Laboratory Tests – 4 (Urine Studies)

I was asked to conclude my discussion of Laboratory Tests with comments on Urine Studies.  Though much of this has been covered previously in our topics about Dysuria, I’ll apologize [done] & repeat it here.  Warning: topic is long (but surely fascinating).

URINALYSIS (UA)

The UA consists of both Dipstick and Microscopic.  Each includes a variety of tests.  The Dipstick is usually performed at point-of-care, & may be the only urine study obtained.

Simple Inspection  —  Urine is usually some shade of yellow.  Other colors may be interesting:

• Red: blood, myoglobin, beets, rifampin, phenytoin, senna, food coloring, porphyria
• Black: blood (pretty rare)
• Green: OTC urinary anesthetics
• Very yellow: check eyes for jaundice

Dipstick  —  Can test for the following (in no particular order):

Leukocyte Esterase, an enzyme in white blood cells (WBCs), is a proxy for finding WBCs on microscopic analysis.  This is a virtual sine qua non for UTIs.  No WBCs = No Infection.

The dipstick is sensitive for >5-10 WBCs per HPF (high-power field) by microscopy.  Causes of false-negatives may include:

• Very dilute urine (e.g. specific gravity <1.005)
• Recent prior void (specimen not in bladder very long)
• Assistant who did UA didn’t wait full time to read result
• Old dipsticks

I’ve often seen the latter two errors occur at point-of-care.  Well-supervised laboratories know better.

“Old dipsticks” doesn’t mean expired, rather that there’d been too much water-vapor exposure from repeatedly opening the container (or leaving it open).  This is more likely to occur toward the end of the batch.  It might be advisable to place 10-15 dipsticks in an old container for first use, then refill it when out, instead of opening the original one 100 times.

In women, the dipstick’s Leukocyte Esterase isn’t at all specific, because it can’t tell if the WBCs came from the urinary tract or the vagina.  We’ll discuss this more below, under “Microscopic UA”. True urinary pyuria also occurs with Urethritis due to chlamydia or gonorrhea, which are more likely than UTIs in men (especially young men). A variety of obscure diseases (renal TB, etc.) also cause pyuria.

Nitrites are secreted by E. coli and other coliforms.  However, the dipstick is calibrated to correlate with a culture result of ≥10⁵ colonies, which is so high as to be almost useless [see under “Urine Cultures” below].  If Nitrites are positive, you’ve probably got a UTI.  But a negative isn’t helpful at all.

Blood (microscopic hematuria), can be easily detected by a dipstick. Excessive vitamin C ingestion may cause a false-positive. Myoglobin from rhabdomyalysis also gives a positive dipstick for blood, though RBCs are absent on microscopic. Hematuria is defined by ≥2 RBCs/HPF on microscopic, though I usually like to see at least 4. Trace hemolyzed hematuria, without RBCs, can be ignored.

In a patient with lower urinary tract symptoms, hematuria is very suggestive of UTI, as long as menses isn’t present.  A UTI with hematuria is no different than one without; same treatment, same prognosis.

The first step in addressing hematuria is to repeat the test. If the second specimen is positive, culture it. Hematuria without WBCs is unlikely to be a UTI, but the possibility exists, & you’d hate to delve into CT’s and cystoscopies without ruling out a simple infection.

Culture-negative hematuria is problematic, because it’s common & invariably benign, but occasionally not.  The work-up is a renal CT (CT Urogram) & cystoscopy, to see neoplasms.  They’ll also identify various other pathologies, but the main purpose is to rule out cancer.

On the one hand, we don’t want to pursue aggressive testing that statistically has little yield, since hematuria really is common. Certainly order everything in patients >50 y.o., and long-term heavy smokers. Bladder cancer is otherwise highly unlikely, but various renal cancers occur at any age, so a renal CT is hard to avoid when hematuria is persistent.

UTI patients usually don’t require cultures, must less tests-of-cure.  But anyone whose UTI includes hematuria requires a post-treatment UA, to be sure the blood has cleared.  If not, deal with it as you would anybody with hematuria, since infections can make tumors bleed.

Hematuria + Proteinuria requires Nephrology referral, for likely renal biopsy. There are a whole host of glomerulonephritides that will eventually cause frank renal failure; some are treatable. Hematuria with RBC casts (see below) always goes to nephrology.

Protein is only important if it is repeatedly 30 mg/dL or more (1+). It can be ignored if it’s only “trace.” It can also be ignored in the context of a UTI, contamination, or anything that results in a UA with numerous cells. Other causes of false-positive proteinuria include chlorhexidine or benzalkonium wipes, semen, and alkaline pH (>7.0).

I divide Proteinuria into 3 categories, defined by a 24-hr. urine collection:

• <1 gram = unlikely to require work-up
• >3-4 grams = nephrotic range (ominous)
• 2-3 grams = equivocal

It’s controversial whether a spot measurement of albumin-to-creatinine ratio, which is much more convenient, would suffice.   For an initial assessment, it may not be reliable.  See our blurb about obtaining & evaluating 24-hr. urine collections.

However, before you even consider a 24-hr. urine, rule-out Orthostatic Proteinuria.  This is a common physiologic condition in which healthy persons spill some protein while up & around (especially with exercise).  Give the patient a urine cup, instruct them to void immediately upon arising in the morning (walk, don’t run, to the toilet).  Have them store the specimen in a refrigerator, & bring it in the same day.

If that’s negative, repeat it.  Negative again, & you’ve avoided the 24-hour.  The hardest thing about this is convincing the patient that it’s OK to stick the urine in the fridge.  I tell them that urine is sterile — even if you drank it, you’d get way fewer germs than kissing someone.

pH is usually <5.0 — a normally acetic urine.  Those from 5.0 to 7.0 are also acetic, but might be significant in certain rare renal conditions, which wouldn’t be worked-up based on an incidental high pH.  After all, healthy vegetarians may well excrete urine with pH >7.0.

The pH is mainly useful in the context of a UTI; if it’s ≥7.0, it suggests possible infection with a urea-splitting species such as Proteus, which is associated with renal stones, possibly a nidus for recurrent infection.  Recurrent UTIs with high pH warrant a renal image.

Specific Gravity (Sp. Gr.) is a marker for hydration (or lack thereof).  Patients with vomiting or diarrhea warrant special caution if the Sp. Gr. is >1.030.  Conversely, a Sp. Gr. <1.005 is a very dilute urine, which might suggest false-negative values for other dipstick tests.  For example, a patient with classic UTI symptoms but negative leukocyte esterase may have a true UTI if the Sp. Gr. is <1.005.  Urine pregnancy tests may be false-negative if the urine is very dilute.

Whenever testing is performed for legal reasons (like commercial driver licenses), or as drug abuse screens, always include a Sp. Gr. to validate adequate concentration (r/o purposeful dilution to avoid detection).  Don’t trust them if <1.005.  I’ve seen urine specimens with a Sp. Gr. of 1.000 (= water)!  However, very dilute urine is also compatible with diabetes insipidus in the right context; also with hyponatremia, & even simple over-hydration.

Glucose in urine usually suggests diabetes.  However, some patients have low thresholds, so serum levels are necessary for diagnosis.  In the right context, glycosuria with normal serum glucose suggests proximal renal tubular dysfunction, viz. Fanconi’s syndrome.  This is very rare, but a crucial abnormality in HIV+ patients taking tenofovir, which is present in various antiretroviral combination pills, including Truvada^® (also approved as pre-exposure prophylaxis, aka PrEP).  Miss this, & the person is a set-up for osteoporosis & pathologic fractures.

Ketones spill into urine as a result of starvation.  They’re rarely important, except in symptomatic patients with type-1 diabetes.  In ketoacidosis, ketones are also present in serum, which never occurs without the urine dipstick showing 4+ or whatever its maximum is.

In other words, low levels of ketones on urine dipstick are not indicative of ketoacidosis.  Maximal levels may be, but you have to test the serum, & a urine dipstick may not be reliable.  We used to have tablets to test ketones, but they’re flammable & thus a no-no (though years ago, our ER used to simply hide them when inspectors came by).  Never send a urine out for serum ketones, because if positive, the patient will be dead before results are back.  Send to ER if you suspect ketoacidosis.

Urobilinogen on dipsticks is something I’ve never found useful.  Bilirubin either.

Microscopic Urinalysis

Microscopic exam can detect various cells and other findings.  But in terms of RBCs and WBCs, a dipstick may be more reproducible, because it’s performed on an unspun specimen.  Looking at unspun urine under the microscope has no yield, so lab techs centrifuge the specimen in a test tube, pour off the supernatant (liquid), and examine the sediment of cells & gunk at the bottom.

This process has no standardization; each lab tech & clinician extracts it their own way.  I used to use the handle of  a cotton swab to tease out the sediment, but many people just tap the tube until it falls down the side.  I’ve seen drops of mere supernatant examined, yielding absurdly false negatives.  Unfortunately, we rarely get to watch our labs at work.

White Blood Cells  —  These don’t give you any more information than the “Leukocyte Esterase” of a dipstick.  But if the urine was very dilute, the centrifuged microscopic might be more accurate.  If a normally-concentrated urine tested positive by dipstick but negative on micro, I’d trust the former over possible lab-tech mishandling.

Red Blood Cells —  Here it’s harder, because we don’t want to order CT scans for hematuria without RBCs in the UA.  But who’s to say the sediment was examined properly, or the RBCs lysed due to long transit time.  Frank hematuria (≥ 1+) without RBCs deserves a few repeats.

Epithelial Cells  —  This is the most valuable parameter to me, since it’s the only way to suspect contamination.  Anything more than “rare” or “few” Epi’s (not “a few”) means there’s no way to tell where the WBCs originated.  Unless otherwise specified, “Epi’s” means the large vaginal cells shaped like polygons.  Uroepithelial cells are smooth, oval-shaped, but uncommon.

Of course, anyone with a bona fide UTI might well give a dirty specimen, so you can’t rule it out due to contamination.  How to strive for a clean catch?  Certainly not by just handing a towelette and preaching, “Clean yourself & pee in the cup.”  I spend 30-60 seconds explaining step-by-step:

• We want to know what germ is inside you, not on the skin.  So try as hard as possible that the urine doesn’t touch the skin.
• Spread your legs real wide apart, & hold the labia apart (demonstrate in the air with thumb & index finger).  Clean with the towelettes, but don’t let go.
• Start to pee in the toilet to wash outside germs away, then without stopping, catch some directly into the cup.  Finish peeing in the toilet.
• Remember, try real hard to make sure the urine doesn’t touch the skin.

I don’t have any data, but seem to get decent specimens (no Epi’s).  I’m a firm believer that if a person understands a rationale, they’re more likely to do it right.  Never tell a woman, “wipe from front to back” — it makes absolutely no difference, & only serves to confuse.

Casts — These can be important, & hard to find. By definition, they come from the kidneys. Lab techs screen 10 high-power fields for a UA; nephrologists & urologists spend several minutes examining an entire slide for a lone cast. Different types include:

• WBC Casts: Pyelonephritis or Glomerulonephritis
• RBC Casts: Glomerulonephritis; needs renal biopsy without a doubt
• Granular Casts: In context of rising serum creatinine, indicative of renal tubular etiology (as opposed to pre-renal causes like dehydration, heart failure, etc.)
• Waxy Casts: May have been old granular casts
• Hyaline Casts: Not significant

Crystals  —  Primarily significant if you think a patient has a kidney stone.  Uric Acid or Cystine crystals identify the type of stone.  Calcium crystals may confirm suspicion of stone, but don’t pinpoint the metabolic cause, since all stones have calcium in them.  Asymptomatic calcium crystals don’t mean anything.

URINE CULTURE & SENSITIVITIES (C&S)

It’s fascinating to the point of hilarity how medical lore and “Old Doctors’ Tales” survive through generations of practicing clinicians.  Ask almost anyone [even yourself???] how to define a UTI by culture, & you’ll undoubtedly hear/say, “100,000 (10⁵)” colony-forming units (CFU) per ml.  Says who?

Says (Said) Harvard’s Edward Kass in the late 1950s, who published several papers showing that 100,000 CFU/ml was the best way to distinguish between pyelonephritis on the one hand, & urine contamination among asymptomatic healthy women on the other.  Not particularly relevant to diagnosing plain old cystitis for one.  And even for Pyelo, it didn’t mean that lower numbers aren’t positive, just that ≥100,000 CFU/ml can’t be dismissed as contamination.

Of course, Dr. Kass would never have expected the clinical world to latch onto his number as magic.  In 1982, Stamm et al. found that a mere 100 (10²) CFU/ml was able to identify women with acute dysuria & pyuria (sure sounds like a UTI to me) versus those without.  Subsequent studies reproduced similar results.

Yet numerous clinicians, trained over the last 30 years, still quote “100,000.”  Clinical labs are a little better, but often won’t perform susceptibility tests on <10,000 – 25,000 CFUs.  And as we noted, Nitrite tests on dipstick are calibrated to correlate with 100,000 CFU/ml.  Alas.

Bottom Line:  A “no-growth” urine culture rules out UTI, unless of course the patient had happened to somehow score even one dose of an antibiotic.  Otherwise, any number of organisms is compatible with the diagnosis.  So is a contaminated specimen.

“Organisms” means gram-negative bacilli (“rods”), i.e. enteric bacteria that comprise normal bowel flora.  Cultures positive for any number of gram-positive organisms (skin flora) should be ignored.  The only exception is Staphylococcus saprophyticus, a bona fide UTI pathogen.  Not too common.

The main role for Urine Cultures is to obtain susceptibility tests.  In simple cystitis it’s not worth a C&S, since most antibiotics work well.  Even if there’s in vitro resistance, a drug may be so heavily excreted in the urine that intra-bladder concentrations do just fine.  Susceptibility results, both MICs & Bauer-Kirby disk diffusion methods, calibrate to hematogenous drug levels.

The C&S is essential if we suspect Pyelonephritis, where treatment requires hematogenous delivery to renal parenchyma, & wrong guess about antibiotics can lead to urosepsis.  In addition to the obviously symptomatic patient with pyelo, also order a C&S for UTI’s in:

• Immunocompromised or otherwise at-risk hosts
• Men & Children
• Cystitis symptoms that have gone on a week or more (the bug is more likely to have ascended to the renal pelvis)
• Pregnant women

And that’s it for urine studies. Hope you haven’t held it in all this time while reading.

P.S.  DiagnosisDude is on vacation in July; next post in August.

P.P.S.  Am running low on topics; please comment if there’s something you’d like to hear about.