Adnan Khan

Introduction. Chronic Kidney Disease (CKD) is defined in patients with a glomerular filtration rate less than 60 mL/min/1.73 m². Patients typically develop a myriad of complications including, but not limited to, edema, anemia, uremia, hyperkalemia, and heart disease. An important neurological complication of CKD is the three times higher prevalence of cognitive dysfunction in CKD patients than in healthy people.¹ The cognitive dysfunction ranges from mild impairment to more severe forms of dementia. Studies have shown that the pathogenesis behind this cognitive impairment may be due to the buildup of protein-bound indoxyl sulfate (IS), which accumulates in CKD due to the uremic disruption of gut microbiota and increased tryptophan metabolism.² Further studies have been conducted to detail the mechanistic effects of indoxyl sulfate on the cognitive system. Methods. Studies were chosen that used unilaterally nephrectomized mice or rats treated with IS to determine its effects. The IS-treated mice were subject to cognitive tests and compared to control mice for evidence of cognitive decline.^1-3 IS-induced mice were also tested for lipid peroxidation products and inflammatory markers to determine the effect of IS on oxidative stress and neuroinflammation respectively.² Finally, IS-treated mice were measured for dopamine and serotonin levels in different regions of the brain.³ Studies reporting therapeutic strategies for clearing IS were also reviewed.^4,5 Results. High levels of IS were found to have a strong association with worsening cognitive decline in CKD subjects.^1-3 IS-treated mice had increased levels of lipid peroxidation products, indicating increased oxidative stress.² IS-treated mice also had higher levels of inflammatory markers in the cortical tissues.² Additionally, IS-treated mice showed lower levels of monoamines (dopamine and serotonin) in the brainstem.³ Therapeutically, studies showed that AST-120 improves clearance of IS from circulation and improves cognitive symptoms by decreasing oxidative stress and neuroinflammation.^2,4 Additionally, bioartificial kidneys show improved IS clearing mechanisms that may also improve cognitive symptoms.⁵ Conclusions. These studies have shown increasing evidence that IS accumulation in CKD is the underlying cause of cognitive decline in patients through three main mechanisms: induced oxidative stress, increased neuroinflammation, and decreased monoamine levels in the brainstem. Therapeutic strategies to improve cognitive symptoms should be aimed at improving IS clearance. AST-120 is the pharmaceutical option that has not yet been approved in the US. Bioartifical kidneys show promise but still have not been fully developed.

1. Lin YT, Wu PH, Liang SS, et al. Protein-bound uremic toxins are associated with cognitive function among patients undergoing maintenance hemodialysis. Sci Rep. 2019;9(1):20388. Published 2019 Dec 31. doi:10.1038/s41598-019-57004-7
2. Sun CY, Li JR, Wang YY, et al. Indoxyl sulfate caused behavioral abnormality and neurodegeneration in mice with unilateral nephrectomy. Aging (Albany NY). 2021;13(5):6681-6701. doi:10.18632/aging.202523
3. Karbowska M, Hermanowicz JM, Tankiewicz-Kwedlo A, et al. Neurobehavioral effects of uremic toxin-indoxyl sulfate in the rat model. Sci Rep. 2020;10(1):9483. Published 2020 Jun 11. doi:10.1038/s41598-020-66421-y
4. Li LC, Chen WY, Chen JB, et al. The AST-120 Recovers Uremic Toxin-Induced Cognitive Deficit via NLRP3 Inflammasome Pathway in Astrocytes and Microglia. Biomedicines. 2021;9(9):1252. Published 2021 Sep 17. doi:10.3390/biomedicines9091252
5. King J, Swapnasrita S, Truckenmüller R, Giselbrecht S, Masereeuw R, Carlier A. Modeling indoxyl sulfate transport in a bioartificial kidney: Two-step binding kinetics or lumped parameters model for uremic toxin clearance?. Comput Biol Med. 2021;138:104912. doi:10.1016/j.compbiomed.2021.104912