Clinical and diagnostic features of Bartter and Gitelman syndromes

Clinical and diagnostic features of Bartter and Gitelman syndromes Background: Bartter and Gitelman syndromes are autosomal recessive disorders of renal tubular salt handling. Due to their rarity, limited long-term data are available to inform prognosis and management. Methods: Long-term longitudinal data were analysed for 45 children with pathogenic variants in SLC12A1 (n ¼ 8), KCNJ1 (n ¼ 8), CLCNKB (n ¼ 17), BSND (n ¼ 2) and SLC12A3 (n ¼ 10) seen at a single centre between 1984 and 2014. Median follow-up was 8.9 [interquartile range (IQR) 0.7–18.1] years. Results: Polyhydramnios and prematurity were seen in children with SLC12A1 and KCNJ1 mutations. Patients with CLCNKB mutations had the lowest serum potassium and serum magnesium and the highest serum bicarbonate levels. Fractional excretion of chloride was >0.5% in all patients prior to supplementation. Nephrocalcinosis at presentation was present in the majority of patients with SLC12A1 and KCNJ1 mutations, while it was only present in one patient with CLCNKB and not in SLC12A3 or BSND mutations. Growth was impaired, but within the normal range (median height standard deviation score 1.2 at the last follow-up). Impaired estimated glomerular filtration rate (eGFR <90 mL/min/1.73 m ) at the last follow-up 2 2 was seen predominantly with SLC12A1 [71 mL/min/1.73 m (IQR 46–74)] and KCNJ1 [62 mL/min/1.73 m (IQR 48–72)] mutations. Pathological albuminuria was detected in 31/45 children. Conclusions: Patients with Bartter and Gitelman syndromes had a satisfactory prognosis during childhood. However, decreased eGFR and pathologic proteinuria was evident in a large number of these patients, highlighting the need to monitor glomerular as well as tubular function. Electrolyte abnormalities were most severe in CLCNKB mutations both at presentation and during follow-up. Fractional excretion of chloride prior to supplementation is a useful screening investigation in children with hypokalaemic alkalosis to establish renal salt wasting. Key words: Bartter syndrome, chronic kidney disease, Gitelman syndrome, hypokalaemic metabolic alkalosis, renal tubular disease Received: August 8, 2017. Editorial decision: September 12, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/302/4616522 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Clinical features of Bartter and Gitelman | 303 gene—SLC12A1, KCNJ1, CNCKB, BSND and SLC12A3—to investigate Introduction genotype/phenotype correlation. The Mann–Whitney U test was Bartter syndrome (BS) and Gitelman syndrome (GS) are rare used to investigate differences between individual genotypes and autosomal recessive tubulopathies with a prevalence of 1in Kruskal–Wallis was used to evaluate differences between multi- 100 000 and 25 in 100 000, respectively [1]. BS occurs as a result ple groups; statistical significance was defined as P < 0.05. of mutations in genes coding for proteins mainly responsible for Median values are given with IQRs throughout. Due to the salt and water reabsorption in the thick ascending loop of Henle small size, the BSND group was excluded from statistical analysis. (TAL), while dysfunction of the sodium chloride co-transporter in the distal convoluted tubule (DCT) results in GS. BS can be further Molecular analysis subdivided based on the underlying genetics (Table 1)[2–6]. Two broad phenotypes exist in BS: antenatal BS, due to Genotyping was performed by the North East Thames Regional Genetics Service, located at GOSH, using a kit to assess a panel mutations in SLC12A1, KCNJ1, BSND (with sensorineural hearing of 37 tubular disease genes, as described previously [9]. loss) and in some cases of CLCNKB; and classic BS, typically associated with mutations in CLCNKB. Recently a transient antenatal BS was described in boys with mutations in MAGED2 Results [7]. Biochemical hallmarks of BS and GS include hyperaldoster- Molecular results onism with hypokalaemic, hypochloraemic metabolic alkalosis. Some specific biochemical abnormalities can give clues as to Mutations in disease-causing genes are summarized in Table 3. the underlying genotype, summarized in Table 1. For example, Homozygous variants were identified in 30/45 patients and patients with KCNJ1 mutations can present with transient compound heterozygous variants in the remaining 15/45 hyperkalaemia followed by the more typical hypokalaemia; patients. Whole gene deletion was responsible for 50% of muta- increased urinary calcium excretion and nephrocalcinosis are tions in CLCNKB. present in SLC12A1 and KCNJ1 mutations, whereas patients with SLC12A3 mutations have hypocalciuria; and patients with CLCNKB Initial presentation and SLC12A3 mutations typically develop hypomagnesaemia. Biochemical and clinical features at presentation are summar- As with most rare diseases, there is little data available ized in Table 2 and Figure 1. about the long-term disease course to inform management and prognosis. Prenatal and perinatal history In this study we describe the presenting features and long- Polyhydramnios was documented in 8/8 of SLC12A1, 7/8 KCNJ1, term outcomes of 45 patients with BS and GS. 7/17 CLCNKB, 1/2 BSND and 0/10 SLC12A3 cases. Gestational age (GA) was significantly lower in SLC12A1, KCNJ1 and BSND mutations compared with CLCNKB and SLC12A3 (P < 0.001). Materials and methods Demographic data Diagnosis and presentation The diagnosis of BS or GS was made before the age of 1 year in Biochemical and clinical data were analysed for 45 children pre- 27/35 BS patients (8/8 SLC12A1, 8/8 KCNJ1, 9/17 CLCNKB and 2/2 senting to Great Ormond Street Hospital (GOSH) between 1984 BSND) compared with 1/10 GS patients. Children diagnosed and 2014. Results were collected at presentation and throughout before 1 year of age presented with a history of polyhydramnios, follow-up, summarized in Table 2. Estimated glomerular filtra- polyuria and hypochloraemic metabolic alkalosis. The remain- tion rate (eGFR) was calculated using the modified Schwartz ing patients were diagnosed during childhood with failure to formula, with a k-value of 33 [8]. The median follow-up was 8.9 thrive (four CLCNKB), persistent muscle cramping (one CLCNKB, [interquartile range (IQR) 0.5–18.1] years. one SLC12A3), fainting spells (one SLC12A3) and incidentally noted biochemical derangement during intercurrent illness Statistical analysis (one CLCNKB, seven SLC12A3). Data analysis was performed using SPSS (IBM, Armonk, NY, USA). Median plasma potassium concentration at presentation Patients were analysed according to the underlying disease was lowest in CLCNKB mutations [2.6 mmol/L (IQR 2.1–2.9)], Table 1. Clinical and genetic classification of BS and GS Genetic Clinical phenotype OMIM subtype Gene/locus Protein Features Antenatal BS 601678 Type I SLC12A1/15q21.1 NKCC2 Polyhydramnios, prematurity, polyuria, nephrocalci- nosis, failure to thrive Antenatal BS 241200 Type II KCNJ1/11q24.3 ROMK1 Polyhydramnios, prematurity, polyuria, nephrocalci- nosis, failure to thrive, transient hyperkalaemia Classic BS 607364 Type III CLCNKB/1p36.13 CLC-Kb Failure to thrive, hypomagnesaemia Antenatal BS with 602522 Type IV BSND/1p32.3 Barttin Polyhydramnios, prematurity, polyuria, nephrocalci- sensorineural deafness nosis, failure to thrive, sensorineural deafness GS 263800 GS SLC12A3/16q13 NCCT Hypocalciuria, hypomagnesaemia Transient antenatal BS 300971 Type V MAGED2 MAGED2 Severe polyhydramnios, prematurity, hypercalciuria, spontaneous resolution OMIM: Online Mendelian Inheritance in Man. Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/302/4616522 by Ed 'DeepDyve' Gillespie user on 20 June 2018 304 | P.R. Walsh et al. Table 2. Clinical and biochemical characteristics at presentation BS GS Parameter SLC12A1 (n ¼ 8) KCNJ1 (n ¼ 8) CLCNKB (n ¼ 17) BSND (n ¼ 2) SLC12A3 (n ¼ 10) P-value GA, weeks 32 (27–33) 30 (28–33) 40 (38–40) 32 40 (40–40) <0.001 Polyhydramnios, 8/0 7/1 7/10 0/2 0/10 <0.001 present/absent Sex, M/F 4/4 4/4 12/5 0/2 7/4 N.S. Height, Z-score 1.28 (4.9 to 0.62) 2.2 (3.0 to 0.4) 2.1 (4.9 to 0.11) 0.0 (1.1 to 0.5) N.S. 2 1 6 8 Weight, Z-score 3.49 (4.22 to 1.00) 2.31 (3.49 to 0.22) 1.82 (3.49 to 0.63) 0.52 (N/A) N.S. Sodium, [133–146 mmol/L] 146 (143–148) 142 (135–148) 135 (130–140) (116–130) 139 (135–140) 0.001 Potassium [3.5–5.5 mmol/L] 3.4 (2.9–3.9) 3.8 (3.6–6.0) 2.6 (2.1–2.9) (2.1–3.0) 2.8 (2.4–3.0) <0.001 1 1 1 Chloride [96–106 mmol/L] 103 (98–110) 103 (101–109) 95 (81–98) (59–79) 98 (96–101) 0.001 1 1 Bicarbonate [18–28 mmol/L] 25 (25–29) 25 (23–28) 29 (26–33) (24–81) 30 (28–31) 0.01 1 1 2 1 Magnesium [0.6–0.9 mmol/L] 0.97 (0.91–1.17) 0.94 (0.73–1.07) 0.76 (0.59–0.90) (0.55–0.74) 0.67 (0.58–0.83) 0.005 1 2 8 5 FENa, % 0.36 (0.17–1.23) 0.82 (0.37–2.51) 0.87 (0.39–1.25) Not obtained 0.55 (0.30–0.95) N.S 3 6 11 9 FECl, % 1.6 (0.8–5.4) 1.25 (N/A) 3.9 (1.4–6.1) Not obtained 2.1 (N/A) N.S. Age-adjusted calcium:creatinine 1.17 (0.88–2.00) 1.37 (0.82–2.04) 0.61 (0.14–1.34) (1.50–1.64) 0.09 (0.05–0.21) <0.001 ratio, normalized to upper limit of normal Nephrocalcinosis, 8/0 8/0 2/15 0/2 0/10 <0.001 present/absent Median values given with interquartile ranges in parentheses. Reference range given in square brackets. Superscript numbers indicate the number of patients with missing data. P-values for Kruskal–Wallis analysis comparing SLC12A1, KCNJ1, CLCNKB and SLC12A3. M: male; F: female; N.S.: Not significant. while two children with KCNJ1 were noted to have transient 14 years, when his height was 126 cm (SDS4.37) and was stopped hyperkalaemia at presentation (Figure 1). at the age of 17 years, when his height was 154 cm (SDS3.02). Fractional excretions of chloride (FECl) and sodium (FENa) at Patient 23 started GH at the age of 6 years when his height was presentation were calculated in children where the data were 102 cm (SDS3.78). This coincided with indomethacin being dis- available (FECl in 15 children and FENa in 28 patients) and are continued due to a gastrointestinal bleed. His height SDS remained summarized in Table 2. FENa ranged from 0.1 to 6.4%, while essentially unchanged for the following 2 years (SDS3.88) despite FECl >0.5% was seen in all patients with available data, prior to GH treatment. At the age of 8 years, indomethacin was restarted commencing supplementation. In patients where both values (and GH continued) and his height SDS improved to 2.75 over the were available (n ¼ 15), the median FENa was 0.7% (IQR 0.3–1.2) following year. At the last follow-up (still on GH and indometha- cin) at the age of 12 years, his height was 133 cm (SDS2.26). and FECl was 1.62% (IQR 1.2–5.5). Normal urine calcium:creatinine (UCC) ratio varies with age, therefore the results were normalized to an age-adjusted upper Persistent hypokalaemia Persistent hypokalaemia, defined as potassium <3.5 mmol/L on limit of normal. This was elevated in 5/8 SLC12A1, 5/8 KCNJ1,7/ 17 CLCNKB and 2/2 BSND patients. Ultrasound scan at presenta- at least two consecutive blood tests, was seen in 41 children. Mild hypokalaemia (2.5–3.5 mmol/L) was present in 28 children tion was performed in all children to assess for nephrocalcino- (BS 22, GS 6), moderate hypokalaemia (2.0–2.5 mmol/L) was seen sis; this was seen in 8/8 SLC12A1, 8/8 KCNJ1, 2/17 CLCNKB, 0/2 BSND and 0/10 SLC12A3 patients. in 9 children (BS 6, GS 3) and severe hypokalaemia (<2.0 mmol/ L) was noted in 4 children (3 CLCNKB and 1 BSND). At the last follow-up, plasma potassium was decreased Course of clinical and biochemical data (<3.5 mmol/L) in 36 patients (BS 26/35 and GS 10/10). Plasma Growth bicarbonate was elevated (>28 mmol/L) in 20 patients (BS 18/35 The median height [standard deviation score (SDS)] at presenta- and GS 2/10) and plasma magnesium was decreased tion was 1.6 (IQR 3.88 to 0.04), this was not statistically dif- (<0.6 mmol/L) in 7 patients (BS 3/35 and GS 4/10) (Figure 1). ferent from the follow-up [1.2 (IQR 3to 1.7)]. Subgroup analysis of the genotypes revealed no statistical difference Complications between height at presentation and follow-up (SDS): SLC12A1, Two children with CLCNKB mutations were admitted for optimi- P ¼ 0.35; KCNJ1,P ¼ 0.6; CLCNKB,P ¼ 0.39; SLC12A3,P ¼ 0.59. zation of potassium supplementation (serum potassium 1.3 mmol/L and 1 mmol/L), one due to symptoms of hypokalae- Growth hormone treatment mic paralysis (Patient 13), which resolved following increased Growth hormone (GH) deficiency has previously been reported in potassium supplementation, and the second due to concerns children with BS [11]. In this cohort, GH was used in three patients regarding compliance (Patient 15). (1, 10 and 23) due to documented GH deficiency based on formal The median serum magnesium level at the last follow-up glucagon stimulation tests. In Patient 1, it was started at the age of was lowest in GS patients [0.62 mmol/L (IQR 0.55–0.71)]. 8 years, when her height was 110 cm (SDS3.29). She was also Hypomagnesaemia was associated with both CLCNKB and treated with gonadotropin-releasing hormone analogues to delay SLC12A3 mutations; while there was a trend to lower magne- puberty. Treatment was stopped at the age of 16 years, when her sium with increasing age, this was not statistically significant. height was 153 cm (SDS1.42). Patient 10 started GH at the age of No arrhythmias were noted. Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/302/4616522 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Clinical features of Bartter and Gitelman | 305 Table 3. Causative mutations identified Gene Patient Sex Nucleotide Protein Status SLC12A1 1 Female c.1316G>A p.(Arg439Gln) Homozygous 2 Male c.1215G>A p.?(Loss of splice site) Homozygous 3 Female c.811G>C/c.1316G>A p.(Ala271Pro/p.Arg439Gln Compound heterozygous 4.1 Female c.450_451del/c.967G>A p.(Asp150Glufs*4)/p.(Glu323Lys) Compound heterozygous 4.2 Male c.450_451del/c.967G>A p.(Asp150Glufs*4)/p.(Glu323Lys) Compound heterozygous 5 Male c. 1327G>A/c.2805dup p.(G443R)/p.(Trp936fs) Compound heterozygous 6.1 Male c.3165-?_*1þ?del p.? (exon 26 deletion) Homozygous 6.2 Female c.3165-?_*1þ?del p.? (exon 26 deletion) Homozygous KCNJ1 7 Male c.1-?_*1þ?del p.? (exon 1 deletion) Homozygous 8 Male c.277T>G p.(Phe93Val) Homozygous 9.1 Female c.716delG p.(Gly239Glufs*14) Homozygous 9.2 Female c.716delG p.(Gly239Glufs*14) Homozygous 10 Female c.658C>T p.(Leu220Phe) Homozygous 11.1 Female c.657C>G p.(Ser219Arg) Homozygous 11.2 Male c.657C>G p.(Ser219Arg) Homozygous 12 Male c.657C>G p.(Ser219Arg) Homozygous CLCNKB 13 Male c.(?-1)_(*1_?)del p.? (gene deletion) Homozygous 14.1 Female c.875G>T p.(Cys292Phe) Homozygous 14.2 Male c.875G>T p.(Cys292Phe) Homozygous 15 Female c.(?-1)_(*1_?)del p.? (gene deletion) Homozygous 16 Female c.(?-1)_(*1_?)del p.? (gene deletion) Homozygous 17 Male c.1693del/c.968þ 1G>A p.(Glu565Argfs*7)/p.(?) Compound heterozygous 18 Male c.(?-1)_(*1_?)del p.? (gene deletion) Homozygous 19 Male c.(?-1)_(*1_?)del p.? (gene deletion) Homozygous 20 Female c.1987A>T p.(Arg663*) Homozygous 21 Male c.1395delG p.(Tyr465*) Homozygous 22 Male c.(?-1)_(*1_?)del p.? (gene deletion) Homozygous 23 Female c.(?-1)_(*1_?)del p.? (gene deletion) Homozygous 24 Male c.(?-1)_(*1_?)del p.? (gene deletion) Homozygous 25 Male c.182C>A/c.373G>A p.(Ala61Asp)/p.(Glu125Lys) Compound heterozygous 26 Male c.1897delC p.(Leu633*) Homozygous 27 Female c.1929þ 1G>A/c.887G>A p.?/p.(Gly296Asp) Compound heterozygous 28 Male c.182C>A/c.373G>A p.(Ala61Asp)/p.(Glu1125Lys) Compound heterozygous BSND 29 Female c.452delC p.(Pro151Leufs*27) Homozygous 30 Female c.125G>A/c.139G>A p.(Ser42Asn)/p.(Gly47Arg) Compound heterozygous SLC12A3 31 Male c.2221G>A/c.3002C>A p.(Gly741Arg)/p.(Ala1001Asp) Compound heterozygous 32 Male c.1202C>A/c.2965 p.(Ala401Asp)/p.(Gly989Arg) Compound heterozygous 33 Male c.2221G>A/c.3052C>T p.(Gly741Arg)/p.(Arg1018*) Compound heterozygous 34 Female c.2878_2879insAGGGGTGCACCCTG p.(Val960Glufs*12) Homozygous 35.1 Female c.626G>A/c.1577A>G p.(Arg209Gln)/p.(Asn526Ser) Homozygous 35.2 Female c.626G>A/c.1577A>G p.(Arg209Gln)/p.(Asn526Ser) Compound heterozygous 36 Male c.647G>A/c.2221G>A p.(Gly216Glu)/p.(Gly741Arg) Compound heterozygous 37 Male c.424G>T/c.2952-?_*1þ?del p.(Val142Leu)/p.?(Exon 26 deletion) Compound heterozygous 38 Female c.2221G>A p.(Gly741Arg) Compound heterozygous 39 Male c.506-1G>A/c.1180þ 1G>T p.?/p.? (splice site) homozygous Compound heterozygous Listed are the mutations identified in the 45 patients. Listing of a single variant indicates homozygosity. Reference sequences used for annotation were as follows: BSND NM_057176.2, CLCNKB NM_000085.3, KCNJ1 NM_000220.2, SLC12A1 NM_000338.2, SLC12A3 NM_000339.2. two developed abdominal pain (Patients 17 and 24) and one Medications at last follow-up developed excessive bruising days after commencing treatment Sodium supplementation was prescribed for 14/45 patients (BS 12/ (Patient 23). 35 and GS 2/10), potassium supplementation for 38/45 patients (BS Indomethacin was temporarily discontinued in two other 30/35, GS 8/10) and magnesium supplementation for 12/45 patients children. One child (Patient 8) developed necrotizing enteroco- (BS 7/35 and GS 5/10). Prostaglandin inhibitors (ibuprofen or indo- litis at 17 days of age; indomethacin was eventually recom- methacin) were prescribed in 20/45 patients (BS 20/35 and GS 0/10). menced at 3 months due to ongoing severe polyuria. The second child developed gastrointestinal bleeding during the first year of life (Patient 21); indomethacin was gradually rein- Side effects of medication troduced. Indomethacin was substituted with ibuprofen in Indomethacin four patients: two because of parental preference (Patients 9.1 Indomethacin was used in 30/35 BS and 2/10 GS patients. and 9.2), one due to abdominal pain that settled after switch- Indomethacin was permanently discontinued in three children: ing (Patient 4.1) and one who developed peptic ulcer disease Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/302/4616522 by Ed 'DeepDyve' Gillespie user on 20 June 2018 306 | P.R. Walsh et al. Fig. 1. Biochemical data at presentation and last follow-up. Dotted lines indicate upper and lower limits of reference range. (A) Potassium at presentation and (B) at last follow-up. (C) Bicarbonate at presentation and (D) at last follow-up. (E) Magnesium at presentation and (F) at last follow-up. (G) Urine calcium:creatinine ratio at presentation. (H) eGFR at last follow-up. *P< 0.05. Bicarbonate as measured in the laboratory (initial bicarbonate calculated on blood gas analysis was 80 mmol/L, described in detail by Plumb et al. [10]). that settled with antacid treatment and switching to ibuprofen biochemical improvement. One patient received amiloride (Patient 20). because of dramatic alkalosis (Patient 29) [10]. Potassium-sparing diuretics Spironolactone was used in 6/35 BS patients. In one (Patient 24), Chronic kidney disease At the last follow-up, 27/45 children (BS 22/35 and GS 5/10) had it was discontinued at age 15 years due to gynaecomastia and in a second (Patient 15) it was discontinued due to lack of an eGFR<90 mL/min/1.73 m . Pathological albuminuria (urine Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/302/4616522 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Clinical features of Bartter and Gitelman | 307 albumin:creatinine ratio >2.5 mg/mmol in boys and >3.5 mg/ prostaglandins. Reports of GH deficiency in patients with GS mmol in girls) was detected in 31/45 children (BS 28/35 and GS would argue against an effect of prostaglandins [16, 17]. Yet, 3/10). There was no statistically significant association of devel- these reported patients had no genetic confirmation of the diag- opment of CKD with either hypokalaemia, nephrocalcinosis or nosis, thus it is unclear if they truly had GS or rather BS Type 3. urinary concentrating ability. More systematic investigations are needed to address this One child (patient 24) with BS Type 3 developed nephrotic- question. range proteinuria (3.3 g/day) and underwent a kidney biopsy at the age of 14 years, when his eGFR was 60 mL/min/1.73 m ,which Treatment demonstrated focal segmental glomerular sclerosis. An angioten- Supplementation with sodium and/or potassium was the most sin-converting enzyme inhibitor was commenced at low dose frequently prescribed intervention; this is in keeping with previ- (enalapril 0.06 mg/kg/day), but was temporarily stopped due to an ously described cohorts [18–20]. Yet, the small differences in increase in creatinine by almost 50% (from 123 to 183 mmol/L). potassium levels between presentation and follow-up (see When subsequently restarted at half the dose, proteinuria decreased to 1.8 g/day with stable plasma creatinine (135 mmol/L). Figure 1) demonstrate the difficulties in improving this parame- One patient with CKD Stage 3 (Patient 33) had been diag- ter by supplementation, as an increased blood level results in nosed with vesico-ureteric reflux at 3 years of age after suffering an increased filtered load and thus, typically, increased urinary from recurrent urinary tract infections. losses. In our cohort, treatment with NSAIDs at the last follow-up Urinary concentrating ability was used in more than half of children with BS. Treatment with Maximal urine osmolalities (Uosm) obtained at clinic visits were NSAIDs was generally well tolerated, although side effects that compared according to genotype for those with available data. prompted temporary or permanent withdrawal were seen in The average maximal Uosm in patients with SLC12A1 and seven patients. Such withdrawal occurred with indomethacin, KCNJ1 mutations was 285 6 8 (SEM) mOsm/kg (n ¼ 11), com- yet this was also the most frequently used NSAID. Thus, pared with 547 6 17 for CLCNKB (n ¼ 12) and 634 6 65 for whether complications are more commonly associated with SLC12A3. indomethacin compared with other NSAIDs cannot be answered In all, six patients (all with antenatal BS) had formal desmo- from our study. Treatment with so-called cyclooxygenase-2 pressin (DDAVP) tests because of concerns over the urinary con- inhibitors has been suggested for patients with BS, and we centrating ability. Of these, four patients (1, 2, 8 and 9.1) showed increasingly prescribe it in our current patients, but none of the evidence of secondary nephrogenic diabetes insipidus (sNDI) patients in this historic cohort received this class of drug [21]. with Uosm below plasma osmolality (Posm) after DDAVP. The Treatment and tolerance of hypokalaemia is a controversial two others (Patients 9.2 and 12) showed evidence of topic in hypokalaemic alkalosis, as hypokalaemia can be associ- isosthenuria, with Uosm only mildly increasing to 345 and ated with complications, yet excessive supplementation can 367 mOsm/kg, respectively, after stimulation with DDAVP. also be harmful [22]. Interestingly, despite persistent hypokalae- mia (serum potassium <3.0 mmol/L) in 35/45 patients during Extrarenal complications follow-up, only 1 patient experienced overt symptoms, in the Intellectual impairment was not systematically evaluated in all form of hypokalaemic paralysis (serum potassium 1.3 mmol/L); patients but was documented in three patients (2, 10, 11.1) and no arrhythmias were detected with hypokalaemia, but this was was mostly ascribed to complications from prematurity. Patient also not routinely screened for. 10 also has ataxia with cerebellar atrophy, which was deemed The classic clinical features of hypovolaemia, hyperaldoster- familial, as his sister and aunt (who do not have BS) are also onism and the consequent hypokalaemic, hypochloraemic met- affected. abolic alkalosis can be seen with both renal and extrarenal salt- wasting states, e.g. chronic and severe gastro-oesophageal Discussion reflux or congenital chloride diarrhoea, and it can be challeng- This study describes the long-term outcome for a large cohort ing to distinguish between them. The data presented in this of patients with BS and GS. Overall, the prognosis appears rea- cohort suggest that FENa cannot reliably distinguish between sonable, with the most serious complications related to prema- renal and extrarenal salt wasting. This is consistent with the turity. Genotype–phenotype correlation broadly confirms concept that in the long-term salt homeostasis must be in a results seen in previous cohorts. steady state, as persistent excess salt excretion would lead to life-threatening hypovolaemia. In this cohort, all patients with Growth available data had an FECl >0.5% prior to commencing electro- lyte supplementation, suggesting that this may be a better indi- Growth was below average for the cohort, but the mean height cator for renal salt loss, as FECl in extrarenal salt-losing was within two standard deviations. Height SDS improved conditions is expected to be minimal. Given the importance of slightly with treatment, from 1.6 at presentation to 1.2 at the sodium for volume homeostasis, the tubules prioritize sodium last follow-up. GH deficiency has been recurrently reported in reabsorption above other cations, especially potassium, so that BS [11, 12–15]. In our cohort, three patients were treated with sodium losses can be minimized. However, both sodium GH. Of interest is the observation in Patient 23, with BS Type 3, and potassium need to be accompanied by an anion, typically only showed catch-up growth with concomitant non-steroidal chloride and therefore FECl is better suited to detect renal salt anti-inflammatory drug (NSAID) treatment. Most reports of GH wasting. Obviously these measurements should be obtained deficiency in BS concern patients with CLCNKB mutations, the prior to supplementation, or when the patient is clinically hypo- type of BS with the most severe biochemical abnormalities. This volaemic. After commencing supplementation, increased renal raises the question whether GH secretion and response is impaired by severe hypokalaemia, alkalosis and/or elevated excretion may simply reflect the increased intake. Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/302/4616522 by Ed 'DeepDyve' Gillespie user on 20 June 2018 308 | P.R. Walsh et al. Chronic kidney disease In summary, we report a large cohort of children with BS and GS with long-term follow-up data treated in a single centre Impaired GFR and pathological glomerular proteinuria was seen over a 30-year period. This demonstrates the overall prognosis in a substantial number of children during follow–up, in keeping in children with BS and GS is reasonable; the majority of chil- with previous cohorts [19, 20, 23, 24]. In our cohort this was dren reached a height that was within the normal range and more common in BS than GS. There are a number of possible there were very few complications resulting from extreme elec- explanations for this. One possibility is that this is secondary to trolyte abnormalities. In this cohort, impaired GFR and patho- nephrocalcinosis; however, in the four children with CLCNKB logical albuminuria were seen in a large proportion of children, mutations and CKD, there was no evidence of nephrocalcinosis, highlighting the need for follow-up of glomerular as well as tub- suggesting this is not the cause in these patients. Long-term ular function in these patients. treatment with NSAIDs is linked to an increased risk of CKD [25], however, the doses used in BS and GS are relatively small (typically 1–2 mg/kg/day of indomethacin) compared with Funding doses used for analgesia. Moreover, patients with BS have D.B. and R.K. received support from the European Union, increased levels of prostaglandins involved in the regulation FP7 [grant agreement 2012-305608, ‘European Consortium of renal perfusion and treatment with NSAIDs does not sup- for High-Throughput Research in Rare Kidney Diseases press these, but brings them closer to the normal range. Previous data suggest that the use of NSAIDs in children with (EURenOmics)’], Kidney Care UK and Kids Kidney Research. BS is not linked to histological evidence of NSAID-induced D.B., W.v.H. and R.K. are supported by the National Institute renal damage [18]. for Health Research Biomedical Research Centre at Great A third possibility is chronic hypokalaemia, which in rats Ormond Street Hospital for Children NHS Foundation Trust leads to hypertrophy and ultimately renal fibrosis with elevated and University College London. transforming growth factor b [26]. Yet, results from adults with BS and GS suggest that the severity of hypokalaemia is not Conflict of interest statement directly linked to the degree of CKD [27]. Stimulants of the renin–angiotensin–aldosterone system in None declared. BS and GS include chronic volume depletion, and in BS, ‘short- circuiting’ of the juxta-glomerular apparatus [6, 10]. There is References experimental and epidemiological work that demonstrates a damaging effect of elevated aldosterone levels on podocytes, 1. Ji W, Foo JN, O’Roak BJ et al. Rare independent mutations in thus leading to CKD [28, 29]. Potentially this may also contribute renal salt handling genes contribute to blood pressure varia- to the CKD seen in children with BS and GS. tion. Nat Genet 2008; 40: 592–599 Prematurity is an emerging risk factor for CKD [30]. As human 2. Simon DB, Bindra RS, Mansfield TA et al. Mutations in the nephrogenesis is not complete until 36 weeks post-gestation, chloride channel gene, CLCNKB, cause Bartter’s syndrome children born prematurely have an incomplete endowment of type III. Nat Genet 1997; 17: 171–178 nephrons and therefore undergo ex utero nephrogenesis. In our 3. Simon DB, Karet FE, Hamdan JM et al. Bartter’s syndrome, cohort, patients with CLCNKB mutations and CKD were born at hypokalaemic alkalosis with hypercalciuria, is caused by term, thus prematurity in these children is unlikely to be the pri- mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet mary cause of CKD in these patients, but it is a likely contributor 1996; 13: 183–188 in patients with antenatal BS. 4. Simon DB, Karet FE, Rodriguez-Soriano J et al. Genetic heter- The progression of CKD in BS and GS is likely multifactorial ogeneity of Bartter’s syndrome revealed by mutations in the and therefore patients need regular follow-up to monitor glo- Kþ channel, ROMK. Nat Genet 1996; 14: 152–156 merular as well as tubular function. 5. Simon DB, Nelson-Williams C, Bia MJ et al. Gitelman’s var- iant of Bartter’s syndrome, inherited hypokalaemic alkalo- Urinary concentrating ability sis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. Nat Genet 1996; 12: 24–30 We previously reported the presence of an sNDI in two patients 6. Kleta R, Bockenhauer D. Bartter syndromes and other salt- (1 and 2) [31, 32] and confirm this complication in two further losing tubulopathies. Nephron Physiol 2006; 104: 73–80 patients with marked polyuria (8 and 9.1). In contrast, the sister 7. Laghmani K, Beck BB, Yang SS et al. Polyhydramnios, transi- of Patient 9.1 (9.2), as well as Patient 12, showed isosthenuria, ent antenatal Bartter’s syndrome, and MAGED2 mutations. consistent with dysfunction of the loop of Henle [33]. While N Engl J Med 2016; 374: 1853–1863 sNDI is seen only in patients with antenatal BS, the discrepant 8. Gonzalez Celedon C, Bitsori M et al. Progression of chronic findings in the siblings Patients 9.1 and 9.2 argue against a clear renal failure in children with dysplastic kidneys. Pediatr genotype effect; we also did not note substantial differences in Nephrol 2007; 22: 1014–1020 their plasma electrolytes or urinary calcium concentration. 9. Besouw MT, Bienias M, Walsh P et al. Clinical and molecular Clinically these patients pose a management problem: BS is pri- aspects of distal renal tubular acidosis in children. Pediatr marily a salt-wasting disorder and consequently supplementa- Nephrol 2017; 6: 987–996 tion with salt is a mainstay of treatment. Yet, patients with NDI 10. Plumb LA, van’t Hoff W, Kleta R et al. Renal apnoea: extreme need to minimize their salt intake to reduce the osmotic load. disturbance of homoeostasis in a child with Bartter syn- Indeed, the patients with confirmed sNDI all had recurrent hypernatraemic dehydration (maximal plasma sodium concen- drome type IV. Lancet 2016; 388: 631–632 11. Buyukcelik M, Keskin M, Kilic BD et al. Bartter syndrome and trations of 165, 161, 148 and 153 mmol/L) and salt supplementa- growth hormone deficiency: three cases. Pediatr Nephrol tion was either never prescribed or discontinued in these four patients. 2012; 27: 2145–2148 Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/302/4616522 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Clinical features of Bartter and Gitelman | 309 23. Brochard K, Boyer O, Blanchard A et al. Phenotype–genotype 12. Adachi M, Tajima T, Muroya K et al. Classic Bartter syndrome complicated with profound growth hormone deficiency: a correlation in antenatal and neonatal variants of Bartter case report. J Med Case Rep 2013; 7: 283 syndrome. Nephrol Dial Transplant 2009; 24: 1455–1464 13. Bogdanovic R, Draaken M, Toromanovic A et al. A novel 24. Peters M, Jeck N, Reinalter et al. Clinical presentation of CLCN5 mutation in a boy with Bartter-like syndrome and genetically defined patients with hypokalaemic salt-losing partial growth hormone deficiency. Pediatr Nephrol 2010; 25: tubulopathies. Am J Med 2002; 112: 183–190 2363–2368 25. Ingrasciotta Y, Sultana J, Giorgianni F et al. Association of 14. Akil I, Ozen S, Kandiloglu AR et al. A patient with Bartter syn- individual non-steroidal anti-inflammatory drugs and drome accompanying severe growth hormone deficiency chronic kidney disease: a population-based case control and focal segmental glomerulosclerosis. Clin Exp Nephrol study. PLoS One 2015; 10: e0122899 2010; 14: 278–282 26. Tsao T, Fawcett J, Fervenza FC et al. Expression of insulin- 15. Bettinelli A, Borsa N, Bellantuono R et al.Patients with biallelic like growth factor-I and transforming growth factor-b in mutations in the chloride channel gene CLCNKB: long-term hypokalaemic nephropathy in the rat. Kidney Int 2001; 59: management and outcome. Am J Kidney Dis 2007; 49: 91–98 96–105 16. Slyper AH. Growth, growth hormone testing and response to 27. Walsh SB, Unwin E, Vargas-Poussou R et al. Does hypokalae- growth hormone treatment in Gitelman syndrome. J Pediatr mia cause nephropathy? An observational study of renal Endocrinol Metab 2007; 20: 257–259 function in patients with Bartter or Gitelman syndrome. QJ 17. Min SR, Cho HS, Hong J et al. Gitelman syndrome combined Med 2011; 104: 939–944 with complete growth hormone deficiency. Ann Pediatr 28. Siragy HM, Carey RM. Role of the intrarenal renin- Endocrinol Metab 2013; 18: 36–39 angiotensin-aldosterone system in chronic kidney disease. 18. Reinalter SC, Gro ¨ ne HJ, Konrad M et al. Evaluation of long- Am J Nephrol 2010; 31: 541–550 term treatment with indomethacin in hereditary hypokale- 29. Lu Y, Ku E, Campese VM. Aldosterone in the pathogenesis of mic salt-losing tubulopathies. J Pediatr 2001; 139: 398–406 chronic kidney disease and proteinuria. Curr Hypertens Rep 19. Bettinelli A, Borsa N, Bellantuono R et al. Patients with bial- 2010; 12: 303–306 lelic mutations in the chloride channel gene CLCNKB: long- 30. Carmody JB, Charlton JR. Short-term gestation, long-term term management and outcome. Am J Kidney Dis 2007; 49: risk: prematurity and chronic kidney disease. Pediatrics 2013; 91–98 131: 1168–1179 20. Puricelli E, Bettinelli A, Borsa N et al. Long-term follow-up of 31. Bockenhauer D, Cruwys M, Kleta R et al. Antenatal Bartter’s patients with Bartter syndrome type I and II. Nephrol Dial syndrome: why is this not a lethal condition? Q J Med 2008; Transplant 2010; 25: 2976–2981 101: 927–942 21. Kleta R, Basoglu C, Kuwertz-Broking E. New treatment options 32. Bockenhauer D, van’t Hoff W, Dattani M et al. Secondary for Bartter’s syndrome. N Engl J Med 2000; 343: 661–662 nephrogenic diabetes insipidus as a complication of inher- 22. Blanchard A, Bockenhauer D, Bolignano D et al. Gitelman ited renal diseases. Nephron Physiol 2010; 116: p23–p29 syndrome: consensus and guidance from a Kidney Disease: 33. Bockenhauer D, Bichet DG. Inherited secondary nephrogenic Improving Global Outcomes (KDIGO) Controversies diabetes insipidus: concentrating on humans. Am J Physiol Conference. Kidney Int 2017; 91: 24–33 Renal Physiol 2013; 304: F1037–F1042 Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/302/4616522 by Ed 'DeepDyve' Gillespie user on 20 June 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Kidney Journal Oxford University Press

Clinical and diagnostic features of Bartter and Gitelman syndromes

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European Renal Association - European Dialysis and Transplant Association
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© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA.
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Abstract

Background: Bartter and Gitelman syndromes are autosomal recessive disorders of renal tubular salt handling. Due to their rarity, limited long-term data are available to inform prognosis and management. Methods: Long-term longitudinal data were analysed for 45 children with pathogenic variants in SLC12A1 (n ¼ 8), KCNJ1 (n ¼ 8), CLCNKB (n ¼ 17), BSND (n ¼ 2) and SLC12A3 (n ¼ 10) seen at a single centre between 1984 and 2014. Median follow-up was 8.9 [interquartile range (IQR) 0.7–18.1] years. Results: Polyhydramnios and prematurity were seen in children with SLC12A1 and KCNJ1 mutations. Patients with CLCNKB mutations had the lowest serum potassium and serum magnesium and the highest serum bicarbonate levels. Fractional excretion of chloride was >0.5% in all patients prior to supplementation. Nephrocalcinosis at presentation was present in the majority of patients with SLC12A1 and KCNJ1 mutations, while it was only present in one patient with CLCNKB and not in SLC12A3 or BSND mutations. Growth was impaired, but within the normal range (median height standard deviation score 1.2 at the last follow-up). Impaired estimated glomerular filtration rate (eGFR <90 mL/min/1.73 m ) at the last follow-up 2 2 was seen predominantly with SLC12A1 [71 mL/min/1.73 m (IQR 46–74)] and KCNJ1 [62 mL/min/1.73 m (IQR 48–72)] mutations. Pathological albuminuria was detected in 31/45 children. Conclusions: Patients with Bartter and Gitelman syndromes had a satisfactory prognosis during childhood. However, decreased eGFR and pathologic proteinuria was evident in a large number of these patients, highlighting the need to monitor glomerular as well as tubular function. Electrolyte abnormalities were most severe in CLCNKB mutations both at presentation and during follow-up. Fractional excretion of chloride prior to supplementation is a useful screening investigation in children with hypokalaemic alkalosis to establish renal salt wasting. Key words: Bartter syndrome, chronic kidney disease, Gitelman syndrome, hypokalaemic metabolic alkalosis, renal tubular disease Received: August 8, 2017. Editorial decision: September 12, 2017 V C The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/302/4616522 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Clinical features of Bartter and Gitelman | 303 gene—SLC12A1, KCNJ1, CNCKB, BSND and SLC12A3—to investigate Introduction genotype/phenotype correlation. The Mann–Whitney U test was Bartter syndrome (BS) and Gitelman syndrome (GS) are rare used to investigate differences between individual genotypes and autosomal recessive tubulopathies with a prevalence of 1in Kruskal–Wallis was used to evaluate differences between multi- 100 000 and 25 in 100 000, respectively [1]. BS occurs as a result ple groups; statistical significance was defined as P < 0.05. of mutations in genes coding for proteins mainly responsible for Median values are given with IQRs throughout. Due to the salt and water reabsorption in the thick ascending loop of Henle small size, the BSND group was excluded from statistical analysis. (TAL), while dysfunction of the sodium chloride co-transporter in the distal convoluted tubule (DCT) results in GS. BS can be further Molecular analysis subdivided based on the underlying genetics (Table 1)[2–6]. Two broad phenotypes exist in BS: antenatal BS, due to Genotyping was performed by the North East Thames Regional Genetics Service, located at GOSH, using a kit to assess a panel mutations in SLC12A1, KCNJ1, BSND (with sensorineural hearing of 37 tubular disease genes, as described previously [9]. loss) and in some cases of CLCNKB; and classic BS, typically associated with mutations in CLCNKB. Recently a transient antenatal BS was described in boys with mutations in MAGED2 Results [7]. Biochemical hallmarks of BS and GS include hyperaldoster- Molecular results onism with hypokalaemic, hypochloraemic metabolic alkalosis. Some specific biochemical abnormalities can give clues as to Mutations in disease-causing genes are summarized in Table 3. the underlying genotype, summarized in Table 1. For example, Homozygous variants were identified in 30/45 patients and patients with KCNJ1 mutations can present with transient compound heterozygous variants in the remaining 15/45 hyperkalaemia followed by the more typical hypokalaemia; patients. Whole gene deletion was responsible for 50% of muta- increased urinary calcium excretion and nephrocalcinosis are tions in CLCNKB. present in SLC12A1 and KCNJ1 mutations, whereas patients with SLC12A3 mutations have hypocalciuria; and patients with CLCNKB Initial presentation and SLC12A3 mutations typically develop hypomagnesaemia. Biochemical and clinical features at presentation are summar- As with most rare diseases, there is little data available ized in Table 2 and Figure 1. about the long-term disease course to inform management and prognosis. Prenatal and perinatal history In this study we describe the presenting features and long- Polyhydramnios was documented in 8/8 of SLC12A1, 7/8 KCNJ1, term outcomes of 45 patients with BS and GS. 7/17 CLCNKB, 1/2 BSND and 0/10 SLC12A3 cases. Gestational age (GA) was significantly lower in SLC12A1, KCNJ1 and BSND mutations compared with CLCNKB and SLC12A3 (P < 0.001). Materials and methods Demographic data Diagnosis and presentation The diagnosis of BS or GS was made before the age of 1 year in Biochemical and clinical data were analysed for 45 children pre- 27/35 BS patients (8/8 SLC12A1, 8/8 KCNJ1, 9/17 CLCNKB and 2/2 senting to Great Ormond Street Hospital (GOSH) between 1984 BSND) compared with 1/10 GS patients. Children diagnosed and 2014. Results were collected at presentation and throughout before 1 year of age presented with a history of polyhydramnios, follow-up, summarized in Table 2. Estimated glomerular filtra- polyuria and hypochloraemic metabolic alkalosis. The remain- tion rate (eGFR) was calculated using the modified Schwartz ing patients were diagnosed during childhood with failure to formula, with a k-value of 33 [8]. The median follow-up was 8.9 thrive (four CLCNKB), persistent muscle cramping (one CLCNKB, [interquartile range (IQR) 0.5–18.1] years. one SLC12A3), fainting spells (one SLC12A3) and incidentally noted biochemical derangement during intercurrent illness Statistical analysis (one CLCNKB, seven SLC12A3). Data analysis was performed using SPSS (IBM, Armonk, NY, USA). Median plasma potassium concentration at presentation Patients were analysed according to the underlying disease was lowest in CLCNKB mutations [2.6 mmol/L (IQR 2.1–2.9)], Table 1. Clinical and genetic classification of BS and GS Genetic Clinical phenotype OMIM subtype Gene/locus Protein Features Antenatal BS 601678 Type I SLC12A1/15q21.1 NKCC2 Polyhydramnios, prematurity, polyuria, nephrocalci- nosis, failure to thrive Antenatal BS 241200 Type II KCNJ1/11q24.3 ROMK1 Polyhydramnios, prematurity, polyuria, nephrocalci- nosis, failure to thrive, transient hyperkalaemia Classic BS 607364 Type III CLCNKB/1p36.13 CLC-Kb Failure to thrive, hypomagnesaemia Antenatal BS with 602522 Type IV BSND/1p32.3 Barttin Polyhydramnios, prematurity, polyuria, nephrocalci- sensorineural deafness nosis, failure to thrive, sensorineural deafness GS 263800 GS SLC12A3/16q13 NCCT Hypocalciuria, hypomagnesaemia Transient antenatal BS 300971 Type V MAGED2 MAGED2 Severe polyhydramnios, prematurity, hypercalciuria, spontaneous resolution OMIM: Online Mendelian Inheritance in Man. Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/302/4616522 by Ed 'DeepDyve' Gillespie user on 20 June 2018 304 | P.R. Walsh et al. Table 2. Clinical and biochemical characteristics at presentation BS GS Parameter SLC12A1 (n ¼ 8) KCNJ1 (n ¼ 8) CLCNKB (n ¼ 17) BSND (n ¼ 2) SLC12A3 (n ¼ 10) P-value GA, weeks 32 (27–33) 30 (28–33) 40 (38–40) 32 40 (40–40) <0.001 Polyhydramnios, 8/0 7/1 7/10 0/2 0/10 <0.001 present/absent Sex, M/F 4/4 4/4 12/5 0/2 7/4 N.S. Height, Z-score 1.28 (4.9 to 0.62) 2.2 (3.0 to 0.4) 2.1 (4.9 to 0.11) 0.0 (1.1 to 0.5) N.S. 2 1 6 8 Weight, Z-score 3.49 (4.22 to 1.00) 2.31 (3.49 to 0.22) 1.82 (3.49 to 0.63) 0.52 (N/A) N.S. Sodium, [133–146 mmol/L] 146 (143–148) 142 (135–148) 135 (130–140) (116–130) 139 (135–140) 0.001 Potassium [3.5–5.5 mmol/L] 3.4 (2.9–3.9) 3.8 (3.6–6.0) 2.6 (2.1–2.9) (2.1–3.0) 2.8 (2.4–3.0) <0.001 1 1 1 Chloride [96–106 mmol/L] 103 (98–110) 103 (101–109) 95 (81–98) (59–79) 98 (96–101) 0.001 1 1 Bicarbonate [18–28 mmol/L] 25 (25–29) 25 (23–28) 29 (26–33) (24–81) 30 (28–31) 0.01 1 1 2 1 Magnesium [0.6–0.9 mmol/L] 0.97 (0.91–1.17) 0.94 (0.73–1.07) 0.76 (0.59–0.90) (0.55–0.74) 0.67 (0.58–0.83) 0.005 1 2 8 5 FENa, % 0.36 (0.17–1.23) 0.82 (0.37–2.51) 0.87 (0.39–1.25) Not obtained 0.55 (0.30–0.95) N.S 3 6 11 9 FECl, % 1.6 (0.8–5.4) 1.25 (N/A) 3.9 (1.4–6.1) Not obtained 2.1 (N/A) N.S. Age-adjusted calcium:creatinine 1.17 (0.88–2.00) 1.37 (0.82–2.04) 0.61 (0.14–1.34) (1.50–1.64) 0.09 (0.05–0.21) <0.001 ratio, normalized to upper limit of normal Nephrocalcinosis, 8/0 8/0 2/15 0/2 0/10 <0.001 present/absent Median values given with interquartile ranges in parentheses. Reference range given in square brackets. Superscript numbers indicate the number of patients with missing data. P-values for Kruskal–Wallis analysis comparing SLC12A1, KCNJ1, CLCNKB and SLC12A3. M: male; F: female; N.S.: Not significant. while two children with KCNJ1 were noted to have transient 14 years, when his height was 126 cm (SDS4.37) and was stopped hyperkalaemia at presentation (Figure 1). at the age of 17 years, when his height was 154 cm (SDS3.02). Fractional excretions of chloride (FECl) and sodium (FENa) at Patient 23 started GH at the age of 6 years when his height was presentation were calculated in children where the data were 102 cm (SDS3.78). This coincided with indomethacin being dis- available (FECl in 15 children and FENa in 28 patients) and are continued due to a gastrointestinal bleed. His height SDS remained summarized in Table 2. FENa ranged from 0.1 to 6.4%, while essentially unchanged for the following 2 years (SDS3.88) despite FECl >0.5% was seen in all patients with available data, prior to GH treatment. At the age of 8 years, indomethacin was restarted commencing supplementation. In patients where both values (and GH continued) and his height SDS improved to 2.75 over the were available (n ¼ 15), the median FENa was 0.7% (IQR 0.3–1.2) following year. At the last follow-up (still on GH and indometha- cin) at the age of 12 years, his height was 133 cm (SDS2.26). and FECl was 1.62% (IQR 1.2–5.5). Normal urine calcium:creatinine (UCC) ratio varies with age, therefore the results were normalized to an age-adjusted upper Persistent hypokalaemia Persistent hypokalaemia, defined as potassium <3.5 mmol/L on limit of normal. This was elevated in 5/8 SLC12A1, 5/8 KCNJ1,7/ 17 CLCNKB and 2/2 BSND patients. Ultrasound scan at presenta- at least two consecutive blood tests, was seen in 41 children. Mild hypokalaemia (2.5–3.5 mmol/L) was present in 28 children tion was performed in all children to assess for nephrocalcino- (BS 22, GS 6), moderate hypokalaemia (2.0–2.5 mmol/L) was seen sis; this was seen in 8/8 SLC12A1, 8/8 KCNJ1, 2/17 CLCNKB, 0/2 BSND and 0/10 SLC12A3 patients. in 9 children (BS 6, GS 3) and severe hypokalaemia (<2.0 mmol/ L) was noted in 4 children (3 CLCNKB and 1 BSND). At the last follow-up, plasma potassium was decreased Course of clinical and biochemical data (<3.5 mmol/L) in 36 patients (BS 26/35 and GS 10/10). Plasma Growth bicarbonate was elevated (>28 mmol/L) in 20 patients (BS 18/35 The median height [standard deviation score (SDS)] at presenta- and GS 2/10) and plasma magnesium was decreased tion was 1.6 (IQR 3.88 to 0.04), this was not statistically dif- (<0.6 mmol/L) in 7 patients (BS 3/35 and GS 4/10) (Figure 1). ferent from the follow-up [1.2 (IQR 3to 1.7)]. Subgroup analysis of the genotypes revealed no statistical difference Complications between height at presentation and follow-up (SDS): SLC12A1, Two children with CLCNKB mutations were admitted for optimi- P ¼ 0.35; KCNJ1,P ¼ 0.6; CLCNKB,P ¼ 0.39; SLC12A3,P ¼ 0.59. zation of potassium supplementation (serum potassium 1.3 mmol/L and 1 mmol/L), one due to symptoms of hypokalae- Growth hormone treatment mic paralysis (Patient 13), which resolved following increased Growth hormone (GH) deficiency has previously been reported in potassium supplementation, and the second due to concerns children with BS [11]. In this cohort, GH was used in three patients regarding compliance (Patient 15). (1, 10 and 23) due to documented GH deficiency based on formal The median serum magnesium level at the last follow-up glucagon stimulation tests. In Patient 1, it was started at the age of was lowest in GS patients [0.62 mmol/L (IQR 0.55–0.71)]. 8 years, when her height was 110 cm (SDS3.29). She was also Hypomagnesaemia was associated with both CLCNKB and treated with gonadotropin-releasing hormone analogues to delay SLC12A3 mutations; while there was a trend to lower magne- puberty. Treatment was stopped at the age of 16 years, when her sium with increasing age, this was not statistically significant. height was 153 cm (SDS1.42). Patient 10 started GH at the age of No arrhythmias were noted. Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/302/4616522 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Clinical features of Bartter and Gitelman | 305 Table 3. Causative mutations identified Gene Patient Sex Nucleotide Protein Status SLC12A1 1 Female c.1316G>A p.(Arg439Gln) Homozygous 2 Male c.1215G>A p.?(Loss of splice site) Homozygous 3 Female c.811G>C/c.1316G>A p.(Ala271Pro/p.Arg439Gln Compound heterozygous 4.1 Female c.450_451del/c.967G>A p.(Asp150Glufs*4)/p.(Glu323Lys) Compound heterozygous 4.2 Male c.450_451del/c.967G>A p.(Asp150Glufs*4)/p.(Glu323Lys) Compound heterozygous 5 Male c. 1327G>A/c.2805dup p.(G443R)/p.(Trp936fs) Compound heterozygous 6.1 Male c.3165-?_*1þ?del p.? (exon 26 deletion) Homozygous 6.2 Female c.3165-?_*1þ?del p.? (exon 26 deletion) Homozygous KCNJ1 7 Male c.1-?_*1þ?del p.? (exon 1 deletion) Homozygous 8 Male c.277T>G p.(Phe93Val) Homozygous 9.1 Female c.716delG p.(Gly239Glufs*14) Homozygous 9.2 Female c.716delG p.(Gly239Glufs*14) Homozygous 10 Female c.658C>T p.(Leu220Phe) Homozygous 11.1 Female c.657C>G p.(Ser219Arg) Homozygous 11.2 Male c.657C>G p.(Ser219Arg) Homozygous 12 Male c.657C>G p.(Ser219Arg) Homozygous CLCNKB 13 Male c.(?-1)_(*1_?)del p.? (gene deletion) Homozygous 14.1 Female c.875G>T p.(Cys292Phe) Homozygous 14.2 Male c.875G>T p.(Cys292Phe) Homozygous 15 Female c.(?-1)_(*1_?)del p.? (gene deletion) Homozygous 16 Female c.(?-1)_(*1_?)del p.? (gene deletion) Homozygous 17 Male c.1693del/c.968þ 1G>A p.(Glu565Argfs*7)/p.(?) Compound heterozygous 18 Male c.(?-1)_(*1_?)del p.? (gene deletion) Homozygous 19 Male c.(?-1)_(*1_?)del p.? (gene deletion) Homozygous 20 Female c.1987A>T p.(Arg663*) Homozygous 21 Male c.1395delG p.(Tyr465*) Homozygous 22 Male c.(?-1)_(*1_?)del p.? (gene deletion) Homozygous 23 Female c.(?-1)_(*1_?)del p.? (gene deletion) Homozygous 24 Male c.(?-1)_(*1_?)del p.? (gene deletion) Homozygous 25 Male c.182C>A/c.373G>A p.(Ala61Asp)/p.(Glu125Lys) Compound heterozygous 26 Male c.1897delC p.(Leu633*) Homozygous 27 Female c.1929þ 1G>A/c.887G>A p.?/p.(Gly296Asp) Compound heterozygous 28 Male c.182C>A/c.373G>A p.(Ala61Asp)/p.(Glu1125Lys) Compound heterozygous BSND 29 Female c.452delC p.(Pro151Leufs*27) Homozygous 30 Female c.125G>A/c.139G>A p.(Ser42Asn)/p.(Gly47Arg) Compound heterozygous SLC12A3 31 Male c.2221G>A/c.3002C>A p.(Gly741Arg)/p.(Ala1001Asp) Compound heterozygous 32 Male c.1202C>A/c.2965 p.(Ala401Asp)/p.(Gly989Arg) Compound heterozygous 33 Male c.2221G>A/c.3052C>T p.(Gly741Arg)/p.(Arg1018*) Compound heterozygous 34 Female c.2878_2879insAGGGGTGCACCCTG p.(Val960Glufs*12) Homozygous 35.1 Female c.626G>A/c.1577A>G p.(Arg209Gln)/p.(Asn526Ser) Homozygous 35.2 Female c.626G>A/c.1577A>G p.(Arg209Gln)/p.(Asn526Ser) Compound heterozygous 36 Male c.647G>A/c.2221G>A p.(Gly216Glu)/p.(Gly741Arg) Compound heterozygous 37 Male c.424G>T/c.2952-?_*1þ?del p.(Val142Leu)/p.?(Exon 26 deletion) Compound heterozygous 38 Female c.2221G>A p.(Gly741Arg) Compound heterozygous 39 Male c.506-1G>A/c.1180þ 1G>T p.?/p.? (splice site) homozygous Compound heterozygous Listed are the mutations identified in the 45 patients. Listing of a single variant indicates homozygosity. Reference sequences used for annotation were as follows: BSND NM_057176.2, CLCNKB NM_000085.3, KCNJ1 NM_000220.2, SLC12A1 NM_000338.2, SLC12A3 NM_000339.2. two developed abdominal pain (Patients 17 and 24) and one Medications at last follow-up developed excessive bruising days after commencing treatment Sodium supplementation was prescribed for 14/45 patients (BS 12/ (Patient 23). 35 and GS 2/10), potassium supplementation for 38/45 patients (BS Indomethacin was temporarily discontinued in two other 30/35, GS 8/10) and magnesium supplementation for 12/45 patients children. One child (Patient 8) developed necrotizing enteroco- (BS 7/35 and GS 5/10). Prostaglandin inhibitors (ibuprofen or indo- litis at 17 days of age; indomethacin was eventually recom- methacin) were prescribed in 20/45 patients (BS 20/35 and GS 0/10). menced at 3 months due to ongoing severe polyuria. The second child developed gastrointestinal bleeding during the first year of life (Patient 21); indomethacin was gradually rein- Side effects of medication troduced. Indomethacin was substituted with ibuprofen in Indomethacin four patients: two because of parental preference (Patients 9.1 Indomethacin was used in 30/35 BS and 2/10 GS patients. and 9.2), one due to abdominal pain that settled after switch- Indomethacin was permanently discontinued in three children: ing (Patient 4.1) and one who developed peptic ulcer disease Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/302/4616522 by Ed 'DeepDyve' Gillespie user on 20 June 2018 306 | P.R. Walsh et al. Fig. 1. Biochemical data at presentation and last follow-up. Dotted lines indicate upper and lower limits of reference range. (A) Potassium at presentation and (B) at last follow-up. (C) Bicarbonate at presentation and (D) at last follow-up. (E) Magnesium at presentation and (F) at last follow-up. (G) Urine calcium:creatinine ratio at presentation. (H) eGFR at last follow-up. *P< 0.05. Bicarbonate as measured in the laboratory (initial bicarbonate calculated on blood gas analysis was 80 mmol/L, described in detail by Plumb et al. [10]). that settled with antacid treatment and switching to ibuprofen biochemical improvement. One patient received amiloride (Patient 20). because of dramatic alkalosis (Patient 29) [10]. Potassium-sparing diuretics Spironolactone was used in 6/35 BS patients. In one (Patient 24), Chronic kidney disease At the last follow-up, 27/45 children (BS 22/35 and GS 5/10) had it was discontinued at age 15 years due to gynaecomastia and in a second (Patient 15) it was discontinued due to lack of an eGFR<90 mL/min/1.73 m . Pathological albuminuria (urine Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/302/4616522 by Ed 'DeepDyve' Gillespie user on 20 June 2018 Clinical features of Bartter and Gitelman | 307 albumin:creatinine ratio >2.5 mg/mmol in boys and >3.5 mg/ prostaglandins. Reports of GH deficiency in patients with GS mmol in girls) was detected in 31/45 children (BS 28/35 and GS would argue against an effect of prostaglandins [16, 17]. Yet, 3/10). There was no statistically significant association of devel- these reported patients had no genetic confirmation of the diag- opment of CKD with either hypokalaemia, nephrocalcinosis or nosis, thus it is unclear if they truly had GS or rather BS Type 3. urinary concentrating ability. More systematic investigations are needed to address this One child (patient 24) with BS Type 3 developed nephrotic- question. range proteinuria (3.3 g/day) and underwent a kidney biopsy at the age of 14 years, when his eGFR was 60 mL/min/1.73 m ,which Treatment demonstrated focal segmental glomerular sclerosis. An angioten- Supplementation with sodium and/or potassium was the most sin-converting enzyme inhibitor was commenced at low dose frequently prescribed intervention; this is in keeping with previ- (enalapril 0.06 mg/kg/day), but was temporarily stopped due to an ously described cohorts [18–20]. Yet, the small differences in increase in creatinine by almost 50% (from 123 to 183 mmol/L). potassium levels between presentation and follow-up (see When subsequently restarted at half the dose, proteinuria decreased to 1.8 g/day with stable plasma creatinine (135 mmol/L). Figure 1) demonstrate the difficulties in improving this parame- One patient with CKD Stage 3 (Patient 33) had been diag- ter by supplementation, as an increased blood level results in nosed with vesico-ureteric reflux at 3 years of age after suffering an increased filtered load and thus, typically, increased urinary from recurrent urinary tract infections. losses. In our cohort, treatment with NSAIDs at the last follow-up Urinary concentrating ability was used in more than half of children with BS. Treatment with Maximal urine osmolalities (Uosm) obtained at clinic visits were NSAIDs was generally well tolerated, although side effects that compared according to genotype for those with available data. prompted temporary or permanent withdrawal were seen in The average maximal Uosm in patients with SLC12A1 and seven patients. Such withdrawal occurred with indomethacin, KCNJ1 mutations was 285 6 8 (SEM) mOsm/kg (n ¼ 11), com- yet this was also the most frequently used NSAID. Thus, pared with 547 6 17 for CLCNKB (n ¼ 12) and 634 6 65 for whether complications are more commonly associated with SLC12A3. indomethacin compared with other NSAIDs cannot be answered In all, six patients (all with antenatal BS) had formal desmo- from our study. Treatment with so-called cyclooxygenase-2 pressin (DDAVP) tests because of concerns over the urinary con- inhibitors has been suggested for patients with BS, and we centrating ability. Of these, four patients (1, 2, 8 and 9.1) showed increasingly prescribe it in our current patients, but none of the evidence of secondary nephrogenic diabetes insipidus (sNDI) patients in this historic cohort received this class of drug [21]. with Uosm below plasma osmolality (Posm) after DDAVP. The Treatment and tolerance of hypokalaemia is a controversial two others (Patients 9.2 and 12) showed evidence of topic in hypokalaemic alkalosis, as hypokalaemia can be associ- isosthenuria, with Uosm only mildly increasing to 345 and ated with complications, yet excessive supplementation can 367 mOsm/kg, respectively, after stimulation with DDAVP. also be harmful [22]. Interestingly, despite persistent hypokalae- mia (serum potassium <3.0 mmol/L) in 35/45 patients during Extrarenal complications follow-up, only 1 patient experienced overt symptoms, in the Intellectual impairment was not systematically evaluated in all form of hypokalaemic paralysis (serum potassium 1.3 mmol/L); patients but was documented in three patients (2, 10, 11.1) and no arrhythmias were detected with hypokalaemia, but this was was mostly ascribed to complications from prematurity. Patient also not routinely screened for. 10 also has ataxia with cerebellar atrophy, which was deemed The classic clinical features of hypovolaemia, hyperaldoster- familial, as his sister and aunt (who do not have BS) are also onism and the consequent hypokalaemic, hypochloraemic met- affected. abolic alkalosis can be seen with both renal and extrarenal salt- wasting states, e.g. chronic and severe gastro-oesophageal Discussion reflux or congenital chloride diarrhoea, and it can be challeng- This study describes the long-term outcome for a large cohort ing to distinguish between them. The data presented in this of patients with BS and GS. Overall, the prognosis appears rea- cohort suggest that FENa cannot reliably distinguish between sonable, with the most serious complications related to prema- renal and extrarenal salt wasting. This is consistent with the turity. Genotype–phenotype correlation broadly confirms concept that in the long-term salt homeostasis must be in a results seen in previous cohorts. steady state, as persistent excess salt excretion would lead to life-threatening hypovolaemia. In this cohort, all patients with Growth available data had an FECl >0.5% prior to commencing electro- lyte supplementation, suggesting that this may be a better indi- Growth was below average for the cohort, but the mean height cator for renal salt loss, as FECl in extrarenal salt-losing was within two standard deviations. Height SDS improved conditions is expected to be minimal. Given the importance of slightly with treatment, from 1.6 at presentation to 1.2 at the sodium for volume homeostasis, the tubules prioritize sodium last follow-up. GH deficiency has been recurrently reported in reabsorption above other cations, especially potassium, so that BS [11, 12–15]. In our cohort, three patients were treated with sodium losses can be minimized. However, both sodium GH. Of interest is the observation in Patient 23, with BS Type 3, and potassium need to be accompanied by an anion, typically only showed catch-up growth with concomitant non-steroidal chloride and therefore FECl is better suited to detect renal salt anti-inflammatory drug (NSAID) treatment. Most reports of GH wasting. Obviously these measurements should be obtained deficiency in BS concern patients with CLCNKB mutations, the prior to supplementation, or when the patient is clinically hypo- type of BS with the most severe biochemical abnormalities. This volaemic. After commencing supplementation, increased renal raises the question whether GH secretion and response is impaired by severe hypokalaemia, alkalosis and/or elevated excretion may simply reflect the increased intake. Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/302/4616522 by Ed 'DeepDyve' Gillespie user on 20 June 2018 308 | P.R. Walsh et al. Chronic kidney disease In summary, we report a large cohort of children with BS and GS with long-term follow-up data treated in a single centre Impaired GFR and pathological glomerular proteinuria was seen over a 30-year period. This demonstrates the overall prognosis in a substantial number of children during follow–up, in keeping in children with BS and GS is reasonable; the majority of chil- with previous cohorts [19, 20, 23, 24]. In our cohort this was dren reached a height that was within the normal range and more common in BS than GS. There are a number of possible there were very few complications resulting from extreme elec- explanations for this. One possibility is that this is secondary to trolyte abnormalities. In this cohort, impaired GFR and patho- nephrocalcinosis; however, in the four children with CLCNKB logical albuminuria were seen in a large proportion of children, mutations and CKD, there was no evidence of nephrocalcinosis, highlighting the need for follow-up of glomerular as well as tub- suggesting this is not the cause in these patients. Long-term ular function in these patients. treatment with NSAIDs is linked to an increased risk of CKD [25], however, the doses used in BS and GS are relatively small (typically 1–2 mg/kg/day of indomethacin) compared with Funding doses used for analgesia. Moreover, patients with BS have D.B. and R.K. received support from the European Union, increased levels of prostaglandins involved in the regulation FP7 [grant agreement 2012-305608, ‘European Consortium of renal perfusion and treatment with NSAIDs does not sup- for High-Throughput Research in Rare Kidney Diseases press these, but brings them closer to the normal range. Previous data suggest that the use of NSAIDs in children with (EURenOmics)’], Kidney Care UK and Kids Kidney Research. BS is not linked to histological evidence of NSAID-induced D.B., W.v.H. and R.K. are supported by the National Institute renal damage [18]. for Health Research Biomedical Research Centre at Great A third possibility is chronic hypokalaemia, which in rats Ormond Street Hospital for Children NHS Foundation Trust leads to hypertrophy and ultimately renal fibrosis with elevated and University College London. transforming growth factor b [26]. Yet, results from adults with BS and GS suggest that the severity of hypokalaemia is not Conflict of interest statement directly linked to the degree of CKD [27]. Stimulants of the renin–angiotensin–aldosterone system in None declared. BS and GS include chronic volume depletion, and in BS, ‘short- circuiting’ of the juxta-glomerular apparatus [6, 10]. There is References experimental and epidemiological work that demonstrates a damaging effect of elevated aldosterone levels on podocytes, 1. Ji W, Foo JN, O’Roak BJ et al. Rare independent mutations in thus leading to CKD [28, 29]. Potentially this may also contribute renal salt handling genes contribute to blood pressure varia- to the CKD seen in children with BS and GS. tion. Nat Genet 2008; 40: 592–599 Prematurity is an emerging risk factor for CKD [30]. As human 2. Simon DB, Bindra RS, Mansfield TA et al. Mutations in the nephrogenesis is not complete until 36 weeks post-gestation, chloride channel gene, CLCNKB, cause Bartter’s syndrome children born prematurely have an incomplete endowment of type III. Nat Genet 1997; 17: 171–178 nephrons and therefore undergo ex utero nephrogenesis. In our 3. Simon DB, Karet FE, Hamdan JM et al. Bartter’s syndrome, cohort, patients with CLCNKB mutations and CKD were born at hypokalaemic alkalosis with hypercalciuria, is caused by term, thus prematurity in these children is unlikely to be the pri- mutations in the Na-K-2Cl cotransporter NKCC2. Nat Genet mary cause of CKD in these patients, but it is a likely contributor 1996; 13: 183–188 in patients with antenatal BS. 4. Simon DB, Karet FE, Rodriguez-Soriano J et al. Genetic heter- The progression of CKD in BS and GS is likely multifactorial ogeneity of Bartter’s syndrome revealed by mutations in the and therefore patients need regular follow-up to monitor glo- Kþ channel, ROMK. Nat Genet 1996; 14: 152–156 merular as well as tubular function. 5. Simon DB, Nelson-Williams C, Bia MJ et al. Gitelman’s var- iant of Bartter’s syndrome, inherited hypokalaemic alkalo- Urinary concentrating ability sis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporter. 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Nephron Physiol 2010; 116: p23–p29 syndrome: consensus and guidance from a Kidney Disease: 33. Bockenhauer D, Bichet DG. Inherited secondary nephrogenic Improving Global Outcomes (KDIGO) Controversies diabetes insipidus: concentrating on humans. Am J Physiol Conference. Kidney Int 2017; 91: 24–33 Renal Physiol 2013; 304: F1037–F1042 Downloaded from https://academic.oup.com/ckj/article-abstract/11/3/302/4616522 by Ed 'DeepDyve' Gillespie user on 20 June 2018

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Clinical Kidney JournalOxford University Press

Published: Nov 10, 2017

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