AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

Hypochloremic alkalosis is common in hospitalized children and is rare in outpatient settings. In neonatal ICUs (NICUs), this form of alkalosis frequently results from diuretic therapy for bronchopulmonary dysplasia. Hypochloremic alkalosis due to loss of gastric acid via nasogastric tube suctioning is also common in pediatric ICUs. Other rare, but serious, causes must be considered in any child presenting with failure to thrive, poor development, and a family history of neonatal demise and metabolic alkalosis in the absence of diuretic or laxative abuse. Repeated vomiting may be a clue that the patient has severe gastroesophageal reflux or pyloric stenosis.

History of polyhydramnios is helpful; polyhydramnios may result from polyuria or congenital diarrhea. A lack of both symptoms may help identify cystic fibrosis. Severe hypochloremic metabolic alkalosis may be the presenting metabolic derangement for multiple conditions. Molecular diagnostic procedures sometimes help resolve differential diagnoses. Severe brain damage and psychomotor retardation may occur in children with delayed diagnosis and treatment.

Pathophysiology

Hypochloremic alkalosis results from either low chloride intake or excessive chloride wasting. Low chloride intake is very uncommon. Excessive chloride wasting often occurs in hospitalized children, usually due to diuretic therapy or nasogastric tube suctioning. Chloride-wasting syndromes, including Bartter syndrome, congenital chloride-losing diarrhea (CLD), and cystic fibrosis, result from renal tubular loss, defective electrolyte transport across intestinal epithelia, or chloride loss via the skin, respectively.

Frequency

International

Frequency of hypochloremic alkalosis is unknown, both in the United States and worldwide.

Mortality/Morbidity

• Anorexia and polyuria eventually lead to malnutrition and growth failure. Chronic dehydration frequently causes constipation. A small muscle mass and muscle wasting are frequently seen in patients following a late diagnosis or in untreated patients.
• CNS effects include cerebral dysfunction and defective cognitive function resulting from chronic hypoperfusion in moderate-to-severe metabolic alkalosis due to hypokalemic and hypochloremic states. Hypopnea is due to depression of respiratory drive. CNS calcification occurs in some patients for unclear reasons. Seizure disorder, brain atrophy, and mental retardation are other known sequelae.
• Depending on the renal disorder, complications may include nephrocalcinosis, interstitial nephropathy, hypercalcemia, hyperuricemia, hypertension during the late stages of renal damage, and renal failure.

Race

Hypochloremic alkalosis may be more common worldwide than previously accepted. Many cases of CLD have emerged from Eastern Europe and Middle Eastern Arab countries; indeed, the largest purported series arose from Saudi Arabia.¹ Fewer cases in the English language literature have been reported in the Far East and North America, perhaps because of cultural and academic barriers.

Sex

Males and females are affected in equal numbers.

Age

• CLD can manifest before birth as severe midtrimester polyhydramnios. Metabolic derangements may manifest as early as the first few days of life.
• Bartter syndrome may present at any age but occurs primarily in infants before 1 year of age.
• Hypochloremic alkalosis resulting from cystic fibrosis is infrequent in infancy but can become more severe in summer because of excessive chloride loss from sweating.
• Drug-related hypochloremic alkalosis is observed at all ages.

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

• Prenatal and neonatal history
• • Prenatal polyhydramnios is present in most patients with congenital forms of metabolic alkalosis, especially chloride-losing diarrhea (CLD). Premature birth resulting from polyhydramnios is common in patients with Bartter syndrome and CLD.
  • Lack of meconium is highly suggestive of intrauterine diarrhea.
  • Prolonged neonatal jaundice may be present.
  • History of hypotonia and lethargy without sepsis is significant in patients with early-onset hypochloremia and hypokalemia.
• Infant history
• • History of repeated vomiting may be suggestive of severe gastroesophageal reflux or pyloric stenosis.
  • Failure to thrive is common.
  • Constipation is very common in patients with Bartter syndrome. Diarrhea, when watery, is highly suggestive of CLD.
  • A salty taste when kissed may help detect patients with cystic fibrosis.
  • CNS dysfunctions (lethargy, confusion, or seizure) are observed in patients with severe alkalosis.
  • Neuromuscular symptoms include weakness and muscle cramps.
  • Other symptoms (abdominal distension, dry skin, apathy, loss of interests, and frequent hospital admissions because of recurrent dehydration) are significant diagnostic clues during childhood.
• Family history: Consanguinity, recurrent prematurity, neonatal demise, and psychomotor retardation are helpful clues for familial conditions.
• Psychosocial history: This may include loss of interests and behavioral problems, which were reported in patients with chronic hypochloremic alkalosis. Difficulty in school performance may be a consequence of the disorder.
• Other: In hospitalized patients with hypochloremic metabolic alkalosis, the physician should always ask about nasogastric tube suctioning and oral secretions. Overzealous use of loop or thiazide diuretics, especially in ICUs, is another important factor.

Physical

• General findings
• • Patients with hypochloremic alkalosis are commonly small for age, lethargic, or apathetic.
  • Signs of chronic dehydration (such as skin tenting and poor peripheral perfusion) may be evident upon presentation.
• Growth parameters
• • Weight and height usually fall below the reference range in patients with chronic disease, but are not affected in patients with acute disease.
  • In one series, both weight and height were in the lowest 3% in more than 60% of patients with CLD.¹
• CNS findings
• • CNS manifestations vary from mild to severe, depending on the severity of alkalosis.
  • Confusion, apathy, disorientation, excessive sleeping, seizure, and stupor may be present.
• Abdominal findings
• • Depending on the cause, the abdomen may be scaphoid (in Bartter syndrome) or distended (in CLD). Peristaltic waves can be observed in children with CLD. Exacerbated bowel sounds are also present in CLD.
  • Hard stools may occur in patients with Bartter syndrome.
  • Hepatomegaly may be present and suggests cystic fibrosis.
• Musculoskeletal findings: These include muscle wasting, atrophy, and hypotonia.
• Respiratory findings: These include shallow breathing and hypopnea in severely affected children.

Causes

• Chloride-responsive alkalosis (extrarenal chloride loss)
• • Causes include recurrent vomiting, gastric acid loss, diuretic-induced alkalosis (loop or thiazide diuretics), and posthypercapnic metabolic alkalosis.
  • CLD, cystic fibrosis, and laxative abuse are also potential causes.
• Chloride-resistant alkalosis (with either euvolemia or hypovolemia)
• • Renal chloride wasting, as well as severe potassium and magnesium depletion, may occur in patients with Bartter syndrome and, rarely, in patients with Gitelman syndrome.²
  • Chloride-resistant alkalosis may result from acute administration of exogenous alkali, as is seen in patients with milk-alkali syndrome or following massive blood transfusion.
  • Rare cases include hypercalcemia due to vitamin D toxicity and hyperparathyroidism and nonreabsorbable anions.

DIFFERENTIALS

Section 4 of 12  

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• Acknowledgments
• Multimedia
• References

Other Problems to be Considered

Gitelman syndrome
Pyloric stenosis
Laxative abuse
Loop or thiazide diuretic abuse

WORKUP

Section 5 of 12  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

• Amniocentesis
• • Amniotic fluid sodium and chloride concentrations may reflect fetal values; these are high in fetuses with chloride-losing diarrhea (CLD). Levels may also be elevated in patients with Bartter syndrome.
  • Although this study is not routine, a₁-fetoprotein levels may be elevated.
• Blood workup
• • Serum electrolyte levels may be within the reference range, especially in neonates and treated patients.
  • Typical findings include low concentrations of serum chloride, sodium, and potassium.
  • Serum pH and bicarbonate, calcium, uric acid, hemoglobin (if patient is not anemic), renin, and aldosterone levels may be elevated.
  • The serum rennin level is exponentially high in line with secondary hyperaldosteronism due to chronic volume depletion, and this finding is supported by low or normal blood pressure measurements.
  • Attention must be paid in interpreting the serum potassium level in relation to the state of metabolic alkalosis. For example, the potassium shift from serum into the intracellular compartment increases as the serum pH is high; in other words, the potassium level is less than normal by 0.6 mmol/L when measured at a serum pH of 7.5.
• Urine and stool electrolytes
• • In patients with Bartter syndrome, urine chloride, sodium, and potassium concentrations are usually measured. Urine calcium-to-creatinine and uric acid–to–creatinine ratios are usually high. Stool electrolytes cannot be measured because of well-formed or hard stool. Fractional excretion (F_ex) studies are more reliable than absolute values. Usually, results are higher than reference range values, as follows:
  • • F_ex sodium concentration greater than 1%
    • F_ex potassium concentration greater than 35%
    • F_ex chloride concentration greater than 2.5% (2.7% +/- 1.1%)
  • In patients with CLD, urine chloride concentration is very low or undetectable (<10 mmol/L). Stool is usually watery, and electrolyte studies are very helpful and diagnostic, as follows:
  • • Stool chloride concentration is greater than 100 mmol/L.
    • Stool sodium and potassium concentrations are elevated.
    • Stool chloride concentration is greater than stool sodium plus potassium concentrations, which is normally less than either. Chloride concentrations are lowest in colonic secretions and are usually less than 35 mmol/L.
    • Ratio of stool chloride to combined sodium and potassium concentrations is greater than 0.6.
  • Patients with cystic fibrosis typically demonstrate high sweat chloride and sodium concentrations. Urine chloride concentration is usually very low, and stools are usually not watery as they are in patients with CLD.
• Renal function: Renal function is usually normal. Glomerular filtration rate (GFR) may be low in patients with severe disease.
• Liver function tests: Liver function test results are usually within the reference range in patients with CLD and Bartter syndrome but may be deranged in patients with cystic fibrosis.

Imaging Studies

• Ultrasonography
• • Prenatal ultrasonography may be useful in the detection of minimal polyhydramnios and assessment of intestinal fluid content, which is increased in patients with CLD.
  • Postnatal ultrasonography may be useful in the evaluation of a fluid-filled bowel, which is characteristically increased in patients with CLD. Ultrasonography may also assist in the evaluation of renal echogenicity, nephrocalcinosis, medullary or diffuse calcinosis, and renal growth.
• Wrist radiography: This may be performed to assess bone age in infants with growth failure. Wrist radiography may also help assess bone density and the presence of rickets.
• Brain CT scanning: Brain CT scans are useful for evaluation of brain growth and calcifications.
• Upper gastrointestinal series: An upper gastrointestinal series assists in detecting gastroesophageal reflux and pyloric stenosis, which are case-dependent conditions.³
• Renal nuclear scanning: This may help assess renal function but is not useful in all patients.
• Brain MRI: This is helpful in patients who present with seizures.

Other Tests

• Electroencephalography: This is helpful in patients who present with seizures.
• Genetic studies
• • DNA diagnosis is available for most congenital disorders that cause hypochloremic metabolic alkalosis.
  • For CLD, the CLD (SLC26A3) locus is on band 7q22-q31.1.^{4, 5}
  • Bartter syndrome is identified by NKCC2, ROMK, and CLCNKB;⁶ Bartter syndrome with deafness is identified by BSND; and Bartter syndrome with autosomal dominant hypocalcemia is identified by CASR.
  • For cystic fibrosis, the CFTR locus is on band 7q31.2.
  • For Gitelman syndrome, the NCCT locus is on 16q.

Procedures

Physiologic studies of renal tubules by performing maximal free water clearance during hypotonic saline diuresis is indicated.

• Oral water at 20 mL/kg is administered over 30 minutes, followed by one-half isotonic sodium chloride solution 600 mL/m²/h for 2-3 hours. During this time, urine is collected in aliquots over 30-minute periods for 4-6 aliquots. These samples are sent for evaluation of creatinine, sodium, potassium, and chloride levels, and for osmolality, pH, and volume.
• Usually, urine is diluted by administration of oral water.
• Halfway through each collection, a blood sample is obtained for evaluation of creatinine, sodium, potassium, and chloride levels, and for pH and osmolality.
• Calculate the clearance of each substance, then determine the ratio by dividing water clearance by the sum of chloride clearance and water clearance: (water clearance)/(chloride clearance + water clearance).
• Usually, the results of the above equation reflect the percentage of distal tubule sodium and chloride reabsorption. Normal values are up to 85-90%, which means that the percentage of chloride and sodium excreted should be 10-15% (this is corrected to 100 mL GFR). In patients with Bartter syndrome, the percentage of chloride and sodium excreted can reach 35% or more.

Histologic Findings

Renal biopsy is not usually indicated, but, if performed, it may reveal interstitial fibrosis and calcium/urate crystal deposition.

TREATMENT

Section 6 of 12  

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• Introduction
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• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical Care

• Acute emergency management (0-6 h)
• • Assess dehydration status to determine if it is chronic or superimposed by acute dehydration. If the patient is in shock, treatment should be directed toward aggressive resuscitation with isotonic fluid, preferably normal saline.
  • Always remember to obtain blood and urine samples for testing of electrolytes before any form of therapy; this is of great help in differentiating etiologic factors in new cases.
  • Initial management includes assessment of dehydration status and severity of hypochloremia, hypokalemia, hyponatremia, and metabolic alkalosis.
  • Always remember not to treat chronic acid-base disturbances rapidly because more serious complications may be prevented by meticulous and slow correction. For example, initial blood work shows the following results: 120 mmol/L sodium, 2.0 mmol/L potassium, 80 mmol/L chloride, 40 mmol/L bicarbonate, and pH 7.5. In this child, assess cardiac function; if dysrhythmia is absent, rapid correction of this severe hypokalemia is not needed. In this case, 5% dextrose in 0.9 isotonic sodium chloride solution plus potassium chloride 20 mEq/L administered at a maintenance rate per 24 hours can be a safe measure.
• Maintenance management (over the next 72 h)
• • Maintenance therapy depends on how much improvement occurred after 6 hours of initial fluid and electrolyte administration.
  • The aim is to increase the serum potassium concentration very slowly as the serum bicarbonate level drops. This helps prevent a sharp increase in serum potassium concentration and its subsequent detrimental effects on cardiac conductivity.
• Long-term management (after 72 h)
• • Intravenous fluids can be discontinued. The physician should calculate the average amounts of chloride, sodium, and potassium administered per day that was required to correct the serum electrolyte levels. The total amount can then be orally administered in 3-4 divided doses per day. In most patients, the average chloride dose required is 4-10 mEq/kg/d in the form of sodium and potassium salts.
  • Other management procedures depend on the primary cause of hypochloremic alkalosis.

Surgical Care

• Surgical intervention is usually unnecessary. If ileus is suspected in a child with severe hypokalemia, treatment is potassium chloride administration and not surgical intervention.
• If the cause of hypochloremic alkalosis is an upper gastrointestinal tract abnormality, such as gastroesophageal reflux or pyloric stenosis, surgical or endoscopic intervention is indicated.

Consultations

• Pediatric nephrologist - Should always be consulted in these acid-base disorders
• Pediatric gastroenterologist
• Genetic counselor
• Social workers
• Pediatric nutritionist
• Pediatric endocrinologist - To exclude other causes of growth failure

Diet

• Kilojoule intake should meet the patient's catabolic status, usually 100-150% of the recommended daily allowance (RDA).
• Additional protein should be ingested to prevent malnutrition.
• Fat requirements depend on the individual patient. For example, if the patient has cystic fibrosis, special dietary needs should be followed.
• Provide multivitamins and hematinics as required.
• Provide supplemental trace elements (eg, zinc) in patients with deficiency, such as some patients with chloride-losing diarrhea (CLD).
• High sodium and potassium diets are required for all children with chronic metabolic alkalosis secondary to Bartter syndrome or CLD.

Activity

• Normal activity should be recommended in children unless CNS damage is severe, which requires special restrictions.
• Children with refractory severe hypokalemia should avoid extended exposure to heat, especially in hot climates. Exposure to heat may cause dehydration and may exacerbate the condition.

MEDICATION

Section 7 of 12  

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Replacement of electrolytes with chloride salts is the most important mode of therapy for hypochloremic alkalosis. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used in patients with Bartter syndrome. Hydrochloric acid (HCl) and carbonic anhydrase inhibitors may be used in some acute situations.

Drug Category: Electrolytes

These agents are used to correct disturbances in fluid and electrolyte homoeostasis or acid-base balance. They are also used to reestablish osmotic equilibrium of specific ions.

Drug Category: Nonsteroidal anti-inflammatory drugs

These agents have analgesic, anti-inflammatory, and antipyretic activities. The mechanism of action is unknown, but NSAIDs may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may also occur, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions.

Drug Category: Carbonic anhydrase inhibitors

The major pharmacologic action of acetazolamide is the noncompetitive inhibition of the enzyme carbonic anhydrase. Carbonic anhydrase is located at the luminal border of cells of the proximal tubule. Urine volume increases with enzyme inhibition (proximal tubule reabsorption of water is reduced by approximately one third), which promotes an alkaline pH. This results in a subsequent decrease in the excretion of titratable acid and ammonia. Increases in urinary excretion of bicarbonate and sodium lead to metabolic acidosis.

Drug Category: Acidifying agents

Consequences of severe metabolic alkalosis include increased susceptibility to ventricular arrhythmia and a left shift of the oxyhemoglobin dissociation curve. HCl is particularly useful in patients with hepatic or renal impairment, which often precludes more standard treatments.

Drug Category: Xanthine oxidase inhibitors

These agents are effective for treating diuretic-induced hyperuricemia and renal complications resulting in hyperuricemia.

FOLLOW-UP

Section 8 of 12  

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• Follow-up
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• Acknowledgments
• Multimedia
• References

Further Inpatient Care

• Assess hydration status and electrolyte levels.
• Obtain a full nutritional assessment, calculate energy intake, and ensure adequate energy intake through oral or nasogastric methods.
• Educate the caregiver regarding the primary disease and how to prevent recurrence of dehydration.
• Ask the clinical pharmacist to discuss the importance and methods of drug administration, timing, and adverse effects with the caregiver, in addition to storage of medications at home.
• Discharge medication instructions should be written clearly, and a supply sufficiently large to last until the patient is seen in the outpatient clinic should be prescribed.

Further Outpatient Care

• Patients should receive regular follow-up examinations by a physician and nurse clinician at least once every month in infants and less frequently in older children and children who are more stable.
• Review medications at each visit. Refill medications and adjust doses depending on clinical status and laboratory results.
• Preclinic laboratory workup includes a biochemical profile and monitoring of urine electrolytes.
• Patients with chronic diseases, such as Bartter syndrome, chloride-losing diarrhea (CLD), and cystic fibrosis, should have lifelong follow-up care.
• Repeat radiologic studies as required. For example, kidney ultrasonography may be needed to assess the degree of nephrocalcinosis in children with Bartter syndrome.
• Assess growth parameters and evaluate the need for growth hormone therapy in consultation with a pediatric endocrinologist.
• Assess renal function and minimize the use of nephrotoxic agents if possible.

Deterrence/Prevention

• In patients with CLD, encourage fluid intake to prevent renal damage resulting from recurrent dehydration.
• Instruct patients or caregivers to avoid long periods of exposure to hot climates, which may exacerbate dehydration episodes.
• Treat constipation in patients with Bartter syndrome.
• Treat any intercurrent febrile illnesses, especially urinary tract infections, to prevent further renal damage.

Complications

• Disease-related complications
• • Nephrocalcinosis and nephrolithiasis may occur in patients with Bartter syndrome and in patients with CLD.
  • In patients with cystic fibrosis, liver damage and recurrent chest infection may lead to hepatic and pulmonary failure, respectively.
  • End-stage renal disease (ESRD) may occur in patients in whom compliance is poor. ESRD can occur in all conditions mentioned, including Bartter syndrome and CLD.
• Drug-related complications
• • Indomethacin-induced nephrotoxicity should be carefully assessed.
  • Acetazolamide treatment may compromise respiratory function in children with lung disease.

Prognosis

• Prognosis is usually good for patients with Bartter syndrome, provided the patient complies well with treatment. Children who receive effective treatment have minimal risk of severe renal damage.
• In patients with CLD, renal failure and ESRD may complicate the picture if diagnosis and treatment are delayed.
• In patients with cystic fibrosis, prognosis depends on the severity of lung and liver involvement.

MISCELLANEOUS

Section 9 of 12  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical/Legal Pitfalls

• Medicolegal issues should be considered when prenatal diagnosis is offered to mothers with familial diseases, such as cystic fibrosis, Bartter syndrome, or chloride-losing diarrhea (CLD). Therapeutic abortions are not legal in some countries. Physicians should take special precautions when discussing abortions, depending on the social and religious background of the patient.

Special Concerns

• Future pregnancies in women with a child with hypochloremic alkalosis should be monitored in a tertiary care center so that early diagnosis and intervention are available at delivery.

ACKNOWLEDGMENTS

Section 10 of 12  

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• References

The author would like to thank Gloria Matthews (University of Texas Health Science Center at San Antonio Pediatrics) for her expert assistance with grants administration.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Pinar Ozand, MD, PhD, to the development and writing of this article.

MULTIMEDIA

Section 11 of 12  

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• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Media file 1:  Infant with severe metabolic alkalosis resulting from congenital chloride-losing diarrhea.
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Media file 2:  Watery stool from an infant with congenital chloride-losing diarrhea. Chloride level was 205 mmol/L.
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Media file 3:  Renal ultrasonograph of an infant with congenital chloride-losing diarrhea showing diffuse sclerosis.
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Media type:  Ultrasound

Media file 4:  Severe nephrocalcinosis in a 2-year-old child with Bartter syndrome.
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Media type:  Ultrasound

Media file 5:  Visible bowel loops in an infant with congenital chloride-losing diarrhea.
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Media type:  Photo

REFERENCES

Section 12 of 12

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• References

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2. Naesens M, Steels P, Verberckmoes R. Bartter's and Gitelman's syndromes: from gene to clinic. Nephron Physiol. 2004;96(3):p65-78. [Medline].
3. Hulka F, Campbell TJ, Campbell JR, Harrison MW. Evolution in the recognition of infantile hypertrophic pyloric stenosis. Pediatrics. Aug 1997;100(2):E9. [Medline].
4. Hoglund P, Haila S, Socha J, et al. Mutations of the Down-regulated in adenoma (DRA) gene cause congenital chloride diarrhoea. Nat Genet. Nov 1996;14(3):316-9. [Medline].
5. Makela S, Kere J, Holmberg C. SLC26A3 mutations in congenital chloride diarrhea. Hum Mutat. Dec 2002;20(6):425-38. [Medline].
6. Simon DB, Bindra RS, Mansfield TA, et al. Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III. Nat Genet. Oct 1997;17(2):171-8. [Medline].
7. Hanna JD, Scheinman JI, Chan JC. The kidney in acid-base balance. Pediatr Clin North Am. Dec 1995;42(6):1365-95. [Medline].
8. Jacobson HR. Chloride-responsive metabolic alkalosis. In: Seldin DW, Gieb G, eds. The Regulation of Acid-Base Balance. Lippincott-Raven;1989:431-57.
9. Rose BD. Causes of metabolic alkalosis. UpToDate. Available at http://www.uptodate.com/.
10. Rose BD. Treatment of metabolic alkalosis. UpToDate. Available at http://www.uptodate.com/.
11. Rose BD. Urine electrolytes in diagnosis of metabolic alkalosis. UpToDate. Available at http://www.uptodate.com/.
12. Simon DB, Karet FE, Hamdan JM, et al. Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet. Jun 1996;13(2):183-8. [Medline].
13. Wang J, Cortina G, Wu SV, Tran R, Cho JH, Tsai MJ, et al. Mutant neurogenin-3 in congenital malabsorptive diarrhea. N Engl J Med. Jul 20 2006;355(3):270-80. [Medline].

Article Last Updated: Jan 11, 2008