Gitelman Syndrome – 12 Interesting Facts
- The salt-losing tubulopathies are rare diseases that can present in infancy or later in childhood with renal salt wasting, hypokalemic hypochloremic metabolic alkalosis, and normal blood pressure despite hyperreninemia and hyperaldosteronism
- Gitelman syndrome patients have a mild or even incidental presentation, with hypokalemic metabolic alkalosis, hypomagnesemia, hypocalciuria, and normal blood pressure.
- Depending on the setting, certain red flags should prompt the clinician to consider GS, including:
- Polyhydramnios in the neonatal intensive care unit
- Chronic weakness exacerbated by gastrointestinal losses in the urgent setting
- Poor growth identified at the well-child visit
- Assessment of the basic metabolic panel and serum magnesium can be informative and can guide next steps.
- Neonatal and pediatric practitioners should consider salt-losing tubulopathies in patients with unexplained hypokalemic hypochloremic metabolic alkalosis, especially when gastrointestinal losses and diuretic or laxative use are ruled out.
- Investigation of urinary potassium and urinary chloride measurement should be pursued and, if they are excessive, renal salt wasting should be implicated.
- Focused genetic testing may also be beneficial.
- Treatment may include ample fluid delivery, electrolyte replacement, nutritional support, prostaglandin inhibition, and disruption of renin-angiotensin aldosterone axis.
- Inclusion of patients in national and international registries may improve classification and treatment of these rare conditions and could provide a framework for future clinical trials.
Introduction
- Gitelman Syndrome (GS), or familial hypokalemia-hypomagnesemia, is an autosomal recessive disorder characterized by hypokalemic metabolic alkalosis, hypomagnesemia, and hypocalciuria.1
Background Information
- GS affects the distal convoluted tubule (DCT).
- GS is a complex disorder with overlapping clinical and biochemical features due to defects in renal salt handling.
- Therapy is challenging despite major advances in knowledge about mechanism and genotypic correlations.2
- GS and related salt-losing tubulopathies should be considered in a variety of settings in the pediatric patient with hypokalemic hypochloremic metabolic alkalosis:
- Patients may present in the neonatal intensive care unit with prematurity and polyuria
- In the emergency room with muscle weakness and rhabdomyolysis
- At a well child examination with short stature, constipation, and nocturia
Etiology and Risk Factors
Etiology
Fig. 1. DCT diagram. NCC, defective in Gitelman syndrome and the target of thiazide diuretics, reabsorbs sodium and chloride from the urine. Na-K-ATPase actively pumps sodium into the blood but requires KCNJ10 (affected in EAST syndrome) to maintain a basolateral potassium gradient. Chlroide enters the blood via CLCKNB (defective in BS III). Magnesium is reabsorbed via action of TRPM6, the activity of which is indirectly impaired in GS.Abbreviations: BS, Bartter syndrome; DCT, distal convoluted tubule; NCC, sodium-chloride cotransporter; GS, Gitelman syndrome (Adapted from Kleta R, Bockenhauer D. Salt-Losing Tubulopathies in Children: What’s New, What’s Controversial? J Am Soc Nephrol 2018;29(3):727–39.)
- GS is caused by biallelic inactivating mutations in the SLC12A3 gene encoding the thiazide-sensitive sodium chloride cotransporter (NCC) in the DCT (Fig. 1).
- Greater than 350 mutations have been reported.3
- Chronic thiazide treatment has been described as akin to GS.4
Diagnosis
Approach to Diagnosis
- In 2016, a Kidney Disease: Improving Global Outcomes (KDIGO) consensus statement regarding GS was published, providing an initial framework to guide clinical quality and future investigations.3
- Although variants of GS are genotypically distinct, there is considerable overlap in clinical presentation.
- All share the characteristics of renal salt wasting, hypokalemic hypochloremic metabolic alkalosis, and low or normal blood pressure despite hyperreninemia and hyperaldosteronism.
- Hypercalciuria, with or without medullary nephrocalcinosis, is present in some variants.
- Often, the diagnosis is fortuitous, with detection of incidental hypokalemia in a routine blood sample.
- A careful history, physical examination, and laboratory evaluation should be undertaken (Table 1), with genetic testing to be considered to confirm the fundamental defect and diagnosis.
Staging or Classification
- Classification schemes of GS and related syndromes are in evolution.
- Historically, patients were categorized by phenotypic characteristics.
- However, emerging data about genetic variants and unique and distinct mechanisms of salt-wasting present a new gene-based framework for classification.
- Moreover, there is variation in clinical presentation even when the same gene is affected.
- Mutation type also affects phenotype, offering an additional framework for categorization.
- As disease mechanisms and causes of phenotypic variation are further elucidated, classification schemes may use a combination of clinical and biochemical characteristics with gene mutation and affected transport mechanism.
- Table 2 summarizes current acknowledged GS types, as well as related variants, and lists gene mutations and products, as well as typical clinical characteristics.
Workup
History
- Symptoms usually occur after the age of 6 years4 but may not present until adolescence or adulthood.
- Neonates may present with polyhydramnios, prematurity, and poor growth.
- Older children may present with symptoms of chronic hypokalemia, such as:
- Constipation
- Muscle cramps
- Weakness
- Poor growth
- Salt craving
- Nocturia
- Vomiting
- Seizures, rhabdomyolysis, pseudogout, and pseudotumor cerebri have been reported345
Physical Examination
- Chondrocalcinosis, pubertal delay, and tetany are potential findings.
Laboratory Tests
Table
Table 1. Preliminary workup in patient with suspected Gitelman syndrome
| Specimen or Test | Expected Result | |
|---|---|---|
| Blood | Basic metabolic panel (Na, K, Cl, bicarbonate, BUN, creatinine, glucose) | Hyponatremia or normonatremia, hypokalemia, hypochloremia, metabolic alkalosis |
| Renin | Elevated | |
| Aldosterone | Elevated | |
| Magnesium | Low | |
| Urine | Potassium | Elevated (>2 mmol/mmol or >18 mEq/g) |
| Spot potassium or creatinine ratio or transtubular potassium gradienta | Elevated (>2) | |
| Chloride | Elevated (>0.5%) | |
| Fractional excretion of chloride | Normal or low, consistent with isosthenuria or hyposthenuria | |
| Osmolality Calcium Calcium or creatinine ratiob | Low |
Caption: Abbreviations: BUN, blood urea nitrogen; Cl, chloride; K, potassium; Na, sodium. a Only valid if urine osm > serum osm and urine Na greater than 25 mEq/L. b Normal ranges vary; for reference ranges by age, see Blanchard et al., Kidney Int, 2018: 91, 24–33.3
Diagnostic Procedures
- Biopsy is not typically pursued because clinical and genotypic diagnoses can be reached by other means.
- Findings feature juxtaglomerular hypertrophy and hyperplasia6 but appearance rarely assists in distinguishing between the various genotypes.
Differential Diagnosis
- Similar tubulopathies include:
- Antenatal Bartter syndrome (ABS) or hyperprostaglandin E syndrome (HPES)
- Classic Bartter syndrome (CBS)
- The differential diagnosis of hypokalemic hypochloremic metabolic alkalosis includes:
- Pyloric stenosis
- Diuretic use
- Congenital chloride diarrhea
- Laxative abuse
- Cystic fibrosis
- Other features (ie, age, medication history, and lack of gastrointestinal losses or pulmonary disease) can be helpful to distinguish between a salt-wasting tubulopathy and another cause.
- If diuretic use is not suspected, urinary chloride measurement, elevated in Bartter syndrome (BS) and GS, can decipher between renal and nonrenal causes of chloride loss.
- In a premature neonate with polyuria and poor weight gain, it may be tempting to suspect nephrogenic diabetes insipidus (NDI).
- However, these cases distinguish themselves from salt-wasting tubulopathies because NDI typically causes elevated serum sodium and lacks potassium and chloride urinary losses.7
- Table 3 describes additional distinguishing characteristics that may refine diagnosis.
Table
Table 2. Types of Bartter syndrome, Gitelman syndrome, and related conditions
| Disorder | OMIM, Gene | Gene Product | Inheritance | Features |
|---|---|---|---|---|
| BS Variants | ||||
| BS I (ABS, HPES) | 601678, SLC12A1 | NKCC2 | AR | Polyhydramnios, prematurity, hypokalemic hypochloremic alkalosis, nephrocalcinosis, with or without concentrating defect |
| BS II (ABS with transient hyperkalemia and acidosis, HPES) | 241200, KCNJ1 | ROMK1 | AR | Polyhydramnios, prematurity, transient hyperkalemia and acidosis, then hypokalemic hypochloremic alkalosis, nephrocalcinosis, with or without concentrating defect |
| BS III (CBS) | 607364, CLCNKB | ClC-Kb | AR; many sporadic | Variable age at presentation with severity corresponding to type of gene mutation; hypokalemic hypochloremic alkalosis |
| BS IVa and BS IVb (ABS or HPES with sensorineural deafness) | 602522, BSND CLCNKA, CLCNKB | Bartter ClC-Ka and ClC-Kb | AR | Polyhydramnios, prematurity, hypokalemic hypochloremic alkalosis, sensorineural deafness, with or without concentrating defect |
| BS V (transient ABS) | 300971, MAGED2 | MAGED2 | XR | Severe polyhydramnios, hypokalemic hypochloremic alkalosis with symptoms resolving within the first few months of life |
| AD hypocalcemic hypercalciuria | 601199, L125P | CaSR | AD | Hypocalcemic hypocalciuria, hypokalemic hypochloremic alkalosis, suppressed PTH |
| GS variants | ||||
| GS | 263800, SLC12A3 | NCC | AR | Present in later childhood or adulthood with weakness, lethargy, carpopedal spasm, hypokalemic alkalosis, hypomagnesemia, hypermagnesiuria and hypocalciuria |
| EAST syndrome (SeSAME) | 612780, Kir4.1 | KCNJ10 | AR | Epilepsy, ataxia, sensorineural deafness, hypokalemic hypochloremic alkalosis |
| Other variants | ||||
| CLDN10 mutations | 617579, CLDN10 | Claudin-10 | AR | Hypokalemic metabolic alkalosis with hypocalciuria but normal to elevated magnesium |
Caption: Abbreviations: ABS, Antenatal Bartter syndrome; AD, autosomal dominant; AR, autosomal recessive; CaSR, calcium-sensing receptor; CBS, Classic Bartter syndrome; ClC-Ka, chloride channel-Ka; ClC-Kb, chloride channel-Kb; GS, Gitelman syndrome; HPES, hyperprostaglandin E syndrome; MAGED, melanoma-associated antigen-D2; NCC, thiazide-sensitive NaCl cotransporter; NKCC2, furosemide-sensitive Na-K-2Cl cotransporter; OMIM, online Mendelian inheritance in man; PTH, parathyroid hormone; ROMK, renal outer medullary K channel; SeSAME, seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalances; XR, X-linked recessive.
Table
Table 3. Features that distinguish Bartter and Gitelman syndrome variants
| Variant | Age of Onset | Serum K | Serum Cl | Serum Mg | Serum Renin, Aldosterone | Urine Ca/Cr | Other Distinct Features |
|---|---|---|---|---|---|---|---|
| BS I | AN | Low | Low | Normal | High, high | High | – |
| BS II | AN | High, then low | Low | Normal | High, high | High | Transient hyperkalemia |
| BS III | N, C, A | Low | Very low | Normal | High, high | Low, normal, or high | – |
| BS IVa, IVb | AN | Low | Low | Normal | High, high | Normal or High | Sensorineural deafness |
| BS V | AN | Low | Low | Normal | High, high | – | Transient features |
| Hypocalcemia hypercalciuria | – | Low | Low | Normal | High, high | High | Family history, hypocalcemia, suppressed PTH |
| GS | C, A | Low | Low | Low | High, high | Low | – |
| EAST syndrome | – | Low | Low | Low | High, high | Low | Epilepsy, ataxia, sensorineural deafness |
Caption: Abbreviations: A, adult; AN, antenatal; BS, Bartter syndrome; C, child; Ca/Cr, spot calcium to creatinine ratio; GS, Gitelman syndrome; Mg, magnesium; N, neonate.
Treatment
Approach to Treatment
- Acute management in dehydrated patients involves correcting water losses and repleting electrolytes.
- Chronically, patients require electrolyte supplementation and inhibition of prostaglandin production and/or the RAAS,8 although comprehensive clinical studies examining efficacy and outcome are lacking.
Nondrug and Supportive Care
- Patients with GS are typically prescribed oral salt replacement therapy, although normalizing serum electrolytes with an ongoing tubular leak is challenging, optimal frequency of dosing is ill-defined, and serum levels greatly depend on the timing of last dose.
- In young children, oral sodium chloride replacement may be necessary early in life but increased dietary salt intake in older children is usually sufficient.8
- Potassium supplementation is often used, and GS patients also require high magnesium intake.
- Growth and pubertal delay has been shown to be reversible by adequate magnesium and potassium supplementation when combined with indomethacin,9 although it is unclear what the specific target levels of potassium or magnesium should be.310
Drug Therapy
- Indomethacin may relieve symptoms of salt-losing tubulopathy.
- Monitoring of side effects is essential because indomethacin use has been associated with ulcers, necrotizing colitis, and gastrointestinal perforations in preterm infants.11
- The use of potassium-sparing diuretics in patients with GS is controversial. Spironolactone, eplerenone, and amiloride may increase serum potassium levels, reverse metabolic alkalosis, and partially correct hypomagnesemia in patients.
- However, exacerbation of salt-wasting and risk of volume depletion are concerns.
- Growth problems are a common presenting symptom in this population; therefore, when fluid, salt, and nutrition management has been optimized, growth hormone (GH) therapy should be considered.
- GH deficiency has been reported in concert with GS.1213
- However, even in cases with normal insulin-like growth factor (IGF-1) and GH levels, patients often experience poor growth.
- Patients do respond to GH therapy,1314 although cost of GH treatment is a consideration.
Follow-up
Complications
- Risk for prolonged QT and cardiac arrhythmias due to persistent hypokalemia and hypomagnesemia are concerns.151617
Referral
- GS rarely advances to end-stage renal disease and renal failure.
- In those who have progressed as a result of chronic nephropathy or medication side effects, renal transplant has proven successful.1819
References
1.Gitelman HJ, Graham JB, Welt LG. A new familial disorder characterized by hypokalemia and hypomagnesemia. Trans Assoc Am Physicians 1966;79:221–35.
2.Al Shibli A, Narchi H. Bartter and Gitelman syndromes: Spectrum of clinical manifestations caused by different mutations. World J Methodol 2015;5:55–61.
3.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.
4.Knoers, Nine VAM, Levtchenko EN. Gitelman syndrome. Orphanet J Rare Dis 2008;3:22.
5.Smilde TJ, Haverman JF, Schipper P, et al. Familial hypokalemia/hypomagnesemia and chondrocalcinosis. J Rheumatol 1994;21:1515–9.
6.Bartter FC, Pronove P, Gill JR, et al. Hyperplasia of the juxtaglomerular complex with hyperaldosteronism and hypokalemic alkalosis. A new syndrome. 1962. J Am Soc Nephrol 1998;9:516–28.
7.Bockenhauer D, Bichet DG. Pathophysiology, diagnosis and management of nephrogenic diabetes insipidus. Nat Rev Nephrol 2015;11:576–88.
8.Fremont OT, Chan JCM. Understanding Bartter syndrome and Gitelman syndrome. World J Pediatr 2012;8:25–30.
9.Liaw LC, Banerjee K, Coulthard MG. Dose related growth response to indometacin in Gitelman syndrome. Arch Dis Child 1999;81:508–10.
10.Kleta R, Bockenhauer D. Salt-losing tubulopathies in children: what’s new, what’s controversial? J Am Soc Nephrol 2018;29(3):727–39.
11.Marlow N, Chiswick ML. Neonatal Bartter’s syndrome, indomethacin and necrotising enterocolitis. Acta Paediatr Scand 1982;71:1031–2.
12.Boer LA, Zoppi G. Bartter’s syndrome with impairment of growth hormone secretion. Lancet 1992;340:860.
13.Buyukcelik M, Keskin M, Kilic BD, et al. Bartter syndrome and growth hormone deficiency: three cases. Pediatr Nephrol 2012;27:2145–8.
14.Requeira O, Rao J, Baliga R. Response to growth hormone in a child with Bartter’s syndrome. Pediatr Nephrol 1991;5:671–2.
15.Scognamiglio R, Negut C, Calo` LA. Aborted sudden cardiac death in two patients with Bartter’s/Gitelman’s syndromes. Clin Nephrol 2007;67:193–7.
16.Foglia PE, Bettinelli A, Tosetto C, et al. Cardiac work up in primary renal hypokalaemia-hypomagnesaemia (Gitelman syndrome). Nephrol Dial Transplant 2004;19:1398–402.
17.Bettinelli A, Borsa N, Bellantuono R, et al. Patients with biallelic mutations in the chloride channel gene CLCNKB: long-term management and outcome. Am J Kidney Dis 2007;49:91–8.
18.Kim JY, Kim GA, Song JH, et al. A case of living-related kidney transplantation in Bartter’s syndrome. Yonsei Med J 2000;41:662–5.
19.Calo` LA, Marchini F, Davis PA, et al. Kidney transplant in Gitelman’s syndrome. Report of the first case. J Nephrol 2003;16:144–7.
