ANTICANCER RESEARCH 33: 5525-5530 (2013)

The Need for Repeated Urological Evaluation in Low-risk Patients with Microscopic After Negative Diagnostic Work-up

RENATE PICHLER1, ISABEL HEIDEGGER1, NICOLAI LEONHARTSBERGER1, BRIGITTE STÖHR1, FRIEDRICH AIGNER2, JASMIN BEKTIC1, WOLFGANG HORNINGER1 and HANNES STEINER1

Departments of 1Urology and 2Radiology, Medical University of Innsbruck, Innsbruck, Austria

Abstract. Aim: To evaluate the role of repeated urological (RBCs) per high-powered field (HPF) on microscopic evaluation after negative initial diagnostic work-up of evaluation of urinary sediment gathered from two or three asymptomatic (AMH) in low-risk patients. urinalysis specimen with no evidence of infection (1). In Patients and Methods: Criteria for patient inclusion were a contrast to macrohematuria, asymptomatic microscopic complete negative initial diagnostic assessment including hematuria is often an incidental finding during a routine ultrasound (US), cystoscopy, upper urinary tract (UUT) imaging check-up (1). Microhematuria may occur just once, but more using intravenous urography (IVU) or multiphasic computed frequently, it is a recurrent occurrence persisting for a lifetime. tomography (CT), absence of risk factors and a follow-up Due to the possible intermittent nature of microhematuria (1, period of at least three years. Based on our institutional 3, 4), detection, screening and, in particular, follow-up of practice, urinalysis was repeated yearly; cystoscopy with US microscopic hematuria is more difficult than it may appear (1). was repeated three years after initial work-up. The oncological Regarding the American Association of Urology (AUA) outcome was evaluated across a mean follow-up of 8 (range: guidelines of 2012 on diagnosis, evaluation and follow-up of 3.7-10.2) years. Results: A case series of 87 (32.2% of 270) low- asymptomatic microhematuria (AMH) in adults, complete risk patients, 56 women and 31 men, with a mean age of 52.4 initial diagnostic evaluation with cystoscopy and radiological (range: 19-87) years was studied. Three years after initial work- evaluation of the upper urinary tract (multi-phasic computed up, cystoscopy confirmed no bladder carcinoma in any of these tomography urography, with and without contrast and 87 patients. Prostate cancer was diagnosed in one (1.1%) excretory phase) should be performed for all patients with patient. In five (5.6%) patients, nephrological evaluation due to AMH (5). In cases of persistent microscopic hematuria after concomitant on follow-up demonstrated chronic negative urological work-up, yearly urinalysis should be renal insufficiency (n=3), IgA nephropathy (n=1) and papillary conducted (as “recommendation grade C”) and repeat necrosis of the kidney (n=1). Conclusion: Low-risk patients with evaluation within three to five years in case of persistent AMH persistent AMH after negative urological evaluation have a should be considered (“expert opinion”) (5). Focusing on the neglectable risk of developing bladder cancer on follow-up. “optimal strategy” of follow-up protocol after negative initial Newly-discovered proteinuria on follow-up should be clarified work-up of AMH, insufficient and inhomogenous data by a nephrologist, as proteinuria could be a sign of significant (frequency of re-testing, description of repeat and initial glomerular disease. evaluation methods) are described in the literature to date, lacking stratification of risk factors (6-10). Therefore, we The prevalence of microhematuria in the general population performed a retrospective analysis among patients with ranges from 0.19% to 38% (1, 2). According to Grossfeld et persistent AMH and no risk factors for urothelial cancer, al., microhematuria is defined by three or more red cells followed-up at our Department for at least three years after complete negative initial work-up, with repeated urinalysis once every year and re-evaluation with cystoscopy and ultrasound three years later as an institutional practice. Correspondence to: Hannes Steiner, MD, Associate Professor of Urology, Department of Urology, Medical University Innsbruck, Anichstrasse 35, 6020 Innsbruck, Austria. Tel: +43 51250481137, Patients and Methods Fax: +43 5125046781137, e-mail: [email protected] After approval from the local Ethical Committee (study number Key Words: Hematuria, second malignancy, bladder cancer, urinary UN4000;280/4.22) we retrospectively investigated clinical records tract malignancy, repeat evaluation, screening. of 270 patients with AMH diagnosed at our Department between

0250-7005/2013 $2.00+.40 5525 ANTICANCER RESEARCH 33: 5525-5530 (2013)

July 1999 and March 2001. Additionally, the initial assessment of necrosis (n=1) and chronic renal insufficiency (n=3). Out of microhematuria included a careful record of medical history of risk these five patients, two (2.3%) had to start dialysis because factors (tobacco smoking, exposure to aromatic amines, polycyclic of chronic renal insufficiency (vascular nephropathy due to aromatic hydrocarbons and chlorinated hydrocarbons, exposure to arteriosclerosis) 2.5 and 4 years after diagnostic ionizing radiation or treatment with cyclophosphamide and pioglitazone) as described by EAU Guidelines on Non-Muscle- microhematuria assessment. Unilateral nephrectomy due to invasive Urothelial Carcinoma of the Bladder 2013 (11), physical infected renal cysts (initial urosepsis) was necessary in one and laboratory examination to rule out other causes (infections, patient (1.1%) with known polycystic 5.4 , cystitis, prostatitis, trauma, viral infections, years after diagnostic work-up of microhematuria. This microhematuria after exercise or menstruation) (5). woman developed renal insufficiency postoperatively and Criteria for study inclusion were a complete initial diagnostic dialysis was also initiated. Additionally, the main attention urological assessment of microhematuria [according to the AUA was drawn to the incidence of malignancies of the urinary guidelines 2012 of asymptomatic microhematuria (5)] including ultrasound, cystoscopy and upper urinary tract (UUT) imaging tract, which occurred after negative diagnostic evaluation. (intravenous urography or computed tomography) in combination Therefore, cystoscopy and sonography was repeated three with a follow-up period of at least three years after negative years after initial work-up in all patients. No bladder diagnostic microhematuria work-up. A total of 64 (23.7%) patients carcinoma was found in any of the 87 patients. No were excluded from the study population due to a follow-up of less abnormality was detected on ultrasound. In one patient than three years, 113 (41.9%) patients were excluded due to missing (1.1%), adenocarcinoma of the prostate was diagnosed 6.4 results of diagnostic examinations, or risk factors and two (0.7%) years after evaluation of AMH. At the time of diagnosis, the patients noticed gross hematuria due to urinary tract infection during the diagnostic work-up. The initial detection of malignancy patient was 71.7 years old and was treated with radical (urothelial cancer of the bladder) was a further exclusion criterion in prostatectomy (Gleason score 6 (3+3), pT2a NX MX R0). four (1.5%) patients. AMH (one or recurrent episodes) with complete negative work-up (ultrasound, cystoscopy and UUT Discussion imaging) and available follow-up of at least three years was determined in 87 (32.2%) low-risk patients (study population) with Microscopic hematuria is a common finding in no risk factors for urothelial cancer (11), (Figure 1). Based on our approximately 21% of the population of the United States of institutional follow-up protocol at that time, urinalysis (yearly) and cystoscopy with sonography (three years later) was repeated after America (12). As urothelial cancer is the most frequently negative work-up for all patients on follow-up. occurring malignancy in patients on microhematuria Variables such as age, gender, maximum available follow-up after screening (13, 14) with an overall detection rate up to 5% initial diagnostic negative work-up of microhematuria, incidence of (15, 16) (in our study: 1.5%) and a positive predictive value genitourinary carcinoma and other diseases resulting in chronic (PPV) of 1.7% for bladder cancer in case of AMH (17), renal insufficiency on follow-up were evaluated. Statistically, precise urological evaluation, including cystoscopy and descriptive analysis (frequency distribution, mean, median and multi-phasic CT urography as imaging procedure, is always range) was used and all statistical analyses were performed with SPSS version 20 (IBM, Armonk, New York, USA). mandatory in every patient with recurrent or persistent microhematuria, especially in those with known risk factors Results such as male gender, age >35 years, past or current smoking, analgesic abuse, exposure to chemicals or carcinogenic Fulfilling the inclusion criteria, 87 (32.2%) out of 270 agents, history of gross hematuria, pelvic irradiation, chronic patients with AMH and a mean age of 52.4 (range: 19-87) urinary tract infection, irritative voiding symptoms (5). years were retrospectively identified. Risk factors such as Variables such as malignant cytology, advanced age and tobacco smoking, exposure to aromatic amines, polycyclic smoking history seem to be the strongest predictors of aromatic hydrocarbons and chlorinated hydrocarbons, bladder cancer in patients with AMH (18, 19). Since the exposure to ionizing radiation, schistosomiasis or treatment prevalence of bladder cancer was found to be higher (15.7%) with cyclophosphamide and pioglitazone (11) were confirmed using a newly developed normogram in patients with AMH in no patient and they were therefore defined as ‘low-risk’ (20), a stratification of risk factors seems to be advantageous patients. The study population consisted of 56 (64.4%) for screening, as well as for follow-up after negative work- women and 31 (35.6%) men. The mean available follow-up up. Therefore, we evaluated the significance of repeated was 8 (range: 3.7-10.2) years after the initial negative work- urological evaluation after negative initial work-up in cases up of AMH. Figure 1 represents an overview of patients’ of persistent AMH in low-risk patients. Currently, characteristics by inclusion and exclusion criteria. On follow- insufficient oncological data are available on long-term up, yearly urinalysis confirmed persistent AMH in all 87 follow up of patients with persistent AMH regarding the risk patients, with concomitant proteinuria in five (5.6%) patients. of subsequent urothelial malignancy (6-10). Searching Nephrological evaluation was necessary in patients with through the literature, we found a total of five studies with proteinuria and confirmed IgA (n=1), papillary varied oncological follow-up results after (different) initial

5526 Pichler et al: Urological Follow-up of Microscopic Hematuria in Low-risk Patients

Figure 1. Flow chart: Study population with inclusion/exclusion criteria and follow-up scheme.

diagnostic protocols of microscopic hematuria. For example, follow-up of three years (telephone interview, questionnaire) Mishriki et al. followed-up 213 patients after negative full (7). Finally, Emamian et al. followed-up 30 patients with AMH work-up (US, cystoscopy and intravenous urography) microscopic hematuria after negative initial assessment with for 13 years. Follow-up was performed by medical and sonography, one (3.3%) patient developed bladder cancer hospital records, in 15 (7%) patients, a full urological re- after 1.5 years of follow-up (hospital case records) (9). In evaluation was carried out: 84.5% had negative urinalyses on summary, it can be stated that the incidence rate of urothelial follow-up and no urological malignancy was detected (8). cancer on follow-up after incomplete initial work-up (7, 9) Additionally, Madeb et al. evaluated 234 patients with was more than twice as high as in the patient group after full complete urological (negative) assessments of AMH (IVU or (6, 8, 10) initial evaluation. The risk that a patient with AMH CT scan, cystoscopy and cytology). During the 14-year after normal urological investigations will subsequently have follow-up, two patients (0.85%) developed bladder cancer at urological malignancy is dependent on the accuracy of the 6.7 and 11.4 years after their negative evaluations and one initial work-up, and may therefore vary with time and among died of bladder cancer 7.6 years after his last screening (6). centers. However, after a thorough initial urological Murakami et al. followed-up 563 patients (after performing investigation of AMH, the majority of patients will remain US, IVU, cytology and cystoscopy intially) during a mean cancer-free during follow-up (5). As published data on the follow-up of 3.8 years. Bladder cancer was confirmed in literature (Table I) are not conclusive regarding patients’ three (1.59%) patients. The follow-up protocol included selection, frequency of re-testing, follow-up protocols and repeated full evaluation every six months for at least three the description of repeat and initial evaluation methods, it is years (10). In our study, all patients (n=87) also underwent impossible to draw any conclusion about the “optimal” complete initial work-up (including cystoscopy and IVU or strategy of follow-up protocol in cases of persistent multiphasic CT). On a follow-up of 3 years, no case of microscopic hematuria. Ideally, the development of a bladder cancer was verified. With performing no initial homogeneous normogram for the prediction of bladder urological evaluation, Wakui et al. confirmed no association cancer (screening and follow-up) considering risk factors between microcytic hematuria and risk of urothelial (11) seems to be indicated to help optimizing referral malignancy (incidence rate 0%) in 869 patients after a patterns (timing and prioritization) of patients with AMH

5527 ANTICANCER RESEARCH 33: 5525-5530 (2013)

Table I. Literature overview of the incidence of urogenital malignancy on follow-up of patients with microscopic hematuria (after negative initial evaluation).

Authors N Initial urologic Mean follow-up Urothelial (year) (Ref.) work-up (years) cancer (%)

Murakami et al. (1990) (10) 563 US+IVU, cystoscopy, 3.8 (Repeated full evaluation 1.59% Bladder cytology every 6 months) Emamian et al. (1995) (9) 30 US 1.5 (Hospital case record) 3.3% Bladder Wakui et Shiigai. (2000) (7) 869 (Microcytic No 3 (Telephone interview, 0% Bladder hematuria) questionaire) Mishriki et al. (2008) (8) 213 US, IVU, cystoscopy 13 (Medical and hospital records; 0% Bladder in 15 patients: full re-evaluation) Madeb et al. (2010) (6) 234 IVU, cystoscopy, cytology 14 0.85% Bladder Present study 87 US, IVU or CT, 8 (US+cystoscopy 0% Bladder cystoscopy, cytology after 3 years)

(20). As the detection rate of urinary tract cancer during insufficiency was noticed in patients with hematuria and diagnostic work-up was increased in the ‘high-risk’ versus concomitant proteinuria (14.9%). Renal biopsy (performed in the ‘low-risk’ population (11.1% vs. 0.2%) (21), regular patients who had a moderate degree of proteinuria) revealed evaluations in the high-risk group are recommended in IgA nephropathy (68.2%), non-IgA mesangial proliferative literature (22, 23). Therefore, we agree with the statement glomerulonephritis (GN) (12.6%), membranous nephropathy that patients at high risk for urinary tract malignancies in (6%), minimal change nephritis (5.3%) and focal and particular need complete upper and lower urinary tract segmental glomerular sclerosis (2.6%) (26). Yamagata et al. evaluation as an initial diagnostic tool (1, 14), with repeated reported an incidence of concomitant proteinuria in 9.5% of evaluation in cases of persistent or recurrent AMH after 404 patients with microscopic hematuria with a mean follow- negative urological work-up. This is especially true in up of 6.3 years. The highest risk of developing renal patients with changes of clinical scenario, such as a insufficiency was confirmed in patients with hematuria and substantial increase in the degree of AMH, gross hematuria, proteinuria developed over 40 years (27). In our study, 5.6% pain or other new symptoms (5). Edwards et al. showed that (n=5) out of 87 patients manifested concomitant proteinuria the probability of missing malignant disease (using the during long-term follow-up. Careful observation and protocol likelihood ratio) was 1% in cases of microscopic management of this selective patient cohort seems to be useful hematuria based on a 4-year follow-up, but this rose to >4% on follow-up of persistent microscopic hematuria (26). Hall et in patients with the presence of risk factors (macroscopic al. recommended renal biopsy in patients with persistent hematuria, male, age >60 years), (24). On the contrary, in asymptomatic microscopic hematuria and low-grade ‘low-risk’ patients we did not identify any case of bladder proteinuria, identifying potentially progressive nephropathies cancer on cystoscopy three years after negative urological in more than 70% of patients (46% IgA nephropathy, 26% evaluation of AMH and therefore, in the absence of risk other nephropathies) and hypertension in 56% on a mean factors or symptoms, it is difficult to justify repeated follow-up of 46±12 months (28). In the study of Mishriki et urological evaluations in our opinion. Yearly urinalyses al., approximately 30.3% (n=10) of patients with persistent should also be conducted on follow-up to detect patients at microscopic hematuria were referred for nephrological risk for other non-malignant diseases such as glomerular evaluation because of manifested proteinuria; 4 (40%) of these nephropathy, proteinuria, renal disease (5). Regarding the patients underwent renal biopsy and were diagnosed with IgA risk of developing renal insufficiency or end-stage renal nephropathy (8). Early detection of concomitant proteinuria disease (ESRD) in patients with persistent isolated may have significant impact on a patient’s life because of three microhematuria, Vivante et al. confirmed an incidence rate facts: firstly, proteinuria in patients with IgA nephropathy of 34,0/100,000 person-years and 26 (0.70%) of 3,690 young during follow-up is the single most important risk factor for adults developed ESRD after a mean follow-up of 21.8 years renal failure (36% within 20 years) (29); secondly, the degree (5). An association between isolated hematuria and renal of proteinuria is widely recognized as a marker of the severity insufficiency was not confirmed, but we should keep in mind of and as a predictor of future decline that 10.6% of patients with asymptomatic hematuria in glomerular filtration rate (30) and thirdly, an additional manifested concomitant proteinuria after a mean follow-up relationship between proteinuria levels and cardiovascular risk period of 5.80±4.42 years. The highest rate of renal seems to exist (30).

5528 Pichler et al: Urological Follow-up of Microscopic Hematuria in Low-risk Patients

Conclusion 6 Madeb R, Golijanin D, Knopf J, Davis M, Feng C, Fender A, Stephenson L and Messing EM: Long-term outcome of patients In summary, ‘low-risk’ patients with persistent AMH after with a negative work-up for asymptomatic microhematuria. Urology 75(1): 20-25, 2010. complete negative urological evaluation have a negligible risk 7 Wakui M and Shiigai T: Urinary tract cancer screening through of developing bladder cancer on follow-up. Therefore, in the analysis of urinary volume distribution. Int J Urol absence of risk factors or symptoms (irritative voiding 7(7): 248-253, 2000. symptoms, flank pain, new developed gross hematuria), it is 8 Mishriki SF, Nabi G and Cohen NP: Diagnosis of urologic difficult to justify repeated urological evaluations. Prospective malignancies in patients with asymptomatic dipstick hematuria: and multi-institutional randomized trials with homogeneous prospective study with 13 years’ follow-up. Urology 71(1): 13- and long-term follow-up protocols are necessary, firstly to 16, 2008. demonstrate in detail the subsequent incidence of 9 Emamian SA, Nielsen MB and Pedersen JF: Can dipstick screening for hematuria identify individuals with structural renal genitourinary cancer after negative work-up in cases of abnormalities? A sonographic evaluation. Scand J Urol Nephrol persistent microscopic hematuria, comparing ‘low- risk’ to 30(1): 25-27, 1996. ‘high-risk’ patients; secondly, to verify the risk of 10 Murakami S, Igarashi T, Hara S and Shimazaki J: Strategies for ESRD/nephropathy in patients with persistent asymptomatic asymptomatic microscopic hematuria: a prospective study of hematuria (with and without proteinuria). The limitation of 1,034 patients. J Urol 144(1): 99-101, 1990. this study is the small sample size of 87 patients 11 Babjuk M, Burger M, Zigeuner R, Shariat SF, van Rhijn BW, retrospectively evaluated, with subsequent restricted means of Compérat E, Sylvester RJ, Kaasinen E, Böhle A, Palou Redorta J and Rouprêt M: EAU Guidelines on Non-Muscle-invasive interpretation. As the likelihood of finding significant Urothelial Carcinoma of the Bladder: Update 2013. Eur Urol urological diseases on subsequent work-up (particulary 64(4): 639-653, 2013. urological cancer) appears to be related to risk factors, the 12 Trivedi D and Messing EM: Commentary: the role of cytologic focus of AMH follow-up should be placed on early detection analysis of voided in the work-up of asymptomatic of patients at higher risk of developing urothelial cancer, microhematuria. BMC urology 9: 13, 2001. affirming the recommended AUA follow-up schedules in 13 Grossfeld GD, Wolf JS, Litwin MS, Hricak H, Shuler CL, Agerter cases of persistent microhematuria. Appropiate timing and DC and Carroll PR: Asymptomatic microscopic hematuria in frequency of re-evaluation should be decided on an individual adults: Summary of the AUA Best Practice Policy Recommenda- tions. American Family Physician 63: 1145-1154, 2001. basis, focusing on symptomatic patients with risk factors. 14 Grossfeld GD, Litwin MS, Wolf JS, Hricak H, Shuler CL, Agerter DC and Carroll PR: Evaluation of asymptomatic Acknowledgements microscopic hematuria in adults: The American urological Association Best Practice Policy - Part II. Urology 57: 604-610, We would like to thank Tanja Frank for her support and 2001. 15 Schmitz-Dräger BJ, Tirsar LA, Schmitz-Dräger C, Dörsam J, contribution to this work. Mellan Z, Bismarck E and Ebert T: Immunocytology in the assessment of patients with asymptomatic hematuria. World J References Urol 26(1): 31-37, 2008. 16 Edwards TJ, Dickinson AJ, Natale S, Gosling J and McGrath JS: 1 Grossfeld GD, Litwin MS, Wolf JS, Hricak H, Shuler CL, A prospective analysis of the diagnostic yield resulting from the Agerter DC and Carroll PR: Evaluation of asymptomatic attendance of 4020 patients at a protocol-driven haematuria microscopic hematuria in adults: The American Urological clinic. BJU Int 97(2): 301-5, 2006. Association Best Practice Policy- Part1. Urology 57: 599-603, 17 Sugimura K, Ikemoto SI, Kawashima H, Nishisaka N and 2001. Kishimoto T: Microscopic hematuria as a screening marker for 2 Boman H, Hedelin H, Jacobsson S and Holmäng S: Newly urinary tract malignancies. Int J Urol 8(1): 1-5, 2001. diagnosed bladder cancer: the relationship of initial symptoms, 18 Badalament RA, Hermansen DK, Kimmel M, Gay H, Herr HW, degree of microhematuria and tumor marker status. J Urol 168: Fair WR, Whitmore WF Jr. and Melamed MR: The sensitivity 1955-1959, 2002. of bladder wash flow cytometry, bladder wash cytology, and 3 Cohen RA and Brown RS: Microscopic hematuria. N Engl J voided cytology in the detection of bladder carcinoma. Cancer Med 348: 2330-2338, 2003. 1;60(7): 1423-1427, 1987. 4 Nabi G, Greene D and Donnel MO: Suspicious urinary cytology 19 Shariat SF, Sfakianos JP, Droller MJ, Karakiewicz PI, Meryn S with negative evaluation for malignancy in the diagnostic and Bochner BH: The effect of age and gender on bladder investigation of hematuria: how to follow- up? J Clin Pathol 57: cancer: a critical review of the literature. BJU Int 105(3): 300- 365-368, 2004. 308, 2010. 5 Davis R, Jones JS, Barocas DA, Castle EP, Lang EK, Leveillee 20 Cha EK, Tirsar LA, Schwentner C, Hennenlotter J, Christos PJ, RJ, Messing EM, Miller SD, Peterson AC, Turk TM and Weitzel Stenzl A, Mian C, Martini T, Pycha A, Shariat SF and Schmitz- W: American Urological Association: Diagnosis, evaluation and Dräger BJ: Accurate risk assessment of patients with follow-up of asymptomatic microhematuria (AMH) in adults: asymptomatic hematuria for the presence of bladder cancer. AUA guideline. J Urol 188(6 Suppl): 2473-2481, 2012. World J Urol 30(6): 847-852, 2012.

5529 ANTICANCER RESEARCH 33: 5525-5530 (2013)

21 Loo RK, Lieberman SF, Slezak JM, Landa HM, Mariani AJ, 27 Yamagata K, Takahashi H, Tomida C, Yamagata Y and Koyama Nicolaisen G, Aspera AM and Jacobsen SJ: Stratifying risk of A: Prognosis of asymptomatic hematuria and/or proteinuria in urinary tract malignant tumors in patients with asymptomatic men. High prevalence of IgA nephropathy among proteinuric microscopic hematuria. Mayo Clin Proc 88(2): 129-138, 2013. patients found in mass screening. Nephron 91(1): 34-42, 2002. 22 Hiatt RA and Ordoñez JD: Dipstick urinalysis screening, 28 Hall CL, Bradley R, Kerr A, Attoti R and Peat D: Clinical value asymptomatic microhematuria, and subsequent urological of renal biopsy in patients with asymptomatic microscopic cancers in a population-based sample. Cancer Epidemiol hematuria with and without low-grade proteinuria. Clin Nephrol Biomarkers Prev 3(5): 439-443, 1994. Erratum in: Cancer 62(4): 267-72, 2004. Epidemiol Biomarkers Prev 3(6): 523, 1994. 29 Le W, Liang S, Hu Y, Deng K, Bao H, Zeng C and Liu Z: Long- 23 Messing EM, Young TB, Hunt VB, Newton MA, Bram LL, term renal survival and related risk factors in patients with IgA Vaillancourt A, Hisgen WJ, Greenberg EB, Kuglitsch ME and nephropathy: results from a cohort of 1155 cases in a Chinese Wegenke JD: Hematuria home screening: repeat testing results. adult population. Nephrol Dial Transplant 27(4): 1479-1485, J Urol 154(1): 57-61, 1995. 2012. 24 Edwards TJ, Dickinson AJ, Gosling J, McInerney PD, Natale S 30 Cravedi P and Remuzzi G: Pathophysiology of proteinuria and and McGrath JS: Patient-specific risk of undetected malignant its value as an outcome measure in CKD. Br J Clin Pharmacol disease after investigation for haematuria, based on a 4-year 76(4): 516-523, 2013. follow-up. BJU Int 107(2): 247-252, 2011. 25 Vivante A, Afek A, Frenkel-Nir Y, Tzur D, Farfel A, Golan E, Chaiter Y, Shohat T, Skorecki K and Calderon-Margalit R: Persistent asymptomatic isolated microscopic hematuria in Israeli adolescents and young adults and risk for end-stage renal disease. JAMA 306(7): 729-736, 2011. 26 Yamagata K, Yamagata Y, Kobayashi M and Koyama A: A long- Received October 15, 2013 term follow-up study of asymptomatic hematuria and/or Revised November 6, 2013 proteinuria in adults. Clin Nephrol 45(5): 281-288, 1996. Accepted November 7, 2013

5530