Disturbed brain-to-blood elimination of β-amyloid (Aβ) promotes cerebral Aβ accumulation in Alzheimer's disease. Considering that the kidneys are involved in Aβ elimination from the blood, we evaluated how chronic kidney disease (CKD) affects plasma Aβ. In 106 CKD patients stages 3-5 (including 19 patients on hemodialysis and 15 kidney recipients), 53 control subjects with comparable vascular risk profile and 10 kidney donors, plasma Aβ was determined using electrochemiluminescence immunoassay and gel electrophoresis followed by Western blotting. Plasma Aβ increased with CKD stage (control = 182.98 ± 76.73 pg/ml; CKD3A = 248.34 ± 103.77 pg/ml; CKD3B = 259.25 ± 97.74 pg/ml; CKD4 = 489.16 ± 154.16 pg/ml; CKD5 = 721.19 ± 291.69 pg/ml) and was not influenced by hemodialysis (CKD5D = 697.97 ± 265.91 pg/ml). Renal transplantation reduced plasma Aβ (332.57 ± 162.82 pg/ml), whereas kidney donation increased it (251.51 ± 34.34 pg/ml). Gel electrophoresis confirmed stage-dependent elevation namely of Aβ1-40, the most abundant Aβ peptide. In a multivariable regression including age, sex, estimated glomerular filtration rate (eGFR), potassium, hemoglobin, urine urea, and urine total protein, the factors eGFR (β = -0.42, p < 0.001), hemoglobin (β = -0.17, p = 0.020), and urine protein (β = 0.26, p = 0.008) were associated with plasma Aβ. In a regression including age, sex, eGFR, potassium, hemoglobin and the vascular risk factors systolic blood pressure, smoking, LDL, HDL, HbA1c, body mass index, brain-derived natriuretic peptide and fibrinogen, the factors eGFR (β = -0.53, p < 0.001), body mass index (β = -0.17, p = 0.022), and fibrinogen (β = 0.18, p = 0.024) were associated with plasma Aβ. Our results demonstrate a stage-dependent plasma Aβ increase that is augmented by loss of glomerulotubular integrity, low body weight, and inflammation, demonstrating a multifaceted role of renal dysfunction in Aβ retention.
Keywords: Alzheimer’s disease; Chronic kidney disease; Neurovascular hypothesis; Peripheral sink hypothesis; Plasma β-amyloid; Vascular risk factor.