Chronic Kidney Disease Induces Inflammatory CD40+ Monocyte Differentiation via Homocysteine Elevation and DNA Hypomethylation.

Rationale:Patients with chronic kidney disease (CKD) develop hyperhomocysteinemia and have a higher cardiovascular mortality than those without hyperhomocysteinemia by 10-fold. Objective:We investigated monocyte differentiation in human CKD and cardiovascular disease (CVD). Methods and Results:We identified CD40 as a CKD-related monocyte activation gene using CKD-monocyte -mRNA array analysis and classified CD40 monocyte (CD40+CD14+) as a stronger inflammatory subset than the intermediate monocyte (CD14++CD16+) subset. We recruited 27 patients with CVD/CKD and 14 healthy subjects and found that CD40/CD40 classical/CD40 intermediate monocyte (CD40+CD14+/CD40+CD14++CD16–/CD40+CD14++CD16+), plasma homocysteine, S-adenosylhomocysteine, and S-adenosylmethionine levels were higher in CVD and further elevated in CVD+CKD. CD40 and CD40 intermediate subsets were positively correlated with plasma/cellular homocysteine levels, S-adenosylhomocysteine and S-adenosylmethionine but negatively correlated with estimated g...