significantly lower risk of death (odds ratio, 0.48 [0.31-0.76]; P = 0.011). Conclusions.: Corticosteroid-free regimens were associated with a lower risk of death in KT recipients with COVID-19. Long-term exposure to corticosteroids impairs immune functions and may predispose solid organ transplant recipients to severe forms of COVID-19.

Background.: Kidney transplant recipients (KTRs) are at elevated risk of malignancy. Data on the safety and efficacy of immune checkpoint inhibitors (ICIs) in this population remain limited. We aimed to reassess the benefit-risk profile of ICI therapy in KTRs using a multicenter cohort, in the recent era. Methods.: We conducted a retrospective cohort study of all KTRs treated with ICIs for advanced or metastatic cancer, across 6 transplant centers. We evaluated cancer response, acute rejection (AR) incidence, graft survival, and patient survival. Results.: From 2015 to 2024, 34 KTRs were analyzed. The most common cancers were cutaneous (56%) and non–small cell lung cancer (32%). Pembrolizumab was the most used ICI (53%). The objective response rate was 38%, with a median progression-free survival of 5.5 mo and an overall survival of 10.7 mo. Biopsy-proven AR occurred in 26.5% of patients, at a median time of 52 d after ICI start. All rejection episodes involved T cells, and one-third showed additional humoral features. No clinical predictors of AR were identified. Among all patients, 29% had a favorable outcome (tumor response without ICI-induced graft loss), 12% experienced a tumor response with graft loss, 59% had progression disease without graft loss, and 3% experienced the worst outcome (progression disease with graft loss). Conclusions.: Our study suggests that ICI therapy is a viable option for KTRs with poor-prognosis cancers, demonstrating a 38% tumor response rate and a lower incidence of graft loss (15%) compared with previously reported rates. Prospective studies are needed to optimize the use of ICI in KTRs.

Kidney transplant (KT) recipients are at increased risk of developing severe forms of COVID-19. Little is known about the immunological mechanisms underlying disease severity in these patients receiving T-cell targeting immunosuppressive drugs. We investigated the relationship between T cell responsiveness at the beginning of the infection and the risk of subsequent progression to respiratory failure. We performed a multicentric prospective study in KT recipients with a positive RT-PCR COVID-19 test and only mild symptoms at inclusion. Blood samples were collected at baseline in a cell culture system containing T cell stimuli. We assessed T cell responsiveness by computing the ratio between the levels of Th1, Th2, Th17 and Treg cytokines produced after polyclonal stimulation and the number of blood lymphocytes. We then used an unsupervised classification approach to stratify patients into low and high T cell responders and a penalized logistic regression to evaluate the association between T cell responsiveness and progression to severe pneumonia. Forty-five patients were included. All patients who progressed to severe pneumonia (24.4%, n = 11) were low T cell responders at baseline (p = 0.01). In multivariate analysis, low T cell responsiveness at baseline was the main risk factor for subsequent progression to severe pneumonia. This study provides novel insights into the mechanisms underlying COVID-19 severity in organ transplant recipients and data of interest to clinicians managing immunosuppressive drugs in these patients.

Sodium is reabsorbed all along the renal tubules. The positive impacts of sodium-glucose cotransporter-2 inhibitors (SGLT2i), angiotensin receptor neprilysin inhibitor (ARNI) and mineralocorticoid receptor antagonists (MRA) on hard renal and/or cardiac endpoints calls for the role of diuretics in nephroprotection and cardioprotection in patients with diabetes mellitus to be reviewed. Here, we review: (a) the mechanisms of action of the available natriuretics; (b) the physiological adaptations to chronic loop diuretic usage that lead to increased sodium reabsorption in the proximal and distal convoluted tubules; (c) the physiology of sodium retention in patients with diabetes mellitus; and (d) the mechanisms of aldosterone breakthrough. We show the rationale for combined diuretics to target not only the loop of Henle, but also the proximal and distal convoluted tubules. Indeed, higher residual proteinuria in patients treated with renin-angiotensin-aldosterone system (RAAS) blockers portends poorer renal and cardiovascular outcomes. Diuretics are known to optimize the reduction of proteinuria, in addition to RAAS blockers, but may favor aldosterone breakthrough in the absence of MRA. The aim of our study is to support a combined diuretics strategy to improve the management of patients with diabetes mellitus and chronic kidney disease or heart failure.

Main problem The number of kidney transplant candidates with prosthetic heart valves (PHVs) is increasing. Yet, outcomes of kidney transplantation in these patients are still unclear. This is the first report of post-transplant outcomes in patients with PHVs at time of kidney transplantation. Methods We conducted a matched cohort study among recipients from the multicentric and prospective DIVAT cohort to compare outcomes in patients with left-sided PHVs at time of transplantation and a group of recipients without PHV matched according to age, dialysis time, initial disease, pre-transplant DSA, diabetes and cardiovascular events. Results Of 23018 patients, 92 patients with PHVs were included and compared to 276 patients without PHV. Delayed graft function and post-operative bleeding occurred more frequently in patients with PHVs. Kidney graft survival was similar between groups. 5-year overall survival was 68.5 % in patients with PHV versus 87.9 % in patients without PHV (HR, 2.72[1.57–4.70], p=0.0004). Deaths from infection, endocarditis and bleeding were more frequent in patients with PHV. Mechanical valves, but not bioprosthetic valves, were independent risk factors for mortality (HR, 2.89[1.68-4.97], p=0.0001). Conclusions Patients with PHV have high mortality rates after kidney transplantation. These data suggest that mechanical valves, but not biological valves, increase risks of post-transplant mortality.