Ferric citrate kills two birds with one stone, doubly benefiting patients with chronic kidney disease

Patients with chronic kidney disease (CKD) usually have higher phosphate levels and lower iron levels in their blood, both of which are associated with increased risk of cardiovascular disease and death. Today, we will introduce a drug that can both reduce phosphorus and supplement iron - ferric citrate .

The drug can both increase iron levels in CKD patients not undergoing dialysis and reduce phosphate levels in CKD patients undergoing dialysis, thus having a dual therapeutic effect.

The prevalence of hyperphosphatemia in hemodialysis patients remains high, and restoring phosphate balance has long been an important goal of CKD treatment. From 1970 to 1990, aluminum-based and calcium-based phosphate binders were commonly used to control hyperphosphatemia in patients with end-stage renal disease. However, the aluminum toxicity of aluminum-based binders and the hypercalcemia and metastatic calcification caused by calcium-based binders have promoted the development of calcium-free and aluminum-free phosphate binders. At present, patients with different degrees of CKD need to take a certain amount of phosphate binders, but each category still has some potential disadvantages that may affect patient compliance and safety. The 2017 KDIGO guidelines recommend that the dose of calcium-based phosphate binders should be limited for adult patients with CKD stages 3 to 5 who are receiving phosphate-lowering treatment.

Ferric citrate is an oral, calcium-free, iron-based phosphate binder. After oral administration of ferric citrate, the dissociated Fe3+ can bind phosphate in the gastrointestinal tract to form iron phosphate, reducing the absorption of phosphorus in the small intestine. At the same time, the ferric citrate absorbed by the intestine can increase the levels of serum iron, ferritin, and transferrin saturation. Previous clinical studies have shown that ferric citrate can play a role in lowering phosphorus, reducing fibroblast growth factor-23 (FGF23) levels, supplementing iron, and improving anemia in CKD patients. FGF23 is an essential hormone mainly secreted by osteoblasts. Elevated FGF23 concentrations in CKD patients may have adverse effects on multiple systems, and reducing FGF23 levels in CKD patients may improve patient prognosis. Several randomized trials have shown that compared with placebo, ferric citrate can not only reduce serum phosphate concentrations in CKD patients, but also increase transferrin saturation and ferritin levels, while reducing circulating FGF23 levels.

Ferric citrate is an effective, safe and affordable treatment option for CKD patients with hyperphosphatemia and anemia. Studies have shown that ferric citrate has a significant effect on lowering phosphorus and correcting anemia compared with placebo. Its phosphorus-lowering effect is comparable to that of traditional phosphorus-lowering drugs, and its effect in treating anemia is more significant. The results of a comprehensive analysis of two randomized, placebo-controlled trials showed that for patients with advanced non-dialysis-dependent CKD with iron deficiency anemia and with or without relative hyperphosphatemia, ferric citrate treatment may cause a slight increase in diarrhea, constipation, nausea and other non-serious gastrointestinal symptoms, but no major or unexpected safety issues occurred. In addition, it is beneficial for the treatment of iron deficiency anemia and bone and mineral metabolism. In 2023, a multicenter randomized controlled trial of Chinese patients found that ferric citrate was as effective as positive drugs. In addition, most of the clinical adverse events experienced by patients were mild and tolerated by patients.

Currently, ferric citrate has been approved in many countries for use as an enteral phosphate binder and iron replacement product for adult CKD patients. In 2014, the U.S. Food and Drug Administration approved ferric citrate as a phosphate-lowering agent for CKD dialysis patients to control serum phosphate levels in adult CKD patients receiving dialysis treatment, and also as an iron replacement product to treat iron deficiency anemia in adult CKD patients not receiving dialysis. In the European Union, ferric citrate can be used to control hyperphosphatemia in adult CKD patients. In Japan, ferric citrate can be used to treat hyperphosphatemia in CKD patients. In Taiwan, ferric citrate can be used to control hyperphosphatemia in adult CKD patients receiving hemodialysis.

Research on the use of ferric citrate in the pediatric CKD population has also been conducted. Studies have shown that ferric citrate may be able to simultaneously reduce phosphate levels and treat iron deficiency in pediatric dialysis patients. However, larger studies are still needed to further evaluate its safety and effectiveness in the pediatric CKD population.