Inherited non-FGF23-mediated phosphaturic disorders: A kidney-centric review

Abstract

Phosphate is freely filtered by the glomerulus and reabsorbed exclusively in the proximal tubule by two key transporters, NaPiIIA and NaPiIIC, encoded by SLC34A1 and SLC34A3, respectively. Regulation of these transporters occurs primarily through the hormone FGF23 and, to a lesser degree, PTH. Consequently, inherited non-FGF23 mediated phosphaturic disorders are due to generalised proximal tubular dysfunction, loss-of-function variants in SLC34A1 or SLC34A3 or excess PTH signalling. The corresponding disorders are Renal Fanconi Syndrome, Infantile Hypercalcaemia type 2, Hereditary Hypophosphataemic Rickets with Hypercalciuria and Familial Hyperparathyroidism. Several inherited forms of Fanconi renotubular syndrome (FRTS) have also been described with the underlying genes encoding for GATM, EHHADH, HNF4A and NDUFAF6. Here, we will review their pathophysiology, clinical manifestations and the implications for treatment from a kidney-centric perspective, focussing on those disorders caused by dysfunction of renal phosphate transporters. Moreover, we will highlight specific genetic aspects, as the availability of large population genetic databases has raised doubts about some of the originally proposed gene-disease associations concerning phosphate transporters or their associated proteins.

Keywords: NaPiIIA; NaPiIIC; PTH; familial hyperparathyroidism; hereditary hypoposphataemic rickets with hypercalciuria; infantile hypercalcaemia type 2; phosphaturia; renal fanconi syndrome.