One of the main roles of the kidneys is processing and excreting waste through the production of urine. When kidneys fail, the compounds that the kidneys normally excrete, such as phosphate, begin to build up in the body. This condition can eventually lead to hyperphosphatemia (high serum phosphorus) and trigger a cascade of hormonal disorders. Such disorders include secondary hyperparathyroidism and elevation of certain phosphatonins (FGF-23) which can result in untoward effects on bone homeostasis and vascular diseases leading to further decreases in kidney function and increased risk of cardiovascular disease and death.
The prevalence of chronic kidney disease (CKD) in the world is about 7.2% with up to 20 million patients in North America. Each year, over 100,000 patients in the US begin dialysis or undergo kidney transplantation for end-stage renal disease. Long before it reaches end stage, CKD causes significant morbidity and mortality ranking currently as the 12thhighest cause of death and 17th highest cause of disability worldwide.
Elevation of body phosphorus associated to hormonal imbalance in CKD
Among those hormones, FGF23 regulates phosphorus and vitamin D metabolism. Its levels increase progressively beginning in early CKD. FGF23 promotes phosphaturia (elimination of phosphorus in the urine) and decreases production of active vitamin D. Recent studies in CKD patients with normal levels of serum phosphate suggest that increased FGF23 is associated with mortality, left ventricular hypertrophy, endothelial dysfunction, and progression of CKD. Reducing phosphate uptake is a rational approach to reducing FGF23, maintaining vitamin D levels, and normalizing parathyroid hormone (PTH). High levels of PTH, referred to as secondary hyperparathyroidism (SPTH), is highly prevalent in CKD and leads to bone disorders.
Hyperphosphatemia
Hyperphosphatemia (elevated serum phosphorus) occurs as a result of progressive loss of kidney function in CKD. When CKD progresses to end-stage renal disease (ESRD or dialysis), hyperphosphatemia has been shown to increase the risk of morbidity and mortality in those patients.
First line treatments of hyperphosphatemia in ESRD include phosphorus-restricted diets coupled with phosphate binders to reduce the impact of dietary phosphate absorption. However, current phosphate binders require frequent administration of large pills and have limited efficacy in controlling phosphate. In addition, phosphate binders are frequently coupled with active vitamin D therapy to control SPTH; however active vitamin D therapy has the problem of exacerbating dietary phosphate absorption as a result of its up-regulation of intestinal phosphate transport.
Early intervention on phosphorus in CKD
Historically, phosphate lowering drugs have been limited to use in patients with ESRD. Recently recognized is the potential benefit that phosphorus lowering drugs would provide to CKD patients who are not on dialysis. The belief is that aggressive intervention with phosphate lowering drugs would result in a normalization of many hormonal disorders (FGF23, vitamin D, and PTH) experienced by CKD patients. Via its unique mechanism of action, i.e., inhibition of phosphate uptake from the gut and into the blood-stream, RDX002 will allow for aggressive management of phosphorus absorption when used alone or in combination with traditional phosphate binding drugs.
