Nephrogenic systemic fibrosis (NSF) is a devastating condition associated with gadolinium (Gd3+) based contrast-agents (GBCAs) in patients with severe end stage or chronic kidney disease (ESRD or CKD). A severe multiple organ condition, that includes lungs, heart, diaphragm, bone, skin and skeletal muscles, is characteristic of the disease. GBCAs are important contrast agents for magnetic resonance imaging (MRI) - a powerful medical tool that provides 3D internal imaging of different soft tissues such as brain, muscle, heart, tumors, blood vessels and areas of inflammation. Release of free Gd3+ from the contrast-agent is thought to play a major role in the pathophysiology of NSF since free Gd3+ is toxic. The primary cause and etiology of Gd3+ release from GBCAs in NSF remains unknown. We have strong evidence that a small (2.2 kDa), acidic, highly-reactive, phosphorylated and protease resistant bone-matrix peptide (ASARM-peptide) plays a major role. ASARM-peptides are potent inhibitors of mineralization that bind strongly to Ca2+ and hydroxyapaptite. Of note, the ionic radius of Gd3+ (107.8 pm) is close to that of Ca2+ (114 pm) and this element interferes with Ca2+ activated or mediated biochemical and physiological processes. Increased ASARM-peptides are responsible for bone-mineralization abnormalities and contribute to renal phosphate-handling defects in familial hypophosphatemic rickets and tumor induced osteomalacia. The ASARM-peptide is proteolytically released into bone and circulation from a family of bone- matrix proteins (SIBLINGs) that characteristically have ASARM-motifs. These proteins all map to a single cluster on chromosome 4 in mice and 5 in humans. They include DMP1, MEPE, osteopontin, dentin sialo phosphoprotein (DSPP), bone-sialoprotein, statherin and enamelin. We hypothesize that a subset of renal-compromised patients with renal osteodystrophy, abnormal ASARM-peptide levels and reduced renal clearance of GBCAs are at high risk for NSF because of: (A) Increased binding of ASARM-peptide to GBCA and (B) ASARM-induced destabilization of the Gd3+-GBCA complex resulting in localized release of toxic Gd3+.
Our aims are to: (1). Determine whether ASARM-peptide in vitro and in vivo specifically binds to GBCAs particularly those associated with NSF; (2) Determine whether ASARM-peptide in vivo and in vitro induces release of free Gd3+ from the GBCA complex; (3) Determine whether a bio-engineered 4.2 kDa peptide (SPR4) stabilizes the Gd3+-GBCA complex by competitively binding to ASARM-peptide; (4) Use a rat model of NSF to show whether SPR4-peptide is an adjuvant for preventing the disease or reducing risk in patients requiring GBCA enhanced MRI scans: (5) Determine whether ASARM peptides and Gd3+ complexes are increased in human NSF samples and associated with disease.
Nephrogenic systemic fibrosis (NSF) is a devastating condition associated with gadolinium (Gd) containing contrast-agents (GBCA) that are used for Magnetic Resonance Imaging (MRI). A sub group of patients with severe or chronic kidney disease are at risk of developing NSF following GBCA enhanced MRI scans. The aims of this study will be to determine the cause, unravel the risk groups and provide a peptide adjuvant to help prevent or reduce the risk of disease.
