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PEDIATRICS Vol. 112 No. 3 September 2003, pp. 628-633

The Neonatal Variant of Bartter Syndrome and Deafness: Preservation of Renal Function

Hanna Shalev, MD^*, Melly Ohali, MD, Leonid Kachko, MD and Daniel Landau, MD^*

^* Department of Pediatrics
Pathology, Soroka University Medical Center
Department of Pediatrics, Barzilai Medical Center, Ben-Gurion University of the Negev, Beer-Sheva, Israel

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Background. A subtype of antenatal Bartter syndrome and sensorineural deafness (BSND) was originally described among families from southern Israel, and its gene (Barttin, OMIM #606412) has recently been identified. A report has suggested that these children develop chronic renal insufficiency during childhood attributable to chronic tubulointerstitial fibrosis and atrophy.

Methods. Data from 13 infants with BSND, who were born during a 20-year period in our institution, were retrospectively analyzed.

Results. All pregnancies were complicated by polyhydramnion and premature birth. All patients have sensorineural deafness, as well as hypokalemic metabolic alkalosis. Persistent hypercalciuria or nephrocalcinosis were absent in most children. All children have been treated with indomethacin (2 mg/kg/d) and potassium supplementation. The current average serum creatinine and calculated creatinine clearance from the older group (n = 8; mean age: 8.8 ± 1.4 years) is 60.8 ± 16.5 µmol/L and 95 ± 20 mL/min/1.73m², respectively. Kidney biopsies from two 7-year-old patients revealed mild focal tubulointerstitial fibrosis and minimal mesangial proliferation but no glomerulosclerosis.

Conclusions. Early renal function deterioration is not a uniform finding among children with BSND mutations.

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Key Words: Bartter’s disease • hearing loss • sensorineural • glomerular filtration rate • nephritis • interstitial

Abbreviations: BS, Bartter syndrome • BSND, Bartter syndrome with sensorineural deafness • GFR, glomerular filtration rate

Inherited hypokalemic tubulopathies have previously been summarized under the term Bartter syndrome (BS). All disease variants follow autosomal recessive inheritance and share characteristic clinical features: renal salt-wasting, hypokalemic metabolic alkalosis, and normotensive hyperreninemic hyperaldosteronism. Pathophysiologic and nephro pharmacologic studies^1,2 performed before any knowledge of the exact afflicted gene, assumed that BS would be attributable to defective chloride reabsorption in the distal nephron. Indeed, all later identified genes encode for proteins differentially located along this part of the nephron. The neonatal variant of BS can be now classified genetically into 4 subtypes.³ In type I BS, the sodium potassium-2 chloride (NKCC2) luminal channel is mutated. In type II BS, the luminal ROMK potassium channel is affected. Type III BS is related to mutations in the basolateral ClC-Kb chloride channel. The recently identified form of BS includes infants with uniformly concomitant sensorineural deafness (BSND), a condition originally described in a Bedouin kindred of southern Israel.⁴ Its recently identified gene (Barttin, OMIM #606412) encodes a ß-subunit for basolateral chloride channels in the distal tubule, including ClC-Kb.⁵ A report suggested that these children also develop chronic renal insufficiency.⁶ We report here our experience with a group of children with the originally described syndrome, who now comprise a larger group of patients, being followed for several years since birth.

	MATERIALS AND METHODS

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Data were collected from medical records of all infants with BSND born in, and followed by, our institution during the past 20 years. All infants belong to a previously described extended family of Bedouin origin.⁷ Laboratory data and growth parameters were summarized from medical records. The 8 older children (>4 years of age) have recently been reassessed, including renal sonography, blood and urine tests, and growth parameters. Percutaneous kidney biopsies were performed in 2 children after informed consent was obtained from the parents.

	RESULTS

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Thirteen liveborn infants with BSND were identified during the past 20 years in our institution. All children were born to 9 couples, but they belong to the same Bedouin tribe and the analysis of their family tree can trace back to a common founding father. All families showed a positive and significant linkage to a locus on chromosome 1p. Recently, a G28A mutation in exon 1 of the Barttin gene, resulting in a glycine to serine replacement, has been characterized in 2 of our affected patients.⁸ Given the high level of consanguinity and the existence of a common founding father for all families, we assume this is the only mutation in our families. There are currently 11 children under our care, aged 6 months to 21 years, all but 1 (patient 8 in the tables) followed since birth. Two infants died during the first 6 months of life as a result of infectious complications, but with normally functioning kidneys. Pregnancies of all affected children were complicated with polyhydramnion and premature birth (Table 1). Prenatal diagnosis based on linkage analysis was performed in 3 pregnancies, using fetal DNA obtained from chorionic villous samples. One pregnancy was terminated based on the prenatal diagnosis of a homozygous affected fetus. In 2 cases parents refused termination of pregnancy and 2 affected infants were born. In 4 pregnancies, including the 1 genetically diagnosed case and 3 polyhydramnion-complicated pregnancies among women with a previously affected infant with BSND, indomethacin therapy to the mother was tried (150 mg/d) following closely the fetal ductus arteriosus, as previously recommended.⁹ This intervention could not prevent premature delivery or significantly decrease the degree of polyhydramnion.

View this table: [in this window] [in a new window]   TABLE 1. Neonatal Manifestations

 
All infants were born prematurely. After birth they suffered from massive polyuria, weight loss, and dehydration. They were managed with intravenous fluids. Hypokalemic metabolic alkalosis, hyperreninemic hyperaldosteronism, and increased excretion of urine prostaglandin E₂ were documented in several infants during the neonatal period, as previously described.⁴ Eight of the 12 infants followed during their neonatal period in our center developed serious bacterial infections (urinary tract infection: [3]; bacterial sepsis: [6]). All infections appeared at an age over 3 days. The average length of hospital stay after birth was 9.3 ± 3.1 week. Two infants died as a result of complications of prematurity (respiratory failure and sepsis). Sensorineural deafness was diagnosed in all cases, 3 of them diagnosed by a flat brain auditory-evoked response during the neonatal period.

Serum creatinine and electrolytes were followed on a regular basis (every 3 months) in all children. Hypokalemia was found in many cases during these visits (as low as 1.8 mmol/L), despite potassium chloride supplementation (average: 1.5–3 meq/kg/d). Serum creatinine was relatively elevated during the first years of life. However, no further deterioration in kidney function could be documented (Fig 1). An average serum creatinine level from the whole group, based on multiple measurements along with their follow-up in our clinic is 52.2 ± 3.5 µmol/L (0.59 ± 0.04 mg/dL). The average most recent serum creatinine level is 60.8 ± 16.5 µmol/L (0.69 ± 0.2 mg/dL), corresponding to a calculated creatinine clearance (using the Schwartz formula¹⁰) of 95 ± 20 mL/min/1.73 m². Proteinuria did not appear in any case during this follow-up period, not even in the oldest patient, now aged 21 years. In this patient, renal sonogram shows a unilateral and single renal cortical cyst. Another child (patient 1 in the tables) showed episodic elevations of serum urea and creatinine. Calculated creatinine clearance was 77 mL/min/1.73 m². A kidney biopsy was performed at age 7 years, showing mild mesangial hypercellularity and mild focal tubulointerstitial fibrosis. Some globally sclerosed glomeruli have been seen, but no glomerulosclerosis was seen in the remaining glomeruli. A second child (patient 2 in the tables) had a renal biopsy performed at the age of 7 years. His calculated creatinine clearance at that time was 97 mL/min/1.73 m². Renal tissue showed only hyperplasia of the juxtaglomerular apparatus, mild mesangial hypercellularity, and mild inner medullary fibrosis (Fig 2).

View larger version (12K): [in this window] [in a new window]   Fig 1. Serum creatinine (mg/dL) in 8 patients with BSND >4 years of age at their last evaluation. Creatinine levels at the first year of life (besides patients 5 and 8, for whom serum creatinine levels are available only from age 1.5 and 15 years, respectively) and the last measured level are depicted for each separate patient. To convert serum creatinine values to µmol/L, multiply by 88.4. The dashed lines represented the normal range of serum creatinine adjusted for age.

 

View larger version (90K): [in this window] [in a new window]   Fig 2. Light microscope section of kidney of patient 2. Calculated creatinine clearance at time of biopsy: 97 mL/min/1.73 m2. A, (Semi-thin section, stained with a methylene blue-azure II-basic fuchscin solution; x400 magnification): glomerulus shows a mild mesangial cell proliferation. Capillary loops are intact. The juxtaglomerular apparatus shows hyperplasia of both granular cells and macula densa. The proximal tubuli are normal. B, (AFOG stain, x400 magnification): corticomedullary junction shows fibrosis and tubular atrophy (mostly at the inner medullary area).

 
All children under our care required numerous hospitalizations owing to electrolyte imbalance associated with fever, vomiting, and a tendency toward dehydration during the first 3 years of life. Eight children >4 years of age are currently being followed in our clinic, all but one since birth. The oldest patient is now 21 years old. Contrary to what was suspected immediately after birth, there is no persistent hypercalciuria in most children and only 1 child has sonographic evidence for nephrocalcinosis (Table 2). Indomethacin therapy and potassium supplementation were given to all children, starting after the age of 3 months. None of our children has been treated with indomethacin at a dose higher than 2 to 3 mg/kg/d. This intervention improved the degree of polyuria. However, growth remained stunted: all patients except one have short stature (mean height standard deviation score: –3.3 ± 1.2) (Fig 3).

View this table: [in this window] [in a new window]   TABLE 2. Current Laboratory Values Associated With Hypokalemic Metabolic Alkalosis

 

View larger version (12K): [in this window] [in a new window]   Fig 3. Height (A) and weight (B) standard deviation scores for the 8 children with BSND >4 years of age at their last evaluation.

 

	DISCUSSION

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A very similar clinical antenatal BS phenotype with a unique association with sensorineural deafness could be linked to mutations in a novel protein, designated Barttin.⁸ Subsequently, Barttin was shown to activate chloride currents up to 20-fold in the oocyte expression system.⁵ ClC-K channels are expressed along the distal nephron from the thin ascending limb to the collecting duct and are essential for chloride exit across the basolateral membrane. Additionally, ClC-K channels contribute to endolymph secretion in the inner ear. Loss of function of their common ß-subunit barttin, therefore, is invariably associated with congenital sensorineural deafness. Clinically, these infants show the same clinical manifestation as antenatal BS in terms of prenatal polyhydramnion, prematurity, and postnatal polyuria. The initial clinical presentation and immediate neonatal course among this group of children is similar to the one originally described by us and later described by Jeck et al.⁶ The rate of neonatal infections in our group (8 of 12, or 67%) is much higher than expected for their degree of prematurity. A recent survey has found a 30% rate of late-onset sepsis among very low birth weight infants in Israel.¹¹ The exact reason for this infection tendency is not known. However, it is interesting that despite these infections during the neonatal period, no major long-term deterioration in kidney function is seen in our group of patients.

The report by Jeck et al⁶ describes a group of children with a neonatal variant of BS and sensorineural deafness. All children in this series come from families of Mideastern origin, and show mutations at the Barttin gene.⁸ Most clinical and genetic characteristics in Jeck’s report are consistent with our original report on the clinical characteristics of this new syndrome,⁴ based on the investigation of an extended Bedouin family from southern Israel. The major difference with Jeck’s report is that most of the children in their cohort exhibit a gradual and irreversible deterioration in glomerular filtration rate (GFR). Pathologic analysis was described in only 1 of the 8 patients who showed an extensive process of predominant tubulointerstitial fibrosis, tubular atrophy, and global glomerulosclerosis. The authors speculate on the possible mechanisms of such renal manifestation, mainly whether it is an inherent manifestation of the basic genetic renal disease (up to the stage of calling this variant of BS hypokalemic salt tubulopathy with chronic renal failure and sensorineural deafness) or an acquired phenomenon. There are a few isolated reports of chronic renal insufficiency associated with hypokalemic tubulopathy,^12,13 all of them showing evidence for chronic renal insufficiency beyond adult age. Many of these reports were done before the new genetic developments, and so could obviously not relate to the specific gene mutated. All these previous reports also show a pathologic picture of chronic tubulointerstitial nephropathy with tubular atrophy. In the cohort described in the current report, average serum creatinine is 52.2 ± 3.5 µmol/L (0.59 ± 0.04 mg/dL). The fact that most of the children in our cohort are growth-retarded could have overestimated the GFR calculation by serum creatinine. However, no patient showed evidence of glomerulopathy (such as proteinuria, hematuria, or hypertension). Furthermore, based on repeated measurements of serum creatinine (Fig 1), no patient showed any evidence of deterioration in his kidney function during childhood. Kidney biopsy showed mild mesangial hypercellularity and tubulointestitial fibrosis. These findings are more similar to what has been described by Reinalter et al,¹⁴ in a group of patients with antenatal BS attributable to defects in different genes (ROMK, NKCC2, ClCKb and, at that time, some left undefined), who have been treated with indomethacin for several years. None of the patients in that report who had mutations in the ROMK gene showed evidence for renal damage, whereas in the remaining patients mild degrees of focal tubular atrophy, interstitial fibrosis, and mesangial hypercellularity were described. However, no patient in that report (as in ours) developed any sign of irreversible deterioration in kidney function. The potential mechanisms that could lead to kidney damage in BS may include: possible damage at the early neonatal life (when many of these infants experience prematurity and a tendency for dehydration), the possibility of hypokalemic nephropathy,¹⁵ and the potential nephrotoxicity of long-term use of nonsteroidal antiinflammatory agents.¹⁶ Contrary to Jeck’s report, none of our children has been treated with indomethacin at a dose higher than 2 to 3 mg/kg/d. In comparison, children in Jeck’s report received indomethacin in doses as high as 9 mg/kg/d. Response to indomethacin was inconclusive in our group, based both on the poor response to prenatal maternal administration of this drug (to try to halt polyhydramnion’s progression) and the weak response to indomethacin regarding improvement in growth rate, contrary to other forms of BS,¹⁷ and similar to the cohort described by Jeck et al. Increased urinary prostaglandin secretion is a known manifestation of BS, mainly of its neonatal variants. Therefore, therapy with prostaglandin synthetase inhibitors has been used successfully in many children with BS.¹⁸ However, indomethacin has potential nephrotoxic effects when used for extended periods of time¹⁹ or in the developing kidney,²⁰ which should be taken into account when a decreased GFR is seen in such cases. Recently we have shown that children with BS attributable to ROMK mutations keep their serum potassium levels at the normal range during indomethacin therapy.²¹ The observation by Reinalter et al that ROMK affected patients had almost no evidence for renal damage whereas all other BS groups had the above mentioned tubulointerstitial changes (and yet both groups received indomethacin to the same extent) supports the hypothesis that hypokalemic induced renal damage may play a more important role in this complication.

Recently, the gene for this new syndrome was identified, and includes the description of mutations from both Jeck’s cohort and our patients.⁸

In a recent publication,²² the specific Gly-10-Ser mutation is associated with a very mild disturbance in current-voltage relationship in comparison with the wild-type Barttin gene function. For example, the mean gestational age at birth of our cohort was significantly higher than that described by Jeck et al (32 ± 3 vs 30 ± 2 weeks; P < .05), hinting for a milder phenotype. Therefore, the possibility of differing susceptibility for renal damage in different types of mutations in this newly identified gene should also be taken into consideration. We conclude that chronic renal failure should not be an essential association in this unique form of hypokalemic tubulopathy and deafness.

	FOOTNOTES

 
Received for publication Aug 30, 2002; Accepted Jan 21, 2003.

Address correspondence to Daniel Landau, MD, Pediatric Nephrology Unit, Department of Pediatrics, Soroka University Medical Center, Box 151, Beer-Sheva 84101, Israel. E-mail: ldaniel{at}bgumail.bgu.ac.il

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PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Web of Science (15) Citing Articles via Google Scholar Google Scholar Articles by Shalev, H. Articles by Landau, D. Search for Related Content PubMed PubMed Citation Articles by Shalev, H. Articles by Landau, D. Related Collections Genitourinary Tract Social Bookmarking                         What's this?