Bartter syndrome

Bartter syndrome is a congenital tubulopathy, i.e., a kidney disease—specifically affecting a part of the nephron in the region of the ascending limb of the loop of Henle—in which the tubular reabsorptive capacity is impaired (a defect of the renal reabsorption of minerals), causing a combined disturbance of water and electrolyte metabolism. The syndrome arises as a consequence of impaired tubular transport and excretion of ions. It is caused by mutations in several genes encoding several transport systems in the loop of Henle—namely the sodium–potassium–chloride cotransporter (Na‑K‑2Cl), the potassium channel, and the chloride channel. The consequence is excessive urinary loss of minerals (sodium, potassium, and chlorides), resulting hypokalemia, and hypochloremic metabolic alkalosis in the blood (i.e., a disturbance of the internal environment). The incidence of this disease (occurrence in the population in Europe) is 1/1,000,000. A decreased sodium level at the macula densa (an active part of the nephron that regulates blood pressure by increasing or decreasing hormones) increases RAAS activity (a hormone system—renin, angiotensin, aldosterone); as a result, aldosterone increases and thus secondary hyperaldosteronism is diagnosed, with all clinical manifestations (however, blood pressure is normal in this case). In some patients, intellectual disability or progressive renal failure may be associated.

Causes

The syndrome is the result of genetic mutations in several genes encoding multiple transport systems of mineral channels. This disease is congenital. There are several types of defects, which then cause different degrees of severity of the disease. The disease usually begins to manifest in early or later childhood. Inheritance is autosomal recessive, meaning that two affected genes from both parents are required for the disease to manifest—inheritance is rare in this case.

Symptoms and Diagnosis

Suspicion may arise from the symptoms listed below; in blood samples we find decreased concentrations of basic ions, especially potassium, and a disturbance of the internal environment is also present—metabolic alkalosis in the blood. In urine, we find increased mineral loss. When examining acid–base balance in the blood, alkalosis is found. The disease and its specific type can then be detected by specialized genetic testing.

We recognize 6 subtypes of Bartter syndrome according to the channel defect:

• Type I – defect of the Na⁺/K⁺/2Cl⁻ cotransporter (NKCC2, SLC12A gene); manifests already in infancy; these are usually prematurely born children; during pregnancy polyhydramnios (excessive amount of amniotic fluid) was diagnosed.
• Type II – defect of the ATP‑dependent apical potassium channel (ROMK1, KCNJ1 gene); phenotypically the same as type I.
• Type III – defect of the basolateral chloride channel (ClC‑Kb, CLCNKB gene); in 30% of patients hypomagnesemia is present (absent in types I and II).
• Type IVa – defect of the β‑subunit of the basolateral chloride channel (Barttin, BSND gene); characteristic triad: Bartter syndrome, renal failure, hearing impairment.
• Type IVb – combined dysfunction of two chloride channels ClC‑Ka and ClC‑Kb (CLCNKA and CLCNKB genes), prenatal manifestation, polyhydramnios.
• Type V – transient form (defect in the MAGED2 gene), polyhydramnios during pregnancy, excessive salt loss with secondary metabolic alkalosis; spontaneously disappears in the first months of life.

Diagnosis 

Based on clinical symptoms, electrolyte disturbances, and disturbance of the internal environment, the physician initiates broad differential diagnostics in order to confirm the tubulopathy and electrolyte disorder (most often during hospitalization at an internal medicine clinic). Laboratory results from blood and urine and ultrasound examination may help; however, the definitive diagnosis is established by genetic testing.

Treatment

We cannot cure the disease; treatment is symptomatic. It is important to provide patients with sufficient fluids and minerals to compensate for urinary losses. Therefore, regular monitoring of the blood mineralogram via the general practitioner is important. In some cases, renal failure may develop over time—therefore the patient is followed by a nephrologist; in end‑stage renal failure the patient is included in a dialysis program.

• postihnutie obličkových kanálikov, ktoré slúžia k spätnému vstrebávaniu iónov a tekutín z prvovytvoreného moču. To vedie k nadmerným stratám niektorých minerálov do moču (napr. draslíka, sodíka, vápnika a chlóru) a tiež k stratám vody. V niektorých prípadoch dochádza k zlyhávaniu obličiek.
• zvýšené hladiny RAAS a aldosterónu a vzniká sekundárny hyperaldosteronizmus aj s prítomnými klinickými prejavmi (krvný tlak je normálny)
• nadmerné močenie s veľkými stratami tekutín a s tým súvisiacím smädom. Nedostatok tekutín vedie k dehydratácii, prítomná býva únava, znížená výkonnosť a sklon k nízkemu tlaku. Straty draslíka vedú zvyčajne k zníženej koncentrácii draslíka v krvi (hypokalémia) so všetkými jej dôsledkami (svalová slabosť, poruchy srdcového rytmu a pod).
• niektoré formy choroby sú spojené aj so zvýšenými stratami vápnika do moču (hyperkalciúria). Vápnik potom môže začať vytvárať močové kamene. Nedostatok vápnika v krvi potom môže spôsobiť svalové kŕče.
• poruchy rastu
• metabolická alkalóza v krvi
• možná mentálna retardácia