Chronic renal failure in a boy with classic Bartter’s syndrome due to a novel mutation in CLCNKB coding for the chloride channel

Abstract

We describe a 17-year-old Chinese boy who presented with progressive muscle weakness and renal failure. He was diagnosed as BS of unknown type at the age of 9 months and treated with indomethacin (2 mg/kg/day) and potassium chloride (KCl) supplementation (1.5 mEq/kg/day) for hypokalemia (2.5 mmol/l). At the age of 12 years, serum K+ was 3.0 mmol/l and creatinine reached 2.0 mg/dl. On admission, his blood pressure was normal but volume status was depleted. Urinalysis was essentially normal. Biochemical studies showed hypokalemia (K+ 2.4 mmol/l) with a high transtubular K+ gradient (TTKG) 9.6, metabolic alkalosis (HCO3- 28.4 mmol/l), normomagnesemia (2.0 mg/dl), severe renal failure (BUN 94 mg/dl, Cr 6.3 mg/dl), and hypocalciuria (urine calcium/creatinine ratio 0.02 mg/mg). Abdominal sonography revealed bilateral small size kidneys without nephrocalcinosis or renal stones. After the withdrawal of indomethacin with regular KCl and adequate fluid supplementation for 1 year, serum creatinine and K+ levels have been maintained at 4.0 mg/dl and 3.3 mmol/l, respectively. Direct sequencing of NKCC2, ROMK, ClC-Kb, and NCCT in this patient disclosed a novel homozygous missense mutation (GGG to GAG, G470E) in CLCNKB. This G470E mutation was not identified in 100 healthy Chinese subjects. Long-term therapy of non-steroidal anti-inflammatory drugs (NSAIDs), prolonged hypokalemia, chronic volume depletion, and underlying genetic variety may contribute to the deterioration of his renal function. The cautious use of NSAIDs, aggressive correction of hypokalemia, and avoidance of severe volume depletion may prevent the irreversible renal damage in patients with BS due to a Cl- channel defect.

A CLC-ec1 mutant reveals global conformational change and suggests a unifying mechanism for the CLC Cl–/H+ transport cycle

“…While the mechanistic details linking Helix O-Q movements between outward-and inwardfacing states are currently unknown, it is of interest to note that many disease-causing mutations occur in this segment, in both CLC channels (Saviane et al, 1999;Pusch, 2002;Bignon et al, 2020) and transporters (Lourdel et al, 2012;Veeramah et al, 2013). In Helix O, for example, mutation of a highly conserved glycine residue occurring mid-helix can cause Dent's disease (CLC-5, (Smith et al, 2009)) or Bartter syndrome (CLC -Kb, (Lin et al, 2009)). In WT CLC-ec1, the helix is kinked at this glycine; in QQQ, the helix is straight ( Figure 5figure supplement 3E,F).…”

Bartter syndrome type III with glomerular dysplasia and chronic kidney disease: A case report

“…ClC-Kb is a member of the ClC chloride channel family, is expressed in the coarse ascending branch, distal convoluted tubule and cortical collecting tubule of the Henle loop, and regulates the reabsorption of Cl in renal tubules ( 5 ). Inactivated ClC will reduce the reabsorption of chloride and sodium in renal tubules, and the loss of NaCl and water will activate the renin-angiotensin-aldosterone system (RAAS), which will lead to the loss of potassium and renal fibrosis ( 8 ).…”

“…At the age of 12, the creatinine was 2.0 mg/dl, and at the age of 17, the creatinine reached 6.3 mg/dl. After stopping indomethacin, his serum creatinine was decreased ( 8 ). Therefore, the author speculated that the long-term use of NSAIDs caused renal damage.…”

“…Therefore, the author speculated that the long-term use of NSAIDs caused renal damage. Two scholars have concluded that some studies have shown that the secretion of urinary prostaglandin E2 (PGE2) in BS patients caused by chloride channel defects is reduced, which will not benefit from the long-term use of NSAIDs ( 8 , 15 ).…”

Ion Channels in Renal Disease

“…Moreover, when the same mutation was made in ClC-Ka channels, no alteration of ClC-Ka currents was observed, suggesting that in spite of the 90% homology, the two channels also have specific residues that gate and activate the channel 44 . A severe clinical manifestation of Bartter syndrome in a young boy was associated with a missense mutation in ClC-Kb of G470E 47 . Although this mutation has not been tested in vitro, it is predicted that the current will be decreased, as the mutation is located in a transmembrane region.…”