Osteoprotegerin and kidney disease

Abstract

Vascular calcification in chronic kidney disease (CKD) patients is associated to increased mortality. Osteoprotegerin (OPG) is a soluble tumor necrosis factor (TNF) superfamily receptor that inhibits the actions of the cytokines receptor activator of nuclear factor kappa-B ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL) by preventing their binding to signaling receptors in the cell membrane. OPG-deficient mice display vascular calcification while OPG prevented calcification of cultured vascular smooth muscle cells and protected kidney cells from TRAIL-induced death. OPG may be a biomarker in patients with kidney disease. Circulating OPG is increased in predialysis, dialysis and transplant CKD patients and may predict vascular calcification progression and patient survival. By contrast, circulating OPG is decreased in nephrotic syndrome. In addition, free and exosome-bound urinary OPG is increased in human kidney disease. Increased urinary OPG has been associated with lupus nephritis activity. Despite the association of high OPG levels with disease, experimental functional information available suggests that OPG might be protective in kidney disease and in vascular injury in the context of uremia. Thus, tissue injury results in increased OPG, while OPG may protect from tissue injury. Recombinant OPG was safe in phase I randomized controlled trials. Further research is needed to fully define the therapeutic and biomarker potential of OPG in patients with kidney disease.

Utility of temporal profiles of new cardio-renal and pulmonary candidate biomarkers in chronic heart failure

“…OPG levels predicted progression of vascular calcification and survival in pre-dialysis, dialysis, and renal-transplant patients [11]. In CKD patients, OPG levels were found to be markedly increased in those who had diabetes, which was also observed in our CHF patients [28].…”

“…Cardio-renal candidate biomarkers included osteopontin (OPN), which is associated with accumulation of monocytes/macrophages in injured renal tissues including both glomeruli and tubules [8], and which is mainly overexpressed in cardiac non-myocytes during pathological cardiac remodeling [9]; osteoprotegerin (OPG), which is involved in bone metabolism, endocrine function, and immunity [10], and is secreted mainly by osteoblasts and by vascular smooth muscle and endothelial cells, but also in the renal tissue [11]; matrix extracellular phosphoglycoprotein (MEPE), which is another molecule that regulates bone metabolism, and in particular phosphates handling in the renal tubules [12]; trefoil factor-3 (TFF3), which is a member of the trefoil factor peptide family secreted by the renal tubulocites in response to injury [13]; heparin-binding protein (HBP), which is released from neutrophils upon activation, after which it induces vascular leakage, edema formation, and inflammatory reactions which play a role in sepsis-induced acute kidney injury (AKI) [14][15][16]; epidermal growth factor receptor (EGFR), which is a tyrosine kinase receptor found to be involved in acute and chronic renal injury [17]; and kallikrein 6 (KLK-6) which is a recently identified member of the kallikrein gene family and is involved in degradation of extracellular matrix during tumor invasion and metastasis, but also in demyelization and spinal cord injury [18,19].…”

Osteoprotegerin in Chronic Kidney Disease: Associations with Vascular Damage and Cardiovascular Events

“…OPG, originally discovered as an inhibitor of [32] or TRAIL [33]. OPG levels are increased in CKD (for a detailed review see Montañez-Barragán et al [34] and eGFR is one of the most important determinants of OPG values [35]. Although we found an association between OPG levels and markers of CKD-MBD (like calcium, phosphate, and FGF23) in the univariable correlation analysis, when adjusting for other cofactors (including eGFR), this association was lost.…”

Molecular Mechanisms of Vascular Calcification in Chronic Kidney Disease: The Link between Bone and the Vasculature

“…Emerging clinical studies have demonstrated a positive correlation of serum RANKL and its decoy receptor, osteoprotegerin (OPG), with vascular calcification in CKD [61–63]. In elderly hemodialysis CKD patients, serum OPG is increased along with increased PTH and phosphorus and decreased fetuin-A [61].…”

“…A recent study demonstrated increased circulating OPG in predialysis, dialysis, and transplant CKD patients and suggested a role of OPG in predicting the progression of vascular calcification in CKD [62]. In patients with CKD stage 5, higher OPG levels are positively correlated with RANKL and PTH and negatively correlated with the bone resorption marker, TRAP5b [63]. The function of RANKL and OPG in regulating vascular calcification in CKD is unknown.…”