Calciprotein particle counts associate with vascular remodelling in chronic kidney disease
Authors: Feenstra Lian , Reijrink Melanie , Pasch Andreas , Smith Edward R , Visser Lotte M , Bulthuis Marian , Lodewijk Monique E , Mastik Mirjam F , Greuter Marcel J W , Slart Riemer H J A , Mulder Douwe J , Pol Robert A , te Velde-Keyzer Charlotte A , Krenning Guido , Hillebrands Jan-Luuk ,   TransplantLines Investigators, Adelita Ranchor V , Neto Antonio W Gomes , Diepstra Arjan , Bouke Hepkema G , Tji Gan C , Doorenbos Caecilia S E , te Velde-Keyzer Charlotte A , van Leer-Buter Coretta , Daan Touw J , Hak Eelko , Erik Verschuuren A M , Frank Bodewes A J A , Klont Frank , Dijkstra Gerard , Gertrude Nieuwenhuis-Moeke J , Blokzijl Hans , Henri Leuvenink G D , Niesters Hubert G M , Cas Swarte J , Sanders Jan-Stephan F , Damman Kevin , van Pelt L Joost , van Londen Marco , de Boer Marieke T , Siebelink Marion J , van den Heuvel Marius C , Vos Michel J , Erasmus Michiel E , Douwes Rianne M , Slart Riemer J H J A , Weersma Rinse K , Pol Robert A , Porte Robert J , de Meijer Vincent E , Lexmond Willem S 
Published: August 2024

Abstract

Aims
Calciprotein particles (CPPs) are circulating calcium and phosphate nanoparticles associated with the development of vascular calcification (VC) in chronic kidney disease (CKD). Although recent studies have been focusing on associations of CPPs with the presence of VC in CKD, insights in the underlying processes and mechanisms by which CPPs might aggravate VC and vascular dysfunction in vivo are currently lacking. Here, we assessed the overall burden of abdominal VC in healthy kidney donors and CKD patients and subsequently performed transcriptome profiling in the vascular tissue obtained from these subjects, linking outcome to CPP counts and calcification propensity.

Methods and results
Calcification scores were quantified in renal arteries, iliac arteries, and abdominal aorta using computed tomography (CT) scans of kidney donors and CKD patients. The vascular tissue was collected from kidney donors (renal artery) and CKD patients (iliac artery), after which bulk RNA sequencing and gene set enrichment analysis (GSEA) were performed on a subset of patients. Calcification propensity (crystallization time, T50) was measured using nephelometry and CPP counts with microparticle flow cytometric analysis. Increased calcification scores (based on CT) were found in CKD patients compared to kidney donors. Transcriptome profiling revealed enrichment for processes related to endothelial activation, inflammation, extracellular matrix (ECM) remodelling, and ossification in CKD vascular biopsies compared to kidney donors. Calcification propensity was increased in CKD, as well as CPP counts, with the latter being significantly associated with markers of vascular remodelling.

Conclusion
Our findings reveal that CKD is characterized by systemic VC with increased calcification propensity and CPP counts. Transcriptome profiling showed altered vascular gene expression with enrichment for endothelial activation, inflammation, ECM remodelling, and ossification. Moreover, we demonstrate, for the first time, that vascular remodelling processes are associated with increased circulating CPP counts. Interventions targeting CPPs are promising avenues for alleviating vascular remodelling and VC in CKD.