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Primary Hyperoxaluria Type 1

Table of Contents

Primary Hyperoxaluria Type 1

HP1; Oxalosis 1; Glycolic Aciduria; Alanine-Glyoxylate Aminotransferase Deficiency; Peroxisomal Alanine Glyoxylate Aminotransferase Deficiency; Hepatic AGT Deficiency

Primary hyperoxaluria type 1 (PH1) is a rare disorder that may include recurrent kidney stones; blood in the urine; and urinary tract infections. Left untreated, PH1 can result in end-stage renal disease, which is life-threatening. Explore symptoms, causes and genetics of this condition.

Kidney with Kidney Stone

Image by TheVisualMD

Summary

Kidney stones

Image by Martingerg/Wikimedia

Kidney stones

What are kidney stones? Kidney Stone is a crystalline and hard mineral material, which is formed within the kidney or in our urinary tract. A kidney stone is a common cause of hematuria (blood in the urine) and is often severe pain in the stomach, groin or flank. Kidney Stone is sometimes called Renal Calculi.

Image by Martingerg/Wikimedia

What Is Primary Hyperoxaluria Type 1?

Primary hyperoxaluria type 1 (PH1) is a rare disorder that mainly affects the kidneys. It results from 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, forming the main component of kidney and bladder stones (calcium oxalate).

Signs and symptoms of PH1 vary in severity and may begin any time from infancy to early adulthood. Symptoms may include recurrent kidney stones; blood in the urine; and urinary tract infections. Left untreated, PH1 can result in end-stage renal disease, which is life-threatening.

PH1 is due to mutations in a gene called AGXT. Inheritance is autosomal recessive.

Early treatment is important for maintaining kidney function. Each person's treatment plan depends on his/her symptoms and the severity of the condition. Management may involve high fluid intake; vitamin B6 (pyridoxine); calcium-oxalate crystallization inhibitors (citrate, pyrophosphate, and magnesium); kidney stone therapies; and dialysis in some cases. Liver and/or kidney transplantation may be needed.

Source: Genetic and Rare Diseases (GARD) Information Center

Additional Materials (2)

Ureteroscopic stone removal

Drawing of the bladder, ureter, and kidney with a cross section of a ureteroscope inserted through the bladder into the ureter, where a stone blocks urine flow. Labels point to the kidney, ureter, stone, bladder, ureteroscope, and eyepiece. Inset is a cross section of the ureter that shows a wire basket at the end of the ureteroscope capturing the stone.

Image by NIDDK Image Library

Kidney Stone

Kidney stones are small, hard crystalline deposits that form inside the kidneys and are passed painfully through the urinary tract. There are different types of kidney stones as well as a variety of causes, including metabolic disorders, diet (high protein or high sodium), and infections. In general, however, stones result when there is an imbalance of bodily fluids, dissolved minerals, and pH (crystals form under conditions that are more acidic than normal). Risk factors include obesity, dehydration, age (most common in adults age 40 and older), sex (more likely in men), and a family history of kidney stones.

Image by TheVisualMD

Ureteroscopic stone removal

NIDDK Image Library

Kidney Stone

TheVisualMD

Causes

Protein AGXT PDB 1h0c

Image by Emw/Wikimedia

Protein AGXT PDB 1h0c

Structure of the AGXT protein. Based on PyMOL rendering of PDB 1h0c.

Image by Emw/Wikimedia

What Causes Primary Hyperoxaluria Type 1?

AGXT. This gene gives the body instructions for making an enzyme called alanine-glyoxylate aminotransferase. This enzyme is found in cell structures called peroxisomes in liver cells. It converts a compound called glyoxylate to the amino acid glycine.

Mutations in the AGXT gene lead to a decrease in the amount or function of the enzyme, preventing the breakdown of glyoxylate. This is turn causes glyoxylate to accumulate, and it is converted to oxalate instead of glycine. Excess oxalate that is not excreted from the body then combines with calcium to form calcium oxalate, which damages the kidneys and other organs.

Source: Genetic and Rare Diseases (GARD) Information Center

AGXT Gene: Alanine--Glyoxylate Aminotransferase

Ideogram of human chromosome 2

Image by Office of Biological and Environmental Research of the U.S. Department of Energy Office of Science, the Biological and Environmental Research Information System, Oak Ridge National Laboratory.

Ideogram of human chromosome 2

Selected genes, traits, and disorders associated with the chromosome listed; (blue and violet) regions reflecting the unique patterns of light and dark bands seen on human chromosomes stained to allow viewing through a light microscope; (red) the centromere, or constricted portion, of each chromosome; (yellow) chromosomal regions that vary in staining intensity and sometimes are called hererochromatin (meaning “different color”); (lines between yellow) variable regions, called stalks, that connect a very small chromosome arm (a “satellite”) to the chromosome.

Image by Office of Biological and Environmental Research of the U.S. Department of Energy Office of Science, the Biological and Environmental Research Information System, Oak Ridge National Laboratory.

AGXT Gene: Alanine--Glyoxylate Aminotransferase

Normal Function

The AGXT gene provides instructions for making an enzyme called alanine-glyoxylate aminotransferase. This enzyme is found in liver cells, specifically within cell structures called peroxisomes. These structures are important for several cellular activities, such as ridding the cell of toxic substances and helping to break down certain fats. In the peroxisome, alanine-glyoxylate aminotransferase converts a compound called glyoxylate to the protein building block (amino acid) glycine.

Health Conditions Related to Genetic Changes

Primary hyperoxaluria

More than 175 mutations in the AGXT gene have been found to cause primary hyperoxaluria type 1. This condition is caused by the overproduction of a substance called oxalate. Excess amounts of this substance lead to kidney and bladder stones, which can begin anytime from childhood to early adulthood with kidney disease developing at any age. Deposition of oxalate in multiple other tissues throughout the body (systemic oxalosis) can cause additional health problems.

Most of the AGXT gene mutations decrease or eliminate alanine-glyoxylate aminotransferase activity, which impairs the conversion of glyoxylate to glycine. Other mutations cause the enzyme to be misplaced in cells, transporting it to structures called mitochondria instead of to peroxisomes. While the enzyme in the mitochondria retains activity, it cannot access glyoxylate, which is in peroxisomes. All AGXT gene mutations result in the accumulation of glyoxylate, which is converted to oxalate instead of glycine. The oxalate is filtered through the kidneys and is either excreted in urine as a waste product or combines with calcium to form calcium oxalate, a hard compound that is the main component of kidney and bladder stones. Increased oxalate levels in the blood can lead to systemic oxalosis, particularly affecting bones and the walls of blood vessels in people with primary hyperoxaluria type 1.

Other Names for This Gene

AGT
AGT1
AGXT1
alanine glyoxylate aminotransferase
alanine-glyoxylate aminotransferase
alanine-glyoxylate aminotransferase (oxalosis I; hyperoxaluria I; glycolicaciduria; serine-pyruvate aminotransferase)
alanine-glyoxylate transaminase
L-alanine: glyoxylate aminotransferase 1
pyruvate (glyoxylate) aminotransferase
serine-pyruvate aminotransferase
serine:pyruvate aminotransferase
SPAT
SPT

Genomic Location

The AGXT gene is found on chromosome 2.

Source: MedlinePlus Genetics

Inheritance

Newborn autosomal recessive pattern of inheritance

Image by Thomas Shafee and TheVisualMD

Newborn autosomal recessive pattern of inheritance

Newborn autosomal recessive pattern of inheritance

Image by Thomas Shafee and TheVisualMD

How Is Primary Hyperoxaluria Type 1 Inherited?

25% chance to be affected
50% chance to be an unaffected carrier like each parent
25% chance to be unaffected and not a carrier

Source: Genetic and Rare Diseases (GARD) Information Center

Symptoms

Renal Tubular Acidosis

Renal Tubular Acidosis

Significant bilateral nephrocalcinosis (calcification of the kidneys) on a frontal X-ray (radiopacities (white) in the right upper and left upper quadrant of the image), as seen in distal renal tubular acidosis.

What Are the Signs and Symptoms of Primary Hyperoxaluria Type 1?

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.

Source: Genetic and Rare Diseases (GARD) Information Center

Additional Materials (1)

Kidney Disease caused by diabetes and hypertension

Kidney Disease caused by diabetes and hypertension

Image by TheVisualMD

Kidney Disease caused by diabetes and hypertension

TheVisualMD

Treatment

Oral rehydration solution

Image by Sachinthonakkara

Oral rehydration solution

Oral rehydration solution (250 ml):Sodium chloride - 0.65g; Potassium chloride - 0.375g; Trisodium citrate - 0.72g; Glucose - 3.375g

Image by Sachinthonakkara

How Might Primary Hyperoxaluria Type 1 Be Treated?

The goal of treatment for primary hyperoxaluria type 1 (PH1) is to minimize calcium oxalate deposition and maintain renal function. Early diagnosis and prompt therapy is critical to preserve the function of the kidneys for as long as possible.

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)
supplementation 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.

Source: Genetic and Rare Diseases (GARD) Information Center

Prognosis

Prognosis Icon

Image by mcmurryjulie/Pixabay

Prognosis Icon

Image by mcmurryjulie/Pixabay

What Is the Long-Term Outlook for People with Primary Hyperoxaluria Type 1?

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.

Source: Genetic and Rare Diseases (GARD) Information Center

Related HealthJournals

Primary Hyperoxaluria

Primary hyperoxaluria is a rare condition characterized by recurrent kidney and bladder stones. It often results in end stage renal disease (ESRD), a life-threatening condition. There are three types of primary hyperoxaluria that differ in their severity and genetic cause. Explore symptoms, causes, and genetics.

Primary Hyperoxaluria Type 2

Primary hyperoxaluria type 2 is a rare condition characterized by recurrent kidney and bladder stones and it often results in end stage renal disease (ESRD). Symptom onset may occur in childhood or adolescence. Explore symptoms, causes and genetics of this condition.

Kidney Stones in Children

A kidney stone is a solid, pebble-like piece of material that can form in a child’s kidney when minerals in the urine are too high. Kidney stones rarely cause permanent damage if treated by a health care professional.

Kidney Stones

A kidney stone is a solid piece of material that forms in the kidney from substances in the urine. Symptoms include vomiting, blood in your urine, and more. Find a full list of symptoms and treatments available.

Gallstones

Gallstones are hard, pebble-like pieces of material, usually made of cholesterol or bilirubin, that develop in your gallbladder. When gallstones block your bile ducts, they can cause sudden pain, which means you need medical attention right away. Find out symptoms, causes, and what you can do to lower your risk of gallstones.

Lithotripsy

The destruction of a calculus of the kidney, ureter, bladder, or gallbladder by physical forces, including crushing with a lithotriptor through a catheter. Focused percutaneous ultrasound and focused hydraulic shock waves may be used without surgery.

Kidney Disease

Kidney disease means your kidneys are damaged and can’t filter blood the way they should. Kidney disease is common. You are at greater risk for kidney disease if you have diabetes or high blood pressure. Kidney disease throws the whole body out of balance. Learn about kidney disease, screening tests and how to keep your kidneys healthy.

Kidney Tests

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Primary Hyperoxaluria Type 1

Primary hyperoxaluria type 1 (PH1) is a rare disorder that may include recurrent kidney stones; blood in the urine; and urinary tract infections. Left untreated, PH1 can result in end-stage renal disease, which is life-threatening. Explore symptoms, causes and genetics of this condition.

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