Evolving Approaches to CKD-MBD Address Cardiovascular and Fracture Risk

Patients with chronic kidney disease (CKD) and end-stage kidney disease (ESKD) face disproportionately high morbidity and mortality from cardiovascular disease and in the aftermath of bone fractures.

In a new review article, investigators from the University of Florida outlined the latest strategies for reducing those risks. The review was published in the World Journal of Nephrology.¹

The authors explained that reduced kidney function in patients with CKD or ESKD leads to pathological changes in mineral metabolism, a condition known as mineral and bone disorder (MBD).

“The management of MBD historically focused on bringing phosphate and calcium levels towards the normal range and addressing the abnormalities in parathyroid hormone (PTH),” they said.

That’s largely because excess serum phosphate can lead to a host of complications, including all-cause death, cardiovascular disease, and bone fractures, they noted.^2,3 Still, the tactic of treating these parameters has not succeeded in curbing excess morbidity and mortality from vascular and bone disease within the CKD and ESKD populations, the investigators wrote.¹

That has led scientists to start to look at other potential targets, such as αKlotho and fibroblast growth factor 23 (FGF23). The authors noted that serum FGF23 levels increase as early as CKD stage 2.

“In ESKD, FGF23 levels can rise as high as 1000-fold above the normal level and correlate increased [cardiovascular] mortality,” the authors wrote. Thus, they said, targeting FGF23 might lower the risk of MBD-associated complications.

Meanwhile, αKlotho is a cofactor of FGF23 and is necessary in order for FGF receptors to bind to the kidneys. Lower levels of αKlotho have been associated with an increased risk of mortality in patients with kidney disease. Hence, some hypothesize that upregulating αKlotho might limit vascular and kidney damage. However, there are not yet any such αKlotho-upregulation therapies available in humans.

The investigators next outlined phosphate management therapeutics, including metal-based phosphatase binders. Some, such as aluminum-based binders, are no longer recommended because of high levels of systemic aluminum absorption. Newer metal-based binders, including iron-based phosphate binders, have shown promise, though their impact on mortality and hospitalizations remains understudied, the investigators said. Resin-based phosphate binders can bring gastrointestinal side effects and often require as many as a dozen meal-timed tablets per day, making adherence a challenge.

The newest phosphate-targeting strategy is the phosphate absorption inhibitor tenapanor (Xphozah; Ardelyx), which was approved in 2023. The pill has minimal systemic absorption and can prevent intestinal absorption of phosphate, though it can lead to diarrhea in some patients, the authors explained.

The investigators next turned to the risks associated with vascular and soft-tissue calcifications, which they said may help explain the increased risk of cardiovascular complications. They highlighted the novel calcimimetic therapy cinacalcet (Sensipar; Amgen), which enhances the receptivity of calcium-sensing receptors on the parathyroid gland and has been found to reduce the risk of cardiovascular mortality, sudden cardiac death, and heart failure.⁴

Another novel agent is myo-inositol hexaphosphate (SNF472), which is designed to treat peripheral artery disease in patients with ESKD by stopping the formation and growth of hydroxyapatite crystals. These crystals contribute to the development of vascular complications. The investigators said more studies are needed to understand how this medication affects bone density and the risk of bone fractures.

The authors noted that bone disease in general is another important topic worthy of further study among patients with CKD and ESKD. Management of bone disease is not well defined in kidney disease, they said, though several approaches have been attempted. Anti-resorptive therapies have been tried, though patients with advanced kidney disease were not included in clinical trials, leading some to discourage their use in these patients.

Cinacalcet is also seen as a potential tool to reduce the risk of bone fracture, though the existing literature suggests it mainly benefits patients aged 65 and older, the authors noted.

The investigators closed their report by explaining that while therapies like tenapanor and SNF472 have shown promise, and αKlotho could be an interesting future target, more work is needed to curb the risk of vascular and bone disease in patients with CKD and ESKD.

“Further high-quality studies are needed to better prevent, diagnose, and treat vascular and bone disease in patients with advanced CKD and ESKD,” they concluded.

References:

1. Ilkun O, Jazayeri F, Kazory A. Emerging treatments and current strategies for mineral, vascular, and bone disorders in chronic kidney disease. World J Nephrol. 2026;15(1):114146. doi:10.5527/wjn.v15.i1.114146

2. Block GA, Klassen PS, Lazarus JM, Ofsthun N, Lowrie EG, Chertow GM. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol. 2004;15(8):2208-2218. doi:10.1097/01.ASN.0000133041.27682.A2

3. Block GA, Kilpatrick RD, Lowe KA, Wang W, Danese MD. CKD-mineral and bone disorder and risk of death and cardiovascular hospitalization in patients on hemodialysis. Clin J Am Soc Nephrol. 2013;8(12):2132-2140. doi:10.2215/CJN.04260413

4. Moe SM, Chertow GM, Parfrey PS, et al. Cinacalcet, fibroblast growth factor-23, and cardiovascular disease in hemodialysis: the evaluation of cinacalcet HCl therapy to lower cardiovascular events (EVOLVE) trial. Circulation. 2015;132(1):27-39. doi:10.1161/CIRCULATIONAHA.114.013876