Evaluation of T Cell Response to SARS-CoV-2 in Kidney Transplant Recipients Receiving Monoclonal Antibody Prophylaxis and the Utility of a Bivalent mRNA Vaccine Booster Dose.

Monoclonal antibodies have been administered to kidney transplant recipients (KTRs) with a poor or non-responder status to SARS-CoV-2 vaccination. The cellular response to SARS-CoV-2 has been poorly studied in this context. We assessed the T cell response to SARS-CoV-2 in 97 patients on the day of the injection of tixagevimab/cilgavimab using an IFNγ enzyme-linked immunospot assay (ELISPOT). Among the 97 patients, 34 (35%) developed COVID-19 before the injection. Twenty-nine (85.3%) had an ELISPOT compatible with a SARS-CoV-2 infection. There was no difference between KTRs under belatacept or tacrolimus treatment. Sixty-three patients (64.9%) had no known COVID-19 prior to the ELISPOT, but nine (14.3%) had a positive ELISPOT. In 21 KTRs with a positive ELISPOT who received a booster dose of a bivalent mRNA vaccine, median antibody titers and spike-reactive T cells increased significantly in patients under tacrolimus but not belatacept. Our study emphasizes the potential usefulness of the exploration of immune cellular response to SARS-CoV-2 by ELISPOT. In KTRs with a positive ELISPOT and under CNI therapy, a booster dose of mRNA vaccine seems effective in inducing an immune response to SARS-CoV-2.

Anti SARS-CoV-2 Monoclonal Antibodies in Pre-Exposure or Post-Exposure in No- or Weak Responder to Vaccine Kidney Transplant Recipients: Is One Strategy Better than Another?

Background: Kidney transplant recipients (KTRs) are likely to develop severe COVID-19 and are less well-protected by vaccines than immunocompetent subjects. Thus, the use of neutralizing anti-SARS-CoV-2 monoclonal antibodies (mAbs) to confer a passive immunity appears attractive in KTRs. Methods: This retrospective monocentric cohort study was conducted between 1 January 2022 and 30 September 2022. All KTRs with a weak antibody response one month after three doses of mRNA vaccine (anti spike IgG < 264 (BAU/mL)) have received tixagevimab-cilgavimab in pre-exposure (group 1), post-exposure (group 2) or no specific treatment (group 3). We compared COVID-19 symptomatic hospitalizations, including intensive care unit hospitalizations, oxygen therapy, and death, between the three groups. Results: A total of 418 KTRs had SARS-CoV-2 infection in 2022. During the study period, we included 112 KTRs in group 1, 40 KTRs in group 2, and 27 KTRs in group 3. The occurrence of intensive care unit hospitalization, oxygen therapy, and COVID-19 death was significantly increased in group 3 compared to group 1 or 2. In group 3, 5 KTRs (18.5%) were admitted to the intensive care unit, 7 KTRs (25.9%) needed oxygen therapy, and 3 KTRs (11.1%) died. Patients who received tixagevimab-cilgavimab pre- or post-exposure had similar outcomes. Conclusions: This retrospective real-life study supports the relative effectiveness of tixagevimab-cilgavimab on COVID-19 infection caused by Omicron, used as a pre- or post-exposure therapy. The continued evolution of Omicron variants has made tixagevimab-cilgavimab ineffective and reinforces the need for new therapeutic monoclonal antibodies for COVID-19 active on new variants.

Conversion From Intravenous In-Hospital Belatacept Injection to Subcutaneous Abatacept Injection in Kidney Transplant Recipients During the First COVID-19 Stay-at-Home Order in France.

The first COVID-19 stay-at-home order came into effect in France on 17 March 2020. Immunocompromised patients were asked to isolate themselves, and outpatient clinic visits were dramatically reduced. In order to avoid visits to the hospital by belatacept-treated kidney transplant recipients (KTRs) during the initial period of the pandemic, we promptly converted 176 KTRs at two French transplant centers from once-monthly 5 mg/kg in-hospital belatacept infusion to once-weekly 125 mg subcutaneous abatacept injection. At the end of follow-up (3 months), 171 (97.16%) KTRs survived with a functioning graft, 2 (1.14%) had died, and 3 (1.70%) had experienced graft loss. Two patients (1.1%) experienced acute T cell-mediated rejection. Nineteen patients (10.80%) discontinued abatacept; 47% of the KTRs found the use of abatacept less restrictive than belatacept, and 38% would have preferred to continue abatacept. Mean eGFR remained stable compared to baseline. Seven patients (3.9%) had COVID-19; among these, two developed severe symptoms but survived. Only one patient had a de novo DSA. Side effects of abatacept injection were uncommon and non-severe. Our study reports for the first time in a large cohort that once-weekly injection of abatacept appears to be feasible and safe in KTRs previously treated with belatacept.

Weaning of maintenance immunosuppressive therapy in lupus nephritis (WIN-Lupus): results of a multicentre randomised controlled trial.

OBJECTIVES: Lupus nephritis (LN) is a frequent complication of systemic lupus erythematosus (SLE). Severe (proliferative) forms of LN are treated with induction immunosuppressive therapy (IST), followed by maintenance IST, to target remission and avoid relapses. The optimal duration of maintenance IST is unknown. The WIN-Lupus trial tested whether IST discontinuation after 2‒3 years was non-inferior to IST continuation for two more years in proliferative LN. METHODS: WIN-Lupus was an investigator-initiated multicentre randomised controlled trial. Patients receiving maintenance IST with azathioprine or mycophenolate mofetil for 2-3 years, and hydroxychloroquine, were randomised (1:1) into two groups: (1) IST continuation and (2) IST discontinuation. The primary endpoint was the relapse rate of proliferative LN at 24 months. Main secondary endpoints were the rate of severe SLE flares, survival without renal relapse or severe flare, adverse events. RESULTS: Between 2011 and 2016, 96 patients (out of 200 planned) were randomised in WIN-Lupus: IST continuation group (n=48), IST discontinuation group (n=48). Relapse of proliferative LN occurred in 5/40 (12.5%) patients with IST continuation and in 12/44 (27.3%) patients with IST discontinuation (difference 14.8% (95% CI -1.9 to 31.5)). Non-inferiority was not demonstrated for relapse rate; time to relapse did not differ between the groups. Severe SLE flares (renal or extrarenal) were less frequent in patients with IST continuation (5/40 vs 14/44 patients; p=0.035). Adverse events did not differ between the groups. CONCLUSIONS: Non-inferiority of maintenance IST discontinuation after 2‒3 years was not demonstrated for renal relapse. IST discontinuation was associated with a higher risk of severe SLE flares. TRIAL REGISTRATION NUMBER: NCT01284725.

CD86 occupancy in belatacept-treated kidney transplant patients is not associated with clinical and infectious outcomes.

The CD86 occupancy assay has been developed to measure the number of CD86 molecules unbound to belatacept, but its association with clinical outcomes has not been assessed yet. All kidney transplant patients switched to belatacept in our center between 2016 and 2018 were included. Blood samples were collected before each infusion for 1 year to assess CD86 occupancy by CD86 antibody cytometry staining on the surface of CD14+ monocytes. Results were expressed as the median fluorescence intensity (MFI) value of CD86 staining. At each infusion, the MFIDay of infusion /MFIDay 0 ratio was calculated. Forty-one patients were consecutively included. After every 2-week infusion period, CD86 MFI ratio dropped from 1.00 to 0.73 [0.57-0.98], p = .07. However, this ratio progressively increased to 0.78 [0.53-1.13] at 1 year, which was not statistically different from pre-switch ratio, p = .4. Over the first year, the MFI ratio coefficient of variation was 31.58% [23.75-38.31]. MFI ratio was not different between patients with or without opportunistic infections: 0.73 [0.60-0.88] versus 0.80 [0.71-1.00], p = .2, or between patients with or without EBV DNAemia, p = .2. Despite previous in vitro results, the CD86 occupancy assay suffers from a high intra-individual variability and does not appear to be relevant to clinical outcomes.

ANCA-Negative Pauci-immune Necrotizing Glomerulonephritis: A Case Series and a New Clinical Classification.

RATIONALE & OBJECTIVE: Pauci-immune necrotizing glomerulonephritis (PING) is usually associated with the presence of antineutrophil cytoplasmic antibodies (ANCA). However, a minority (2%-3%) of patients with PING do not have detectable ANCA. We assessed the clinical spectrum and outcome of patients with ANCA-negative PING. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: 74 patients with ANCA-negative PING diagnosed in 19 French nephrology centers between August 2006 and December 2018 were included in the series. Patients' medical files were reviewed, and kidney biopsies were centrally reexamined by pathologists who were masked to the diagnosis. FINDINGS: Median age at diagnosis was 69 (IQR, 61-76) years. The clinical and pathological features were remarkable for a high frequency of extrarenal manifestations (54%), nephrotic syndrome (32%), and endocapillary hypercellularity (31%). Three main subtypes of ANCA-negative PING were observed: infection-associated (n=9[12%]), malignancy-associated (n=6[8%]), and primary (n=57[77%]). For patients with primary PING, induction treatment included mainly corticosteroids (n=56[98%]), cyclophosphamide (n=37[65%]), and rituximab (n=5[9%]). Maintenance treatment consisted mainly of corticosteroids (n=42[74%]), azathioprine (n=18[32%]), and mycophenolate mofetil (n=11[19%]). After a median follow-up period of 28 months, 28 (38%) patients had died and 20 (27%) developed kidney failure (estimated glomerular filtration rate<15mL/min/1.73m2). Eleven (21%) patients (9 with primary and 2 with malignancy-associated PING) relapsed. LIMITATIONS: Retrospective study and limited number of patients; electron microscopy was not performed to confirm the absence of glomerular immune deposits. CONCLUSIONS: Within the spectrum of ANCA-negative PING, infection and malignancy-associated forms represent a distinct clinical subset. This new clinical classification may inform the management of ANCA-negative PING, which remains a severe form of vasculitis with high morbidity and mortality rates despite immunosuppressive treatments.

SARS-CoV-2-specific Humoral and Cellular Immunities in Kidney Transplant Recipients and Dialyzed Patients Recovered From Severe and Nonsevere COVID-19.

Kidney transplantation and dialysis are two major risk factors for severe forms of coronavirus disease 2019 (COVID-19). The dynamics of the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in this population remain largely unknown. METHODS: We report here the analysis of anti-SARS-CoV-2 antibody- and T cell-mediated immune responses in 26 kidney transplant recipients (KTRs) and 11 dialyzed patients (DPs) who recovered from COVID-19. RESULTS: After a mean time of 83 ± 26 d post-symptom onset for KTRs and 97 ± 31 d for DPs, 20 KTRs (76.9%) and 10 DPs (90.9%) displayed anti-S1 immunoglobulin G SARS-CoV-2 antibodies (P = 0.34), at similar titers in both groups. SARS-CoV-2-specific interferon-γ-producing T cells were evidenced in 26 KTRs (100%) and 10 DPs (90.9%). Total numbers of SARS-CoV-2-reactive T cells were high and not statistically different between the 2 groups. No correlation between the severity of the disease and the number of reactive T cells was found in KTRs. In 5 KTRs, also evaluated 10 mo after COVID-19, weak or absent antibody response was observed, whereas specific memory T-cell response was detected in all cases. CONCLUSION: T-cell response persisted up to 3 mo post-symptom onset, even in KTRs in whom full immunosuppressive regimen was reinstated at recovery, and seems to be present up to 10 mo after infection. Our findings have implications in the understanding of the natural course of the disease in transplant patients and DPs.

Antibody and T Cell Response to SARS-CoV-2 Messenger RNA BNT162b2 Vaccine in Kidney Transplant Recipients and Hemodialysis Patients.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with a high rate of mortality in patients with ESKD, and vaccination is hoped to prevent infection. METHODS: Between January 18 and February 24, 2021, 225 kidney transplant recipients (KTRs) and 45 patients on hemodialysis (HDPs) received two injections of mRNA BNT162b2 vaccine. The postvaccinal humoral and cellular response was explored in the first 45 KTRs and ten HDPs. RESULTS: After the second dose, eight HDPs (88.9%) and eight KTRs (17.8%) developed antispike SARS-CoV-2 antibodies (P<0.001). Median titers of antibodies in responders were 1052 AU/ml (IQR, 515-2689) in HDPs and 671 AU/ml (IQR, 172-1523) in KTRs (P=0.40). Nine HDPs (100%) and 26 KTRs (57.8%) showed a specific T cell response (P=0.06) after the second injection. In responders, median numbers of spike-reactive T cells were 305 SFCs per 106 CD3+ T cells (IQR, 95-947) in HDPs and 212 SFCs per 106 CD3+ T cells (IQR, 61-330) in KTRs (P=0.40). In KTRs, the immune response to BNT162b2 seemed influenced by the immunosuppressive regimen, particularly tacrolimus or belatacept. CONCLUSION: Immunization with BNT162b2 seems more efficient in HDPs, indicating that vaccination should be highly recommended in these patients awaiting a transplant. However, the current vaccinal strategy for KTRs may not provide effective protection against COVID-19 and will likely need to be improved.

T cell and antibody responses to SARS-CoV-2: Experience from a French transplantation and hemodialysis center during the COVID-19 pandemic.

Immunosuppressed organ-transplanted patients are considered at risk for severe forms of COVID-19. Moreover, exaggerated innate and adaptive immune responses might be involved in severe progression of the disease. However, no data on the immune response to SARS-CoV-2 in transplanted patients are currently available. Here, we report the first assessment of antibody and T cell responses to SARS-CoV-2 in 11 kidney-transplanted patients recovered from RT-PCR-confirmed (n = 5) or initially suspected (n = 6) COVID-19. After reduction of immunosuppressive therapy, RT-PCR-confirmed COVID-19 transplant patients were able to mount vigorous antiviral T cell and antibody responses, as efficiently as two nontherapeutically immunosuppressed COVID-19 patients on hemodialysis. By contrast, six RT-PCR-negative patients displayed no antibody response. Among them, three showed very low numbers of SARS-CoV-2-reactive T cells, whereas no T cell response was detected in the other three, potentially ruling out COVID-19 diagnosis. Low levels of T cell reactivity to SARS-CoV-2 were also detected in seronegative healthy controls without known exposure to the virus. These results suggest that during COVID-19, monitoring both T cell and serological immunity might be helpful for the differential diagnosis of COVID-19 but are also needed to evaluate a potential role of antiviral T cells in the development of severe forms of the disease.

Opportunistic infections after conversion to belatacept in kidney transplantation.

BACKGROUND: Belatacept (bela) rescue therapy seems to be a valuable option for calcineurin inhibitor chronic toxicity in kidney transplantation. Nevertheless, the risk of infection associated with bela is not well reported. METHODS: We report the rate of opportunistic infections (OPI) after a switch to bela in a multicentric cohort of 280 kidney transplant patients. RESULTS: Forty-two OPI occurred in 34 patients (12.1%), on average 10.8 ± 11.3 months after the switch. With a cumulative exposure of 5128 months of bela treatment, we found an incidence of 0.008 OPI/month of exposure, and 9.8 OPI/100 person-years. The most common OPI was cytomegalovirus (CMV) disease in 18/42 OPI (42.9%) and pneumocystis pneumonia in 12/42 OPI (28.6%). Two patients presented a progressive multifocal leucoencephalopathy and two patients developed a cerebral Epstein-Barr virus-induced post-transplant lymphoproliferative disease. OPI led to death in 9/34 patients (26.5%) and graft failure in 4/34 patients (11.8%). In multivariate analysis, estimated glomerular filtration rate <25/mL/min/1.73 m2 on the day of the switch and the use of immunosuppressive agents before transplantation were associated with the occurrence of OPI. We found a higher rate of infection-related hospitalization (24.1 versus 12.3/100 person-years, P = 0.0007) and also a higher rate of OPI (13.2 versus 6.7/100 person-years, P = 0.005) in the early conversion group (within 6 months). CONCLUSIONS: The risk of OPI is significant post-conversion to bela and may require additional monitoring and prophylactic therapy, particularly regarding pneumocystis pneumonia and CMV disease. These data need to be confirmed in a larger case-control study.

Atypical and secondary hemolytic uremic syndromes have a distinct presentation and no common genetic risk factors.

Secondary hemolytic uremic syndrome (HUS) is a heterogeneous group of thrombotic microangiopathies associated with various underlying conditions. Whether it belongs to the spectrum of complement-mediated HUS remains controversial. We analysed the presentation, outcome, and frequency of complement gene rare variants in a cohort of 110 patients with secondary HUS attributed to drugs (29%), autoimmune diseases (24%), infections (17%), malignancies (10%), glomerulopathies (9%), extra-renal organ transplantation (8%), and pancreatitis (3%). The frequency of complement gene rare variants was similar in patients with secondary HUS (5%) and in healthy individuals (6% and 8% in French and European controls, respectively). At diagnosis, 40% of patients required dialysis and 18% had neurological manifestations. Fifty percent of patients received plasmatherapy and 35% were treated with eculizumab. Haematological and complete renal remission was achieved in 80% and 24% of patients, respectively. Thirty-nine percent of patients progressed to chronic kidney disease (stages 3-4) and an additional 37% reached end-stage renal disease. Eleven percent of patients died, most often from complications of the underlying cause of HUS. Only one patient experienced an HUS relapse. Patients treated with eculizumab presented with more severe HUS and were more likely to require dialysis at the time of diagnosis as compared to patients not treated with eculizumab. Rates of hematological remission, chronic kidney disease (stages 3-4), and end-stage renal disease were similar in the two groups. Secondary HUS is an acute nonrelapsing form of HUS, not related to complement dysregulation. The efficacy of eculizumab in this setting is not yet established.

Bone impairment in oxalosis: An ultrastructural bone analysis.

Deposition of calcium oxalate crystals in the kidney and bone is a hallmark of systemic oxalosis. Since the bone compartment can store massive amounts of oxalate, patients present with recurrent low-trauma fractures, bone deformations, severe bone pains and specific oxalate osteopathy on plain X-ray. Bone biopsy from the iliac crest displays specific features such as oxalate crystals surrounded by a granulomatous reaction due to an invasion of bone surface by macrophages. We present data obtained in 10 samples from 8 patients with oxalosis (16-68 years) who underwent iliac crest bone biopsy and bone quality analysis using modern methods (microradiography, microindentation, Fourier Transform InfraRed Microspectroscopy, transmission electron microscopy) in addition to histomorphometry. Disseminated calcium oxalate deposits (whewellite) were found in the bone marrow space (with a granulomatous reaction) but not in the bone matrix. Calcium oxalate deposits were totally surrounded by macrophages and multinucleated giant cells, and a phagocytosis activity was sometimes observed. Very few calcium oxalate crystals were directly in close contact with the mineral substance of the bone. Bone mineralization was not modified by the presence of calcium oxalate even in close vicinity. Bone quality analysis also revealed a harder bone than normal, perhaps in relationship with decreased carbonate content in the mineral. This increase in bone hardness could explain a more "brittle" bone. In patients with oxalosis, the formation and growth of calcium oxalate crystals in the bone appeared independent of apatite. The mechanisms leading to nucleation and growth of oxalate deposits are still unclear and deserve further studies.

[Online hemodiafiltration: is it really more expensive?]. / Hémodiafiltration en ligne : y a-t-il réellement un surcoût ?

Online hemodiafiltration has been shown to have many benefits in terms of morbi-mortality and to increase middle weight molecules removal. However, this technique is supposed to have an additional cost which may be an obstacle to increase its development in hemodialysis centers. The aim of the study is to achieve an accurate pharmaco-economic evaluation for determining the real overcost of online hemodiafiltration (OL-HDF) in comparison with high flux hemodialysis (HF-HD) using standard priming. We have identified the additional costs related to the consumables and monitors and the additional costs imposed by the technique itself (water consumption and microbiological analysis). In the center, more than 28,000 sessions per year are performed with 70% in OL-HDF (90% post-dilution). The consumable overcost ranges from -2.55 to +3.35 euros per session depending on the monitor and on the HDF modality. The overcost of microbiological analysis is +1.1 euros per session. The theoretical additional water consumption is calculated from different dialysat flow rates and OL-HDF modality. Its ranges from +50.8L to +74.8L per session increasing the water overcost from +0.15 to +0.23 euros per session. This accurate evaluation shows that the cost difference of OL-HDF depends on monitor used and on the OL-HDF modality. In our center, it ranges from -1.29 to +4.58 euros per session.