Objectives: We aimed to identify novel serum micro(mi)RNAs associated with incident end-stage renal disease (ESRD) in Chinese with type 2 diabetes.

Methods: We conducted a nested case-control study in patients with type 2 diabetes enrolled in the Hong Kong Diabetes Registry between 1995 and 2007. Cases were patients who were free from ESRD at enrolment but developed renal endpoint as defined as eGFR < 15 ml/min/1.73m2 or dialysis during follow-up until 2015. Controls were patients who had normal renal function at both baseline and during observation period. MicroRNAs were extracted from stored serum collected at baseline. Discovery cohort included 22 cases and 21 controls and miRNAs were screened by Agilent microRNA microarray. Validation cohort included 361 ESRD cases and 241 T2D controls and miRNAs were quantitated using qRT-PCR. Two spike-in miRNAs were used to control for efficiency in RNA extraction and reverse transcription. Batch difference was adjusted by a positive RNA control.

Results: In the discovery analysis, miR-X and miR-Y were elevated with respective fold-change of 5.97 and 4.43 in patients with incident ESRD compared to those without renal events on follow-up. Pathway analysis revealed that the two miRNAs may involve in signaling transduction, adrenergic signaling, or relate to peroxisome. Increased levels of miR-X and miR-Y were also detected in the validation cohort. Using binary logistic regression adjusted for age, sex and disease duration, doubling of miR-X and miR-Y were associated with 14.2% and 26.3% higher odds of progressing to ESRD, respectively. The association remained significant for miR-Y when further adjusted for metabolic indices, baseline albuminuria and eGFR.

Conclusions: Baseline serum levels of miR-X and miR-Y are independently associated with higher risk of incident ESRD. These results indicate the potential of circulating miRNAs to serve as prognostic indicators for disease progression.


B. Fan: None. H. Lee: None. C.K.P. Lim: None. R. Choy: None. J.C. Chan: Consultant; Self; Bayer AG. Other Relationship; Self; Bayer AG. Consultant; Self; Sanofi. Other Relationship; Self; Sanofi, Eli Lilly and Company, Amgen Inc.. Consultant; Self; AstraZeneca, Merck & Co., Inc., Pfizer Inc.. Other Relationship; Self; Pfizer Inc.. Board Member; Self; Asia Diabetes Foundation. Stock/Shareholder; Self; GemVCare. Other Relationship; Self; Merck Sharp & Dohme Corp.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novartis AG, Eli Lilly and Company. A. Luk: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc.. Research Support; Self; Sanofi. R.C. Ma: Research Support; Self; AstraZeneca, Bayer AG, Merck Sharp & Dohme Corp., Pfizer Inc.. Advisory Panel; Self; Boehringer Ingelheim GmbH, Nippon Boehringer Ingelheim Co. Ltd..

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