Quantitative Assessment of the Effect of Chronic Kidney Disease on Plasma P-Tau217 Concentrations.

Abstract

Chronic kidney disease (CKD) is known to be associated with increased plasma phosphorylated tau217 (p-tau217) concentrations, potentially confounding the utility of plasma p-tau217 measurements as a marker of amyloid pathology in individuals with suspected Alzheimer disease (AD). In this study, we quantitatively investigate the relationship of plasma p-tau217 concentrations vs estimated glomerular filtration rate (eGFR) in individuals with CKD with and without amyloid pathology. This was a retrospective examination of data from 2 observational cohorts from either the Mayo Clinic Study of Aging or the Alzheimer's Disease Research Center cohorts. p-Tau217 was determined using the ALZpath Simoa p-tau217 immunoassay and an immunoprecipitation mass spectrometry assay that simultaneously measures p-tau217 and nonphosphorylated-tau217 (np-tau217) to determine %p-tau217 ([p-tau217/nonphosphorylated-tau217]) × 100%) (C₂N Diagnostics). Amyloid positivity was defined by amyloid-PET and a centiloid of ≥25. Log-log linear regression fits were used to quantitatively predict increases in plasma p-tau217 associated with decreasing eGFR. Participants (n = 202, mean age of 78 years, 38% female) with diagnoses of cognitive unimpairment (n = 109), mild cognitive impairment (n = 71), and dementia (n = 22) were included. In all, 114 (56%) of all participants were amyloid-PET positive (A+). In addition, 86 (43%) of all participants were classified as having CKD (CKD stages 3-4). p-Tau217 concentrations were significantly higher in A- participants with an eGFR of <60 (mL/min/1.73 m²), as compared with those with eGFR >60 A- participants. For an eGFR of 45 vs 60 in the A- cohort, the calculated percentage changes were +31%, +55%, and +19%, for ALZpath p-tau217, C₂N p-tau217, and C₂N %p-tau217, respectively. For the A+ cohort, the corresponding calculated percentage changes were +17%, +15%, and -5%, respectively. CKD was associated with increased p-tau217 concentrations when measuring p-tau217 by ALZpath and C₂N methodologies, but the effect was mitigated by the use of %p-tau217. These results indicate limitations for the utility of plasma p-tau217 measurements in individuals with significant renal impairment (eGFR <45 or CKD stage 3b or greater). Determination of eGFR should be considered to avoid inaccurate classification of the presence of AD-related pathology by plasma p-tau217 in individuals with CKD. This study provides Class II evidence that in individuals with CKD stage 3 (especially stage 3b) or higher, p-tau217 concentrations are increased, with a greater increase in amyloid-PET-negative individuals.