Oral molecule prevents kidney stones and restores survival in mice

Scientists at the Buck Institute for Research on Aging have shown that an orally administered small molecule, N-propargylglycine (N-PPG), can completely prevent the formation of calcium oxalate kidney stones, protect against kidney failure, and fully restore normal survival in a mouse model of Primary Hyperoxaluria Type 2 (PH2), a rare and currently untreatable genetic disorder that causes progressive kidney failure in infants and young adults. An estimated 1,700 people suffer from the disease in the US, although experts believe many more cases go undiagnosed.

The findings, published in Kidney International, are the result of a unique collaboration between Buck Institute scientists studying breast cancer and Huntington's disease. The discovery represents a significant step toward a much-needed therapy for patients with PH2, a lethal inborn error of a metabolic disease without any available treatments.

Primary hyperoxaluria is a group of rare inherited metabolic disorders in which the body overproduces oxalate, a compound that, at high levels, forms calcium oxalate crystals in the kidneys. These crystals cause recurrent kidney stones, progressive kidney damage, and in severe cases, end-stage kidney failure. While the most common form of the disease, PH Type 1, now has two approved RNA-based therapies that are partially effective, patients with PH2 and PH3 have no therapeutic options and often face kidney and liver transplantation in an effort to extend their survival.

The Buck team's approach targets a key enzyme called hydroxyproline dehydrogenase (HYPDH/PRODH2), that resides in liver and kidney mitochondria and catalyzes the first step in breaking down hydroxyproline, an amino acid derived largely from collagen turnover. This breakdown pathway generates glyoxylate, which in PH2 patients is not properly metabolized and instead produces excess amounts of oxalate. By blocking HYPDH/PRODH2 with N-PPG, the researchers were able to cut off the excess oxalate production at its source, preventing its damaging precipitation as calcium oxalate (CaOx) kidney stones.