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Review: Isolated Asymptomatic Hematuria in the Adult
Review: Isolated Asymptomatic Hematuria in the Adult BY LTC JOHN B. COPLEY, MD, FACP, MC
ABSTRACT: The term "isolated asymptomatic hematuria," as it relates to both gross and microscopic hematuria, is defined; and the pros and cons of detection techniques used to localize the source of the hematuria are discussed. An algorithm is provided to optimize detection of structural defects and intrinsic renal disease in an effort to avoid subjecting the patient with this difficultto-diagnose problem to unnecessary invasive tests. Although invasive tests should be performed where deemed necessary in the clinician's aggressive search to detect any structural abnormality, controversial areas of the evaluation of these patients are addressed. To justify various branch points of the algorithm, a discussion of both renal cell carcinoma and primary renal hematuria is proffered. KEY INDEXING TERMS: Hematuria; Algorithm; Urine; Isolated; Asymptomatic. [Am J Med Sci 1986; 291(2)101-111.)
A
perPlexing clinical problem is the patient with hematuria and no evidence of renal or systemic disease. It is usually difficult to decide to what extent to pursue a diagnosis, especially whether to perform renal angiography or renal biopsy when etiology and prognosis so often times remain uncertain after a thorough evaluation. Accordingly, this article reviews isolated asymptomatic hematuria in the adult and provides the clinician with an introduction to the significance of such a finding as well as with an algorithm for appropriate evaluation and follow-up. Included is a discussion of prognosis. The hematuria may be microscopic or gross, intermittent or continous, and by definition is isolated. These patients have no other abnormality on urinalysis, do not have significant proteinuria, do have normal renal function, and are not hypertensive. Patient history and physical examination are otherwise not suggestive ofintrinsic renal disease. Detection of Hematuria
From the Nephrology Service, Department of Medicine, Brooke Army Medical Center, Fort Sam Houston, Texas. The author thanks Fern Crouse, Carolyn Martinez, and Sandy Helms for their clerical and editorial assistance. The views expressed herein are those of the author and do not necessarily reflect the views of the US Army or the Department of Defense. Reprint requests: LTC John B. Copley, MD, Department of Medicine (HSHEMDN), Brooke Army Medical Center, Fort Sam Houston, TX 78234-6200.
Gross hematuria implies an abnormality emanating from within the urinary tract. It is usually alarming and prompts the patient to seek medical attention. However, asymptomatic microscopic hematuria is often discovered only at routine urinalysis; but, after contamination is excluded, this too implies a urinary tract abnormality. The usual method for detecting microscopic hematuria is the urinalysis paper strip dipstick. This
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
consists of a reagent strip test containing orthotolidine and buffered organic peroxidase. Hemoglobin catalyzes the oxidation reaction between these two substances and results in a measurable color change against a standard scale. The dipstick is designed to detect free hemoglobin or hemoglobin contained in red blood cells (RBCs). It is more sensitive for hemoglobin than for intact RBCs. 1 False-negative results occur 1%2 to 8%3 of the time in the settings of concentrated urine, of urine that contains a substantial amount of protein or formaldehyde, or of urine that contains vitamin C in concentrations greater than 10 mg/100m1. 1 • 3 Other ascorbic acids, such as those used as preservatives in tetracycline, can also result in falsenegative testing. False-positive tests occur with chlorine, with other oxidizing agents, or with bacterial peroxidases. 1 The dipstick detects hemolysis when urine free hemoglobin exceeds 0.05-0.3 mg hemoglobin per 100 ml urine (up to ten lysed RBCs per ml)/ and it also can detect myoglobin. Hemolysis occurs to some extent in 90% of urine specimens containing blood. 4 The microscopic examination is a reasonably sensitive way of detecting RBCs. The dipstick can detect 2.5-5 X 106 RBCs per 100 ml [25 to 50 RBCs per microliter, 3 RBCs per high power field (hpf)),2,5,6 and the microscopic examination 1.2 x 106 RBCs per 100 ml. 5 Gross hematuria represents at least 5 X 106 RBCs per mm 3 , which corresponds to approxi-
101
Isolated Hematuria
mately 0.5-1 ml of RBCs per liter of solution. Although the detection of erythrocytes in urine is relatively simple, the clear separation of normal excretion rates from abnormal may be more difficult. The definition of normalcy is ambiguous and can vary depending on the reference consulted. Confusion is compounded by work performed by several groups/'s which establishes the importance of quantitative urine microscopy in defining abnormal hematuria (greater than 3,000 erythrocytes per milliliter of urine is considered abnormal). The same groups emphasize the inaccuracies of using the spun urinary sediment for detecting significant hematuria. Quantitative methods of urinalysis are used only rarely, however, and most attempts at defining normalcy are based on the spun urinary sediment. These definitions may further be influenced by urinalysis technique. The reader is referred to standard laboratory textbooks for proper methodology . Larcom and Carter, using spun urinary sediments, studied 3,000 consecutive single-voided specimens from young men applying for employment. In 2,484 cases, no RBCs were found; in 2% of patients, there were 2-3 RBC/hpf; and in 0.7%, 4-5 RBC/hpf. 9 Wright studied 5,000 consecutive male urine specimens received at a life insurance company, and 97% had less than 5 RBClhpf. IO Thus, 5 RBC/hpf probably represents 2 standard deviations from the norm. Most authorsl,l1 accept up to 2-3 RBClhpf as normal. Females generally are allowed one more red blood cell than males due to difficulties in urine collection technique. In all instances, it is important to assess the clinical situation. Strenuous exercise may increase amounts of hematuria without any underlying pathologic process. Furthermore, development of 1 RBClhpf in an individual over 40 years of 102
age may herald clinically important pathology if prior urinalyses had been negative. An Addis count is more precise in determining abnormal amounts of hematuria. This procedure has been standardized so that less than 600,000 RBCs per 12-hour urine collection is considered normal. 9,12-14 An Addis count, however, is a tedious quantitative method. In addition, the number of RBCs per 12 hours has not been precisely correlated to semi-quantitative spun urine sediments. I. 9.10.15 Several studies have shown that the normal number of cells for children and adults is the same. 12.15 Localization of Source of Hematuria
It would facilitate patient evaluation if a means were available for determining if hematuria emanates from the upper versus the lower urinary tract. Cystoscopy performed during periods of gross hematuria should be capable of detecting blood effluxing from one or both ureteral orifices. The source of microscopic hematuria, on the other hand, can be difficult to ascertain. The "three-glass test" represents an effort at localizing the source. Three separate aliquots of urine are collected during voiding, and the numbers of red cells in each aliquot are compared. Initial hematuria (Le., RBCs in the first aliquot) implies hematuria of urethral origin; total hematuria (Le., RBCs in all three samples) implicates the upper urinary tract; and terminal hematuria (i.e., RBCs in the last aliquot) implies prostatic hematuria or hematuria emanating from the bladderneck. Sensitivity and specificity of this test are unknown. Another method for determining the source of hematuria involves Hemostix sampling of ureteral urines. 16 This is done at cystoscopy with a special scope that incorporates a dipstick indicator that can be reacted with ure-
teral urine. The technique has not been substantiated by further study. Fairley and Birch have found phase-contrast microscopy helpful for determining localization. 17 On evaluation of red blood cell morphology, they found that 55 of 58 patients with glomerular disease had dysmorphic urinary RBCs and that nonglomerular disease was associated with normomorphic RBCs. The technique has not been fully substantiated by subsequent investigation but seems promising. Fassett et aI,S using similar methodology, made an incorrect assessment of the site of bleeding in only 4% of patients. These same authors accurately differentiated between glomerular and nonglomerular RBCs by using scanning electron microscopy on urine sediment. IS Finally, certain findings predict the source of hematuria. When urine color is brown or smokey, hematuria probably emanates from the kidney. Extrarenal hematuria is often associated with pink or red urine. Red blood cell casts always indicate a renal origin for the hematuria. Blood clots are associated with extrarenal hematuria and generally are absent when hematuria emanates from the kidney. Associated proteinuria, greater than 500 mg/24 hours, implies an intrarenal source, although further study is needed to substantiate this observation. Algorithm for Evaluation of Hematuria
Hematuria, either gross or microscopic, can be a presenting manifestation of urinary tract disease. However, prospective studies of isolated. asymptomatic hematuria are lacking, and retrospective studies either base their conclusions on incomplete evaluation for etiology or deal with hematuria in the elderly.19-23 Therefore, sequence of testing and extent of evaluation are controversial at best. Several algorithms February 1986 Volume 291 Number 2
Copley
for the diagnosis of hematuria have been published, but all approach the problem in a general manner rather than addressing the patient with isolated asymptomatic hematuria. 24 •25 The purpose of this algorithm (Figure 1) is not to provide a methodology for evaluation of all forms of intrinsic renal disease, but to provide a matrix to be used to evaluate the difficult-to-diagnose adult patient with isolated hematuria. The intent is to optimize detection of intrinsic renal disease and structural lesions such that invasive ·tests can be avoided. Invasive testing is used
when deemed necessary, and structural abnormalities are aggressively sought or ruled out. Evaluation per the algorithm is not continued once an etiology for the hematuria is found or if testing indicates intrinsic renal disease, although further structural evaluation is not necessarily precluded. The patient with underlying renal disease who develops new hematuria also is excluded, but probably deserves thorough testing. The algorithm begins with the patient's history. The hematuria should be characterized as to gross or microscopic, intermittent
or constant. If gross hematuria is episodic, it should be ascertained if microscopic hematuria is persistent, intermittent, or absent between episodes. Duration of hematuria must be documented. Depending on the clinical situation, it is prudent to wait approximately 3 months, with repeat urinalysis performed at least monthly, before embarking on an expensive and possibly invasive evaluation. All patients over the age of 40 should be evaluated extensively, even after a single episode of hematuria. Evaluation of younger patients can be individualized at the discretion of the clin-
HEMATURIA
HISTORY. PHYSICAL EXAMINATION (H • PI
INTRINSIC RENAL DISEASE
( + ) EVAL I RX AS APPROPRIATE (
STOP
--'~=.:.:.::.:.:::.:.._-'--'.c:;.c.-"-'-
-
--------1
(GLOMERULAR. INTERSTITIAL)
I
)
RENAL BIOPSY? I EVAL I RX AS APPROPRIATE I
_ _-'-_ _ __
ABNORMAL (pROTEIN : 200 my· SOD mg?1
SEROLOGIES ele .•
'--------n------j-r==UR=IN=E=P==RO==T==EI=N==EL=EC==T==RO=P=H=OR=E=SI=S'-- INTRINSIC RENAL DISEASE
1----
ETIOLOGY EVALI RX AS APPROPRIATE
SECOND LINE LABORATORY
EVAL I RX AS APPROPRIATE
1-_ _ _ _ _ _ _ _ _ _ _ _ _
ETIOLOGY INTRINSIC RENAL DISEASE
NO ETIOLOGY
( + )
1 - - - - EVALlRX
•
AS APPROPRIATE
DEPENDS ON S. CREATININE AND CONTRA INDICATIONS FOR RADIOCONTRAST DYE. ALTERNATIVE: RENAL ULTRASOUND
t GROSS UNILATERAL HEMATURIA PROBABLY SHOULD BE FURTHER EVALUATED WITH COMPUTERIZED TOMOGRAPHY AND RADIONUCLIDE SCAN AND NOT BIOPSIED.
Figure 1. Algorithm for evaluation of Isolated asymptomatic hematuria. EVALlRX: evaluate and treat, H + P: history and physical, HR: hour; IVP: Intravenous pyelogram, S: serum. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
10~
Isolated Hematuria
TABLE 1 Causes of Isolated Hematuria Cause Hematologic · Coagulopathy Hemoglobinopathy (sickle cell) Renal Glomerular disease Primary
History
Bleeding diathesis. family history. anemia. medication. Anemia. family history.
Physical Examination
Petechial rash. splenomegaly. ecchymoses. Ecchymoses. petechial rash.
Flank pain. None.
Normal. Hypertension.
Secondary (includes vasculitis)
Arthralgias/arthritis. skin rash (malar/ discoid lupus). serositis/pleurisy. Raynaud·s. photosensitivity. ulcerations of digits/nails or nose/mouth. alopecia. sore throat. seizures. psychosis. dysphagia. abdominal pain. diabetes mellitus.
Hypertension. Roth's spots. mouth or nasal ulcerations. pharyngitis. alopecia. petechial or other skin rash. cardiopulmonary examination. abdominal examination (masses. bruits. organomegaly. sequelae of liver disease). edema. arthritis. extremity ulcerations. fever.
Hereditary
Family history. Hearing or ocular disorders.
Normal. Hypertension. hearing. funduscopic examination.
Tuberculosis and other chronic urinary tract Infections (include age at onset). stones. analgesics. medicines or other drugs. sicca syndrome. diabetes mellitus. systemic lupus erythematosus. sickle cell disease. toxIns. radiation. heavy metals. living in Balkan countries. family history. headaches. nocturia. urgency.
Hypertension. skin color. arthritis. flank pain. suprapubic pain.
Flank/abdominal pain. dysuria. nocturia. urgency. frequency. fever. chills. Family history. pulmonary symptoms. weight loss. night sweats. flank pain. fever. dysuria. or silent.
Costovertebral angle tenderness.
Interstitial disease
Infections Pyelonephritis
Tuberculosis
Other Malformations Cystic
Travel to "exotic" places. Family history. flank pain. history of stones or Infection. Nocturia.
Abdominal examination. hypertension.
Weight loss. fever. flank or abdominal pain.
Abdominal examination.
Abdominal pain. flank pain.
Abdominal examination (mass. bruits). arrhythmia. other embolic manifestations.
Thrombosis
Flank or abdominal pain.
Edema.
Cortical or papillary necrosis
Flank or abdominal pain. oliguria. fever.
Flank/abdominal pain.
Clots In urine. history trauma.
Flank/abdominal pain.
Vascular Neoplasms Ischemic Embolism
Trauma 104
Pulmonary examination.
Hemangiomas. telangiectasias.
February 1986 Volume 291 Number 2
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TABLE 1 Causes of Isolated Hematuria (continued) History
Cause Postrenal Mechanical stones Obstruction Vesicoureteral reflux Other Inflammatory Periureteritis Cystitis Prostatitis Epididymitis Urethritis Neoplasm Endometriosis Benign prostatic hypertrophy (BPH) Exercise False Vaginal/rectal Factitious
ician. Conceivably, only a portion of the algorithm will be accomplished until the initial 3-month period elapses. Further episodes of hematuria mandate complete evaluation per the algorithm. If hematuria occurs only once in an individual less than 40 years old, periodic follow-up is permissible. It may well be that intermittent hematuria is no less ominous than sustained hematuria and that the association of microscopic hematuria with intermittent gross hematuria bears little consequence. Historically, it is important to note if hematuria occurs in association with fever, upper respiratory infection, gastroenteritis, ex-
Physical Examination
History stones, abdominal/flank pain. Abdominal/flank pain.
Abdominal/flank pain. Abdominallflank fullness or pain.
Backlflank pain. Dysuria, back/suprapubic pain, frequency, urgency, nocturia. Dysuria, fever, suprapubic/back pain, frequency, urgency. Scrotal pain, fever, dysuria, urgency, frequency. Urethral discharge, dysuria, frequency, urgency. Weight loss, back/suprapubic pain. Hematuria with menses, abdominal/ suprapubic pain. Nocturia, frequency, urgency, dysuria, dribbling. Physical exercise.
Abdominal/flank pain. Abdominal/suprapubic pain.
Vaginal discharge, constipation, hematochezia. Automanipulation.
Rectallvaginal examination.
ercise,26 or menses. 27 Hematuria may occur with "stress" in general,28 and it has also been reported with diseases involving structures adjacent to the urinary tract. A diagnosis of exerciserelated hematuria is predicated on its disappearance within 48 hour after exercise. 26 "Loin-pain hematuria syndrome" requires abnormal angiography for diagnosis. 29 Hematuria associated with anticoagulants may be secondary to an occult neoplasm, and such must be excluded.20 Hematuria has also been reported in conjunction with an exaggerated lumbar lordosis. s Table 1 provides a differential diagnosis of isolated hematuria in
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Rectal examination. Rectal and genitourinary examination. Rectal and genitourinary examination. Rectal and genitourinary examination. Pelvic examination. Rectal examination.
all age groups. History and physical examination are emphasized as they often provide critical indicators of underlying etiology. Urinalysis must be closely scrutinized. If the dipstick examination shows significant proteinuria or if sediment examination discloses red blood cell or other suggestive casts, then intrinsic renal disease is likely and should be evaluated and treated as appropriate. It is at this point that phase contrast microscopy or scanning electron microscopy should be employed. Dysmorphic cells are indicative of a glomerular source and intrinsic renal disease, keeping in mind that intrinsic renal disease other than 105
Isolated HematurIa
glomerular may be associated with normomorphic cells. 8.17 ,18 The most difficult to diagnose is isolated hematuria in a patient with a noncontributory history and physical examination, normomorphic cells, and no abnormality on urinalysis. The differential diagnosis of isolated hematuria applies to this select group of patients, as well. However, the relative frequency of occurrence of each abnormality in both the under- and over-age-40 groups is unknown. Retrospective studies imply that the prevalence of malignancy and benign neoplasm can approach 33% in the over-age-40 groUp.19-20 These neoplasms occur much less frequently in the under-age-40 group, but the prevalence of underlying intrinsic renal disease is quite high. Infection and calculous disease probably occur equally often in both age groups. An initial test for the patient with isolated asymptomatic hematuria per the algorithm is a urine culture. If positive, the patient is evaluated and treated as appropriate. When reculture is negative, the urine should again be assessed for the presence of hematuria. If hematuria persists, the algorithm is re-entered. If initial culture is negative, first-line laboratory studies should be accomplished (Table 2). Additionally, a 24-hour urine collection for protein and creatinine clearance is performed at this time. Presently, it is unknown how much proteinuria can exist solely as a result of gross hematuria. Studies remain to be done, but greater than 500 mg of protein per 24 hours is probably . abnormal and implies intrinsic renal disease. With microscopic hematuria, proteinuria greater than 200 mg per day is probably abnormal. Usually, a urine protein electrophoresis performed in conjunction with the 24-hour urine collection will facilitate patient evaluation. Especially with gross hematuria, this combina106
tion will determine if detected protein is hemoglobin from lysed RBCs. Irrespective of what is determined by the laboratory evaluation, the next step is structural examination of the kidney, preferably by bolus excretory urography with tomography. However, the safety of this test is dependent on the serum creatinine level and contraindications for radiocontrast dye. Alternatives to the excretory urogram are renal ultrasonography or, possibly, radionuclide renal scan. If structural examination discloses a lesion or abnormal kidney size, the patient should be evaluated and treated as appropriate. If evaluation is negative, second-line laboratory is then accomplished (Table 2).
Urine cultures for acid-fast bacilli are performed on first-voided urine, but only if intermediate strength purified protein derivative skin testing, excretory urography, chest films, or family history is suggestive of infection or exposure. First-voided urine cytology should be performed on all individuals older than age 40. Structural examination is considered appropriate even ifprior testing discloses intrinsic disease. Furthermore, serologies and other second-line laboratory tests are indicated to evaluate intrinsic renal disese. Thus, it is after completion of this laboratory evaluation that the patient with intrinsic renal disease departs from the algorithm to be evaluated and treated as appropriate.
TABLE 2 Laboratory Evaluation First-line Complete blood count Platelet count Multiphasic chemistry screen (BUN, creatinine) Sickle cell screen (for black patients; may include hemoglobin electrophoresis) Second-line Prothrombin time, partial thromboplastin time, bleeding time Intermediate strength PPD Erythrocyte sedimentation rate Serologies Serum protein electrophoresis Antinuclear antibody, complement levels (C3, C4, CH 50 ) Cryoglobulin screen Optional (as clinically indicated) Antistreptococcal enzyme titers
VDRL Hepatitis B surface antigen Skin or throat cultures Chest roentgenogram Urine acid-fast bacilli cultures (3) Urine cytologies (3) BUN: Blood urea nitrogen, PPD: purified protein derivative, VORL: Venereal Disease Research Laboratory.
February 1986 Volume 291 Number 2
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Continuation of the algorithm next requires that cystoscopy be performed, preferably during episodes of gross hematuria, if such exists, to determine if blood emanates from one or both ureters. A lesion found at cystoscopy should be evaluated and treated as appropriate. Evaluation of gross and unilateral hematuria is controversia1. 30 Both tumo~ and vascular abnormality can present in this fashion, as can glomerulonephritis. 3t Profuse bleeding can result in substantial blood loss or clot retention. Aggressive evaluation is therefore indicated. The next branch of the algorithm, performed if cystoscopy is normal or fails to disclose an etiology for the hematuria, pertains to the patient's age. When older than age 40 years, angiography, computerized tomography (CT), or nuclear magnetic resonance (NMR) should be performed. Because the sensitivity of CT and NMR when compared with angiography for detection of small structural abnormalities is unknown, the author prefers angiography. If positive for a lesion, the patient is evaluated and treated as appropriate. If negative, then it is permissible to follow the patient long-term or to perform a renal biopsy. When the patient is younger than age 40, a descriptive diagnosis of isolated asymptomatic hematuria is given. The patient then is either followed long-term or is subjected to renal biopsy per the clinician's discretion. For insurance and employment purposes, the definitive diagnosis usually afforded by renal biopsy at this point may be important. Any decision to biopsy, however, must weigh attendant risks 32 against possible benefits. The establishment of a nonneoplastic renal cause can often save repeated radiologic and urologic procedures. However, only rarely is a treatable disease found. Biopsy for unilateral gross hematuria in the under-40 patient is probably not indicated.
Further structural evaluation, CT scan, radionuclide scan, and angiography may be indicated. Long-term follow-up should occur at 6-month intervals and should consist of another history and physical examination, urinalysis, complete blood count, multiphasic chemistry screen to include BUN and creatinine, and urine cytology if the patient is older than age 40. Additionally, in the over-age-40 patient, if CT rather than angiography was performed, it should be repeated at yearly intervals. This follow-up is indicated even in the event that biopsy is accomplished and whether it is normal or abnormal. Follow-up to an abnormal biopsy need not include structural evaluation or urine cytology. An attempt is made to detect either a structural abnormality or intrinsic renal disease. Further testing with the suggestion of either is at the discretion of the clinician, especially whether to include periodic cystoscopy in the over-age40 patient and retrograde pyelography. Of note, only approximately 5% of patients with bladder cancer are less than 45 years of age. 33 Tumors of the upper urinary tract also tend to occur in older individuals. 33 The author realizes the age-related recommendations in the algorithm for thorough structural evaluation are controversial and further discusses this question in the next section. Renal Cell Carcinoma
Primary tumors of the kidney account for 2%-3% of all malignancies, and of these, 90% are renal cell carcinomas. 34 The natural history of renal cell carcinoma reveals that this malignancy is unpredictable, with little information available concerning the fate of untreated individuals, although prolonged survival has been seen with metastases. 35 Additionally, the tumor can recur up to 31 years after nephrectomy performed for surgical cure. 36 Sponta-
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
neous regression of metastatic lesions has been reported. 35 Finally, a 2.5% metastatic rate in tumors less than 3 cm in diameter was reported in 1938.37 Although this study was based on necropsy records, it is unknown to what extent the search for metastases was conducted. The natural history of untreated disease after the onset of microhematuria has not been studied. It appears, however, that renal cell carcinoma is slowgrowing: doubling time is estimated to be 300 days.3s Early detection does improve survival,36 and the 5-year survival rate of surgically treated tumor located within the kidney capsule is 67%. This percentage decreases to 33.5% with nodal involvement. 36 Recurrence is always a possibility. Therefore, because of the unpredictable nature of the tumor, hematuria merits evaluation irrespective of its duration but especially if the hematuria began after age 40. Clinical manifestations in 309 patients with renal cell carcinoma 39 included hematuria in 59%, but only 9% had the classic triad of pain, mass, and gross hematuria. Although rare, simple cysts and tumor can co-exist (incidence of approximately 1%).40 A simple renal cyst is not a frequent cause of hematuria, and the combination of the two requires further evaluation. The tumor generally occurs later in life, as only approximately 4% occur under age 40. 41 The mean age for presentation is between 55 and 60 years. 34 Evaluation of the over-age-40 patient who presents with iso-. lated asymptomatic hematuria must be directed at ruling out a malignancy. The algorithm represents a step-wide approach to do so. Thus, the patient is sequentially evaluated with bolus nephrotomography, cystoscopy, and urine cytologies. The latter will be positive only 70/0-8% of the time in patients who have renal 107
Isolated Hematuria
cell carcinoma. 42 This positivity requires tumor erosion into a major collecting system. However, urine cytology will be positive in carcinoma of the uroepithelium of the bladder and upper tracts approximately 70% of the time. Therefore, cytology is indispensable for detecting in situ carcinoma, even when cystoscopy and excretory urography are norma1. 43 Controversy abounds concerning required evaluation of the over-40 patient with hematuria who has undergone normal bolus nephrotomography,44 i.e., the need for subsequent selective renal angiography and the sensitivity of CT in detecting small structural lesions. Of major issue is the accuracy of nephrotomography in detecting renal cell carcinoma, which is believed by some to be as high as 95% if the procedure is of satisfactory quality. In a 1968 study45 of nephrotomograms performed in 127 patients, the false-negative rate was 4% when tomography was compared with surgical pathologic or autopsy study specimens. In a more recent study of bolus nephrotomography,46 10% of the time cancer was misdiagnosed as a benign lesion. Most reports fail to consider the confidence levels involved in the adequacy of the study. In other reviews,46,47 only 75% of the time did the quality of the study allow a high level of confidence. The sensitivity and specificity of nephrotomography have not been prospectively studied to compare angiography or CT in detecting lesions in hematuria patients. The majority of studies compare abnormal excretory urogram findings with angiography or CT. As yet, a comparison prospective study has not been done in the over-age-40 patients with hematuria who have normal nephrotomography and who are then evaluated with both angiography and CT. In one comparison retrospecti ve study, 48 vascular changes and tumors were found at 108
angiography when excretory urography (tomography not specified) had been normal. The implication is that angiography is more sensitive than excretory urography in detecting the source of hematuria. The same is probably true of CT. Considering that nephrotomography has a 95% accuracy rate, it is possible that 5% of individuals with renal cell carcinoma will have a false-negative study. If tumors less than 3 cm in diameter truly are rarely metastatiac,37 then CT may well be an appropriate test following normal bolus nephrotomography. Certainly, 3 cm is well within resolution capacity of modern CT scanners. Importantly, negative CT should be followed by a repeat study annually. To recommend selective renal angiography, it is necessary that the study be accurate in detecting renal masses and not be associated with excessive morbidity and mortality. The accuracy of angiography in detecting renal masses is 98%-99%, especially when performed with epinephrine,44,46,49 and complications of angiography are few. In a large survey50 of 11,402 transfemoral renal angiograms conducted in 142 centers, there was a 0.71 % incidence of serious complications and 2.9% incidence of minor complications that were without late sequelae. Mortality was 0.06%, but death occurred only in high-risk patients. It can be concluded that angiography is more accurate than nephrotomography and that it is associated with acceptable morbidity and mortality rates that are less' than the false-negative rate of nephrotomography. Conceivably, after further study, CT may someday obviate the need for angiography. Primary Renal Hematuria
In patients younger than 40 years of age, the algorithm dictates either renal biopsy or longterm follow-up. Long-term followup is acceptable, and biopsy is
optional. Ifbiopsy is accomplished with normal or negative evaluation to this point, it will be abnormal 72%-94% of the time,28,51-58 except in cases of unilateral gross hematuria. Diagnoses uncovered will most often be primary renal hematuria, IgA nephropathy (20%-55% incidence),52,54 familial benign essential hematuria, hereditary nephritis, or an unexpected abnormality in about 5%.51,56 In those 6%-28% of patients found to have a normal renal biopsy, etiology of the hematuria could be renal venous abnormalities59 or an activated renal fibrinolysis system as evidenced by increased urinary kinase levels, assuming that loin-pain-hematuria syndrome, stress- and exercise-associated hematuria, and sampling error have been excluded. Primary renal hematuria remains a somewhat obscure entity that is synonymous with benign recurrent hematuria, idiopathic hematuria, essential hematuria, recurrent hematuria, or symptomless hematuria. The term "primary renal hematuria" is borrowed from Hayslett. 28 This author, however, uses the term to define a subset of hematuria patients. All have an abnormal renal biopsy that does not contain IgA immunofluorescence (IF) and cannot be categorized into a "defined" renal biopsy diagnosis. Light microscopy may show mesangial hypercellularity or matrix increase, a lesion indentical to that often seen with IgA nephropathy. Several investigators have reported associated IgM IF or mesangial C3 or IgG, but IF is often negative. 51 ,54,55,57,58 Unfortuately, many studies that address isolated hematuria were accomplished before the recognition of IgA nephropathy as a separate disease entity.60-62 Immunofluorescence usually was not performed, and those studies in which it was performed often reported only partial data,55,58 making interpretation difficult. Other February 1986 Volume 291 Number 2
Copley
light microscopy abnormalities include arteriolar nephrosclerosis and tubulointerstitial abnormalities of interstitial hypercellularity, tubular atrophy, or fibrosis. Electron microscopy will often show minor capillary loop basement membrane changes as well as occasional deposits.5i Findings do not allow specific morphologic classification. The clinical presentation of patients with primary renal hematuria is relatively indistinct except from the standpoint of age. In a review of 371 patients, only 6% were older than age 40. 56 Thus, there is little age overlap between individuals with primary renal hematuria and those with renal cell carcinoma (Figure 2). Men are affected more often than women, with 68% of cases being male in the mentioned review. 56 The hematuria can be gross (30%-63% incidence)52,53,63 or microscopic, recurrent or intermittent (66% incidence),53 or persistent (33% incidence).53 Exercise, stress, and infection (including upper respiratory infection or gastroenteritis) can precipitate hematuria episodes. The amount of proteinuria detected varies but is usually less than 500 mg per 24 hours, and red blood cell or hemoglobin casts can be seen 40%-60% of the time. 52 ,53 Loin pain can be persistent and extremely severe, similar in nature to that whi~h occurs with IgA nephropathy.63 Clinically, it is not possible to differentiate primary renal hematuria from IgA nephropathy.63 Prognosis of primary renal hematuria is considered excellent. Several studies have reported spontaneous remission within 5 years of discovery in more than 50% of patients. Few develop a decrease in renal function or elevation of blood pressure. 60-62 However, many studies that attempt to assess prognosis are deficient: many lack renal biopsy IF or serologic evaluations 60- 62 ; many include patients with either a hearing impairment, a positive family
40 37 35 32 30 27 I-
z
UJ
u
a:
18
20
17
UJ
Q.
14 10
10
6· 4
0-9
10-19
20-29 30-39
40-49
PATIENT AGE
50-59
60-69
70-79
·6 %, AGE 40 AND ABOVE
Figure 2. Age of patients with primary renal hematuria (cross-hatched). and renal cell carcinoma (open). Adapted from Ochsner et al 41 and Pollack and 001. 56
history of hematuria, or evidence of antecedent streptococcal infection53, 57, 60-62, 64; and duration of hematuria and follow-up may be for periods less than that required to demonstrate progression of the nephropathy to renal insufficiency.52,53,55,57,58,60,61,64 Repeat renal biopsy, which might show resolution or progression of a proliferative glomerulonephritis, has been infrequently accomplished. 58 ,6o,64 Actually, the prognosis of patients with primary renal hematuria is unknown, but is probably favorable. Most studies indicate that greater than one gram of protein per day begets a worse prognosis. 28,61,62,64 Familial Benign. Essential Hematuria
Less commonly detected at renal biopsy in patients evaluated per the algorithm is familial benign essential hematuria. Clinically, it may present as microscopic hematuria, is autosomal dominant, and is associated with minimal proteinuria. Renal function usually remains normal, and
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
prognosis is excellent. Diagnosis is made at renal biopsy. Electron microscopy discloses a thin glomerular basement membrane, and light microscopy shows normal to minimal changes within glomeruli. 65 Immunofluorescence is usually negative. It is considered by some authors to be a forme fruste of hereditary nephritis (AIport's syndrome).51 Need for Further Clinical Investigations
Currently, no information is available to support the contention that intermittent hema- . turia is no less ominous than sustained hematuria or that the association of microscopic hematuria with intermittent gross hematuria bears little consequence. Further study is definitely needed to determine the frequency of occurrence of the various etiologies of isolated asympatomatic hematuria in both the under- and over40 age groups. In addition, a prospective study of CT, angiography, and nephrotomography is needed to determine the true sen109
Isolated Hematuria
sitivity and specificity of the three procedures for detecting the source of hematuria. Continued research in these areas would, perhaps, answer many questions existing in the current controversies. References 1. Bradley M, Schumann GB, Ward PCJ: Examination of urine. In: Henry JB, ed: Clinical Diagnosis and Management of Laboratory Methods. Philadelphia, WB Saunders Co, 1979, p 559. 2. Budinger JM, Cavallo M: Detection of hematuria with a paper-strip indicator. Am J Clin Pathol 42:621Hl29, 1964. 3. James JA, Liebschutz NH: Evaluation of a new "dip and read" test for hematuria. Am J Clin Pathol 38:554-556, 1962. 4. Adams EC, Fetter MD, Free HM, Free AH: Hemolysis in hematuria. J Urol 88:427-430, 1962. 5. Elder TR, Barry JL, Folcik PM, . Knights EM Jr: Simplified test for hematuria. Ann Intern Med 56:957-959, 1962. 6. Leonards JR: Simple test for hematuria compared with established tests. JAMA 179:163-164, 1962. 7. Kesson AM, Talbott JM, Gyory AZ: Microscopic examination of urine. Lancet 2:809-812, 1978. 8. Fassett RG, Horgan BA, Mathew TH: Detection of glomerular bleeding by phase-contrast microscopy. Lancet 1: 1432-1434, 1982. 9. Larcom RC, Carter GH: Erythrocytes in urinary sediment: Identification and normal limits. J Lab Clin Med 33:875-880, 1948. 10. Wright WT: Cell counts in urine. Arch Intern Med 103:76-78, 1959. 11. Northway JD: Hematuria in children. J Pediatr 78:381-396, 1971. 12. Snoke AW: The normal Addis sediment count in children. J Pediatr 12:473-478,1938. 13. Addis T: A clinical classification of Bright's disease. JAMA 85:163-167, 1925. 14. Lippman RW: Urine and Urinary Sediment. Springfield, Charles C Thomas Publisher, 1961, p 103. 15. Lyttle JD: The Addis sediment count in normal children. J Clin Invest 12: 87-93, 1933. 16. Jacobellis U, Fabiano A, Tallarigo C: New technique to localize the origin of idiopathic microscopic hematuria. J Urol127:475-476,1982. 17. Fairley KF, Birch DF: Hematuria: A simplified method for identifying glomerular bleeding. Kidney Int 21: 105-108, 1982. 18. Fassett RG, Horgan BA, Gove D,
110
Mathew TH: Scanning electron microscopy of glomerular and nonglomerular red blood cells. Clin Nephrol20:11-16, 1983. 19. Carson CC, Segura JS, Greene LF: Clinical importance of microhematuria. JAMA 241:149-150, 1979. 20. Golin AL, Howard RS: Asymptomatic microscopic hematuria. J Urol 124: 389-391, 1980. 21. Doss AK: Hematuria. Urol Cutan Rev 51:671Hl80,1947. 22. Lee LW, Davis E: Gross urinary hemorrhage: a symptom, not a disease. JAMA 153:782-784, 1953. 23. Froom P, Ribak J, Benbassat J: Significance of microhaematuria in young adults. Br Med J 288:20-22, 1984. 24. Benson GS, Brewer ED: Hematuria: Algorithms for diagnosis. JAMA 246: 993-995, 1981. 25. Gottesman JE, Kelly ME: Diagnosis and management of upper-tract bleeding. In: Weekly Urology Update Series, Princeton, Biomedia, Inc, 1979, pp 2-7. 26. Siegel AJ, Hennekens CH, Solomon HS, van Boeckel B: Exercise related hematuria. JAMA 241:391-392, 1979. 27. Klein RS, Cattolica EV: Ureteral endometriosis. Urology 13:447-482, 1979. 28. Hayslett JP: Primary hematuria. KF 9:11-14, 1976. 29. Burden RP, Booth LJ, Ockenden BG, Boyd WN, Higgins PMCR, Aber GM: Intrarenal vascular changes in adults with recurrent haematuria and loin pain-a clinical, histological and angiographic study. Q J Med 44:433447,1975. 30. Lano MD, Wagoner RD, Leary FJ: Unilateral essential hematuria. Mayo Clin Proc 54:88-90, 1979. 31. Chester AC, Diamond LH, Argy WP, Schreiner GE: Unilateral primary hematuria. JAMA 240:2759, 1978. 32. Wickre CG, Golper TA: Complications of percutaneous needle biopsy of the kidney. Am J Nephrol 2:173-178, 1982. 33. Myers RP: Tumors of the renal pelvis, ureter and urinary bladder. In: Kendall AR, Karafin L, eds: Goldsmith Practice of Surgery, Urology. Hagerstown, Harper and Row, 1979, pp 7-10. 34. Kantor AF: Current concepts in the epidemiology and etiology of primary renal cell carcinoma. J Urol117:415417,1977. 35. Cronin RE, Kaehny WD, Miller PD, Stables DD, Gabow PA, Ostroy PR, Schrier RW: Renal cell carcinoma: unusual systemic manifestations. Medicine 55:291-311, 1976. 36. McNichols DW, Segura JW, DeWeerd JH: Renal cell carcinoma: Long-term survival and late recurrence. J Urol 126:17-23, 1981.
37. Bell ET: A classification of renal tumors with observations on the frequency of the various types. J Urol 39:238-243, 1938. 38. Rabes HM: Growh kinetics of human renal adenocarcinoma. In: Sufrin G, Beckley SA, eds: Renal Adenocarcinoma, Vol 49. UICC Technical Report Series, Geneva, International Union Against Cancer, 1980, p 78. 39. Skinner DG, Colvin RB, Vermillion CD, Pfister RC, Leadbetter WF: Diagnosis and management of renal cell carcinoma. Cancer 28:1165-1177, 1971. 40. Emmett JL, Levine SR, Woolner LB: Co-existence of renal cyst and tumor: Incidence in 1007 cases. Br J Urol 35:403-410, 1963. 41. Ochsner MG, Brannon W, Pond HS, Goodier EH: Renal cell carcinoma: Review of 26 years of experience at the Ochsner Clinic. J Urol 110:643-646, 1973. 42. Garnick MD: Advanced renal cell cancer. Kidney Int 20:127-136, 1981. 43. Abuelo JG: The diagnosis of hematuria. Arch Intern Med 143:967-970, 1983. 44. Richie JP, Skinner DG: Renal neoplasia. In: Brenner BM, Rector FC, eds: The Kidney. Philadelphia, WB Saunders Co, 1981, p 2111. 45. Evans J: The accuracy of diagnostic radiology. JAMA 204:131-135, 1968. 46. Clayman RV, Williams RD, Fraley EE: The pursuit of the renal mass. N Engl J Med 300:72-74,1979. 47. Lang EK: The accuracy ofroentgenographic techniques in the diagnosis of renal mass lesions. Radiology 98:119128,1971. 48. Jonsson K: Renal angiography in patients with hematuria. AJR 116: 758-765,1972. 49. Lang EK: Roentgenographic assessment of asymptomatic renal lesions. Radiology 109:257-269, 1973. 50. Lang EK: Complications of retrograde percutaneous arteriography. JUral 90:604-610, 1963. 51. Glassock RJ, Cohen AH, Bennett CM, Martinez-Maldonado M: Primary glomerular diseases. In: Brenner BM, Rector FC, eds: The Kidney. Philadelphia, WB Saunders Co, 1981, p 1398. 52. Kupor LR, Mullins JD, McPhaul JJ: Immunopathologic findings in idiopathic renal hematuria. Arch Intern Med 135:1204-1211,1975. 53. Labovitz ED, Stein muller SR, Henderson LW, McCurdy DK, Goldberg M: "Benign" hematuria with focal glomerulitis in adults. Ann Intern Med 77:723-729,1972. 54. Michael J, Jones NF, Davies DR, Tighe JR: Recurrent haematuria: Role of renal biopsy and investigative morbidity. Br Med J 1:686-688, 1976. 55. Pardo V, Berian MG, Levi DF, Strauss
February 1986 Volume 291 Number 2
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J: Benign: primary hematuria. Am J Med 67:817-822, 1979. 56. Pollak VE, Ooi BS: Asymptomatic hematuria. Pastgrad Med 62:115-120, 1977. 57. Sinniah R, Pwee HS, Lim CH: Glomerular lesions in asymptomatic microscopic hematuria discovered on routine medical examination. Clin Nephral 5:216-228, 1976. 58. Van de Putte LBA, De La Riviere GB, van Breda Vriesman PJC: Recurrent or persistent hematuria. N Engl J Med 290:1165-1170,1974.
59. Hayashi M, Kume T, Nihira H: Abnormalities of renal venous system and unexplained renal hematuria. JUral 124:12-16, 1980. 60. Ayoub EM, Vernier RL: Benign recurrent hematuria. Am J Dis Child 109: 217-223, 1965. 61. Johnston C, Shuler S: Recurrent haematuria in childhood. Arch Dis Child 44:483-486,1969. 62. Singer DB, Hill LL, Rosenberg HS, Marshall J. Swenson R: Recurrent hematuria in childhood. N Engl J Med 279:7-12, 1968.
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63. Copley JB, Hasbargen JA: "Primary" hematuria: A prospective evaluation. Kidney Int 25:161,1984. 64. Hendler E, Kashgarian M, Hayslett J: Clinicopathological correlation of primary hematuria. Lancet 1:458-463, 1972. 65. Rogers PW, Kurtzman NA, Bunn SM, White MG: Familial benign essential hematuria. Arch Intern Med 131:257262,1973.
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ABSTRACT: The term "isolated asymptomatic hematuria," as it relates to both gross and microscopic hematuria, is defined; and the pros and cons of detection techniques used to localize the source of the hematuria are discussed. An algorithm is provided to optimize detection of structural defects and intrinsic renal disease in an effort to avoid subjecting the patient with this difficultto-diagnose problem to unnecessary invasive tests. Although invasive tests should be performed where deemed necessary in the clinician's aggressive search to detect any structural abnormality, controversial areas of the evaluation of these patients are addressed. To justify various branch points of the algorithm, a discussion of both renal cell carcinoma and primary renal hematuria is proffered. KEY INDEXING TERMS: Hematuria; Algorithm; Urine; Isolated; Asymptomatic. [Am J Med Sci 1986; 291(2)101-111.)
A
perPlexing clinical problem is the patient with hematuria and no evidence of renal or systemic disease. It is usually difficult to decide to what extent to pursue a diagnosis, especially whether to perform renal angiography or renal biopsy when etiology and prognosis so often times remain uncertain after a thorough evaluation. Accordingly, this article reviews isolated asymptomatic hematuria in the adult and provides the clinician with an introduction to the significance of such a finding as well as with an algorithm for appropriate evaluation and follow-up. Included is a discussion of prognosis. The hematuria may be microscopic or gross, intermittent or continous, and by definition is isolated. These patients have no other abnormality on urinalysis, do not have significant proteinuria, do have normal renal function, and are not hypertensive. Patient history and physical examination are otherwise not suggestive ofintrinsic renal disease. Detection of Hematuria
From the Nephrology Service, Department of Medicine, Brooke Army Medical Center, Fort Sam Houston, Texas. The author thanks Fern Crouse, Carolyn Martinez, and Sandy Helms for their clerical and editorial assistance. The views expressed herein are those of the author and do not necessarily reflect the views of the US Army or the Department of Defense. Reprint requests: LTC John B. Copley, MD, Department of Medicine (HSHEMDN), Brooke Army Medical Center, Fort Sam Houston, TX 78234-6200.
Gross hematuria implies an abnormality emanating from within the urinary tract. It is usually alarming and prompts the patient to seek medical attention. However, asymptomatic microscopic hematuria is often discovered only at routine urinalysis; but, after contamination is excluded, this too implies a urinary tract abnormality. The usual method for detecting microscopic hematuria is the urinalysis paper strip dipstick. This
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
consists of a reagent strip test containing orthotolidine and buffered organic peroxidase. Hemoglobin catalyzes the oxidation reaction between these two substances and results in a measurable color change against a standard scale. The dipstick is designed to detect free hemoglobin or hemoglobin contained in red blood cells (RBCs). It is more sensitive for hemoglobin than for intact RBCs. 1 False-negative results occur 1%2 to 8%3 of the time in the settings of concentrated urine, of urine that contains a substantial amount of protein or formaldehyde, or of urine that contains vitamin C in concentrations greater than 10 mg/100m1. 1 • 3 Other ascorbic acids, such as those used as preservatives in tetracycline, can also result in falsenegative testing. False-positive tests occur with chlorine, with other oxidizing agents, or with bacterial peroxidases. 1 The dipstick detects hemolysis when urine free hemoglobin exceeds 0.05-0.3 mg hemoglobin per 100 ml urine (up to ten lysed RBCs per ml)/ and it also can detect myoglobin. Hemolysis occurs to some extent in 90% of urine specimens containing blood. 4 The microscopic examination is a reasonably sensitive way of detecting RBCs. The dipstick can detect 2.5-5 X 106 RBCs per 100 ml [25 to 50 RBCs per microliter, 3 RBCs per high power field (hpf)),2,5,6 and the microscopic examination 1.2 x 106 RBCs per 100 ml. 5 Gross hematuria represents at least 5 X 106 RBCs per mm 3 , which corresponds to approxi-
101
Isolated Hematuria
mately 0.5-1 ml of RBCs per liter of solution. Although the detection of erythrocytes in urine is relatively simple, the clear separation of normal excretion rates from abnormal may be more difficult. The definition of normalcy is ambiguous and can vary depending on the reference consulted. Confusion is compounded by work performed by several groups/'s which establishes the importance of quantitative urine microscopy in defining abnormal hematuria (greater than 3,000 erythrocytes per milliliter of urine is considered abnormal). The same groups emphasize the inaccuracies of using the spun urinary sediment for detecting significant hematuria. Quantitative methods of urinalysis are used only rarely, however, and most attempts at defining normalcy are based on the spun urinary sediment. These definitions may further be influenced by urinalysis technique. The reader is referred to standard laboratory textbooks for proper methodology . Larcom and Carter, using spun urinary sediments, studied 3,000 consecutive single-voided specimens from young men applying for employment. In 2,484 cases, no RBCs were found; in 2% of patients, there were 2-3 RBC/hpf; and in 0.7%, 4-5 RBC/hpf. 9 Wright studied 5,000 consecutive male urine specimens received at a life insurance company, and 97% had less than 5 RBClhpf. IO Thus, 5 RBC/hpf probably represents 2 standard deviations from the norm. Most authorsl,l1 accept up to 2-3 RBClhpf as normal. Females generally are allowed one more red blood cell than males due to difficulties in urine collection technique. In all instances, it is important to assess the clinical situation. Strenuous exercise may increase amounts of hematuria without any underlying pathologic process. Furthermore, development of 1 RBClhpf in an individual over 40 years of 102
age may herald clinically important pathology if prior urinalyses had been negative. An Addis count is more precise in determining abnormal amounts of hematuria. This procedure has been standardized so that less than 600,000 RBCs per 12-hour urine collection is considered normal. 9,12-14 An Addis count, however, is a tedious quantitative method. In addition, the number of RBCs per 12 hours has not been precisely correlated to semi-quantitative spun urine sediments. I. 9.10.15 Several studies have shown that the normal number of cells for children and adults is the same. 12.15 Localization of Source of Hematuria
It would facilitate patient evaluation if a means were available for determining if hematuria emanates from the upper versus the lower urinary tract. Cystoscopy performed during periods of gross hematuria should be capable of detecting blood effluxing from one or both ureteral orifices. The source of microscopic hematuria, on the other hand, can be difficult to ascertain. The "three-glass test" represents an effort at localizing the source. Three separate aliquots of urine are collected during voiding, and the numbers of red cells in each aliquot are compared. Initial hematuria (Le., RBCs in the first aliquot) implies hematuria of urethral origin; total hematuria (Le., RBCs in all three samples) implicates the upper urinary tract; and terminal hematuria (i.e., RBCs in the last aliquot) implies prostatic hematuria or hematuria emanating from the bladderneck. Sensitivity and specificity of this test are unknown. Another method for determining the source of hematuria involves Hemostix sampling of ureteral urines. 16 This is done at cystoscopy with a special scope that incorporates a dipstick indicator that can be reacted with ure-
teral urine. The technique has not been substantiated by further study. Fairley and Birch have found phase-contrast microscopy helpful for determining localization. 17 On evaluation of red blood cell morphology, they found that 55 of 58 patients with glomerular disease had dysmorphic urinary RBCs and that nonglomerular disease was associated with normomorphic RBCs. The technique has not been fully substantiated by subsequent investigation but seems promising. Fassett et aI,S using similar methodology, made an incorrect assessment of the site of bleeding in only 4% of patients. These same authors accurately differentiated between glomerular and nonglomerular RBCs by using scanning electron microscopy on urine sediment. IS Finally, certain findings predict the source of hematuria. When urine color is brown or smokey, hematuria probably emanates from the kidney. Extrarenal hematuria is often associated with pink or red urine. Red blood cell casts always indicate a renal origin for the hematuria. Blood clots are associated with extrarenal hematuria and generally are absent when hematuria emanates from the kidney. Associated proteinuria, greater than 500 mg/24 hours, implies an intrarenal source, although further study is needed to substantiate this observation. Algorithm for Evaluation of Hematuria
Hematuria, either gross or microscopic, can be a presenting manifestation of urinary tract disease. However, prospective studies of isolated. asymptomatic hematuria are lacking, and retrospective studies either base their conclusions on incomplete evaluation for etiology or deal with hematuria in the elderly.19-23 Therefore, sequence of testing and extent of evaluation are controversial at best. Several algorithms February 1986 Volume 291 Number 2
Copley
for the diagnosis of hematuria have been published, but all approach the problem in a general manner rather than addressing the patient with isolated asymptomatic hematuria. 24 •25 The purpose of this algorithm (Figure 1) is not to provide a methodology for evaluation of all forms of intrinsic renal disease, but to provide a matrix to be used to evaluate the difficult-to-diagnose adult patient with isolated hematuria. The intent is to optimize detection of intrinsic renal disease and structural lesions such that invasive ·tests can be avoided. Invasive testing is used
when deemed necessary, and structural abnormalities are aggressively sought or ruled out. Evaluation per the algorithm is not continued once an etiology for the hematuria is found or if testing indicates intrinsic renal disease, although further structural evaluation is not necessarily precluded. The patient with underlying renal disease who develops new hematuria also is excluded, but probably deserves thorough testing. The algorithm begins with the patient's history. The hematuria should be characterized as to gross or microscopic, intermittent
or constant. If gross hematuria is episodic, it should be ascertained if microscopic hematuria is persistent, intermittent, or absent between episodes. Duration of hematuria must be documented. Depending on the clinical situation, it is prudent to wait approximately 3 months, with repeat urinalysis performed at least monthly, before embarking on an expensive and possibly invasive evaluation. All patients over the age of 40 should be evaluated extensively, even after a single episode of hematuria. Evaluation of younger patients can be individualized at the discretion of the clin-
HEMATURIA
HISTORY. PHYSICAL EXAMINATION (H • PI
INTRINSIC RENAL DISEASE
( + ) EVAL I RX AS APPROPRIATE (
STOP
--'~=.:.:.::.:.:::.:.._-'--'.c:;.c.-"-'-
-
--------1
(GLOMERULAR. INTERSTITIAL)
I
)
RENAL BIOPSY? I EVAL I RX AS APPROPRIATE I
_ _-'-_ _ __
ABNORMAL (pROTEIN : 200 my· SOD mg?1
SEROLOGIES ele .•
'--------n------j-r==UR=IN=E=P==RO==T==EI=N==EL=EC==T==RO=P=H=OR=E=SI=S'-- INTRINSIC RENAL DISEASE
1----
ETIOLOGY EVALI RX AS APPROPRIATE
SECOND LINE LABORATORY
EVAL I RX AS APPROPRIATE
1-_ _ _ _ _ _ _ _ _ _ _ _ _
ETIOLOGY INTRINSIC RENAL DISEASE
NO ETIOLOGY
( + )
1 - - - - EVALlRX
•
AS APPROPRIATE
DEPENDS ON S. CREATININE AND CONTRA INDICATIONS FOR RADIOCONTRAST DYE. ALTERNATIVE: RENAL ULTRASOUND
t GROSS UNILATERAL HEMATURIA PROBABLY SHOULD BE FURTHER EVALUATED WITH COMPUTERIZED TOMOGRAPHY AND RADIONUCLIDE SCAN AND NOT BIOPSIED.
Figure 1. Algorithm for evaluation of Isolated asymptomatic hematuria. EVALlRX: evaluate and treat, H + P: history and physical, HR: hour; IVP: Intravenous pyelogram, S: serum. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
10~
Isolated Hematuria
TABLE 1 Causes of Isolated Hematuria Cause Hematologic · Coagulopathy Hemoglobinopathy (sickle cell) Renal Glomerular disease Primary
History
Bleeding diathesis. family history. anemia. medication. Anemia. family history.
Physical Examination
Petechial rash. splenomegaly. ecchymoses. Ecchymoses. petechial rash.
Flank pain. None.
Normal. Hypertension.
Secondary (includes vasculitis)
Arthralgias/arthritis. skin rash (malar/ discoid lupus). serositis/pleurisy. Raynaud·s. photosensitivity. ulcerations of digits/nails or nose/mouth. alopecia. sore throat. seizures. psychosis. dysphagia. abdominal pain. diabetes mellitus.
Hypertension. Roth's spots. mouth or nasal ulcerations. pharyngitis. alopecia. petechial or other skin rash. cardiopulmonary examination. abdominal examination (masses. bruits. organomegaly. sequelae of liver disease). edema. arthritis. extremity ulcerations. fever.
Hereditary
Family history. Hearing or ocular disorders.
Normal. Hypertension. hearing. funduscopic examination.
Tuberculosis and other chronic urinary tract Infections (include age at onset). stones. analgesics. medicines or other drugs. sicca syndrome. diabetes mellitus. systemic lupus erythematosus. sickle cell disease. toxIns. radiation. heavy metals. living in Balkan countries. family history. headaches. nocturia. urgency.
Hypertension. skin color. arthritis. flank pain. suprapubic pain.
Flank/abdominal pain. dysuria. nocturia. urgency. frequency. fever. chills. Family history. pulmonary symptoms. weight loss. night sweats. flank pain. fever. dysuria. or silent.
Costovertebral angle tenderness.
Interstitial disease
Infections Pyelonephritis
Tuberculosis
Other Malformations Cystic
Travel to "exotic" places. Family history. flank pain. history of stones or Infection. Nocturia.
Abdominal examination. hypertension.
Weight loss. fever. flank or abdominal pain.
Abdominal examination.
Abdominal pain. flank pain.
Abdominal examination (mass. bruits). arrhythmia. other embolic manifestations.
Thrombosis
Flank or abdominal pain.
Edema.
Cortical or papillary necrosis
Flank or abdominal pain. oliguria. fever.
Flank/abdominal pain.
Clots In urine. history trauma.
Flank/abdominal pain.
Vascular Neoplasms Ischemic Embolism
Trauma 104
Pulmonary examination.
Hemangiomas. telangiectasias.
February 1986 Volume 291 Number 2
CopleV'
TABLE 1 Causes of Isolated Hematuria (continued) History
Cause Postrenal Mechanical stones Obstruction Vesicoureteral reflux Other Inflammatory Periureteritis Cystitis Prostatitis Epididymitis Urethritis Neoplasm Endometriosis Benign prostatic hypertrophy (BPH) Exercise False Vaginal/rectal Factitious
ician. Conceivably, only a portion of the algorithm will be accomplished until the initial 3-month period elapses. Further episodes of hematuria mandate complete evaluation per the algorithm. If hematuria occurs only once in an individual less than 40 years old, periodic follow-up is permissible. It may well be that intermittent hematuria is no less ominous than sustained hematuria and that the association of microscopic hematuria with intermittent gross hematuria bears little consequence. Historically, it is important to note if hematuria occurs in association with fever, upper respiratory infection, gastroenteritis, ex-
Physical Examination
History stones, abdominal/flank pain. Abdominal/flank pain.
Abdominal/flank pain. Abdominallflank fullness or pain.
Backlflank pain. Dysuria, back/suprapubic pain, frequency, urgency, nocturia. Dysuria, fever, suprapubic/back pain, frequency, urgency. Scrotal pain, fever, dysuria, urgency, frequency. Urethral discharge, dysuria, frequency, urgency. Weight loss, back/suprapubic pain. Hematuria with menses, abdominal/ suprapubic pain. Nocturia, frequency, urgency, dysuria, dribbling. Physical exercise.
Abdominal/flank pain. Abdominal/suprapubic pain.
Vaginal discharge, constipation, hematochezia. Automanipulation.
Rectallvaginal examination.
ercise,26 or menses. 27 Hematuria may occur with "stress" in general,28 and it has also been reported with diseases involving structures adjacent to the urinary tract. A diagnosis of exerciserelated hematuria is predicated on its disappearance within 48 hour after exercise. 26 "Loin-pain hematuria syndrome" requires abnormal angiography for diagnosis. 29 Hematuria associated with anticoagulants may be secondary to an occult neoplasm, and such must be excluded.20 Hematuria has also been reported in conjunction with an exaggerated lumbar lordosis. s Table 1 provides a differential diagnosis of isolated hematuria in
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
Rectal examination. Rectal and genitourinary examination. Rectal and genitourinary examination. Rectal and genitourinary examination. Pelvic examination. Rectal examination.
all age groups. History and physical examination are emphasized as they often provide critical indicators of underlying etiology. Urinalysis must be closely scrutinized. If the dipstick examination shows significant proteinuria or if sediment examination discloses red blood cell or other suggestive casts, then intrinsic renal disease is likely and should be evaluated and treated as appropriate. It is at this point that phase contrast microscopy or scanning electron microscopy should be employed. Dysmorphic cells are indicative of a glomerular source and intrinsic renal disease, keeping in mind that intrinsic renal disease other than 105
Isolated HematurIa
glomerular may be associated with normomorphic cells. 8.17 ,18 The most difficult to diagnose is isolated hematuria in a patient with a noncontributory history and physical examination, normomorphic cells, and no abnormality on urinalysis. The differential diagnosis of isolated hematuria applies to this select group of patients, as well. However, the relative frequency of occurrence of each abnormality in both the under- and over-age-40 groups is unknown. Retrospective studies imply that the prevalence of malignancy and benign neoplasm can approach 33% in the over-age-40 groUp.19-20 These neoplasms occur much less frequently in the under-age-40 group, but the prevalence of underlying intrinsic renal disease is quite high. Infection and calculous disease probably occur equally often in both age groups. An initial test for the patient with isolated asymptomatic hematuria per the algorithm is a urine culture. If positive, the patient is evaluated and treated as appropriate. When reculture is negative, the urine should again be assessed for the presence of hematuria. If hematuria persists, the algorithm is re-entered. If initial culture is negative, first-line laboratory studies should be accomplished (Table 2). Additionally, a 24-hour urine collection for protein and creatinine clearance is performed at this time. Presently, it is unknown how much proteinuria can exist solely as a result of gross hematuria. Studies remain to be done, but greater than 500 mg of protein per 24 hours is probably . abnormal and implies intrinsic renal disease. With microscopic hematuria, proteinuria greater than 200 mg per day is probably abnormal. Usually, a urine protein electrophoresis performed in conjunction with the 24-hour urine collection will facilitate patient evaluation. Especially with gross hematuria, this combina106
tion will determine if detected protein is hemoglobin from lysed RBCs. Irrespective of what is determined by the laboratory evaluation, the next step is structural examination of the kidney, preferably by bolus excretory urography with tomography. However, the safety of this test is dependent on the serum creatinine level and contraindications for radiocontrast dye. Alternatives to the excretory urogram are renal ultrasonography or, possibly, radionuclide renal scan. If structural examination discloses a lesion or abnormal kidney size, the patient should be evaluated and treated as appropriate. If evaluation is negative, second-line laboratory is then accomplished (Table 2).
Urine cultures for acid-fast bacilli are performed on first-voided urine, but only if intermediate strength purified protein derivative skin testing, excretory urography, chest films, or family history is suggestive of infection or exposure. First-voided urine cytology should be performed on all individuals older than age 40. Structural examination is considered appropriate even ifprior testing discloses intrinsic disease. Furthermore, serologies and other second-line laboratory tests are indicated to evaluate intrinsic renal disese. Thus, it is after completion of this laboratory evaluation that the patient with intrinsic renal disease departs from the algorithm to be evaluated and treated as appropriate.
TABLE 2 Laboratory Evaluation First-line Complete blood count Platelet count Multiphasic chemistry screen (BUN, creatinine) Sickle cell screen (for black patients; may include hemoglobin electrophoresis) Second-line Prothrombin time, partial thromboplastin time, bleeding time Intermediate strength PPD Erythrocyte sedimentation rate Serologies Serum protein electrophoresis Antinuclear antibody, complement levels (C3, C4, CH 50 ) Cryoglobulin screen Optional (as clinically indicated) Antistreptococcal enzyme titers
VDRL Hepatitis B surface antigen Skin or throat cultures Chest roentgenogram Urine acid-fast bacilli cultures (3) Urine cytologies (3) BUN: Blood urea nitrogen, PPD: purified protein derivative, VORL: Venereal Disease Research Laboratory.
February 1986 Volume 291 Number 2
Copley
Continuation of the algorithm next requires that cystoscopy be performed, preferably during episodes of gross hematuria, if such exists, to determine if blood emanates from one or both ureters. A lesion found at cystoscopy should be evaluated and treated as appropriate. Evaluation of gross and unilateral hematuria is controversia1. 30 Both tumo~ and vascular abnormality can present in this fashion, as can glomerulonephritis. 3t Profuse bleeding can result in substantial blood loss or clot retention. Aggressive evaluation is therefore indicated. The next branch of the algorithm, performed if cystoscopy is normal or fails to disclose an etiology for the hematuria, pertains to the patient's age. When older than age 40 years, angiography, computerized tomography (CT), or nuclear magnetic resonance (NMR) should be performed. Because the sensitivity of CT and NMR when compared with angiography for detection of small structural abnormalities is unknown, the author prefers angiography. If positive for a lesion, the patient is evaluated and treated as appropriate. If negative, then it is permissible to follow the patient long-term or to perform a renal biopsy. When the patient is younger than age 40, a descriptive diagnosis of isolated asymptomatic hematuria is given. The patient then is either followed long-term or is subjected to renal biopsy per the clinician's discretion. For insurance and employment purposes, the definitive diagnosis usually afforded by renal biopsy at this point may be important. Any decision to biopsy, however, must weigh attendant risks 32 against possible benefits. The establishment of a nonneoplastic renal cause can often save repeated radiologic and urologic procedures. However, only rarely is a treatable disease found. Biopsy for unilateral gross hematuria in the under-40 patient is probably not indicated.
Further structural evaluation, CT scan, radionuclide scan, and angiography may be indicated. Long-term follow-up should occur at 6-month intervals and should consist of another history and physical examination, urinalysis, complete blood count, multiphasic chemistry screen to include BUN and creatinine, and urine cytology if the patient is older than age 40. Additionally, in the over-age-40 patient, if CT rather than angiography was performed, it should be repeated at yearly intervals. This follow-up is indicated even in the event that biopsy is accomplished and whether it is normal or abnormal. Follow-up to an abnormal biopsy need not include structural evaluation or urine cytology. An attempt is made to detect either a structural abnormality or intrinsic renal disease. Further testing with the suggestion of either is at the discretion of the clinician, especially whether to include periodic cystoscopy in the over-age40 patient and retrograde pyelography. Of note, only approximately 5% of patients with bladder cancer are less than 45 years of age. 33 Tumors of the upper urinary tract also tend to occur in older individuals. 33 The author realizes the age-related recommendations in the algorithm for thorough structural evaluation are controversial and further discusses this question in the next section. Renal Cell Carcinoma
Primary tumors of the kidney account for 2%-3% of all malignancies, and of these, 90% are renal cell carcinomas. 34 The natural history of renal cell carcinoma reveals that this malignancy is unpredictable, with little information available concerning the fate of untreated individuals, although prolonged survival has been seen with metastases. 35 Additionally, the tumor can recur up to 31 years after nephrectomy performed for surgical cure. 36 Sponta-
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neous regression of metastatic lesions has been reported. 35 Finally, a 2.5% metastatic rate in tumors less than 3 cm in diameter was reported in 1938.37 Although this study was based on necropsy records, it is unknown to what extent the search for metastases was conducted. The natural history of untreated disease after the onset of microhematuria has not been studied. It appears, however, that renal cell carcinoma is slowgrowing: doubling time is estimated to be 300 days.3s Early detection does improve survival,36 and the 5-year survival rate of surgically treated tumor located within the kidney capsule is 67%. This percentage decreases to 33.5% with nodal involvement. 36 Recurrence is always a possibility. Therefore, because of the unpredictable nature of the tumor, hematuria merits evaluation irrespective of its duration but especially if the hematuria began after age 40. Clinical manifestations in 309 patients with renal cell carcinoma 39 included hematuria in 59%, but only 9% had the classic triad of pain, mass, and gross hematuria. Although rare, simple cysts and tumor can co-exist (incidence of approximately 1%).40 A simple renal cyst is not a frequent cause of hematuria, and the combination of the two requires further evaluation. The tumor generally occurs later in life, as only approximately 4% occur under age 40. 41 The mean age for presentation is between 55 and 60 years. 34 Evaluation of the over-age-40 patient who presents with iso-. lated asymptomatic hematuria must be directed at ruling out a malignancy. The algorithm represents a step-wide approach to do so. Thus, the patient is sequentially evaluated with bolus nephrotomography, cystoscopy, and urine cytologies. The latter will be positive only 70/0-8% of the time in patients who have renal 107
Isolated Hematuria
cell carcinoma. 42 This positivity requires tumor erosion into a major collecting system. However, urine cytology will be positive in carcinoma of the uroepithelium of the bladder and upper tracts approximately 70% of the time. Therefore, cytology is indispensable for detecting in situ carcinoma, even when cystoscopy and excretory urography are norma1. 43 Controversy abounds concerning required evaluation of the over-40 patient with hematuria who has undergone normal bolus nephrotomography,44 i.e., the need for subsequent selective renal angiography and the sensitivity of CT in detecting small structural lesions. Of major issue is the accuracy of nephrotomography in detecting renal cell carcinoma, which is believed by some to be as high as 95% if the procedure is of satisfactory quality. In a 1968 study45 of nephrotomograms performed in 127 patients, the false-negative rate was 4% when tomography was compared with surgical pathologic or autopsy study specimens. In a more recent study of bolus nephrotomography,46 10% of the time cancer was misdiagnosed as a benign lesion. Most reports fail to consider the confidence levels involved in the adequacy of the study. In other reviews,46,47 only 75% of the time did the quality of the study allow a high level of confidence. The sensitivity and specificity of nephrotomography have not been prospectively studied to compare angiography or CT in detecting lesions in hematuria patients. The majority of studies compare abnormal excretory urogram findings with angiography or CT. As yet, a comparison prospective study has not been done in the over-age-40 patients with hematuria who have normal nephrotomography and who are then evaluated with both angiography and CT. In one comparison retrospecti ve study, 48 vascular changes and tumors were found at 108
angiography when excretory urography (tomography not specified) had been normal. The implication is that angiography is more sensitive than excretory urography in detecting the source of hematuria. The same is probably true of CT. Considering that nephrotomography has a 95% accuracy rate, it is possible that 5% of individuals with renal cell carcinoma will have a false-negative study. If tumors less than 3 cm in diameter truly are rarely metastatiac,37 then CT may well be an appropriate test following normal bolus nephrotomography. Certainly, 3 cm is well within resolution capacity of modern CT scanners. Importantly, negative CT should be followed by a repeat study annually. To recommend selective renal angiography, it is necessary that the study be accurate in detecting renal masses and not be associated with excessive morbidity and mortality. The accuracy of angiography in detecting renal masses is 98%-99%, especially when performed with epinephrine,44,46,49 and complications of angiography are few. In a large survey50 of 11,402 transfemoral renal angiograms conducted in 142 centers, there was a 0.71 % incidence of serious complications and 2.9% incidence of minor complications that were without late sequelae. Mortality was 0.06%, but death occurred only in high-risk patients. It can be concluded that angiography is more accurate than nephrotomography and that it is associated with acceptable morbidity and mortality rates that are less' than the false-negative rate of nephrotomography. Conceivably, after further study, CT may someday obviate the need for angiography. Primary Renal Hematuria
In patients younger than 40 years of age, the algorithm dictates either renal biopsy or longterm follow-up. Long-term followup is acceptable, and biopsy is
optional. Ifbiopsy is accomplished with normal or negative evaluation to this point, it will be abnormal 72%-94% of the time,28,51-58 except in cases of unilateral gross hematuria. Diagnoses uncovered will most often be primary renal hematuria, IgA nephropathy (20%-55% incidence),52,54 familial benign essential hematuria, hereditary nephritis, or an unexpected abnormality in about 5%.51,56 In those 6%-28% of patients found to have a normal renal biopsy, etiology of the hematuria could be renal venous abnormalities59 or an activated renal fibrinolysis system as evidenced by increased urinary kinase levels, assuming that loin-pain-hematuria syndrome, stress- and exercise-associated hematuria, and sampling error have been excluded. Primary renal hematuria remains a somewhat obscure entity that is synonymous with benign recurrent hematuria, idiopathic hematuria, essential hematuria, recurrent hematuria, or symptomless hematuria. The term "primary renal hematuria" is borrowed from Hayslett. 28 This author, however, uses the term to define a subset of hematuria patients. All have an abnormal renal biopsy that does not contain IgA immunofluorescence (IF) and cannot be categorized into a "defined" renal biopsy diagnosis. Light microscopy may show mesangial hypercellularity or matrix increase, a lesion indentical to that often seen with IgA nephropathy. Several investigators have reported associated IgM IF or mesangial C3 or IgG, but IF is often negative. 51 ,54,55,57,58 Unfortuately, many studies that address isolated hematuria were accomplished before the recognition of IgA nephropathy as a separate disease entity.60-62 Immunofluorescence usually was not performed, and those studies in which it was performed often reported only partial data,55,58 making interpretation difficult. Other February 1986 Volume 291 Number 2
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light microscopy abnormalities include arteriolar nephrosclerosis and tubulointerstitial abnormalities of interstitial hypercellularity, tubular atrophy, or fibrosis. Electron microscopy will often show minor capillary loop basement membrane changes as well as occasional deposits.5i Findings do not allow specific morphologic classification. The clinical presentation of patients with primary renal hematuria is relatively indistinct except from the standpoint of age. In a review of 371 patients, only 6% were older than age 40. 56 Thus, there is little age overlap between individuals with primary renal hematuria and those with renal cell carcinoma (Figure 2). Men are affected more often than women, with 68% of cases being male in the mentioned review. 56 The hematuria can be gross (30%-63% incidence)52,53,63 or microscopic, recurrent or intermittent (66% incidence),53 or persistent (33% incidence).53 Exercise, stress, and infection (including upper respiratory infection or gastroenteritis) can precipitate hematuria episodes. The amount of proteinuria detected varies but is usually less than 500 mg per 24 hours, and red blood cell or hemoglobin casts can be seen 40%-60% of the time. 52 ,53 Loin pain can be persistent and extremely severe, similar in nature to that whi~h occurs with IgA nephropathy.63 Clinically, it is not possible to differentiate primary renal hematuria from IgA nephropathy.63 Prognosis of primary renal hematuria is considered excellent. Several studies have reported spontaneous remission within 5 years of discovery in more than 50% of patients. Few develop a decrease in renal function or elevation of blood pressure. 60-62 However, many studies that attempt to assess prognosis are deficient: many lack renal biopsy IF or serologic evaluations 60- 62 ; many include patients with either a hearing impairment, a positive family
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10
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PATIENT AGE
50-59
60-69
70-79
·6 %, AGE 40 AND ABOVE
Figure 2. Age of patients with primary renal hematuria (cross-hatched). and renal cell carcinoma (open). Adapted from Ochsner et al 41 and Pollack and 001. 56
history of hematuria, or evidence of antecedent streptococcal infection53, 57, 60-62, 64; and duration of hematuria and follow-up may be for periods less than that required to demonstrate progression of the nephropathy to renal insufficiency.52,53,55,57,58,60,61,64 Repeat renal biopsy, which might show resolution or progression of a proliferative glomerulonephritis, has been infrequently accomplished. 58 ,6o,64 Actually, the prognosis of patients with primary renal hematuria is unknown, but is probably favorable. Most studies indicate that greater than one gram of protein per day begets a worse prognosis. 28,61,62,64 Familial Benign. Essential Hematuria
Less commonly detected at renal biopsy in patients evaluated per the algorithm is familial benign essential hematuria. Clinically, it may present as microscopic hematuria, is autosomal dominant, and is associated with minimal proteinuria. Renal function usually remains normal, and
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prognosis is excellent. Diagnosis is made at renal biopsy. Electron microscopy discloses a thin glomerular basement membrane, and light microscopy shows normal to minimal changes within glomeruli. 65 Immunofluorescence is usually negative. It is considered by some authors to be a forme fruste of hereditary nephritis (AIport's syndrome).51 Need for Further Clinical Investigations
Currently, no information is available to support the contention that intermittent hema- . turia is no less ominous than sustained hematuria or that the association of microscopic hematuria with intermittent gross hematuria bears little consequence. Further study is definitely needed to determine the frequency of occurrence of the various etiologies of isolated asympatomatic hematuria in both the under- and over40 age groups. In addition, a prospective study of CT, angiography, and nephrotomography is needed to determine the true sen109
Isolated Hematuria
sitivity and specificity of the three procedures for detecting the source of hematuria. Continued research in these areas would, perhaps, answer many questions existing in the current controversies. References 1. Bradley M, Schumann GB, Ward PCJ: Examination of urine. In: Henry JB, ed: Clinical Diagnosis and Management of Laboratory Methods. Philadelphia, WB Saunders Co, 1979, p 559. 2. Budinger JM, Cavallo M: Detection of hematuria with a paper-strip indicator. Am J Clin Pathol 42:621Hl29, 1964. 3. James JA, Liebschutz NH: Evaluation of a new "dip and read" test for hematuria. Am J Clin Pathol 38:554-556, 1962. 4. Adams EC, Fetter MD, Free HM, Free AH: Hemolysis in hematuria. J Urol 88:427-430, 1962. 5. Elder TR, Barry JL, Folcik PM, . Knights EM Jr: Simplified test for hematuria. Ann Intern Med 56:957-959, 1962. 6. Leonards JR: Simple test for hematuria compared with established tests. JAMA 179:163-164, 1962. 7. Kesson AM, Talbott JM, Gyory AZ: Microscopic examination of urine. Lancet 2:809-812, 1978. 8. Fassett RG, Horgan BA, Mathew TH: Detection of glomerular bleeding by phase-contrast microscopy. Lancet 1: 1432-1434, 1982. 9. Larcom RC, Carter GH: Erythrocytes in urinary sediment: Identification and normal limits. J Lab Clin Med 33:875-880, 1948. 10. Wright WT: Cell counts in urine. Arch Intern Med 103:76-78, 1959. 11. Northway JD: Hematuria in children. J Pediatr 78:381-396, 1971. 12. Snoke AW: The normal Addis sediment count in children. J Pediatr 12:473-478,1938. 13. Addis T: A clinical classification of Bright's disease. JAMA 85:163-167, 1925. 14. Lippman RW: Urine and Urinary Sediment. Springfield, Charles C Thomas Publisher, 1961, p 103. 15. Lyttle JD: The Addis sediment count in normal children. J Clin Invest 12: 87-93, 1933. 16. Jacobellis U, Fabiano A, Tallarigo C: New technique to localize the origin of idiopathic microscopic hematuria. J Urol127:475-476,1982. 17. Fairley KF, Birch DF: Hematuria: A simplified method for identifying glomerular bleeding. Kidney Int 21: 105-108, 1982. 18. Fassett RG, Horgan BA, Gove D,
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Mathew TH: Scanning electron microscopy of glomerular and nonglomerular red blood cells. Clin Nephrol20:11-16, 1983. 19. Carson CC, Segura JS, Greene LF: Clinical importance of microhematuria. JAMA 241:149-150, 1979. 20. Golin AL, Howard RS: Asymptomatic microscopic hematuria. J Urol 124: 389-391, 1980. 21. Doss AK: Hematuria. Urol Cutan Rev 51:671Hl80,1947. 22. Lee LW, Davis E: Gross urinary hemorrhage: a symptom, not a disease. JAMA 153:782-784, 1953. 23. Froom P, Ribak J, Benbassat J: Significance of microhaematuria in young adults. Br Med J 288:20-22, 1984. 24. Benson GS, Brewer ED: Hematuria: Algorithms for diagnosis. JAMA 246: 993-995, 1981. 25. Gottesman JE, Kelly ME: Diagnosis and management of upper-tract bleeding. In: Weekly Urology Update Series, Princeton, Biomedia, Inc, 1979, pp 2-7. 26. Siegel AJ, Hennekens CH, Solomon HS, van Boeckel B: Exercise related hematuria. JAMA 241:391-392, 1979. 27. Klein RS, Cattolica EV: Ureteral endometriosis. Urology 13:447-482, 1979. 28. Hayslett JP: Primary hematuria. KF 9:11-14, 1976. 29. Burden RP, Booth LJ, Ockenden BG, Boyd WN, Higgins PMCR, Aber GM: Intrarenal vascular changes in adults with recurrent haematuria and loin pain-a clinical, histological and angiographic study. Q J Med 44:433447,1975. 30. Lano MD, Wagoner RD, Leary FJ: Unilateral essential hematuria. Mayo Clin Proc 54:88-90, 1979. 31. Chester AC, Diamond LH, Argy WP, Schreiner GE: Unilateral primary hematuria. JAMA 240:2759, 1978. 32. Wickre CG, Golper TA: Complications of percutaneous needle biopsy of the kidney. Am J Nephrol 2:173-178, 1982. 33. Myers RP: Tumors of the renal pelvis, ureter and urinary bladder. In: Kendall AR, Karafin L, eds: Goldsmith Practice of Surgery, Urology. Hagerstown, Harper and Row, 1979, pp 7-10. 34. Kantor AF: Current concepts in the epidemiology and etiology of primary renal cell carcinoma. J Urol117:415417,1977. 35. Cronin RE, Kaehny WD, Miller PD, Stables DD, Gabow PA, Ostroy PR, Schrier RW: Renal cell carcinoma: unusual systemic manifestations. Medicine 55:291-311, 1976. 36. McNichols DW, Segura JW, DeWeerd JH: Renal cell carcinoma: Long-term survival and late recurrence. J Urol 126:17-23, 1981.
37. Bell ET: A classification of renal tumors with observations on the frequency of the various types. J Urol 39:238-243, 1938. 38. Rabes HM: Growh kinetics of human renal adenocarcinoma. In: Sufrin G, Beckley SA, eds: Renal Adenocarcinoma, Vol 49. UICC Technical Report Series, Geneva, International Union Against Cancer, 1980, p 78. 39. Skinner DG, Colvin RB, Vermillion CD, Pfister RC, Leadbetter WF: Diagnosis and management of renal cell carcinoma. Cancer 28:1165-1177, 1971. 40. Emmett JL, Levine SR, Woolner LB: Co-existence of renal cyst and tumor: Incidence in 1007 cases. Br J Urol 35:403-410, 1963. 41. Ochsner MG, Brannon W, Pond HS, Goodier EH: Renal cell carcinoma: Review of 26 years of experience at the Ochsner Clinic. J Urol 110:643-646, 1973. 42. Garnick MD: Advanced renal cell cancer. Kidney Int 20:127-136, 1981. 43. Abuelo JG: The diagnosis of hematuria. Arch Intern Med 143:967-970, 1983. 44. Richie JP, Skinner DG: Renal neoplasia. In: Brenner BM, Rector FC, eds: The Kidney. Philadelphia, WB Saunders Co, 1981, p 2111. 45. Evans J: The accuracy of diagnostic radiology. JAMA 204:131-135, 1968. 46. Clayman RV, Williams RD, Fraley EE: The pursuit of the renal mass. N Engl J Med 300:72-74,1979. 47. Lang EK: The accuracy ofroentgenographic techniques in the diagnosis of renal mass lesions. Radiology 98:119128,1971. 48. Jonsson K: Renal angiography in patients with hematuria. AJR 116: 758-765,1972. 49. Lang EK: Roentgenographic assessment of asymptomatic renal lesions. Radiology 109:257-269, 1973. 50. Lang EK: Complications of retrograde percutaneous arteriography. JUral 90:604-610, 1963. 51. Glassock RJ, Cohen AH, Bennett CM, Martinez-Maldonado M: Primary glomerular diseases. In: Brenner BM, Rector FC, eds: The Kidney. Philadelphia, WB Saunders Co, 1981, p 1398. 52. Kupor LR, Mullins JD, McPhaul JJ: Immunopathologic findings in idiopathic renal hematuria. Arch Intern Med 135:1204-1211,1975. 53. Labovitz ED, Stein muller SR, Henderson LW, McCurdy DK, Goldberg M: "Benign" hematuria with focal glomerulitis in adults. Ann Intern Med 77:723-729,1972. 54. Michael J, Jones NF, Davies DR, Tighe JR: Recurrent haematuria: Role of renal biopsy and investigative morbidity. Br Med J 1:686-688, 1976. 55. Pardo V, Berian MG, Levi DF, Strauss
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J: Benign: primary hematuria. Am J Med 67:817-822, 1979. 56. Pollak VE, Ooi BS: Asymptomatic hematuria. Pastgrad Med 62:115-120, 1977. 57. Sinniah R, Pwee HS, Lim CH: Glomerular lesions in asymptomatic microscopic hematuria discovered on routine medical examination. Clin Nephral 5:216-228, 1976. 58. Van de Putte LBA, De La Riviere GB, van Breda Vriesman PJC: Recurrent or persistent hematuria. N Engl J Med 290:1165-1170,1974.
59. Hayashi M, Kume T, Nihira H: Abnormalities of renal venous system and unexplained renal hematuria. JUral 124:12-16, 1980. 60. Ayoub EM, Vernier RL: Benign recurrent hematuria. Am J Dis Child 109: 217-223, 1965. 61. Johnston C, Shuler S: Recurrent haematuria in childhood. Arch Dis Child 44:483-486,1969. 62. Singer DB, Hill LL, Rosenberg HS, Marshall J. Swenson R: Recurrent hematuria in childhood. N Engl J Med 279:7-12, 1968.
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63. Copley JB, Hasbargen JA: "Primary" hematuria: A prospective evaluation. Kidney Int 25:161,1984. 64. Hendler E, Kashgarian M, Hayslett J: Clinicopathological correlation of primary hematuria. Lancet 1:458-463, 1972. 65. Rogers PW, Kurtzman NA, Bunn SM, White MG: Familial benign essential hematuria. Arch Intern Med 131:257262,1973.
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