Another Tool in the Fight Against Phosphate Toxicity: Where Will It Fit and What Does It Tell Us about Phosphate Homeostasis?

Efforts to control phosphate retention/hyperphosphatemia in CKD have focused on limiting gastrointestinal phosphate absorption through dietary and pharmacologic means. Suffice it to say that these measures have proven to be woefully inadequate for individuals with advanced kidney failure. Thomas et al.¹ have presented evidence that blocking renal phosphate reabsorption through an orally administered agent (PF-06869206; designated Npt2a-I) that selectively inhibits the type IIa sodium phosphate cotransporter (Npt2a) effectively lowers serum phosphate in a mouse model in the setting of normal kidney function and CKD (5/6 nephrectomy model). These findings raise hopes that we now have a more effective and palatable therapy for this universal complication of CKD, a complication implicated in the development of accelerated cardiovascular disease and disabling bone disease in this patient population. This agent may also be useful in expanding our understanding of phosphate homeostasis in particular and mineral metabolism generally.

Reabsorption of filtered phosphate is accomplished through the coordinated actions of Npt2a, Npt2c, and Pit2 (a type III sodium phosphate cotransporter) located on the apical membrane of renal proximal tubule cells, which transport phosphate from glomerular ultrafiltrate into the cells, and an as yet uncharacterized protein or proteins located on the basolateral membrane, which transport reabsorbed phosphate into the blood compartment. In mouse, Npt2a accounts for 70%–80% of the reabsorption of filtered phosphate. Predictably, Thomas et al.¹ show that Npt2a-I dramatically increased urine phosphate excretion and decreased serum phosphate in the C57BL/6J mouse model after 3 hours accompanied by an equally predictable increase in the apical membrane expression of Npt2a. The increase in apical membrane expression of Npt2a was likely due to both stimulation of the forward trafficking of Npt2a molecules already present in the cell and inhibition of endocytosis of Npt2a already present in the apical membrane, because total cellular Npt2a expression was not different at 3 hours than at baseline. The parathyroid hormone (PTH) level after Npt2a-I administration rapidly decreased, correlating with the decline in serum phosphate, and this was followed by a “rebound” overshoot in both serum phosphate and PTH levels at the 24-hour mark when Npt2a-I would be absent. At 24 hours, the Npt2a expression was actually lower in the inhibitor-treated kidneys than the vehicle-treated kidneys, likely a result of the rebound increase in serum PTH levels. The PTH response to serum phosphate level in the absence of any change in serum calcium reinforces the growing recognition that, even in the absence of CKD, serum phosphate is a potent and independent regulator of PTH. Likewise, the rapidity of the changes in apical membrane expression of Npt2a in response to serum phosphate and PTH reinforces the role of this transporter as an immediate responder. In contrast, there was no change in fibroblast growth factor 23 (FGF23) at the 3-hour time point but an increase at the 24-hour timepoint after Npt2a-I administration at the time when both phosphate and PTH were higher than baseline. This finding is consistent with human studies showing no change in FGF23 level 3 hours after a dietary phosphate load² and suggests a more chronic role for FGF23 in regulation of phosphate homeostasis.

There was an additive effect of PTH and Npt2a-I on urine phosphate excretion and serum phosphate. The authors suggest that the decrease in Npt2a transporter surface expression with PTH facilitated the ability of Npt2a-I to inhibit the remaining transporters. An alternative explanation is that there is a pool of Npt2a not regulated by PTH but inhibitable by the pharmacologic agent. This conclusion is supported by the observation that the proximal tubule handling of phosphate with advancing CKD does not correlate completely with GFR and rising PTH or FGF23 levels. Studies in a model of endogenous hyperparathyroidism demonstrate persistent presence of Npt2a even with significantly elevated PTH levels.³

Npt2a-I increased urinary Na, Cl, and calcium but had no effect on urine K or pH, consistent with a predominantly proximal tubule effect. The natriuresis occurred without changes in the expression of NHE3, the major proximal tubule sodium transporter, suggesting that the natriuresis is due to Npt2a inhibition only. The increase in urine calcium in the absence of a change in serum calcium suggests a multiorgan effect; the renal losses are likely due to decreased proximal tubule calcium reabsorption accompanying decreased sodium reabsorption plus distal tubule calcium wasting due to the decrease in PTH. These studies were performed only at the 3-hour timepoint, and therefore, whether the effect also disappeared or rebounded in the opposite direction at 24 hours is not known. The fact that the calciuric effect is actually more sensitive to Npt2a-I may indicate that the major effect of Npt2a-I on calcium excretion is due to the distal nephron effect; however, this is speculative.

The authors are appropriately cautious in promising a cure for the hyperphosphatemia of CKD in human beings.¹ The relative contributions of the different phosphate transporters to human renal phosphate handling are unknown but likely differ from mouse kidney. Mice lacking Npt2a expression show a phenotype of phosphate wasting, skeletal abnormalities, and kidney stones, whereas the absence of Npt2c yields no obvious mineral metabolism defects. In contrast, inactivating mutations of Npt2c in humans are associated with the well-defined syndrome of hereditary hypophosphatemic rickets with hypercalciuria, whereas inactivating mutations of Npt2a have been associated with a somewhat milder clinical picture, suggesting a lesser role for Npt2a in human renal phosphate homeostasis. This supposition is supported by data published by the team that developed Npt2a-I showing a lower mRNA expression of Npt2a than either Npt2c or the type III sodium phosphate cotransporters in fresh kidney and isolated proximal tubule cells.⁴ Questions about the efficacy and implementation of such an inhibitor are numerous. Will its effects be altered by circadian rhythms in serum phosphate levels? How will clinicians know when to start these agents? Will they need to look at alternative “readouts,” such as serum PTH and FGF23 levels, to assess response as well as serum phosphate? What about long-term efficacy and safety? These concerns in no way diminish the excitement for both clinicians and investigators in the discovery of an orally available renal phosphate transport inhibitor, a new tool to treat hyperphosphatemia and explore mechanisms of mineral metabolism.

Disclosures

None.

Funding

Dr. Lederer is supported by a grant from the Department of Veterans Affairs Merit Review Board (I01CX001614).