The Aging Kidney Harms the Brain
A good deal of evidence points to declining kidney function as a cause of declining cognitive function in aging. There are strong correlations between loss of kidney function and risk of dementia, for example. Correlation isn't a smoking gun in matters of aging, however: it is possible for any one of the underlying forms of molecular damage that cause aging, or for intermediate consequences of that damage, to give rise to otherwise unrelated pathologies in different parts of the body. Those pathologies appear more often in people with greater amounts of that form of damage, and thus appear correlated.
Nonetheless, there are good reasons to think that kidney failure and its downstream consequences contribute meaningful to neurodegeneration, perhaps largely by degrading the function of the vascular system. Vascular aging can cause damage and dysfunction in brain tissue via numerous mechanisms, including the pressure damage of hypertension, similar damage resulting from an acceleration of atherosclerosis, failing to delivery sufficient nutrients and oxygen to the energy-hungry brain, and disruption of the blood-brain barrier, allowing inflammatory cells and molecules into the brain.
The kidney and the brain, as high-flow end organs relying on autoregulatory mechanisms, have unique anatomic and physiological hemodynamic properties. Similarly, the two organs share a common pattern of microvascular dysfunction as a result of aging and exposure to vascular risk factors (e.g., hypertension, diabetes, and smoking) and therefore progress in parallel into a systemic condition known as small vessel disease (SVD). Many epidemiological studies have shown that even mild renal dysfunction is robustly associated with acute and chronic forms of cerebrovascular disease.
Beyond ischemic SVD, kidney impairment increases the risk of acute cerebrovascular events related to different underlying pathologies, notably large artery stroke and intracerebral hemorrhage. Other chronic cerebral manifestations of SVD are variably associated with kidney disease. Observational data have suggested the hypothesis that kidney function influences cerebrovascular disease independently and adjunctively to the effect of known vascular risk factors, which affect both renal and cerebral microvasculature. In addition to confirming this independent association, recent large-scale human genetic studies have contributed to disentangling potentially causal associations from shared genetic predisposition and resolving the uncertainty around the direction of causality between kidney and cerebrovascular disease.
Accelerated atherosclerosis, impaired cerebral autoregulation, remodeling of the cerebral vasculature, chronic inflammation, and endothelial dysfunction can be proposed to explain the additive mechanisms through which renal dysfunction leads to cerebral SVD and other cerebrovascular events. Genetic epidemiology also can help identify new pathological pathways which wire kidney dysfunction and cerebral vascular pathology together. The need for identifying additional pathological mechanisms underlying kidney and cerebrovascular disease is attested to by the limited effect of current therapeutic options in preventing cerebrovascular disease in patients with kidney impairment.