Auteur : Tri@dmin

Influence of Blood Pressure and Calcineurin Inhibitors on Kidney Function After Heart or Liver Transplantation

Abstract

BACKGROUND:

Chronic kidney disease is common after heart or liver transplantation, with calcineurin inhibitors (CNI) considered the key contributor. A possible influence of posttransplant blood pressure has not been extensively examined.

METHODS:

Data from adult recipients of a first heart or liver transplant were analyzed regarding the relationship between blood pressure at year 1, renal function at year 5, and CNI therapy.

RESULTS:

Whereas we confirmed the well-known detrimental effect of increased 1-year systolic blood pressure on 5-year kidney graft survival, heart or liver graft survival were not affected. However, among 2,534 heart transplant recipients with good renal function at year 1, increasing systolic blood pressure at year 1 was associated with higher rates of poor renal function at year 5 posttransplant. This association was confirmed on multivariate analysis overall (odds ratio [OR] 1.25 per 20 mmHg increment, P<0.001) and within subgroups. Similar results were observed in 1,822 liver transplant recipients (OR 1.35, P<0.001). Neither the type of CNI nor CNI dose or trough level at year 1 showed a significant association with kidney function at year 5.

CONCLUSIONS:

One-year blood pressure was identified as the major modifiable risk factor associated with deteriorating kidney function between years 1 to 5 after heart or liver transplantation.

December 2017 / Transplantation – Morath C, Opelz G, Döhler B, Zeier M, Süsal C

HLA Matching in Pediatric Kidney Transplantation: HLA Poorly Matched Living Donor Transplants Versus HLA Well-Matched Deceased Donor Transplants

Résumé
In this registry analysis, pediatric kidney graft survival of well HLA matched kidneys from deceased donors compares favorably with that of grafts from poorly HLA matched living donors, increasing the debate over counselling and allocation policies. Supplemental digital content is available in the text.

Novembre 2017 / Transplantation – Opelz G, Döhler B, Middleton D et Süsal C

Plus d’informations : http://journals.lww.com/transplantjournal/Abstract/2017/11000/HLA_Matching_in_Pediatric_Kidney_Transplantation__.27.aspx

Mutations in signal recognition particle SRP54 cause syndromic neutropenia with Shwachman-Diamond–like features

Abstract

Shwachman-Diamond syndrome (SDS) (OMIM #260400) is a rare inherited bone marrow failure syndrome (IBMFS) that is primarily characterized by neutropenia and exocrine pancreatic insufficiency. Seventy-five to ninety percent of patients have compound heterozygous loss-of-function mutations in the Shwachman-Bodian-Diamond syndrome (sbds) gene. Using trio whole-exome sequencing (WES) in an sbds-negative SDS family and candidate gene sequencing in additional SBDS-negative SDS cases or molecularly undiagnosed IBMFS cases, we identified 3 independent patients, each of whom carried a de novo missense variant in srp54 (encoding signal recognition particle 54 kDa). These 3 patients shared congenital neutropenia linked with various other SDS phenotypes. 3D protein modeling revealed that the 3 variants affect highly conserved amino acids within the GTPase domain of the protein that are critical for GTP and receptor binding. Indeed, we observed that the GTPase activity of the mutated proteins was impaired. The level of SRP54 mRNA in the bone marrow was 3.6-fold lower in patients with SRP54-mutations than in healthy controls. Profound reductions in neutrophil counts and chemotaxis as well as a diminished exocrine pancreas size in a SRP54-knockdown zebrafish model faithfully recapitulated the human phenotype. In conclusion, autosomal dominant mutations in SRP54, a key member of the cotranslation protein-targeting pathway, lead to syndromic neutropenia with a Shwachman-Diamond–like phenotype.

October 2017 / The Journal of Clinical Investigation – Carapito R, Konantz M, Paillard C, Miao Z, Pichot A, S. Leduc M, Yang Y, L. Bergstrom K, H. Mahoney D, L. Shardy D, Alsaleh G, Naegely L, Kolmer A, Paul N, Hanauer A, Rolli V, S. Müller J, Alghisi E, Sauteur L, Macquin C,  Morlon A, Sancho C.S, Amati-Bonneau P, Procaccio V, Mosca-Boidron A.-L., Marle N, Osmani N, Lefebvre O, G. Goetz J, Unal S, A. Akarsu N, Radosavljevic M, Chenard M-P, Rialland F, Grain A, Béné M-C, Eveillard M, Vincent M, Guy J,  Faivre L, Thauvin-Robinet C, Thevenon J, Myers K, D. Fleming M, Shimamura A, Bottollier-Lemallaz E, Westhof E, Lengerke C, Isidor B et Bahram S

Endothelial precursor cell cross-match using Tie-2-enriched spleen cells

Abstract

Background

Non-HLA antibodies against human endothelial progenitor cells (EPC) in pre-transplant recipient serum can have a deleterious influence on the graft. EPC enriched from peripheral blood have been commonly used for EPC cross-matching. In the present study, we describe cross-matches using EPC enriched from fresh or frozen-thawed spleen cell preparations, thereby widening the sample source for deceased-donor cross-matching and retrospective studies.

Methods

EPC cross-matches were performed retrospectively using spleen cells and the flow cytometric XM-ONE cross-match test kit.

Results

Healthy controls (n = 28) showed no IgG antibodies against EPC. When sera of 11 random dialysis patients were studied, 2 patients (18%) exhibited IgG EPC antibodies. When pre-transplant sera of 20 kidney graft recipients with good long-term graft outcome (serum creatinine 1.0 ± 0.2 mg/dL measured 2463 ± 324 days post-transplant) were investigated using frozen-thawed and then separated Tie-2-enriched spleen cells of the original transplant donor, 3 patients (15%) had pre-transplant IgG EPC antibodies. When pre-transplant sera of 5 patients with intra-operative graft loss were studied employing the original donor spleen cells, 4 (80%) patients showed IgG EPC antibodies.

Conclusions

Cross-matches with spleen cell-derived EPC using the XM-ONE assay are technically possible. Our very preliminary experience suggests clinical relevance.

© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Septembre 2017 / Clinical Transplantation – Daniel V, Süsal C, Scherer S, Tran H, Gombos P, Trojan K, Sadeghi M, Morath C, Opelz G.

Biglycan expression in the melanoma microenvironment promotes invasiveness via increased tissue stiffness inducing integrin-β1 expression

Abstract

Novel targeted and immunotherapeutic approaches have revolutionized the treatment of metastatic melanoma. A better understanding of the melanoma-microenvironment, in particular the interaction of cells with extracellular matrix molecules, may help to further improve these new therapeutic strategies.We observed that the extracellular matrix molecule biglycan (Bgn) was expressed in certain human melanoma cells and primary fibroblasts when evaluated by microarray-based gene expression analysis. Bgn expression in the melanoma tissues correlated with low overall-survival and low progression-free-survival in patients. To understand the functional role of Bgn we used gene-targeted mice lacking functional Bgn. Here we observed that melanoma growth, metastasis-formation and tumor-related death were reduced in Bgn-/- mice compared to Bgn+/+ mice. In vitro invasion of melanoma cells into organotypic-matrices derived from Bgn-/- fibroblasts was reduced compared to melanoma invasion into Bgn-proficient matrices. Tissue stiffness as determined by atomic-force-microscopy was reduced in Bgn-/- matrices. Isolation of melanoma cells and fibroblasts from the stiffer Bgn+/+ matrices revealed an increase in integrin-β1 expression compared to the Bgn-/- fibroblast matrices. Overexpression of integrin-β1 in B16-melanoma cells abolished the survival benefit seen in Bgn-/- mice. Consistent with the studies performed in mice, the abundance of Bgn-expression in human melanoma samples positively correlated with the expression of integrin-β1, which is in agreement with results from the organotypic invasion-assay and the in vivo mouse studies.This study describes a novel role for Bgn-related tissue stiffness in the melanoma-microenvironment via regulation of integrin-β1 expression by melanoma cells in both mice and humans.

Juin 2017 / Oncotarget – écrit par Andrlová H, Mastroianni J, Madl J, Kern JS, Melchinger W, Dierbach H, Wernet F, Follo M, Technau-Hafsi K, Has C, Rao Mittapalli V, Idzko M, Herr R, Brummer T, Ungefroren H, Busch H, Boerries M, Narr A, Ihorst G, Vennin C, Schmitt-Graeff A, Minguet S, Timpson P, Duyster J, Meiss F, Römer W, Zeiser R