Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

WNT Pathway Signalling in Kidney Transplants with Microvascular Injury

ABSTRACT: Kidney transplant recipients with biopsy-proven microvascular injury (MVI) have increased risk for allograft failure. MVI is often caused by antibody-mediated injury that is resistant to available treatments. Current diagnostic methods are also inadequate, with interobserver variability in traditional pathology reads, variable assessment of circulating donor-specific antibody between HLA laboratories, and peritubular capillary C4d staining. Molecular assessments of kidney biopsies can provide improved sensitivity for diagnosing MVI and other allograft pathology, while improving reproducibility and objectivity. Most molecular classifiers have been based on whole genome sequencing to develop diagnostic tests, but have provided limited therapeutic targets. In this study, we pursued a candidate gene approach to measure WNT pathway genes in residual clinical FFPE biopsies with and without MVI. We focused on the WNT pathway because of previous translational studies that implicated this pathway in chronic renal allograft injury as well as vascular injury in native chronic kidney disease. Case-control study of 95 residual FFPE biopsies with MVI (g+ptc score >= 2, n=50) or Stable (g+ptc score < 2 and no other major abnormalities, n=45). Biopsies were retrieved from a biorepository of over 500 kidney transplant biopsies. We compared expression of 180 WNT pathway genes and 30 custom skipe-in targets (derived from previous studies of endothelial injury in transplantation) between MVI and Stable groups, with correction for multiple comparisons using FDR < 5%. This dataset is part of the TransQST collection.

ORGANISM(S): Homo sapiens

SUBMITTER: Michael Seifert

PROVIDER: E-GEOD-115989 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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WNT pathway signaling is associated with microvascular injury and predicts kidney transplant failure.

Seifert Michael E ME Gaut Joseph P JP Guo Boyi B Jain Sanjay S Malone Andrew F AF Geraghty Feargal F Della Manna Deborah L DL Yang Eddy S ES Yi Nengjun N Brennan Daniel C DC Mannon Roslyn B RB

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 20190510 10

Microvascular injury is associated with accelerated kidney transplant dysfunction and allograft failure. Molecular pathology can identify new mechanisms of microvascular injury while improving on the diagnostic and prognostic capabilities of traditional histology. We conducted a case-control study of archived kidney biopsy specimens stored up to 10 years with microvascular injury (n = 50) compared with biopsy specimens without histologic injury (n = 45) from patients of similar age, race, and se ...[more]

PMID: 30916889

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Project description:C3 glomerulopathy (C3G), which encompasses C3 glomerulonephritis (C3GN) and dense deposit disease (DDD), results from dysregulation of the alternative complement pathway. Data on disease recurrence after kidney transplantation is limited, and details on histologic features of recurrent C3G are scarce. We aimed to evaluate C3G recurrence in the allograft, with a focus on histologic presentation and progression. We retrospectively analyzed 18 patients with native kidney failure attributed to C3G (12 C3GN and 6 DDD) who received a kidney transplant from January 2016 to January 2023. Demographic, genetic, clinical, and histologic data were studied. The Nanostring 770 genes immune profiling panel was used for transcriptomic analysis. Disease recurrence was the primary outcome. During a median follow-up period of 37 (18, 56) months, C3G recurrence occurred in 16 (89%) of patients (11 with C3GN and 5 with DDD), at a median of 33 (13, 141) days post-transplantation. Over a third (38%) of recurrent cases were detected in protocol biopsies, and only 31% of patients presented with >300 mg/g of proteinuria. Recurrence in index biopsies was mainly established through a combination of immunofluorescence and electron microscopy findings, while it showed only subtle histologic alterations and no characteristic transcriptomic signals. Over time, histologic chronicity indices increased, but all allografts were functioning at the end of follow-up. Patients with recurrence of C3GN and DDD showed overlapping immunofluorescence and electron microscopy findings and had similar recurrence rate and time to recurrence. The majority of patients with native kidney failure attributed to C3G developed disease recurrence very early after kidney transplantation, usually with minimal proteinuria, mild histologic alterations, and favorable short-term allograft survival. Immunofluorescence and electron microscopy played crucial role in detecting early, sub-clinical recurrence of C3GN and DDD, which showed significant overlapping features. To identify transcriptomic signals that may distinguish recurrent C3G, we utilized the 770 genes PanCancer Immune Profiling Panel in a discovery cohort of native kidney biopsies followed by a testing cohort of allograft biopsies. For the discovery cohort, we residual tissue from formalin-fixed paraffin-embedded samples (FFPE) was used from 18 native kidney biopsies with C3G (11 C3GN and 7 DDD) and 36 native biopsies with other glomerular diseases (GD controls: 15 IgA nephropathy, 14 membranous nephropathy, 7 diffuse podocytopathy). For the testing cohort, we ass essedresidual FFPE tissue was used from 13 index allograft biopsies with recurrent C3G (combining 10 from our study with enough residual tissue and 3 additional cases that were added to increase sample size) and 41 allograft glomerular disease (GD) controls. Since recurrent GD is overall more commonly encountered than de novo GD although the frequency of latter might be underestimated20, the GD controls were selected to roughly reflect this notion [15 de novo GD (5 membranous nephropathy, 6 immune complex-mediated glomerulonephritis not otherwise specified, 3 IgA nephropathy, 1 HCV-associated glomerulonephritis) and 26 recurrent GD (10 membranous nephropathy, 8 IgA nephropathy, 7 diffuse podocytopathy, 1 HCV-associated glomerulonephritis)].

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Dataset Information

WNT Pathway Signalling in Kidney Transplants with Microvascular Injury

Publications

WNT pathway signaling is associated with microvascular injury and predicts kidney transplant failure.

Similar Datasets

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