Chronic kidney disease : a clinical model of premature vascular aging

Patients with chronic kidney disease (CKD) are prone to develop an accelerated vascular aging phenotype characterized by vascular calcification (VC), a major culprit of cardiovascular complications and premature death. While VC has been recognized as an active pathophysiologic process with involvement of specific mediators and effectors, the coexistence of traditional risk factors (i.e., high age, diabetes, hypertension, dyslipidemia), inflammaging stimuli and pharmacological interventions (e.g., phosphate binders, warfarin and statin therapy) adds to the complexity of the course and consequences of different types of VC (e.g., intima and media VC, micro- and macrocalcification) in the context of CKD. This work attempts to further explore the prognostic value, predictive markers as well as collateral therapeutic consequence of VC in uremic milieu.

Study I explores the associations of the composites of coronary artery calcium (CAC) score, i.e., CAC density and CAC volume, with mortality risk in patients with CKD stage 5 (CKD G5). We found that while mortality risk increases with higher CAC score and CAC volume, CAC density shows an inverse-J shaped pattern, with the crude mortality rate being highest in the middle tertile of CAC density. Study II evaluates the overlapping presence of aortic valve calcium (AVC) and CAC and the prognostic value of AVC in CKD5 patients. We found a more common overlap of AVC and CAC in CKD G5 than that observed in general population. High AVC score is associated with increased all-cause mortality independent of presence of CAC, traditional risk factors and inflammation. Study III investigates phenotypic factors associated with the presence of biopsy-verified media VC in CKD G5 patients using the relaxed linear separability feature selection model. We identified through a mapping and ranking process, 17 features including novel biomarkers and traditional risk factors that can differentiate patients with media VC from those without. These results, if confirmed, may inform future investigations on media VC without the need of arterial biopsies. Study IV assesses the association of commonly prescribed phosphate binder sevelamer with gut microbial metabolites in CKD G5 patients. We found that sevelamer therapy associates with increased gut-derived uremic toxins and poor vitamin K status, suggesting potential tradeoffs of sevelamer therapy in CKD. Study V explores the plausible association between plasma dephosphorylated-uncarboxylated matrix Gla-protein (dp-ucMGP, a circulating marker of functional vitamin K deficiency), VC and mortality in CKD G5 patients. We found an independent association between high dpucMGP levels and increased mortality risk that is not modified by presence of CAC and AVC in CKD G5.

List of scientific papers

I. Mukai H, Dai L, Chen Z, Lindholm B, Ripsweden J, Brismar TB, Heimbürger O, Barany P, Qureshi AR, Söderberg M, Bäck M, Stenvinkel P. Inverse J-shaped relation between coronary arterial calcium density and mortality in advanced chronic kidney disease. Nephrol Dial Transplant. 2020;35(7):1202-1211.
https://doi.org/10.1093/ndt/gfy352

II. Dai L, Plunde O, Qureshi AR, Lindholm B, Brismar TB, Schurgers LJ, Söderberg M, Ripsweden J, Bäck M, Stenvinkel P. Aortic Valve Calcium Associates with All-Cause Mortality Independent of Coronary Artery Calcium and Inflammation in Patients with End-Stage Renal Disease. J Clin Med. 2020;9(2):607.
https://doi.org/10.3390/jcm9020607

III. Dai L, Debowska M, Lukaszuk T, Bobrowski L, Barany P, Söderberg M, Thiagarajan D, Frostegård J, Wennberg L, Lindholm B, Qureshi AR; Waniewski J, Stenvinkel P. Phenotypic features of vascular calcification in chronic kidney disease. J Intern Med. 2020;287(4):422-434.
https://doi.org/10.1111/joim.13012

IV. Dai L, Meijers BK, Bammens B, De loor H, Schurgers LJ, Qureshi AR, Stenvinkel P, Evenepoel P. Sevelamer Use in End-Stage Kidney Disease (ESKD) Patients Associates with Poor Vitamin K Status and High Levels of Gut-Derived Uremic Toxins: A Drug–Bug Interaction? Toxins (Basel). 2020;12(6):351.
https://doi.org/10.3390/toxins12060351

V. Dai L, Li L, Erlandsson H, Jaminon A, Qureshi AR, Ripsweden J, Brismar TB, Witasp A, Heimbürger O, Jørgensen H, Barany P, Lindholm B, Evenepoel P, Schurgers L, Stenvinkel P. Functional vitamin K insufficiency, vascular calcification and mortality in advanced chronic kidney disease: a cohort study. PLoS One. 2021;16(2): e0247623.
https://doi.org/10.1371/journal.pone.0247623