Interrupting the AKI-to-CKD continuum : insights from anti-inflammatory therapy and nephrectomy-induced recovery

Abstract

Acute kidney injury (AKI) remains a major global health burden with high morbidity and mortality and is increasingly recognized as an important risk factor for chronic kidney disease (CKD). Renal repair after AKI is often insufficient or maladaptive, contributing to persistent inflammation, tubular atrophy, fibrosis, and loss of function. This thesis investigated two complementary strategies to enhance renal recovery after ischemic AKI: anti-inflammatory treatment with dexamethasone and post-injury contralateral nephrectomy (Nx), with particular attention to the timing of intervention and the cellular mechanisms underlying recovery. In a unilateral ischemia-reperfusion injury (UIRI) mouse model, temporary suppression of inflammation with dexamethasone reduced inflammatory and fibrotic responses during treatment. However, these beneficial effects diminished after treatment cessation and did not prevent progressive renal atrophy, indicating that short-term anti-inflammatory therapy alone is insufficient to permanently alter the fibrogenic trajectory after ischemic injury. In contrast, contralateral Nx triggered a pronounced endogenous regenerative response. Time-course experiments in mice and rats identified a critical therapeutic window, with Nx performed three days after UIRI resulting in substantial structural and functional recovery and prevention of CKD, whereas delayed Nx failed to provide comparable benefits. Early Nx reduced tubular atrophy, inflammation, and fibrosis and was associated with improved metabolic responses. Moreover, Nx enhanced the expansion of Pax2-positive tubular epithelial cells while limiting the persistent accumulation of polyploid tubular epithelial cells, suggesting a shift from maladaptive repair towards effective regeneration. Interestingly, Nx appears to initially aggravate tubular injury and increase cell death and lipid peroxidation. This transient injury was accompanied by enhanced tubular debris clearance, including AIM-KIM-1-mediated clearance by tubular epithelial cells. These observations suggest to formulate the hypothesis that Nx induces a controlled secondary wave of injury that facilitates the removal of damaged or maladaptive cells and creates conditions favorable for subsequent tissue remodeling and regeneration. Together, this thesis demonstrates that the fate of the kidney after AKI can be profoundly influenced by both the nature and timing of intervention. While transient suppression of inflammation provides limited long-term protection, Nx reveals a remarkable intrinsic regenerative capacity of the injured kidney. Although Nx itself is not clinically applicable as a therapy, elucidating the mechanisms underlying Nx-induced recovery may uncover novel therapeutic strategies to promote endogenous renal regeneration and prevent the AKI-to-CKD transition.