Pill burden, adverse events signal new treatments needed for phosphorus management
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Shivam Joshi, MD, knows he has few options for his patients on dialysis when it comes to the management of hyperphosphatemia. And none are very effective.
“Phosphate binders tend to be large, numerous and expensive,” Joshi, a nephrologist at the Orlando VA Medical Center, told Healio/Nephrology News & Issues.
While not all patients require binders, food sold at grocery stores and fast-food restaurants often have high levels of phosphorus, Joshi said. “One definitely wants to avoid processed foods that can have several phosphorus-containing ingredients with 100% bioavailability. Since it is not listed on nutrition labels, consumers don’t always know the phosphorus content,” he said.
Sharon M. Moe, MD, the director of the division of nephrology and Stuart A. Kleit Professor of Medicine at the Indiana University School of Medicine, offers guidance to her patients about avoiding phosphorus.
“Nearly all foods contain phosphorus, especially those high in protein and dairy products,” she told Healio/Nephrology News & Issues. “However, the major ‘hidden’ source is in the preservatives used in boxed and canned foods as these are more readily absorbed in the intestine and are less recognized by patients.”
Phosphate additives also contain sodium or potassium.
“I recommend that patients shop the external perimeter of the grocery store, which is generally unprocessed food,” she said.
Treatment value
Binders have limited effectiveness, Moe said. “All phosphate binders bind the phosphorus in food, which is why these have to be taken with meals. The differences between calcium and non-calcium phosphate binders are not due to phosphorus binding, but rather the other part of the compound,” she told Healio/Nephrology News & Issues. “Excess calcium from calcium binders leads to arterial calcification. Sevelamer may have effects by binding other things; some are good, like decreasing lipids and inflammation, but it can also bind some vitamins and drugs.
“Use of the iron-based binders may contribute to increase iron intake,” Moe said.
Joshi has looked at other options to control phosphorus, including directing his patients to a whole-food plant-based diet. Phosphorus is often contained in prepared foods, but plant-based phosphorus is mostly bound as phytates, which means it is not absorbable, he said.
Joshi said the opportunity to reduce the impact of hyperphosphatemia and reduce the use of binders is appealing to patients.
“If patients are able to reduce their need for phosphorus binders through dietary change, many of them are interested in doing so,” he told Healio/Nephrology News & Issues.
A study published in the JAMA by Catherine Sullivan, MS, RD, LD, and colleagues showed that patients who were educated on avoiding foods that listed phosphorus on the label saw improvements in controlling hyperphosphatemia compared with a control group that received no education. “After 3 months, the decline in serum phosphorus levels was 0.6 mg/dL larger among intervention vs. control participants,” the researchers wrote.
The patients who received education on phosphorus also had statistically significant increases in reading ingredient lists and nutrition facts labels. Sullivan and colleagues discovered, however, that many foods do not contain labeling for phosphorus.
“Policymakers should consider both the health costs associated with high phosphorus intake and hyperphosphatemia, as well as policy approaches to address this problem,” they wrote. “Mandatory labeling of phosphorus content may help patients to better monitor and limit their phosphorus intake and may encourage manufacturers to limit the use of phosphorus-containing additives.”
Phosphorus intake
Left untreated, excessive phosphorus can lead to long-term complications.
“Hyperphosphatemia is a direct vascular toxin and causes arterial calcification,” Moe told Healio/Nephrology News & Issues. “This can be in coronary arteries where it causes heart attacks, in the aorta where it contributes to left ventricular hypertrophy, peripheral arteries where it causes ischemia and can lead to amputations, and in small arteries of the skin where it causes calciphylaxis-skin necrosis.
“All of these problems will increase mortality,” she said.
A new study is underway that may help clinicians determine what phosphorus levels should require intervention. Myles Wolf, MD, MMSc, the Charles Johnson, MD, Distinguished Professor of Medicine and chief of the division of nephrology at Duke University School of Medicine, told Healio/Nephrology News & Issues that determining the risk level of phosphorus will lead to more consistent patient management.
Source: Shawn Rocco/Duke Health
Called HiLo: Pragmatic trial of higher vs. lower serum phosphate targets in patients undergoing hemodialysis, the study began March 13, 2020, with funding from the National Institute of Diabetes and Digestive and Kidney Diseases, and has plans to enroll 4,400 patients by the time the study ends on April 30, 2025, Wolf, the principal investigator, said.
“Despite tremendous time, energy and cost expended on lowering serum phosphate in patients undergoing dialysis, we have no clinical trial-grade evidence that demonstrates that our current approach improves patient longevity or quality of life,” Wolf told Healio/Nephrology News & Issues. “Our current therapeutic paradigm is shaped by opinion-based clinical practice guidelines that are based on human observational and preclinical studies, not randomized clinical trials.”
Wolf said a more evidence-based approach could help reduce the high dose of binders, something patients would welcome. “There are several potential concerns we have with binders now,” Wolf said, “including a heavy pill burden; excess cost to patients; excess calcium intake; restricted diet aimed at avoiding phosphate and reduced appetite due to the excessive pill burden.
“Taken together, binders may exacerbate malnutrition, and patients who fail to meet the desired phosphate target, despite their best efforts are at risk of being labeled as ‘noncompliant,’ which may subconsciously adversely affect the quality of care delivered by their health teams,” he said.
The primary hypothesis for the study is to “determine whether less stringent control of serum phosphate to target levels of greater than 6.5 mg/dL will yield a reduction in the hierarchical composite outcome of time to all-cause mortality and all-cause hospitalization among patients with [end-stage renal disease] ESRD undergoing hemodialysis,” according to the study description on ClincialTrials.gov. The current standard approach of targeting serum phosphate levels is less than 5.5 mg/dL.
More information on enrolling patients in the trial is available at hilo@duke.edu.
Compliance
A recent survey completed by the National Kidney Foundation found patients with hyperphosphatemia struggle to comply with binder use. The NKF said 475 patients on dialysis who are currently prescribed phosphate binders and take an average of seven binders per day participated in the survey, which was conducted online between Sept. 28, 2022, and Oct. 8, 2022.
The results showed that more than 80% of respondents “struggle to manage their serum phosphorus levels, with more than 90% citing a need for new treatment options,” according to an NKF press release on the survey.
“Despite best efforts with current treatment strategies, a significant proportion of patients have persistent hyperphosphatemia, placing them at an increased risk for mineral and bone disorder complications, including vascular disease,” Joseph Vassalotti, MD, chief medical officer for the NKF, said in the release. “These survey results point to the difficulty people living with kidney diseases treated with dialysis have coping with low phosphorus diet and current medication schedules.”
Other results from the survey showed the following:
- 18% of patients reported consistently maintaining their phosphorus within range on a monthly basis; and
- as many as 88% of respondents reported at least some difficulty taking phosphate binders, with 60% reporting adverse events from their phosphate binder pills, including nausea, diarrhea, constipation and vomiting.
The survey was conducted by the NKF and sponsored by the Patient Advisory Council of Ardelyx Inc.
Dawn P. Edwards has many years of experience with dialysis – and dealing with the discomfort and challenges of hyperphosphatemia.
“I have to take 12 ‘horse pills’ a day and I am already on fluid restrictions,” Edwards, who is on nocturnal home hemodialysis, said during her testimony at a recent hearing on a new phosphorus treatment under development by Ardelyx. “Taking over five pills a meal is overwhelming.”
- References:
- NKF and Ardelyx Inc. survey finds dialysis patients struggle to maintain serum phosphorus levels. www.kidney.org/news/nkf-and-ardelyx-inc-survey-finds-dialysis-patients-struggle-to-maintain-serum-phosphorus-levels. Published Nov. 4, 2022. Accessed Nov. 20, 2022.
- Sullivan C, et al. JAMA. 2009;doi:10.1001/jama.2009.96.
- www.healio.com/news/nephrology/20221117/fda-committee-votes-in-favor-of-xphozah-for-phosphate-control-in-patients-on-dialysis
- www.healio.com/news/nephrology/20220306/plantbased-diets-may-help-reduce-phosphorous-levels-for-patients-on-dialysis
- For more information:
- Shivam Joshi, MD, can be reached at shivam.joshi@va.gov.
- Sharon M. Moe, MD, can be reached at smoe@iu.edu.
- Myles Wolf, MD, MMSc, can be reached at myles.wolf@duke.edu.
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