Calciprotein particle counts associate with vascular remodelling in chronic kidney disease

Lian Feenstra; Melanie Reijrink; Andreas Pasch; Edward R Smith; Lotte M Visser; Marian Bulthuis; Monique E Lodewijk; Mirjam F Mastik; Marcel J W Greuter; Riemer H J A Slart; Douwe J Mulder; Robert A Pol; Charlotte A Te Velde-Keyzer; TransplantLines Investigators; Guido Krenning; Jan-Luuk Hillebrands

doi:10.1093/cvr/cvae164

Calciprotein particle counts associate with vascular remodelling in chronic kidney disease

Cardiovasc Res. 2024 Aug 5:cvae164. doi: 10.1093/cvr/cvae164. Online ahead of print.

Authors

Lian Feenstra¹, Melanie Reijrink^{1

2}, Andreas Pasch^{3

4}, Edward R Smith^{5

6}, Lotte M Visser¹, Marian Bulthuis¹, Monique E Lodewijk¹, Mirjam F Mastik¹, Marcel J W Greuter⁷, Riemer H J A Slart^{8

9}, Douwe J Mulder², Robert A Pol¹⁰, Charlotte A Te Velde-Keyzer¹¹; TransplantLines Investigators; Guido Krenning¹², Jan-Luuk Hillebrands¹

Collaborators

TransplantLines Investigators:
Adelita V Ranchor, Antonio W Gomes Neto, Arjan Diepstra, Bouke G Hepkema, C Tji Gan, Caecilia S E Doorenbos, Charlotte A Te Velde-Keyzer, Coretta van Leer-Buter, Daan J Touw, Eelko Hak, Erik A M Verschuuren, Frank A J A Bodewes, Frank Klont, Gerard Dijkstra, Gertrude J Nieuwenhuis-Moeke, Hans Blokzijl, Henri G D Leuvenink, Hubert G M Niesters, J Cas Swarte, Jan-Stephan F Sanders, Kevin Damman, L Joost van Pelt, Marco van Londen, Marieke T de Boer, Marion J Siebelink, Marius C van den Heuvel, Michel J Vos, Michiel E Erasmus, Rianne M Douwes, Riemer J H J A Slart, Rinse K Weersma, Robert A Pol, Robert J Porte, Vincent E de Meijer, Willem S Lexmond

Affiliations

¹ Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
² Department of Internal Medicine, Division of Vascular Medicine, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
³ Calciscon AG, Biel, Switzerland.
⁴ Institute of Physiology and Pathophysiology, Johannes Kepler University Linz, Linz, Austria.
⁵ Department of Nephrology, Royal Melbourne Hospital, Parkville, Victoria, Australia.
⁶ Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.
⁷ Department of Radiology, Medical Imaging Center, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁸ Department of Nuclear Medicine and Molecular Imaging, Medical Imaging Center, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁹ Department of Biomedical Photonic Imaging, Faculty of Science and Technology, University of Twente, Enschede, the Netherlands.
¹⁰ Department of Vascular and Transplant Surgery, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
¹¹ Department of Internal Medicine, Division of Nephrology, University of Groningen, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
¹² Department of Clinical Pharmacy and Pharmacology, Division Experimental Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

PMID: 39102822
DOI: 10.1093/cvr/cvae164

Abstract

Aims: Calciprotein particles (CPPs) are circulating calcium and phosphate nanoparticles associated with development of vascular calcification (VC) in chronic kidney disease (CKD). Although recent studies have been focusing on associations of CPPs with 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 overall burden of abdominal VC in healthy kidney donors and CKD patients, and subsequently performed transcriptome profiling in 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. 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) was 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, of which the latter significantly associated with markers of vascular remodelling.

Conclusions: 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.

Keywords: Chronic kidney disease (CKD); calcification propensity (crystallization time T50); calciprotein particles (CPPs); endothelial activation; vascular calcification; vascular remodelling.