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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
Author(s)
Motshwari, Dipuo Dephney
Date Issued
2022
Type
Thesis
Publisher
Cape Peninsula University of Technology
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.
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.
Additional information
Thesis (DPhil (Biomedical Sciences))--Cape Peninsula University of Technology, 2022
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