Evaluation of intestinal phosphate binding to improve the safety profile of oral sodium phosphate bowel cleansing.

Stef Robijn,Anja Verhulst,Patrick C D’Haese,Benjamin A Vervaet,Utpal Sen

doi:10.1371/journal.pone.0116590

Abstract

Prior to colonoscopy, bowel cleansing is performed for which frequently oral sodium phosphate (OSP) is used. OSP results in significant hyperphosphatemia and cases of acute kidney injury (AKI) referred to as acute phosphate nephropathy (APN; characterized by nephrocalcinosis) are reported after OSP use, which led to a US-FDA warning. To improve the safety profile of OSP, it was evaluated whether the side-effects of OSP could be prevented with intestinal phosphate binders. Hereto a Wistar rat model of APN was developed. OSP administration (2 times 1.2 g phosphate by gavage) with a 12h time interval induced bowel cleansing (severe diarrhea) and significant hyperphosphatemia (21.79 ± 5.07 mg/dl 6h after the second OSP dose versus 8.44 ± 0.97 mg/dl at baseline). Concomitantly, serum PTH levels increased fivefold and FGF-23 levels showed a threefold increase, while serum calcium levels significantly decreased from 11.29 ± 0.53 mg/dl at baseline to 8.68 ± 0.79 mg/dl after OSP. OSP administration induced weaker NaPi-2a staining along the apical proximal tubular membrane. APN was induced: serum creatinine increased (1.5 times baseline) and nephrocalcinosis developed (increased renal calcium and phosphate content and calcium phosphate deposits on Von Kossa stained kidney sections). Intestinal phosphate binding (lanthanum carbonate or aluminum hydroxide) was not able to attenuate the OSP induced side-effects. In conclusion, a clinically relevant rat model of APN was developed. Animals showed increased serum phosphate levels similar to those reported in humans and developed APN. No evidence was found for an improved safety profile of OSP by using intestinal phosphate binders.

Highlights

Colonoscopy is the standard procedure for diagnostic evaluation of the colon, with more than 14 million examinations performed annually in the United States alone. [1] As its efficacy largely depends on the degree to which fecal material is removed from the colon, bowel cleansing is carried out for which frequently oral sodium phosphate (OSP) solutions or tablets are used
Prevention of Acute Phosphate Nephropathy and colonic evacuation. [2,3] The major advantage of OSP is the relatively low volume required for efficient bowel cleansing, generally resulting in a higher patient compliance and better efficacy compared to other agents such as polyethylene glycol (PEG). [4,5,6,7,8,9,10,11] For years, a standard OSP procedure consisted of two 45 ml doses which had to be taken with a time interval of 10–12 hours
Renal biopsy findings include calcium phosphate (CaP) deposits in the distal tubules and collecting ducts, often accompanied by tubular atrophy and mild to moderate interstitial fibrosis, which led to the term “acute phosphate nephropathy” (APN). [12,14,27] This condition can be attributed to the acute OSP load which leads to significantly increased serum phosphate levels that stimulate PTH secretion which, in turn, leads to endocytosis of the NaPi-2a/c co-transporters from the brush border of the proximal tubules

Summary

Introduction

Colonoscopy is the standard procedure for diagnostic evaluation of the colon, with more than 14 million examinations performed annually in the United States alone. [1] As its efficacy largely depends on the degree to which fecal material is removed from the colon, bowel cleansing is carried out for which frequently oral sodium phosphate (OSP) solutions or tablets are used. [12,14,27] This condition can be attributed to the acute OSP load which leads to significantly increased serum phosphate levels that stimulate PTH secretion which, in turn, leads to endocytosis of the NaPi-2a/c co-transporters from the brush border of the proximal tubules. This endocytosis inhibits renal phosphate reabsorption and, results in significant urinary phosphate wasting. [28,29,30] After OSP administration, serum phosphate levels double compared to baseline and urinary phosphate excretion increases eightfold, which may result in intratubular CaP crystal formation and retention. This endocytosis inhibits renal phosphate reabsorption and, results in significant urinary phosphate wasting. [28,29,30] After OSP administration, serum phosphate levels double compared to baseline and urinary phosphate excretion increases eightfold, which may result in intratubular CaP crystal formation and retention. [12,29,31,32]

Methods

Results

Conclusion