meeting report www.kidney-international.org Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference OPEN Anne Blanchard1,2,3,4, Detlef Bockenhauer5,6, Davide Bolignano7, Lorenzo A. Calo` 8, Etienne Cosyns9, Olivier Devuyst10, David H. Ellison11, Fiona E. Karet Frankl12,13, Nine V.A.M. Knoers14, Martin Konrad15, Shih-Hua Lin16,17 and Rosa Vargas-Poussou2,18 1Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; 2Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Centre d’Investigation Clinique, Paris, France; 3Centre d’Investigation Clinique 1418, Institut National de la Santé et de la Recherche Médicale, Paris, France; 4UMR 970, Institut National de la Santé et de la Recherche Médicale, Paris, France; 5Centre for Nephrology, University College London, London, UK; 6Great Ormond Street Hospital for Children National Health Service Foundation Trust, London, UK; 7Institute of Clinical Physiology, National Research Council, Reggio, Calabria, Italy; 8Department of Medicine, Nephrology, University of Padova, Padova, Italy; 9Wanze, Belgium; 10Institute of Physiology, University of Zurich, Zurich, Switzerland; 11Division of Nephrology and Hypertension, Oregon Health and Science University, Veterans Affairs Portland Health Care System, Portland, Oregon, USA; 12Department of Medical Genetics, University of Cambridge and Cambridge University Hospitals National Health Service Trust, Cambridge, UK; 13Division of Renal Medicine, University of Cambridge and Cambridge University Hospitals National Health Service Trust, Cambridge, UK; 14Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands; 15Department of General Pediatrics, University Children’s Hospital, Münster, Germany; 16Division of Nephrology, Department of Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 17Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan; and 18Centre de Référence des Maladies Rénales Héréditaires de l’Enfant et de l’Adulte, Paris, France Gitelman syndrome (GS) is a rare, salt-losing tubulopathy an initial framework to enable clinical auditing and thus characterized by hypokalemic metabolic alkalosis with improve quality control of care. hypomagnesemia and hypocalciuria. The disease is Kidney International (2017) 91, 24–33; http://dx.doi.org/10.1016/ recessively inherited, caused by inactivating mutations in j.kint.2016.09.046 the SLC12A3 gene that encodes the thiazide-sensitive KEYWORDS: hypokalemic metabolic alkalosis; hypomagnesemia; salt-losing sodium-chloride cotransporter (NCC). GS is usually detected tubulopathy; SLC12A3; thiazide-sensitive sodium-chloride cotransporter during adolescence or adulthood, either fortuitously or in Copyright ª 2016, International Society of Nephrology. Published by association with mild or nonspecific symptoms or both. The Elsevier Inc. This is an open access article under the CC BY-NC-SA license (http://creativecommons.org/licenses/by-nc-sa/4.0/). 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 itelman syndrome (GS), also referred to as familial managed by a liberal salt intake together with oral hypokalemia-hypomagnesemia, is a salt-losing tubul- magnesium and potassium supplements. A general G opathy characterized by hypokalemic metabolic alka- problem in rare diseases is the lack of high quality evidence losis with hypomagnesemia and hypocalciuria.1,2 With a to inform diagnosis, prognosis, and management. We prevalence at w1 to 10 per 40,000, and potentially higher report here on the current state of knowledge related to in Asia,3 GS is arguably the most frequent inherited tubulop- the diagnostic evaluation, follow-up, management, and athy.4 The disease is caused by biallelic inactivating mutations treatment of GS; identify knowledge gaps; and propose a in the SLC12A3 gene encoding the thiazide-sensitive sodium- research agenda to substantiate a number of issues related chloride cotransporter (NCC) expressed in the apical mem- to GS. This expert consensus statement aims to establish brane of cells lining the distal convoluted tubule.5 To date, >350 mutations scattered throughout SLC12A3 have been identified in GS patients.6,7 The majority of patients are com- Correspondence: Olivier Devuyst, Institute of Physiology, University of pound heterozygous for SLC12A3 mutations, but a significant Zurich, Winterthurerstrasse 190, CH-8057, Zurich, Switzerland. E-mail: [email protected], or Nine V.A.M. Knoers, Department of Genetics, number of GS patients are found to carry only a single Center for Molecular Medicine, University Medical Center Utrecht, PO Box SLC12A3 mutation. 85090, 3508 AB, Utrecht, the Netherlands. E-mail: [email protected] The presence of both hypocalciuria and hypomagnesemia The authors contributed equally to this report and are listed is highly predictive for the clinical diagnosis of GS, although alphabetically. hypocalciuria is highly variable and hypomagnesemia may be 1,8,9 Received 4 August 2016; revised 14 September 2016; accepted 28 absent. The use of clinical and biological features to September 2016 differentiate from other salt-losing nephropathies is difficult 24 Kidney International (2017) 91, 24–33 A Blanchard et al.: Gitelman syndrome: a KDIGO conference report meeting report in some cases. A GS-like phenotype, including hypomagne- Clinical characteristics and diagnosis semia and hypocalciuria, has also been associated with GS presents mainly in adolescents and adults but can also be mutations in the CLCNKB gene encoding the chloride encountered in children, as early as in the neonatal channel ClC-Kb, the cause of classic Bartter syndrome ([cBS] period.15,18 The key clinical complaints and manifestations or Bartter syndrome type III). The localization of ClC-Kb in suggesting a diagnosis of GS (Table 1) include the following: the distal convoluted tubule explains the phenotypic overlap salt craving (i.e., preference for salty food or a salted treat with GS.10,11 Genetic testing is increasingly available for GS, during childhood); muscle weakness, fatigue, limited sport but it remains expensive. performance or endurance; episodes of fainting, cramps, GS has long been considered a benign tubulopathy, usually tetany, paresthesia, carpopedal spasms; growth retardation, detected during adolescence or adulthood. Indeed, the con- pubertal delay, short stature; thirst or abnormal drinking dition may be asymptomatic or associated with relatively mild behavior; episodes of abdominal pain. Dizziness, vertigo, or nonspecific symptoms or both such as muscular weakness, polyuria, nocturia, palpitations, joint pain, and visual prob- fatigue, salt craving, thirst, nocturia, or cramps. However, this lems may be reported in adults. view has been challenged by reports emphasizing the The proposed biochemical criteria for suspecting a diag- phenotypic variability and potential severity of the disease.12 nosis of GS (Table 2) include the following: documented Cruz et al.13 showed that GS is associated with a significant chronic hypokalemia (<3.5 mmol/l) concomitant with inap- reduction in the quality of life—similar to that associated propriate renal potassium wasting (spot urine, potassium- with congestive heart failure or diabetes. Severe manifesta- creatinine ratio >2.0 mmol/mmol [>18 mmol/g]), in tions, such as early onset (before age 6 years), growth retar- absence of potassium-lowering drugs; metabolic alkalosis; hy- dation, chondrocalcinosis, tetany, rhabdomyolysis, seizures, pomagnesemia (<0.7 mmol/l [<1.70 mg/dl], [Supplementary – and ventricular arrhythmia have been described.13 15 Of note, Table S1]); inappropriate renal magnesium wasting19 (frac- in many reports of severe complications, the diagnosis of GS tional excretion of magnesium >4%);19,20 hypocalciuria (spot was established on clinical rather than genetic grounds, urine, calcium-creatinine ratio <0.2 mmol/mmol [<0.07 potentially creating confusion with related disorders including mg/mg] in adults, [Supplementary Table S1]; normal ranges of cBS. Yet, phenotypic variability has also been documented in calcium-creatinine ratio are different in children, genetically confirmed GS patients, including in patients with [Supplementary Table S2]); high renin (activity or plasma identical SLC12A3 mutations.16 A combination of genotype, levels); fractional excretion of chloride >0.5%; normal or low sex, modifier genes, compensatory mechanisms, as well as blood pressure; normal renal ultrasound with absence of environmental factors or dietary habits might be involved in nephrocalcinosis or renal abnormalities. If plasma electrolyte such variability.17 levels are normal or close to normal in a patient taking GS is usually managed by a liberal salt (NaCl) intake, potassium or magnesium supplements or both, these sup- together with oral magnesium and potassium supplements. plements should be stopped for at least 48 hours in order to Potassium-sparing diuretics, renin angiotensin system potentially unmask the abnormalities. Plasma and urine blockers including angiotensin-converting-enzyme inhibitors samples should be obtained concomitantly. No evidence and angiotensin receptor blockers, and nonsteroidal anti- supports the need for 24-hour urine collection; spot urine inflammatory