Chronic Kidney Disease Induces Cognitive Impairment in the Early Stage

Abstract

Objective

Previous research indicates a link between cognitive impairment and chronic kidney disease (CKD), but the underlying factors are not fully understood. This study aimed to investigate the progression of CKD-induced cognitive impairment and the involvement of cognition-related proteins by developing early- and late-stage CKD models in Sprague-Dawley rats.

Methods

The Morris water maze test and the step-down passive avoidance task were performed to evaluate the cognitive abilities of the rats at 24 weeks after surgery. Histopathologic examinations were conducted to examine renal and hippocampal damage. Real-time PCR, Western blotting analysis, and immunohistochemical staining were carried out to determine the hippocampal expression of brain-derived neurotrophic factor (BDNF), choline acetyltransferase (ChAT), and synaptophysin (SYP).

Results

Compared with the control rats, the rats with early-stage CKD exhibited mild renal damage, while those with late-stage CKD showed significantly increased serum creatinine levels as well as apparent renal and brain damage. The rats with early-stage CKD also demonstrated significantly impaired learning abilities and memory compared with the control rats, with further deterioration observed in the rats with late-stage CKD. Additionally, we observed a significant downregulation of cognition-related proteins in the hippocampus of rats with early-stage CKD, which was further exacerbated with declining renal function as well as worsening brain and renal damage in rats with late-stage CKD.

Conclusion

These results suggest the importance of early screening to identify CKD-induced cognitive dysfunction promptly. In addition, the downregulation of cognition-related proteins may play a role in the progression of cognitive dysfunction.

Keywords

chronic kidney disease / cognitive impairment / Morris water maze test / brain-derived neurotrophic factor / choline acetyltransferase / synaptophysin

References

[1] VaidyaSR, AeddulaNRChronic Renal Failure, 2021, Treasure Island, StatPears Publishing

[2] WebsterAC, NaglerEV, MortonRL, et al.. Chronic Kidney Disease. Lancet, 2017, 389(10075): 1238-1252

[3] Kurella TamuraM, YaffeK, HsuCY, et al.. Cognitive Impairment and Progression of CKD. Am J Kidney Dis, 2016, 68(1): 77-83

[4] Rodríguez-AngaritaCE, Sanabria-ArenasRM, Vargas-JaramilloJD, et al.. Cognitive impairment and depression in a population of patients with chronic kidney disease in Colombia: a prevalence study. Can J Kidney Health Dis, 2016, 3: 26

[5] SarnakMJ, TighiouartH, ScottTM, et al.. Frequency of and risk factors for poor cognitive performance in hemodialysis patients. Neurology, 2013, 80(5): 471-480

[6] BugnicourtJM, GodefroyO, ChillonJM, et al.. Cognitive disorders and dementia in CKD: the neglected kidney-brain axis. J Am Soc Nephrol, 2013, 24(3): 353-363

[7] MurrayAM. Cognitive impairment in the aging dialysis and chronic kidney disease populations: an occult burden. Adv Chronic Kidney Dis, 2008, 15(2): 123-132

[8] BronasUG, PuzantianH, HannanM. Cognitive Impairment in Chronic Kidney Disease: Vascular Milieu and the Potential Therapeutic Role of Exercise. Biomed Res Int, 2017, 2017: 2726369

[9] FosterR, WalkerS, BrarR, et al.. Cognitive Impairment in Advanced Chronic Kidney Disease: The Canadian Frailty Observation and Interventions Trial. Am J Nephrol, 2016, 44(6): 473-480

[10] PusswaldG, TropperE, Kryspin-ExnerI, et al.. Health-Related Quality of Life in Patients with Subjective Cognitive Decline and Mild Cognitive Impairment and its Relation to Activities of Daily Living. J Alzheimers Dis, 2015, 47(2): 479-486

[11] ThancharoenO, WaleekhachonloetO, LimwattananonC, et al.. Cognitive impairment, quality of life and healthcare utilization in patients with chronic kidney disease stages 3 to 5. Nephrology (Carlton), 2020, 25(8): 625-633

[12] YaffeK, PeltzCB, EwingSK, et al.. Long-term Cognitive Trajectories and Mortality in Older Women. J Gerontol A Biol Sci Med Sci, 2016, 71(8): 1074-1080

[13] Sanon AigbogunM, OberdhanD, DoaneMJ, et al.. Disconnect in Assessments of Autosomal Dominant Polycystic Kidney Disease Burden Between Patients and Physicians: A Survey Study. Int J Nephrol Renovasc Dis, 2021, 14: 105-115

[14] SzerlipHM, EdwardsML, WilliamsBJ, et al.. Association Between Cognitive Impairment and Chronic Kidney Disease in Mexican Americans. J Am Geriatr Soc, 2015, 63(10): 2023-2028

[15] TorresRV, EliasMF, SeligerS, et al.. Risk for cognitive impairment across 22 measures of cognitive ability in early-stage chronic kidney disease. Nephrol Dial Transplant, 2017, 32(2): 299-306

[16] Yeh YC, Huang MF, Liang SS, et al. Indoxyl sulfate, not p-cresyl sulfate, is associated with cognitive impairment in early-stage chronic kidney disease. Neurotoxicology, 2016,53148–152

[17] ZammitAR, KatzMJ, ZimmermanME, et al.. Low eGFR is associated with dysexecutive and amnestic mild cognitive impairment. Alzheimers Dement (Amst), 2015, 1(2): 152-159

[18] LuB, NagappanG, LuY. BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol, 2014, 220: 223-250

[19] NonomuraT, HatanakaH. Neurotrophic effect of brain-derived neurotrophic factor on basal forebrain cholinergic neurons in culture from postnatal rats. Neurosci Res, 1992, 14(3): 226-233

[20] SalaR, ViegiA, RossiFM, et al.. Nerve growth factor and brain-derived neurotrophic factor increase neurotransmitter release in the rat visual cortex. Eur J Neurosci, 1998, 10(6): 2185-2191

[21] JamalM, ItoA, TanakaN, et al.. The Role of Apolipoprotein E and Ethanol Exposure in Age-Related Changes in Choline Acetyltransferase and Brain-Derived Neurotrophic Factor Expression in the Mouse Hippocampus. J Mol Neurosci, 2018, 65(1): 84-92

[22] PoirelO, MellaS, VideauC, et al.. Moderate decline in select synaptic markers in the prefrontal cortex (BA9) of patients with Alzheimer’s disease at various cognitive stages. Sci Rep, 2018, 8(1): 938

[23] WatanabeK, FujiiH, GotoS, et al.. Newly Developed Rat Model of Chronic Kidney Disease-Mineral Bone Disorder. J Atheroscler Thromb, 2018, 25(2): 170-177

[24] MiskowiakKW, VinbergM, MacoveanuJ, et al.. Effects of Erythropoietin on Hippocampal Volume and Memory in Mood Disorders. Biol Psychiatry, 2015, 78(4): 270-277

[25] KoIG, KimCJ, KimH. Treadmill exercise improves memory by up-regulating dopamine and down-regulating D(2) dopamine receptor in traumatic brain injury rats. J Exerc Rehabil, 2019, 15(4): 504-511

[26] MooreJF, SharerJD. Methods for Quantitative Creatinine Determination. Curr Protoc Hum Genet, 2017, 93: A.3O.1-A.3O.7

[27] VossJL, BridgeDJ, CohenNJ, et al.. A Closer Look at the Hippocampus and Memory. Trends Cogn Sci, 2017, 21(8): 577-588

[28] EtgenT, SanderD, ChoncholM, et al.. Chronic kidney disease is associated with incident cognitive impairment in the elderly: the INVADE study. Nephrol Dial Transplant, 2009, 24(10): 3144-3150

[29] Gounden V, Bhatt H, Jialal I. Renal Function Tests. StatPearls. Treasure Island (FL) ineligible companies. Disclosure: Harshil Bhatt declares no relevant financial relationships with ineligible companies. Disclosure: Ishwarlal Jialal declares no relevant financial relationships with ineligible companies.: StatPearls Publishing Copyright © 2023, StatPearls Publishing LLC.; 2023.

[30] BurnsCM, KnopmanDS, TupperDE, et al.. Prevalence and Risk of Severe Cognitive Impairment in Advanced Chronic Kidney Disease. J Gerontol A Biol Sci Med Sci, 2018, 73(3): 393-399

[31] CiesielskaN, SokołowskiR, MazurE, et al.. Is the Montreal Cognitive Assessment (MoCA) test better suited than the Mini-Mental State Examination (MMSE) in mild cognitive impairment (MCI) detection among people aged over 60? Meta-analysis. Psychiatr Pol, 2016, 50(5): 1039-1052

[32] OlsenRK, SebanayagamV, LeeY, et al.. The relationship between eye movements and subsequent recognition: Evidence from individual differences and amnesia. Cortex, 2016, 85: 182-193

[33] VossJL, GonsalvesBD, FedermeierKD, et al.. Hippocampal brain-network coordination during volitional exploratory behavior enhances learning. Nat Neurosci, 2011, 14(1): 115-120

[34] YeeLT, WarrenDE, VossJL, et al.. The hippocampus uses information just encountered to guide efficient ongoing behavior. Hippocampus, 2014, 24(2): 154-164

[35] KurajohM, KadoyaM, MorimotoA, et al.. Plasma brain-derived neurotrophic factor concentration is a predictor of chronic kidney disease in patients with cardiovascular risk factors - Hyogo Sleep Cardio-Autonomic Atherosclerosis study. PLoS One, 2017, 12(6): e0178686

[36] NakahashiT, FujimuraH, AltarCA, et al.. Vascular endothelial cells synthesize and secrete brain-derived neurotrophic factor. FEBS Lett, 2000, 470(2): 113-117

[37] SartoriusA, HellwegR, LitzkeJ, et al.. Correlations and discrepancies between serum and brain tissue levels of neurotrophins after electroconvulsive treatment in rats. Pharmacopsychiatry, 2009, 42(6): 270-276

[38] ChuS, GuJ, FengL, et al.. Ginsenoside Rg5 improves cognitive dysfunction and beta-amyloid deposition in STZ-induced memory impaired rats via attenuating neuroinflammatory responses. Int Immunopharmacol, 2014, 19(2): 317-326

[39] ReetaKH, SinghD, GuptaYK. Edaravone attenuates intracerebroventricular streptozotocin-induced cognitive impairment in rats. Eur J Neurosci, 2017, 45(7): 987-997

[40] BullochK, DamavandyT, BadamchianM. Characterization of choline O-acetyltransferase (ChAT) in the BALB/C mouse spleen. Int J Neurosci, 1994, 76(1–2): 141-149

[41] Ho YS, Lau CF, Lee K, et al. Impact of unilateral ureteral obstruction on cognition and neurodegeneration. Brain Res Bull, 2021,169112–169127

[42] Liang C, Tan S, Huang Q, et al. Pratensein ameliorates β-amyloid-induced cognitive impairment in rats via reducing oxidative damage and restoring synapse and BDNF levels. Neurosci Lett, 2015,59248–59253

[43] ChenT, WuY, WangY, et al.. Brain-Derived Neurotrophic Factor Increases Synaptic Protein Levels via the MAPK/Erk Signaling Pathway and Nrf2/Trx Axis Following the Transplantation of Neural Stem Cells in a Rat Model of Traumatic Brain Injury. Neurochem Res, 2017, 42(11): 3073-3083

[44] YeQ, ZengC, LuoC, et al.. Ferrostatin-1 mitigates cognitive impairment of epileptic rats by inhibiting P38 MAPK activation. Epilepsy Behav, 2020, 103(PtA): 106670

[45] ZhangCY, HeFF, SuH, et al.. Association between chronic kidney disease and Alzheimer’s disease: an update. Metab Brain Dis, 2020, 35(6): 883-894

[46] XieZ, TongS, ChuX, et al.. Chronic Kidney Disease and Cognitive Impairment: The Kidney-Brain Axis. Kidney Dis (Basel), 2022, 8(4): 275-285

[47] OhYS, KimJS, ParkJW, et al.. Arterial stiffness and impaired renal function in patients with Alzheimer’s disease. Neurol Sci, 2016, 37(3): 451-457

[48] MiglinasM, CesnieneU, JanusaiteMM, et al.. Cerebrovascular disease and cognition in chronic kidney disease patients. Front Cardiovasc Med, 2020, 7: 96

[49] ViggianoD, WagnerCA, MartinoG, et al.. Mechanisms of cognitive dysfunction in CKD. Nat Rev Nephrol, 2020, 16(8): 452-469

[50] WuY, ShangY, SunSG, et al.. Protective effect of erythropoietin against 1-methyl-4-phenylpyridinium-induced neurodegenaration in PC12 cells. Neurosci Bull, 2007, 23(3): 156-164

[51] MauriceT, MustafaMH, DesrumauxC, et al.. Intranasal formulation of erythropoietin (EPO) showed potent protective activity against amyloid toxicity in the Aβ 25–35 non-transgenic mouse model of Alzheimer’s disease. J Psychopharmacol, 2013, 27(11): 1044-1057

[52] Rodriguez CruzY, StrehaianoM, Rodriguez ObayaT, et al.. An intranasal formulation of erythropoietin(Neuro-EPO) prevents memory deficits and amyloid toxicity in the APPSwe transgenic mouse model of Alzheimer’s disease. J Alzheimers Dis, 2017, 55(1): 231-248

[53] MohamedAR, SolimanGY, IsmailCA, et al.. Neuroprotective role of vitamin D3 in colchicine-induced Alzheimer’s disease in rats. Alexandr J Med, 2014, 51(2): 127-136

[54] LlewellynDJ, LangaKM, LangIA. Serum 25-hydroxyvitamin D Concentration and cognitive impairment. J Geriatr Psychiatry Neurol, 2009, 22(3): 188-195

[55] HenselN, SchönA, KonenT, et al.. Fibroblast growth factor 23 signaling in hippocampal cells: impact on neuronal morphology and synaptic density. J Neurochem, 2016, 137(5): 756-769

[56] DrewDA, WeinerDE. Cognitive impairment in chronic kidney disease: keep vascular disease in mind. Kidney Int, 2014, 85(3): 505-507

[57] de DonatoA, BuonincontriV, BorrielloG, et al.. The Dopamine System: Insights between Kidney and Brain. Kidney Blood Press Res, 2022, 47(8): 493-505

[58] Reza-ZaldívarEE, Sandoval-AvilaS, Gutiérrez-MercadoYK, et al.. Human recombinant erythropoietin reduces sensorimotor dysfunction and cognitive impairment in rat models of chronic kidney disease. Neurologia (Engl Ed), 2020, 35(3): 147-154

[59] LiG, ZhaoM, ChengX, et al.. FG-4592 Improves Depressive-Like Behaviors through HIF-1-Mediated Neurogenesis and Synapse Plasticity in Rats. Neurotherapeutics, 2020, 17(2): 664-675