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

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

Hyperoxaluria: a gut-kidney axis?

Hyperoxaluria leads to urinary calcium oxalate (CaOx) supersaturation, resulting in the formation and retention of CaOx crystals in renal tissue. CaOx crystals may contribute to the formation of diffuse renal calcifications (nephrocalcinosis) or stones (nephrolithiasis). When the innate renal defense mechanisms are suppressed, injury and progressive inflammation caused by these CaOx crystals, together with secondary complications such as tubular obstruction, may lead to decreased renal function and in severe cases to end-stage renal failure. For decades, research on nephrocalcinosis and nephrolithiasis mainly focused on both the physicochemistry of crystal formation and the cell biology of crystal retention. Although both have been characterized quite well, the mechanisms involved in establishing urinary supersaturation in vivo are insufficiently understood, particularly with respect to oxalate. Therefore, current therapeutic strategies often fail in their compliance or effectiveness, and CaOx stone recurrence is still common. As the etiology of hyperoxaluria is diverse, a good understanding of how oxalate is absorbed and transported throughout the body, together with a better insight in the regulatory mechanisms, is crucial in the setting of future treatment strategies of this disorder. In this review, the currently known mechanisms of oxalate handling in relevant organs will be discussed in relation to the different etiologies of hyperoxaluria. Furthermore, future directions in the treatment of hyperoxaluria will be covered. Kidney International (2011) 80, 1146-1158; doi:10.1038/ki.2011.287; published online 24 August 201

(A) Renal calcium content, (B) renal phosphate content and (C) histomorphometrical quantification of Von Kossa stained kidney sections.

<p>Data are presented as individual values (circles) and median (horizontal bars). (* P<0.05 vs control; n = 6 per group; statistical test: Mann–Whitney-U).</p

Serum (A) phosphate, (B) calcium, (C) intact PTH and (D) intact FGF-23 levels.

<p>Data are presented as mean ± standard deviation. (^a P<0.05 vs baseline; ^b P<0.05 vs control) (12: 12 hours after the first OSP dose; 15: 3 hours after the second OSP dose and 18: 6 hours after the second OSP dose; n = 6 per group; statistical tests: Mann–Whitney-U and Wilcoxon-signed-rank).</p

Von Kossa stained renal sections, representative of each treatment group.

<p>Magnification x31.25.</p

Serum creatinine levels.

<p>Data are presented as mean ± standard deviation. (^a P<0.05 vs baseline; ^b P<0.05 vs control; 18: 6 hours after the second OSP dose; n = 6 per group; statistical tests: Mann–Whitney-U and Wilcoxon-signed-rank).</p

Correlations between serum parameters in animals receiving OSP.

<p>** p<0.01</p><p>Correlations between serum parameters in animals receiving OSP.</p

Immunohistochemical analysis of the apical (closed arrows) and intracellular (open arrows) NaPi-2a expression in the kidney.

<p>Immunohistochemical analysis of the apical (closed arrows) and intracellular (open arrows) NaPi-2a expression in the kidney.</p