Kidney–brain axis inflammatory cross-talk: from bench to bedside

Abstract

Epidemiologic data suggest that individuals at all stages of chronic kidney disease (CKD) have a higher risk of developing neuropsychiatric disorders, cognitive impairment, and dementia. This risk is generally explained by the high prevalence of both symptomatic and subclinical ischemic cerebrovascular lesions. However, other potential mechanisms, including cytokine/chemokine release, production of reactive oxygen species (ROS), circulating and local formation of trophic factors and of renin-angiotensin system (RAS) molecules, could also be involved, especially in the absence of obvious cerebrovascular disease. In this review, we discuss experimental and clinical evidence for the role of these mechanisms in kidney-brain cross-talk. In addition, we hypothesize potential pathways for the interactions between kidney and brain and their pathophysiological role in neuropsychiatric and cognitive changes found in patients with CKD. Understanding the pathophysiologic interactions between renal impairment and brain function is important in order to minimize the risk for future cognitive impairment and to develop new strategies for innovative pharmacological treatment.

β‐ RA reduces DMQ /CoQ ratio and rescues the encephalopathic phenotype in Coq9 R239X mice

“…While we were not able to reveal how the peripheral tissues communicate with the brain in this situation, a recent study about gene therapy in a mouse model of Leigh syndrome also suggests that the correction of the gene defect in peripheral tissues is important to reduce brain pathology (Di Meo et al , ). The studies about the kidney–brain, heart–brain, or liver–brain cross‐talk, as well as the presence of a gut–brain axis, would support the concept of an influence of peripheral tissues in the brain pathology, and reactive astrogliosis in particular (Mayo et al , ; Butterworth, ; Rothhammer et al , , ; Miranda et al , ; Thackeray et al , ).…”

Renal Contributions in the Pathophysiology and Neuropathological Substrates Shared by Chronic Kidney Disease and Alzheimer’s Disease

“…Despite the recognized association between cognitive conditions and renal failure, direct evidence connecting brain injury to CKD is still absent. In this context, various hypotheses have been designed as supplementary pathways for kidney–brain communication, comprising renin–angiotensin system, oxidative stress, vascular injury, and inflammation [ 40 ]. It is worth noting that the crosstalk between kidney and brain appears to be bidirectional, as conditions of the central nervous system, such as traumatic brain injury and migraine, are independent risk factors for CKD as well [ 41 , 42 ].…”

“…As the CNS immune system might be impaired by the inflammatory processes, the brain function can also be modulated by various mediators, such as pro-inflammatory cytokines, interleukines-1β (IL-1β), and the tumor necrosis factor (TNF), which may pass the blood–brain barrier (BBB) leading to neuropsychiatric alterations [ 40 ]. In patients with CKD, the concentrations of these cytokines, as well as elevated pro-inflammatory enzymes, such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), appear to be positively controlled by the activation of nuclear-factor kappa-light-chain enhancer of activated B cells (NF-κB) [ 73 ].…”

“…The latest results of cytokine actions in the brain offer certain clues about the physiopathology of precise CNS disorders [ 75 ]. The potential mechanisms of kidney–brain crosstalk regarding inflammatory molecules are based on the fact that cytokines, such as IL-1β, interleukine-6 (IL-6), the TNF, and transforming growth factor β (TGF-β) frequently involved in the pathogenesis of CKD, may influence remote organs, such as the brain, reinforcing the idea of a kidney–brain inflammatory crosstalk [ 40 , 76 ].…”

“…Another important aspect related to the inflammatory theory is the oxidative stress defined to be the consequence of the imbalance between the oxidant system (production of free radicals) and antioxidant system, in favor of the oxidants, with destructive and pathogenic potential by disruption of proteins, lipids, and nucleic acids, with function losses and apoptosis [ 77 ], and other studies have shown that oxidative stress is related to the onset and development of diverse diseases like CKD and neurodegenerative disorders [ 40 , 78 ]. Various studies reported a reverse relationship between markers of oxidative stress and the filtration rate, which suggests that as the renal function is impaired, the species of free radicals gradually increase [ 78 ].…”