Molecular Diagnosis of Antibody-Mediated Rejection in Human Kidney Transplants

Sellarès, Joana; Reeve, J.; Loupy, Alexandre; Mengel, Michael; Sis, B.; Skene, Alison; Freitas, D. G. de; Kreepala, Chatchai; Hidalgo, Luis; Famulski, Konrad S.; Halloran, Philip F.

doi:10.1111/ajt.12150

Cited by 248 publications

(297 citation statements)

References 62 publications

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“…The biopsy assessment has been detailed elsewhere (4,10,12). Biopsies were processed for histologic examination (periodic acid-Schiff, hematoxylin and eosin, and trichrome) and tested for DSA as per local standard of care.…”

Section: Histology Classificationmentioning

confidence: 99%

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Identifying Subphenotypes of Antibody-Mediated Rejection in Kidney Transplants

Halloran

Lopez

Pereira

2016

American Journal of Transplantation

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The key lesions in antibody-mediated kidney transplant rejection (ABMR) are microcirculation inflammation (peritubular capillaritis and/or glomerulitis lesions, abbreviated ''pg'') and glomerular double contours (cg lesions). We used these features to explore subphenotypes in 164 indication biopsies with ABMR-related diagnoses: 137 ABMR (109 pure and 28 mixed with T cellmediated rejection [TCMR]) and 27 transplant glomerulopathy (TG), identified from prospective multicenter studies. The lesions indicated three ABMR subphenotypes: pgABMR, cgABMR, and pgcgABMR. Principal component analysis confirmed these subphenotypes and showed that TG can be reclassified as pgcgABMR (n ¼ 17) or cgABMR (n ¼ 10). ABMR-related biopsies included 45 pgABMR, 90 pgcgABMR, and 25 cgABMR, with four unclassifiable. Dominating all time intervals was the subphenotype pgcgABMR. The pgABMR subphenotype presented earliest (median <2 years), frequently mixed with TCMR, and was most associated with nonadherence. The cgABMR subphenotype presented late (median 9 years). Subphenotypes differed in their molecular changes, with pgABMR having the most histologic-molecular discrepancies (i.e. potential errors). Donor-specific antibody (DSA) was not identified in 29% of pgcgABMR and 46% of cgABMR, but failure rates and molecular findings were similar to cases where DSA was known to be positive. Thus, ABMR presents distinct subphenotypes, early pg-dominant, late cg-dominant, and combined pgcg phenotype, differing in time, molecular features, accompanying TCMR, HLA antibody, and probability of nonadherence.

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Section: Histology Classificationmentioning

confidence: 99%

“…The first 403 were interpreted centrally by Drs B. Sis and M. Mengel (9,10). During these studies, we discovered the importance of C4d-negative ABMR, and biopsies were interpreted accordingly (5).…”

Section: Histology Classificationmentioning

confidence: 99%

Identifying Subphenotypes of Antibody-Mediated Rejection in Kidney Transplants

Halloran

Lopez

Pereira

2016

American Journal of Transplantation

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“…On the other hand, enzymelinked immunosorbent assay (ELISA) or flow cytometry based techniques are less invasive and more useful for clinical purposes by measuring the levels of chemokines in urine or blood samples [7][8][9][10][11][12]. Alternatively, chemokine mRNA can be measured by polymerase chain reaction or microarray in tissues or leukocytes of patients [8,13,14].…”

Section: Chemokines: General Conceptsmentioning

confidence: 99%

“…CCL2/MCP-1 was the first CC chemokine to be discovered, acting as a potent chemotactic factor for monocytes, and has been one of the most studied biomarkers [6,10,13,[17][18][19][20][21][22][23][24][25][26][27][28]. Many studies have associated CCL2/MCP-1 with glomerulopathies [6,13,[19][20][21][22][23][24][25][26] and with renal transplantation [10,27,28].…”

Section: Chemokines In Renal Diseasesmentioning

confidence: 99%

“…Many studies have associated CCL2/MCP-1 with glomerulopathies [6,13,[19][20][21][22][23][24][25][26] and with renal transplantation [10,27,28]. Wada and coworkers found significantly elevated urinary levels of this chemokine in adults with diabetic nephropathy, whereas serum levels remained similar to those of healthy volunteers [21].…”

Section: Chemokines In Renal Diseasesmentioning

confidence: 99%

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Chemokines as Potential Markers in Pediatric Renal Diseases

Silva¹,

Pereira²,

Teixeira³

et al. 2016

Biomarkers in Kidney Disease

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Glomerular diseases and obstructive uropathies are the two most frequent causes of chronic kidney disease (CKD) in children. Recently, biomarkers have become a focus of clinical research as potentially useful diagnostic tools in pediatric renal diseases. Among several putative biomarkers, chemokines emerge as promising molecules since they play relevant roles in the pathophysiology of pediatric renal diseases. The evaluation of these inflammatory mediators might help in the management of diverse renal diseases in children and the detection of patients at high risk to develop CKD. The aim of this paper is to revise general aspects of chemokines and the potential link between chemokines and the most common pediatric renal diseases by including experimental and clinical evidence.

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Molecular Diversity of Clinically Stable Human Kidney Allografts

et al. 2021

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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 PARTICIPANTSIn 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 MEASURESThe 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. RESULTSWithin 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 [T H 1] 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 < .001) and graft loss at 5-year follow-up (r = 0.17). A drop by 10 mL/min/1.73m 2 in estimated glomerular filtration rate was estimated as a threshold in allograft transitioning from hSTA/mSTA to hSTA/mAR. 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.

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Molecular Diagnosis of Antibody-Mediated Rejection in Human Kidney Transplants

Cited by 248 publications

References 62 publications

Identifying Subphenotypes of Antibody-Mediated Rejection in Kidney Transplants

Identifying Subphenotypes of Antibody-Mediated Rejection in Kidney Transplants

Chemokines as Potential Markers in Pediatric Renal Diseases

Molecular Diversity of Clinically Stable Human Kidney Allografts

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