22/9/22, 16:15 Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations - UpToDate

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Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical

manifestations
Authors: David H Ellison, MD, FASN, FAHA, Martin Konrad, MD
Section Editors: Richard H Sterns, MD, Michael Emmett, MD, Patrick Niaudet, MD
Deputy Editor: John P Forman, MD, MSc

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Aug 2022. | This topic last updated: Jun 24, 2022.

INTRODUCTION AND DEFINITION

Salt-losing tubulopathies are a group of inherited disorders that result in impaired salt reabsorption by the kidney tubules resulting in salt excretion in excess of
what is required for homeostasis. These disorders can be separated into hypokalemic and hyperkalemic salt-wasting tubulopathies.

This topic presents an overview of the classification of inherited salt-wasting tubulopathies and clinical features and pathophysiology of hypokalemic salt-losing
tubulopathies. The diagnosis and treatment of hypokalemic salt-wasting tubulopathies in children and adults are presented separately:

● (See "Bartter and Gitelman syndromes in children: Clinical manifestations, diagnosis, and management".)
● (See "Bartter and Gitelman syndromes in adults: Diagnosis and management".)

Inherited hyperkalemic salt-wasting tubulopathies, which phenotypically resemble a state of hypoaldosteronism, are discussed in other topics:

● (See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)", section on 'Inherited disorders'.)
● (See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)", section on 'Pseudohypoaldosteronism type 1'.)
● (See "Genetic disorders of the collecting tubule sodium channel: Liddle's syndrome and pseudohypoaldosteronism type 1".)

For a discussion of the full spectrum of tubulopathies, the reader is referred elsewhere [1].

DEFINITIONS: TUBULAR REABSORPTION AND TUBULOPATHIES

● Tubular reabsorption is the process in which large amounts of ultrafiltrate produced by the kidney during the excretion of waste products are recovered by
the kidney tubules. Water and many solutes are reabsorbed back into the bloodstream by the action of transporters, channels, and paracellular pathways
along the kidney tubules thereby maintaining homeostasis. Tubular reabsorption is energy-intensive, which is why the kidneys match the heart as having the
highest resting metabolic expenditure (approximately 440 kcal/kg per day) [2].

● Tubulopathy is defined as dysfunction of the kidney tubules, typically causing defects in reabsorption; these can be either inherited or acquired. The list of
inherited tubulopathies is long, given the array of transported solutes [1].

● Salt-losing (or salt-wasting) tubulopathies are defined as disorders in which salt (ie, sodium) reabsorption is impaired resulting in excretion of salt in
excess of what is required for homeostasis. Hypokalemic salt-losing tubulopathies are those in which salt-wasting occurs proximal to the potassium-
secreting segments of the distal nephron, resulting is excessive potassium excretion. These tubulopathies are among the most common encountered in
clinical practice ( table 1) [3].

CLASSIFICATION

Salt-wasting tubulopathies can be classified in various ways:

● Phenotypic classification:

• Classic Bartter-like phenotype, antenatal Bartter-like phenotype, or Gitelman-like phenotype – Before the causative variants were identified, an
eponymous nomenclature was used to describe hypokalemic salt-losing tubulopathies as either Bartter or Gitelman syndromes. However, with the
discovery of the underlying genes responsible for these disorders, it became clear that pathologic variants in the same gene can produce significant
phenotypic diversity among different individuals with overlap among the two named syndromes ( figure 1 and figure 2). As an example, variants in
the chloride channel ClC-Kb originally associated with "classic" Bartter syndrome can sometimes present with phenotypes resembling "antenatal" Bartter
syndrome or Gitelman syndrome, and the phenotype can also switch from one to another [4-6]. Phenotypic variability is also present with disorders
caused by dysfunction of the apical sodium potassium chloride entry pathway (NKCC2), the apical potassium recycling pathway (ROMK; Kir1.1 or KCNJ1),
and the sodium-chloride cotransporter (NCC).

Accordingly, hypokalemic inherited tubulopathies are better described phenotypically as classic Bartter-like, antenatal Bartter-like, and Gitelman-like
phenotypes, as used in this topic as well as in other content within UpToDate. The terms Bartter syndrome (types 1 through 5) and Gitelman syndrome
are now used in association with specific genotypes, rather than denoting a uniform phenotype.

• Pseudohypoaldosteronism type 1 – The inherited hyperkalemic salt-wasting tubulopathies, which result most commonly from variants in the epithelial
sodium channel (ENaC), are called pseudohypoaldosteronism type 1 because they resemble a state of aldosterone deficiency but are associated with
normal or elevated aldosterone concentrations. These disorders are discussed elsewhere. (See "Etiology, diagnosis, and treatment of hypoaldosteronism
(type 4 RTA)", section on 'Inherited disorders' and "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)", section on
'Pseudohypoaldosteronism type 1' and "Genetic disorders of the collecting tubule sodium channel: Liddle's syndrome and pseudohypoaldosteronism
type 1".)

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● Genetic classification – Given the phenotypic heterogeneity among these disorders, genetic classification has been suggested as the best method for
categorization [1], at least when such information is available ( table 1). Salt-losing hypokalemic tubulopathies are autosomal recessive, digenic (ie,
requiring pathologic variants at two loci), or X-linked disorders, with similar but distinct metabolic abnormalities and presentations. The variants causing
these disorders may be missense, nonsense, splice site variants, or complete gene deletions [5,7,8]. These variants most often appear to disrupt protein
folding, leading to protein degradation [9,10], and there is some evidence that the phenotypic severity is related to the nature of the protein defect [5]; yet
two individuals who inherit the same variants can have different phenotypic presentations [11], and the determinants of phenotype remain uncertain
( table 1) [12].

● Nephron site classification – In addition to phenotypic presentation and the underlying genetic cause, salt-wasting tubulopathies have also been classified
according to the site along the nephron where the primary defect occurs [13]:

• The hypokalemic salt-losing tubulopathies result from gene variants that affect proteins that regulate sodium and chloride reabsorption, which are
located in the thick ascending limb and the distal convoluted tubule ( figure 1 and figure 2).

• The hyperkalemic salt-losing tubulopathies result from gene variants that affect the ENaC or the mineralocorticoid hormone receptor located along the
aldosterone-sensitive distal nephron. (See "Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)", section on 'Inherited disorders' and
"Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA)", section on 'Pseudohypoaldosteronism type 1' and "Genetic disorders of the
collecting tubule sodium channel: Liddle's syndrome and pseudohypoaldosteronism type 1".)

Disorders of the proximal tubule typically do not lead to salt wasting because compensatory mechanisms in later tubule segments can reabsorb salt that is
not reabsorbed proximally. Also, tubuloglomerular feedback (TGF) results in decreased intraglomerular pressures and thereby decreased filtration. However,
some patients with proximal tubule dysfunction can present with hypovolemia and, if bicarbonate supplements are used to correct metabolic acidosis, also
with hypokalemia. The reader is referred elsewhere for a discussion of proximal tubule disorders and other non-salt-wasting tubulopathies [1]. (See "Etiology
and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Proximal (type 2) RTA'.)

CLINICAL MANIFESTATIONS

Clinical manifestations vary. The most severely affected individuals (eg, Bartter syndrome types 1, 2, 4a, 4b, and 5) present antenatally, with polyhydramnios, or
neonatally, with hypovolemia and hypokalemia ( table 2). (See "Bartter and Gitelman syndromes in children: Clinical manifestations, diagnosis, and
management", section on 'Clinical features: Bartter syndrome'.)

Milder cases typically present with polyuria, fatigue, failure to thrive, and muscle cramps later in childhood/adolescence or as adults (eg, Bartter syndrome types 3
and Gitelman syndrome); acute symptoms (eg, muscle cramps) are more common and prominent during episodes of hypovolemia (such as after intense exercise).
Some patients may remain asymptomatic as they are able to reduce salt excretion to low levels and preserve extracellular fluid volume.

However, there are features that are common to all of the hypokalemic tubulopathies.

Features common to hypokalemic salt-wasting tubulopathies — Clinical features common in all hypokalemic salt-wasting tubulopathies (ie, Bartter-like and
Gitelman-like phenotypes) include [4,14-21]:

● Chronic hypokalemia, which may be associated with a prolonged QT interval and an increased risk of ventricular arrhythmias and sudden death in both
Gitelman and Bartter syndromes [14,15,22-26]
● Chronic metabolic alkalosis
● Salt craving, thirst, and polydipsia
● Polyuria and nocturia, which are more pronounced in Bartter as compared with Gitelman syndrome
● Low to normal blood pressure
● Fatigue, muscle cramps [27]

Additional features common to Bartter-like and Gitelman-like phenotypes, which can be revealed with further testing, include [14] (see "Bartter and Gitelman
syndromes in children: Clinical manifestations, diagnosis, and management" and "Bartter and Gitelman syndromes in adults: Diagnosis and management"):

● Elevated plasma aldosterone

● Hyperreninemia
● A spot potassium-to-creatinine ratio >13 mEq/g creatinine (>1.5 mEq/mmol creatinine), indicating renal potassium wasting
● Inappropriately elevated spot urine chloride concentration (>15 to 20 mEq/L and or a fractional excretion of chloride >0.5 percent)

Additional features of the Bartter-like phenotype — Additional clinical features that are more characteristic of the Bartter-like phenotype include (see "Bartter
and Gitelman syndromes in children: Clinical manifestations, diagnosis, and management", section on 'Clinical features: Bartter syndrome'):

● Hypercalciuria – Hypercalciuria is a major distinguishing feature that can help differentiate the Bartter-like phenotype from the Gitelman-like phenotype.
Hypercalciuria can result in nephrocalcinosis, which may be seen on abdominal imaging. Nephrocalcinosis is particularly common in patients with Bartter
syndromes type 1 and 2.

● Increased prostaglandin E2 (PGE2) – Increased production of PGE2 is usually present with the Bartter-like phenotype, and this contributes to salt wasting,
low blood pressure, and polyuria [28]. In addition, markedly elevated systemic prostaglandin levels may produce fever, vomiting, and diarrhea, which are all
prominent features of the antenatal and neonatal forms of Bartter syndrome. PGE2 is not measured in clinical practice, but the fact that the Bartter-like
phenotype often improves with nonsteroidal antiinflammatory drugs (NSAIDs) suggests that levels are high.

● Younger age at presentation – Although not always the case, patients with Bartter syndrome typically present at a younger age (ie, antenatally, neonatally,
or in early childhood) compared with an older presentation in patients with Gitelman syndrome.

● Impaired urinary concentrating ability – Polyuria and antenatal polyhydramnios are common manifestations of impaired concentrating ability seen in
patients with all types of Bartter syndrome; although less severe, they are also common in Gitelman syndrome (20 to 50 percent), where they are possibly
the result of the hypokalemia [14].

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● Sensorineural deafness – Patients with Bartter syndrome type 4a/b have sensorineural deafness.

● Chronic kidney disease – Chronic kidney disease may be a late manifestation in patients with Bartter syndrome, particularly individuals with Bartter
syndromes types 1 and 4 compared with those who have types 2 and 3 [5,15,29,30]. Additional risk factors that contribute to chronic kidney injury include
premature birth, nephrocalcinosis, chronic hypovolemia, and chronic treatment with NSAIDs [5]. The magnitude of chronic kidney disease in Bartter
syndrome type 3 was illustrated in a case series of 77 individuals who were followed for a median of eight years. Chronic kidney disease, defined as
proteinuria and a decline in glomerular filtration rate (GFR), developed in 19 patients (25 percent); one required hemodialysis, and four required kidney
transplantation [5].

● Transient disease in some patients – The prenatal course of Bartter syndrome 5 is severe (in terms of onset and degree of polyhydramnios), and perinatal
mortality is significant. However, in infants who survive, all clinical signs and biochemical abnormalities disappear over time. At the age of two years, the
disease resolves completely in almost all patients.

Additional features of the Gitelman-like phenotype — Additional clinical features that are more characteristic of the Gitelman-like phenotype than the Bartter-
like phenotype include:

● Hypocalciuria – Patients with the Gitelman-like phenotype have hypocalciuria (spot urine calcium-to-creatinine concentration ratio <0.2 mmol/mmol);
hypercalciuria is not seen.

● Hypomagnesemia – Hypomagnesemia, associated with renal magnesium wasting (fractional excretion of magnesium >4 percent), is pronounced with the
Gitelman-like phenotype. Complications of hypomagnesemia in these patients include cramping and tetany as well as calcium pyrophosphate deposits both
in joints (chondrocalcinosis—see below) and, rarely, in the sclera [14].

● Pseudogout (calcium pyrophosphate crystal deposition [CPPD]) – This form of chronic, painful arthritis is an increasingly recognized complication of the
Gitelman-like phenotype [31,32]. Magnesium deficiency contributes to calcium pyrophosphate precipitation (chondrocalcinosis) in two ways: First,
hypomagnesemia directly increases calcium pyrophosphate precipitation [31], and second, magnesium is a critical activating cofactor for tissue-nonspecific
alkaline phosphatase. Consequently, hypomagnesemia reduces alkaline phosphatase activity and raises pyrophosphate levels, thereby increasing the risk of
calcium pyrophosphate precipitation [32,33].

● Older age at presentation – The Gitelman-like phenotype typically presents after puberty with non-specific symptoms or can even present
asymptomatically.

● Neurologic manifestations – Patients with a KCNJ10 variant may present with EAST syndrome, which is characterized by epilepsy, ataxia, sensorineural
deafness, and salt-wasting tubulopathy [34,35]. A similar presentation (characterized by deafness and tubulopathy) can occur with variants in KCNJ16 [36,37].
The proteins produced by KCNJ10 and KCNJ16 are believed to form heteromeric basolateral potassium channels along the distal nephron, although the
protein produced by KCNJ16 also participates in channel formation along the proximal tubule. Of note, the clinical presentation of the patients with KCNJ16
variants may include some features of proximal tubule dysfunction.

PATHOPHYSIOLOGY

Normal sodium reabsorption — The thick ascending limb of Henle's loop and the distal convoluted tubule form a functional unit that actively reabsorbs sodium
and chloride from the tubular fluid. Both segments are relatively watertight and therefore prevent osmotically driven water absorption.

● Thick ascending limb – Approximately 30 percent of the filtered sodium load is absorbed along the thick ascending limb, which contributes to medullary
interstitial hypertonicity via counter current multiplication and generates the osmotic driving force for water reabsorption in the collecting duct. As a result,
disturbances in salt reabsorption in the thick ascending limb result in both salt wasting and reduced urinary concentrating capacity (ie, water loss).

Most sodium reabsorption in the thick ascending limb depends upon the luminal furosemide-sensitive sodium-potassium-2-chloride cotransporter (NKCC2);
approximately one-half of the sodium is reabsorbed transcellularly and one-half is reabsorbed paracellularly by intercellular pathways ( figure 2). Most
potassium that enters the thick ascending limb cell recycles back to the tubular urine through the potassium channel (ROMK; Kir1.1 or KCNJ1), and chloride
passes across the basolateral membrane mainly via chloride channels. The combination of apical potassium recycling and basolateral chloride exit generates
a transepithelial (lumen positive) voltage gradient that provides a driving force for paracellular transport of sodium, calcium, and magnesium. The essential
functions of the thick ascending limb therefore not only include the reabsorption of sodium chloride but also a large fraction of filtered magnesium and
calcium.

● Distal convoluted tubule – Sodium chloride reabsorption in the distal convoluted occurs almost exclusively by the transcellular route mediated by the
electroneutral thiazide-sensitive sodium-chloride cotransporter (NCC) that is structurally related to the NKCC2 protein but transports one sodium ion
together with one chloride ion without potassium ( figure 1).

Both tubular segments have similar pathways for basolateral chloride exit. Specifically, two highly homologous ClC-K type chloride channel proteins (ClC-Ka and
ClC-Kb) associate with their beta subunit, barttin, to form a basolateral chloride channel. This channel accounts for the transport of the majority of reabsorbed
chloride ions.

In the transition zone between the thick ascending limb and distal convoluted tubule, a plaque of specialized epithelial cells forms the macula densa, which
together with adjacent extraglomerular mesangial cells and granular cells of the afferent arterioles appendant to the same nephron form the juxtaglomerular
apparatus. Macula densa cells serve an important function in coupling renal hemodynamics with tubular reabsorption in that they monitor the sodium chloride
concentration of the tubular fluid. The tubule sodium chloride concentration in the fluid leaving the thick ascending limb of Henle is a function of both the rate of
thick ascending limb of Henle salt reabsorption and the volume of tubule fluid. Via paracrine signaling molecules, especially prostaglandin E2 (PGE2), the macula
densa provides a feedback mechanism that adapts glomerular filtration to tubular reabsorption (tubuloglomerular feedback [TGF]) [38]. In case of an increased
sodium chloride concentration and flow sensed by the macula densa, TGF induces afferent arteriole vasoconstriction and decreased renin release (which reduces
the glomerular filtration rate [GFR]), whereas a decreased macula densa sodium chloride concentration dilates the afferent arteriole and increases renin release
(which increases GFR).

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"Sensing" of the tubular sodium chloride concentration by the macula densa requires the same transport proteins that are required for normal function of thick
ascending limb cells (ie, NKCC2, ROMK, ClC-K, and barttin).

Thus, impaired activity of any of the thick ascending limb transport proteins not only results in salt wasting due to reduced thick ascending limb salt-reabsorbing
capacity but also abrogates TGF, which would otherwise reduce the filtered sodium chloride load by decreasing glomerular filtration. This dissociation of the
tubular sodium chloride concentration from glomerular filtration further aggravates salt wasting by uncoupling tubular reabsorption from renal hemodynamics.

Bartter-like phenotype

Defects in sodium chloride reabsorption — The clinical features in patients with the Bartter-like phenotype result from a defect in sodium chloride
reabsorption in the cortical and medullary thick ascending limbs of the loop of Henle ( figure 2). Defects in various genes, and consequently their corresponding
protein products, produce the Bartter-like phenotype by impairing sodium chloride reabsorption at these sites ( table 1):

● Defects in the apical (luminal) sodium-potassium-chloride entry pathway (NKCC2 encoded by SLC12A1) – Defective NKCC2 function impairs transcellular and
paracellular sodium transport and mimics the effects of loop diuretics, which block this pathway directly; this is one reason that the Bartter-like phenotype
resembles the effects of loop diuretics.

● Defects in the apical potassium recycling pathway (ROMK [also referred to as Kir.1, KCNJ1] encoded by KCNJ1) – A ROMK defect inhibits sodium chloride
reabsorption along this segment because potassium must recycle from cells into the luminal fluid to maintain the action of NKCC2. As discussed below, this
channel also participates in aldosterone-driven potassium secretion along distal segments, thereby rendering the phenotypic presentation of the Bartter-like
phenotype due to ROMK defects distinct from other causes of this phenotype (in that hypokalemia is not as severe).

● Defects in the basolateral chloride exit pathway (ClC-Ka encoded by CLCNKA, ClC-Kb encoded by CLCNKB, or barttin encoded by BSND) – A defect in any of
several components of a chloride channel exit pathway inhibits transepithelial sodium chloride transport because chloride must leave the cell across the
basolateral membrane (sodium leaves via the Na+ K+ ATPase). The combination of apical potassium recycling and basolateral chloride exit normally
generates a transepithelial voltage, oriented in the lumen-positive direction ( figure 3).

● Defects that disrupt trafficking of NKCC2 and NCC to the apical membrane (MAGED2) – Some patients who have a severe antenatal Bartter-like phenotype
have variants in the MAGED2 gene. This disorder is characterized by severe polyhydramnios, prematurity, salt wasting, and a variable degree of transient
hypercalciuria; few patients develop nephrocalcinosis. These features resolve within the first two years of life [39,40]. The mechanism by which MAGED2
variants disrupt trafficking of NKCC2 and NCC is not clear [39].

Mechanisms underlying associated clinical findings

● Hypokalemia – Hypokalemia is a characteristic diagnostic feature of all but one form of Bartter syndrome, and the underlying mechanism differs based on
the causative defective gene/protein product:

• Variants in the genes encoding the NKCC2 and the ClC-Kb result in decreased sodium chloride and fluid reabsorption in the thick ascending limbs of the
loop of Henle, increased sodium and fluid delivery to the aldosterone-sensitive distal tubule, and high circulating aldosterone concentrations due to
volume depletion and hyperreninemia. Increased sodium delivery enhances sodium reabsorption through aldosterone activated epithelial sodium
channels (ENaC) in the distal tubule, and potassium is excreted in exchange for sodium. Potassium loss leads to hypokalemia.

• Variants in the gene encoding ROMK (also referred to as Kir.1 or KCNJ1) affect both potassium recycling along the thick ascending limb ( figure 2) and
aldosterone-stimulated potassium secretion in the distal nephron. In affected cases, excess potassium excretion is mediated partly by increased
potassium delivery out of the loop of Henle (decreased loop segment reabsorption) and partly by flow mediated processes in the collecting duct via big
potassium (BK) channels [41]. However, hypokalemia may initially be absent in some children with ROMK variants, and in fact, some newborns may
exhibit hyperkalemia [6,42]. Potassium concentrations ultimately decline but tend to be higher in patients with ROMK channel defects than in those with
other Bartter syndromes [6].

● Hypochloremic metabolic alkalosis – Hypochloremic metabolic alkalosis is the result of multiple factors, including the excessive loss of chloride relative to
bicarbonate and activation of hydrogen ion secretion along the aldosterone-sensitive distal nephron (via the H+ ATPase). The mechanisms that activate
hydrogen ion secretion in the distal nephron are similar to those responsible for potassium secretion at this site: Increased sodium delivery (and
reabsorption via ENaC) results in hyperpolarization, creating an electrochemical gradient for hydrogen ion secretion, and an elevation in aldosterone levels
(due to volume depletion and hyperreninemia) potentiates this process [43]. Enhanced hydrogen ion secretion along the thick ascending limb, via the
sodium-proton exchanger NHE3, may be another mechanism for metabolic alkalosis [44].

● Polyuria and impaired concentrating ability – Polyuria due to impaired concentrating ability is a key characteristic of the Bartter-like phenotype. The
urinary concentrating defect is due mainly to impaired sodium transport along the thick ascending limb [45], but high prostaglandin levels and chronic
hypokalemia may also contribute. Defective salt reabsorption in utero also results in polyhydramnios since fetal urine is an important contributor to
amniotic fluid volume [39]. (See "Clinical manifestations and causes of nephrogenic diabetes insipidus", section on 'Hypokalemia'.)

● Low to normal blood pressure – Patients with the Bartter-like phenotype have low to normal blood pressure, despite activation of the renin-angiotensin
system. Low to normal blood pressure results from chronic extracellular fluid volume depletion caused by salt wasting (described above) along the thick
ascending limb and paradoxical vasodilation.

Two factors likely contribute to vasodilation. First, RGS-2 (a regulator of G-protein signaling) is activated, which inhibits Gq protein binding to effectors such
as phospholipase C and also stimulates expression of the endothelial subunit of nitric oxide synthase mRNA, thereby raising nitric oxide concentrations and
consequently reducing vascular resistance [46]. Second, vasodilation may result from increased generation of vasodilatory prostaglandin E2 (PGE2). PGE2
production is often markedly elevated in these patients, especially in the antenatal subgroup [6]. Macula densa cells are particularly high in cyclooxygenase 2
[38]. The increased renal production of PGE2 in Bartter syndrome results from impaired entry of sodium chloride into macula densa cells at the end of the
thick ascending limb of the loop of Henle [47-49], which activates p38 MAP kinase that [50,51], over time, increases expression of cyclooxygenase 2 [48,52].

● Hyperreninemia and elevated levels of angiotensin II and aldosterone – Volume-independent production of renin by juxtaglomerular cells contributes to
hyperreninemia in patients with the Bartter-like phenotype. Decreased sodium chloride entry into macula densa cells also stimulates renin production [53-

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57]. This volume-independent hyperreninemia, in combination with chronic extracellular fluid volume depletion, is responsible for the high circulating levels
of angiotensin II and aldosterone.

● Beneficial effects of nonsteroidal antiinflammatory drugs (NSAIDs) – The ability of inhibitors of prostaglandin synthesis, such as NSAIDs, to mitigate
some of the clinical and laboratory abnormalities of patients with the Bartter-like phenotype is a result of their ability to blunt enhanced generation of PGE2.
Enhanced PGE2 generation directly stimulates renin production [28,58,59] and reduces salt transport along both the medullary thick ascending limb (by
inhibiting NKCC2) [60] and along the collecting duct [61], contributing to the salt-wasting tendency.

● Hypercalciuria and increased magnesium urinary excretion – Both calcium and magnesium are reabsorbed along the thick ascending limb via a
paracellular pathway (between cells) driven by the lumen-positive transepithelial voltage ( figure 2). Reduced sodium absorption in the thick ascending
limb or impaired basolateral chloride transport reduces transepithelial voltage and decreases calcium and magnesium reabsorption.

The paracellular pathway's ion-selective properties are determined by claudins and other proteins [62]. Two different types of claudin are expressed in a
mosaic pattern among the cells along the thick ascending limb [63]: those that permit divalent cations to traverse (calcium and magnesium, claudins 16 and
19 [64]) and those that are selective for monovalent cations (mostly claudin 10 [65]). The driving force for divalent cation reabsorption is twice that for
monovalent ions, owing to their charge, making divalent cation absorption highly dependent upon the positive lumen charge generated by cellular transport
mechanisms. Thus, reduced sodium chloride transport in the thick ascending limb decreases renal calcium and magnesium reabsorption. As a result, urinary
calcium excretion is increased, accounting for the occurrence of nephrocalcinosis in some of these patients.

Although the loop of Henle is normally responsible for reabsorbing 70 percent of filtered magnesium [66], hypomagnesemia is less pronounced in those
with a Bartter-like phenotype than it is in disease processes that affect the distal convoluted tubule (eg, Gitelman syndrome) [4,67]. This is because patients
with the Bartter-like phenotype develop hypertrophy of the distal convoluted tubule [68], which is the site of the apical magnesium entry pathway, TRPM6
[69,70].

Gitelman-like phenotype — The Gitelman-like phenotype shares many features with the Bartter-like phenotype, and in fact, the two were once viewed as
identical, until it was recognized that some features, especially urinary calcium excretion and the degree of hypomagnesemia, were different. The
pathophysiology of the Gitelman-like phenotype is similar, but not identical, to that of the Bartter-like phenotype.

Defects in sodium chloride reabsorption — In patients with the Gitelman-like phenotype, transepithelial sodium chloride transport through distal convoluted
tubule cells is impaired ( figure 1). Defects in multiple genes, and consequently their corresponding protein products, may produce the phenotype by impairing
sodium chloride reabsorption at this site ( table 1) [8,14,35,71-78]:

● Defects in the NCC (encoded by SLC12A3) disrupt the entry pathway for sodium and chloride at the apical membrane of distal convoluted tubule cells [14].
Defective NCC function almost precisely mimics the effects of thiazide diuretics, which block this pathway directly; this is why the Gitelman-like phenotype
resembles the effects of thiazide diuretics.

● Defects in ClC-Kb (encoded by CLCNKB) usually results in the Bartter-like phenotype, as discussed above, but less commonly may generate a Gitelman-like
phenotype [76-78]. This channel, which is expressed in the thick ascending limb, is also expressed in distal convoluted tubule cells, where it modulates the
intracellular chloride concentration [79].

● Defects in Kir4.1 encoded by KCNJ10 lead to the EAST syndrome (epilepsy, ataxia, sensorineural deafness, and tubulopathy); the tubulopathy in the EAST
syndrome produces a Gitelman-like phenotype [35,75]. Heteromers of Kir4.1 and Kir5.1 encoded by KCNJ16 are essential for determining the intracellular
chloride concentration of distal convoluted tubule cells, thereby modulating WNK kinases and NCC [79-81]. The same channels are expressed along the thick
ascending limb and connecting tubule, but EAST syndrome variants do not appear as pathological in those segments [82]. Variants in KCNJ16 may also cause
an EAST-like syndrome, as noted above [36,37].

Mechanisms underlying associated clinical findings

● Hypokalemic metabolic alkalosis – Hypokalemia and alkalosis are typical of the Gitelman-like phenotype:

• Hypokalemia – The distal convoluted tubule plays a central role in potassium homeostasis, even though it does not transport potassium. In healthy
individuals, the plasma potassium concentration strongly regulates NCC activity via a basolateral potassium channel (Kir4.1/5.1) and a basolateral
chloride channel (ClC-Kb) [80,81]. Hyperkalemia reduces potassium exit from the tubular cell, increases intracellular chloride, and turns off WNK kinases,
thereby downregulating NCC [79,83]. While variants in genes encoding NCC decrease its activity directly, other variants in genes encoding the Kir4.1/5.1
potassium channel or the ClC-Kb chloride channel turn off NCC because they disrupt the signaling pathway. As a result, there is increased sodium and
fluid delivery to the more distal parts of the nephron, which stimulates potassium secretion, especially when aldosterone levels are high. In healthy
individuals, activation of NCC by hypokalemia mitigates kaliuresis [84]; in individuals lacking functional NCC, this mechanism is absent, and kaliuresis can
be unrelenting, resulting in hypokalemia.

• Metabolic alkalosis – The same combination of increased distal sodium and fluid delivery and elevated aldosterone levels stimulate hydrogen ion
secretion, resulting in metabolic alkalosis in patients with the Gitelman-like phenotype. The hypokalemia and reduced total body potassium stores further
enhance systemic and renal bicarbonate generation and reclamation.

● Hypocalciuria – Hypocalciuria is another cardinal feature of the Gitelman-like phenotype and has been used as a diagnostic criterion, although it is not
specific [4,14]. The underlying mechanisms leading to hypocalciuria remain uncertain. Data including animal studies suggest that hypocalciuria is due to
thiazide-like induced volume depletion that increases calcium reabsorption proximally [85-90]. However, other studies found that patients with a Gitelman-
like phenotype have persistent hypocalciuria even after extracellular fluid volume repletion, contradicting the hypothesis that increased calcium
reabsorption is due only to hypovolemia-induced enhancement of sodium reabsorption by the thick ascending limb [91]. In addition, expression of the
TRPV5 calcium channel, as well as the calcium binding protein, calbindin-D28K, was enhanced in a mouse knock-in model of Gitelman syndrome; similar
findings were identified in a patient with the Gitelman-like phenotype who underwent kidney biopsy [92].Thus, it seems most likely that both proximal and
distal processes are involved in both thiazide-induced and Gitelman-related hypocalciuria [88].

● Hypomagnesemia – Hypomagnesemia is often striking in patients with a Gitelman-like phenotype (and was a feature first identified by Gitelman) [93].
Plasma magnesium levels are typically lower in these patients than in those with a Bartter-like phenotype. The primary apical magnesium reabsorptive
channel, TRPM6, is expressed predominantly along the more proximal part of the distal convoluted tubule, called DCT1 ( figure 4). In this segment, nearly

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all apical sodium entry is mediated by NCC. Thus, when NCC is deficient or non-functional, this segment of the renal tubule atrophies or grows abnormally
during development (eg, mice lacking NCC have nearly absent DCT1 segments) [94]; other models of the Gitelman-like phenotype similarly manifest atrophy
of the DCT1 [92]. These morphologic changes are accompanied by strikingly decreased expression of the magnesium channel, TRPM6 [85], likely accounting
for the profound magnesium wasting, as more distal segments do not appear able to compensate for this dysfunction.

SUMMARY

● Definition – Salt-losing (or salt-wasting) tubulopathies are defined as disorders in which salt (ie, sodium) reabsorption is impaired resulting in excretion of
salt in excess of what is required for homeostasis. Hypokalemic salt-losing tubulopathies are those in which salt wasting occurs proximal to the potassium-
secreting segments of the distal nephron, resulting is excessive potassium excretion. These tubulopathies are among the most common encountered in
clinical practice ( table 1). (See 'Definitions: Tubular reabsorption and tubulopathies' above.)

● Classification – Hypokalemic salt-losing tubulopathies can be classified according to the patient's phenotype (ie, classic Bartter-like, antenatal Bartter-like, or
Gitelman-like phenotypes), genotype (eg, Bartter syndrome types 1 through 5, Gitelman syndrome), or the site of the nephron that is affected (ie, thick
ascending limb or distal convoluted tubule) ( figure 1 and figure 2). (See 'Classification' above.)

● Clinical manifestations – The most severely affected individuals (eg, Bartter syndrome types 1, 2, 4a, 4b, and 5) present antenatally, with polyhydramnios,
or neonatally, with hypovolemia and hypokalemia ( table 2) (see "Bartter and Gitelman syndromes in children: Clinical manifestations, diagnosis, and
management"). Milder cases typically present with polyuria, fatigue, failure to thrive, and muscle cramps later in childhood/adolescence or as adults (eg,
Bartter syndrome type 3 and Gitelman syndrome). Features that are common to all of the hypokalemic tubulopathies (ie, Bartter-like and Gitelman-like
phenotypes) include (see 'Clinical manifestations' above):

• Chronic hypokalemia
• Chronic metabolic alkalosis
• Salt craving, thirst, and polydipsia
• Polyuria and nocturia
• Low to normal blood pressure
• Fatigue, muscle cramps

Additional clinical features for each phenotype, which may help differentiate between the two:

• Bartter-like phenotype – Hypercalciuria, increased prostaglandin E2 (PGE2) production, impaired urine concentrating ability, sensorineural deafness,
chronic kidney disease, and a younger age at presentation.

• Gitelman-like phenotype – Hypocalciuria, hypomagnesemia, pseudogout, neurologic manifestations, and an older age at presentation.

● Pathophysiology

• Bartter-like phenotype – The clinical features in patients with the Bartter-like phenotype result from a defect in sodium chloride reabsorption in the
cortical and medullary thick ascending limbs of the loop of Henle ( figure 2). Defects in various genes, and consequently their corresponding protein
products, produce the Bartter-like phenotype by impairing sodium chloride reabsorption at these sites, mimicking the effects of loop diuretics
( table 1). Hypokalemia, hypochloremic metabolic alkalosis, polyuria, low to normal blood pressure, and hypercalciuria all result from impaired sodium
chloride reabsorption in the thick ascending limb. (See 'Bartter-like phenotype' above.)

• Gitelman-like phenotype – In patients with the Gitelman-like phenotype, transepithelial sodium chloride transport through distal convoluted tubule
cells is impaired ( figure 1). Defects in multiple genes, and consequently their corresponding protein products, may produce the phenotype by
impairing sodium chloride reabsorption at this site, mimicking the effects of thiazide diuretics ( table 1). Hypokalemia, hypochloremic metabolic
alkalosis, low to normal blood pressure, hypocalciuria, and hypomagnesemia all result from impaired sodium chloride reabsorption by convoluted tubule
cells. (See 'Gitelman-like phenotype' above.)

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GRAPHICS

Classification of salt-wasting tubulopathies

OMIM¶

Gene Protein Common name Phenotype Inheritance Segment

(Phenotype/Gene)

SLC12A1 NKCC2 Bartter syndrome type 1 Antenatal Bartter syndrome AR TAL #601678/*600839

KCNJ1 KCNJ1/Kir1.1 (ROMK) Bartter syndrome type 2 Antenatal Bartter syndrome AR TAL #241200/*600359

CLCNKB ClC-Kb Bartter syndrome type 3 Classic Bartter syndrome AR TAL/DCT #607364/*602023
and Gitelman-like syndrome

BSND Barttin Bartter syndrome type 4a Antenatal Bartter syndrome AR TAL/DCT/ear #602522/*606412
and sensorineural deafness

CLCNKA and CLCNKB ClC-Ka and ClC-Kb Bartter syndrome type 4b Antenatal Bartter syndrome Digenic AR TAL/DCT/ear #613090/*602024 and
and sensorineural deafness *602023

MAGED2 MAGE-D2 Bartter syndrome type 5 Antenatal Bartter syndrome XR TAL/DCT #300971/*300470
(transient)

SLC12A3 NCC Gitelman syndrome Gitelman syndrome AR DCT #263800/*600968

KCNJ10 KCNJ10/Kir4.1 EAST syndrome Gitelman-like syndrome and AR DCT/CNS/ear #612780/*602028

extrarenalΔ

KCNJ16 KCNJ16/Kir5.1 Hypokalemic tubulopathy with Hypokalemia, mixed AR PCT/DCT/CNS/ear◊ #619406/*605722

deafness acid/base disturbance and
deafness

NR3C2 MR Pseudohypoaldosteronism type PHA1A AD CNT/CD #177735/*600983

1A

SCNN1A ENaC alpha subunit Pseudohypoaldosteronism type PHA1B AR CNT/CD #264350/*600228

1

SCNN1B ENaC beta subunit Pseudohypoaldosteronism type PHA1B AR CNT/CD #264350/*600760

1

SCNN1G ENaC gamma subunit Pseudohypoaldosteronism type PHA1B AR CNT/CD #264350/*600761

1

NKCC2: apical sodium potassium chloride entry pathway; KCNJ1/Kir1.1 (ROMK): apical potassium recycling pathway; ClC: chloride channel; NCC: sodium chloride
cotransporter; ENaC: epithelial sodium channel; AR: autosomal recessive; AD: autosomal dominant; XR: X-linked recessive; PCT: proximal convoluted tubule; TAL: thick
ascending limb; DCT: distal convoluted tubule; PHA: pseudohypoaldosteronism; CNT/CD: connecting tubule/collecting duct; MR: mineralocorticoid receptor.

¶ Online Mendelian Inheritance in Man. In OMIM, phenotypes are designated with # and genes are designated with *.

Δ EAST syndrome includes extrarenal manifestations including epilepsy, ataxia, and sensorineural deafness.

◊ Channel expression is not limited to the DCT, but the phenotypic manifestations are.

Adapted with permission of American Society of Nephrology, from: Downie ML, Lopez Garcia SC, Kleta R, Bockenhauer D. Inherited tubulopathies of the kidney: Insights from genetics. Clin J Am Soc Nephrol 2021;
16:620; permission conveyed through Copyright Clearance Center, Inc. Copyright © 2021.

Graphic 131049 Version 1.0

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Distal convoluted tubule cell

Schematic diagram of distal convoluted tubule cell demonstrating the location

of NCC protein, which is dysfunctional in Gitelman syndrome (GS), and ClC-Kb,
which is dysfunctional in Bartter syndrome 3 (which can produce a Gitelman-
like syndrome [GLS] clinical phenotype). The transmembrane voltage in this
segment is near to 0. Basolateral potassium channels are composed of 2
subunits encoded by KCNJ10 and KCNJ16, known as Kir4.1 and Kir5.1,
respectively. Mutations in KCNJ10 cause EAST (epilepsy, ataxia, sensorineural
deafness, tubulopathy) syndrome. Mutations in KCNJ16 cause hypokalemic
tubulopathy and deafness (HKTD). Distal convoluted tubule cells are atrophied
in patients with GLS.

Na+ : sodium ion; Cl– : chloride ion; K+ : potassium ion; Mg2+ : magnesium ion;
BS: Bartter syndrome; ClC: chloride channel; MAGED2: melanoma-associated
antigen D2; Na/KATP: sodium-potassium ATPase; NCC: sodium-chloride
cotransporter; TRPM6: transient receptor potential cation channel subfamily M
member 6.

Courtesy of David H Ellison, MD, FASN, FAHA.

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Thick ascending limb cell

Schematic diagram of thick ascending limb cell demonstrating proteins that are
affected in patients with Bartter syndrome (BS). BS is classified based on the
affected protein as noted in the diagram:
BS1 – NKCC2
BS2 – ROMK/KCNJ1/Kir1.1
BS3 (includes Gitelman-like syndrome) – ClC-Kb
BS4a – Barttin
BS4b – ClC-Ka and ClC-Kb
BS5 – MAGE-D2
Note that the combined actions of the ROMK and the basolateral chloride
channels lead to epithelial polarization, with the lumen positive with respect to
blood. This drives paracellular cation reabsorption.

MAGED2: melanoma-associated antigen D2; Na+ : sodium ion; BS: Bartter

syndrome; Na/KATP: sodium-potassium ATPase; NKCC2: sodium-potassium-
chloride cotransporter; Cl– : chloride ion; K+ : potassium ion; Ca2+ : calcium ion;
Mg2+ : magnesium ion; ROMK/KCNJ1/Kir1.1: apical potassium channel; ClC:
chloride channel.

Courtesy of David H Ellison, MD, FASN, FAHA.

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Clinical characteristics of Bartter syndrome (BS) and Gitelman syndrome (GS)[1-5]

  BS 1 BS 2 BS 3 BS 4a BS 4b Type 5* GS

Affected gene SLC12A1 KCNJ1 CLCNKB BSND CLCNKA;

MAGED2 SLC12A3
CLCNKB

Typical age of Antenatal Antenatal 0 to 5 years Antenatal Antenatal Antenatal >6 years
presentation

Polyhydramnios Severe Severe Absent to mild Severe Severe Very severe Absent

Prematurity Common Common Rare Common Common Always No

Neonatal Common Common Rare Common Common Common Absent

hypovolemia¶

Hypokalemia Always Transient neonatal Always Always Always Always Always

hyperkalemia
followed by
hypokalemia

Calcium excretion High High Variable but usually Variable Variable Variable Low
normal

Nephrocalcinosis Very common Very common Rare and, if Rare and, if Rare and, if Rare Absent
present, mild present, mild present, mild

Magnesium Normal Normal Normal to high Normal to high Normal to high Unknown High
excretion

Poor weight gain Common Common Common Common Common No Can be seen in
and growth prepubertal
failure individuals.

Short stature may

be seen in affected
adolescents and
adults.

Other findings       Sensorineural Sensorineural Large for Chondrocalcinosis

hearing loss hearing loss gestational age;
transient disease

Bartter and Gitelman syndromes are inherited hypokalemic salt-losing tubulopathies, characterized by hypochloremic metabolic alkalosis. Clinical characteristics are noted
based on the affected gene. However, variants in the same gene can produce phenotypic diversity. Refer to UpToDate topics on BS/GS for additional content.

* BS type 5 is characterized by severe polyhydramnios with complete resolution of disease within several months to two years after birth.

¶ Neonatal hypovolemia presents by the first few days of life due to massive polyuria (often exceeding 10 mL/kg/hr).

References:
1. Cunha TDS, Heilberg IP. Bartter syndrome: causes, diagnosis, and treatment. Int J Nephrol Renovasc Dis 2018; 11:291.
2. Kömhoff M, Laghmani K. Curr Opin Nephrol Hypertens 2017; 26:419.
3. Legrand A, Treard C, Roncelin I, et al. Clin J Am Soc Neprhol 2018; 13:242.
4. Blanchard A, Bockenhauer D, Bolignano D, et al. Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 2017; 91:24.
5. Konrad M, Nijenhuis T, Ariceta G, et al. Diagnosis and management of Bartter syndrome: executive summary of the consensus and recommendations from the European Rare Kidney Disease Reference
Network Working Group for Tubular Disorders. Kidney Int 2021; 99:324.

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Spectrum of mutations in Gitelman syndrome and classic Bartter

syndrome (Bartter syndrome type 3)

Prevalence of mutation types in SLC12A3 that cause Gitelman syndrome and in CLCNKB that
cause classic Bartter syndrome (type 3).

References:
1. Republished with permission of American Society of Nephrology, from: Vargas-Poussou R, Dahan K, Kahila D, et
al. Spectrum of mutations in Gitelman syndrome. J Am Soc Nephrol 2011; 22:693; permission conveyed through
Copyright Clearance Center, Inc.
2. Republished with permission of American Society of Nephrology, from: Seys E, Andrini O, Keck M, et al. Clinical
and genetic spectrum of Bartter syndrome type 3. J Am Soc Nephrol 2017; 28:2540; permission conveyed
through Copyright Clearance Center, Inc.

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Segmental distribution of divalent cation transport

Schematic diagram of cells of the distal nephron, including thick ascending limb
(TAL) cells, distal convoluted tubule (DCT) cells, and distal convoluted tubule
2/connecting tubule cells (DCT2/CNT). Calcium (Ca2+ ) and magnesium (Mg2+ )
traverse a paracellular pathway along the TAL composed of the claudins 16 and 19.
Mg2+ is reabsorbed along the DCT via an apical channel, TRPM6. Ca2+ , by contrast,
is reabsorbed along the DCT2/CNT by a different apical channel, TRPV5. Disruption
of transport processes along one segment leads to compensation of transport
along others.

Courtesy of David H Ellison, MD, FASN, FAHA.

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Contributor Disclosures
David H Ellison, MD, FASN, FAHA No relevant financial relationship(s) with ineligible companies to disclose. Martin Konrad, MD No relevant financial relationship(s) with ineligible
companies to disclose. Richard H Sterns, MD No relevant financial relationship(s) with ineligible companies to disclose. Michael Emmett, MD No relevant financial relationship(s)
with ineligible companies to disclose. Patrick Niaudet, MD No relevant financial relationship(s) with ineligible companies to disclose. John P Forman, MD, MSc No relevant
financial relationship(s) with ineligible companies to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through
requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of
evidence.

Conflict of interest policy

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