Ⅵ Occult

Occult Hematuria Detected on Health Screening

JMAJ 47(5): 240–246, 2004

Tsuneharu MIKI* and Masahiro NAKAO**

*Professor, Department of , Kyoto Prefectural University of Medicine, Graduate School of Medical Science **Professor, Department of Urology, Meiji University of Oriental Medicine

Abstract: The detection rate of occult hematuria found on health screening is considerably high, ranging from 2.8% to 16%, which is double or triple that of . in adults that cause hematuria can be broadly divided into three groups: systemic involving the , renal parenchymal disease, and . Systemic diseases causing damage to the kidney include , mellitus, and many other diseases. Important renal paren- chymal diseases are and its related diseases. When systemic diseases and renal parenchymal diseases are excluded, there is a high possibility of urologic diseases such as malignant tumor, urolithiasis, and urinary tract infec- tion. In children, it is also necessary to consider both pediatric and urologic dis- eases. In particular, hereditary and congenital urinary tract malformation are clinically important. Occult hematuria, which is frequently found on health screenings, has various possible causes. In approximately 80% of the cases detected, however, the cause was not discovered and a positive diagnosis was not possible. Therefore, it is important to develop effective strategies for diagnosing the cause of microscopic hematuria. Key words: Occult hematuria; Mass screening

Introduction vation of urinary sediment under high (400- fold) magnification. Hematuria is classified as Hematuria is defined by the presence of red macroscopic (visible to the naked eye) or micro- blood cells (RBCs) in . RBCs in urine are scopic (recognized only under a microscope), generally regarded as pathologic when 3–5 or or by the presence/absence of concomitant more per field are found by microscopic obser- symptoms as symptomatic or asymptomatic.

This article is a revised English version of a paper originally published in the Journal of the Japan Medical Association (Vol. 128, No. 5, 2002, pages 767–771). The Japanese text is a transcript of a lecture originally aired on February 18, 2002, by the Nihon Shortwave Broadcasting Co., Ltd., in its regular program “Special Course in Medicine”.

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Table 1 Diseases That Cause Microscopic Hematuria in Adults (%)

No. of Systemic Urologic Urinary tract Author(s) cases diseaseGlomerulonephritis tumorUrolithiasis

Kinoshita et al.2) 794 88 (11) 73 (9) 5 (0.6) 35 (4.4) Murakami et al.4) 637 8 (1.3) 21 (3.3) 17 (2.7) Morita et al.5) 315 23 (7.3) 7 (2.2) 12 (3.8) 25 (7.9) 44 (14) Saida et al.6) 607 41 (6.8) 4 (0.6) 47 (7.7) 108 (18) Hattori et al.7) 339 7 (2.1) 2 (0.6) 16 (4.7) 23 (6.8) Marumo et al.8) 750 65 (8.7) 3 (0.4) 19 (2.5) 4 (0.5)

Occult hematuria found on mass screening is tension, which cause damage to the kidney, asymptomatic and microscopic in most cases, account for 7.3–11%. Glomerulonephritis, a and accounts for 2.8–16% of subjects.1–3) Sys- clinically significant disease related to abnor- temic disease, renal parenchymal disease, and mal urine test results, is found in 2.1–9% of urologic disease are the main causes of this subjects. Urologic tumor is found in 0.4–3.8% condition. In spite of close examination, the of subjects. Although its frequency is relatively etiology remains unclear in about 80% of cases, low, this disease is life-threatening and there- indicating the difficulty in determining the fore clinically significant. When the subject is cause of occult hematuria. 40 years old or older, the presence of hematuria, This paper reviews diseases that may cause even if it is microscopic, warrants consultation clinically relevant occult hematuria detected with a urologist. Urolithiasis is diagnosed in on mass screening and discusses how to exam- 2.5–7.9% of subjects, and urinary tract infec- ine and treat it in adults. Occult hematuria in tion in 0.5–18% of subjects. Both conditions children is also outlined briefly. are relatively common and should be kept in mind when occult hematuria has been found on Occult Hematuria in Mass Screening health screening. Guidelines have not been established for the Hematuria is found frequently among mass follow-up observation of patients with asymp- screening subjects, with the reported incidence tomatic hematuria. It is, however, important ranging from 2.8% to 16%. Although the fre- that any condition likely to lead to renal failure quency varies according to the target of screen- should not be overlooked. Based on their long- ing, the detection rate is usually double or term observation of subjects with abnormal triple that of proteinuria.1–3) The percentage of urine test results, Yamagata et al. reported that subjects positive for occult hematuria generally about 50% of subjects positive for hematuria increases with age.1) The rate is higher in alone experienced disappearance of hematuria, women, and that may be explained by the about 40% showed no change, and about 10% higher incidence of and eventually developed proteinuria and were contamination by menstrual blood. diagnosed as having chronic nephritis. In addi- The diseases causing microscopic hematuria tion, they reported that 75% of subjects who and their frequencies as reported in the litera- were positive for proteinuria with or without tures are listed in Table 1.2,4–8) Among the vari- hematuria were later diagnosed as having ous causes of microscopic hematuria, systemic chronic nephritis.3) Subjects positive for hema- diseases such as diabetes mellitus and hyper- turia alone showed very little worsening of

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renal function, whereas 10% of subjects posi- Table 2 Systemic Diseases That May Cause Hematuria tive for proteinuria and 30% of those positive Hypertension Necrotizing angiitis Diabetes mellitus for both hematuria and proteinuria developed Hyperuricemia Amyloidosis Sarcoidosis increased levels within 10 years.3) Collagen disease Multiple myeloma Leukemia Thus, when hematuria alone is positive, the Goodpasture’s Hemophilia Thrombocytopenic probability is low that it will develop into a syndrome purpura serious disease in the future. Therefore, we consider it sufficient to follow the course of the condition through non-invasive tests, such as urinalysis, blood examination, and ultra- sion pyelography (DIP), , CT, and sonography. MRI should be performed.

Diagnostic Procedures for Hematuria Diseases That May Cause Hematuria

Urinalysis performed as part of a health Diseases that may cause hematuria are screening usually employs a paper strip test. broadly divided into three groups: systemic Therefore, when the test has indicated hema- disease, renal parenchymal disease, and uro- turia, it is necessary to carry out microscopic logic disease. observation of urinary sediments to determine the severity of hematuria. It is also important 1. Systemic disease to look for irregularities in the size and shape Systemic diseases that may cause hematuria of RBCs, and the presence of white blood cells and proteinuria and lead to renal failure include and casts in urine. In addition, the following hypertension, necrotizing angiitis, diabetes mel- examinations should be performed: a general litus, hyperuricemia, amyloidosis, sarcoidosis, physical examination; blood pressure measure- collagen diseases such as systemic ery- ment; complete blood count; blood biochemical thematosus (SLE), multiple myeloma, leukemia, tests for BUN, creatinine, and serum electro- Goodpasture’s syndrome etc. (Table 2).1,9) Dis- lytes; serological assays of ASLO, immuno- eases showing hemorrhagic diathesis, such as globulins, and complement; urinary cytology, hemophilia and thrombocytopenic purpura, and ultrasonography of the kidney and urinary while not causing renal disorders, can be the tract. cause of hematuria.9) In general, these diseases In general, the possibility of renal paren- are seldom detected by occult hematuria on chymal disease is high when the following are health screening, but they are often found as a noted: proteinuria, urinary casts, in the result of other or labora- lower limbs and face, hypertension, renal dys- tory findings. Nevertheless, it should be noted function, elevated levels of ASLO and IgA, that while many diseases can cause microscopic decreased complement, and bilateral renal hematuria, it is difficult to diagnose any of atrophy. Subjects who have clinical signs and them positively as the cause. They should be laboratory findings suggesting the presence of regarded as probable diagnoses after other renal parenchymal disease should be referred possible causative diseases have been excluded. for detailed examination by a nephrologist. The final diagnosis should be made by . 2. Renal parenchymal disease When such abnormalities are not found, Glomerulonephritis, a well-known renal pa- when urinary cytology shows positive results, renchymal disease, must be differentiated from or when ultrasonography suggests urologic dis- a similar condition called persistent hema- ease, urologic examinations such as drip infu- turia/proteinuria syndrome, which is associ-

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Table 3 Renal Diseases That Cause Hematuria renal pelvic and ureteral , and often manifest with macroscopic hema- 1. Primary glomerulonephritis Chronic glomerulonephritis turia as the initial sign. Although it is uncom- (including IgA nephropathy) mon to find these diseases through close Persistent hematuria/proteinuria syndrome examination of microscopic hematuria, it is 2. Hereditary nephritis Alport’s syndrome important not to overlook them because they Thin basement membrane disease are life threatening. If the urinary cytology and DIP, which are useful tests for renal pelvic and , indicate the possibility of cancer, further ex- ated with persistent hematuria and proteinuria amination by CT, retrograde pyelography, or without renal dysfunction. From the viewpoint ureteroscopy should be performed to establish of treatment, it is critical that these two condi- the diagnosis. Bladder cancer is the most fre- tions be differentiated (Table 3).9) Glomeru- quent disease in the field of urology. Both lonephritis is highly likely when RBCs in urine the urinary cytology and cystoscopy are useful are irregular in size or shape, when hematuria for diagnosing this disease. Almost all cases of is accompanied with proteinuria or cancer can be diagnosed by cystoscopy. casts, when there is hypertension or accompa- is usually detectable by nying edema in the lower limbs, when blood ultrasonography when the tumor measures test reveals renal dysfunction, or when there is 3cm or more in diameter. Definitive diagnosis elevated ASLO or IgA or decreased comple- is obtained by CT or MRI. Hematuria rarely ment. It is also necessary to consider hereditary serves as a clue to the presence of nephrites such as Alport’s syndrome, in which cancer, whose major symptoms are , nephritis is accompanied with impaired hear- pollakisuria, sense of residual urine etc. This ing, and thin basement membrane disease, in disease, however, should also be considered as which benign recurrent hematuria is present. the cause of hematuria. These diseases are more likely to show the Another important disease entity is uro- presence of a family history (Table 3). The lithiasis, which are classified into renal stones, definitive diagnoses of these conditions are es- ureteral stones, and bladder stones, according tablished by histopathological determination to their site. Although renal and ureteral stones of the glomerular abnormalities, and treatment are commonly accompanied with severe back modalities are then determined. Therefore, pain or flank pain, it is not uncommon for these when these diseases are suspected, it is neces- conditions to be detected by examination on sary to refer the subject to a nephrologist. occult hematuria. Urolithiasis occur more fre- quently than malignant tumors and more often 3. Urologic disease cause microscopic hematuria, thus requiring Urologic diseases are highly likely to be attention. Ultrasonography, DIP, or CT is re- involved when the above-mentioned systemic quired to establish the diagnosis. diseases and renal parenchymal diseases are Urinary tract infection is also a frequent excluded, necessitating close examination by cause of hematuria. Since white blood cells and urologists. are found in the urine, it is not difficult The most important urologic diseases de- to make this diagnosis. Appropriate antibiotic tected by hematuria are malignant tumors such therapy based on the results of bacterial cul- as renal cell carcinoma, renal pelvic and ture of the urine should be given to the patient. cancer, bladder cancer, and . In general, is accompanied with Among these tumors, renal cell carcinoma, and back pain, and cystitis is accompa-

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Table 4 Urologic Diseases That Cause Hematuria secondary urine test, and those with abnormal results on the secondary test are subjected to a 1. Malignant tumor Renal cell carcinoma, tertiary examination consisting of urinalysis Renal pelvic and ureteral cancer, including urinary sediment, medical examina- Bladder cancer, Prostate cancer tion by a physician, measurement of blood 2. Urolithiasis Kidney stones, Ureteral stones, Bladder stones pressure, and . The follow-up plan 3. Urinary tract infection and the management of daily activities are Pyelonephritis, Cystitis, Renal and urinary tract clarified to a greater extent than in adults.1,3) tuberculosis The positivity rate for occult hematuria on 4. Others primary urinary screening was reported to be 1.9% among 4,930,000 elementary school chil- dren and 5.1% among 2,420,000 junior high school students. The corresponding rates on nied with micturition pain, pollakisuria, and secondary screening are 0.5% among 120,000 cloudy urine. However, when there are few elementary school children and 0.9% among symptoms, chronic urinary tract infection 170,000 junior high school students. These should be suspected. In such cases, urolithiasis, percentages are two- to threefold higher than , vesicoureteral reflux, prostate those for proteinuria.12) As a result of tertiary hypertrophy, or neurogenic bladder may be an screening of those positive for occult hematuria underlying condition, and close examination of together with those positive for proteinuria, the urinary tract is required. If asymptomatic nephritis was found in 1.0% and urinary tract microscopic hematuria and pyuria are persis- infection in 2% of 12,140 elementary school tent, renal and urinary tract tuberculosis is a children, while nephritis was found in 0.8% and possibility that should not be overlooked urinary tract infection in 1.8% of 10,145 junior (Table 4). high school students.12) In addition to the above diseases, a variety of Although few detailed reports exist on the diseases of the kidney and urinary tract can causes of microscopic hematuria in children, cause hematuria. These include , poly- urinary tract infection, hydronephrosis, vesico- cystic kidney, , atrophic kid- ureteral reflux, urinary tract stones, and nephri- ney, idiopathic renal , hydronephrosis, tis have been detected as causes (Table 5).1,13) double and ureter, ureteral steno- Among children with abnormal urine test sis, vesicoureteral reflux, vesical diverticulum, results, including proteinuria on health screen- , radiation cystitis, bladder neck ing in schools, the frequency of glomerulo- contracture, prostatic hypertrophy, , nephritis is high, and hereditary nephrites such prostatic stones, , and urethral as Alport’s syndrome and thin basement mem- caruncle etc. It is therefore important to refer brane disease are also important causative con- to urologists for closer examination.10,11) ditions. Among renal disorders associated with systemic diseases, nephritis due to purpura, Occult Hematuria in Children nephritis due to SLE, and Goodpasture’s syn- drome are important. Hemorrhagic diseases When examining children, it is necessary to such as hemophilia and thrombocytopenic consider both urologic and pediatric diseases. purpura can also cause hematuria. Urinary For health screening of school children in tract infection and urolithiasis may also be Japan, the Tokyo system has been widely detected through occult hematuria. adopted, by which children with abnormal re- In addition, children may present congenital sults on a primary urine test are subjected to a renal and urinary tract diseases including poly-

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Table 5 Diseases That Cause Microscopic Hematuria in Children

Urinary tract Vesicoureteral Polycystic Author(s) infectionHydronephrosis refluxUrolithiasis Nephritis kidney Others Total

Murakami et al.1) 0 (0) 3 (1.1) 0 (0) 1 (0.4) 6 (2.2) 1 (0.4) 264 275 Kawamura et al.13) 13 (12) 8 (7.5) 4 (3.8) 3 (2.8) 2 (1.9) 0 (0) 76 106

Table 6 Pediatric Diseases That Cause Hematuria cystic kidney, congenital hydronephrosis, and vesicoureteral reflux. Congenital hydronephro- 1. Primary glomerulonephritis sis and vesicoureteral reflux can be detected by 2. Hereditary nephritis Alport’s syndrome, abnormal urine test results including hema- Thin basement membrane diseases turia, although pyelonephritis is a more com- 3. Systemic disease mon clue to find them. Therefore, it is neces- 4. Urinary tract infection sary to perform diagnostic imaging procedures Pyelonephritis, Cystitis 5. Congenital anomaly such as ultrasonography, intravenous pyelo- Polycystic kidney, Congenital hydronephrosis, graphy, and cystography in cooperation with Vesicoureteral reflux pediatricians and urologists (Table 6).1,14) No imaging techniques are employed by the Tokyo system even for tertiary screening; this should 1) be reconsidered in the future. REFERENCES However, if hematuria is the only abnormal- ity found in health screening in school, the 1) Murakami, M. and Ashida, M.: 6. How to diag- nose hematuria detected on health screening. probability of detecting serious diseases that Urology MOOK, 4. How to Diagnose and require treatment or close follow-up is as low Treat Hematuria (Ed. Koiso, K.). Kanehara & 1) as 5%, suggesting that the clinical significance Co., Ltd., Tokyo, 1992; pp.80–93. (in Japanese) of microscopic hematuria is low in children as 2) Kinoshita, H., Murakami, Y., Katsuoka, Y. et well as in adults. Thus, follow-up observation al.: Considerations of microscopic hematuria generally seems to be sufficient for positive found in subjects of general health examina- examinees, with no need for renal biopsy or tion. Japan Medical Journal 1983; 3097: 29–34. strict control of daily activities including limita- (in Japanese) tions on diet and exercise. 3) Yamagata, K. and Koyama, T.: Diagnosis of asymptomatic hematuria/proteinuria. Japan Medical Journal 2000; 3972: 1–8. (in Japanese) Conclusion 4) Murakami, N., Igarashi, T., Yamanishi, T. et al.: Clinical study of asymptomatic hematuria. Jpn Occult hematuria found on health screening J Urol 1986; 77: 1078–1081. (in Japanese) has been outlined, with most attention focused 5) Morita, H., Takemura, S., Okada, K. et al.: on adult cases. Although the detection of Clinical study of asymptomatic microscopic hematuria on health screenings is frequent, it hematuria. Nishinihon J Urol 1987; 49: 1121– rarely leads to diagnosis of the causative dis- 1125. (in Japanese) 6) Saita, H., Ohyama, A., Ikemiya, Y. et al.: A ease. It is important to establish effective clinical study on microscopic hematuria in measures for diagnosing the cause of occult mass examinations. Nishinihon J Urol 1988; hematuria and to provide useful methods of 50: 1831–1835. (in Japanese) follow-up observation. 7) Hattori, R., Kinukawa, T., Matsuura, O. et al.: Clinical features of asymptomatic microhema-

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turia—First Report—. Jpn J Urol 1987; 78: Evaluation of asymptomatic microscopic hema- 1045–1050. (in Japanese) turia in adults: the American Urological Asso- 8) Marumo, K. and Murai, S.: Clinical signifi- ciation best practice policy—Part II: patient cance of secondary screening for asymptomatic evaluation, cytology, voided markers, imaging, microscopic hematuria. Rinsho Hinyokika cystoscopy, evaluation, and follow- 1999; 53: 39–43. (in Japanese) up. Urology 2001; 57: 604–610. 9) Miura, M. and Sakai, H.: 3. Classification of 12) Murakami, M.: Screening for proteinuria and medical diseases causing hematuria. Urology hematuria in school children: methods and MOOK, 4. How to Diagnose and Treat Hema- results. Acta Paediatr Jpn 1990; 32: 682–689. turia (Ed. Koiso, K.). Kanehara & Co., Ltd., 13) Kawamura, T. and Ohashi, M.: Hematuria Tokyo, 1992; pp.14–21. (in Japanese) seen from the viewpoint of various medical 10) Grossfeld, G.D., Litwin, M.S., Wolf, J.S. et al.: fields: Pediatric urology. Chiryo 1987; 69: 99– Evaluation of asymptomatic microscopic he- 105. (in Japanese) maturia in adults: the American Urological 14) Ishihara, Y. and Ito, T.: 2. How to diagnose Association best practice policy—Part I: defi- pediatric diseases causing hematuria. Urol- nition, detection, prevalence, and etiology. ogy MOOK, 4. How to Diagnose and Treat Urology 2001; 57: 599–603. Hematuria (Ed. Koiso, K.). Kanehara & Co., 11) Grossfeld, G.D., Litwin, M.S., Wolf, J.S. et al.: Ltd., Tokyo, 1992; 46–52. (in Japanese)

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