Urinalysis

Urinalysis is the physical, chemical and microscopic examination of urine. It has three parts: appearance (colour, clarity, odour), reagent strip chemistry (specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, leucocyte esterase, nitrite) and microscopy of the sediment (cells, casts, crystals, organisms). The dipstick is a fast point-of-care screen, and microscopy gives the detail needed to localise disease in the kidney or urinary tract.

It is among the commonest laboratory tests, used to screen for urinary tract infection, kidney disease, diabetes and liver disease, and to assess haematuria and proteinuria. A normal urinalysis has a high negative predictive value for urinary tract infection, but the dipstick can miss low grade proteinuria and non-albumin proteins.

Urinary tract infection affects about 50% of women at some point in life, and chronic kidney disease affects about 10% of adults worldwide, often unrecognised until late. Microscopic haematuria is found in 2 to 5% of adults, with urinary tract cancer found in about 2 to 5% of those assessed.

Indications. Urinary symptoms, suspected infection, loin pain, fever in infants, diabetes and kidney disease screening and monitoring, hypertension, pregnancy (proteinuria, glycosuria and infection), pre-operative assessment, jaundice, suspected rhabdomyolysis or haemolysis, toxic exposure, and monitoring of nephrotoxic drugs.

Specimen. A midstream clean catch fresh sample, ideally the first morning void, which is the most concentrated. Examine within 2 hours, or refrigerate for up to 24 hours (cells lyse, casts dissolve and bacteria multiply in dilute alkaline urine left at room temperature). In infants, a clean catch, urethral catheter or suprapubic sample is preferred to bag urine, which has contamination rates over 50%. Avoid sampling during menstruation.

Appearance. Normal urine is pale to dark yellow and clear.

• Red or brown: haematuria, haemoglobinuria or myoglobinuria (rhabdomyolysis), porphyria, beetroot, rifampicin, and phenazopyridine.
• Dark brown or tea coloured: bilirubin (conjugated hyperbilirubinaemia), concentrated urine, and methyldopa or metronidazole.
• Cloudy or turbid: infection with pus, phosphate crystals in alkaline urine, chyluria, and mucus.
• Green or blue: propofol, methylene blue, and Pseudomonas infection.
• Milky: pyuria, chyluria, and lipiduria.

Specific gravity and osmolality. Normal 1.003 to 1.030. Fixed at about 1.010 (isosthenuria) suggests advanced kidney disease or acute tubular necrosis. Values over 1.030 with glycosuria or contrast media are spurious. High specific gravity with oliguria suggests pre-renal states.

pH. Normal 4.5 to 8.0. Acid urine (under 5.5) is found in metabolic acidosis, diabetes, high protein diet and starvation. Alkaline urine (over 7.0) occurs with urease producing organisms (Proteus), renal tubular acidosis, vomiting, vegetarian diet, and old specimens.

Protein. The dipstick detects albumin at about 150 to 300 mg/L (1+ about 30 mg/dL, 2+ 100, 3+ 300, 4+ 2000 or more). It misses light chains and low grade albuminuria. False positives: alkaline urine, quaternary ammonium cleaners, and gross haematuria. A positive dipstick is quantified by protein-to-creatinine or albumin-to-creatinine ratio. Transient proteinuria follows fever, exercise and orthostasis.

Glucose. Appears when plasma glucose exceeds the renal threshold of about 10 mmol/L (180 mg/dL). Causes: diabetes mellitus, pregnancy, SGLT2 inhibitor treatment, Fanconi syndrome, and familial renal glycosuria. Vitamin C can cause false negatives.

Ketones. Detects acetoacetate, not beta hydroxybutyrate. Positive in diabetic ketoacidosis, starvation, fasting, vomiting, alcohol and low carbohydrate diets, and also with SGLT2 inhibitors (including euglycaemic ketoacidosis, where blood ketones are needed).

Bilirubin and urobilinogen. Bilirubin in urine indicates conjugated hyperbilirubinaemia from hepatocellular or obstructive disease, and appears before jaundice. Urobilinogen is raised in haemolysis and hepatocellular disease, and absent in complete biliary obstruction.

Blood. The dipstick detects intact red cells, haemoglobin and myoglobin (sensitive to 5 to 20 red cells per microL). Positive dipstick with no red cells on microscopy suggests haemoglobinuria or myoglobinuria. False positives include menstrual contamination, bacterial peroxidase, and oxidising agents. False negatives include vitamin C.

Leucocyte esterase and nitrite. Leucocyte esterase indicates white cells (pyuria, over 10 to 25 cells per microL). Nitrite indicates conversion of nitrate by Gram negative bacteria and needs urine to be in the bladder for 4 hours or more. Both positive: sensitivity about 75% and specificity about 80 to 90% for urinary tract infection. Negative both: urinary tract infection is unlikely (negative predictive value over 90% in adults), though not in the very young. Nitrite is negative in Enterococcus, Staphylococcus saprophyticus and Pseudomonas infections.

Microscopy of sediment.

• Red cells: over 3 per high power field is abnormal. Dysmorphic cells (acanthocytes) and red cell casts indicate glomerular bleeding, and isomorphic cells suggest lower tract bleeding.
• White cells: over 5 per high power field is pyuria. Sterile pyuria (with negative culture) suggests prior antibiotics, tuberculosis, chlamydia, stones, interstitial nephritis or catheter.
• Epithelial cells: squamous cells over 15 per high power field suggest contamination. Renal tubular epithelial cells suggest tubular injury.
• Casts: hyaline casts occur in dehydration and exercise. Red cell casts indicate glomerulonephritis. White cell casts indicate pyelonephritis or interstitial nephritis. Granular and muddy brown casts indicate acute tubular necrosis. Waxy casts indicate chronic kidney disease. Fatty casts and oval fat bodies (Maltese cross) indicate nephrotic syndrome.
• Crystals: calcium oxalate (envelope or dumbbell shapes), uric acid (rhomboid), triple phosphate (coffin lid), cystine (hexagonal, diagnostic of cystinuria), and drug crystals (sulfadiazine, aciclovir, indinavir, ciprofloxacin).
• Organisms: bacteria, yeast, Trichomonas vaginalis, and Schistosoma haematobium eggs.

Critical values and findings needing immediate action.

• Red cell casts or dysmorphic red cells with proteinuria, hypertension or oedema: rapidly progressive glomerulonephritis needs urgent nephrology referral.
• Dipstick blood with no red cells and dark urine after injury, exertion, or seizures: rhabdomyolysis, check creatine kinase and potassium.
• Glycosuria and ketonuria with symptoms: diabetic ketoacidosis, check glucose and blood gas.
• Nitrite and leucocyte esterase positive with fever, loin pain or vomiting: pyelonephritis. In pregnancy, an infant or a man, the infection is complicated.
• Painless macroscopic haematuria at any age, or microscopic haematuria in a smoker over 40 years: urgent urological assessment for cancer.
• Cystine crystals: cystinuria and stone risk.

Interferences and pitfalls.

• Contamination (squamous cells, mixed flora) is the commonest cause of misleading culture results. A repeat sample is taken.
• High vitamin C intake gives false negatives for glucose, blood, nitrite and bilirubin.
• Very dilute urine reduces sensitivity of protein and leucocyte esterase. Very concentrated urine increases it.
• Dipstick protein detects albumin, not light chains. Myeloma needs protein electrophoresis and free light chains, and urine sulfosalicylic acid test.
• Delay at room temperature lyses cells and casts, and raises pH.
• Asymptomatic bacteriuria is treated in pregnancy and before urological surgery only, since treatment in other patients causes harm and resistance.
• A dipstick negative sample does not exclude infection in the immunosuppressed, neutropenic, neonates, and those with catheter or neurogenic bladder.
• Exercise, fever and menstruation cause transient haematuria and proteinuria, and a repeat sample is needed after 48 hours.
• Haematuria with a positive dipstick should be confirmed by microscopy before investigation.

Special groups.

• Children and infants: urinary tract infection may present only with fever, and a catheter or suprapubic sample is needed when dipstick is positive in a sick infant.
• Pregnancy: protein over 1+, glycosuria and bacteriuria need follow up for pre-eclampsia, gestational diabetes and infection.
• Older adults: asymptomatic bacteriuria and pyuria are common (up to 20 to 50% in care home residents), and symptoms decide treatment.
• Catheterised patients: bacteriuria is universal, and treatment is for symptoms only.
• Regions: schistosomiasis is a frequent cause of terminal haematuria, and tuberculosis a cause of sterile pyuria.

Follow up tests. Urine culture and sensitivity, urine albumin-to-creatinine and protein-to-creatinine ratio, serum creatinine and eGFR, urea and electrolytes, glucose and HbA1c, blood ketones, creatine kinase, protein electrophoresis, free light chains, complement and autoantibodies (ANA, ANCA, anti-GBM) in nephritic sediment, renal ultrasound, CT urogram, cystoscopy, urine cytology, urine for tuberculosis, and urine microscopy for schistosomiasis.