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The proper evaluation of microscopic hematuria (MH) in an asymptomatic adult is a subject of controversy.Part of the problem arises from the fact that the majority of studies that suggest that MH heralds significant urologic disease come from highly selected populations of patients and do not necessarily represent the scope of the problem in the population at large.In fact, the few population-based studies that are available for review suggest that the positive predictive value for finding significant pathology is extremely low.[i]^,[ii],[iii] Thus, the debate.So what to do with a patient found to have MH?

The U.S. Preventive Services Task Force as well as the Canadian Task Force and the American Cancer Society do not recommend screening for hematuria in asymptomatic persons.1^,[iv] (Screening is only recommended for persons with heavy exposure to cigarette smoke and other bladder carcinogens). A routine urinalysis, however, is still frequently performed as part of a pre-employment physical or for insurance purposes.People with MH are then referred to their primary care provider, who has to decide what to do with the abnormal result.

Before proceeding, we need to define what MH means.This is, surprisingly, a controversial area.Different investigators have used variable definitions for MH, and have used a variety of methods to diagnose MH.Most, but not all, studies that used microscopy to define MH, used ³1 red blood cell/high power field (rbc/hpf) as the cutoff.The microscopy method, however, is unreliable because it depends on how a particular laboratory handles the specimen.[v]^,[vi] Two recent reviews differed in their definition of MH: one used ³1 rbc/hpf, the other used 3 rbc/hpf.4^,[vii] A standard textbook accepts 1-3 rbc/hpf as normal.[viii]In older individuals, especially men, however, the development of even one rbc/hpf may herald significant disease.

The dipstick method for detecting MH is another modality that is in common use. Numerous studies have used the dipstick for screening certain individuals for urologic cancer.[ix]^,[x]^,[xi]^,[xii] The dipstick will be positive when between 2-5 rbc/hpf are present.The sensitivity of the dipstick for MH (with microscopy used as the gold standard) is in the range of 91-100 percent.The specificity for MH is 65 to 99 percent.1^,4,8Another complicating factor is that rbc’s can lyse, especially in very dilute urine.Thus, it is possible that the dipstick will be positive, but the microscopy will show no rbc’s (the dipstick detects the hemoglobin that is released).8 Consequently, a positive dipstick will be assumed to be a false positive, when it may be more accurate than microscopy.In fact, several screening studies that evaluated the performance of the dipstick in detecting significant urologic disease have found what they considered significant lesions in dipstick-positive but microscopy-negative patients.10There are several situations where the dipstick will be false-positive, such as when it detects myoglobin, and when oxidizing agents are present (e.g. bacterial peroxidases, chlorine, and povidone).False-negative results occur when the urine contains vitamin C, and when urine is very concentrated.4^,[xiii]

The prevalence of asymptomatic MH varies from 1 to 13 percent, depending on the population studied and the method used to detect MH.Of four recent population-based studies, two evaluated similar populations: men ³ age 35 and postmenopausal women ³ age 55, but they used different methods to detect MH.2,3 The study that used a single dipstick had a prevalence of 2.9 percent 3 ;the study that used microscopy with at least 1 rbc/hpf detected asymptomatic MH in 13 percent.2 Neither study found increased prevalence with age.The prevalence among men age ³ 40 was four percent in another study if MH is defined as ³1 rbc/hpf.[xiv] Among young men, point prevalence was 5.2 percent if defined as 2-4 rbc/hpf, with cumulative incidence of 38.7 percent over 15 years.5Prevalence among premenopausal women is unknown because population-based studies excluded them because of possible confusion due to menstrual bleeding.

The pressure to evaluate all cases of MH stems from the fear that an occult neoplasm will be missed.About 40,000 new cases of bladder cancer and 18,000 new cases of renal cell cancer are diagnosed in the U.S. each year.Bladder cancer occurs in men three times as frequently as it occurs in women, and it is uncommon below the age of 40 (although there are multiple anecdotal reports in the literature and many urologists advocate full evaluation of all patients with MH regardless of age).[xv]Renal cell carcinoma is also more frequent in men than in women with a ratio of 2:1. Peak age is between 55 and 60 years.[xvi]

The question is who should undergo an evaluation and how complete should it be? The most important reason to work up a patient with MH is to diagnose a treatable cancer earlyand prolonga patient’s life.Studies in selected populations of men over the age of 50 using the dipstick for screening purposes detected significant numbers of malignancy in those with at least one positive dipstick (defined as at least trace).Messing et al. found that 21 percent of those screened had at least one positive dipstick, 8.3 percent of those evaluated had genitourinary (GU) malignancy and 24.5 percent had other significant lesions.12 Similarly, Britton et al. foundthat 20 percent of men over age 60 had a positive dipstick.A bladder tumor was found in 3.6 percent of those evaluated and prostate cancer in one percent.10 An unusually high number of patients in the Messing study, however, had environmental and/or occupational exposure to known carcinogens. 

    In population-based studies, Mohr et al. found that the prevalence of MH was 13 percent, but only 2.3 percent had serious GU disease and only 0.5 percent had GU malignancy.2To evaluate the sensitivity and specificity of MH for serious GU disease, the same authors compared findings in patients with MH (test-positive) and in patients with negative urinalyses (test-negative).They found that minor GU diseases were not significantly different between test-positive and test-negative patients.There was a slightly higher frequency of moderately severe GU disease and GU cancer in test-positive patients.The significant difference in cancer existed only for prostate cancer, which is not the malignancy expected to be diagnosed through a MH evaluation.Positive predictive value (PPV) was only two percent for serious GU disease and sensitivity was only 20 percent, even in elderly men.[xvii]

A similar population-based study found a sensitivity for GU malignancy of 2.9 percent and PPV of a single positive dipstick of 0.5 percent.More importantly, they found that the proportion of patients with significant GU disease, including malignancy, among patients with asymptomatic MH was not significantly different from the group without MH.3Froom et al. found only one malignancy among 1000 young men aged 18-33.5These studies have been criticized because most patients did not have complete GU evaluations.In referred populations, the yield of an evaluation is much higher: GU malignancy has been diagnosed in 1.1 percent,13 2.2 percent,[xviii] 2.3 percent,[xix] 8.5 percent,[xx] 8.6 percent,[xxi] 9.7 percent,[xxii] and 13 percent.[xxiii] Other highly significant and life-threatening lesions have been diagnosed in 5 to 20 percent, depending on the definition used and the study.17,18,19,21,22A recent prospective study of patients referred to a “hematuria clinic,” similarly found very high rates of malignancy among patients with MH; five percent had cancer.[xxiv]

Most reports have not found the degree of hematuria to be an important determinant in whether a significant lesion will be found.8, 17, 21, 22 Some have found that the yield for significant lesions increases as the degree of MH increases; however, there was no “safe” lower limit of MH.19It is also felt that transient MH should not be fully investigated, but intermittent or persistent MH should be evaluated.4Some investigators feel, however, that even a single abnormal test should be evaluated, especially in older men.10^,[xxv]

The majority of reports support the view that men, especially those over age 50, are more likely to have significant disease, particularly cancer, than women.2,18There is a paucity of studies regarding the work up of MH in women, as few of them correlated their findings with the patient’s gender.Bard conducted a prospective study of 177 women with long follow-up (up to 11 years).[xxvi]No case of bladder cancer (or other malignancy) was discovered, and the author concluded that cystoscopy is not warranted in asymptomatic women. This was also the only study that found a statistically significant association between increasing grade of MH and the presence of GU lesions.

TABLE 1: Medical history in patients with hematuria
 

Exclude pseudohematuria – drugs, vegetable dyes, pigments Factitious – Munchausen’s syndrome, narcotic-seeking behavior Bleeding diathesis Clots – indicate nonglomerular bleeding; large thick clots (bladder), small stringy clots (upper tract) Relation of gross hematuria to urinary stream – initial (urethral distal to urogenital diaphragm), total (bladder proper or uppertract), terminal (bladder neck or prostatic urethra) Painful hematuria – urinary tract infection or calculus, papillary necrosis, passage of clots, obstruction, glomerulonephritis Genitourinary history – flank trauma or pain, frequency, nocturia, dysuria; prior stones, tissue passage or infections; vaginal or penile discharge; sexual activity; presence of urinary catheter Relation to menstruation – endometriosis Sickle cell disease or trait Medications (Table 3) Systemic symptoms – fever, rash, joint pain, weight loss Infection? – night sweats, sore throat, impetigo, tooth extraction or other invasive procedures, diarrhea, travel to areas endemic for Schistosoma haematobium Risk factors for urologic cancer? – age > 40, tobacco use, analgesic abuse, pelvic irradiation, S. haematobium, occupational exposure to dyestuffs and rubber compounds Family history – hematuria, renal disease, sickle cell disease, deafness, bleeding diathesis Prior evaluation

Adapted from source 5.

[AL1]The initial task is to obtain a detailed history, including a full family history, to ascertain that the patient is truly asymptomatic.Some of the pertinent medical history to obtain is listed in Table 1.There are numerous causes of MH, and Table 2 provides a list of the most common of these causes.A special note on the anticoagulated patient with MH should be made. A 1991 prospective study found that the difference in the incidence and prevalence of hematuria was not statistically significant between anticoagulated patients and controls, and there was a GU lesion in the majority of such patients.The conclusion was that MH should not be attributed to anticoagulation alone,[xxvii] and that anticoagulated patients should be treated in the same way as other patients with MH.[xxviii]

A careful drug history should be elicited to exclude any drug-induced causes of MH (see Table 3).A full physical exam and certain laboratory studies should be included as well (see Table 4).If a patient was referred from a workplace, Medicaid office, or insurance company, then a repeat UA is warranted, especially if certain historical information was obtained (e.g. heavy exercise prior to initial UA).[xxix]

Figure 1: Algorithm for the evaluation of microhematuria

TABLE 2: Causes of isolated microscopic hematuria
 

Renal parenchymal origin  IgA nephropathy Membranoproliferative glomerulonephritis Glomerular C3 deposition Lupus nephritis Schonlein-Henoch nephritis Goodpasture’s syndrome Renal vasculitis Benign hematuria Alpert’s syndrome Thin glomerular basementmembrane disease Interstitial nephritis Analgesic nephropathy Pyelonephritis Sickle cell nephropathy Polycystic kidney Trauma/surgery/biopsy Exercise

Urinary tract diseases Prostatitis Prostatic hypertrophy Trauma/surgery Neoplasia Obstructive uropathy Cysts Varices/telangiectasia Papillary necrosis Periurethritis Ureterocele Endometriosis Infections (e.g. MTb)  Infestations (e.g. schistosomiasis) Radiation Diverticulum Drug-induced cystitis Ex vacuo hematuria Urethral prolapse Meatal ulcers Condylomata acuminatum  Foreign bodies Catheters Exercise

Systemic coagulation disorders Platelet defect Coagulation protein deficiency Scurvy Therapeutic anticoagulation Renal vessel diseases  C3 arteriolar deposition Arterial emboli or thrombosis Renal vein thrombosis Arterial or venous malformation

Adapted from source 7. 

TABLE 3: Drug-induced hematuria: Urologic lesions & examples of incriminated drugs
 

Pseudohematuria – phenytoin, ibuprofen, levodopa, rifampin, nitrofurantoin, quinine Glomerulonephritis – mercury or gold compounds, penicillamine, heroin, probenecid Vasculitis – allopurinol, colchicine, diphenhydramine, furosemide, isoniazide, penicillins Thrombotic microangiopathy – chemotherapy Acute interstitial nephritis – penicillins, rifampin, ibuprofen, sulfonamides, phenytoin Chronic interstitial nephritis – analgesics, alcohol (with papillary necrosis), lithium (without) Intrarenal obstruction – methotrexate, sulfonamides Nephrolithisis – trimaterene, vitamin D, acetazolamide, indinavir Urinary tract carcinoma – analgesic abuse Interstitial cystitis – cyclophosphamide, penicillins, danazol Urinary tract lesion not always present – anticoagulants Site unknown - NSAIDs

Adapted from source 5.

TABLE 4: Laboratory evaluation of hematuria (not every test is for every patient)
 

As determined by clues from the history and physical: ·Prothrombin time, partial thromboplastin time, bleeding time (if bleeding diathesis) ·Urine culture (if dysuria or pyuria) ·Abdominal xray ·3-glass urine test ·PPD, urine for AFB, chest xray ·Urinary eosinophils ·Acid phosphatase ·Serum and urine protein electrophoresis ·Lactate dehydrogenase (disproportionately elevated c/w other LFTs in renal embolus) ·Serology for mononucleosis ·Screening studies: Screening studies: ·Creatinine, BUN, calcium, uric acid, bicarbonate, potassium, phosphorus ·Platelet count, hematocrit, white blood cell count ·Urinalysis in other family members (looking for thin basement membrane nephropathy) ·Hemoglobin electrophoresis (in patients with gross hematuria of black or Mediterranean ancestry) ·Urinary cytology Patients with evidence of glomerular disease: ·24-hour urinary protein ·antinuclear antibody, antibody to basement membrane, serum complement, cryoglobulins ·streoptococcal serologies, hepatitis B and C serology, RPR, HIV testing ·blood cultures ·Serum and urine protein electrophoresis

Adapted from source 5.

The exam of the urine for patients with confirmed MH should include routine microscopy, urine culture, and a careful evaluation of the urine sediment. Presence of protein on dipstick should prompt a 24-hour collection of urine for protein. Further exam for casts (e.g. rbc or wbc) suggests a glomerular origin.Special stains (e.g. Hansel’s) can detect eosinophils.RBC morphology can be evaluated further if available. This area is not standardized. Using phase-contrast microscopy, two distinct populations of RBCs can be identified.If at least 80 percent of RBCs are dysmorphic (i.e. distorted in shape), the site of bleeding is likely glomerular.If at least 80 percent of all RBCs are isomorphic (i.e. normal morphology), them the site is probably urologic.When the two populations are present in similar proportion, they are defined as mixed. This method, however, is prone to inter-observer variability and some authors have found that it is reproducible in only 62 percent of samples.[xxx] Acanthocytes, another type of a distorted RBC, are quite specific for glomerular bleeding.If at least five percent of the RBCs are acanthocytes, then sensitivity for glomerular disease is 52-99 percent and specificity is 98-100 percent.7

Another method of RBC analysis involves the Coulter counter, which measures the MCV of urinary RBCs.This method is somewhat more objective.It produces two populations of cells as well: the low MCV associated with glomerular MH and the higher MCV associated with nonglomerular MH.5,7,[xxxi],[xxxii]Its low sensitivity for mild MH, however, limits its utility.

If the work up thus far points toward a glomerular lesion, then a kidney biopsy should be considered.This issue is debatable because in an asymptomatic patient with normal creatinine and no significant proteinuria, the biopsy result will most likely not change management.Thus, watchful waiting is considered appropriate by many clinicians.Probably the only reason to proceed with a biopsy would be to establish a diagnosis and allow the work-up to terminate.In fact, in the majority of patients with isolated MH and negative GU work up who had a kidney biopsy, IgA nephropathy was the most common diagnosis (20-56 percent in different studies).One prospective study found that 78 percent of patients that had a negative GU work up had abnormal biopsy results: 49 percent of these had IgA nephropathy, 29 percent had multiple other diagnoses.[xxxiii]Given the variable natural history of IgA nephropathy, renal biopsy would probably be most useful in a younger patient (age < 40).Many physicians prefer to follow these patients and do a kidney biopsy if proteinuria or hypertension develops.7

At this point the work up should proceed according to age.For patients age < 40, the next step should be a renal ultrasound with a plain radiograph of the abdomen.Whether the ultrasound should be done instead of the IVP is again controversial.Spencer et al conducted a prospective study comparing ultrasound with IVP.They concluded that, combined with a plain abdominal radiograph, it is safe and accurate, and was “superior” to IVP as the primary imaging study.[xxxiv]Another study had similar conclusions.[xxxv]In fact, a decision-analysis found that IVP adds little to the accuracy, but it increases cost and morbidity.The radiation exposure of a single IVP is equivalent to 15 chest Xrays.Mild allergic reactions to the dye are quite frequent; death occurs in between 1 to 7 per 100,000 contrast injections.Acute renal failure occurs in at least 0.15 percent on IVP’s.1The authors suggest that it can be replaced with ultrasound with only a small sacrifice in accuracy (that is, it could possibly miss the very rare tumors of the ureter).[xxxvi]

Ultrasonography is also better at classifying the renal masses.If the above procedures are unremarkable, it is useful to measure the 24 hour urinary calcium and uric acid excretion in younger patients as hypercalciuria and/or hyperuricosuria were frequent causes of isolated MH.[xxxvii]At this point it is reasonable to stop and follow the younger patient.

For patients age ³ 40, the first diagnostic procedure should be cystoscopy.For men age < 40 and for women, cystoscopy was found to be of little value.23,[xxxviii]Cytology, however, can be obtained and cystoscopy done if the cytology is abnormal, but this test is not a sensitive one.Britton et al. found that urine cytology had a high specificity when used as a secondary screening test.10If cystoscopy is negative, then a renal ultrasound with a plain abdominal radiograph should be obtained.

If the work up to this point is negative, an IVP can be considered if the suspicion remains high to exclude the rare ureteral lesions (e.g. abnormal urine cytology with a negative work up in an elderly man).Other second-line studies to be considered on an individual basis include CT, angiography, doppler (to exclude vascular abnormalities) and retrograde pyelography.6 

Once the patient has been thoroughly evaluated and no abnormality has been found, how should such a patient be followed?Most urologists in the past have advocated repeat UA and cytology every six months, with cystoscopy and IVP alternating biannually.21Follow-up studies revealed that long term follow-up is not adhered to and is not productive.Howard et al. now recommend repeat evaluation only if gross hematuria or symptoms develop.³⁶ (It is reasonable, however, to repeat UAs, cytology and possibly renal ultrasound and/or cystoscopy every six months to one year, especially in a patient considered at high risk).Patients suspected of having glomerular disease should have periodic detailed history and physical as well as serum BUN/creatinine and urine for protein.It has been shown that most lesions, if present, will become manifest within two to three years, at which time patients should be re-evaluated only if the clinical scenario changes.

        To a great extent, the patients that are evaluated for MH are somehow selected by their own doctors.Most abnormal UAs are not acted upon, except perhaps to obtain a repeat UA.2,14This is in itself a selection process.There is a lack of randomized, controlled studies in the hematuria literature, and there is a definite lack of information regarding women, especially young women.The benefit of working up a MH patient must be weighed against the risk of such an evaluation.The algorithm in Figure 1 may be used as a guide for working up a patient with MH, although this process may need to be individualized.

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