14 research outputs found

    Endothelial Cell Amplification of Regulatory T Cells Is Differentially Modified by Immunosuppressors and Intravenous Immunoglobulin

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    Immunosuppressive treatment is a prerequisite for both organ transplantation and tolerance of the allograft. However, long-term immunosuppression has been associated with a higher incidence of malignancies and infections. Immunosuppressors mainly target circulating immune cells and little is known of their “off-target” effects, such as their impact on endothelial cells (ECs). In chronic antibody-mediated rejection (AMR), the allograft endothelium is a target of damage, histologically detected as transplant glomerulopathy, and which correlates with poor graft survival. Under inflammatory conditions, EC expression of HLA class II antigens can lead to CD4+-T lymphocyte alloactivation and selective expansion of pro-inflammatory Th17 and pro-tolerance Treg subsets. This response can be modified and preactivation of the EC by HLA-DR antibody binding promoted a proinflammatory Th17 response. However, whether or not immunosuppressors alter EC immunogenicity has not been examined. In alloimmunized patients with AMR, cyclosporine A (CsA) and mycophenolic acid (MPA) are often combined with intravenous immunoglobulins (IVIgs). This study reports changes in the microvascular EC phenotype and function after treatment with CsA, MPA, or IVIg. Both CsA and MPA decreased HLA-DR and increased CD54 expression, whereas IVIg increased HLA-DR expression. Interleukin 6 secretion was reduced by all three immunomodulators. Preincubation of ECs with CsA or MPA limited, while IVIg amplified, Treg expansion. Because CsA, MPA, and IVIg are known for their ability to act upon leukocytes, we confirmed that ECs maintained their immunoregulatory role when allogeneic leukocytes were pretreated with CsA, MPA, or IVIg. The results reveal that individual immunosuppressors, used in the induction and maintenance of renal allograft tolerance, had direct and distinct effects on ECs. Results of experiments associating IVIg with either CsA or MPA underlined the differences observed using individual immunosuppressors. Paradoxically, CsA or MPA may increase EC mediated inflammatory responses and long-term exposure may contribute to limitation of allograft tolerance. In contrast, IVIg interaction with the endothelium may mediate some of its immunosuppressive effects through promotion of Treg expansion, contributing to the maintenance of allograft tolerance

    Arteriovenous fistulas thrombosis in hemodialysis patients with COVID-19

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    International audienceBackground: The current Coronavirus disease 2019 (COVID-19) outbreak is associated with significant mortality, especially in patients suffering from end stage renal disease (ESRD) and hemodialysis patients. Several previous studies reported an over-risk of arterial and venous thrombosis, in particular pulmonary embolism and venous thrombosis of catheter in COVID19 patients in intensive care unit. However, arteriovenous fistula (AVF) thrombosis has rarely been reported yet in these patients. AVF thrombosis is a serious complication that impacts significantly patients outcome. Here, we aim to describe characteristics and prognosis of a cohort of COVID-19 hemodialysis (HD) patients presenting with AVF thrombosis. Methods: In the Ile de France region (Paris area) during the March 11th–April 30th 2020 period, fistula thrombosis cases were collected among COVID-19 hemodialysis patients in seven dialysis units and in interventional vascular departments. These patients’ characteristics were analyzed through a review of the patient’s medical records. Results: Seventeen patients were included in our study (median age 69 years). Ten patients (59%) were men. Ten patients (59%) were diabetic and 88% had a high blood pressure. The mortality rate in these patients was 47%. All thrombosis treated with a declotting procedures (64%) were successfully cleared, but with early relapse in 36%. Conclusion: Our study highlights AVF thrombosis as a severe complication in COVID-19 hemodialysis patients that contributed to the severity and accelerated death

    Exome Sequencing and Prediction of Long-Term Kidney Allograft Function

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    International audienceCurrent strategies to improve graft outcome following kidney transplantation consider information at the human leukocyte antigen (HLA) loci. Cell surface antigens, in addition to HLA, may serve as the stimuli as well as the targets for the anti-allograft immune response and influence long-term graft outcomes. We therefore performed exome sequencing of DNA from kidney graft recipients and their living donors and estimated all possible cell surface antigens mismatches for a given donor/recipient pair by computing the number of amino acid mismatches in trans-membrane proteins. We designated this tally as the allogenomics mismatch score (AMS). We examined the association between the AMS and post-transplant estimated glomerular filtration rate (eGFR) using mixed models, considering transplants from three independent cohorts (a total of 53 donor-recipient pairs, 106 exomes, and 239 eGFR measurements). We found that the AMS has a significant effect on eGFR (mixed model, effect size across the entire range of the score: -19.4 [-37.7, -1.1], P = 0.0042, χ2 = 8.1919, d.f. = 1) that is independent of the HLA-A, B, DR matching, donor age, and time post-transplantation. The AMS effect is consistent across the three independent cohorts studied and similar to the strong effect size of donor age. Taken together, these results show that the AMS, a novel tool to quantify amino acid mismatches in trans-membrane proteins in individual donor/recipient pair, is a strong, robust predictor of long-term graft function in kidney transplant recipients

    Vancomycin-Associated Cast Nephropathy

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    International audienceVancomycin is a widely prescribed antibiotic, but the exact nature of vancomycin-associated nephrotoxicity is unclear, in particular when considering the frequent coadministration of aminoglycosides. We describe here the initial case of a 56-year-old woman with normal renal function developing unexplained ARF without hypovolemia after administration of vancomycin without coadministration of aminoglycosides. Studying the patient’s renal biopsy specimen, we ascertained that obstructive tubular casts composed of noncrystal nanospheric vancomycin aggregates entangled with uromodulin explained the vancomycin-associated ARF. We developed in parallel a new immunohistologic staining technique to detect vancomycin in renal tissue and confirmed retrospectively that deleterious vancomycin-associated casts existed in eight additional patients with acute tubular necrosis in the absence of hypovolemia. Concomitant high vancomycin trough plasma levels had been observed in each patient. We also reproduced experimentally the toxic and obstructive nature of vancomycin-associated cast nephropathy in mice, which we detected using different in vivo imaging techniques. In conclusion, the interaction of uromodulin with nanospheric vancomycin aggregates represents a new mode of tubular cast formation, revealing the hitherto unsuspected mechanism of vancomycin-associated renal injury

    Recipient/Donor incompatibility quantified by exome sequencing and calculation of allogenomics mismatch score (AMS).

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    <p><b>(A)</b> Hypothesis: Post-transplantation kidney graft function is associated with the number of amino acids coded by the donor genome that the recipient’s immune system could recognize as non-self. <b>(B)</b> Examples of donor/recipient amino-acid mismatches at one protein position, and resulting contributions to the allogenomics mismatch score. The allogenomics mismatch score is calculated by summing contributions over a set of genomic polymorphisms (see <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1005088#sec007" target="_blank">Methods</a> for details). <b>(C)</b> Equations for the allogenomics model. Score contributions are summed across all genomic positions of interest (set <i>P</i>) to yield the allogenomics score Δ(<i>r</i>,<i>d</i>). <i>G</i><sub><i>r</i>,<i>p</i></sub>: genotype of recipient <i>r</i> at genomic site/position <i>p</i>. <i>G</i><sub><i>d</i>,<i>p</i></sub>: genotype of donor <i>d</i> at site <i>p</i>. Alleles of a genotype are denoted with the letter <i>a</i>.</p

    Relationship between the allogenomics mismatch score (AMS) and kidney graft function at 12, 24 or 36 months following transplantation in the Discovery cohort.

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    <p>DNA was isolated from 10 pairs of kidney graft recipients and their living kidney donors (Discovery set). Whole exome sequencing of the donor genomes and recipient genomes was performed and the sequencing information was used to calculate allogenomics mismatch scores based on amino acid mismatches in trans-membrane proteins. The panels depict the relationship between the allogenomics mismatch scores and serum creatinine levels at 12, 24 and 36 months post transplantation (Panels A, B and C, respectively) and the relationship between the allogenomics mismatch scores and estimated glomerular filtration rate at 12, 24 and 36 months post transplantation (Panels D, E and F, respectively). Both serum creatinine levels and eGFR correlate in a time-dependent fashion with the allogenomics mismatch score with the strongest correlations being observed at 36 months post-transplantation.</p
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