The Interaction of Central Nervous System and Acute Kidney Injury: Pathophysiology and Clinical Perspectives

Abstract

Acute kidney injury (AKI) is a common disorder in critically ill hospitalized patients. Its main pathological feature is the activation of the sympathetic nervous system and the renin-angiotensin system (RAS). This disease shows a high fatality rate. The reason is that only renal replacement therapy and supportive care can reduce the impact of the disease, but those measures cannot significantly improve the mortality. This review focused on a generalization of the interaction between acute kidney injury and the central nervous system (CNS). It was found that the CNS further contributes to kidney injury by regulating sympathetic outflow and oxidative stress in response to activation of the RAS and increased pro-inflammatory factors. Experimental studies suggested that inhibiting sympathetic activity and RAS activation in the CNS and blocking oxidative stress could effectively reduce the damage caused by AKI. Therefore, it is of significant interest to specify the mechanism on how the CNS affects AKI, as we could use such mechanism as a target for clinical interventions to further reduce the mortality and improve the complications of AKI. Systematic Review Registration: [www.ClinicalTrials.gov], identifier [registration number].

Keywords: acute kidney injury; central nervous system; neuromodulation; paraventricular hypothalamic; sympathetic nervous system.

FIGURE 1

Modification of the central nervous system pathways involved in sympathetic activation during acute kidney injury (AKI). Activation of renal afferent sensory nerves, which project to the paraventricular nucleus (PVN) of the hypothalamus, promotes pre-sympathetic neuronal activity and inhibits GABAergic neuronal activity. By projecting from the PVN to norepinephrinergic neurons in the rostral ventrolateral medulla (RVLM), norepinephrine (NE) levels are increased, thereby promoting sympathetic nervous system (SNS) activity, which further leads to renal vasoconstriction, decreased glomerular filtration rate (GFR), and sodium and water retention.

FIGURE 2

The role of proinflammatory cytokines and angiotensin II (Ang II) in the paraventricular nuclear (PVN) during acute kidney injury (AKI). The systemic inflammatory response to AKI leads to an increase in central nervous system (CNS) pro-inflammatory cytokines. Both Ang II and pro-inflammatory cytokines stimulate NAD(P)H oxidase activity and activate the NF-κB signaling pathway, leading to further cytokine synthesis and Ang II binding to the Ang II type 1 (AT₁) receptor, creating positive feedback loops. The activation of the NF-κB signaling pathway also leads to an increase in norepinephrine (NE) release, promoting sympathetic nervous system (SNS) activity, further exacerbating kidney injury.