Clinical characteristics: Primary hyperoxaluria type 1 (PH1) is caused by deficiency of the liver peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. When AGT activity is reduced or absent, glyoxylate is converted to oxalate, which cannot be metabolized and must be excreted by the kidneys. Insoluble calcium oxalate crystals form due to high urinary oxalate concentration. Urinary crystals aggregate, leading to nephrolithiasis (i.e., calcium oxalate kidney stones) in the renal pelvis / urinary tract; often the crystals deposit in kidney parenchyma (nephrocalcinosis). The age at presentation of PH1 ranges from infancy (age <12 months) in 10% of individuals, childhood/adolescence (age 1-17 years) in 70%, and adulthood (age ≥18 years) in 20%.

The natural history of untreated PH1 is (1) progressive decline in kidney function due to complications of nephrolithiasis (e.g., urinary obstruction, infection) and nephrocalcinosis, and (2) in persons with advanced chronic kidney disease (CKD), high plasma oxalate concentrations result in other organ and tissue damage from calcium oxalate deposition (i.e., "oxalosis"), most commonly in the bones, heart, and retina. In the absence of treatment, progression of oxalosis results in death from kidney failure and/or other organ involvement.

Diagnosis/testing: The diagnosis of PH1 is established in a proband with supportive laboratory findings (excess excretion of oxalate in the urine and/or markedly increased plasma oxalate concentration) and biallelic pathogenic variants in AGXT identified by molecular genetic testing.

Management: Targeted therapies: (1) Pyridoxine (vitamin B₆) to reduce liver oxalate production in individuals with missense AGXT variants known to be pyridoxine responsive; (2) RNA interference (RNAi) therapeutics (lumasiran and nedosiran) that target specific hepatic enzymes to reduce liver overproduction of oxalate; and (3) liver transplantation to restore normal hepatic AGT enzyme activity.

Supportive care: Goal is to reduce stone formation, reduce frequency of symptomatic stone events, and preserve kidney function. Advanced loss of kidney function may require dialysis and kidney transplantation. Kidney and liver transplantation can be performed simultaneously or sequentially.

Surveillance: Individuals with PH1 require lifelong care including regularly scheduled assessments of (1) kidney function and urinalysis; (2) urine volume and urine oxalate excretion; (3) kidney ultrasound examination; and (4) signs and symptoms of systemic oxalosis (most commonly involving bones, heart, and retina). The frequency of these assessments is based on the individual's kidney function.

Agents/circumstances to avoid: Intravascular volume depletion; high doses of nonsteroidal anti-inflammatory drugs or any pharmacologic agent that can compromise kidney function; intake of vitamin C exceeding the recommended daily allowance; loop diuretics; large intake of foods high in oxalate (e.g., chocolate, rhubarb, starfruit).

Evaluation of relatives at risk: Family screening for PH1, particularly sibs of the proband, is warranted given intrafamilial variability, significant disease risks even in asymptomatic family members, and availability of therapeutic agents highly effective in reducing urine oxalate.

Pregnancy management: Although pregnancy does not appear to be an important risk factor for developing end-stage kidney disease (ESKD) in most women with PH1, close monitoring is warranted by both an obstetrician and nephrologist during pregnancy and the postpartum period. Of note, the recently approved targeted therapies, lumasiran and nedosiran, have not been studied during human pregnancy. While preclinical animal studies have been reassuring, pending more clinical data the authors would advise women to discontinue use of either therapy prior to becoming pregnant and during pregnancy.

Genetic counseling: PH1 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an AGXT pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the AGXT pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.