Bartter Syndrome Workup

Updated: May 11, 2023
  • Author: Lynda A Frassetto, MD; Chief Editor: Vecihi Batuman, MD, FASN  more...
  • Print
Workup

Approach Considerations

The severity and site of the mutation determines the age at which symptoms first develop. Completely dysfunctional mutations in the receptors and ion channels in the thick ascending limb of the loop of Henle (TALH) are probably not compatible with life.

Most cases of Bartter syndrome are discovered in infancy or early adolescence. Bartter syndrome can also be diagnosed prenatally, when the fetus develops polyhydramnios and intrauterine growth retardation. Many of the neonates are born prematurely. Children diagnosed early in life usually have more severe electrolyte disorders and symptoms. Because of Bartter syndrome's heterogeneity, patients with minimal symptomatology may be discovered relatively late.

Electrocardiography

An electrocardiogram (ECG) may reveal changes characteristic of hypokalemia, such as flattened T waves and prominent U waves.

Histologic findings

Although kidney biopsy is not usually required, histologic findings may be useful in confirming the diagnosis of Bartter syndrome.

In neonatal and classic Bartter syndrome, the cardinal finding is hyperplasia of the juxtaglomerular apparatus. Less frequently, hyperplasia of the medullary interstitial cells is present.

Glomerular hyalinization, apical vacuolization of the proximal tubular cells, tubular atrophy, and interstitial fibrosis may be present as a consequence of chronic hypokalemia.

Inpatient care

For patients initially diagnosed in the hospital, the goal is to stabilize the patient sufficiently for discharge. This includes stabilization of potassium and other electrolytes, as well as volume and, perhaps, acid-base parameters.

Consultations

Contact a nephrologist or pediatric nephrologist whenever a patient fitting the clinical picture of Bartter or Gitelman syndrome is identified. The specialist can assist with the initial diagnosis and carry out periodic outpatient evaluation of growth, development, renal function, serum electrolytes, and response to therapy.

Monitoring

Patients initially need frequent outpatient follow-up care until the metabolic abnormalities caused by the renal tubular transporter mutation are stabilized with medications. The length of time to stability depends on the severity of the mutation and the degree of patient compliance.

Next:

Laboratory Studies

Potassium

Initiate timed urine collection to determine potassium levels. In hypokalemia, normal kidneys retain potassium. [34] Elevated urinary potassium levels with low blood potassium levels suggest that the kidneys are having problems retaining potassium.

Aldosterone

Next, initiate timed urine collection to determine aldosterone levels. Aldosterone levels should be low in volume-replete patients. If urinary aldosterone levels are high despite volume replacement, there is an abnormal stimulation of aldosterone.

Patients with primary hyperaldosteronism in a volume-replete state usually have normal to high blood pressure. Low or low-normal blood pressure with high aldosterone excretion suggests that the primary problem is something else and that the aldosterone response is secondary to the undiagnosed primary abnormality.

Chloride

Next, initiate a timed urine collection to determine chloride levels. Extrarenal volume depletion is a possible reason for low blood pressure, high aldosterone excretion, and potassium loss. In this case, the kidneys retain sodium and chloride, and urinary chloride concentrations should be low.

High urine chloride levels with low blood pressure, high aldosterone secretion, and high urinary potassium levels are found only with long-term diuretic use and Bartter or Gitelman syndrome. If diuretic abuse is suspected, a urine screen for diuretics can be ordered. Otherwise, the diagnosis is Bartter or Gitelman syndrome.

Calcium/magnesium

Patients with Bartter syndrome have high urinary excretion of calcium and normal urinary excretion of magnesium, except for type V Bartter syndrome. Patients with type V Bartter syndrome have elevated urinary calcium and urinary magnesium level.

In patients with Gitelman syndrome, the opposite is true, with tests showing low urinary excretion of calcium and high urinary excretion of magnesium.

Hyperuricemia

Hyperuricemia is present in 50% of patients with Bartter syndrome. In Gullner syndrome, hypouricemia is present, secondary to impaired proximal tubular function.

Complete blood count

Polycythemia may be present from hemoconcentration.

Parathyroid hormone and serum phosphate

In an international study that included 285 patients with Bartter syndrome, 56% of patients with Bartter syndrome type I and II had hyperparathyroidism (parathyroid hormone [PTH] level > 7.0 pmol/L). A significant number of patients, especially those with type III Bartter sydnrome, had low serum phosphate levels, which appeared to be associated with renal phosphate wasting. Serum phosphate levels and urinary phosphate excretion did not correlate with PTH. [35]

Mutationswith

Mutations in the different transporters cause Bartter syndrome. The older methods of determining the presence of mutations require more detailed physiologic investigations, including determination of serum magnesium levels and further urine collections to assess calcium, magnesium, and PGE2 levels.

In Bartter syndrome, urine calcium excretion is high, leading to nephrocalcinosis, while serum magnesium levels are normal except for type V Bartter syndrome. Patients with type V Bartter syndrome have both hypocalcemia and hypomagnesemia.

With the transporter mutations that cause Gitelman syndrome, hypomagnesemia is common and is accompanied by hypocalciuria.

Genetic analysis has become the preferred methodology for determining whether a mutation in one of the transporters has occurred. An analysis of the genes for the transporters shows multiple problems leading to abnormal gene function, including missense, frame-shift, loss-of-function, and large deletion mutations. (Not all mutations lead to a marked loss of function.) [36, 37, 38, 39, 40, 41]

Thiazide testing

The thiazide test may be used to aid in the diagnosis of Gitelman syndrome. In this test, patients are given an oral dose of 50 mg (1 mg/kg in children and adolescents). Urine electrolytes are then measured, and electrolyte excretion is evaluated as fractional excretion, with creatinine as a marker for glomerular filtration rate. [42]

Over 3 hours, patients with Gitelman syndrome typically show a blunted fractional clearance of chloride (< 2.3%), whereas patients with Bartter syndrome and pseudo–Bartter syndrome show a normal response; indeed, patients with pseudo–Bartter syndrome may have an increased response.  Colussi and colleagues concluded that in patients a Gitelman syndrome phenotype marked by normotensive hypokalemic alkalosis, thiazide test results allow sufficiently sensitive and specific prediction of the Gitelman syndrome genotype that genetic testing may be unnecessary. [42]

On thiazide testing, normomagnesemic patients may exhibit a stronger reaction than hypomagnesemic patients. In a comparison study of 17 Gitelman syndrome patients with SLC12A3 gene mutations, including five patients with no history of hypomagnesemia, and 20 healthy controls, a sevenfold increase in sodium and chloride excretion was seen in the controls after thiazide administration, while an approximately twofold increase was seen in the normomagnesemic Gitelman syndrome patients, and no change was observed in the hypomagnesemic Gitelman syndrome patients. Clearance of chloride in one patient with chronic renal insufficiency was overestimated. These researchers recommended that in patients with chronic renal insufficiency, chloride and sodium clearance rates rather than the fractional excretion should be used in the evaluation of the thiazide test results. [43]

Amniotic fluid

If the diagnosis is being made prenatally, assess the amniotic fluid. The chloride content may be elevated in either Gitelman or Bartter syndrome. Increased aldosterone levels and low total protein levels in amniotic fluid have also been reported. [44]

Glomerular filtration rate

The glomerular filtration rate (GFR) is preserved during the early stages of the disease; however, it may decrease as a result of chronic hypokalemia. One study, however, hypothesizes that GFR is affected more by secondary hyperaldosteronism than by hypokalemia. [45]

Previous
Next:

Imaging Studies

Neonatal Bartter syndrome can be diagnosed best prenatally by ultrasonography. The fetus may have polyhydramnios and intrauterine growth retardation. Amniotic chloride levels may be elevated. [46]

After birth, especially if the disease is diagnosed in older patients who have hypercalciuria, consider a renal ultrasonogram or flat plate of the abdomen for nephrocalcinosis. Sonographic findings include diffusely increased echogenicity, hyperechoic pyramids, and interstitial calcium deposition.

Because continued calcium loss may affect bones, dual-energy radiographic absorptiometry scans to determine bone mineral density may be advisable in older patients.

Nephrocalcinosis can occur and is often associated with hypercalciuria. It can be diagnosed with abdominal radiographs, intravenous pyelograms (IVPs), renal ultrasonograms, or spiral computed tomography (CT) scans.

Previous