Renal agenesis

Definition

Renal agenesis is the failure of kidney formation during fetal development. Renal agenesis can be unilateral, with one kidney present, or bilateral, with no kidneys or very little kidney present. The two types of renal agenesis have very different clinical courses, with unilateral agenesis being more favorable.

Description

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 at the back just below the ribcage. Each kidney contains microscopic filter lobules called nephrons that transfer bodily waste products from the bloodstream to the urinary system. Functional nephrons are critical for maintaining bodily functions and for eliminating the buildup of waste products that can be life-threatening.

Unilateral renal agenesis

Unilateral renal agenesis results from defects in fetal development that cause only one kidney to form. Having a solitary kidney instead of two is not necessarily life-threatening. The solitary kidney usually enlarges, and is able to perform most bodily functions to a degree sufficient for life. When a solitary kidney does negatively affect health, it is through very subtle and gradual changes that may not be noticed initially. Over long periods of time, changes, such as an increase in blood pressure, may require specific preventative measures or treatments. Having a solitary kidney also means that if injury or disease leads to renal failure, there is no back-up kidney to take over. In this circumstance, the consequences of a diseased unilateral kidney can be life-threatening.

Bilateral renal agenesis

Bilateral renal agenesis is a genetic disorder involving the failure of both kidneys to form during fetal development. Fetal kidney development begins between five and seven weeks of gestation. During development, the fetus is cushioned, protected, and maintained at constant temperature in a substance known as amniotic fluid. Fetal urine production begins in early gestation and is responsible for the majority of the amniotic fluid present in the second and third trimesters of pregnancy. The fetus continuously swallows amniotic fluid, which is reabsorbed in the fetal gastrointestinal tract and excreted back into the amniotic cavity by the kidneys. Because amniotic fluid is maintained by fetal urine, a fetus with no kidneys has little amniotic fluid to surround and protect it in the amniotic sac. This condition is known as oligohydramnios, and results in physical compression of the fetus in the womb. Bilateral renal agenesis causes a set of physical complications known as Potter's syndrome. While bilateral renal agenesis is not the only cause of Potter's syndrome, the lack of both kidneys naturally results in Potter's syndrome symptoms. Only 20% of all Potter syndrome cases are caused by bilateral renal agenesis. The amniotic membrane sticking to the fetus, and the compression, cause further physical malformations, including the squashed facial features characteristic of Potter syndrome.

Compression and lack of amniotic fluid also lead to a serious defect in lung development. The fetal urine is critical for proper lung development. Fetal urine helps to expand the airways and supplies the amino acid proline, a critical amino acid for lung development. Upon leaving the womb, an infant must rely on the lungs and on breathing air to receive oxygen for life. Alveoli are the many small sacs deep in the lungs that are responsible for exchanging oxygen with the blood. If the alveoli are underdeveloped (pulmonary hypoplasia) at birth, the infant cannot breathe properly and will go into respiratory distress. In most cases, the condition is fatal within the first few months of postnatal life. The cause of death is pulmonary hypoplasia, with consequent respiratory insufficiency. There are rare cases in which a portion of one kidney has formed and some lung development occurs. These cases are also often fatal. If sufficient lung development is present, an infant with bilateral renal agenesis may be rescued through dialysis and eventual kidney transplant.

Genetic profile

Bilateral renal agenesis (BRA) is a rare condition thought to occur in sporadic and autosomal recessive forms. Sporadic forms of BRA have an unknown cause that may or may not be genetic. It is thought that BRA can be inherited in an autosomal recessive form, caused by the inheritance of two defective copies of a gene. Each parent contributes one copy of a gene. In autosomal recessive inheritance, if both copies are defective, the result is disease. If only one defective copy is present, the disease does not occur, but the defective gene can still be passed on to subsequent generations. If both parents are carrying a defective gene, each offspring has a one in four (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.

BRA is also more common when a parent has a distinct kidney malformation, especially unilateral renal agenesis. Research has demonstrated that unilateral renal agenesis and bilateral renal agenesis are genetically related. For this reason, when bilateral renal agenesis is detected in an infant, an ultrasound is performed on the kidneys of parents and siblings. Approximately 9% of first-degree relatives of infants with bilateral renal agenesis have some type of asymptomatic renal malformation.

As of 2005, the exact genetic causes of both unilateral and bilateral renal agenesis are unknown. It is speculated that both conditions are caused by mutations in the genes involved in fetal kidney development. Normal fetal kidney development involves an essential interaction between the forming kidney buds (ureteric bud) and a tissue known as the metanephric mesenchyme. The interaction of the ureteric bud with the metanephric mesenchyme is necessary for kidney formation. The interaction is controlled by a combination of genes, cellular-signaling molecules that control gene expression (transcription factors), and cellular-signaling molecules that control cell growth (growth factors). Animal studies have identified several of the factors that can be mutated to cause renal agenesis. Research is ongoing to determine the cause in humans.

As of 2005, the cutting edge of renal agenesis research is at the Potter syndrome tissue bank where scientists are running experiments on tissue donations from parents of children born with bilateral renal agenesis. Researchers are collecting tissue samples from the neonates and blood samples from family members in an effort to discover the gene mutations responsible for the condition. The Potter syndrome tissue bank is the only one of its kind in the world.

Demographics

Unilateral kidney agenesis is fairly common, occurring in approximately one per 1,000 live births in the United States. Bilateral renal agenesis occurs in one per 3,000 live births. There is no association of renal agenesis with race. Males have a higher rate of developing Potter syndrome than females. Individuals with bilateral renal agenesis present with the condition as neonates, whereas individuals with unilateral renal agenesis may not be aware of their condition even as adults. Unilateral renal agenesis is usually discovered in an adult undergoing tests for some other condition.

Signs and symptoms

Unilateral renal agenesis

Most people born with a solitary kidney do not experience any noticeable signs or symptoms that would indicate they have unilateral renal agenesis. A solitary kidney is usually discovered when the individual is having ultrasound imaging or surgery for some other problem. However, having unilateral renal agenesis can cause gradual changes in bodily functions that lead to unhealthy clinical conditions. A potential complication of a solitary kidney is high blood pressure.

Kidneys normally contribute to maintaining a healthy blood pressure in two ways. Kidneys regulate how much fluid flows through the bloodstream and how much fluid is excreted from the body. The more fluid that flows through the bloodstream, the more the blood pressure increases. Kidneys also release a hormone called renin that works as part of a team of hormones to expand or contract blood vessels. The more contraction of blood vessels there is, the higher the blood pressure. Many individuals who are born with a solitary kidney eventually develop slightly higher blood pressure.

In addition, one kidney doing the work of two kidneys can cause more wear and tear than normally would occur. A solitary kidney may eventually be slightly damaged, causing excessive protein to be excreted from the body through the urine. This condition is known as proteinuria, and is a sign of kidney damage. Another potential complication of having a solitary kidney is reduced efficiency at removing waste from the bloodstream. 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), a potential complication of unilateral renal agenesis. As long as these complications are controlled, individuals with a solitary kidney often experience no actual symptoms.

Bilateral renal agenesis

There are many signs of bilateral renal agenesis during neonatal (first six weeks of life) care. Potter facies are facial features associated with Potter syndrome from bilateral renal agenesis. The facies include a squashed facial appearance, flattened nose, recessed chin, prominent epicanthal folds (fold of skin from root of nose to eyebrow), and low-set abnormal ears. A poor or absent urine output during the first 48 hours of life, respiratory distress, and poorly developed lungs are all indicative signs. The degree of lung development corresponds with the extent and duration of the oligohydramnios. Respiratory distress is often the cause of death.

Diagnosis

Unilateral renal agenesis

A diagnosis of unilateral renal agenesis can be made using various imaging techniques such as an ultrasound, or directly through surgery. Diagnosis of unilateral renal agenesis is usually made in asymptomatic adults, while they are investigating some other condition. Complications of unilateral renal agenesis may include proteinuria and reduced GFR. A diagnosis of proteinuria is made through urinalysis. 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, and indicates kidney damage. The GFR can be measured by injecting a contrast medium into the bloodstream. The injection is followed by a 24-hour period of urine collection to determine how much of the medium was filtered through the kidney. A more recent method of determining GFR is by measuring blood creatinine levels and performing 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.

Bilateral renal agenesis

Bilateral renal agenesis is investigated if there is a history of oligohydramnios, prenatal sonograms depicting renal agenesis, or unilateral renal agenesis in the family. If an infant has bilateral renal agenesis, blood tests will show altered levels of electrolytes and minerals that the kidney typically filters and normalizes. Renal function and GFR can be assessed through measuring blood levels of creatinine. Urinalysis, if any urine is present, is used to detect proteinuria. Ultrasound imaging can reveal renal agenesis both before and after birth, but the prenatal condition is not as easily visualized. Chest x rays, although undesirable in an infant, can be used to assess lung development. In neonates who die from this condition, an autopsy is recommended to confirm the diagnosis.

Treatment and management

Unilateral renal agenesis

No treatment is necessary for unilateral renal agenesis other than controlling complications if they arise. Kidney function is monitored by regular physical examinations that check blood pressure and blood and urine tests. These tests are usually done once a year, and are designed to assess whether the unilateral kidney is functioning properly. Regular monitoring is critical because if the solitary kidney becomes diseased or damaged, there is no back-up kidney available to maintain life.

Normal blood pressure is defined as a measurement of 120/80 or lower. High blood pressure is defined as a measurement of 140/90 or higher. Individuals with unilateral renal agenesis are advised to maintain blood pressure levels below 130/80 to prevent kidney damage. If medication is required to control blood pressure, individuals with unilateral renal agenesis may need blood pressure medications that also protect kidney functions. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers are two classes of blood pressure medication that can also protect kidney function and reduce proteinuria. Diuretics may also be used to help lower blood pressure by removing excess fluid from the body.

Individuals with unilateral renal agenesis do not need to follow a special diet, but should limit daily sodium intake to avoid developing high blood pressure. While a special diet is not required, some methods of dieting are contraindicated. High-protein diets are not advised for individuals with unilateral renal agenesis. Because protein breakdown products add stress to the kidneys as they remove waste from the bloodstream, excessive protein intake puts an extra burden on the solitary kidney. Normal, moderate amounts of protein intake are recommended in unilateral renal agenesis. Alcohol and caffeine intake should also be limited. Individuals with unilateral renal agenesis are often advised to avoid contact sports unless protective gear is worn. Damage to the single functional kidney could quickly become life-threatening.

Bilateral renal agenesis

Neonates born with bilateral renal agenesis are immediately placed in the neonatal intensive care unit. The level of renal and respiratory function is immediately assessed. Evaluation is also made of any other malformations in bodily systems. Once the long-term prognosis of survival is determined, a treatment plan can be addressed. If a neonate with bilateral renal agenesis has severe respiratory distress from severe pulmonary hypoplasia, no further treatment may be the decided course of action. If lung development is sufficient to respond to treatment, mechanical ventilation can supply respiratory support. Management of renal failure involves a complex course of action taken to address all the consequent complications. Adequate nutrition with restricted sodium and fluid intake may be achieved through a nasogastric feeding tube. Medications and vitamin supplementation can be used to address electrolyte imbalances from lack of kidney function. Because the kidney is responsible for vitamin D formation, vitamin D therapy is important. Calcium carbonate is also supplemented because the kidneys are not present to regulate calcium levels in the blood.

Children with chronic renal failure often have poor growth and require supplemental human growth hormone (Genotropin, Humatrope, Nutropin). Human growth hormone stimulates the growth of bone, skeletal muscle, and organs. Human growth hormone acts in conjunction with another medication, erythropoietin, to increase the number of red blood cells and address the additional complication of anemia. Anemia occurs because the kidneys are not present to produce erythropoietin, which is responsible for the stimulation of red blood cell production in the bone marrow. Epoetin alfa (Epogen, Procrit) is a synthetic form of erythropoietin used in the treatment of bilateral renal agenesis. Anemia is also treated with iron supplements, which can be given orally or administered through an injection.

Renal failure causes hypertension; infants with bilateral renal agenesis may require hypertension medications in addition to restricted sodium and fluids. In renal failure, hypertension is caused by fluid overload. To treat the hypertension associated with bilateral renal agenesis, diuretic agents (Lasix) are used. Diuretic agents promote the excretion of water and electrolytes from the body. They decrease blood pressure by decreasing the amount of fluid present in the blood vessels. Other hypertensive medications may also be used, as is appropriate for the patient's age. Dialysis is required to function as a blood filter replacement for the kidney. Frequent dialysis treatments remain necessary until the infant is old enough to receive a kidney transplant.

Prognosis

In the absence of kidney injury or disease, the prognosis for unilateral renal agenesis is excellent. Individuals with unilateral renal agenesis usually lead normal, healthy lives. Avoidance of injury and basic health practices are important to maintain this quality of life.

Bilateral renal agenesis has a very poor prognosis. It is usually fatal in the first few days of life. The usual cause of death is respiratory failure and acute renal failure during the neonatal period. If survival progresses to early childhood, patients may have chronic lung disease or chronic renal failure. If the lungs have sufficient development, a kidney transplant is necessary for survival. After a kidney transplant, the prognosis is improved.

Resources

BOOKS

Moore, Keith L., and T. V. N. Persaud. The Developing Human, Clinically Oriented Embryology, Seventh Edition. St. Louis, MO: Elsevier Science, 2003.

WEBSITES

Parent Permission for Participation in the Potter Syndrome Tissue Bank. (April 14, 2005.) <http://potterssyndrome.org/bendonconsent.html>.

Sairam, Vellore K., Luther Travis. "Potter Syndrome." E-medicine. April 1, 2003 (April 14, 2005). <http://www.emedicine.com/ped/topic1878.htm>.

"Solitary Kidney." National Kidney and Urologic Diseases Information Clearinghouse. May 2004 (April 14, 2005). <http://kidney.niddk.nih.gov/kudiseases/pubs/solitarykidney/>.

ORGANIZATIONS

National Kidney and Urologic Diseases Information Clearinghouse. 3 Information Way, Bethesda, MD 20892-3580. (800) 891-5390. E-mail: [email protected]. (April 22, 2005.) <http://kidney.niddk.nih.gov/about/index.htm>.

Potter's Syndrome Support Group Main Forum. (April 22, 2005.) http://forums.delphiforums.com/n/main.asp?webtag=potterssyndrome&nav=start&prettyurl=%2Fpotterssyndrome%2Fstart.

Maria Basile, PhD