Compensatory nephron hypertrophy: mechanisms, pathophysiology dynamics, and clinical implications in acute kidney injury and chronic kidney disease

Compensatory nephron hypertrophy (CNH) is a critical adaptive response to nephron loss, observed in conditions such as living kidney donation, congenital solitary kidney, acute kidney injury (AKI), and chronic kidney disease (CKD). This review integrates current insights on the molecular mechanisms, pathophysiological consequences, and clinical significance of CNH, highlighting its dual role as both a protective and maladaptive process. At the cellular level, CNH is driven by hypertrophy rather than proliferation, mediated by the mTOR signaling pathway, with predominant effects in glomeruli and proximal tubules. In AKI, CNH facilitates recovery by enhancing single-nephron glomerular filtration rate and tubular function, yet aberrant repair-marked by persistent cell cycle arrest and activation of profibrotic pathways-can lead to fibrosis and CKD progression. In CKD, CNH compensates for progressive nephron loss but contributes to glomerular hyperfiltration, proteinuria, and tubulointerstitial fibrosis, accelerating renal decline. Clinically, CNH sustains short-term renal function in donors and solitary kidney patients, but long-term studies reveal increased risks of hypertension, CKD, and cardiovascular disease. Therapeutic strategies, including ACE inhibitors, ARBs, and emerging agents targeting mTOR or TGF-β, aim to mitigate maladaptive CNH, while SGLT2 inhibitors offer promise in reducing hyperfiltration. This review underscores the linkage of AKI and CKD within the CNH framework and advocates for personalized approaches-integrating biomarkers, genetics, and regenerative therapies-to optimize renal outcomes. By elucidating the mechanisms and clinical course of CNH, we provide a foundation for future research and targeted interventions to balance adaptation and prevent pathology in reduced nephron states.