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Review
. 2023 Sep 18;16(12):2365-2377.
doi: 10.1093/ckj/sfad241. eCollection 2023 Dec.

Drugs with a negative impact on cognitive function (Part 1): chronic kidney disease as a risk factor

Sophie Liabeuf  1   2 , Vesna Pešić  3 , Goce Spasovski  4 , Romaldas Maciulaitis  5   6 , Mickaël Bobot  7 , Ana Farinha  8 , Carsten A Wagner  9 , Robert J Unwin  10 , Giovambattista Capasso  11   12 , Inga Arune Bumblyte  5 , Gaye Hafez  13 ; CONNECT Action (Cognitive Decline in Nephro-Neurology European Cooperative Target)
Collaborators, Affiliations
Review

Drugs with a negative impact on cognitive function (Part 1): chronic kidney disease as a risk factor

Sophie Liabeuf et al. Clin Kidney J. .

Abstract

People living with chronic kidney disease (CKD) frequently suffer from mild cognitive impairment and/or other neurocognitive disorders. This review in two parts will focus on adverse drug reactions resulting in cognitive impairment as a potentially modifiable risk factor in CKD patients. Many patients with CKD have a substantial burden of comorbidities leading to polypharmacy. A recent study found that patients seen by nephrologists were the most complex to treat because of their high number of comorbidities and medications. Due to polypharmacy, these patients may experience a wide range of adverse drug reactions. Along with CKD progression, the accumulation of uremic toxins may lead to blood-brain barrier (BBB) disruption and pharmacokinetic alterations, increasing the risk of adverse reactions affecting the central nervous system (CNS). In patients on dialysis, the excretion of drugs that depend on kidney function is severely reduced such that adverse and toxic levels of a drug or its metabolites may be reached at relatively low doses, unless dosing is adjusted. This first review will discuss how CKD represents a risk factor for adverse drug reactions affecting the CNS via (i) BBB disruption associated with CKD and (ii) the impact of reduced kidney function and dialysis itself on drug pharmacokinetics.

Keywords: adverse drug reactions; chronic kidney disease; cognitive impairment; drug prescription.

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Conflict of interest statement

S.L., A.F., R.M., G.C., V.P. and G.H. declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article. C.A.W. reports honoraria from Kyowa Kirin and Mecice. R.J.U. is currently employed by AstraZeneca BioPharmaceuticals R&D, Cambridge, UK. I.A.B. reports honoraria from Amgen and AstraZeneca. M.B. reports congress invitations from Otsuka, Vifor and Sanofi.

Figures

Graphical Abstract
Graphical Abstract
Figure 1:
Figure 1:
Impact of CKD on drug pharmacokinetics and the BBB. (A) BBB disruption. CKD is associated with alterations of the BBB leading to high number of CNS ADRs. (B) Distribution. A subject with late-stage CKD presented with low albumin levels, conformational changes in albumin molecule (such as carbamylation), competition between protein-associated uremic toxins and protein-bound drugs for albumin binding resulting in elevated free drugs fractions. (C) Metabolization. Severe CKD will result in decrease of expression and activity of drug-metabolizing enzymes such as CYP450 leading to unpredictable pharmacokinetics. (D) Elimination. CKD is associated with alteration of drug transporters. Example of competition between toxins and drugs as substrates of the OAT in renal proximal tubule leading to potential accumulation of drugs.
Figure 2:
Figure 2:
The effect of hemodialysis on blood concentrations of drugs that are removable by convective or diffusive processes [38, 40]. (A) Example of small solute removal during dialysis and (B) removal of vancomycin (high molecular weight) through low-flux (red) vs high-flux (green) membranes.
See this image and copyright information in PMC

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