Key Takeaways

  • This study investigated the cause of the elevation in circulating fibroblast growth factor 23 (FGF23), a strong risk factor for adverse renal outcomes and death in individuals with acute kidney injury
  • Of more than 5,000 molecules screened from human renal venous blood, the strongest association with FGF23 was for glycerol-3-phosphate (G-3-P). Acute kidney injury, which increases FGF23 levels, rapidly increased circulating G-3-P in mice and humans
  • The authors describe a pathway that links increased G-3-P to increased FGF23 via increases in lysophosphatidic acid
  • It was possible to block the stimulatory effect of G-3-P on FGF23 by inhibiting G-3-P acyltransferase isoform 2, and acute kidney injury, which increases FGF23 levels, rapidly increased circulating G-3-P in mice and humans

Kidney injury results in an increased level of circulating fibroblast growth factor 23 (FGF23), which is a strong independent risk factor for adverse renal outcomes and death. Accumulating evidence shows that high FGF23 levels may have a direct role in these outcomes by damaging not only the kidney but also the immune and cardiovascular systems. But what causes the initial elevation of FGF23 remains poorly understood.

Petra Simic, MD, PhD, nephrologist, and Eugene P. Rhee, MD, chief of the Division of Nephrology at Massachusetts General Hospital, and colleagues report that FGF23 levels increase almost immediately after acute kidney injury (AKI), even before changes in blood phosphate or calcium, suggesting that the injured kidney releases a factor that directly stimulates FGF23 production.

Using proteomics and metabolomics, the researchers identified kidney-derived glycerol-3-phosphate (G-3-P), a downstream product of glycolysis, as a key factor. They report their findings in The Journal of Clinical Investigation.

Identification of G-3-P

The research team first screened human renal venous blood for molecules that correlate with circulating FGF23 levels. Of more than 5,000 molecules, G-3-P was the only one that achieved proteome-wide or metabolome-wide significance.

The Kidney-to-Bone and Bone Marrow Signaling Axis

The researchers injected wild-type mice with G-3-P and observed increased FGF23 production in bone and bone marrow via increases in lysophosphatidic acid (LPA), which activates the LPA receptor 1. The stimulatory effect of G-3-P on both LPA and FGF23 production was blocked when the researchers inhibited G-3-P acyltransferase isoform 2 (GPAT2) in cells, suggesting that GPAT2 converts circulating G-3-P to LPA.

Mouse Model of AKI

In mice that had kidney ischemia induced, the researchers observed that G-3-P levels increased in the kidneys, compared with control mice, and there was downstream G-3-P accumulation in plasma and bone marrow. As in mice without kidney injury, G-3-P stimulated FGF23 production via GPAT, LPA and LPA receptor 1.

Case-Control Study

The researchers measured plasma G-3-P levels in 26 individuals immediately before and after cardiac surgery: 13 individuals who subsequently developed AKI and 13 matched controls who did not. Immediately after surgery, G-3-P increased significantly more in patients with AKI than in controls. There was a modest correlation between the immediate postoperative G-3-P levels and the subsequent rise in FGF23.

Clinical Relevance of the Findings

The dramatic elevation in FGF23 levels that occur with kidney injury may contribute to the significant risk of adverse renal outcomes and death. This study is important because the newly identified upstream regulators of FGF23 production may prove to be amenable to small-molecule antagonist drugs, which would make it easier to titrate and deliver therapy for FGF23 excess in AKI and beyond.