Table 1.

Experimental evidence associating carbamylated proteins and CKD complications.

CKD Complications	Carb. Compounds	Models		Key Findings	Refs.
Vascular damages	LDL *	Φ	Human leukemic T cells, human fibroblasts	Impairs cLDL binding to the hepatic LDL receptor	[11,39]
		Σ	IV injection in healthy subjects IV injection in rabbits	Delays LDL clearance
		Φ	Human EPCs, HAECs	Increases EPC senescence Increases HCAEC death via MAPK Uncouples eNOS and reduces NO production Increases ROS production Inhibits angiogenesis	[34,40,41]
		Σ	IV injection in mice	Impairs aortic endothelium-dependent relaxation
		Φ	HCAECs, human monocyte cell line	Increases expression of ICAM-1 and VCAM-1 on HCAECs Increases monocyte adhesion to endothelial cells via LOX-1	[42,43]
		Φ	HCAECs	Triggers LDL transcytosis via CD-36, SR-A1, SREC-1	[43]
		Σ	IV injection in mice	Induces subendothelial LDL accumulation
		Φ	Peritoneal macrophages	Promotes lipid loading and foam cell formation through SR-A1	[11]
		Φ	Human CASMCs, human VSMCs	Increases expression of ICAM-1 and VCAM-1 on CASMCs Increases CASMC proliferation Increases VSMC proliferation via SR-A1	[11,42,44]
	HDL *	Φ	Bovine aortic endothelial cells	Induces cell apoptosis	[11]
		Φ	HAECs	Inhibits cell migration and proliferation Inhibits angiogenesis	[45]
		Φ	Human monocyte cell line	Impairs cholesterol efflux Promotes cholesterol accumulation and lipid droplet formation via SR-BI	[46,47]
	Type I collagen	Φ	Human monocytes	Increases monocyte adhesion Increases MMP-9 production and activation	[48]
		Φ	Biochemical assay	Induces local conformational changes in the triple helixImpairs fibrillogenesis	[49]
	Elastin	Σ	ApoE-/- mice fed with cyanate-supplemented water	Increases aortic elastic fibre stiffness Increases aortic pulse wave velocity	[29]
	Mitochondrial proteins *	Φ	Human VSMCs	Promotes mitochondrial dysfunctions and oxidative stress Inhibits ENPP1 and reduces PPi production Increases cell calcification	[26]
		Σ	Nephrectomised rats fed with urea-supplemented diet	Increases aorta calcification by suppressing PPi production
	Uromodulin	Φ	Human VSMCs	Impairs interaction with and trapping of TNF-α and IL-1β Loses inhibitory effects on osteo-/chondrogenic transdifferentiation	[50]
	Sortilin *	Φ	Human CASMCs	Promotes cell calcification by increasing ALPL and RUNX2 expression and TNAP activity Increases the binding of IL-6, amplifying cell calcification	[51]
		Ψ	Rat aorta	Increases calcification of aortic rings
Renal Fibrosis	Albumin *	Σ	IP injection in Axolotl	Induces expression of fibronectin and pro-fibrogenic factors (NF-κB, TGF-β1, PDGF-AB, IL-8, ET-1) in tubular cells	[52]
	FBS proteins	Φ	Mesangial cells	Increases cell proliferation Increases synthesis of collagen I and IV	[53]
	Type I Collagen	Φ	Biochemical assay	Increases resistance to MMP-1, MMP-8 and MMP-13	[54]
Haemostasis dysfunctions	Fibrinogen *	Φ	Biochemical assay	Alters fibrinogen structure Interferes with factor XIIIa-mediated fibrin cross-linking and impairs fibrin polymerization Induces clot resistance to fibrinolysis	[55]
	Fibrino-peptide A	Φ	PMNs	Increases neutrophil chemotaxis
EPO resistance	EPO	Φ	Human leukemic cell line	Impairs binding to EPO receptor	[56]
		Σ	SC injections in mice SC injections in rats	Impairs EPO effect on haemoglobin concentrations and haematocrit	[56,57]
Insulin resistance	Insulin	Φ	Rat hepatocytes, rat adipocytes	Decreases binding activity Decreases glucose oxidation	[58]
	Free L-Asn *	Φ	Rat adipocytes	Reduces insulin-sensitive glucose uptake	[59]
Immune response disorders	IgG	Φ	Biochemical assay	Impairs C1q binding to IgG Inhibits formation of C4b and C3b	[60]
		Φ	Lymphoma cell line	Decreases cell lysis
	Type I collagen	Φ	PMNs	Inhibits degranulation and ROS release	[49]

CASMC: coronary artery smooth muscle cells; eNOS: endothelial nitric oxide synthase; EPC: endothelial progenitor cells; EPO: erythropoietin; HAEC: human aortic endothelial cells; HDL: high-density lipoprotein; IP: intraperitoneal; IV: intravenous; LDL: low-density lipoprotein; MMP: matrix metalloproteinase; PMN: polymorphonuclear neutrophils; PPi: pyrophosphate; ROS: reactive oxygen species; SC: subcutaneous; TNAP: tissue nonspecific alkaline phosphatase; VSMC: vascular smooth muscle cells. Φ In vitro studies; Ψ ex vivo studies; Σ in vivo studies; * carbamylated compounds found in patients with CKD [21,26,40,45,51,55,59,61,62].