eMedicine Specialties > Nephrology > Hereditary Kidney Disorders

Bartter Syndrome: Differential Diagnoses & Workup

Author: Lynda A Frassetto, MD, Associate Clinical Professor, Department of Internal Medicine, University of California at San Francisco School of Medicine
Contributor Information and Disclosures

Updated: Sep 18, 2009

Differential Diagnoses

Hypomagnesemia

Other Problems to Be Considered

Diuretic abuse
Gitelman syndrome
Hyperprostaglandin E syndrome
Familial hypomagnesemia with hypercalciuria/nephrocalcinosis
Activating mutations of the CaSR calcium sensing receptor

Workup

Laboratory Studies

  • 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.
  • Initiate timed urine collection to determine potassium levels. 
    • In hypokalemia, normal kidneys retain potassium.14
    • Elevated urinary potassium levels with low blood potassium levels suggest the kidneys are having problems retaining potassium.
  • Next, initiate timed urine collection to determine aldosterone levels. 
    • Aldosterone levels should be low 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 the primary problem is something else, and the aldosterone response is secondary to the undiagnosed primary abnormality.
  • Then, 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.
  • Mutations in the different transporters cause Bartter syndrome. Mutations can be determined in the following ways: 
    • The older methods 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. Some mutations lead to marked loss of function, while others do not.15,16

Imaging Studies

  • Antenatal Bartter syndrome can be diagnosed best by ultrasonography. The fetus may have polyhydramnios and intrauterine growth retardation. Amniotic chloride levels may be elevated.17
  • After birth, especially if the disease is diagnosed in older patients who have hypercalciuria, consider a renal ultrasound 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.

Other Tests

  • 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.2,3,4,5

More on Bartter Syndrome

Overview: Bartter Syndrome
Differential Diagnoses & Workup: Bartter Syndrome
Treatment & Medication: Bartter Syndrome
Follow-up: Bartter Syndrome
References
Further Reading
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References

  1. Bartter FC, Pronove P, Gill JR. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. American Journal of Medicine. 1962;33:811-828.

  2. Simon DB, Bindra RS, Mansfield TA, Nelson-Williams C, Mendonca E, Stone R, et al. Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III. Nat Genet. Oct 1997;17(2):171-8. [Medline].

  3. Simon DB, Karet FE, Hamdan JM, DiPietro A, Sanjad SA, Lifton RP. 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].

  4. Simon DB, Karet FE, Rodriguez-Soriano J, Hamdan JH, DiPietro A, et al. Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK. Nat Genet. Oct 1996;14(2):152-6. [Medline].

  5. Simon DB, Nelson-Williams C, Bia MJ, Ellison D, Karet FE, Molina AM, et al. Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet. Jan 1996;12(1):24-30. [Medline].

  6. Riazuddin S, Anwar S, Fischer M, et al. Molecular basis of DFNB73: mutations of BSND can cause nonsyndromic deafness or Bartter syndrome. Am J Hum Genet. Aug 2009;85(2):273-80. [Medline].

  7. Janssen AG, Scholl U, Domeyer C, et al. Disease-causing dysfunctions of barttin in Bartter syndrome type IV. J Am Soc Nephrol. Jan 2009;20(1):145-53. [Medline].

  8. Jentsch TJ, Maritzen T, Zdebik AA. Chloride channel diseases resulting from impaired transepithelial transport or vesicular function. J Clin Invest. Aug 2005;115(8):2039-46. [Medline].

  9. Veizis IE, Cotton CU. Role of kidney chloride channels in health and disease. Pediatr Nephrol. Jun 2007;22(6):770-7. [Medline]. [Full Text].

  10. Chen YH, Lin JJ, Jeansonne BG, et al. Analysis of claudin genes in pediatric patients with Bartter's syndrome. Ann N Y Acad Sci. May 2009;1165:126-34. [Medline].

  11. Rudin A. Bartter's syndrome. A review of 28 patients followed for 10 years. Acta Med Scand. 1988;224(2):165-71. [Medline].

  12. Fallen K, Banerjee S, Sheehan J, et al. The Kir channel immunoglobulin domain is essential for Kir1.1 (ROMK) thermodynamic stability, trafficking and gating. Channels (Austin). Jan-Feb 2009;3(1):57-68. [Medline]. [Full Text].

  13. Madrigal G, Saborio P, Mora F, Rincon G, Guay-Woodford LM. Bartter syndrome in Costa Rica: a description of 20 cases. Pediatr Nephrol. Jun 1997;11(3):296-301. [Medline].

  14. Assadi F. Diagnosis of hypokalemia: a problem-solving approach to clinical cases. Iran J Kidney Dis. Jul 2008;2(3):115-22. [Medline]. [Full Text].

  15. Adachi M, Asakura Y, Sato Y, Tajima T, Nakajima T, Yamamoto T, et al. Novel SLC12A1 (NKCC2) mutations in two families with Bartter syndrome type 1. Endocr J. 2007;54(6):1003-7. [Medline].

  16. Aoi N, Nakayama T, Tahira Y, Haketa A, Yabuki M, Sekiyama T, et al. Two novel genotypes of the thiazide-sensitive Na-Cl cotransporter (SLC12A3) gene in patients with Gitelman's syndrome. Endocrine. Apr 2007;31(2):149-53. [Medline].

  17. Dane B, Yayla M, Dane C, Cetin A. Prenatal diagnosis of Bartter syndrome with biochemical examination of amniotic fluid: case report. Fetal Diagn Ther. 2007;22(3):206-8. [Medline].

  18. Abdel-al YK, Badawi MH, Yaeesh SA, Habib YQ, al-Khuffash FA, al-Ghanim MM, et al. Bartter's syndrome in Arabic children: review of 13 cases. Pediatr Int. Jun 1999;41(3):299-303. [Medline].

  19. Aurell M, Rudin A. Effect of captopril on blood pressure, renal function, the electrolyte balance and the renin-angiotensin system in Bartter's syndrome. Nephron. 1983;33(4):274-8. [Medline].

  20. Brimacombe JR, Breen DP. Anesthesia and Bartter's syndrome: a case report and review. AANA J. Apr 1993;61(2):193-7. [Medline].

  21. Clementsen P, Hoegholm A, Hansen CL, Damkjaer M, Christensen P, Giese J. Bartter's syndrome--treatment with potassium, spironolactone and ACE-inhibitor. J Intern Med. Feb 1989;225(2):107-10. [Medline].

  22. Dillon MJ, Shah V, Mitchell MD. Bartter's syndrome: 10 cases in childhood. Results of long-term indomethacin therapy. Q J Med. Jul 1979;48(191):429-46. [Medline].

  23. Gitelman HJ, Graham JB, Welt LG. A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians. 1966;79:221-35. [Medline].

  24. Jest P, Pedersen KE, Klitgaard NA, Thomsen N, Kjaer K, Simonsen E. Angiotensin-converting enzyme inhibition as a therapeutic principle in Bartter's syndrome. Eur J Clin Pharmacol. 1991;41(4):303-5. [Medline].

  25. Kleta R, Bockenhauer D. Bartter syndromes and other salt-losing tubulopathies. Nephron Physiol. 2006;104(2):p73-80. [Medline].

  26. Konrad M, Leonhardt A, Hensen P, Seyberth HW, Köckerling A. Prenatal and postnatal management of hyperprostaglandin E syndrome after genetic diagnosis from amniocytes. Pediatrics. Mar 1999;103(3):678-83. [Medline].

  27. Kramer BK, Bergler T, Stoelcker B, Waldegger S. Mechanisms of Disease: the kidney-specific chloride channels ClCKA and ClCKB, the Barttin subunit, and their clinical relevance. Nat Clin Pract Nephrol. Jan 2008;4(1):38-46. [Medline].

  28. Mackie FE, Hodson EM, Roy LP, Knight JF. Neonatal Bartter syndrome--use of indomethacin in the newborn period and prevention of growth failure. Pediatr Nephrol. Dec 1996;10(6):756-8. [Medline].

  29. O'Sullivan E, Monga M, Graves W. Bartter's syndrome in pregnancy: a case report and review. Am J Perinatol. Jan 1997;14(1):55-7. [Medline].

  30. Scheinman SJ, Guay-Woodford LM, Thakker RV, Warnock DG. Genetic disorders of renal electrolyte transport. N Engl J Med. Apr 15 1999;340(15):1177-87. [Medline].

  31. Schlingmann KP, Konrad M, Seyberth HW. Genetics of hereditary disorders of magnesium homeostasis. Pediatr Nephrol. 2004;19:13-25.

  32. Yokoyama T. [Endocrinological analysis before and after living-related renal transplantation in a patient of Bartter's syndrome]. Nippon Jinzo Gakkai Shi. Oct 1995;37(10):580-6. [Medline].

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Further Reading

Related eMedicine topics:
Bartter Syndrome [Pediatrics: General Medicine]
Hypercalciuria [Pediatrics: General Medicine]
Hypercalciuria [Urology]
Hypokalemia [Emergency Medicine]
Hypokalemia [Nephrology]
Hypokalemia [Pediatrics: Cardiac Disease and Critical Care Medicine]
Hypomagnesemia [Emergency Medicine]
Hypomagnesemia [Nephrology]
Hypomagnesemia [Pediatrics: General Medicine]

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Keywords

Bartter syndrome, Bartter’s syndrome, hypomagnesemia, hypercalciuria, nephrocalcinosis, hypokalemia, Gitelman syndrome, Gitelman’s syndrome, salt wasting, salt-wasting syndrome, salt-wasting disorder, salt-losing nephropathy, hyperplasia, juxtaglomerular complex, chloride channel, hyperaldosteronism, hypokalemic metabolic alkalosis, renin-angiotensin-aldosterone system, RAAS

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Contributor Information and Disclosures

Author

Lynda A Frassetto, MD, Associate Clinical Professor, Department of Internal Medicine, University of California at San Francisco School of Medicine
Lynda A Frassetto, MD is a member of the following medical societies: American College of Physicians and American Society of Nephrology
Disclosure: Nothing to disclose.

Medical Editor

Frank C Brosius III, MD, Nephrology Program Director, Professor of Internal Medicine and Physiology, Department of Internal Medicine, Division of Nephrology, University of Michigan School of Medicine
Frank C Brosius III, MD is a member of the following medical societies: Alpha Omega Alpha, American Diabetes Association, American Society of Nephrology, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

George R Aronoff, MD, Director, Professor, Departments of Internal Medicine and Pharmacology, Section of Nephrology, Kidney Disease Program, University of Louisville School of Medicine
George R Aronoff, MD is a member of the following medical societies: American Federation for Medical Research, American Society of Nephrology, Kentucky Medical Association, and National Kidney Foundation
Disclosure: Nothing to disclose.

CME Editor

Rebecca J Schmidt, DO, FACP, FASN, Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine
Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association
Disclosure: Abbott Grant/research funds Speaking and teaching; Genzyme Honoraria Consulting; Amgen Honoraria Speaking and teaching; Ortho Biotech Honoraria Speaking and teaching

Chief Editor

Vecihi Batuman, MD, FACP, FASN, Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Medicine Service, Southeast Louisiana Veterans Health Care System
Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, and International Society of Nephrology
Disclosure: Nothing to disclose.

 
 
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