Editorial
Time to Shift our Mindset to a Phosphate-Centric Approach for Prevention of Cardiovascular Calcification in the Dialysis Population
2023 Volume 30 Issue 11 Pages 1549-1551
Details
2023 Volume 30 Issue 11 Pages 1549-1551
See article vol. 30: 1568-1579
Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD). One of the major reasons for the high incidence of cardiovascular mortality is cardiovascular calcification (CVC)1), which includes vascular calcification and cardiac valvular calcification. CVC is characterized by the deposition of calcium phosphate crystals in vessel walls and/or cardiac valves and is associated with the development of cardiovascular diseases and events. CVC often hinders appropriate treatment, such as coronary artery intervention, peripheral arterial disease therapy, or kidney transplantation surgery. CVC was once regarded as a passive process but is now regarded as a complex cell-mediated process that resembles the physiology of bone formation. Multiple cellular mechanisms are involved in CVC pathogenesis2). Phenotypic change of vascular smooth muscle cells (VSMCs) from a contractile phenotype to an osteochondrogenic phenotype is a representative phenomenon in the cell-mediated CVC process. Other mechanisms, including VSMC apoptosis, extracellular vesicle synthesis and release, extracellular matrix degradation, and very recently calciprotein particle (CPP) formation, also have critical roles in CVC pathophysiology. CPPs are nanosized particles composed of calcium, phosphate, and other proteins such as fetuin-A. Secondary CPPs, rather than primary CPPs, are considered the culprits for CVC based on the so-called CPP hypothesis3).
The reason for the high prevalence of CVC in CKD patients is the accumulation of multiple risk factors. CKD patients are often exposed to traditional risk factors for atherosclerosis and arteriosclerosis, such as hypertension, diabetes mellitus, dyslipidemia, and smoking, and these traditional risk factors can accelerate CVC. Importantly, CKD patients also tend to be complicated with non-traditional and uremia-related risk factors for CVC, such as oxidative stress, inflammation, uremic toxin retention, anemia, protein-energy wasting, and CKD-mineral and bone disorder (CKD-MBD). Among these factors, CKD-MBD has emerged as a potent inducer of CVC4). Because the kidney is the main route for phosphate excretion from the human body, hyperphosphatemia and hypophosphatemia are prominent features of CKD-MBD and are highly prevalent in the CKD population.
Basic studies have consistently demonstrated that high phosphate conditions initiate and accelerate calcium mineral deposition around cultured VSMCs and valvular interstitial cells (VICs). Importantly, phosphate loading accelerates the formation of secondary CPPs, ultimately leading to CVC. There is also increasing epidemiological evidence for associations of hyperphosphatemia or phosphate loading with increased risks of cardiovascular morbidity and mortality in dialysis-independent and dialysis-dependent CKD populations5). Phosphate loading induces multiple processes in the complex CVC pathology. Increased circulating concentrations of parathyroid hormone and fibroblast growth factor in response to phosphate overload may be involved in CVC progression. Thus, control of serum phosphate within a target range is believed to prevent progression of CVC. The CKD-MBD guideline issued by the Japanese Society for Dialysis Therapy in 2012 recommends that serum phosphate should be controlled within the range of 3.5 to 6.0 mg/dL in hemodialysis patients6). A long-standing clinical query regarding serum phosphate control in hemodialysis patients is whether a lower serum phosphate level within the target range can further prevent CVC progression or whether it is sufficient to simply avoid hyperphosphatemia (serum phosphate ≥ 6 mg/dL).
In this issue of Journal of Atherosclerosis and Thrombosis, Shimizu and colleagues conducted a post-hoc analysis using the dataset from a randomized controlled trial (RCT) that compared the impacts of lanthanum carbonate and calcium carbonate, two major phosphate binders for hemodialysis patients, on the progression of coronary artery calcification (CAC)7). The main results of the RCT were published recently8). Briefly, progression of CAC and cardiac valvular calcification were significantly slower in patients treated with lanthanum carbonate than in patients treated with calcium carbonate. In the post-hoc analysis, Shimizu et al.7) determined the time-dependent phosphate loading during an intervention period of 18 months by calculating the area under the curve (AUC) for serum phosphate ＞4.5 mg/dL. When the patients were divided into two groups according to the median AUC value (0.44), patients with a higher AUC exhibited higher progression rates of CAC and cardiac valvular calcification than patients with a lower AUC, even after adjustment for potential confounding factors. Based on these results, the authors concluded that better time-averaged phosphate control may contribute to slower progression of CAC and highlighted the importance of controlling serum phosphate within a low-normal range. In line with that study and using the same approach, Lopes et al.9) recently showed that a higher AUC for serum phosphate ＞4.5 mg/dL was associated with increased risks of cardiovascular mortality in patients undergoing maintenance hemodialysis. Moreover, the EPISODE study, an RCT designed to compare the impacts of two different target ranges for serum phosphate among maintenance hemodialysis patients, recently demonstrated that strict control of serum phosphate retarded CAC progression in hemodialysis patients with serum phosphate 3.5–4.5 mg/dL versus patients with serum phosphate 5.0–6.0 mg/dL10). The results of the EPISODE study confirm the clinical significance of strict serum phosphate management in patients undergoing hemodialysis. Although CVC may be a surrogate marker for cardiovascular disease and events, strict serum phosphate control is a reasonable approach for prevention of CVC and may ultimately improve the prognosis of CKD patients (Fig.1).
Abbreviations: CKD, chronic kidney disease; CPM, calciprotein monomer; CPP, calciprotein particle; CVC, cardiovascular calcification; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; FGF23, fibroblast growth factor 23; PEW, protein-energy wasting; Pi, inorganic phosphate; PTH, parathyroid hormone; VICs, valvular interstitial cells; VSMCs, vascular smooth muscle cells.
At present, the combination of oral phosphate binder administration, dietary phosphate restriction program, and adequate inorganic phosphate removal through dialysis is the cornerstone treatment for improved control of serum phosphate. However, the current approach is insufficient to achieve more strict serum phosphate control in all hemodialysis patients. In the future, novel drugs, including pan-phosphate transporter inhibitors and sodium/hydrogen exchanger isoform 3 inhibitors, will become available. These drugs are expected to change the clinical situation for disordered phosphate metabolism in CKD patients. Until then, our best strategy is to control serum phosphate to as low a level as possible within the normal serum phosphate range together with appropriate management of modifiable risk factors, including blood pressure levels. Finally, the study findings urge us to shift our mindset to a phosphate-centric approach for the prevention of CVC progression in patients undergoing hemodialysis therapy.
Shunsuke Yamada and Toshiaki Nakano have received lecture fees and research funding from the following pharmaceutical companies: Kyowa Kirin Co. Ltd., Kissei Pharmaceutical Co. Ltd., Sanwa Kagaku Kenkyusho Co. Ltd., and Torii Pharmaceutical Co. Ltd.
The authors thank Alison Sherwin, PhD, from Edanz (https://jp.edanz.com/ac), for editing a draft of this manuscript.
