Excerpt from Bartter Syndrome

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Background

In 1962, Frederic Bartter first observed the association of hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic metabolic alkalosis.¹ With the advent of polymerase chain reaction (PCR) and molecular genetic analysis techniques in the 1980s, it was found to be not one disease but several different abnormalities occurring in 4 transporters in 2 parts of the kidneys but with similar pathophysiologic consequences.

Bartter described this combination of juxtaglomerular hyperplasia, hyperaldosteronism, and hypokalemic alkalosis in 2 African American patients, a 25-year-old man with a long history of slow growth, weakness, and fatigue, and a 5-year-old boy. On high-sodium diets, both patients had normal blood pressure and high urinary aldosterone excretion associated with low plasma potassium levels and excessive sodium and chloride urinary excretion, resulting in hyperbicarbonatemia.

Initially, Bartter syndrome was considered a vascular disease. In the 1970s, when prostaglandins were discovered, patients with Bartter syndrome were discovered to overproduce prostaglandins. If treated with a prostaglandin inhibitor, aldosterone levels returned to normal, but plasma potassium levels did not. Subsequently, experimental potassium deficiency induced prostaglandin production and many of the symptoms of Bartter syndrome. This suggested that the problem was not an intravascular problem but a renal tubular problem.

Primarily through the work of Richard Lifton and colleagues, 4 areas of renal tubular defects have been described.^{2, 3, 4, 5} They are in the Na-K-2Cl transporter (now known as Bartter syndrome I), caused by mutations in the SLC12A1 gene; the apical potassium channel (Bartter syndrome II), caused by mutations in the ROMK1 gene; and two defects associated with the basal chloride channel in the thick ascending limb of Henle (TALH), one due to mutations in the CLCNKB gene (Bartter syndrome III) and another due to mutations in the CLCNKA (or BSDN) gene that alters a subunit protein named barttin, which is required for potassium-chloride membrane currents. 

A fifth defect results from loss-of-function mutations in the SLC12A3 gene that codes for the thiazide-sensitive Na-Cl cotransporter in the distal convoluted tubule (DCT). Known as Gitelman syndrome, mutations in this gene lead to similar but milder physiologic abnormalities in renal sodium, calcium, magnesium, and potassium handling.

The importance of the chloride channel in Bartter syndrome and Gitelman syndrome as well as some other nonrenal diseases, such as Dent disease, has been recognized, and it is now apparent that quite a few diseases, including cystic fibrosis, myotonia, deafness, and osteopetrosis, result from chloride channel disorders. The reviews by Jentsch et al and Veizis et al describe the detail of the various chloride channel mutations.^{6, 7}

Pathophysiology

Bartter and Gitelman syndromes are renal tubular salt-wasting disorders in which the kidneys cannot reabsorb chloride in the TALH or the DCT, depending on the mutation.

Chloride is passively absorbed along most of the proximal tubule but is actively transported in the TALH and the DCT. Failure to reabsorb chloride results in a failure to reabsorb sodium and leads to excessive sodium and chloride (salt) delivery to the distal tubules, leading to excessive salt and water loss from the body.

Other pathophysiologic abnormalities result from excessive salt and water loss. The renin-angiotensin-aldosterone system (RAAS) is a feedback system activated with volume depletion. Long-term stimulation may lead to hyperplasia of the juxtaglomerular complex.

Angiotensin II (ANG II) is directly vasoconstrictive, increasing both systemic and renal arteriolar constriction, which helps prevent systemic hypotension. It directly increases proximal tubular sodium reabsorption.

ANG II–induced renal vasoconstriction, along with potassium deficiency, produces a counterregulatory rise in vasodilating prostaglandin E (PGE) levels. High PGE levels are associated with growth inhibition in children.

High levels of aldosterone also enhance potassium and hydrogen exchange for sodium. Excessive intracellular hydrogen ion accumulation is associated with hypokalemia and intracellular renal tubule potassium depletion. This is because hydrogen is exchanged for potassium to maintain electrical neutrality. It may lead to intracellular citrate depletion because the alkali salt is used to buffer the intracellular acid and then lowers urinary citrate excretion. Hypocitraturia is an independent risk factor for renal stone formation.

Excessive distal sodium delivery increases distal tubular sodium reabsorption and exchange with the electrically equivalent potassium or hydrogen ion. This, in turn, promotes hypokalemia, while lack of chloride reabsorption promotes inadequate exchange of bicarbonate for chloride, and the combined hypokalemia and excessive bicarbonate retention lead to metabolic alkalosis.

Persons with Bartter syndrome often have hypercalciuria. Normally, reabsorption of the negative chloride ions promotes a lumen-positive voltage, driving paracellular positive calcium and magnesium absorption. Continued reabsorption and secretion of the positive potassium ions into the lumen of the TALH also promotes reabsorption of the positive calcium ions through paracellular channels. Dysfunction of the TAL chloride transporters prevents urine calcium reabsorption in the TALH. Excessive urine calcium excretion may be one factor in the nephrocalcinosis observed in these patients.

Calcium is usually reabsorbed in the DCT. Theoretically, chloride is reabsorbed through the thiazide-sensitive Na-Cl cotransporter and transported from the cell through a basolateral chloride channel, reducing intracellular chloride concentration. The net effect is increased activity of the voltage-dependent calcium channels and enhanced electrical gradient for calcium reabsorption from the lumen.

In Gitelman syndrome, dysfunction of the Na-Cl cotransporter NCCT leads to hypocalciuria and hypomagnesemia. In the last several years, the understanding of magnesium handling by the kidney has improved and advances in genetics have allowed the differentiation of a variety of magnesium-handling mutations.

While the variants that make up Bartter syndrome may or may not have hypomagnesemia, it is pathognomonic for Gitelman syndrome. The mechanism of the impaired magnesium reabsorption is still unknown; studies in NCCT knockout mice demonstrate increased apoptosis of DCT cells, which would then lead to diminished reabsorptive surface area.

Frequency

International

Estimates of prevalence vary from country to country.

In Costa Rica, the frequency of neonatal Bartter syndrome is approximately 1.2 cases per 100,000 live births and is higher if all preterm births are considered. No evidence of consanguinity was found in the Costa Rican cohort.

In Kuwait, the prevalence of consanguineous marriages or related families in patients with Bartter syndrome is higher than 50%, and prevalence in the general population is 1.7 cases per 100,000 persons.

In Sweden, the frequency has been calculated as 1.2 cases per 1 million persons. Of the 28 patients Rudin reported, 7 came from 3 families; the others were unrelated.⁸

Mortality/Morbidity

The severity and site of the mutation determines the age at which symptoms first develop. Completely dysfunctional mutations in the receptors and ion channels in the TALH are probably not compatible with life.

• Most cases of Bartter syndrome are discovered in infancy or early adolescence. Bartter syndrome can also be diagnosed prenatally, when the fetus develops polyhydramnios and intrauterine growth retardation. Many of the neonates are born prematurely. Children diagnosed early in life usually have more severe electrolyte disorders and symptoms. Because of Bartter syndrome's heterogeneity, patients with minimal symptomatology may be discovered relatively late.
• Patients with Gitelman syndrome tend to have milder symptoms than those with Bartter syndrome and to present in adolescence and early adulthood. Often, patients have minimal symptomatology and lead relatively normal lives. Of the 28 patients Rudin reported, 22 probably had Gitelman syndrome.⁸ Many had no symptoms. Electrolyte abnormalities were found when the patients presented for other problems.

Race

Bartter and Gitelman syndromes have no predilection for any racial or ethnic group.

Sex

Bartter and Gitelman syndromes are inherited as autosomal recessive syndromes. Neither syndrome has a predilection for either sex.

Age

• Bartter syndrome can be diagnosed antenatally, within the first few days of life, or during childhood or adolescence, depending on the severity of the disease.
• Gitelman syndrome is often not diagnosed until adolescence or early adulthood.

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