Primary hyperoxaluria (PH) is a rare genetic disorder that leads to recurrent kidney and bladder stones, often progressing to end-stage renal disease (ESRD). PH impairs the kidneys' ability to filter fluids and waste and can be life-threatening. The disorder is caused by an overproduction of oxalate, which is normally excreted in urine. Excess oxalate combines with calcium to form kidney and bladder stones, damaging the kidneys and other organs, and causing symptoms such as blood in the urine and urinary tract infections (UTIs). As kidney function declines, oxalate accumulates in the body (systemic oxalosis), leading to several possible complications, including bone fractures.
There are three types of primary hyperoxaluria, each varying in severity and genetic cause. Type 1 usually presents in childhood to early adulthood and can lead to ESRD at any age. Type 2 is similar but with later onset of ESRD, while Type 3 typically begins in early childhood, although its full pathobiology is not well understood. Mutations in the AGXT, GRHPR, and HOGA1 genes are responsible for PH types 1, 2, and 3, respectively.
The genes involved encode enzymes responsible for the breakdown of amino acids and other compounds. The HOGA1 gene produces an enzyme involved in breaking down an amino acid, hydroxyproline, resulting in the formation of glyoxylate. This glyoxylate is further processed by enzymes encoded by the AGXT and GRHPR genes. Mutations in thesegenes reduce the production or activity of enzymes, leading to the improper breakdown of glyoxylate. As a result, glyoxylate accumulates and is converted into oxalate. Excess oxalate, when not excreted, combines with calcium to form deposits that can damage the kidneys and other organs.
PH1 is the most severe form, with over 70% of patients developing end-stage kidney disease, including those with sporadic kidney stones.
