The kidney-brain axis in neurodegeneration encompasses the bidirectional communication pathways through which renal (kidney) dysfunction contributes to and interacts with neurodegenerative processes in the central nervous system. This axis operates through multiple overlapping mechanisms: the accumulation of neurotoxic uremic solutes when kidney filtration capacity declines, the deposition of alpha-synuclein (αSyn) in renal tissue in Parkinson's disease (PD), the shared expression and pathogenic role of leucine-rich repeat kinase 2 (LRRK2) in both kidney and brain, and the systemic inflammatory milieu that connects chronic kidney disease (CKD) to accelerated neurodegeneration. Epidemiological evidence demonstrating that CKD patients have a significantly elevated risk of developing PD, and that PD patients show higher rates of renal dysfunction, provides clinical support for a kidney-brain axis that operates bidirectionally in both directions.
The kidney-brain axis in neurodegeneration encompasses the bidirectional communication pathways through which renal (kidney) dysfunction contributes to and interacts with neurodegenerative processes in the central nervous system. This axis operates through multiple overlapping mechanisms: the accumulation of neurotoxic uremic solutes when kidney filtration capacity declines, the deposition of alpha-synuclein (αSyn) in renal tissue in Parkinson's disease (PD), the shared expression and pathogenic role of leucine-rich repeat kinase 2 (LRRK2) in both kidney and brain, and the systemic inflammatory milieu that connects chronic kidney disease (CKD) to accelerated neurodegeneration. Epidemiological evidence demonstrating that CKD patients have a significantly elevated risk of developing PD, and that PD patients show higher rates of renal dysfunction, provides clinical support for a kidney-brain axis that operates bidirectionally in both directions.
The clinical importance of this axis extends beyond academic curiosity: uremic toxins accumulate in the bloodstream of patients with CKD and contribute to cognitive impairment, neurological dysfunction, and potentially the acceleration of proteinopathies like αSyn aggregation. The kidneys express many of the same proteins implicated in neurodegeneration—including LRRK2, αSyn, and tau—making them both potential targets and contributors to neuropathology. Understanding this axis opens therapeutic opportunities to slow neurodegeneration through renal-protective strategies, reduction of uremic toxin burden, and modulation of shared molecular pathways.
Uremic toxins are the diverse array of solutes that accumulate in the blood when kidney function declines below the threshold needed for their clearance. These compounds are conventionally classified into three groups based on their physicochemical properties and removal characteristics. The first group comprises small water-soluble compounds (molecular weight < 500 Da), including urea, creatinine, guanidines, and hippurates. The second group comprises medium-sized molecules (500-60,000 Da), including cytokines, advanced glycation end products (AGEs), and myocilin. The third group comprises protein-bound solutes—the most difficult to remove by conventional dialysis—including indoxyl sulfate, p-cresyl sulfate, hippuric acid, and indole-3-acetic acid[@watabe2023].
The protein-bound uremic toxins are particularly relevant to neurodegeneration because they are poorly removed by standard hemodialysis and accumulate to high concentrations in CKD patients. Indoxyl sulfate and p-cresyl sulfate, generated by gut microbial metabolism of tryptophan and tyrosine respectively, have been most extensively studied for their neurotoxic effects[@wang2019]. These metabolites are normally filtered by the glomerulus and excreted in urine, but in CKD they accumulate to concentrations 10-100 times above physiological levels, exerting toxic effects on multiple organ systems including the brain.
Indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are prototypic protein-bound uremic toxins with well-documented neurotoxic effects[@zhang2022]. Produced by gut bacteria from dietary tryptophan and tyrosine, these metabolites are normally conjugated in the liver to硫酸酯 forms (indoxyl sulfate, p-cresyl sulfate) and excreted by the kidneys. In CKD, both the overproduction from dysbiotic guts and the reduced renal clearance cause marked accumulation. In experimental models, IS and PCS induce oxidative stress in neurons, promote mitochondrial dysfunction, activate microglia, and accelerate dopaminergic neuron death[@sun2021].
The mechanisms of IS/PCS neurotoxicity include activation of the aryl hydrocarbon receptor (AhR) signaling pathway, leading to upregulation of pro-inflammatory genes. They also generate reactive oxygen species through mitochondrial electron transport chain disruption, activate NF-κB signaling in both neurons and glia, and impair the blood-brain barrier. In mesencephalic neuron-glia cultures, IS treatment reproduces features of PD including increased αSyn expression, reduced tyrosine hydroxylase (TH) levels, and microglial activation. The demonstration that IS and PCS accelerate αSyn aggregation in cellular and animal models provides a potential mechanistic link between CKD and PD risk.
Chronic kidney disease is a state of chronic systemic inflammation driven by multiple mechanisms: retention of pro-inflammatory cytokines due to reduced renal clearance, increased oxidative stress from uremic solutes, endothelial dysfunction, and intestinal dysbiosis with a "leaky gut" that allows bacterial endotoxin translocation[@luo2023]. This inflammatory milieu reaches the brain through multiple routes: by crossing the compromised blood-brain barrier, by activating the vagal afferent system, and by triggering hepatic inflammation that subsequently affects the brain. The result is chronic neuroinflammation characterized by microglial activation, elevated pro-inflammatory cytokines in the brain parenchyma, and a shift in microglial phenotype toward a pro-inflammatory, damaging state.
Alpha-synuclein is not confined to the nervous system—it is expressed in multiple peripheral tissues including the kidney[@huang2018]. Immunohistochemical studies have documented αSyn expression in the epithelial cells of the renal proximal tubule, with particularly high levels in the S3 segment. In PD patients, studies have found both increased total αSyn and phosphorylated αSyn (pSer129) deposits in kidney tissue, detected at autopsy and in biopsy studies. The presence of αSyn in the kidney is clinically significant because urinary αSyn levels have been explored as a potential biomarker of PD, reflecting peripheral αSyn burden that may correlate with CNS pathology.
The distribution of αSyn in the kidney parallels its functional relevance: proximal tubule cells handle massive amounts of filtrate and are rich in mitochondria, the organelles most affected by αSyn toxicity. The kidney's high metabolic rate and exposure to circulating toxins make it vulnerable to the same processes that damage dopaminergic neurons. Notably, αSyn deposits in the kidney may be detectable early in PD, potentially providing a peripheral biomarker window into CNS pathology.
The identification of αSyn in the kidney has motivated interest in urinary biomarkers for PD diagnosis and progression monitoring. αSyn is detectable in urine from PD patients, and studies have shown associations between urinary αSyn levels and disease severity, duration, and motor scores. Alpha-synuclein in urine may derive from renal tissue, the urothelium, or circulating sources, and the relative contributions of these compartments remain under investigation. Other urinary biomarkers linked to PD include the dopamine metabolite homovanillic acid (HVA), 8-hydroxy-2'-deoxyguanosine (8-OHdG) as a marker of oxidative stress, and various inflammatory cytokines.
Whether αSyn expressed in peripheral organs like the kidney contributes to CNS pathology through propagation is an active area of investigation. The prion-like spreading hypothesis of αSyn pathology suggests that misfolded αSyn from peripheral sites could reach the brain through several routes: via the vagus nerve (which innervates the kidney), through the bloodstream if the kidney releases αSyn into circulation, or through the glymphatic system if kidney-derived toxins compromise it. While the evidence for peripheral αSyn directly seeding CNS aggregation is less compelling than for the gut-to-brain route, the kidney-brain axis still contributes to neurodegeneration through uremic toxin production and inflammatory amplification.
LRRK2 (leucine-rich repeat kinase 2) is a large multi-domain protein kinase that is most strongly associated with PD through the identification of pathogenic mutations that cause familial PD and common variants that influence sporadic PD risk[@chen2021]. Beyond its well-characterized expression in the brain—particularly in dopaminergic neurons of the substantia nigra, striatum, and cortex—LRRK2 is robustly expressed in peripheral organs, with particularly high levels in the kidney, lung, and immune cells. In the kidney, LRRK2 is expressed primarily in the proximal tubule cells, where its expression level is comparable to or higher than in the brain[@takahashi2019].
The normal physiological function of LRRK2 in the kidney is incompletely understood but appears to relate to endosomal trafficking, lysosomal function, and cellular stress responses. LRRK2 localizes to endosomes and lysosomes in proximal tubular cells, where it regulates trafficking pathways critical for reabsorption of filtered proteins and maintenance of cellular homeostasis. Studies in LRRK2 knockout mice have revealed age-dependent kidney phenotypes including increased lysosomal storage, altered autophagy, and accumulation of autofluorescent lipofuscin in proximal tubule cells, indicating that LRRK2 is important for renal cellular homeostasis[@chen2019].
The link between LRRK2 and kidney disease is suggested by several lines of evidence. LRRK2-knockout mice develop age-dependent tubulointerstitial kidney disease with features reminiscent of human kidney aging, including tubular atrophy, interstitial fibrosis, and glomerulosclerosis. Studies of PD patients carrying LRRK2 G2019S mutations have revealed higher rates of renal dysfunction compared to PD patients without LRRK2 mutations, particularly in older patients. Whether this represents a direct effect of mutant LRRK2 on the kidney or is secondary to PD pathology and treatment complications (e.g., levodopa metabolism affecting renal function) is still debated.
Notably, LRRK2 G2019S mutations appear to increase the risk of developing CKD in PD patients, potentially through effects on tubular cell function. In vitro studies have shown that mutant LRRK2 disrupts lysosomal and autophagic function in renal cells, impairing their ability to handle protein traffic and cellular debris. This raises the possibility that LRRK2-targeted therapies developed for PD could have beneficial effects on the kidney. Conversely, kidney-specific LRRK2 dysfunction could theoretically contribute to the systemic inflammatory milieu and uremic toxin burden that affect the brain.
LRRK2 is highly expressed in immune cells—particularly monocytes, macrophages, and dendritic cells—where it regulates inflammatory responses and phagocytosis[@wallings2015]. LRRK2 expression in microglia (the brain's resident immune cells) is upregulated by inflammatory stimuli, and LRRK2 mutations alter microglial morphology and function. In peripheral immune cells, LRRK2 modulates the response to bacterial components and cytokines. Given the prominent role of both LRRK2 and immune system activation in PD, and the link between kidney inflammation and neurodegeneration, LRRK2's expression in immune cells may represent a shared pathway connecting renal and CNS pathology through systemic inflammation.
Multiple epidemiological studies have demonstrated that CKD patients have an elevated risk of developing PD, with hazard ratios ranging from 1.3 to 2.0 depending on the study population and CKD definition[@cheng2010]. The association persists after adjusting for potential confounders including age, sex, cardiovascular disease, diabetes, and hypertension, and is stronger with more severe or longer-duration CKD. The proposed mechanisms linking CKD to PD risk include uremic toxin accumulation, systemic inflammation, shared genetic susceptibility (LRRK2), and the effects of proteinopathies that affect both organs.
Patients with PD show elevated rates of renal dysfunction compared to age-matched controls, and this association is independent of levodopa exposure (which can affect renal function through its effects on dopamine and vascular tone)[@hemelgarn2013]. The exact prevalence varies across studies, but estimates suggest that 20-40% of PD patients have reduced estimated glomerular filtration rate (eGFR). Contributing factors include the direct effects of PD pathology on the kidney (αSyn deposition, LRRK2 dysfunction), medication-related effects (levodopa, diuretics), autonomic dysfunction affecting renal perfusion, and shared cardiovascular risk factors. Some PD medications, including levodopa and dopamine agonists, may affect renal function, complicating the interpretation of epidemiological associations.
PD pathology affects the autonomic nervous system early in the disease course, and autonomic dysfunction directly influences kidney function through effects on renal blood flow, sympathetic innervation, and fluid balance. The kidneys receive dense sympathetic innervation, and excessive renal sympathetic activity promotes sodium retention, reduces GFR, and contributes to hypertension. PD patients with orthostatic hypotension—a manifestation of autonomic failure—have altered renal perfusion pressures that may contribute to kidney dysfunction over time. Neuropathy of the renal nerves may also contribute, and constipation (another autonomic feature) predisposes to uremic toxin accumulation through reduced excretion.
Reducing the neurotoxic burden from uremic toxins represents the most direct therapeutic strategy targeting the kidney-brain axis. Dietary modifications to reduce precursor availability—such as restricting protein intake to decrease indoxyl sulfate and p-cresyl sulfate production—have shown some benefit in CKD patients but may be difficult to implement long-term. Probiotics and prebiotics that shift gut microbial metabolism away from uremic toxin production are under investigation, though evidence for specific microbial interventions remains preliminary. Activated charcoal and AST-120 (an oral adsorbent) have been studied to adsorb uremic toxins in the gut and reduce their systemic absorption.
LRRK2 kinase inhibitors are in clinical development for PD and could have dual benefits for both brain and kidney pathology. These compounds would target the CNS manifestations of LRRK2 dysfunction while simultaneously addressing the lysosomal and cellular homeostatic defects in renal proximal tubular cells. If LRRK2 dysfunction in the kidney contributes significantly to uremic toxin burden or systemic inflammation, LRRK2 inhibition could provide renal benefits in addition to neuroprotective effects.
Aggressive management of CKD to slow its progression and reduce uremic toxin accumulation benefits the brain through reduced neurotoxic exposure. Angiotensin receptor blockers and SGLT2 inhibitors have demonstrated renoprotective effects and may have additional anti-inflammatory benefits relevant to neurodegeneration. Optimizing blood pressure control, managing diabetes, and avoiding nephrotoxic medications are fundamental aspects of CKD management that also reduce the systemic inflammatory burden that reaches the brain. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown remarkable benefits in CKD progression and cardiovascular outcomes, and their anti-inflammatory effects may extend to neuroprotection.
The kidney-brain neurodegeneration axis connects to multiple other mechanisms:
The kidney-brain neurodegeneration axis represents a critical but underappreciated pathway connecting peripheral organ dysfunction to CNS pathology:
Understanding the kidney-brain axis provides new mechanistic insights and therapeutic angles for neurodegenerative diseases, particularly PD, where the link to renal pathology is increasingly well established.