One of my favorite aspects of being a nephrologist is rounding at the dialysis unit. Using a team-based approach (with the patient at the center of the team) we work together to achieve optimal, patient-centered outcomes. Patients interact with the facility administrator, social worker, dietician, nurses, and technicians multiple times per week and when acute issues arise, we can often troubleshoot them quickly, provide guidance and interventions, and monitor for improvement. However, one aspect of dialysis rounds that can feel unsatisfactory for the patient and the healthcare team is the management of hyperphosphatemia. In their Perspective published in AJKD, Scialla et al discuss the current state of evidence for the use of phosphorus binders in both non-dialysis CKD and end-stage kidney disease.
Disorders of mineral metabolism, including hyperphosphatemia, have been associated with all-cause, cardiovascular, and fracture-related morbidity and mortality in patients with chronic kidney disease, including patients on hemodialysis. The net absorption of dietary phosphorus through the intestinal tract is estimated at 40-80% and is dependent on the type of diet as well as hormones such as active vitamin D. In patients without advanced kidney failure, >95% of the excretion of phosphorus is through urine, regulated by PTH and FGF-23. Phosphorus is found naturally in foods that are rich in protein (meat, poultry, fish, dairy products), including some plant sources (including various seeds, nuts, and legumes). An additional major source of dietary phosphorus intake is via preservatives and additives found in processed foods. Phosphorus salts that are used for extending shelf life, enhancing flavor, and improving color often have complex names which make it difficult to identify them as phosphorus-containing moieties and the FDA does not require manufacturers to disclose the quantity of phosphorus per serving of these additives on food labels. In addition, given that these additives are in the inorganic form and not protein-bound, 90% or more may be absorbed in the GI tract, compared to the 40-60% absorption of phosphorus from natural foods. It is not surprising, therefore, that modification of dietary phosphorus intake while meeting other nutritional goals is a significant challenge.
Prescribing medication to decrease intestinal phosphorus absorption seems like a reasonable way to try to combat this potentially modifiable risk factor for poor outcomes. According to the Dialysis Outcomes and Practice Patterns Study (DOPPS), calcium-based and sevelamer-based products are most commonly used (40% and 30% respectively). A combination of these products are used in 15% of patients and the remaining 15% are prescribed other agents including lanthanum carbonate or the new iron-based agents. Scialla, et al. discuss the evidence, or lack thereof, for the use of phosphate binders in patients with CKD.
In patients with CKD not requiring dialysis, there is little evidence that the use of phosphorus binders is beneficial. Serum phosphorus remains normal until late CKD (stage 4-5). PTH and FGF-23 effectively maintain stable serum phosphorus by increasing fractional excretion of phosphorus as glomerular filtration decreases (FGF-23 also reduces gut absorption of phosphorus by downregulating active vitamin D). While this may have a beneficial impact on phosphorus control, the impacts of alterations in PTH and FGF-23 may lead to adverse cardiac morbidity and mortality, and this is an area of ongoing study.
Only 9 randomized clinical trials have compared the use of various phosphorus binders in non-dialysis CKD (See Table 1 above). The largest few studies included approximately 200 patients and the outcomes assessed were biochemical, not patient-centered or clinical. Lessons learned from other classes of medications, such as erythropoietin-stimulating agents, have taught us that focusing exclusively on surrogate rather than clinical or patient outcomes, can lead to treatments that not only may not be beneficial, but in fact could even cause harm. The authors here point out that given the lack of data that the surrogate outcomes studied lead to clinically meaningful outcomes, phosphorus binders should likely only be used in non-dialysis CKD in severe cases.
Similarly, there is a lack of randomized clinical data in end-stage kidney disease to indicate directly beneficial effects of phosphate lowering on patient-centered or clinical outcomes. However, it is known that abnormalities in phosphorus and phosphate-regulatory pathways including PTH and FGF-23 are implicated in bone disease and conditions including pruritis and calciphylaxis which certainly negatively impact patients’ quality of life. Given that hyperphosphatemia can become severe in patients on dialysis, the authors conclude that the use of phosphorus-lowering binders is indicated in dialysis patients. Cardiovascular outcomes are certainly of concern to patients and trials such as Hi-Lo and PHOSPHATE are underway to determine if targeting a lower phosphorus level has a beneficial impact on cardiovascular events in dialysis patients.
Many nephrologists determine which binders to prescribe to dialysis patients based on the serum calcium level. Hypercalcemia, which may be promoted by the use of calcium-based binders, increases the risk of vascular calcification. In addition, sevelamer-based binders may have a beneficial effect of lowering serum cholesterol and reducing inflammatory markers, while newer iron-based binders may have beneficial effects on iron homeostasis, thereby reducing the need for IV iron and ESAs. Phosphate binder selection is further complicated by other factors of very high importance to patients including medication costs, pill burden, and side effects. Scialla, et al. note that until we have better evidence that non-calcium based binders have a clear advantage for clinical outcomes, their use over calcium-based binders may not outweigh the potential downsides including healthcare costs and GI side effects. See Table 2 below for a list of available binders
Lastly, the authors note that the data on calcium-based versus non-calcium based binders for treatment of hyperphosphatemia in patients on dialysis has come from relatively low quality studies with moderate-to-high likelihood of bias for several reasons, including small study size, high rates of attrition, open-label design, lack of power, incomplete reporting of data, high degrees of heterogeneity in findings, and sponsorship from industry. The LANDMARK Study is ongoing and aims to compare the risk of cardiovascular events with lanthanum carbonate versus calcium carbonate in over 2,300 patients on dialysis. At this time, there is not enough evidence to universally favor one class of phosphorus binders over another for patients with kidney disease. The authors describe the evolution of guidelines regarding restricting total calcium intake from phosphorus binders in patients with kidney disease, from K/DOQI (2003) to KDIGO (2009) to the updated KDIGO guidelines (2017) and acknowledge that the evidence is rated as 2B for patients with non-dialysis CKD and expert opinion for patients on dialysis.
Control of serum phosphorus and related bone-mineral disorders in patients with CKD including those on dialysis often feels like a figurative and literal burden that can be difficult to overcome. Nutritional counseling and the selection of the best available, accessible, and tolerable mediations remain the mainstays of minimizing morbidity and mortality. Despite the very real challenges, real-world management of this aspect of kidney disease is an opportunity for the patient and healthcare team to work closely to achieve desired patient-centered targets and for innovation in medical management within nephrology.
Title: State-of-the-Art Management of Hyperphosphatemia in Patients With CKD: An NKF-KDOQI Controversies Perspective
Authors: Julia J. Scialla, Jessica Kendrick, Jaime Uribarri, Csaba P. Kovesdy, Orlando M. Gutiérrez, Elizabeth Yakes Jimenez, and Holly J. Kramer