BARTTER SYNDROMEDr.Afnan Shamraiz

PGr.Paeds

ATH

Background

Bartter syndrome, originally described by Bartter and colleagues in 1962, represents a set of closely related, autosomal recessive renal tubular disorders characterized by hypokalemia, hypochloremia, metabolic alkalosis, and hyperreninemia with normal blood pressure. The underlying renal abnormality results in excessive urinary losses of sodium, chloride, and potassium.

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 distal convoluted tubule (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 systemic and renal arteriolar constriction, which helps to 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 tight junctions. Dysfunction of the TALH 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 sodium chloride 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 sodium chloride 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 patients the variants that make up Bartter syndrome may or may not havehypomagnesemia, this condition 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.

The ClC-Kb channel is found in the basolateral membrane of the TALH, while the barttin subunits of ClC-Ka and ClC-Kb are found in the basolateral membrane of the marginal cells of the cochlear stria vascularis.

In the inner ear, an Na-K-2Cl pump, called NKCC1, on the basolateral membrane increases intracellular levels of sodium, potassium, and chloride. Potassium excretion across the apical membrane against a concentration gradient produces the driving force for the depolarizing influx of potassium through the ion channels of the sensory hair cells required for hearing. The sodium ion is excreted across the basolateral membrane by the Na-K-adenosine triphosphatase (ATPase) pump, and the ClC-K channels allow the chloride ion to exit to maintain electroneutrality.

Sensorineural deafness associated with type IV Bartter syndrome, a neonatal form of the disease (see Etiology), is due to defects in the barttin subunit of the ClC-Ka and CIC-Kb channels.

Mutations in only the ClC-Kb subunit, as occurs in type III Bartter syndrome, do not result in sensorineural deafnes

Etiology

Defects in either the sodium chloride/potassium chloride cotransporter or the potassium channel affect the transport of sodium, potassium, and chloride in the thick ascending limb of the loop of Henle (TALH). The result is the delivery of large volumes of urine with a high content of these ions to the distal segments of the renal tubule, where only some sodium is reabsorbed and potassium is secreted.

Familial and sporadic forms of Bartter and Gitelman syndromes exist. When inherited, these syndromes are passed on as autosomal recessive conditions.

Normal transport mechanism

Normal transport mechanisms in the thick ascending limb of the loop of Henle. Reabsorption of sodium chloride is achieved with the sodium chloride/potassium chloride cotransporter, which is driven by the low intracellular concentrations of sodium, chloride, and potassium. Low concentrations are maintained by the basolateral sodium pump (sodium-potassium adenosine triphosphatase), the basolateral chloride channel (ClC-kb), and the apical potassium channel (ROMK).

NORMAL

Neonatal (type I and type II) Bartter syndrome

An autosomal recessive mode of inheritance is observed in some patients with neonatal Bartter syndrome, although many cases are sporadic.

At least 2 genotypes have been identified in neonatal Bartter syndrome. Type I results from mutations in the sodium chloride/potassium chloride cotransporter gene (NKCC2; locus SLC12A1 on chromosome bands 15q15-21). Type II results from mutations in the ROMK gene (locus KCNJ1 on chromosome bands 11q24-25).

Type I neonatal Bartter syndrome. Mutations in the sodium chloride/potassium chloride cotransporter gene result in defective reabsorption of sodium, chloride, and potassium.

Type II neonatal Bartter syndrome. Mutations in the ROMK gene result in an inability to recycle potassium from the cell back into the tubular lumen, with resultant inhibition of the sodium chloride/potassium chloride cotransporter.

Classic (type III) Bartter syndrome

Some patients have an autosomal recessive mode of inheritance in classic Bartter syndrome, although many cases are sporadic.

In classic Bartter syndrome, the defect in sodium reabsorption appears to result from mutations in the chloride-channel gene (on band 1p36). The consequent inability of chloride to exit the cell inhibits the sodium chloride/potassium chloride cotransporter.

Classic Bartter syndrome. Mutations in the ClC-kb chloride channel lead to an inability of chloride to exit the cell, with resultant inhibition of the sodium chloride/potassium chloride cotransporter.

Increased delivery of sodium chloride to the distal sites of the nephron leads to salt wasting, polyuria, volume contraction, and stimulation of the renin-angiotensin-aldosterone axis. These effects, combined with biologic adaptations of downstream tubular segments, specifically the distal convoluted tubule (DCT) and the collecting duct, result in hypokalemic metabolic alkalosis.[2]

The hypokalemia, volume contraction, and elevated angiotensin levels increase intrarenal prostaglandin E2 (PGE2) synthesis, which contributes to a vicious cycle by further stimulating the renin-aldosterone axis and inhibiting sodium chloride reabsorption in the TALH.

Type IV Bartter syndrome

Studies have identified a novel type IV Bartter syndrome.[10, 23,

24] This is a type of neonatal Bartter syndrome associated with sensorineural deafness and has been shown to be caused by mutations in the BSND gene.[23, 25,

26] BSND encodes barttin, an essential beta subunit that is required for the trafficking of the chloride channel ClC-K (ClC-Ka and ClC-Kb) to the plasma membrane in the TALH and the marginal cells in the scala media of the inner ear that secrete potassium ion D rich endolymph.[10] Thus, loss-of-function mutations in barttin cause Bartter syndrome with sensorineural deafness.

In contrast to other Bartter types, the underlying genetic defect in type IV is not directly in an ion-transporting protein. The defect instead indirectly interferes with the barttin-dependent insertion in the plasma membrane of chloride channel subunits ClC-Ka and ClC-Kb.

Type V Bartter syndrome

Other observations have identified type V Bartter syndrome. This is another type of neonatal Bartter syndrome that is associated with sensorineural deafness, but it is not caused by mutations in the BSND gene. Type V Bartter syndrome has been shown to be a digenic disorder resulting from loss-of-function mutations in the genes that encode the chloride channel subunits ClC-Ka and ClC-Kb.[27] The specific genetic defect includes a large deletion in the gene that encodes ClC-Kb (ie, CLCNKB) and a point mutation in the gene that encodes ClC-Ka (CLCNKA).

Summary of Pathophysiology

Hypokalemic salt-losing tubulopathies_Zelikovic_Nephrology Dialysis Transplant_2003

A summary of currently identified genotype-phenotype correlations in Bartter syndrome is in the table below. For completion, the genetic defect found in Gitelman syndrome (the thiazide-sensitive sodium chloride cotransporter, encoded by the gene NCCT) is also included.

Bartter Syndrome Genotype-Phenotype Correlations

Genetic Type Defective Gene Clinical Type

Bartter type I NKCC2 Neonatal

Bartter type II ROMK Neonatal

Bartter type III CLCNKB Classic

Bartter type IV BSND Neonatal with deafness

Bartter type V CLCNKB and CLCNKA Neonatal with deafness

Gitelman syndrome NCCT Gitelman syndrome

Cascade of events

Salt loss

Volume depletion

Renin/aldosterone secretion / JGA hyperplasia

autonomous hyperreninemic hyperaldosteronism

Enhanced K and H secertion at the collecting tubule

Hypokalemia and metabolic alkalosis result

Epidemiology

International occurrence Bartter syndrome is rare, and estimates of its occurrence vary

from country to country. In the United States, the precise incidence is unknown.

In Costa Rica, the frequency of neonatal Bartter syndrome is approximately 1.2 cases per 100,000 live births but 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.[14]

Age-related demographics

Neonatal Bartter syndrome can be suspected before birth or can be diagnosed immediately after birth. In the classic form, symptoms begin in neonates or in infants aged 2 years or younger. Gitelman syndrome is often not diagnosed until adolescence or early adulthood.[15, 16]

PRESENTATION

History

Neonatal Bartter syndrome Maternal polyhydramnios, secondary to fetal

polyuria, is evident by 24-30 weeks' gestation. Delivery often occurs before term. The newborn has massive polyuria (rate as high as 12-50 mL/kg/h).

The subsequent course is characterized by life-threatening episodes of fluid loss, clinical volume depletion, and failure to thrive. Volume depletion increases thirst, and the normal response is to increase fluid intake.

A subset of patients with neonatal Bartter syndrome (types IV and V) develop sensorineural deafness.

Classic Bartter syndrome

Patients have a history of maternal polyhydramnios and premature delivery. Symptoms include the following:

Polyuria Polydipsia Vomiting Constipation Salt craving Tendency for volume depletion Failure to thrive Linear growth retardation

Other symptoms

Other symptoms, which appear during late childhood, include fatigue, muscle weakness, cramps, and recurrent carpopedal spasms.

Developmental delay and minimal brain dysfunction with nonspecific electroencephalographic changes are also present.

Physical Examination

Neonatal Bartter syndrome Patients are thin and have reduced muscle

mass and a triangularly shaped face, which is characterized by a prominent forehead, large eyes, protruding ears, and drooping mouth. Strabismus is frequently present. Blood pressure is within the reference range.

A subset of patients with Bartter syndrome (types IV and V) develop sensorineural deafness, which is detectable with audiometry.

Classic Bartter syndrome

The patient's facial appearance may be similar to that encountered in the neonatal type. However, this finding is infrequent.

Patients with Gitelman syndrome tend to have milder symptoms than do those with Bartter syndrome and to present in adolescence and early adulthood. Often, patients have minimal symptomatology and lead relatively normal lives.[14]

Consider possible renal tubular disorder if patients, especially dehydrated infants and young children, are found to have hypokalemia and a high serum bicarbonate concentration that do not correct with potassium and chloride replacement treatment.

Clinical and biochemical features of Gitelman's syndrome and the various types of Bartter's syndrome

Differential Diagnosis  Conditions to consider in the differential diagnosis of Bartter syndrome

include the following: Diuretic abuse Gitelman syndrome Hyperprostaglandin E syndrome Familial hypomagnesemia with hypercalciuria/nephrocalcinosis Activating mutations of the CaSR calcium-sensing receptor Cyclical vomiting Congenital chloride diarrhea Gullner syndrome - Familial hypokalemic alkalosis with proximal

tubulopathy Mineralocorticoid excess Pyloric stenosis Hypomagnesemia Cystic fibrosis Hypochloremic alkalosis Hypokalemia

Morbidity and mortality Significant morbidity and mortality occur if

Bartter syndrome is untreated. With treatment, the outlook is markedly improved; however, long-term prognosis remains guarded because of the slow progression to chronic renal failure due to interstitial fibrosis.

Sensorineural deafness Sensorineural deafness associated with

Bartter syndrome IV is due to defects in the barttin subunit of the ClC-Ka and CIC-Kb channels.

Nephrocalcinosis A review of 61 cases of Bartter syndrome reported 29 with

nephrocalcinosis, a condition that is often associated with hypercalciuria.

Renal failure Renal failure is fairly uncommon in Bartter syndrome. In a

review of 63 patients, 5 developed progressive renal disease requiring dialysis or transplantation.

In 2 reports of patients who underwent biopsies before developing end-stage renal disease (ESRD), 1 patient had interstitial nephritis, and the other had mesangial and interstitial fibrosis.

One report relates the case of a patient developing reversible acute renal failure from rhabdomyolysis due to hypokalemia.

Short stature/growth retardation Nearly all patients with Bartter syndrome

have growth retardation. In a review of 66 patients, 62 had growth retardation, often severe (below the fifth percentile for age). Treatment with potassium, indomethacin, and growth hormone (GH) has been effective.

Additional complications Other complications in Bartter syndrome

include the following: Cardiac arrhythmia and sudden death - May

result from electrolyte imbalances Failure to thrive and developmental delay -

Common in untreated patients Significant decrease in bone mineral density

- Has been documented in patients with either the neonatal or classic form

Workup Approach Considerations 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 thick ascending limb of the loop of Henle (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.

Electrocardiography An electrocardiogram (ECG) may reveal changes characteristic

of hypokalemia, such as flattened T waves and prominent U waves.

Histologic findings Although renal biopsy is not usually required, histologic findings

may be useful in confirming the diagnosis of Bartter syndrome. In neonatal and classic Bartter syndrome, the cardinal finding is

hyperplasia of the juxtaglomerular apparatus. Less frequently, hyperplasia of the medullary interstitial cells is present.

Glomerular hyalinization, apical vacuolization of the proximal tubular cells, tubular atrophy, and interstitial fibrosis may be present as a consequence of chronic hypokalemia.

Laboratory Studies

Potassium Initiate timed urine collection to determine potassium levels. In hypokalemia, normal

kidneys retain potassium.[18] Elevated urinary potassium levels with low blood potassium levels suggest that the kidneys are having problems retaining potassium.

Aldosterone Next, initiate timed urine collection to determine aldosterone levels. Aldosterone levels

should be high in volume-replete patients. If urinary aldosterone levels are high despite volume replacement, there is an abnormal stimulation of aldosterone.

Patients with primary hyperaldosteronism in a volume-replete state usually have normal to high blood pressure. Low or low-normal blood pressure with high aldosterone excretion suggests that the primary problem is something else and that the aldosterone response is secondary to the undiagnosed primary abnormality.

Chloride Next, initiate a timed urine collection to determine chloride levels.

Extrarenal volume depletion is a possible reason for low blood pressure, high aldosterone excretion, and potassium loss. In this case, the kidneys retain sodium and chloride, and urinary chloride concentrations should be low.

High urine chloride levels with low blood pressure, high aldosterone secretion, and high urinary potassium levels are found only with long-term diuretic use and Bartter or Gitelman syndrome. If diuretic abuse is suspected, a urine screen for diuretics can be ordered. Otherwise, the diagnosis is Bartter or Gitelman syndrome.

Calcium/magnesium Patients with Bartter syndrome have high urinary excretion of calcium

and normal urinary excretion of magnesium. In patients with Gitelman syndrome, the opposite is true, with tests

showing low urinary excretion of calcium and high urinary excretion of magnesium.

Hyperuricemia Hyperuricemia is present in 50% of patients with Bartter syndrome, whereas

in Gullner syndrome, hypouricemia, secondary to impaired proximal tubular function, is present.

Complete blood count Polycythemia may be present from hemoconcentration. Mutations Mutations in the different transporters cause Bartter syndrome. The older

methods of determining the presence of mutations require more detailed physiologic investigations, including determination of serum magnesium levels and further urine collections to assess calcium, magnesium, and PGE2 levels.

In Bartter syndrome, urine calcium excretion is high, leading to nephrocalcinosis, while serum magnesium levels are normal.

With the transporter mutations that cause Gitelman syndrome, hypomagnesemia is common and is accompanied by hypocalciuria.

Genetic analysis has become the preferred methodology for determining if a mutation in one of the transporters has occurred. An analysis of the genes for the transporters shows multiple problems leading to abnormal gene function, including missense, frame-shift, loss-of-function, and large deletion mutations. (Not all mutations lead to a marked loss of function.)[3, 4, 5, 6, 19, 20]

Amniotic fluid If the diagnosis is being made prenatally, assess

the amniotic fluid. The chloride content may be elevated in either Gitelman or Bartter syndrome.

Glomerular filtration rate The glomerular filtration rate (GFR) is preserved

during the early stages of the disease; however, it may decrease as a result of chronic hypokalemia. One study, however, hypothesizes that GFR is affected more by secondary hyperaldosteronism than by hypokalemia.[29]

Imaging Studies

Neonatal Bartter syndrome can be diagnosed best prenatally by ultrasonography. The fetus may have polyhydramnios and intrauterine growth retardation. Amniotic chloride levels may be elevated.[21]

After birth, especially if the disease is diagnosed in older patients who have hypercalciuria, consider a renal ultrasonogram or flat plate of the abdomen for nephrocalcinosis. Sonographic findings include diffusely increased echogenicity, hyperechoic pyramids, and interstitial calcium deposition.

Because continued calcium loss may affect bones, dual-energy radiographic absorptiometry scans to determine bone mineral density may be advisable in older patients.

Nephrocalcinosis can occur and is often associated with hypercalciuria. It can be diagnosed with abdominal radiographs, intravenous pyelograms (IVPs), renal ultrasonograms, or spiral computed tomography (CT) scans.

Treatment

Approach Considerations

Since first described in 1962, several types of medical treatment have been used, including the following:

Sodium and potassium supplements - Used for the electrolyte imbalances

Aldosterone antagonists and diuretic spironolactone - Are mainstays of therapy

Angiotensin-converting enzyme (ACE) inhibitors - Used to counteract the effects of angiotensin II (ANG II) and aldosterone

Indomethacin - Used to decrease prostaglandin excretion Growth hormone (GH) - Used to treat short stature Calcium or magnesium supplements - May occasionally be

needed if tetany or muscle spasms are present

Pregnancy-related considerations Reports associated with Bartter syndrome in

pregnant women are limited because Bartter syndrome is a rare disease. Complications related to electrolyte loss (eg, hypokalemia, hypomagnesemia) responded well to supplementation. Fetuses were unaffected and carried to term.

In Rudin's report of 28 pregnant patients, no problems were noted except asymptomatic hypokalemia.[14] In another study, of 40 patients, 30 reported normal pregnancies and terminated by normal parturition; however, many of the patients who were pregnant probably had Gitelman syndrome

Inpatient care For patients initially diagnosed in the hospital, the goal is to stabilize the

patient sufficiently for discharge. This includes stabilization of potassium and other electrolytes, as well as volume and, perhaps, acid-base parameters.

Consultations Contact a nephrologist or pediatric nephrologist whenever a patient fitting

the clinical picture of Bartter or Gitelman syndrome is identified. The specialist can assist with the initial diagnosis and carry out periodic outpatient evaluation of growth, development, renal function, serum electrolytes, and response to therapy.

Monitoring Patients initially need frequent outpatient follow-up care until the

metabolic abnormalities caused by the renal tubular transporter mutation are stabilized with medications. The length of time to stability depends on the severity of the mutation and the degree of patient compliance.

Renal Transplantation Bartter and Gitelman syndromes, by themselves, do not

lead to chronic renal insufficiency; however, in patients with these syndromes who develop end-stage renal disease (ESRD) for other reasons, transplants from living relatives are an option and result in normal urinary handling of sodium, potassium, calcium, and magnesium.

Reports of renal transplants from living relatives in ESRD patients with Bartter syndrome suggest that many endocrinologic abnormalities in Bartter syndrome improve or normalize after transplantation.

Because the genetic abnormality in Bartter syndrome may be found only in the kidneys (which is certain in Na-K-Cl cotransporter but may not be the case for some of the other mutations), transplantation corrects the problem by replacing unhealthy kidneys with normal ones

Preemptive Surgery

One approach to the management of severe Bartter syndrome involves preemptive nephrectomy and renal transplantation.[30] The rationale for this approach lies in the fact that Bartter syndrome is an incurable genetic disease, and the poorly controlled forms may result in frequent life-threatening episodes of dehydration and electrolyte imbalances. Preemptive bilateral nephrectomies and successful kidney transplantation prior to the onset of ESRD has resulted in correction of metabolic abnormalities and excellent graft function.

Diet and Activity

Diet Adequate salt and water intake is necessary to

prevent hypovolemia, and adequate potassium intake is essential to replace urinary potassium losses. Patients should consume foods and drinks that contain high levels of potassium (eg, tomatoes, bananas, orange juice).

With growth retardation, adequate overall nutritional balance (protein-calorie intake) is important. Whether other dietary supplements (eg, citrate, magnesium, vitamins) are helpful is not clear.

Activity

No restriction on general activity is required, but precautions against dehydration should be taken. Patients should avoid strenuous exercise avoided because of the danger of dehydration and functional cardiac abnormalities secondary to potassium imbalance.

Prognosis

early diagnosis and appropriate treatment may improve growth and neurointellectual development.

sustained hypokalemia and hyperreninemia can cause progressive tubulointerstitial nephritis, resulting in end-stage-renal disease.

With early treatment of the electrolyte imbalances the prognosis is good.

Bone age is appropriate for chronological age, and pubertal and intellectual development are normal with treatment.

The disease does not recur in the patient with a transplanted kidney.

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