G e n i t o u r i n a r y I m a g i n g • R ev i ew van der Molen and Hovius Dutch Guidelines on Hematuria
FOCUS ON:
Genitourinary Imaging Review
Aart J. van der Molen1 Marina C. Hovius 2 van der Molen AJ, Hovius MC
Hematuria: A Problem-Based Imaging Algorithm Illustrating the Recent Dutch Guidelines on Hematuria OBJECTIVE. To present a problem-based algorithm in the work-up of patients with Hematuria. Since the 2010 Dutch Guideline on Hematuria was problem-based, this served as an illustration for such an approach.. CONCLUSION. The work-up of hematuria should be individualized and risk-based. Given the a priori low likelihood of cancer in hematuria, risk categories should be established and imaging algorithms should be tailored to populations at low-risk, medium-risk and highrisk for developing urothelial cancer.
H
Keywords: CT, guideline, hematuria, ultrasound, urography, x-ray DOI:10.2214/AJR.11.8255 Received November 11, 2011; accepted after revision November 27, 2011. Dr. Hovius was chair of the multidisciplinary Working Group for the Guideline Hematuria of The Dutch Association of Urology in 2009–2011. 1 Department of Radiology, C-2S, Leiden University Medical Center, Albinusdreef 2, NL-2333 ZA Leiden, The Netherlands. Address correspondence to A. J. van der Molen (
[email protected]). 2 Department of Urology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands.
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ematuria is a frequent reason for physician consultation in clinical practice and urologic referral. In The Netherlands, hematuria constitutes up to 8% of urology consultations. Its reported incidence is variable—16% in a large screening study for bladder cancer of men older than 50 years [1] and 20% in a similar study of men older than 60 years [2]. The prevalence in primary care is unknown. Hematuria is commonly subdivided into macroscopic (i.e., visible) hematuria and recurrent asymptomatic microscopic (i.e., nonvisible) hematuria. As the basis for this review, macroscopic and recurrent microscopic hematuria are used because this is the most common subdivision radiologists will encounter in daily use. The most accepted definition of macroscopic hematuria is red urine. Microscopic hematuria is defined as more than three erythrocytes per high-power field from two of three urinary sediments without a urinary tract infection, or menstruation on microscopic evaluation [3–5]. Hematuria can be caused by a variety of vascular, glomerular, interstitial, or uroepithelial disorders [6] (Table 1). The main focus in the workup of hematuria is tumor detection, either urothelial cell cancer or renal cell carcinoma (RCC). Few complete guidelines on the diagnosis and management of hematuria exist in the literature. The well-known American Urological Association (AUA) best practice policy dates back to 2001 but only dealt with microscopic hematuria [4, 5] and is currently
under revision. Kelly et al. [7] published a clinical review on assessment and management of nonvisible hematuria in primary care. Only Rodgers et al. in 2006 [8] dealt in an extensive systematic review with both forms of hematuria. This review will illustrate the recommendations for adults of the recent hematuria guidelines prepared by a multidisciplinary working group of experts in urology, nephrology, radiology, and clinical chemistry in The Netherlands, initiated by the Dutch Association of Urology [9]. The Clinical Picture: Microscopic Versus Macroscopic Hematuria When obtaining a patient’s medical history, an estimation of the risk for malignancy can be made. The traditional risk factors include macroscopic hematuria, smoking, age, sex, micturition complaints, urothelial cancer, radiotherapy of the small pelvis, chronic urinary tract infection, and working with aromatic amines in the chemical industry [10, 11]. Reliable data on the incidence of invasive and noninvasive cancers can be taken from the Dutch Cancer Registry, which is maintained by all Dutch hospitals (available at www.cijfersoverkanker.nl; see also Tables 2 and 3). Recurrent Microscopic Hematuria The risk of urologic malignancy is much lower with microscopic than with macroscopic hematuria. Depending on the population studied, in up to 8.9% of patients with recurrent microscopic hematuria, a malig-
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Dutch Guidelines on Hematuria nancy was found [12–20] (Table 4). Interestingly, in some studies, age was already set at 50 years, and below that age, no malignancy was found [12, 14]. In the largest cohort studied, upper urinary tract urothelial cell cancer was found in 0.2%, RCC in 1%, and bladder cancer in 3.7% of patients. In men younger than 50 years and in women younger than 70 years, no cases of upper urinary tract urothelial cell cancer were found [13]. Macroscopic Hematuria In patients with macroscopic hematuria, the risk for malignancy is high. Malignancy can be found in 10–28% of cases overall and in up to 10% of patients younger than 40 years [12–14, 16, 19–21] (Table 5). In the study of Edwards et al. [13], upper urinary tract urothelial cell cancer was found in 0.5% and RCC in 2% of patients, and 16.5% of patients were diagnosed with bladder cancer (90% of cancers). In patients with macroscopic hematuria younger than 50 years, no cases of upper urinary tract urothelial cell cancer were found. Nephrologic Causes of Hematuria Nephrologic causes of hematuria should be considered early in the workup of both microscopic and macroscopic hematuria because up to 10% of cases of hematuria can be nephrologic [16]. The most frequent causes include IgA nephropathy and thin basement membrane nephropathy. There is no simple test to differentiate urologic from nephrologic hematuria. Most tests depend on pattern recognition and urinalysis, especially the urine sediment. The most important clues include the presence of hypertension, reduced renal function, proteinuria, and the presence of dysmorphic erythrocytes in the urine sediment. If the percentage of dysmorphic erythrocytes increases above 20%, a glomerular cause is likely; if the percentage of dysmorphic erythrocytes is above 80%, a glomerular cause is almost certain [8]. Another pointer to glomerular disease is the presence of acanthocytes. Proteinuria is also associated with nephrologic causes. In practice, screening urine test strips become positive for urine protein concentrations of 100–300 mg/L. For diagnosis, a common cutoff value represents an albumin excretion level of more than 300 mg/24 hour. Reduced renal function is commonly defined as a estimated glomerular filtration rate according to the Modification of Diet in Renal Disease Study Group criteria [22] less than 60 mL/min/1.73 m2 (i.e., chronic kidney disease grade III).
TABLE 1: Frequent Causes of Hematuria Vascular Arterial embolism or thrombosis Arteriovenous malformation or arteriovenous fistula Renal vein thrombosis Nutcracker syndrome (compression of left renal vein) Glomerular IgA nephropathy Alport disease and thin basal membrane nephropathy Other primary or secondary glomerulonephritides Interstitial Allergic interstitial nephritis Analgetic nephropathy Renal cystic diseases
urine” is more suitable and recommended [23]. Analysis should follow rapidly, preferably within 1 hour for sediment analysis and 2 hours for dipstick testing. Laboratory Diagnosis: Urine Cytology The sensitivity of urine cytology for the diagnosis of urothelial cell cancer is low, and a negative result does not exclude patients from further testing [24]. It has been shown in multiple studies that the addition of urine cytology in the primary analysis of hematuria does not contribute to diagnosis [25, 26], which is usually made by cystoscopy or imaging. Laboratory Diagnosis: Urine Culture The addition of cultures of urine may be indicated if the sediment shows leukocytes. Hematuria can be associated with urinary tract infection, but also with noninfectious bladder inflammation such as in interstitial cystitis.
Pyelonephritis Renal transplant rejection Uroepithelial Malignancy: urothelial cell carcinoma, renal cell carcinoma Heavy physical exercise Trauma Papillary necrosis Cystitis, urethritis, prostatitis (usually infectious) Parasitic diseases Urolithiasis
Laboratory Diagnosis: Clinical Chemistry Clinical chemistry tests are most important to support a nephrologic diagnosis. Renal function parameters can be established by serum creatinine levels and Modification of Diet in Renal Disease Study Group estimated glomerular filtration rate. Hematuria in patients with hemorrhagic diathesis or patients using antithrombotic medication is not necessarily benign and warrants further diagnosis. Screening coagulation tests and international normalized ratio (INR) are recommended.
When analyzing hematuria, the patient’s blood pressure, renal function parameters, urinary sediment, and level of proteinuria should be evaluated in all cases. Patients with microscopic hematuria in combination with proteinuria should preferably be analyzed by a nephrologist. If the initial analysis is inconclusive, a urologic evaluation should be advised.
Cystoscopy Flexible cystoscopy remains the reference standard for diagnosis of hematuria of the lower urinary tract. However, limited data are available for the precise role of cystoscopy in various forms of hematuria, and no evidence-based guidance can be established. A cutoff value for age above which cystoscopy should be performed can therefore not be given. In women with asymptomatic microscopic hematuria, cystoscopy may be less informative [15]. The American Urological Association best practice policy suggests that, in patients at low risk for urothelial cancer, cystoscopy may be avoided [4, 5]. Imaging of the bladder should preferably precede cystoscopy, so it can aid the urologist and improve diagnostic yield.
Nonimaging Diagnosis of Hematuria Laboratory Diagnosis: Urinalysis Even though most urine samples are early morning urine, for analysis of corpuscular elements, the so-called “second morning
Ureterorenoscopy Ureterorenoscopy is performed under general anesthesia. It can be considered after imaging fails or when pathologic abnormality is found at imaging but the results of urine cy-
Radiation Miscellaneous Hypercalciuria Hyperuricosuria Sickle cell disease Note—Data are reprinted/adapted with permission from [6].
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van der Molen and Hovius TABLE 2: Dutch Cancer Registry Data for Invasive Urologic Tumors in 2009, by Patient Sex and Age Patient Sex, Localization
Patient Age (y) Total
≤ 24 25–29 30–34 35–39 40–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79 80–84 85–89 90–94 ≥ 95
Women Kidney
810
9
3
1
11
19
24
67
77
111
118
110
114
96
37
10
3 0
Renal
87
0
0
0
1
0
1
3
3
9
15
12
20
14
8
1
Ureter
49
0
0
0
0
1
2
3
2
4
3
8
8
10
7
1
0
Bladder
707
0
0
0
3
5
18
37
48
72
95
97
111
107
82
29
3
Urinary tract or other
10
0
0
0
0
0
1
1
1
3
1
0
2
1
0
0
0
1663
9
3
1
15
25
46
111
131
199
232
227
255
228
134
41
6
Kidney
1281
6
3
5
22
38
70
114
167
204
202
188
144
80
29
6
3
Renal
133
0
0
0
1
2
1
7
9
14
21
24
20
21
13
0
0
Ureter
107
0
0
0
0
0
1
3
7
9
16
17
23
19
11
1
0
Bladder
2076
0
0
4
4
12
37
64
138
239
303
376
385
298
175
36
5
28
0
0
0
0
0
0
1
2
1
1
6
10
6
1
0
0
3625
6
3
9
27
52
109
189
323
467
543
611
582
424
229
43
8
Total for women Men
Urinary tract or other Total for men
Note—Data are no. of tumors.
TABLE 3: Dutch Cancer Registry Data for Noninvasive or In Situ Urologic Tumors in 2009, by Patient Sex and Age Patient Sex, Localization
Patient Age (y) Total
≤ 24 25–29 30–34 35–39 40–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79 80–84 85–89 90–94 ≥ 95
Women Kidney
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Renal
21
0
0
0
0
0
0
0
0
2
1
1
12
4
1
0
0
Ureter
25
0
0
0
0
0
0
1
1
4
3
6
3
3
1
3
0
Bladder
614
0
1
3
2
7
17
34
69
88
93
89
94
70
37
5
5
Urinary tract or other
1
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1
0
661
0
1
3
2
7
17
35
70
94
97
96
109
77
39
9
5
Kidney
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Renal
60
0
0
0
1
0
4
4
8
9
7
9
11
7
0
0
0
Total for women Men
Ureter Bladder Urinary tract or other Total for men
62
0
0
0
0
0
0
4
1
11
10
19
12
5
0
0
0
2320
2
4
11
13
34
60
108
198
297
363
397
419
259
126
24
5
16
0
0
0
0
0
0
0
1
3
1
2
5
3
0
1
0
2458
2
4
11
14
34
64
116
208
320
381
427
447
274
126
25
5
Note—Data are no. of tumors.
tology are negative. It has been shown that ureterorenoscopy is more sensitive than retrograde pyelography in tumor detection [27]. It may also be considered for unilateral hematuria in young patients, which is commonly caused by renal hemangioma [28]. These can be treated in the same session by ureterorenoscopy laser photocoagulation. Radiologic Diagnosis of Hematuria Radiologic imaging plays a pivotal role in the diagnosis of hematuria. However, the
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performances of individual imaging techniques within a specific diagnostic algorithm for hematuria have not been studied well. Sensitivity and specificity need to be deducted from diseases that are the major causes of hematuria: urolithiasis, infection, RCC, and urothelial cell cancer. Abdominal Radiographs The role of the plain abdominal radiograph in hematuria is very limited. In recent large studies on the effect of imaging modalities in
the acute abdomen, radiography showed virtually no additional value in diagnosis [29– 31]. Only in the diagnosis of stone disease does it still play a role because of its low cost and general availability. However, its overall sensitivity for renal and ureteral stones is only 45–60% in multiple studies [32, 33]. Unenhanced CT is now the reference standard for stone detection, and even very-lowdose unenhanced CT techniques with a radiation dose comparable to that of abdominal radiographs have shown better results [34].
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Dutch Guidelines on Hematuria TABLE 4: Studies on the Incidence of Malignancy in Microscopic Nonvisible Hematuria Study Type, Reference
Patients With Hematuria
Patients With Microhematuria
Malignancy Urolithiasis (%)
Malignancy in Women ≤ 40 Years Old (%)
Malignancy in Men ≤ 40 Years Old (%)
Pathology (%)
0 (≤ 50)
0 (≤ 50)
43
Prospective 581
247
8.9a ≠ 12a
Edwards et al. [13]
4020
1950
4.8 ≠ NA
1.1
0.7
13
Sultana et al. [14]
614
381
5 ≠ 4.7
0 (≤ 50)
0
NA
Murakami et al. [15]
1034
1034
2.9 ≠ NA
0
0
54
Khadra et al. [16]
1930
982
5.4 ≠ 4
0
1.7
32
Lang et al. [17]b
600
600
7.3 ≠ 0
NA
NA
43
Jaffe et al. [18]
372
3≠ 8
NA
NA
43
Boman et al. [12]
75 after 3 mos
Retrospective 404
140
3≠ 6
0 (total 8% stones)
0
NA
1509
443
5≠ 0
NA
NA
24
El-Galley et al. [19] Hovius et al. [20]
Note—NA = not applicable. aIncludes 10 cases of prostate carcinoma. bAnalysis of patients with CT urography: persistent microscopic hematuria after initial negative analysis.
Ultrasound Ultrasound is suitable as first-line diagnostic test, especially in young patients with nonurologic diseases. A large study showed a high specificity but moderate sensitivity for the diagnosis of bladder tumors [35]. In comparison with excretory urography, ultrasound showed a higher sensitivity for bladder tumors and equal (i.e., moderate) sensitivity for upper urinary tract tumors [36, 37]. Ultrasound alone is not sensitive (19–32%) for stone detection [38, 39], but its sensitivity for combined stone detection and pyelocalyceal dilatation is much better. Combined Radiograph and Ultrasound Since the 1980s, it has been known that the combination of radiograph and ultrasound is
sufficiently accurate for diagnosis in hematuria, improved compared with excretory urography. The combination is inferior to unenhanced CT for stone disease but does not miss significant disease. Studies found sensitivities of 77–79%, with negative predictive values of 46–68% [40, 41]. With modern ultrasound techniques, such as tissue harmonic imaging, sensitivity for the combination can be improved [42]. The role of contrastenhanced ultrasound is not yet well defined. Excretory Urography Excretory urography has long been the cornerstone for evaluation of the upper urinary tract. However, even though metaanalyses show the highest positive and negative likelihood ratio of unenhanced CT for stone
diagnosis [43], the European Urological Association (EAU) guideline lags behind, and the 2009 version still recommends excretory urography for stone diagnosis [44]. For hematuria, multiple studies have now shown the superiority of CT urography over excretory urography. There is also a low sensitivity (< 60%) for renal tumors smaller than 3 cm for excretory urography [45]. CT Urography CT urography provides detailed information on the urinary tract. The problem in interpretation of the results is variability in the definitions of what CT urography actually entails, and, therefore, the CTU Working Group of the European Society of Urogenital Radiology has tried to suggest a definition as follows:
TABLE 5: Studies on the Incidence of Malignancy in Macroscopic Visible Hematuria Study Type, Reference
Patients With Hematuria
Patients With Macrohematuria
Malignancy Urolithiasis (%)
Malignancy in Patients ≤ 40 Years Old
Malignancy in Patients > 40 Years Old
NA
NA
Pathology (%)
Prospective Boman et al. [12]
24a ≠ 5.4a
581
211
79
Edwards et al. [13]
4020
2071
19 ≠ 0
6.7% men; 1% women
NA
27
Sultana et al. [14]
614
233
28 ≠ 0
10% (≤ 50 years old)
35% (≥ 50 years old)
35
Khadra et al. [16]
1930
948
24 ≠ 0
0.8% men; 0% women
21% men; 16% women
47
Mishriki et al. [21]
578
578
19.5b ≠ 0
NA
NA
36
404
264
10 ≠ 12
NA
NA
NA
1509
1032
23 ≠ 0
NA
NA
60
Retrospective El-Galley et al. [19] Hovius et al. [20]
Note—NA = not applicable. aIncludes 18 cases of prostate carcinoma. bIncludes 2.4% prostate carcinoma.
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van der Molen and Hovius CT urography is a diagnostic examination optimized for imaging the kidneys, ureters, and bladder. It uses MDCT with thin slices, IV administration of iodinated contrast medium, and (at least) imaging in the excretory phase. This definition implies that not every CT performed in the excretory phase during routine abdominal CT is CT urography. Patients scheduled for CT urography are specifically prepared (e.g., oral administration of water, infusion of physiologic saline, and low dose of furosemide) to optimize imaging of the ureters and bladder. Isotropic CT datasets are acquired, which can generate high-quality images of the urinary tract in any desired plane [46]. CT has a high sensitivity for RCC tumors larger than 10 mm [47]. RCC staging is usually not performed with CT urography but with renal CT protocols that include unenhanced, corticomedullary, and nephrographic phase scans [48]. Most CT urography data have been established for hematuria. CT urography can identify the cause of hematuria in 33–43% of cases. For identification of the cause of hematuria, the overall sensitivity is 92–100%, and the specificity is 89–97% [17, 49, 50]. A recent small metaanalysis showed a pooled sensitivity of 96% and specificity of 99% [51]. In specific populations, the detection of urothelial cell cancer by CT urography is high and superior to that by excretory urography [52–54], with relatively the lowest detection rate in the ureter. CT urography also performs well in the lower urinary tract and, in selected cases, can obviate flexible diagnostic cystoscopy so that patients may proceed directly to rigid therapeutic cystoscopy [55–57]. Although it has not been formally
studied in detail, CT urography performed before cystoscopy may also increase the sensitivity for cystoscopy [58, 59]. Retrograde Ureteropyelography Invasive retrograde ureteropyelography can be used for more detailed characterization of filling defects and other pathologic findings of the pyelocalyceal systems. In the time of excretory urography, retrograde ureteropyelography was used in patients with limited opacification of the upper urinary tracts, such as in patients with obesity or decreased renal function. However, with the increasing use of MDCT urography and ureterorenoscopy, its role has diminished significantly. It has been shown that, in highrisk patients, CT urography is equivalent to retrograde ureteropyelography in the upper urinary tract [54], so that retrograde ureteropyelography is used only as a second- or third-line imaging modality of the upper urinary tracts when ultrasound or CT urography findings are negative and hematuria persists or in case of an afunctional kidney. MR Urography (MRU) MRU has inherent advantages in that it does not require ionizing radiation, has a high contrast resolution, has good sensitivity for contrast media, and has the possibility for better tissue characterization than other imaging techniques do. However, MRU is costly, technically demanding, and not widely practiced. Therefore, MRU expertise is available only in specific dedicated centers. MRU is usually performed as a combination of static fluid T2-weighted and dynam-
ic contrast-enhanced T1-weighted sequences. It is good for pediatric diseases and for the evaluation of obstructive disease [59, 60]. There are hardly any comparative data on the role of MRU in hematuria. It could be equivalent to CT urography for many causes of hematuria, but it is commonly reserved for children, pregnant patients, and patients who are hypersensitive to iodinated contrast media. Toward a Problem-Based (Risk-Based) Imaging Algorithm Because of the difference in cost and radiation burden of the various radiologic modalities, the disease prevalence and the risk profile of the patient determine, to a large extent, which modalities will be used in the evaluation of hematuria [46, 61]. Thus, in fact, a problem-based imaging algorithm may better be specified as a risk-based algorithm (see Figs. A1–A4 in the Appendix). Obviously, ultrasound and MRU have advantages in that no ionizing radiation is used, but MRU is the most expensive examination. Ultrasound is less costly but is the most operator dependent. The radiation dose of abdominal radiographs is low, approximately 0.2–0.7 mSv [62]. For CT, radiation dose is variable, but for unenhanced CT, it is relatively low (2–3 mSv) [63] and can even be brought below 1 mSv. In contrast, CT urography is associated with much higher doses. Even when optimized in average-sized patients, a pilot study showed that CT urography delivered an average dose of 16 mSv for two phase CT urography protocols and 22 mSv for three phase CT urography (van der Molen AJ, presented at the
TABLE 6: Summary of a Risk-Based Approach to Imaging of Hematuria Risk of Malignancy Characteristics
Low
Type of hematuria
Microhematuria
Microhematuria
Medium Macrohematuria
Macrohematuria
High
Age (y)
≤ 50
> 50
≤ 50
> 50
First line
(Ultrasound) or (cystoscopy)
Ultrasound or cystoscopy
Ultrasound or cystoscopy
CT urography or cystoscopy
Second line
If first line negative, stop
If first line negative and risk or persisting hematuria, CT urography
If first line negative and risk or persisting hematuria, CT urography
If first line negative and persisting hematuria, urine cytology
Third Line
If second line negative and risk or persisting hematuria, urine cytology
If second line negative and risk or persisting hematuria, urine cytology
If second line positive, retrograde ureteropyelography or ureterorenoscopy
Fourth Line
If third line positive, retrograde ureteropyelography or ureterorenoscopy
If third line positive, retrograde ureteropyelography or ureterorenoscopy
Note—See Appendix for additional details.
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Dutch Guidelines on Hematuria TABLE 7: Illustration of Possible Individualized Patient Risk Score and Justification of CT Urography Risk Factors for Urologic Malignancy
Risk Score
Type of hematuria Macroscopic
4
Microscopic, persistent
2
Age > 50 years
3
Lifestyle Smoking
2
Analgesic abuse (phenacetin)
1
Exposure Chemical carcinogens (e.g., aromatic amines)
1
Occupational carcinogens (e.g., rubber manufacture)
1
Patient history Known urothelial cell cancer upper urinary tract
4
Known urothelial cell cancer bladder
4
Known urolithiasis
2
Multiple urinary tract infections
2
Pelvic irradiation
2
Note—CT urography is justifiable as first-line diagnosis in patients with a score ≥ 7.
2010 annual meeting of the American Roentgen Ray Society). The applicability of one phase CT urography with an average dose of 8–9 mSv or low-dose CT urography [64] may be much broader and can be brought in the order of excretory urography doses (3–5 mSv). In general, when CT urography is used for the evaluation of hematuria, the primary goal is urothelial cell cancer tumor detection, which requires high-resolution imaging. The CT urography protocol and radiation dose should be adapted to the clinical question and risk profile of the patient. The most accessible parameters for selection are the age of the patient and the type of hematuria. Although in the literature an age of 40 years is frequently used as cutoff value, Dutch Cancer Registry data show that, in The Netherlands, a cutoff value of 50 years is equally well acceptable for CT urography evaluation of urothelial cell cancer of the upper urinary tract. Given the high radiation dose of CT urography, the use of multiphase examinations should be limited where possible without sacrificing its superior diagnostic potential. CT urography can be used either as a first-line diagnostic or as a problem-solving test (Table 6). For first-line diagnosis, CT urography should be reserved for patients with a high pretest probability for malignancy [46, 65]— that is, patients 50 years old or older with macroscopic hematuria or with the presence
of other risk factors. Ultrasound may still be performed, but its use is limited to fine-tune the CT urography protocol (e.g., the selection of appropriate delay times of excretory phase imaging in cases of unilateral obstruction). In patients with a low-to-average risk profile for malignancy, such as patients younger than 50 years with macroscopic hematuria or patients of any age with microscopic hematuria, CT urography is best reserved as a problemsolving modality if the first-line diagnostic tests are inconclusive and significant complaints or symptoms persist. Among patients younger than 50 years with microscopic hematuria, nonurologic causes have a high prevalence. In these young patients, a diagnostic test without radiation, such as ultrasound, will be the best choice as first-line modality [66]. For the other patient categories, urolithiasis will be the most frequent cause of the hematuria. In these patients, unenhanced CT has the highest sensitivity and could be the examination of choice. However, in daily practice, these low-dose studies are not without problems: their specificity may not be as high as suggested in the “ideal world” of the literature, and ureters may be difficult to identify, especially in the small pelvis. Also, interpretation is more time intensive than that for a combination of ultrasound and abdominal radiography, especially in less experienced hands. Logistically, it may be very
difficult for radiology departments to screen all unenhanced CT examinations to determine whether patients with negative results will belong to a higher risk category and require additional contrast-enhanced scan phases in the same examination. Therefore, the Working Group of the Dutch Hematuria Guideline has opted for CT urography as the next step in the workup of hematuria in these patient categories. However, CT urography is not without limitations, and the positive predictive value is only moderate because many benign pathologic abnormalities will mimic cancer [67]. There are still as many CT urography protocol variations as research groups. Many of these protocols have been described in detail by the CTU Working Group of the European Society of Urogenital Radiology [48]. It is advised to give patients oral water and to add to the CT urography by using low doses of furosemide (5–10 mg). The protocol should be adapted to the clinical question and to the risk of the patient for harboring a malignancy. In patients at highest risk, a standard-dose three phase CT urography protocol and a single contrast medium bolus will give the most flexibility, and it provides the opportunity to individualize the excretory phase by using low-dose test images of ureteral filling. However, standard-dose two phase CT urography protocols using a split contrast medium bolus may work equally well. For patients with benign diseases or who are at lower risk for malignancy, the radiation dose should be taken into close consideration, and low-dose techniques should be used. This can be accomplished by using a combination of optimized technique parameters, modern iterative reconstruction techniques, or by combining phases in split-bolus or triple-bolus contrast injection techniques, resulting in nephrographic-excretory or even corticomedullar-nephrographic-excretory combination phases [68]. A Vision for the Future Beyond this guideline and still very much in the design phase, the initial steps taken in the Dutch Guideline toward a problem- or risk-based approach in the workup of hematuria could be taken one step further. As has been shown in the quantification of the risk for contrast-induced nephropathy during percutaneous coronary interventions, a more optimal risk analysis could integrate information from history, physical examination, laboratory tests, or even results of previous imaging tests [69, 70]. All such factors can then be combined into a weighted score of the personal risk for
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van der Molen and Hovius urologic malignancy. Obviously, such a score should need to be derived by thorough multivariate analysis of large groups of patients with hematuria and subsequently validated in clinical practice. CT urography used as a first-line imaging test for hematuria can be justified if patients have a certain cutoff risk score, and the aggressiveness in the workup can be based on the risk profile of the patient. (Just for purpose of illustrating such an approach, a personal nonvalidated suggestion is shown in Table 7, modeled on a concept by Cowan NC, presented at the 2010 annual meeting of the European Society of Urogenital Radiology.) Conclusion In the workup of hematuria, an individualized problem-based approach to analysis and workup takes over from a one-size-fits-all approach. Patients are now categorized into risk categories according to their clinical presentation and risk factors, and the workup is adapted to that category. The radiologic diagnosis of the upper urinary tract has benefited from the introduction of MDCT urography. This optimized high-resolution imaging technique has silently taken over the role of excretory urography for evaluation of the upper urinary tract. This process has largely been based on data of the diagnostic superiority of CT over other techniques and the preference of radiologists for cross-sectional over projective techniques. To a lesser degree, it has been based on the results of comparative randomized clinical trials with outcome analysis. Imaging is key in the analysis of hematuria, but it should be realized that CT urography is a high-dose examination, upper urinary tract urothelial cell cancer is a rare disease, and the risk for malignancy in many patients with microscopic hematuria is relatively low. Therefore, the use of CT urography should be justified by weighing benefits versus risks, and CT urography protocols should be optimized to radiation dose. This can be accomplished well by this risk-based approach to the workup of hematuria, whereby initial screening is performed with ultrasound and CT urography as a first-line modality is reserved for patients at high risk of malignancy. References 1. Messing EM, Madeb R, Young T, et al. Long term outcome of hematuria home screening for bladder cancer in men. Cancer 2006; 107:2173–2179 2. Britton JP, Dowell AC, Whelan P, Harris CM. A community study of bladder cancer screening by detection of occult urinary bleeding. J Urol 1992;
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van der Molen and Hovius Appendix 1: Diagnostic Algorithms for Asymptomatic Hematuria
Stop Negative Consider ultrasound and cystoscopy Negative findings
Positive
Treat as appropriate Asymptomatic microscopic hematuria < 50 years old
Blood pressure Urinary sediment (+dysmorphic erythrocytes) Urine protein MDRD ≠ eGFR Positive findings Nephrology consultation (consider urological evaluation)
Fig. A1—Asymptomatic microscopic hematuria in patients younger than 50 years. MDRD ≠ eGFR = Modification of Diet in Renal Disease estimated glomerular filtration rate.
Positive
Treat as appropriate
Negative
Stop
Positive
Treat as appropriate
Positive
Retrograde ureteropyelography or ureterorenoscopy
Negative
Stop
Negative
Stop
CT urography Positive Ultrasound and cystoscopy Negative findings
Asymptomatic microscopic hematuria ≥ 50 years old
Blood pressure Urinary sediment (+dysmorphic erythrocytes) Urine protein MDRD ≠ eGFR
Negative
CT urography Positive
Risk factors and persisting microhematuria*
Negative
Urine cytology
Positive findings Nephrology consultation (consider urological evaluation)
Fig. A2—Asymptomatic microscopic hematuria in patients 50 years old or older. *Within several weeks, two of three urinary sediments were positive for blood (> 3 erythrocytes/high-power field). MDRD ≠ eGFR = Modification of Diet in Renal Disease estimated glomerular filtration rate. (Appendix 1 continues on next page)
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Dutch Guidelines on Hematuria Appendix 1: Diagnostic Algorithms for Asymptomatic Hematuria (continued)
Positive
Treat as appropriate
Negative
Stop
Positive
Treat as appropriate
Positive
Retrograde ureteropyelography or ureterorenoscopy
Negative
Stop
Negative
Stop
CT urography Positive Ultrasound and cystoscopy Negative findings
Macroscopic hematuria < 50 years old
Negative
CT urography Positive
Risk factors and persisting micro- or macrohematuria*
Blood pressure Dysmorphic erythrocytes Urine protein MDRD ≠ eGFR (Urinary sediment)
Negative
Urine cytology
Positive findings Consider nephrology consultation in addition to urological evaluation
Fig. A3—Macroscopic hematuria in patients younger than 50 years. *Within several weeks, two of three urinary sediments were positive for blood (> 3 erythrocytes/ high-power field). MDRD ≠ eGFR = Modification of Diet in Renal Disease estimated glomerular filtration rate.
Positive
Treat as appropriate
Positive
Retrograde ureteropyelography or ureterorenoscopy
Negative
Stop
CT urography and cystoscopy
Negative
Negative findings
Macroscopic hematuria ≥ 50 years old
Blood pressure MDRD ≠ eGFR (Urinary sediment) (Urine protein)
Urine cytology
Negative
Positive findings Nephrology consultation in addition to urological evaluation
Fig. A4—Macroscopic hematuria in patients 50 years old or older. MDRD ≠ eGFR = Modification of Diet in Renal Disease estimated glomerular filtration rate.
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