Urinalysis in the diagnosis of renal

disease
INTRODUCTION
Patients with renal disease have a variety of different clinical
presentations. Some have symptoms that are directly referable
to the kidney (gross hematuria, flank pain) or to extrarenal
sites of involvement (edema, hypertensive, signs of uremia).
Many patients, however, are asymptomatic and are noted on
routine examination to have an elevated plasma creatinine
concentration or an abnormal urinalysis.
Once renal disease is discovered, the presence or degree of renal
dysfunction is assessed and the underlying disorder is diagnosed.
Although the history and physical examination can be helpful, the
most useful information is initially obtained from estimation of the
glomerular filtration rate (GFR) and examination of the urinary
sediment.
Estimation of the glomerular filtration rate (GFR) is used clinically to
assess the degree of renal impairment and to follow the course of the
disease. However, the GFR provides no information on the cause of
the renal disease. This is achieved by the urinalysis and, if necessary,
radiologic studies and/or renal biopsy.
URINALYSIS The major noninvasive diagnostic tool
available to the clinician is the urinalysis. Although examination of
the urine can also provide some information about disease
severity, such a direct relationship between the urinalysis
and severity is not always present.
In a patient with acute glomerulonephritis, for example,
Unormalization of the urinalysis represents
resolution of the active inflammatory processU.
However, this can reflect either recovery or healing with irreversible
glomerular scarring and nephron loss. In this setting, repeat renal
biopsy may be required to accurately estimate the status of the
renal disease [1] .
Despite these potential limitations, a complete urinalysis
should be performed in all patients with renal disease. The
specimen should be examined within 30 to 60 minutes of
voiding; a midstream specimen is adequate in men, but the
external genitalia should first be cleaned in women to avoid
contamination with vaginal secretions. The urine should be
centrifuged at 3000 rpm for three to five minutes, and the
supernatant then poured into a separate tube. A small amount
of sediment should be placed on a slide, while the supernatant
should be tested for color (particularly for color suggesting the
presence of heme pigments), protein, pH, concentration, and
glucose.
Color
Normal urine is clear and light yellow in color; it is
lighter when dilute and darker when concentrated, such as after an
overnight water restriction.
The urine may also have a variety of other colors, including shades
of red or brown. The intermittent excretion of red to brown urine is
observed in a variety of clinical settings [2,3] .
The initial step in the evaluation of this problem is centrifugation of
the urine to see if the red color is in the urine sediment or the
supernatant
Hematuria is responsible if the red color is seen only in the
urine sediment, with the supernatant being clear
If, on the other hand, it is the supernatant that is red, then the
supernatant should be tested for heme with a urine dipstick.
UA red supernatant that is negative for heme is a rare finding
that can be seen in several conditions
These include use of Uthe bladder analgesic
phenazopyridineU or a variety of other medications, food dyes,
the ingestion of beets in susceptible subjects, and porphyria
UA red supernatant that is positive for heme is usually due to
myoglobinuria or hemoglobinuriaU.
UHemoglobinuria and myoglobinuria can be usually be
distinguished by looking at the plasma which is red
with hemoglobinuria and its normal color with
myoglobinuria.
UFalse positive heme reactions may be seen if
semen is present in the urine, if the urine is
alkaline (pH >9), or contaminated with oxidizing
agents used to clean the perineumU [4] .
Rarely, the urine has other colors.
These include:
White due to pyuria, phosphate crystals, chyluria [5,6] , or
propofol [7] .
Green due to the administration of methylene blue [8] ,
propofol [9-11] , or amitriptyline).
Black due to hemoglobinuria [12,13] or ochronosis, most often
due to alkaptonuria, which is also called black urine disease.
The black urine in ochronosis results from urinary excretion of
homogentisic acid (HGA).
The black color may only be apparent after the urine stands for
some time, permitting oxidation of HGA. (See "Disorders of
tyrosine metabolism", section on Alkaptonuria).
Purple due to bacteriuria in patients with urinary catheters.
(See "Urinary tract infection associated with indwelling bladder
catheters", section on Purple urine bag syndrome).
In addition, other colors can occur in children with inborn errors
of metabolism
Protein
The urine dipstick primarily detects albumin but not other proteins,
such as immunoglobulin light chains. This test is highly specific,
but not very sensitive for the detection of proteinuria; it becomes
positive only when protein excretion exceeds 300 to 500 mg/day.
Thus, the regular urine dipstick is an
insensitive method to detect
microalbuminuria, which is the earliest
clinical manifestation of diabetic
nephropathy and is associated with
increased cardiovascular risk in patient
with and without diabetes.
U In type 1 diabetes, the development of a positive dipstick for albumin
is a relatively late event, occurring at a time when there is already
substantial structural injury.
There are also a variety of dipsticks that can be used to test
for microalbuminuria, such as :
o Clinitek Microalbumin Dipsticks and
o Micral-Test II test strips
The semiquantitative categories on the dipsticks should be
used with caution and only as a rough guide since, at a given of
albumin excretion, the albumin concentration will vary with the
urine volume. A dilute urine, for example, will underestimate
the degree of proteinuria, while a highly concentrated urine
may have a 3+ response on the regular dipstick but not be
indicative of heavy proteinuria.
UFalse-positive results are common with many iodinated
radiocontrast agents [14] .
UThus, the urine should not be tested for protein with the
dipstick for at least 24 hours after a contrast study.
Sulfosalicylic acid test
In contrast to the urine dipstick, SSA detects all proteins in the urine
[15] .
This characteristic makes the SSA test particularly useful in older
patients who present with acute renal failure, a benign urinalysis, and
a negative or trace dipstick.
In this setting, myeloma kidney, in which immunoglobulin light chains
form casts that obstruct the tubules, must be excluded. A significantly
positive SSA test in conjunction with a negative dipstick usually
indicates the presence of nonalbumin proteins in the urine, most often
immunoglobulin light chains.
Similar to the urine dipstick, radiocontrast agents can cause false
positive SSA results [3] .
The sulfosalicylic acid (SSA) test is performed by
mixing one part urine supernatant (eg, 2.5 mL) with
three parts 3 percent sulfosalicylic acid, and grading
the resultant turbidity according to the following
schema (the numbers in parentheses represent the
approximate protein concentration) [2] :
U 0 = no turbidity (0 mg/dL)
U trace = slight turbidity (1 to 10 mg/dL)
U 1+ = turbidity through which print can be read (15 to 30
mg/dL)
U 2+ = white cloud without precipitate through which heavy
black lines on a white background can be seen (40 to 100
mg/dL)
U 3+ = white cloud with fine precipitate through which heavy
black lines cannot be seen (150 to 350 mg/dL)
U 4+ = flocculent precipitate (>500 mg/dL)
Quantitative measurement of urinary
protein excretion
Most patients with persistent proteinuria should undergo a
quantitative measurement of protein excretion. This can be
accomplished by a 24-hour urine measurement; however,
collecting these specimens may be cumbersome in ambulatory
care settings.
An alternative and preferred method is calculating the total
protein-to-creatinine or albumin-to-creatinine ratio (mg/mg) on
a urine sample [16-18] .
With elevated urinary protein levels, it is important to
understand how to differentiate between relatively benign (eg,
orthostatic proteinuria) or common causes of proteinuria (eg,
diabetic proteinuria) and uncommon causes that require
nephrology consultation.
Hydrogen ion concentration
The urine hydrogen ion concentration, measured as the pH,
reflects the degree of acidification of the urine.
The urine pH ranges from 4.5 to 8.0, depending upon the systemic
acid-base balance.
The major clinical use of the urine pH occurs in patients with
metabolic acidosis.
The appropriate response to this disorder is to increase urinary acid
excretion, with the urine pH falling below 5.3 and usually below 5.0.
A higher value may indicate the presence of one of the forms of renal
tubular acidosis.
Distinction between the various types of RTA can be made by
measurement of the urine pH and the fractional excretion of
bicarbonate at different plasma bicarbonate concentrations.
The diagnostic use of the urine pH requires that the urine be sterile.
Infection with any pathogen that produces urease, such as Proteus
mirabilis, can result in a urine pH above 7.0 to 7.5.
Osmolality and specific gravity
The solute concentration of the urine (or other solution) is a
function of the number of solute particles per unit volume; it is most
accurately measured by the osmolality of the solution.
The plasma osmolality is maintained within a very narrow range
(approximately 285 mosmol/kg), principally because the kidney is
able to excrete urine with an osmolality markedly different from that
of plasma
SINCE THE URINARY CONCENTRATION VARIES
MARKEDLY BASED UPON VOLUME STATUS, THE
URINE OSMOLALITY IS USEFUL ONLY WHEN
CORRELATED WITH THE CLINICAL STATE. THIS
MEASUREMENT IS MOST USEFUL IN THE DIAGNOSIS
OF PATIENTS WITH HYPONATREMIA,
HYPERNATREMIA, AND POLYURIA.
If an osmometer is unavailable, the concentration of the urine can
be assessed by measuring the specific gravity, which is defined as
the weight of the solution compared with that of an equal volume of
distilled water. The specific gravity generally varies with the
osmolality. However, the presence of large molecules in the urine,
such as glucose or radiocontrast media, can produce large
changes in specific gravity with relatively little change in osmolality.
Glucose
The presence of glucose in the urine as detected semiquantitatively
with a dipstick may be due to either the inability of the kidney to
reabsorb filtered glucose in the proximal tubule despite normal
plasma levels (renal glucosuria) or urinary spillage because of
abnormally high plasma concentrations.
IN PATIENTS WITH NORMAL RENAL FUNCTION, SIGNIFICANT
GLUCOSURIA DOES NOT GENERALLY OCCUR UNTIL THE
PLASMA GLUCOSE CONCENTRATION IS ABOVE 180 MG/DL (10
MMOL/L).
Renal glucosuria can occur as an isolated defect but is more
commonly observed in association with additional manifestations of
proximal dysfunction, including :
o hypophosphatemia,
o hypouricemia,
o renal tubular acidosis, and
o aminoaciduria
This constellation is called the Fanconi syndrome and may result
from a variety of disorders, particularly multiple myeloma.
The use of urinary glucose levels to screen for and monitor
diabetes mellitus is limited for a number of reasons. These include
the relative insensitivity of the measurement (since moderate
hyperglycemia is required before a positive test is obtained); its
dependence upon the urine volume; and its value which reflects
the mean plasma glucose concentration and not the level at the
time of measurement
Dipstick detection of hematuria and
pyuria
Microscopic hematuria may be discovered incidentally when
heme (either red blood cells or hemoglobin) is detected on a
dipstick. Dipsticks for hemoglobin detect 1 to 2 RBCs per high
powered field and are therefore at least as sensitive as urine sediment
examination, but result in more false positive tests.
False positive results may occur with alkaline urine with a pH greater
than 9, contamination with oxidizing agents used to clean the
perineum, and semen present in the urine after ejaculation.
By comparison, false negative tests are unusual; as a result, a negative
dipstick reliably excludes abnormal hematuria [19] .
Although red cells may be lysed in dilute urine, the hemoglobin that is
released will be detected by the dipstick.
Dipsticks may also detect leukocyte esterase and nitrite, the former
corresponding to pyuria and the latter to Enterobacteriaceae which
convert urinary nitrate to nitrite.
Although this test is a simple and inexpensive screen for urinary tract
infection, it may also detect pyuria not associated with infection.
Significant causes of sterile pyuria include :
o interstitial nephritis,
o renal tuberculosis, and
o nephrolithiasis
URINE SEDIMENT
Hematuria and pyuria by dipstick may be useful as a screening
test.
However, a microscopic examination of the urine sediment is
essential in the evaluation of renal disease, as it permits detection
of elements which cannot be found by dipstick alone (eg, red and
white blood cells and casts, and epithelial cells or casts).
SMALL AMOUNTS OF CRYSTALS, BACTERIA, CELLS,
OR CASTS MAY BE OBSERVED IN HEALTHY
INDIVIDUALS.
In a normal patient, for example, one high power field may contain
0 to 4 white blood cells and 0 to 2 red blood cells, and one cast
may be observed in 10 to 20 low powered fields [20] .
In addition, crystals of uric acid, calcium oxalate, or phosphate may
occasionally be seen.
The specimen is ideally examined within 30 to 60 minutes of
voiding. The urine should be centrifuged at 3000 rpm for three to
five minutes, most of the supernatant poured out, and the pellet
resuspended with gentle shaking of the tube.
A small amount of the resuspended sediment is poured on the
slide. The urine sediment examination should be performed by a
clinician trained in urine microscopy, as the diagnostic yield
compared to a laboratory urinalysis may be substantially greater
[21] .
Crystalluria
Whether crystals form in the urine depends upon a variety of
factors, including :
o the degree of supersaturation of constituent molecules,
o the urine pH, and
o the presence of inhibitors of crystallization
Many different forms may be observed in normal patients and in
those with defined disorders:
Uric acid crystals
Uric acid crystals as well as amorphous urates are observed in
acid urine, a milieu which favors the conversion of the relatively
soluble urate salt into the insoluble uric acid
Calcium phosphate or calcium oxalate crystals
The formation of calcium oxalate crystals is not dependent upon the
urine pH, while calcium phosphate crystals only form in a relatively
alkaline urine
Cystine crystals
Cystine crystals, with their characteristic hexagonal shape, are
diagnostic of cystinuria
Magnesium ammonium phosphate crystals
Magnesium ammonium phosphate (struvite) and calcium carbonate-
apatite are the constituents of struvite stones
Normal urine is undersaturated with ammonium phosphate
and struvite stone formation occurs only when ammonia
production is increased and the urine pH is elevated to
decrease the solubility of phosphate.
BOTH OF THESE REQUIREMENTS MAY BE MET
WHEN URINARY TRACT INFECTION OCCURS
WITH A UREASE-PRODUCING ORGANISM, SUCH
AS PROTEUS OR KLEBSIELLA.
ALTHOUGH THE OBSERVATION OF CRYSTALS IN THE
URINE IS MOST FREQUENTLY OF LITTLE DIAGNOSTIC
IMPORTANCE, THERE ARE SEVERAL NOTABLE
EXCEPTIONS.
These include :
U1.. the presence of cystine or ammonium magnesium
phosphate crystals (as mentioned above),
U2.. the combination of acute renal failure and calcium oxalate
crystals (a setting consistent with ethylene glycol ingestion),
and
U3.. the presence of a larger number of uric acid crystals
occurring in association with acute renal failure (consistent
with tumor lysis syndrome).
Bacteria
The presence of bacteria in a urine sediment is most frequently
due to contamination of the specimen upon collection.
Although normal urine is sterile, asymptomatic bacteriuria is
increasingly recognized but is usually not treated.
Cells
The cellular elements found in the urinary sediment include :
o red blood cells,
o white blood cells, and
o epithelial cells
Infrequently :
o tumor cells may also be observed, thereby suggesting the
diagnosis of genitourinary malignancy (eg, bladder cancer) and/or
o infiltration of the renal parenchyma with malignant
cells (eg, lymphoma).
Hematuria
The presence of hematuria can be benign or reflect serious underlying
disease
HEMATURIA MAY BE GROSSLY VISIBLE OR
MICROSCOPIC.
Microscopic hematuria is commonly defined as the presence of
more than 2 red blood cells per high powered field in a spun urine
sediment
The color change in gross hematuria does not necessarily reflect a
large degree of blood loss since as little as 1 mL of blood per liter
of urine can induce a visible color change.
As previously mentioned, the intermittent excretion of red to brown
urine can be observed without red blood cells.
Hematuria may be transient or persistent. Transient
hematuria is relatively common in young subjects and is not usually
indicative of disease in this population.
UHOWEVER, EVEN TRANSIENT HEMATURIA CAN REPRESENT
UNDERLYING MALIGNANCY IN PATIENTS OVER AGE 50.
Transient hematuria can also occur with urinary tract infection
(eg, cystitis or prostatitis). This is typically accompanied by pyuria and
bacteriuria and patients may often complain of dysuria.
Persistent hematuria should always be evaluated. Among the
more common pathologic causes are :
o kidney stones,
o malignancy, and
o glomerular disease
THUS, AN IMPORTANT ASPECT OF EVALUATION IS DETERMINING WHETHER THE
HEMATURIA IS GLOMERULAR IN ORIGIN OR EXTRAGLOMERULAR.
UFindings strongly suggestive of glomerular disease are :
o red cell casts,
o proteinuria, and
o dysmorphic red cells, particularly acanthocytes
The small number of red cells in normal urine are also dysmorphic,
suggesting a glomerular origin [23] .
Pyuria
White cells are slightly larger than red cells and can be identified by
their characteristic granular cytoplasm and multilobed nuclei (since
most are neutrophils
UInfection is the most common cause of pyuria alone;U the
routine urine culture may be negative with tuberculous infection.
UPYURIA HAS LESS DIAGNOSTIC VALUE IF IT
OCCURS IN ASSOCIATION WITH OTHER :
o UCELLULAR CASTS,
o UADDITIONAL CELLULAR ELEMENTS, AND/OR
PROTEINURIA
In addition to neutrophils, eosinophils and lymphocytes may also be
seen in the urine.
These cells can be identified by a Wright's stain of the sediment.
Although it has been proposed that the finding of eosinophiluria is
relatively specific and might be diagnostic of acute interstitial
nephritis, the diagnostic accuracy of urinary eosinophils is uncertain
Urinary lymphocytes may be observed in disorders associated with
infiltration of the kidney by lymphocytes, such as chronic
tubulointerstitial disease. ("Renal disease in sarcoidosis").
Epithelial cells
Epithelial cells may appear in the urine after being
shed from anywhere within the genitourinary tract.
However, only renal tubular cells are diagnostically significant.
Renal tubular cells are 1.5 to 3 times larger than white cells and
contain a round, large nucleus. SINCE IT IS DIFFICULT TO
DISTINGUISH RENAL TUBULAR CELLS FROM LOWER
URINARY TRACT CELLS, THE PRESENCE OF
EPITHELIAL CELLS IN CASTS IS THE ONLY RELIABLE
FINDING TO INDICATE A RENAL ORIGIN OF THE CELL.
Although an occasional finding of an epithelial cell cast is normal,
increased numbers suggest a number of disorders, including :
o acute tubular necrosis,
o pyelonephritis, and the
o nephrotic syndrome
Novel assays
Glomerular epithelial cells, or podocytes, are involved in maintenance
of the filtration barrier in the glomerular capillary tuft, and are the
principal site of injury or genetic abnormality in certain
glomerulopathies.
Podocytes are normally absent or present in only very small quantities
in the urine of individuals without kidney disease, or with inactive
glomerular diseases [24] , but excretion appears to increase with
active disease, and decrease with treatment [24-26] .
It has been suggested that podocyturia may be a better marker of
ongoing glomerular damage than proteinuria, but the test is not yet
available clinically [27] .
Casts
Casts conform to the shape of the renal tubule in which they
formed and are therefore cylindrical with regular margins. All casts
have an organic matrix composed primarily of Tamm-Horsfall
mucoprotein.
Many different types of casts may be observed. Some can be
found in normal individuals, while others are diagnostic of
significant renal disease [28] .
The observation of cells within a cast is highly significant since
their presence is diagnostic of an intrarenal origin.
Hyaline casts
Hyaline casts, which are only slightly more refractile than water, Uare
not indicative of disease and are primarily observed U :
o with small volumes of concentrated urine or
o with diuretic therapy
they may occur at a frequency of 10 casts per high powered field.
Red cell casts
The finding of red cell casts, even if only one is seen, is virtually
diagnostic of glomerulonephritis or vasculitis
White cell casts
The presence of white cell casts and pyuria alone is most consistent
with :
o a tubulointerstitial disease or
o acute pyelonephritis
They may also be observed with many glomerular disorders.
Epithelial cell casts
Acute tubular necrosis and acute glomerulonephritis, disorders in
which epithelial cells are desquamated, may be associated with
epithelial cell casts
Fatty casts
Among patients with significant proteinuria, the degeneration of cells
within epithelial casts may result in a characteristic "Maltese cross"
appearance and a fatty cast
These droplets are composed of cholesterol esters and cholesterol,
which may also be observed free in the urine.
Granular casts
Granular casts, which are observed in numerous disorders,
represent degenerating cellular casts or aggregated
proteins
Waxy casts
Waxy casts are thought to be the last stage of the degeneration of
a granular cast Since this degenerative process is probably slow, it
is most likely observed in nephrons with very diminished flow.
Waxy casts are therefore most consistent with the presence of
advanced renal failure.
Broad casts
AS WITH WAXY CASTS, BROAD CASTS, WHICH ARE WIDER THAN
OTHER CASTS AND TEND TO HAVE A GRANULAR OR WAXY
APPEARANCE, ARE THOUGHT TO FORM IN THE LARGE TUBULES OF
NEPHRONS WITH LITTLE FLOW. THEY ARE MOST OFTEN OBSERVED
IN PATIENTS WITH ADVANCED RENAL FAILURE.
PATTERNS
The diagnostic value of the urinalysis in the patient with renal
disease lies in the association between different patterns of urinary
findings and different renal diseases.
In many cases, the urinary findings point toward one or only a few
disorders
1.. HEMATURIA WITH RED CELL CASTS, DYSMORPHIC
RED CELLS, PROTEINURIA, AND/OR LIPIDURIA
This constellation of findings is virtually diagnostic of glomerular
disease or vasculitis
However, the absence of these pathognomonic changes in patients
with hematuria does not exclude these disorders.
2.. Multiple granular and epithelial cell casts with
free epithelial cells
These findings are strongly suggestive of acute tubular necrosis in
a patient with acute renal failure, although their absence does not
exclude this diagnosis
In this setting, ischemic or toxic injury to the tubular epithelial cells
can lead to cell sloughing into the tubular lumen due either to cell
death or to defective cell-to-cell or cell-to-basement membrane
adhesion [29] .
In addition to acute tubular necrosis, similar urinary abnormalities
can also be induced by marked hyperbilirubinemia alone (plasma
bilirubin concentration usually above 8 to 10 mg/dL or 136 to 170
mol/L); how this occurs is not clear [30] .
3.. Pyuria with white cell and granular or waxy casts
and no or mild proteinuria
This constellation is suggestive of tubular or interstitial
disease or urinary tract obstruction
White cells and white cell casts can also be seen in acute
glomerulonephritis, particularly postinfectious
glomerulonephritis; in this setting, however, there are also
other signs of glomerular disease, such as hematuria, red
cell casts, and proteinuria.
4.. Hematuria and pyuria with no or variable casts
(excluding red cell casts)
These findings may be seen in acute interstitial nephritis,
glomerular disease, vasculitis, obstruction, and renal
infarction.
Eosinophiluria may also be seen with acute interstitial
nephritis, but the absence of this finding does not exclude
the diagnosis.
5.. Hematuria alone
The significance of isolated hematuria (ie, without other cellular
elements or casts, including red cell casts) varies with the clinical
setting.
It is suggestive of vasculitis or obstruction In the patient with acute
renal failure, and of urolithiasis in the patient with flank pain.
It can also be found with mild glomerular disease (particularly
postinfectious glomerulonephritis, IgA nephropathy, thin basement
membrane disease, and hereditary nephritis), polycystic kidney
disease, and with extrarenal disorders such as tumors, and prostatic
disease.
6.. Pyuria alone
Assuming no contamination with vaginal secretions (which
is unlikely if there are no large vaginal epithelial cells in the
sediment), pyuria alone is usually indicative of urinary tract
infection (including tuberculosis).
Sterile pyuria suggests some form of tubulointerstitial
disease, such as analgesic nephropathy.
7.. Normal or near-normal (few cells with little or no
casts or proteinuria; hyaline casts are not an
abnormal finding)
In Patients With Acute Renal Failure, A Relatively Normal
Urinalysis Suggests Prerenal Disease, Urinary Tract Obstruction,
Hypercalcemia, Myeloma Kidney (Although The SSA Test Should
Be Markedly Positive), Some Cases Of Acute Tubular Necrosis, Or
A Vascular Disease With Glomerular Ischemia But Not Infarction
(Scleroderma, Atheroemboli [Which Are Irregularly Shaped And Do
Not Completely Occlude Vessels], And Rare Cases Of Polyarteritis
Nodosa Affecting The Renal Arteries But Not The Glomeruli).
WITH CHRONIC RENAL DISEASE, DISORDERS
THAT SHOULD BE CONSIDERED INCLUDE:
o prerenal disease (as with congestive heart failure),
o urinary tract obstruction,
o benign nephrosclerosis, and
o tubular or interstitial diseases