Primary Hyperoxaluria Type 1

Primary Hyperoxaluria Type 1

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 renal disease (ESRD). 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 renal 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 renal stones and a mild-to-moderate reduction in kidney function. The natural history of untreated PH1 is one of progressive decline in renal 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 ESRD 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 alanine:glyoxylate-aminotransferase (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: Reduction of calcium oxalate supersaturation in the urine to minimize stone formation; reduction of calcium oxalate supersaturation in the plasma in individuals with ESRD to minimize systemic deposition of calcium oxalate crystals; treatment of kidney stones; reduction of oxalate biosynthesis; dialysis; organ transplantation as either liver transplantation or combined liver/kidney transplantation.

Prevention of primary manifestations: To reduce calcium oxalate supersaturation in the urine: maintenance of high fluid intake; inhibition of calcium oxalate crystal formation with potassium or sodium citrate, pyrophosphate-containing solutions. To reduce oxalate biosynthesis: pyridoxine supplements for those who are pyridoxine responsive.

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:
- In those with reduced GFR (<60 mL/min/1.73 m2): regular measurement of plasma oxalate and more frequent monitoring of kidney function.
- 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 x-ray examination 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 diagnosis for pregnancies 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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