Author Response: Kidney Function, Kidney Function Decline, and the Risk of Dementia in Older Adults

Abstract

I read the article by Xu et al. 1 with interest. However, I would like to raise a few questions about the study. The published literature shows a strong difference between patients who received a prescription for a cholinesterase inhibitor (ChEI) and those who did not. 2 The authors also mention that they had trouble matching the 2 groups because their groups differed significantly. Although the authors tried to correct for this, it does not seem that the stage or severity of comorbidities was considered in this study, despite its critical clinical relevance to survival Editors' Note: Long-term Effects of Cholinesterase Inhibitors on Cognitive Decline and Mortality Dr. Xu et al. compared cognitive trajectories and the occurrence of severe dementia or death in 11,652 patients started on cholinesterase inhibitors (ChEIs) vs 5,826 untreated patients with Alzheimer dementia (AD) in the Swedish Dementia Registry. During an average of 5 years of follow-up, they found that ChEIs were associated with modest but persistent cognitive benefits with lower mortality. Galantamine was the only ChEI that was associated with a significantly lower risk of developing severe dementia. In response, Dr. Kuschpel noted that there were important baseline differences between patients who were and were not treated with ChEIs, with associated difficulties matching the 2 groups for analyses. Dr. Kuschpel also highlighted the importance of considering the stage and severity of comorbidities about survival estimates and is skeptical of the sizeable mortality reduction with ChEIs seen in the study, given the lack of precedence, the absence of a plausible molecular mechanism, and potential confounding by prescription bias. Concerns are raised about potential discrepancies in numbers between the abstract and the results section about observed differences in Mini-Mental State Examination (MMSE) scores. Responding to these comments, the authors argue that although there were significant baseline differences between the 2 groups, they were able to achieve a well-matched cohort, although they acknowledge the possibility of residual and unknown confounders, especially in the absence of data on comorbidity severity. They cite the previous work by their group observing reductions in myocardial infarction, stroke, and mortality with ChEI use, as well as a lower 2-year mortality with galantamine seen in a prior randomized-controlled trial. They note that previous trials of ChEIs have had considerably shorter follow-up durations. In summary, this exchange highlights the uncertain causal association between ChEI use and lower mortality in patients with AD, and the challenges of convincingly demonstrating such an association with observational data. Robust validation of this association would have important implications for the care of patients with AD.

CKD Associates with Cognitive Decline in Middle-Aged and Older Adults with Long-Standing Type 1 Diabetes

“… 31 – 33 However most, though not all, studies have shown similar associations with milder kidney disease. 6 , 34 – 38 In this study, we were able to capture changes in CKD status over time both in eGFR and albuminuria, a unique advantage over other cohorts studied, and we demonstrated that adverse cognitive effects may begin with eGFR as high as 60–74 ml/min per 1.73 m 2 . We found a dose-response relationship between worsened categories of eGFR and cognitive function consistent with other studies in the general population.…”

“…[31][32][33] However most, though not all, studies have shown similar associations with milder kidney disease. 6,[34][35][36][37][38] In this study, we were able to capture changes in CKD status over time both in eGFR and albuminuria, a Associations between cognitive function and overall categorical albuminuria or eGFR groups were assessed using an F-test. f Normoalbuminuria: albumin excretion rate ,30 mg/24 hours.…”