Halloran Philip F, Böhmig Georg A, Bromberg Jonathan, Einecke Gunilla, Eskandary Farsad A, Gupta Gaurav, Myslak Marek, Viklicky Ondrej, Perkowska-Ptasinska Agnieszka, Madill-Thomsen Katelynn S
Alberta Transplant Applied Genomics Centre, Edmonton, AB, Canada.
Division of Nephrology and Transplant Immunology, Department of Medicine, University of Alberta, Edmonton, AB, Canada.
Front Med (Lausanne). 2022 Apr 7;9:817324. doi: 10.3389/fmed.2022.817324. eCollection 2022.
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).
由于捐献-植入过程以及诸如排斥反应等各种移植后应激因素，所有移植肾都会受到一定程度的损伤。因为移植肾经常接受活检，所以它们为探索肾脏对各种原因所致损伤的全面反应提供了契机。明确移植器官中的实质损伤对于临床管理很重要，因为它决定了肾脏功能和存活情况。在本研究中，我们对国际多中心肾脏移植基因表达谱研究（INTERCOMEX研究）期间收集的1526份肾移植指征活检的全基因组微阵列结果中与实质损伤相关的情况进行了分类。我们通过对先前在各种损伤状态中确定的基因集和分类器的分数进行原型分析（AA）来定义损伤组。在该人群中定义了六组及其特征：无损伤、轻度损伤、两类急性肾损伤（“AKI”，AKI1和AKI2）、慢性肾脏病（CKD）以及CKD合并AKI。我们比较了两类急性肾损伤，即AKI1和AKI2。AKI1功能较差且实质去分化增加，但对损伤和炎症的反应极小，相反，与上皮极性和黏附连接相关的基因PARD3表达增加。相比之下，AKI2功能较差且对损伤的反应增加、有明显炎症以及巨噬细胞活性增加。在随机森林分析中，功能（估计肾小球滤过率）和移植物丢失的最重要预测因素是基于损伤的分子分数，而非排斥分数。AKI1和AKI2在3年移植物存活率方面存在差异，AKI2组存活率更高。因此，对损伤诱导基因表达的损伤原型分析显示了肾脏对损伤反应中的新异质性，揭示了AKI1，这是一类功能较差但炎症或对损伤反应极小的早期移植，一种被称为PC3的异常反应，以及失败风险增加。鉴于实质损伤与肾脏存活之间的关系，进一步明确肾移植中损伤表型对于增进理解可能具有重要意义，这可能对理解原发性肾脏疾病有所帮助（ClinicalTrials.gov #NCT01299168）。
