Dataset Information

Molecular Diversity of Clinically Stable Human Kidney Allografts.

ABSTRACT:

Importance

Clinical decision and immunosuppression dosing in kidney transplantation rely on transplant biopsy tissue histology even though histology has low specificity, sensitivity, and reproducibility for rejection diagnosis. The inclusion of stable allografts in mechanistic and clinical studies is vital to provide a normal, noninjured comparative group for all interrogative studies on understanding allograft injury.

Objective

To refine the definition of a stable allograft as one that is clinically, histologically, and molecularly quiescent using publicly available transcriptomics data.

Design, setting, and participants

In this prognostic study, the National Center for Biotechnology Information Gene Expression Omnibus was used to search for microarray gene expression data from kidney transplant tissues, resulting in 38 studies from January 1, 2017, to December 31, 2018. The diagnostic annotations included 510 acute rejection (AR) samples, 1154 histologically stable (hSTA) samples, and 609 normal samples. Raw fluorescence intensity data were downloaded and preprocessed followed by data set merging and batch correction.

Main outcomes and measures

The primary measure was area under the receiver operating characteristics curve from a set of feature selected genes and cell types for distinguishing AR from normal kidney tissue.

Results

Within the 28 data sets, the feature selection procedure identified a set of 6 genes (KLF4, CENPJ, KLF2, PPP1R15A, FOSB, TNFAIP3) (area under the curve [AUC], 0.98) and 5 immune cell types (CD4+ T-cell central memory [Tcm], CD4+ T-cell effector memory [Tem], CD8+ Tem, natural killer [NK] cells, and Type 1 T helper [TH1] cells) (AUC, 0.92) that were combined into 1 composite Instability Score (InstaScore) (AUC, 0.99). The InstaScore was applied to the hSTA samples: 626 of 1154 (54%) were found to be immune quiescent and redefined as histologically and molecularly stable (hSTA/mSTA); 528 of 1154 (46%) were found to have molecular evidence of rejection (hSTA/mAR) and should not have been classified as stable allografts. The validation on an independent cohort of 6 months of protocol biopsy samples in December 2019 showed that hSTA/mAR samples had a significant change in graft function (r?=?0.52, P?Conclusions and relevanceThe results of this prognostic study suggest that the InstaScore could provide an important adjunct for comprehensive and highly quantitative phenotyping of protocol kidney transplant biopsy samples and could be integrated into clinical care for accurate estimation of subsequent patient clinical outcomes.

SUBMITTER: Rychkov D

PROVIDER: S-EPMC7835722 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Molecular Diversity of Clinically Stable Human Kidney Allografts.

Rychkov Dmitry D Sur Swastika S Sirota Marina M Sarwal Minnie M MM

JAMA network open 20210104 1

<h4>Importance</h4>Clinical decision and immunosuppression dosing in kidney transplantation rely on transplant biopsy tissue histology even though histology has low specificity, sensitivity, and reproducibility for rejection diagnosis. The inclusion of stable allografts in mechanistic and clinical studies is vital to provide a normal, noninjured comparative group for all interrogative studies on understanding allograft injury.<h4>Objective</h4>To refine the definition of a stable allograft as on ...[more]

PMID: 33492376

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Project description:The fate of transplanted kidneys is substantially influenced by graft quality, with transplantation of kidneys from elderly and expanded criteria donors (ECDs) associated with higher occurrence of delayed graft function, rejection, and inferior long-term outcomes. However, little is known about early molecular fingerprints of these events in different donor categories. Borderline changes represent the most frequent histological finding early after kidney transplantation. Therefore, we examined outcomes and transcriptomic profiles of early-case biopsies diagnosed as borderline changes in different donor categories. In this single-center, retrospective, observational study, we compared midterm outcomes of kidney transplant recipients with early borderline changes as a first pathology between ECD (n = 109), standard criteria donor (SCDs, n = 109), and living donor (LD, n = 51) cohorts. Intragraft gene expression profiling by microarray was performed in part of these ECD, SCD, and LD cohorts. Although 5 year graft survival in patients with borderline changes in early-case biopsies was not influenced by donor category (log-rank P = 0.293), impaired kidney graft function (estimated glomerular filtration rate by Chronic Kidney Disease Epidemiology Collaboration equation) at M3, 1, 2, and 3 years was observed in the ECD cohort (P < 0.001). Graft biopsies from ECD donors had higher vascular intimal fibrosis and arteriolar hyalinosis compared to SCD and LD (P < 0.001), suggesting chronic vascular changes. Increased transcripts typical for ECD, as compared to both LD and SCD, showed enrichment of the inflammatory, defense, and wounding responses and the ECM-receptor interaction pathway. Additionally, increased transcripts in ECD vs. LD showed activation of complement and coagulation and cytokine-cytokine receptor pathways along with platelet activation and cell cycle regulation. Comparative gene expression overlaps of ECD, SCD, and LD using Venn diagrams found 64 up- and 16 down-regulated genes in ECD compared to both LD and SCD. Shared increased transcripts in ECD vs. both SCD and LD included thrombospondin-2 (THBS2), angiopoietin-like 4 (ANGPTL4), collagens (COL6A3, COL1A1), chemokine CCL13, and interleukin IL11, and most significantly, down-regulated transcripts included proline-rich 35 (PRR35) and fibroblast growth factor 9. Early borderline changes in ECD kidney transplantation are characterized by increased regulation of inflammation, extracellular matrix remodeling, and acute kidney injury transcripts in comparison with both LD and SCD grafts.

Project description:The fate of transplanted kidneys is substantially influenced by the graft quality as transplantation of kidneys from elderly and expanded criteria deceased donors (ECD) is associated with higher occurrence of delayed graft function, rejection and inferior long term outcome. Little is known about early molecular fingerprints of these events in different donor categories. Borderline changes represent the most frequent histological finding early after kidney transplantation. Therefore, transcriptomic profiles of early case biopsies diagnosed as borderline changes were studied in ECD, standard criteria deceased donors (SCD) and living donor (LD) kidney transplantation using RNA microarray (Agilent SurePrintG3). The increased transcripts typical for ECD as compared to LD (n=437) showed enrichment of extracellular matrix (ECM) -receptor interaction (p=0.004) and complement and coagulation pathways (p=0.004) and GO terms related to platelet activation, blood coagulation, regulation of cell cycle, acute inflammatory response, wound healing or defense response (p<0.001). Gene annotation analysis of transcripts with increased expression in ECD grafts compared to SCD (n=244) showed the highest enrichment of inflammatory response (p=0.013), response to wounding (p=0.001) and defense response (p=0.005) and ECM-receptor interaction pathway (p=0.043). Comparative gene expression overlaps of ECD, SCD and LD using Venn’s diagrams found 62 up- and 16 down-regulated genes in ECD compared to both LD and SCD. Shared increased transcripts in ECD vs. both SCD and LD included, thrombospondin 2 (THBS2), angiopoietin-like 4 (ANGPTL4), collagens (COL6A3, COL1A1), chemokines CCL13 or interleukin IL11 and most significant down-regulated transcripts included proline rich 35 (PRR35) and fibroblast growth factor 9 (FGF9). Transcriptomic profile of higher inflammation and extracellular matrix remodeling in early borderline changes in the ECD kidney allografts suggest mechanisms how ischemia/reperfusion injury aggravates alloimmune response in the presence of chronic vascular changes.

Dataset Information

Molecular Diversity of Clinically Stable Human Kidney Allografts.

Importance

Objective

Design, setting, and participants

Main outcomes and measures

Results

Publications

Molecular Diversity of Clinically Stable Human Kidney Allografts.

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