Asymptomatic microscopic hematuria—Is investigation necessary?

J Clin Epidemiol Vol. 50, No. 11, pp. 1197-1200, Copyright 0 1997 Elsevier Science Inc.

1997 Pll

0895-4356/97/$17.00 SO8954356(97)00124-8

ELSEVIER

Asymptomatic Microscopic HematuriaIs Investigation Necessary? Paul F~oom,‘~*Juck

FTOOTTI,~ and Joseph Ribak’

‘DEPARTMENT OF EPIDEMIOLOGY, SACKLER SCHOOL OF MEDICINE, UNIVERSITY OF TEL AVIV, RAMAT AVIV, ISRAEL, AND ‘DEPARTMENT OF FAMILY MEDICINE, UNIVERSITY OF NEW YORK AT STONY BROOK, STONY BROOK, NEW YORK

ABSTRACT.

Microscopic hematuria is common in asymptomatic adults, but the benefit of screening the general population for blood in the urine has not been established. On the other hand, most studies of referred patients with putatively asymptomatic microscopic hematuria have reported a 2-l 1% prevalence of urothelial malignancies, leading to the recommendation that all patients with microscopic hematuria be thoroughly investigated. Urinalysis is inexpensive and highly acceptable to the general population, but is neither a sensitive, nor specific test, and has poor predictive value for urothelial malignancies, and nephrological diseases. Furthermore the benefits of early detection of such diseases has not been established. We conclude that screening urinalysis cannot be recommended. Studies are needed to determine which constellation of findings primary physicians use to select patients for referral to centers with urological and nephrological expertise. I CLIN EPIDEMIOL 50; 11:1197-1200, 1997. 0 1997 Elsevier Science Inc.

KEY WORDS.

Microscopic

hematuria,

screening,

INTRODUCTION hematuria is common in asymptomatic adults [1,2], but the benefit of screening the general population for blood in the urine has not been established. Most studies of referred patients with putatively asymptomatic microscopic hematuria, have reported a 2-l 1% prevalence of urothelial malignancies [3-lo], leading to the recommendation that all patients with microscopic hematuria be thoroughly investigated [lo-131. Furthermore, since the degree of microscopic hematuria does not differentiate between those with and without urothelial malignancies [8], some recommend that “any red blood cell seen in a centrifuged specimen of urine be considered significant” and that a complete investigation into its cause is mandatory [12]. Although it is unclear what criteria were used by primary physicians to select patients for referral, “asymptomatic microscopic hematuria” suggests that they were discovered incidentally and that all adults would benefit from a screening urinalysis. Microscopic

SCREENING TESTS The recommendation to use a test to screen the general population requires fulfillment of strict criteria [13]. The disease must be an important health problem. The screening test must have adequate sensitivity and specificity. La*Address for correspondence: Health and Rehabilitation, Accepted for publication

Paul Froom, M.D., P.O. Box 3, Raanana on 11 June 1997.

Institute 43100,

of Occupational Israel.

asymptomatic

disease

tent or early symptomatic stages of the disease must be recognizable. The screening test and subsequent treatment must be acceptable to the general population and suitable diagnostic and treatment facilities be available. The intervention must lead to a decrease in morbidity and mortality, with minimal side effects of the work-up of false positive tests, and at acceptable cost.

URINALYSIS In some respects, urinalysis is an ideal screening test. It is inexpensive, and highly acceptable to the general population. Facilities for diagnosis and treatment of urinary cancers are generally available and latent stages can be identified. Unfortunately urinalysis is not a sufficiently specific or sensitive test for urothelial malignancies. In a recent report, only 1 of 9 patients with bladder tumors discovered by 5706 screening abdominal ultrasonographies had microscopic hematuria [14]. The main causes for the relatively low sensitivity and accuracy of the high power field method are differences in the volumes of the centrifuged specimen and discarded supernatant, thoroughness of mixing the specimen before and after centrifugation, and the width of the sediment layered on the slide [ 15,161. In addition, excretion of red blood cells in urine of patients with urothelial malignancies may be intermittent [17]. Morphology of red blood cells has not been shown to adequately discriminate between glomerular and non-glo-

1198

merular hematuria. In a meta-analysis, the proportion of dysmorphic red cells and their mean corpuscular volume misclassified 7-20% of those with non-glomerular bleeding [18]. Distinctive doughnut-shaped cells with blebs were reported to increase specificity to 100% in a small cohort [ 191, but additional studies with larger numbers of asymptomatic patients studied prospectively are needed to confirm these results.

PREDICTIVE VALUE OF MICROSCOPIC HEMATURIA There have been only a few studies of the predictive value of asymptomatic microscopic hematuria for urothelial malignancies in the general population. Microscopic hematuria in young men aged 18-33 was very common when tested yearly over a 15year period. Of 1000 men, 38.7% had microscopic hematuria (2-4 red blood cells [RBCs] per high power field [HPF]) at least once and 16.1% had at least 2 positive tests over any one five-year period [2]. Only one case of transitional cell carcinoma was found during the 15 year follow-up period. This patient had one positive urinalysis three years before discovery of the tumor, prompted by the appearance of macroscopic hematuria, but testing during the two years before diagnosis was negative. Mohr et al. [20] extended these observations to a cohort of Rochester Minnesota residents over age 35. The cohort came from a random sample stratified by three age groups: 35-54, 5574, and 75 years or older. Women in the youngest age group were not included because of the possibility of contamination by menstrual bleeding. The investigators compared 635 patients with isolated asymptomatic microhematuria to an equal number of age matched controls. Over a follow-up period of 12 years, they found six cases of bladder cancer in those with hematuria compared with four cases among the controls. Two cases of renal cancer were found in those with asymptomatic microhematuria, but were diagnosed 7 and 10 years after its onset. In population studies of older men, a high prevalence of hematuria and concomitant urological malignancy has been reported. Messing et al. [17], in a study of 333 healthy men of 626 men above age 50, solicited from a university health maintenance organization and general internal medicine health clinics, found hematuria at least once on multiple dipsticks 9.96% with 3/19 (15.8%) who agreed to cystoscopy having a urological malignancy. Britton et al. [2 l] studied 578 of 855 men aged 60-85 invited to attend the health center for a health check-up; 13% had hematuria by dipstick. A bladder tumor was detected in four (6.6%), and epithelial dysplasia detected in five (8.2%) of the 61 men who agreed to further investigation. Although these studies did not evaluate age matched controls, they raise a concern that microscopic hematuria should not be ignored in older patients, and a large randomized study of elderly males with long-term follow-up is needed to address this controversial problem.

P. Froom et al.

POSSIBLE BENEFITS OF EARLY DETECTION OF UROLOGICAL DISEASES The benefit of early detection of bladder cancers is uncertain. Early intervention may decrease morbidity and mortality in those with muscular infiltrative disease at diagnosis, but the natural history of superficial bladder cancer that makes up 80% of the total is variable and early diagnosis may not improve survival [22]. Only lo-15% of those with superficial tumors will subsequently progress to invasion of muscle, and most will recur after complete endoscopic removal of the initial tumor [23,24]. Intravesical instillation of chemotherapeutic agents can reduce the rate of recurrence, but has not been proven to lower the incidence of subsequent muscle invasion [23,24]. In a recent meta-analysis of data from randomized clinical trials, the authors concluded that neoadjuvant cisplatin-based chemotherapy for locally advanced bladder cancer has not been shown to improve survival and any planned clinical trial should include a “no chemotherapy” control arm [25]. Renal carcinoma comprises less than one-seventh of urinary cancers and can be detected by ultrasonography with the finding of a solid renal mass being 92% specific for renal carcinoma. Smaller tumors discovered at an early stage appear to have a better prognosis than those found later [26,27], with those having tumors confined to the kidney (stage 1) having a 60-75% five-year survival rate [28]. Urinalysis however, is not a sensitive test to detect renal cell carcinoma, and in high risk groups ultrasonography may be a more appropriate screening test. The predictive value of the urinalysis in the detection of other moderately serious lesions [9], such as hydronephrosis or ureteral calculi is unknown.

POSSIBLE BENEFITS OF EARLY DETECTION OF NEPHROLOGICAL

DISEASES

The significance of an early diagnosis of IgA nephropathy is uncertain and its treatment in the absence of proteinuria is controversial [29-331. Some recommend biopsy to make a definite diagnosis, give prognostic advice, and determine need for long-term follow-up [32]. Others disagree [29,31]; only 5% of 349 pediatric nephrologists would biopsy a 9-year-old boy with 20 RBCs/HPF and no evidence of proteinuria [33]. Abnormalities such as proteinuria, elevated blood pressure, the presence of RBC casts, an elevated serum creatinine, or a family history of renal failure may prompt an investigation. This may have increasing clinical importance since the use of angiotensin-converting enzyme (ACE) inhibitors [34] and fish oil [35] may retard the progression to end stage renal disease and reduce the degree of proteinuria. It should be emphasized that therapeutic trials that convincingly show a long-term beneficial effect on the progression of renal insufficiency in IgA nephropathy are wanting [36]. Furthermore, such trials do not include pa-

Asymptomatic

Microscopic

tients with microscopic reduced renal function.

1199

Hematuria

hematuria

without

proteinuria

3. Whelan P, Britton JP, Dowel1 AC. Three-year follow-up of bladder tumours found on screening. Br J Urol1993; 72: 893896. TH, Waymont B, Dunn JA, Hughes MA, Wallace 4. Lynch DMA. Rapid diagnostic service for patients with haematuria. Br J Urol 1994; 73: 147-151. of microscopic 5. Davides KC, King LM, Jacobs D. Management hematuria: Twenty-year experience with 150 cases in a community hospital. Urology 1986; 28: 453-455. Gillatt DA, O’Reilly PH. Haematuria analysed-A prospective study. J Royal Sot Med 1987; 80: 559-560. Thompson IM. The evaluation of microscopic hematuria: A population based study. J Urol 1987; 138: 1189-1190. Carson CC, Segura JW, Green LF. Clinical importance of microhematuria J Am Med Assoc 1979; 241: 149-150. Greene LF, O’Shaughnessy EJ, Hendricks ED. Study of five hundred patients with asymptomatic microhematuria. J Am

or

RECOMMENDATIONS High standards of evidence are required to evaluate tests used for preventive services [37]. Since pre-symptomatic detection increases costs, and can cause anxiety and inconvenience, the physician must be certain that the benefits exceed the harm. Therefore, the standards of evidence are more stringent than those used to treat a sick patient who initiates an episode of care [37]. Urinary cancers are rare in men and women under the age of 45. In those over age 65 they do cause significant morbidity and mortality, but there is no evidence that early detection and intervention will decrease overall mortality. Furthermore, investigation of those with microscopic hematuria by intravenous pyelography and cystoscopy can result in 3 per 1000 life-threatening complications [lo]. Urinalysis is neither a sensitive, nor specific test, and has poor predictive value for urothelial malignancies. Thus, regardless of age, neither the American College of Physicians nor the Canadian task force recommends urinalysis as a routine test [37]. The U.S. Preventative Services Task Force grades their recommendation for urinalysis in persons over age 60 as intermediate, recognizing that the evidence is too weak to supporte ither a positive or negative recomtnendation [37]. Recommendations may differ for patients with asymptomatic microhematuria who are referred by primary care physicians for additional investigation. Most studies report detection of a high prevalence of urothelial malignancies in patients referred with microscopic hematuria, even in those less than 50 years old [10,38], although the prevalence may be low in referred females [39]. The selection process that results in a high prevalence of serious urological lesions found in referral centers may be due to the fact that referring physicians consider factors other than a single screening urinalysis (e.g., degree and persistence of hematuria, symptoms). Similarly the presence of proteinuria, hypertension, or renal insufficiency may prompt physicians to refer a patient for nephrological evaluation. Studies are needed to determine which constellation of findings physicians use to select patients for referral. Finally, the high prevalence of malignant urothelial disease in older men in the general population raises the question whether or not improved screening methods could lead to increased detection and decreased morbidity and mortality from such diseases, and warrants randomized cohort studies with a long follow-up period. References 1. Freni SC, Henderik GJ, Ho1 C. Centrifugation techniques reagent strips in the assessment of microhaematuria.

and

J Clin

Path01 1977; 30: 336-340. 2. Froom P, Ribak J, Benbassat J. Significance ria in young adults. Br Med J 1984; 288:

of microhaematu-

20-22.

Med Assoc 1956; 161: 610-613. 10

Mariani AJ, Mariani MC, Macchioni C, Stams UK, Hariharan A, Moriera A. The significance of adult hematuria: 1,000 hematuria evaluations including a risk benefit and costeffectiveness analysis. J Urol 1989; 141: 350-355. 11. Sutton JM. Evaluation of hematuria in adults. J Am Med

Assoc 1990; 263: 2475-2480. 12. Firfer

R. Clinical

importance

of microhematuria.

J

Am Med

Assoc 1979; 241: 165-166. 13. Cadman D, Chambers ing the effectiveness

LW, Feldmen WR, Sackett DL. Assessof community screening programs. J Am

Med Assoc 1984; 251: 1580-1585. T, Kasaya T, Imada S. Bladder tumors detected by 14. Shimazui transabdominal ultrasonography. NipponsHinyokika-GakkaiZasshi 1992; 83: 1847-1851. 15. Bee DE, Gordon JP, Paul KL. Hemoglobinuria and hematuria: Accuracy and precision of laboratory diagnosis. Clin Chem 1979; 25: 1696-1699. 16. Gadeholt H. Quantitative estimation of urinary sediment with special regard to sources of error. Br Med J 1964; i: 1547-

1550. 17.

18.

19.

20.

21.

?? “I.

Messing EM, Young TB, Hunt VB, Emoto SE, Wehbie JM. The significance of asymptomatic microhematuria in men 50 or more years old: Findings of a home screening study using urinary dipsticks. J Ural 1987; 137: 919-925. Offringa M, Benbassat J. The value of urinary red cell shape in the diagnosis of glomerular and post-glomerular haematuria. A meta-analysis. Postgrad Med J 1992; 68: 648-654. Kitamoto Y, Tomita M, Akamine M, Inoue T, ltoh J, Takamori H, Sato T. Differentiation of hematuria using a uniquely shaped red cell. Nephron 1993; 64: 32-36. Mohr DN, Offord KP, Melton LJ. Isolated asymptomatic microhematuria: A cross-sectional ayalysis of test-positive and test-negative patients. J Gen Intern Med 1987; 2: 318-374. Britton JP, Dowel1 AC, Whelan P. Dipstick haematuria and bladder cancer in men over 60: Results of a community study. Br Med J 1989; 299: 1010-1012. Schroder FH. Microscopic haematuria; requires investigation.

Br Med J 1994; 309: 70-72. 23. Richie JP. Intravesical chemotherapy: Treatment selection, techniques and results. Urol Clin NA 1992; 19: 521-527. 24. Levi F, La Vecchia C, Randimbison L, Franceschi S. Incidence of infiltrative cancer following superficial bladder carcinoma. Int J Cancer 1993; 55: 419-421. 25. Ghersi D, Steward LA, Parmar MKB, Coppin C, MartinezPineiro J, Raghavan D, Wallace MA. Does neoadjuvant cisplatin-based chemotherapy improve the survival of patients with locally advanced bladder cancer: A meta-analysis of individual patient data from randomized clinical trials. Br J Urol

1995; 75: 206-213.

1200

26. Aso Y, Homma Y. A survey on incidental renal cell carcinoma in Japan. J Urol 1992; 147: 340-343. 27. Ozen H, Colowick A, Freiha FS. Incidentally discovered solid renal masses: What are they? Br J Urol 1993; 72: 274-276. 28. Waters WB, Richie JP. Aggressive surgical approach to renal cell carcinoma. Review of 130 cases. J Urol 1979; 306-309. 29. Pardo V, Berian MG, Levi D, Strauss J. Benign primary hematuria. clinicopathologic study of 65 patients. Am J Med 1979;

67: 8174322. 30. Ibels LS, Gyory

AZ. IgA Nephropathy: Analysis of the natural history, important factors in the progression of renal disease and a review of the literature. Medicine 1994;73: 79-102. 3 1. Copley JB, Hasbargen JA. Idiopathic hematuria. Arch Intern

P. Froom

34.

33.

Topham PS, Harper SJ, Furness PN, Karris KPG, Walls J, Feehally J. Glomerular disease as a cause of isolated microscopic haematuria. Quart J Med 1994;87: 329-335. Feld LG, Stapleton FB, Duffy L. Renal biopsy in children with asymptomatic hematuria or proteinuria: Survey of pediatric nephrologists. Pediatr Nephrol 1993;7: 441-443.

Cattran DC, Greenwood C, Ritchie S. Long-term benefits of angiotensin-converting enzyme inhibitor therapy in patients with severe immunoglobulin A nephropathy: A comparison to patients receiving treatment with other antihypertensive agents and to patients receiving no therapy. Am J Kidney Dis

1994;23: 247-254. 35.

Donadio JV Jr, Bergstralh EJ, Offord KP, Spencer DC, Holley KE. A controlled trial of fish oil in IgA nephropathy. N Engl J Med 1994; 331: 1194-1199. 36. Galla JH. IgA nephropathy. Kidney Int 1995;47: 377-387. 37. Sox HC. Preventive health services in adults. N Engl J Med

1994;330: 1589-1595. 38.

Med 1987; 147:434-437. 32.

et al.

Gartman

E. The

significance

of hematuria

in young

men.

J

Urol 1956;75: 135-142. 39.

Bard RH. in women

The significance and its economic

1988;148:2629-2632.

of asymptomatic implications.

microhematuria

Arch Intern Med