Extracorporeal Photopheresis Reduces Fibrotic and Inflammatory Transcriptomic Biological Marker of Chronic Antibody-mediated Kidney Rejection.

Background: The benefit of extracorporeal photopheresis on the course of kidney transplant rejection is unknown. The aim of our study was to investigate the variations in transcriptomics on graft biopsies when extracorporeal photopheresis was used to treat chronic humoral rejection after kidney transplantation. Methods: We retrospectively analyzed the mRNA expression of 770 genes of interest in graft biopsies performed before and after treatment. Eight patients received an average of 23 extracorporeal photopheresis sessions over 4 mo between the 2 biopsies. Results: Transcriptomic analysis of the graft biopsies identified a significant (adjusted P < 0.05) increase in CAV1 mRNA in all patients and a significant decrease in CD19, IL21, PAX5, and SFTPA2 mRNAs in 7 of 8 patients. Conclusions: In patients treated with extracorporeal photopheresis for chronic humoral rejection after renal transplantation, omic analysis of repeated biopsies shows a reduction in fibrotic and inflammatory transcriptomic biologicals markers.

Immune modulation with extracorporeal photopheresis in renal transplantation: proof of concept clinical outcomes and perspective / Immunomodulation par photo-chimiothérapie extracorporelle en transplantation rénale : preuves de concept, données cliniques et perspectives

For 30 years, photopheresis is used to treat graft versus host disease and heart or lung allograft rejection. In this review, we discuss the place of photopheresis in kidney transplantation both in prevention or treatment of rejection. Mechanisms of action in kidney transplantation are mainly based on results observed in graft versus host disease and in heart or lung transplantation. Photopheresis may induce innate and adaptive immunity changes with restauration of a favourable Th1/Th2 immune balance, an expansion of LT /LB reg subsets, and a local enrichment in IL-10. French national clinical and mechanistic studies are underway to define the place of photopheresis therapy in immunomodulation strategies in kidney transplantation.

Depuis presque 30 ans, l'utilisation de la photo-chimiothérapie (PEC) a montré son efficacité dans le contrôle de la maladie du greffon contre l'hôte et dans le traitement du rejet d'allogreffe cardiaque et pulmonaire. L'utilisation de la PEC en transplantation rénale pourrait apporter un bénéfice thérapeutique sans majoration du risque infectieux ou oncologique, tant en prévention que dans le traitement du rejet. Il existe peu de données sur les mécanismes d'action de la PEC, les principales hypothèses reposant sur les résultats observés dans la maladie du greffon contre l'hôte ou en transplantation cardiaque et pulmonaire. La PEC induirait des modifications de l'immunité innée et adaptative dont la restauration d'un équilibre de la balance Th1/Th2 et une expansion des sous-populations LT/B régulatrices ainsi qu'une modification de l'environnement cytokinique avec enrichissement en IL-10. En France, des études cliniques et mécanistiques sont en cours pour affiner la place de la PEC dans les stratégies d'immunomodulation en transplantation rénale.

The challenging follow-up of pregnancy in women with known thrombotic thrombocytopenic purpura: a single-center experience of a preemptive management protocol.

BACKGROUND: Although thrombotic thrombocytopenic purpura frequently affects women of childbearing age, there is no clear recommendation for the management of subsequent pregnancies in women with established thrombotic thrombocytopenic purpura. METHODS: This single-center, retrospective, observational study included all women with hereditary thrombotic thrombocytopenic purpura or immune thrombotic thrombocytopenic purpura who had had at least one subsequent pregnancy after thrombotic thrombocytopenic purpura diagnosis between 2003 and 2022. The strategy comprised weekly surveillance of platelet count during pregnancy (and quarterly monitoring of ADAMTS13 activity) for women with immune thrombotic thrombocytopenic purpura, without any routine prophylactic treatment. In case of thrombocytopenia < 150,000/mm3 (with or without hemolysis relapse), women with hereditary thrombotic thrombocytopenic purpura systematically received plasma infusions twice weekly until platelet count normalized. RESULTS: A total of 13 patients were included (7 with hereditary thrombotic thrombocytopenic purpura and 6 with immune thrombotic thrombocytopenic purpura, with 20 planned pregnancies (11 and 9, respectively). All pregnancies resulted in live births, and all mothers survived. There was a marked improvement in pregnancy terms in the hereditary thrombotic thrombocytopenic purpura group compared to index pregnancies (37 [35;39] versus 31 [24;38] weeks, p = 0.037) and birth weights (3265 [3029;3410] versus 2160 [1240;2705] grams, p = 0.016), with need for plasma support mostly starting during the third trimester (5/7 patients, 7/11 pregnancies). A single hereditary thrombotic thrombocytopenic purpura relapse occurred, with rapid resolution after plasma support intensification. There were no relapses in the immune thrombotic thrombocytopenic purpura group, with ADAMTS13 activity systematically above 40% during all monitored pregnancies. CONCLUSION: These real-life data support the feasibility of a preemptive approach to pregnancy monitoring in women with known thrombotic thrombocytopenic purpura who undergo active surveillance within a multidisciplinary network.

The Versatile Role of miR-21 in Renal Homeostasis and Diseases.

MicroRNAs (miRNAs) are small, non-coding RNA species that control gene expression and confer robustness to biological processes. Over the last two decades, their important roles during kidney development, homeostasis and the treatment of diseases have been established, in particular during the onset and progression of various forms of acute and chronic renal disorders. In recent years, miR-21, one of the best-characterized miRNAs to date, has received much attention in renal physiology in particular given its high degree of conservation and expression in kidneys, as well as its potent pathogenic role in various debilitating renal diseases. This review summarizes the current knowledge on miR-21's involvement in both renal homeostasis and diseases, in particular its double-edged-sword role in acute versus chronic kidney injuries. Finally, we also discuss the potential of miR-21 as a biomarker and therapeutic target in renal diseases.

[Uremic calciphylaxis]. / La calciphylaxie urémique.

Uremic calciphylaxis is a rare disease that affects patients with chronic end-stage renal disease. It is a pathology of the microvessels of the dermis and hypodermis which are calcified and whose thrombosis leads to skin necrosis. Calciphylaxis lesions can be distal and axial. They lead to pain, infection and are associated with denutrition and in high mortality rate (40-80% at 1 year). This general review describes the clinical and para-clinical presentations of calciphylaxis. It summarizes the current knowledge on its pathogenesis and the therapeutical options that can be proposed to improve the management and attempt to reduce the mortality of patients with uremic calciphylaxis.

Endopeptidase Cleavage of Anti-Glomerular Basement Membrane Antibodies in vivo in Severe Kidney Disease: An Open-Label Phase 2a Study.

BACKGROUND: The prognosis for kidney survival is poor in patients presenting with circulating anti-glomerular basement membrane (GBM) antibodies and severe kidney injury. It is unknown if treatment with an endopeptidase that cleaves circulating and kidney bound IgG can alter the prognosis. METHODS: An investigator-driven phase 2a one-arm study (EudraCT 2016-004082-39) was performed in 17 hospitals in five European countries. A single dose of 0.25 mg/kg of imlifidase was given to 15 adults with circulating anti-GBM antibodies and an eGFR <15 ml/min per 1.73m2. All patients received standard treatment with cyclophosphamide and corticosteroids, but plasma exchange only if autoantibodies rebounded. The primary outcomes were safety and dialysis independency at 6 months. RESULTS: At inclusion, ten patients were dialysis dependent and the other five had eGFR levels between 7 and 14 ml/min per 1.73m2. The median age was 61 years (range 19-77), six were women, and six were also positive for anti-neutrophil cytoplasmic antibodies. Then 6 hours after imlifidase infusion, all patients had anti-GBM antibodies levels below the reference range of a prespecified assay. At 6 months 67% (ten out of 15) were dialysis independent. This is significantly higher compared with 18% (nine out of 50) in a historical control cohort (P<0.001, Fisher's exact test). Eight serious adverse events (including one death) were reported, none assessed as probably or possibly related to the study drug. CONCLUSIONS: In this pilot study, the use of imlifidase was associated with a better outcome compared with earlier publications, without major safety issues, but the findings need to be confirmed in a randomized controlled trial.Clinical Trial registration number: EUDRACT 2016-004082-39 https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-001377-28/results.

Impaired renal function before kidney procurement has a deleterious impact on allograft survival in very old deceased kidney donors.

As the use of elderly kidney donors for transplantation is increasing with time, there is a need to understand which factors impact on their prognosis. No data exist on the impact of an impaired renal function (IRF) in such population. 116 kidney recipients from deceased kidney donors over 70 years were included from 2005 to 2015 in a single-center retrospective study. IRF before organ procurement was defined as a serum creatinine above 1.0 mg/dl or a transient episode of oligo-anuria. Mean ages for donors and recipients were respectively 74.8 ± 3.5 and 66.7 ± 8.0. Graft survival censored for death at 5 years was of 77%. Using a multivariate analysis by Cox model, the only predictor of graft loss present in the donor was IRF before organ procurement (HR 4.2 CI95[1.8-9.7]). IRF was also associated with significant lower estimated glomerular filtration rates up to 1 year post-transplantation. By contrast, KDPI score (median of 98 [96-100]), was not associated with the risk of graft failure. Then, IRF before kidney procurement may define a risk subgroup among very-old deceased kidney donors, in whom pre-implantatory biopsies, dual kidney transplantation or calcineurin inhibitor-free immunosuppressive regimen could help to improve outcomes.

Successful Reuse of Kidney Graft After Early Recurrence of Primary Focal and Segmental Glomerulosclerosis.

Primary focal and segmental glomerulosclerosis (FSGS) frequently recurs after transplantation and is associated with a poor prognosis. We describe here the successful kidney graft reuse in an adult recipient, 8 months after early primary FSGS recurrence resistant to all available therapeutics. Patient 1, a 23-year-old man, followed for kidney failure secondary to primary FSGS, was first transplanted in 2018 with a deceased donor graft. Unfortunately, we observed an immediate recurrence of biopsy-proven primary FSGS. After 4 lines of treatment (intravenous cyclosporine+corticosteroids, plasma exchanges, immunoadsorption, and rituximab), the patient was still highly nephrotic and kidney function was slowly deteriorating. After approval from both the patient and the health authority (Biomedicine Agency), the graft was detransplanted 8 months after transplantation and reimplanted in patient 2, a 78-year-old nonimmunized and anephric recipient (bi-nephrectomy 2 years previously for bilateral renal carcinoma). We observed immediate kidney function and progressive resolution of proteinuria (serum creatinine of 1.2mg/dL and proteinuria of 0.1 g/d 1 year later). Biopsies performed after surgery showed persistent FSGS lesions with a decrease in overall foot-process effacement. To our knowledge, this is the first reported case showing that kidney graft transfer may still be a viable option for refractory primary FSGS several months after transplantation.

Association between acute graft pyelonephritis and kidney graft survival: A single-center observational study.

The association between acute graft pyelonephritis (AGPN) and graft failure in kidney transplant recipients (KTR) remains controversial. In this single-center observational study, we aimed to assess the incidence of AGPN as a time-dependent posttransplantation event. We also examined the association between the diagnosis of AGPN and graft outcomes. In total, we evaluated 1480 patients who underwent kidney transplantation between January 2007 and December 2017. During a median follow-up of 5.04 years, we observed 297 AGPN episodes that occurred in 158 KTR. To evaluate the association between AGPN and clinical outcomes, we performed Cox proportional hazards regression analyses in which AGPN was entered as a time-dependent covariate. AGPN was independently associated with an increased risk of graft loss (hazard ratio = 1.66; 95% confidence interval [CI]: 1.05-2.64, p < .03) and a persistently decreased eGFR (fixed effect on intercept: -2.29 ml/min/1.73 m2 ; 95% CI: from -3.23 to -1.35, p < .01). However, neither mortality nor biopsy-proven acute rejection was found to correlate with AGPN. Moreover, recurrent AGPN episodes did not appear to have an additive detrimental impact on graft loss. These data represent a promising step in understanding whether AGPN prevention may decrease the risk of graft loss in KTR.