Diagnostic and Clinical Utility of Assessing Renal Functional Reserve: Unmasking Subclinical Kidney Disease

Subclinical CKD (sCKD) represents an under-recognised phase of renal vulnerability in which structural injury and impaired physiological adaptability precede detectable changes in serum creatinine, eGFR, or albuminuria. Current diagnostic frameworks rely heavily on static biomarkers that lack sensitivity at higher GFR ranges, leaving a substantial "blind spot" in early disease detection. Renal functional reserve (RFR), the increase in GFR in response to a metabolic or physiological stressor, offers a dynamic assessment of kidney health that may reveal latent renal dysfunction before overt CKD manifests. This review discusses the physiological basis, methodological approaches, and emerging clinical applications of RFR testing. Protein ingestion and intravenous amino acid infusion are the most established stimuli, eliciting coordinated vasodilatory and neurohormonal responses that transiently augment GFR. Measurement techniques range from gold-standard exogenous filtration markers to more pragmatic tools such as creatinine clearance, cystatin C, and Doppler ultrasound-based assessments; each carries advantages and limitations that have historically impeded standardization and broader clinical uptake. Evidence across multiple clinical contexts demonstrates that blunted RFR frequently accompanies early renal injury despite preserved eGFR and normoalbuminuria. RFR has also shown promise for perioperative risk stratification and may help identify individuals at heightened susceptibility to nephrotoxic exposures or hemodynamic stress. Despite its potential, RFR implementation remains constrained by protocol heterogeneity, labour-intensive measurement methods, and limited reproducibility. Future priorities include the development of standardized, feasible protocols and validation in large prospective cohorts. RFR represents a promising tool to close the diagnostic gap in sCKD, offering a path toward earlier detection, personalized intervention, and more proactive kidney health management.