Kidney dysfunction often leads to neurological impairment, yet the complex kidney-brain relationship remains elusive. We employed spatial and bulk metabolomics to investigate a mouse model of rapid kidney failure induced by mouse double minute 2 (Mdm2) conditional deletion in the kidney tubules to interrogate kidney and brain metabolism. Pathway enrichment analysis of a focused plasma metabolomics panel pinpointed tryptophan metabolism as the most altered pathway with kidney failure. Spatial metabolomics showed toxic tryptophan metabolites in the kidneys and brains, revealing a connection between advanced kidney disease and accelerated kynurenine degradation. In particular, the excitotoxic metabolite quinolinic acid was localized in ependymal cells in the setting of kidney failure. These findings were associated with brain inflammation and cell death. Separate mouse models of ischemia-induced acute kidney injury and adenine-induced chronic kidney disease also exhibited systemic inflammation and accumulating toxic tryptophan metabolites. Patients with advanced chronic kidney disease (stage 3b-4 and stage 5) similarly demonstrated elevated plasma kynurenine metabolites, and quinolinic acid was uniquely correlated with fatigue and reduced quality of life. Overall, our study identifies the kynurenine pathway as a bridge between kidney decline, systemic inflammation, and brain toxicity, offering potential avenues for diagnosis and treatment of neurological issues in kidney disease.

Center for Precision Medicine and

Department of Biochemistry and Structural Biology

Department of Cell Systems and Anatomy The University of Texas Health Science Center at San Antonio San Antonio Texas USA

Department of Pathology and Laboratory Medicine The University of Texas Health Science Center at San Antonio San Antonio Texas USA

Department of Pharmacology

Department of Physiology Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic

Department of Population Health Sciences and

Division of Nephrology Department of Medicine The University of Texas Health Science Center at San Antonio San Antonio Texas USA

Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases and

South Texas Veterans Health Care System Audie L Murphy VA Hospital San Antonio Texas USA

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bioRxiv. 2024 May 10:2024.05.07.592801. doi: 10.1101/2024.05.07.592801. PubMed

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Baluarte JH. Neurological complications of renal disease. Semin Pediatr Neurol. 2017;24(1):25–32. doi: 10.1016/j.spen.2016.12.004. PubMed DOI

Goyal A, et al. Acute kidney injury. In: StatPearls. Treasure Island (FL); 2023.

Pereira M, et al. Acute kidney injury in patients with severe sepsis or septic shock: a comparison between the ‘Risk, Injury, Failure, Loss of kidney function, End-stage kidney disease’ (RIFLE), Acute Kidney Injury Network (AKIN) and Kidney Disease: Improving Global Outcomes (KDIGO) classifications. Clin Kidney J. 2017;10(3):332–340. doi: 10.1093/ckj/sfw107. PubMed DOI PMC

CDC. Chronic Kidney Disease in the United States, 2023. https://www.cdc.gov/kidney-disease/php/data-research/?CDC_AAref_Val=https://www.cdc.gov/kidneydisease/publications-resources/CKD-national-facts.html Updated May 15, 2024. Accessed February 14, 2025.

Kovesdy CP. Epidemiology of chronic kidney disease: an update 2022. Kidney Int Suppl (2011) 2022;12(1):7–11. doi: 10.1016/j.kisu.2021.11.003. PubMed DOI PMC

Thomas R, et al. Chronic kidney disease and its complications. Prim Care. 2008;35(2):329–44, vii. doi: 10.1016/j.pop.2008.01.008. PubMed DOI PMC

Fletcher BR, et al. Symptom burden and health-related quality of life in chronic kidney disease: a global systematic review and meta-analysis. PLoS Med. 2022;19(4):e1003954. doi: 10.1371/journal.pmed.1003954. PubMed DOI PMC

Liu HS, et al. Regional cerebral blood flow in children and young adults with chronic kidney disease. Radiology. 2018;288(3):849–858. doi: 10.1148/radiol.2018171339. PubMed DOI PMC

Ikram MA, et al. Kidney function is related to cerebral small vessel disease. Stroke. 2008;39(1):55–61. doi: 10.1161/STROKEAHA.107.493494. PubMed DOI

Lau WL, et al. Chronic kidney disease increases cerebral microbleeds in mouse and man. Transl Stroke Res. 2020;11(1):122–134. doi: 10.1007/s12975-019-00698-8. PubMed DOI PMC

Rosner MH, et al. Classification of uremic toxins and their role in kidney failure. Clin J Am Soc Nephrol. 2021;16(12):1918–1928. doi: 10.2215/CJN.02660221. PubMed DOI PMC

Bobot M, et al. Uremic toxic blood-brain barrier disruption mediated by AhR activation leads to cognitive impairment during experimental renal dysfunction. J Am Soc Nephrol. 2020;31(7):1509–1521. doi: 10.1681/ASN.2019070728. PubMed DOI PMC

Saito R, et al. Systems biology analysis reveals role of MDM2 in diabetic nephropathy. JCI Insight. 2016;1(17):e87877. doi: 10.1172/jci.insight.87877. PubMed DOI PMC

Thomasova D, et al. MDM2 prevents spontaneous tubular epithelial cell death and acute kidney injury. Cell Death Dis. 2016;7(11):e2482. doi: 10.1038/cddis.2016.390. PubMed DOI PMC

Zhang J, et al. High-throughput metabolomics and diabetic kidney disease progression: evidence from the Chronic Renal Insufficiency (CRIC) Study. Am J Nephrol. 2022;53(2–3):215–225. doi: 10.1159/000521940. PubMed DOI PMC

Cantaluppi V, et al. Interaction between systemic inflammation and renal tubular epithelial cells. Nephrol Dial Transplant. 2014;29(11):2004–2011. doi: 10.1093/ndt/gfu046. PubMed DOI

Ostergaard C, et al. Soluble urokinase receptor is elevated in cerebrospinal fluid from patients with purulent meningitis and is associated with fatal outcome. Scand J Infect Dis. 2004;36(1):14–19. doi: 10.1080/00365540310017366. PubMed DOI

De Almeida SM, et al. Higher cerebrospinal fluid soluble urokinase-type plasminogen activator receptor, but not interferon γ-inducible protein 10, correlate with higher working memory deficits. J Acquir Immune Defic Syndr. 2022;90(1):106–114. doi: 10.1097/QAI.0000000000002924. PubMed DOI PMC

Garcia-Monco JC, et al. Soluble urokinase receptor (uPAR, CD 87) is present in serum and cerebrospinal fluid in patients with neurologic diseases. J Neuroimmunol. 2002;129(1–2):216–223. doi: 10.1016/S0165-5728(02)00186-8. PubMed DOI

Hayek SS, et al. Soluble urokinase receptor and acute kidney injury. N Engl J Med. 2020;382(5):416–426. doi: 10.1056/NEJMoa1911481. PubMed DOI PMC

Kita T, et al. Effects of systemic and central nervous system localized inflammation on the contributions of metabolic precursors to the L-kynurenine and quinolinic acid pools in brain. J Neurochem. 2002;82(2):258–268. doi: 10.1046/j.1471-4159.2002.00955.x. PubMed DOI

Fukui S, et al. Blood-brain barrier transport of kynurenines: implications for brain synthesis and metabolism. J Neurochem. 1991;56(6):2007–2017. doi: 10.1111/j.1471-4159.1991.tb03460.x. PubMed DOI

Lugo-Huitron R, et al. Quinolinic acid: an endogenous neurotoxin with multiple targets. Oxid Med Cell Longev. 2013;2013:104024. doi: 10.1155/2013/104024. PubMed DOI PMC

Schwarcz R, et al. Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci. 2012;13(7):465–477. doi: 10.1038/nrn3257. PubMed DOI PMC

Ali BH, et al. New model for adenine-induced chronic renal failure in mice, and the effect of gum acacia treatment thereon: comparison with rats. J Pharmacol Toxicol Methods. 2013;68(3):384–393. doi: 10.1016/j.vascn.2013.05.001. PubMed DOI

Ali BH, et al. Some physiological and histological aspects of the gastrointestinal tract in a mouse model of chronic renal failure. J Pharmacol Toxicol Methods. 2014;69(2):162–166. doi: 10.1016/j.vascn.2013.09.001. PubMed DOI

de Jong WH, et al. Plasma tryptophan, kynurenine and 3-hydroxykynurenine measurement using automated on-line solid-phase extraction HPLC-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2009;877(7):603–609. doi: 10.1016/j.jchromb.2009.01.015. PubMed DOI

Karakawa S, et al. Simultaneous analysis of tryptophan and its metabolites in human plasma using liquid chromatography–electrospray ionization tandem mass spectrometry. CHROMATOGRAPHY. 2019;40(3):127–133. doi: 10.15583/jpchrom.2019.010. DOI

Zheng X, et al. Kynurenine 3-monooxygenase is a critical regulator of renal ischemia-reperfusion injury. Exp Mol Med. 2019;51(2):1–14. doi: 10.1038/s12276-019-0210-x. PubMed DOI PMC

Debnath S, et al. Tryptophan metabolism in patients with chronic kidney disease secondary to type 2 Diabetes: relationship to inflammatory markers. Int J Tryptophan Res. 2017;10:1178646917694600. doi: 10.1177/1178646917694600. PubMed DOI PMC

Connor TJ, et al. Induction of indolamine 2,3-dioxygenase and kynurenine 3-monooxygenase in rat brain following a systemic inflammatory challenge: a role for IFN-gamma? Neurosci Lett. 2008;441(1):29–34. doi: 10.1016/j.neulet.2008.06.007. PubMed DOI

Mithaiwala MN, et al. Neuroinflammation and the kynurenine pathway in CNS disease: molecular mechanisms and therapeutic implications. Cells. 2021;10(6):1548. doi: 10.3390/cells10061548. PubMed DOI PMC

Chouraki V, et al. Association of amine biomarkers with incident dementia and Alzheimer’s disease in the Framingham Study. Alzheimers Dement. 2017;13(12):1327–1336. doi: 10.1016/j.jalz.2017.04.009. PubMed DOI PMC

Schwarz MJ, et al. Increased 3-hydroxykynurenine serum concentrations differentiate Alzheimer’s disease patients from controls. Eur Arch Psychiatry Clin Neurosci. 2013;263(4):345–352. doi: 10.1007/s00406-012-0384-x. PubMed DOI

Klatt S, et al. A six-metabolite panel as potential blood-based biomarkers for Parkinson’s disease. NPJ Parkinsons Dis. 2021;7(1):94. doi: 10.1038/s41531-021-00239-x. PubMed DOI PMC

Li Y, et al. Behavioral deficits are accompanied by immunological and neurochemical changes in a mouse model for Neuropsychiatric Lupus (NP-SLE) Int J Mol Sci. 2015;16(7):15150–15171. doi: 10.3390/ijms160715150. PubMed DOI PMC

Zwilling D, et al. Kynurenine 3-monooxygenase inhibition in blood ameliorates neurodegeneration. Cell. 2011;145(6):863–874. doi: 10.1016/j.cell.2011.05.020. PubMed DOI PMC

Hayek SS, et al. Soluble urokinase receptor and chronic kidney disease. N Engl J Med. 2015;373(20):1916–1925. doi: 10.1056/NEJMoa1506362. PubMed DOI PMC

Yu L, et al. Diagnostic and prognostic significance of suPAR in traumatic brain injury. Neurol India. 2014;62(5):498–502. doi: 10.4103/0028-3886.144439. PubMed DOI

Frak W, et al. Role of uremic toxins, oxidative stress, and renal fibrosis in chronic kidney disease. Antioxidants (Basel) 2024;13(6):687. doi: 10.3390/antiox13060687. PubMed DOI PMC

Lv W, et al. Oxidative stress and renal fibrosis: recent insights for the development of novel therapeutic strategies. Front Physiol. 2018;9:105. doi: 10.3389/fphys.2018.00105. PubMed DOI PMC

Pawlak K, et al. Kynurenine, quinolinic acid--the new factors linked to carotid atherosclerosis in patients with end-stage renal disease. Atherosclerosis. 2009;204(2):561–566. doi: 10.1016/j.atherosclerosis.2008.10.002. PubMed DOI

Clark AJ, et al. Hepatocyte nuclear factor 4α mediated quinolinate phosphoribosylltransferase (QPRT) expression in the kidney facilitates resilience against acute kidney injury. Kidney Int. 2023;104(6):1150–1163. doi: 10.1016/j.kint.2023.09.013. PubMed DOI PMC

Parrott JM, et al. Kynurenine metabolic balance is disrupted in the hippocampus following peripheral lipopolysaccharide challenge. J Neuroinflammation. 2016;13(1):124. doi: 10.1186/s12974-016-0590-y. PubMed DOI PMC

Liu M, et al. Acute kidney injury leads to inflammation and functional changes in the brain. J Am Soc Nephrol. 2008;19(7):1360–1370. doi: 10.1681/ASN.2007080901. PubMed DOI PMC

Guillemin GJ. Quinolinic acid, the inescapable neurotoxin. FEBS J. 2012;279(8):1356–1365. doi: 10.1111/j.1742-4658.2012.08485.x. PubMed DOI

Leipnitz G, et al. Quinolinic acid reduces the antioxidant defenses in cerebral cortex of young rats. Int J Dev Neurosci. 2005;23(8):695–701. doi: 10.1016/j.ijdevneu.2005.08.004. PubMed DOI

Behan WM, et al. Oxidative stress as a mechanism for quinolinic acid-induced hippocampal damage: protection by melatonin and deprenyl. Br J Pharmacol. 1999;128(8):1754–1760. doi: 10.1038/sj.bjp.0702940. PubMed DOI PMC

Ting KK, et al. Effect of quinolinic acid on human astrocytes morphology and functions: implications in Alzheimer’s disease. J Neuroinflammation. 2009;6:36. doi: 10.1186/1742-2094-6-36. PubMed DOI PMC

Tavares RG, et al. Quinolinic acid stimulates synaptosomal glutamate release and inhibits glutamate uptake into astrocytes. Neurochem Int. 2002;40(7):621–627. doi: 10.1016/S0197-0186(01)00133-4. PubMed DOI

Tavares RG, et al. Quinolinic acid inhibits glutamate uptake into synaptic vesicles from rat brain. Neuroreport. 2000;11(2):249–253. doi: 10.1097/00001756-200002070-00005. PubMed DOI

Kang Y, et al. A Multi-ligand imaging study exploring GABaergic receptor expression and inflammation in multiple sclerosis. Mol Imaging Biol. 2020;22(6):1600–1608. doi: 10.1007/s11307-020-01501-z. PubMed DOI PMC

Bayon-Cordero L, et al. GABA receptor agonists protect from excitotoxic damage induced by AMPA in oligodendrocytes. Front Pharmacol. 2022;13:897056. doi: 10.3389/fphar.2022.897056. PubMed DOI PMC

Long Z, et al. Decreased GABA levels in anterior cingulate cortex/medial prefrontal cortex in panic disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2013;44:131–135. doi: 10.1016/j.pnpbp.2013.01.020. PubMed DOI PMC

Guerriero RM, et al. Glutamate and GABA imbalance following traumatic brain injury. Curr Neurol Neurosci Rep. 2015;15(5):27. doi: 10.1007/s11910-015-0545-1. PubMed DOI PMC

Zimmermann S, et al. Chronic kidney disease leads to microglial potassium efflux and inflammasome activation in the brain. Kidney Int. 2024;106(6):1101–1116. doi: 10.1016/j.kint.2024.06.028. PubMed DOI

Karbowska M, et al. Neurobehavioral effects of uremic toxin-indoxyl sulfate in the rat model. Sci Rep. 2020;10(1):9483. doi: 10.1038/s41598-020-66421-y. PubMed DOI PMC

Moroni F, et al. Increase in the content of quinolinic acid in cerebrospinal fluid and frontal cortex of patients with hepatic failure. J Neurochem. 1986;47(6):1667–1671. doi: 10.1111/j.1471-4159.1986.tb13071.x. PubMed DOI

Heyes MP, et al. Elevated cerebrospinal fluid quinolinic acid levels are associated with region-specific cerebral volume loss in HIV infection. Brain. 2001;124(pt 5):1033–1042. doi: 10.1093/brain/124.5.1033. PubMed DOI

Valle M, et al. CSF quinolinic acid levels are determined by local HIV infection: cross-sectional analysis and modelling of dynamics following antiretroviral therapy. Brain. 2004;127(pt 5):1047–1060. doi: 10.1093/brain/awh130. PubMed DOI

Watne LO, et al. Cerebrospinal fluid quinolinic acid is strongly associated with delirium and mortality in hip-fracture patients. J Clin Invest. 2023;133(2):e163472. doi: 10.1172/JCI163472. PubMed DOI PMC

Bell MJ, et al. Quinolinic acid in the cerebrospinal fluid of children after traumatic brain injury. Crit Care Med. 1999;27(3):493–497. doi: 10.1097/00003246-199903000-00023. PubMed DOI

Drewes JL, et al. Quinolinic acid/tryptophan ratios predict neurological disease in SIV-infected macaques and remain elevated in the brain under cART. J Neurovirol. 2015;21(4):449–463. doi: 10.1007/s13365-015-0334-2. PubMed DOI PMC

Kohler C, et al. Quinolinic acid phosphoribosyltransferase: preferential glial localization in the rat brain visualized by immunocytochemistry. Proc Natl Acad Sci U S A. 1987;84(10):3491–3495. doi: 10.1073/pnas.84.10.3491. PubMed DOI PMC

Ryden A, et al. Understanding the patient experience of chronic kidney disease stages 2-3b: a qualitative interview study with Kidney Disease Quality of Life (KDQOL-36) debrief. BMC Nephrol. 2022;23(1):201. doi: 10.1186/s12882-022-02826-3. PubMed DOI PMC

Gregg LP, et al. Fatigue in nondialysis chronic kidney disease: correlates and association with kidney outcomes. Am J Nephrol. 2019;50(1):37–47. doi: 10.1159/000500668. PubMed DOI PMC

Yapa HE, et al. Alterations in symptoms and health-related quality of life as kidney function deteriorates: a cross-sectional study. J Clin Nurs. 2021;30(11–12):1787–1796. doi: 10.1111/jocn.15738. PubMed DOI

Schefold JC, et al. Increased indoleamine 2,3-dioxygenase (IDO) activity and elevated serum levels of tryptophan catabolites in patients with chronic kidney disease: a possible link between chronic inflammation and uraemic symptoms. Nephrol Dial Transplant. 2009;24(6):1901–1908. doi: 10.1093/ndt/gfn739. PubMed DOI

Groven N, et al. Kynurenine metabolites and ratios differ between Chronic Fatigue Syndrome, Fibromyalgia, and healthy controls. Psychoneuroendocrinology. 2021;131:105287. doi: 10.1016/j.psyneuen.2021.105287. PubMed DOI

Akesson K, et al. Kynurenine pathway is altered in patients with SLE and associated with severe fatigue. Lupus Sci Med. 2018;5(1):e000254. doi: 10.1136/lupus-2017-000254. PubMed DOI PMC

Robbins RN, et al. Kynurenine metabolism as a mechanism to improve fatigue and physical function in postmenopausal breast cancer survivors following resistance training. J Funct Morphol Kinesiol. 2022;7(2):45. doi: 10.3390/jfmk7020045. PubMed DOI PMC

O’Connor JC, et al. Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry. 2009;14(5):511–522. doi: 10.1038/sj.mp.4002148. PubMed DOI PMC

Raison CL, et al. CSF concentrations of brain tryptophan and kynurenines during immune stimulation with IFN-alpha: relationship to CNS immune responses and depression. Mol Psychiatry. 2010;15(4):393–403. doi: 10.1038/mp.2009.116. PubMed DOI PMC

Aufhauser DD, Jr Improved renal ischemia tolerance in females influences kidney transplantation outcomes. J Clin Invest. 2016;126(5):1968–1977. doi: 10.1172/JCI84712. PubMed DOI PMC

Elliot SJ, et al. Estrogen deficiency accelerates progression of glomerulosclerosis in susceptible mice. Am J Pathol. 2003;162(5):1441–1448. doi: 10.1016/S0002-9440(10)64277-0. PubMed DOI PMC

Traykova-Brauch M, et al. An efficient and versatile system for acute and chronic modulation of renal tubular function in transgenic mice. Nat Med. 2008;14(9):979–984. doi: 10.1038/nm.1865. PubMed DOI PMC

Grier JD, et al. Conditional allele of mdm2 which encodes a p53 inhibitor. Genesis. 2002;32(2):145–147. doi: 10.1002/gene.10066. PubMed DOI

Yamamoto T, et al. Renal L-type fatty acid--binding protein in acute ischemic injury. J Am Soc Nephrol. 2007;18(11):2894–2902. doi: 10.1681/ASN.2007010097. PubMed DOI

Pena MJ, et al. The effects of atrasentan on urinary metabolites in patients with type 2 diabetes and nephropathy. Diabetes Obes Metab. 2017;19(5):749–753. doi: 10.1111/dom.12864. PubMed DOI

Sharma K, et al. Metabolomics reveals signature of mitochondrial dysfunction in diabetic kidney disease. J Am Soc Nephrol. 2013;24(11):1901–1912. doi: 10.1681/ASN.2013020126. PubMed DOI PMC

Pallerla P, et al. Evaluation of amino acids and other related metabolites levels in end-stage renal disease (ESRD) patients on hemodialysis by LC/MS/MS and GC/MS. Anal Bioanal Chem. 2023;415(26):6491–6509. doi: 10.1007/s00216-023-04926-x. PubMed DOI

Sharma K, et al. Endogenous adenine mediates kidney injury in diabetic models and predicts diabetic kidney disease in patients. J Clin Invest. 2023;133(20):e170341. doi: 10.1172/JCI170341. PubMed DOI PMC

Schneider CA, et al. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9(7):671–675. doi: 10.1038/nmeth.2089. PubMed DOI PMC

Bankhead P, et al. QuPath: open source software for digital pathology image analysis. Sci Rep. 2017;7(1):16878. doi: 10.1038/s41598-017-17204-5. PubMed DOI PMC

Adeera Levin PES, Rudy W. Chapter 1: Definition and classification of CKD. Kidney Int Suppl (2011) 2013;3(1):19–62. doi: 10.1038/kisup.2012.64. PubMed DOI PMC

Levey AS, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604–612. doi: 10.7326/0003-4819-150-9-200905050-00006. PubMed DOI PMC

Mendoza TR, et al. The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer. 1999;85(5):1186–1196. doi: 10.1002/(SICI)1097-0142(19990301)85:5<1186::AID-CNCR24>3.0.CO;2-N. PubMed DOI

Gonzalez AM, et al. Patient and caregiver priorities for outcomes in CKD: a multinational nominal group technique study. Am J Kidney Dis. 2020;76(5):679–689. doi: 10.1053/j.ajkd.2020.03.022. PubMed DOI

Pang Z, et al. Using MetaboAnalyst 5.0 for LC-HRMS spectra processing, multi-omics integration and covariate adjustment of global metabolomics data. Nat Protoc. 2022;17(8):1735–1761. doi: 10.1038/s41596-022-00710-w. PubMed DOI