ERKNet Gitelman Syndrome Consensus from a KDIGO Controversies Conference Rosa Vargas-Poussou ERKNet Gitelman syndrome KDIGO consensus Anne Blanchard Paris, France Detlef Bockenhauer London, UK Davide Bolignano Calabria, Italy Lorenzo A. Calo Padova, Italy Etienne Cosyns Wanze, Belgium Olivier Devuyst Zurich, Switzerland David H. Ellison Portland, Oregon, USA Fiona E. Karet Frankl Cambridge, UK Nine V.A.M. Knoers Utrecht, The Netherlands Martin Konrad Münster, Germany Shih-Hua Lin Taipei, Taiwan Rosa Vargas-Poussou Paris, France Kidney International (2017) 91, 24–33; http://dx.doi.org/10.1016/j.kint.2016.09.046 ERKNet Gitelman Syndrome • Salt losing tubulopathy • Autosomal recessive inheritance • Prevalence: 1 to 10 per 40,000 • Most frequent inherited tubulopathy ERKNet Distal convoluted tubule Thiazides Cl - Na+ Na+ K+ K+ Kir4.1 Ca2+ Cl- Ca2+ Kv1.1 K+ Na+ Ca2+ TRPM6 HNF1Beta Mg2+ + Na+ Na 2+ H+ Mg Reabsorption: Na+ 7% Ca2⁺ and Mg2⁺ 10% ERKNet Pendrine + - Na - Cl + - Cl - K Cl HCO3 Thiazides + Na + - Na Cl + + - 2⁺ Na K 2+ HCO3 Mg 10% Ca Cl- Na+ 7% 2+ Ca2+ Ca + - + Na Cl - H Mg2+ HCO3 Mg2+ + + + Na + Na H+ Na Na NDCBE 70% + + - H H HCO3 HCO3 Hypomagnesemia - Cl Na+ ACII 20% Hypocalciuria + + 2⁺ + K Na Mg H Na + K+ 2% 70% CO H O 2 2 2Cl - Na+ Furosemide Na+ K+ K+ (-) (+) K+ Cl - Amiloride ENaC Barttine + - + Na Cl Na + K K+ K+ + + - H Na HCO3 ++ + K+ Aldostérone Ca Na Chronic hypovolemia Mg++ + NH4 H O Claudines 2 (-) RM H2O (+) Vte Hypokalemia. Metabolic alkalosis ERKNet Gitelman syndrome • Mainly in adolescents and adults 9.5% 16% 7% Med IQR: 25 (14-38) ERKNet Low blood pressure Asymptomatic Salt loss Fortuitous detection of hypokalemia salt craving muscle weakness fatigue cramps constipation tetanic episodes Prolonged QT Hypokalemia Hypomagnesemia Abdominal pain carpopedal spasms chondrocalcinosis rhabdomyolysis Glucose intolerance/ Insulin resistance Sclerochoroidal calcifications ventricular arrhythmias. Clinical Manifestations ERKNet Salt craving, cramps, muscle weakness, fatigue, dizzines, nocturia, palpitations, Most common paresthesia, thirst, polydipsia, low BP > 50% Fainting, polyuria, arthralgia, chondrocalcinosis, prolonged QT, Prominent febrile episodes 20 - 50% Early onsent, failure to thrive, pubertal delay, vertigo, ataxia, carpopedal spasm, tetany, Occasional vomiting, constipation, enuresis paralysis < 20 % Seizure, tachycardia, rhabdomyolisis, pseudotumor cerebri, sclerochoroidal Rare calcifications (case reports) Criteria for diagnosis ERKNet Minimal Blood Urines K < 3.5 mmol/L K/creat. > 2 mmol/mmol Chronic Renal Hypokalemia > 18 mmol/g Metabolic Alkalosis Bicarbonate > 28 mmol/l Cl wasting Fractional Exc Cl > 0.5% Frequent (their absence does not exclude the diagnosis) Blood Urines Chronic Renal Mg <0.7 mmol/l Fractional Exc Mg >4% Hypomagnesemia [<1.70 mg/dl] Hypocalciuria Ca/creat. <0.2 mmol/mmol <0.07 mg/mg Hyperreninism High plasma renin Low or normal blood pressure Normal renal ultrasound ERKNet Differential diagnosis Renal 1. Classic Bartter syndrome Thiazides Cl - Na+ Na+ K+ K+ Kir4.1 2. Diseases associated with Ca2+ Cl- mutations of the HNF1B gene Ca2+ Kv1.1 K+ Na Ca2+ TRPM6 HNF1Beta + 3. EAST syndrome Mg2+ + Na+ H+ Na Mg2+ 4. Autoimmune disorders 5. Diuretics Extrarenal 1. Cystic Fibrosis 2. Chronic vomiting 3. Laxative abuse ERKNet Genetic diagnosis • Established diagnosis • Accredited lab – Biallelic mutations in the • Techniques SLC12A3 gene – Sanger • Adapted follow-up – MLPA • Counselling • NGS panel • Whole exome/genome Genetic diagnosis ERKNet Sequencing + MLPA 1198 probands Mutations 3% 6% 6% 6% 12% 13% 14% 55% 55% 16% 14% Missense (n=158) Compound heterozygous (n = 697) Frameshift (n=39) Homozygous (n = 174) Splicing (n=28) one heterozygous mutation (n = 127) Nonsens (n=18) No mutation (n = 165) CLCNKB (n=35) Inframe (n=7) Grands réarrangements (n=18) Mutation detection rate 88% ERKNet Treatment 1 • ad libitum NaCl intake • Individualized lifelong oral Side effects Symptoms supplementation Fatigue – Potassium (target 3.0 mmol/l) Cramps • KCl 40 mmol / 1-2 mmol/kg in Ulcer children Vomiting Muscle – Magnesium (target 0.6 mmol/l) diarrhea weakness • 300 mg/day • Avoid drugs associated with hypokalemia and hypomagnesemia • Education Treatment 2 ERKNet • Potassium-sparing diuretics, Indomethacin • RAS inhibitors 75 mg/day 150 mg/day 20 mg/day Blanchard A et al. JASN 2015 doi:10.1681/ASN.2014030293 ERKNet Benign tubulopathy ? • Reduction of quality of • Annual follow-up in a life nephrology clinic: monitoring complications • Growth retardation – Renal function/proteinuria • Chondrocalcinosis – ECG • Ventricular arrhythmia – Glycaemia – Ultrasound X- ray • Hypertension – Ophthalmology exam. • Glucose intolerance • Cardiology workup ERKNet Knowledge gaps and research questions for Gitelman syndrome 1 • Blood pressure control, • Genetic aspects – hypertension – Genetic heterogeneity, • Cardiovascular complications: causal/modifier – conduction, myocardium, predictive – pathogenicity of variants effort ECG, reproducibility, age effect, – Prevalence of SLC12A3 mutations QT interval, and electrolyte levels in exome database • Metabolic complications: – Effect of the carrier state, – glucose tolerance, role of magnesium geographic variations balance – Genotype-phenotype correlations, • Patient-related outcomes – Sex effect – Quality of life, disability, sociology, – Establishing prevalence of the perception of symptoms disease and the carrier state – Disability scores – Self-management techniques ERKNet Knowledge gaps and research questions for Gitelman syndrome 2 • Intervention • Outcome and natural history – Effect of high NaCl supplementation – Registry, biobanking – Effect of sport, increased muscular – Growth, activity, sports mass, potassium supplementation after – Glucose intolerance and metabolic exercise profile – Optimal target values for K and Mg – Renal function, concentration defect, • Mother and child proteinuria, chronic kidney disease, cysts – Pregnancy and fetal development – Cardiovascular complications • Monitoring – Rare complications: pseudotumor – non-invasive, frequency, possible cerebri, pectus excavatum, link with transcutaneous measurements autoimmunity ERKNet Conclusion • Described 1966 • Long-term studies to assess • Genetics 1996 the natural history • Clinical variability • Prevalence of complications • Complications • Evidence-based treatments • Causes of variability ERKNet Sick day rules 1 • Do not stop medication • Medical advice if : • If you feel unwell, chek your – pass out/faint K and Mg – become dizzy • If diarrhea or vomiting, é – develop tingling or muscle weakness fluid intake and add salt to – notice an irregular heartbeat anything you drink (palpitations) • Medical advice if you – have painful muscular spasms cannot keep anything down – unusual symptoms for 24 h .