Frailty describes the cumulative subtle health deficits leading to an increased vulnerability to insults among older individuals or disease-laden ones. The prevalence of frailty increases substantially and relentlessly over declining renal function. Frailty in patients with chronic kidney disease (CKD) carries kidney-specific risk factors, clinical correlates and outcomes associations, hence alternatively termed frail kidney phenotype by researchers. Pathogenetically, miRNAs participate extensively in the development and aggravation of frailty, including the occurrence of frail kidney phenotype in CKD patients. These understandings spark profound interest in discovering biomarkers for identifying this detrimental phenotype, and extracellular miRNAs emerge as potentially useful ones. Pilot studies identify promising miRNA candidates for evaluating intermediates and surrogates of frail kidney phenotype, and more are underway. Several potential miRNA species in biologic fluids, such as circulating miR-29b and miR-223 (as inflammatory markers), exosomal miR-16-5p, miR-17/92 cluster members, and miR-106-5p (for uremic vasculopathy), serum exosomal miR-203a-3p (for uremic sarcopenia) have been examined and can be promising choices. Nonetheless, there remains research gap in affirming the direct connections between specific miRNAs and frail kidney phenotype. This stems partially from multiple limitations less well acknowledged before. From this perspective, we further outline the limitations and precautions prior to validating specific extracellular miRNA(s) for this purpose, from the definition of frailty definition, the functional and tissue specificity of miRNAs, the severity of CKD, and various technical considerations. It is expected that more affirmative studies can be produced for extending the utility of extracellular miRNAs in predicting frail kidney phenotype.
