Heterogeneous afferent arteriolopathy: a key concept for understanding blood pressure-dependent renal damage

Hypertension, aging, and other factors are associated with arteriosclerosis and arteriolosclerosis, primary morphological features of nephrosclerosis. Although such pathological changes are not invariably linked with renal decline but are prevalent across chronic kidney disease (CKD), understanding kidney damage progression is more pragmatic than precisely diagnosing nephrosclerosis itself. Hyalinosis and medial thickening of the afferent arteriole, along with intimal thickening of small arteries, can disrupt the autoregulatory system, jeopardizing glomerular perfusion pressure given systemic blood pressure (BP) fluctuations. Consequently, such vascular lesions cause glomerular damage by inducing glomerular hypertension and ischemia at the single nephron level. Thus, the interaction between systemic BP and afferent arteriolopathy markedly influences BP-dependent renal damage progression in nephrosclerosis. Both dilated and narrowed types of afferent arteriolopathy coexist throughout the kidney, with varying proportions among patients. Therefore, optimizing antihypertensive therapy to target either glomerular hypertension or ischemia is imperative. In recent years, clinical trials have indicated that combining renin-angiotensin system inhibitors (RASis) and sodium-glucose transporter 2 inhibitors (SGLT2is) is superior to using RASis alone in slowing renal function decline, despite comparable reductions in albuminuria. The superior efficacy of SGLT2is may arise from their beneficial effects on both glomerular hypertension and renal ischemia. A comprehensive understanding of the interaction between systemic BP and heterogeneous afferent arteriolopathy is pivotal for optimizing therapy and mitigating renal decline in patients with CKD of any etiology. Therefore, in this comprehensive review, we explore the role of afferent arteriolopathy in BP-dependent renal damage. Heterogeneous Afferent Arteriolopathy: A Key Concept for Optimizing Antihypertensive Therapy.