Daratumumab for antibody-mediated rejection: Is it time to target the real culprit?

We report the case of a sensitized woman who underwent successful transplantation after a desensitization protocol, with an optically normal 8-day biopsy. At 3 months, she developed active antibody-mediated rejection (AMR) due to preformed donor-specific antibodies. It was decided to treat the patient with daratumumab, an anti-CD38 monoclonal antibody. The mean fluorescence intensity of donor-specific antibodies decreased, pathologic signs of AMR regressed, and kidney function returned to normal. A molecular assessment of biopsies was retrospectively performed. By doing so, regression of the molecular signature of AMR was evidenced between the second and third biopsies. Interestingly, the first biopsy revealed a gene expression profile of AMR, which helped retrospectively classify this biopsy as AMR, illustrating the relevance of molecular phenotyping of biopsy in high-risk situations such as desensitization.

Belatacept rescue conversion in kidney transplant recipients with vascular lesions (Banff cv score >2): a retrospective cohort study.

BACKGROUND: Immunosuppression in kidney transplant recipients with decreased graft function and histological vascular changes can be particularly challenging. The impact of a late rescue conversion to belatacept on kidney graft survival in this context has never been studied. METHODS: We report a bicentric retrospective cohort study comparing a calcineurin inhibitor (CNI) to belatacept switch versus CNI continuation in 139 kidney transplant recipients with histological kidney vascular damage (cv ≥2, g + cpt ≤1, i + t ≤1) and low estimated glomerular filtration rate (≤40 mL/min/1.73 m²). Primary outcome was death-censored graft survival. RESULTS: During the study follow-up, 10 graft losses (14.5%) occurred in the belatacept group (n = 69) versus 26 (37.1%) in the matched CNI group (n = 70) (P = .005). Death-censored graft survival was significantly higher in the belatacept group (P = .001). At 3 years, graft survival was 84.0% in the belatacept group compared with 65.1% in the control group. Continuing CNI was an independent risk factor for graft loss [hazard ratio (HR) 3.46; P < .005]. The incidence of cellular rejection after the conversion was low (4.3% in both groups) and not significantly different between groups (P = .84). Patients switched to belatacept developed significantly less donor-specific antibodies de novo. Belatacept was an independent risk factor for the occurrence of opportunistic infections (HR 4.84; P < .005). CONCLUSION: The replacement of CNI with belatacept in patients with decreased allograft function and vascular lesions is associated with an improvement in graft survival and represents a valuable option in a context of organ shortage. Caution should be exercised regarding the increased risk of opportunistic infection.

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.

Impact of Calcineurin Inhibitor-Based Immunosuppression Maintenance During the Dialysis Period After Kidney Transplant Failure on the Next Kidney Graft Outcome: A Retrospective Multicenter Study With Propensity Score Analysis.

The impact of immunosuppressive therapy (IS) strategies after kidney transplant failure (KTF) on potential future new grafts is poorly established. We assessed the potential benefit of calcineurin inhibitor (CNI)-based IS maintenance throughout the dialysis period on the outcome of the second kidney transplant (KT). We identified 407 patients who underwent a second KT between January 2008 and December 2018 at four French KT centers. Inverse probability of treatment weighting was used to control for potential confounding. We included 205 patients with similar baseline characteristics at KTF: a total of 53 received at least CNIs on the retransplant day (G-CNI), and 152 did not receive any IS (G-STOP). On the retransplant date, G-STOP patients experienced a longer pretransplant dialysis time, were more often hyperimmunized, and underwent more expanded-criteria donor KTs than G-CNI patients. During the second KT follow-up period, rejection episodes were similar in both groups. The 10-year survival rates without death and dialysis were 98.7% and 59.5% in G-CNI and G-STOP patients, respectively. In the multivariable analysis, CNI-based IS maintenance was associated with better survival (hazard ratio: 0.08; 95% confidence interval: 0.01-0.58, p = 0.01). CNI-based IS maintenance throughout the dialysis period after KTF may improve retransplantation outcomes.

[Whole-body training using HUBER® system in physical therapy rehabilitation: a systematic review]. / Rééducation globale à l'aide du système HUBER® en kinésithérapie : une revue systématique de la littérature.

INTRODUCTION: HUBER®, an isometric strengthening device, has been promoted as rehabilitation tool for a wide population of patients presenting heterogenous profiles. METHODS: Medline and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched. Only interventional studies aiming to assess the effectiveness of HUBER® device (any versions, any protocol of intervention used) on physical rehabilitation outcomes of adults were included. Quality of studies was assessed using Cochrane RoB tools. RESULTS: Out of 142 references, six interventional studies were included in this systematic review. The number of participants included per study varied from 12 to 53, length of intervention varied from 4 to 8 weeks and number of sessions per week varied from 2 to 4. Different profiles of participants were included. Globally, training sessions using the HUBER® device showed moderate beneficial effects on the following outcomes: morphological characteristics, strength, balance and muscle power. The overall quality of the included studies was, however, rated as moderate to low. CONCLUSION: Because of its capacity to collect various physiological parameters simultaneously, the HUBER® device seems to be an interesting rehabilitation tool.

INTRODUCTION: HUBER® est un dispositif de renforcement isométrique qui a été développé comme outil de rééducation pour des profils de patients présentant des pathologies variées. Méthodes : Medline et le registre Cochrane des essais contrôlés (CENTRAL) ont été consultés. Seules les études interventionnelles visant à évaluer l'efficacité du dispositif HUBER® (toutes versions, tout protocole d'intervention utilisé) sur les objectifs de la réadaptation physique des adultes ont été incluses. La qualité des études a été évaluée à l'aide des outils Cochrane RoB. Résultats : Sur 142 références identifiées par notre stratégie de recherche, six études interventionnelles répondaient à nos critères d'inclusion et ont été incluses dans cette revue systématique. Le nombre de participants inclus par étude variait de 12 à 53, la durée de la rééducation s'étendait de 4 à 8 semaines et le nombre de séances par semaine variait de 2 à 4. Différents profils de participants ont été inclus. Globalement, les entraînements utilisant le dispositif HUBER® ont montré des effets bénéfiques significatifs modérés sur les mesures suivantes : caractéristiques morphologiques, force, équilibre et puissance musculaire. La qualité globale des études incluses a toutefois été jugée modérée à faible. CONCLUSION: En raison de sa capacité à évaluer simultanément différents paramètres physiologiques, le dispositif HUBER® semble être un outil de rééducation intéressant.

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.

6-Sulfo LacNAc monocytes are quantitatively and functionally disturbed in systemic sclerosis patients.

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis, microangiopathy, and autoantibodies. We previously reported that circulating follicular helper T (cTfh) cells are increased in SSc and induce plasmablast differentiation. However, mechanisms leading to cTfh cell expansion and activation in SSc remain to be established. Tfh cells require IL-12 for their expansion and differentiation. 6-Sulfo LacNAc monocytes (slanMo), a subset of monocytes, have a higher capacity to produce IL-12 and to induce CD4+ T cell proliferation in comparison with dendritic cells (DC) or classical monocytes. The aim of this study was to perform a quantitative and functional analysis of monocytes and DC and to correlate them with cTfh cell expansion and clinical manifestations in SSc. Using flow cytometry, we analyzed different monocyte subsets including slanMo and DC from 36 SSc patients and 26 healthy controls (HC). In vitro culture experiments of sorted slanMo were performed for functional analysis and cytokine production. We observed that slanMo, intermediate and non-classical monocytes were increased in SSc in comparison with HC. Furthermore, the increase in slanMo cells was more potent in patients with diffuse SSc. We observed a significant positive correlation between slanMo and cTfh cell levels in SSc patients but not in HC. Other monocyte subsets did not correlate with cTfh cell expansion. In addition, we observed that in vitro, slanMo cells from SSc patients produced less IL-12 than slanMo from HC. SlanMo are increased in SSc and may participate in the activation of cTfh cells in SSc.

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.

Regulatory B cell imbalance correlates with Tfh expansion in systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune disease with fibrosis, microangiopathy and immune dysfunction. B cell abnormalities characterised by autoantibody production and polyclonal B cell activation play an important role in the pathogenesis of SSc. We previously identified an expansion of functional and activated circulating T follicular helper (cTfh) cells in SSc patients. The aim of this study was to analyse the frequency of regulatory B (Breg) cell subsets and the correlation with Tfh in SSc patients. METHODS: Circulating Breg cells CD24hiCD38hi and CD27+CD24hi levels and cTfh cells CD4+CXCR5+PD1+ were determined by cytometry in 50 SSc patients and 32 healthy subjects. RESULTS: The frequency of Breg cells CD24hiCD38hi and CD24hiCD27+ was significantly reduced in patients with SSc as compared to controls (p=0.02 and p<0.001, respectively). In contrast, when examining the CD21low B cell subset, the frequency was significantly increased in SSc patients compared to healthy controls, (p<0.001). There was no difference in Breg cell levels in patients with diffuse SSc and limited SSc. However, CD24hiCD27+ Breg cell frequency was significantly decreased in SSc patients with pulmonary arterial hypertension (p=0.014), but not in patients with interstitial lung disease (p=0.058). Furthermore, we observed a negative correlation between cTfh and CD24hiCD27+ Breg cell levels in SSc patients but not in healthy controls (p=0.02). CONCLUSIONS: These results suggest that Breg cell subsets may participate in the regulation of cTfh and disease severity. Decreased CD24hiCD27+ Breg cell frequency may contribute to the development of SSc.

Ipilimumab-induced renal granulomatous arteritis: a case report.

BACKGROUND: Immune Checkpoint Inhibitors (ICPIs) are promising new drugs in treatment of advanced tumours targeting cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD1) or its ligand (PDL-1). Ipilimumab is a monoclonal antibody targeting the CTLA-4 receptor used in treatment of metastatic melanoma. By increasing activity of the immune system, ICPIs lead to immune-related adverse events, such as dermatitis, colitis or hepatitis. ICPIs-related kidney adverse events are rare and acute tubulointerstitial nephritis with or without granuloma have mainly been reported. CASE PRESENTATION: We report a case of acute kidney injury in a patient with melanoma treated by ipilimumab. Kidney biopsy revealed acute interlobular and juxtaglomerular granulomatous arteritis, which has not yet been reported in patients treated by ICPIs. Kidney function partially recovered after ipilimumab discontinuation and oral prednisone. Unfortunately, the patient died a few months later from progression of his melanoma. CONCLUSION: This case highlights a new mechanism of acute kidney injury related to ICPIs and supports the interest of kidney biopsy in case of ICPIs related acute renal failure.

Minimization of maintenance immunosuppressive therapy after renal transplantation comparing cyclosporine A/azathioprine or cyclosporine A/mycophenolate mofetil bitherapy to cyclosporine A monotherapy: a 10-year postrandomization follow-up study.

Long-term outcomes in renal transplant recipients withdrawn from steroid and submitted to further minimization of immunosuppressive regimen after 1 year are lacking. In this multicenter study, 204 low immunological risk kidney transplant recipients were randomized 14.2 ± 3.7 months post-transplantation to receive either cyclosporine A (CsA) + azathioprine (AZA; n = 53), CsA + mycophenolate mofetil (MMF; n = 53), or CsA monotherapy (n = 98). At 3 years postrandomization, the occurrence of biopsy for graft dysfunction was similar in bitherapy and monotherapy groups (21/106 vs. 26/98; P = 0.25). At 10 years postrandomization, patients' survival was 100%, 94.2%, and 95.8% (P = 0.25), and death-censored graft survival was 94.9%, 94.7%, and 95.2% (P = 0.34) in AZA, MMF, and CsA groups, respectively. Mean estimated glomerular filtration rate was 70.4 ± 31.1, 60.1 ± 22.2, and 60.1 ± 19.0 ml/min/1.73 m(2), respectively (P = 0.16). The incidence of biopsy-proven acute rejection was 1.4%/year in the whole cohort. None of the patients developed polyomavirus-associated nephropathy. The main cause of graft loss (n = 12) was chronic antibody-mediated rejection (n = 6). De novo donor-specific antibodies were detected in 13% of AZA-, 21% of MMF-, and 14% of CsA-treated patients (P = 0.29). CsA monotherapy after 1 year is safe and associated with prolonged graft survival in well-selected renal transplant recipient (ClinicalTrials.gov number: 980654).

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.

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.

Triple positive profile in antiphospholipid syndrome: prognosis, relapse and management from a retrospective multicentre study.

OBJECTIVE: Antiphospholipid syndrome (APS) is defined by the association of thromboembolic and/or obstetrical clinical manifestations and the presence of antiphospholipid antibodies. The objective of our study was to evaluate the impact of the triple-positive profile in a cohort of 204 APS patients. METHODS: We conducted a retrospective study, including patients with primary or secondary APS, meeting the Sydney criteria with at least one thrombotic and/or obstetrical complication. Clinical characteristics and the risk of relapse (defined by the occurrence of a new thrombotic event and/or a new adverse obstetrical event) between triple-positive and non-triple-positive APS patients were compared. RESULTS: 204 patients were included in our study, 68 were triple-positive and 136 were single or double positive. 122 patients (59.8%) had primary APS. 67 patients (32.8%) had obstetrical APS, with a higher rate among triple-positive patients (45.6% vs 26.5%, p=0.010), and 170 patients (83.3%) had thrombotic APS, without difference between triple-positive and others. Thrombotic events were more often venous (56.4%) than arterial (37.7%). Triple-positive patients had more placental complications than others (17.6% vs 2.9%, p=0.001) and more non-criteria events (48.5% vs 25.7%, p=0.002). Among non-criteria events, there was a higher frequency of Sneddon syndrome in triple-positive patients (7.4% vs 0.7%, p=0.028). The relapse rate was higher in triple-positive patients than in others (63.2% vs 39,7%, p=0002). In multivariate analysis, the triple-positive profile was associated with a higher risk of relapse (HR 1.63; 95% CI 1.04 to 2.55; p=0.031). CONCLUSION: The triple-positivity is associated with a higher risk of relapse and obstetrical complications.