Acidosis, cognitive dysfunction and motor impairments in patients with kidney disease

Abstract

Metabolic acidosis, defined as a plasma or serum bicarbonate concentration <22 mmol/L, is a frequent consequence of chronic kidney disease (CKD) and occurs in ~10-30% of patients with advanced stages of CKD. Likewise, in patients with a kidney transplant, prevalence rates of metabolic acidosis range from 20% to 50%. CKD has recently been associated with cognitive dysfunction, including mild cognitive impairment with memory and attention deficits, reduced executive functions and morphological damage detectable with imaging. Also, impaired motor functions and loss of muscle strength are often found in patients with advanced CKD, which in part may be attributed to altered central nervous system (CNS) functions. While the exact mechanisms of how CKD may cause cognitive dysfunction and reduced motor functions are still debated, recent data point towards the possibility that acidosis is one modifiable contributor to cognitive dysfunction. This review summarizes recent evidence for an association between acidosis and cognitive dysfunction in patients with CKD and discusses potential mechanisms by which acidosis may impact CNS functions. The review also identifies important open questions to be answered to improve prevention and therapy of cognitive dysfunction in the setting of metabolic acidosis in patients with CKD.

Keywords: acidosis; chronic kidney disease; cognitive dysfunction; klotho; motor function.

Graphical Abstract

FIGURE 1

Prevalence of MCI and metabolic acidosis (MA) in patients with reduced kidney function. The prevalence of MCI and MA as a function of eGFR is estimated from several studies that reported the prevalence of MCI or MA in patients with reduced kidney function [1, 3, 5, 7, 8]. Cross-sectional studies analysing the prevalence of both clinical entities in the same cohort of patients have not been reported to date.

FIGURE 2

Model summarizing possible links between CKD, metabolic acidosis and cognitive dysfunction and motor deficits. Reduced kidney function causes, among other consequences, accumulation of uraemic toxins and metabolic acidosis, and both may act on the brain to reduce central functions. In addition, immune functions are altered by both factors, leading to higher levels of pro-inflammatory factors that may also affect the brain. Reduced kidney function is also associated with reduced renal expression of α-klotho and reduced circulating levels of soluble α-klotho. Whether brain α-klotho expression is directly affected has not been examined. α-Klotho has neuroprotective functions.