Oxalate metabolism and the primary hyperoxalurias

Abstract

The primary hyperoxalurias are a group of rare hereditary calcium oxalate kidney stone diseases, the best characterized of which are primary hyperoxaluria type 1 (PH1) and type 2 (PH2). Deficiencies of alanine: glyoxylate aminotransferase (AGT) in PH1 and glyoxylate/hydroxypyruvate reductase (GR/HPR) in PH2 lead to the increased synthesis and excretion of the metabolic end product, oxalate. Insoluble calcium oxalate crystallizes out in the kidney and urinary tract, leading to kidney dysfunction and eventually complete organ failure. More than 100 mutations have been found in PH1, but less than 20 in PH2. The crystal structures of both AGT and GR/HPR have been solved, enabling rationalization of the untoward effects of at least some of the mutations, as well as how in PH1 some of the mutations interact synergistically with the common Pro11Leu polymorphism. A wide variety of enzyme phenotypes are found in PH1, but perhaps the most spectacular is the unparalleled peroxisome-to- mitochondrion AGT mistargeting caused by a combination of the Pro11Leu polymorphism and Gly170Arg mutation. Although remaining catalytically active in this location, mitochondrial AGT is metabolically ineffective. Classic stone treatments, such as hydration and crystallization inhibitors, are applicable to PH1 and PH2. However, some treatments such as pyridoxine therapy and liver transplantation (enzyme replacement therapy) are restricted to PH1. © 2011 Springer-Verlag London Limited.