Archetypal Analysis of Injury in Kidney Transplant Biopsies Identifies Two Classes of Early AKI

Frontiers in Medicine

The INTERCOMEX Investigators¹  Katelynn S. Madill-Thomsen²  Marek Myslak³  Ondrej Viklicky⁴  Gunilla Einecke⁵  Jonathan Bromberg⁶  Agnieszka Perkowska-Ptasinska⁷  Farsad A. Eskandary⁸  Georg A. Böhmig⁸  Philip F. Halloran⁹  Gaurav Gupta^1,10 

[1] ;Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada;Department of Clinical Interventions, Department of Nephrology and Kidney Transplantation Samodzielny Publiczny Wojewódzki Szpital Zespolony (SPWSZ) Hospital, Pomeranian Medical University, Szczecin, Poland;Department of Nephrology and Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czechia;Department of Nephrology, Hannover Medical School, Hannover, Germany;Department of Surgery, University of Maryland, Baltimore, MD, United States;Department of Transplantation Medicine, Nephrology and Internal Diseases, Medical University of Warsaw, Warsaw, Poland;Division of Nephrology and Dialysis, Department of Medicine III, Medical University of Vienna, Vienna, Austria;Division of Nephrology and Transplant Immunology, Department of Medicine, University of Alberta, Edmonton, AB, Canada;Division of Nephrology, Virginia Commonwealth University, Richmond, VA, United States;

关键词: biopsy;    kidney transplantation;    injury;    archetypes;    gene expression;   

DOI  :  10.3389/fmed.2022.817324

来源: DOAJ

【 摘 要 】

All transplanted kidneys are subjected to some degree of injury as a result of the donation-implantation process and various post-transplant stresses such as rejection. Because transplants are frequently biopsied, they present an opportunity to explore the full spectrum of kidney response-to-wounding from all causes. Defining parenchymal damage in transplanted organs is important for clinical management because it determines function and survival. In this study, we classified the scenarios associated with parenchymal injury in genome-wide microarray results from 1,526 kidney transplant indication biopsies collected during the INTERCOMEX study. We defined injury groups by using archetypal analysis (AA) of scores for gene sets and classifiers previously identified in various injury states. Six groups and their characteristics were defined in this population: No injury, minor injury, two classes of acute kidney injury (“AKI,” AKI1, and AKI2), chronic kidney disease (CKD), and CKD combined with AKI. We compared the two classes of AKI, namely, AKI1 and AKI2. AKI1 had a poor function and increased parenchymal dedifferentiation but minimal response-to-injury and inflammation, instead having increased expression of PARD3, a gene previously characterized as being related to epithelial polarity and adherens junctions. In contrast, AKI2 had a poor function and increased response-to-injury, significant inflammation, and increased macrophage activity. In random forest analysis, the most important predictors of function (estimated glomerular filtration rate) and graft loss were injury-based molecular scores, not rejection scores. AKI1 and AKI2 differed in 3-year graft survival, with better survival in the AKI2 group. Thus, injury archetype analysis of injury-induced gene expression shows new heterogeneity in kidney response-to-wounding, revealing AKI1, a class of early transplants with a poor function but minimal inflammation or response to injury, a deviant response characterized as PC3, and an increased risk of failure. Given the relationship between parenchymal injury and kidney survival, further characterization of the injury phenotypes in kidney transplants will be important for an improved understanding that could have implications for understanding native kidney diseases (ClinicalTrials.gov #NCT01299168).

【 授权许可】

Unknown