Phosphorous Binder Equivalent Dose

Ever encountered this situation?  You're going about your daily business and discover that one of your patients on hemodialysis has an elevated phosphorous.

You skim through the list of prerequisites and see that yes, the nutritionist has been by to review dietary sources of phosphorous, the dialysis nurse has checked in on adherence to phosphorous binding medications, there's no activated vitamin D on the med list and you've explored increasing the frequency of dialysis or moving to extended nocturnal with the patient before and it's not in the cards.

Is there anything rational that can be done with the phosphorous binder dose to improve phosphorous control?  Thanks to the good work of the folks at the Frequent Hemodialysis Network (FHN) trial the answer is yes.

During the trial the investigators faced the question of whether or not changes or substitutions in multi-binder regimens represented increases or decreases in phosphorous binding capacity.  In order to answer this question the investigators combed through stool and urinary phosphorous recovery studies of individuals given various phosphate binders.   In these trials individuals were given test meals with known amounts of phosphorous.  The amount of free phosphorous appearing in the stool or urine was measured with and without binders with the difference being considered the amount of phosphorous being bound to binders in the gut.

With this information in hand the FHN group additionally looked at parallel group trials were patients on dialysis were given one of two binders and then had their doses titrated to equal serum phosphorous levels.  What emerged was a picture of the relative phosphorous binding capacity of various common binders.  Below is a table of commonly used phosphorous binders and the derived phosphate binder equivalent doses.

As you can see, all the phosphate binder equivalent doses are referenced to 1g of calcium carbonate.  So as an example, 5 tabs of 800mg sevelamer carbonate binds an equivalent amount of phosphorous (5 times 0.6 = 3) to 3 tabs of 500mg lanthanum carbonate (3 times 1.0 = 3).

Now, where ones phosphorous should ideally be is unclear (as nicely pointed out over at PBF a while back) as is the choice of agent (unless you count the realization that chronic aluminum binders where a bad deal).

Both the KDOQI and KDIGO guidelines don't endorse any one class binders over any other (again, excluding aluminum) though KDIGO gives a "2C = we suggest based on low grade evidence" that calcium based binders be restricted in the presence of arterial calcification, adynamic bone disease or persistently low PTH.  KDOQI, based on expert opinion, suggests that the amount of calcium from binders be limited to 1.5g/day (there are 200mg of calcium in a 500mg calcium carbonate tab and 169mg of calcium in a 667mg tab of calcium acetate).

I think we need to have a talk about your diet

The picture above comes from a case report in KI where a PD patient presented with hypertension and edema. She was normally compliant and a plain film of her abdomen was performed to make sure that her catheter was properly sited. Densely radiopaque material was found to be present throughout her colon. There was no history of recent contrast studies and she was asymptomatic. What could cause this radiographic appeareance?

The answer to this mystery lay in her medications. She had been started on the phosphate binder lanthanum carbonate 3 months previously. Lanthanum is a rare earth metal which lies next to barium on the periodic table and has a high affinity for phosphate. It has little systemic absorption and low solubility and remains largely in the intestine after ingestion. It is a high density material with a density between that of bone and metal. The CT above shows lanthanum tablets in the stomach which have a higher density (3000HU) than the radiocontrast in the aorta (450HU). This accumulation appears to cause no ill effects and disappears once the drug is stopped or with the use of laxatives. The main issue is that it may interfere with the interpretation of xrays and radiologists should be informed that a patient is on this drug prior to abdominal imaging in order to prevent confusion.

The PPI Paradox

Millions of people take long-term proton pump inhibitors for acid-related GI complaints. These agents are very effective and appear to have an excellent safety profile. However, they may also have interesting effects on calcium and phosphate balance that I recently became aware of.

PPIs act via inhibition of the parietal cell H+/K+ ATPase, producing an ‘inhibitory complex’ which blocks HCl secretion and results in loss of the normal acidic environment of the upper GI tract. Ordinarily, this acidic milieu facilitates the release of ionized calcium from insoluble calcium salts, improving calcium solubility, which is necessary for its absorption. Reduced absorption of calcium is believed to explain the increased rates of osteopenia and fracture seen in medical states associated with achlorhydria, such as pernicious anemia and post-gastrectomy. Furthermore, several studies show that long-term PPI therapy, particularly at high doses, is associated with an increased risk of hip fracture. Also, long-term PPI use can lead to hypomagnesemia with a low fractional excretion of Mg, suggesting a similar mechanism may be responsible.

Based on these observations, I began to wonder if PPIs would decrease the efficacy of calcium-based phosphate binders, via a reduction in the ionized fraction available to bind phosphate in the gut. There is almost nothing written on this, apart from a single, small, prospective Japanese study that did indeed show that acid suppression significantly reduced the phosphorus binding ability of calcium carbonate, resulting in impaired phosphate control in hemodialysis patients.

Then, just to keep things interesting, I found another study that suggests that PPIs may have the opposite effect when given with non-calcium containing binders. In a retrospective analysis of 108 HD patients, more patients taking a PPI plus a phosphate binder achieved phosphorus control, defined as an average phosphorus level below 6 mg/dL and "a calcium × phosphate product level less than 55, than did those taking only a phosphate binder (76% vs 24%; P = .001). However, the benefits were only observed in those taking sevelamer; these authors did not replicate the findings from the aforementioned study from Japan. The mechanism behind this observation are not known.

So there you have it: there is a suggestion from this rudimentary evidence that PPIs may potentially impair phosphate control when given with calcium-containing binders, but paradoxically improve control when given with non-calcium containing binders. This could form the kernel of an interesting clinical study…

Lipid-Lowering Effect of Renagel

This has been known for awhile, but it is worth repeating--sevelamer (Renagel), in addition to its ability to act as a phosphate binder, also results in LDL cholesterol-lowering effects.

Two of the early articles (a 1998 Clinical Nephrology study by Wilkes et al, as well as this 1998 NDT paper by Goldberg et al), first noted this unexpected association.  In the former paper, a group of dialysis patients subjected to sevelamer hydrochloride therapy following a phos-binder washout period was noted to have a 35.9% fall in LDL cholesterol with an HDL cholesterol level that remained relatively stable.  This LDL-lowering effect is also present in the newer formulation of Renagel, sevelamer carbonate.  

It is unclear exactly what this lipid-lowering effect may indicate, especially considering the repeated finding that statins appear to be less efficacious in CKD/ESRD patients than in the general population in terms of lowering cardiovascular mortality.  Still, it is tempting to speculate that cholesterol-lowering should be a good thing for CKD/ESRD patients given their high rate of CVD.  The jury is still out in terms of what is the optimal phosphate binder to use in a given clinical scenario, but the lipid-lowering effect of Renagel does make it somewhat unique from the other phosphate binders available.  

Phosphate Binders Lower Mortality in ESRD Patients

I heard a talk today by one of the fellows in our program who is also the senior author on this recent JASN article: Phosphorus Binders and Survival on Dialysis.

Interestingly, even though the current KDOQI Guidelines recommend the use of phosphate binders to maintain serum phosphorus levels within the normal range, there has never been a randomized controlled trial demonstrating the superiority of their use compared to placebo. The FDA approval of phosphate binders is based primarily on their ability to lower serum phosphorus, rather than any hard outcomes such as mortality or cardiovascular disease.

Furthermore, the practice of prescribing phosphate binders is so ingrained in nephrologists, and is considered the standard-of-care based on the current practice guidelines, that it would be considered ethically inappropriate to conduct a phosphate binder-versus-placebo prospective study today.

As such, the authors of the above study looked at a cohort of over 10,000 patients within the Fresenius dialysis system and divided them into two groups, which were followed prospectively: those who were prescribed phosphate binders, and those who were not. Obviously, it is difficult to completely eliminate confounders in a study like this, but the authors attempted to do so by performing a technique known as propensity score matching, in which patients with similar baseline characteristics are matched with one another and those at the extremes (e.g., too healthy, too sick) are excluded from the study. I'm no stat-man myself, but a friend of mine who is claims that propensity score matching is becoming the accepted standard for these types of epidemiologic studies. In any case, the authors of this study found a substantially decreased one-year mortality in patients who were treated with phosphate binders compared to those who were not.

Sevelamer Carbonate

Renagel (sevelamer hydrochloride) is one of the most utilized phosphate binders in the U.S., though its superiority compared to other (and cheaper) phosphate binders remains controversial. One of the theoretical benefits of using Renagel is that it should not contribute to hypercalcemia, a possible side effect of the common calcium-containing phosphate binders (e.g., calcium acetate, calcium carbonate), which could possibly contribute to the increased vascular calcification seen in ESRD patients.

One of the drawbacks of using sevelamer hydrochloride--particularly in advanced CKD patients who have not yet reached dialysis--is its tendency to cause a metabolic acidosis, based on the hydrochloride moiety which forms the salt. To get around this, the drug company (Genzyme) has manufactured another form of sevelamer, this time conjugated to carbonate. The drug (sevelamer carbonate) is being marketed under the name "Renvela". We'll see how it works.

DCOR Trial

The DCOR Trial was a Genzyme-funded randomized control trial--somebody recently told me the largest ever conducted in a dialysis population--designed to compare the phosphate binder sevelamer (Renagel) with Ca-containing phosphate binders (calcium acetate a.k.a. Phoslo or calcium carbonate). The theory behind the trial is that since cardiovascular disease is the #1 killer of ESRD patients, and since vascular calcifications are hypothesized to cause accelerated atherosclersosis, then a non-calcium-containing phosphorus binder such as sevelamer would be expected to not contribute as much to vascular calcifications and cardiovascular disease.

Sounds good, but the primary end-point of mortality was identical in the two groups. In "sub-group analysis", there was allegedly a trend towards benefit in the sevelamer group in those >65 years of age or those who had been taking the medication for >2 years, but overall there seems to be a consensus that this represents a negative trial.

In related news, sevelamer costs significantly more than calcium acetate (and certainly more than calcium carbonate for that matter). You make the call as to which phosphate binder is better for your patients...