The Novel Sorbent ZO is an Effective Oral Gut Phosphate Binder: Therapeutic Implications for the CKD- and ESRD-associated Hyperphosphatemia

Hyperphosphatemia due to declining kidney function is linked to disease progression and increased cardiovascular morbidity and mortality. Despite current oral phosphate binders, many patients with chronic kidney disease (CKD) and end stage kidney disease (ESKD) fail to maintain target serum phosphate concentrations, with poor adherence to these binders due to the high pill burden required to effectively capture dietary phosphate as a key contributing factor. Importantly, up to 50% of patients on dialysis and phosphate binders still have abnormally high serum phosphate. Our collaborator from HemoCleanse showed that the novel sorbent ZO (a hydroxide-loaded anion exchanger) to be an effective gut phosphate binder, leading to reduced serum and urinary phosphorus levels in rats on normal chow. Working in cooperation with Union Carbide and Purdue University, HemoCleanse was instrumental in bringing zirconium cyclosilicate into use as a potassium sorbent. 

Here, we evaluated whether ZO could lower serum and urinary phosphorus levels in mice fed a calcium-free/high oxalate diet that we also used to assess if ZO can bind oxalate in the gut. Urine, blood, and stool samples were collected on days 0, 8, 15, and 22. Following baseline sample collection, the mice received the high oxalate diet with or without (Control) ZO. Urine, serum, and fecal phosphorus levels were measured by a chemistry autoanalyzer. Seru total CO2 was measured by a chemistry autoanalyzer. Urine pH was measured by a pH meter. 

When compared with the changes in Control mice, ZO reduced 24-h urinary phosphorus excretion by ~13.2%, 25.7%, and 29.2% after 1, 2, and 3 weeks, respectively. ZO also reduced serum phosphorus by ~18%, 14.2%, and 25.1% (similar to the rats’ data) after 1, 2, and 3 weeks, respectively. Free fecal phosphorus concentration (was not assessed in the rats’ studies) is remarkably reduced (~70-80%) by ZO over this 3-week period. ZO is expected to increase rather than decrease fecal phosphorus excretion and our findings indicate that phosphate binding by ZO is so strong that it is not available to be measured by our assay. Importantly, the fecal samples were processed using 5M HCL digestion following published methods, and all samples were similarly acidified to a pH <1. ZO releases hydroxide when it binds phosphate, which can potentially lead to metabolic alkalosis if significantly absorbed systemically. Serum bicarbonate and urine pH are similar in ZO-treated and Control mice, reflecting no or minimal absorption of the released hydroxide. Importantly, ZO has no significant toxic effects on gastrointestinal and renal tissues in preliminary studies. 

We conclude that ZO decreases serum and urinary phosphorus levels in mice fed a high oxalate diet as observed in rats fed a normal chow, which is remarkable given the potential competition from the high dietary oxalate in binding to ZO. ZO reduces serum and urinary phosphorus levels likely via effective gut phosphate binding as reflected by the remarkably reduced free fecal phosphorus concentration. This study was done as part of another study using a high oxalate diet to assess if ZO can bind oxalate in the gut and it is important to show that ZO is capable of effectively binding phosphate in the gut at higher dietary phosphate intake to mimic the situations of many CKD and ESRD patients who are not compliant with dietary phosphate restrictions, which will be done in future studies. Showing that ZO effectively inhibits gut phosphate absorption in the setting of a liberalized phosphate diet, leading to reduced serum phosphorus concentration, will have remarkable nutritional benefits to CKD and ESKD patients.