Clinical Information

Increased urinary oxalate frequently leads to kidney stone formation and kidney insufficiency. Identifying the cause of hyperoxaluria has important implications in therapy, management, and prognosis.

Hyperoxalurias are classified as primary and secondary. Primary hyperoxaluria is an inherited disorder of oxalate metabolism, while secondary hyperoxaluria is an acquired condition resulting from either increased intake of dietary oxalate or altered intestinal oxalate absorption. Primary hyperoxalurias are classified into types 1, 2, and 3.

Hyperoxaluria type 1 (PH1) is an autosomal recessive disorder resulting in a deficiency of peroxisomal alanine:glyoxylate aminotransferase due to variants in the AGXT gene. It is characterized by increased urinary oxalic, glyoxylic, and glycolic acids. PH1 is the most common type with manifestations that include deposition of calcium oxalate in the kidneys (nephrolithiasis, nephrocalcinosis) and kidney failure. Calcium oxalate deposits can be further deposited in other tissues, such as the heart and eyes, and lead to a variety of additional symptoms. Age of onset is variable with a small percentage of patients presenting in the first year of life with failure to thrive, nephrocalcinosis, and metabolic acidosis. Approximately half of affected individuals show manifestations of PH1 in late childhood or early adolescence, and the remainder present in adulthood with recurrent kidney stones. Some individuals with PH1 respond to supplemental pyridoxine therapy.

Hyperoxaluria type 2 (PH2) is due to a defect in GRHPR gene resulting in a deficiency of the enzyme hydroxypyruvate reductase. PH2 is inherited in an autosomal recessive manner and is identified by an increase in urinary oxalic and glyceric acids. Like PH1, PH2 is characterized by deposition of calcium oxalate in the kidneys (nephrolithiasis, nephrocalcinosis), and kidney failure. Most individuals have symptoms of PH2 during childhood, and it is thought that PH2 is less common than PH1.

Hyperoxaluria type 3 (PH3), due to recessive variants in HOGA1 (formerly DHDPSL), occurs in a small percentage of individuals with primary hyperoxaluria. HOGA1 encodes a mitochondrial 4-hydroxy-2-oxoglutarate aldolase that catalyzes the 4th step in the hydroxyproline pathway. PH3 is characterized biochemically by increased urinary excretion of oxalate and 4-hydroxy-2-oxoglutarate (HOG). As with PH types 1 and 2, PH type 3 is characterized by calcium-oxalate deposition in the kidneys or kidney stone formation. Most individuals with PH3 have early onset disease with recurrent kidney stones and urinary tract infections as common symptoms. Kidney failure is not a characteristic of PH3. Of note, individuals with heterozygous variants in HOGA1 can have variable and intermittent elevations of urine oxalate.

Secondary hyperoxalurias are due to hyperabsorption of oxalate (enteric hyperoxaluria); total parenteral nutrition in premature infants; ingestion of oxalate, ascorbic acid, or ethylene glycol; or pyridoxine deficiency, and may respond to appropriate therapy.

A diagnostic workup in an individual with hyperoxaluria demonstrates increased concentration of oxalate in urinary metabolite screening. If glycolate, glycerate, or HOG is present, a primary hyperoxaluria is indicated. Confirmatory testing includes molecular analysis for PH1, PH2, or PH3 (CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies; refer to the Hyperoxaluria Diagnostic Algorithm for specific Gene List IDs).