Clin Exp Nephrol DOI 10.1007/s10157-014-1001-2
GUIDELINE
Japanese guidelines of the management of hematuria 2013 Shigeo Horie • Shuichi Ito • Hirokazu Okada • Haruhito Kikuchi • Ichiei Narita • Tsutomu Nishiyama • Tomonori Hasegawa • Hiroshi Mikami Kunihiro Yamagata • Tomoji Yuno • Satoru Muto
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Japanese Society of Nephrology, The Japanese Urological Association, The Japanese Society for Pediatric Nephrology, Japanese Society of Laboratory Medicine and Japanese Association of Medical Technologists 2014
Preface 1. Introduction Urinalysis is a component of annual health examinations upon which Japan prides itself, as our citizens enjoy the great benefit of access to this screening throughout most of their lives. Nevertheless, although hematuria is manifested with great frequency, screenings and subsequent clinical diagnoses have no adequate standardization. Moreover, In 2013, Japanese Society of Nephrology, Japanese Urological Association, Japanese Society for Pediatric Nephrology, Japanese Society of Laboratory Medicine and Japanese Association of Medical Technologists jointly published Japanese guidelines of the management of hematuria in Nihon Jinzo Gakkai Shi. 2013;55(5):861–946 (in Japanese). This is the English version. Chairman: S. Horie. S. Horie (&) Chairperson of the JSN Committee for Diagnostic Guidelines for Hematuria 2013, Japanese Society of Nephrology, The Japanese Urological Association, Department of Urology, Juntendo University Graduate School of Medicine, Tokyo, Japan e-mail: [email protected] S. Ito The Japanese Society for Pediatric Nephrology, Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan H. Okada Japanese Society of Nephrology, Department of Nephrology, Saitama Medical School, Saitama, Japan H. Kikuchi Japanese Society of Laboratory Medicine, Department of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan
hematuria can be symptomatic of renal and urological diseases, and advancements in the diagnostic process are profoundly linked to effective usage of medical resources. We established a panel to create new Guidelines in the form of clinical questions (CQ), drawing on five professional societies and the Japan Medical Association for panel members. This represents the first global set of CQbased hematuria guidelines, and the content contained by the 21 CQs are highly relevant to every medical practitioner relying on urinalysis. 2. Purpose Diagnostic Guidelines for Hematuria were issued in Japan in 2006, with clinical indices for hematuria patient screening, diagnosis, and treatment. However, 6 years have elapsed since their publication, and content divergent from today’s I. Narita Japanese Society of Nephrology, Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan T. Nishiyama The Japanese Urological Association, Department of Urology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan T. Hasegawa Department of Social Medicine, Toho University School of Medicine, Tokyo, Japan H. Mikami Japan Medical Association, General Hospital Higashikouri, Osaka, Japan
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clinical practice has become strikingly evident. With that in mind, we have revised this Guideline, keeping appropriate management of hematuria patients as our primary goal. As Japan faces an unprecedented aging society, we can expect to see a rise in the number of patients citing hematuria as their primary complaint. This new Guideline is largely significant in addressing the issues of efficient health economics and the diagnosis and treatment best suited to protecting the health of hematuria patients. By fusing the expertise of specialists from nephrology, urology, pediatrics, and laboratory science, we were able to forge guidelines transcending the borders of discrete medical departments.
to the interval from September 1990 through 2011. Our Guidelines cite only peer-reviewed articles, with the exception of CQ3, for which PubMed did not yield an adequate response. In this case, we utilized JAMAS. When necessary, we cite older literature. Some journal articles which were not appropriate for citation, or which lacked peer review, were used as background reference.
3. Background of the Guidelines development (including panel members and their specialties)
1)
6. Evidence levels and recommendation grades: Criteria for determining evidence level and recommendation grade
2) With the intent of revising the 2006 Diagnostic Guidelines for Hematuria, we solicited panel members from the Japanese Society of Nephrology, the Japanese Urological Association, the Japanese Society for Pediatric Nephrology, the Japanese Society of Laboratory Medicine, the Japanese Society of Medical Technologists, and the Japan Medical Association, as well as diagnostic guideline specialists. The format for this revision involves the clinical questions (CQ) format and a recommendation grading system.
3) 4)
4. A cautionary note on the use of this guideline
5)
This Guideline is established for physicians caring for hematuria patients. This includes the spectrum of doctors from residents to specialists. Hematuria, meanwhile, includes occult blood and microscopic as well as macroscopic hematuria. The hematuria patients for whom these Guidelines are created include children and adults of all ages. Pediatric patients are defined as children who have not yet completed high school.
6)
5. Methods and timeframe used in gathering evidence Literature searches utilized the PubMed and Japan Medical Abstracts Society (JAMAS) databases and were restricted K. Yamagata Japanese Society of Nephrology, Department of Nephrology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan T. Yuno Japanese Association of Medical Technologists, Clinical Laboratory, Kanazawa Red Cross Hospital, Kanazawa, Japan S. Muto Japanese Society of Nephrology, The Japanese Urological Association, Department of Urology, Teikyo University School of Medicine, Tokyo, Japan
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7)
Reference (research) standards are automatically determined from the research design. The research design’s standard determines the metaanalysis/systematic review. If there are numerous research designs, the one with the lowest level would apply (example: if a cohort study has a meta-analysis of level 4, meta-analysis mixing a randomized controlled trial and cohort study would also be designated as level 4). A single-arm intervention study (with no comparison group) would be level 4. The recommendation grade would depend on the above factors. Whenever the evidence level and the recommendation grade diverge, explanation is provided. As there was no approved literature providing answers to CQ3 and CQ21, we determined the recommendation grade through informal discussion and consensus. Evidence levels and recommendation grades are as follows:
[Evidence level] 1. 2. 3. 4.
5. 6.
Systematic review/meta-analysis Randomized controlled trial Non-randomized controlled trial Analytical epidemiological study (cohort study or case–control study)/single-arm intervention study (no comparison group) Descriptive study (case report or case series) Not based on patient data; professional opinion of a specialist or advisory committee
[Recommendation grade] A. B. C1. C2. D.
Has a solid scientific basis and is strongly endorsed Has a scientific basis, and is endorsed Has no scientific basis, but is endorsed Has no scientific basis, and cannot be endorsed Is scientifically demonstrated to be ineffective or harmful, and cannot be endorsed
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7. Public comment A draft of these Guidelines appeared on the websites of relevant professional organizations, and public input was sought prior to their final incorporation. Abbreviations
CQ2 What is the recommended urine collection method for hematuria diagnosis?
[Statement] Intense exercise should be avoided before screening. Use of a clean container is recommended. Specification of urine sampling time, such as mid-stream urine, early morning first-void urine or random sample, is also recommended. (Recommendation grade A)
AMH
asymptomatic microhematuria
ASH
asymptomatic hematuria
AUA
American Urological Association
[Comment]
BMI
body mass index
CT
computed tomography
FCM
flow cytometry
HPF
high power field
IVP
intravenous pyelogram
JCCLS
Japanese Committee for Clinical Laboratory Standards
The Japanese Committee for Clinical Laboratory Standardization (JCCLS) has issued two documents concerning routine urinalysis: Proposed Guideline for the Urinary Reagent Method [1] and Standard Guideline for Urinary Sediment [2]. Generally, a midstream urine sample is used and physical exercise before collection of urine should be avoided as it may cause hematuria or hemoglobinuria.
NMR
nuclear magnetic resonance
PSA
prostate specific antigen
RBC
red blood cell
TBMD
thin basement membrane disease
CQ3 Do urine blood test strips produced by various manufacturers differ in their sensitivity?
[Statement] Although data sheets indicate no differences in sensitivity among various urine test strips, some differences were observed when measuring urine samples.
I. Hematuria: definition and screening methods
[Comment]
CQ1 Do hematuria standards differ by age or gender?
The Japanese Committee for Clinical Laboratory Standards (JCCLS) defined that 1? of a urine blood reagent strip should correspond to 0.06 mg/dL of hemoglobin or about 20 erythrocytes/lL in 2004. However, the upper and/or lower limits of 1? and other ranks (2? , 3? , etc.) have not been standardized. Results of a JCCLS investigation using pooled urine samples spiked with hemoglobin showed considerable differences among test strip manufacturers.
[Statement] Red cell count distribution in urine varies with age and gender. However, since the significance of establishing hematuria standards for each group is unclear, more than 20 erythrocytes/lL or 5 erythrocytes/high power field (HPF) is considered to be the definition of hematuria. [Comment] Neither review articles discussing red cell count in the urine from healthy persons [1, 2] nor the American Urological Association (AUA)’s [3] Best Practice Policy concerning asymptomatic microscopic hematuria distinguish between age or gender in their definitions of hematuria. Moreover, Copley described that the normal number of red cells for children and adults is the same [2]. The standard of hematuria is globally defined as more than 5 erythrocytes/HPF in many reports [2, 4]. Japan’s own definitive text—the Standard Guideline for Urinary Sediment examination JCCLS GP1-P4—also states that below 4 erythrocytes/HPF are observed in the urine from healthy men and women [5].
CQ4 What is the recommended urine collection method for medical checkup?
[Statement] Adding to the methods described in CQ2, 1) utilizing early morning first-void and mid-stream urine and 2) refraining from ingestion of foods rich in ascorbic acid (vitamin C) are recommended. (Recommendation Grade B) [Comment] The fundamentals of urine collection do not change for medical checkups. However, in medical checkups for schoolchildren, collection of early morning first-void urine is indicated to avoid hematuria caused by physical
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exercise. Since the urine test strip for blood uses the peroxidase-like action of hemoglobin, if a substance with a reduction action exists, it will yield a false negative result. Therefore ingestion of foods rich in ascorbic acid (vitamin C), which is the most frequent reducing substance appearing in urine, should be avoided the night preceding a checkup.
non-glomerular hematuria cannot be ruled out even when glomerular hematuria is morphologically suspected.
CQ5 Can you distinguish glomerular hematuria from non-glomerular hematuria by morphological analysis of urinary erythrocytes?
[Statement]
CQ6 What are the differences between dysmorphic
type RBC2 and isomorphic type RBC (see Footnote 2) in the information about urinary erythrocyte morphology acquired by an autoanalyzer?
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[Statement] •
•
•
There are various shapes and sizes of urinary erythrocytes in hematuria. Information pertaining to urinary erythrocyte morphology is therefore useful in deciding the origin of hematuria. Even if glomerular hematuria is morphologically suspected, urinary tract disease other than glomerular disease cannot be ruled out. Moreover, not all types of hematuria can be properly classified. As results of the morphological discrimination method vary among examiners, it is recommended that screening follow the Standard Guideline for Urinary Sediment Examination [Japanese Committee for Clinical Laboratory Standard (JCCLS), Document GP1-P4, Proposed Guideline], which is the standard examination method in Japan.
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[Comment] In non-glomerular hematuria such as hematuria originated from the lower urinary tract, urinary erythrocytes take the form of atrophy or disc and their morphologies are nearly identical although varying somewhat in size. Furthermore, they are most likely to be rich in hemoglobin. Such erythrocytes are called isomorphic RBCs (glomerular type RBCs1). In contrast, erythrocytes in glomerular hematuria often present with various forms of casts, including erythrocyte casts and proteinuria. These erythrocytes most often appear in various forms, such as a doughnut shape with humps or a target shape, in the same specimen, and are called dysmorphic RBCs (non-glomerular type RBSs) (see Footnote 1). Erythrocyte morphology is generally observed and evaluated at the time of urinary sediment examination using a light microscope in Japan, whereas it is often done using a phase-contrast microscope in other countries. Facilities increasingly use a urinary formed-element analyzer using flow cytometry. None of these methods are capable of classifying all types of hematuria. Therefore, 1
Terms which are recommended by JCCLS.
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In Japan, urinary components that are observed by an autoanalyzer are distinguished as information pertaining to urinary formed elements from the results of urinary sediment examination. A urinary formed-element analyzer using cytometry can discriminate among blood cells, epithelial cells, casts and other formed elements by processing scattered light from particles as well as light signals corresponding to fluorescence intensity. Urinary erythrocytes can be distinguished based on the bias of the particle size distribution curve of discriminated erythrocytes. Taking advantage of the feature that erythrocytes from the glomeruli are generally smaller than those from other sites, it is possible to classify erythrocytes into dysmorphic and isomorphic type RBC depending on shifts in particle size toward the smaller and larger sides, respectively. Making the above classification may not always be possible, as hematuria specimens may contain a small number of erythrocytes, urine properties such as high acid content may be present, or urine may be very hypotonic or the specimen in a poor state of preservation following collection. Additionally, there may be a mixed dysmorphic/isomorphic RBC type.
[Comment] The measurement principle of the urinary formed-element analyzer using cytometry is that particle elements are displayed on a scattergram for analysis by measuring their scattering light and fluorescence provoked by laser light after they are stained with fluorochrome for exact characterization of their sizes, shapes and nuclei. This analytical method can characteristically depict a clear distribution of broadly-divided particle elements (a particle size distribution pattern), although it has limited ability for minute
2
The terms ‘‘isomorphic type RBC’’ and ‘‘dysmorphic type RBC’’ are used instead of ‘‘isomorphic RBC’’ and ‘‘dysmorphic RBC’’ in the case of autoanalyzer-acquired information about urinary erythrocyte morphology for convenience and to avoid confusion. This is because the latter terms represent erythrocyte morphology in the case of urinary sediment analysis.
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classification of elements other than erythrocytes and leukocytes. Morphological observation of urinary erythrocytes is usually made with urinary sediment examination in Japan. However, there is a major flaw in this examination, which employs microscopic observation of urinary sediment acquired by urine centrifugation, due to cellular element destruction caused by centrifugation, supernatant residual erythrocytes and apparent low measurement values in the hypotonic urine. In contrast, the cytometry-based urinary formed-element analyzer, which analyzes non-centrifuged urine, is superior in quantitative performance. Moreover, it presumably can distinguish dysmorphic RBCs in a glomerular hematuria specimen, which often has variouslyformed erythrocytes (humped doughnut- and target-shaped, for example) because these dysmorphic RBCs often fall on the smaller size side of the particle size distribution due to their tiny volume resulting from hemoglobin loss. Nevertheless, this analyzer does not always clearly distinguish urine specimens due to too few urinary erythrocytes, properties such as high acidity or hypotonicity, or their composite components.
CQ8 Are further examinations recommended for ‘‘chance hematuria,’’ which is asymptomatic hematuria detected incidentally, such as during a health checkup? What characterizes those patients requiring further examination?
[Statement] 1. 2.
3.
4.
5.
II. Epidemiology of hematuria CQ7 Does gender, race, age, or urine collection method
affect the positive rate of hematuria during health checkups? [Statement] • • • •
Females show a higher positive rate of hematuria than males. The positive rate of hematuria increases with age. The effect of race on the positive rate of hematuria is unknown. Urine collection methods do not affect the positive rate of hematuria.
[Comment] Females show a higher positive rate of hematuria in all generations. The positive rate of hematuria increases with age. The positive rate of hematuria in the general population is 1.7–21.1 % in Europe and the USA [1, 2], 3.9 % [4] to 16.0 % in Asia, and, in Africa, 0.55 % for pediatrics and 17.7 % for adults. A long-term observational study of asymptomatic hematuria showed that hematuria disappeared in approximately 45 % of subjects, 40 % of hematuric patients had persistent hematuria, and 10.6 % manifested proteinuria during the observation period [5].
6.
7.
It is unclear whether chance hematuria is directly associated with a poor prognosis of life expectancy. Almost 10 % of patients with hematuria alone have been known to develop proteinuria later in the clinical course. As proteinuria is a significant risk factor for the development of end stage kidney disease, it is recommended that such patients be referred to a nephrologist. (Recommendation Grade B) In long-term prognosis, patients with hematuria are at higher risk for progression to end stage kidney disease compared to those without hematuria. Urological investigations are not recommended when reexamination is negative or when no red blood cells are detected in the urine. (Recommendation Grade C2) Urological investigations for urinary tract malignancies are recommended when reexamination is positive or when red blood cells are detected. (Recommendation Grade B, refer to CQ9) Urinary tract malignancies are detected by diagnostic work-up in a small percent of patients with chance hematuria. A follow-up examination is recommended annually in cases with persistent hematuria, even without any abnormality in the work-up and after ruling out urinary tract disease. (Recommendation Grade B)
[Comment] It is still unclear whether chance hematuria, which is asymptomatic hematuria alone, detected incidentally (during a health checkup), is directly associated with a poor prognosis for life expectancy. Prognosis for survival and kidney function in young Japanese patients (including schoolchildren) with microscopic hematuria alone is sufficiently good—at least for around 10 years [1–4]. However, hematuria is an independent risk factor in the development of CKD by glomerular diseases [5, 6]. The short-term prognosis of asymptomatic hematuria alone is generally good. Hematuria spontaneously disappeared in 20–30 % of such patients within several years [7, 8]. As urinary tract malignancies are detected by diagnostic work-up [9, 10] in a small percent of patients with chance hematuria, clinicians should remain alert to this possibility. In cases with chance hematuria, urological investigations for urinary tract malignancies are recommended when the
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reexamination is positive or when red blood cells are detected [8]. In long-term prognosis, almost 10 % of patients with hematuria alone have been known to develop proteinuria later in the clinical course. Moreover, as proteinuria is a significant risk factor in the development of end stage kidney disease, it is recommended that such patients be referred to a nephrologist [11–13].
III. Diagnosis of microscopic hematuria CQ9 Do you recommend screening for urinary tract
malignancies in all subjects with microscopic hematuria? [Statement] Screening for urinary tract malignancies is recommended for patients with microscopic hematuria. (Recommendation Grade B) Such patients having one of the risk factors of urinary tract malignancies should receive screening. (Recommendation Grade B) [Comment] Urinary tract malignancies represent 10 % of all malignancies in male and 3 % in female. Urinary tract malignancy onset increases after age 45 in both genders, with an abrupt increase observed after age 60. Males in their 40 s or above, smokers, those exposed to chemical substances, patients with gross hematuria, individuals with a prior history of urological diseases, urgency, patients with a history of urinary tract infection, individuals with frequent usage of NSAIDs (especially phenacetin), pelvic organ radiation recipients, and those with a prior history of cyclophosphamide usage, are known to be at risk for urinary malignancies [1]. Microscopic hematuric patients with one of those risk factors should receive screening for urinary tract malignancies, including cystoscopy examination. Microscopic hematuric patients without any risk factors, on the other hand, should receive non-invasive screening, such as ultrasound sonography or urinary cytology. CQ10 Is regular screening for uroepithelial malignancies recommended for patients with asymptomatic, microscopic hematuria who once tested negatively?
[Statement] Regular screening for uroepithelial malignancies is not recommended for patients with asymptomatic, non-
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glomerular-type, microscopic hematuria who once tested negatively, since the incidence of uroepithelial malignancies is very low. (Recommendation Grade C2) Rescreening for uroepithelial malignancies is recommended even for such patients when they experience symptoms such as macroscopic hematuria or difficulty in urination. (Recommendation Grade C1) [Comment] Regular screening for uroepithelial malignancies was previously recommended for patients with asymptomatic, microscopic hematuria who once tested negatively because 1–3 % of such patients developed uroepithelial malignancies within approximately 3 years. However, recent prospective cohort studies reported none to few such patients developing uroepithelial malignancies, possibly due to improvement in screening accuracy [1–4]. Therefore, in recent clinical guidelines of other societies [5, 6] and in ours, regular screening for such patients is not recommended. CQ11 Is kidney biopsy recommended to improve the clinical outcome of patients with microscopic hematuria?
[Statement] Kidney biopsy is recommended for patients with microscopic hematuria in combination with proteinuria as they are at a high risk for end stage kidney failure and the pathological finding-guided care is expected to improve their clinical outcome. (Recommendation Grade C1) Kidney biopsy is not recommended for patients with asymptomatic, microscopic hematuria in the absence of proteinuria as their risk for end stage kidney failure is low. (Recommendation Grade C2) However, a regular urinalysis is recommended for such patients when their hematuria is glomerular-type. (Recommendation Grade C1) [Comment] Proteinuria is proved to be an independent, strong risk factor for end stage kidney failure, and the risk is higher in coexistence with hematuria [1]. Therefore, kidney biopsy is recommended for patients with microscopic hematuria in combination with proteinuria as they are at a high risk for end stage kidney failure and the pathological finding-guided care is expected to improve their clinical outcome. Recently, asymptomatic, isolated microscopic hematuria was also proven to be an independent but weak risk factor for end stage kidney failure by a large cohort study in Israel spanning more than 20 years [2]. In this study, however, urinalysis was not performed during the observation period. In a cohort study on patients with asymptomatic,
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microscopic hematuria in Japan, 50 % tested negative for hematuria while 10 % tested positive for proteinuria during the observation period [3]. Another study from Japan also revealed that a considerable number of patients in a cohort study with asymptomatic, microscopic hematuria developed chronic glomerulonephritis [4]. These results suggest that some patients with asymptomatic, microscopic hematuria who test positive for proteinuria develop end-stage kidney failure due to advanced, chronic glomerulonephritis. Therefore, kidney biopsy is not recommended for patients with asymptomatic, microscopic hematuria in the absence of proteinuria, while a regular urinalysis is recommended for such patients, especially those with glomerular-type hematuria, since they are at risk for chronic glomerulonephritis.
IV. Diagnosis of macroscopic hematuria CQ12 What kind of diseases lead to macroscopic hematuria in adults?
[Statement] Macroscopic hematuria is caused by urologic diseases, except in patients under the age of 25. [Comments] As symptomatic macroscopic hematuria can presumably be diagnosed based on symptoms, except for the symptom of hematuria itself, this section focuses on asymptomatic macroscopic hematuria in adults. Based on the onset age for familial bladder cancer, excluding cases of children and young people under the age of 25, the key cause of macroscopic hematuria is urologic diseases [1–3]. In general, as the degree of hematuria increased so did the yield of life-threatening lesions [4, 5]. Adult patients with macroscopic hematuria are recommended to undergo urologic examinations. Urologic diseases: urothelial cancer (bladder cancer, renal pelvic and/or ureteral cancer), renal cell cancer, benign prostate hypertrophy, renal arterio-venous malformation, glomerular renal diseases, urolithiasis, hemorrhagic cystitis, and idiopathic renal bleeding. CQ13 What kind of diagnostic imaging is recommended for macroscopic hematuria?
[Statement] •
Abdominal ultrasonography is a minimally invasive test used in the diagnosis of most urothelial cancers,
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and is recommended as screening for macroscopic hematuria. (Recommendation Grade B) In the diagnosis of urothelial cancer, computed tomographic urography (CT Urography) has relatively high sensitivity and specificity and is a primary imaging modality. CT urography is recommended as the main form of diagnostic imaging. (Recommendation Grade B) Magnetic resonance imaging (MRI) is more useful than CT for bladder and prostatic diseases. Magnetic resonance urography (MRU) does not use iodine-based contrast media and is mainly recommended to diagnose obstructive urinary tract lesions. (Recommendation Grade B) Intravenous pyelography has been recognized as a useful tool in the diagnosis of urothelial cancer; however, recent advances in diagnostic imaging with CT urography, which provides a greater amount of information, have resulted in an increase in CT urography usage and less frequent use of intravenous pyelography. Intravenous pyelography is not recommended as an examination for macroscopic hematuria. (Recommendation Grade C2)
[Comments] Intravenous pyelography was previously recognized for its usefulness in macroscopic hematuria screening; however, with advances in imaging modalities in recent years, CT urography has largely replaced it, as the latter yields vast amounts of information [1–3]. In urothelial cancer diagnosis, CT Urography has relatively high sensitivity and specificity, and is a primary imaging modality for examination of macroscopic hematuria [4]. However, it cannot replace cystoscopy in the examination of the urinary bladder lesions [5]. Diagnoses for macroscopic hematuria can be performed with multimodal examinations including initial abdominal sonography of the urinary bladder, CT urography, and cystoscopy [6]. CQ14 Is urine cytology recommended for macroscopic hematuria?
[Statement] Urine cytology is recommended for diagnosis of urothelial cancer. (Recommendation Grade B) [Comments] Specificity of urine cytology is high [1]. The detection rate of urothelial cancer is increased by repeated urine cytology [2, 3]. Urine cytology is a minimally invasive examination supporting histologic diagnosis of flat lesions
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such as carcinoma in situ in the urothelium; it also serves as a urothelial cancer follow-up exam. Urine cytology is useful in screening for urothelial cancer. Whenever the possibility of urothelial cancer exists, multiple urine cytology screening is performed. Urine cytology has a specificity rate of almost 100 %; however, the sensitivity is low and negative urine cytology cannot rule out cancer. As sensitivity for low atypical urothelial cancer is low, care must be taken when interpreting the result. CQ15 Is the same screening recommended for patients with macroscopic hematuria during anticoagulant treatment as for patients not undergoing the treatment?
[Statement] Normal screening for macroscopic hematuria is recommended for patients undergoing anticoagulant treatment. (Recommendation Grade B) [Comments] It has been reported that the frequency of hematuria in patients treated with anticoagulants is the same as that in the control group. Additionally, cancer was diagnosed in approximately one quarter of patients with macroscopic hematuria treated with anticoagulant medication. Diseases requiring treatment, such as urolithiasis and benign prostatic hyperplasia, are often found in patients with macroscopic hematuria. It is necessary to confirm any past anticoagulant treatment when taking a patient’s medical history; however, standard macroscopic hematuria screening is also necessary for patients treated with anticoagulant drugs such as warfarin or aspirin [1, 2]. CQ16 Is surveillance for macroscopic hematuria
without findings recommended? [Statement] Tight surveillance for recurrent macroscopic hematuria is recommended. (Recommendation Grade B) [Comments] Subsequent disease remains undetected in approximately 80 % of patients diagnosed as being disease-free. As urological cancer was subsequently diagnosed in more than 10 % of recurrent macroscopic hematuria [1–3], tight surveillance for recurrent macroscopic hematuria is required as needed [4]. Recently, advances in ureterorenoscopes and ureterorenoscopy have facilitated evaluation and treatment of chronic macroscopic hematuria. Ureterorenoscopy is recommended during surveillance [5–7].
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V. Diagnosis and management in children with microscopic hematuria detected by urinary screening at school CQ17 Reasons for discovery, morbidity, and primary diseases of hematuria in children
[Statement] Most hematuria in children is detected by screening at schools, by public health agencies at age 3, and incidentally during other screenings. Children with gross hematuria are usually taken to the hospital for medical by their guardians. Major primary diseases leading to non-glomerular hematuria in children are hypercalciuria and the nutcracker phenomenon, and those of glomerular hematuria are thinbasement membrane disease and IgA nephropathy. Typically, however, no primary disease is discovered. Malignancy is a rare cause of hematuria in children. CQ18 Follow-up of children with hematuria and timing of referral to a pediatric nephrologist
[Statement] If children with hematuria have no complications from proteinuria, renal impairment, hypertension, urinary stones, or malignancy, quarterly follow-up is recommended in the first year following discovery of hematuria. Thereafter, follow-up urinalysis once or twice a year and an annual blood examination are recommended until the resolution of hematuria. (Recommendation Grade C1) [Comment] Referral to a pediatric nephrologist should be considered if the patient suffers from: (1) glomerulonephritis and interstitial nephritis (excepting acute poststreptococcal glomerulonephritis), (2) malignancy, (3) kidney or urinary tract trauma, (4) urinary stones, (5) congenital cystic kidney diseases, renal hypoplasia or dysplasia, severe hydronephrosis or hydroureter, (6) impaired renal function, or (7) hypertension. CQ19 Examinations for children with hematuria
[Statement] A medical interview for diagnosis, measurement of weight, height and blood pressure, urinalysis, and blood examinations based on a detailed examination in school urinary screening system should be performed (Recommendation Grade B). Ultrasound, which is a non-invasive examination, is strongly recommended.
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Renal biopsy for diagnosis is necessary if chronic glomerulonephritis is suspected (Recommendation Grade B). [Comment] Indications of renal biopsy are as follows: (1) dipstick proteinuria, with the morning urinary protein/creatinine ratio and its duration being: (a) 1 ? or 0.2–0.4 for 6 to 12 months, (b) 2 ? or 0.5–0.9 for 3 to 6 months, (c) 3 ? or 1.0–1.5 for 1 to 3 months or (d) 4 ? or more than 2 at any time; (2) gross hematuria; (3) hypoalbuminemia (\ 3.0 g/dL); (4) hypocomplementemia (except for acute poststreptococcal glomerulonephritis); (5) renal impairment; and (6) hypertension.
2. Copley JB. Isolated asymptomatic hematuria in the adult. Am J Med Sci. 1986;291:101–11. 3. Grossfeld GD, Litwin MS, Wolf JS, Hricak H, Shuler CL, Agerter DC, et al. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy-part I: definition, detection, prevalence, and etiology. Urology. 2001;57:599–603. 4. Vivante A, Afek A, Renkel-Nir Y, Tzur D, Farfel A, Golan E, et al. Persistent asymptomatic isolated microscopic hematuria in Israeli adolescents and young adults and risk for end-stage renal disease. JAMA. 2011;306:729–36. 5. Editorial board for JCCLS Standard Guideline for Urinary Sediment Examination GP1–P4. Examination of Urinary Sediment 2010. Japanese Association of Medical Technologists; 2011. p. 1–10.
CQ2 CQ20 Malignancy as a rare cause of hematuria
in children [Statement] Malignancy is a rare cause of hematuria in children. However, kidney and urinary tract ultrasound is strongly recommended to exclude the possibility. Enhanced computed tomography is not the first choice (Recommendation Grade B). Routine follow-up with ultrasound is recommended in patients at high risk for Wilms’ tumor, including those with Denys–Drash syndrome, Beckwith–Wiedemann syndrome, WAGR syndrome, aniridia, hemihypertrophy, Sotos syndrome, von Recklinghausen syndrome, and horseshoe kidney (Recommendation Grade B). CQ21 Nutrition and exercise in children with hematuria
[Statement] If children with microscopic hematuria have no complications from hypertension, massive edema, or obvious exacerbation of renal function and proteinuria by exercise, no exercise and dietary restrictions are needed (Recommendation Grade C2). [Comment] If patients with asymptomatic hematuria and proteinuria do not have the problems described above, all activities except for intense exercise are allowed. Patients with gross hematuria should be referred to pediatric nephrologists.
References I. Hematuria: definition and screening methods
CQ1 1. Sutton JM. Evaluation of hematuria in adults. JAMA. 1990;263:2475–80.
1. Committee on Urinary Regent Paper Testing. JCCLS Document GP3-P1 Guideline ‘‘Urinary Reagent Method’’ Japanese Committee for Clinical Laboratory Standards. Jpn J Clin Lab Stand. 2001;16:33–55. 2. Editorial board for JCCLS Standard Guideline for Urinary Sediment Examination GP1-P4. Examination of Urinary Sediment 2010. Japanese Association of Medical Technologists; 2011. p. 1–10. II. Epidemiology of hematuria
CQ7 1. Ritchie CD, Bevan EA, Collier SJ. Importance of occult haematuria found at screening. Br Med J Clin Res Ed. 1986;292:681–3. 2. Thompson IM. The evaluation of microscopic hematuria: a population-based study. J Urol. 1987;138:1189–90. 3. Messing EM, Young TB, Hunt VB, et al. Home screening for hematuria: results of a multiclinic study. J Urol. 1992;148:289–92. 4. Chen W, Liu Q, Wang H, et al. Prevalence and risk factors of chronic kidney disease: a population study in the Tibetan population. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc Eur Ren Assoc. 2011;26:1592–9. 5. Yamagata K, Yamagata Y, Kobayashi M, Koyama A. A longterm follow-up study of asymptomatic hematuria and/or proteinuria in adults. Clin Nephrol. 1996;45:281–8.
CQ8 1. Yazaki T, Nemoto S, Ishikawa H, Kanoh S, Koiso K, Terasaki T, Tojo S. Long-term follow-up of patients with asymptomatic hematuria. Nihon Jinzo Gakkaishi. 1985;27:1247–51. 2. Murakami S, Igarashi T, Hara S, Shimazaki J. Strategies for asymptomatic microscopic hematuria: a prospective study of 1,034 patients. J Urol. 1991;144:99–101. 3. Hisano S, Kwano M, Hatae K, Kaku Y, Yamane I, Ueda K, Uraqoh K, Honda S. Asymptomatic isolated microhaematuria: natural history of 136 children. Pediatr Nephrol. 1991;5:578–81. 4. Takebayashi S, Yanase K. Asymptomatic urinary abnormalities found via the Japanese school screening program: a clinical, morphological and prognostic analysis. Nephron. 1992;61:82–8. 5. Vivante A, Afek A, Frenkel-Nir Y, Tzur D, Farfel A, Golan E, Chaiter Y, Shohat T, Skorecki K, Calderon-Margalit R. Persistent asymptomatic isolated microscopic hematuria in Israeli
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Clin Exp Nephrol adolescents and young adults and risk for end-stage renal disease. JAMA. 2011;306:729–36. 6. Iseki K, Ikemiya Y, Iseki C, Takishita S. Proteinuria and the risk of developing end-stage renal disease. Kidney Int. 2003;63:1468–74. 7. Kovacevic Z, Javanovic D, Rabrenovic V, Dimitrijevic J, Djukanovic J. Asymptomatic microscopic haematuria in young males. Int J Clin Pract. 2008;62:406–12. 8. Mishriki SF, Nabi G, Cohen NP. Diagnosis of urologic malignancies in patients with asymptomatic dipstick hematuria: prospective study with 13 years’ follow-up. Urology. 2008;71:13–6. 9. Khan MA, Shaw G, Paris AM. Is microscopic haematuria a urological emergency? BJU Int. 2002;90:355–7. 10. Paul AB, Collie DA, Wild SR, Chisholm GD. An integrated haematuria clinic. Br J Clin Pract. 1993;47:128–30. 11. Assadi FK. Value of urinary excretion of microalbumin in predicting glomerular lesions in children with isolated microscopic hematuria. Pediatr Nephrol. 2005;20:1131–5. 12. Chow KM, Kwan BC, Li PK, Szeto CC. Asymptomatic isolated microscopic haematuria: long-term follow-up. QJM. 2004;97: 739–45. 13. Yamagata K, Yamagata Y, Kobayashi M, Koyama A. A longterm follow-up study of asymptomatic hematuria and/or proteinuria in adults. Clin Nephrol. 1996;45:281–8. III. Diagnosis of microscopic hematuria
CQ9 1. Grossfeld GD, Litwin MS, Wolf JS Jr, Hricak H, Shuler CL, Agerter DC, et al. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy—part II: patient evaluation, cytology, voided markers, imaging, cystoscopy, nephrology evaluation, and follow-up. Urology. 2001;57:604–10.
CQ10 1. Howard RS, Golin AL. Long-term follow-up of asymptomatic microhematuria. J Urol. 1991;145:335–6. 2. Khadra MH, Pickard RS, Charlton M, Powell PH, Neal DE. A prospective analysis of 1,930 patients with hematuria to evaluate current diagnostic practice. J Urol. 2000;163:524–7. 3. Chow KM, Kwan BC, Li PK, Szeto CC. Asymptomatic isolated microscopic hematuria: long-term follow-up. Q J Med. 2004;97:739–45. 4. Mishiriki SF, Nabi G, Cohen NP. Diagnosis of urologic malignancies in patients with asymptomatic dipstick hematuria: prospective study with 13 years’ follow-up. Urology. 2008;71:13–6. 5. Cohen RA, Brown RS. Microscopic hematuria. N Engl J Med. 2003;348:2330–8. 6. Kelly JD, Fawcett DP, Goldberg LC. Assessment and management of non-visible haematuria in primary care. BMJ. 2009;338:a3021.
CQ11 1. Iseki K. The Okinawa screening program. J Am Soc Nephrol. 2003;14:S127–30. 2. Vivante A, Afek A, Frenkel-Nir Y, Tzur D, Farfel A, Golan E, Chaiter Y, Shohat T, Skorecki K, Calderon-Margalit R. Persistent asymptomatic isolated microscopic hematuria in Israeli
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adolescents and young adults and risk for end-stage renal disease. JAMA. 2011;306:729–36. 3. Yamagata K, Takahashi H, Tomida C, Yamagata Y, Koyama A. Prognosis of asymptomatic hematuria and/or proteinuria in men. High prevalence of IgA nephropathy among proteinuric patients found in mass screening. Nephron. 2000;91:34–42. 4. Yamagata K, Ishida K, Sairenchi T, Takahashi H, Ohba S, Shiigai T, Narita M, Koyama A. Risk factors for chronic kidney disease in a community-based population: a 10-year follow-up study. Kidney Int. 2007;71:159–66. IV. Diagnosis of macroscopic hematuria
CQ12 1. Brandt A, Bermejo JL, Sundquist J, Hemminki K. Age of onset in familial cancer. Ann Oncol. 2008;19:2084–8. 2. Bruyninckx R, Buntinx F, Aertgeerts B, Van Casteren V. The diagnostic value of macroscopic haematuria for the diagnosis of urological cancer in general practice. Br J Gen Pract. 2003; 53:31–5. 3. Buntinx F, Wauters H. The diagnostic value of macroscopic haematuria in diagnosing urological cancers: a meta-analysis. Fam Pract. 1997;14:63–8. 4. Thiruchelvam N, Mostafid H. Do patients with frank haematuria referred under the two-week rule have a higher incidence of bladder cancer? Ann R Coll Surg Engl. 2005;87:345–7. 5. 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 cost-effectiveness analysis. J Urol. 1989;141:350–5.
CQ13 1. Edwards TJ, Dickinson AJ, Natale S, Gosling J, McGrath JS. A prospective analysis of the diagnostic yield resulting from the attendance of 4020 patients at a protocol-driven haematuria clinic. BJU Int. 2006;97:301–5. 2. Knox MK, Cowan NC, Rivers-Bowerman MD, Turney BW. Evaluation of multidetector computed tomography urography and ultrasonography for diagnosing bladder cancer. Clin Radiol. 2008;63:1317–25. 3. Chlapoutakis K, Theocharopoulos N, Yarmenitis S, Damilakis J. Performance of computed tomographic urography in diagnosis of upper urinary tract urothelial carcinoma, in patients presenting with hematuria: systematic review and meta-analysis. Eur J Radiol. 2010;73:334–8. 4. Mueller-Lisse UG, Mueller-Lisse UL, Hinterberger J, Schneede P, Meindl T, Reiser MF. Multidetector-row computed tomography (MDCT) in patients with a history of previous urothelial cancer or painless macroscopic haematuria. Eur Radiol. 2007;17:2794–803. 5. Sudakoff GS, Dunn DP, Guralnick ML, Hellman RS, Eastwood D, See WA. Multidetector computerized tomography urography as the primary imaging modality for detecting urinary tract neoplasms in patients with asymptomatic hematuria. J Urol. 2008;179:862–7. 6. Blick CG, Nazir SA, Mallett S, Turney BW, Onwu NN, Roberts IS, et al. Evaluation of diagnostic strategies for bladder cancer using computed tomography (CT) urography, flexible cystoscopy and voided urine cytology: results for 778 patients from a hospital haematuria clinic. BJU Int. 2011;110:84–94.
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CQ14 1. Nabi G, Greene DR, O’Donnell M. How important is urinary cytology in the diagnosis of urological malignancies? Eur Urol. 2003;43:632–6. 2. Turco P, Houssami N, Bulgaresi P, Troni GM, Galanti L, Cariaggi MP, et al. Is conventional urinary cytology still reliable for diagnosis of primary bladder carcinoma? Accuracy based on data linkage of a consecutive clinical series and cancer registry. Acta Cytol. 2011;55:193–6. 3. Koss LG, Deitch D, Ramanathan R, Sherman AB. Diagnostic value of cytology of voided urine. Acta Cytol. 1985;29:810–6.
3.
4.
5.
6.
CQ15 1. Avidor Y, Nadu A, Matzkin H. Clinical significance of gross hematuria and its evaluation in patients receiving anticoagulant and aspirin treatment. Urology. 2000;55:22–4. 2. Van Savage JG, Fried FA. Anticoagulant associated hematuria: a prospective study. J Urol. 1995;153:1594–6.
7.
after investigation for haematuria, based on a 4-year follow-up. BJU Int. 2011;107:247–52. Mishriki SF, Grimsley SJ, Nabi G. Incidence of recurrent frank hematuria and urological cancers: prospective 6.9 years of followup. J Urol. 2009;182:1294–8. Mishriki SF, Vint R, Somani BK. Half of visible and half of recurrent visible hematuria cases have underlying pathology: prospective large cohort study with long-term followup. J Urol. 2012;187:1561–5. Mugiya S, Ozono S, Nagata M, Takayama T, Furuse H, Ushiyama T. Ureteroscopic evaluation and laser treatment of chronic unilateral hematuria. J Urol. 2007;178:517–20. Brito AH, Mazzucchi E, Vicentini FC, Danilovic A, Chedid Neto EA, Srougi M. Management of chronic unilateral hematuria by ureterorenoscopy. J Endourol. 2009;23(8):1273–6. Araki M, Uehara S, Sasaki K, Monden K, Tsugawa M, Watanabe T, Monga M, Nasu Y, Kumon H. Ureteroscopic management of chronic unilateral hematuria: a single-center experience over 22 years. PLoS ONE. 2012;7(6):e36729.
CQ16 1. Sells H, Cox R. Undiagnosed macroscopic haematuria revisited: a follow-up of 146 patients. BJU Int. 2001;88:6–8. 2. Edwards TJ, Dickinson AJ, Gosling J, McInerney PD, Natale S, McGrath JS. Patient-specific risk of undetected malignant disease
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GUIDELINE
Japanese guidelines of the management of hematuria 2013 Shigeo Horie • Shuichi Ito • Hirokazu Okada • Haruhito Kikuchi • Ichiei Narita • Tsutomu Nishiyama • Tomonori Hasegawa • Hiroshi Mikami Kunihiro Yamagata • Tomoji Yuno • Satoru Muto
•
Japanese Society of Nephrology, The Japanese Urological Association, The Japanese Society for Pediatric Nephrology, Japanese Society of Laboratory Medicine and Japanese Association of Medical Technologists 2014
Preface 1. Introduction Urinalysis is a component of annual health examinations upon which Japan prides itself, as our citizens enjoy the great benefit of access to this screening throughout most of their lives. Nevertheless, although hematuria is manifested with great frequency, screenings and subsequent clinical diagnoses have no adequate standardization. Moreover, In 2013, Japanese Society of Nephrology, Japanese Urological Association, Japanese Society for Pediatric Nephrology, Japanese Society of Laboratory Medicine and Japanese Association of Medical Technologists jointly published Japanese guidelines of the management of hematuria in Nihon Jinzo Gakkai Shi. 2013;55(5):861–946 (in Japanese). This is the English version. Chairman: S. Horie. S. Horie (&) Chairperson of the JSN Committee for Diagnostic Guidelines for Hematuria 2013, Japanese Society of Nephrology, The Japanese Urological Association, Department of Urology, Juntendo University Graduate School of Medicine, Tokyo, Japan e-mail: [email protected] S. Ito The Japanese Society for Pediatric Nephrology, Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan H. Okada Japanese Society of Nephrology, Department of Nephrology, Saitama Medical School, Saitama, Japan H. Kikuchi Japanese Society of Laboratory Medicine, Department of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan
hematuria can be symptomatic of renal and urological diseases, and advancements in the diagnostic process are profoundly linked to effective usage of medical resources. We established a panel to create new Guidelines in the form of clinical questions (CQ), drawing on five professional societies and the Japan Medical Association for panel members. This represents the first global set of CQbased hematuria guidelines, and the content contained by the 21 CQs are highly relevant to every medical practitioner relying on urinalysis. 2. Purpose Diagnostic Guidelines for Hematuria were issued in Japan in 2006, with clinical indices for hematuria patient screening, diagnosis, and treatment. However, 6 years have elapsed since their publication, and content divergent from today’s I. Narita Japanese Society of Nephrology, Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan T. Nishiyama The Japanese Urological Association, Department of Urology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan T. Hasegawa Department of Social Medicine, Toho University School of Medicine, Tokyo, Japan H. Mikami Japan Medical Association, General Hospital Higashikouri, Osaka, Japan
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clinical practice has become strikingly evident. With that in mind, we have revised this Guideline, keeping appropriate management of hematuria patients as our primary goal. As Japan faces an unprecedented aging society, we can expect to see a rise in the number of patients citing hematuria as their primary complaint. This new Guideline is largely significant in addressing the issues of efficient health economics and the diagnosis and treatment best suited to protecting the health of hematuria patients. By fusing the expertise of specialists from nephrology, urology, pediatrics, and laboratory science, we were able to forge guidelines transcending the borders of discrete medical departments.
to the interval from September 1990 through 2011. Our Guidelines cite only peer-reviewed articles, with the exception of CQ3, for which PubMed did not yield an adequate response. In this case, we utilized JAMAS. When necessary, we cite older literature. Some journal articles which were not appropriate for citation, or which lacked peer review, were used as background reference.
3. Background of the Guidelines development (including panel members and their specialties)
1)
6. Evidence levels and recommendation grades: Criteria for determining evidence level and recommendation grade
2) With the intent of revising the 2006 Diagnostic Guidelines for Hematuria, we solicited panel members from the Japanese Society of Nephrology, the Japanese Urological Association, the Japanese Society for Pediatric Nephrology, the Japanese Society of Laboratory Medicine, the Japanese Society of Medical Technologists, and the Japan Medical Association, as well as diagnostic guideline specialists. The format for this revision involves the clinical questions (CQ) format and a recommendation grading system.
3) 4)
4. A cautionary note on the use of this guideline
5)
This Guideline is established for physicians caring for hematuria patients. This includes the spectrum of doctors from residents to specialists. Hematuria, meanwhile, includes occult blood and microscopic as well as macroscopic hematuria. The hematuria patients for whom these Guidelines are created include children and adults of all ages. Pediatric patients are defined as children who have not yet completed high school.
6)
5. Methods and timeframe used in gathering evidence Literature searches utilized the PubMed and Japan Medical Abstracts Society (JAMAS) databases and were restricted K. Yamagata Japanese Society of Nephrology, Department of Nephrology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan T. Yuno Japanese Association of Medical Technologists, Clinical Laboratory, Kanazawa Red Cross Hospital, Kanazawa, Japan S. Muto Japanese Society of Nephrology, The Japanese Urological Association, Department of Urology, Teikyo University School of Medicine, Tokyo, Japan
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7)
Reference (research) standards are automatically determined from the research design. The research design’s standard determines the metaanalysis/systematic review. If there are numerous research designs, the one with the lowest level would apply (example: if a cohort study has a meta-analysis of level 4, meta-analysis mixing a randomized controlled trial and cohort study would also be designated as level 4). A single-arm intervention study (with no comparison group) would be level 4. The recommendation grade would depend on the above factors. Whenever the evidence level and the recommendation grade diverge, explanation is provided. As there was no approved literature providing answers to CQ3 and CQ21, we determined the recommendation grade through informal discussion and consensus. Evidence levels and recommendation grades are as follows:
[Evidence level] 1. 2. 3. 4.
5. 6.
Systematic review/meta-analysis Randomized controlled trial Non-randomized controlled trial Analytical epidemiological study (cohort study or case–control study)/single-arm intervention study (no comparison group) Descriptive study (case report or case series) Not based on patient data; professional opinion of a specialist or advisory committee
[Recommendation grade] A. B. C1. C2. D.
Has a solid scientific basis and is strongly endorsed Has a scientific basis, and is endorsed Has no scientific basis, but is endorsed Has no scientific basis, and cannot be endorsed Is scientifically demonstrated to be ineffective or harmful, and cannot be endorsed
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7. Public comment A draft of these Guidelines appeared on the websites of relevant professional organizations, and public input was sought prior to their final incorporation. Abbreviations
CQ2 What is the recommended urine collection method for hematuria diagnosis?
[Statement] Intense exercise should be avoided before screening. Use of a clean container is recommended. Specification of urine sampling time, such as mid-stream urine, early morning first-void urine or random sample, is also recommended. (Recommendation grade A)
AMH
asymptomatic microhematuria
ASH
asymptomatic hematuria
AUA
American Urological Association
[Comment]
BMI
body mass index
CT
computed tomography
FCM
flow cytometry
HPF
high power field
IVP
intravenous pyelogram
JCCLS
Japanese Committee for Clinical Laboratory Standards
The Japanese Committee for Clinical Laboratory Standardization (JCCLS) has issued two documents concerning routine urinalysis: Proposed Guideline for the Urinary Reagent Method [1] and Standard Guideline for Urinary Sediment [2]. Generally, a midstream urine sample is used and physical exercise before collection of urine should be avoided as it may cause hematuria or hemoglobinuria.
NMR
nuclear magnetic resonance
PSA
prostate specific antigen
RBC
red blood cell
TBMD
thin basement membrane disease
CQ3 Do urine blood test strips produced by various manufacturers differ in their sensitivity?
[Statement] Although data sheets indicate no differences in sensitivity among various urine test strips, some differences were observed when measuring urine samples.
I. Hematuria: definition and screening methods
[Comment]
CQ1 Do hematuria standards differ by age or gender?
The Japanese Committee for Clinical Laboratory Standards (JCCLS) defined that 1? of a urine blood reagent strip should correspond to 0.06 mg/dL of hemoglobin or about 20 erythrocytes/lL in 2004. However, the upper and/or lower limits of 1? and other ranks (2? , 3? , etc.) have not been standardized. Results of a JCCLS investigation using pooled urine samples spiked with hemoglobin showed considerable differences among test strip manufacturers.
[Statement] Red cell count distribution in urine varies with age and gender. However, since the significance of establishing hematuria standards for each group is unclear, more than 20 erythrocytes/lL or 5 erythrocytes/high power field (HPF) is considered to be the definition of hematuria. [Comment] Neither review articles discussing red cell count in the urine from healthy persons [1, 2] nor the American Urological Association (AUA)’s [3] Best Practice Policy concerning asymptomatic microscopic hematuria distinguish between age or gender in their definitions of hematuria. Moreover, Copley described that the normal number of red cells for children and adults is the same [2]. The standard of hematuria is globally defined as more than 5 erythrocytes/HPF in many reports [2, 4]. Japan’s own definitive text—the Standard Guideline for Urinary Sediment examination JCCLS GP1-P4—also states that below 4 erythrocytes/HPF are observed in the urine from healthy men and women [5].
CQ4 What is the recommended urine collection method for medical checkup?
[Statement] Adding to the methods described in CQ2, 1) utilizing early morning first-void and mid-stream urine and 2) refraining from ingestion of foods rich in ascorbic acid (vitamin C) are recommended. (Recommendation Grade B) [Comment] The fundamentals of urine collection do not change for medical checkups. However, in medical checkups for schoolchildren, collection of early morning first-void urine is indicated to avoid hematuria caused by physical
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exercise. Since the urine test strip for blood uses the peroxidase-like action of hemoglobin, if a substance with a reduction action exists, it will yield a false negative result. Therefore ingestion of foods rich in ascorbic acid (vitamin C), which is the most frequent reducing substance appearing in urine, should be avoided the night preceding a checkup.
non-glomerular hematuria cannot be ruled out even when glomerular hematuria is morphologically suspected.
CQ5 Can you distinguish glomerular hematuria from non-glomerular hematuria by morphological analysis of urinary erythrocytes?
[Statement]
CQ6 What are the differences between dysmorphic
type RBC2 and isomorphic type RBC (see Footnote 2) in the information about urinary erythrocyte morphology acquired by an autoanalyzer?
•
[Statement] •
•
•
There are various shapes and sizes of urinary erythrocytes in hematuria. Information pertaining to urinary erythrocyte morphology is therefore useful in deciding the origin of hematuria. Even if glomerular hematuria is morphologically suspected, urinary tract disease other than glomerular disease cannot be ruled out. Moreover, not all types of hematuria can be properly classified. As results of the morphological discrimination method vary among examiners, it is recommended that screening follow the Standard Guideline for Urinary Sediment Examination [Japanese Committee for Clinical Laboratory Standard (JCCLS), Document GP1-P4, Proposed Guideline], which is the standard examination method in Japan.
•
•
•
[Comment] In non-glomerular hematuria such as hematuria originated from the lower urinary tract, urinary erythrocytes take the form of atrophy or disc and their morphologies are nearly identical although varying somewhat in size. Furthermore, they are most likely to be rich in hemoglobin. Such erythrocytes are called isomorphic RBCs (glomerular type RBCs1). In contrast, erythrocytes in glomerular hematuria often present with various forms of casts, including erythrocyte casts and proteinuria. These erythrocytes most often appear in various forms, such as a doughnut shape with humps or a target shape, in the same specimen, and are called dysmorphic RBCs (non-glomerular type RBSs) (see Footnote 1). Erythrocyte morphology is generally observed and evaluated at the time of urinary sediment examination using a light microscope in Japan, whereas it is often done using a phase-contrast microscope in other countries. Facilities increasingly use a urinary formed-element analyzer using flow cytometry. None of these methods are capable of classifying all types of hematuria. Therefore, 1
Terms which are recommended by JCCLS.
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In Japan, urinary components that are observed by an autoanalyzer are distinguished as information pertaining to urinary formed elements from the results of urinary sediment examination. A urinary formed-element analyzer using cytometry can discriminate among blood cells, epithelial cells, casts and other formed elements by processing scattered light from particles as well as light signals corresponding to fluorescence intensity. Urinary erythrocytes can be distinguished based on the bias of the particle size distribution curve of discriminated erythrocytes. Taking advantage of the feature that erythrocytes from the glomeruli are generally smaller than those from other sites, it is possible to classify erythrocytes into dysmorphic and isomorphic type RBC depending on shifts in particle size toward the smaller and larger sides, respectively. Making the above classification may not always be possible, as hematuria specimens may contain a small number of erythrocytes, urine properties such as high acid content may be present, or urine may be very hypotonic or the specimen in a poor state of preservation following collection. Additionally, there may be a mixed dysmorphic/isomorphic RBC type.
[Comment] The measurement principle of the urinary formed-element analyzer using cytometry is that particle elements are displayed on a scattergram for analysis by measuring their scattering light and fluorescence provoked by laser light after they are stained with fluorochrome for exact characterization of their sizes, shapes and nuclei. This analytical method can characteristically depict a clear distribution of broadly-divided particle elements (a particle size distribution pattern), although it has limited ability for minute
2
The terms ‘‘isomorphic type RBC’’ and ‘‘dysmorphic type RBC’’ are used instead of ‘‘isomorphic RBC’’ and ‘‘dysmorphic RBC’’ in the case of autoanalyzer-acquired information about urinary erythrocyte morphology for convenience and to avoid confusion. This is because the latter terms represent erythrocyte morphology in the case of urinary sediment analysis.
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classification of elements other than erythrocytes and leukocytes. Morphological observation of urinary erythrocytes is usually made with urinary sediment examination in Japan. However, there is a major flaw in this examination, which employs microscopic observation of urinary sediment acquired by urine centrifugation, due to cellular element destruction caused by centrifugation, supernatant residual erythrocytes and apparent low measurement values in the hypotonic urine. In contrast, the cytometry-based urinary formed-element analyzer, which analyzes non-centrifuged urine, is superior in quantitative performance. Moreover, it presumably can distinguish dysmorphic RBCs in a glomerular hematuria specimen, which often has variouslyformed erythrocytes (humped doughnut- and target-shaped, for example) because these dysmorphic RBCs often fall on the smaller size side of the particle size distribution due to their tiny volume resulting from hemoglobin loss. Nevertheless, this analyzer does not always clearly distinguish urine specimens due to too few urinary erythrocytes, properties such as high acidity or hypotonicity, or their composite components.
CQ8 Are further examinations recommended for ‘‘chance hematuria,’’ which is asymptomatic hematuria detected incidentally, such as during a health checkup? What characterizes those patients requiring further examination?
[Statement] 1. 2.
3.
4.
5.
II. Epidemiology of hematuria CQ7 Does gender, race, age, or urine collection method
affect the positive rate of hematuria during health checkups? [Statement] • • • •
Females show a higher positive rate of hematuria than males. The positive rate of hematuria increases with age. The effect of race on the positive rate of hematuria is unknown. Urine collection methods do not affect the positive rate of hematuria.
[Comment] Females show a higher positive rate of hematuria in all generations. The positive rate of hematuria increases with age. The positive rate of hematuria in the general population is 1.7–21.1 % in Europe and the USA [1, 2], 3.9 % [4] to 16.0 % in Asia, and, in Africa, 0.55 % for pediatrics and 17.7 % for adults. A long-term observational study of asymptomatic hematuria showed that hematuria disappeared in approximately 45 % of subjects, 40 % of hematuric patients had persistent hematuria, and 10.6 % manifested proteinuria during the observation period [5].
6.
7.
It is unclear whether chance hematuria is directly associated with a poor prognosis of life expectancy. Almost 10 % of patients with hematuria alone have been known to develop proteinuria later in the clinical course. As proteinuria is a significant risk factor for the development of end stage kidney disease, it is recommended that such patients be referred to a nephrologist. (Recommendation Grade B) In long-term prognosis, patients with hematuria are at higher risk for progression to end stage kidney disease compared to those without hematuria. Urological investigations are not recommended when reexamination is negative or when no red blood cells are detected in the urine. (Recommendation Grade C2) Urological investigations for urinary tract malignancies are recommended when reexamination is positive or when red blood cells are detected. (Recommendation Grade B, refer to CQ9) Urinary tract malignancies are detected by diagnostic work-up in a small percent of patients with chance hematuria. A follow-up examination is recommended annually in cases with persistent hematuria, even without any abnormality in the work-up and after ruling out urinary tract disease. (Recommendation Grade B)
[Comment] It is still unclear whether chance hematuria, which is asymptomatic hematuria alone, detected incidentally (during a health checkup), is directly associated with a poor prognosis for life expectancy. Prognosis for survival and kidney function in young Japanese patients (including schoolchildren) with microscopic hematuria alone is sufficiently good—at least for around 10 years [1–4]. However, hematuria is an independent risk factor in the development of CKD by glomerular diseases [5, 6]. The short-term prognosis of asymptomatic hematuria alone is generally good. Hematuria spontaneously disappeared in 20–30 % of such patients within several years [7, 8]. As urinary tract malignancies are detected by diagnostic work-up [9, 10] in a small percent of patients with chance hematuria, clinicians should remain alert to this possibility. In cases with chance hematuria, urological investigations for urinary tract malignancies are recommended when the
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reexamination is positive or when red blood cells are detected [8]. In long-term prognosis, almost 10 % of patients with hematuria alone have been known to develop proteinuria later in the clinical course. Moreover, as proteinuria is a significant risk factor in the development of end stage kidney disease, it is recommended that such patients be referred to a nephrologist [11–13].
III. Diagnosis of microscopic hematuria CQ9 Do you recommend screening for urinary tract
malignancies in all subjects with microscopic hematuria? [Statement] Screening for urinary tract malignancies is recommended for patients with microscopic hematuria. (Recommendation Grade B) Such patients having one of the risk factors of urinary tract malignancies should receive screening. (Recommendation Grade B) [Comment] Urinary tract malignancies represent 10 % of all malignancies in male and 3 % in female. Urinary tract malignancy onset increases after age 45 in both genders, with an abrupt increase observed after age 60. Males in their 40 s or above, smokers, those exposed to chemical substances, patients with gross hematuria, individuals with a prior history of urological diseases, urgency, patients with a history of urinary tract infection, individuals with frequent usage of NSAIDs (especially phenacetin), pelvic organ radiation recipients, and those with a prior history of cyclophosphamide usage, are known to be at risk for urinary malignancies [1]. Microscopic hematuric patients with one of those risk factors should receive screening for urinary tract malignancies, including cystoscopy examination. Microscopic hematuric patients without any risk factors, on the other hand, should receive non-invasive screening, such as ultrasound sonography or urinary cytology. CQ10 Is regular screening for uroepithelial malignancies recommended for patients with asymptomatic, microscopic hematuria who once tested negatively?
[Statement] Regular screening for uroepithelial malignancies is not recommended for patients with asymptomatic, non-
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glomerular-type, microscopic hematuria who once tested negatively, since the incidence of uroepithelial malignancies is very low. (Recommendation Grade C2) Rescreening for uroepithelial malignancies is recommended even for such patients when they experience symptoms such as macroscopic hematuria or difficulty in urination. (Recommendation Grade C1) [Comment] Regular screening for uroepithelial malignancies was previously recommended for patients with asymptomatic, microscopic hematuria who once tested negatively because 1–3 % of such patients developed uroepithelial malignancies within approximately 3 years. However, recent prospective cohort studies reported none to few such patients developing uroepithelial malignancies, possibly due to improvement in screening accuracy [1–4]. Therefore, in recent clinical guidelines of other societies [5, 6] and in ours, regular screening for such patients is not recommended. CQ11 Is kidney biopsy recommended to improve the clinical outcome of patients with microscopic hematuria?
[Statement] Kidney biopsy is recommended for patients with microscopic hematuria in combination with proteinuria as they are at a high risk for end stage kidney failure and the pathological finding-guided care is expected to improve their clinical outcome. (Recommendation Grade C1) Kidney biopsy is not recommended for patients with asymptomatic, microscopic hematuria in the absence of proteinuria as their risk for end stage kidney failure is low. (Recommendation Grade C2) However, a regular urinalysis is recommended for such patients when their hematuria is glomerular-type. (Recommendation Grade C1) [Comment] Proteinuria is proved to be an independent, strong risk factor for end stage kidney failure, and the risk is higher in coexistence with hematuria [1]. Therefore, kidney biopsy is recommended for patients with microscopic hematuria in combination with proteinuria as they are at a high risk for end stage kidney failure and the pathological finding-guided care is expected to improve their clinical outcome. Recently, asymptomatic, isolated microscopic hematuria was also proven to be an independent but weak risk factor for end stage kidney failure by a large cohort study in Israel spanning more than 20 years [2]. In this study, however, urinalysis was not performed during the observation period. In a cohort study on patients with asymptomatic,
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microscopic hematuria in Japan, 50 % tested negative for hematuria while 10 % tested positive for proteinuria during the observation period [3]. Another study from Japan also revealed that a considerable number of patients in a cohort study with asymptomatic, microscopic hematuria developed chronic glomerulonephritis [4]. These results suggest that some patients with asymptomatic, microscopic hematuria who test positive for proteinuria develop end-stage kidney failure due to advanced, chronic glomerulonephritis. Therefore, kidney biopsy is not recommended for patients with asymptomatic, microscopic hematuria in the absence of proteinuria, while a regular urinalysis is recommended for such patients, especially those with glomerular-type hematuria, since they are at risk for chronic glomerulonephritis.
IV. Diagnosis of macroscopic hematuria CQ12 What kind of diseases lead to macroscopic hematuria in adults?
[Statement] Macroscopic hematuria is caused by urologic diseases, except in patients under the age of 25. [Comments] As symptomatic macroscopic hematuria can presumably be diagnosed based on symptoms, except for the symptom of hematuria itself, this section focuses on asymptomatic macroscopic hematuria in adults. Based on the onset age for familial bladder cancer, excluding cases of children and young people under the age of 25, the key cause of macroscopic hematuria is urologic diseases [1–3]. In general, as the degree of hematuria increased so did the yield of life-threatening lesions [4, 5]. Adult patients with macroscopic hematuria are recommended to undergo urologic examinations. Urologic diseases: urothelial cancer (bladder cancer, renal pelvic and/or ureteral cancer), renal cell cancer, benign prostate hypertrophy, renal arterio-venous malformation, glomerular renal diseases, urolithiasis, hemorrhagic cystitis, and idiopathic renal bleeding. CQ13 What kind of diagnostic imaging is recommended for macroscopic hematuria?
[Statement] •
Abdominal ultrasonography is a minimally invasive test used in the diagnosis of most urothelial cancers,
•
•
•
and is recommended as screening for macroscopic hematuria. (Recommendation Grade B) In the diagnosis of urothelial cancer, computed tomographic urography (CT Urography) has relatively high sensitivity and specificity and is a primary imaging modality. CT urography is recommended as the main form of diagnostic imaging. (Recommendation Grade B) Magnetic resonance imaging (MRI) is more useful than CT for bladder and prostatic diseases. Magnetic resonance urography (MRU) does not use iodine-based contrast media and is mainly recommended to diagnose obstructive urinary tract lesions. (Recommendation Grade B) Intravenous pyelography has been recognized as a useful tool in the diagnosis of urothelial cancer; however, recent advances in diagnostic imaging with CT urography, which provides a greater amount of information, have resulted in an increase in CT urography usage and less frequent use of intravenous pyelography. Intravenous pyelography is not recommended as an examination for macroscopic hematuria. (Recommendation Grade C2)
[Comments] Intravenous pyelography was previously recognized for its usefulness in macroscopic hematuria screening; however, with advances in imaging modalities in recent years, CT urography has largely replaced it, as the latter yields vast amounts of information [1–3]. In urothelial cancer diagnosis, CT Urography has relatively high sensitivity and specificity, and is a primary imaging modality for examination of macroscopic hematuria [4]. However, it cannot replace cystoscopy in the examination of the urinary bladder lesions [5]. Diagnoses for macroscopic hematuria can be performed with multimodal examinations including initial abdominal sonography of the urinary bladder, CT urography, and cystoscopy [6]. CQ14 Is urine cytology recommended for macroscopic hematuria?
[Statement] Urine cytology is recommended for diagnosis of urothelial cancer. (Recommendation Grade B) [Comments] Specificity of urine cytology is high [1]. The detection rate of urothelial cancer is increased by repeated urine cytology [2, 3]. Urine cytology is a minimally invasive examination supporting histologic diagnosis of flat lesions
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such as carcinoma in situ in the urothelium; it also serves as a urothelial cancer follow-up exam. Urine cytology is useful in screening for urothelial cancer. Whenever the possibility of urothelial cancer exists, multiple urine cytology screening is performed. Urine cytology has a specificity rate of almost 100 %; however, the sensitivity is low and negative urine cytology cannot rule out cancer. As sensitivity for low atypical urothelial cancer is low, care must be taken when interpreting the result. CQ15 Is the same screening recommended for patients with macroscopic hematuria during anticoagulant treatment as for patients not undergoing the treatment?
[Statement] Normal screening for macroscopic hematuria is recommended for patients undergoing anticoagulant treatment. (Recommendation Grade B) [Comments] It has been reported that the frequency of hematuria in patients treated with anticoagulants is the same as that in the control group. Additionally, cancer was diagnosed in approximately one quarter of patients with macroscopic hematuria treated with anticoagulant medication. Diseases requiring treatment, such as urolithiasis and benign prostatic hyperplasia, are often found in patients with macroscopic hematuria. It is necessary to confirm any past anticoagulant treatment when taking a patient’s medical history; however, standard macroscopic hematuria screening is also necessary for patients treated with anticoagulant drugs such as warfarin or aspirin [1, 2]. CQ16 Is surveillance for macroscopic hematuria
without findings recommended? [Statement] Tight surveillance for recurrent macroscopic hematuria is recommended. (Recommendation Grade B) [Comments] Subsequent disease remains undetected in approximately 80 % of patients diagnosed as being disease-free. As urological cancer was subsequently diagnosed in more than 10 % of recurrent macroscopic hematuria [1–3], tight surveillance for recurrent macroscopic hematuria is required as needed [4]. Recently, advances in ureterorenoscopes and ureterorenoscopy have facilitated evaluation and treatment of chronic macroscopic hematuria. Ureterorenoscopy is recommended during surveillance [5–7].
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V. Diagnosis and management in children with microscopic hematuria detected by urinary screening at school CQ17 Reasons for discovery, morbidity, and primary diseases of hematuria in children
[Statement] Most hematuria in children is detected by screening at schools, by public health agencies at age 3, and incidentally during other screenings. Children with gross hematuria are usually taken to the hospital for medical by their guardians. Major primary diseases leading to non-glomerular hematuria in children are hypercalciuria and the nutcracker phenomenon, and those of glomerular hematuria are thinbasement membrane disease and IgA nephropathy. Typically, however, no primary disease is discovered. Malignancy is a rare cause of hematuria in children. CQ18 Follow-up of children with hematuria and timing of referral to a pediatric nephrologist
[Statement] If children with hematuria have no complications from proteinuria, renal impairment, hypertension, urinary stones, or malignancy, quarterly follow-up is recommended in the first year following discovery of hematuria. Thereafter, follow-up urinalysis once or twice a year and an annual blood examination are recommended until the resolution of hematuria. (Recommendation Grade C1) [Comment] Referral to a pediatric nephrologist should be considered if the patient suffers from: (1) glomerulonephritis and interstitial nephritis (excepting acute poststreptococcal glomerulonephritis), (2) malignancy, (3) kidney or urinary tract trauma, (4) urinary stones, (5) congenital cystic kidney diseases, renal hypoplasia or dysplasia, severe hydronephrosis or hydroureter, (6) impaired renal function, or (7) hypertension. CQ19 Examinations for children with hematuria
[Statement] A medical interview for diagnosis, measurement of weight, height and blood pressure, urinalysis, and blood examinations based on a detailed examination in school urinary screening system should be performed (Recommendation Grade B). Ultrasound, which is a non-invasive examination, is strongly recommended.
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Renal biopsy for diagnosis is necessary if chronic glomerulonephritis is suspected (Recommendation Grade B). [Comment] Indications of renal biopsy are as follows: (1) dipstick proteinuria, with the morning urinary protein/creatinine ratio and its duration being: (a) 1 ? or 0.2–0.4 for 6 to 12 months, (b) 2 ? or 0.5–0.9 for 3 to 6 months, (c) 3 ? or 1.0–1.5 for 1 to 3 months or (d) 4 ? or more than 2 at any time; (2) gross hematuria; (3) hypoalbuminemia (\ 3.0 g/dL); (4) hypocomplementemia (except for acute poststreptococcal glomerulonephritis); (5) renal impairment; and (6) hypertension.
2. Copley JB. Isolated asymptomatic hematuria in the adult. Am J Med Sci. 1986;291:101–11. 3. Grossfeld GD, Litwin MS, Wolf JS, Hricak H, Shuler CL, Agerter DC, et al. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy-part I: definition, detection, prevalence, and etiology. Urology. 2001;57:599–603. 4. Vivante A, Afek A, Renkel-Nir Y, Tzur D, Farfel A, Golan E, et al. Persistent asymptomatic isolated microscopic hematuria in Israeli adolescents and young adults and risk for end-stage renal disease. JAMA. 2011;306:729–36. 5. Editorial board for JCCLS Standard Guideline for Urinary Sediment Examination GP1–P4. Examination of Urinary Sediment 2010. Japanese Association of Medical Technologists; 2011. p. 1–10.
CQ2 CQ20 Malignancy as a rare cause of hematuria
in children [Statement] Malignancy is a rare cause of hematuria in children. However, kidney and urinary tract ultrasound is strongly recommended to exclude the possibility. Enhanced computed tomography is not the first choice (Recommendation Grade B). Routine follow-up with ultrasound is recommended in patients at high risk for Wilms’ tumor, including those with Denys–Drash syndrome, Beckwith–Wiedemann syndrome, WAGR syndrome, aniridia, hemihypertrophy, Sotos syndrome, von Recklinghausen syndrome, and horseshoe kidney (Recommendation Grade B). CQ21 Nutrition and exercise in children with hematuria
[Statement] If children with microscopic hematuria have no complications from hypertension, massive edema, or obvious exacerbation of renal function and proteinuria by exercise, no exercise and dietary restrictions are needed (Recommendation Grade C2). [Comment] If patients with asymptomatic hematuria and proteinuria do not have the problems described above, all activities except for intense exercise are allowed. Patients with gross hematuria should be referred to pediatric nephrologists.
References I. Hematuria: definition and screening methods
CQ1 1. Sutton JM. Evaluation of hematuria in adults. JAMA. 1990;263:2475–80.
1. Committee on Urinary Regent Paper Testing. JCCLS Document GP3-P1 Guideline ‘‘Urinary Reagent Method’’ Japanese Committee for Clinical Laboratory Standards. Jpn J Clin Lab Stand. 2001;16:33–55. 2. Editorial board for JCCLS Standard Guideline for Urinary Sediment Examination GP1-P4. Examination of Urinary Sediment 2010. Japanese Association of Medical Technologists; 2011. p. 1–10. II. Epidemiology of hematuria
CQ7 1. Ritchie CD, Bevan EA, Collier SJ. Importance of occult haematuria found at screening. Br Med J Clin Res Ed. 1986;292:681–3. 2. Thompson IM. The evaluation of microscopic hematuria: a population-based study. J Urol. 1987;138:1189–90. 3. Messing EM, Young TB, Hunt VB, et al. Home screening for hematuria: results of a multiclinic study. J Urol. 1992;148:289–92. 4. Chen W, Liu Q, Wang H, et al. Prevalence and risk factors of chronic kidney disease: a population study in the Tibetan population. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc Eur Ren Assoc. 2011;26:1592–9. 5. Yamagata K, Yamagata Y, Kobayashi M, Koyama A. A longterm follow-up study of asymptomatic hematuria and/or proteinuria in adults. Clin Nephrol. 1996;45:281–8.
CQ8 1. Yazaki T, Nemoto S, Ishikawa H, Kanoh S, Koiso K, Terasaki T, Tojo S. Long-term follow-up of patients with asymptomatic hematuria. Nihon Jinzo Gakkaishi. 1985;27:1247–51. 2. Murakami S, Igarashi T, Hara S, Shimazaki J. Strategies for asymptomatic microscopic hematuria: a prospective study of 1,034 patients. J Urol. 1991;144:99–101. 3. Hisano S, Kwano M, Hatae K, Kaku Y, Yamane I, Ueda K, Uraqoh K, Honda S. Asymptomatic isolated microhaematuria: natural history of 136 children. Pediatr Nephrol. 1991;5:578–81. 4. Takebayashi S, Yanase K. Asymptomatic urinary abnormalities found via the Japanese school screening program: a clinical, morphological and prognostic analysis. Nephron. 1992;61:82–8. 5. Vivante A, Afek A, Frenkel-Nir Y, Tzur D, Farfel A, Golan E, Chaiter Y, Shohat T, Skorecki K, Calderon-Margalit R. Persistent asymptomatic isolated microscopic hematuria in Israeli
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Clin Exp Nephrol adolescents and young adults and risk for end-stage renal disease. JAMA. 2011;306:729–36. 6. Iseki K, Ikemiya Y, Iseki C, Takishita S. Proteinuria and the risk of developing end-stage renal disease. Kidney Int. 2003;63:1468–74. 7. Kovacevic Z, Javanovic D, Rabrenovic V, Dimitrijevic J, Djukanovic J. Asymptomatic microscopic haematuria in young males. Int J Clin Pract. 2008;62:406–12. 8. Mishriki SF, Nabi G, Cohen NP. Diagnosis of urologic malignancies in patients with asymptomatic dipstick hematuria: prospective study with 13 years’ follow-up. Urology. 2008;71:13–6. 9. Khan MA, Shaw G, Paris AM. Is microscopic haematuria a urological emergency? BJU Int. 2002;90:355–7. 10. Paul AB, Collie DA, Wild SR, Chisholm GD. An integrated haematuria clinic. Br J Clin Pract. 1993;47:128–30. 11. Assadi FK. Value of urinary excretion of microalbumin in predicting glomerular lesions in children with isolated microscopic hematuria. Pediatr Nephrol. 2005;20:1131–5. 12. Chow KM, Kwan BC, Li PK, Szeto CC. Asymptomatic isolated microscopic haematuria: long-term follow-up. QJM. 2004;97: 739–45. 13. Yamagata K, Yamagata Y, Kobayashi M, Koyama A. A longterm follow-up study of asymptomatic hematuria and/or proteinuria in adults. Clin Nephrol. 1996;45:281–8. III. Diagnosis of microscopic hematuria
CQ9 1. Grossfeld GD, Litwin MS, Wolf JS Jr, Hricak H, Shuler CL, Agerter DC, et al. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy—part II: patient evaluation, cytology, voided markers, imaging, cystoscopy, nephrology evaluation, and follow-up. Urology. 2001;57:604–10.
CQ10 1. Howard RS, Golin AL. Long-term follow-up of asymptomatic microhematuria. J Urol. 1991;145:335–6. 2. Khadra MH, Pickard RS, Charlton M, Powell PH, Neal DE. A prospective analysis of 1,930 patients with hematuria to evaluate current diagnostic practice. J Urol. 2000;163:524–7. 3. Chow KM, Kwan BC, Li PK, Szeto CC. Asymptomatic isolated microscopic hematuria: long-term follow-up. Q J Med. 2004;97:739–45. 4. Mishiriki SF, Nabi G, Cohen NP. Diagnosis of urologic malignancies in patients with asymptomatic dipstick hematuria: prospective study with 13 years’ follow-up. Urology. 2008;71:13–6. 5. Cohen RA, Brown RS. Microscopic hematuria. N Engl J Med. 2003;348:2330–8. 6. Kelly JD, Fawcett DP, Goldberg LC. Assessment and management of non-visible haematuria in primary care. BMJ. 2009;338:a3021.
CQ11 1. Iseki K. The Okinawa screening program. J Am Soc Nephrol. 2003;14:S127–30. 2. Vivante A, Afek A, Frenkel-Nir Y, Tzur D, Farfel A, Golan E, Chaiter Y, Shohat T, Skorecki K, Calderon-Margalit R. Persistent asymptomatic isolated microscopic hematuria in Israeli
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adolescents and young adults and risk for end-stage renal disease. JAMA. 2011;306:729–36. 3. Yamagata K, Takahashi H, Tomida C, Yamagata Y, Koyama A. Prognosis of asymptomatic hematuria and/or proteinuria in men. High prevalence of IgA nephropathy among proteinuric patients found in mass screening. Nephron. 2000;91:34–42. 4. Yamagata K, Ishida K, Sairenchi T, Takahashi H, Ohba S, Shiigai T, Narita M, Koyama A. Risk factors for chronic kidney disease in a community-based population: a 10-year follow-up study. Kidney Int. 2007;71:159–66. IV. Diagnosis of macroscopic hematuria
CQ12 1. Brandt A, Bermejo JL, Sundquist J, Hemminki K. Age of onset in familial cancer. Ann Oncol. 2008;19:2084–8. 2. Bruyninckx R, Buntinx F, Aertgeerts B, Van Casteren V. The diagnostic value of macroscopic haematuria for the diagnosis of urological cancer in general practice. Br J Gen Pract. 2003; 53:31–5. 3. Buntinx F, Wauters H. The diagnostic value of macroscopic haematuria in diagnosing urological cancers: a meta-analysis. Fam Pract. 1997;14:63–8. 4. Thiruchelvam N, Mostafid H. Do patients with frank haematuria referred under the two-week rule have a higher incidence of bladder cancer? Ann R Coll Surg Engl. 2005;87:345–7. 5. 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 cost-effectiveness analysis. J Urol. 1989;141:350–5.
CQ13 1. Edwards TJ, Dickinson AJ, Natale S, Gosling J, McGrath JS. A prospective analysis of the diagnostic yield resulting from the attendance of 4020 patients at a protocol-driven haematuria clinic. BJU Int. 2006;97:301–5. 2. Knox MK, Cowan NC, Rivers-Bowerman MD, Turney BW. Evaluation of multidetector computed tomography urography and ultrasonography for diagnosing bladder cancer. Clin Radiol. 2008;63:1317–25. 3. Chlapoutakis K, Theocharopoulos N, Yarmenitis S, Damilakis J. Performance of computed tomographic urography in diagnosis of upper urinary tract urothelial carcinoma, in patients presenting with hematuria: systematic review and meta-analysis. Eur J Radiol. 2010;73:334–8. 4. Mueller-Lisse UG, Mueller-Lisse UL, Hinterberger J, Schneede P, Meindl T, Reiser MF. Multidetector-row computed tomography (MDCT) in patients with a history of previous urothelial cancer or painless macroscopic haematuria. Eur Radiol. 2007;17:2794–803. 5. Sudakoff GS, Dunn DP, Guralnick ML, Hellman RS, Eastwood D, See WA. Multidetector computerized tomography urography as the primary imaging modality for detecting urinary tract neoplasms in patients with asymptomatic hematuria. J Urol. 2008;179:862–7. 6. Blick CG, Nazir SA, Mallett S, Turney BW, Onwu NN, Roberts IS, et al. Evaluation of diagnostic strategies for bladder cancer using computed tomography (CT) urography, flexible cystoscopy and voided urine cytology: results for 778 patients from a hospital haematuria clinic. BJU Int. 2011;110:84–94.
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CQ14 1. Nabi G, Greene DR, O’Donnell M. How important is urinary cytology in the diagnosis of urological malignancies? Eur Urol. 2003;43:632–6. 2. Turco P, Houssami N, Bulgaresi P, Troni GM, Galanti L, Cariaggi MP, et al. Is conventional urinary cytology still reliable for diagnosis of primary bladder carcinoma? Accuracy based on data linkage of a consecutive clinical series and cancer registry. Acta Cytol. 2011;55:193–6. 3. Koss LG, Deitch D, Ramanathan R, Sherman AB. Diagnostic value of cytology of voided urine. Acta Cytol. 1985;29:810–6.
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4.
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6.
CQ15 1. Avidor Y, Nadu A, Matzkin H. Clinical significance of gross hematuria and its evaluation in patients receiving anticoagulant and aspirin treatment. Urology. 2000;55:22–4. 2. Van Savage JG, Fried FA. Anticoagulant associated hematuria: a prospective study. J Urol. 1995;153:1594–6.
7.
after investigation for haematuria, based on a 4-year follow-up. BJU Int. 2011;107:247–52. Mishriki SF, Grimsley SJ, Nabi G. Incidence of recurrent frank hematuria and urological cancers: prospective 6.9 years of followup. J Urol. 2009;182:1294–8. Mishriki SF, Vint R, Somani BK. Half of visible and half of recurrent visible hematuria cases have underlying pathology: prospective large cohort study with long-term followup. J Urol. 2012;187:1561–5. Mugiya S, Ozono S, Nagata M, Takayama T, Furuse H, Ushiyama T. Ureteroscopic evaluation and laser treatment of chronic unilateral hematuria. J Urol. 2007;178:517–20. Brito AH, Mazzucchi E, Vicentini FC, Danilovic A, Chedid Neto EA, Srougi M. Management of chronic unilateral hematuria by ureterorenoscopy. J Endourol. 2009;23(8):1273–6. Araki M, Uehara S, Sasaki K, Monden K, Tsugawa M, Watanabe T, Monga M, Nasu Y, Kumon H. Ureteroscopic management of chronic unilateral hematuria: a single-center experience over 22 years. PLoS ONE. 2012;7(6):e36729.
CQ16 1. Sells H, Cox R. Undiagnosed macroscopic haematuria revisited: a follow-up of 146 patients. BJU Int. 2001;88:6–8. 2. Edwards TJ, Dickinson AJ, Gosling J, McInerney PD, Natale S, McGrath JS. Patient-specific risk of undetected malignant disease
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