Bartter syndrome

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Bartter syndrome
Other namesSalt-wasting nephropathy [1]
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Scheme of renal tubule and its vascular supply.
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Bartter syndrome (BS) is a rare inherited disease characterised by a defect in the thick ascending limb of the loop of Henle, which results in low potassium levels (hypokalemia), [2] increased blood pH (alkalosis), and normal to low blood pressure. There are two types of Bartter syndrome: neonatal and classic. A closely associated disorder, Gitelman syndrome, is milder than both subtypes of Bartter syndrome.[ citation needed ]

Contents

Signs and symptoms

In 90% of cases, neonatal Bartter syndrome is seen between 24 and 30 weeks of gestation with excess amniotic fluid (polyhydramnios). After birth, the infant is seen to urinate and drink excessively (polyuria, and polydipsia, respectively). Life-threatening dehydration may result if the infant does not receive adequate fluids. About 85% of infants dispose of excess amounts of calcium in the urine (hypercalciuria) and kidneys (nephrocalcinosis), which may lead to kidney stones. In rare occasions, the infant may progress to kidney failure. [3]

Patients with classic Bartter syndrome may have symptoms in the first two years of life, but they are usually diagnosed at school age or later. Like infants with the neonatal subtype, patients with classic Bartter syndrome also have polyuria, polydipsia, and a tendency to dehydration, but normal or just slightly increased urinary calcium excretion without the tendency to develop kidney stones. These patients also have vomiting and growth retardation. Kidney function is also normal if the disease is treated, [4] but occasionally patients proceed to end-stage kidney failure. Bartter syndrome consists of low levels of potassium in the blood, alkalosis, normal to low blood pressures, and elevated plasma renin and aldosterone. Numerous causes of this syndrome probably exist. Diagnostic pointers include high urinary potassium and chloride despite low serum values, increased plasma renin, hyperplasia of the juxtaglomerular apparatus on kidney biopsy, and careful exclusion of diuretic abuse. Excess production of prostaglandins by the kidneys is often found. Magnesium wasting may also occur. Homozygous patients experience severe hypercalciuria and nephrocalcinosis. [5]

Pathophysiology

Bartter syndrome is caused by mutations of genes encoding proteins that transport ions across renal cells in the thick ascending limb of the nephron also called as the ascending loop of Henle. [4] Specifically, mutations directly or indirectly involving the Na-K-2Cl cotransporter are key. The Na-K-2Cl cotransporter is involved in electroneutral transport of one sodium, one potassium, and two chloride ions across the apical membrane of the tubule. The basolateral calcium-sensing receptor has the ability to downregulate the activity of this transporter upon activation. Once transported into the tubule cells, sodium ions are actively transported across the basolateral membrane by Na+/K+-ATPases, and chloride ions pass by facilitated diffusion through basolateral chloride channels. Potassium, however, is able to diffuse back into the tubule lumen through apical potassium channels, returning a net positive charge to the lumen and establishing a positive voltage between the lumen and interstitial space. This charge gradient is obligatory for the paracellular reabsorption of both calcium and magnesium ions.[ citation needed ]

Proper function of all of these transporters is necessary for normal ion reabsorption along the thick ascending limb, and loss of any component can result in functional inactivation of the system as a whole and lead to the presentation of Bartter syndrome. Loss of function of this reabsorption system results in decreased sodium, potassium, and chloride reabsorption in the thick ascending limb, as well as abolishment of the lumen-positive voltage, resulting in decreased calcium and magnesium reabsorption. Loss of reabsorption of sodium here also has the undesired effect of abolishing the hypertonicity of the renal medulla, severely impairing the ability to reabsorb water later in the distal nephron and collecting duct system, leading to significant diuresis and the potential for volume depletion. Finally, increased sodium load to the distal nephron elicits compensatory reabsorption mechanisms, albeit at the expense of potassium by excretion by principal cells and resulting hypokalemia. This increased potassium excretion is partially compensated by α-intercalated cells at the expense of hydrogen ions, leading to metabolic alkalosis.[ citation needed ]

Bartter and Gitelman syndromes can be divided into different subtypes based on the genes involved: [6]

NameBartter typeAssociated gene mutationsDefect
neonatal Bartter's syndrometype 1 SLC12A1 (NKCC2) Na-K-2Cl symporter
neonatal Bartter's syndrometype 2 ROMK/KCNJ1 thick ascending limb K+ channel
classic Bartter's syndrometype 3 CLCNKB Cl− channel
Bartter's syndrome with sensorineural deafness type 4 BSND [7] Cl− channel accessory subunit
Bartter's syndrome associated with autosomal dominant hypocalcemiatype 5 CASR [8] activating mutation of the calcium-sensing receptor
Gitelman's syndrome- SLC12A3 (NCCT) Sodium-chloride symporter

Diagnosis

People with Bartter syndrome present symptoms that are identical to those of patients who are on loop diuretics like furosemide, given that the loop diuretics target the exact transport protein that is defective in the syndrome (at least for type 1 Bartter syndrome). The other subtypes of the syndrome involve mutations in other transporters that result in functional loss of the target transporter. Patients often admit to a personal preference for salty foods. [9]

The clinical findings characteristic of Bartter syndrome is hypokalemia, metabolic alkalosis, and normal to low blood pressure. These findings may also be caused by other conditions, which may cause confusion. When diagnosing a Bartter's syndrome, the following conditions must be ruled out as possible causes of the symptomatology:[ citation needed ]

Patients with Bartter syndrome may also have elevated renin and aldosterone levels. [10]

Prenatal Bartter syndrome can be associated with polyhydramnios. [11]

However, Bartter syndrome is also characterized by high renin, high aldosterone, hypercalciuria, and an abnormal Na+-K+-2Cl− transporter in the thick ascending limb of the loop of Henle, whereas Gitelman syndrome causes hypocalciuria and is due to an abnormal thiazide-sensitive transporter in the distal segment. [13]

Pseudo-Bartter's syndrome is a syndrome of similar presentation as Bartter syndrome but without any of its characteristic genetic defects. Pseudo-Bartter's syndrome has been seen in cystic fibrosis, [14] as well as in excessive use of laxatives. [15]

Treatment

Medically supervised sodium, chloride and potassium supplementation is necessary, and spironolactone can be also used to reduce potassium loss. [2] Free and unqualified access to water is necessary to prevent dehydration, as patients maintain an appropriate thirst response. In severe cases where supplementation alone cannot maintain biochemical homeostasis, nonsteroidal anti-inflammatory drugs (NSAIDs) can be used to reduce glomerular filtration and can be very useful, although may cause gastric irritation and should be administered alongside stomach acid suppression therapies. Angiotensin-converting enzyme (ACE) inhibitors can also be used to reduce glomerular filtration rate. In young babies and children, a low threshold to check serum electrolytes during periods of illness compromising fluid intake is necessary. [16]

Surveillance renal ultrasound should be employed to monitor for the development of nephrocalcinosis, a common complication which further augments urinary concentrating difficulty. [17]

Prognosis

The limited prognostic information available suggests that early diagnosis and appropriate treatment of infants and young children with classic Bartter Syndrome may improve growth and perhaps intellectual development. On the other hand, sustained hypokalemia and hyperreninemia can cause progressive tubulointerstitial nephritis, resulting in end-stage kidney disease (kidney failure). With early treatment of the electrolyte imbalances, the prognosis for patients with classic Bartter Syndrome is good.[ citation needed ]

History

The condition is named after Dr. Frederic Bartter, who, along with Dr. Pacita Pronove, first described it in 1960 and in more patients in 1962. [10] [18] [19] [20]

Related Research Articles

<span class="mw-page-title-main">Distal convoluted tubule</span> Feature of kidney anatomy

The distal convoluted tubule (DCT) is a portion of kidney nephron between the loop of Henle and the collecting tubule.

<span class="mw-page-title-main">Renal physiology</span> Study of the physiology of the kidney

Renal physiology is the study of the physiology of the kidney. This encompasses all functions of the kidney, including maintenance of acid-base balance; regulation of fluid balance; regulation of sodium, potassium, and other electrolytes; clearance of toxins; absorption of glucose, amino acids, and other small molecules; regulation of blood pressure; production of various hormones, such as erythropoietin; and activation of vitamin D.

<span class="mw-page-title-main">Electrolyte imbalance</span> Abnormality in the concentration of electrolytes in the body

Electrolyte imbalance, or water-electrolyte imbalance, is an abnormality in the concentration of electrolytes in the body. Electrolytes play a vital role in maintaining homeostasis in the body. They help to regulate heart and neurological function, fluid balance, oxygen delivery, acid–base balance and much more. Electrolyte imbalances can develop by consuming too little or too much electrolyte as well as excreting too little or too much electrolyte. Examples of electrolytes include calcium, chloride, magnesium, phosphate, potassium, and sodium.

<span class="mw-page-title-main">Hypokalemia</span> Insufficient potassium in the blood

Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an abnormal heart rhythm, which is often too slow and can cause cardiac arrest.

<span class="mw-page-title-main">Loop diuretic</span> Diuretics that act along the loop of Henle in the kidneys

Loop diuretics are pharmacological agents that primarily inhibit the Na-K-Cl cotransporter located on the luminal membrane of cells along the thick ascending limb of the loop of Henle. They are often used for the treatment of hypertension and edema secondary to congestive heart failure, liver cirrhosis, or chronic kidney disease. While thiazide diuretics are more effective in patients with normal kidney function, loop diuretics are more effective in patients with impaired kidney function.

<span class="mw-page-title-main">Amiloride</span> Medication

Amiloride, sold under the trade name Midamor among others, is a medication typically used with other medications to treat high blood pressure or swelling due to heart failure or cirrhosis of the liver. Amiloride is classified as a potassium-sparing diuretic. Amiloride is often used together with another diuretic, such as a thiazide or loop diuretic. It is taken by mouth. Onset of action is about two hours and it lasts for about a day.

<span class="mw-page-title-main">Chlortalidone</span> Thiazide-like diuretic drug

Chlortalidone, also known as chlorthalidone, is a thiazide-like diuretic drug used to treat high blood pressure, swelling, diabetes insipidus, and renal tubular acidosis. Because chlortalidone is effective in most patients with high blood pressure, it is considered a preferred initial treatment. It is also used to prevent calcium-based kidney stones. It is taken by mouth. Effects generally begin within three hours and last for up to three days. Long-term treatment with chlortalidone is more effective than hydrochlorothiazide for prevention of heart attack or stroke.

<span class="mw-page-title-main">Thiazide</span> Class of chemical compounds

Thiazide refers to both a class of sulfur-containing organic molecules and a class of diuretics based on the chemical structure of benzothiadiazine. The thiazide drug class was discovered and developed at Merck and Co. in the 1950s. The first approved drug of this class, chlorothiazide, was marketed under the trade name Diuril beginning in 1958. In most countries, thiazides are the least expensive antihypertensive drugs available.

<span class="mw-page-title-main">Gitelman syndrome</span> Genetic kidney disorder

Gitelman syndrome (GS) is an autosomal recessive kidney tubule disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. It is the most frequent hereditary salt-losing tubulopathy. Gitelman syndrome is caused by disease-causing variants on both alleles of the SLC12A3 gene. The SLC12A3 gene encodes the thiazide-sensitive sodium-chloride cotransporter, which can be found in the distal convoluted tubule of the kidney.

Magnesium deficiency is an electrolyte disturbance in which there is a low level of magnesium in the body. Symptoms include tremor, poor coordination, muscle spasms, loss of appetite, personality changes, and nystagmus. Complications may include seizures or cardiac arrest such as from torsade de pointes. Those with low magnesium often have low potassium.

<span class="mw-page-title-main">Metabolic alkalosis</span> Abnormally high tissue pH due to metabolic dysfunction

Metabolic alkalosis is an acid-base disorder in which the pH of tissue is elevated beyond the normal range (7.35–7.45). This is the result of decreased hydrogen ion concentration, leading to increased bicarbonate, or alternatively a direct result of increased bicarbonate concentrations. The condition typically cannot last long if the kidneys are functioning properly.

<span class="mw-page-title-main">Hyperaldosteronism</span> Excess aldosterone in the body

Hyperaldosteronism is a medical condition wherein too much aldosterone is produced. High aldosterone levels can lead to lowered levels of potassium in the blood (hypokalemia) and increased hydrogen ion excretion (alkalosis). Aldosterone is normally produced in the adrenal glands.

<span class="mw-page-title-main">Metolazone</span> Chemical compound

Metolazone is a thiazide-like diuretic marketed under the brand names Zytanix, Metoz, Zaroxolyn, and Mykrox. It is primarily used to treat congestive heart failure and high blood pressure. Metolazone indirectly decreases the amount of water reabsorbed into the bloodstream by the kidney, so that blood volume decreases and urine volume increases. This lowers blood pressure and prevents excess fluid accumulation in heart failure. Metolazone is sometimes used together with loop diuretics such as furosemide or bumetanide, but these highly effective combinations can lead to dehydration and electrolyte abnormalities.

<span class="mw-page-title-main">Liddle's syndrome</span> Medical condition

Liddle's syndrome, also called Liddle syndrome, is a genetic disorder inherited in an autosomal dominant manner that is characterized by early, and frequently severe, high blood pressure associated with low plasma renin activity, metabolic alkalosis, low blood potassium, and normal to low levels of aldosterone. Liddle syndrome involves abnormal kidney function, with excess reabsorption of sodium and loss of potassium from the renal tubule, and is treated with a combination of low sodium diet and potassium-sparing diuretics. It is extremely rare, with fewer than 30 pedigrees or isolated cases having been reported worldwide as of 2008.

<span class="mw-page-title-main">Na–K–Cl cotransporter</span> Group of transport proteins

The Na–K–Cl cotransporter (NKCC) is a transport protein that aids in the secondary active transport of sodium, potassium, and chloride into cells. In humans there are two isoforms of this membrane transport protein, NKCC1 and NKCC2, encoded by two different genes. Two isoforms of the NKCC1/Slc12a2 gene result from keeping or skipping exon 21 in the final gene product.

<span class="mw-page-title-main">Sodium-chloride symporter</span> Protein-coding gene in the species Homo sapiens

The sodium-chloride symporter (also known as Na+-Cl− cotransporter, NCC or NCCT, or as the thiazide-sensitive Na+-Cl− cotransporter or TSC) is a cotransporter in the kidney which has the function of reabsorbing sodium and chloride ions from the tubular fluid into the cells of the distal convoluted tubule of the nephron. It is a member of the SLC12 cotransporter family of electroneutral cation-coupled chloride cotransporters. In humans, it is encoded by the SLC12A3 gene (solute carrier family 12 member 3) located in 16q13.

<span class="mw-page-title-main">Ascending limb of loop of Henle</span>

Within the nephron of the kidney, the ascending limb of the loop of Henle is a segment of the heterogenous loop of Henle downstream of the descending limb, after the sharp bend of the loop. This part of the renal tubule is divided into a thin and thick ascending limb; the thick portion is also known as the distal straight tubule, in contrast with the distal convoluted tubule downstream.

<span class="mw-page-title-main">Dent's disease</span> Medical condition

Dent's disease is a rare X-linked recessive inherited condition that affects the proximal renal tubules of the kidney. It is one cause of Fanconi syndrome, and is characterized by tubular proteinuria, excess calcium in the urine, formation of calcium kidney stones, nephrocalcinosis, and chronic kidney failure.

<span class="mw-page-title-main">Distal renal tubular acidosis</span> Medical condition

Distal renal tubular acidosis (dRTA) is the classical form of RTA, being the first described. Distal RTA is characterized by a failure of acid secretion by the alpha intercalated cells of the distal tubule and cortical collecting duct of the distal nephron. This failure of acid secretion may be due to a number of causes. It leads to relatively alkaline urine, due to the kidney's inability to acidify the urine to a pH of less than 5.3.

<span class="mw-page-title-main">Diuretic</span> Substance that promotes the production of urine

A diuretic is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics increase the excretion of water from the body, through the kidneys. There exist several classes of diuretic, and each works in a distinct way. Alternatively, an antidiuretic, such as vasopressin, is an agent or drug which reduces the excretion of water in urine.

References

  1. ↑ "Bartter syndrome: MedlinePlus Medical Encyclopedia". medlineplus.gov. Retrieved 29 September 2019.
  2. 1 2 "Bartter Syndrome: Tubular and Cystic Kidney Disorders: Merck Manual Home Edition". Archived from the original on 4 January 2008. Retrieved 2007-12-31.
  3. ↑ "Bartter syndrome". Medline Plus. Retrieved 3 July 2021.
  4. 1 2 Rodriguez-Soriano J (1998). "Bartter and related syndromes: the puzzle is almost solved". Pediatr Nephrol. 12 (4): 315–27. doi:10.1007/s004670050461. PMID   9655365. S2CID   41782906.
  5. ↑ Castrop, Hayo; Schießl, Ina Maria (2014). "Physiology and pathophysiology of the renal Na-K-2Cl cotransporter (NKCC2)". American Journal of Physiology. Renal Physiology. 307 (9): F991–F1002. doi:10.1152/ajprenal.00432.2014. PMID   25186299. Archived from the original on 2017-11-23. Retrieved 2016-03-07.
  6. ↑ Naesens M, Steels P, Verberckmoes R, Vanrenterghem Y, Kuypers D (2004). "Bartter's and Gitelman's syndromes: from gene to clinic". Nephron Physiol. 96 (3): 65–78. doi:10.1159/000076752. PMID   15056980. S2CID   9649621.
  7. ↑ Zaffanello M, Taranta A, Palma A, Bettinelli A, Marseglia GL, Emma F (2006). "Type IV Bartter syndrome: report of two new cases". Pediatr. Nephrol. 21 (6): 766–70. doi:10.1007/s00467-006-0090-x. PMID   16583241. S2CID   34031819.
  8. ↑ Vezzoli G, Arcidiacono T, Paloschi V, et al. (2006). "Autosomal dominant hypocalcemia with mild type 5 Bartter syndrome". J. Nephrol. 19 (4): 525–8. PMID   17048213.
  9. ↑ "Bartter syndrome". The National Center For Advancing Translational Sciences. Retrieved 23 July 2021.
  10. 1 2 Bartter FC, Pronove P, Gill JR, MacCardle RC (1962). "Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome". Am J Med. 33 (6): 811–28. doi:10.1016/0002-9343(62)90214-0. PMID   13969763. Reproduced in Bartter FC, Pronove P, Gill JR, MacCardle RC (1998). "Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. 1962". J. Am. Soc. Nephrol. 9 (3): 516–28. doi: 10.1681/ASN.V93516 . PMID   9513916.
  11. ↑ Dane B, Yayla M, Dane C, Cetin A (2007). "Prenatal diagnosis of Bartter syndrome with biochemical examination of amniotic fluid: case report". Fetal Diagn. Ther. 22 (3): 206–8. doi:10.1159/000098719. PMID   17228161. S2CID   45890736.
  12. ↑ Gitelman HJ, Graham JB, Welt LG (1966). "A new familial disorder characterized by hypokalemia and hypomagnesemia". Trans Assoc Am Physicians. 79: 221–35. PMID   5929460.
  13. ↑ "Gitelman Syndrome". The Lecturio Medical Concept Library. Retrieved 23 July 2021.
  14. ↑ Royal Brompton & Harefield Hospital Pseudo-Bartter's syndrome Archived 2011-07-21 at the Wayback Machine Retrieved Mars, 2011
  15. ↑ Metyas, Samy; Rouman, Heba; Arkfeld, Daniel G. (2010). "Pregnancy in a Patient With Gouty Arthritis Secondary to Pseudo-Bartter Syndrome". Journal of Clinical Rheumatology. 16 (5): 219–220. doi:10.1097/RHU.0b013e3181e9312a. PMID   20661067.
  16. ↑ "Bartter Syndrome". The Lecturio Medical Concept Library. Retrieved 3 July 2021.
  17. ↑ "Bartter Syndrome". The Lecturio Medical Concept Library. Retrieved 23 July 2021.
  18. ↑ Proesmans W (2006). "Threading through the mizmaze of Bartter syndrome". Pediatr. Nephrol. 21 (7): 896–902. doi:10.1007/s00467-006-0113-7. PMID   16773399. S2CID   26270693.
  19. ↑ synd/2328 at Who Named It?
  20. ↑ "Bartter's syndrome". www.whonamedit.com.
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