Hyperphosphatemia in Kidney Failure: Pathophysiology, Challenges and Critical Role of Phosphorus Management

Phosphorus is one of the most abundant minerals in the body and plays a pivotal role in numerous cellular processes, including maintenance of skeletal health, integrity of phospholipid bilayers, cell signaling, and synthesis of nucleic acid and adenosine triphosphate (ATP). About 85% of total phosphate is deposited in bone as hydroxyapatite crystals, 14% is present in soft tissues as various organic phosphates, and the remaining 1% is found in extracellular space mainly as inorganic phosphate. The plasma inorganic phosphorus concentration is tightly maintained between 2.5 - 4.5 mg/dL by intertwined interactions between fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH) and vitamin D that tightly regulate the precise balance in the phosphorus trafficking across the gastrointestinal tract, kidneys and bones. Disruption of the tight hemostatic control of phosphorus balance can lead to altered cellular and organ functions that are associated with high morbidity and mortality. In the past three decades, there has been a steady increase in the prevalence of kidney failure (KF) population needing various kidney replacement therapies. The individuals with KF have unacceptably high mortality, and well over half of deaths are related to cardiovascular disease. Abnormal phosphorus metabolism is one of the major factors that is independently associated with vascular calcification and cardiovascular mortality in KF. While overt hyperphosphatemia is observed late during the progression of chronic kidney disease (CKD), a series of adaptive processes involving FGF-23, PTH and vitamin D occur in early stages of CKD attempting to enhance phosphate excretion and maintain plasma phosphorus level in the normal range. However, as CKD worsens, the ability to adequately eliminate phosphorus diminishes, eventually resulting in hyperphosphatemia, which is almost ubiquitous in individuals with KF. Notably, these hormonal imbalances and the associated adverse consequences are driven by the underlying hyperphosphatemic state in KF. Hence, it appears logical to strictly control serum phosphorus and its associated hormonal imbalance. Conventional dialysis is inadequate in removing phosphorus and most patients require dietary restrictions and pharmacologic interventions to manage hyperphosphatemia. Despite high phosphate content, plant-based diets are more efficient in controlling hyperphosphatemia as compared with animal-based diets. However, diet control comes with many challenges with adherence and may place patients at risk for inadequate protein intake and malnutrition that in turn may increase the risk of morbidity and mortality. Phosphate binders help to reduce phosphorus level but come with a sizable pill burden, have high financial cost, associated with poor adherence and psychosocial issues. Additionally, long-term use of binders may increase the risk of calcium, lanthanum or iron overload or promote gastrointestinal side effects that exacerbate malnutrition and affect quality of life. Given aforesaid challenges with phosphorus binders, novel therapies targeting small intestinal phosphate absorption pathways have been investigated. Recently, tenapanor, an agent that blocks paracellular absorption of phosphate via inhibition of enteric sodium-hydrogen-exchanger-3 (NHE3) was approved for the treatment of hyperphosphatemia in KF. While various clinical tools are now available to manage hyperphosphatemia, there is lack of convincing clinical data to demonstrate improvement in outcomes in KF with lowering of phosphorus level to near normal range. Conceivably, deleterious effects associated with hyperphosphatemia could be attributable to disruptions in phosphorus sensing mechanisms and hormonal imbalance thereof. Further exploration of mechanisms that precisely control phosphorus sensing and regulation may facilitate development of strategies to diminish the deleterious effects of phosphorus load and improve overall outcomes in KF.