Bartter’s Syndrome Comes of Age

In 1962, Bartter and co-workers [1] published a description of two patients presenting with a new syndrome characterized by hypokalemia, metabolic alkalosis, hyperaldosteronism with normal blood pressure, decreased pressor responsiveness to infused angiotensin II, and hyperplasia of the juxtaglomerular complex. Since then, many reports, both in children and in adults, have appeared in the literature under the heading of “Bartter’s syndrome.” It is nowadays evident that this term does not represent a unique entity but encompasses a variety of disorders of renal electrolyte transport all characterized by a biochemical picture of hyperreninemic hypokalemic metabolic alkalosis. At the present time this ensemble of patients can be divided into three different genetic and clinical entities [2] :

  1. Neonatal (or antenatal) Bartter’s syndrome is observed in newborn infants and is characterized by polyhydramnios, premature delivery, life-threatening episodes of fever and dehydration during the early weeks of life, growth retardation, hypercalciuria, and early-onset nephrocalcinosis. The inclusion of these neonatal cases under the global heading of Bartter’s syndrome has been a matter of discussion and Seyberth et al [3] have proposed the term “hyperprostaglandin E syndrome” to distinguish them from other cases of Bartter’s syndrome. Recent molecular biology findings have clearly demonstrated that these patients do also present an inherited defect in NaCl transport in the distal nephron so that there is no justification for presenting these patients as a separate entity of primary prostaglandin E2 (PGE2 ) secretion. Two molecular defects have been identified: either at the gene coding for the renal bumetanide-sensitive Na-K-2Cl cotransporter (NKCC2) or at the gene coding for the adenosine triphosphate-sensitive inwardly-rectifying K channel (ROMK). In some families mutations at the genes coding for NKCC2 or ROMK have not been found. This could reflect either incomplete sensitivity of mutation detection or alternatively could be accounted by further genetic heterogeneity.
  2. “Classic” Bartter’s syndrome is mostly observed during infancy and childhood and is characterized clinically by polyuria and growth retardation. Nephrocalcinosis is not present. Very recently, either deletions or mutations at the gene coding for a renal chloride channel gene (ClC-Kb) have been identified.
  3. Gitelman’s syndrome is observed in older children and adults presenting with intermittent episodes of muscle weakness and tetany, hypokalemia and hypomagnesemia. Hypocalciuria is a characteristic finding of this entity. Mutations at the gene coding for the thiazide-sensitive Na-Cl cotransporter (NCCT) have been identified in the majority of patients studied. Obviously the validity of this classification must be confirmed over the near future after all mutations are described and genotypic-phenotypic correlations are better known.

In this issue, Konrad et al [4] describe the effect of prenatal and postnatal indomethacin therapy in a female infant in whom mutations at the ROMK channel gene were demonstrated in amniocytes obtained at 18 weeks of gestation. In contrast to her affected elder brother, maternal indomethacin administration from 26 to 31 weeks of gestation successfully prevented further progression of polyhydramnios and permitted an elective delivery at 35 weeks of gestation. The use of indomethacin soon after birth also allowed for a more benign clinical course. These apparent beneficial effects of indomethacin should be taken, however, with extreme caution and should be weighed against the potential therapeutic risks. Proesmans [5] has presented data on 5 infants with neonatal Barter syndrome showing that PGE2 levels in the amniotic fluid were all very low and, taking into account the dilution factor, probably within normal range. Therefore, administering indomethacin to a mother whose fetus is known to have mutations characteristic of neonatal Bartter’s syndrome, although may prevent progression of polyhydramnios can not be simply indicated because the presence of fetal hyperprostaglandinism. Moreover, it may be a hazardous decision giving the negative effects of prostaglandin synthesis inhibitors on the ductus arteriosus and the developing kidney. If used, a careful clinical and echocardiographic monitoring of the fetus is mandatory.

Also, in Proesmans’ patients, urinary PGE2 excretion was within or slightly above the normal range immediately after birth and remained so if appropriate fluid and electrolyte replacement was achieved. Only when the tremendous loss of electrolytes and water could not be fully compensated was a steady postnatal increase of urinary PGE2 observed. These data indicate that administration of indomethacin in the early postnatal period may not only be unnecessary but also dangerous giving the risk for necrotizing enterocolitis. These newborn infants with mutations at the ROMK channel gene are often mildly hyperkalemic and acidotic during some weeks after birth and indomethacin administration may precipitate a menacing picture of oliguric renal failure and severe hyperkalemia, as in fact occurred in the case reported by Konrad et al. In my experience, in the immediate neonatal period all therapeutic efforts should be directed to correct dehydration and electrolytic imbalance. Continuous saline infusion may be needed to attain this aim. However, at 4 to 6 weeks of life, when massive urinary electrolyte losses have greatly abated and the biochemical profile is shifted from hyperkalemic metabolic acidosis to hypokalemic metabolic alkalosis, the patient may greatly benefit from the administration of indomethacin. As stated by Konrad et al, patients with mutations at the ROMK channel gene are especially sensitive to that drug, and doses well below 1 mg/kg per day may be sufficient to maintain plasma K levels within the normal range.

The comments made above may not be entirely valid when referring to cases of neonatal Bartter’s syndrome caused by mutations at gene coding for the NKCC2 transporter. In these instances massive renal sodium chloride-wasting, hypokalemia, and metabolic alkalosis may be already present at birth and indomethacin therapy may probably be started at the early neonatal period without especial risks. The article by Konrad et al opens new perspectives about the prenatal and postnatal management of patients with neonatal Bartter’s syndrome but only accumulated experience over the next few years shall fully establish the precise regimen of indomethacin administration for each genetic variety as well as the safe balance between clinical benefits and potential risks.

Pediatrics, Volume 103 Number 3 March 1999, Copyright 1999 American Academy of Pediatrics


1 Department of Pediatrics
Hospital de Cruces and Basque
University School of Medicine
48903 Bilbao
Pais Vasco, Spain

Received for publication Nov 30, 1998
accepted Nov 30, 1998.
Address correspondence to Juan Rodriguez-Soriano, MD, Hospital de Cruces, Pza. de Cruces, s/n-Baracaldo, 48903 Vizcaya, Spain.
PEDIATRICS (ISSN 0031 4005). Copyright ? 1999 by the American Academy of Pediatrics.


1. Bartter FC, Pronove P, Gill JR Jr, MacCardle RC. Hyperplasia of juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. Am J Med. 1962;33:811-828

2. Rodriguez-Soriano J. Bartter and related syndromes: the puzzle is almost solved. Pediatr Nephrol. 1998;12:315-327

3. Seyberth HW, Rascher W, Schweer W, Kuhl PG, Mehls O, Scharer K. Congenital hypokalemia with hypercalciuria in preterm infants: a hyperprostaglandinuric tubular syndrome different from Bartter syndrome. J Pediatr. 1985;107:694-701

4. Konrad M, Leonhardt A, Hensen P, Seyberth HW, Kockerling A. Prenatal and postnatal management of hyperprostaglandin E syndrome after genetic diagnosis from amniocytes. Pediatrics. 1999;103:678-683

5. Proesmans W. Bartter syndrome and its neonatal variant. Eur J Pediatr. 1997;156:669-679

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