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Urinalysis – The Secret Life of Urine

Urinalysis – The Secret Life of Urine
Jennifer Waldrop, DVM, DACVECC

Consider first urine’s keystone measurement, specific gravity (USG.)1 There are drugs and therapies that will considerably change your ability to measure specific gravity and so sampling time is important. Urine should be collected prior to furosemide, mannitol, SC and IV fluids. As an example, even a few hours of IV fluids could alter the USG. Even if you are just able to get a drop for USG, you can get a larger sample for dipstick and sediment at any point.

Some argue that a single USG is not a complete picture of urine concentrating ability in a healthy animal, and I would agree. Dogs, for instance, after activity or on a warm day, could drink quite a large amount of water to falsely lower their USG. Most of my patients are not healthy and not drinking a normal amount of water or doing a lot of exercise on a warm day. Arguably, there are post renal diseases that could also lower the USG in many patients, including a urinary tract infection. Normally concentrated urine should be taken as a positive sign; but isosthenuria (1.008-1.012) or incompletely concentrated urine (<1.030) in a dehydrated patient should be taken as a call for further investigation.1,2

OTC Drug Kit

Dipstick analysis is very helpful for the “big 3”- glucose, ketones and protein. Not only can we diagnose chronic conditions such as diabetes mellitus, Fanconi’s and protein-losing nephropathy, but acute conditions such as acute tubular necrosis, ketosis and sepsis-induced microalbuminuria. Other dipstick positives that are significant include bilirubin in a cat and hemoglobin without RBCs for possible exposure to hemolytic toxins (ex. onion, Tylenol®), immune disease, or rhabdomyolysis. Urine can be visibly brown, red or orange for a number of different reasons (ex. hematuria, bilirubinuria and hemoglobinuria) and simple testing by spinning down the sample and dipstick analysis can help point to the origin of the pigmenturia.

Gross protein measurement is not overly helpful as it can be normal in the dog or secondary to post renal causes including blood contamination and infection. A urine protein to creatinine ratio is the gold standard to assess the significance of protein loss and a ratio >1.0 should prompt investigation.1 Most solutes, including protein, are compared to creatinine since creatinine clearance reflects GFR

Ask your patients to wait!

and is unaffected when urine is dilute. Severe infection can increase the ratio to >30; but in one study, blood contamination to 10% total volume of urine still only increased the ratio to 1.8. 3 Small hematuria, as would occur with cystocentesis, should not raise the ratio significantly.

Sediment analysis is very helpful to identify abnormal cells, crystals, casts and bacteria and compare to dipstick analysis for red and white blood cells. Dipsticks are notoriously bad at leukocyte detection. Bacteria detection on plain sediment should be followed by a gram stain. In isosthenuric or poorly concentrated urine, a urine culture would be more valuable than sediment visualization of bacteria or white cells since the urine is highly dilute and bacteria would be far and few between. That said, in my experience cultures have more false negatives in isosthenuric urine and with upper UTIs. I have seen patients with ultrasound evidence of nephritis that will culture negative but are highly responsive to antibiotics. The bacterial load has to be high enough to detect by these technologies; PCR analysis could be more accurate and possibly could be available in the future.

More advanced urine testing has shown promise to diagnose acute kidney injury (AKI), which is very difficult to detect and treat.1,4 Even small changes in urine output during shock or anesthesia can predispose a patient to AKI. The renal tubules are vulnerable to damage from hypoxia given their anatomic location in an area of low oxygen tension. Acute tubular necrosis (ATN) can occur due to renal ischemia from hypotension or hypoxia, prolonged dehydration, sepsis, toxins or medications (ex. aminoglycosides, NSAIDs.) Urine electrolytes (sodium and chloride) can be used to detect ATN along with other solutes including glucose, calcium, magnesium and some tubular brush border enzymes (ex. NAG, alkaline phosphatase and GGT.) Hopefully in the future, more tests using these urinary solutes will become widely available for monitoring patients in real time on aminoglycoside therapy or after exposure to toxic amounts of NSAIDs.

Another indication of significant illness in our patients is vascular leak of proteins, either in chronic diseases (ex. renal failure) or acute (ex. sepsis or pancreatitis.) Although vascular leak occurs systemically and can lead to peripheral edema, GI edema and ileus, and pulmonary edema, the kidneys are finely tuned to small changes in vascular permeability which can have significant consequences in critically ill patients. Microalbuminuria reflects a significant inflammatory event which alters the protein permeability of the glomerulus. In human medicine, microalbuminuria in septic patients is a poor prognostic indicator both in morbidity and mortality.1,5 In two veterinary studies, the same predictive relationship was found for critically ill cats and dogs.5.6 When larger studies are performed, urine albumin:creatinine ratios performed at ICU admit could help predict dogs and cats at risk for organ dysfunction and likely to require longer hospitalization and costly care.

Urine drug testing in the ER is common and can be very helpful, especially as more and more of our patients are exposed to their owner’s medications. Over-the-counter urine drug screening tests are widely available and affordable and can test for a range of drugs including amphetamines, cocaine, marijuana and opiates. There are some limitations to testing for marijuana due to the dog’s alternate metabolism pathway for THC (tetrahydracannabinol.)7 Unfortunately, 50% of dogs exposed to marijuana will not test positive on urine drug screening because of additional conjugated forms of THC that are not detected on OTC drug kits. No urine drug screening test has been validated in dogs and all will have false negatives. A positive urine test for THC is more reliable for diagnosis but may be absent if ingestion was too recent.

Getting urine samples from well behaved dogs can be more difficult than it seems when well-meaning owners lose the sample on your clinic’s front yard. When a urine sample will definitely be part of the visit, caution clients not to let dogs urinate on arrival or ask them to collect a sample themselves. For home sampling, always advise dog owners to get the first elimination of the morning for the most concentrated urine.

What’s in the future for urinalysis? Researchers in urine biomarkers are trying to answer interesting questions such as, can urine connect us to our brains? Urinary biomarkers could become increasingly useful in detecting psychiatric disorders including bipolar disorder, autism and schizophrenia as well as neurodegenerative diseases like multiple sclerosis, stroke and Alzheimers.8 Urine biomarkers could also be used to detect brain cancer.9

References:
1 Waldrop JE. Urine electrolytes, solutes, and osmolality. Vet Clin North Am Small Anim Pract. 2008 May;38(3):503-12
2 www.cliniciansbrief.com/sites/default/files/attachments/Polyuria%20and%20Polydipsia.pdf
3 Bagley RS, Center SA, Lewis RM, et al. The effect of experimental cystitis and iatrogenic blood contamination on the urine protein/creatinine ratio in the dog. J Vet Intern Med 1991;5:66-70
4 Kovarikova S. Urinary Biomarkers in Dogs and Cats: a review. Vet Med 2015;60:589-602
5 Whittemore JC, Marcum BA, Mawby DJ, Coleman MV, Hacket TB, Lappin MR. Associations among albuminuria, C-reactive protein concentrations, survivor prediction index scores, and survival in 78 critically ill dogs. J Vet Intern Med 2011;25:818-824
6 Vaden SL, Turman CA, Harris TL, Marks SL. The prevalence of albuminuria in dogs and cats in an ICU or recovering from anesthesia. J Vet Emerg Crit Care 2010; 20(5):479–487
7 Meola SD et al. Evaluation of trends in marijuana toxicosis in dogs living in a state with legalized medical marijuana: 125 dogs (2005-2010). J Vet Emerg Crit Care 2012;22:690-696
8 An M and Gao Y. Urinary Biomarkers of Brain Diseases. Genom Proteo Bioin 2015;13:345-354
9 Smith ER et al. Urinary Biomarkers Predict Brain Tumor Presence and Response to Therapy. Clin Cancer Res 2008;14:2378-2386