Afferent Renal Nerves Extend the Landscape of the Kidney-Brain Axis in Health and Disease

Emerging evidence suggests a pathophysiological crosstalk between kidney disease and several brain disorders, highlighting the importance of the kidney-brain axis and the potential consequences of its impairment. The kidney-brain axis is a dynamic, intricate bidirectional network essential for maintaining body homeostasis. This crosstalk is influenced by systemic factors such as accumulating endogenous waste products (uremic toxins) and chronic inflammation resulting from impaired kidney function. Beyond waste excretion, the kidneys function as interoceptive organs, detecting mechanical, chemical, and nociceptive stimuli through a dense network of afferent renal nerves. Signals are transmitted to the central nervous system to modulate sympathetic outflow, fluid and electrolyte balance, and blood pressure. Despite a general understanding of the renal innervation anatomy and interoceptive function via the inhibitory renorenal reflex, the specific intricacies of afferent renal nerves are still limited. Significant knowledge gaps remain regarding the phenotype of renal mechano- and chemoreceptors, the precise molecular transducers involved, and their maladaptive remodelling during kidney disease and potential involvement in brain disorders. This review defines the kidney-brain axis as an integrated neurohumoral communication network through which the kidney and brain coordinate and adapt to physiological stresses. We describe the anatomical distribution of efferent and afferent nerves within the nephrons, map the kidney-to-brain signal transmission, describe known molecular pathways, and examine the implications of altered renal afferent signalling in kidney-related comorbidities, including neurological disorders. We shed light on the therapeutic potential of targeting renal sensory nerves to mitigate renal and neurological decline in the context of an ageing global population.