Bartter syndrome

Overview

Bartter syndrome is a hereditary renal tubular condition characterized by a deficiency in salt reabsorption in the thick ascending limb of the loop of Henle, which results in salt wasting, hypokalemia, and metabolic alkalosis. Several genes encoding transporters and channels involved in salt reabsorption in the thick ascending limb are mutated, resulting in distinct kinds of Bartter syndrome.

A deeper knowledge of the altered channels and transporters may lead to specific therapy targets in the future, including medications aimed at correcting deficits in folding or plasma membrane expression of the mutant proteins. 

Bartter syndrome Definition

Bartter syndrome is an autosomal recessive salt reabsorption condition characterized by low/normal blood pressure and extracellular fluid volume loss. High renin, secondary hyperaldosteronism, and increased prostaglandin E2 levels are among the other problems. The most common acid-base manifestation is metabolic alkalosis.

Patients with failure to thrive are frequently seen in infancy. Various phenotypes are characterized based on the location of defective salt transport. The neonatal (antenatal) Bartter syndrome, classical Bartter syndrome, and Gitelman syndrome are all important clinical variations.

Bartter syndrome affects 1 in 1,000,000 people and is far less frequent than Gitelman syndrome.

Etiology

Impaired sodium-potassium-chloride cotransporter (NKCC2) or potassium channel (ROMK) transport affects sodium, potassium, and chloride transit in the thick ascending limb of the loop of Henle (TALH). This leads in greater distal distribution of these ions, with just a little amount of sodium reabsorbed and potassium excreted.

Types of Bartter syndrome:

• Mutations in the sodium chloride/potassium chloride cotransporter gene cause type I. (NKCC2)
• Type II is caused by mutations in the ROMK gene.
• Mutations in the chloride channel gene cause type III (CLC-Kb)
• Type IV is caused by loss-of-function mutations in the barttin gene.
• Mutations in the extracellular calcium ion-sensing receptor and the genes encoding the chloride channel subunits, ClC-Ka and ClC-Kb, cause type V.

Aminoglycoside usage can result in Bartter syndrome. An aminoglycoside-induced Bartter-like syndrome is frequently associated with hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalcemia.

An prenatal version of Bartter syndrome is characterized by severe hypokalemia, metabolic alkalosis, and severe systemic symptoms. Bartter syndromes III and V are more common later in life and have minor symptoms.

Pathophysiology

Bartter syndrome is a renal tubular salt-wasting disorder in which the kidneys are unable to reabsorb sodium and chloride in the loop of Henle's thick ascending limb. This results in increased distal salt delivery and excessive salt and water loss from the body. As a result of the volume depletion, the renin-angiotensin-aldosterone system (RAAS) is activated, resulting in secondary hyperaldosteronism. Long-term stimulation results in hyperplasia of the juxtaglomerular apparatus and, as a result, elevated renin levels.

Excessive distal sodium supply increases distal convoluted tubule sodium reabsorption and exchange with positively charged potassium or hydrogen ions, resulting in increased potassium loss in urine and increased hydrogen H secretion. Hyperaldosteronism causes an increase in bicarbonate as a result of reduced hydrogen ion release.

In Bartter syndrome, urinary concentrating and diluting capacities are impaired. Impaired urinary concentrating ability is caused by faulty salt absorption in the Henle loop. Under normal conditions, the major driving factor for sustaining the concentration gradient in the medulla required for concentrated urine generation is salt absorption in the loop of Henle in the presence of normal ADH. Polyuria, hypokalemia, and increased prostaglandin E2 levels are also implicated.

The altered electrochemical gradient required for calcium and magnesium reabsorption is caused by the faulty sodium chloride transport in the loop of Henle associated with Bartter syndrome, resulting in increased urinary calcium and magnesium loss.

Nephrocalcinosis is a frequent complication of Bartter syndrome. The most plausible explanation is secondary calcium wasting in urine. Chloride transporters in the thick ascending limb of the loop of Henle  fail, leading in calcium malabsorption in loop of Henle. Calcium and magnesium are normally absorbed paracellularly under the influence of positive charge in the lumen due to reabsorption of negatively charged chloride ions.

Types of Bartter syndrome

Type I BS

Type I BS is genetically diverse, with over 63 documented variants, including missense/nonsense mutations, splicing mutations, minor insertions, and small deletions. In previously described instances of type I BS, the majority of patients had homozygous mutations or a mutation in one allele and a significant deletion in the other.

Symptoms of type I BS commonly appear at birth, with severe salt depletion, hyposthenuria, elevated PGE2 production, and failure to thrive. Some of these symptoms develop in pregnancy and can lead to polyhydramnios and preterm birth.

A frequent symptom is severe hypercalciuria, which can progress to nephrocalcinosis and/or osteopenia. Types I and II BS were formerly thought to be prenatal variations, commonly known as "hyperprostaglandin E syndrome," however new research has revealed varying phenotypic expression and severity.

Type I BS must be diagnosed as soon as possible since it is associated with severe morbidity and death if not treated properly. Prenatal diagnosis might be important for initiating proper care, however investigations using amniotic fluid to confirm the diagnosis had contradictory findings. Aldosterone levels in amniotic fluid did not provide reliable diagnostic information, although high chloride levels in amniotic fluid were identified in certain patients with no other electrolyte abnormalities.

Previous research found that amniotic fluid chloride concentrations in prenatal BS patients varied from 114 to 123 mEq/L, which is high when compared to normal amniotic fluid chloride concentrations (approximately 107–109 mEq/L between gestational age of 25 and 37 weeks). An amniotic fluid index that measures total protein and alpha-fetoprotein levels in the amniotic fluid has also been proposed and may be useful. 

Type II BS

Type II BS is also known as the prenatal variety of BS since it manifests itself more commonly in the newborn era with severe symptoms. However, due to the disease's wide phenotypic, late onset of type II BS (equal to type I BS) has also been recorded.

The paradox of potassium squandering in this context may be explained by compensatory overexpression of large potassium (BK) channels, which allow potassium excretion in the high-flow situation of BS.

Hypokalemia is frequently milder in this Bartter type, and temporary hyperkalemia may be detected in the early days of life, most likely due to immature Na+K+ATPase pumps and the expression of the ROMK channel in the cortical collecting duct, where it serves in K+ secretion.

Type III BS

The first patients with these mutations were found to have hypokalemia, salt wasting, polyuria, polydipsia, and growth retardation during infancy or early childhood. 

Nephrocalcinosis can develop in type III BS, however it is less common than in types I and II BS. Urinary calcium levels were heterogeneous in a large Spanish cohort, with hypercalciuria occurring in 31% of patients and hypocalciuria occurring in 23%. Nephrocalcinosis was identified in 20% of type III BS patients 

Type III BS was assumed to represent "typical BS," but significant phenotypic heterogeneity in this group of individuals has been observed, including neonatal BS, prenatal BS, and the Gitelman-like phenotype. In a large type III BS French cohort, the phenotypic variance included around 30% antenatal/neonatal BS, 45 percent classic BS, and 25% Gitelman-like phenotype.

Bartter syndrome Symptoms

A complete history, including a detailed physical examination, is beneficial. Bartter syndrome is most commonly found in children and adolescents who have stunted development as well as symptoms of polyuria, polydipsia, cramping, vomiting, dehydration, constipation, growth delays, and failure to thrive.

Before making the diagnosis, a family history of nephrocalcinosis and a comprehensive personal history should be taken to rule out the potential of covert vomiting and diuretic misuse. Patients are often malnourished, with a high brow, huge eyes, strabismus, protruding ears, sensorineural deafness, and drooping lips. Blood pressures are commonly measured as normal or low. Long-term instances may manifest with high blood pressure.

Children with prenatal Bartter syndrome have polyhydramnios due to intrauterine polyuria and are frequently born preterm. After delivery, it is typical to have fever, sensorineural deafness, severe polyuria, vomiting, and diarrhea, which can lead to dehydration.

Diagnosis of Bartter syndrome

The diagnosis is determined based on important observations in the history and physical exam, which are augmented by specific test abnormalities. In virtually all cases, Bartter syndrome is linked with electrolyte and acid-base abnormalities, including hypokalemia and metabolic alkalosis.

Other anomalies include elevated serum renin and aldosterone levels in some individuals, as well as reduced magnesium and phosphate levels in others. Elevated sodium, potassium, and PGE2 excretion is seen in urine electrolytes. Elevated 24-hour urine calcium excretion aids in the exclusion of Gitelman syndrome, which is characterized by poor calcium excretion. When the content of chloride in the urine is less than 25 meq/L, it helps distinguish it from surreptitious vomiting. In Bartter syndrome, urine chloride levels are usually high (more than 35 meq/L).

With newborn Barrter syndrome, ultrasonography reveals polyhydramnios and intrauterine growth retardation. Chloride levels in amniotic fluid may be high.

To diagnose nephrocalcinosis, abdominal radiographs, intravenous pyelograms (IVPs), renal ultrasonograms, or spiral CT scans can be used. To rule out certain mutations, genetic testing might be considered.

In recent years, genetic identification and detection of many ion channels and their regulatory processes implicated in this illness have aided physicians in better understanding the underlying causes. First, many genotypes were found and assumed to represent groups with similar BS characteristics. However, significant clinical and laboratory disparities among patients in these groups have been gradually revealed, resulting in several presentations of the same entity.

Management

During the newborn period, a saline infusion may be required. The goal is to normalize blood potassium levels, which can be accomplished by oral potassium supplementation, such as KCL 25 to 100 mmol/day. In rare circumstances, ACE inhibitors and angiotensin receptor blockers (ARB) can help reduce increased angiotensin II and aldosterone levels, restrict proteinuria, and boost serum potassium.

Other alternatives include amiloride (5 to 40 mg/day), spironolactone, and an NSAID (indomethacin 1-3 mg/kg/24 hours) to counteract elevated urine PGE2 levels. Because hypomagnesemia can exacerbate potassium wasting, magnesium supplementation should be investigated.

According to certain writers, the use of treatment has resulted in a significant increase in development velocity as well as the stability of metabolic and electrolyte levels.

Gastrointestinal side effects can be frequent and severe, implying the need for routine endoscopic monitoring of these patients who are taking prostaglandin inhibitors for an extended period of time. The use of rofecoxib, a COX2 selective inhibitor, decreased hyperreninemia to the same amount as indomethacin, but with less stomach adverse effects.

However, new evidence indicating a substantial risk of cardiovascular events in individuals taking COX2 selective inhibitors has reduced their usage. As a result, whether COX inhibitors give the highest effectiveness with the fewest adverse effects, and if they should be progressively phased down throughout school age or used indefinitely, remain unanswered concerns.

In prenatal manifestations, maternal therapy with nonsteroidal anti-inflammatory medications (NSAIDs) is contentious since it may impact kidney maturation and the overall number of nephrons. Prenatal BS with severe polyhydramnios was discovered in a recent study, and patients were given NSAIDs until gestational week 31 and thereafter avoided since they may cause early closure of the ductus arteriosus.

This choice should take into account the possibility of early closure of the patent ductus, which might lead to cardiovascular issues.

Differential Diagnosis

• Diuretic abuse
• Cyclical vomiting
• Hyperprostaglandin E syndrome
• Familial hypomagnesemia with hypercalciuria/nephrocalcinosis
• Pyloric stenosis
• Gitelman syndrome
• Cystic fibrosis
• Gullner syndrome - Familial hypokalemic alkalosis with proximal tubulopathy
• Mineralocorticoid excess
• Activating mutations of the CaSR calcium-sensing receptor
• Hypomagnesemia
• Congenital chloride diarrhea
• Hypochloremic alkalosis
• Hypokalemia

Bartter vs Gitelman syndromes

GS is also a rare recessive salt-losing tubulopathy with reduced DCT salt reabsorption that affects 1 in 25,000 people and is likely the most frequent renal salt-wasting condition. Hypokalemia, metabolic alkalosis, hypocalciuria, and hypomagnesemia are common clinical findings.

Previously, BS was separated from GS by clinical features such as early age of start, severity, the presence of hypercalciuria, polyhydramnios, or growth retardation. However, developments in medical understanding have revealed that individuals with BS may appear late, and some symptoms, such as hypercalciuria in BS, are not present in all instances.

In general, the majority of instances of BS occur in newborns, and future complications might include failure to thrive and development retardation. A typical finding of BS is maternal polyhydramnios with preterm labor. There have also been reports of vomiting, diarrhea, and fever.

Some newborns may have a high forehead, triangular face with drooping lips, huge eyes, and pinnae, which are characteristic of BS. Nonetheless, because certain characteristics might be identical, the diagnostic strategy should incorporate genetic testing.

Pseudo bartter syndrome

Nephrotoxic agents (such as aminoglycosides, amphotericin B, and heavy metal poisoning) have also been linked to a BS phenotype.

Extrarenal sodium chloride loss via the gastrointestinal tract (congenital chloride diarrhea) or via the skin (cystic fibrosis) may potentially be linked with the Bartter phenotype, as there is normal tubular function.

Diuretic abuse and bulimia must also be ruled out in all BS suspects. In individuals with bulimia and secretive vomiting, the urine chloride content is low. On the contrary, frequent measurements of urine chloride at various periods may aid in the detection of diuretic usage. Urine chloride concentrations in diuretic abusers are very variable and chronically increased in BS patients.

Prognosis

According to the limited prognostic information available, early diagnosis and treatment of infants and young children with classic Bartter Syndrome may improve growth and possibly intellectual development. Sustained hypokalemia and hyperreninemia, on the other hand, can lead to progressive tubulointerstitial nephritis and end-stage renal disease (kidney failure). Patients with classic Bartter Syndrome have an excellent prognosis if electrolyte abnormalities are treated early.

Cardiac work-up/Anesthesia/Sports

• Hypokalemia, with or without hypomagnesemia, causes the QT interval to lengthen, increasing the risk of ventricular arrhythmias. Because isolated cases of cardiac arrhythmias, long QT intervals, and sudden death in BS patients have been recorded, electrocardiography at rest should be conducted to check rhythm and QT-interval duration. A follow-up cardiology evaluation, as previously indicated for GS,
• is indicated when patients complain of palpitations or syncope (e.g., Holter, stress electrocardiography), or if electrocardiographic abnormalities persist despite attempted improvement of the biochemical abnormalities.
• Medicines that delay sinus rhythm or influence the QT interval, such as negative chronotropic drugs, or agents that might cause or worsen hypomagnesemia, such as proton-pump inhibitors, macrolides, fluorchinolones, gentamicin, or antiviral drugs, should be avoided.
• When individuals with BS undergo anesthesia, extreme caution should be exercised. Hypokalemia and hypomagnesemia can enhance the effects of anesthetic drugs such as neuromuscular blockade during general anesthesia and adrenaline during regional anesthesia. There is, however, no conclusive data to demonstrate that safe preoperative plasma potassium levels exist. Guidelines recommend aiming for potassium levels more than 3.0 mmol/l and magnesium levels greater than 0.5 mmol/l in the general population.
• There is no evidence that involvement in sports is harmful. In any instance, volume depletion should be avoided, and extra salt, electrolytes, or both may be beneficial. Strenuous exercise or competitive practice, on the other hand, should be approached with caution, especially if there is a history of cardiac symptoms or a prolonged QT interval.

Patient Education

• Disease-specific information is critical for BS patients and their families. Age-appropriate personal education, information booklets, web-based material, patient-led forums, and patient/family group support events can all be used to deliver information.
• It is critical that patients understand what to do in an emergency. In the event of a concomitant sickness, "sick day regulations" may be useful.
• In a fraction of BS patients, comorbidities caused by excessive prematurity can impair academic achievement. Various interventions to help these youngsters may be accessible and should be employed depending on the country.
• Work performance in certain patients may be impaired, for example, due to muscular weakness or weariness. Occupational therapists can help patients locate support for their specific problems.
• Patients may be cautious to reveal their disease to employers for fear of losing their employment. Patients, on the other hand, should be encouraged to disclose illness knowledge, ideally by offering BS educational material.

Conclusion 

In summary, BS is an uncommon salt-losing tubulopathy caused by a number of gene abnormalities and diverse types of mutations, with a poor phenotype–genotype link due to interaction with other cotransporters and varying degrees of compensation via alternate routes.

Bartter syndrome can be difficult to identify. Because untreated patients have a high morbidity and mortality rate, the healthcare team, which includes nurses, nephrology nurses, nurse practitioners, physician assistants, and physicians, must collaborate to diagnose and manage the therapy.

Medication selection, drug-drug interactions, and compliance should all be evaluated by the pharmacist. The nurse should help with interprofessional team care coordination and patient education.

Bartter syndrome is difficult to treat, and there is currently no definitive cure. Untreated instances are associated with severe morbidity and death, with chronic renal disease playing a prominent role. Overall prognosis is determined by the level of receptor failure, and despite these facts, most patients may live normal lives if they follow their treatment plan religiously. Early detection and therapy throughout childhood can help to avoid growth retardation.

The team should be aware that Bartter-like syndrome is connected with aminoglycosides and can be observed for 2 to 6 weeks after antibiotics are stopped. This necessitates the team's monitoring of the patient's closure and timely provision of potassium, calcium, and magnesium as needed.