The Molecular Pathology and Etiology of Nephrogenic Systemic Fibrosis

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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.