Familial nephritis is an inheritable form of kidney disease. There are multiple distinct forms of kidney disease that are genetic disorders . The main inheritable types are Alport's syndrome, autosomal recessive polycystic kidney disease , and autosomal dominant polycystic kidney disease. These are all forms of kidney disease in which the nephrons, the basic functional units of the kidney, are diseased or damaged.
Kidneys perform many important bodily functions. Having at least one kidney is necessary for life. Kidneys filter waste and extra fluid from the blood, keep a healthy blood level of electrolytes and minerals such as sodium, phosphorus, calcium, and potassium, help to maintain healthy blood pressure, and release hormones that are important for bodily functions. Normally, there are two fist-sized kidneys present, one on each side of the spinal column of the back just below the rib cage. Each kidney contains microscopic filter lobules called nephrons that transfer bodily waste products from the bloodstream to the urinary system. Healthy nephrons are critical for maintaining bodily functions, and the buildup of waste products can be life-threatening.
Hereditary nephritis (Alport's syndrome) is a genetic disease in which there is significant damage to the nephrons of the kidney. The disease is characterized by the onset of bloody urine in early childhood, which later leads to renal failure. The onset is typically in males before six years of age. After years of recurrent or persistent bloody urine, the kidneys begin to malfunction. Renal dysfunction typically occurs in the third or fourth decade of life, but occasionally before 20 years of age. Alport's syndrome also involves the complication of high-frequency hearing loss and eye complications.
Polycystic kidney disease (PKD) involves the development of renal cysts on the nephrons. A renal cyst is defined as an enclosed sac, or nephron segment, that is dilated to more than 200 micrometers. A cystic kidney is defined as a kidney with three or more cysts. PKD occurs in two forms. The first form is the dominant form (denoting form of inheritance ), known as autosomal dominant PKD (ADPKD). ADPKD is an adult-onset genetic disorder that is a common cause of chronic renal failure. Early in life, the kidneys are a normal size with normal functional capacities. The disease may remain undetected, until in the fourth or fifth decade. At onset, the kidneys become enlarged by cysts that appear along the nephron. The cysts cause pain, damage, and renal failure. Some cases also include cysts on the liver, pancreas, and spleen.
The second form of PKD is the recessive form (denoting form of inheritance), known as autosomal recessive PKD (ARPKD). This form most often has an onset in the first few days of life (neonatal), but may also onset in infants or in juveniles. In younger patients, most complications involve the kidneys, whereas in older patients, most complications involve the liver. With neonatal onset, the kidneys are greatly enlarged and cause the abdomen to protrude. The kidneys may have taken up so much space during fetal development, that the lungs may be underdeveloped (pulmonary hypoplasia). There are many cysts that may contain fluid or blood covering the nephrons. When the onset occurs in the neonatal period, renal failure usually causes fatality within the first two years of life. When the onset is infantile (three to six months of age), the primary symptoms are renal cysts, with an enlarged and damaged liver.
When onset is juvenile (between three and 10 years of life), the most prominent symptom is liver disease and the associated high blood pressure (portal hypertension). In this form, there may only be a few cysts on the nephrons. It is speculated that cancer may also occur with higher prevalence in association with cysts in all forms of ARPKD.
Mendelian genetics demonstrates that an individual inherits two functional copies (alleles) of every non-sex linked gene . One copy is paternally inherited, and the other is maternally inherited. When genes follow the Mendelian inheritance pattern, both the paternal and maternal copies are functionally expressed, regardless of which parent they came from.
There are different modes of inheritance for genetic disorders. An autosomal dominant mode of inheritance means that one gene in the pair needs to have a mutation in order for an individual to become affected with the disease. Since a parent only passes one copy of each gene on to their offspring, there is a 50%, or one in two, chance that a person who has autosomal dominant disorder will pass it on to each of their offspring. Males and females are equally likely to be affected in this mode of inheritance.
Autosomal recessive diseases are caused by the inheritance of two defective copies of a gene. Each parent may contribute one copy of autosomal genes to their offspring. In autosomal recessive inheritance, only if both copies are mutated does disease occur. If only one defective copy is present, the disease does not occur, but the mutated gene can still be passed on to subsequent generations. If both parents are carrying a mutated gene, then each offspring has a 25% chance of inheriting the disease. Populations with a high frequency of healthy individuals carrying defective genes will also have higher prevalence of offspring with the disease.
The sex-linked genes are denoted XX in females and XY in males. A female receives an X gene from each parent. A male receives the X gene maternally and the Y gene paternally. Some genetic disorders display X-linked recessive inheritance. In this mode of inheritance, mothers carrying defective X-linked genes can pass one copy to each offspring. However, because female offspring also receive a normal X-linked gene from the father, female offspring do not actually develop the disease. But since male offspring receive their only X chromosome from the mother, if their mother has the mutated X gene, the males can develop the disease. In this case, the mother is known as a carrier.
Alport's syndrome is a genetic disorder that can be inherited in different ways. The mode of inheritance is X-linked in 85% of cases and autosomal recessive in 15% of cases. Rare cases of autosomal dominant mode of inheritance have also been reported. Alport's syndrome frequently affects the ears and eyes in addition to the kidneys. The inherited defect involves the basement membranes of the affected organs, as a result of mutations in type IV collagen genes. The basement membrane is a sheet-like structure made up of type IV collagen that supports the kidney cells. Type IV collagen is made up of six segments called chains designated A1 through A6. Each chain is encoded for by a distinct gene. These genes are distributed in pairs on three chromosomes. The A1 and A2 chains are encoded by the genes COL4A1 and COL4A2 on chromosome 13; the A3 and A4 chains are encoded by COL4A3 and COL4A4 on chromosome 2; and the A5 and A6 chains are encoded by COL4A5 and COL4A6 on the X chromosome. Alport's syndrome involves mutations in the COL4A3, COL4A4, or COL4A5 genes. All of the A chains encoded for by these genes are present in the basement membranes of the glomerulus (portion of the kidney that filters the blood), cochlea (portion of the ear involved with hearing), and the eye. Consequently, there are abnormalities in the basement membranes causing the symptoms associated with Alport's syndrome.
The gene responsible for ADPKD was first localized to chromosome 16, in the region designated PKD1. A mutation at this locus occurs in 85–90% of ADPKD cases. The remaining 10–15% of cases is linked to chromosome 4 at the locus designated PKD2. An additional unidentified locus may exist, as some cases have been reported with no linkage to either of these loci. The abnormal gene for ARPKD has been localized to chromosome 6.
In the United States, the frequency of Alport's syndrome is estimated at one in 5,000 individuals. There is no distinction between ethnic populations. The X-linked form of Alport's syndrome is the most common and predominantly affects males. However, there are cases of symptoms reported in females carrying the X-linked form of the disease. In a process known as breakthrough expression, some female patients with X-linked Alport's syndrome have mild disease with a normal lifespan. The autosomal recessive form of Alport's syndrome is uncommon and affects both sexes equally.
ADPKD frequency is one in 1,250 live births, and is discovered in every 500–800 autopsies in the world. In the United States, ADPKD frequency is one per every 200–1,000 individuals. ADPKD is responsible for 0.6–1% of end-stage renal disease cases in the United States and Europe. ARPKD has a frequency of one per 10,000 live births. ARPKD is twice as common in females as in males. The onset of ARPKD generally occurs in neonates and children, while the onset of ADPKD is in adults usually between 20 and 40 years of age.
Signs and symptoms
Alport's syndrome usually has an onset of persistent microscopic bloody urine (hematuria). The amount of blood in the urine is too small to be detected visually, but can be detected in a laboratory test. The onset is usually in males before six years of age, and is sometimes exacerbated by upper respiratory illness into visibly bloody urine. The hematuria may last for many years, eventually resulting in renal dysfunction between 20 and 40 years of age. Hearing loss is variable. A high-frequency hearing loss is the most common complication, but may progress as far as complete deafness. Hearing complications are usually present by early adolescence, and may require a hearing aid. Other associated complications may include abnormalities of the cornea or lens of the eye, near-sightedness, degeneration of the retina, and blood platelet abnormalities. Hypertension usually begins by the second decade of life. With the onset of renal insufficiency, anemia and bone degeneration may occur. Females with Alport's disease usually have only a mild version of the disorder with only microscopic hematuria that does not progress to renal failure.
When ARPKD presents in the neonatal period, it is often detected by ultrasound imaging techniques that show the formation of cysts. Other signs that a fetus may have ARPKD are a low level of amniotic fluid or underdevelopment of the lungs. When ARPKD presents in childhood, the symptoms often include a painless abnormal mass detectable in the abdomen that is caused by an enlarged liver and enlarged kidneys. Other initial symptoms often include hypertension, an enlarged spleen, and blood in the urine detectable by laboratory tests or visually. Adolescents may also present with liver disease from ARPKD. ADPKD mostly has signs in a young adult of an abdominal mass with or without abdominal pain. ADPKD also often has initial symptoms of blood in the urine detectable by laboratory tests, or visually, and hypertension.
Alport's syndrome is investigated through multiple tests. Urinalysis in individuals with Alport's syndrome presents with microscopic or visible hematuria. The presence of high protein levels in the urine (proteinuria) is indicative of kidney disease. Proteinuria eventually develops in males with X-linked Alport's syndrome, and in both sexes with the autosomal recessive form of the disease. Proteinuria usually becomes worse as kidney disease progresses. Blood tests are also performed to look for standard protein markers of kidney dysfunction. If kidney disease has progressed, there may also be high cholesterol in the blood. Some cases of autosomal dominant Alport's syndrome also have defects in platelets of the blood.
All children with a medical history that suggests Alport's syndrome are tested for high-frequency hearing loss. To confirm a diagnosis of high-frequency hearing loss, a special tool called an audiometer is used. Eye complications can be diagnosed through an ophthalmologic examination.
Ultrasound imaging studies of the kidneys may be normal in the early stages of Alport's disease. In the later stages of the disease, the kidneys may progressively decrease in size. A renal biopsy is performed to confirm the diagnosis. Physicians search for abnormalities in collagen indicative of Alport's syndrome. The gene mutations that cause collagen abnormalities in the kidneys in Alport's syndrome also cause similar collagen abnormalities in skin. For this reason, a skin biopsy may also be used. Skin biopsies are preferred if the patient has end-stage renal disease, in which case a renal biopsy may be unsafe. Genetic analysis is the only method by which to diagnose asymptomatic carrier females that carry an X-linked Alport's syndrome gene. Genetic analysis is also the only method by which to make a prenatal diagnosis.
PKD can be investigated through a variety of laboratory tests. A basic set of urine and blood tests is performed to assist with diagnosis and subsequent monitoring of the disease. The ability of the kidneys to remove waste from the bloodstream is initially tested. The portion of the kidney that acts as a filter is the glomerulus. A reduced ability to filter the blood is known as a reduced glomerular filtration rate (GFR). Complications of PKD may include proteinuria and reduced GFR. A diagnosis of proteinuria is made through urinalysis. In a primary urinalysis test, a strip of testing paper is dipped into a urine sample to provide an immediate, rough indication of whether or not there is protein in the urine. High levels of protein in the urine indicate kidney damage.
Highly sensitive urinalysis tests are also performed to diagnose proteinuria. These tests calculate the protein-to-creatinine ratio. A high protein-to-creatinine ratio in urine indicates that the kidney is leaking protein that should be kept in the blood, which indicates kidney damage. The GFR can be measured by injecting a measurable substance (a contrast medium) into the bloodstream. The injection is followed by a 24-hour urine collection to determine how much of the medium was filtered through the kidney. A more recent method of determining GFR is to measure blood creatinine levels and perform calculations that involve weight, age, and values assigned for sex and race. If GFR remains consistently below 60, a diagnosis of chronic kidney disease is made.
If PKD is present, blood tests will show altered levels of electrolytes and minerals that the kidney normally filters and normalizes. Such altered levels include low sodium and high potassium blood levels seen in PKD. PKD also alters vitamin D metabolism, which is indicated by blood calcium levels. Urinalysis commonly reveals blood in the urine, and blood tests reveal abnormalities in various blood cell types. Liver function tests are also performed. In the early stages of PKD, liver function may be normal, but as the disease progresses, liver disease becomes a more prominent symptom. Even with successful dialysis and kidney transplantation, liver disease may persist and worsen. Abnormalities of lipid metabolism are also commonly seen with chronic renal failure, occur early in the course of PKD, and progressively worsen as well as renal function.
Ultrasound imaging is an important part of diagnosis for PKD. Prenatal diagnosis of ARPKD using ultrasound imaging is sometimes possible based on enlarged kidneys, a small bladder, and oligohydramnios. No cysts are observed during prenatal ultrasound . These findings may be the same in the dominant form of PKD. Imaging done on infants with ARPKD may reveal small cysts and kidney enlargement. In the diagnosis of ARPKD in older children, ultrasound imaging usually reveals enlarged kidneys with many very small cysts. The presence of large cysts may occur in later stages, and increase in number over time. Ultrasound imaging varies with the age of onset. Older children may also present with an enlarged, cystic liver and a cystic pancreas.
Diagnosis of ADPKD also involves ultrasound imaging, and was the main method prior to genetic linkage studies. Since PKD1 and PKD2 were identified as the genes involved in ADPKD, DNA linkage analysis has been the standard form of diagnosis. Genetic linkage studies have also verified that the ultrasound imaging criteria are accurate in the detection of previously undiagnosed disease. Currently, the criteria for diagnosis include the presence of bilateral cysts with at least two cysts in one kidney. This criterion is most reliable for individuals 30 years of age and older. Sometimes a less stringent criterion is applied to establish a diagnosis for ADPKD between 15 and 29 years of age. The less stringent criteria include the presence of at least two renal cysts total. An individual greater than 60 years of age requires at least four cysts in each kidney for a diagnosis of PKD. Individuals who are considered at risk may be periodically screened with ultrasound imaging. Computer tomography (CA) scan imaging can be used to diagnose the volume of kidney enlargement and cystic hemorrhaging involved in ADPKD.
Treatment and management
For Alport's syndrome, there is no treatment that prevents the progression to end-stage renal disease. However, there is some initial evidence that suggests that cyclosporine therapy or angiotensin-converting enzyme (ACE) inhibitors may slow the rate of progression. Cyclosporine is an immune-suppressing agent that may reduce some of the inflammatory process involved in Alport's syndrome. ACE inhibitors decrease hypertension and pressure on the kidneys. Other therapy treats the complications that arise as a result of Alport's syndrome. Therapy includes erythropoietin for chronic anemia, medications that affect phosphate and vitamin D levels to combat bone loss, bicarbonate to correct acidic blood conditions, and antihypertensive therapy.
Kidney transplantation is also the main treatment to combat end-stage renal disease in individuals with Alport's syndrome. Unfortunately, 3–5% of males develop immune complications after kidney transplant. Those at risk are individuals with early-onset Alport's syndrome, significant hearing loss, and end-stage renal disease by the time they are 20 years of age. The onset of immune complications after kidney transplant usually happens within the first year. Severe complications result, and 75% of the kidney transplants fail within a few weeks of onset. These immune complications are recurrent in patients who receive more than one transplant regardless of time intervals between transplants and experience an absence of immune complications prior to retransplantation. All other subtypes of Alport's syndrome are at very low risk for this complication and usually have successful transplants. Because of the rarity of transplant complications, donor organs are generally recommended. Generally, there is no restriction of activity for individuals with Alport's syndrome.
The hypertension associated with ARPKD requires extensive treatment with antihypertensive agents, particularly the ACE inhibitors, calcium channel blockers, beta-blockers, and sometimes diuretic agents. Antibiotics may be used to treat urinary tract infections. For children with ARPKD and chronic renal dysfunction, the complication of bone loss is treated with calcium and vitamin D supplements and medications that affect phosphate usage. Erythropoietin is used to increase blood levels. Human growth hormone may be used to improve growth. Sodium bicarbonate may be used to treat metabolic acidosis. If severe dehydration occurs as a result of kidney dysfunction and diarrhea or fever, increased water and salt may be used as treatment.
Drug therapy is not a component of the standard treatment for ARPKD or ADPKD. Drug development of compounds that inhibit cystic growth factors is under research. In the meantime, dialysis is an important part of treatment, along with kidney transplantation. Successful kidney transplantation prolongs survival, and may improve growth and development. Individuals with primarily liver complications may also require a liver transplant, depending on the stage of renal disease.
The prognosis for males with X-linked Alport's syndrome and for all patients with autosomal recessive disease is poor. Most patients develop hypertension and end-stage renal disease. Deafness and visual loss may also be components of the poor prognosis. Many patients with a family history of juvenile-onset Alport's syndrome or early-onset deafness usually develop end-stage renal disease by 20–30 years of age. The prognosis is predicted by the amount of proteinuria present.
In contrast, the prognosis for females with X-linked Alport's syndrome is generally good, with most having normal life spans and clinically mild renal disease.
The prognosis of prenatal ARPKD is very poor. Fetuses develop oligohydramnios and pulmonary hypoplasia. Most infants die from respiratory complications shortly after birth. In fetuses with less severe renal disease who survive the neonatal period, end-stage renal failure may still develop and cause death. The prognosis for children with ARPKD is improved if kidney transplantation is successful, but liver disease may still result. ADPKD is a significant cause of chronic renal failure in adults. The prognosis for ADPKD depends to some extent on the age of onset. If the disease is diagnosed before symptoms develop (through ultrasound imaging) and the patient is less than 40 years of age, the risk of developing end-stage renal failure is 2%. The percentage increases to approximately 50% risk by the seventh decade of life. Prognosis is also dependent on the degree of disease progression. Continued improvements in medical management of end-stage renal disease provide hope for improved prognosis in the future.
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Maria Basile, PhD