Small non-coding RNA profiles in chronic kidney disease in the general population and high-risk sub-groups (with hypertension and/or diabetes mellitus) in a South African community-based cohort

Abstract

Background: Chronic kidney disease (CKD) is a major public health concern and contributor to morbidity and mortality globally. Identification of CKD in its early stages is critical to mitigate its progression to advanced stages or development of cardiovascular-associated complications, effectively improving health outcomes. With the established limitations of currently adopted clinical indicators of CKD, identification of more accurate and reliable biomarkers has been the focus of recent clinical research. MicroRNAs are emerging as promising diagnostic and prognostic markers as well as targets for therapeutic intervention for a multitude of disease including CKD. However, published data on the same miRNA signatures in CKD is contradictory across studies and limited studies have explored the value of these miRNAs in CKD in individuals of African ancestry. Therefore, we aimed to identify all published miRNAs found to be associated with CKD and/or measures of kidney function and kidney damage, as well as their expression patterns, in the general population and in high-risk subgroups [hypertension (HTN), diabetes mellitus (DM) and human immunodeficiency virus (HIV)-infected). Furthermore, we aimed to characterize the expression profile of five known whole blood miRNAs (miR-126-3p, miR-30a-5p, miR-1299, miR-182-5p and miR-30e-3p) in the general population with CKD and six novel whole blood miRNAs (hsa-miRnovel- chr1_36178, hsa-miR-novel-chr2_55842, hsa-miR-novel-chr7_76196, hsa-miR-novelchr5_ 67265, hsa-miR-novel-chr15_18383 and hsa-miR-novel-chr13_13519) in high-risk individuals with HTN and DM, for the first time in a South African cohort. Methods: We conducted a systematic search of Medline via PubMed, Scopus, Web of Science, and EBSCOhost databases to identify relevant studies according to a predefined eligibility and exclusion criteria published in English or French languages on or before 31 October 2021. Using quantitative reverse transcriptase PCR (RT-qPCR), we quantified the expression of known whole blood miRNAs in a general population (n= 1449), whilst the quantification of novel whole blood miRNAs was performed in 911 individuals with HTN and/or DM. We used adjusted and unadjusted regression models to assess the association between the studied miRNAs and prevalent CKD as well as markers of kidney function and kidney damage. The area under the receiver operating characteristics curve was used to determine the discriminatory power of the studied novel blood miRNAs to identify those with prevalent CKD. Results: Through a systematic search of the literature, we identified a number of frequently dysregulated miRNAs in CKD (miR-126, miR-223, miR-155, miR-21) and in diabetic kidney disease (DKD) (miR-155, miR-126, miR-192, miR-21, miR-15a-5p, miR-29a, miR-29b and miR-29c). Of these, miR-126 and miR-223 were commonly downregulated in CKD whilst in individuals with DKD, miR-21 and miR-29b were consistently upregulated. In our South African population, an upregulated expression of known whole blood miRNAs in the general population and novel whole blood miRNAs in high-risk individuals, was observed in those with CKD relative to those without CKD. Moreover, upregulated expression of known miRNAs (miR-126-3p, -182-5p and -30e-3p) and all the studied novel miRNAs were independently associated with prevalent CKD. Whilst only the increased expression of hsa-miR-novel-chr2_55842 and hsa-miR-novel-chr7_76196 were independently associated with reduced estimated glomerular filtration rate (eGFR). Furthermore, all the novel whole blood miRNAs were acceptable predictors of CKD, however, only hsa-miR-novelchr13_ 13519 added to CKD prediction beyond conventional factors. Conclusion: This study provides evidence of miRNA dysregulation in CKD in the general population and high-risk individuals for the first time in a South African population. We also highlighted a list of miRNAs with consistent dysregulated patterns commonly studied in the general population with CKD and those with DKD in various geographic locations. The dysregulated miRNA expression pattern suggests that altered miRNA may play a role in the pathogenesis of CKD. These findings form the basis for future research aimed at investigating the clinical value of miRNAs in CKD particularly in Africa.