JOURNAL OF INSURANCE MEDICINE Copyright ᮊ 2004 Journal of Insurance Medicine J Insur Med 2004;36:320±326

BACK TO THE BASICS

The Urinalysis—Inexpensive and Informative Thomas E. Murphy, Jr, MD, FACP, FLMI

The urinalysis dates back 6000 years. Information has evolved from Address: Jefferson Pilot Financial, tasting it for sugar to computer assisted assessment for the presence One Granite Place, PO Box 515, of cells and casts. The gives valuable information about Concord, NH 03302-0515. function in general and the glomeruli in particular. Findings can Correspondent: Thomas E. Murphy, lead to a diagnosis of various medical conditions, most notable be- Jr, MD. ing mellitus. Proteinuria has many implications, including the presence of systemic and the progression of an under- Key words: Urinalysis, proteinuria, lying renal condition. , casts, , kidney. Received: June 28, 2004 Accepted: August 6, 2004

he Babylonians were the first to study COLOR urine 6000 years ago. Then Hippocrates T ● studied the color and appearance of urine Cloudy—phosphates, urates, and leuko- and was said to use the information to make cytes with ● medical diagnoses and even prognosticate Black—melanin, alkaptonurea, metronida- based on this limited information. Question- zole, methyldopa or carbidopa ● 2 able improvement in this prognostication was Brown to Red —myoglobin, blood, free he- made by the ‘‘pisse prophets’’ in medieval moglobin, beets, phenothiazines, phenol- times. The 18th and 19th centuries saw the phthalein ● dawn of chemical and microscopic analysis. Orange to Yellow—bile pigment ● Richard Bright was a strong believer in the Green—pseudomonas, elavil (amitrypty- importance of urinalysis, and at one time all line) ● was referred to as ‘‘Bright’s Foamy—pyridium, proteinuria, conjugated Disease.’’ Robert Boyle discovered litmus pa- bilirubin per in 1670 and with it the testing of pH. Mauments described the testing of urine for pH glucose in 1850, but the modern chemistry strips did not appear until 1956.1 The normal pH is 4.5–7.8. An alkaline The ideal specimen is a clean caught, first urine with a pH Ͼ7 is indicative of voided specimen that is collected midstream with a splitting organism, diuretic us- to avoid urethral contamination and exam- age, , , and re- ined within a matter of hours. The urinalysis spiratory with hyperventilation. contains a large amount of information that An acid urine with a pH Ͻ5 is seen with will be discussed below. acidosis, diarrhea, uncontrolled diabetes mel-

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litus, starvation and dehydration, and respi- are seen in diabetic and alcoholic ketoacidosis

ratory diseases with CO2 retention. and in aspirin poisoning. False positive re- sults can be seen with ascorbic acid and from SPECIFIC GRAVITY3 L-DOPA metabolites. The normal specific gravity (SG) is 1.008– 1.030, and it declines with advancing age re- PROTEINURIA flecting the decreased ability of the kidney to The normal excretion rate of is 150 concentrate the urine. The number and the mg/day. It is made up mostly of Tamm- weight of solutes affect it. By contrast, os- Horsfall mucoprotein, which is produced in molality is determined solely by the number the thick ascending loop of Henle. Low mo- of solutes. As such, glucose and intravenous lecular weight are found in the urine contrast materials raise the specific gravity normally, but most are reabsorbed in the much more than the osmolality. Hyposthe- . Only small amounts of al- nuria refers to a SG Ͻ1.007 and is seen in bumin are normally seen in the urine due to or fluid loading. Isosthe- its charge and molecular weight, both factors nuria is a fixed SG of 1.010 and is seen fre- inhibiting transport across the glomerular quently in glomerular and tubular disease membrane.6 Excessive protein excretion oc- and especially in renal failure. curs through 4 mechanisms: ● Disruption of the capillary wall barrier LEUKOCYTE ESTERASE AND NITRITES4 causing increased filtration of various plas- Esterase is released by lysed urine granu- ma proteins— locytes. It is usually positive when there are ● Tubular damage that inhibits the normal more than 5 leukocytes per high power field. resorptive capacity— When compared to the esterase ● Overflow with excess production of low test has a sensitivity of 80% and a specificity molecular weight plasma proteins—light of 70% for the presence of infection. chains in multiple myeloma Most bacteria that colonize in the urine ● Increased secretion of tissue proteins as- cause nitrates, which are derived from die- sociated with inflammation—pyelonephri- tary metabolites, to be converted to nitrites. tis When both tests are positive, it is highly likely that an infection is present. There are 3 commonly used ways to assess proteinuria: the dipstick, 24-hour urine col- lection, and the protein creatinine ratio (P/ GLUCOSE AND KETONES Cr). The dipstick is useful only if positive, A positive dipstick for glucose generally and then one should proceed with a more ac- occurs when the plasma level exceeds 180 curate measurement of the actual amount of mg/dL. Exceptions are renal glycosuria from protein excreted. It is susceptible to changes a defect in the function of the proximal tubule in the specific gravity of the urine, and as and occasionally in pregnancy when the such, is not reliable. threshold is lower. Glycosuria has a specific- The 24-hour collection is the gold standard, ity of 98% but a sensitivity of only 17% and but unreasonable for an insurance popula- so is not useful as a screening test for dia- tion. The P/Cr is more convenient and highly betes mellitus.5 False negatives can be found correlated to the 24-hour collection.7 As the in individuals on tetracycline and high dose test assumes an excretion of 1 gm of creati- vitamin C. nine in 24 hours and men frequently excrete Ketones are generally detected with the ni- more and women less, Ginsberg7 in graphic troprusside reaction. They are commonly form showed that the normal range for men seen in fasting and starvation. Large amounts is 17–250 mg/gm, and for women 25–355

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mg/gm. First voided specimens may under- increase in prevalence with advancing age.13 estimate the amount of proteinuria given the The overall prevalence of MA in black males known decrease in excretion seen in the re- is 7.7%, 5.4% in Mexican-Americans, and cumbent position.8 False positive results can 5.7% in non-hispanic, white males. In the be seen in highly alkaline urine and with he- population over 20 years of age without clin- moglobin and vaginal secretions. Neverthe- ical proteinuria, the incidence of MA is 29% less, it is still considered the most efficient in those with diabetes mellitus, 16.8% in hy- method of measurement for the insurance pertensives, 15.9% in those with evidence of population. , and 3.3% in healthy Proteinuria can present in various forms: adults. Older age, minority race, diabetes, hyper- ● Transient tension, abnormal serum creatinine, and left ● Functional ventricular hypertrophy were all indepen- ● Orthostatic dently associated with the presence of albu- ● Disease related, which can be nephrotic or minuria after adjusting for other variables. non-nephrotic Depending on the methodology (units) used Functional proteinuria is seen in dehydra- by the lab, microalbuminuria is defined as 3– tion, emotional stress, , heat injury, in- 30 mg/dL, 30–300 mg/24-hour, 30–300 mg/ flammatory processes, intense activity, and gm creatinine, 30–300 mcg/mg creatinine, or acute illnesses, mostly because of increased 0.03–0.3 gm/gm creatinine. cardiac output seen in these states. Microalbuminuria is associated with dis- Orthostatic proteinuria is defined as signif- turbances in glucose metabolism,14 insulin re- icant proteinuria that appears during the day sistance,15 and a more adverse pattern of car- but is not present in a first voided specimen. diovascular risk factors.16 There are several It is seen in 3%–5% of the healthy young theories as to the mechanism of vascular dis- adult population. It usually is seen in indi- ease associated with MA. Pedrinelle and col- viduals Ͻ35 years old, with excretion of less leagues17 have proposed that the glomerular than 1 gm but occasionally up to 3 gm, and albumin leak reflects widespread atheroscle- always with normal urine sediment. It is a rosis-mediated damage to the capillary net- benign condition.9 work. Festa et al18 have shown an association In disease-related proteinuria the degree of of the level of C-reactive protein and fibrin- proteinuria correlates with the progression of ogen with the presence of MA in both type nephrotic syndrome or renal insufficiency.10,11 2 diabetic and nondiabetic individuals. They Mild proteinuria, if stable for ‘‘several years,’’ feel this is evidence of chronic inflammation may not portend a more serious condition. as a potential mediator between MA and ma- However, if it exceeds 1 gm per 24 hours, crovascular disease. In a similar vein, Paisley there is a much greater likelihood that a sig- et al19 provided evidence of an abnormality nificant glomerular lesion exists that can be in nitric oxide (NO)-dependent macrovascu- defined by biopsy. lar endothelial function remote from the kid- Nevertheless, random screening for pro- ney and of low-grade chronic inflammation teinuria in the general population is not cost that was associated with microvascular en- effective, unless it is selectively directed to dothelial dysfunction in patients with pro- high-risk groups such as the elderly and teinuria. those with .12 Albumin excretion correlates with the pro- gression or renal insufficiency due to various etiologies.20 However, it is a modifiable risk Microalbuminuria factor.21,22 The use of angiotensin converting Of the US population over age 6, 7.8% have enzyme inhibitors and angiotensin-receptor microalbuminuria (MA) with a progressive antagonists such as Losartin have been

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● Presence or absence of systemic disease Table 1. Incidence (%) of Cardiovascular Events With ● and Without Microalbuminuria24 Status of other risk factors (eg, BP, lipids, weight, smoking history, age) With Without Microal- Microal- Variables buminuria buminuria HEMATURIA Diabetes History Hematuria is generally defined as greater MI, or CV death 25 13.9 than 3 to 5 red blood cells per high power CHF 8.5 2.5 field of freshly spun urine sediment. Ritchie No Diabetes History et al29 reported that 2.5% of men undergoing MI, stroke or CV death 20.4 13.8 routine screening were found to have micro- CHF 4.6 2.1 scopic hematuria. Others30 have even seen higher frequencies of hematuria, and as such routine screening without a specific indica- tion is no longer recommended.31 shown to decrease the urinary albumin in Determining whether the blood is coming type 2 diabetes mellitus patients independent from the upper or lower parts of the urinary of any associated reduction in blood pres- 23 system is often difficult based on the urinal- sure. ysis alone. If there are casts present, then one The greatest area of concern is cardiovas- can generally be assured that the is cular. Evaluation of data from the Heart Out- from the kidney itself. Without casts some au- comes Prevention Evaluation (HOPE) Study 24 thors believe that the presence of dysmorphic by Gerstein et al showed a substantial dif- red cells implies that the source is the upper ference in vascular endpoints based on the tracts.32 One ‘‘rule of thumb’’ is that if 80% presence or absence of proteinuria (Table 1). of the cells are dysmorphic, then the source MA appears to be a marker of generalized is glomerular. If 80% are normal, then the and indicates an incremental source is the lower tract. Anything in be- risk for cardiovascular mortality in healthy tween could be either. individuals as well as those with known 25, 26 The common causes of isolated hematu- heart disease. ria33,34 are the following: Patients with MA and hypertension have an increased incidence of insulin resistance, ● Stones thicker carotid arteries, higher blood pressure ● (75% of bladder have pain- (BP) levels, left ventricular hypertrophy, and less hematuria) higher cholesterol and triglyceride levels.27 ● Analgesic nephropathy Hypertensive patients with MA have a great- ● Sickle cell er number of cardiovascular events than ● IgA nephropathy35 those without MA.28 ● Benign recurrent hematuria (familial he- It is well known that the presence of mi- maturia, thin glomerular basement mem- croalbuminuria in the adult onset diabetic brane disease) and the nondiabetic is a marker for vascular ● Hypercalciuria (common in young chil- disease. When underwriting such a case, it is dren) essential not to look at albuminuria in isola- In children the most common causes are tion but to also determine the following fac- benign familial, renal malformations, infec- tors: tion, or hypercalciuria. Voiding cystourethro- ● Amount of albuminuria gram (VCUG) and ultrasound are the pri- ● Rate of progression mary procedures assuming normal renal ● Status of the urinary sediment function and no proteinuria. ● Level of renal function In adults the issues can be broken down

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around the age of 50, because after that the They are formed in the distal tubules and en- risk of cancer steadily increases. The evalua- trap cells there. Small numbers of hyaline and tion is different from children as malforma- finely granular casts can be seen in normal tions and genetic diseases, other than poly- urine. All other casts are abnormal. Granular (PCKD), are less likely casts often result from the degeneration of to remain hidden until adulthood. The eval- different cellular casts. The deeply pigmented uation differs in that cystoscopy generally re- or ‘‘muddy brown’’ type is the characteristic places VCUG. Studies36,37 have been done to finding in . Red blood devise an efficient method of evaluation of cell casts are usually indicative of glomeru- microscopic hematuria in the adult. Muraka- lonephritis, but if the cells enter the urinary mi et al37 studied 1217 asymptomatic adults space via the tubular basement membrane, with isolated microscopic hematuria with they can be seen in also. In the cystoscopy, intravenous (IVP), latter condition, there will usually be white and ultrasound. Of the group, 2.9% had high- blood cell casts, bacteria and a positive urine ly significant lesions [24 cancers, 6 aggressive culture. The presence of cellular casts can glomerulonephritis (GN)], and 18.9% had help in diagnosis but do not by themselves moderately significant lesions (108 less ag- aid in prognosis. Factors such as renal func- gressive GN, 50 with urinary calculi among tion and the presence of hypertension are far other findings). Of interest, the cystoscopy more predictive of the severity of the disease. and ultrasound were 100% sensitive in diag- nosing cancer, whereas the IVP missed 57.1% of the renal cancers. In those with a negative CONTAMINANTS AND PROCESSING evaluation but persistent hematuria, they DELAY found no identifiable disease after 3 years of A poorly obtained specimen may contain observation. Mairani et al36 did a similar contaminants such as spores and pollens, fe- study and their major additional contribution cal parasites, fibers, starch granules, and mi- was the observation that the degree of he- crobial overgrowth. Vaginal secretions and maturia was of diagnostic importance in sep- sperm may result in a positive dipstick for arating out those with significant (glomeru- protein. A urinalysis done during menstrua- lar) and life threatening (cancer) lesions. tion may show up to 1.5 gm of protein that Risk factors for significant underlying dis- resolves with retesting in a week (personal ease include: age older than 50, tobacco use, medical observation). This is due to the plas- analgesic abuse, history of pelvic irradiation, cyclophosphamide, and exposure to occupa- ma proteins present with red blood cells. De- tional toxins such as dyes, benzenes, and ar- layed processing may result in decreased omatic amines. clarity due to crystallization of solutes, rising With a negative evaluation, the prognosis pH, loss of ketone bodies, loss of bilirubin, is usually excellent in both adults and chil- and dissolution of cells and casts. dren. Empirical treatment with steroids or cy- totoxic drugs is not indicated in view of the SUMMARY inherently benign prognosis. Within 5 years of discovery, 50% or more of such patients The urinalysis is a source of significant in- will have spontaneously remitted. formation about the anatomy and function of the kidneys and urinary tract. It lends in- sights into the status of systemic diseases CASTS such as diabetes mellitus. Though not as ex- Casts are cylindrical bodies made of citing as many of the newly available diag- Tamm-Horsfall protein that are several times nostic tests, it exceeds most for value per dol- larger than leucocytes and red blood cells. lar spent.

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and/or proteinuria in adults. Clin Nephrol. 1996;45: 36. Maraini AJ, Mariani MC, Macchioni C, et al. The 281–288. Significance of Adult Hematuria: 1000 Hematu- 34. Nieuwhof C, Doorenbos C, Grave W. A prospec- ria Evaluations Including a Risk-Benefit and tive study of the natural history of idiopathic non- Cost-Effectiveness Analysis. J . 1989;141: proteinuric hematuria. Kidney Int. 1996;49:222–225. 350–355. 35. Tanaka H, Kim S-T, Takasugi M. Isolated hema- 37. Murakami S, Igarashi T, Hara S. Strategies for turia in adults: IgA nephropathy is a predominant Asymptomatic Microscopic Hematuria: A Pro- cause of hematuria compared with thin glomeru- spective Study of 1,034 Patients. J Urology. 1990; lar basement membrane nephropathy. Am J Ne- 144:99–101. phrol. 1996;16:412–416.

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