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Urine and Urinalysis

All samples should be midstream and collected in a clean sterile container. Suprapubic aspiration or fresh catheter samples are ideal, but not always practical.

Physical examination

Colour The colour of the urine can vary greatly. Normal urine varies from colourless to dark yellow. Various factors can affect urine colour.¹

Turbidity Cloudy urine may be due to excess phosphate crystals precipitating in alkaline urine, which is of no significance. It can however also be seen in pyuria secondary to infection², chyluria (usually secondary to filariasis)³, hyperuricosuria secondary to a diet high in purine-rich foods⁴, lipiduria ⁵ and hyperoxaluria.⁶

Odour¹ The normal odour is described as urinoid. In concentrated specimens this can be strong but does not imply infection which has a more pungent smell. Alkaline fermentation causes an ammoniacal smell, and patients with diabetic ketoacidosis produce a urine that may have a sweet or fruity odour. Other causes of abnormal odours are cystine decomposition (a sulphuric smell), gastrointestinal-bladder fistulae (a faecal smell), medications (e.g.vitamin B6), and diet (e.g. asparagus).

Dipstick Analysis Immerse the dipstick completely in fresh urine and withdraw immediately, drawing the edge along rim of container to remove excess. Hold the dipstick horizontally before reading.

Specific Gravity SG <1.008 is dilute and >1.020 is concentrated.

Increased specific gravity is seen in conditions causing dehydration, glycosuria, renal artery stenosis, heart failure (secondary to decreased blood flow to the kidneys), inappropriate antidiuretic hormone secretion and proteinuria.^7,8 Some dipsticks give falsely high readings in the presence of dextran solutions and IV radiopaque dyes, ¹ but this varies, so check the manufacturer's leaflet⁹

Decreased specific gravity is seen in excessive fluid intake, renal failure, pyelonephritis, and central and nephrogenic diabetes insipidus.¹⁰ False low readings are associated with alkaline urine (e.g.a high-citrate diet)¹.

pH The range is 4.5 to 8, but urine is commonly acidic (i.e 5.5-6.5) due to metabolic activity.

Acidic urine (low pH) may be caused by diet (e.g. acidic fruits such as cranberries).¹⁰ Urine pH generally reflects the blood pH but in renal tubular acidosis (RTA) this is not the case. In type 1 RTA (distal) the urine is acidic but the blood alkaline. in type 2 (proximal) the urine is initially alkaline but becomes more acidic as the disease progresses.¹¹ Acidic urine may be associated with uric acid calculi.¹²

Alkaline urine (high pH) is seen in the initial stages of type 2 RTA and also with infection with urease-splitting organisms. Alkaline urine may be associated with the formation of stag-horn calculi.¹³

Haematuria Dipstick testing for haematuria is based on the peroxidase activity of erythrocytes. However, haemoglobin and myoglobin will also catalyse this reaction. False positives are also seen in dehydration and menstruation.

False negatives are seen in patients taking captopril and vitamin C, proteinuria, elevated specific gravity, pH less than 5.1, and baceturia^1,14.

Dipstick testing for haematuria is therefore at best a screening tool which needs the support of microscopy to make a definitive diagnosis.

The causes of haematuria can be divided into those occuring at the glomerular level, renal (i.e. non-glomerular) and urological causes. Glomerular haematuria is typically associated with erythrocyte cases, dysmorphic red blood cells and significant proteinuria, although 20% of patients present with haematuria alone.^1,15 Renal haematuria is also associated with significant proteinuria, but there are no associated dysmorphic RBCs or erythrocyte casts.¹ Urologic haematuria is distinguished from other etiologies by the absence of proteinuria, dysmorphic RBCs, and erythrocyte casts.¹ Exercise-induced haematuria is a benign, relatively common condition often is associated with long-distance running. Results of repeat urinalysis after 48 to 72 hours should be negative.¹⁶

Proteinuria Normal urinary proteins include serum globulins, albumin, and proteins secreted by the nephron. Proteinuria is defined as albumin:creatinine ratio >30mg/mmol or albumin concentration >200mg/l. The loss of up to 150 mg of protein per day is normal. This may be expressed as less than 4 mg per hour per square metre of body surface area. ¹⁸ Clinical proteinuria is indicated at greater that 0.5g or protein per day (greater or equal to 0.3g/L on a test strip)

Most dipstick tests will pick up albumin but may not detect low concentrations of Bence-Jones protein or gamma-globulins. Bence-Jones protein can be detected by a specific antibody test on a mid-stream sample, whilst urine gamma-globulins can be detected by urine electrophoresis.

Proteinuria may be transient or persistent. Transient proteinuria is usually due to temporary changes in glomerular haemodynamics, and follows a benign course. Orthostatic proteinuria is a subset of this category, in which the phenomenon is seen after prolonged standing.¹⁹ It is confirmed by obtaining a negative result after eight hours of lying flat.

The causes of persistent proteinuria may be divided into glomerular, tubular and overflow. The commonest is glomerular proteinuria, in which albumin is the primary urine protein. Tubular protein is caused by malfunctioning tubule cells which are unable to reabsorb normally filtered protein. Low-molecular weight proteins predominate in this condition. Overflow proteinuria is caused by low-molecular weight proteins overwhelming the ability of the tubules to reabsorb filtered proteins.¹

Persistent significant proteinuria detected by dipstick requiresfurtherr assessment with 24-hour urinary protein excretion, urinary protein-creatinine ratio, microscopic examination of the urinary sediment, urinary protein electrophoresis, and assessment of renal function.²⁰

Glycosuria Glucose is normally filtered by the glomerulus, but small amounts (1.67mmol/L or 30mg/dL) do reach the urine. ¹⁹ These amounts are usually below the sensitivity level of dipsticks but may occasionally produce a positive result. Causes of glycosuria include diabetes mellitus, Cushing's syndrome, liver and pancreatic disease, and Fanconi's syndrome. ¹

The test is specific for glucose but false positive results may be seen when high levels of ketones are present²¹, and in patients taking levodopa²².

False negatives are seen where specific gravity is elevated²¹, in uricosuria²¹ and in patients taking ascorbic acid²³.

Ketones Ketones are not normally found in urine^1,9. The reagent on a dipstick detects acetic acid, but does not react to acetone or beta-hydroxybutyric acid. A positive test is associated with uncontrolled diabetes²⁴, pregnancy without diabetes²⁵, carbohydrate-free diets²⁶ and starvation²⁷.

False trace results may be seen in highly-pigmented urine and in patients taking levodopa⁹.

Delay in testing a sample may result in a false negative result.¹

Nitrites This test relies on the breakdown of urinary nitrates to nitrites, which are not found in normal urine. Many gram-negative and some gram positive bacteria are capable of producing this reaction, and a positive test suggests their presence in significant numbers (i.e. more than 10,000 per ml). A negative result does not rule out a urinary tract infection.^1,28

Thereagentt is highly sensitive to air exposure, which may cause a false positive response.²⁹

False negative results may be seen where bladder incubation time is shortened (less than 4 hours)⁹, in the absence of dietary nitrate⁹, in the presence of nitrate-reductase negative organisms (e.g. some Mycobateria strains³⁰), when urine specific gravity is elevated¹, where pH is less than 6.0¹, and in the presence of urobilinogen⁹ and urinary vitamin C³¹.

Leucocytes This relies on the reaction of leukocyte esterase produced by neutrophils and a positive result suggests pyuria associated with urinary tract infection.¹ Isolated trace results may be of questionable significance, but repeated ones should not be ignored. ⁹

False positive results may be caused by contamination with vaginal discharge.¹

Elevated urine glucose or oxalic acid concentrations may reduce sensitivity, and this may also be seen in patients taking tetracycline or cefalexin.⁹

Bilirubin and Urobilinogen Unconjugated bilirubin is water insoluble and not normally present in the urine. The presence of conjugated bilirubin indicates further evaluation for liver dysfunction and biliary obstruction. A small amount of urobilinogen is normally found in urine, but significant amounts suggest that further assessment for haemolytic and hepatocellular disease is indicated.¹ Urobilinogen levels can be increased in conditions associated with elevated nitrite levels (e.g. UTIs.¹

Microscopy is best performed on a centrifuged specimen. 10-15mls of freshly-voided urine should be spun at 1,500-3,000 rpm for five minutes, the supernatant decanted, and the sediment resuspended in the remaining liquid. A single drop istransferredd to a clean glass slide and a cover slip applied.¹ The sample is then examined for the following:

• Cells - an excess of leucocytes suggests pyuria, but there is a gender difference. Men normally have fewer than two white blood cells (WBCs) per high power field (HPF), whilst women normally have fewer than five WBCs per HPF. The presence of transitional cells, which are small round cells with large nuclei, is normal. The presence of squamous epithelial cells, which are large irregular cells with small nuclei, suggests contamination.¹ The presence of renal tubule cells indicates renal pathology.³² Dysmorphic erythrocytes may be indicative of glomerular disease.³³
• Casts - protein coagulum forms casts in the renal tubule, trapping any contents within them¹. RBC casts occur in glomerular bleeding, commonly in glomerulonephritis³⁴. The predominant cellular elements determine the type of cast: hyaline, erythrocyte, leukocyte, epithelial, granular, waxy, fatty, or broad.^1,34
• Crystals - these may be seen in healthy patients, but may also be helpful in assessing patients with urinary stones. Uric acid crystals are yellow to orange brown and may be diamond or barrel-shaped. Calcium oxalate crystals can vary in size, and have a refractile square 'envelope' shape. Triple phosphate crystals are colourless, have a 'coffin lid' shape, and may be associated with UTI (particularly Proteus). Cysteine crystals have a hexagonal shape and are colourless.^1,35 Crystals may be seen in the urinary sediment of healthy patients (Figure 4). Calcium oxalate crystals have a refractile square
• Bacteria - Gram staining may be helpful in specimens suspected of being contaminated, and in diagnosing the type of infection. Gram-negative streptococci and staphylococci can be distinguished by their characteristic appearance under high-powered magnification¹. In women, 5 bacteria per high power field represents a count of approximately 100,000 per ml and is the standard concentration for the diagnosis of UTI in a possibly contaminated sample.¹ Some authorities maintain that lower colony counts of 1,000 would be more accurate, particularly in a clean specimen.³⁶In men, any bacteria in a properly collected specimen is significant³⁷.

References Used

1. Simerville JA, Maxted WC, Pahira JJ. Urinalysis: a comprehensive review. Am Fam Physician. 2005 Mar 15;71(6):1153-62. Review.
2. Alper BS, Curry SH. Urinary tract infection in children. Am Fam Physician. 2005 Dec 15;72(12):2483-8. Review.
3. Tandon V, Singh H, Dwivedi US et al Filarial chyluria: long-term experience of a university hospital in India. Int J Urol. 2004 Apr;11(4):193-8; discussion 199.
4. Marangella M. Uric acid elimination in the urine. Pathophysiological implications. Contrib Nephrol. 2005;147:132-48. Review.
5. Neverov NI, Nikitina EA. Lipiduria in the nephrotic syndrome Ter Arkh. 1992;64(6):16-8. Russian.
6. Laube N, Hoppe B, Hesse A. Problems in the investigation of urine from patients suffering from primary hyperoxaluria type 1. Urol Res. 2005 Nov;33(5):394-7. Epub 2005 Sep 8.
7. Urine Specific Gravity Medline Plus 2006
8. Kavouras SA. Assessing hydration status. Curr Opin Clin Nutr Metab Care 2002;5:519-24.
9. Multistix Manufacturer's leaflet
10. Urine pH
11. Renal Tubular Acidosis Merck Manual of Diagnosis and Therapyn 2006
12. Shekarriz B, Stoller ML. Uric acid nephrolithiasis: current concepts and controversies. J Urol. 2002 Oct;168(4 Pt 1):1307-14. Review.
13. Sigel A, Schrott KM, Breun H et al. Classification of staghorn calculus disease of the kidney based on 105 personal cases and a review of the literature Urologe A. 1986 Mar;25(2):101-8. German.
14. Lam MH. False 'hematuria' due to bacteriuria. Arch Pathol Lab Med. 1995 Aug;119(8):717-21.
15. Grossfeld GD, Litwin MS, Wolf JS Jr et al Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy--part II: patient evaluation, cytology, voided markers, imaging, cystoscopy, nephrology evaluation, and follow-up. Urology. 2001 Apr;57(4):604-10. No abstract available.
16. Siegel AJ, Hennekens CH, Solomon HS et al Exercise-related hematuria. Findings in a group of marathon runners. JAMA. 1979 Jan 26;241(4):391-2.
17. Ahmed Z, Lee J. Asymptomatic urinary abnormalities. Hematuria and proteinuria. Med Clin North Am. 1997 May;81(3):641-52. Review.
18. Proteinuria Clinical Answers 2005
19. Springberg PD, Garrett LE Jr, Thompson AL Jr et a; Fixed and reproducible orthostatic proteinuria: results of a 20-year follow-up study. Ann Intern Med. 1982 Oct;97(4):516-9.
20. Carroll MF, Temte JL. Proteinuria in adults: a diagnostic approach. Am Fam Physician. 2000 Sep 15;62(6):1333-40. Review.
21. Urine Glucose Family Practice Notebook
22. Rotblatt MD, Koda-Kimble MA. Review of drug interference with urine glucose tests. Diabetes Care. 1987 Jan-Feb;10(1):103-10. Review.
23. Nagel D, Seiler D, Hohenberger EF et al Investigations of ascorbic acid interference in urine test strips. Clin Lab. 2006;52(3-4):149-53.
24. Hendey GW, Schwab T, Soliz T. Urine ketone dip test as a screen for ketonemia in diabetic ketoacidosis and ketosis in the emergency department. Ann Emerg Med. 1997 Jun;29(6):735-8.
25. Hamdi K, Bastani P, Gafarieh R et al The influence of maternal ketonuria on fetal well-being tests in postterm pregnancy. Arch Iran Med. 2006 Apr;9(2):144-7.
26. Tashev T, Goranov I, Ekimova S et al. Treatment of obesity with a high-protein, high-fat, "carbohydrate-free" diet Vutr Boles. 1976;15(5):50-6. Bulgarian.
27. Toth HL, Greenbaum LA. Severe acidosis caused by starvation and stress. Am J Kidney Dis. 2003 Nov;42(5):E16-9.
28. Pels RJ, Bor DH, Woolhandler S et al Dipstick urinalysis screening of asymptomatic adults for urinary tract disorders. II. Bacteriuria. JAMA. 1989 Sep 1;262(9):1221-4. Review.
29. Gallagher EJ, Schwartz E, Weinstein RS. Performance characteristics of urine dipsticks stored in open containers. Am J Emerg Med. 1990 Mar;8(2):121-3.
30. David H, Traore I,Feuillet A Differential identification of Mycobacterium fortuitum and Mycobacterium chelonei.J Clin Microbiol. 1981 January; 13(1): 6-9.
31. Dolmatov SI, Gozhenko AI, Moskalenko T et al Effect of ascorbic acid on the renal transport of endogenous nitrates and nitrites in humans Eksp Klin Farmakol. 2005 Jan-Feb;68(1):50-2. Russian.
32. Fogazzi GB, Saglimbeni L, Banfi G et al Urinary sediment features in proliferative and non-proliferative glomerular diseases. J Nephrol. 2005 Nov-Dec;18(6):703-10.
33. Nagahama D, Yoshiko K, Watanabe M et al A useful new classification of dysmorphic urinary erythrocytes. Clin Exp Nephrol. 2005 Dec;9(4):304-9.
34. Fogazzi GB, Saglimbeni L, Banfi G et al Urinary sediment features in proliferative and non-proliferative glomerular diseases. J Nephrol. 2005 Nov-Dec;18(6):703-10.
35. Urinalysis - Sketches of urine casts
36. Urinary Tract Infection, Female eMedicine.com
37. Urinary Tract Infection, Male eMedicne.com

Internet and Further Reading

• Grossfeld GD, Wolf JS Jr, Litwan MS et al Asymptomatic microscopic hematuria in adults: summary of the AUA best practice policy recommendations. Am Fam Physician. 2001 Mar 15;63(6):1145-54. Review.

Acknowledgements EMIS is grateful to Dr Laurence Knott for authoring this article. The final copy has passed peer review of the independent Mentor GP authoring team. ©EMIS 2006.

Last issued 30 Aug 2006