Introduction
Chronic kidney disease (CKD)-mineral bone disorder (MBD) is characterized by complex biochemical and hormonal changes. These changes include disturbances in calcium, phosphorus, parathyroid hormone (PTH), and vitamin D. Patients with CKD-MBD have a significantly increased risk of bone fractures, cardiovascular (CV) events, mortality, and CKD progression [1].
Epidemiology
CKD prevalence in Asia varies from 7.0% to 34.3%, affecting 434 million people with 65 million in advanced stages. Between 1990 and 2019, CKD diagnoses and deaths more than doubled with the highest disability burden in Thailand, Malaysia, Singapore, and the Philippines [2]. The burden of CKD-MBD in Southeast Asia remains undercharted, and direct estimates of its prevalence or incidence are sparse. Nonetheless, several proxy indicators and regional data permit some inferences. A recent meta-analysis reported that the global prevalence of secondary hyperparathyroidism (SHPT) in CKD (all stages) was 49.5% (95% CI, 30.2%–68.2%). In the Southern Asia subgroup, the estimate was approximately 84.4% (95% CI, 79.4%–88.3%) [3]. In a Chinese cohort of CKD stages 3–5, proportions with hyperphosphatemia were 2.6% in stage 3a, 2.9% stage 3b, 6.8% stage 4, and 27.1% stage 5. Vascular calcification (abdominal aortic calcification) was observed in 9.8% [4]. For early‐stage CKD (stages 1–2) in China, the prevalence of hyperphosphatemia (serum phosphate >1.45 mmol/L) was 8.3% [5]. The documented high rates of CKD and end-stage kidney disease in Asian countries (including high incidence and prevalence of dialysis) imply a substantial risk for CKD-MBD, given the pathophysiology of MBD in CKD.
Pathophysiology
CKD-MBD develops due to impaired renal capacity to excrete phosphate, which reaches high levels in the blood. As renal function declines, phosphate increases to induce a calcium imbalance and increases the secretion of PTH (Fig. 1) [5]. High levels of PTH cause bone resorption, which weakens the bone, leading to a higher risk of fractures. The metabolic changes also contribute to vascular calcification and serious CV complications. It is vital to minimize the risk of morbidity and mortality in patients with CKD by managing phosphate and hormonal imbalances associated with CKD-MBD [6].
SHPT arises early in CKD, often from stage III, as phosphate retention stimulates PTH secretion directly, through calcium precipitation and hypocalcemia, and indirectly via fibroblast growth factor 23 (FGF-23)–mediated suppression of vitamin D synthesis. Initially, these compensatory mechanisms maintain near-normal mineral levels, but with progressive nephron loss, they become ineffective, resulting in persistently high PTH that further accelerates bone turnover and vascular calcification. SHPT is therefore a central component of CKD-MBD, linking phosphate retention to both skeletal fragility and increased CV mortality [7].
Phosphate binders and their role in chronic kidney disease-mineral bone disorder
Currently, phosphate binders are the gold standard treatment for hyperphosphatemia in patients with advanced CKD (Fig. 2). Phosphate binders exert their action through binding phosphate in the gastrointestinal (GI) tract to prevent resorption into the bloodstream. Phosphate binders are especially important for patients with stage 4 and 5 CKD, in which the kidneys fail to remove phosphate efficiently. The use of phosphate binders decreases the risk of adverse outcomes due to CKD-MBD, including developing bone and CV complications, and improves outcomes for patients with CKD. Phosphate binders also have been noted to reduce inflammatory markers and oxidative stress in hemodialysis (HD) patients [8–10].
Conventional calcium-based phosphate binders and their limitations
Calcium-based phosphate binders, such as calcium carbonate and calcium acetate, have been widely utilized to treat hyperphosphatemia in patients with CKD. They are effective for lowering serum phosphate levels. However, their long-term use poses significant risks due to calcium overload. Excess calcium contributes to vascular calcification, which is a major concern for patients with CKD who are already at an increased risk of CV disease [11].
Clinical guidelines provide specific recommendations for calcium and phosphorus management in CKD to mitigate these concerns. The KDIGO (Kidney Disease: Improving Global Outcomes) guidelines suggest maintaining serum calcium levels within the normal range of 8.5–10.5 mg/dL (2.1–2.6 mmol/L) in patients with stage 3–5D CKD. Similarly, serum phosphate levels should be kept within the normal range of 2.7–4.6 mg/dL (0.87–1.49 mmol/L) for stage 3–5 CKD, while phosphate levels should aim for 3.5–5.5 mg/dL (1.13–1.78 mmol/L) in patients with stage 5D CKD. These recommendations are consistent with the KDOQI (Kidney Disease Outcomes Quality Initiative) guidelines [11,12].
To further limit calcium-related risks, the total elemental calcium intake from calcium-based phosphate binders should not exceed 1,500 mg/day, and total daily calcium intake, including dietary sources, should remain below 2,000 mg. Because of these restrictions, the use of non-calcium phosphate binders has been explored as a safer alternative for hyperphosphatemia treatment in patients with CKD [13].
Non-calcium phosphate binders: sevelamer
Sevelamer is a non-calcium, non-metallic phosphate-binding agent that effectively reduces dietary phosphate absorption by binding to phosphate in the GI tract. It exists in two forms, sevelamer hydrochloride and sevelamer carbonate, and the primary difference is the impact on serum bicarbonate levels. After binding phosphate, sevelamer hydrochloride releases a hydrochloride molecule that lowers serum bicarbonate levels and contributes to metabolic acidosis, which is a concern for patients with CKD. Due to this effect, certain formulations of sevelamer hydrochloride were withdrawn from the market in the United States in 2009. In contrast, sevelamer carbonate does not exhibit this acidifying effect, making it the preferred formulation [14].
Sevelamer offers additional health benefits. Its polymeric amine structure enables bile acid binding, which is similar to bile acid sequestrants used for cholesterol management.
Sevelamer also has the ability to mitigate the risk of hypercalcemia, which is a major concern with calcium-based phosphate binders. Sevelamer is a safer long-term option for patients, particularly those undergoing dialysis who are at a higher risk of complications from hyperphosphatemia [14]. Chan et al. [8] highlighted that while sevelamer is a significant portion of a patient’s daily medication intake, it is the preferable choice because of its non-calcium composition and additional benefits that improve long-term adherence and patient outcomes.
Although sevelamer is more expensive than conventional calcium-based binders, its ability to prevent calcium accumulation and the associated complications justifies its use, especially in populations with high-risk CKD [15]. Sevelamer plays a crucial role in managing CKD-MBD and enhancing patient outcomes because of its pleiotropic benefits including phosphate reduction, lipid-lowering effects, and vascular health improvements.
The novelty of this review lies in its unique focus on Southeast Asia, with perspectives from countries like Thailand, Vietnam, and Malaysia, a region with a high burden of CKD yet limited access to advanced therapies such as sevelamer. Unlike prior global reviews, by emphasizing the pleiotropic benefits of sevelamer and linking clinical evidence with policy and practice gaps, this review provides region-specific insights that can inform both clinical decision-making and health system strategies.
Efficacy and safety of sevelamer
Safety profile
Sevelamer has a favorable safety profile, and it is a well-tolerated treatment option. The most common adverse events related to the GI tract include nausea, vomiting, diarrhea, and constipation. These adverse events are most often mild and managed or prevented by dose reductions or specific symptomatic intervention [18,19]. Because sevelamer does not increase serum calcium levels, patients treated with sevelamer are not at risk for the complications associated with the use of calcium-based phosphate binders (vascular calcification and CV events) [20]. Therefore, sevelamer has a better tolerance profile for the chronic management of hyperphosphatemia with less cardiotoxicity and arterial calcification [21].
Beyond phosphate control in chronic kidney disease: pleiotropic benefits of sevelamer
Hyperphosphatemia in CKD is responsible for several complications including SHPT, bone diseases, and CV complications. While sevelamer manages hyperphosphatemia in CKD, it also manages and resolves other complications. Sevelamer confers several benefits including decreasing low-density lipoprotein cholesterol (LDL-C), contributing to anti-inflammatory action, and reducing markers associated with CV risk. These benefits improve CV outcomes with a decreased mortality in patients with CKD and an enhancement of overall vascular health by reducing systemic inflammation [22]. In the following sections, we discussed additional benefits of sevelamer, emphasizing its crucial role in the comprehensive management of patients with CKD.
Phosphate control and mortality reduction
One of the most intriguing results of the clinical trials on sevelamer is its association with reduced mortality in patients with CKD. Traditional calcium-based phosphate binders are associated with hypercalcemia, leading to vascular calcification and an increased risk of CV disease, which is the most common cause of death among patients with CKD. Managing CV disease is of paramount importance in patients with CKD. Sevelamer effectively reduces serum phosphate levels without increasing calcium level, thereby minimizing the risk of vascular calcification and subsequent CV events [23,24].
Many large multicenter clinical trials demonstrated better survival in patients on sevelamer compared with those on calcium-based phosphate binders. The Dialysis Clinical Outcomes Revisited trial was a randomized, multicenter, open-label study that included over 2,000 patients aged 18 years or older who had received HD for more than 3 months. The study compared the effects of sevelamer and calcium-based phosphate binders on mortality and hospitalization outcomes. Patients in the sevelamer group had lower rates of all-cause hospitalizations (1.7 admissions vs. 1.9 admissions per patient-year, p = 0.02) and fewer hospital days (12.3 days vs. 13.9 days per patient-year, p = 0.03), suggesting a potential benefit in reducing healthcare utilization [22].
Furthermore, one meta-analysis concluded that sevelamer treatment was associated with improvements in patient mortality through the beneficial regulation of lipid metabolism and a negative calcium balance [25]. Another meta-analysis showed that patients treated with sevelamer experienced lower CV mortality due to cardiac arrhythmias compared with patients treated with calcium carbonate (hazard ratio [HR], 0.06; 95% confidence interval [CI], 0.01–0.25; p < 0.001). Similar significant benefits (p < 0.001) were noted for overall CV mortality (HR, 0.09; 95% CI, 0.05–0.19) and all-cause mortality (HR, 0.23; 95% CI, 0.15–0.35) [26].
Calcium-based phosphate binders increase vascular calcification, implying an adverse CV prognosis. Sevelamer does not worsen hypercalcemia and therefore reduces the progression of vascular calcification. A meta-analysis of 127 randomized controlled trials concluded that sevelamer significantly reduced all-cause mortality (risk ratio [RR], 0.610; 95% CI, 0.401–0.929) and hospitalization rates (RR, 0.527; 95% CI, 0.308–0.902). Thus, sevelamer lowers morbidity and mortality in patients with CKD [27]. A recent meta-analysis emphasized that sevelamer was associated with reduced all-cause mortality (RR, 0.28; 95% CI, 0.19−0.41) and vessel calcification score (RR, –0.58; 95% CI, –1.11 to –0.04) and induced less hypercalcemia (mean difference, –0.28; 95% CI, –0.40 to –0.16) and hyperphosphatemia (mean difference, –0.22; 95% CI, –0.32 to –0.13) when compared with calcium-based phosphate binders. The results indicated no significant differences in GI adverse events. Overall, sevelamer is beneficial for decreasing mortality and vessel calcification when used to treat hyperphosphatemia in patients with CKD [25].
Sevelamer possesses anti-calcific properties essential for protecting the vascular system. A switch from calcium-based phosphate binders to sevelamer led to a significant decrease in coronary artery calcification and intermediate endothelial dysfunction, which are predictors of a CV event [28]. These results are explained by the decreased vascular calcification and endothelial dysfunction, both of which are associated with better long-term CV prognosis for CKD patients [29].
Other pleiotropic benefits with impactful clinical consideration
Anti-inflammatory and antioxidant effects
Inflammation and oxidative stress are important mediators of CKD progression and its complications. The majority of patients with CKD have increased levels of cellular inflammatory markers such as interleukin-6 and tumor necrosis factor α, which promote the deterioration of renal function and the progression of CV diseases [30]. Inhibition of inflammatory markers in patients with CKD demonstrates that sevelamer possesses anti-inflammatory effects. One study demonstrated that sevelamer lowered the concentration of C-reactive protein. Because sevelamer decreases inflammation, it may slow the progression of CKD and reduce the risk of CV events directly associated with inflammation [31]. Sevelamer also catalyzes antioxidant activity due to its ability to reduce oxidative stress by quenching free radicals and reducing the synthesis of reactive oxygen species (Fig. 3) [32].
Lipid profile improvement
Sevelamer significantly reduces serum LDL-C and the low-density lipoprotein: high-density lipoprotein ratio in patients receiving dialysis. Improvements were observed as early as 8 weeks after treatment initiation or after switching from calcium-based phosphate binders. These lipid-lowering effects are primarily attributed to the ability of sevelamer to bind bile acids [33].
The Treat-to-Goal study, a randomized clinical trial involving 200 patients receiving long-term HD, was conducted to assess the role of sevelamer in preventing progressive CV calcification commonly observed in patients with end- receiving calcium-based phosphate binders. The study demonstrated that both sevelamer and calcium-based phosphate binders provided comparable control of phosphate levels (end-of-study values: 5.1 ± 1.2 mg/dL and 5.1 ± 1.4 mg/dL, respectively; p = 0.33). However, sevelamer treatment was associated with a significantly slower progression of coronary and aortic calcification. The median percentage increase in calcium score at 52 weeks was 6% with sevelamer vs. 25% with calcium-based phosphate binders for coronary arteries (p = 0.02), and 5% vs. 28%, respectively, for the aorta (p = 0.02). Although LDL-C reduction was not a primary outcome of the study, sevelamer treatment led to a marked decrease in LDL-C levels (from 102 mg/dL at baseline to 65 mg/dL at study completion, with a p-value <0.0001). LDL-C levels were not significantly different in the calcium-based phosphate binder group (102 mg/dL at baseline vs. 103 mg/dL at study completion) [34].
Glycemic control
Emerging evidence suggests that sevelamer may positively affect glycemic control in patients with CKD, particularly those with concomitant diabetes. Although the mechanisms underlying the glycemic control are not completely understood, some studies suggest that sevelamer reduces insulin resistance, improving blood glucose levels. This additional benefit is of great interest because the prevalence of diabetes in patients with CKD is high. Further studies are needed to confirm this benefit of sevelamer [35,36]. Many pivotal clinical trials demonstrate efficacy of sevelamer in managing hyperphosphatemia and its pleiotropic benefits in patients with CKD (Table 1 [23,24,34,37]).
Cost-benefit analyses with sevelamer
Cost-benefit analyses of sevelamer across various healthcare systems have demonstrated its economic advantages over calcium-based phosphate binders. Post-hoc analysis from the INDEPENDENT-CKD study in Italy found that sevelamer led to fewer hospitalizations and lower all-cause mortality, resulting in cost savings of €5,615 per patient over 3 years despite its higher acquisition cost [37]. A Bulgarian cost-minimization analysis comparing sevelamer carbonate and lanthanum carbonate found that sevelamer was more cost-effective in both low-dose and high-dose regimens with a projected 4-year savings ranging from €1.3 to €2.7 million [38]. Similarly, a Markov decision process conducted in the United Kingdom estimated that sevelamer provided an additional 2.05 life years and 1.56 quality-adjusted life years per patient compared with calcium carbonate. The cost-effectiveness ratio was £23,878 per quality-adjusted life year gained, making it a cost-effective first-line treatment for hyperphosphatemia in patients with CKD who were not receiving dialysis [39]. These findings support sevelamer as a clinically and economically viable alternative to calcium-based phosphate binders in managing hyperphosphatemia.
Challenges and barriers to using sevelamer in clinical practice
Managing hyperphosphatemia in patients with CKD-MBD using sevelamer presents several challenges. The most significant barrier is the higher cost compared with conventional calcium-based phosphate binders. In lower-income settings or regions with constrained healthcare budgets, cheaper alternatives are often preferred. Therefore, this limits the widespread adoption of sevelamer. Additionally, accessibility varies across healthcare centers, and rural areas face greater difficulties in obtaining specialty drugs like sevelamer due to distribution and availability constraints [40].
There is also limited awareness of the advantages of sevelamer over calcium-based phosphate binders among healthcare providers. Some physicians are not fully informed about the excellent safety profile and pleiotropic benefits of sevelamer, leading to continued reliance on calcium-based phosphate binders despite the known risks. Expanding educational initiatives for healthcare professionals could improve understanding and promote evidence-based prescribing practices [8].
Patient compliance is also a significant concern because sevelamer requires multiple pills per day. The high pill burden can be particularly discouraging for patients with CKD who are already on multiple medications for various comorbid conditions. Patient education and support programs can enhance adherence and acceptance of sevelamer as part of a long-term treatment plan. Table 2 presents currently used phosphate binders [15,41–43].
To improve accessibility and adherence, healthcare policies should focus on affordability. Targeted educational efforts for both providers and patients can help underscore the benefits of sevelamer. Addressing these barriers will expand the role of sevelamer in hyperphosphatemia and will lead to better long-term outcomes for patients with CKD. In summary, calcium-based phosphate binders are still widely used due to cost considerations, but the integration of sevelamer into treatment regimens for select patients can enhance phosphate control and mitigate risks associated with hypercalcemia. Ongoing education and awareness among healthcare professionals will be vital for optimizing CKD-MBD management (Fig. 4).
Guideline recommendations for managing chronic kidney disease-associated hyperphosphatemia/chronic kidney disease-mineral bone disorder and the role of sevelamer
Sevelamer is a preferred therapeutic intervention by global guidelines (Table 3 [11,44–46]) for the management of hyperphosphatemia in patients with CKD, particularly in patients with an increased risk of hypercalcemia and CV disease. The ability of sevelamer to modulate phosphate and renin-angiotensin system activity without influencing vascular calcification along with other benefits makes it highly desirable in many circumstances.
Malaysia, Thailand, and Vietnam have a high CKD prevalence with a high incidence of CKD-MBD. A key focus within the scope of CKD-MBD is managing hyperphosphatemia. Regional practices in these three countries consider local healthcare systems, availability and accessibility of drugs, and the health status of people in those countries and stress the importance of hyperphosphatemia control to manage CKD-MBD. While calcium-based phosphate binders are still the mainstay of treatment because of their relatively low cost, there is growing acceptance of non-calcium-based phosphate binders, including sevelamer, particularly for patients who are high risk (Table 4 [47–50]).
Practical clinical experience using sevelamer in Southeast Asia
Sevelamer is a key non-calcium phosphate binder in Southeast Asia for managing hyperphosphatemia in patients with CKD-MBD, particularly those at risk of hypercalcemia and vascular calcification. Experts across the region highlight its effectiveness in lowering serum phosphate levels while avoiding calcium accumulation. It is the preferred choice for patients with CV risk or those who cannot tolerate calcium-based phosphate binders. Many physicians initiate treatment at 800 mg three times daily, often requiring dose escalation or combination with low-dose calcium carbonate for optimal phosphate control.
Despite its clinical advantages, accessibility remains a significant challenge in Southeast Asia. The relatively high cost and lack of comprehensive health insurance coverage in several countries have limited its widespread use. Sevelamer is currently a second-line option in many public healthcare settings. The introduction of generic sevelamer has improved access, but affordability continues to remain a barrier. Experts emphasize the need for greater awareness, enhanced physician education, and policy level changes to facilitate early intervention and broader availability. The high pill burden is another challenge, although its relatively neutral taste and tolerability may improve adherence for some patients.
CKD-MBD management in Southeast Asia is often delayed due to late diagnosis and a limited understanding of phosphorus control. Experts stress the importance of structured treatment guidelines, patient education, and multidisciplinary approaches to improve early detection and intervention. Mild GI side effects such as nausea and abdominal discomfort are occasionally reported, although these do not significantly impact adherence.
Overall, sevelamer remains a highly effective phosphate binder with important long-term benefits beyond phosphate control. However, financial constraints, limited insurance support, and regional disparities in access continue to hinder its widespread adoption. Further research, policy reforms, and cost-effective strategies such as combination therapy with calcium-based phosphate binders may optimize its use and improve patient outcomes in CKD-MBD management across Southeast Asia.
Conclusions
Sevelamer is an effective treatment for hyperphosphatemia in patients with CKD, especially in patients at risk for hypercalcemia and vascular calcification. Unlike calcium-based phosphate binders, sevelamer lowers phosphate levels without raising calcium levels and leads to reduced CV risks. It also offers added benefits like lipid-lowering and anti-inflammatory effects. Despite its advantages, the high cost and limited insurance coverage hinder its widespread use. However, experts have highlighted its long-term cost-effectiveness by reducing mortality and other complications. Generic sevelamer has improved access in some areas, although broader adoption requires policy support and awareness. The safety, efficacy, and additional benefits make sevelamer a valuable option, especially for patients needing strict phosphate control without calcium-related risks.
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