Differential Effects of Various Alkyl Citrate Esters and Inorganic Citrate Salts on Calcium Oxalate Crystal Dissolution and Renal Cell Viability

Kidney stone disease (KSD) is a worldwide social and economic burden. Potassium citrate (KCitrate) has been used for preventing KSD recurrence, but many patients develop gastrointestinal symptoms and subsequently discontinue therapy. Alkyl citrate esters have been thought to be safer but with no clear evidence of their efficacy and renal toxicity. This study compared the dissolution efficacies of various alkyl citrate esters (trimethyl citrate or TMC, triethyl citrate or TEC, and isopropyl citrate or IPC) and inorganic citrate salts (NaCitrate, KCitrate, and MgCitrate) on calcium oxalate monohydrate (COM) crystals and their cytotoxic effects on renal cells. At 50 mM (utilizing KCl and EDTA as negative and positive controls, respectively), IPC was the most effective alkyl citrate ester, whereas NaCitrate and KCitrate were the most effective inorganic citrate salts to dissolve COM crystals. These potent compounds were further investigated, whereas others with much fewer dissolution effects were not pursued. Cytotoxic analysis of the three most potent citrate forms revealed that NaCitrate and KCitrate at ≤12.5 mM did not affect renal cell viability, whereas IPC showed obvious cytotoxic effects at all concentrations tested. A time-course study utilizing a nontoxic concentration (12.5 mM) revealed that both NaCitrate and KCitrate reduced COM crystal size to less than a quarter at the end of the assay. Their dissolution capability was confirmed by measuring [Ca²⁺] of the remaining crystalline materials. From these results, NaCitrate and KCitrate are the most favorable for direct dissolution of COM crystals and renal cell tolerance. While alkyl citrate esters may still have a therapeutic role in KSD, their poor direct efficacies and potential renal toxicity must be considered.