What are Rare Kidney Stones?

Four inborn errors of metabolism lead to high concentrations of mineral salts in the urine and severe, recurrent nephrolithiasis. Patients with primary hyperoxaluria (PH), cystinuria, APRT deficiency (dihydroxyadeninuria, DHA), and Dent's disease experience stones beginning in childhood. Deposition of crystals in kidney tissue and loss of kidney function is observed in all disease expression varies widely.

  • Primary Hyperoxaluria
  • Cystinuria
  • APRT Deficiency
  • Dent Disease
  • Lowe Disease

Primary Hyperoxaluria (PH)

What is Primary Hyperoxaluria?

Primary Hyperoxaluria is a rare, inherited disorder characterized by high levels of oxalate in the urine and calcium oxalate kidney stones which can result in reduced kidney function or can cause kidney failure. 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.

Who gets Primary Hyperoxaluria?

Symptoms due to hyperoxaluria may appear anytime from birth to adulthood and presentation can vary from mild to severe. In its many forms, it may be found among all ages, from infants to people in their 70s. 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.

What causes Primary Hyperoxaluria?

The cause of the Primary Hyperoxaluria is not always known, but may result from changes in the way kidneys handle normal amounts of body oxalate. 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 are not enough of these enzymes 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).

How is Primary Hyperoxaluria diagnosed?

Patients that have hyperoxaluria or suspected of having PH will need a comprehensive physical exam, including a medical history, family history, and diet and medication history. Depending on their symptoms, patients may have one or more of the following tests to measure the presence and level of oxalate in the body: blood and urine testing, kidney x-ray or CT scan, liver or kidney biopsy, echocardiogram, eye exam, bone marrow biopsy or family screening.

What is/Is there treatment for Primary Hyperoxaluria?

The treatment for PH patients' needs to be individualized and take into account each patient’s needs, the type and severity of disease, kidney function and how well the patient responds to treatment. Patients need to be closely monitored by their medical team to measure their responses to the following treatments: high fluid intake, medications, diet modifications, kidney stone management, and treatment for kidney failure, dialysis, kidney or combined liver-kidney transplant.

Frequently Asked Questions about Primary Hyperoxaluria

Primary Hyperoxaluria (PH) Type I and Type II both cause increased production of oxalate. 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 of either of these enzymes in the liver.

In patients with PH there is an overproduction of oxalate that occurs due to the abnormalities of specific enzymes in the liver. Though it is the liver that is defective, the oxalate can only be eliminated from the body by the kidney and excreted in the urine and therefore the organ that suffers the most is the kidney.

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.

The goal for patients with PH is to prevent kidney stones, damage to the kidneys and the accumulation of calcium oxalate in the kidneys to other body tissues. It is important for patients to seek qualified medical care that will take into account the patients’ needs, the type and severity of the disease and how well the patient responds to various treatments. Patients should be closely monitored by their physicians during treatment, which may include: medications to reduce oxalate or stone formation, high fluid intake and dietary modifications and possibly kidney and/or liver transplantation.


What is Cystinuria?

Cystinuria is an inherited disease of amino acid transport affecting the absorption of four structurally similar amino acids from excretory pathways. In all people, cystine, ornithine, lysine and arginine are filtered from the blood into the urine. Normally, those amino acids are reclaimed from the urine for recirculation in the blood. However, cystinuric patients lack the necessary ability to transport those molecules. As a result, they become concentrated in the urine where cystine, being uniquely insoluble, tends to crystalize and form cystine stones. The result is recurring stone formation. These stones can pass spontaneously, however larger stones may become stuck in the urinary tract and require surgical intervention for removal. Frequent stone formation, kidney blockage, surgical procedures and resulting consequences can impact kidney function over time.

Who gets Cystinuria?

Cystinuria is a genetic condition passed from parents to children. It is generally accepted that 1 in 10,000 people worldwide are cystinuric. However, as with any genetic disease, the prevalence can vary greatly among communities. As a genetic condition, the disease is present from birth and persists for life. However, symptoms including kidney stone formation, may not occur immediately. While some patients form stones at infancy, others may not be aware of their disease until decades later. Some cystinuric people will never form kidney stones, despite having high urinary cystine concentrations. The underlying cause of why some people seem to be more affected than others is currently unknown.

What causes Cystinuria?

When genes responsible for making specific transport proteins are defective, the transport system fails to transport cystine from the urine. These defective gene copies are inherited from parents and cannot be changed. When cystine cannot be absorbed from the urine, it can concentrate to a point where it forms solid crystals that grow into stones in the urinary tract. Ornithine, arginine and lysine also accumulate in the urine, but are generally soluble even at the elevated concentrations and do not impact the health of the patient.

How is Cystinuria diagnosed?

Cystinuria is usually diagnosed when a person goes to the doctor with the symptoms of kidney stones (generally pain called "renal colic"), and those stones are later found through lab analysis to be composed of cystine. Cystine crystals in the urine are also a diagnostic symptom of the disease. In some areas, genetic screening programs have identified cystinuric individuals based directly on finding the defective copies of the cystine transporter gene. Interestingly, not all people genetically identified as cystinuric go on to be stone-forming patients, indicating that not all people with the disease are equally affected by the symptoms.

What is/Is there treatment for Cystinuria?

As cystinuric is a genetic disease, it cannot be fundamentally cured. Treatment is instead focused on reducing the occurrence of resulting kidney stone formation. All current efforts are aimed at preventing stone formation by decreasing the amount of solid cystine in the urinary tract. Cystine solubility can be improved by increasing urine volume (by consistently drinking large quantities of fluids) or decreasing urinary cystine excretion via dietary changes like reducing salt and protein intake. Cystine becomes more soluble as urinary acidity decreases, and therefore diets (high in vegetables) or medication (bicarbonate or citrate compounds) that promote less-acidic urine are considered powerful in reducing the rate of stone formation. Finally, for the most severely affected patients, medications are available that break apart the cystine and form more soluble complexes. These medications may not be well tolerated by the patient, and therefore careful monitoring is necessary to determine the lowest effective dose necessary.

Adenine Phosphoribosyltransferase (APRT) Deficiency

What is APRT Deficiency?

Adenine phosphoribosyltransferase (APRT) deficiency is an under recognized genetic form of kidney stones and/or kidney failure. A few patients may have eye complaints. Patients with APRT deficiency are not all affected in the same way. Most untreated patients have repeated episodes of kidney stones and/or impaired kidney function while a subset of patients may be free of symptoms.

Who gets APRT Deficiency?

APRT deficiency has been reported world-wide in all ethnic groups and affects both children and adults. Most reported cases come from Japan, France and Iceland but an increasing number of patients are being identified in other countries, including the United States.

What causes APRT Deficiency?

APRT deficiency is an inborn error of adenine metabolism causing high levels of 2,8-dihydroxyadenine in the urine, leading to kidney stones and even kidney failure in untreated patients.

How is APRT Deficiency diagnosed?

APRT deficiency should be suspected in all patients with repeated episodes of kidney stones that are not visualized on a regular x-ray (radiolucent stones), in patients with unexplained impairment of kidney function and in young children with a history of reddish-brown diaper stains. The 2,8-dihydroxyadenine crystals should be easily detected by urine microscopy. The diagnosis can also be made with genetic testing or measurement of APRT enzyme activity. Furthermore, analysis of 2,8-DHA crystals and stone material may confirm the diagnosis.

What is/Is there treatment for APRT Deficiency?

The drug allopurinol effectively prevents kidney stones and impairment of kidney function in patients with APRT deficiency. Most patients require 300-400 mg of allopurinol daily. The maximum suggested daily dose is 600-800 mg. In patients who do not tolerate allopurinol, treatment with febuxostat (Uloric®) should be considered.

Frequently Asked Questions about Adenine Phosphoribosyltransferase Deficiency (APRT)

Adenine phosphoribosyltransferase (APRT) deficiency is inherited in an autosomal recessive manner, meaning that individuals who develop the disease have received one defective copy of the APRT gene from each parent. Thus that if both parents have the defective gene, 25% of the children will have the disease, 50% will be asymptomatic but carry the defective gene, and 25% neither carry the defective gene nor have APRT deficiency. If only one parent has the disease the risk for the children is minimal.

If you have kidney stones that are not seen on a regular x-ray film but are detected with ultrasound or computerized tomography (CT) scan, the stones will most likely be composed of uric acid. However, APRT deficiency and 2,8-dihydroxyadeninuria is also a possible cause of the kidney stones. If you have radiolucent kidney stones you should ask your physician to look for the typical 2,8-dihydroxyadenine crystals in your urine with a microscope.

Dent Disease

What is Dent disease?

Dent disease is a rare genetic disorder that affects the kidneys. Typical problems are leakage of proteins into the urine and large amounts of calcium in the urine. Kidney stones are common. People with Dent disease can develop kidney damage, even kidney failure. Kidney dialysis or transplantation may be necessary. The disease is maybe diagnosed in childhood, but can be silent for years.

Who gets Dent disease?

Males are more often affected by Dent disease than women, but women can also have a mild case of the disease. Dent affects people all over the world. Currently we do not know how many people have Dent.

What causes Dent disease?

The most common Dent disease is a defect in two genes. There are two main types of Dent, type 1 and type2. Type 1 is more common, which is caused by a defect in a protein gene can cause proteinuria (increased amounts of protein in urine). Type 2 is an enzyme abnormality in kidney cell function called that causes hypercalciuria (large amounts of calcium in the urine).

How is Dent disease diagnosed?

Patients that have kidney stone with proteinuria and hypercalciuria can have a genetic test to confirm which gene is not functioning correctly.

What is/Is there treatment for Dent disease?

There is currently no cure for Dent disease, but there are treatments we can offer. Some medications (diuretics) can be given to lower the calcium in the urine and hopefully reduce the risk of kidney stones. Studies have shown that a high citrate diet may delay the loss of kidney function, so potassium citrate can be given to patients with Dent disease. However, studies in patients are badly needed to determine if either of these treatments is effective in Dent disease.

Frequently Asked Questions about Dent Disease

A physician may suspect Dent disease by observing a number of clinical markers including (but not limited to): protein in the urine, excessive amino acid excretion, excessive urinary calcium excretion, reduced levels of parathyroid hormone, increased levels of vitamin D or the presence of kidney stones made of calcium oxalate or calcium phosphate. A definitive diagnosis can be made by genetic testing of the patient. If the patient’s genetic material includes Dent disease-specific mutations, the diagnosis is confirmed.

Men have a more severe form of the disease while women may only have mild symptoms if any at all. Since Dent disease is X-linked, females can be carriers (i.e. have one normal and one affected X chromosome). Although carrier females do not appear to have any serious health consequences, they do often have urinary findings that are not quite normal.

Since it is an X-linked disorder, women or girls can be carriers but usually only have very mild manifestations that can be detected on laboratory tests, but do not cause kidney stones or loss of kidney function.

Many patients are diagnosed as children because of kidney stones, bone disease or abnormally high levels of protein in the urine. However, some persons can remain undiagnosed well into adulthood.

The most common symptoms that patients with Dent disease experience are related to the passage of kidney stones, such as pain or blood in the urine.

Testing the urine for smaller proteins (so called low molecular weight proteins) is a very good screening test, since the urine levels of these proteins are usually quite high in affected patients. Good proteins to test for are retinol binding protein and alpha 1 microglobulin.

A typical clinical presentation with low molecular weight proteinuria and hypercalciuria is very suggestive of Dent disease. The diagnosis can be confirmed by genetic testing of two genes known to cause Dent disease (CLCN5 and ORCL1). There are still some patients who have features of Dent disease but lack mutations in these two genes.

If a male is diagnosed with Dent disease, each of his brothers has a 50% chance of being affected. Screening the urine of these siblings for low molecular weight proteins should detect most of the affected siblings. This might identify persons who would benefit from careful follow-up to treat potential Dent disease manifestations (bone disease, kidney stones, chronic kidney disease). However, whether or not to screen siblings of an affected patient is a decision best made in consultation with your doctor.

There is currently no known cure for Dent disease. However, there are treatments that have been used for certain manifestations of the disease. Oral phosphorous may be necessary for certain patient with bone disease. The diuretic hydrochlorothiazide (or other diuretics in this class) has been used to reduce urinary calcium levels in Dent patients. This should reduce the rate of stone formation, and potentially help to preserve kidney function. Oral potassium citrate has also been used to reduce the rate of stone formation in Dent patients, and was effective in an animal model of the disease. However, since Dent disease is rare, there have not been enough patients to enroll in clinical trials to prove the effectiveness of any one given approach.

Treatment includes keeping the kidneys as healthy as possible and efforts are targeted to reducing kidney scarring and preventing kidney failure associated with Dent disease. Treatments may include medications, diet modifications and possibly kidney transplantation.

Some patients with typical Dent disease findings (high levels of calcium and low molecular weight proteins in the urine) were found to have a mutation the same gene that causes Lowe Syndrome (OCRL1). However, many patients with mutation in the OCRL1 gene do not have these urinary findings, and patients with Lowe Syndrome have not been found with CLCN5 mutations (the gene that has mutations in most patients with Dent disease).

Lowe Syndrome (LS)

What is Lowe Syndrome?

Lowe Syndrome (LS) is a rare genetic condition that causes physical and cognitive disabilities and medical problems. Also called the oculo-cerebro-renal syndrome of Lowe (OCRL), it was first described in 1952 by Dr. Charles Lowe and colleagues.

Who gets Lowe Syndrome?

Lowe Syndrome is a rare disease. It has been identified in most cultures around the world and seems to have the same frequency in all populations. No one knows exactly how many individuals have Lowe syndrome. Estimates in the United States are between one and ten individuals per million people, or about 250-2500 actual cases. Because LS is an X-linked syndrome, the majority of affected individuals are males. There have been a few cases of females diagnosed with Lowe Syndrome. In the case of a female patient with LS, the female typically has one inactive X-chromosome and the active X-chromosome carries the mutation for Lowe Syndrome.

What causes Lowe Syndrome?

Lowe Syndrome is caused by a defective gene that results in the deficiency of an enzyme called phosphatidylinositol 4,5-biphosphate 5 phosphatase. This enzyme is essential to normal metabolic processes that take place in a small part of the cell called the Golgi apparatus. Because of the enzyme deficiency, cell functions that are regulated by the Golgi are abnormal, leading to various developmental defects including cataracts and problems in the brain and kidneys.

How is Lowe Syndrome diagnosed?

To diagnose LS, a small skin sample called a fibroblast is taken and sent to a Biochemical Genetics Laboratory for testing. Some individuals may choose to have blood drawn and sent for testing to determine the DNA mutation of the gene. Prenatal diagnosis is also available at some laboratories.

What is/Is there treatment for Lowe Syndrome?

There is no cure for Lowe Syndrome, but many of the symptoms can be treated effectively through medication, surgery, physical and occupational therapies, vision therapy and orientation and mobility services, and special education. Nutritionists can also play a beneficial role in helping to outline and suggest appropriate diets.

Frequently Asked Questions about Lowe Syndrome

  • Cataracts in both eyes, found at birth or shortly after
  • Glaucoma (in about half the cases)
  • Poor muscle tone and delayed motor development
  • Mental retardation, ranging from borderline to severe
  • Seizures (in about half the cases)
  • Severe behavior problems (in some cases)
  • Kidney involvement ("Leaky" kidneys, or renal tubular acidosis)
  • Short stature
  • Tendency to develop rickets, bone fractures, scoliosis and joint problems
  • Expected life span of about 30-40 years if no complications.

Generally, they are affectionate and sociable, love music, and have a great sense of humor.

There is no cure, but many of the symptoms can be effectively treated through medication, surgery, physical and occupational therapies, and special education.

In 1992 the gene that causes LS was found. In 1995 researchers discovered that the gene defect causes an enzyme deficiency. Researchers are continuing to investigate the function of the gene and the complicated biochemistry and cellular mechanisms of LS. Other areas that researchers have investigated in recent years include behavior problems and clinical care.

In families in which a case of LS has occurred, testing to determine carrier status of at-risk females can be done. Various family planning options are available, including prenatal testing. Families should consult with a geneticist to learn more about their options

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