Primary Hyperoxaluria

Hyperoxaluria is a condition where too much of a substance called oxalate is present in the urine. Increased oxalate in the urine can come from eating too much oxalate in foods, or from over-absorption of oxalate by the intestines due to certain diseases (called enteric hyperoxaluria). Hyperoxaluria is uncommon. In some persons the cause of the disease is not known, but may result from changes in the way kidneys handle normal amounts of body oxalate. In its many forms, it may be found among all ages, from infants to people in their 70s. The highest amounts of oxalate in the urine are seen in diseases in which the liver produces too much oxalate. This occurs in primary hyperoxaluria. Type I and Type II Primary hyperoxaluria (PH) is a rare genetic, or inherited, disorder that is present at birth. In a person with Type 1 primary hyperoxaluria, the liver creates too little of an enzyme called alanine:glyoxylate aminotransferase, or AGT. In Type II, the liver is missing a different enzyme, called glyoxylate reductase (GR) or hydroxpyruvate reductase. Very large amounts of oxalate are produced when there is not enough enzyme in the liver. Over time, oxalate in the urine can cause kidney stones. When very large amounts of oxalate are present in the urine, such as in primary hyperoxaluria, the kidneys can be damaged to the point that they quit working (renal failure). Oxalosis happens after the kidneys fail and the excess oxalate builds up in the blood, and then spreads to the eyes, bones, muscles, blood vessels, heart and other major organs. Milder forms of hyperoxaluria can cause kidney stones. Severe hyperoxaluria also causes kidney stones and, if left untreated, can lead to serious illness and even death. Among patients with primary hyperoxaluria, about 50 percent will have kidney failure by age 15, and about 80 percent will have kidney failure by age 30. For that reason, it is critical that primary hyperoxaluria be diagnosed and treated as early as possible. Patients most often develop the first symptoms, typically kidney stones, anywhere from birth to the mid-20s. But hyperoxaluria may go unrecognized until age 30 to 40. In some patients the first symptom is kidney failure.

Hyperoxaluria may first appear any time from birth to early adulthood, and symptoms can range from mild to severe. Depending on the severity of their disease, the first sign of hyperoxaluria is typically kidney stones. Patients that have a kidney stone get stuck in the urinary tract, are at risk of getting an infection.

Kidney stone symptoms may include:

• Abdominal pain – sudden or severe
• Pain when urinating
• Blood in their urine
• Urge to urinate often
• Fever and chills

Because kidney stones are uncommon in childhood, all children and adolescents who have symptoms of kidney stones or are diagnosed with kidney stones should be screened for hyperoxaluria. Pediatric patients with more severe hyperoxaluria can then be screened for primary hyperoxaluria via more specialized testing.

Primary hyperoxaluria that goes untreated may cause the kidneys to eventually be damaged and may stop working.

Signs of kidney failure include:

• A change in urine output – urine output is decreased or no urine is made
• Feeling generally ill, tiredness, and fatigued
• Nausea, vomiting

Sometimes, a patient may have already progressed to oxalosis and, during an eye examination, his or her ophthalmologist may discover oxalate crystals in the patient's eyes. Oxalosis in its late stages will cause bone disease, the result of oxalate crystals depositing in the bones and joints. It may also cause anemia that is difficult to treat, skin ulcers, and heart problems.

Patients will hyperoxaluria or suspected of having PH will need a comprehensive physical exam, including a medical history, family history, and diet and medication history. Patients, depending on their symptoms, may have one or more of the following tests to measure the presence and level of oxalate in the body:

Blood and urine testing
Patient’s blood and urine samples will be analyzed for chemical content, including oxalate, glycolate and glycerate. Blood samples may also be tested for DNA changes known to cause primary hyperoxaluria.

X-Ray
An X-ray of the kidneys can help to reveal if the patient had kidney stones or calcium oxalate deposits. caused by oxalate.

Kidney ultrasound
Ultrasound uses high-frequency radio waves and computer processing to provide an internal view of the kidneys and urinary tract.

CT scan (Computed tomography)
A series of thin X-ray beams produces two-dimensional, highly detailed images of the kidneys and urinary tract.

Liver or kidney biopsy
If tests (urine analysis, X-ray or others) indicate the patient may have primary hyperoxaluria; a biopsy can help confirm the diagnosis. Liver tissue is analyzed for enzyme deficiencies, and the kidney tissue is analyzed for oxalate deposits. During this procedure, the patient has local anesthesia and a needle is inserted under the skin and into the liver or kidney to collect a small sample of liver or kidney tissue.

Echocardiogram
This ultrasound test can show abnormal deposits of oxalate in the heart.

Eye Exam
An ophthalmologist will determine whether oxalate is being deposited in the eyes.

Bone marrow biopsy
A bone marrow biopsy on patients with kidney failure can determine if the bones have oxalate deposits and if the patient has oxalosis.

Family Screening
If PH is suspected or confirmed, the brothers and sisters of a patient should be tested. The biological parents of a child with primary hyperoxaluria may wish to consider genetic testing if the mother becomes pregnant again.

Tests such as blood levels of oxalate, urine or blood levels of glycolate or glycerate, liver biopsy enzyme analysis, and DNA testing are not generally available, but can be arranged through Mayo Medical Laboratories.

http://www.mayomedicallaboratories.com/mediax/articles/communique/mc2831-0407.PDF

Treatment needs to be individualized for PH patients needs to take into account each patient’s needs, the type and severity of disease and how well the patient responds to treatment. Patients will need to be closely monitored by their medical team to measure their responses to the following treatments:

Diet modifications
Patients with acquired, absorptive or enteric hyperoxaluria will need to follow a diet low in oxalate. Those with enteric hyperoxaluria will also need to limit fat in their diet. Dietary restrictions are not as important in primary hyperoxaluria. A dietician can assist with diet modifications and recommendations.

High fluid intake
Patients with hyperoxaluria who do not have kidney failure will need to increase the amount of water or other liquids they drink. The extra fluid is intended to keep the kidneys flushed, to help prevent the build up of oxalate and prevent formation of kidney stones.

Medications
All patients who may have primary hyperoxaluria receive prescription-level doses of pyridoxine (Vitamin B6). For many patients with Type 1 primary hyperoxaluria, this medication reduces the amount of oxalate produced by their liver. Neutral phosphates and citrate are also effective in reducing calcium oxalate crystals and stones in the urine.

Kidney Stone Management
Large kidney stones that cause pain or other symptoms or are obstructing the flow of urine from the kidneys may require removal or fragmentation by lithotripsy (ESWL). A team of urologists, experienced in stone removal procedures, is available to recommend the best approach.

Treatment for Kidney Failure
Patients with primary and enteric forms of hyperoxaluria may eventually lose kidney function, depending on the severity of their disease, at what stage in the disease they are diagnosed and how well they respond to treatment. In some cases, patients with primary hyperoxaluria will first be diagnosed when their kidneys stop functioning (end-stage renal failure). For patients with kidney failure, treatment entails three approaches, based on each patient's disease characteristics and needs.

Dialysis
An artificial kidney machine is used to remove excess fluids and wastes from the body. However, this is only temporary, until a new kidney can be transplanted, since dialysis typically does not remove as much oxalate as is formed or absorbed each day. While on dialysis, most patients with primary hyperoxaluria will continue to build up oxalate in body tissues, thus developing oxalosis.

Kidney Transplant
A kidney transplant may be a good option for patients with Type I primary hyperoxaluria whose bodies produce less oxalate when taking Vitamin B6, and for most patients with Type II.

Kidney and Liver Transplant
For patients with Type 1 primary hyperoxaluria who do not sufficiently respond to Vitamin B6, a liver and kidney transplant is needed to cure their disease.

Clinical Trials

• Correlation of Disease Expression with Specific Genetic Mutations in Primary Hyperoxaluria
  This study involves a one time blood draw and is being done to identify DNA mutations that can cause Primary Hyperoxaluria. This study is open to patient and family members. This test examines your DNA for mutations (changes in the DNA structure) that cause primary hyperoxaluria types I and II. The DNA results will help in determining a patient’s diagnosis and planning their future care.
• Betaine for Reducing Urinary Oxalate Primary Hyperoxaluria Type 1
  This study is being done to find out what effects Betaine has on Primary Hyperoxaluria (PH). Betaine is a natural product derived from the sugar beet and has been widely studied as a protector of living cells against harmful substances, such as detergents and bacteria. It is known to work on enzymes in the liver, and doctors are hopeful that it may decrease the oxalate levels in specific groups of patients with Primary Hyperoxaluria.
• Evaluating Oxalobacter formigenes in Primary Hyperoxaluria (PH)
  A research trial to determine the effectiveness and safety of Oxalobacter formigenes treatment in patients with PH Type I and II has started. Patient enrollment has started in Europe and the US. This trial is being conducted by OxThera, a clinical stage biotechnology company focused on development of treatments for Primary and Secondary hyperoxaluria.
  Oxalobacter formigenes is a unique oxalate degrading bacteria normally present in the human gut. This bacterium can use only "oxalate" as its food and therefore it efficiently degrades all the oxalate it can find to obtain energy for its survival. When Oxalobacter formigenes is taken the oxalate degrading bacteria are released into the intestine where they continuously degrade oxalate. This excessive break down of oxalate in the intestine may help to pull out the extra oxalate being made by the liver of the PH patients. If the bacterium can do this, less oxalate will be going through the kidneys into the urine.
  Participants in this study will have an equal chance of receiving Oxalobacter formigenes or a placebo. The duration of the study is approximately 6 months and the study medication is a capsule given orally.
• Investigations into the Genotype and Phenotype of Unclassified Hyperoxaluria: Enteric Oxalate Absorption Study
  The purpose of this study is to learn more about a condition called ‘unclassified hyperoxaluria’. People with this condition have large amounts of oxalate (a salt) in their urine, which can cause kidney stones and kidney failure. We do not know what causes the high level of oxalate in the urine. In this study, we will examine how oxalate in the diet affects this condition. This study will measure urinary oxalate excretion using 13C-labelled oral oxalate loads. Flavored gelatin (children) or a capsule (adults or children) containing 13C-labelled (a stable isotope) oxalic acid will be given to each subject. We will compare the results of affected patients to healthy volunteers.

Basic Research
Primary Hyperoxaluria research is ongoing and will include multidisciplinary collaboration with physicians and researchers in Nephrology, Urology, Radiology, Laboratory Medicine and the basic sciences:

• Determination of specific genetic mutations in primary hyperoxaluria patients, and compare how specific mutations correlate with disease outcomes
• Development of newer radiology techniques in order to measure renal calcium content and stones
• Understand how oxalate changes cell function
• Development of a Tissue Bank for urine, plasma, whole blood and liver samples collected from patients to facilitate investigation and collaborative research

The purpose of this registry is to identify as many affected individuals as possible worldwide, and to collect as much clinical information about these patients as is possible. The resulting collection of data will be much larger than any individual center could hope to accumulate, and will be available to all interested physicians and researchers internationally.

Goals of the registry are:

• To increase understanding about Primary Hyperoxaluria
• To provide evidence that can be used to establish patient care guidelines
• To provide the basis for future clinical trials

Registry participation is voluntary and at the discretion of patients and their care providers. All information regarding individuals will be carefully protected in an anonymous, confidential fashion in accordance with Mayo Clinic, United States, and international guidelines.

This Registry’s purpose is to identify as many individuals as possible around the world that are affected with PH, in order to determine how the disease behaves during the course of patients’ lifetimes. It will be a great advantage for physicians and researchers to be able to study and compare the medical information on hundreds of PH patients instead of just a small number of patients.

Because every few patients have PH, even nephrologists and urologists who specialize in kidney diseases are likely to see only 1 or 2 primary hyperoxaluria patients over the course of their entire career. It is very difficult to learn about how oxalate affects patient’s kidneys and other body systems, and difficult to determine what treatments are effective. By doctors and patients sharing their experiences with PH and combining it with information from around the world, everyone will be able to learn more about the disease.

The Registry is a computer database where such information is brought together, analyzed, used to advance understanding of the disease (in this case primary hyperoxaluria), and then results are shared with all physicians and scientists through publications and presentations.

The Registry has the ability to track a patient's health over a period of years and decades, the Registry's information will be valuable as physicians and researchers look for new methods to improve kidney function. The Registry will be useful in finding out which medications or treatments improve the health of PH patients.

• Mayo Clinic Hyperoxaluria Center is a resource for patients and their families and physicians. The center facilitates collaborative research to provide better understanding of this disorder. For more information, please e-mail the Mayo Clinic Hyperoxaluria Center or call 800-270-4637.
• Oxalosis and Hyperoxaluria Foundation (OHF)
  This is the only organization in the world dedicated to improving the care and treatment and finding a cure for Oxalosis, PH and related stone diseases.
• International Registry for Hereditary Calcium Stone Diseases
  The purpose of this registry is to identify worldwide as many affected individuals as possible, and to collect as much clinical information about these patients as is feasible. Website: