Primary hyperoxaluria (PH) encompasses two rare autosomal recessive disorders associated with excess production and urinary excretion of oxalic acid; often the result is progression to renal failure secondary to nephrocalcinosis or recurrent calcium oxalate nephrolithiasis. PH type I (PH1), with a prevalence of 1 to 2 per million individuals, is characterized by increased urinary oxalate and glycolate resulting from deficiency of hepatic alanine-glyoxylate aminotransferase (AGT). PH type II (PH2) is caused by deficiency of glyoxylate reductase/D-glycerate dehydrogenase, resulting in increased urinary oxalate and L-glycerate. Because PH2 is a much rarer form of PH, this discussion concentrates on PH1.

Patients with PH1 lack AGT activity in liver peroxisomes. Multiple phenotypes exist, including loss of AGT activity owing to intraperoxisomal aggregation or to impaired pyridoxine binding, loss of AGT protein from accelerated degradation, and mistargeting of active AGT to mitochondria instead of peroxisomes. More than 40 specific AGT mutations now are known, with each of the foregoing phenotypes linked to at least one mutation. In the absence of peroxisomal AGT, glyoxylate is metabolized inappropriately to oxalate and glycolate. Oxalate is removed from the body by renal excretion; in PH, the urine is oversaturated with oxalate in an attempt to compensate for excessive oxalate production. Calcium oxalate crystals then precipitate in renal tubules and collecting ducts, thus leading to chronic renal injury.

The onset and severity of renal involvement vary in patients with PH. Two-thirds of patients are symptomatic before reaching the age of 5 years, and most present with recurrent episodes of abdominal pain, gross hematuria, and other evidence of urolithiasis. Renal insufficiency, growth failure, and renal tubular acidosis may be present at the time of diagnosis. Abdominal radiography shows urolithiasis and nephrocalcinosis, and renal ultrasonography reveals diffuse, exaggerated echogenicity; kidney size usually is normal. Although more common causes than PH exist for urolithiasis in children, this diagnosis accounts for 1% to 2% of the total cases and must be considered. As many as 10% of patients with PH present in infancy, often with renal failure. The evaluation of any infant with renal failure should include abdominal radiographic and ultrasound studies, which demonstrate the same findings in infants with PH as found in older children, except urolithiasis is absent. In infants with cortical nephrocalcinosis and renal failure, possible causes are PH, chronic glomerulonephritis, and renal cortical necrosis.

Documenting the presence or absence of PH in patients with urolithiasis or nephrocalcinosis requires the collection of a 24-hour urine sample for oxalate or a spot urine sample for the oxalate-to-creatinine ratio in the younger child. High urinary oxalate levels in two collections confirm the diagnosis of hyperoxaluria. The diagnosis of PH1 may be established by demonstrating high urinary glycolate levels in the absence of secondary causes of hyperoxaluria, such as ethylene glycol ingestion or disease or resection of the distal ileum. In children presenting with chronic renal failure and oliguria or anuria, hyperoxaluria may be impossible to document, and serum oxalate assays may prove unreliable. However, oxalate and glycolate assays on whole spent dialysate may provide the diagnosis. The diagnosis is supported by demonstrating calcium oxalate deposits in kidneys and in extrarenal sites such as skin, retina, joints, and bone. Kidney biopsy can be striking when birefringent, pyramid-shaped crystals form rosettes within proximal tubular lumina; positive staining with alizarin red suggests that these are calcium oxalate crystals. Other kidney findings are nonspecific; glomeruli appear normal, but tubular epithelium is destroyed, and severe interstitial inflammation and fibrosis often are present. In most patients, the diagnosis of PH1 is best made or confirmed by molecular analysis of chromosomal DNA to identify specific mutations and/or by directly characterizing AGT abnormalities in liver tissue.