EXPRESS: Circulating and Urinary microRNAs in Diabetic Kidney Disease: Stage and Sample-Specific Signatures with Biomarker Potential - A Systematic Review and Exploratory Meta-Analysis

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease, and early detection remains challenging because conventional biomarkers lack sensitivity. MicroRNAs (miRNAs) have emerged as promising non-invasive biomarkers, but evidence remains inconsistent. This study systematically evaluated dysregulated miRNAs in DKD and their associations with clinical parameters across albuminuria stages. PubMed, Scopus, and Embase were searched for studies assessing miRNA expression in DKD. Standardised mean differences (SMDs) were pooled using random-effects models, and risk of bias was assessed using the Newcastle-Ottawa Scale. The SMD of urinary miRNA124 in normoalbuminuria was 2.04 (95% CI 1.16 - 2.92, I2 = 77.2%, p = <0.00001), microalbuminuria 7.76 (95% CI 5.67 - 9.84, I2 = 78.1%, p = <0.00001), and macroalbuminuria 13.04 (95% CI 10.94 -15.13, I²=40.8%, p<0.00001). Urinary and circulating miRNA21 showed progressive upregulation across normoalbuminuria, microalbuminuria, and macroalbuminuria with SMDs of 3.34 (95% CI -0.56 - 7.24, I2 = 95.9%, p = 0.0933) and 0.50 (95% CI -0.36 -1.36, I²=89.7%, p=0.2520); 4.02 (95% CI 2.69 -5.36, I²=80.0%, p<0.0001) and 1.78 (95% CI 0.00 -3.56, I²=96.7%, p=0.0499); and 4.61 (95% CI 0.18 - 9.03, I²=97.8%, p=0.0413) and 4.77 (95% CI -1.29 -10.82, I²=98.4%, p=0.1230), respectively. Circulating miRNA126 was consistently downregulated in normoalbuminuria, microalbuminuria, and macroalbuminuria with SMDs -0.85 (95% CI -1.87-0.18, I²=95.0%, p=0.1044), -1.59 (95% CI -2.67 - -0.52, I²=93.0%, p=0.0035), and -1.87 (95% CI -4.67- 0.93, I²=98.1%, p=0.1901). Urinary miRNA192 was downregulated, whereas circulating miRNA192 showed inconsistent expression. Correlation analyses demonstrated positive associations between urinary miRNA34a and UACR (r = 0.39) and HbA1c (r = 0.20), while circulating miRNA21 (r = -0.37) and miRNA192 (r = -0.26) were inversely associated with albuminuria. Overall, urinary miRNA124, miRNA21, and miRNA34a, together with circulating miRNA126 and miRNA192, show promise as biomarkers of DKD progression, although prospective validation studies are required.