Nephronophthisis
Related Terms
Autosomal recessive medullary cystic kidney disease, cystic disease of the renal medulla, cysts of the renal medulla-congenital, familial juvenile hyperuricemic nephropathy, familial juvenile nephrophthisis, FJN, medullary cystic kidney disease, NPHP1, polycystic kidney disease-medullary type, renal-retinal dysplasia with medullary cystic disease, Senior-Loken syndrome, uromodulin-associated kidney disease.
Background
Nephronophthisis is an inherited form of progressive kidney disease that affects children. Nephronophthisis is characterized by a progressive destruction of kidney tissue that leads to anemia, which occurs when the level of red blood cells becomes too low; polyuria (frequent urination); polydipsia (excessive thirst); short stature; and eventually kidney failure. If the kidneys fail, waste products accumulate in the blood and the body. As kidney function decreases, symptoms are related to the inability to regulate water and electrolyte balances, to clear waste products from the body, and to promote red blood cell production. Lethargy, weakness, shortness of breath, and generalized swelling may occur.
Nephronophthisis, first described in 1951, is sometimes referred to as familial juvenile nephronophthisis (FJN) or autosomal recessive medullary cystic kidney disease. There are at least four types of nephronophthisis, all of which are associated with the production of large amounts of urine and bedwetting early in life. In type 1 (NPH1), kidney failure develops at about age 13. In type 2 (NPH2), kidney failure usually develops from one to three years of age. In type 3 (NPH3), kidney failure develops at about age 19, and in type 4 (NPH4), kidney failure develops in the teenage years. In addition, about 15% of people with nephronophthisis also experience renal-retinal dysplasia (visual impairment caused by degeneration of the retinas). NPH1 is the most commonly documented type, so this monograph focuses on NPH1.
NPH1 is caused by a mutation or defect in the NPHP1 gene. This gene provides instructions for making the nephrocystin protein, which is essential for normal kidney functioning. This protein serves as a docking protein that interacts with proteins of adherens junctions, which are protein complexes that occur at cell-to-cell junctions, and focal adhesions, which are large groups of cells that serve as a link between a cell and the cell's external environment. In the case of NPH2, the mutated gene INV encodes for inversin, which is normally closely associated with the cytoskeleton and which allows for cell movement. A mutated INV gene may impair the function of cilia, the structures that allow a cell to move around, thereby contributing to cyst development. For NPH3, there is a genetic mutation in the NPHP3 gene, which encodes the protein nephrocystin-3, whose function is unknown. For NPH4, there is a genetic mutation in the NPHP4 gene, which encodes for the nephroretinin protein, whose function is also unknown. All types of nephronophthisis are inherited, or passed down among family members, as an autosomal recessive trait, meaning that an individual must inherit two copies of the defective gene, one from each parent, for the disease to occur.
Nephronophthisis accounts for about 10-20% of chronic kidney failure cases in children and young adults. Both males and females are affected equally, as are all races. It is often discussed with medullary cystic kidney disease, a similar degenerative kidney disease. Both conditions are inherited diseases, with similar renal morphology, characterized by bilateral cysts and end-stage renal disease (ESRD). Medullary cystic kidney disease is a distinct condition inherited as an autosomal dominant trait, and it affects people later in life than nephronophthisis.
There is no known cure for nephronophthisis. Instead, treatment aims to reduce symptoms and prevent complications. Individuals with nephronophthisis generally survive until age 4-15. Cause of death is usually related to kidney failure. As kidney function decreases, symptoms are related to the inability to regulate water and electrolyte balances, to clear waste products from the body, and to promote red blood cell production. As waste products build up in the blood, loss of appetite, lethargy, and fatigue become apparent, and will progress to the point where mental function will decrease and coma may occur. Because the kidneys cannot address the rising acid load in the body, breathing becomes more rapid as the lungs try to buffer the acidity by blowing off carbon dioxide. Blood pressure may rise because of the excess fluid, and this fluid may be deposited in the lungs, causing heart failure.
Signs and symptoms
General: Infantile, juvenile, and adolescent forms of nephronophthisis have been identified. Although the range of characterizations is broad, patients typically present with polyuria (production of large volumes of urine), polydipsia (excessive liquid intake), mild proteinuria (the abnormal appearance of protein in the urine), and, after several months to years, end-stage kidney disease, when dialysis or a kidney transplant is needed for the patient to survive. As kidney function decreases, symptoms are related to the inability to regulate water and electrolyte balances, to clear waste products from the body, and to promote red blood cell production. As waste products build in the blood, loss of appetite, lethargy, and fatigue become apparent and will progress to the point where mental function will decrease and coma may occur. Because the kidneys cannot address the rising acid load in the body, breathing becomes more rapid as the lungs try to buffer the acidity by blowing off carbon dioxide. Blood pressure may rise because of the excess fluid, and this fluid may be deposited in the lungs, causing heart failure. Approximately 10% of individuals with nephronophthisis also have "extrarenal" symptoms, which can include blindness, liver problems, mental retardation, and neurologic involvement affecting the cerebellum.
Excessive thirst: People with nephronophthisis tend to have polydipsia (excessive thirst), which is caused by the decrease in kidney function.
Growth retardation: In children with nephronophthisis, growth retardation and skeletal abnormalities, such as cone-shaped toes and fingers, have been observed.
Increased urination: People with nephronophthisis tend to produce an abnormally high volume of urine because of decreased kidney function. Young people with the condition may also wet the bed at night.
Kidney problems: Kidney damage in nephronophthisis is caused by the accumulation of cysts in the kidney tissue. Cysts are small fluid-filled sacs that grow in the middle or medulla of the kidney. These cysts replace normal kidney tissue, cause the kidney to become enlarged, and lead to loss of kidney function.
Loss of coordination and balance:
Symptoms of nephronophthisis type 1 (NPH1) include underdevelopment or absence of the cerebellar vermis, the part of the brain responsible for coordination and balance.
Visual impairment: About 15% of people who have nephronophthisis have visual impairment caused by damage to the retina. The retina is located in the back of the eye and sends information to the brain through the optic nerve, which also can be damaged and may cause blindness.
Diagnosis
General: Nephronophthisis can be diagnosed during infancy, childhood, or adolescence, and it varies from individual to individual. All patients should receive a complete physical exam and provide a thorough family history. A clinician should ask probing questions about volume of urine produced, pain, vision, and thirst during the patient interview. Nephronophthisis is characterized by progressive destruction of the kidney tissue that leads to anemia (low levels of red blood cells), polyuria (frequent urination), polydipsia (excessive thirst), short stature, and eventually kidney failure.
Blood tests: Blood tests that measure the number of red blood cells and the amount of hemoglobin, the oxygen-carrying component of red blood cells, may help diagnose anemia. For adult men, a hemoglobin level less than 13.0 grams per deciliter is diagnostic of anemia, and for adult women, the diagnostic threshold is below 12.0 grams per deciliter.
Eye exam: An electroretinogram (ERG) measures the electrical responses of various cell types in the retina, including the rods and cones. Electrodes are usually placed on the cornea and the skin near the eye, although it is possible to record the ERG from skin electrodes. During a recording, the patient's eyes are exposed to standardized stimuli. ERG can help with diagnosis of nephronophthisis by identifying whether the cells in the retina have degenerated.
Ultrasound: Ultrasound is a safe, noninvasive imaging method that uses sound waves to take a picture of the kidney. This is the most common imaging method used to check for cysts, which are small fluid-filled sacs.
Imaging studies: Other imaging technologies, such as magnetic resonance imaging (MRI) or a computed tomography (CT) scan can be used to provide a more detailed picture of the kidney. MRI is a noninvasive imaging technique that uses magnetic and radio waves to create an image of tissues within the body. A CT scan is a noninvasive imaging technique that uses a series of X-rays to build a picture of the inside of the body. These imaging techniques can offer more detail than ultrasound, and they may be used to make measurements of kidney or cyst volume and growth. They may be more useful at later stages of the disease. In individuals with nephronophthisis, the kidneys are of normal or moderately reduced size, with a smooth outline, and cysts may or may not be present.
Genetic testing: If nephronophthisis is suspected, a DNA test may be performed to confirm a diagnosis. A sample of the patient's blood is taken and analyzed in a laboratory for the defect in the NPHP1, INV, NPHP3, or NPHP4 genes, depending on which stage of development the disorder occurs, as mutations in these genes have shown to be related to the development of nephronophthisis. If a defect is detected, a positive diagnosis is made.
Prenatal DNA testing: If there is a family history of nephronophthisis, prenatal testing may be performed to determine whether the fetus has the disorder. Amniocentesis and chorionic villus sampling (CVS) can diagnose nephronophthisis. However, because there are serious risks associated with these tests, patients should discuss the potential health benefits and risks with a medical professional.
During amniocentesis, a long, thin needle is inserted through the abdominal wall and into the uterus, and a small amount of amniotic fluid is removed from the sac surrounding the fetus. Cells in the fluid are then analyzed for normal and abnormal chromosomes. This test is performed after 15 weeks of pregnancy. The risk of miscarriage is about one in 200-400 patients. Some patients may experience minor complications, such as cramping, leaking fluid, or irritation where the needle was inserted.
During chorionic villus sampling (CVS), a small piece of tissue (chorionic villi) is removed from the placenta between the ninth and 14th weeks of pregnancy. CVS may be performed through the cervix or through the abdomen. The cells in the tissue sample are then analyzed for the mutation in the NPHP1, INV, NPHP3, or NPHP4 genes. Miscarriage occurs in about 0.5-1% of women who undergo this procedure.
Complications
Anemia: Anemia, which occurs when the levels of red blood cells become too low, is a risk for people with kidney disease and nephronophthisis. As kidney disease worsens, so does anemia. This is likely caused by the decreased ability of the kidney to produce the hormone erythropoietin, which is essential for normal red blood cell production. Symptoms of anemia include fatigue, weakness, pale skin, dizziness, irritability, rapid heartbeat, shortness of breath, and headache.
Gout: Some people with nephronophthisis develop gout. Gout is caused by the accumulation of uric acid crystals in various tissues of the body, particularly the joints. Most of the uric acid is filtered out by the kidneys and passes out of the body in urine. A small amount passes out of the body in stool. But if too much uric acid is being produced or if the kidneys are not able to remove it from the blood normally, the level of uric acid in the blood increases. High levels of uric acid in the blood can cause solid crystals to form within joints. High uric acid levels can also cause kidney failure if left untreated. This causes inflammation, pain, and loss of function and mobility.
High blood pressure: Hypertension (high blood pressure) is seen in some patients with autosomal dominant nephronophthisis. Hypertension occurs before kidney failure in most patients.
Kidney failure: Patients with nephronophthisis may develop kidney failure, which may be life-threatening if not properly treated. Kidney failure in nephronophthisis is caused by the growth of a large number of cysts, which are small fluid-filled sacs, on the kidney.
Vision loss: Because of degeneration of the retina or optic nerve, people with nephronophthisis may have decreased vision or blindness.
Treatment
General: Nephronophthisis is an inherited form of progressive kidney disease that affects children. Nephronophthisis is characterized by progressive destruction of the kidney tissue that leads to anemia (low levels of red blood cells), polyuria (frequent urination), polydipsia (excessive thirst), short stature, and eventually kidney failure. There are four types of nephronophthisis. Types 1 and 4 are known as juvenile nephronophthisis, in which there may be complications in organs other than the kidneys. Types 1, 2, and 4 are caused by mutations or defects in genes that provide instructions for making the protein nephrocystin, while type 3 is caused by mutation in a gene that provides instructions for making the protein inversin. Treatment aims to reduce symptoms and prevent complications. Individuals with nephronophthisis generally survive until age 4-15. Cause of death is usually related to kidney failure. There is no cure for nephronophthisis. Treatment aims to reduce symptoms and prevent complications.
Corrective lenses: Individuals with nephronophthisis and vision problems may benefit from corrective lenses or glasses for nearsightedness. However, neither glasses nor corrective lenses can help optic atrophy, which is common in nephronophthisis.
Dialysis: When the kidneys begin to fail, patients can undergo dialysis to help filter the blood. In hemodialysis, a patient's blood is circulated into an external filter, cleaned, and returned to the body. In peritoneal dialysis, a fluid containing dextrose is introduced into the abdomen through a tube. This solution absorbs the wastes in the body and is then removed.
Drugs: Individuals with nephronophthisis may develop high blood pressure and may require medications to control it.
The first step is usually a prescription for one of five types of medication: a diuretic, a beta-blocker, an ACE (angiotensin-converting enzyme) inhibitor, an angiotensin II receptor antagonist, or a calcium channel blocker.
Allopurinol is a xanthine-oxidase inhibitor, widely used in the prevention of attacks of gout, and it is well tolerated. It is safe to use in patients with renal impairment.However, allopurinol and azathioprine (Imuran?) used together present a risk of a potentially fatal drug interaction, a severe risk of allopurinol use that is of importance to transplant patients being treated with azathioprine for immunosuppression.
Erythropoiesis-stimulating drugs: The hormone erythropoietin is essential for proper production of red blood cells, which contain hemoglobin, the oxygen-carrying component of red blood cells. People with chronic kidney disease, including nephronophthisis, often do not produce enough erythropoietin and therefore develop anemia, which occurs when the levels of red blood cells become too low. Synthetic erythropoietin can be provided as an injection to stimulate the production of red blood cells. Erythropoietin-stimulating drugs include epoetin alfa (Epogen? and Procrit?) and darbepoetin alfa (Aranesp?). Aggressive raising of hemoglobin levels may have adverse effects such as heart disease. Hemoglobin levels should be monitored closely by a qualified healthcare provider. Clinical studies have found that erythropoietin-stimulating agents (ESAs) increase hemoglobin levels and reduce the need for blood transfusions by 40%.
Growth hormone therapy: Children with nephronophthisis who have growth delay may benefit from growth hormone therapy (Nutropin?), which can help individuals with nephronophthisis grow to their fullest potential. Growth hormone does not have any significant side effects when used as a replacement therapy for growth hormone inadequacy or deficiency. Known risks of growth hormone are few and rare.
Pain relievers: Noninflammatory pain relievers, such as nonsteroidal anti-inflammatory drugs or NSAIDs, can be used to reduce pain associated with gout. Some NSAIDs include ibuprofen and naproxen. NSAIDs are safest when low doses are taken for brief periods. Side effects most commonly occur when taking large doses over a prolonged time. Some side effects are mild and go away on their own or after reducing the dose. Others may be more serious and need medical attention. Common side effects of NSAIDs include stomach pain and heartburn, stomach ulcers, increased bleeding tendency, headaches and dizziness, and ringing in the ears. These effects can usually be eliminated by decreasing the dose. Other side effects are allergic reactions such as rashes, wheezing, and throat swelling; liver or kidney problems; high blood pressure; and leg swelling.
Surgery: Surgery may be performed to reduce the size of the cysts growing on the kidneys. This surgery does not provide a cure for the condition, and the cysts may grow back.
Transplantation: Some patients who experience kidney failure may undergo kidney transplantation. An individual with end-stage renal disease may receive a healthy kidney from a living or deceased donor. Kidneys that are transplanted into patients with nephronophthisis do not develop cysts. However, transplantation is associated with complications, including infection and the possibility of rejection of the new organ. To reduce the chance of rejection, patients may need to take immunosuppressive drugs, such as tacrolimus, mycophenolate, prednisone, cyclosporine, rapamycin, or azathioprine. Cyclosporine, considered a breakthrough immunosuppressant when first discovered in the 1980s, ironically causes nephrotoxicity and can result in iatrogenic damage to the newly transplanted kidney.
Integrative therapies
Note: Currently there is limited scientific evidence on the use of integrative therapies for the treatment or prevention of nephronophthisis. The therapies listed below have been studied for related conditions such as kidney failure. The integrative therapies listed below should be used only under the supervision of a qualified healthcare provider and should not be used in replacement of other proven therapies.
Good scientific evidence:
Rhubarb: In laboratory studies, rhubarb has been shown to have positive effects on chronic kidney failure. These studies show promise for human use. In some studies, rhubarb is more effective than captopril, and rhubarb combined with captopril is more effective than either substance alone. Higher-quality studies are necessary to confirm this hypothesis.
Avoid if allergic or hypersensitive to rhubarb, its constituents, or related plants from the Polygonaceae family. Avoid using rhubarb for more than two weeks, because it may induce tolerance in the colon, melanosis coli, laxative dependence, pathological alterations to the colonic smooth muscles, and substantial loss of electrolytes. Avoid with atony, colitis, Crohn's disease, dehydration with electrolyte depletion, diarrhea, hemorrhoids, insufficient liver function, intestinal obstruction (called ileus), irritable bowel syndrome, menstruation, pre-eclampsia, kidney disorders, ulcerative colitis, or urinary problems. Avoid handling rhubarb leaves, as they may cause contact dermatitis. Avoid rhubarb in children younger than 12 years old. Use cautiously with bleeding disorders, cardiac conditions, or constipation. Use cautiously with a history of kidney stones or thin or brittle bones. Use cautiously if taking antipsychotic drugs, anticoagulants, or oral drugs, herbs, or supplements (including calcium, iron, and zinc) with similar effects. Avoid if pregnant or breastfeeding.
Unclear or conflicting scientific evidence:
Arabinogalactan: Although early results of arabinogalactan's effect in patients with chronic kidney failure are promising, more studies are needed.
Avoid if allergic or sensitive to arabinogalactan or larch. People who are exposed to arabinogalactan or larch dust may have irritation of the eyes, lungs, or skin. Use cautiously in people with diabetes, digestive problems, or immune system disorders, and in people who consume a diet that is high in fiber or low in galactose. Arabinogalactan should not be used during pregnancy or breastfeeding.
Arginine: Arginine, or L-arginine, is considered a semiessential amino acid, because although it is normally synthesized in sufficient amounts by the body, supplementation is sometimes required. Research results are mixed as to whether arginine as a therapy by itself directly helps with certain kidney diseases or kidney failure. Arginine may be a helpful adjunct for kidney disease-related conditions, such as anemia, in the elderly. Additional research is needed in this area.
Avoid if allergic to arginine, or with a history of stroke or liver or kidney disease. Avoid if pregnant or breastfeeding. Use caution if taking blood-thinning drugs (like warfarin or Coumadin?) or blood pressure drugs or herbs or supplements with similar effects. Blood potassium levels should be monitored. L-arginine may worsen symptoms of sickle cell disease. Caution is advised in patients taking prescription drugs to control sugar levels.
Astragalus: In traditional Chinese medicine (TCM), astragalus is commonly found in mixtures with other herbs. Western herbalists began using astragalus in the 1800s as an ingredient in various tonics. Several animal and human studies report that kidney damage from toxins and kidney failure may be improved with the use of astragalus-containing herbal mixtures. Overall, this research has been poorly designed and reported. Astragalus alone has not been well evaluated. Better-quality research is necessary before a conclusion can be made.
Avoid if allergic to astragalus, peas, or any related plants. Avoid with a history of Quillaja bark-induced asthma. Avoid if taking aspirin, aspirin products, or herbs or supplements with similar effects. Avoid with inflammation, fever, stroke, transplant, or autoimmune diseases. Stop use two weeks before and immediately after surgery or dental or diagnostic procedures with bleeding risks. Use cautiously with bleeding disorders, diabetes, high blood pressure, lipid disorders, or kidney disorders. Use cautiously if taking blood thinners, blood sugar drugs, diuretics, or herbs and supplements with similar effects. Avoid if pregnant or breastfeeding.
Chitosan: Limited evidence suggests that chitosan may be useful during long-term hemodialysis for patients with kidney failure. Further studies are needed to determine safety and efficacy.
Avoid if allergic or sensitive to chitosan or shellfish. Use cautiously with diabetes or bleeding disorders. Use cautiously if taking drugs, herbs, or supplements that lower blood sugar or increase the risk of bleeding. Chitosan may decrease absorption of fat and fat-soluble vitamins from foods. Chitosan is not recommended during pregnancy or breastfeeding.
Coenzyme Q10: Coenzyme Q10 (CoQ10), which is produced by the human body, is needed for the basic functioning of cells. Early research supports the use of CoQ10 supplements for the treatment of kidney failure. However, more research is needed before a firm conclusion can be made.
Reports on allergic reactions to CoQ10 supplements are lacking. However, there have been reports of rare cases of rash and itching after CoQ10 use. Stop use two weeks before and immediately after surgery or dental or diagnostic procedures that have bleeding risks. Use cautiously with a history of blood clots, diabetes, high blood pressure, heart attack, or stroke. Use cautiously if taking anticoagulants (blood thinners), antiplatelet drugs (e.g., aspirin, warfarin, or clopidogrel), blood pressure drugs, blood sugar drugs, cholesterol drugs, or thyroid drugs. Avoid if pregnant or breastfeeding.
Cordyceps: Cordyceps is a parasitic fungi that has been used as a tonic food in China and Tibet. In traditional Chinese medicine (TCM), cordyceps is used to strengthen kidney function. Studies indicate that cordyceps may improve kidney function in patients with chronic kidney failure. Early research results are promising. However, additional research is needed.
Avoid if allergic or hypersensitive to cordyceps, mold, or fungi. Use cautiously with diabetes, bleeding disorders, or prostate conditions. Use cautiously if taking immunosuppressants, anticoagulants, hormonal replacement therapy, or birth control pills. Avoid with myelogenous-type cancers. Avoid if pregnant or breastfeeding.
Danshen: Danshen (
Salvia miltiorrhiza) is widely used in traditional Chinese medicine (TCM), often in combination with other herbs. Although early evidence is promising, it is unknown whether danshen is a safe and effective treatment for kidney disease.
Avoid if allergic or hypersensitive to danshen. Avoid if taking anticoagulants (blood thinners), digoxin, or hypotensive agents. Avoid with bleeding disorders or low blood pressure, and following cerebral ischemia (inadequate blood flow to the brain). Use cautiously if taking sedatives, hypolipidemics (blood pressure-lowering medications), cardiac glycosides, CYP-metabolized agents, nitrate ester, steroidal agents, or some anti-inflammatories (such as ibuprofen). Use cautiously with altered immune states, arrhythmia (irregular heartbeat), compromised liver function, or a history of glaucoma, stroke, or ulcers. Stop use two weeks before and immediately after surgery or dental or diagnostic procedures that have bleeding risks. Use cautiously if driving or operating heavy machinery. Avoid if pregnant or breastfeeding.
Soy: Due to limited human research, there is not enough evidence to recommend for or against the use of soy in the treatment of kidney diseases, such as chronic renal failure. Patients with kidney disease should speak to their healthcare providers about recommended amounts of dietary protein, as soy is a high-protein food.
Avoid if allergic to soy. Breathing problems and rash may occur in sensitive people. Soy, as a part of the regular diet, is traditionally considered to be safe during pregnancy and breastfeeding, but there are limited scientific data. The effects of high doses of soy or soy isoflavones in humans are not clear, and therefore high doses are not recommended. There has been a case report of vitamin D deficiency rickets in an infant nursed with soybean milk (not specifically designed for infants). People who experience colitis (intestinal irritation) from cow's milk may experience intestinal damage or diarrhea from soy. It is unknown if soy or soy isoflavones share the same side effects as estrogens (e.g., increased risk of blood clots). The use of soy is often discouraged in patients with hormone-sensitive cancers, such as breast, ovarian, or prostate cancer. Other hormone-sensitive conditions, such as endometriosis, may also be worsened. Patients taking blood-thinning drugs (e.g., warfarin) should check with their doctors and/or pharmacists before taking soy supplementation.
Prevention
General: Nephronophthisis is an inherited condition. Therefore, there is currently no known way to prevent the disease. However, a number of options are available for prospective parents with a family history of nephronophthisis.
Genetic testing and counseling: Individuals who have nephronophthisis may meet with a genetic counselor to discuss the risks of having children with the disease. Individuals with a family history of nephronophthisis may meet with a genetic counselor to determine whether they carry the defective NPHP1, INV, NPHP3, or NPHP4 genes. Carriers can be determined through detailed family histories or genetic testing.
Known carriers of nephronophthisis may undergo genetic counseling before they conceive a child. Genetic counselors can explain the options and the associated risks of various tests, including preimplantation genetic diagnosis (PGD), amniocentesis, and chorionic villus sampling (CVS).
Preimplantation genetic diagnosis (PGD) may be used with in vitro (artificial) fertilization. In PGD, embryos are tested for the defective NPHP1, INV, NPHP3, or NPHP4 genes, and only the embryos that are not affected may be selected for implantation. Because nephronophthisis can be detected in a fetus, parents may choose whether to continue the pregnancy. Genetic counselors may assist parents with these difficult decisions.
Author information
This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).
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Causes
Genetic mutation: Nephronophthisis type 1 (NPH1) is caused by a mutation or defect in the NPHP1 gene. This gene provides instructions for making the nephrocystin protein that is essential for normal kidney functioning. In the case of nephronophthisis type 2 (NPH2), the mutated gene INV encodes for inversin, which is normally closely associated with the cytoskeleton and which allows for cell movement. A mutated INV gene may impair the function of cilia, which are the structures that allow a cell to move around, thereby contributing to cyst development. For nephronophthisis type 3 (NPH3), there is a genetic mutation in the NPHP3 gene, which encodes the protein nephrocystin-3, whose function is unknown. For nephronophthisis type 4 (NPH4), there is a genetic mutation in the NPHP4 gene, which encodes for the nephroretinin protein, whose function is also unknown.
Autosomal recessive inheritance: All types of nephronophthisis are inherited or passed down among family members as an autosomal recessive trait, meaning that an individual must inherit two copies of the defective gene, one from each parent, in order for the disease to occur. Individuals who inherit only one copy of the defective NPHP1, INV, NPHP3, or NPHP4 gene generally have no symptoms and are called carriers, because they can pass on the disorder to their children.
If one parent is a carrier, then each child has a 50% chance of inheriting one defective gene and also being a carrier. If both parents are carriers, each child has a 25% chance of inheriting two defective genes, a 50% chance of inheriting only one defective gene, and a 25% chance of inheriting neither defective gene. Therefore, if both parents are carriers, about one out of four children will have nephronophthisis.
NPH1 is caused by a mutation or defect in the NPHP1 gene. This gene provides instructions for making the nephrocystin protein that is essential for normal kidney functioning. NPHP1 serves a docking protein that interacts with proteins of adherens junctions, which are protein complexes that occur at cell-cell junctions; and focal adhesions, which are large groups of cells that serve as a link between a cell and the cell's external environment.
In NPH2 the mutated gene INV encodes for inversin, which is normally closely associated with the cytoskeleton and which allows for cell movement. A mutated INV gene may impair the function of cilia, the structures that allow a cell to move around, thereby contributing to cyst development.
In NPH3, there is a genetic mutation in the NPHP3 gene, which encodes the protein nephrocystin-3, whose function is unknown.
In NPH4, there is a genetic mutation in the NPHP4 gene, which encodes for the nephroretinin protein, whose function is also unknown.
Risk factors
Nephronophthisis is inherited. Therefore, the only known risk factor is a family history of the disease. A family history of consanguinity, meaning having parents who are closely related; early death; or renal disease is present in 67% of patients with nephronophthisis. It is also possible that environmental factors may play a role in the development of genetic diseases such as nephronophthisis.
Types of the disease
General: Nephronophthisis is an inherited form of progressive kidney disease that affects children. Nephronophthisis is characterized by a progressive destruction of the kidney tissue that leads to anemia, or low levels of red blood cells; polyuria (frequent urination); polydipsia (excessive thirst); short stature; and eventually kidney failure. There are four types of nephronophthisis. Types 1 and 4 are known as juvenile nephronophthisis; these may have complications in organs other than the kidneys. Types 1, 2, and 4 are caused by mutations or defects in genes that provide instructions for making the protein nephrocystin, while type 3 is caused by mutation in a gene that provides instructions for making the protein inversin. Treatment aims to reduce symptoms and prevent complications. Individuals with nephronophthisis generally survive until age 4-15. Cause of death is usually related to kidney failure.
Nephronophthisis type 1: Type 1 nephronophthisis (NPH1) is marked by development of kidney failure by about age 13. Besides the general symptoms that occur in all types of nephronophthisis, symptoms specific to this type of the disease include underdevelopment or absence of the cerebellar vermis, the part of the brain responsible for coordination and balance leading to a loss of coordination and balance; coloboma (holes in the optic nerve); degeneration of the optic nerve; development of fibrous tissue in the liver; eye dysfunction; and bone abnormalities.
Nephronophthisis type 2: Type 2 nephronophthisis, also known as infantile nephronophthisis, is characterized by kidney failure and typically develops between ages one and three. All symptoms associated with this type are kidney related.
Nephronophthisis type 3: Type 3 nephronophthisis, also known as adolescent nephronophthisis, is characterized by kidney failure and tends to develop at about age 19. All symptoms associated with this type are kidney related.
Nephronophthisis type 4: Type 4 nephronophthisis (NPH4) is marked by the development of kidney failure during the teenage years. Similar to NPH1, NPH4 may include symptoms that do not involve the kidneys, including underdevelopment or absence of the cerebellar vermis, the part of the brain responsible for coordination and balance, leading to a loss of coordination and balance; coloboma (holes in the optic nerve); degeneration of the optic nerve; development of fibrous tissue in the liver; eye dysfunction; and bone abnormalities.