Molecular pathogenesis of Bartter’s and Gitelman’s syndromes
1998; Elsevier BV; Volume: 54; Issue: 4 Linguagem: Inglês
10.1046/j.1523-1755.1998.00124.x
ISSN1523-1755
AutoresIra Kurtz, Jordan J. Cohen, John T. Harrington, Nicolaos E. Madias, Cheryl J. Zusman,
Tópico(s)Magnesium in Health and Disease
ResumoA 42-year-old man presented to UCLA with a history of chronic hypokalemia and hypomagnesemia. His medical history was unremarkable except for occasional cramps in his calves. He had no history of laxative or diuretic abuse or of vomiting, and he was taking no medications. His 47-year-old brother also had a history of chronic hypokalemia and hypomagnesemia and severe intermittent muscle cramps. He was being treated with amiloride and magnesium supplementation. Both parents and a third brother were asymptomatic and had no electrolyte abnormalities. Physical examination revealed a well-developed white male in no distress. His blood pressure was 110/70 mm Hg; heart rate, 72 beats/min; jugular venous pressure was estimated to be 7 cm; his chest was clear to auscultation. Cardiovascular examination disclosed a regular rate and rhythm, and no murmurs, rubs, or gallops; his abdomen was nontender without hepatosplenomegaly. Neurologic examination revealed cranial nerves 2-12 intact, no sensory or motor deficit, and no Chvostek or Trousseau sign. He did not have peripheral edema. Laboratory values were: serum sodium, 136 mEq/liter; potassium, 2.4 mEq/liter; chloride, 94 mEq/liter; total CO2, 28 mEq/liter; venous pH, 7.47 and PCO2, 38 mm Hg; BUN, 10 mg/dl; serum creatinine, 0.7 mg/dl; ionized calcium, 1.25 mmol/liter; total calcium, 9.2 mg/dl; phosphorus, 3.2 mg/dl; magnesium, 1.1 mg/dl; supine plasma renin, 16.6 ng/ml/hr; supine aldosterone, 168 pg/ml; PTH, 13 pg/ml; 1,25(OH)2 vitamin D, 42 pg/ml. Urine chemistries were: sodium, 64 mEq/liter; potassium, 42 mEq/liter; chloride, 58 mEq/liter; calcium, 1 mg/dl; magnesium, 4.3 mg/dl; phosphorus, 67.4 mg/dl; and creatinine, 81 mg/dl. A diuretic screen was negative. The patient was discharged on no medications and has remained asymptomatic. Dr. Ira Kurtz (Chief, Division of Nephrology, Max Factor Professor of Medicine, Center for Health Sciences, UCLA School of Medicine, Los Angeles, California): When Dr. Jay Stein presented a Nephrology Forum on Bartter's syndrome (BS) in this journal 13 years ago1.Stein J.H. Nephrology Forum: The pathogenetic spectrum of Bartter's syndrome.Kidney Int. 1985; 28: 85-93Abstract Full Text PDF PubMed Scopus (108) Google Scholar, he noted that "several questions remain to be clarified: Is Bartter's syndrome the consequence of a single defect, or rather the clinical phenotype of a variety of tubular defects? Is the syndrome caused by a defect in sodium chloride transport per se or by a primary potassium-wasting state? Are syndromes associated with magnesium and calcium loss, as well as potassium wasting, pathophysiologically linked?" These prescient questions can now be answered with more certainty because of the recent advances in our understanding of the molecular basis for Bartter's/Gitelman's syndromes. The patient being discussed today presented with the following electrolyte abnormalities: hypokalemia with renal K+ wasting (high fractional excretion); a chloride-resistant metabolic alkalosis, elevated plasma renin, elevated plasma aldosterone (relative to the serum K+ concentration), hypomagnesemia with renal magnesium wasting (high fractional excretion), decreased urine calcium excretion, and normal blood pressure. These findings are compatible with either diuretic abuse due to thiazide-like diuretics or Gitelman's syndrome (GS). Because of the family history and the negative diuretic screen, a diagnosis of Gitelman's syndrome was made. In the absence of marked symptoms over many years, we elected not to treat the patient's electrolyte disturbances. The patient under discussion has the classic features of GS2.H.J. Gitelman, J.B. Graham, L.G. Welt A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Phys 79:221-235Google Scholar,3.Gitelman H.J. Graham J.B. Welt L.G. A familial disorder characterized by hypokalemia and hypomagnesemia.Ann NY Acad Sci. 1969; 162: 856-864Crossref PubMed Scopus (41) Google Scholar. Patients with this disorder are normotensive and have a chloride-resistant metabolic alkalosis, increased plasma renin and aldosterone/K+ ratio, hypokalemia, hypomagnesemia, and hypocalciuria. The syndrome was first described in 1966 by Gitelman et al in three patients, two of whom were sisters2.H.J. Gitelman, J.B. Graham, L.G. Welt A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Phys 79:221-235Google Scholar. The metabolic abnormalities in Gitelman's syndrome shared many of the features of BS, a disorder first reported by Bartter et al four years earlier and with which it has subsequently been frequently confused in the literature4.Bartter F.C. Pronove P. Gill J.R.J. Macardle R.C. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis.Am J Med. 1962; 33: 811-828Abstract Full Text PDF PubMed Scopus (685) Google Scholar. Interestingly, the first case of BS might have been reported in 1957, when Rosenbaum and Hughes described an infant with hypokalemia, metabolic alkalosis, polyuria, growth failure, and recurrent episodes of volume depletion5.Rosenbaum P. Hughes M. Persistent, probably congenital hypokalemic metabolic alkalosis with hyaline degeneration of the renal tubules and normal urinary aldosterone.Am J Dis Child. 1957; 94: 560Google Scholar. The patients reported by Bartter et al shared many of the features of GS in that they had a hypokalemic, chloride-resistant metabolic alkalosis, with elevated plasma renin levels and normal blood pressure. Unlike GS, the patients with BS had a urinary concentrating defect and growth failure and subsequently were shown to be hypercalciuric6.Mccredie D.A. Rotenberg E. Williams A.L. Hypercalciuria in potassium-losing nephropathy: a variant of Bartter's syndrome.Aust Pediatr J. 1974; 10: 286-295PubMed Google Scholar. Despite these known differences, most clinicians fail to distinguish between these syndromes. Indeed, it appears that most patients reported in the literature with BS in fact have GS7.Gladziwa U. Schwarz R. Gitter A.H. Bijman J. Seyberth H. Beck F. Ritz E. Gross P. Chronic hypokalaemia of adults: Gitelman's syndrome is frequent but classical Bartter's syndrome is rare.Nephrol Dial Transplant. 1995; 10: 1607-1613PubMed Google Scholar. Bartter's and Gitelman's syndromes can be distinguished clinically (Table 1) as well as on the basis of differences in divalent cation metabolism8.Houser M. Zimmerman B. Davidman M. Smith C. Sinaiko A. Fish A. Idiopathic hypercalciuria associated with hyperreninemia and high urinary prostaglandin E.Kidney Int. 1984; 26: 176-182Abstract Full Text PDF PubMed Scopus (25) Google Scholar, 9.Uribarri J. Alveranga D. Oh M.S. Kukar N.M. Del Monte M.L. Carroll H.J. Bartter's syndrome due to a defect in salt reabsorption in the distal convoluted tubule.Nephron. 1985; 40: 52-56Crossref PubMed Scopus (33) Google Scholar, 10.Colussi G. Macaluso M. Brunati C. Minetti L. Calcium metabolism and calciotropic hormone levels in Gitelman's syndrome.Miner Electrolyte Metab. 1994; 20: 294-301PubMed Google Scholar, 11.Rudin A. Sjogren B. Aurell M. Low urinary calcium excretion in Bartter's syndrome (letter).N Engl J Med. 1984; 310: 1190PubMed Google Scholar, 12.Rudin A. Aurell M. Wilske J. Low urinary calcium excretion in Bartter's syndrome.Scand J Urol Nephrol. 1988; 22: 35-39PubMed Google Scholar, 13.Sutton R.A. Mavichak V. Halabe A. Wilkins G.E. Bartter's syndrome: evidence suggesting a distal tubular defect in a hypocalciuric variant of the syndrome.Miner Electrolyte Metab. 1992; 18: 43-51PubMed Google Scholar, 14.Bettinelli A. Bianchetti M.G. Girardin E. et al.Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndromes.J Pediatr. 1992; 120: 38-43Abstract Full Text PDF PubMed Scopus (306) Google Scholar. In BS, symptoms are dictated by the patient's age at presentation. Polyuria and polydipsia are always present in children and adults with BS and can be the only presenting symptoms. Most cases of BS present in neonates15.Mackie F.E. Hodson E.M. Roy L.P. Knight J.F. Neonatal Bartter syndrome–use of indomethacin in the newborn period and prevention of growth failure.Pediatr Nephrol. 1996; 10: 756-758Crossref PubMed Scopus (27) Google Scholar, 16.Proesmans W. Devlieger H. Van Assche A. Eggermont E. Vandenberghe K. Lemmens F. Sieprath P. Lijnen P. Bartter syndrome in two siblings–antenatal and neonatal observations.Int J Pediatr Nephrol. 1985; 6: 63-70PubMed Google Scholar, 17.Seyberth H.W. How can you differentiate neonatal Bartter's syndrome from hyperprostaglandin (-uria) E2 syndrome?.Pediatr Nephrol. 1994; 8: 407Crossref Scopus (9) Google Scholar, 18.Williams M.P. Jones C.L. Johnstone L.M. Walker R.G. Mccredie D.A. Powell H.R. An extreme example of the neonatal form of Bartter's syndrome.Pediatr Nephrol. 1996; 10: 496-497Crossref Scopus (8) Google Scholar, 19.Wong W. Hulton S.A. Taylor C.M. Raafat F. Lote C.J. Lindop G. A case of neonatal Bartter's syndrome.Pediatr Nephrol. 1996; 10: 414-418Crossref Scopus (11) Google Scholar, 20.Proesmans W.C. The neonatal form of Bartter's syndrome: current findings in etiology and physiopathology.Verh K Acad Geneeskd Belg. 1992; 54: 253-293Google Scholar, 21.Deschenes G. Burguet A. Guyot C. Hubert P. Garabedian M. Dechaux M. Loirat C. Broyer M. Antenatal form of Bartter's syndrome.Ann Pediatr. 1993; 40: 95-101Google Scholar. Maternal polyhydramnios with premature labor is a common finding, presumably because of excessive urine production in utero6.Mccredie D.A. Rotenberg E. Williams A.L. Hypercalciuria in potassium-losing nephropathy: a variant of Bartter's syndrome.Aust Pediatr J. 1974; 10: 286-295PubMed Google Scholar, 21.Deschenes G. Burguet A. Guyot C. Hubert P. Garabedian M. Dechaux M. Loirat C. Broyer M. Antenatal form of Bartter's syndrome.Ann Pediatr. 1993; 40: 95-101Google Scholar, 22.Sieck U.V. Ohlsson A. Fetal polyuria and hydramnios associated with Bartter's syndrome.Obstet Gynecol. 1984; 63: 22S-24SPubMed Google Scholar. Some of the infants have an appearance typical of BS, including a prominent forehead, triangular facies with drooping mouth, and large eyes and pinnae Figure 123.James T. Holland N.H. Preston D. Bartter syndrome. Typical facies and normal plasma volume.Am J Dis Child. 1975; 129: 1205-1207Crossref PubMed Scopus (22) Google Scholar, 24.Ohlson A. Sieck U. Cumming W. Akhtar M. Serenius F. A variant of Bartter's syndrome.Acta Pediatr Scand. 1984; 73: 868-874Crossref Scopus (62) Google Scholar, 25.Landau D. Shalev H. Ohaly M. Carmi R. Infantile variant of Bartter syndrome and sensorineural deafness: a new autosomal recessive disorder.Am J Med Genet. 1995; 59: 454-459Crossref PubMed Scopus (79) Google Scholar. Subsequent difficulties in the neonate include failure to thrive and growth retardation21.Deschenes G. Burguet A. Guyot C. Hubert P. Garabedian M. Dechaux M. Loirat C. Broyer M. Antenatal form of Bartter's syndrome.Ann Pediatr. 1993; 40: 95-101Google Scholar. Vomiting, diarrhea, and fever have been reported, and a variant of neonatal BS has been described with sensorineural deafness25.Landau D. Shalev H. Ohaly M. Carmi R. Infantile variant of Bartter syndrome and sensorineural deafness: a new autosomal recessive disorder.Am J Med Genet. 1995; 59: 454-459Crossref PubMed Scopus (79) Google Scholar. Neonatal BS can be diagnosed prenatally by finding elevated amniotic fluid chloride and aldosterone concentrations26.Massa G. Proesmans W. Devlieger H. Vandenberghe K. Van Assche A. Eggermont E. Electrolyte composition of the amniotic fluid in Bartter syndrome.Eur J Obstet Gynecol Reprod Biol. 1987; 24: 335-340Abstract Full Text PDF Scopus (23) Google Scholar,27.Shalev H. Ohaly M. Meizner I. Carmi R. Prenatal diagnosis of Bartter syndrome.Prenat Diagn. 1994; 14: 996-998Crossref PubMed Scopus (19) Google Scholar.Table 1Clinical differences between Bartter's and Gitelman's syndromes Open table in a new tab Figure 1Two patients with neonatal Bartter's syndrome described by Landau et al.25.Landau D. Shalev H. Ohaly M. Carmi R. Infantile variant of Bartter syndrome and sensorineural deafness: a new autosomal recessive disorder.Am J Med Genet. 1995; 59: 454-459Crossref PubMed Scopus (79) Google Scholar Both patients have the typical facial appearance with prominent forehead, triangular face, drooping mouth, and large eyes and pinnae.View Large Image Figure ViewerDownload (PPT) Seyberth and colleagues have suggested that the severe neonatal form of BS be called the hyperprostaglandin E2 syndrome17.Seyberth H.W. How can you differentiate neonatal Bartter's syndrome from hyperprostaglandin (-uria) E2 syndrome?.Pediatr Nephrol. 1994; 8: 407Crossref Scopus (9) Google Scholar, 28.Seyberth H.W. Rascher W. Schweer H. Kuhl P.G. Mehls O. Scharer K. Congenital hypokalemia with hypercalciuria in preterm infants: a hyperprostaglandinuric tubular syndrome different from Bartter syndrome.J Pediatr. 1985; 107: 694-701Abstract Full Text PDF PubMed Scopus (142) Google Scholar, 29.Seyberth H.W. Koniger S.J. Rascher W. Kuhl P.G. Schweer H. Role of prostaglandins in hyperprostaglandin E syndrome and in selected renal tubular disorders.Pediatr Nephrol. 1987; 1: 491-497Crossref PubMed Scopus (71) Google Scholar. Indeed, an increased rate of PGE2 excretion is a common feature in BS30.Fichman M.P. Telfer N. Zia P. Speckart P. Golub M. Rude R. Role of prostaglandins in the pathogenesis of Bartter's syndrome.Am J Med. 1976; 60: 785-797Abstract Full Text PDF PubMed Scopus (120) Google Scholar, 31.Bartter F.C. Gill JR, J.R. Frolich J.C. Bowden R.E. Hollifield J.W. Radfar N. Keiser H.R. Oates J.A. Seyberth H. Taylor A.A. Prostaglandins are overproduced by the kidneys and mediate hyperreninemia in Bartter's syndrome.Trans Assoc Am Physicians. 1976; 89: 77-91PubMed Google Scholar, 32.Norby L. Flamenbaum W. Lentz R. Ramwell P. Prostaglandins and aspirin therapy in Bartter's syndrome.Lancet. 1976; 2: 604-606Abstract PubMed Scopus (55) Google Scholar, 33.Dunn M.J. Nephrology Forum: Prostaglandins and Bartter's syndrome.Kidney Int. 1981; 19: 86-102Abstract Full Text PDF PubMed Scopus (49) Google Scholar. Indomethacin has been used to decrease the incidence of polyhydramnios in pregnant patients with and without BS, although complications in the neonate, including acute renal failure, tricuspid regurgitation, and patent ductus arteriosus have been reported19.Wong W. Hulton S.A. Taylor C.M. Raafat F. Lote C.J. Lindop G. A case of neonatal Bartter's syndrome.Pediatr Nephrol. 1996; 10: 414-418Crossref Scopus (11) Google Scholar, 34.Seidel C. Reinalter S. Seyberth H.W. Scharer K. Pre-pubertal growth in the hyperprostaglandin E syndrome.Pediatr Nephrol. 1995; 9: 723-728Crossref PubMed Scopus (28) Google Scholar, 35.Pomeranz A. Korzets Z. Dolfin Z. Eliakim A. Bernheim Wolach B. Acute renal failure in the neonate induced by the administration of indomethacin as a tocolytic agent.Nephrol Dial Transplant. 1996; 11: 1139-1141Crossref PubMed Scopus (13) Google Scholar, 36.Cabrol D. Jannet D. Pannier E. Treatment of symptomatic polyhydramnios with indomethacin.Eur J Obstet Gynecol. 1996; 66: 11-15Abstract Full Text PDF PubMed Scopus (17) Google Scholar. In addition, indomethacin appears to improve the rate of growth in these children34.Seidel C. Reinalter S. Seyberth H.W. Scharer K. Pre-pubertal growth in the hyperprostaglandin E syndrome.Pediatr Nephrol. 1995; 9: 723-728Crossref PubMed Scopus (28) Google Scholar. Given that the neonatal form seems to differ only in severity from the childhood and adult disorder, the term neonatal BS rather than hyperprostaglandin E2 syndrome appears justified. In contrast to BS, GS is a milder disease and doesn't present symptomatically in the neonatal period7.Gladziwa U. Schwarz R. Gitter A.H. Bijman J. Seyberth H. Beck F. Ritz E. Gross P. Chronic hypokalaemia of adults: Gitelman's syndrome is frequent but classical Bartter's syndrome is rare.Nephrol Dial Transplant. 1995; 10: 1607-1613PubMed Google Scholar,37.Mccredie D.A. Variants of Bartter's syndrome.Pediatr Nephrol. 1996; 10: 419-421PubMed Google Scholar. Patients with GS are not volume depleted clinically. They can have a plasma aldosterone concentration that is not markedly elevated, as in the patient presented today, because their hypokalemia suppresses adrenal aldosterone production. Furthermore, patients with GS are often asymptomatic, or they only have neuromuscular complaints consisting of intermittent muscle spasms, cramps, or tetany2.H.J. Gitelman, J.B. Graham, L.G. Welt A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Phys 79:221-235Google Scholar, 3.Gitelman H.J. Graham J.B. Welt L.G. A familial disorder characterized by hypokalemia and hypomagnesemia.Ann NY Acad Sci. 1969; 162: 856-864Crossref PubMed Scopus (41) Google Scholar, 37.Mccredie D.A. Variants of Bartter's syndrome.Pediatr Nephrol. 1996; 10: 419-421PubMed Google Scholar, 38.Gitelman H.G. Hypokalemia, hypomagnesemia, and alkalosis: a rose is a rose–or is it?.J Pediatr. 1992; 120: 79-80Abstract Full Text PDF PubMed Scopus (29) Google Scholar, 39.Mccredie D.A. Distinguishing between Bartter's syndrome and Gitelman's syndrome.Pediatr Nephrol. 1995; 9: 402Crossref Scopus (3) Google Scholar. Polyuria and polydipsia are not a feature of GS. In a subset of patients with electrolyte abnormalities indistinguishable from those of GS, arthritis in several joints due to chondrocalcinosis has been reported both in sporadic cases40.Bauer F.M. Glasson P. Vallotton M.B. Courvoisier B. Bartter's syndrome, chondrocalcinosis and hypomagnesemia.Schweiz Med Wochenschr. 1979; 109: 1251-1256PubMed Google Scholar, 41.Resnick D. Rausch J.M. Hypomagnesemia with chondrocalcinosis.J Can Assoc Radiologists. 1984; 35: 214-216PubMed Google Scholar, 42.Salvarani C. Rossi F. Macchioni P.L. Barrichi R. Cappozoli N. Castellani S. Ghirrelli L. Veneziani M. Scarti L. Portioli I. Bartter's syndrome and chondrocalcinosis: a possible role for hypomagnesemia in the deposition of calcium pyrophosphate dihydrate (CPPD) crystals.Clin Exp Rheumatol. 1989; 7: 415-420PubMed Google Scholar, 43.De Heide L.J. Birkenhager J.C. Bartter's syndrome, hypomagnesaemia and chondrocalcinosis.Neth J Med. 1991; 39: 148-152PubMed Google Scholar, and recently in a familial form44.Smilde T.J. Haverman J.F. Schipper P. Hermus A.R.M.M. Van Leibergen F.J.H.M. Jansen J.L.J. Kloppenborg P.W.C. Koolen M.I. Familial hypokalemia/hypomagnesemia and chondrocalcinosis.J Rheumatol. 1994; 21: 1515-1519PubMed Google Scholar. Several differences in divalent cation metabolism allow the two syndromes to be easily distinguished based on simple laboratory measurements Figure 2. Patients with BS have fasting hypercalciuria, whereas those with GS have a low urinary calcium excretion6.Mccredie D.A. Rotenberg E. Williams A.L. Hypercalciuria in potassium-losing nephropathy: a variant of Bartter's syndrome.Aust Pediatr J. 1974; 10: 286-295PubMed Google Scholar, 9.Uribarri J. Alveranga D. Oh M.S. Kukar N.M. Del Monte M.L. Carroll H.J. Bartter's syndrome due to a defect in salt reabsorption in the distal convoluted tubule.Nephron. 1985; 40: 52-56Crossref PubMed Scopus (33) Google Scholar, 10.Colussi G. Macaluso M. Brunati C. Minetti L. Calcium metabolism and calciotropic hormone levels in Gitelman's syndrome.Miner Electrolyte Metab. 1994; 20: 294-301PubMed Google Scholar, 11.Rudin A. Sjogren B. Aurell M. Low urinary calcium excretion in Bartter's syndrome (letter).N Engl J Med. 1984; 310: 1190PubMed Google Scholar, 12.Rudin A. Aurell M. Wilske J. Low urinary calcium excretion in Bartter's syndrome.Scand J Urol Nephrol. 1988; 22: 35-39PubMed Google Scholar, 14.Bettinelli A. Bianchetti M.G. Girardin E. et al.Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndromes.J Pediatr. 1992; 120: 38-43Abstract Full Text PDF PubMed Scopus (306) Google Scholar, 45.Fanconi A. Schachenmann G. Nussli R.A.P. Chronic hypokalemia with growth retardation, normotensive hyperrenin-hyperaldosteronism ("Bartter's syndrome") and hypercalciuria.Helv Paediatr Acta. 1971; 26: 144-163PubMed Google Scholar. In addition to hypercalciuria, medullary nephrocalcinosis is usually present in BS but is always absent in GS. The hypercalciuria in BS can predate the appearance of overt nephrocalcinosis. In addition to hypocalciuria, all patients with GS characteristically have hypomagnesemia and a high fractional excretion of magnesium2.H.J. Gitelman, J.B. Graham, L.G. Welt A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Phys 79:221-235Google Scholar,10.Colussi G. Macaluso M. Brunati C. Minetti L. Calcium metabolism and calciotropic hormone levels in Gitelman's syndrome.Miner Electrolyte Metab. 1994; 20: 294-301PubMed Google Scholar. The patient presented today had a normal Umg/Ucr of 0.05. In GS, urinary magnesium excretion reflects the dietary intake and only exceeds the normal excretion rate when patients are ingesting magnesium supplements2.H.J. Gitelman, J.B. Graham, L.G. Welt A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Phys 79:221-235Google Scholar,10.Colussi G. Macaluso M. Brunati C. Minetti L. Calcium metabolism and calciotropic hormone levels in Gitelman's syndrome.Miner Electrolyte Metab. 1994; 20: 294-301PubMed Google Scholar. In BS, both the absolute urinary calcium excretion and the fractional excretion rate are increased. Despite the hypocalciuria in GS, the serum total and ionized calcium concentrations are normal, as in the patient presented today10.Colussi G. Macaluso M. Brunati C. Minetti L. Calcium metabolism and calciotropic hormone levels in Gitelman's syndrome.Miner Electrolyte Metab. 1994; 20: 294-301PubMed Google Scholar. Colussi et al also reported that serum PTH levels are in the low normal range in GS, possibly because of the inhibitory effect of hypomagnesemia on PTH secretion10.Colussi G. Macaluso M. Brunati C. Minetti L. Calcium metabolism and calciotropic hormone levels in Gitelman's syndrome.Miner Electrolyte Metab. 1994; 20: 294-301PubMed Google Scholar. In contrast, hypomagnesemia is not a typical finding in BS. A modest or transient decrease in serum magnesium has been reported in some neonates with BS. However, these infants generally are extremely ill, and whether the hypomagnesemia is due to extrarenal causes (vomiting, diarrhea) has not been excluded. Hypomagnesemia in adults diagnosed with BS in most cases is due to the failure to diagnose GS9.Uribarri J. Alveranga D. Oh M.S. Kukar N.M. Del Monte M.L. Carroll H.J. Bartter's syndrome due to a defect in salt reabsorption in the distal convoluted tubule.Nephron. 1985; 40: 52-56Crossref PubMed Scopus (33) Google Scholar,46.Delaney V.B. Oliver J.F. Simms M. Costello J. Bourke E. Bartter's syndrome: physiological and pharmacological studies.Q J Med. 1981; 50: 213-232Google Scholar. Patients with BS and GS also differ in that the former have elevated 1,25(OH)2D levels8.Houser M. Zimmerman B. Davidman M. Smith C. Sinaiko A. Fish A. Idiopathic hypercalciuria associated with hyperreninemia and high urinary prostaglandin E.Kidney Int. 1984; 26: 176-182Abstract Full Text PDF PubMed Scopus (25) Google Scholar, 10.Colussi G. Macaluso M. Brunati C. Minetti L. Calcium metabolism and calciotropic hormone levels in Gitelman's syndrome.Miner Electrolyte Metab. 1994; 20: 294-301PubMed Google Scholar, 12.Rudin A. Aurell M. Wilske J. Low urinary calcium excretion in Bartter's syndrome.Scand J Urol Nephrol. 1988; 22: 35-39PubMed Google Scholar, 47.Restrepo De Rovetto C. Welch T.R. Hug G. Clark K.E. Bergstrom W. Hypercalciuria with Bartter syndrome: evidence for an abnormality of vitamin D metabolism.J Pediatr. 1989; 115: 397-404Abstract Full Text PDF PubMed Scopus (49) Google Scholar and PGE2 excretion rates30.Fichman M.P. Telfer N. Zia P. Speckart P. Golub M. Rude R. Role of prostaglandins in the pathogenesis of Bartter's syndrome.Am J Med. 1976; 60: 785-797Abstract Full Text PDF PubMed Scopus (120) Google Scholar, 31.Bartter F.C. Gill JR, J.R. Frolich J.C. Bowden R.E. Hollifield J.W. Radfar N. Keiser H.R. Oates J.A. Seyberth H. Taylor A.A. Prostaglandins are overproduced by the kidneys and mediate hyperreninemia in Bartter's syndrome.Trans Assoc Am Physicians. 1976; 89: 77-91PubMed Google Scholar, 33.Dunn M.J. Nephrology Forum: Prostaglandins and Bartter's syndrome.Kidney Int. 1981; 19: 86-102Abstract Full Text PDF PubMed Scopus (49) Google Scholar, 48.Gill JR, J.R. Frolich J.C. Bowden R.E. Taylor A.A. Keiser H.R. Seyberth W.H. Oates J.A. Bartter F.C. Bartter's syndrome: a disorder characterized by high urinary prostaglandins and a dependence of hyperreninemia on prostaglandin synthesis.Am J Med. 1976; 61: 43-51Abstract Full Text PDF PubMed Scopus (25) Google Scholar. The increased serum 1,25(OH)2D in patients with BS occurs in the presence of normal 25-OHD, 24,25(OH)2D, PTH, and phosphorus levels47.Restrepo De Rovetto C. Welch T.R. Hug G. Clark K.E. Bergstrom W. Hypercalciuria with Bartter syndrome: evidence for an abnormality of vitamin D metabolism.J Pediatr. 1989; 115: 397-404Abstract Full Text PDF PubMed Scopus (49) Google Scholar. The mechanism for elevated serum 1,25(OH)2D levels in BS is unknown. Previous studies have shown that PGE2 stimulates the hydroxylation of 25-(OH)D in thyroparathyroidectomized rats and in chick and rat kidney cells49.Yamada M. Matsumoto T. Takahashi N. Suda T. Ogata E. Stimulatory effect of prostaglandin E2 on 1-alpha,25-dihydroxyvitamin D3 synthesis in rats.Biochem J. 1983; 216: 237-240Crossref PubMed Scopus (15) Google Scholar, 50.Wark J.D. Taft J.L. Michelangeli V.P. Veroni M.C. Larkins R.G. Biphasic action of prostaglandin E2 on conversion of 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 in chick renal tubules.Prostaglandins. 1984; 27: 453-463Crossref PubMed Scopus (9) Google Scholar, 51.H. Kurose, YM Sonn, A. Jafari, Sj Birge, LV Avioli Effects of prostaglandin E2 and indomethacin on 25-hydroxyvitamin D3-1-alpha-hydroxylase activity in isolated kidney cells of normal and streptozotocin-induced diabetic rats. Calcif Tissue Int 37:625-1985Google Scholar. Restrepo de Rovetto et al have argued that PGE2 stimulates the activity of 1α-hydroxylase, which results in elevated 1,25(OH) levels in BS47.Restrepo De Rovetto C. Welch T.R. Hug G. Clark K.E. Bergstrom W. Hypercalciuria with Bartter syndrome: evidence for an abnormality of vitamin D metabolism.J Pediatr. 1989; 115: 397-404Abstract Full Text PDF PubMed Scopus (49) Google Scholar. Indomethacin therapy reduces the elevated 1,25(OH)2D levels, Ca2+ excretion, and PGE2 excretion in BS8.Houser M. Zimmerman B. Davidman M. Smith C. Sinaiko A. Fish A. Idiopathic hypercalciuria associated with hyperreninemia and high urinary prostaglandin E.Kidney Int. 1984; 26: 176-182Abstract Full Text PDF PubMed Scopus (25) Google Scholar,47.Restrepo De Rovetto C. Welch T.R. Hug G. Clark K.E. Bergstrom W. Hypercalciuria with Bartter syndrome: evidence for an abnormality of vitamin D metabolism.J Pediatr. 1989; 115: 397-404Abstract Full Text PDF PubMed Scopus (49) Google Scholar. A second unproven possibility is that the renal calcium leak per se increases plasma 1,25(OH)2D levels. The BS/GS literature is replete with additional metabolic abnormalities that have contributed to the confusion regarding the pathogenesis of these syndromes. Most disputed has been the role of excess prostaglandin excretion in the pathogenesis of the electrolyte abnormalities29.Seyberth H.W. Koniger S.J. Rascher W. Kuhl P.G. Schweer H. Role of prostaglandins in hyperprostaglandin E syndrome and in selected renal tubular disorders.Pediatr Nephrol. 1987; 1: 491-497Crossref PubMed Scopus (71) Google Scholar, 30.Fichman M.P. Telfer N. Zia P. Speckart P. Golub M. Rude R. Role of prostaglandins in the pathogenesis of Bartter's syndrome.Am J Med. 1976; 60: 785-797Abstract Full Text PDF PubMed Scopus (120) Google Scholar, 31.Bartter F.C. Gill JR, J.R. Frolich J.C. Bowden R.E. Hollifield J.W. Radfar N. Keiser H.R. Oates J.A. Seyberth H. Taylor A.A. Prostaglandins are overproduced by the kidneys and mediate hyperreninemia in Bartter's syndrome.Trans Assoc Am Physicians. 1976; 89: 77-91PubMed Google Scholar, 32.Norby L. Flamenbaum W. Lentz R. Ramwell P. Prostaglandins and aspirin therapy in Bartter's syndrome.Lancet. 1976; 2: 604-606Abstract PubMed Scopus (55) Google Scholar, 52.Brouhard B.H. Prostaglandins and hypokalemia.J Pediatr. 1985; 107: 738-740Abstract Full Text PDF PubMed Scopus (3) Google Scholar, 53.Calo L. Cantaro S. Piccoli A. Favaro S. Bonfante L. Borsatti A. Full pattern of urinary prostaglandins in Bartter's syndrome.Nephron. 1990; 56: 451-452Crossref Scopus (8) Google Scholar, 54.Chan J.C. Gill JR, J.R. Bartter F.C. Lack of evidence for a role for prostaglandins in the mediation of impaired urinary concentrating ability in Bartter's syndrome.Nephron. 1983; 35: 116-119Crossref Scopus (10) Google Scholar, 55.Hornych A. Krief C. Aumont J. Urinary prostaglandins in Bartter's and pseudo-Bartter's syndrome.Uremia Invest. 1985; 9: 203-210Google Scholar, 56.Winterborn M.H. Hewitt G.J. Mitchell M.D. The role of prostaglandins in Bartter's syndrome.Int J Pediatr Nephrol. 1984; 5: 31-38PubMed Google Scholar. Indeed 17 years ago, a Nephrology Forum presented by Dr. Michael Dunn was devoted to the role of prostaglandins in BS33.Dunn M.J. Nephrology Forum: Prostaglandins and Bartter's syndrome.Kidney Int. 1981; 19: 86-102Abstract Full Text PDF PubMed Scopus (49) Google Scholar. Patients with GS usually have normal PGE2 excretion rates7.Gladziwa U. Schwarz R. Gitter A.H. Bijma
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