Tests
1st tests to order
serum bicarbonate
Test
The most sensitive test for most forms of RTA. The finding of low serum bicarbonate concentration is the usual starting point for investigating metabolic acidosis.[41][4] Typically, between 15 to 19 mEq/L in proximal RTA; classic distal RTA may present with a lower serum bicarbonate; hypobicarbonatemia is not as severe in hyperkalemic distal (type IV) RTA. In incomplete RTA the bicarbonate is typically normal in the absence of acid loading.
A severe depression of serum bicarbonate (<18 mEq/L, or even <15 mEq/L) is the usual starting point for the diagnosis of Fanconi syndrome. Once it is determined that the bicarbonate is appropriately low, a blood gas determination of arterial pH is mandatory to exclude the diagnosis of respiratory alkalosis.
Result
low
serum chloride
Test
In the absence of confounding conditions, patients with complete forms of RTA are hyperchloremic, but chloride is usually normal in incomplete distal RTA. If both the serum bicarbonate and chloride are below normal and the serum sodium is normal, the patient has an anion gap disorder.
If metabolic acidosis is confirmed by measurement of pH and bicarbonate concentration, the finding of increased chloride levels advances the diagnosis to hyperchloremic metabolic acidosis.
Result
elevated
serum sodium
Test
If both the serum sodium and chloride are elevated, the possibility of true dehydration is considered.
Result
expect normal
serum potassium
Test
Serum potassium below 3.5 mEq/L is typical for proximal RTA and classic distal RTA; a serum potassium above 5.0 is typical for hyperkalemic distal RTA.[4]
Result
variable
arterial blood pH
Test
By definition the arterial blood pH must be below normal (<7.35) to make the diagnosis of classic distal RTA, proximal RTA (including Fanconi syndrome), and hyperkalemic distal RTA unless the patient has a mixed acid-base picture due to the presence of a concomitant alkalotic disorder.[35][41][4]
Incomplete distal RTA often has normal arterial pH and can only be diagnosed after provocative testing.
If the arterial pH is normal or higher in the absence of a second acid-base disorder, a patient with low serum bicarbonate and potassium has respiratory alkalosis and not RTA.
It has been suggested that children at low percentile height for age have arterialized venous pH measurement before age of 3 years.[134][136] However, an analysis of children in the Netherlands and Belgium found decreasing weight in children aged younger than 3 years to be a sufficient reason to perform a blood gas analysis, but this investigation was not effective in children older than 3 years.[134]
Result
low
serum anion gap
Test
In all types of RTA, the anion gap is normal (<12 mEq/L), whereas an increased serum anion gap indicates the presence of another type of acidosis.[130]
A normal anion gap with acidosis limits the diagnostic possibilities to RTA, diarrheal loss of bicarbonate, and acid ingestion.
Result
normal
urine pH
Test
Most sensitive and specific test for diagnosis of classic distal RTA. The diagnosis of classic distal RTA is made when urine pH cannot be lowered below 5.5 in the face of hyperchloremic metabolic acidosis with abnormally low arterial pH.[35][41][4]
The urine pH is less than 5.5 in patients with untreated proximal RTA.[2] Urine pH is also low in hyperkalemic distal RTA.
Result
>5.5 in classic distal RTA
Tests to consider
serum aldosterone
Test
Most sensitive and specific test for aldosterone deficiency, a cause of hyperkalemic distal RTA. Recommended to be performed in patients with hyperkalemic distal RTA, who are not taking any medications known to cause the disorder.
Aldosterone deficiency is marked by low aldosterone despite hyperkalemia and acidemia. In aldosterone resistance the level is normal or elevated.
Result
low in aldosterone deficiency states, normal or high in aldosterone resistance
urine anion gap
Test
Only performed if distal RTA is suspected and urine pH is above 5.3 during acidemia.
The urine anion gap (UAG) is calculated using the equation: urinary cations [sodium + potassium] – urinary anions [chloride]. In the setting of normal kidney function and hyperchloremic metabolic acidosis, the UAG is less than zero.[124] When the UAG is positive, it indicates low urinary ammonium.[125]
Result
positive
measurement of fractional bicarbonate excretion
Test
Standard test for proximal RTA. The fractional excretion of bicarbonate (FE bicarbonate %) from urine and blood bicarbonate and creatinine is calculated.
FE bicarbonate % = 100 × (urine bicarbonate/serum bicarbonate)/(urine creatinine/serum creatinine).
In proximal RTA, the FE bicarbonate % exceeds 10% to 15% when serum bicarbonate exceeds 20 to 22 mEq/L.[4]
Result
bicarbonaturia in proximal RTA
urine PCO₂ bicarbonate infusion
Test
0.9% sodium bicarbonate is infused until urine bicarbonate concentration reaches 80 mEq/L. Urine is collected under oil or drawn into a syringe immediately after voiding. The urine PCO₂ is determined with a blood gas analyzer. Measurement is made before and after the sodium bicarbonate is infused.
Urine PCO₂ does not rise in distal RTA. If distal acidification is normal, the measured urine PCO₂ will be >70 mmHg (torr) after the infusion of enough bicarbonate to produce a urinary bicarbonate concentration >80 mEq/L.[128]
Result
PCO₂ does not rise in distal RTA
furosemide test
Test
The effect of a dose of 40 or 80 mg furosemide on urine pH and potassium concentration is compared with pre-furosemide values. Urine results are measured hourly for up to 3 hours. Normal individuals lower pH to <5.5, and increase urine potassium.
The test is used to test for acidification defects when metabolic acidosis is not overt. If furosemide does not lower urine pH to below 5.5 but urine potassium rises significantly, distal RTA is present.[4][91] If the pH fails to fall and urine potassium does not rise, the results suggest aldosterone deficiency or resistance.
Result
pH >5.5 and elevated potassium (distal RTA); pH >5.5 and normal potassium (aldosterone deficiency)
ammonium chloride loading test
Test
Only performed if distal RTA is suspected based on underlying conditions, but the clinical acid-base status is normal and urine pH is appropriate.
Ammonium chloride is given orally at a dose of 0.1 g/kg lean body weight for 1 (short test) or 3 (long test) days. In normal people the urine pH falls below 5.5 and the urine ammonium excretion triples.[4][137] Patients with classic distal RTA fail to lower pH.
Result
pH >5.5 (classic distal RTA)
furosemide and fludrocortisone test
Test
For diagnosis in incomplete RTA without overt acidosis.
A baseline urine sample is collected, after which the patient is given 40 mg of furosemide and 1 mg of fludrocortisone. Urine is collected hourly for 6 hours. Patients with distal RTA fail to lower urine pH to <5.3; normal controls lower pH below 5.3 after 3 hours.[138]
Result
pH >5.3 (distal RTA)
urine glucose
Test
The presence of glucosuria during normoglycemia indicates inappropriate excretion of glucose and supports the diagnosis of Fanconi syndrome in a patient with proximal RTA. Direct measurement, rather than the measurement of urine-reducing substances, should be used.
Result
glucose present in the urine on a spot sample when serum glucose obtained at the same time is normal in Fanconi syndrome
tubular maximum (Tm) reabsorption of phosphate
Test
Urine and blood samples are collected at the same time and submitted for measurement of phosphate and creatinine concentration.
The Tm reabsorption of phosphate per glomerular filtration rate is calculated as: plasma phosphate - (urinary phosphate × plasma creatinine/urinary creatinine). The results are best interpreted in consultation with a specialist.[139]
Result
decreased in Fanconi syndrome
fractional excretion of amino acids
Test
Total free urinary amino acids (TAA) are first determined screening tests (thin layer chromatography). Exact measurement of serum and urine TAA may be made with gas chromatography or other methods.
Fractional excretion of TAA is calculated as: [1-(urinary amino acids × plasma creatinine)/(plasma amino acids × urinary creatinine)]/100. The results are interpreted by comparison with prior cases.[140]
Result
increased in Fanconi syndrome
ultrasound
Test
The test should be performed in patients with hyperkalemic distal RTA who do not have aldosterone deficiency and are not taking drugs known to be associated with hyperkalemic distal RTA. It should also be performed when there is any history suggestive of prostatism in a patient with hyperkalemic distal RTA.
Result
some degree of dilatation of the ureter, renal pelvis, and caliectasis
CT/spiral CT
Test
CT can be used to assess the urinary tract for obstruction when ultrasound is unavailable or ultrasound examination is limited by patient size. CT can also be used to assess for stones and ureteral obstruction.
Result
dilatation of the ureter and renal pelvis and caliectasis mark significant obstruction; nephrocalcinosis and/or nephrolithiasis may be seen directly
nuclear renal scan
Test
Nuclear renal scans are more sensitive for the detection of obstruction than ultrasound or CT. Nuclear scans are performed to assess possible obstruction in patients with hyperkalemic distal RTA with no obvious cause.
Result
delayed clearance of radionuclide from the renal pelvis; no response to furosemide
Emerging tests
molecular genetic testing for hereditary distal RTA (type I)
Test
Hereditary distal RTA should be suspected in individuals with suggestive clinical, laboratory, and radiologic findings.[5] Molecular genetic testing approaches include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing, depending on phenotype.
Result
diagnosis is established in a proband with distal RTA and biallelic pathogenic variants in ATP6V0A4, ATP6V1B1, FOXI1, or WDR72, or a heterozygous or biallelic pathogenic variants in SLC4A1*
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