Molecular Stratification of Chronic Kidney Disease

Abstract

AbstractCurrent classification of chronic kidney disease (CKD) into stages based on the indirect measures of kidney functional state, estimated glomerular filtration rate and albuminuria, is agnostic to the heterogeneity of underlying etiologies, histopathology, and molecular processes. We used genome-wide transcriptomics from patients’ kidney biopsies, directly reflecting kidney biological processes, to stratify patients from three independent CKD cohorts. Unsupervised Self-Organizing Maps (SOM), an artificial neural network algorithm, assembled CKD patients into four novel subgroups, molecular categories, based on the similarity of their kidney transcriptomics profiles. The unbiased, molecular categories were present across CKD stages and histopathological diagnoses, highlighting heterogeneity of conventional clinical subgroups at the molecular level. CKD molecular categories were distinct in terms of biological pathways, transcriptional regulation and associated kidney cell types, indicating that the molecular categorization is founded on biologically meaningful mechanisms. Importantly, our results revealed that not all biological pathways are equally activated in all patients; instead, different pathways could be more dominant in different subgroups and thereby differentially influencing disease progression and outcomes. This first kidney-centric unbiased categorization of CKD paves the way to an integrated clinical, morphological and molecular diagnosis. This is a key step towards enabling precision medicine for this heterogeneous condition with the potential to advance biological understanding, clinical management, and drug development, as well as establish a roadmap for molecular reclassification of CKD and other complex diseases.One sentence summaryUnbiased grouping of patients based on kidney biopsy transcriptomics profiles generated a novel molecular categorization of chronic kidney disease.