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Guo W, Ji P, Xie Y. Genetic diagnosis and treatment of hereditary renal tubular disease with hypokalemia and alkalosis. J Nephrol 2023; 36:575-591. [PMID: 35994232 DOI: 10.1007/s40620-022-01428-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 07/29/2022] [Indexed: 10/15/2022]
Abstract
Renal tubules play an important role in maintaining water, electrolyte, and acid-base balance. Renal tubule dysfunction can cause electrolyte disorders and acid-base imbalance. Clinically, hypokalemic renal tubular disease is the most common tubule disorder. With the development of molecular genetics and gene sequencing technology, hereditary renal tubular diseases have attracted attention, and an increasing number of pathogenic genes related to renal tubular diseases have been discovered and reported. Inherited renal tubular diseases mainly occur due to mutations in genes encoding various specific transporters or ion channels expressed on the tubular epithelial membrane, leading to dysfunctional renal tubular reabsorption, secretion, and excretion. An in-depth understanding of the molecular genetic basis of hereditary renal tubular disease will help to understand the physiological function of renal tubules, the mechanism by which the kidney maintains water, electrolyte, and acid-base balance, and the relationship between the kidney and other systems in the body. Meanwhile, understanding these diseases also improves our understanding of the pathogenesis of hypokalemia, alkalosis and other related diseases and ultimately promotes accurate diagnostics and effective disease treatment. The present review summarizes the most common hereditary renal tubular diseases (Bartter syndrome, Gitelman syndrome, EAST syndrome and Liddle syndrome) characterized by hypokalemia and alkalosis. Further detailed explanations are provided for pathogenic genes and functional proteins, clinical manifestations, intrinsic relationship between genotype and clinical phenotype, diagnostic clues, differential diagnosis, and treatment strategies for these diseases.
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Affiliation(s)
- Wenkai Guo
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, 100853, People's Republic of China
- School of Medicine, Nankai University, Tianjin, 300071, People's Republic of China
| | - Pengcheng Ji
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, 100853, People's Republic of China
| | - Yuansheng Xie
- Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, 100853, People's Republic of China.
- School of Medicine, Nankai University, Tianjin, 300071, People's Republic of China.
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Chen SY, Jie N. Gitelman syndrome: A case report. World J Clin Cases 2022; 10:5893-5898. [PMID: 35979117 PMCID: PMC9258353 DOI: 10.12998/wjcc.v10.i17.5893] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 02/24/2022] [Accepted: 04/03/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gitelman syndrome (GS) is an autosomal recessive salt-losing renal tubulopathy arising from mutations in the thiazide-sensitive Na-Cl cotransporter gene. Due to its low incidence and lack of awareness, GS can be easily misdiagnosed or missed in diagnosis.
CASE SUMMARY A 24-year-old male presented with > 4 years of repeated limb weakness without any treatment. The previous day, the patient was bitten by ants and showed weakness of the lower limbs. The patient had hypokalemia (1.66-2.83 mmol/L), hypomagnesemia (0.4 mmol/L), hypocalciuria (1.51-2.46 mmol/d), metabolic alkalosis (7.47-7.54), normal blood pressure, and increased activity of aldosterone and plasma renin activity (PRA) (PRA 6.4 and 16.45 ng/mL/h and aldosterone 330.64 and 756.82 pg/mL in the supine and upright position, respectively). In addition, SLCI2A3 gene mutation with GS was diagnosed. Oral and intravenous supplementation with potassium and magnesium was initiated. Serum magnesium returned to 0.48 mmol/L and serum potassium returned to 3.08 mmol/L, alleviating the patient’s fatigue symptoms.
CONCLUSION GS should be considered in patients with hypokalemia complicated with hypomagnesemia. Genetic testing is essential to confirm the diagnosis.
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Affiliation(s)
- Shi-Yuan Chen
- Department of Endocrinology, Longhua Central Hospital, Shenzhen 518110, Guangdong Province, China
| | - Ning Jie
- Department of Endocrinology, Longhua Central Hospital, Shenzhen 518110, Guangdong Province, China
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3
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Organs-on-chip technology: a tool to tackle genetic kidney diseases. Pediatr Nephrol 2022; 37:2985-2996. [PMID: 35286457 PMCID: PMC9587109 DOI: 10.1007/s00467-022-05508-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 02/01/2022] [Accepted: 02/10/2022] [Indexed: 01/10/2023]
Abstract
Chronic kidney disease (CKD) is a major healthcare burden that takes a toll on the quality of life of many patients. Emerging evidence indicates that a substantial proportion of these patients carry a genetic defect that contributes to their disease. Any effort to reduce the percentage of patients with a diagnosis of nephropathy heading towards kidney replacement therapies should therefore be encouraged. Besides early genetic screenings and registries, in vitro systems that mimic the complexity and pathophysiological aspects of the disease could advance the screening for targeted and personalized therapies. In this regard, the use of patient-derived cell lines, as well as the generation of disease-specific cell lines via gene editing and stem cell technologies, have significantly improved our understanding of the molecular mechanisms underlying inherited kidney diseases. Furthermore, organs-on-chip technology holds great potential as it can emulate tissue and organ functions that are not found in other, more simple, in vitro models. The personalized nature of the chips, together with physiologically relevant read-outs, provide new opportunities for patient-specific assessment, as well as personalized strategies for treatment. In this review, we summarize the major kidney-on-chip (KOC) configurations and present the most recent studies on the in vitro representation of genetic kidney diseases using KOC-driven strategies.
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Nuñez-Gonzalez L, Carrera N, Garcia-Gonzalez MA. Molecular Basis, Diagnostic Challenges and Therapeutic Approaches of Bartter and Gitelman Syndromes: A Primer for Clinicians. Int J Mol Sci 2021; 22:11414. [PMID: 34768847 PMCID: PMC8584233 DOI: 10.3390/ijms222111414] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 12/18/2022] Open
Abstract
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.
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Affiliation(s)
- Laura Nuñez-Gonzalez
- Grupo de Xenetica e Bioloxia do Desenvolvemento das Enfermidades Renais, Laboratorio de Nefroloxia (No. 11), Instituto de Investigacion Sanitaria de Santiago (IDIS), Complexo Hospitalario de Santiago de Compostela (CHUS), 15706 Santiago de Compostela, Spain;
- Grupo de Medicina Xenomica, Complexo Hospitalario de Santiago de Compostela (CHUS), 15706 Santiago de Compostela, Spain
| | - Noa Carrera
- Grupo de Xenetica e Bioloxia do Desenvolvemento das Enfermidades Renais, Laboratorio de Nefroloxia (No. 11), Instituto de Investigacion Sanitaria de Santiago (IDIS), Complexo Hospitalario de Santiago de Compostela (CHUS), 15706 Santiago de Compostela, Spain;
- Grupo de Medicina Xenomica, Complexo Hospitalario de Santiago de Compostela (CHUS), 15706 Santiago de Compostela, Spain
- RedInRen (Red en Investigación Renal) RETIC (Redes Temáticas de Investigación Cooperativa en Salud), ISCIII (Instituto de Salud Carlos III), 28029 Madrid, Spain
| | - Miguel A. Garcia-Gonzalez
- Grupo de Xenetica e Bioloxia do Desenvolvemento das Enfermidades Renais, Laboratorio de Nefroloxia (No. 11), Instituto de Investigacion Sanitaria de Santiago (IDIS), Complexo Hospitalario de Santiago de Compostela (CHUS), 15706 Santiago de Compostela, Spain;
- Grupo de Medicina Xenomica, Complexo Hospitalario de Santiago de Compostela (CHUS), 15706 Santiago de Compostela, Spain
- RedInRen (Red en Investigación Renal) RETIC (Redes Temáticas de Investigación Cooperativa en Salud), ISCIII (Instituto de Salud Carlos III), 28029 Madrid, Spain
- Fundación Pública Galega de Medicina Xenomica—SERGAS, Complexo Hospitalario de Santiago de Compotela (CHUS), 15706 Santiago de Compostela, Spain
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Francini F, Gobbi L, Ravarotto V, Toniazzo S, Nalesso F, Spinella P, Calò LA. The Dietary Approach to the Treatment of the Rare Genetic Tubulopathies Gitelman's and Bartter's Syndromes. Nutrients 2021; 13:nu13092960. [PMID: 34578838 PMCID: PMC8467039 DOI: 10.3390/nu13092960] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/19/2021] [Accepted: 08/24/2021] [Indexed: 02/06/2023] Open
Abstract
Gitelman’s (GS) and Bartter’s (BS) syndromes are rare, inherited autosomal recessive tubulopathies characterized by hypokalemia, metabolic alkalosis, renal sodium, chloride, and potassium and magnesium-wasting. While the treatment based on potassium, sodium, chloride, and magnesium supplementation in addition to other pharmacologic options are widely established, recommendations about the dietary approach to GS and BS still remain generic. In this review we focus on the dietary strategies to increase sodium, potassium, and magnesium intake in GS and BS patients. Potassium and magnesium-rich foods and supplements are considered together with those that may reduce through different mechanisms the potassium and magnesium plasma level. Magnesium supplementation is often poorly tolerated, causing abdominal pain and diarrhea in most patients. New formulations using liposome and, in particular, sucrosomial technology have been recently proposed for magnesium supplementation in order to increase magnesium supplement tolerability and intestinal absorption. The dietary approach to GS and BS may be very important in the therapeutic approach to these syndromes. Due to the relevance of the dietary approach to these syndromes, a nutritional counseling should always be recommended and the nutritionist should join nephrologists in the follow-up of GS and BS patient care.
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Affiliation(s)
- Francesco Francini
- Department of Medicine (DIMED), Clinical Nutrition, University of Padova, 35128 Padova, Italy; (F.F.); (S.T.); (P.S.)
| | - Laura Gobbi
- Nephrology, Dialysis and Transplantation Units, Department of Medicine (DIMED), University of Padova, 35128 Padova, Italy; (L.G.); (V.R.); (F.N.)
| | - Verdiana Ravarotto
- Nephrology, Dialysis and Transplantation Units, Department of Medicine (DIMED), University of Padova, 35128 Padova, Italy; (L.G.); (V.R.); (F.N.)
| | - Silvia Toniazzo
- Department of Medicine (DIMED), Clinical Nutrition, University of Padova, 35128 Padova, Italy; (F.F.); (S.T.); (P.S.)
| | - Federico Nalesso
- Nephrology, Dialysis and Transplantation Units, Department of Medicine (DIMED), University of Padova, 35128 Padova, Italy; (L.G.); (V.R.); (F.N.)
| | - Paolo Spinella
- Department of Medicine (DIMED), Clinical Nutrition, University of Padova, 35128 Padova, Italy; (F.F.); (S.T.); (P.S.)
| | - Lorenzo A Calò
- Nephrology, Dialysis and Transplantation Units, Department of Medicine (DIMED), University of Padova, 35128 Padova, Italy; (L.G.); (V.R.); (F.N.)
- Correspondence: ; Tel.: +39-04-9821-3071
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Review and Analysis of Two Gitelman Syndrome Pedigrees Complicated with Proteinuria or Hashimoto's Thyroiditis Caused by Compound Heterozygous SLC12A3 Mutations. BIOMED RESEARCH INTERNATIONAL 2021; 2021:9973161. [PMID: 34046503 PMCID: PMC8128541 DOI: 10.1155/2021/9973161] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/25/2021] [Accepted: 05/03/2021] [Indexed: 02/07/2023]
Abstract
Gitelman syndrome (GS) is an autosomal recessive inherited salt-losing renal tubular disease, which is caused by a pathogenic mutation of SLC12A3 encoding thiazide-sensitive Na-Cl cotransporter, which leads to disturbance of sodium and chlorine reabsorption in renal distal convoluted tubules, resulting in phenotypes such as hypovolemia, renin angiotensin aldosterone system (RAAS) activation, hypokalemia, and metabolic alkalosis. In this study, two GS families with proteinuria or Hashimoto's thyroiditis were analyzed for genetic-phenotypic association. Sanger sequencing revealed that two probands carried SLC12A3 compound heterozygous mutations, and proband A carried two pathogenic mutations: missense mutation Arg83Gln, splicing mutation, or frameshift mutation NC_000016.10:g.56872655_56872667 (gcggacatttttg>accgaaaatttt) in exon 8. Proband B carries two missense mutations: novel Asp839Val and Arg904Gln. Both probands manifested hypokalemia, hypomagnesemia, hypocalcinuria, metabolic alkalosis, and RAAS activation; in addition, the proband A exhibited decreased urinary chloride, phosphorus, and increased magnesium ions excretion, complicated with Hashimoto's Thyroiditis, while the proband B exhibited enhanced urine sodium excretion and proteinuria. The older sister of proband B with GS also had Hashimoto's thyroiditis. Electron microscopy revealed swelling and vacuolar degeneration of glomerular epithelial cells, diffuse proliferation of mesangial cells and matrix, accompanied by a small amount of low-density electron-dense deposition, and segmental fusion of epithelial cell foot processes in proband B. Light microscopy showed mild mesangial hyperplasia in the focal segment of the glomerulus, hyperplasia, and hypertrophy of juxtaglomerular apparatus cells, mild renal tubulointerstitial lesions, and one glomerular sclerosis. So, long-term hypokalemia of GS can cause kidney damage and may also be susceptible to thyroid disease.
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Zhang L, Huang K, Wang S, Fu H, Wang J, Shen H, Lu Z, Chen J, Bao Y, Feng C, Dong G, Mao J. Clinical and Genetic Features in 31 Serial Chinese Children With Gitelman Syndrome. Front Pediatr 2021; 9:544925. [PMID: 33996672 PMCID: PMC8116576 DOI: 10.3389/fped.2021.544925] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 03/19/2021] [Indexed: 11/13/2022] Open
Abstract
Gitelman syndrome (GS, OMIM 263800) is a genetic congenital tubulopathy associated with salt loss, which is characterized by hypokalemic metabolic toxicity, hypocalciuria, and hypomagnesemia. GS, which is typically detected in adolescence or adulthood, has long been considered a benign tubular lesion; however, the disease is associated with a significant decrease in the quality of life. In this study, we assessed the genotype-phenotype correlations based on the medical histories, clinical symptoms, laboratory test results, and whole-exome sequencing profiles from pediatric patients with GS. Between January 2014 and December 2020, all 31 consecutively enrolled patients complained of fatigue, salt craving, and muscle weakness. Sixteen patients demonstrated growth retardation, and five patients presented with nocturia and constipation. All patients presented with hypokalemic metabolic alkalosis, normal blood pressure, hyperaldosteronism, and a preserved glomerular filtration rate, and 24 of the 31 (77.4%) patients had hypomagnesemia. Homozygous, compound heterozygous, and heterozygous mutations in SLC12A3 were detected in 4, 24, and 3 patients, respectively. GS patients often present with muscle weakness and fatigue caused by hypokalemia and hypomagnesemia. Therefore, early diagnosis of GS is important in young children to reduce the possibility of growth retardation, tetany, and seizures. Next-generation sequencing such as whole-exome or whole-genome sequencing provides a practical tool for the early diagnosis and improvement of GS prognosis. Further whole-genome sequencing is expected to reveal more variants in SLC123A among GS patients with single heterozygous mutations.
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Affiliation(s)
- Lingxia Zhang
- Department of Nephrology, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Ke Huang
- Department of Endocrinology, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Shugang Wang
- Chigene (Beijing) Translational Medical Research Center, Yizhuang, China
| | - Haidong Fu
- Department of Nephrology, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Jingjing Wang
- Department of Nephrology, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Huijun Shen
- Department of Nephrology, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Zhihong Lu
- Department of Nephrology, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Junyi Chen
- Department of Nephrology, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Yu Bao
- Department of Nephrology, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Chunyue Feng
- Department of Nephrology, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Guanping Dong
- Department of Endocrinology, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Jianhua Mao
- Department of Nephrology, The Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
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Structure and mechanism of the cation-chloride cotransporter NKCC1. Nature 2019; 572:488-492. [PMID: 31367042 DOI: 10.1038/s41586-019-1438-2] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 06/24/2019] [Indexed: 01/01/2023]
Abstract
Cation-chloride cotransporters (CCCs) mediate the electroneutral transport of chloride, potassium and/or sodium across the membrane. They have critical roles in regulating cell volume, controlling ion absorption and secretion across epithelia, and maintaining intracellular chloride homeostasis. These transporters are primary targets for some of the most commonly prescribed drugs. Here we determined the cryo-electron microscopy structure of the Na-K-Cl cotransporter NKCC1, an extensively studied member of the CCC family, from Danio rerio. The structure defines the architecture of this protein family and reveals how cytosolic and transmembrane domains are strategically positioned for communication. Structural analyses, functional characterizations and computational studies reveal the ion-translocation pathway, ion-binding sites and key residues for transport activity. These results provide insights into ion selectivity, coupling and translocation, and establish a framework for understanding the physiological functions of CCCs and interpreting disease-related mutations.
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9
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Uzunlulu M, Dumanoglu B. Gitelman Syndrome Presenting with Hypomagnesemia, Hypokalemia and Hypocalciuria: A Case Report. Medeni Med J 2019; 34:314-317. [PMID: 32821454 PMCID: PMC7433730 DOI: 10.5222/mmj.2019.39000] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2018] [Accepted: 03/23/2019] [Indexed: 11/05/2022] Open
Abstract
Gitelman syndrome is a a rarely seen autosomal recessive renal tubulopathy characterized by inherited hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. The diagnosis of Gitelman syndrome is usually established during adolescence, but is also observed in childhood and even in the adulthood period. In this case report, we presented a 19-year-old male patient who was diagnosed as Gitelman Syndrome and admitted to the hospital with symptoms of muscle weakness, cramps and weakness.
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Affiliation(s)
- Mehmet Uzunlulu
- Istanbul Medeniyet University Goztepe Training and Researh Hospital, Department of Internal Medicine, Istanbul, Turkey
| | - Betul Dumanoglu
- Istanbul Medeniyet University Goztepe Training and Researh Hospital, Department of Internal Medicine, Istanbul, Turkey
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10
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Blanchard A, Bockenhauer D, Bolignano D, Calò LA, Cosyns E, Devuyst O, Ellison DH, Karet Frankl FE, Knoers NVAM, Konrad M, Lin SH, Vargas-Poussou R. Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 2017; 91:24-33. [PMID: 28003083 DOI: 10.1016/j.kint.2016.09.046] [Citation(s) in RCA: 207] [Impact Index Per Article: 25.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 09/14/2016] [Accepted: 09/28/2016] [Indexed: 12/18/2022]
Abstract
Gitelman syndrome (GS) is a rare, salt-losing tubulopathy characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. The disease is recessively inherited, caused by inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter (NCC). GS is usually detected during adolescence or adulthood, either fortuitously or in association with mild or nonspecific symptoms or both. The disease is characterized by high phenotypic variability and a significant reduction in the quality of life, and it may be associated with severe manifestations. GS is usually managed by a liberal salt intake together with oral magnesium and potassium supplements. A general problem in rare diseases is the lack of high quality evidence to inform diagnosis, prognosis, and management. We report here on the current state of knowledge related to the diagnostic evaluation, follow-up, management, and treatment of GS; identify knowledge gaps; and propose a research agenda to substantiate a number of issues related to GS. This expert consensus statement aims to establish an initial framework to enable clinical auditing and thus improve quality control of care.
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Affiliation(s)
- Anne Blanchard
- Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Centre d'Investigation Clinique, Paris, France; Centre d'Investigation Clinique 1418, Institut National de la Santé et de la Recherche Médicale, Paris, France; UMR 970, Institut National de la Santé et de la Recherche Médicale, Paris, France
| | - Detlef Bockenhauer
- Centre for Nephrology, University College London, London, UK; Great Ormond Street Hospital for Children National Health Service Foundation Trust, London, UK
| | - Davide Bolignano
- Institute of Clinical Physiology, National Research Council, Reggio, Calabria, Italy
| | - Lorenzo A Calò
- Department of Medicine, Nephrology, University of Padova, Padova, Italy
| | | | - Olivier Devuyst
- Institute of Physiology, University of Zurich, Zurich, Switzerland.
| | - David H Ellison
- Division of Nephrology and Hypertension, Oregon Health and Science University, Veterans Affairs Portland Health Care System, Portland, Oregon, USA
| | - Fiona E Karet Frankl
- Department of Medical Genetics, University of Cambridge and Cambridge University Hospitals National Health Service Trust, Cambridge, UK; Division of Renal Medicine, University of Cambridge and Cambridge University Hospitals National Health Service Trust, Cambridge, UK
| | - Nine V A M Knoers
- Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
| | - Martin Konrad
- Department of General Pediatrics, University Children's Hospital, Münster, Germany
| | - Shih-Hua Lin
- Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan
| | - Rosa Vargas-Poussou
- Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Centre d'Investigation Clinique, Paris, France; Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Paris, France
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11
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A 4-year-old boy presenting with persistent urinary incontinence: Answers. Pediatr Nephrol 2017; 32:769-771. [PMID: 27350624 DOI: 10.1007/s00467-016-3442-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Revised: 05/31/2016] [Accepted: 06/02/2016] [Indexed: 10/21/2022]
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13
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Tsutsui H, Hamano T, Kawaura Y, Inaba S, Miyamori I, Yasujima M, Yoneda M, Kuriyama M. A case of Gitelman syndrome associated with idiopathic intracranial hypertension. Intern Med 2011; 50:1493-6. [PMID: 21757836 DOI: 10.2169/internalmedicine.50.5305] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
An 18-year-old woman with Gitelman syndrome (GS) associated with idiopathic intracranial hypertension (IIH) is described. She was obese and showed a 10 kg gain in body weight over a period of 8 months. She presented with headache, vomiting, and diplopia. She had bilateral papilledema, and right abducens palsy. CSF examination demonstrated high pressure (over 320 mmH(2)O) with normal cytochemistry. Brain MRI was normal. She showed mild alkalosis, hypokalemia, hypomagnesemia, increased plasma renin activity, and normal blood pressure. Two heterozygous mutations in the SLC12A3 gene were identified. Therefore, she was diagnosed as GS with IIH. We should keep in mind the possible occurrence of IIH in GS.
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Affiliation(s)
- Hiromi Tsutsui
- The Second Department of Internal Medicine, Division of Neurology, University of Fukui, Japan
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14
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Hinschberger O, Martzolff L, Ioannou G, Baumann D, Jaeger F, Kieffer P. [Acquired Gitelman syndrome associated with Sjögren's syndrome and scleroderma]. Rev Med Interne 2010; 32:e96-8. [PMID: 20888090 DOI: 10.1016/j.revmed.2010.08.017] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2009] [Revised: 08/20/2010] [Accepted: 08/20/2010] [Indexed: 12/01/2022]
Abstract
Tubulopathy can complicate autoimmune diseases. It is usually a distal tubular acidosis, but Fanconi syndrome or Bartter syndrome has been exceptionally reported. We report a case of acquired Gitelman syndrome in a 32-year-old male who also presented diffuse scleroderma autoimmune thyroiditis, and Sjögren's syndrome. Only three cases of Sjögren syndrome associated with Gitelman syndrome have been previously reported in literature. The absence of other cases in the family and absence of mutation SLC12A3 emphasise the relation between autoimmune disease and this tubulopathy.
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Affiliation(s)
- O Hinschberger
- Service de médecine interne et soins continus, centre hospitalier de Mulhouse, 20, rue du Docteur-Laennec, 68134 Mulhouse cedex, France
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Nakamura A, Shimizu C, Nagai S, Yoshida M, Aoki K, Kondo T, Miyoshi H, Wada N, Tajima T, Terauchi Y, Yoshioka N, Koike T. Problems in diagnosing atypical Gitelman's syndrome presenting with normomagnesaemia. Clin Endocrinol (Oxf) 2010; 72:272-6. [PMID: 19508680 DOI: 10.1111/j.1365-2265.2009.03649.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
OBJECTIVE Gitelman's syndrome, recognized as a variant of Bartter's syndrome, is characterized by hypokalaemic metabolic alkalosis in combination with hypomagnesaemia and hypocalciuria. Overlapping biochemical features in Gitelman's syndrome and Bartter's syndrome has been observed. Here, we investigated the clinical, biochemical, and genetic characteristics of five, chronic, nonhypertensive and hypokalaemic Japanese patients. METHODS Serum and urinary electrolytes, plasma renin activity and plasma aldosterone concentration were measured in five patients (four males and one female) with hypokalaemia. Renal clearance tests were performed and distal fractional chloride reabsorption calculated. Finally, mutational analysis of the thiazide-sensitive Na-Cl co-transporter gene was performed. RESULTS Symptoms in patients varied from mild (muscle weakness and numbness) to severe (tetany and foot paralysis). All patients were normotensive or hypotensive, and all had hypokalaemia, hypocalciuria, and hyperreninaemic hyperaldosteronism. However, two male patients had normomagnesaemia, while the remainder was hypomagnesaemic. Renal clearance tests showed that the administration of furosemide decreased distal fractional chloride reabsorption, while thiazide ingestion failed to decrease it. Genetic analysis identified six thiazide-sensitive Na-Cl co-transporter gene mutations, including two novel ones. Therefore, on the basis of the confirmatory renal clearance tests and mutational analysis, a diagnosis of Gitelman's syndrome was made in these patients. CONCLUSIONS Two of the five patients diagnosed with Gitelman's syndrome were normomagnesaemic, which is uncommon in this syndrome. Our study indicates that renal clearance tests and mutation analysis can play an important role in diagnosing Gitelman's syndrome more precisely.
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Affiliation(s)
- Akinobu Nakamura
- Department of Medicine II, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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Aoki K, Tajima T, Yabushita Y, Nakamura A, Nezu U, Takahashi M, Kimura M, Terauchi Y. A novel initial codon mutation of the thiazide-sensitive Na-Cl cotransporter gene in a Japanese patient with Gitelman's syndrome. Endocr J 2008; 55:557-60. [PMID: 18520105 DOI: 10.1507/endocrj.k07e-113] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
We here report a novel mutation of the thiazide-sensitive Na-Cl cotransporter (TSC) (SLC12A3) gene in a Japanese patient with Gitelman's syndrome (GS). GS is characterized by a renal disorder and is associated with hypokalemia, hypomagnesemia, metabolic alkalosis and hypocalciuria arising from the defective tubular reabsorption of magnesium and potassium. This disease is reportedly caused by mutations in the TSC gene. A 52-year-old man was referred to our hospital because of sleeplessness and tinnitus. He exhibited hypokalemia, hypomagnesemia, hypocalciuria, metabolic alkalosis and hyperreninemic hyperaldosteronism. A renal clearance study revealed that the administration of furosemide decreased chloride reabsorption; however, the ingestion of thiazide failed to decrease chloride reabsorption. A diagnosis of GS was made based on the clinical features, laboratory data and renal function test results. Sequencing of the patient's genomic DNA revealed an A to T transition at the initial codon of exon 1 of the TSC gene (c1A>T). Knowledge of this novel mutation may be helpful for understanding the pathophysiology of GS and the function of TSC as well as for providing genetic counseling.
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Affiliation(s)
- Kazutaka Aoki
- Department of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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