Prophylactic treatment of FSGS recurrence in patients who relapsed in a previous kidney graft.

BACKGROUND AND HYPOTHESIS: Recurrence of focal segmental glomerulosclerosis (FSGS) is common after kidney transplantation and is classically associated with a significant decrease in graft survival. A major risk factor is a prior history of FSGS recurrence on a previous graft. This analysis reports the impact of a prophylactic treatment of FSGS recurrence in very high-risk patients who experienced a recurrence on a previous graft. METHODS: We performed a retrospective multicentre observational study in 25 French transplantation centres. The inclusion criteria were patients aged more than 18 years who had undergone kidney transplant between December 31, 2004, and December 31, 2020, and who had a history of FSGS recurrence on a previous graft. RESULTS: We identified 66 patients: 40 received prophylactic treatment (PT+), including intravenous cyclosporine and/or rituximab and/or plasmapheresis, and 26 did not receive any prophylactic treatment (PT-). The time to progression to end-stage kidney disease was similar between groups. The PT + group was younger at FSGS diagnosis and at the time of kidney retransplantation and lost their previous graft faster. The overall recurrence rate was 72.7% (76.9% in the PT- group and 70.0% in the PT + group, P = 0.54). At least partial remission was achieved in 87.5% of patients. The 5-year graft survival was 67.7% (95% CI: 53.4 to 78.4%): 65.1% (95%CI: 48.7 to 77.4%) in patients with FSGS recurrence vs. 77.3% (95% CI: 43.8 to 92.3%) in patients without recurrence (P = 0.48). CONCLUSION: Our study suggests that prophylactic treatment should not be used routinely in patients receiving a second transplantation after recurrence of FSGS on a previous graft. The recurrence rate is high regardless of the use of prophylactic treatment. However, the 5-year graft survival remains satisfactory.

CAR-T Cells and the Kidney: Insights from the WHO Safety Database.

BACKGROUND: Chimeric antigen receptor T (CAR-T) cells have proven to be a game changer for treating several hematologic malignancies. Randomized controlled trials have highlighted potential life-threatening adverse drug reactions (ADRs), including cytokine release syndrome (CRS). Acute renal failure (ARF) has also been reported in 20% of the patients treated. However, an analysis of renal safety supported by large-scale real-life data seems warranted. PATIENTS AND METHODS: We queried VigiBase® for all reports of the Standardised MedDRA Query "acute renal failure" (ARF) involving a CAR-T cell, registered until 24 July 2022. Disproportionality for this ADR was analyzed through calculation of the Information Component [IC (95% confidence interval)]. A positive lower end of the 95% confidence interval of the IC is the threshold used in statistical signal detection in VigiBase®. The same analysis was carried out for various hydroelectrolytic disorders. RESULTS: We gathered 224 reports of ARF, and 125 reports of hydroelectrolytic disorders involving CAR-T cells. CAR-T cells were disproportionately reported with ARF [IC 1.5 (1.3-1.7)], even after excluding reports mentioning CRS. A significant disproportionate reporting was also found for hypernatremia [IC 3.1 (2.2-3.8)], hyperphosphatemia [IC 3.1 (1.8-3.9)], hypophosphatemia [IC 2.0 (0.6-2.9)], metabolic acidosis [IC 1.8 (1.2-2.2)], hyponatremia [IC 1.6 (1.1-2.0)], and hypercalcemia [IC 1.4 (0.5-2.1)]. There was no disproportionate reporting of dyskalemia. CONCLUSIONS: This study is limited by the inherent flaws of pharmacovigilance approaches. Nonetheless, our findings suggest that ARF and an array of hydroelectrolytic disorders are potential ADRs of CAR-T cell therapy, in real-life settings and in a nonselected population.

Risk factors associated with immune checkpoint inhibitor-induced acute kidney injury compared with other immune-related adverse events: a case-control study.

Background: Immune checkpoint inhibitors (ICIs) foster anti-cancer immune responses. Their efficacy comes at the cost of immune-related adverse events (IRAEs). The latter affects various organs, including kidneys, mostly as acute tubulointerstitial nephritis, the pathophysiology of which remains unclear. We conducted a multicentre case-control study to compare the characteristics of patients with renal IRAEs (ICI-AKI) with those of patients diagnosed with other IRAEs. Methods: We queried the French pharmacovigilance database for all adverse events involving ICIs. Reports were classified as ICI-AKI or extrarenal IRAE. For each ICI-AKI report, four reports of extrarenal IRAEs were randomly included (control group, 4:1 ratio). Variables showing an association with a P < 0.05 were included as covariates in a multivariate analysis. Results: Therefore, 167 ICI-AKI reports were compared with 668 extrarenal IRAEs. At least one concomitant extrarenal IRAE was mentioned in 44.3% of ICI-AKI reports. Patients with ICI-AKI were significantly older than patients with extrarenal IRAEs (69.1 versus 64.6 years; P = 0.0135), and chronic kidney disease was significantly more prevalent (12.0% versus 3.3%; P = 0.0125). Patients with ICI-AKI were significantly more likely to be treated with fluindione [adjusted odds ratio (OR) 6.53, 95% confidence interval (95% CI) 2.21-19.31; P = 0.0007], a non-steroidal anti-inflammatory drug (NSAID, OR 3.18, 95% CI 1.07-9.4; P = 0.0368) or a proton-pump inhibitor (PPI, OR 2.18, 95% CI 1.42-3.34; P = 0.0004). Conclusion: This study is limited by a lack of data, preventing confirmation of numerous reports therefore not included in the analysis. We are unable to draw definite pathophysiological conclusions from our data. Nonetheless, we suggest that ICIs may be a 'second-hit' that precipitates acute kidney injury caused by another concomitant drug (fluindione, NSAID or PPI).

Absence of Mortality Differences Between the First and Second COVID-19 Waves in Kidney Transplant Recipients.

Introduction: SARS-CoV-2 pandemic evolved in 2 consecutive waves during 2020. Improvements in the management of COVID-19 led to a reduction in mortality rates among hospitalized patients during the second wave. Whether this progress benefited kidney transplant recipients (KTRs), a population particularly vulnerable to severe COVID-19, remained unclear. Methods: In France, 957 KTRs were hospitalized for COVID-19 in 2020 and their data were prospectively collected into the French Solid Organ Transplant (SOT) COVID registry. The presentation, management, and outcomes of the 359 KTRs diagnosed during the first wave were compared to those of the 598 of the second wave. Results: Baseline comorbidities were similar between KTRs of the 2 waves. Maintenance immunosuppression was reduced in most patients but withdrawal of antimetabolite (73.7% vs. 58.4%, P < 0.001) or calcineurin inhibitor (32.1% vs. 16.6%, P < 0.001) was less frequent during the second wave. Hydroxychloroquine and azithromycin that were commonly used during the first wave (21.7% and 30.9%, respectively) but were almost abandoned during the second wave. In contrast, the use of high dose corticosteroids doubled (19.5% vs. 41.6%, P < 0.001). Despite these changing trends in COVID-19 management, 60-day mortality was not statistically different between the 2 waves (25.3% vs. 23.9%; Log Rank, P = 0.48) and COVID-19 hospitalization period was not associated with death due to COVID-19 in multivariate analysis (Hazard ratio 0.89, 95% confidence interval 0.67-1.17, P = 0.4). Conclusion: We conclude that changing of therapeutic trends during 2020 did not reduce COVID-19 related mortality among KTRs. Our data indirectly support the importance of vaccination and neutralizing monoclonal anti-SARS-CoV-2 antibodies to protect KTRS from severe COVID-19.

New Strategies for Volume Control in Patients with Diabetes Mellitus, a Narrative Review.

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.

Association Between Maintenance Immunosuppressive Regimens and COVID-19 Mortality in Kidney Transplant Recipients.

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.

Evolution of humoral lesions on follow-up biopsy stratifies the risk for renal graft loss after antibody-mediated rejection treatment.

BACKGROUND: The standard-of-care protocol, based on plasma exchanges, high-dose intravenous immunoglobulin and optimization of maintenance immunosuppression, can slow down the evolution of antibody-mediated rejection (AMR), but with high interindividual variability. Identification of a reliable predictive tool of the response to AMR treatment is a mandatory step for personalization of the follow-up strategy and to guide second-line therapies. METHODS: Interrogation of the electronic databases of 2 French university hospitals (Lyon and Strasbourg) retrospectively identified 81 renal transplant recipients diagnosed with AMR without chronic lesions (cg score ≤1) at diagnosis and for whom a follow-up biopsy had been performed 3-6 months after initiation of therapy. RESULTS: The evolution of humoral lesions on follow-up biopsy (disappearance versus persistence versus progression) correlated with the risk for allograft loss (logrank test, P = .001). Patients with disappearance of humoral lesions had ∼80% graft survival at 10 years. The hazard ratio for graft loss in multivariate analysis was 3.91 (P = .04) and 5.15 (P = .02) for patients with persistence and progression of lesions, respectively. The non-invasive parameters classically used to follow the intensity of humoral alloimmune response (evolution of immunodominant DSA mean fluorescence intensity) and the decline of renal graft function (estimated glomerular filtration rate decrease and persistent proteinuria) showed little clinical value to predict the histological response to AMR therapy. CONCLUSION: We conclude that invasive monitoring of the evolution of humoral lesions by the mean of follow-up biopsy performed 3-6 months after the initiation of therapy is an interesting tool to predict long-term outcome after AMR treatment.

A Single Dose of BNT162b2 Messenger RNA Vaccine Induces Airway Immunity in Severe Acute Respiratory Syndrome Coronavirus 2 Naive and Recovered Coronavirus Disease 2019 Subjects.

BACKGROUND: Mucosal antibodies can prevent virus entry and replication in mucosal epithelial cells and therefore virus shedding. Parenteral booster injection of a vaccine against a mucosal pathogen promotes stronger mucosal immune responses following prior mucosal infection compared with injections of a parenteral vaccine in a mucosally naive subject. We investigated whether this was also the case for the BNT162b2 coronavirus disease 2019 (COVID-19) messenger RNA vaccine. METHODS: Twenty recovered COVID-19 subjects (RCSs) and 23 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-naive subjects were vaccinated with, respectively, 1 and 2 doses of the BNT162b2 COVID-19 vaccine. Nasal epithelial lining fluid (NELF) and plasma were collected before and after vaccination and assessed for immunoglobulin G (IgG) and IgA antibody levels to Spike and for their ability to neutralize binding of Spike to angiotensin-converting enzyme-2 receptor. Blood was analyzed 1 week after vaccination for the number of Spike-specific antibody-secreting cells (ASCs) with a mucosal tropism. RESULTS: All RCSs had both nasal and blood SARS-CoV-2-specific antibodies at least 90 days after initial diagnosis. In RCSs, a single dose of vaccine amplified preexisting Spike-specific IgG and IgA antibody responses in both NELF and blood against both vaccine homologous and variant strains, including Delta. These responses were associated with Spike-specific IgG and IgA ASCs with a mucosal tropism in blood. Nasal IgA and IgG antibody responses were lower in magnitude in SARS-CoV-2-naive subjects after 2 vaccine doses compared with RCSs after 1 dose. CONCLUSIONS: Mucosal immune response to the SARS-CoV-2 Spike protein is higher in RCSs after a single vaccine dose compared with SARS-CoV-2-naive subjects after 2 doses.

Overcoming barriers to widespread use of CAR-Treg therapy in organ transplant recipients.

Preventing allograft rejection has been the main challenge of transplantation medicine since the discovery of immune responses against foreign HLA molecules in the mid-20th century. Prevention of rejection currently relies on immunosuppressive drugs, which lack antigen specificity and therefore increase the risk for infections and cancers. Adoptive cell therapy with donor-reactive regulatory T cells (Tregs) has progressively emerged as a promising approach to reduce the need for pan-immunosuppressive drugs and minimize morbidity and mortality in solid-organ transplant recipients. Chimeric antigen receptor (CAR) technology has recently been used successfully to generate Tregs specific for donor HLA molecules and overcome the limitations of Tregs enrichment protocols based on repetitive stimulations with alloantigens. While this novel approach opens new possibilities to make Tregs therapy more feasible, it also creates additional challenges. It is essential to determine which source of therapeutic Tregs, CAR constructs, target alloantigens, safety strategies, patients and immunosuppressive regimens are optimal for the success of CAR Treg therapy. Here, we discuss unmet needs and strategies to bring donor-specific CAR Treg therapy to the clinic and make it as accessible as possible.

Low T Cell Responsiveness in the Early Phase of COVID-19 Associates with Progression to Severe Pneumonia in Kidney Transplant Recipients.

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.

Kidney transplantation from expanded criteria donors: an increased risk of urinary complications - the UriNary Complications Of Renal Transplant (UNyCORT) study.

OBJECTIVES: To assess the impact of expanded criteria donors (ECD) on urinary complications in kidney transplantation. PATIENTS AND METHODS: The UriNary Complications Of Renal Transplant (UNyCORT) is a cohort study based on the French prospective Données Informatisées et VAlidées en Transplantation/Computerized and VAlidated Data in Transplantation (DIVAT) cohort. Data were extracted between 1 January 2002 and 1 January 2018 with 1-year minimum follow-up, in relation to 44 pre- and postoperative variables. ECD status was included according to United Network for Organ Sharing (UNOS) definition. The primary outcome of the UNyCORT study was the association between the donor's ECD/standard criteria donors (SCD) status and urinary complications at 1 year in uni- and multivariate analysis. Sub-group analysis, stratified analysis on ECD/SCD donor's status and transplant failure analysis were then conducted. RESULTS: Between 1 January 2002 and 1 January 2018, 10 279 kidney transplants in adult recipients were recorded within the DIVAT network. A total of 8559 (83.4%) donors were deceased donors and 1699 (16.6%) were living donors (LD). Among donation after circulatory death (DCD) donors, 224 (2.85%) were uncontrolled DCD and 93 (1.09%) were controlled DCD donors. A total of 3617 (43.9%) deceased donors were ECD. The overall urological complication rate was 16.26%. The donor's ECD status was significantly associated with an increased risk of urological complications at 1 year in multivariate analysis (odds ratio: 1.50, 95% CI 1.31-1.71; P < 0.001) and especially with stenosis and ureteric fistulae at 1 year. There is no association with LD, uncontrolled and controlled DCD. The placement of an endo-ureteric stent was beneficial in preventing urinary complications in all donors and particularly in ECD donors. CONCLUSION: The donor's ECD status is associated with a higher likelihood of stenosis and ureteric fistulae at 1 year. Recipients of grafts from ECD donors should probably be considered for closer urological monitoring and systematic preventive measures.

Safety and cross-variant immunogenicity of a three-dose COVID-19 mRNA vaccine regimen in kidney transplant recipients.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: A third dose of the BNT162b2 vaccine increases both cross-variant neutralizing antibody and cellular responses in KT recipients with an acceptable tolerability profile. FUNDING: Nice University Hospital, University Cote d'Azur.

Timing of Kidney Clamping and Deceased Donor Kidney Transplant Outcomes.

BACKGROUND AND OBJECTIVES: The fact that metabolism and immune function are regulated by an endogenous molecular clock that generates circadian rhythms suggests that the magnitude of ischemia reperfusion, and subsequent inflammation on kidney transplantation, could be affected by the time of the day. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated 5026 individuals who received their first kidney transplant from deceased heart-beating donors. In a cause-specific multivariable analysis, we compared delayed graft function and graft survival according to the time of kidney clamping and declamping. Participants were divided into those clamped between midnight and noon (ante meridiem [am] clamping group; 65%) or clamped between noon and midnight (post meridiem [pm] clamping group; 35%), and, similarly, those who underwent am declamping (25%) or pm declamping (75%). RESULTS: Delayed graft function occurred among 550 participants (27%) with am clamping and 339 (34%) with pm clamping (adjusted odds ratio, 0.81; 95% confidence interval, 0.67 to 0.98; P=0.03). No significant association was observed between clamping time and overall death-censored graft survival (hazard ratio, 0.92; 95% confidence interval, 0.77 to 1.10; P=0.37). No significant association of declamping time with delayed graft function or graft survival was observed. CONCLUSIONS: Clamping between midnight and noon was associated with a lower incidence of delayed graft function, whereas declamping time was not associated with kidney graft outcomes.

Cohort study: "Outcomes of kidney transplantation in patients with prosthetic heart valves".

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. We conducted a matched cohort study among recipients from the multicentric and prospective DIVAT cohort to compare the 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, pretransplant DSA, diabetes, and cardiovascular events. Of 23 018 patients, 92 patients with PHVs were included and compared to 276 patients without PHV. Delayed graft function and postoperative 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 vs. 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]. 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.

Improved cell signaling analysis by biofunctionalized nanospheres and imaging flow cytometry.

The analysis of immune cell signaling is critical for the understanding of the biology and pathology of the immune system, and thus a mandatory step for the development of efficient biomarkers and targeted therapies. Phosflow, which has progressively replaced the traditional western blot approach, relies on flow cytometry to analyze various signaling pathways at a single-cell level. This technique however suffers a lack of sensitivity largely due to the low signal/noise ratio that characterizes cell signaling analysis. In this study, we describe a new technique, which combines the use of biofunctionalized nanospheres (i.e., synthetic particulate antigens, SPAg) to stimulate the immune cells in suspension and imaging flow cytometry to identify homogenously-stimulated cells and quantify the activity of the chosen signaling pathway in selected subcellular regions of interest. Using BCR signaling as model, we demonstrate that SIBERIAN (SPAg-assIsted suB-cEllulaR sIgnaling ANalysis) allows assessing immune cell signaling with unprecedented sensitivity and specificity.