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1.  National Practice Recommendations for Hematuria: How to Evaluate in the Absence of Strong Evidence? 
The Permanente Journal  2009;13(1):37-46.
Hematuria is one of the most common conditions confronting clinical urologists and is present in many genitourinary pathology conditions. Although researchers have studied hematuria symptoms in an effort to determine the best diagnostic pathway, the existing lack of scientific evidence has created variations in clinical practice. The literature does not provide enough evidence to significantly alter the need to assess these patients. Consequently, many patients with microscopic or gross hematuria undergo low-yield workups that include invasive testing and imaging with radiation. In 2007, a national group of Kaiser Permanente (KP) urology chiefs agreed that national practice recommendations were needed to address existing variations in the management and workup of hematuria. Using a KP guideline methodology, the group reached a consensus agreement on the following recommendations: 1) referral to urology is recommended for all people with gross hematuria or high-grade hematuria (>50 red blood cells per high-power field [RBCs/HPF]) on a single urinalysis (UA); 2) referral to urology and urologic evaluation is recommended for men or women with asymptomatic microscopic hematuria or symptomatic hematuria that produces >3 RBCs/HPF on two of three properly performed and collected urinalyses; and 3) voided urinary cytology should be eliminated from asymptomatic hematuria screening protocol. The test is not sensitive enough to obviate further workup if findings are negative, and elimination of this screening test is estimated to save millions of dollars across the US. Hematuria on a UA should be reported as 0 to 3 RBC/HPF, 4 to 10 RBC/HPF, 11 to 25 RBC/HPF, 26 to 50 RBC/HPF, >50 RBC/HPF, or gross hematuria. This approach will also reduce radiation exposure.
PMCID: PMC3034463  PMID: 21373244
2.  High Risk Patients with Hematuria Are Not Evaluated According to Guideline Recommendations 
Cancer  2010;116(12):2954-2959.
Purpose
To determine whether high risk patients with hematuria receive evaluation according to guideline recommendations.
Materials and Methods
We recently performed a screening study for bladder cancer using a urine-based tumor marker in 1502 subjects at high risk based on age over 50, ≥10-year smoking history, and/or a 15 year or more environmental exposure. We evaluated use of urinalysis (UA) within 3 years preceding the screening study. Chart review was performed to determine if this subset with microhematuria received any additional evaluation.
Results
Of 1502 study participants, routine urinalysis was performed in 73.2% and 164 (14.9%) subjects had documented hematuria (>3 RBCs/HPF) prior to inclusion. Of these, 42.1% had no further evaluation. Additional testing included repeat urinalysis (36%), urine culture (15.2%), cytology (10.4%), imaging (22.6% overall: 15.9% CT, 4.3% IVP; 2.4% MRI) and cystoscopy (12.8%).
Three subjects with microscopic hematuria (2%) were subsequently found to have bladder cancer during the screening study but were not referred for evaluation based on their hematuria. The source of hematuria was unknown in 65%, infection in 22%, benign prostatic enlargement in 10% and renal stone disease in 4% but these results are based on incomplete evaluation since only 12.8% underwent cystoscopy.
Conclusions
Subjects at high risk for bladder cancer based on ≥10 years of smoking or environmental exposure with microscopic hematuria are rarely evaluated thoroughly and only 12.8% were referred for urologic evaluation. Further studies are needed to evaluate both the utilization and effectiveness of guidelines for hematuria.
doi:10.1002/cncr.25048
PMCID: PMC2940122  PMID: 20564400
Hematuria; Guidelines Recommendations; bladder cancer
3.  Accurate Risk Assessment of Patients with Asymptomatic Hematuria for the Presence of Bladder Cancer 
World journal of urology  2012;30(6):847-852.
Purpose
Bladder cancer is frequently diagnosed during a workup for hematuria. However, most patients with microscopic hematuria and many with gross hematuria are not appropriately referred to urologists. We hypothesized that in patients presenting with asymptomatic hematuria, the risk of having bladder cancer can be predicted with high accuracy. Towards this end, we analyzed risk factors in patients with asymptomatic hematuria and developed a nomogram for the prediction of bladder cancer presence.
Methods
Data from 1,182 consecutive subjects without a history of bladder cancer undergoing initial evaluation for asymptomatic hematuria were collected at three centers. Clinical risk factors including age, gender, smoking status, and degree of hematuria were recorded. All subjects underwent standard workup including voided cytology, upper tract imaging, and cystourethroscopy. Factors associated with the presence of bladder cancer were evaluated by univariable and multivariable logistic regression analyses. The multivariable analysis was used to construct a nomogram. Internal validation was performed using 200 bootstrap samples.
Results
Of the 1,182 subjects who presented with asymptomatic hematuria, 245 (20.7%) had bladder cancer. Increasing age (OR=1.03, p<0.0001), smoking history (OR=3.72, p<0.0001), gross hematuria (OR=1.71, p=0.002), and positive cytology (OR=14.71, p<0.0001) were independent predictors of bladder cancer presence. The multivariable model achieved 83.1% accuracy for predicting the presence of bladder cancer.
Conclusions
Bladder cancer presence can be predicted with high accuracy in patients who present with asymptomatic hematuria. We developed a nomogram to help optimize referral patterns (i.e., timing and prioritization) of patients with asymptomatic hematuria.
doi:10.1007/s00345-012-0979-x
PMCID: PMC4004026  PMID: 23124847
urinary bladder neoplasms; hematuria; nomograms; early detection of cancer; carcinoma
4.  Thin glomerular basement membrane disease: light microscopic and electron microscopic studies. 
Journal of Korean Medical Science  1997;12(3):234-239.
Benign recurrent hematuria usually indicates a good prognosis. This condition is associated with abnormally thin glomerular basement membranes. Of 680 renal biopsy cases in which lower urinary tract disease had been excluded by careful study, 25 cases from seven children and eighteen adults met the criteria for thin glomerular basement membrane disease, placing the incidence of the disease at 3.7%. The mean patient age was 32.4 years and the male to female ratio was 1 to 5.3. The primary finding was microscopic hematuria in eighteen patients and gross hematuria in five patients. Among eighteen patients who had microscopic hematuria, one patient also exhibited proteinuria and one patient suffered from acute renal failure due to acute drug-induced interstitial nephritis. Proteinuria was only found in one patient. All of the patients had normal renal function, with the exception of one who suffered from acute renal failure. The duration of hematuria from the time of detection to the date of biopsy ranged from 3 months to 30 years with a mean interval of 56.6 months. No apparent evidence of familial hematuria in any patient was noted. Under light microscopy most glomeruli were normal. However, five cases showed focal global sclerosis. Under immunofluorescence microscopy seventeen cases were negative for all immunoglobulins, for complement, and for fibrinogen. Eight cases showed nonspecific mesangial deposition of fibrinogen and/or IgM. Ultrastructurally, extensive diffuse thinning of the GBM was a constant finding. The mean thickness of the GBM was 203.2 +/- 28.3 nm (n = 25); the thickness in adult (201.4 +/- 27.5 nm; n = 18) did not differ from that in children (208.1 +/- 32.0 nm; n = 7).
PMCID: PMC3054286  PMID: 9250920
5.  Commentary: the role of cytologic analysis of voided urine in the work-up of asymptomatic microhematuria 
BMC Urology  2009;9:13.
Microscopic hematuria is a common finding in patients presenting to both primary care doctors as well as urologists. Sources of microscopic hematuria include infection, stones, inflammatory disorders as well as cancer of the genitourinary tract, particularly urothelial cancer. A primary focus in the urologic workup of hematuria is to rule out cancer. This is done using radiographic studies as well as procedures such as cystoscopy and bladder biopsy. As the authors state in their article titled "The utility of serial urinary cytology in the initial evaluation of the patient with microscopic hematuria", cytologic analysis of voided urine, though attractive due to its noninvasive nature, has been found to have the neither the sensitivity, cost-effectiveness, nor the ease of administration necessary to replace more invasive diagnostics in the evaluation of microscopic hematuria.
doi:10.1186/1471-2490-9-13
PMCID: PMC2753578  PMID: 19744318
6.  Macroscopic Hematuria—A Leading Urological Problem in Patients on Anticoagulant Therapy: Is the Common Diagnostic Standard Still Advisable? 
ISRN Urology  2012;2012:710734.
All urological standards of care are based on the past definition of the clinical importance of macroscopic hematuria. The aim of the study was to assess the phenomenon of iatrogenic hematuria in current clinical practice and analyze its origins in patients receiving anticoagulant drugs. Retrospective analysis of clinical documentation of 238 patients that were consulted for hematuria in 2007–2009 by 5 consultant urologists was performed. In the group of 238 patients with hematuria, 155 (65%) received anticoagulants. Abnormalities of urinary tract were found in 45 (19%) patients. Estimated cost of a single neoplasm detection reached the value of 3252 Euro (mean 3-day hospitalization). The strong correlation between the presence of hematuria and anticoagulant treatment was observed. Authors suggest to redefine the present and future role of hematuria from a standard manifestation of serious urological disease to a common result of a long-term anticoagulant therapy.
doi:10.5402/2012/710734
PMCID: PMC3329860  PMID: 22567422
7.  Hemoglobinuria Misidentified as Hematuria: Review of Discolored Urine and Paroxysmal Nocturnal Hemoglobinuria 
Discolored urine is a common reason for office visits to a primary care physician and urology referral. Early differentiation of the type or cause of discolored urine is necessary for accurate diagnosis and prompt management.
Paroxysmal nocturnal hemoglobinuria is a clonal disorder caused by acquired somatic mutations in the PIG-A gene on the X- chromosome of hemopoietic stem cells and leads to deficiency of surface membrane anchor proteins. The deficiency of these proteins leads to an increased risk of hemolysis of erythrocytes and structural damage of platelets, resulting in a clinical syndrome characterized by complement-mediated intravascular hemolytic anemia, bone marrow failure, and venous thrombosis. Patients with this clinical syndrome present with paroxysms of hemolysis, causing hemoglobinuria manifesting as discolored urine. This can be easily confused with other common causes of discolored urine and result in extensive urologic work-up. Three commonly confused entities of discolored urine include hematuria, hemoglobinuria, and myoglobinuria. Specific characteristics in a dipstick test or urinalysis can guide differentiation of these three causes of discolored urine.
This article begins with a case summary of a woman presenting with cranberry-colored urine and a final delayed diagnosis of paryxysmal nocturnal hemoglobinuria. Her hemoglobinuria was misdiagnosed as hematuria, leading to extensive urologic work-up. The article also gives an overview of the approach to diagnosing and treating discolored urine.
doi:10.4137/CMBD.S11517
PMCID: PMC4222305  PMID: 25512715
discolored urine; hematuria; hemoglobinuria; myoglobinuria; paroxysmal nocturnal hemoglobinuria; GPI-AP (glycosylphosphatidylionositol—anchor proteins); CD55; CD59
8.  The Clinical Significance of a Retroaortic Left Renal Vein 
Korean Journal of Urology  2010;51(4):276-280.
Purpose
A retroaortic left renal vein (RLRV) is located between the aorta and the vertebra and drains into the inferior vena cava. Urological symptoms can be caused by increased pressure in the renal vein. To evaluate the clinical importance of RLRV, we reviewed patients' medical records and radiologic findings.
Materials and Methods
Nine patients who were studied with multidetector computed tomography at our institution from January 2003 to December 2009 had urologic symptoms with RLRV. We retrospectively reviewed these patients' medical records and analyzed their clinical characteristics.
Results
The patients' mean age was 46.0±20.1 years (range, 17-65 years) and the male to female ratio was 5 to 4. The urologic symptoms of the initial diagnosis were various (hematuria: 5 of the 9 patients; left flank pain: 4 of the 9 patients; inguinal pain: 1 of the 5 male patients; and gross hematuria: 1 of the 9 patients). The distribution among the type I, II, III, and IV of RLRV was 6, 2, 1, and 0 patients, respectively. The concomitant diseases were ureteropelvic junction obstruction (UPJO; 2 of the 9 patients) and varicocele (2 of the 5 male patients). One patient with UPJO underwent pyeloplasty and the other patient with UPJO underwent nephrectomy due to a nonfunctional atrophied kidney. The microscopic hematuria was not resolved with conservative management for long-term follow-up.
Conclusions
Hematuria and inguinal or flank pain seem to be common in patients with RLRV. The most common type of RLRV was type I. It appeared that the microscopic hematuria continued in the long-term follow-up.
doi:10.4111/kju.2010.51.4.276
PMCID: PMC2858856  PMID: 20428432
Abnormalities; Renal veins; Tomography
9.  Interactions between Non-Physician Clinicians and Industry: A Systematic Review 
PLoS Medicine  2013;10(11):e1001561.
In a systematic review of studies of interactions between non-physician clinicians and industry, Quinn Grundy and colleagues found that many of the issues identified for physicians' industry interactions exist for non-physician clinicians.
Please see later in the article for the Editors' Summary
Background
With increasing restrictions placed on physician–industry interactions, industry marketing may target other health professionals. Recent health policy developments confer even greater importance on the decision making of non-physician clinicians. The purpose of this systematic review is to examine the types and implications of non-physician clinician–industry interactions in clinical practice.
Methods and Findings
We searched MEDLINE and Web of Science from January 1, 1946, through June 24, 2013, according to PRISMA guidelines. Non-physician clinicians eligible for inclusion were: Registered Nurses, nurse prescribers, Physician Assistants, pharmacists, dieticians, and physical or occupational therapists; trainee samples were excluded. Fifteen studies met inclusion criteria. Data were synthesized qualitatively into eight outcome domains: nature and frequency of industry interactions; attitudes toward industry; perceived ethical acceptability of interactions; perceived marketing influence; perceived reliability of industry information; preparation for industry interactions; reactions to industry relations policy; and management of industry interactions. Non-physician clinicians reported interacting with the pharmaceutical and infant formula industries. Clinicians across disciplines met with pharmaceutical representatives regularly and relied on them for practice information. Clinicians frequently received industry “information,” attended sponsored “education,” and acted as distributors for similar materials targeted at patients. Clinicians generally regarded this as an ethical use of industry resources, and felt they could detect “promotion” while benefiting from industry “information.” Free samples were among the most approved and common ways that clinicians interacted with industry. Included studies were observational and of varying methodological rigor; thus, these findings may not be generalizable. This review is, however, the first to our knowledge to provide a descriptive analysis of this literature.
Conclusions
Non-physician clinicians' generally positive attitudes toward industry interactions, despite their recognition of issues related to bias, suggest that industry interactions are normalized in clinical practice across non-physician disciplines. Industry relations policy should address all disciplines and be implemented consistently in order to mitigate conflicts of interest and address such interactions' potential to affect patient care.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Making and selling health care goods (including drugs and devices) and services is big business. To maximize the profits they make for their shareholders, companies involved in health care build relationships with physicians by providing information on new drugs, organizing educational meetings, providing samples of their products, giving gifts, and holding sponsored events. These relationships help to keep physicians informed about new developments in health care but also create the potential for causing harm to patients and health care systems. These relationships may, for example, result in increased prescription rates of new, heavily marketed medications, which are often more expensive than their generic counterparts (similar unbranded drugs) and that are more likely to be recalled for safety reasons than long-established drugs. They may also affect the provision of health care services. Industry is providing an increasingly large proportion of routine health care services in many countries, so relationships built up with physicians have the potential to influence the commissioning of the services that are central to the treatment and well-being of patients.
Why Was This Study Done?
As a result of concerns about the tension between industry's need to make profits and the ethics underlying professional practice, restrictions are increasingly being placed on physician–industry interactions. In the US, for example, the Physician Payments Sunshine Act now requires US manufacturers of drugs, devices, and medical supplies that participate in federal health care programs to disclose all payments and gifts made to physicians and teaching hospitals. However, other health professionals, including those with authority to prescribe drugs such as pharmacists, Physician Assistants, and nurse practitioners are not covered by this legislation or by similar legislation in other settings, even though the restructuring of health care to prioritize primary care and multidisciplinary care models means that “non-physician clinicians” are becoming more numerous and more involved in decision-making and medication management. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic), the researchers examine the nature and implications of the interactions between non-physician clinicians and industry.
What Did the Researchers Do and Find?
The researchers identified 15 published studies that examined interactions between non-physician clinicians (Registered Nurses, nurse prescribers, midwives, pharmacists, Physician Assistants, and dieticians) and industry (corporations that produce health care goods and services). They extracted the data from 16 publications (representing 15 different studies) and synthesized them qualitatively (combined the data and reached word-based, rather than numerical, conclusions) into eight outcome domains, including the nature and frequency of interactions, non-physician clinicians' attitudes toward industry, and the perceived ethical acceptability of interactions. In the research the authors identified, non-physician clinicians reported frequent interactions with the pharmaceutical and infant formula industries. Most non-physician clinicians met industry representatives regularly, received gifts and samples, and attended educational events or received educational materials (some of which they distributed to patients). In these studies, non-physician clinicians generally regarded these interactions positively and felt they were an ethical and appropriate use of industry resources. Only a minority of non-physician clinicians felt that marketing influenced their own practice, although a larger percentage felt that their colleagues would be influenced. A sizeable proportion of non-physician clinicians questioned the reliability of industry information, but most were confident that they could detect biased information and therefore rated this information as reliable, valuable, or useful.
What Do These Findings Mean?
These and other findings suggest that non-physician clinicians generally have positive attitudes toward industry interactions but recognize issues related to bias and conflict of interest. Because these findings are based on a small number of studies, most of which were undertaken in the US, they may not be generalizable to other countries. Moreover, they provide no quantitative assessment of the interaction between non-physician clinicians and industry and no information about whether industry interactions affect patient care outcomes. Nevertheless, these findings suggest that industry interactions are normalized (seen as standard) in clinical practice across non-physician disciplines. This normalization creates the potential for serious risks to patients and health care systems. The researchers suggest that it may be unrealistic to expect that non-physician clinicians can be taught individually how to interact with industry ethically or how to detect and avert bias, particularly given the ubiquitous nature of marketing and promotional materials. Instead, they suggest, the environment in which non-physician clinicians practice should be structured to mitigate the potentially harmful effects of interactions with industry.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001561.
This study is further discussed in a PLOS Medicine Perspective by James S. Yeh and Aaron S. Kesselheim
The American Medical Association provides guidance for physicians on interactions with pharmaceutical industry representatives, information about the Physician Payments Sunshine Act, and a toolkit for preparing Physician Payments Sunshine Act reports
The International Council of Nurses provides some guidance on industry interactions in its position statement on nurse-industry relations
The UK General Medical Council provides guidance on financial and commercial arrangements and conflicts of interest as part of its good medical practice website, which describes what is required of all registered doctors in the UK
Understanding and Responding to Pharmaceutical Promotion: A Practical Guide is a manual prepared by Health Action International and the World Health Organization that schools of medicine and pharmacy can use to train students how to recognize and respond to pharmaceutical promotion.
The Institute of Medicine's Report on Conflict of Interest in Medical Research, Education, and Practice recommends steps to identify, limit, and manage conflicts of interest
The University of California, San Francisco, Office of Continuing Medical Education offers a course called Marketing of Medicines
doi:10.1371/journal.pmed.1001561
PMCID: PMC3841103  PMID: 24302892
10.  High-grade microscopic hematuria in adult men can predict urothelial malignancy 
Introduction:
Microscopic hematuria in men younger than 40 is a confusing issue to urologists, especially when these men have normal radiological findings. We report our experience in looking for urologic malignancy in this group of patients.
Methods:
We conducted a prospective study for men with vague urological symptoms. We included men under 40 years old, men with microscopic hematuria greater than 25 red blood cells/high power field in 2 properly collected mid-stream urine samples, and men with free urine culture and normal multiphasic computed tomography abdomen and pelvis studies. All patients underwent diagnostic cystoscurethroscopy. If there were no lesions, multiple random biopsies were taken. In cases of apparently normal cystoscopic findings and associated renal colic, uretroscopy was done to the suspected side.
Results:
Only 20 patients fulfilled our inclusion criteria. The mean age of the patients were 34; 2 patients presented with pain. The other 18 patients were presenting with mild recurrent lower urinary tract symptoms. Cystoscopy showed small papillary low-grade tumour in 3 patients. All random biopsies were free of malignancy. Unilateral uretroscopy for the 2 cases presented with pain detected carcinoma in situ in one of them.
Conclusion:
Cystoscopy is highly recommended for young adult men, with significant levels of microscopic hematuria, due to the 20% incidence rate of associated urological malignancy. Random bladder biopsies, in the absence of suspicious lesions, have no diagnostic role, and should not be done. Uretroscopy is advised for patients with microscopic hematuria and loin pain, even in the absence of suspicious radiological findings.
doi:10.5489/cuaj.1746
PMCID: PMC4113579  PMID: 25132893
11.  Dipstick urine analysis screening among asymptomatic school children 
Background:
Mass urinary screening is a useful tool to identify children with asymptomatic progressive renal diseases. A dipstick urinalysis screening was conducted to detect such prevalence and to set up a more effective screening program for children.
Patients and Methods:
A cross sectional study was carried out in seven nurseries and primary schools in different regions of Lebanon (Beirut, North Lebanon, and Valley of Bekaa) between February 2010 and March 2010. Eight hundred seventy asymptomatic children were enrolled in this study. First morning mid steam urine samples were obtained from students and were tested by dipstick method. Children with abnormal findings were re-tested after fifteen days.
Results:
Twenty five (2.9%) children had urinary abnormalities at the first screening; Eighteen (72%) of them still had abnormal results at the second screening. Among all the students, hematuria was the most common abnormality found with a prevalence of 1.5%, followed by nitrituria (0.45%), combined hematuria and nitrituria (0.45%) and proteinuria (0.1%). Urinary abnormalities were more common in females than in males. With respect to age, most positive results were detected at 6 years of age. Hematuria and proteinuria were mainly present in the North of Lebanon.
Conclusion:
Asymptomatic urinary abnormalities might be detected by urine screening program at school age. Further work-up should be offered to define the exact etiology of any abnormal finding and to determine whether early detection of renal disorders in childhood will lead to effective interventions and reduction in the number of individuals who develop end-stage renal disease.
doi:10.4297/najms.2011.3179
PMCID: PMC3336909  PMID: 22540088
Dipstick urine analysis; renal failure in school aged children; urine analysis screening
12.  Test Characteristics of Urinalysis to Predict Urologic Injury in Children 
Objective:
To use receiver operator characteristic curve methodology to determine the test characteristics of microscopic hematuria for identifying urologic injuries in children who underwent computed tomography (CT) of the abdomen and pelvis as part of a trauma evaluation.
Methods:
We performed a retrospective medical record review of all children from 0 to 12 years of age who presented to our pediatric emergency department within a Level 1 trauma center, had an abdominal and pelvic CT and a microscopic urinalysis as part of an initial evaluation for trauma. Urologic injury was defined as any injury to the kidneys, ureters or bladder. We defined hematuria from the microscopic urinalysis and reported by the clinical laboratory as the exact number of red blood cells per high power field (RBC/hpf).
Results:
Of the 502 children in the study group, 17 (3%; 95% CI [2%–5.4%]) had evidence of urologic injury on the abdominal or pelvic CT. Microscopic urinalysis for those children with urologic injury ranged from 0 to15,544 RBC/hpf. The remaining 485 children without urologic injury had a range of hematuria from 0 to 20,596 RBC/hpf. A receiver operating characteristic curve was generated and the area under the curve is 0.796 (95% CI [0.666–0.925]).
Conclusion:
If the abdominal and pelvic CT is used as the criterion standard for identifying urologic trauma, the microscopic urinalysis has moderate discriminatory power to predict urologic injury.
PMCID: PMC3099601  PMID: 21691520
13.  Asymptomatic Microscopic Hematuria Revisited 
Canadian Family Physician  1985;31:2179-2185.
The literature states that asymptomatic microscopic hematuria (AMH) is a sensitive indicator of underlying pathology and deserves investigation. However, studies to date have been done on urological outpatients and, because of referral and sampling bias, the findings may not be applicable to a family practice population. The positive predictive value of AMH may be very low in a family practice. The recommended investigations are invasive, expensive, and cause morbidity and mortality. Further studies must examine the significance of AMH in the general population. Such studies would help to identify at risk patients and, perhaps, allow investigations to be tailored to these patients, while the physician maintains a high degree of suspicion and keeps a watchful eye on the others.
PMCID: PMC2327735  PMID: 21274136
Asymptomatic microscopic hematuria; family practice; urology
14.  The Use of Molecular Analyses in Voided Urine for the Assessment of Patients with Hematuria 
PLoS ONE  2013;8(10):e77657.
Introduction
Patients presenting with painless hematuria form a large part of the urological patient population. In many cases, especially in younger patients, the cause of hematuria is harmless. Nonetheless, hematuria could be a symptom of malignant disease and hence most patients will be subject to cystoscopy. In this study, we aimed to develop a prediction model based on methylation markers in combination with clinical variables, in order to stratify patients with high risk for bladder cancer.
Material and Methods
Patients (n=169) presenting with painless hematuria were included. 54 patients were diagnosed with bladder cancer. In the remaining 115 patients, the cause of hematuria was non-malignant. Urine samples were collected prior to cystoscopy. Urine DNA was analyzed for methylation of OSR1, SIM2, OTX1, MEIS1 and ONECUT2. Methylation percentages were calculated and were combined with clinical variables into a logistic regression model.
Results
Logistic regression analysis based on the five methylation markers, age, gender and type of hematuria resulted in an area under the curve (AUC) of 0.88 and an optimism corrected AUC of 0.84 after internal validation by bootstrapping. Using a cut-off value of 0.307 allowed stratification of patients in a low-risk and high-risk group, resulting in a sensitivity of 82% (44/54) and a specificity of 82% (94/115). Most aggressive tumors were found in patients in the high-risk group. The addition of cytology to the prediction model, improved the AUC from 0.88 to 0.89, with a sensitivity and specificity of 85% (39/46) and 87% (80/92), retrospectively.
Conclusions
This newly developed prediction model could be a helpful tool in risk stratification of patients presenting with painless hematuria. Accurate risk prediction might result in less extensive examination of low risk patients and thereby, reducing patient burden and costs. Further validation in a large prospective patient cohort is necessary to prove the true clinical value of this model.
doi:10.1371/journal.pone.0077657
PMCID: PMC3797079  PMID: 24143252
15.  Primary Localized Amyloidosis of Urinary Bladder: A Case Report and Review of Literature 
Nephro-urology Monthly  2013;5(5):994-996.
Amyloidosis is a disorder of protein metabolism characterized by extracellular deposition of abnormal protein fibrils. It may either be localized to any organ or systematically distributed throughout the body. The biochemical nature of proteins varies but the physical and tinctorial properties are shared by all the amyloidogenic proteins. In the West, it is mainly composed of amyloid light (AL) type immunoglobulin (Ig) light chains. Amyloidosis of the genitourinary tract is rare except for the kidney and isolated primary amyloidosis of the urinary bladder is even rarer. It mainly presents as intermittent painless gross hematuria. It mimics transitional cell carcinoma on imaging and endoscopic examination. We herein present a case of fifty six-years-old male with history of painless hematuria for three months. Cystoscopy revealed a 1 cm hyperemic area on the posterior wall of urinary bladder. The biopsy showed features of amyloidosis and amyloid A (AA) immunostaining was negative. Extensive workup was done to exclude other sites of involvement and a final diagnosis of primary localized amyloidosis of the urinary bladder was made. The patient is on regular follow-up.
doi:10.5812/numonthly.10870
PMCID: PMC3955294  PMID: 24693509
Amyloidosis; Urogenital System; Urinary Bladder
16.  Immunocytology Is Strong Predictor of Bladder Cancer Presence in Patients With Painless Hematuria: A Multicentre Study 
European urology  2011;61(1):185-192.
Background
Although the performance of immunocytology has been established in the surveillance of patients with urothelial carcinoma of the bladder (UCB), its value in the initial detection of UCB in patients with painless hematuria remains unclear.
Objective
To determine whether immunocytology improves our ability to predict the likelihood of UCB in patients with painless hematuria. Further, to test the clinical benefit of immunocytology in this setting using decision curve analysis.
Design, setting, and participants
The subjects were 1182 consecutive patients without a history of UCB presenting with painless hematuria and were enrolled at three centres.
Intervention
All patients underwent upper-tract imaging, cystourethroscopy, voided urine cytology, and immunocytology analysis. Bladder tumors were biopsied and histologically confirmed as UCB.
Measurements
Multivariable regression models were developed. Area under the curve was measured and compared using the DeLong test. A nomogram was constructed from the full multivariable model. Decision curve analysis was performed to evaluate the clinical benefit associated with use of the multivariable models including immunocytology.
Results and limitations
Immunocytology had the largest contribution to a multivariable model for the prediction of UCB (odds ratio: 18.3; p < 0.0001), which achieved a 90.8% predictive accuracy. Decision curve analysis revealed that models incorporating immunocytology achieved the highest net benefit at all threshold probabilities.
Conclusions
Immunocytology is a strong predictor of the presence of UCB in patients who present with painless hematuria. Incorporation of immunocytology into predictive models improves diagnostic accuracy by a statistically and clinically significant margin. The use of immunocytology in the diagnostic workup of patients with hematuria appears promising and should be further evaluated.
doi:10.1016/j.eururo.2011.08.073
PMCID: PMC3628750  PMID: 21924544
Cystoscopy; Decision curve analysis; Early detection of cancer; Hematuria; Immunocytology; Nomograms; Urinary bladder neoplasms
17.  Renal Trauma from Recreational Accidents Manifests Different Injury Patterns than Urban Renal Trauma 
The Journal of urology  2012;188(1):163-168.
Purpose
The majority of blunt renal trauma is a consequence of motor vehicle collisions and falls. Prior publications based on urban series have shown that significant renal injuries are almost always accompanied by gross hematuria alone or microscopic hematuria with concomitant hypotension. We present a series of blunt renal trauma sustained during recreational pursuits, and describe the mechanisms, injury patterns and management.
Materials and Methods
Database review from 1996 to 2009 identified 145 renal injuries. Children younger than age 16 years, and trauma involving licensable motor vehicles, penetrating injuries and work related injuries were excluded from analysis. Grade, hematuria, hypotension, age, gender, laterality, mechanism, management, injury severity score and associated injuries were recorded.
Results
We identified 106 patients meeting the criteria and 85% of the injuries were snow sport related. Age range was 16 to 76 years and 92.5% of patients were male. There were 39 grade 1 injuries, 30 grade 2, 22 grade 3, 12 grade 4 and 3 grade 5 injuries. Gross hematuria was present in 56.7%, 77.2% and 83.3% of grade 2, grade 3 and grade 4 injuries, respectively. None of the patients with grade 2 or greater injuries and microscopic hematuria had hypotension except 1 grade 5 pedicle injury. The nephrectomy and renorrhaphy rate for grade 1 to grade 4 injuries was 0%.
Conclusions
Compared to urban series of blunt renal trauma, recreationally acquired injuries appear to follow different patterns, including a paucity of associated injuries or hypotension. If imaging were limited to the presence of gross hematuria, or microscopic hematuria with hypotension, 23% of grade 2 to grade 4 injuries would be missed. Men are at higher risk than women. However, operative intervention is rarely helpful.
doi:10.1016/j.juro.2012.03.003
PMCID: PMC3754430  PMID: 22591969
kidney; multiple trauma; retrospective studies; wounds; nonpenetrating; injury severity score
18.  Diagnosis and Treatment of Benign Prostatic Hyperplasia 
OBJECTIVE
To define primary care physicians’ (PCPs) practices in managing patients with benign prostatic hyperplasia (BPH), and to compare these practices to portions of the Agency for Health Care Policy and Research BPH guideline and urologists’ practices.
DESIGN
Mail survey.
PARTICIPANTS
Nationwide random sample of PCPs and urologists, selected from the American Medical Association Registry.
METHODS
Initial mailing, postcard reminder, second mailing, telephone reminder, final mailing.
MAIN RESULTS
Primary care physicians (n = 444, response = 51%) reported seeing a median of 35 patients with BPH over the preceding year, in contrast to 240 for urologists (n = 394, response = 68%). Regarding tests recommended by the guideline, two thirds of PCPs reported rarely or never using the American Urological Association (AUA) symptom index, nearly all reported routinely performing digital rectal examinations, and many (66%) reported routinely ordering tests to determine the serum creatinine level. Although considered “optional” by the guideline, more than 90% of PCPs reported routinely ordering a prostate-specific antigen test, while infrequently using other optional tests. Regarding “not recommended” studies, a substantial minority reported selectively or routinely ordering intravenous pyelography (34%) and renal ultrasound (33%), while two thirds reported rarely or never ordering these tests. Eighty-six percent of PCPs reported prescribing medications for BPH over the preceding year; α blockers to a median of 12 patients, and finasteride to a median of 2. Variation in urology referral thresholds was suggested in responses to two patient scenarios.
CONCLUSIONS
Primary care physicians are actively managing patients with BPH. Some of their diagnostic evaluations vary from the recommendations of a national guideline and urologists’ practices. Referral thresholds appear to vary considerably.
doi:10.1046/j.1525-1497.1997.012004224.x
PMCID: PMC1497095  PMID: 9127226
prostatic hyperplasia; primary care physicians; practice patterns; practice guideline
19.  Cytological findings in routine voided urine samples with hematuria from a tertiary care center in south India 
Background:
Regardless of the availability of newer and more sophisticated modalities of investigation, urinary tract cytology still remains the most commonly used non-invasive test for the diagnosis of bladder cancer.
Aims:
As hematuria is the commonest presenting symptom in patients with malignancy of urinary tract, we undertook this study to know the usefulness of urine cytology in evaluation of the hematuric patients for malignancy.
Materials and Methods:
A total of 21,557 fresh voided urine samples received at our tertiary care referral centre over a period of three years were included in the study. Of these, 1428 cases had hematuria, criteria of either gross or microscopic.
Results:
Among these hematuric cases included in the study, 32.5% (464 cases) were found to have positive finding of atypical cells. In these cases with atypia, 9.5% (136 cases) were proved to have malignancy both with the histopathological biopsy and cystoscopic findings. Other cases of atypia were found to be of reactive origin, either due to instrumentation or foreign body. A large number of hematuric cases, that is, 964 cases (67.5%) were negative for atypical cells.
Conclusions:
The limited ability of urine cytology to detect low grade bladder tumors, its subjectivity and lack of uniformity in reporting, all render urine cytology a less than perfect tool. With added collaboration between clinician and cytopathologist, urine cytology can be used an adjunct tool in evaluation of patients with hematuria.
doi:10.4103/0970-9371.93211
PMCID: PMC3307445  PMID: 22438611
Atypical cells; hematuria; urine cytology
20.  The value of cystoscopy as an initial diagnostic modality for asymptomatic microscopic hematuria. 
Journal of Korean Medical Science  2001;16(3):309-312.
For the patients who visit outpatient clinics due to asymptomatic microscopic hematuria, cystoscopy has been looked upon as rather invasive compared to other diagnostic methods. We tried to elucidate the actual diagnostic value of cystoscopy in the initial evaluation of asymptomatic microscopic hematuria. We reviewed the results of cystoscopic examinations in 213 patients who visited our hospital due to asymptomatic microscopic hematuria. No definite lesion that could explain the microscopic hematuria was detected by means of IVP, urine cytology, and other nephrologic evaluations for all the patients. Among the abnormal cystoscopic findings in 55 patients, the lesions suspected to be directly related to microscopic hematuria were classified as 'significant lesions' (31 patients, 17.6%) which include entities such as bladder cancer (1.31%). 27 of 31 patients with significant lesions (85.2%) were over 50 yr old, and furthermore, 3 patients who were diagnosed as bladder tumor by cystoscopy were over 60 yr. Cystoscopy should be utilized as initial diagnostic modality in older patients with asymptomatic microscopic hematuria to rule out any possibility of bladder cancer occurrence. Further studies are needed to justify implementation of cystoscopy as an initial diagnostic modality in younger patients with asymptomatic microscopic hematuria.
PMCID: PMC3054750  PMID: 11410691
21.  The pitfalls of electronic health orders: development of an enhanced institutional protocol after a preventable patient death 
Background
Continuous bladder irrigation (CBI) is a long-standing treatment used in the setting of gross hematuria and other acute bladder issues. Its use has traditionally been reserved for patients under direct urologic care, but with the constraints of modern large-hospital healthcare, many patients have CBI administered by providers unfamiliar with its use and potential complications.
Findings
There were 136 CBI orders placed in 2013 by non-urologic providers. The biggest hazard found in our analysis was the requirement for entering a rate of irrigation administration. Nurses with no experience with CBI viewed this order as an indication to administer via an infusion pump, which can easily exceed the mechanical integrity of the bladder and increase the risk of bladder perforation. Our panel also found that due to lack of experience by nurses and non-urologic providers, that signs and symptoms of CBI dysfunction were not common knowledge. Also we found that non-urologic providers were unfamiliar with administration and dosing of medications for CBI patients to help with the intrinsic discomfort with CBI administration.
Conclusions
In our revised order set we found that removing the requirement for an infusion rate, along with placing warnings in the CPOE, helped staff better understand this possible complication. We created a best practice alert in our CPOE to strongly recommend the urology service be consulted. Communication text boxes were added to the order set to help staff be aware of the signs and symptoms of CBI dysfunction, along with a guide for trouble shooting.
doi:10.1186/s13037-014-0039-0
PMCID: PMC4193978  PMID: 25309624
MeSH; Hematuria; Communication; Delivery of health care; Urinary bladder; Consultants
22.  Management of the early and late presentations of rheumatoid arthritis: a survey of Ontario primary care physicians. 
OBJECTIVE: To examine primary care physicians' management of rheumatoid arthritis, ascertain the determinants of management and compare management with that recommended by a current practice panel. DESIGN: Mail survey (self-administered questionnaire). SETTING: Ontario. PARTICIPANTS: A stratified computer-generated random sample of 798 members of the College of Family Physicians of Canada. OUTCOME MEASURES: Proportions of respondents who chose various items in the management of two hypothetical patients, one with early rheumatoid arthritis and one with late rheumatoid arthritis. Scores for investigations, interventions and referrals for each scenario were generated by summing the recommended items chosen by respondents and then dividing by the total number of items recommended in that category. The scores were examined for their association with physician and practice characteristics and physician attitudes. RESULTS: The response rate was 68.3% (529/775 eligible physicians). Recommended investigations were chosen by more than two thirds of the respondents for both scenarios. Referrals to physiotherapy, occupational therapy and rheumatology, all recommended by the panel, were chosen by 206 (38.9%), 72 (13.6%) and 309 (58.4%) physicians respectively for early rheumatoid arthritis. These proportions were significantly higher for late rheumatoid arthritis (p < 0.01). In multiple regression analysis, for early rheumatoid arthritis, internship or residency training in rheumatology was associated with higher investigation and intervention scores, for late rheumatoid arthritis, older physicians had higher intervention scores and female physicians had higher referral scores. CONCLUSIONS: Primary care physicians' investigation of rheumatoid arthritis was in accord with panel recommendations. However, rates of referral to rheumatologists and other health care professionals were very low, especially for the early presentation of rheumatoid arthritis. More exposure to rheumatology and to the role of physiotherapy, occupational therapy and social work during primary care training is strongly recommended.
PMCID: PMC1335220  PMID: 8823213
23.  Relationships between family physicians’ referral for palliative radiotherapy, knowledge of indications for radiotherapy, and prior training: a survey of rural and urban family physicians 
Background
The primary objective of this research was to assess the relationship between FPs’ knowledge of palliative radiotherapy (RT) and referral for palliative RT.
Methods
1001 surveys were sent to FPs who work in urban, suburban, and rural practices. Respondents were tested on their knowledge of palliative radiotherapy effectiveness and asked to report their self-assessed knowledge.
Results
The response rate was 33%. FPs mean score testing their knowledge of palliative radiotherapy effectiveness was 68% (SD = 26%). The majority of FPs correctly identified that painful bone metastases (91%), airway obstruction (77%), painful local disease (85%), brain metastases (76%) and spinal cord compression (79%) can be effectively treated with RT, though few were aware that hemoptysis (42%) and hematuria (31%) can be effectively treated. There was a linear relationship between increasing involvement in palliative care and both self-assessed (p < 0.001) and tested (p = 0.02) knowledge. FPs had higher mean knowledge scores if they received post-MD training in palliative care (12% higher; p < 0.001) or radiotherapy (15% higher; p = 0.002). There was a strong relationship between FPs referral for palliative radiotherapy and both self-assessed knowledge (p < 0.001) and tested knowledge (p = 0.01).
Conclusions
Self-assessed and tested knowledge of palliative RT is positively associated with referral for palliative RT. Since palliative RT is underutilized, further research is needed to assess whether family physician educational interventions improve palliative RT referrals. The current study suggests that studies could target family physicians already in practice, with educational interventions focusing on hemostatic and other less commonly known indications for palliative RT.
doi:10.1186/1748-717X-7-73
PMCID: PMC3484047  PMID: 22607650
Cancer; Palliative radiotherapy; Family physician; Education; Knowledge; Palliative care
24.  Management of common musculoskeletal problems: a survey of Ontario primary care physicians. 
BACKGROUND: In Canada, primary care physicians manage most musculoskeletal problems. However, their training in this area is limited, and some aspects of management may be suboptimal. This study was conducted to examine primary care physicians' management of 3 common musculoskeletal problems, ascertain the determinants of management and compare management with that recommended by a current practice panel. METHODS: A stratified computer-generated random sample of 798 Ontario members of the College of Family Physicians of Canada received a self-administered questionnaire by mail. Respondents selected various items in the management of 3 hypothetical patients: a 77-year-old woman with a shoulder problem, a 64-year-old man with osteoarthritis of the knee and a 30-year-old man with an acutely hot, swollen knee. Scores reflecting the proportion of recommended investigations, interventions and referrals selected for each scenario were calculated and examined for their association with physician and practice characteristics and physician attitudes. RESULTS: The response rate was 68.3% (529/775 eligible physicians). For the shoulder problem, all of the recommended items were chosen by the majority of respondents. However, of the items not recommended, ordering blood tests was selected by almost half (242 [45.7%]) as was prescribing an NSAID (236 [44.7%]). For the knee osteoarthritis the majority of respondents chose the recommended items except exercise (selected by only 175 [33.1%]). Of the items not recommended, tests were chosen by about half of the respondents and inappropriate referrals (chiefly for orthopedic surgery) were chosen by a quarter. For the acutely hot knee, the majority of physicians chose all of the recommended items except use of ice or heat (selected by only 188 [35.6%]). Although most (415 [78.5%]) of the respondents selected the recommended joint aspiration for this scenario, 84 (15.9%) omitted this investigation or referral to a specialist. The selection of recommended items was strongly associated with training in musculoskeletal specialties during medical school and residency. INTERPRETATION: Primary care physicians' management of 3 common musculoskeletal problems was for the most part in accord with panel recommendations. However, the unnecessary use of diagnostic tests, inappropriate prescribing of NSAIDs, low use of patient-centred options such as exercise, and lack of diagnostic suspicion of infectious arthritis are cause for concern. The results point to the need for increased exposure to musculoskeletal problems during undergraduate and residency training and in continuing medical education.
PMCID: PMC1229226  PMID: 9580733
25.  Utility of serial urinary cytology in the initial evaluation of the patient with microscopic hematuria 
BMC Urology  2009;9:12.
Background
We determine the utility of serial urinary cytologies in patients presenting with microscopic hematuria who were evaluated with upper and lower urinary tract studies to rule out a malignancy.
Methods
Two hundred and thirty-seven patients with the diagnosis of microscopic hematuria were evaluated at an inner-city tertiary care hospital. Of these 239 patients, 182 patients had 405 cytologies obtained as part of their evaluation for hematuria. In addition, all patients had their lower urinary tract and upper tract thoroughly evaluated.
Results
Two hundred and seventy four cytology samples were read as normal, 104 (26%) as atypia, 7 (2%) as suspicious/malignant, and 20 (5%) as unsatisfactory. Seventeen patients (9.3%) had biopsy confirmed bladder cancer. Of these 17 patients, 2 had normal cytology, 11 had atypia, and 5 had suspicious/malignant. No patient had a positive cytology and a negative biopsy. Overall the number of hematuric patients harboring bladder cancer was small (7%). Cytology #1 detected 4 cases of cancer, cytology #2 detected an additional case and cytology #3 did not detect any additional cancers.
Conclusion
Because of this low prevalence of bladder cancer in patients presenting with microscopic hematuria and the low sensitivity of detecting bladder cancers, the utility of urinary cytology in the initial evaluation of patients with hematuria may be minimal. The exact role of urinary cytology in the evaluation of hematuria is unknown.
doi:10.1186/1471-2490-9-12
PMCID: PMC2751768  PMID: 19744317

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