| Abstract|| |
Chronic hypokalemia is the main finding in patients with Gitelman’s syndrome (GS). GS, a variant of Bartter’s syndrome, is an autosomal recessive renal disorder characterized by hypokalemia, hypomagnesemia, metabolic alkalosis, and hypocalciuria. GS is caused by inactivating mutations in the thiazide-sensitive sodium-chloride cotransporter gene. It is also called the “milder” form of Bartter’s syndrome, as patients with GS are usually diagnosed in adulthood during routine investigation. Our objective is to highlight the impact of correct distinction between the causes of hypokalemia on management and the need of long-term follow- up after the restoration of normokalemic status. Herein, we report an asymptomatic 40-year-old male, whose persistent hypokalemia was due to GS. The diagnosis was first established by laboratory tests, and he was treated with low-dose aldosterone antagonists (spironolactone), angiotensin-converting enzyme inhibitors, and potassium and magnesium supplements. Genetic testing confirmed the diagnosis of GS and revealed a rare mutation. We conclude that GS is a rare and real diagnostic and therapeutic challenge, for which a close collaboration between endocrinologists and nephrologists is mandatory, as also the thorough genetic investigation of the mutations associated with this syndrome.
|How to cite this article:|
Mamalis D, Stratigou T, Vallianou NG, Ioannidis GG, Apostolou T. Persistent hypokalemia due to a rare mutation in gitelman's syndrome. Saudi J Kidney Dis Transpl 2020;31:259-62
|How to cite this URL:|
Mamalis D, Stratigou T, Vallianou NG, Ioannidis GG, Apostolou T. Persistent hypokalemia due to a rare mutation in gitelman's syndrome. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2020 Apr 4];31:259-62. Available from: http://www.sjkdt.org/text.asp?2020/31/1/259/279949
| Introduction|| |
Hypokalemia is a common clinical problem. It can result from reduced potassium intake, increased translocation from extracellular spaces into the cells (as a transient condition) or, most commonly, from increased gastrointestinal or urinary losses. Increased potassium secretion in the distal nephron may account for such losses, for example, due to the use of diuretics or endogenous mineralo-corticoid excess.
Clinically, the absence of remarkable arterial hypertension and occasional symptoms of hypo- kalemia, together with a biochemical constellation of persistent, refractory hypokalemia, metabolic alkalosis, secondary hyperaldostero- nism, mild hypomagnesemia, and hypocal- ciuria, are suggestive of Gitelman’s syndrome (GS). This autosomal recessive inheritable renal syndrome is caused by inactivating mutations in the thiazide-sensitive sodium- chloride cotransporter gene (NCCT). In contrast to patients with “true” Bartter’s syndrome, who are symptomatic during childhood, patients with GS are usually diagnosed in adulthood during routine investigation. Some reports indicate that patients are generally asymptomatic at presentation, as in our case, and other reports range from mild weakness, cramps, and fatigue to severe complications, such as tetany, paralysis, and rhabdo- myolysis.,,, In this report, we discuss about the establishment of the diagnosis, the challenges faced in the therapeutic approach of the patient as well as the necessity of genetic control and further investigation of the importance of rare mutations revealed by the genetic testing.
| Case Report|| |
Informed consent was obtained from the patient before publishing the case.
A 40-year-old male was referred to our outpatient due to persistent hypokalemia accidentally discovered three months ago in a routine test. The patient was asymptomatic. His blood pressure (BP) was 125/78 mm Hg, whereas in Holter procedure, a mean systolic/ diastolic BP of 129/85 mm Hg and a moderate diastolic arterial hypertension would be identified. Biochemical analysis showed hypoka- lemia (2.5 mmol/L, normal range: 3.5-4.5 mmol/L), although he was already on potassium substitution, hypomagnesemia (1.7 mg/ dL, normal range: 1.8-2.4 mg/dL), and hypo- chloremia (89 mEq/L, normal range: 98-107 mEq/L). His renal function was not impaired (eGFR: 83 mL/min/1.73m2), so was his hepatic enzymes. His calcium level was normal, although he had reduced calcium excretion in 24-h urine collection (21 mg/24 h specimen, normal range: 100-300 mg/24 h specimen). Furthermore, an increased potassium excretion in urine was noted (144 mEq/24 h, normal range: 25-120 mEq/24 h). The initial arterial blood gas analysis showed slight alkalosis (pH: 7.47, partial pressure of CO2: 40.4 mm Hg, partial pressure of O2: 75.1 mm Hg, HCO3: 28.8 mmol/L). There was no evidence of hyperthyroidism, his blood glucose was 106 mg/dL, whereas his HbA1c was normal (5.6%). An oral glucose tolerance test was recently performed (prior to his address to us), where an impaired fasting glucose (IFG), as well as impaired glucose tolerance (IGT), was recorded (blood glucose value rose from 107 mg/dL in t = 0 min to181 mg/dL in 2 h). The morning value of cortisol was within the normal range (12.2 μg/dL, normal range: 6.219.4 μg/dL), so was the adrenocorticotropic hormone (ACTH: 30.2 pg/mL, normal range: 7-64 pg/mL). His level of active renin was highly elevated (995/924 μίϋ/mL measured on two different days, normal range: 2.8-39.9 μίϋ/mL), so was aldosterone (37.4/37.4 ng/dL, normal range:1-16 ng/dL). No pathological findings were no tedon abdominal magnetic resonance imaging and ultrasound of renal arteries and heart. His past medical history was unremarkable, while he reported no use of laxatives or diuretics, nor consumption of licorice, episodes of vomiting, or diarrhea that could justify the above-mentioned findings.
Under these circumstances, we considered a tubulopathy causing renal potassium loss. The biochemical constellation of normal renal function, hypokalemia and mild hypomagne- semia, secondary hyperreninemia, and hyper- aldosteronism was suggestive of either Bartter’s syndrome or GS, and due to the decreased calcium urinary secretion, a provisional diagnosis of GS was made.
We continued treatment with potassium supplements twice per day and started treatment with a low dose of an aldosterone antagonist (spironolactone: 25 mg/day), angiotensin- converting enzyme (ACE) inhibitors (ramipril: 2.5 mg/day), and potassium and magnesium supplements. In addition, the patient was advised to consume foods rich in potassium and to avoid strenuous exercise and sweating. At the first follow-up visit one and a half months later, the potassium levels had increased to 3.1 mmol/L and his BP ranged from 105 to 120/70 to 82 mm Hg. Hence, a gradual increase in the dosage of spirono- lactone to 50 mg/day was made. One month later, his potassium blood level was in the lower normal range (3.5 mmol/L) and it was kept so in the next follow-ups (monthly in the beginning, two months afterward, and six months later).At his last checkup, one year after his first presentation to our center, his potassium levels remained in normal range 3.5 mmol/L and the potassium excretion in 24 h urine collection was also in normal range (105 mEq/24 h, normal value: 25-120 mEq/24 h).
A genetic study was conducted in order to verify the diagnosis. A heterogeneous exchange SLC12A3:c.1298C>T to the exon 16 of the gene SLC12A3 was found. This exchange causes replacement of proline with leukine (SLC12A3:p.Pro643Leu).
| Discussion|| |
Our patient, a 40-year-old previously healthy Caucasian male, had persistent asymptomatic hypokalemia. The IFG and IGT could not justify his prolonged hypokalemia. Our patient showed neither clinical nor biochemical signs of thyrotoxicosis. Besides, the cortisol value excluded Cushing’s syndrome as a cause of his decreased potassium levels.
Our patient presented with hypokalemia but without hypertension or edema. His active renin and aldosterone levels were elevated, demonstrating clearly the secondary hyper- aldosteronism, characteristic of his chronic disorder. In normotensive patients with secondary hyperaldosteronism, not only diuretic use or abuse but also tubulopathy causing renal potassium loss should be considered. Normal renal function, hypokalemia, hypomagnesemia, and alkalosis are diagnostic for GS, a disease mostly detected in young adults.
As discussed by Knoers and Levtchenko, this autosomal recessive disease (OMIM 263800) is the most frequent inherited salt-losing renal tubulopathy (prevalence estimated at 1:40,000). In the great majority of patients, it is caused by one of more than 140 described mutations in the solute carrier family 12, SLC12A3 gene (chromosome 16q13), encoding the renal thiazide-sensitive NCCT, expressed in the apical membrane of the first part of the distal convoluted tubule. An inherited origin of our patient’s disease was not obvious.
Impaired NaCl reabsorption results in mild volume depletion. Secondary hyperreninemic hyperaldosteronism tends to correct sodium homeostasis at the expense of depletion of potassium and hydrogen ions, resulting in hypokalemia and metabolic alkalosis.
Elevated magnesium excretion in the proximal tubule is assumed to cause hypomagne- semia. Occasionally, associated chondrocal- cinosis is probably caused in cases of chronic hypomagnesemia. The pathogenesis of hypo- calciuria is not entirely clear but may be due either to extracellular volume contraction and increased passive calcium reabsorption in the proximal tubule or to reduced luminal NaCl entry into distal convoluted tubular cells, cellular hyperpolarization, and a basolateral calcium shift. Hypophosphatemia is not regularly observed. Apart from tubular dysfunction (with reduced phosphate reabsorption), metabolic alkalosis can increase phosphate excretion, and the accompanying hypokalemia further increases renal phosphate clearance.
The differential diagnosis includes classical Bartter’s syndrome (especially Type III). In classical Bartter’s syndrome, patients typically present with severe symptoms (polyuria, polydipsia, dehydration, and vomiting) in early childhood and often exhibit dysmorphic characteristics. Retardation of growth or mental development is a feature of untreated Bartter’s syndrome. Different subtypes can be distinguished. All of them are characterized biochemically by hypokalemic metabolic alkalosis, but in contrast to the hypocalciuria in GS, Bartter’s syndrome is characterized by hyper- calciuria.
Therapeutic options in GS are limited. As the tubulopathy cannot be modified, supplementation of potassium and magnesium is the cornerstone of therapy. However, the typically high substitution doses are associated with partly unacceptable gastrointestinal side effects. Thus, asymptomatic stable hypokalemia and borderline hypomagnesemia are a realistic therapeutic goal. Sufficient salt intake is important because low NaCl supply exaggerates volume depletion and increases the compensatory secondary hyperaldosteronism, resul- ting in intensified hypokalemia.
Although the use of an aldosterone antagonist can stabilize the hypokalemia, it competes with the compensatory secondary hyperaldos- teronism. This can result in hypovolemia, possibly accentuated hyponatremia, and eventually symptomatic hypotonia. Similar effects occur with the use of ACE inhibitors or angiotensin- 2 receptor blockers. Apart from isolated cases in which renal insufficiency developed, GS usually carries a very good prognosis.
Our patient was treated with a low dose of an aldosterone antagonist, He received in addition a low dose of ACE inhibitor, a tolerated dose of magnesium, and potassium supplements.
By applying this therapeutic regimen, a stable normokalemia (at about3.5 mmol/L) was established. During the following year, our patient steadily remained in a stable normokalemic status.
A genetic study was conducted in order to verify the diagnosis. A heterogeneous exchange SLC12A3:c.1298C>T to the exon 16 of the gene SLC12A3 was established. This exchange causes replacement of proline with leukine (SLC12A3:p.Pro643Leu). This change has already been described in one patient with GS, who was discovered in a transform with a second replacement. It has been registered to base the NHLBI exome variant with a frequency of 0.003%. This mutation has been registered as unknown importance according to the criteria MUTADATBASE, even if it theoretically refers to pathogenicity.
| Conclusion|| |
GS is a rare disorder and a real diagnostic and therapeutic challenge, for which a close collaboration between endocrinologists and nephrologists is mandatory. Equally mandatory is the thorough genetic investigation of the mutations related to this syndrome.
Conflict of interest: None declared.
| References|| |
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;91:24-33.
Kung AW. Clinical review: Thyrotoxic periodic paralysis: A diagnostic challenge. J Clin Endocrinol Metab 2006;91:2490-5.
Stewart PM. Tissue-specific Cushing’s syndrome, 11-hydroxysteroid-dehydrogenase and redefinition of corticosteroid hormone action. Eur J Endocrinol 2003;149:163-8.
Gitelman HJ, Graham JB, Welt LG. A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians 1966;79:221-35.
KnoersNV, Levtchenko EN. Gitelman syndrome. Orphanet J Rare Dis 2008;3:22.
Katopodis K, Elisaf M, Siamopoulos KC. Hypophosphataemia in a patient with Gitelman’s syndrome. Nephrol Dial Transplant 1996;11:2090-2.
Peters M, Jeck N, Reinalter S, et al. Clinical presentation of genetically defined patients with hypokalemic salt-losing tubulopathies. Am J Med 2002;112:183-90.
Knobel U, Modarres G, Schneemann M, Schmid C. Gitelman’s syndrome with persistent hypokalemia - don’t forget licorice, alcohol, lemon juice, iced tea and salt depletion: A case report. J Med Case Rep 2011;5:312.
Ferrannini E, Taddei S, Santoro D, et al. Independent stimulation of glucose metabolism and Na+-K+ exchange by insulin in the human forearm. Am J Physiol 1988;255:E953-8.
Cruz DN, Shaer AJ, Bia MJ, Lifton RP, Simon DB. Yale Gitelman’s and Bartter’s Syndrome Collaborative Study Group. Gitelman’s syndrome revisited: An evaluation of symptoms and health-related quality of life. Kidney Int 2001;59:710-7.
Natalia G Vallianou
Department of Endocrinology, Diabetes and Metabolism, Evangelismos Hospital, Athens