Primary Hyperoxaluria Type 1

In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993.
[updated ].


Clinical characteristics: Primary hyperoxaluria type 1 (PH1) is caused by a deficiency of the liver peroxisomal enzyme alanine:glyoxylate-aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. When AGT activity is absent, glyoxylate is converted to oxalate, which forms insoluble calcium oxalate crystals that accumulate in the kidney and other organs. Individuals with PH1 are at risk for recurrent nephrolithiasis (deposition of calcium oxalate in the renal pelvis / urinary tract), nephrocalcinosis (deposition of calcium oxalate in the renal parenchyma), or end-stage kidney disease (ESKD). Age at onset of symptoms ranges from infancy to the sixth decade. Approximately 10% of affected individuals present in infancy or early childhood with nephrocalcinosis, with or without nephrolithiasis, and failure to thrive related to kidney failure. The majority of individuals with PH1 present in childhood or early adolescence, usually with symptomatic nephrolithiasis and normal or reduced kidney function. The remainder of affected individuals present in adulthood with recurrent kidney stones and a mild-to-moderate reduction in kidney function. The natural history of untreated PH1 is one of progressive decline in kidney function as a result of calcium oxalate deposits in kidney tissue and complications of nephrolithiasis (e.g., obstruction and infection) with eventual progression to oxalosis (widespread tissue deposition of calcium oxalate) and death from ESKD and/or complications of oxalosis.

Diagnosis/testing: The diagnosis of PH1 is established in a proband with hyperoxaluria or hyperoxalemia by identification biallelic pathogenic variants in AGXT on molecular genetic testing. Failure to identify at least one AGXT pathogenic variant should prompt examination for other types of primary hyperoxaluria and in occasional circumstances may require consideration of liver biopsy to assay the activity of the enzyme AGT. However, given the wide availability of genetic testing, liver biopsy to obtain tissue for enzymatic activity is now rarely employed.

Management: Treatment of manifestations: The primary strategy in prevention and treatment of the renal and systemic complications of PH1 is reduction of hepatic overproduction of oxalate. Until recently, the two options were pharmacologic doses of pyridoxine (limited to those individuals responsive to pyridoxine determined by their AGXT genotype) or liver transplantation (most often combined with or performed sequentially with kidney transplantation in persons with ESKD). In 2020 the FDA and EMA approved lumasiran, an mRNAi therapeutic agent that reduces the amount of glyoxylate substrate available for metabolic conversion to oxalate by targeting the hepatic enzyme glycolate oxidase (an enzyme distinct from AGT that is in the same metabolic pathway). Since lumasiran targets glycolate oxidase, it is expected to be effective in all individuals with PH1, independent of AGXT genotype.

Strategies to minimize calcium oxalate crystal and stone formation by reducing urinary calcium oxalate supersaturation include: high oral fluid intake; alkalization of the urine using oral potassium citrate; and/or oral solutions that increase urinary pyrophosphate.

Surveillance: At regular intervals, obtain serum creatinine to estimate glomerular filtration rate (GFR), renal ultrasound examinations or other kidney imaging, urinalysis; and periodic fundoscopic eye examinations. Additionally:

  1. In those with reduced GFR (<60 mL/min/1.73 m2): regular measurement of plasma oxalate and more frequent monitoring of kidney function.

  2. In individuals with greatly reduced GFR (<30 mL/min/1.73 m2) or rapid deterioration in function: frequent assessment of serum creatinine and plasma oxalate. At regular intervals obtain radiographs of the long bones, electrocardiogram for conduction abnormalities, echocardiogram for evidence of oxalate cardiomyopathy, hemoglobin, thyroid function testing, and frequent clinical evaluation for additional complications of oxalosis.

Agents/circumstances to avoid: Dehydration from any cause can lead to irreversible kidney failure and should be strictly avoided. Individuals with PH1 should avoid intake of vitamin C that exceeds the recommended daily allowance, loop diuretics, high doses of nonsteroidal anti-inflammatory medications or other medications that can compromise kidney function; and large intake of foods high in oxalate (e.g., chocolate, rhubarb, starfruit).

Evaluation of relatives at risk: Early diagnosis of at-risk relatives enables early institution of treatment and preventive measures.

Genetic counseling: PH1 is inherited in an autosomal recessive manner. At conception, each sib of a proband with PH1 has a 25% risk of being affected, a 50% risk of being an asymptomatic carrier, and a 25% risk of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if both pathogenic variants have been identified in a family. Assay of AGT enzymatic activity prenatally is not generally offered because it requires a fetal liver biopsy.

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