Kidney Function, Kidney Function Decline, and the Risk of Dementia in Older Adults
A Registry-Based Study

We thank Dr. Fischereder for the comments on our study.¹ Our goal was to explore the association between kidney function and the risk of dementia, not to imply causation. While underlying mechanisms remain unclear, they do not preclude our findings from being plausible. Subsequent studies confirm an association between cognitive impairment and markers of kidney dysfunction.^2,3 Experimental evidence suggests that uremia-induced chronic inflammation, oxidative stress, hypercoagulation, vitamin-D deficiency, klotho deficiency, hyperparathyroidism, anemia, and impaired peripheral amyloid-β clearance may lead to dementia.⁴ Besides, chronic kidney disease (CKD) may be a risk mediator for other conditions that cause dementia, such as smoking, hypertension, diabetes, and lipid disorders.⁴ It is important to note that our study reported similar associations in persons with and without diabetes or hypertension.

The hypothesis regarding dementia risk in individuals with high glomerular filtration rate (GFR) is interesting, but impossible to dissect from our report. Individuals with high GFR may be persons with glomerular hyperfiltration, or with an illness that results in low muscle mass. Our findings cannot inform on dementia risks for kidney donors, though the procedure is not thought to have adverse long-term health effects, including on kidney function. Carefully conducted studies with 10-years of follow-up show a consistent rise in GFR during the first few years after kidney donation, followed by a GFR decline that appears slower than the GFR decline in controls.⁵ Regardless of whether kidney dysfunction is the cause or mediator, our research highlights a population likely to benefit from dementia screening.

Disclosure

The authors report no relevant disclosures. Contact [email protected] for full disclosures.  

References

1. Xu H, Garcia-Ptacek S, Trevisan M, et al. Kidney Function, Kidney Function Decline, and the Risk of Dementia in Older Adults: A Registry-Based Study [published online ahead of print, 2021 May 5]. Neurology. 2021;96(24):e2956-e2965. doi:10.1212/WNL.0000000000012113
2. Scheppach JB, Coresh J, Wu A, et al. Albuminuria and Estimated GFR as Risk Factors for Dementia in Midlife and Older Age: Findings From the ARIC Study. Am J Kidney Dis. 2020;76(6):775-783. doi:10.1053/j.ajkd.2020.03.015
3. Richard EL, McEvoy LK, Oren E, et al. Markers of Kidney Function and Longitudinal Cognitive Ability Among Older Community-Dwelling Adults: The Rancho Bernardo Study. J Alzheimers Dis. 2021;83(1):319-331. doi:10.3233/JAD-201605
4. Wang J, Gu BJ, Masters CL, Wang YJ. A systemic view of Alzheimer disease - insights from amyloid-β metabolism beyond the brain [published correction appears in Nat Rev Neurol. 2017 Oct 13;:]. Nat Rev Neurol. 2017;13(10):612-623. doi:10.1038/nrneurol.2017.111
5. Goyal N, Levey AS. GFR after kidney donation: early recovery and subsequent decline. Kidney Int. 2020;98(1):57-59. doi:10.1016/j.kint.2020.04.025

This registry-based analysis reports a strong correlation between renal function, estimated from a creatinine-based formula, and dementia.¹ However, the pathological mechanism underlying this observation remains unclear. As direct effects of creatinine on cognitive function are highly unlikely, further discussion is needed to determine if causes or consequences of declining renal function are responsible for this association. In the case of reduced estimated glomerular filtration rate (eGFR) after living kidney donation from otherwise healthy individuals, such a differentiation is urgently needed. In later stages of chronic kidney disease, accumulation of unspecified uremic toxins may be one potential explanation—however, such a mechanism must be questioned at eGFR between 60 and 89 ml/min present in a large proportion of healthy individuals.

On the other hand, microvascular renal disease from Diabetes mellitus, smoking, or tobacco abuse accounts for approximately 50% of advanced chronic kidney disease. Among other comorbidities, diabetes mellitus, hypertension, and tobacco abuse are also significantly more prevalent with decreasing eGFR in this cohort. As outlined in the analysis of eGFR-decline, progressive renal injury is additionally associated with increasing risk for dementia. Another indicator towards a common cause for dementia and renal impairment is the increasing risk of dementia in individuals with eGFR > 105 ml/min, which may be found in diabetes mellitus. While the authors adjust their analyses for the above comorbidities statistically, it would be interesting to see a subgroup analysis evaluating if dementia is more prevalent in individuals who are free from Diabetes mellitus, hypertension, or tobacco abuse. Due to a potential increased risk for dementia, the ethical justification of living kidney donation should be questioned.

Disclosure

The authors report no relevant disclosures. Contact [email protected] for full disclosures.  

References

1. Xu H, Garcia-Ptacek S, Trevisan M, et al. Kidney Function, Kidney Function Decline, and the Risk of Dementia in Older Adults: A Registry-Based Study [published online ahead of print, 2021 May 5]. Neurology. 2021;96(24):e2956-e2965. doi:10.1212/WNL.0000000000012113