Progression of Chronic Kidney Disease Following Acute Kidney Injury: Role of Self-perpetuating vs. Hemodynamic-induced Fibrosis

The relative contribution of self-perpetuating- vs. hemodynamic-induced fibrosis to the progression of chronic kidney disease (CKD) following acute kidney injury (AKI) is unclear. In the present study, male Sprague-Dawley rats underwent right uninephrectomy and were instrumented with a blood pressure radiotelemeter. Two weeks later separate groups of rats were subjected to 40 minutes renal ischemia-reperfusion or sham surgery and followed for 4 or 16 weeks to determine the extent to which glomerulosclerosis and tubulointerstitial fibrosis as a result of the AKI – CKD transition (i.e., at 4 weeks post AKI) change over time during the progression of CKD (i.e., at 16 weeks post AKI). On average, tubulointerstitial fibrosis was ~3-fold lower (P<0.05) whereas glomerulosclerosis was ~6-fold higher (P<0.05) at 16 vs. 4 weeks post AKI. At 16 weeks post AKI, marked tubulointerstitial fibrosis was only observed in rats exhibiting marked glomerulosclerosis, proteinuria, and kidney weight consistent with a hemodynamic pathogenesis of renal injury. Moreover, quantitative analysis between blood pressure and renal injury revealed a clear and modest blood pressure threshold (average 16 week systolic blood pressure of ~127 mmHg) for the development of glomerulosclerosis. In summary, very modest levels of blood pressure may be playing a substantial role in the progression of renal disease following AKI in settings of preexisting CKD associated with 50% loss of renal mass. In contrast, these data do not support a major role of self-perpetuating tubulointerstitial fibrosis in the progression CKD following AKI in such settings.