Physiopathology of Phosphate Disorders

Abstract

Intracellular phosphate is critical for cellular processes such as signaling, nucleic acid synthesis, and membrane function. Extracellular phosphate (Pi) is an important component of the skeleton. Normal levels of serum phosphate are maintained by the coordinated actions of 1,25-dihydroxyvitamin D3, parathyroid hormone and fibroblast growth factor-23, which intersect in the proximal tubule to control the reabsorption of phosphate via the sodium-phosphate cotransporters Npt2a and Npt2c. Furthermore, 1,25-dihydroxyvitamin D3 participates in the regulation of dietary phosphate absorption in the small intestine. Clinical manifestations associated with abnormal serum phosphate levels are common and occur as a result of genetic or acquired conditions affecting phosphate homeostasis. For example, chronic hypophosphatemia leads to osteomalacia in adults and rickets in children. Acute severe hypophosphatemia can affect multiple organs leading to rhabdomyolysis, respiratory dysfunction, and hemolysis. Patients with impaired kidney function, such as those with advanced CKD, have high prevalence of hyperphosphatemia, with approximately two-thirds of patients on chronic hemodialysis in the United States having serum phosphate levels above the recommended goal of 5.5 mg/dL, a cutoff associated with excess risk of cardiovascular complications. Furthermore, patients with advanced kidney disease and hyperphosphatemia (>6.5 mg/dL) have almost one-third excess risk of death than those with phosphate levels between 2.4 and 6.5 mg/dL. Given the complex mechanisms that regulate phosphate levels, the interventions to treat the various diseases associated with hypophosphatemia or hyperphosphatemia rely on the understanding of the underlying pathobiological mechanisms governing each patient condition.

Figure 1.

Phosphate Homeostasis, Maintaining normal serum P_i levels involves the coordinated actions of the parathyroid hormone (PTH), fibroblastic growth factor-23 (FGF-23), 1,25-dihydroxyvitamin D3 on target organs such as the parathyroid gland, small intestine, kidneys and bones. When Pi levels increase FGF-23 is secreted from the bone and PTH is secreted from the parathyroid gland. FGF-23 binds to the FGF receptor and its coreceptor Klotho in the proximal renal tubule, while PTH binds to the PTH receptor (PTH1R). The actions of FGF-23 include inhibition of 1α-hydroxylase and the P_i transporters Npt2a and Npt2c with the net effect of decreasing P_i reabsorption in the kidneys and indirectly reducing P_i absorption in the intestine due to reduced levels of 1,25-dihydroxyvitamin D3. PTH also reduces the abundance of Npt2a and Npt2c; however, it has a stimulatory effect on 1α-hydroxylase, which is critical to maintain normal levels of calcium. Abbreviations: 1,25 (OH)₂ vit D, 1,25-dihydroxyvitamin D3; PTH, parathyroid hormone; FGF-23, fibroblast growth factor-23; PTH1R, parathyroid hormone–related peptide receptor type 1; Npt2a, type II sodium phosphate cotransporter a; Npt2b, type II sodium phosphate cotransporter b; Npt2c, type II sodium phosphate cotransporter c; FGF-R, fibroblast growth factor receptor; Kl, klotho.

Figure 2.

Phosphate phenotypes in genetically modified mouse models, Knockout of Npt2a and Npt2c demonstrate the contribution of each of these transporters for renal P_i transport in mice. Npt2a contributes to 70% of renal P_i reabsorption. Mice Npt2a−/− have hyperphosphaturia and lower levels of serum P_i. Incontrast, Npt2c−/− mice do not have a phosphate phenotype, but exhibit hypercalcemia, hypercalciuria, and increased 1,25-dihydroxyvitamin D3 levels. One should notice that the findings of the relative contributions of Npt2a and Npt2c to P_i homeostasis might differ in humans. Npt2c mutations have been found in patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH), while Npt2a mutations have not been clearly associated with abnormal P_i handling in humans. Npt2a/c double knockout mice show more severe hypophosphatemia, phosphaturia, increased 1,25-dihydroxyvitamin D3 levels, and hypercalciuria, similar to patients with HHRH. Abbreviations: DKO, double knockout; Npt2a, type II sodium phosphate cotransporter a; Npt2c, type II sodium phosphate cotransporter c.

Figure 3.

Approach to hyperphosphatemia management in patients with CKD. KDIGO 2017 guidelines suggest lowering elevated phosphate levels toward the normal range in patients with CKD G3a–G5D rather than preventive phosphate lowering. Initial intervention includes dietary modification and medication management. *Reasonable to consider phosphate source in making dietary recommendation as phosphate derived from plants is less absorbed than that from animals or food additives. **The use of calcium-containing phosphate binders is generally restricted to a selected group of patients with CKD without hypercalcemia, vascular calcification or adynamic bone disease.