The diagnosis and treatment of Gitelman syndrome in adults_West China Medical Journal

Authors：

TANG Lizhi ,  TONG Nanwei

Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

TONG Nanwei, Email: tongnw@scu.edu.cn

Keywords：

Gitelman syndrome; Renal tubulopathy; Hypokalemic metabolic alkalosis; SLC12A3 gene

DOI：

10.7507/1002-0179.201803135

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Gitelman syndrome (GS) is an autosomal recessive kidney disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. The disorder is named for Gitelman, an American nephrologist. He first described it in 1966, after observing a pair of sisters with the disorder. The disorder is caused by inactivating mutations in the SLC12A3 gene, resulting in improper function of the thiazide-sensitive sodium-chloride co-transporter located in the distal convoluted tubule of the kidney. GS was formerly considered a subset of Bartter syndrome until the distinct genetic and molecular bases of these disorders were identified. GS is usually managed by a liberal salt intake together with oral magnesium and potassium supplements. This review aims to establish an initial framework to enable clinical auditing and thus improve quality control of care.

Citation： TANG Lizhi, TONG Nanwei. The diagnosis and treatment of Gitelman syndrome in adults. West China Medical Journal, 2018, 33(5): 605-610. doi: 10.7507/1002-0179.201803135 Copy

1.	Gitelman HJ, Graham JB, Welt LG. A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians, 1966, 79(79): 221-235.
2.	Takeuchi Y, Mishima E, Shima H, et al. Exonic mutations in the SLC12A3 gene cause exon skipping and premature termination in Gitelman syndrome. J Am Soc Nephrol, 2015, 26(2): 271-279.
3.	Bettinelli A, Bianchetti MG, Girardin E, et al. Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndromes. J Pediatr, 1992, 120(1): 38-43.
4.	Fukuyama S, Hiramatsu M, Akagi M, et al. Novel mutations of the chloride Channel Kb gene in two Japanese patients clinically diagnosed as Bartter syndrome with hypocalciuria. J Clin Endocrinol Metab, 2004, 89(11): 5847-5850.
5.	Gitelman 综合征诊治专家共识协作组. Gitelman 综合征诊治专家共识. 中华内科杂志, 2017, 56(9): 712-716.
6.	Peters M, Jeck N, Reinalter S, et al. Clinical presentation of genetically defined patients with hypokalemic salt-losing tubulopathies. Am J Med, 2002, 112(3): 183-190.
7.	Pachulski RT, Lopez F, Sharaf R. Gitelman’s not-so-benign syndrome. N Engl J Med, 2005, 353(8): 850-851.
8.	Blanchard A, Bockenhauer D, Bolignano D, et al. Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int, 2017, 91(1): 24-33.
9.	Calò L, Punzi L, Semplicini A. Hypomagnesemia and chondrocalcinosis in Bartter’s and Gitelman’s syndrome : review of the pathogenetic mechanisms. Am J Nephrol, 2000, 20(5): 347-350.
10.	Gupta R, Hu V, Reynolds T, et al. Sclerochoroidal calcification associated with Gitelman syndrome and calcium pyrophosphate dihydrate deposition. J Clin Pathol, 2005, 58(12): 1334-1335.
11.	Godefroid N, Riveira-Munoz E, Saint-Martin C, et al. A novel splicing mutation in SLC12A3 associated with Gitelman syndrome and idiopathic intracranial hypertension. Am J Kidney Dis, 2006, 48(5): e73-e79.
12.	Bettinelli A, Tosetto C, Colussi G, et al. Electrocardiogram with prolonged QT interval in Gitelman disease. Kidney Int, 2002, 62(2): 580-584.
13.	Colussi G, Bettinelli A, Tedeschi S, et al. A thiazide test for the diagnosis of renal tubular hypokalemic disorders. Clin J Am Soc Nephrol, 2007, 2(3): 454-460.
14.	Bouwer ST, Coto E, Santos F, et al. The Gitelman syndrome mutation, IVS9+1G>T, is common across Europe. Kidney Int, 2007, 72(7): 898.
15.	Ma J, Ren H, Lin L, et al. Genetic features of Chinese patients with gitelman syndrome: sixteen novel SLC12A3 mutations identified in a new cohort. Am J Nephrol, 2016, 44(2): 113-121.
16.	Qin L, Shao L, Ren H, et al. Identification of five novel variants in the thiazide-sensitive NaCl co-transporter gene in Chinese patients with Gitelman syndrome. Nephrology (Carlton), 2009, 14(1): 52-58.
17.	Shao L, Ren H, Wang W, et al. Novel SLC12A3 mutations in Chinese patients with Gitelman’s syndrome. Nephron Physiol, 2008, 108(3): p29-p36.
18.	Shao L, Liu L, Miao Z, et al. A novel SLC12A3 splicing mutation skipping of two exons and preliminary screening for alternative splice variants in human kidney. Am J Nephrol, 2008, 28(6): 900-907.
19.	Morton A. Eplerenone in the treatment of Gitelman’s syndrome. Intern Med J, 2008, 38(5): 377.
20.	Mascetti L, Bettinelli A, Simonetti GD, et al. Pregnancy in inherited hypokalemic salt-losing renal tubular disorder. Obstet Gynecol, 2011, 117(2 Pt 2): 512-516.
21.	Basu A, Dillon RD, Taylor R, et al. Is normalisation of serum potassium and magnesium always necessary in Gitelman Syndrome for a successful obstetric outcome?. BJOG, 2004, 111(6): 630-634.
22.	Calò LA, Caielli P. Gitelman’s syndrome and pregnancy: new potential pathophysiological influencing factors, therapeutic approach and materno-fetal outcome. J Matern Fetal Neonatal Med, 2012, 25(8): 1511-1513.
23.	Oppermann M, Padberg S, Kayser A, et al. Angiotensin-Ⅱ receptor 1 antagonist fetopathy--risk assessment, critical time period and vena cava thrombosis as a possible new feature. Br J Clin Pharmacol, 2013, 75(3): 822-830.
24.	Pucci M, Sarween N, Knox E, et al. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in women of childbearing age: risks versus benefits. Expert Rev Clin Pharmacol, 2015, 8(2): 221-231.
25.	Gallagher H, Soar J, Tomson C. New guideline for perioperative management of People with inherited salt-wasting alkaloses. Br J Anaesth, 2016, 116(6): 746-749.

1. Gitelman HJ, Graham JB, Welt LG. A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians, 1966, 79(79): 221-235.
2. Takeuchi Y, Mishima E, Shima H, et al. Exonic mutations in the SLC12A3 gene cause exon skipping and premature termination in Gitelman syndrome. J Am Soc Nephrol, 2015, 26(2): 271-279.
3. Bettinelli A, Bianchetti MG, Girardin E, et al. Use of calcium excretion values to distinguish two forms of primary renal tubular hypokalemic alkalosis: Bartter and Gitelman syndromes. J Pediatr, 1992, 120(1): 38-43.
4. Fukuyama S, Hiramatsu M, Akagi M, et al. Novel mutations of the chloride Channel Kb gene in two Japanese patients clinically diagnosed as Bartter syndrome with hypocalciuria. J Clin Endocrinol Metab, 2004, 89(11): 5847-5850.
5. Gitelman 综合征诊治专家共识协作组. Gitelman 综合征诊治专家共识. 中华内科杂志, 2017, 56(9): 712-716.
6. Peters M, Jeck N, Reinalter S, et al. Clinical presentation of genetically defined patients with hypokalemic salt-losing tubulopathies. Am J Med, 2002, 112(3): 183-190.
7. Pachulski RT, Lopez F, Sharaf R. Gitelman’s not-so-benign syndrome. N Engl J Med, 2005, 353(8): 850-851.
8. Blanchard A, Bockenhauer D, Bolignano D, et al. Gitelman syndrome: consensus and guidance from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int, 2017, 91(1): 24-33.
9. Calò L, Punzi L, Semplicini A. Hypomagnesemia and chondrocalcinosis in Bartter’s and Gitelman’s syndrome : review of the pathogenetic mechanisms. Am J Nephrol, 2000, 20(5): 347-350.
10. Gupta R, Hu V, Reynolds T, et al. Sclerochoroidal calcification associated with Gitelman syndrome and calcium pyrophosphate dihydrate deposition. J Clin Pathol, 2005, 58(12): 1334-1335.
11. Godefroid N, Riveira-Munoz E, Saint-Martin C, et al. A novel splicing mutation in SLC12A3 associated with Gitelman syndrome and idiopathic intracranial hypertension. Am J Kidney Dis, 2006, 48(5): e73-e79.
12. Bettinelli A, Tosetto C, Colussi G, et al. Electrocardiogram with prolonged QT interval in Gitelman disease. Kidney Int, 2002, 62(2): 580-584.
13. Colussi G, Bettinelli A, Tedeschi S, et al. A thiazide test for the diagnosis of renal tubular hypokalemic disorders. Clin J Am Soc Nephrol, 2007, 2(3): 454-460.
14. Bouwer ST, Coto E, Santos F, et al. The Gitelman syndrome mutation, IVS9+1G>T, is common across Europe. Kidney Int, 2007, 72(7): 898.
15. Ma J, Ren H, Lin L, et al. Genetic features of Chinese patients with gitelman syndrome: sixteen novel SLC12A3 mutations identified in a new cohort. Am J Nephrol, 2016, 44(2): 113-121.
16. Qin L, Shao L, Ren H, et al. Identification of five novel variants in the thiazide-sensitive NaCl co-transporter gene in Chinese patients with Gitelman syndrome. Nephrology (Carlton), 2009, 14(1): 52-58.
17. Shao L, Ren H, Wang W, et al. Novel SLC12A3 mutations in Chinese patients with Gitelman’s syndrome. Nephron Physiol, 2008, 108(3): p29-p36.
18. Shao L, Liu L, Miao Z, et al. A novel SLC12A3 splicing mutation skipping of two exons and preliminary screening for alternative splice variants in human kidney. Am J Nephrol, 2008, 28(6): 900-907.
19. Morton A. Eplerenone in the treatment of Gitelman’s syndrome. Intern Med J, 2008, 38(5): 377.
20. Mascetti L, Bettinelli A, Simonetti GD, et al. Pregnancy in inherited hypokalemic salt-losing renal tubular disorder. Obstet Gynecol, 2011, 117(2 Pt 2): 512-516.
21. Basu A, Dillon RD, Taylor R, et al. Is normalisation of serum potassium and magnesium always necessary in Gitelman Syndrome for a successful obstetric outcome?. BJOG, 2004, 111(6): 630-634.
22. Calò LA, Caielli P. Gitelman’s syndrome and pregnancy: new potential pathophysiological influencing factors, therapeutic approach and materno-fetal outcome. J Matern Fetal Neonatal Med, 2012, 25(8): 1511-1513.
23. Oppermann M, Padberg S, Kayser A, et al. Angiotensin-Ⅱ receptor 1 antagonist fetopathy--risk assessment, critical time period and vena cava thrombosis as a possible new feature. Br J Clin Pharmacol, 2013, 75(3): 822-830.
24. Pucci M, Sarween N, Knox E, et al. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in women of childbearing age: risks versus benefits. Expert Rev Clin Pharmacol, 2015, 8(2): 221-231.
25. Gallagher H, Soar J, Tomson C. New guideline for perioperative management of People with inherited salt-wasting alkaloses. Br J Anaesth, 2016, 116(6): 746-749.

West China Medical Journal

The diagnosis and treatment of Gitelman syndrome in adults

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