Association between cholinesterase inhibitors and kidney function decline in patients with Alzheimer’s dementia

Abstract

Preclinical evidence shows that activation of the cholinergic anti-inflammatory pathway (CAP) may have direct and indirect beneficial effects on the kidney. Cholinesterase inhibitors (ChEIs) are specific Alzheimer’s dementia (AD) therapies that block the action of cholinesterases and activate CAP. Here, we explored a plausible effect of ChEIs on slowing kidney function decline by comparing the risk of CKD progression among patients with newly diagnosed AD that initiated ChEI or not within 90 days. Using complete information of routine serum creatinine tests, we evaluated changes in estimated glomerular filtration rate (eGFR) and defined the outcome of chronic kidney disease (CKD) progression as the composite of an eGFR decline of over 30%, initiation of dialysis/transplant or death attributed to CKD. A secondary outcome was death. Inverse probability of treatment-weighted Cox regression was used to estimate hazard ratios. Among 11, 898 patients, 6,803 started on ChEIs and 5,095 did not. Mean age was 80 years (64% women) and the mean eGFR was 68 ml/min/1.73m2. During a median 3.0 years of follow-up, and compared to non-use, ChEI use was associated with 18% lower risk of CKD progression (1,231 events, adjusted hazard ratio 0.82; 95% confidence interval 0.71-0.96) and a 21% lower risk of death (0.79; 0.72-0.86). Results were consistent across subgroups, ChEI subclasses and after accounting for competing risks. Thus, in patients with AD undergoing routine care, use of ChEI (vs no-use) was associated with lower risk of CKD progression. Preclinical evidence shows that activation of the cholinergic anti-inflammatory pathway (CAP) may have direct and indirect beneficial effects on the kidney. Cholinesterase inhibitors (ChEIs) are specific Alzheimer’s dementia (AD) therapies that block the action of cholinesterases and activate CAP. Here, we explored a plausible effect of ChEIs on slowing kidney function decline by comparing the risk of CKD progression among patients with newly diagnosed AD that initiated ChEI or not within 90 days. Using complete information of routine serum creatinine tests, we evaluated changes in estimated glomerular filtration rate (eGFR) and defined the outcome of chronic kidney disease (CKD) progression as the composite of an eGFR decline of over 30%, initiation of dialysis/transplant or death attributed to CKD. A secondary outcome was death. Inverse probability of treatment-weighted Cox regression was used to estimate hazard ratios. Among 11, 898 patients, 6,803 started on ChEIs and 5,095 did not. Mean age was 80 years (64% women) and the mean eGFR was 68 ml/min/1.73m2. During a median 3.0 years of follow-up, and compared to non-use, ChEI use was associated with 18% lower risk of CKD progression (1,231 events, adjusted hazard ratio 0.82; 95% confidence interval 0.71-0.96) and a 21% lower risk of death (0.79; 0.72-0.86). Results were consistent across subgroups, ChEI subclasses and after accounting for competing risks. Thus, in patients with AD undergoing routine care, use of ChEI (vs no-use) was associated with lower risk of CKD progression. Inflammation is a common and prognostically unfavorable manifestation of several noncommunicable chronic diseases such as hypertension, type 2 diabetes, heart failure, rheumatoid arthritis, inflammatory bowel disease, and chronic kidney disease (CKD).1Furman D. Campisi J. 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Sung S.S. et al.Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes.J Clin Invest. 2016; 126: 1939-1952Crossref PubMed Scopus (203) Google Scholar Indirect mechanisms by which CAP activation may favorably affect kidney function include reduction in inflammatory mediators16Hoeger S. Fontana J. Jarczyk J. et al.Vagal stimulation in brain dead donor rats decreases chronic allograft nephropathy in recipients.Nephrol Dial Transplant. 2014; 29: 544-549Crossref PubMed Scopus (23) Google Scholar,17Hoeger S. Bergstraesser C. Selhorst J. et al.Modulation of brain dead induced inflammation by vagus nerve stimulation.Am J Transplant. 2010; 10: 477-489Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar as well as regulation of heart rate and blood pressure via parasympathetic (vagal nerve) stimulation.5Hilderman M. Bruchfeld A. 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Vollset S.E. et al.Global, regional, and national burden of Alzheimer's disease and other dementias, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016.Lancet Neurol. 2019; 18: 88-106Abstract Full Text Full Text PDF PubMed Scopus (1347) Google Scholar, 21Buckley A of dementia systematic of the PubMed Scopus Google Scholar, H. S. et effects of inhibitors on cognitive decline and 2021; Scopus Google Scholar ChEIs the to and of action of in the of and M. et of inhibitors in Alzheimer's 2021; PubMed Scopus Google Scholar is that the effects of ChEIs the cholinergic in the K.J. The inflammatory reflex.Nature. 2002; 420: 853-859Crossref PubMed Scopus (2727) Google Scholar and studies have associated the use of ChEIs in patients with AD with a lower risk of and K. S. et inhibitors and risk of and death in with 2018; PubMed Scopus Google Scholar, D. A. et al.The use of inhibitors and the risk of and a in with Alzheimer's J. 2013; PubMed Scopus Google Scholar, C. E. to inhibitors in Alzheimer's Neurol. 2014; PubMed Scopus Google Scholar the of CAP activation in kidney we an comparing CKD progression among with AD were initiated on ChEIs or not. patients with an of dementia in the for cognitive a in with the to and patients with dementia in The include the type of dementia and D. et the for the of and of dementia patients in clinical Scopus Google Scholar was with the a of in to health in from the and information during A. et al.The and J. 2016; PubMed Scopus Google Scholar The were with other and national for complete information on health kidney or and for with to a with to the risk of CKD progression among patients ChEI or not within after an of that we patients an of AD or AD dementia by the of in and in the and patients with a of serum or creatinine in with an health the of the dementia or within patients undergoing kidney dialysis or with a of kidney or with ChEI the of the dementia as well as with the of dementia in the for ChEI is to AD and we to that the The of the was after the dementia a which ChEI was initiated or not. 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S. M. et function, kidney function and the risk of dementia in a 2021; Scopus Google Scholar the that cognitive E. Szoeke C.E.I. Vollset S.E. et al.Global, regional, and national burden of Alzheimer's disease and other dementias, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016.Lancet Neurol. 2019; 18: 88-106Abstract Full Text Full Text PDF PubMed Scopus (1347) Google Scholar, 21Buckley A of dementia systematic of the PubMed Scopus Google Scholar, H. S. et effects of inhibitors on cognitive decline and 2021; Scopus Google Scholar the of kidney function through activation of the CAP that compared with initiation of ChEI within 90 from AD was associated with a 18% lower risk of CKD progression. Results were consistent across and across ChEI The to a of accounting for the competing risk of death. are not of other studies the effect of ChEIs on kidney function, and the of analysis The CAP is a through which the autonomic the K.J. The inflammatory reflex.Nature. 2002; 420: 853-859Crossref PubMed Scopus (2727) Google Scholar dysfunction with an and parasympathetic nerve activity is in a of chronic D. Campisi J. Verdin E. et al.Chronic inflammation in the etiology of disease across the life span.Nat Med. 2019; 25: 1822-1832Crossref PubMed Scopus (1807) Google Scholar circuit the is to macrophage release in the via in the of nerve M. M. et nerve is for cholinergic pathway control of in A. PubMed Scopus Google M. M. et in a vagus nerve PubMed Scopus Google Scholar A of studies have that the of vagus nerve stimulation and stimulation can kidney damage and the kidney from by the CAP through the M. Deng J. Lai H. et al.Vagus nerve stimulation ameliorates renal ischemia-reperfusion injury through inhibiting NF-κB activation and iNOS protein expression.Oxid Med Cell Longev. 2020; 20207106525Google Scholar, 12Inoue T. Abe C. Kohro T. et al.Non-canonical cholinergic anti-inflammatory pathway-mediated activation of peritoneal macrophages induces Hes1 and blocks ischemia/reperfusion injury in the kidney.Kidney Int. 2019; 95: 563-576Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 13Uni R. Inoue T. Nakamura Y. et al.Vagus nerve stimulation even after injury ameliorates cisplatin-induced nephropathy via reducing macrophage infiltration.Sci Rep. 2020; 10: 9472Crossref PubMed Scopus (12) Google T. Abe C. Sung S.S. et al.Vagus nerve stimulation mediates protection from kidney ischemia-reperfusion injury through α7nAChR+ splenocytes.J Clin Invest. 2016; 126: 1939-1952Crossref PubMed Scopus (203) Google Scholar a activation of the CAP chronic allograft nephropathy effects for the S. Fontana J. Jarczyk J. et al.Vagal stimulation in brain dead donor rats decreases chronic allograft nephropathy in recipients.Nephrol Dial Transplant. 2014; 29: 544-549Crossref PubMed Scopus (23) Google Scholar that use of may autonomic and and inflammatory via CAP S.J. Shi Z.W. Wang X. et al.Activation of the cholinergic anti-inflammatory pathway attenuated angiotension II-dependent hypertension and renal injury.Front Pharmacol. 2021; 12593682Google Scholar rats with kidney failure, with the ChEI rats from kidney dysfunction in a via activation of Wang J. Wang et renal through the cholinergic anti-inflammatory and pathway in 2020; PubMed Scopus Google Scholar other effects of CAP activation may such as stimulation of the vagal nerve to heart rate and blood Y. effect of inhibitors used in Alzheimer's to PubMed Scopus Google Scholar of through and is by and in 2005; PubMed Scopus Google Scholar or kidney K. M. T. T. in the kidney of the role of PubMed Scopus Google M. and afferent nerve a role in renal Sci. PubMed Scopus Google Scholar is the effects of CAP activation in a of patients with the for by for the inflammatory and the ratio of heart rate De K. et al.The cholinergic anti-inflammatory and effects in with the in a 2021; 12: PubMed Scopus Google Scholar the in autonomic a pilot of patients with disease, of patients clinical after activation of CAP for V. D. et al.Chronic vagus nerve stimulation in disease: a pilot Motil. 2016; PubMed Scopus Google Scholar of patients with rheumatoid that CAP activation and the of S.S. S. et al.Vagus nerve stimulation and disease in rheumatoid A. 2016; PubMed Scopus Google Scholar in a pilot of persons on activation of CAP by stimulation of the vagus nerve to in inflammatory M. Bruchfeld A. The cholinergic anti-inflammatory pathway in chronic kidney disease-review and vagus nerve stimulation clinical pilot study.Nephrol Dial Transplant. 2020; 35: 1840-1852Crossref PubMed Scopus (18) Google Scholar a the and parasympathetic balance the autonomic function of such as as in the of the The and parasympathetic is to a role in the and A. H. of the with and in health and Neurol. 2021; 12: PubMed Scopus Google Scholar that parasympathetic are a of of the are and of in the are that the effects of ChEIs the stimulation of the cholinergic in cognitive analysis in introducing the Med. PubMed Scopus Google in 2005; Google Scholar a been to be associated with CKD C. D. et and chronic kidney disease a study.Nephrol Dial Transplant. 2018; PubMed Scopus Google Scholar in patients may be a to the effect of ChEIs on balance of and parasympathetic C. 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