REN-related kidney disease is an inherited condition that affects kidney function. This condition causes slowly progressive kidney disease that usually becomes apparent during childhood. As this condition progresses, the kidneys become less able to filter fluids and waste products from the body, resulting in kidney failure. Individuals with REN-related kidney disease typically require dialysis (to remove wastes from the blood) or a kidney transplant between ages 40 and 70.

People with REN-related kidney disease sometimes have low blood pressure. They may also have mildly increased levels of potassium in their blood (hyperkalemia). In childhood, people with REN-related kidney disease develop a shortage of red blood cells (anemia), which can cause pale skin, weakness, and fatigue. In this disorder, anemia is usually mild and begins to improve during adolescence.

Many individuals with this condition develop high blood levels of a waste product called uric acid. Normally, the kidneys remove uric acid from the blood and transfer it to urine so it can be excreted from the body. In REN-related kidney disease, the kidneys are unable to remove uric acid from the blood effectively. A buildup of uric acid can cause gout, which is a form of arthritis resulting from uric acid crystals in the joints. Individuals with REN-related kidney disease may begin to experience the signs and symptoms of gout during their twenties.

Mutations in the REN gene cause REN-related kidney disease. This gene provides instructions for making a protein called renin that is produced in the kidneys. Renin plays an important role in regulating blood pressure and water levels in the body.

Mutations in the REN gene that cause REN-related kidney disease result in the production of an abnormal protein that is toxic to the cells that normally produce renin. These kidney cells gradually die off, which causes progressive kidney disease.

Normal Function

The REN gene provides instructions for making a protein called renin, which is produced in the kidneys. This protein is part of the renin-angiotensin system, which regulates blood pressure and the balance of fluids and salts in the body. In the first step of this process, renin converts a protein called angiotensinogen into angiotensin I. Through an additional step, angiotensin I is converted to angiotensin II. Angiotensin II causes blood vessels to narrow (constrict), which results in increased blood pressure. Angiotensin II also stimulates production of the hormone aldosterone, which triggers the absorption of water and salt by the kidneys. The increased amount of fluid in the body also increases blood pressure. Proper blood pressure during fetal growth, which delivers oxygen to the developing tissues, is required for normal development of the kidneys, particularly of structures called the proximal tubules, and other tissues. In addition, angiotensin II may play a more direct role in kidney development, perhaps by affecting growth factors involved in development of kidney structures.

Health Conditions Related to Genetic Changes

REN-related kidney disease

At least four mutations in the REN gene have been found to cause REN-related kidney disease, a condition in which the kidneys become less able to filter fluids and waste products from the body, resulting in kidney failure. Individuals with this condition have one mutated copy and one normal copy of the REN gene in each cell. The mutations involved in REN-related kidney disease either change or remove a protein building block (amino acid) in the renin protein. These changes occur in a region of the protein known as the signal sequence, and they impair normal processing of renin. The abnormal protein is toxic to the kidney cells that normally produce renin. The renin-producing cells gradually die off, which disrupts the renin-angiotensin system and causes progressive kidney disease.

Renal tubular dysgenesis

At least 11 mutations in the REN gene have been found to cause a severe kidney disorder called renal tubular dysgenesis. This condition is characterized by abnormal kidney development before birth, the inability to produce urine (anuria), and severe low blood pressure (hypotension). These problems result in a reduction of amniotic fluid (oligohydramnios), which leads to a set of birth defects known as the Potter sequence.

Renal tubular dysgenesis can be caused by mutations in both copies of any of the genes involved in the renin-angiotensin system. Most REN gene mutations that cause this disorder prevent the production of any renin protein, which results in a nonfunctional renin-angiotensin system. Without this system, the kidneys cannot control blood pressure. Because of low blood pressure, the flow of blood is reduced (hypoperfusion), and the body does not get enough oxygen during fetal development. As a result, kidney development is impaired, leading to the features of renal tubular dysgenesis.

Other Names for This Gene

• angiotensin-forming enzyme
• angiotensinogenase
• FLJ10761
• HNFJ2
• RENI_HUMAN
• renin precursor, renal
• renin preproprotein

Genomic Location

Autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN) is inherited in an autosomal dominant pattern. All individuals inherit two copies of each gene. In autosomal dominant conditions, having a mutation in just one copy of the REN gene causes the person to have the disease. Some people are born with an autosomal dominant condition due to a new genetic mutation (de novo) and do not have a history of this condition in their family. There is nothing either parent can do, before or during pregnancy, to cause a child to have this.

Each child of an individual with an autosomal dominant condition has a 50% or 1 in 2 chance of inheriting the REN mutation and ADTKD-REN. Children who inherit the REN mutation will have ADTKD-REN. They may be more or less severely affected than their parent.