Bartter and Gitelman syndromes.

Bartter and Gitelman syndromes belong to salt-losing tubulopathies. These rare diseases may be associated with severe electrolyte disorders. Early identification of tubulopathies is essential for appropriate management. Progress in molecular genetics enabled the identification of genes and pathophysiologic mechanisms associated with these diseases. Here, we review etiology and diagnostics of these disorders from the light of current knowledge. Additionally, we discuss contemporary therapeutic approaches.

Molecular Basis, Diagnostic Challenges and Therapeutic Approaches of Bartter and Gitelman Syndromes: A Primer for Clinicians.

Gitelman and Bartter syndromes are rare inherited diseases that belong to the category of renal tubulopathies. The genes associated with these pathologies encode electrolyte transport proteins located in the nephron, particularly in the Distal Convoluted Tubule and Ascending Loop of Henle. Therefore, both syndromes are characterized by alterations in the secretion and reabsorption processes that occur in these regions. Patients suffer from deficiencies in the concentration of electrolytes in the blood and urine, which leads to different systemic consequences related to these salt-wasting processes. The main clinical features of both syndromes are hypokalemia, hypochloremia, metabolic alkalosis, hyperreninemia and hyperaldosteronism. Despite having a different molecular etiology, Gitelman and Bartter syndromes share a relevant number of clinical symptoms, and they have similar therapeutic approaches. The main basis of their treatment consists of electrolytes supplements accompanied by dietary changes. Specifically for Bartter syndrome, the use of non-steroidal anti-inflammatory drugs is also strongly supported. This review aims to address the latest diagnostic challenges and therapeutic approaches, as well as relevant recent research on the biology of the proteins involved in disease. Finally, we highlight several objectives to continue advancing in the characterization of both etiologies.

Gitelman Syndrome in Pregnancy: A Clinical Challenge.

PURPOSE: Disease progress may be affected by pregnancy-related changes, and underlying conditions may also affekt pregnancy outcomes in women with Gitelman syndrome (GS). Case presentation A 35-year-old woman with GS (gravida 2 para 1) was referred to our hospital to start routine antenatal care follow-up at 6 weeks of gestation. At the age of 31, she had been diagnosed with GS after her first uneventful pregnancy. Upon early admission, her serum Mg+level was 0.51 mmol/L and her serum K+level 2.7 mmol/L with normal kidney function tests. She was already taking oral combined potassium citrate and potassium bicarbonate supplementation once a day before pregnancy. At the eighth gestational week, the medication was changed to an oral potassium color sachet of 1.5 gram per day until labor because of the insufficient dosage to maintain optimum potassium levels. She was also taking 365 milligrams of oral magnesium oxide twice a day before and during pregnancy. In the third trimester of the pregnancy, her serum Mg+level was 0.48 mmol/L and serum K+level 2.8 mmol/L. Because of the previous uterine surgery history, she underwent an elective cesarean operation at 39 weeks' gestation under spinal anesthesia and delivered a healthy 3090-gram female infant. CONCLUSION: Increased need for potassium and magnesium supplementation should be the critical considerations when managing pregnant patients with GS.

Clinical and laboratory features of female Gitelman syndrome and the pregnancy outcomes in a Chinese cohort.

AIM: Gitelman syndrome (GS) is a rare inherited salt-losing renal tubulopathy. Data on clinical features and the pregnancy outcome for female GS patients in a large cohort are lacking. The study was aimed to explore the phenotype and pregnant issue for female GS patients. METHODS: GS cases from the National Rare Diseases Registry System of China (NRSC) were collected, and detailed clinical, laboratory and genetic data were analysed. Articles on pregnancy in GS were also systemically reviewed. RESULTS: A total of 101 GS patients were included; among them, 42.6% were female and 79.2% showed hypomagnesaemia. A lower proportion of female patients presented before 18 years of age, with less frequently reported polyuria, higher serum potassium and less urine sodium and chloride excretions. There was no gender difference in the sodium-chloride cotransporter (NCC) dysfunction evaluated by hydrochlorothiazide test. Twelve of the 43 female GS patients delivered after disease symptom onset, and their pregnancies were generally uneventful. As a group, pregnant GS patients had lower potassium levels in the first-trimester (P = .002) requiring higher potassium supplementation. After delivery, serum potassium (P = .02) and magnesium (P = .03) increased significantly. Both caesarean section and vaginal delivery were safe. CONCLUSION: Female GS patients may have a less severe phenotype with generally favourable outcomes of pregnancy. Intensive monitoring and increased potassium supplementation are necessary during pregnancy, especially in the first-trimester.

Inherited salt-losing tubulopathy: An old condition but a new category of tubulopathy.

Bartter syndrome (BS) and Gitelman syndrome (GS) are syndromes associated with congenital tubular dysfunction, characterized by hypokalemia and metabolic alkalosis. Clinically, BS is classified into two types: the severe antenatal/neonatal type, which develops during the fetal period with polyhydramnios and preterm delivery; and the relatively mild classic type, which is usually found during infancy with failure to thrive. GS can be clinically differentiated from BS by its age at onset, usually after school age, or laboratory findings of hypomagnesemia and hypocalciuria. Recent advances in molecular biology have shown that these diseases can be genetically classified into type 1 to 5 BS and GS. As a result, it has become clear that the clinical classification of antenatal/neonatal BS, classic BS, and GS does not always correspond to the clinical symptoms associated with the genotypes in a one-to-one manner; and there is clinically no clear differential border between type 3 BS and GS. This has caused confusion among clinicians in the diagnosis of these diseases. It has been proposed that the disease name "inherited salt-losing tubulopathy" can be used for cases of tubulopathies accompanied by hypokalemia and metabolic alkalosis. It is reasonable to use this term prior to genetic typing into type 1-5 BS or GS, to avoid confusion in a clinical setting. In this article, we review causative genes and phenotypic correlations, diagnosis, and treatment strategies for salt-losing tubulopathy as well as the clinical characteristics of pseudo-BS/GS, which can also be called a "salt-losing disorder".

Peptide Receptor Radionuclide Therapy-Induced Gitelman-like Syndrome.

Peptide receptor radionuclide therapy (PRRT) is a molecular-targeted therapy in which a somatostatin analogue (a small peptide) is coupled with a radioligand so that the radiation dose is selectively administered to somatostatin receptor-expressing metastasized neuroendocrine tumors, particularly gastroenteropancreatic. Reported toxicities include myelotoxicity and nephrotoxicity, the latter manifesting as decreased kidney function, often developing months to years after treatment completion. We present a case of PRRT-induced kidney toxicity manifesting as a severe Gitelman-like tubulopathy with preserved kidney function. Because profound hypokalemia and hypocalcemia can lead to life-threatening arrhythmias, we highlight the necessity for careful monitoring of serum and urine electrolytes in patients receiving PRRT.

Bartter's and Gitelman's syndrome.

PURPOSE OF REVIEW: The clinical presentations of Bartter's syndrome and Gitelman's syndrome will be reviewed including two most recently described hypokalemic salt-losing tubulopathies. By taking the quite heterogeneous presentations and the apparently different pathophysiologies as the basis, the applicability of the physiologic classification has been tested. RECENT FINDINGS: According to the physiologic approach, salt-losing tubulopathies can be divided into two major groups (with completely different tubular defects): first, disorders of the thick ascending limb of Henle's loop (loop disorders); second, disorders of the distal convolute tubule (DCT disorders). A combination of these two groups with complety different tubular defects will finally lead to a third group: the combined loop/DCT disorders. On the basis of pharmacologic tests (pharmacotyping), it appears that the Bartter's syndrome V belongs to the DCT group, whereas the most recently described transient antenatal Bartter's syndrome best fits in the group with the loop and DCT combination.Besides secondary hyperaldosteronism, loop disorders present a whole spectrum of (secondary) pathophysiologic characteristics with significant diagnostic and therapeutic impact, such as polyhydramnios, hyperprostaglandinuria, nephrogenic diabetes insipidus, and nephrocalcinosis. Recent reports indicate that neonatal hyperparathyroidism has also to be added to the clinical presentation of isolated loop disorders. SUMMARY: As long as gene therapy is not available, the overall therapeutic management follows the clinical presentation, which leads to the underlying pathophysiology of renal salt wasting. Thus, when dealing with Bartter's syndrome and Gitelman's syndrome, the correct physiologic and pharmacologic characterization appears to be essential for a sound diagnostic and therapeutic patient management.

Mutation profile and treatment of Gitelman syndrome in Chinese patients.

BACKGROUND: Gitelman syndrome (GS) is a rare autosomal recessive disease caused by loss-of-function mutations in the SLC12A3 gene, and is characterized by hypokalemia and metabolic alkalosis. In this study, we aimed to study the genotype, phenotype, and treatment in 42 GS patients, the largest sample size so far in mainland China. METHOD: We retrospectively studied the clinical data and genetic characteristics of 42 patients diagnosed with GS in Peking Union Medical College Hospital from 2012 to 2015. Therapeutic efficacy of spironolactone and potassium supplements was also studied retrospectively. RESULTS: Eighty-one mutation alleles were found in 42 patients, and total of 52 distinctly different mutation alleles were identified, of which 15 were new mutation alleles. p.Asp486Asn was a hotspot in our series, with the allele frequency being 19.7 % (16/81), and was found in 13 patients (31.0 %). Treatment with spironolactone or potassium supplements alone significantly increased serum potassium concentration by 0.36 ± 0.37 and 0.45 ± 0.35 mmol/l, respectively (both P < 0.05), and combined therapy with spironolactone and potassium increased serum potassium concentration by 0.69 ± 0.64 mmol/l (P < 0.05). CONCLUSIONS: 18.5 % (15/81) mutation sites identified in 42 Chinese GS patients are novel. p.Asp486Asn mutation is a hotspot, which is different from the reports from other countries. Spironolactone could moderately elevate serum potassium level, and spironolactone in combination with potassium supplements tended to be more effective.

[Expert consensus for the diagnosis and treatment of patients with Gitelman syndrome].

Gitelman syndrome (GS) is an autosomal recessive, salt-losing tubulopathy caused by inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter (NCC). GS is characterized by hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria. GS is one of the most common inherited renal tubulopathy with a prevalence estimated at about one to ten per 40 000 people. The prevalence of GS is even higher in Asia than other countries. The majority of GS patients present mild and nonspecific symptoms during adolescence or adulthood. Common clinical manifestations are associated with electrolyte abnormalities, such as muscle weakness, salt craving and tetany. However, the phenotype of GS is highly variable and links to the quality of life. Diagnosis of GS is based on the clinical symptoms, biochemical abnormalities (normal/low blood pressure, metabolic alkalosis, hypomagnesemia, hypocalciuria and increased activity of renin-angiotensin- aldosterone system) and genetic test. Genetic diagnosis of GS is recommended for all patients and the diagnosis is confirmed when biallelic inactivating SLC12A3 mutations are identified. The differential diagnosis includes renal tubular acidosis, primary hyperaldosteronism, Bartter syndrome, Liddle syndrome and other diseases that cause hypokalemia. Among them Bartter syndrome (especially type Ⅲ) is the most important genetic disorder to consider due to its similar manifestations with GS. All GS patients are encouraged to keep high-sodium diet. Magnesium and potassium supplements (oral or intravenous) are usually given to GS patients to improve clinical symptoms. Other medicines such as aldosterone receptor antagonists, angiotensin-converting-enzyme inhibitors (ACEIs), angiotensin Ⅱ receptor blockers (ARBs) and prostaglandin synthetase inhibitors (PGSIs) are alternative choices of treating hypokalemia, but the side-effects of these medication should be well considered. Management of GS includes health education, complication evaluation and regular follow-up. Annual evaluation by a nephrologist is recommended. Extra evaluation and treatment depend on special conditions, such as pregnancy, perioperative or growth period. Antenatal diagnosis for GS is technically feasible but not recommend due to the benign prognosis in the majority of patients. In general, this expert consensus statement aims to establish an initial framework for the better diagnosis, treatment and management of Chinese patients with GS.

[A case of Gitelman syndrome with physical retardation].

Gitelman syndrome is a rare disease. It is easy to be misdiagnosed and missed diagnosis due to the diverse clinical symptoms. A girl with long-term hypokalemia, who presented with intermittent pain of lower limb muscle and physical retardation, was treated in Xiangya Hospital, Central South University. Laboratory examination confirmed the severe hypokalemia and metabolic alkalosis. Gene sequencing indicated SLC12A3 gene mutation and the patient was finally diagnosed as Gitelman syndrome. Patients with chronic hypokalemia and metabolic alkalosis need to conduct gene sequencing to confirm the diagnosis. Gene therapy is expected to be the most effective treatment for this disease.

Two cases of successful pregnancy in patients with Gitelman's syndrome.

Gitelman's syndrome (GS) is a distal convoluted tubule (DCT) defect clinically characterized by hypokalemic metabolic alkalosis. Pregnancy in women with GS often results in severe hypomagnesemia and hypokalemia. We report two cases of successful pregnancies, after previous fetal loss, in patients with GS managed with aggressive oral and intravenous electrolyte repletion. These cases illustrate increased potassium and magnesium requirements over the course of the pregnancies and are notable due to the high doses of electrolytes required. They also demonstrate the possibility of successful pregnancy outcomes with frequent laboratory monitoring and aggressive titration of electrolyte replacement either orally or intravenously to maintain appropriate serum levels necessary to provide a suitable environment for fetal development.

[Chronic pain and artificial diseases]. / Chronischer Schmerz und artifizielle Erkrankungen.

A 34-year-old woman presented with a complex pain disorder and a previous diagnosis of the rare Gitelman syndrome but with a negative genetic test. The patient was admitted to a routine ward for treatment of the pain but was transferred to the intensive care unit after suffering severe hypokalemia and a narcoleptic attack. In the period of intensive care all blood parameters were stable but on release to the normal ward severe hypokalemia immediately reoccurred. With consent the patient's belongings were inspected and many diuretics and laxatives were found. The patient admitted to uncontrolled self-medication so that the diagnosis of Gitelman syndrome also appeared to be an artificial disorder.

[Anesthesiological management of Gitelman syndrome : Teaching example on physiology and pathophysiology of electrolyte balance]. / Anästhesiologisches Management des Gitelman-Syndroms : Lehrbeispiel zur Physio- und Pathophysiologie des Elektrolythaushalts.

Gitelman syndrome is a rare autosomal recessive inherited disease that affects the thiazide-sensitive sodium chloride cotransport channels and the magnesium channels of the distal renal tubuli. Characteristic features are hypokalemia, hypomagnesemia, metabolic alkalosis and hypocalciuria. This case report presents the anesthesiological management of the Gitelman syndrome. The article demonstrates the pathophysiology, symptoms, diagnosis and therapy of this disease from the anesthesiologists point of view.

[Gitelman syndrome in pregnancy--a severe hypokalemia with favorable perinatal prognosis]. / Gitelmanuv syndrom v tehotenství - tezká hypokalémie s príznivou perinatální prognózou.

Gitelman syndrom is a rare congenital tubulopathy characterized by hypokalemia, hypomagnesemia, metabolic alkalosis and hypocalciuria. We report a case of a 32-year-old patient admitted for asymptomatic hypokalemia and hypomagnesemia in the 30th week of gestation. A diagnosis of Gitelman syndrom was made and intravenous administration of potassium chloride in high doses combined with spironolactone was started. Despite intensive potassium supplementation (8 g/day), the serum potassium levels remained at the lower limit of normality throughout the pregnancy. The patient delivered a healthy female 2670 g/48 cm after labor induction in the 39th week of gestation. A summary of 22 so far published cases of Gitelman syndrome in pregnancy is presented. The analysis of published case studies suggests a need for ion supplementation, reduction of urinary potassium wasting, monitoring of fetal well-being and amniotic fluid levels. Pregnancy has a very favorable perinatal prognosis despite critical serum levels of potassium and magnesium throughout the pregnancy.

Bartter- and Gitelman-like syndromes: salt-losing tubulopathies with loop or DCT defects.

Salt-losing tubulopathies with secondary hyperaldosteronism (SLT) comprise a set of well-defined inherited tubular disorders. Two segments along the distal nephron are primarily involved in the pathogenesis of SLTs: the thick ascending limb of Henle's loop, and the distal convoluted tubule (DCT). The functions of these pre- and postmacula densa segments are quite distinct, and this has a major impact on the clinical presentation of loop and DCT disorders - the Bartter- and Gitelman-like syndromes. Defects in the water-impermeable thick ascending limb, with its greater salt reabsorption capacity, lead to major salt and water losses similar to the effect of loop diuretics. In contrast, defects in the DCT, with its minor capacity of salt reabsorption and its crucial role in fine-tuning of urinary calcium and magnesium excretion, provoke more chronic solute imbalances similar to the effects of chronic treatment with thiazides. The most severe disorder is a combination of a loop and DCT disorder similar to the enhanced diuretic effect of a co-medication of loop diuretics with thiazides. Besides salt and water supplementation, prostaglandin E2-synthase inhibition is the most effective therapeutic option in polyuric loop disorders (e.g., pure furosemide and mixed furosemide-amiloride type), especially in preterm infants with severe volume depletion. In DCT disorders (e.g., pure thiazide and mixed thiazide-furosemide type), renin-angiotensin-aldosterone system (RAAS) blockers might be indicated after salt, potassium, and magnesium supplementation are deemed insufficient. It appears that in most patients with SLT, a combination of solute supplementation with some drug treatment (e.g., indomethacin) is needed for a lifetime.

Quadriparesis in an adult--Gitelman syndrome.

A 24 years old soldier presented with sudden onset of weakness in all four limbs. There was no history of any antecedent respiratory infection, fever, diarrhoea or vomiting. Neurological examination of limbs revealed reduced tone and power in all limbs. Although the tendon reflexes were diminished they could be elicited in all limbs. Rest of the clinical examination was unremarkable. Serum potassium was 2.1 mmol/l, sodium 138 mmol/l, bicarbonate 35.3 mmol/l, urea 5.7 mmol/l, creatinine 69 umol/l and serum creatine kinase (CK) was 686 U/l. Power in the patient's limbs gradually improved to normal by following afternoon after potassium chloride infusion. Serum chloride was 93 mmol/l, bicarbonate 33.4 mmol/l, calcium 2.1 mmol/l, urine sodium 134 mmol/l, urine potassium 82 mmol/l, urine chloride 156 mmol/l and urine pH 6.0. Urinary calcium excretion was 2.2 mmol in 24 hours. Serum magnesium was 0.7 mmol/l. A diagnosis of Gitelman syndrome was made. He is doing well on spironolactone, potassium chloride supplementation and high sodium diet, maintaining serum potassium level between 3.5 and 4.5 mmol/l.

Hypokalemic rhabdomyolysis in a child with Gitelman's syndrome.

We report here the first published case of a pediatric patient with Gitelman's syndrome (GS) in whom hypokalemia-associated rhabdomyolysis developed. A 13-year-old girl was admitted with weakness of the extremities, walking difficulty and calf pain. Laboratory data showed a serum potassium level of 2.1 mmol/l and a serum creatinine phosphokinase level of 1,248 IU/l plus myoglobinemia. The presence of normomagnesemia was the basis for a genetic analysis of the thiazide-sensitive sodium chloride cotransporter gene, which revealed compound heterozygous mutations in this gene. Prompt fluid expansion and potassium supplementation led to regression of the muscle symptoms. Hypokalemia can be a rare cause of rhabdomyolysis in patients with GS, even in childhood. We emphasize that genetic analysis is advisable to determine whether the suspicion of GS is warranted.

[Bartter-Gitelman syndromes]. / Syndromes de Bartter­Gitelman.

Bartter-Gitelman syndromes are rare inherited autosomal recessive salt-losing tubulopathies characterized by severe and chronic hypokalemia associated with metabolic alkalosis and secondary hyperaldosteronism. Bartter syndrome results from a furosemide-like defect in sodium reabsorption in the Henle's loop leading to hypercalciuria and defect in urinary concentration capacity. The antenatal Bartter syndrome is defined by polyhydramnios and an infantile polyuria with severe dehydration whereas classic Bartter syndrome appears during childhood or adulthood. Gitelman syndrome is a thiazide-like salt-losing tubulopathy. It is associated with hypomagnesemia, hypocalciuria without defect in urinary concentration capacity. The diagnosis is most often made in adolescents or adults. Clinical symptoms include tetany, delay in the height-weight growth curves, chronic tiredness, muscle weakness, myalgia and vertigo. Nephrocalcinosis in Bartter syndrome could lead to chronic kidney disease. Antenatal Bartter syndrome requires hospitalization in intensive care unit to manage the severe newborn dehydration. Chondrocalcinosis is the major complication in the Gitelman syndrome. The corner stones of treatment is the fluid and electrolyte management Bartter and Gitelman syndromes need lifelong oral supplementations of potassium, salt (Bartter) and magnesium (Gitelman). Indomethacin is efficient to reduce water and electrolyte loss in Bartter. In Gitelman, potassium-sparing diuretics may be helping for severe hypokaliemia but they will reinforce hypovolemia.

[Gitelman syndrome]. / Síndrome de Gitelman.

Gitelman syndrome is one of the salt losing tubulopathies. Hypokalemia and hypomagnesemia appear in the setting of the partial blockade of salt absorption in the distal tubule. We conducted a descriptive study of a case series of five patients with Gitelman syndrome (4 women, from 28 to 85 years) in our institution, between the years 2004 and 2015. The most frequent form of diagnosis in our series was by laboratory finding. The only acknowledged clinical symptom was malaise. Regarding laboratory findings, the mean potassemia was of 2.5 ± 0.5 mmol/l, with a minimum value of 2.1 mmol/l. Additionally, the serum magnesium value was of 1.3 ± 0.3 mg/dl. In conclusion, we observed that the forms of presentation consist of biochemical alterations with or without nonspecific manifestations, which currently represents the greatest diagnostic difficulty and reinforces the importance to achieve a timely diagnosis, especially in young patients with critical serum potassium values.

El síndrome de Gitelman forma parte de las denominadas tubulopatías perdedoras de sal. El bloqueo parcial de la reabsorción de sodio en el túbulo contorneado distal determina la aparición de hipokalemia e hipomagnesemia. Se realizó un estudio descriptivo de una serie de cinco casos de síndrome de Gitelman (4 mujeres, de 28 a 85 años de edad) atendidos en nuestra institución entre los años 2004 y 2015. La forma de diagnóstico más frecuente en nuestra serie fue por hallazgo de laboratorio. El único síntoma clínico manifestado en forma espontánea fue astenia. En cuanto a los valores de laboratorio, la potasemia fue 2.5 ± 0.5 mmol/l, con un valor mínimo de 2.1. Adicionalmente, el valor de magnesio en sangre fue 1.3 ± 0.3 mg/dl. Como conclusión, observamos que las formas de presentación consisten en alteraciones bioquímicas con o sin manifestaciones inespecíficas, lo que representa actualmente la mayor dificultad diagnóstica y refuerza la importancia de lograr un diagnóstico oportuno, en especial en pacientes jóvenes y con valores críticos de potasio sérico.