The reversible part of cognitive impairment in chronic kidney disease: can mice help men break the TEMPOLimit?

Abstract

Discussing the non-adherence to diet or medication with chronic haemodialysis patients can be an utterly frustrating experience, especially if one does this thrice a week. It is also a reflection of the fact that for more than half a century, nephrologists have been focusing on cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. Over the last decade, however, burgeoning evidence has accumulated to show that CKD also affects the patient’s brain. CKD is accompanied by severe cognitive impairment as recently reviewed by Elias et al. [1]. Kurella et al. [2] could show that decreased estimated glomerular filtration rate (GFR) in postmenopausal women is significantly associated with impairment in global cognition, executive function, language and memory. A community-based cross-sectional study found that global performance and specific cognitive functions are negatively affected early in CKD [3]. Interestingly, not only decreases in GFR but also elevated urinary albumin/creatinine ratios are independently associated with faster decline in cognitive function [4]. In a 5-year longitudinal community-based study, change in renal functioning over time was related to change observed in global cognitive ability, verbal episodic memory and abstract reasoning [5]. Moreover, moderate renal impairment has been shown to be associated with an excess risk of incident dementia among individuals in good to excellent health [6]. Naturally, cognitive impairment cannot be revealed during the discussions about phosphate binders and anti-hypertensives. The backbone for detection of cognitive impairment are psychometric tests, first introduced in 1944 by the US Army in the Army Individual Test Battery—Manual of Directions and Scoring. Part of this test battery was the trail making test (TMT), a neuropsychological test of visual attention and task switching. It consists of two parts in which the subject is instructed to connect a set of 25 dots as fast as possible while still maintaining accuracy (TMT A) [7]. It can provide information about visual search speed, scanning, speed of processing, mental flexibility as well as executive functioning that are evaluated in the TMT B [7]. It is more sensitive to detecting decline in cognitive function in different stages of CKD than the Modified Mini-Mental State Examination (3MS) [8]. The severity of cognitive impairment is best epitomized by the fact that a high school educated 50-yearold person is able to finish the TMT B in ∼1 min, whereas ∼20% of dialysis patients in the same age group are not able to finish the TMT B in 5 min [9]. The pathophysiological mechanisms leading to cognitive impairment in CKD are still not clearly understood. They may range from effects of urea to the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA [10, 11]). Of note, there is an irreversible and a reversible component of cognitive impairment in CKD (Figure 1). The underlying diseases causing CKD, mostly arterial hypertension and diabetes, go along with structural cerebral changes. This is best epitomized by the facts that CKD5D patients have a 6-fold age-adjusted relative risk of stroke when compared with the general population [12]. Also, the prevalence of asymptomatic silent cerebral infarction is four to five times higher in dialysis patients than in ageand sex-matched controls [13]. A recent systematic review of structural neuroimaging findings in CKD came to the conclusion that cerebral atrophy and cerebral density changes in patients with CKD are frequently seen along with cerebral vascular disease, including deep white matter