| LABORATORY EVALUATION OF RENAL FUNCTION |
Serum creatinine and urea concentrations change inversely with changes in GFR and are therefore useful in gauging the degree of renal dysfunction. Changes in serum creatinine concentration more reliably reflect changes in GFR than do changes in serum urea concentrations. Creatinine is formed spontaneously at a constant rate from creatine, and blood concentrations depend almost solely upon GFR. Urea formation is influenced by a number of factors such as liver function, protein intake and rate of protein catabolism. Urea excretion also depends upon hydration status and the extent of water reabsorption as well as upon GFR.Determination of creatinine clearance, from measurement of creatinine concentration in both a 24 hour urine collection and a serum specimen, provides a clinically useful estimate of GFR.
Excretion rates of creatinine or urea (quantity in urine/day) do not change in renal disease, unless impairment is rapid (as in acute renal failure) or is sufficiently severe to cause oliguria, and so do not provide information about the status of renal function.
Protein in urine is noticeably increased in renal disease of any etiology, except obstruction, and is therefore a very sensitive, general screening test for renal disease, though not specific. The extent of proteinuria also provides useful information. The greatest degree of proteinuria is found in the nephrotic syndrome ( > 3 - 4 g/day). In renal disease with the nephritic syndrome, the urinary protein excretion rate is usually about 1 - 2 g/day. In tubulo-interstitial disease, urine protein is generally less than 1 g/day. Only in the nephrotic syndrome is the urine protein loss sufficiently great to result in hypoproteinemia.
Protein in serum can generally be maintained at concentrations above the lower limit of normal by increased hepatic protein synthesis so long as protein loss is less than about 3 g/day.
Hyperphosphatemia, hyperuricemia and acidosis (metabolic with an anion gap) do not develop until there is 70-80% loss of functional capacity (i.e., in the renal failure stage) so that measurements of serum phosphate, uric acid or bicarbonate, do not provide a very sensitive indication of the possibility of renal disease. However, measurement of serum phosphate and uric acid is useful for monitoring the effect of therapy during chronic renal disease and/or the effects of attempts to minimize increased serum concentrations by restricting dietary intake of phosphate and nucleotides. Acidosis is generally mild and without pathophysiologic consequences until the uremic stage.
Calcium deficiency, which occurs during the renal failure stage of chronic renal disease because of deficient renal activation of vitamin D, does not usually result in frank hypocalcemia because secondary hyperparathyroidism develops as a compensatory response to maintain serum calcium concentrations within the normal range. Bone calcium, however, is lost in the process causing renal osteodystrophy which is typically a mild form of osteomalacia and is only rarely the more severe osteitis deformans (Van Ricklenhausen's disease) classically associated with primary hyperparathyroidism. Calcium deficiency and consequent osteomalacia is treated with activated vitamin D. Although calcium metabolism is abnormal, serum calcium determinations are not useful for detecting or assessing the severity of renal disease, but are useful for monitoring the effectiveness of vitamin D therapy and assuring that hypocalcemia is prevented.
Sodium and potassium homeostasis is maintained, so long as intake is not extremely variable, unless renal dysfunction is sufficiently severe to cause oliguria. Electrolyte determinations are, therefore, not useful for detecting or assessing the progression of renal disease.
Evaluation of renal sodium reabsorption is, however, valuable for assessing tubule function and is useful for distinguishing whether rapidly developing azotemia is due to acute renal failure or to prerenal azotemia from a compensatory decrease in renal blood flow due to hypovolemia. In cases of prerenal azotemia, without hypoxic damage to renal tubule cells despite decreased renal blood flow, aldosterone effectively stimulates sodium reabsorption and urine sodium concentration is generally less than 30 mEq/L. In acute renal failure, aldosterone elevation is ineffective in stimulating sodium reabsorption because of tubular damage so that urine sodium concentration is generally at least 25 mEq/L and often greater than 50 mEq/L.
However, there is considerable overlap in urine sodium concentrations between cases of prerenal azotemia and acute renal failure. The fraction of filtered sodium excreted (FENa) is a more discriminating parameter for evaluating tubular function and is determined by measurement of both serum and urine concentrations of sodium and creatinine:
Urinalysis
Urine specimens are readily and inexpensively examined in a routine manner by the use of "dip sticks" for semiquantitatively estimating the concentrations of a number of components, most commonly glucose, ketones, bilirubin, urobilinogen, protein, hemoglobin, and pH. The routine urinalysis also includes measurement of specimen volume, determination of specific gravity or osmolality and microscopic examination of the urine sediment for cells, casts and crystals. The entire group of tests is clinically useful for evaluating a wide variety of pathologic conditions, and the following are particularly useful for evaluating renal disease.______________________________________________________________________
Test Normal Results
appearance clear and straw colored or yellow
volume 0.8 - 1.8 L/24 hours
protein undetectable (< 150 mg/24 hours)
hemoglobin undetectable
microscopic few leukocytes
examination absence of red cells
presence of hyaline casts is normal
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random 24 hr. after 12 hr. after fluid
fluid fast load
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specific
gravity 1.002 - 1.03 1.015 - 1.025 > 1.025 < 1.005
(or osmol- 900 - 1250 mOsM < 100 mOsM
ality)
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The appearance of urine is altered by the presence of blood or leukocytes. Blood imparts a red to brown color and leukocytes cause urine to appear turbid. Blood in the urine is characteristic of glomerulonephritis, but may be due to trauma or tumor anywhere along the urinary tract or bladder. Urinary white cells are characteristic of tubulointerstitial disease, but may also result from bladder infection. The presence of cells in casts is far more specific for renal disease.Urine volume is influenced by water intake and by concentrating ability. Minimum urine volume during fluid fasting is normally about 300 - 500 ml/day. During the progression of renal disease, minimum urine volume increases to 2 L/day when concentrating ability is completely lost at the renal failure stage. Polyuria is defined as a daily urine volume greater than 2 L/day. In end stage, GFR is so reduced that maximum urine volume is less than 400 ml/day (oliguria). Daily urine volume rarely drops so low as to be considered anuric ( <50 ml/day).
Proteinuria is present in renal disease of almost any etiology to varying degrees as discussed above. The only other pathologic condition associated with remarkable proteinuria is multiple myeloma. The reagents impregnated in urine dipsticks react only to albumin. This is sufficient for detecting increased protein from renal disease but increased urine protein from light chain excretion in cases of multiple myeloma will not be detected. The sensitivity of dipsticks for detecting protein is about 25 mg/dl which is equivalent to about 200 - 500 mg in a 24 hour urine collection. Quantitative methods are used to determine total protein in 24 hour urine collections.
Hematuria is most characteristic of glomerulonephritis, but may be due to trauma or tumor anywhere along the urinary tract or bladder. The presence of red cells in casts is more specific for renal disease.
The finding of casts is the most important observation from the microscopic examination of the urinary sediment. Casts are normally formed within tubules from gellation of the Tamm-Horsfall mucoprotein secreted by the tubule epithelia of the ascending loop of Henle. The mucoprotein accounts for about 30 - 50 mg of total urine protein excreted per day. Cast formation is favored by sluggish flow, acid, and high protein content. Sluggish flow permits the formation of larger casts within larger collecting ducts. Cells trapped in casts disintegrate to a greater degree the slower the flow and the longer the cast remains in the collecting ducts. A granular cast is shown to the right, below.
Microscopic Appearance of a Granular Cast |
- Hyaline casts of Tamm-Horsfall protein are present in normal urine.
- Red cell casts predominate in acute glomerulonephritis.
- White cell casts predominate in tubulointerstitial disease.
- Granular casts result from disintegration of cellular casts and may be coarsely or finely granular depending on the degree of disintegration of the cellular elements.
- Broad, waxy casts represent complete disintegration of embedded components, suggesting sluggish flow; the broad nature of these casts is due to their formation in larger collecting ducts. These casts appear in more severe stages of renal disease and are sometimes referred to as "renal failure casts".
At end stage, diluting ability is minimal, and specific gravity becomes fixed at 1.010 regardless of fluid intake.
Specific gravity results are not reliable when urine contains an appreciable amount of protein. Osmolality must be measured in order to evaluate concentrating ability in urine specimens with a high protein content.
Diluting ability, determined from the specific gravity or osmolality following a fluid load, is used for evaluating Syndrome of Inappropriate ADH.
| Specimen | Protein Concentration | Osmolality (mOsM) | Specific Gravity (g/ml) | Interpretation |
|---|---|---|---|---|
| Normal | - | 1200 | 1.040 | normal |
| Renal Disease | - | 300 | 1.010 | renal disease |
| Renal Disease | 2 g/dl | 300 | 1.030 | normal |
Creatinine Clearance:Glomerular filtration rate is estimated, in clinical practice, from the creatinine clearance which is calculated from measurements of serum creatinine concentration (Crs), urine creatine concentration (Cru), and the urine volume (V) collected over a time period (t, usually expressed in minutes):
The normal range is for males 85 - 125 ml/min
females 75 - 115 ml/min
Glomerular filtration rate is proportional to body surface area and the above range is for the average adult with a surface area of 1.73 square meters. It is particularly important when evaluating renal function of children to correct the measured creatinine clearance to what it would be if the child had a body surface area of 1.73 sq. meter. The "corrected" creatinine clearance is obtained by multiplying the measured creatinine clearance X 1.73 and dividing by actual body surface area. Nomograms are available from which body surface area is related to height and weight. Sample calculation of creatinine clearance:
Crs = 3.2 mg/dl
Cru = 60.0 mg/dl
V = 2400 ml
t = 24 hours = 24 hr. x 60 min/hr = 1440 min.
creatinine clearance = [(60 mg/dl)x2400 ml/1440 min]/(3.3 mg/dl)
= 30 ml/min.
Note that (Cru x V/t) = creatinine excretion rate (amount of creatinine excreted per day) and for the example above Don't confuse the terms excretion rate and clearance.
Relationship Between Azotemia and GFR
Cr.Cl. = (140-age) x body weight/72kg
serum creatinine
Serum creatinine concentrations rarely exceed 15 mg/dl, even in uremia and end stage, apparently because of increased secretion and decreased production rate.Urea, however, is formed at variable rates (increased in cases of high protein diet, G.I. bleed, catabolic states - cachexia, increased steroids from therapy or Cushing's syndrome) and excretion also depends upon extent of water reabsorption as well as upon GFR.
Changes in serum creatinine concentration, therefore, more specifically reflect changes in GFR than do changes in serum urea concentration.
However, the serum urea/creatinine ratio does provide information about the status of any of the possible causes mentioned above, other than decreased GFR, affecting serum urea concentrations.
The serum urea/creatinine ratio is normally about 15. The ratio is also 15 in cases of renal disease when creatinine and urea both increase inversely with decreased GFR. The ratio is increased in any of the above mentioned conditions which effect an increase in serum urea concentration.
Prerenal azotemia results from compensatory decreased renal blood flow from hypovolemia (shock, dehydration) with consequent decreased GFR and increased water reabsorption so that the ratio is greater than 15. The serum urea/creatinine ratio is a readily available parameter used to distinguish between prerenal azotemia and acute renal failure. However, evaluation of renal sodium reabsorption is better for this purpose.
Evaluation of renal sodium excretionHypovolemic conditions which lead to a compensatory decrease in renal blood flow may, if sufficiently severe and/or sudden, lead to acute renal failure from acute tubular necrosis. In either case, patients present with oliguria and rapidly developing azotemia. In such cases, it is important to distinguish between prerenal azotemia and acute renal failure. Investigation of renal sodium excretion provides more definitive information about the status of renal function in such cases than does the serum urea/creatinine ratio. In hypovolemic conditions, sodium reabsorbtion is maximally stimulated and urine sodium concentration is generally less than 30 mEq/L with normal tubular function. However, a considerable percentage of cases with acute renal failure exhibit similarly low concentrations of urine sodium. Most diagnostically distinguishing is the fraction of filtered sodium excreted (FENa).
FENa = Nau x Crs x 100
Nas Cru
< 1 with adequate tubular function
> 2 with acute tubular necrosis
Summary of Tests for Evaluating Renal Function:
- Detection:
- increased urine protein
- presence of red and/or white cells in urine sediment
- presence of casts (w/wo cells) in urine sediment
- decreased specific gravity (or osmolality) of urine specimen after fluid fast
- increased serum creatinine and urea
- decreased creatinine clearance
- Monitoring the extent of renal dysfunction:
- serum creatinine or urea concentration
- creatinine clearance
- Laboratory Findings in Specific Syndromes:
- Nephrotic Syndrome
- proteinuria > 3 g/day
- hypoproteinemia and consequent edema; the protein loss may be
- selective (predominantly albumin loss), or
- nonselective (both large and small proteins lost)
- hyperlipidemia
- azotemia is not a necessary component of the syndrome, but may be present
- Nephritic Syndrome
- hematuria, proteinuria ( < 2 g/day)
- red cell casts
- azotemia
- Tubulointerstitial Disease
- cloudy urine from high WBC
- white cell casts
- proteinuria ( < 1 g/day)
- azotemia
- Acute Renal Failure
- sudden oliguria
- rapidly developing azotemia (serum creatinine increases at a maximum rate of about 2 mg/dl per day)
- broad waxy casts (renal failure casts)
- serum urea/creatinine ratio ~ 15
- urine sodium concentration > 40 mEq/L
- FENa > 2
- Nephrotic Syndrome
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