Examination of the urine can provide important clues to underlying kidney disease. A urine specimen should be collected in midstream or by bladder catheterization and examined within 1 hour after collection to avoid destruction of formed elements. Urinalysis includes a dipstick examination followed by microscopy if the dipstick has positive findings. The dipstick examination measures urinary pH, specific gravity, protein, hemoglobin, glucose, ketones, bilirubin, nitrites, and leukocyte esterase. Microscopy of centrifuged urinary sediment permits examination of formed elements—crystals, cells, casts, and infectious organisms. A bland (normal) sediment is common, especially in CKD and acute nonparenchymal disorders, such as limited effective blood flow to the kidney or urinary obstruction. Urinary casts form when urine flow is slow, leading to precipitation of Tamm-Horsfall mucoprotein in the renal tubule; if there are many red or white blood cells in the urine, cellular casts may form. The presence of protein on dipstick examination strongly suggests underlying glomerular disease. If the glomerular basement membrane (GBM) is damaged (eg, by inflammation), red blood cells may leak into the urinary space and appear dysmorphic (also called acanthocytes). Thus, proteinuria, hematuria with acanthocytes, and red blood cells casts (eFigure 22–1) are highly suggestive of glomerulonephritis. Heavy proteinuria and lipiduria are indicative of nephrotic syndrome. Granular casts (also called “muddy brown casts”) and renal tubular epithelial cells alone or in casts are hallmarks of acute tubular necrosis (ATN). White blood cells (including neutrophils and eosinophils), white blood cell casts (Table 22–1), and proteinuria of varying degree can be seen with pyelonephritis and interstitial nephritis; Wright and Hansel stains can detect eosinophiluria, though this is neither sensitive nor specific for any particular type of kidney disease. Pyuria alone can indicate a urinary tract infection. Proteinuria and hematuria are discussed more thoroughly below.
Table 22–1.Significance of specific urinary casts. ||Download (.pdf) Table 22–1. Significance of specific urinary casts.
|Type ||Significance |
|Hyaline casts || |
Not indicative of kidney disease
Concentrated urine, febrile disease, diuretic therapy, after strenuous exercise
|Red cell casts ||Glomerulonephritis |
|White cell casts || |
Indicative of infection or inflammation
Pyelonephritis, interstitial nephritis
|Renal tubular cell casts ||Acute tubular necrosis, interstitial nephritis |
|Granular (muddy brown) casts ||Nonspecific; can indicate acute tubular necrosis |
|Broad waxy casts || |
Indicative of stasis in enlarged collecting tubules
Chronic kidney disease
Red blood cell cast. (Used, with permission, from Jean Olson, MD.)
Proteinuria is defined as excessive protein excretion in the urine, generally greater than 150 mg/24 hours in adults. Proteinuria more than 1–2 g/day is usually a sign of underlying glomerular kidney disease, whereas proteinuria less than 1 g/day can be due to multiple causes along the nephron segment, as listed below. Proteinuria can be accompanied by other clinical abnormalities—elevated blood urea nitrogen (BUN) and serum creatinine levels, abnormal urine sediment, or evidence of systemic illness (eg, fever, rash, vasculitis).
There are several reasons proteinuria may develop: (1) Functional proteinuria is a benign process stemming from stressors such as acute illness, exercise, and “orthostatic proteinuria.” The latter condition, generally found in people under 30 years of age, usually causes protein excretion less than 1 g/day. The orthostatic nature of the proteinuria is confirmed by measuring an 8-hour overnight supine urinary protein excretion, which should be less than 50 mg. (2) Overload proteinuria can result from overproduction of circulating, filterable plasma proteins (monoclonal gammopathies), such as Bence Jones proteins associated with plasma cell myeloma. Protein electrophoresis from the serum or urine will exhibit a discrete, monoclonal protein spike. Other examples of overload proteinuria include myoglobinuria in rhabdomyolysis and hemoglobinuria in hemolysis. (3) Glomerular proteinuria results from effacement of epithelial cell foot processes and altered glomerular permeability with an increased filtration fraction of normal plasma proteins, as in diabetic nephropathy. Protein electrophoresis will have a pattern exhibiting a large albumin spike indicative of the increased permeability of albumin across the damaged GBM. (4) Tubular proteinuria occurs as a result of faulty reabsorption of normally filtered proteins in the proximal tubule, such as beta-2-microglobulin and immunoglobulin light chains. Causes may include ATN, toxic injury (lead, aminoglycosides, and certain antiretrovirals), drug-induced interstitial nephritis, and hereditary metabolic disorders (Wilson disease and Fanconi syndrome).
Evaluation of proteinuria by urinary dipstick does not actually measure protein but instead detects the negative electrochemical charge that characterizes albumin. As a result, positively charged Bence Jones proteins are missed with dipstick analysis. Bence Jones proteins can be detected by the addition of sulfosalicylic acid to the urine specimen or by directly measuring urine protein (discussed below). It should be noted that, because urinary dipstick simply detects negative electrochemical charge, alkaline urine (pH > 7.0) can cause false-positive results.
While urinary dipstick is commonly used as a screening test for proteinuria, formal investigation typically requires direct evaluation of daily urinary protein excretion. This can be estimated with a random urine sample or measured from a timed urine collection (typically over 24 hours). Collection of a random urine sample is far simpler, and the ratio of urinary protein-to-creatinine concentration ([Uprotein]/[Ucreatinine]) correlates with a 24-hour urinary protein collection (less than 0.2 is normal and corresponds to excretion of less than 200 mg/24 hours). In a 24-hour urine collection, proteinuria more than 150 mg is abnormal and greater than 3.5 g is consistent with nephrotic range proteinuria. One benefit of a random urinary protein-to-creatinine ratio is the minimization of error from overcollection or undercollection of urine in the 24-hour specimen. A kidney biopsy may be indicated to determine the cause of abnormal proteinuria, if present, particularly if accompanied by abnormal GFR. The clinical sequelae of proteinuria are discussed in the section on Nephrotic Spectrum Glomerular Diseases.
Hematuria is clinically significant if there are more than three red blood cells per high-power field on at least two occasions. It is usually detected incidentally by the urine dipstick examination or clinically following an episode of macroscopic hematuria. The diagnosis must be confirmed via microscopic examination, as false-positive dipstick tests can be caused by myoglobin, oxidizing agents, beets and rhubarb, hydrochloric acid, and bacteria. Transient hematuria is common, but it is less often of clinical significance in patients younger than 40 years due to lower concern for malignancy.
Hematuria may be due to renal or extrarenal causes. Extrarenal causes are addressed in Chapter 23. Renal causes account for approximately 10% of cases and are best considered anatomically as glomerular or extraglomerular. Glomerular causes include glomerulonephritis (eg, immunoglobulin A [IgA] nephropathy), thin basement membrane disease and other hereditary disorders (eg, Alport syndrome), and systemic nephritic syndromes (eg, lupus nephritis). The most common extraglomerular sources include cysts; calculi; interstitial nephritis; and, most worrisome, genitourinary neoplasms from the kidney, prostate, or bladder (see Chapter 39). Currently, due to insufficient evidence, the United States Preventive Services Task Force gives no recommendation to screen for hematuria to test for bladder cancer in asymptomatic adults.