Effect of phosphate on intestinal zinc absorption in 5/6 nephrectomized rats

Background and objectives: Zinc is an essential trace element and maintains several important biological processes in human body by serving as a component of various enzymes and transcription factors. In chronic kidney disease (CKD), more than 80% of the patients show hypozincemia. Hypozincemia is one of the adverse prognostic factors of CKD. However, the pathogenesis of hypozincemia in CKD remains unclear and its treatment is not well established. Zinc homeostasis is mainly regulated by intestinal absorption. In this study, we aimed to elucidate the pathogenesis of hypozincemia in CKD, focusing on intestinal zinc absorption. Methods: We performed experiments in normal rats and in a rat model of CKD generated by 5/6 Nephrectomy. To evaluate intestinal zinc absorption capacity of rats, the area under the plasma zinc concentration-time curve (AUC) was measured after administration of ZnSO4 solution with or without phosphate. The solubility of zinc in the solution was examined using a 0.22 μm filter. Results: CKD rats had lower plasma zinc levels and higher phosphate levels than those of control rats. The AUC in CKD rats after administration of ZnSO4 alone was significantly decreased compared to control rats, suggesting that intestinal zinc absorption may be reduced in CKD. Renal dysfunction often leads to excess accumulation of phosphate in the body, including intestinal lumen. To explore the mechanisms of reduced AUC in CKD rats, we examined the relationship between phosphate and zinc metabolism. In rats fed a high-phosphate diet, plasma zinc levels significantly decreased compared to rats fed a control diet. Furthermore, we found that the AUC in normal rats decreased as increase in phosphate concentration of the administered solution. The solubility of zinc in the solution decreased in a phosphate concentration-dependent manner, which was also seen in the physiological intraluminal pH range (pH 6~8). Conclusions: This study suggests that hypozincemia in CKD may be, in part, induced by excess phosphate, which reduces the solubility of intraluminal zinc and inhibits its absorption. Therefore, dietary phosphate restriction may help to ameliorate hypozincemia as well as hyperphosphatemia in CKD patients. Further clinical investigation will be needed.