#3022 REDUCED TUBULAR MIR-190A-5P: A NOVEL BIOMARKER FOR STRATIFICATION OF PATIENTS WITH CHRONIC KIDNEY DISEASE
Authors: Baird David , Zang Jinnan , Wong Ryan , Connor Katie , Cairns Carolynn , Reck Maximilian , Hughes Jeremy , Mark Patrick , Maxwell Alexander Peter , Mckay Gareth , Simpson David , Denby Laura , Conway Bryan 
Published: June 2023

Abstract

Background and Aims
Circulating microRNA (miRNAs) have been proposed as potential diagnostic and prognostic biomarkers and are functionally important in disease pathogenesis. In this study, we used an unbiased measurement of circulating miRNAs in patients with type 2 diabetes to identify a miRNA differentially expressed in kidney disease before moving to a larger, unselected cohort of patients with CKD to assess its potential to predict progression in CKD.

Method
MiRNA next generation sequencing (NGS) studies were undertaken to measure differential expression of plasma miRNAs in a discovery cohort of 3 groups; individuals with type 2 diabetic kidney disease (T2DKD, n = 9), age and sex matched patients with type 2 diabetes mellitus and normal renal function (T2DNRF, n = 13) and patients without diabetes and with normal renal function (NDNRF, n = 11). Differentially expressed miRs were validated in a separate cohort of the same groups (each n = 10). The prognostic value of miR-190a-5p in a general CKD population was assessed using the seNSOR cohort (n = 395, excluding patients on RRT, with an eGFR of &lt; = 20 ml/min/1.73 m2 or AKI at recruitment). The primary outcome of CKD progression was defined as reaching ESKD (starting RRT or maintaining an eGFR &lt;15mls/min) or &gt;30% reduction in renal function from eGFR at baseline. Reaching ESKD alone was used as a secondary outcome.

Results
MiR-190a-5p was the only miRNA differentially expressed between T2DKD and both control groups in both the discovery and validation cohorts. In the seNSOR cohort, miR-190a-5p levels correlated positively with eGFR (rho = 0.12, p = 0.04) and inversely with age (rho = -0.12, p = 0.04). MiR-190a-5p levels below the median predicted CKD progression in individuals with minimal and moderate albuminuria (ACR &lt; 3mg/mmol and 3-300mg/mmol respectively) but not in those with severe albuminuria (ACR&gt;300mg/mmol, see figure). In those without severe albuminuria, miR-190a-5p levels predicted CKD progression in multivariate Cox proportional hazards models (HR 0.8, 95% CI: 0.66-0.96, p = 0.015), independently of baseline eGFR, ACR, age, SBP, DBP and sex. When participants with an ACR &gt; 300mg/mmol were included, miR-190a-5p was not predictive of the composite CKD progression endpoint (multivariate HR 0.86, p = 0.064) but was predictive for reaching ESKD alone (multivariate HR 0.68, 95% CI: 0.5-0.93, p = 0.015). Analysis of miR-190 expression in individual renal cell types in the reversible unilateral ureter obstruction mouse model revealed that it is enriched in proximal tubule cells and falls significantly following injury before increasing again the repair phase.

Conclusion
miR-190a-5p is expressed by healthy proximal renal tubular cells and serum miR-190a-5p levels correlate positively with eGFR. Low serum miR-190a-5p levels may predict progression of CKD in patients with low or moderate proteinuria independently of existing risk factors.