Sevelamer: A Phosphate Binder Friend With Benefits?
Hello. This is Jeffrey Berns from the Perelman School of Medicine in Philadelphia. I am Editor-in-Chief of Medscape Nephrology.
I was making rounds in the hospital a couple of weeks ago with some of the fellows, and we got to talking about the role of endotoxemia in the setting of obstructive jaundice and acute kidney injury. One thing led to another, and we ended up discussing the potential role of endotoxin as a factor in morbidity and mortality among patients with chronic kidney disease (CKD) and those with end-stage renal disease. When we went into the literature and looked a little bit, I found a March 2012 paper in the Clinical Journal of the American Society of Nephrology reporting the results of what was called the INDEPENDENT Study, by Di Iorio and colleagues. This was a relatively small, randomized, but unblinded study in patients with CKD stages III-IV (and a few with stage V CKD) that compared the phosphate binder sevelamer with calcium carbonate. By way of full disclosure, I have no financial interest one way or another in any phosphate binder.
Over a 2-year period, these investigators found a statistically significant, and quite substantial, reduction in all-cause mortality in the patients with CKD who received sevelamer vs calcium carbonate. They also found a trend toward a reduction, although not statistically significant, in the need for initiation of dialysis. The authors also observed a cholesterol-lowering effect of sevelamer, which has been observed before. In addition, there seemed to be a reduction, although not robust, in C-reactive protein (CRP) levels, which raises the possibility that there is some pleiotropic, anti-inflammatory effect of sevelamer that is not seen with the calcium-containing phosphate binders.
Subsequently, I looked a bit more at the literature and found some potential basis for an anti-inflammatory or an antioxidant effect, perhaps, of sevelamer that the other binders may not have. For example, a cross-sectional clinical study in 2009 by Jaber's group showed that sevelamer use was associated with lower endothelin levels in the blood and reductions or lower levels of interleukin (IL)-6 and CRP presumably from the effect of sevelamer binding endotoxin in the gut and thus reducing systemic inflammation.
In 2010, Hauser found that sevelamer reduced tumor necrosis factor (TNF) alpha and endothelin levels in a uremic rat model. In a clinical study in 2011, sevelamer was compared again with calcium acetate, and sevelamer use was associated with reductions in CRP, IL-6, IL-10, and endothelin. Other effects of sevelamer have been reported in the literature, including changes in glycated hemoglobin, advanced glycation end products, fibroblast growth factor-23, TNF alpha, fetuin-A, and so forth. So it raises the possibility that sevelamer may have effects that the other phosphate binders do not have, which extend beyond the phosphate-binding effects and may extend into the anti-inflammatory, antioxidant, antiatherogenic realm.
This is an interesting literature, still very preliminary, but it does make you consider the potential role for this particular phosphate binder compared with the others. It would be great to see some larger randomized controlled trials with very sophisticated analyses of these inflammatory markers and some hard cardiovascular and mortality endpoints. Keep your eyes out; I suspect we will see more about sevelamer's non-phosphate-binding effects in the future.
This is Jeff Berns, Editor-in-Chief of Medscape Nephrology. Thanks for listening.
Hello. This is Jeffrey Berns from the Perelman School of Medicine in Philadelphia. I am Editor-in-Chief of Medscape Nephrology.
I was making rounds in the hospital a couple of weeks ago with some of the fellows, and we got to talking about the role of endotoxemia in the setting of obstructive jaundice and acute kidney injury. One thing led to another, and we ended up discussing the potential role of endotoxin as a factor in morbidity and mortality among patients with chronic kidney disease (CKD) and those with end-stage renal disease. When we went into the literature and looked a little bit, I found a March 2012 paper in the Clinical Journal of the American Society of Nephrology reporting the results of what was called the INDEPENDENT Study, by Di Iorio and colleagues. This was a relatively small, randomized, but unblinded study in patients with CKD stages III-IV (and a few with stage V CKD) that compared the phosphate binder sevelamer with calcium carbonate. By way of full disclosure, I have no financial interest one way or another in any phosphate binder.
Over a 2-year period, these investigators found a statistically significant, and quite substantial, reduction in all-cause mortality in the patients with CKD who received sevelamer vs calcium carbonate. They also found a trend toward a reduction, although not statistically significant, in the need for initiation of dialysis. The authors also observed a cholesterol-lowering effect of sevelamer, which has been observed before. In addition, there seemed to be a reduction, although not robust, in C-reactive protein (CRP) levels, which raises the possibility that there is some pleiotropic, anti-inflammatory effect of sevelamer that is not seen with the calcium-containing phosphate binders.
Subsequently, I looked a bit more at the literature and found some potential basis for an anti-inflammatory or an antioxidant effect, perhaps, of sevelamer that the other binders may not have. For example, a cross-sectional clinical study in 2009 by Jaber's group showed that sevelamer use was associated with lower endothelin levels in the blood and reductions or lower levels of interleukin (IL)-6 and CRP presumably from the effect of sevelamer binding endotoxin in the gut and thus reducing systemic inflammation.
In 2010, Hauser found that sevelamer reduced tumor necrosis factor (TNF) alpha and endothelin levels in a uremic rat model. In a clinical study in 2011, sevelamer was compared again with calcium acetate, and sevelamer use was associated with reductions in CRP, IL-6, IL-10, and endothelin. Other effects of sevelamer have been reported in the literature, including changes in glycated hemoglobin, advanced glycation end products, fibroblast growth factor-23, TNF alpha, fetuin-A, and so forth. So it raises the possibility that sevelamer may have effects that the other phosphate binders do not have, which extend beyond the phosphate-binding effects and may extend into the anti-inflammatory, antioxidant, antiatherogenic realm.
This is an interesting literature, still very preliminary, but it does make you consider the potential role for this particular phosphate binder compared with the others. It would be great to see some larger randomized controlled trials with very sophisticated analyses of these inflammatory markers and some hard cardiovascular and mortality endpoints. Keep your eyes out; I suspect we will see more about sevelamer's non-phosphate-binding effects in the future.
This is Jeff Berns, Editor-in-Chief of Medscape Nephrology. Thanks for listening.
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