Eplerenone for Gitelman Syndrome in Pregnancy

Abstract

Gitelman syndrome (GS) is an autosomal recessive renal tubulopathy because of mutations in the gene for the thiazide-sensitive sodium chloride co-transporter in the distal convoluted tubule. GS is characterized by hypokalaemia, secondary hyperaldosteronism, hypocalciuria and hypomagnesaemia. Little is known about GS in pregnancy. Eplerenone is an aldosterone antagonist and potassium-sparing diuretic used to treat hypertension and cardiac failure. We report the use of eplerenone to treat GS in pregnancy with a successful outcome for mother and baby.A 21 years old nulliparous woman presented with longstanding lethargy, muscle cramps, nausea, thirst and nocturia. Serum potassium was 2.6 mmol/L, urine potassium was inappropriately high consistent with renal loss, there was mild hypomagnesaemia, hypocalcuria and secondary hyperaldosteronism. She denied diuretic use. She had otherwise been well with no significant past medical history. GS was confirmed by DNA sequence analysis revealing compound heterozygosity with pathogenic mutations in exon 18 (2186G > T) and exon 25 (2872A > T) in the SLC12A3 gene. She was intolerant of oral potassium and magnesium supplements, spironolactone and non-steroidal anti-inflammatory drugs because of nausea, and intolerant of amiloride because of tinnitus. Treatment with a combination of eplerenone 50 mg twice a day and perindopril 2.5 mg each morning resulted in resolution of her symptoms and a serum potassium at the lower end of the normal range. After preconception counselling her perindopril was ceased, and she elected to fall pregnant while continuing treatment with eplerenone. Other than intermittent vomiting in first trimester her confinement was uneventful, with her serum potassium ranging between 2.6 and 2.9 mmol/L, a healthy baby girl weighing 3630 g born by vaginal delivery at 39 weeks gestation. The babies' potassium was normal. Two years post delivery mother and baby are well.Twelve pregnancies to mothers with GS have been described previously, all with an uneventful pregnancy course and excellent outcome, despite inability to normalize maternal serum potassium and magnesium levels even with large doses of oral supplements. 1,2 The aim in pregnancy should be to give adequate therapy to prevent maternal symptoms. Spironolactone and amiloride have been used in pregnancies complicated by GS syndrome in addition to electrolyte supplementation. Amniotic fluid levels should be monitored as oligohydramnios was reported in 5 of the 12 pregnancies. Eplerenone was used in our mother because of her intolerance to spironolactone, amiloride and oral potassium and magnesium supplements. We are only aware of one previous report of eplerenone use in pregnancy, commenced at 32 weeks gestation in a 41 years old woman with diastolic heart failure. 3 A healthy newborn was delivered, the gestation was not stated. In animal studies the only noticeable risk of foetal abnormalities occurred when laboratory animals were given doses well over 1000 times the recommended daily dose of eplerenone. Epler...

Eplerenone use in primary aldosteronism during pregnancy

“…Clinical trials are clearly neither feasible nor appropriate and any information to guide clinicians will have to come from anecdotal reports such as this. To the best of our knowledge, this is the fourth report of the use of eplerenone in pregnancy and only the second of its use for the treatment of PA in this setting (the others being in the context of Gitelman's syndrome 6 and congestive heart failure 7). In the previous case of PA in pregnancy 8, a healthy male infant was born at 35 weeks after the mother had received 8 weeks of eplerenone 50 mg twice daily to control resistant hypertension and hypokalemia.…”

Indomethacin, Amiloride, or Eplerenone for Treating Hypokalemia in Gitelman Syndrome

“…This biologic and hormonal phenotype mimics the electrolytic consequences of chronic administration of thiazide diuretics, which specifically block NCC in the kidney. [12][13][14] The rationale behind administering the epithelial sodium channel inhibitor amiloride and the MR antagonist eplerenone is, thus, to neutralize the compensatory mechanisms in the distal nephron that are responsible for hypokalemia in patients with GS.…”

“…9,10 In the case of persistent symptomatic hypokalemia or intolerance to supplementation, potassium-sparing diuretics, such as amiloride, or mineralocorticoid receptor (MR) antagonists (spironolactone or eplerenone) usually constitute the first therapeutic option. [11][12][13][14] Another option is low-dose indomethacin, a nonselective inhibitor of cyclooxygenase 1 (COX-1) and COX-2. 11,15 However, evidence is limited for all these treatment options, and no randomized controlled trial has so far compared their efficacy, tolerability, or safety in patients with GS.…”

PROGRESS IN PRIMARY ALDOSTERONISM: Mineralocorticoid receptor antagonists and management of primary aldosteronism in pregnancy

“…However, spironolactone was never proved to be safe in pregnancy. Nevertheless, as indicated by Morton et al (48), spironolactone was commonly used in hypertension, pre-eclampsia, liver disease, and myasthenia gravis in pregnancy before 1980. Two trials exist investigating the effect of spironolactone treatment on the RAAS and the excretion of different steroids in pregnant women with edema (49,50).…”

“…We found one case report describing an uneventful pregnancy under treatment with eplerenone in a woman with APA delivering a healthy boy with a follow-up of 2 years (21). Additionally, a safe and effective use of eplerenone was reported in a mother with Gitelman syndrome (48) as well as in a mother with a diastolic heart failure (61) (see Table 2). …”