Early acute microvascular kidney transplant rejection in the absence of anti-HLA antibodies is associated with preformed IgG antibodies against diverse glomerular endothelial cell antigens

International audienceBACKGROUND: Although anti-HLA antibodies (Abs) cause most antibody-mediated rejections of renal allografts, non-anti-HLA Abs have also been postulated to contribute. A better understanding of such Abs in rejection is needed.METHODS: We conducted a nationwide study to identify kidney transplant recipients without anti-HLA donor-specific Abs who experienced acute graft dysfunction within 3 months after transplantation and showed evidence of microvascular injury, called acute microvascular rejection (AMVR). We developed a crossmatch assay to assess serum reactivity to human microvascular endothelial cells, and used a combination of transcriptomic and proteomic approaches to identify non-HLA Abs.RESULTS: We identified a highly selected cohort of 38 patients with early acute AMVR. Biopsy specimens revealed intense microvascular inflammation and the presence of vasculitis (in 60.5%), interstitial hemorrhages (31.6%), or thrombotic microangiopathy (15.8%). Serum samples collected at the time of transplant showed that previously proposed anti-endothelial cell Abs-angiotensin type 1 receptor (AT1R), endothelin-1 type A and natural polyreactive Abs-did not increase significantly among patients with AMVR compared with a control group of stable kidney transplant recipients. However, 26% of the tested AMVR samples were positive for AT1R Abs when a threshold of 10 IU/ml was used. The crossmatch assay identified a common IgG response that was specifically directed against constitutively expressed antigens of microvascular glomerular cells in patients with AMVR. Transcriptomic and proteomic analyses identified new targets of non-HLA Abs, with little redundancy among individuals.CONCLUSIONS: Our findings indicate that preformed IgG Abs targeting non-HLA antigens expressed on glomerular endothelial cells are associated with early AMVR, and that cell-based assays are needed to improve risk assessments before transplant

A novel biological assay to detect the active form of TGF-β in urine to monitor renal allograft rejection

A novel biological assay to detect the active form of TGF-β in urine to monitor renal allograft rejection.BackgroundTransforming growth factor-β (TGF-β) plays an important role in renal fibrosis. Measurement of the concentration of the active form of TGF-β particularly in urine may help our understanding of the mechanism of chronic allograft nephropathy and could be used as a diagnostic tool. However, TGF-β release and activation are complex and, consequently, there is currently no accurate way to measure TGF-β activity.MethodsTGF-β-sensitive BL41 cells were stably transfected with a reporter plasmid harboring a synthetic TGF-β-inducible DNA sequence upstream from the luciferase gene. Cells were incubated with urine samples from normal donors or transplanted recipients with or without patent nephropathy, and the active form of TGF-β was determined as luciferase activity.ResultsWe have established a cell line which expresses luciferase activity in response to active TGF-β in a dose-dependent manner. Moreover, the use of a histone deacetylase inhibitor greatly increased sensitivity to TGF-β and also stabilized luciferase inductibility. This test is highly specific to active TGF-β. Detectable levels of TGF-β were found in urine from patients with renal dysfunction due to acute or chronic renal allograft rejection (P < 0.001), but not in that from patients with stable, correctly functional kidneys.ConclusionWe describe a highly sensitive and specific assay for active TGF-β. We also show that, in cases of renal allograft, TGF-β expression is highly and significantly correlated with acute or chronic rejections

Skewed T cell responses to Epstein-Barr virus in long-term asymptomatic kidney transplant recipients

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Invasive cutaneous Neoscytalidium infections in renal transplant recipients: a series of five cases

International audienceBackground: Neoscytalidium species (formerly Scytalidium species) are black fungi that usually cause cutaneous infections mimicking dermatophytes lesions. Very few publications have reported invasive or disseminated infections. Case presentation: In this paper, we report the clinical presentations, treatments and outcomes of five cases of invasive Neoscytalidium infections with cutaneous involvement, including two cases with disseminated infection, in five renal transplant recipients. To our knowledge, this is the first report of a series—albeit small—of renal transplant patients in whom this infection was identified. All cases occurred in a single hospital in Paris, France, between 2001 and 2011. Patients all originate from tropical area. Conclusion: Treatments of Neoscytalidium infection varied greatly, underlining the lack of a recommendation for a standardized treatment. All patients were cured after long-term antifungal therapy and/or surgical excision. Interestingly, one patient with disseminated infection involving the left elbow, the right leg, the lungs and the nasal septum was cured by medical therapy only without surgery. This may suggest that in contrast to others mycoses (such as mucormycosis), an adequate medical treatment could be sufficient for treating Neoscytalidium. We also point out the difficulties we had in diagnosing two patients with Kaposi's sarcoma because of the similarity of the lesions. Furthermore, our report underlines the need to check for this rare infection in immunocompromised kidney transplant recipients originating from tropical areas

Use of a Belatacept-based Immunosuppression for Kidney Transplantation From Donors After Circulatory Death: A Paired Kidney Analysis

International audienceBackground. Efficacy and safety of belatacept have not been specifically reported for kidney transplantations from donors after circulatory death.Methods. In this retrospective multicenter paired kidney study, we compared the outcome of kidney transplantations with a belatacept-based to a calcineurin inhibitor (CNI)-based immunosuppression. We included all kidney transplant recipients from donors after uncontrolled or controlled circulatory death performed in our center between February 2015 and October 2020 and treated with belatacept (n = 31). The control group included the recipients of the contralateral kidney that were treated with CNI in 8 other centers (tacrolimus n = 29, cyclosporine n = 2).Results. There was no difference in the rate of delayed graft function. A higher incidence of biopsy-proven rejections was noted in the belatacept group (24 versus 6 episodes). Estimated glomerular filtration rate (eGFR) was significantly higher in the belatacept group at 3-, 12-, and 36-mo posttransplant, but the slope of eGFR was similar in the 2 groups. During a mean follow-up of 4.1 y, 12 patients discontinued belatacept and 2 patients were switched from CNI to belatacept. For patients who remained on belatacept, eGFR mean value and slope were significantly higher during the whole follow-up. At 5 y, eGFR was 80.7 ± 18.5 with belatacept versus 56.3 ± 22.0 mL/min/1.73 m2 with CNI (P = 0.003). No significant difference in graft and patient survival was observed.Conclusions. The use of belatacept for kidney transplants from either uncontrolled or controlled donors after circulatory death resulted in a better medium-term renal function for patients remaining on belatacept despite similar rates of delayed graft function and higher rates of cellular rejection

Phenotypic features of NK cells in kidney transplant recipients (KTRs) and healthy controls (HCs).

Percentage of A) CD56Bright, B) CD57+, C) NKG2A+, D) NKG2C+, E) NKp30+, F) NKp46+, G) Kir2DL2/3+, H) Kir3DL1+, I) CD69+, J) HLA-DR+, K) Siglec-7+ and L) PD-1+ in CD3-CD56+ NK cells from 10 kidney transplant recipients (KTRs) and 12 healthy controls (HCs). Expression was measured at the surface by flow cytometry on thawed PBMCs. Horizontal bars indicate the median. Exact P-values were calculated with a two-tailed Mann-Whitney test.</p

Primary antibodies used in intracellular cytokine staining assay.

Primary antibodies used in intracellular cytokine staining assay.</p

Primary antibodies used for T cell detailed phenotype.

Primary antibodies used for T cell detailed phenotype.</p