Primary Hyperoxaluria Type 1
Primary hyperoxaluria type 1 is a rare condition that arises due to a mutation in the AGXT gene. AGXT codes for an enzyme that removes oxalate. However, the mutation leads to the production of alanine-glyoxylate aminotransferase (AGXT) that does not function properly.
Primary hyperoxaluria type 1 is characterized by the buildup of a substance called oxalate, which normally is filtered through the kidneys and excreted in the urine. In people with PH1, the accumulated oxalate is deposited in the kidneys and urinary tract. It combines with calcium to form the main component of kidney and bladder stones. Deposits of calcium oxalate can lead to kidney damage, kidney failure, and injury to other organs.
The symptoms and severity of primary hyperoxaluria type 1 (PH1) can vary. The age that symptoms begin ranges from birth to the sixth decade of life (although there are exceptions). About 19% of people with PH1 have a severe, very early-onset form that becomes apparent within a few months after birth. At the milder end of the spectrum, some people with PH1 go without any symptoms for over 40 or 50 years. The median age of onset is about 5-6 years.
Features of renal involvement can range from nephrocalcinosis and renal failure in infancy, to only occasional stones diagnosed in adulthood. Kidney stones are commonly the first sign of hyperoxaluria. Symptoms of kidney stones can include sudden abdominal or flank pain; blood in the urine; frequent urge to urinate; pain while urinating; or fever and chills.
Untreated PH1 leads to kidney failure, which is life-threatening. Symptoms of kidney failure can include decreased or no urine output; feeling ill or tired; loss of appetite; nausea and vomiting; and pale skin due to anemia.
Individuals with Primary hyperoxaluria (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)
- End-stage renal disease (ESRD) with a history of renal stones or calcinosis
Age at onset of symptoms typically ranges from one to 25 years.
Approximately 10% of affected individuals present before age four to six months with severe disease, often associated with
- Failure to thrive
- Metabolic acidosis
Approximately 80%-90% of affected individuals present in late childhood or early adolescence, usually with symptomatic nephrolithiasis.
Fewer than 10% of affected individuals present in adulthood with recurrent renal stones.
The natural history of untreated PH1 is one of inexorable decline in renal function as a result of progressive nephrolithiasis/nephrocalcinosis, with eventual progression to oxalosis (widespread tissue deposition of calcium oxalate) and death from ESRD.
Mutations in the AGXT gene causes primary hyperoxaluria type 1. Inheritance is autosomal recessive.
The breakdown and processing of certain sugars and protein building blocks (amino acids) produces a substance called glyoxylate. Normally, glyoxylate is converted to the amino acid glycine or to a compound called glycolate through the action of two enzymes, alanine-glyoxylate aminotransferase and glyoxylate reductase/hydroxypyruvate reductase, respectively.
Mutations in the AGXT gene cause a shortage of this enzyme, which prevents the conversion of glyoxylate to glycine or glycolate. As levels of glyoxylate build up, it is converted to oxalate. Oxalate combines with calcium to form calcium oxalate deposits, which can damage the kidneys and other organs.
- Maintainance of high fluid intake to maximize calcium oxalate solubility in the urine is the most important preventive measure in an asymptomatic individual with AGXT disease-causing mutations. Recommendations vary, but aiming for a minimum of 2.5 L/m2 is likely to achieve the desired urine concentration of oxalate lower than 0.5 mmol/L. This fluid intake must continue throughout the 24-hour day; in small children this may require use of a nasogastric or gastrostomy tube [Leumann & Hoppe 2001].
- Pyridoxine supplements in those individuals identified to be pyridoxine responsive (see Treatment of Manifestations)
- Addition of potassium or sodium citrate (100-150 mg/kg/day in 3-4 divided doses) or neutral orthophosphate (20-60 mg/kg/day) for primary prevention
Diagnosis relies upon measurement of urine oxalate:creatinine ratio, plasma oxalate concentration, and assay of AGXT catalytic activity from liver biopsy. AGXT is the only gene known to be associated with primary hyperoxaluria type 1. Targeted mutation analysis of specific AGXT mutations can detect 50%-70% of mutations. Sequence analysis can detect at least one AGXT mutation in approximately 100% of affected individuals.
The progression and severity of primary hyperoxaluria type 1 (PH1) varies. Specific mutations in the responsible gene (AGXT) may correspond with particular symptoms, disease progression, and response to treatment. For example, some people with PH1 respond to treatment with vitamin B6 (pyridoxine), while others do not. Some research suggests that specific mutations in the AGXT gene are associated with later onset end stage renal failure.
The outlook is very poor if PH1 is left untreated. An early and accurate diagnosis leading to aggressive supportive treatment is a major factor in short- and long-term outcomes. In the future, the prognosis may be improved by new therapies.
General therapies for preventing kidney stones benefit all people with PH1. Recommendations for this include:
- Drinking large amounts of fluid
- Oral potassium citrate to inhibit calcium oxalate crystallization
- Drugs such as thiazides to decrease calcium in the urine
- Avoiding significant intake of vitamin C or D (they promote stone formation)
- Ssupplementation of dietary calcium
Treatment for kidney stones may involve shock wave lithotripsy, percutaneous nephrolithotomy, and/or ureteroscopy.
Reducing the body's production of oxalate involves treatment with pyridoxine. While only about 10%-30% of people with PH1 respond to treatment with pyridoxine, it has been recommended that all people with PH1 receive a minimum 3-month trial at the time of initial diagnosis.
Dialysis to remove oxalate in people with PH1 has limitations, but may be indicated in specific circumstances in some people with PH1.
Lastly, organ transplantation is an option for therapy. There has been much discussion among experts regarding the best transplantation strategy for people with PH1. Depending on each person's response to other therapies and the disease severity, options may include combined liver-kidney transplant; sequential liver-kidney transplant; an isolated kidney transplant, or an isolated liver transplant.
Other therapies for PH1 are under investigation and may become options for people with PH1 in the future.
People with questions about the treatment of PH1 for themselves or family members should speak with their doctor for treatment options and advice.
- Reduction of calcium oxalate supersaturation.
- The general therapies for nephrolithiasis benefit all individuals with primary hyperoxaluria type 1 (PH1).
- Drinking large volumes of fluid (2-3 L/m2/24 hours) at regular intervals over the entire day/night prevents calcium oxalate supersaturation.
- Drugs such as the thiazides and potassium citrate (potassium magnesium citrate) or neutral orthophosphates can decrease urinary calcium excretion and inhibit stone formation, respectively