Division of Nephrology Bone and Mineral MetabolismUniversity of KentuckyLexingtionUSA Email: hhmall{at}uky.edu
Sir,
We are pleased our editorial prompted interest in the nephrology community and that Dr Amato agrees with our description of historical and recent developments in hyperphosphataemia management in chronic kidney disease [1].
As detailed in our editorial, the 30 year search for optimizing phosphorus control through the use of phosphate binding agents has presented nephrologists with new challenges. As we have attempted to regain mineral homeostasis with the aid of phosphate binders in a patient population without renal excretion, we have come to recognize the important regulatory role of bone and intestinal absorption. We have learned that excessive accumulation of aluminium, the standard phosphate binder in the 1970s, is associated with bone and brain toxicity. We have also learned that years of excess calcium intake from calcium salts, the standard binding therapy over the last two decades, is associated with cardiovascular calcification and increased risk for cardiovascular morbidity and death. Thus, the nephrology community has continued its search for phosphate binding agents free of the risks of toxicities.
In their letter, and Aterinil Amato raises questions concerning the tolerability of sevelamer hydrochloridea non-absorbed, aluminum-free, calcium-free phosphate binderbased on their own clinical observations of associated gastrointestinal discomfort and their interpretation of the results of a multi-centre, open-label, dose-titration study designed to examine the efficacy of this binding agent [2].
In my clinical experience, gastrointestinal complaints associated with sevelamer are relatively rare, particularly in patients who have not previously received phosphate binders. In patients switching from calcium-based binders, it may be beneficial to avoid abrupt discontinuation of calcium salts. The dose of calcium-binder should be titrated down as the sevelamer dose is titrated up, while maintaining phosphorus control. Use of stool softeners should be reduced accordingly.
In the study that and Aterinil Amato cites, the mean starting daily dose was 4.0 g sevelamer; the mean daily dose at the end of the 8 week treatment period was 5.4 g sevelamer [2]. Fifteen out of 168 patients, or 8.9% (not 10.4% as Dr Amato states), were discontinued due to adverse events. The investigators did not indicate how many of the adverse events that led to discontinuation from the study were due to gastrointestinal discomfort; however, they did note that sevelamer was well tolerated and that no differences in adverse effects were observed across the dose level groups [2].
In a long-term, open-label study of sevelamer (n=192 haemodialysis patients; mean daily dose=5.3 g sevelamer), summarized in our editorial, gastrointestinal complaints led to study withdrawal in seven patients, or 3.6%, of patients [3]. The authors noted that drug-related adverse events were infrequent and generally mild.
In an open-label, randomized, crossover study comparing efficacy and safety of sevelamer and calcium acetate, there were no statistically significant differences in the incidence of gastrointestinal complaints between the two groups (34% for sevelamer treatment vs 28% for calcium acetate; P=0.26) [4]. No serious adverse events related to the binders occurred in either group. The investigators noted that while gastrointestinal adverse events were common in both treatment groups, these events were often related to the dialysis procedure, and did not lead to differences between the groups' medication compliance or study withdrawal rates.
Similarly, an earlier randomized, placebo-controlled, double-blind trial of sevelamer found no significant differences in adverse events between the placebo and sevelamer groups [5].
In summary, clinical studies indicate that sevelamer is typically, relatively well tolerated. The incidence of adverse events and gastrointestinal discomfort associated with sevelamer are similar to placebo and calcium acetate, and may be related to other aspects of haemodialysis treatment. Amato's anecdotal observation of gastrointestinal discomfort with increasing sevelamer doses in his patients is surprising, as dose-titration studies have not shown a dose-relationship with adverse events [2]. A plethora of dietary, disease and treatment variables make it difficult to define a causal relationship between sevelamer dose and gastrointestinal discomfort. Differences in diet, dose titration and use of supplemental binders between Amato's and Arterinls patients in Italy and the patients in the various US clinical trials may account for some of these discrepancies.
We must evaluate binders based on their effectiveness to reduce serum phosphorus, while avoiding the larger hazards of toxicities and cardiovascular calcification. The ideal binder would regain phosphorus-calcium balance, and have an adverse events profile and compliance rate similar to placebo. Have we arrived yet?
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