Northwestern Medicine researchers have pinpointed a surprising culprit behind anemia in kidney disease: a hormone that acts as the body's own brake on red blood cell production. The discovery, published in Blood by Valentin David, Ph.D., the Frank Krumlovsky, MD, Professor of Medicine in the Division of Nephrology and Hypertension, reveals how FGF23—a phosphate-regulating hormone produced by bone cells and blood-forming cells—suppresses the very process that creates red blood cells when iron is scarce.
For decades, scientists knew that elevated FGF23 levels were associated with impaired red blood cell production in patients with iron deficiency anemia and chronic kidney disease. Yet the mechanism remained unclear: which cells producing FGF23 were responsible, and how exactly did the hormone interfere with this vital process? David's team engineered mice with selective deletions of FGF23 in either osteocytes—the most abundant cells in mature bone—or erythroid cells, the precursors to red blood cells. When these mice were placed on iron-deficient diets, the researchers could finally see the full picture.
Both osteocytes and erythroid cells contributed FGF23 to the bloodstream, but the breakthrough came when scientists deleted FGF23 specifically from erythroid cells in iron-deficient mice. The anemia was corrected. In another striking finding, when researchers deleted furin—an enzyme that breaks down FGF23—anemia actually worsened, confirming FGF23's suppressive role. "When iron availability is limited, such as in iron deficiency anemia or anemia of chronic kidney disease, this hormone acts as a brake and stops the erythroid progenitors from consuming all the available iron only to differentiate into poorly functional mature erythroid cells," David explained.
The implications extend to chronic kidney disease, a condition affecting millions worldwide where anemia is a relentless complication. When the team deleted FGF23 from erythroid cells in animal models of kidney disease, it prevented anemia from developing altogether. This suggests the hormone functions as a protective mechanism—a paracrine factor that limits red blood cell production when iron is insufficient, preventing the body from squandering scarce iron on dysfunctional cells.
Yet the challenge for future treatment is subtle and important. FGF23's elevated levels in chronic kidney disease do cause anemia, but the hormone also serves a critical protective function: it prevents phosphate from accumulating to dangerous levels in the blood. Simply eliminating FGF23 would solve one problem while creating another. "I think part of the problem is that FGF23 in chronic kidney disease triggers so many negative effects, but its presence still mitigates hyperphosphatemia," David noted. "That's part of the problem: we need to reduce it but not eliminate it."
The path forward, David suggests, lies in precision targeting—developing therapies that reduce specific versions of FGF23 or block production in particular cell types rather than shutting down the hormone entirely. This kind of nuanced approach could spare patients from anemia while preserving the hormone's beneficial effects on phosphate regulation. As David puts it, researchers are "slowly but surely driving towards finding mechanisms to actually target specific isoforms and cells that produce FGF23 in chronic kidney disease and other conditions." The discovery opens a new chapter in understanding how our bodies regulate blood cell production and offers hope for millions living with kidney disease and its complications.