Aluminum citrate blocks toxicity of calcium oxalate crystals by preventing binding with cell membrane phospholipids

Renal damage from ethylene glycol and primary hyperoxaluria is linked to accumulation of calcium oxalate monohydrate (COM) crystals in the renal proximal tubule (PT). In vitro studies have shown that aluminum citrate (AC), uniquely among citrate salts, blocks COM cytotoxicity to tubular cells. These studies were designed to evaluate the interaction of COM with membrane phospholipids and the ability of AC to reduce COM toxicity by interfering with this interaction.

Interaction of COM with phospholipids was assessed using differential scanning calorimetric analysis of structural changes in specific liposomes. Interaction of COM with cell membranes was studied by measuring binding of radiolabeled crystals by human PT (HPT) cells.

Analysis of liposomes prepared from phosphatidylserine (PS) or phosphatidylcholine (PC) showed that COM interfered with the gel-liquid transition of PS liposomes, but not that of PC liposomes. AC reversed the COM-induced changes in liposomal structure. AC inhibited the binding of [(14)C]-COM by HPT cells in a concentration-dependent manner. AC blocked COM binding by interacting with the crystal surface and not the cell membrane.

These results indicate that AC blocks the binding of COM by PT cells, and consequently its cytotoxicity, by attaching to the surface of the crystal. Thus, AC, or a related compound that works by the same mechanism, could be a useful adjunct therapy to reduce the renal damage produced by severe hyperoxaluria.