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

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
Literature review current through: Dec 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".)

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].

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).

"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 [53-57]. 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 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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Topic 2344 Version 36.0

References