Salt-wasting Tubulopathy Research Articles

Long-term outcome of Bartter syndrome in 54 patients: A multicenter study in Korea.

Bartter syndrome (BS) is a rare salt-wasting tubulopathy caused by mutations in genes encoding sodium, potassium, or chloride transporters of the thick ascending limb of the loop of Henle and/or the distal convoluted tubule of the kidney. BS is characterized by polyuria, failure to thrive, hypokalemia, metabolic alkalosis, hyperreninemia, and hyperaldosteronism. Potassium and/or sodium supplements, potassium-sparing diuretics, and nonsteroidal anti-inflammatory drugs can be used to treat BS. While its symptoms and initial management are relatively well known, long-term outcomes and treatments are scarce. We retrospectively reviewed 54 Korean patients who were clinically or genetically diagnosed with BS from seven centers in Korea. All patients included in this study were clinically or genetically diagnosed with BS at a median age of 5 (range, 0-271) months, and their median follow-up was 8 (range, 0.5-27) years. Genetic diagnosis of BS was confirmed in 39 patients: 4 had SLC12A1 gene mutations, 1 had KCNJ1 gene mutations, 33 had CLCNKB gene mutations, and 1 had BSND mutation. Potassium chloride supplements and potassium-sparing diuretics were administered in 94% and 68% of patients, respectively. The mean dosage of potassium chloride supplements was 5.0 and 2.1 mEq/day/kg for patients younger and older than 18 years, respectively. Nephrocalcinosis was a common finding of BS, and it also improved with age in some patients. At the last follow-up of 8 years after the initial diagnosis, 41% had short stature (height less than 3rd percentile) and impaired kidney function was observed in six patients [chronic kidney disease (CKD) G3, n = 4; CKD G5, n = 2]. BS patients require a large amount of potassium supplementation along with potassium-sparing agents throughout their lives, but tend to improve with age. Despite management, a significant portion of this population exhibited growth impairment, while 11% developed CKD G3-G5.

Three uncommon mutations of the SLC12A3 gene in gitelman syndrome: case reports and review of the literature

BackgroundGitelman syndrome is a rare autosomal recessive salt-wasting tubulopathy characterized by low potassium and magnesium levels in the blood, decreased excretion of calcium in the urine, and metabolic alkalosis. It is commonly caused by an inactivating mutation in the SLC12A3 gene (16q13), which encodes a thiazide-sensitive sodium chloride cotransporter. Here, we present three cases with the same clinical and laboratory findings that showed different mutations in the SLC12A3 gene.Case presentationThree children, a 14-year-old boy, a 7-year-old girl, and an 11-year-old boy, were admitted to our hospital at different times with nausea, weakness, muscle cramps in hands, and failure to thrive complaints. Blood tests showed hypokalemia, hypomagnesemia and metabolic alkalosis. Patients were referred to Pediatric Nephrology Clinic and diagnosed with Gitelman syndrome. Genetic tests of three cases showed homozygous mutations of c.1928C > T, p.Pro643Leu, c.248G > A, p.Arg83Gln, and c.1919A > G, p.N640S in the SLC12A3 gene exists, respectively. Potassium chloride, magnesium replacements, and indomethacin were given for treatment to patients. During follow-up, patients' heights and weights were increased dramatically, and nausea complaints were over.ConclusionDifferent mutations in the SLC12A3 gene in Gitelman syndrome can be detected but clinical, and laboratory findings were generally similar. Treatment with potassium, magnesium supplements, and indomethacin showed significant improvements in symptoms.

PHYSICAL THERAPY INTERVENTION FOR PATIENT WITH EAST SYNDROME- A CASE STUDY.

EAST syndrome is autosomal recessive disorder due to mutations in gene KCNJ10, a gene encoding a potassium channel expressed in the brain, eye, ear and kidney. It is characterized by four cardinal features; Epilepsy, Ataxia, Sensorineural deafness, and renal salt-wasting Tubulopathy, thus the acronym EAST syndrome. It was rst described as a distinct clinical entity in 2009 by Bockenhauer and scholl, who named this condition EAST syndrome and SeSAME syndrome for Seizures, Sensorineural deafness, Ataxia, Mental retardation and Electrolyte imbalance respectively. Neurodevelopmental delay is evident in most patients with EAST syndrome that were old enough to be assessed; Thus, physiotherapy intervention also plays a vital role in EAST syndrome along with medical management. From physiotherapy perspective; symptomatic management to Improve overall health, wellbeing and motor control becomes ultimate goal in the patient with EAST syndrome. As there is no specic physical therapy treatment approach and no specic tool to evaluate function for children with EAST syndrome; for clinically presented delay development and ataxia, Neurodevelopment therapy (NDT) was utilized as treatment approach and Gross motor function measure (GMFM) & Gross motor performance measure (GMPM) were utilized for assessment in this case study to track progress on follow ups. Result showed marked improvement in GMFM and GMPM scores at follow ups and concluded that Physical therapy intervention improves the gross motor function as well as gross motor performance in patient with EAST syndrome.

A novel heterozygous duplication of the SLC12A3 gene in two Gitelman syndrome pedigrees: indicating a founder effect

Gitelman syndrome is an autosomal recessive salt-wasting tubulopathy caused by mutations in the SLC12A3 gene. A female and a male sibling from two unrelated Greek-Cypriot families presenting with a severe salt-wasting tubulopathy due to compound heterozygous mutations of a novel duplication and a previously reported missense mutation in the SLC12A gene are described. Sanger sequencing was used to identify possible mutations in the SLC12A3 gene. For the detection of duplications/conversions and deletions in the same gene, Multiplex ligation probe amplification (MLPA) analysis was performed. Direct sequencing and MLPA analysis of the SLC12A3 gene identified two compound heterozygous mutations in both unrelated probands. Both probands were identified to carry in compound heterozygosity the known p.Met581Lys and a novelheterozygous duplication of exons 9-14 (E9_E14dup). The diagnosis of Gitelman syndrome was made through clinical assessment, biochemical screening and genetic analysis. The identification of the novel SLC12A3 duplication seems to be characteristic of Greek-Cypriot patients and suggests a possible ancestral mutational event that has spread in Cyprus due to a possible founder effect. Testing for Gitelman syndrome probable variants can be performed before proceeding to a full gene sequencing dropping the diagnostic cost. In addition, this report adds to the mutational spectrum observed.

Effect of nonsteroidal anti-inflammatory drugs in children with Bartter syndrome.

Bartter syndrome (BS) is a salt-wasting tubulopathy with induced expression of cyclooxygenase-2 in the macula densa, leading to increased prostaglandin production and hyperreninemia. Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently used in BS; however, there is limited information on the impact of NSAIDs at treatment initiation or the potential utility of plasma renin level to guide therapy in patients with BS. We included 19 patients with BS treated with NSAIDs between 1994 and 2016. We assessed serum levels of renin, aldosterone, electrolytes, calcium, phosphorus, vitamin D, and intact parathyroid hormone (iPTH) before and after treatment initiation. We also recorded modifications in sodium and potassium supplements and changes in urine calcium. Median age at diagnosis was 0.9months [IQR 0-6.9]. Seven patients had BS types 1 or 2, 12 had BS type 3 and two had no mutation identified. There was a trend towards a decrease in sodium chloride supplementation after initiation of NSAIDs. When defining response to treatment based on the normalization of plasma renin level, responders had a greater reduction in their electrolytes supplementation. NSAIDs treatment was associated with a reduction in urine calcium. Before treatment, half of the patients had elevated iPTH, but iPTH normalized following initiation of NSAIDs in all but one patient. This study confirms that NSAIDs reduce urine wasting of sodium and calcium in patients with BS. Monitoring serum renin levels may be useful to identify the lowest effective dose of NSAIDs that optimizes reduction of urine electrolyte losses.

Barttin Regulates the Subcellular Localization and Posttranslational Modification of Human Cl-/H+ Antiporter ClC-5.

Dent disease 1 (DD1) is a renal salt-wasting tubulopathy associated with mutations in the Cl-/H+ antiporter ClC-5. The disease typically manifests with proteinuria, hypercalciuria, nephrocalcinosis, and nephrolithiasis but is characterized by large phenotypic variability of no clear origin. Several DD1 cases have been reported lately with additional atypical hypokalemic metabolic alkalosis and hyperaldosteronism, symptoms usually associated with another renal disease termed Bartter syndrome (BS). Expression of the Bartter-like DD1 mutant ClC-5 G261E in HEK293T cells showed that it is retained in the ER and lacks the complex glycosylation typical for ClC-5 WT. Accordingly, the mutant abolished CLC ionic transport. Such phenotype is not unusual and is often observed also in DD1 ClC-5 mutants not associated with Bartter like phenotype. We noticed, therefore, that one type of BS is associated with mutations in the protein barttin that serves as an accessory subunit regulating the function and subcellular localization of ClC-K channels. The overlapping symptomatology of DD1 and BS, together with the homology between the proteins of the CLC family, led us to investigate whether barttin might also regulate ClC-5 transport. In HEK293T cells, we found that barttin cotransfection impairs the complex glycosylation and arrests ClC-5 in the endoplasmic reticulum. As barttin and ClC-5 are both expressed in the thin and thick ascending limbs of the Henle’s loop and the collecting duct, interactions between the two proteins could potentially contribute to the phenotypic variability of DD1. Pathologic barttin mutants differentially regulated trafficking and processing of ClC-5, suggesting that the interaction between the two proteins might be relevant also for the pathophysiology of BS. Our findings show that barttin regulates the subcellular localization not only of kidney ClC-K channels but also of the ClC-5 transporter, and suggest that ClC-5 might potentially play a role not only in kidney proximal tubules but also in tubular kidney segments expressing barttin. In addition, they demonstrate that the spectrum of clinical, genetic and molecular pathophysiology investigation of DD1 should be extended.

Effect of non-steroidal anti-inflammatory drugs in children with Bartter syndrome

Introduction Bartter syndrome (BS) is a congenital salt-wasting tubulopathy with an induced expression of cyclooxygenase-2 in the macula densa leading to hyperreninemia. Renin Angiotensin Aldosterone system (RAAs) activation leads to hypokalaemic alkalosis. NSAIDs are now currently used in BS, however few studies have investigated the effect of NAIDs on RAAs activation, biological parameters and treatment modifications. Material and methods We included 19 patients with BS treated with NAIDs between 1994 and 2016. We assessed renin and aldosterone serum levels, serum electrolytes, calcium, phosphorus, Vitamin D and PTH before and after treatment initiation. We also recorded modifications in sodium and potassium supplements and adverse events. Results Median age and weight at treatment initiation were 7 [4–49] months and 6175 [4360–13,675] grams respectively. Serum renin and aldosterone levels significantly decreased from 1532 [952–2638] to 226 [132–704] pg/mL (P Conclusion In this report, we confirm the major benefit of NSAIDs treatment in patients with BS. We also assess that monitoring renin serum level is of interest to adapt patients’ treatments. Finally, we demonstrate a beneficial effect of NSAIDs both on the decrease of the calciuria and the decrease of bone turn-over.

Novel mutation in the SLC12A3 gene in a Sri Lankan family with Gitelman syndrome & coexistent diabetes: a case report

BackgroundGitelman syndrome (GS) is a rare autosomal recessively inherited salt-wasting tubulopathy associated with mutations in the SLC12A3 gene, which encodes for NaCl cotransporter (NCC) in the kidney.Case presentationIn this report, we describe two siblings from a Sri Lankan non-consanguineous family presenting with hypokalaemia associated with renal potassium wasting, hypomagnesemia, hypocalciuria and hypereninemic hyperaldosteronism with normal blood pressure. Genetic testing showed that both were homozygotes for a novel missense mutation in exon 10 of the SLC12A3 gene [NM_000339.2, c.1276A > T; p.N426Y], which has not previously been reported in the literature in association with GS. Their mother was a heterozygous carrier for the same mutation. The father was not alive at the time of testing. This novel mutation extends the spectrum of known SLC12A3 gene mutations and further supports the allelic heterogeneity of GS. Interestingly both siblings had young onset Diabetes with strong family history.ConclusionThese findings have implications in providing appropriate genetic counseling to the family with regard to the risk associated with inbreeding, the detection of carrier/presymptomatic relatives. It further expands the known spectrum of genotypic and phenotypic characteristics of Gitelman syndrome.

Successful treatment with two siblings affected classic Bartter syndrome

Classic Bartter syndrome is a salt-wasting tubulopathy caused by mutations in the CLCNKB (chloride channel Kb) gene. Classic Bartter syndrome is characterized by early childhood onset. Herein, we report two Vietnamese siblings affected classic Bartter syndrome.

Classic Bartter syndrome complicated with profound growth hormone deficiency: a case report

IntroductionClassic Bartter syndrome is a salt-wasting tubulopathy caused by mutations in the CLCNKB (chloride channel Kb) gene. Although growth hormone deficiency has been suggested as a cause for persistent growth failure in patients with classic Bartter syndrome, in our opinion the diagnoses of growth hormone deficiency has been unconvincing in some reports. Moreover, Gitelman syndrome seems to have been confused with Bartter syndrome in some cases in the literature. In the present work, we describe a new case with CLCNKB gene mutations and review the reported cases of classic Bartter syndrome associated with growth hormone deficiency.Case presentationOur patient was a Japanese boy diagnosed as having classic Bartter syndrome at eight months of age. The diagnosis of Bartter syndrome was confirmed by CLCNKB gene analysis, which revealed compound heterozygous mutations with deletion of exons 1 to 3 (derived from his mother) and ΔL130 (derived from his father). His medical therapy consisted of potassium (K), sodium chloride, spironolactone, and anti-inflammatory agents; this regime was started at eight months of age. Our patient was very short (131.1cm, -4.9 standard deviation) at 14.3 years and showed profoundly impaired growth hormone responses to pharmacological stimulants: 0.15μg/L to insulin-induced hypoglycemia and 0.39μg/L to arginine. His growth response to growth hormone therapy was excellent.ConclusionsThe present case strengthens the association between classic Bartter syndrome and growth hormone deficiency. We propose that growth hormone status should be considered while treating children with classic Bartter syndrome.

CLCNKB mutations causing mild Bartter syndrome profoundly alter the pH and Ca2+ dependence of ClC-Kb channels

ClC-Kb, a member of the ClC family of Cl(-) channels/transporters, plays a major role in the absorption of NaCl in the distal nephron. CLCNKB mutations cause Bartter syndrome type 3, a hereditary renal salt-wasting tubulopathy. Here, we investigate the functional consequences of a Val to Met substitution at position 170 (V170M, α helix F), which was detected in eight patients displaying a mild phenotype. Conductance and surface expression were reduced by ~40-50%. The regulation of channel activity by external H(+) and Ca(2+) is a characteristic property of ClC-Kb. Inhibition by external H(+) was dramatically altered, with pKH shifting from 7.6 to 6.0. Stimulation by external Ca(2+) on the other hand was no longer detectable at pH 7.4, but was still present at acidic pH values. Functionally, these regulatory modifications partly counterbalance the reduced surface expression by rendering V170M hyperactive. Pathogenic Met170 seems to interact with another methionine on α helix H (Met227) since diverse mutations at this site partly removed pH sensitivity alterations of V170M ClC-Kb. Exploring other disease-associated mutations, we found that a Pro to Leu substitution at position 124 (α helix D, Simon et al., Nat Genet 1997, 17:171-178) had functional consequences similar to those of V170M. In conclusion, we report here for the first time that ClC-Kb disease-causing mutations located around the selectivity filter can result in both reduced surface expression and hyperactivity in heterologous expression systems. This interplay must be considered when analyzing the mild phenotype of patients with type 3 Bartter syndrome.

Renal phosphate handling in Gitelman syndrome—the results of a case–control study

Patients with Gitelman syndrome, a hereditary salt-wasting tubulopathy, have loss-of-function mutations in the SLC12A3 gene coding for the thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubule. Since the bulk of filtered phosphate is reabsorbed in the proximal tubule, renal phosphate wasting is considered exceptional in Gitelman syndrome. We investigated the renal handling of inorganic phosphate in 12 unselected Italian patients affected with Gitelman syndrome (5 females and 7 males, aged 6.0-18 years, median age 12 years) and in 12 healthy subjects matched for gender and age (controls). The diagnosis of Gitelman syndrome among the patients had been made clinically and confirmed by molecular biology studies. The biochemical hallmarks of Gitelman syndrome, namely hypochloremia, hypokalemia, hypomagnesemia, increased urinary excretion of sodium, chloride, potassium and magnesium and reduced urinary excretion of calcium, were present in the 12 patients. In addition, both the plasma inorganic phosphate concentration (median and interquartile range: 1.28 [1.12-1.36] vs. 1.61 [1.51-1.66)] mmol/L) and the maximal tubular reabsorption of inorganic phosphate (1.08 [0.99-1.22] vs. 1.41 [1.38-1.47] mmol/L) were significantly lower (P < 0.001) in Gitelman patients than in control subjects. Circulating levels of 25-hydroxyvitamin D, intact parathyroid hormone and osteocalcin were similar in patients and controls. The results of our case-control study disclose a hitherto unrecognized tendency towards renal phosphate wasting with mild to moderate hypophosphatemia in Gitelman syndrome.

Localization of Tubular Adaptation to Renal Sodium Loss in Gitelman Syndrome

Gitelman syndrome (GS) is a salt-wasting tubulopathy that results from the inactivation of the human thiazide-sensitive sodium chloride cotransporter located in the distal convoluted tubule. Tubular adaptation to renal sodium loss has been described and localized in the distal tubule in experimental models of GS but not in humans with GS. The tubular adaptation to renal sodium loss is described. Osmole-free water clearance and endogenous lithium clearance with furosemide infusion are used to compare 7 patients with genetically confirmed GS and 13 control participants. Neither endogenous lithium clearance nor osmole-free water clearance disclosed enhanced proximal fluid reabsorption in patients with GS. These patients displayed significantly lower osmole-free water clearance factored by inulin clearance (7.1 ± 1.9 versus 10.1 ± 2.2; P<0.01) and significantly lower fractional sodium reabsorption in the diluting nephron (73.2% ± 7.1% versus 86.1% ± 4.7%; P<0.005), consistent with the inactivation of the thiazide-sensitive sodium chloride cotransporter. The furosemide-induced reduction rate of fractional sodium reabsorption in the diluting segment was higher in patients with GS (75.6% ± 6.1% versus 69.9% ± 3.2%; P<0.039), suggesting that sodium reabsorption would be enhanced in the cortical part of the thick ascending limb of the loop of Henle in patients with GS. These findings suggest that tubular adaptation to renal sodium loss in GS would be devoted to the cortical part of the thick ascending limb of the loop of Henle in humans.

The salt-wasting phenotype of EAST syndrome, a disease with multifaceted symptoms linked to the KCNJ10 K+ channel

Mutations in the K+ channel gene KCNJ10 (Kir4.1) cause the autosomal recessive EAST syndrome which is characterized by epilepsy, ataxia, sensorineural deafness, and a salt-wasting tubulopathy. The renal salt-wasting pathology of EAST syndrome is caused by transport defects in the distal convoluted tubule where KCNJ10 plays a pivotal role as a basolateral K+ channel. This review on EAST syndrome outlines the molecular aspects of the physiology and pathophysiology of KCNJ10 in the distal convoluted tubule.

Mutation of the Na+-K+-2Cl−cotransporter NKCC2 in mice is associated with severe polyuria and a urea-selective concentrating defect without hyperreninemia

The bumetanide-sensitive Na(+)-K(+)-2Cl(-) cotransporter NKCC2, located in the thick ascending limb of Henle's loop, plays a critical role in the kidney's ability to concentrate urine. In humans, loss-of-function mutations of the solute carrier family 12 member 1 gene (SLC12A1), coding for NKCC2, cause type I Bartter syndrome, which is characterized by prenatal onset of a severe polyuria, salt-wasting tubulopathy, and hyperreninemia. In this study, we describe a novel chemically induced, recessive mutant mouse line termed Slc12a1(I299F) exhibiting late-onset manifestation of type I Bartter syndrome. Homozygous mutant mice are viable and exhibit severe polyuria, metabolic alkalosis, marked increase in plasma urea but close to normal creatininemia, hypermagnesemia, hyperprostaglandinuria, hypotension,, and osteopenia. Fractional excretion of urea is markedly decreased. In addition, calcium and magnesium excretions are more than doubled compared with wild-type mice, while uric acid excretion is twofold lower. In contrast to hyperreninemia present in human disease, plasma renin concentration in homozygotes is not increased. The polyuria observed in homozygotes may be due to the combination of two additive factors, a decrease in activity of mutant NKCC2 and an increase in medullary blood flow, due to prostaglandin-induced vasodilation, that impairs countercurrent exchange of urea in the medulla. In conclusion, this novel viable mouse line with a missense Slc12a1 mutation exhibits most of the features of type I Bartter syndrome and may represent a new model for the study of this human disease.