Bartters Syndrome Kir11 Clinical features

In 1962, Bartter described two patients who had very low plasma K+ levels and metabolic acidosis, yet elevated plasma renin and aldosterone levels. Subsequently, it has become clear that the syndrome he described is both phenotypically and genetically heterogeneous, and at least three subtypes have been distinguished. The first of these is the classical Bartter's syndrome for which the underlying genetic defect remains unknown. The second, known as the Gitelman variant, is characterised by late age of onset and very low urinary Ca2+ and Mg2+ concentrations, and results from mutations in the gene encoding the NaCl cotransporter (NCCT). The third variant is known as antenatal Bartter's syndrome or hyper-prostaglandin E syndrome. It is a life-threatening disorder that presents in utero with a marked fetal polyuria and it can precipitate premature birth. Newborns show severe salt-wasting, moderate hypokalaemia and metabolic acidosis, and elevated urinary excretion of prostaglandins. In addition, there is a marked loss of Ca2+ in the urine and as a consequence, osteopenia (bone loss) and nephrocalcinosis (kidney stones). Unsurprisingly, affected infants show failure to thrive. Recent studies have shown that antenatal Bartter's syndrome is genetically heterogeneous and may result from mutations in the genes encoding the inwardly rectifying K+ channel Kir1.1 (KCNJ1; Bartter's syndrome type II), the NaK2Cl cotransporter (SCL12A1, Bartter's syndrome type I) or the voltage-gated Cl" channel CLC-Kb (CLCNKB, Bartter's syndrome type III; see Chapter 10). These variants may be distinguished clinically because hypokalaemia is less pronounced (3.0-3.5 mM) in patients with mutations in KCNJ1, and the course of the disease is less severe.

Analysis of mutations

At least 11 mutations in KCNJ1 have been described to date, which are distributed over the entire coding region of the gene (Fig. 8.11; Derst et al, 1997; Int Collab Study Group on Bartter's syndrome, 1997). Two mutations produce truncated proteins that are expected to lead to a non-functional channel. Nine missense mutations that result in amino acid substitutions have also been identified. The functional effects of some of these mutations were examined by Derst and colleagues (1997), who found that when they were introduced into Kir1.1 either no measureable current (D108H or P110L), or only a very small current (V72E, A198T and V315G) was produced. It therefore appears that the loss of Kir1.1 channel activity is the primary cause of Bartter's syndrome. The mechanism by which the Bartter's mutations result in a loss or reduction of channel activity is still unclear, but it is noteworthy that those mutations that occur in the N and C termini are associated with reduced currents, whereas those that occur within the highly conserved transmembrane regions of the protein result in the total loss of channel activity.

Kir1.1 is alternatively spliced to give several different transcripts that are expressed in different parts of the nephron. To date, however, all mutations associated with Bartter's syndrome have been found within exon 5, which forms the central core of the protein and is common to all Kir1.1 isoforms. Thus, Kir1.1 channels all along the nephron will be affected by the Bartter's mutations. Kir 1.1 is also expressed in several other tissues, including the spleen, lung and eye but specific defects in these organs in Bartter's syndrome have not been reported.

W99C

W99C

V315G

FIGURE 8.11 MUTATIONS IN Kir1.1 CAUSE BARTTER'S SYNDROME

* R338 stop Frameshift

V315G

FIGURE 8.11 MUTATIONS IN Kir1.1 CAUSE BARTTER'S SYNDROME

Putative membrane topology of Kir1.1 with the mutations associated with Bartter's syndrome marked.

Why does loss of Kir1.1 cause Bartter's syndrome?

Kir1.1 is expressed in the apical membrane of distal kidney tubule cells, principally those of the thick ascending loop of Henle, the distal convoluted tubule and the collecting ducts (Lee & Hebert, 1995). It plays a key role in K+ recycling in the loop of Henle, a process which is important for salt uptake. This is illustrated in Fig. 8.12, which shows the ion transport pathways across a cell of the thick ascending loop of Henle. The activity of the Na/K-ATPase in the basolateral membrane generates an electrochemical gradient which facilitates the uptake of Na+ ions from the tubule lumen via the NaK2Cl cotransporter in the apical membrane. The accompanying Cl" ions leave the cell via channels in the basolateral membrane; consequently there is a net transport of NaCl from the tubule lumen into the blood. Most of the K+ ions that enter the cell via the NaK2Cl cotransporter recycle back into the tubule lumen through Kir1.1 channels in the apical membrane. This K+ recycling ensures a constant supply of K+ ions that enables the continuous operation of the NaK2Cl cotransporter, and thus NaCl uptake, despite the fact that K+ ions in the luminal fluid are ~20 times lower than those of Na+ or Cl". In the absence of Kir1.1, as in Bartter's syndrome, K+ recycling is prevented and NaCl uptake is impeded. This leads to a high salt concentration in the urine which induces an osmotic diuresis and accounts for the salt-wasting, polyuria and low plasma volume characteristic of Bartter's syndrome. A similar phenotype is observed with loop diuretics, such as frusemide, which inhibit the NaK2Cl cotransporter.

FIGURE 8.12 SALT TRANSPORT IN THE THICK ASCENDING LOOP OF HENLE

The apical membrane of the TAL contains a NaK2Cl cotransporter which mediates the uptake of one Na+, one K+ and two Cl" ions. Energy for this process is provided by the Na+ gradient generated by the activity of the Na/K-ATPase in the basolateral membrane. Some of the K+ ions translocated by the NaK2Cl cotransporter are recycled across the apical membrane via Kir1.1 channels. This recycling is required for salt uptake and in its absence there will be Na+, Cl" and K+ loss.

Tubi lurrii

Tubi lurrii

FIGURE 8.12 SALT TRANSPORT IN THE THICK ASCENDING LOOP OF HENLE

The apical membrane of the TAL contains a NaK2Cl cotransporter which mediates the uptake of one Na+, one K+ and two Cl" ions. Energy for this process is provided by the Na+ gradient generated by the activity of the Na/K-ATPase in the basolateral membrane. Some of the K+ ions translocated by the NaK2Cl cotransporter are recycled across the apical membrane via Kir1.1 channels. This recycling is required for salt uptake and in its absence there will be Na+, Cl" and K+ loss.

Apical

Basolateral

Apical

Basolateral

Because much of the K+ taken up by the NaK2Cl cotransporter recycles across the apical membrane, whereas all of the transported Cl" leaves via the basolateral membrane, the potential in the interstitial fluid is normally ~6 mV more negative than that in the tubule lumen. This transepithelial potential facilitates the uptake of positive ions, such as Ca2+, via paracellular pathways. If Kirl.l is non-functional, the transepithelial potential is markedly reduced, hindering Ca+ uptake and contributing to the hypercalciuria seen in Bartter's syndrome.

Hypokalaemia is also found in Bartter's syndrome. This occurs because a small amount of the Na+ that passes down the nephron is absorbed in more distal parts of the tubule by the epithelial Na+ channel (ENaC). As explained in Chapter 13 (page 240), increased activity of ENaC is accompanied by enhanced K+ secretion, thereby reducing the plasma K+ concentration. Clearly, K+ channels other than Kirl.la must be involved in this K+ secretion.

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Responses

  • Tomacca
    How does bartter syndrome affect the lungs?
    8 years ago
  • Bailey Miller
    What are the effects of bartter syndrome on the lungs?
    8 years ago

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