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.

Rituximab for recurrence of primary focal segmental glomerulosclerosis after kidney transplantation: Results of a nationwide study.

Rituximab (RTX) therapy for primary focal segmental glomerulosclerosis recurrence after kidney transplantation (KT) has been extensively debated. We aimed to assess the benefit of adding RTX to plasmapheresis (PP), corticosteroids, and calcineurin inhibitors (standard of care, SOC). We identified 148 adult patients who received KT in 12/2004-12/2018 at 21 French centers: 109 received SOC (Group 1, G1), and 39 received immediate RTX along with SOC (Group 2, G2). In G1, RTX was introduced after 28 days of SOC in the event of failure (G1a, n = 19) or PP withdrawal (G1b, n = 12). Complete remission (CR) was achieved in 46.6% of patients, and partial remission (PR) was achieved in 33.1%. The 10-year graft survival rates were 64.7% and 17.9% in responders and nonresponders, respectively. Propensity score analysis showed no difference in CR+PR rates between G1 (82.6%) and G2 (71.8%) (p = .08). Following the addition of RTX (G1a), 26.3% of patients had CR, and 31.6% had PR. The incidence of severe infections was similar between patients treated with and without RTX. In multivariable analysis, infection episodes were associated with hypogammaglobulinemia <5 g/L. RTX could be used in cases of SOC failure or remission for early discontinuation of PP without increasing the risk of infection.

Decreased Expression of Connexin 43 Blunts the Progression of Experimental GN.

GN refers to a variety of renal pathologies that often progress to ESRD, but the molecular mechanisms underlying this progression remain incompletely characterized. Here, we determined whether dysregulated expression of the gap junction protein connexin 43, which has been observed in the progression of renal disease, contributes to GN progression. Immunostaining revealed de novo expression of connexin 43 in damaged glomeruli in patients with glomerular diseases as well as in mice after induction of experimental GN. Notably, 2 weeks after the induction of GN with nephrotoxic serum, mice with a heterozygous deletion of the connexin 43 gene (connexin 43+/-) had proteinuria, BUN, and serum creatinine levels significantly lower than those of wild-type animals. Additionally, the connexin 43+/- mice showed less crescent formation, tubular dilation, monocyte infiltration, and interstitial renal fibrosis. Treatment of cultured podocytes with connexin 43-specific blocking peptides attenuated TGF-ß-induced cytoskeletal and morphologic changes and apoptosis as did treatment with the purinergic blocker suramin. Finally, therapeutic treatment of GN mice with connexin 43-specific antisense oligodeoxynucleotide improved functional and structural renal parameters. These findings suggest that crosstalk between connexin 43 and purinergic signaling contributes to podocyte damage in GN. Given that this protein is highly induced in individuals with glomerular diseases, connexin 43 may be a novel target for therapeutic treatment of GN.

Factors That Predict a Sustained Humoral Response to COVID-19 Vaccines in Kidney Transplant Recipients.

INTRODUCTION: Kidney transplant recipients (KTRs) produce a weak humoral response to coronavirus disease 2019 (COVID-19) vaccines. However, the factors associated with the quality of the serological response to three doses of COVID-19 vaccine have not been unambiguously identified. METHODS: We included KTRs followed in the Nephrology Department at Amiens University Hospital (Amiens, France) between June and December 2021 who had received three doses of a COVID-19 mRNA vaccine (or two doses plus an episode of polymerase chain reaction-confirmed COVID-19). The lack of a humoral response was defined as an antibody titer below 7.1 binding antibody units (BAU)/mL, and an optimal response was defined as an antibody titer above 264 BAU/mL. RESULTS: Of the 371 patients included, 246 (66.3%) were seropositive, and 97 (26.1%) had an optimal response. In a multivariate analysis, the only factor associated with seropositivity was a history of COVID-19 [odds ratio (OR) 87.2; 95% confidence interval (CI) (7.88-965.0); p < 0.0001], while the main factors associated with non-response were female sex [OR 0.28; 95%CI (0.15-0.51); p < 0.0001], less than 36 months between kidney transplantation and vaccination [OR 0.26; 95%CI (0.13-0.52); p < 0.0001], a higher creatinine level [OR 0.33; 95%CI (0.19-0.56); p < 0.0001], the use of tacrolimus [OR 0.23; 95%CI (0.12-0.45); p < 0.0001], the use of belatacept [OR 0.01; 95%CI (0.001-0.20); p = 0.002] and three-drug immunosuppression [OR 0.39; 95%CI (0.19-0.78); p = 0.015]. A history of COVID-19 was associated with an optimal response [OR 4.03; 95%CI (2.09-7.79); p < 0.0001], while an older age at vaccination [OR 0.97; 95%CI (0.95-0.99); p = 0.002], less than 36 months between kidney transplantation and vaccination [OR 0.35; 95%CI (0.18-0.69); p = 0.002], a higher creatinine level [OR 0.60; 95%CI (0.38-0.93); p = 0.02], three-drug immunosuppression [OR 0.45; 95%CI (0.27-0.76); p = 0.003] were associated with a poorer response. CONCLUSION: We identified factors associated with a humoral response to a COVID-19 mRNA vaccine in KTRs. These findings might help physicians to optimize vaccination in KTRs.

Magnesium sulphate in patients with thrombotic thrombocytopenic purpura (MAGMAT): a randomised, double-blind, superiority trial.

PURPOSE: Studies have suggested benefits from magnesium sulphate in thrombotic thrombocytopenic purpura (TTP). We aimed to measure the effects of magnesium sulphate supplementation on TTP recovery. METHODS: In this multicenter, randomised, double-blind, controlled, superiority study, we enrolled adults with a clinical diagnosis of TTP. Patients were randomly allocated to receive magnesium sulphate (6 g intravenously followed by a continuous infusion of 6 g/24 h for 3 days) or placebo, in addition to the standard treatment. The primary outcome was the median time to platelet normalisation (defined as a platelet count ≥ 150 G/L). Efficacy and safety were assessed by intention-to-treat. RESULTS: Overall, we enrolled 74 participants, including one who withdrew his/her consent. Seventy-three patients were further analyzed, 35 (48%) allocated to magnesium sulphate and 38 (52%) to placebo. The median time to platelet normalisation was 4 days (95% confidence interval [CI], 3-4) in the magnesium sulphate group and 4 days (95% CI 3-5) in the placebo group. The cause-specific hazard ratio of response was 0.93 (95% CI 0.58-1.48, p = 0.75). The number of patients with ≥ 1 serious adverse reactions was similar in the two groups. By day 90, four patients in the magnesium sulphate group and two patients in the placebo group had died (p = 0.42). The most frequent adverse event was low blood pressure occurring in 34% in the magnesium sulphate group and 29% in the placebo group (p = 0.80). CONCLUSION: Among patients with TTP, the addition of magnesium sulphate to the standard of care did not result in a significant improvement in time to platelet normalisation.

Flow cytometry crossmatching to investigate kidney-biopsy-proven, antibody-mediated rejection in patients who develop de novo donor-specific antibodies.

INTRODUCTION: The appearance of de novo donor-specific anti-human leukocyte antigen antibodies (dnDSAs) after kidney transplantation is independently associated with poor long-term allograft outcomes. The objective of the present study was to evaluate the predictive value of a flow cytometry crossmatching (FC-XM) assay after the appearance of dnDSAs related to antibody-mediated allograft rejection (ABMR) after kidney transplantation. MATERIALS AND METHODS: A total of 89 recipients with dnDSAs after transplantation were included. The crossmatching results were compared with the dnDSA profile (the mean fluorescence intensity (MFI), the complement-binding activity, and the IgG subclass profile) and the biopsy's morphological features. RESULTS: Of the 89 patients, 59 (66%) were positive in an FC-XM assay, 17 (19%) had complement-binding DSAs, 55 (62%) were positive for IgG1 and/or IgG3 in a solid phase assay, and 45 (51%) had morphological biopsy features linked to ABMR. CONCLUSION: An FC-XM assay was unable to discriminate between cases with or without ABMR on biopsy findings; it had a low positive predictive value (<70%) and a low negative positive predictive value (<42.9%), taking into account the sensitivity of our assay (limit of detection: DSAs with an MFI >3000). In this context, the height of the MFI of the dnDSAs might be enough for a high positive predictive value for ABMR and additional testing for complement binding activity can remain optional.

[Fanconi syndrome in a 22-year-old African patient]. / Syndrome de Fanconi chez un patient de 22 ans d'origine africaine.

Acquired Fanconi syndrome can occur in patients with monoclonal gammopathy or after exposure to heavy metals or drug agents such as ifosfamide, and some antiretroviral therapies. Fanconi syndrome is characterized by a dysfunctional of the proximal tubular responsible in its complete form for polyuria, hypokalemia, glycosuria, hypophosphatemia and low molecular weight proteinuria. We report the case of a 22-year-old patient hospitalized with an acute renal failure secondary to a tubulo-interstitial nephritis associated with a complete Fanconi syndrome in a context of a poor general condition and fever. We described and analyzed the process leading to the diagnosis.