The study, “Renal Phosphate Handling: Independent Effects of Circulating FGF23, PTH, and Calcium,” was published in the journal JMBR Plus and was led by a team from Ireland.
XLH is caused by mutations in the PHEX gene that lead to abnormally high levels of the protein FGF23. As a result, the amount of phosphate that is reabsorbed by the kidneys lowers, ultimately leading to low phosphate levels in the body (hypophosphatemia).
The parathyroid glands, located in the base of the neck, secrete parathyroid hormone (PTH). Like FGF23, PTH can alter bodily phosphate levels. When the parathyroid glands secrete abnormally high levels of PTH, it is termed hyperparathyroidism, while hypoparathyroidism refers to PTH deficiency.
Given the common processes that mediate the effects of both PTH and FGF23, PTH status could affect the effect of FGF23 excess on kidney phosphate reabsorption. As such, “if parathyroid status alters the effect of FGF23 excess, then the magnitude of the causal effect of FGF23 on [kidney phosphate reabsorption] could be lessened by hypoparathyroidism or it could be augmented by hyperparathyroidism,” the scientists wrote.
In this study, researchers assessed three groups of patients: 27 patients with FGF23–dependent hypophosphatemia (FDH, which includes XLH and related conditions), 17 with hypoparathyroidism, and 30 with chronic kidney disease (CKD).
Results showed that phosphate reabsorption in the kidneys was negatively correlated with FGF23, PTH, and bodily calcium levels — that is, individuals with higher levels of each of these parameters were statistically more likely to have less kidney phosphate reabsorption.
Using further statistical analyses, the researchers demonstrated that 77.4% of the variation in kidney phosphate reabsorption could be explained by FGF23, PTH, and calcium levels. Also, the interaction with FGF23 and PTH explained a small, but statistically significant amount of this variation.
The researchers also reported on an individual who had both XLH and hypoparathyroidism who underwent treatment with a recombinant (lab-made) analog of PTH. In this patient, PTH treatment markedly decreased kidney phosphate reabsorption, again consistent with the connection between PTH and FGF23.
Overall, “parathyroid status can alter renal phosphate handling in clinical states of FGF23 excess,” the scientists wrote.
They said these findings have clinical implications: phosphate supplements used to treat XLH can cause hyperparathyroidism. According to the team, therapies that target FGF23 directly (i.e., burosumab, marketed under the name Crysvita) likely would reduce the frequency of this side effect.
Limitations of this study include the small sample size and that some factors that may be relevant for kidney phosphate reabsorption — such as levels of iron and of other hormones — were not analyzed, the scientists wrote. More research is needed into the mechanisms by which PTH alters the effect of FGF23 on kidney phosphate reabsorption, they added.
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