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Clinical Pathology

Laboratory Tests to Evaluate Tubular Function

By Dayyal Dg.Twitter Profile | Updated: Tuesday, 02 January 2024 11:41 UTC
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Human kidney and nephron.
Human kidney and nephron.

These diagnostic assessments are designed to evaluate the performance of two crucial components of the kidney – the proximal and distal tubules. Proximal tubular function tests, such as Fractional Excretion of Sodium (FENa) and Tubular Reabsorption of Phosphate (TRP), gauge the efficiency of reabsorption in the proximal tubule. On the other hand, tests for distal tubular function, like the Urine Acidification Test, focus on the tubule's ability to maintain the body's acid-base balance. These tests play an important role in diagnosing renal disorders by providing valuable information on the specific functionalities of these intricate renal structures.

Tests to Assess Proximal Tubular Function

The renal tubules play a crucial role in reabsorbing 99% of the glomerular filtrate to retain vital substances such as glucose, amino acids, and water.

Glycosuria

Renal glycosuria manifests as the excretion of glucose in urine despite normal blood glucose levels. This occurrence results from a specific tubular lesion impairing glucose reabsorption, rendering renal glycosuria a benign condition. Notably, glycosuria may also manifest in Fanconi syndrome.

Generalized aminoaciduria

Proximal renal tubular dysfunction leads to the excretion of multiple amino acids in urine due to defective tubular reabsorption.

Tubular proteinuria (Low molecular weight proteinuria)

Under normal conditions, low molecular weight proteins, such as β2 –microglobulin, retinol-binding protein, lysozyme, and α1 –microglobulin, undergo filtration by glomeruli and complete reabsorption by proximal renal tubules. Tubular damage disrupts this process, causing the excretion of these proteins in urine, detectable by urine protein electrophoresis. Elevated levels of these proteins in urine indicate renal tubular damage.

Urinary concentration of sodium

When both blood urea nitrogen (BUN) and serum creatinine levels are acutely elevated, distinguishing between prerenal azotemia (renal underperfusion) and acute tubular necrosis becomes essential. In prerenal azotemia, renal tubules function normally, reabsorbing sodium, whereas in acute tubular necrosis, tubular function is impaired, resulting in decreased sodium absorption. Consequently, the urinary sodium concentration is < 20 mEq/L in prerenal azotemia and > 20 mEq/L in acute tubular necrosis.

Fractional excretion of sodium (FENa)

Given that urinary sodium concentration can be influenced by urine volume, calculating the fractional excretion of sodium provides a more accurate assessment. This metric represents the percentage of filtered sodium that has been absorbed and excreted. In cases of acute renal failure, especially in oliguric patients, FENa serves as a reliable means of early differentiation between pre-renal failure and renal failure due to acute tubular necrosis.

The formula for calculating FENa is as follows:

(Urine sodium × Plasma creatinine) ÷ (Plasma sodium × Urine creatinine) × 100%

In pre-renal failure, this ratio is less than 1%, reflecting maximal sodium conservation by tubules stimulated by aldosterone secretion due to reduced renal perfusion. In acute tubular necrosis, the ratio exceeds 1% since tubular cell injury hampers maximum sodium reabsorption. Ratios above 3% strongly suggest acute tubular necrosis.

Tests to Assess Distal Tubular Function

Urine specific gravity

The normal range for urine specific gravity is 1.003 to 1.030, contingent upon the individual's state of hydration and fluid intake.

  1. Causes of Increased Specific Gravity:
    • Reduced renal perfusion (with preservation of tubular concentrating ability),
    • Proteinuria,
    • Glycosuria,
    • Glomerulonephritis,
    • Urinary tract obstruction.
  2. Causes of Reduced Specific Gravity:

As a test for renal function, urine specific gravity provides insights into the renal tubules' ability to concentrate the glomerular filtrate. This concentrating capability is compromised in diseases affecting the renal tubules.

A fixed specific gravity of 1.010, impervious to alteration with changes in fluid intake, serves as an indicator of chronic renal failure.

Urine osmolality

The measurement of urine/plasma osmolality stands as the most commonly employed test to assess tubular function. This method, highly sensitive to concentration ability, quantifies the number of dissolved particles in a solution. In contrast, specific gravity, measuring the total mass of solute in relation to water mass, is influenced by the number and nature of dissolved particles, making osmolality a preferred measurement. Osmolality is expressed as milliOsmol/kg of water.

When solutes are dissolved in a solvent, alterations occur in properties such as freezing point, boiling point, vapor pressure, or osmotic pressure. Osmolality measurement, conducted with an instrument known as an osmometer, captures these changes.

The urine/plasma osmolality ratio aids in distinguishing pre-renal azotemia (higher ratio) from acute renal failure due to acute tubular necrosis (lower ratio). Similar urine and plasma osmolality values indicate defective tubular reabsorption of water.

Water deprivation test

When baseline urine osmolality is inconclusive, the water deprivation test is performed. This test involves restricting water intake for a specified period, followed by the measurement of specific gravity or osmolality. In normal cases, urine osmolality should rise in response to water deprivation. Failure to increase prompts administration of desmopressin to differentiate between central and nephrogenic diabetes insipidus. A urine osmolality > 800 mOsm/kg or specific gravity ≥1.025 after dehydration indicates normal renal tubular concentration ability, although normal results do not exclude the presence of renal disease.

Results may be skewed if the patient is on a low-salt, low-protein diet or experiencing major electrolyte and water disturbances.

Water loading antidiuretic hormone suppression test

This test gauges the kidney's ability to dilute urine after water loading. After an overnight fast, the patient drinks 20 ml/kg of water in 15-30 minutes. Urine is collected hourly for 4 hours to measure volume, specific gravity, and osmolality. Plasma antidiuretic hormone levels and serum osmolality are measured at hourly intervals.

Normal results entail excreting over 90% of water in 4 hours, with specific gravity falling to 1.003 and osmolality to < 100 mOsm/kg. Impairments occur in renal function, adrenocortical insufficiency, malabsorption, obesity, ascites, congestive heart failure, cirrhosis, and dehydration. The test is contraindicated in patients with cardiac failure or kidney disease due to the risk of fatal hyponatremia in case of water load failure.

Ammonium chloride loading test (Acid load test)

Utilized in diagnosing distal or type 1 renal tubular acidosis, this test follows exclusion of other causes of metabolic acidosis. After overnight fasting, urine pH and plasma bicarbonate are measured. A pH less than 5.4 with low plasma bicarbonate confirms normal acidifying ability of renal tubules. In cases where neither of these results is obtained, further testing is warranted. The patient receives oral ammonium chloride (0.1 gm/kg) after an overnight fast, and urine samples collected hourly for 6-8 hours. Ammonium ion dissociation produces H+ and NH3, making blood acidic. A pH less than 5.4 in any sample confirms normal acidifying ability of distal tubules.

References

  • Gaw A, Murphy MJ, Cowan RA, O’Reilly DSJ, Stewart MJ, Shepherd J. Clinical Biochemistry: An Illustrated Colour Text (3rd Ed). Edinburgh: Churchill Livingstone 2004.
  • Johnson CA, Levey AS, Coresh J, Levin A, Lau J, Eknoyan G. Clinical practice guidelines for chronic kidney disease in adults: Part II. Glomerular filtration rate, proteinuria, and other markers Am Fam Physician 2004;70:1091-7.
  • Stevens LA, Coresh J, Green T, Levey AS. Assessing kidney function-measured and estimated glomerular filtration rate. N Engl J Med 2006;354:2473-83.
  • Stevens LA, Levey AS. Measurement of kidney function. Med Clin N Am 2005;89:457-73.
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