Progression of Chronic Kidney Disease After Acute Kidney Injury Role of Self-Perpetuating Versus Hemodynamic-Induced Fibrosis

The incidence of acute kidney injury (AKI) is rising and continues to be associated with elevated acute mortality rates. During the past decade, it has been clearly established that AKI is also associated with an increased risk of developing chronic kidney disease (CKD), end-stage renal disease, and the associated increases in long-term morbidity and mortality. Moreover, the risk of developing end-stage renal disease after recovery from AKI is substantially greater in patients with preexisting CKD. Yet, considerable uncertainty exists on the relative contribution of the various mechanisms that have been proposed to accelerate progression of renal disease after AKI, especially in preexisting CKD states. AKI can impact many different cell types along the entire length of the nephron and lead to a heterogeneous injury pattern; however, the main pathology associated with AKI is tubulointerstitial fibrosis (TIF), especially within the inner cortical and outer medullary regions, with only minimal to modest levels of glomerular injury. In the acute stages after AKI, severely injured tubular epithelial cells and microvascular endothelial cells can undergo both necrosis and apoptosis and lead to the entire loss of their associated nephrons with ensuing TIF. Although most sublethally injured tubules do recover normal structure and function after AKI, a subset of tubules remain in a dedifferentiated state and continue to release profibrotic and proinflammatory molecules. The impaired recovery of such tubules is thought to be related to pathological processes initiated during AKI, such as, hypoxia, cellular senescence, maladaptive repair, and inflammation that can also contribute to the loss of nephrons and development of TIF after AKI. Of note, the loss of nephrons and ensuing TIF that develops acutely after AKI (ie, 1–4 weeks after injury), because of either lethally injured cells or impaired recovery of sublethally injured cells, denotes the AKI–CKD transition. In contrast to the AKI–CKD transition, the progression of CKD after AKI requires injury to and loss of nephrons that were either uninjured during AKI or had essentially recovered from the AKI episode. In all forms of CKD progression, the loss of renal function correlates best with the level of TIF. Yet, there is considerable uncertainty on the pathogenesis of de novo TIF after recovery from AKI. Such mechanisms of TIF production can be broadly separated into those pathways initiated Abstract—The relative contribution of self-perpetuating versus hemodynamic-induced fibrosis to the progression of chronic kidney disease (CKD) after 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 up for 4 or 16 weeks to determine the extent to which glomerulosclerosis and tubulointerstitial fibrosis as a result of the AKI–CKD transition (ie, at 4 weeks post AKI) change over time during the progression of CKD (ie, 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 versus 4 weeks post AKI. At 16 weeks post AKI, marked tubulointerstitial fibrosis was only observed in rats exhibiting marked glomerulosclerosis, proteinuria, and kidney hypertrophy 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 mm Hg) for the development of glomerulosclerosis. In summary, modest levels of blood pressure may be playing a substantial role in the progression of renal disease after 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 after AKI in such settings. (Hypertension. 2016;68:921-928. DOI: 10.1161/HYPERTENSIONAHA.116.07749.) • Online Data Supplement