Urine sediment after centrifuge normally contains 2 to 3 RBCs per high power field (RBC/HPF) on microscopic exam.    There is consensus that ≥3 RBC/HPF in 2 of 3 urine specimens signals non-visible hematuria (NVH). However, fewer RBCs from just 1 specimen should not exclude patients with risk for malignancy from a complete evaluation, because intermittent bleeding may occur.  
The most important initial diagnostic step is a detailed history, with the aim of identifying risk factors for malignancy. History may also indicate less serious causes (e.g., recent exercise or sexual activity, UTI, and menstruation).
The risk of urinary tract malignancy increases with age >40 years, tobacco use, previous radiation exposure, and certain occupational exposures (dyes, benzenes, aromatic amines) and medications such as phenacetin (available only in Japan]), cyclophosphamide, and aristolochic acid in some herbal weight loss preparations).  If malignancy is suspected, based on a high-risk profile, then evaluation of the entire urinary tract, including upper tract imaging and cystoscopy for the lower tract, is required.        By contrast, the workup of low-risk patients can be more focused toward the suspected cause without a complete urinary tract survey.
Considering the source of bleeding by anatomic site offers an organized approach. The upper urinary tract includes the kidneys (glomerular or nonglomerular) and ureters, with remaining structures in the lower urinary tract. These dividing lines are useful to apply during the history and physical exam, as well as when ordering diagnostic tests, because no one diagnostic test evaluates the urinary tract completely.
Diagnostic testing must first confirm the presence of NVH. Secondly, testing may distinguish an upper tract glomerular source from other causes, allowing a more refined workup, but upper and lower tract diagnostic tests (imaging and cystoscopy) remain necessary in all patients with risk factors for urinary tract malignancy. Using urinary tumor markers for diagnosing urinary tract cancer has not demonstrated adequate specificity for reliable diagnosis in research trials. However, the markers may play a role in assessing treatment efficacy and in identifying recurrences after treatment.  
The most often identified cancer in patients with NVH is bladder transitional cell carcinoma.      The US Preventive Services Task Force estimates a positive predictive value of 5% to 8% for NVH indicating bladder cancer and recommends against routine screening.   Evidence B One case-control study including people with renal neoplasms found that patients with ≥4 RBC/HPF or ≥5 RBC/HPF in a single urine sample were twice as likely to have concomitant NVH (odds ratio of 2.2 for ≥4 RBC/HPF and 2.0 for ≥5 RBC/HPF) as patients without malignancy. 
Department of Family and Community Medicine
Texas Tech University Health Sciences Center at the Permian Basin
TJB declares that he has no competing interests.
Regional Chief Medical Informatics Officer
Medical Director Haven Health Clinics
Department of Family Medicine
Texas Tech University Health Sciences Center
BAL declares that she has no competing interests.
Department of Family Medicine
University of Texas Health Science Center
RT declares that he has no competing interests.
Consultant Urological Surgeon
Bart's and The London NHS Trust
JM declares that he has no competing interests.
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