Altered Laboratory Tests in Renal Disease

The kidneys excrete metabolic waste products and regulate the serum concentration of a variety of substances. At some stage during the course of renal disease, the following routinely measured substances often become abnormal and the extent of the abnormality generally depends on the severity of the disease.

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:

FENa = ( Nau/Nas) / ( Cru/Crs)

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
                random         24 hr.     after 12 hr.       after fluid
                                           fluid fast           load
   gravity   1.002 - 1.03  1.015 - 1.025     > 1.025          < 1.005 
   (or osmol-                            900 - 1250 mOsM      < 100 mOsM
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

Specific gravity is measured for the purpose of determining concentrating ability. The result has meaning for this purpose only when the specimen has been collected following a 12 hour fluid fast. Normal kidneys can concentrate urine so that the concentration of osmotically active substances is 3 - 4 times greater than that of plasma. When concentrating ability is completely lost, the osmolality of urine can be no greater than that of serum. Specific gravity is much easier to measure than is osmolality and generally the two results correlate well. Normal specific gravity of a concentrated urine specimen is greater than 1.025. The specific gravity of a urine specimen from a fluid fasted patient with renal disease, sufficiently severe so that concentrating ability is completely lost, is 1.010.
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.

Differences between Specific Gravity and Osmolality Results

The specific gravity or osmolality of urine specimens is measured primarily for the purpose of evaluating renal concentrating ability; less commonly as part of the work-up for evaluating SIADH in which diluting ability is deficient. Evaluation of renal concentrating ability by measurement of specific gravity or osmolality of a urine specimen provides a simple renal function screening test. Measurement of specific gravity is simplest, but measurement of osmolality avoids the foibles of a specific gravity result influenced by the presence of a significant amount of high molecular weight material such as protein or glucose. The table below illustrates how the presence of protein influences specific gravity results but not osmolality results.

Specimen Protein
Normal - 1200 1.040 normal
Renal Disease - 300 1.010 renal disease
Renal Disease 2 g/dl 300 1.030 normal

The molar concentration corresponding to 2 g/dl protein is less than 1 mM, so that osmolality is not affected. However, 2 g/dl protein imparts 20 mg/ml to the specific gravity increasing it from 1.010 to 1.030; from a value corresponding to lack of concentrating ability to a value corresponding to normal concentrating ability. Because of its affect on specific gravity, concentrating ability must be evaluate on the basis of osmolality results, and not specific gravity results, whenever protein concentration is increased in urine specimens.

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):

Creatinine Clearance = (Cru x V/t) / Crs
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

= (60 mg/dl)x(2400 ml)/(1440 min) = 1 g/day
Don't confuse the terms excretion rate and clearance.

Relationship Between Azotemia and GFR

The creatinine excretion rate is relatively constant from day to day for any one individual, even for patients with renal disease and as the disease progresses. Values measured for a large group of individuals range between about 1-2 g/day. Since the creatinine excretion rate is constant for any one individual, the creatinine clearance and serum creatinine concentration are related in a simple reciprocal manner and the same information is obtained from each determination, at least in principle, i.e.:

Cr.Cl. = (Cr. excretiion rate)/(serum creatinine)

The creatinine clearance is, however, considered more sensitive for detecting early renal disease, than is the serum creatinine concentration, because the normal range is less broad. An age and weight correction has been reported to provide a more reliable relationship between serum creatinine and creatinine clearance:

        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.

The Serum Urea/Creatinine Ratio:

Both urea and creatinine are excreted almost exclusively by glomerular filtration. Creatinine is formed at a relatively constant rate and serum concentrations depend almost exclusively on GFR and thereby quite specifically reflect GFR .
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 excretion

Hypovolemic 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:
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:

  1. 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
  2. Nephritic Syndrome
    • hematuria, proteinuria ( < 2 g/day)
    • red cell casts
    • azotemia
  3. Tubulointerstitial Disease
    • cloudy urine from high WBC
    • white cell casts
    • proteinuria ( < 1 g/day)
    • azotemia
  4. 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