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Chronic Kidney Disease (CKD) is characterized by progressive kidney damage evidenced by a reduction in the glomerular filtration rate. Cognitive dysfunction is common in patients with CKD and the exact physiopathology of cognitive impairment in CKD is not completely understood. Biomarkers related to vascular endothelial injury are elevated in CKD patients on hemodialysis. Serum levels of Klotho protein are significantly lower in patients with CKD than in healthy patients, also reducing cerebral Klotho levels. The Klotho protein, produced by the kidney, coreceptor of FGF23, appears to be necessary for neuroprotection.
To understand the correlation of the Klotho protein with cognitive disorders, 52 patients were selected, 40 with non-dialytic CKD followed at the Nephrology outpatient clinic of the Walter Cantídio University Hospital (HUWC), Federal University of Ceará (UFC). Of these, 29 patients with mild CKD (GFR estimated at 45 to 59mL/min/1.73m² or GFR > 60mL/min/1.73m² and abnormal albuminuria, defined by an UACR > 30mg/g), and 11 patients with moderate to severe CKD (estimated GFR < 45 mL/min/1.73m²). 12 patients from the group control (estimated GFR > or equal to 60 mL/min/ 1.73m² and normal albuminuria defined by RACU < 30mg/g). The patients were evenly distributed with regard to age, gender, BMI, comorbidities, hours of sleep, family history of dementia, and lifestyle habits such as smoking, drinking and illicit drug use. There was no statistically significant difference between any of these variables in the groups. Cognitive function was assessed through the application of the following neuropsychological tests: Rey's Auditory-Verbal Learning Test (RAVLT), Five Digit Test (FDT), Foward and backward digit span, Corsi's Cube Task, Stroop Test, Trial Making Test (TMT) and Phonemic and Semantic verbal fluency tasks. Serum levels of Klotho, FGF23 and endothelial injury biomarkers (VCAM-1, Angiopoietin 1 and 2) were measured using the ELISA technique.
The main result of this study was to show, for the first time, in CKD patients off dialysis, an association between a reduction in serum Klotho and negative outcomes in a series of neuropsychological tests. We were able to verify what has been repeatedly demonstrated in recent research: serum Klotho levels were significantly decreased in patients with moderate/severe CKD, KL= 0.38 ng/mL (0.17 - 3.18), and patients with mild CKD, KL= 0.2 ng/mL (0.17 - 1.46), compared to the control group, KL=1.61 ng/mL (0.28 - 2.03) (p=0.015). In this study, can be demonstrated that serum levels of the endothelial injury biomarker VCAM-1 were significantly higher in patients with moderate/severe CKD when compared to the control group, with statistical evidence, control group: 604 ± 180ng/mL, mild CKD group: 726 ± 275 ng/mL, moderate/severe CKD group: 920 ± 162 ng/mL (p=0,012). Serum levels of another biomarker of endothelial damage, Angiopoietin 2, were significantly inversely proportional to the decrease in GFR. Control group: 1.57 (0.94 - 2.04) ng/mL, Mild CKD group: 1.56 (1.13 - 2.65) ng/mL, Moderate/severe CKD group: 4.21 (2.16 - 4.96) ng/mL (p= 0.003). An important result of this clinical study was to attest the inverse relationship between Klotho levels and VCAM-1, demonstrating that a reduction in Klotho is associated with an increase in this biomarker of endothelial damage, with the progression of CKD (p=0,019) and associated with worse outcome in several domains of cognition on neurocognitive tests. Increased FGF23 levels were associated with reduced glomerular filtration rate (rho=-0,636, p=0,035) and lower scores on a RAVLT memory test (rho= -0.626, p=0,04) in patients with moderate/severe CKD.
We were able to demonstrate an increase in serum Klotho levels and an increase in the endothelial damage markers VCAM-1 and Angiopoietin 2 in CKD patients when compared to the control group. There was an inverse correlation between decreased Klotho levels and an increase in the endothelial damage marker VCAM-1 in moderate/severe CKD patients. Another relevant finding of this study was that reduced serum levels of Klotho are associated with worse results in different neurocognitive tests in patients with CKD without a previous clinical diagnosis of cerebrovascular disease, with worse results being seen in different cognitive domains such as memory, attention and executive functions. Increased serum levels of VCAM-1 are also associated with worse results in neurocognitive tests and this correlation was not found with the other markers of endothelial damage (Angiopoietin 1 and 2). This finding of decreased serum levels of Klotho, an increase in VCAM-1 and cognitive impairment in patients with moderate/severe CKD strengthens the hypothesis of endothelial damage and consequent vascular disease as an
important factor in the pathophysiology of cognitive impairment in patients with CKD. These data correlate serum Klotho protein with cognitive impairment and suggest that serum Klotho levels are a marker of incipient cognitive impairment, even in patients without a clinical diagnosis of cerebrovascular disease.