A. Identifying benign hematuria and its approach
B. Correct interpretation of “Dipstick” Hematuria
C. Evaluation of Asymptomatic Microscopic Hematuria in normal patient population vs. those at high risk for urological malignancy.
D. Test of choice for symptomatic hematuria ( Urolithiasis, Cystitis etc)
E. Evaluation of Asymptomatic Hematuria
F. If upper tract imaging for Asymptomatic Hematuria is chosen, what is the initial test of choice? – Many get confused about the initial test for upper tract imaging becauses several sources state several different things. Students are stuck between the choices CT urogram vs. Traditional Intravenos Pyelogram. The guidelines have been updated recently and there is an increasing trend towards CT Urogram even in asymptomatic hematuria ( please check the explaination below).
Here is a summary on how to approach Hematuria on your exam as well as in your office. All the recommendations are taken from AUA, American college of radiology guidelines on appropriate imaging choice.
Hematuria: The following Q and A aaproach will help you understand the principal concepts of Hematuria.
How do you test for Hematuria?
The initial office test that we use to detect hematuria is “Dipstick“. Dipstick is highly sensitive but not specific. False negatives are very rare but false positives are common. Dipstick detects “BLOOD” but it does not say whether this “blood” is an RBC or a Pigment. Remember that pigments such as myoglobin ( as in rhabdomyolysis) or Hemoglobin ( as in hemoglobinuria, Black water fever) can stain as “Blood” on dipstick. So, please do not automatically assume that everything that stains as “blood” on a dipstick is an RBC. In order to know if there is true hematuria, the next step is to do urine microscopy. If the urine reveals RBCs then there is true hematuria. However, if the dipstick reads “blood” and if the urine did not reveal RBCs on microscopy then you are dealing with a pigment – either myoglobinuria ( rhabdomyolysis) or hemoglobinuria. At this point, if the CPK is also elevated it suggests that the etiology of blood on the dipstick is Rhabdomyolysis.
So, a dipstick hematuria should always be confirmed with urine microscopy!
If dipstick is negative for blood, it excludes abnormal hematuria ( false-negative results are unusual with dipstick testing).
Benign causes of “Red” urine but negative dipstick test – In some conditions, you may see a red urine resembling “Gross hematuria” but dipstick is negative for blood. This should not be called hematuria. This is just reddish discoloration of urine.
Occurs in :
a) Ingestion of red pigmented foods ( eg: beets, berries, rhubarbs, paprika)
b) Drugs like Rifampin or Phenazopyridine derivatives ( remember these drugs only cause reddish urine but NOT a positive dipstick).
c) Diseases such as “Porphyria”
Causes of a Positive Dipstick but no true Hematuria: Here Dipstick stains positive for blood but no RBCs in the urine
a) Myoglobinuria ( Rhabdomyolysis, vigorous exercise)
b) Hemoglobinuria ( Intravascular hemolysis)
Is the Hematuria associated with pain? – Understand the causes of painless hematuria are different from painful hematuria. Painless hematuria is often from tumors of the urinary tract, bladder cancer or glomerulonephritis. Painful hematuria is often associated with urolithiasis ( renal calculi) or inflammation/ infection of the bladder ( Cystitis).
What will be the approach to identify the source of Hematuria? – The work up for hematuria may involve invasive and expensive approaches. So, it is important to determine the nature of hematuria so that you can limit investigations to the real and pathological hematurias.
Gross Hematuria: Reddish or Tea colored urine, dipstick positive for blood and urine microscopy shows RBCs. Any patient with gross hematuria should always be referred for urological evaluation unless this is secondary to an infection. If a woman has gross hematuria but the urine dipstick also reveals leucoesterase or nitrite or if the woman has symptoms of UTI ( dysuria etc) or if the cultures are growing bacteria, this can be treated as UTI ( cystitis) with antibiotics with out referring for further evaluation. Even in this setting of infection, if there are risk factors for urological malignancy the patient should still be referred for further evaluation ( since hematuria from cancer can also be intermittent).
Runner’s hematuria or March hematuria is another benign condition that presents as gross hematuria after a severe physical activity. In such cases, patients may be observed for resolution however, if the hematuria is persistent or if the patient has any risk factors for having a urological malignancy, must be referred to a urologist
Microscopic Hematuria: Grossly, urine looks normal. Dipstick positive for blood and urine microscopy reveals RBCs.
Microscopic Hematuria is often intermittent and most causes are usually benign. So, it is important to define a significant microscopic hematuria that requires further investigations.
Microhematuria is defined as three or more red blood cells per high-power microscopic field (RBCs/HPF) in two out of three properly collected and prepared specimens. Repeat urinalyses to establish whether significant hematuria is present must be done within 3 to 6 months of the initial test.
Minimal microhematuria ( i.e; one or 2 rbcs per HPF ) in asymptomatic young adults does not require any evaluation. ( many studies have indicated that small amounts of blood may be released into the urine of persons with no detectable pathology in the urinary tracts)
In patients with risk factors for having a urological malignancy, a microhematuria even in one or more samples must be considered significant and be evaluated.
Some benign causes of Microhematuria :
B) Sexual activity
If UTI is present ( symptoms and dipstick for leucoesterase are clues that point towards infection) – treat it with antibiotics and repeat urinalysis after the infection has cleared.
E) Benign Prostatic Hypertrophy
Now, carefully look for other charecterestics of urinalysis – Presence of other findings on the microscopic urinalysis such as RBC casts or Dysmorphic RBCs or proteinuria or the labs revealing elevated serum creatinine suggests a the hematuria is originating from the kidney/ glomerulus itself ( eg: Glomerulonephritis, IgA nephropathy). In such cases, the next step in evaluating hematuria is referral to a nephrologist ( not urologist) and a renal biopsy.
Further Approach to Microscopic Hematuria
Symptomatic Hematuria: In painful hematuria –> first rule out infection and renal colic. If infection is absent or if there is a pain similar to renal colic ( classic flank pain) – consider renal stones as the cause of Hematuria. The best initial step in evaluating the cause of painful hematuria that is not explained by UTI is Non-Contrast CT scan (Spiral CT) ( test of choice for imaging renal calculi).
In pregnant women, ultrasound can be performed to avoid radiation exposure.
Asymptomatic MicroHematuria : Patients without the classic flank pain of urolithiasis should be evaluated extensively. Once benign causes such as infection and the kidney ( glomerular) origin are ruled out, further approach should be defined based on the patient’s risk profile.
A) For patients with low risk of urological disease, a less extensive work-up may be appropriate ( First do upper tract imaging and if this is negative, add urine cytology+cystoscopy).
B) If the patient is a high risk of having a urological malignancy, extensive work-up is needed ( see the risk factors below) –> Upper tract imaging + cystoscopy+ urine cytology all are needed. Urine cytology should be obtained in all patients with asymptomatic hematuria since it is an easy and non invasive step. Sensitivity of urine cytology is only 48% but remember that if it is positive it is highly specific for urological cancer ( 94% specificity)
Risk factors for urological cancer ( bladder ca):
1. Heavy somkers
2. Occupational exposure to aniline dyes
3. History of Gross hematuria
4. History of pelvic irradiation
5. Age > 40 years
6. Analgesic abuse
7. Presence of irritative voiding symptoms
8. Previous use of Cyclophosphamide ( increases the risk of bladder cancer where as ongoing use often causes hemorrhagic cystitis as a adverse effect)
What imaging studies should be done as initial step in evaluating Asymptomatic Hematuria?
For both high risk and low risk patients, upper tract imaging must be performed as an initial step. For upper tract imaging, CT urography ( i.e; non-contrast CT followed by contrast CT imaging from kidney to bladder) is best recommended initial test now to evaluate asymptomatic hematuria. CT urography is less affected by overlying bowel gas and is more sensitive for detecting small tumors and calculi than the IVP. Students often confuse this with other choices such as ultrasound and Intravenos pyelogram. IVP used to be the best preferred test for upper tract imaging in hematuria evaluation but now CT urogram is becoming the preferred method. IVP and ultrasound are good to image the urinary tract but they do not completely assess the renal parenchyma. If you order an IVP, you may eventually need to order a CT urogram again to image the parenchyma better – so, in order to avoid ordering multiple studies, CT urogram is recommended as the best initial test.
For complete access to streaming video lecture on Nephrology, visit PayPerView
Self -Assessment Questions ( Copy Right: USMLEGalaxy, LLC)
1. A 24 y/o athlete presents to your office with complaints of reddish discolation of urine. He claims that he has been exercising and running vigorously for the past two days. He is very determined to lose the extra weight that he has put up in the recent months and has been fasting in the nights for the past one week. His past medical history is significant for two abdominal surgeries which included laparotomy and appendicectomy in the past for intermittent severe abdominal pain. The patient does not smoke but does occassional consumes alcohol in binges. He did involve in one such alcohol binge last night. Physical examination is benign except for decreased power and reflexes in bilateral lower extremities. There is no rash. His urine specimen was grossly red in color. Urine dipstick was negative for protein, blood, leucoesterase and nitrite. Urine microscopy did not reveal any RBCs, WBCs or Casts. Serum creatinine and complete blood count are with in normal limits. A Creatinine Phosphokinase ( CPK) level has been ordered but is not yet available. The most likely cause of this patient’s reddish urine is :
B) Paroxysmal Nocturnal Hemoglobinuria
C) Acute Intermittent Porphyria
D) Need to obtain CPK level for correct diagnosis
E) Gross Hematuria
2) A 55 y/o woman with history of well controlled DM Type II presents for her regular follow-up visit. She has no new complaints. She has been well controlled on Metformin alone with a hemoglobin A1c of 6.5. Physical examination is benign except for decreased sensation in her bilateral lower extremities consistent with diabetic neuropathy and bilater lower extremity edema. Her last urinary microalbumin about one year ago was negative. A repeat dipstick test now is positive for trace protein and blood but negative for leucoesterase and nitrite. Subsequent urine microscopy reveals only 4 dysmorphic RBCs/HPF and red cell casts. Labs reveal elevated serum creatinine at 1.4. The next step in approaching this patient’s hematuria is:
A) Obtain CPK level
B) 24 hour urine for microalbumin
C) Referral to Urologist
D) Repeat urinalysis in 3 months
E) Referral to Nephrologist and renal biopsy
F) Start emperic antibiotic therapy for UTI
3) A 65 y/o man with history of chronic smoking and COPD presents for follow up visit in your office after being discharged from the hospital about three weeks ago. The patient was admitted and treated in the hospital for community acquired pneumonia and COPD exacerbation. During his hospital stay he was noted to have microscopic hematuria on routine urinalysis. The patient denies any symptoms now. His COPD is well controlled on tiotropium inhaler. His allergies include Isoniazid and Penicillin. Past medical history is significant for a positive PPD test ( latent tuberculosis) for which he has been on treatment with Rifampin for past three months. Physical examination is benign. Labarotory investigations reveal a normal CBC and serum creatinine. Dipstick is positive for blood. A repeat urinalysis during this visit reveals persistent microscopic hematuria with 3 RBCs/HPF. A urine cytology has been ordered. The next appropriate step in evaluating this patient’s hematuria is:
A) Repeat urinalysis in 3 months
B) Urine cultures
C) Intravenos pyelogram
D) CT urogram + Cystoscopy
E) Stop Rifampin
4) A 45 y/o woman presents to the Emergency room with complaints of severe flank pain and nausea. Patient’s past medical history reveals chronic smoking and occupational exposure to aniline dyes. Physical examination reveals mild right costo-vertebral angle tenderness. The patient is afebrile. Labarotory investigations reveal urine dipstick positive for blood but negative for leucoesterase and nitrite. Urinalysis reveals numerous RBCs per HPF. There are no RBC casts or WBC casts. Urine HCG is negative. The next step in managing this patient’s Hematuria is:
A) Start intravenos antibiotic therapy
B) Obtain Non Contrast CT scan
C) CT urogram + Cystoscopy
D) Intravenos pyelogram
5) A 32 y/o man presents to your office for a regular annual physical. The patient is otherwise in very good health.. He is not on any medications. He has no history of smoking or alcoholism. He works as a physician assistant. Physical examination is benign. He denies any symptoms such as gross red colored urine or dysuria or fever. A urine drug screen is normal. A urinalysis reveals 5RBCs/HPF with no casts or wbc. Other labs are within normal limits. A urine cytology has been ordered. The next step in approaching this patient’s hematuria?
A) Repeat urinalysis in 3 months
B) Non contrast CT scan
C) CT urogram
E) CT urogram and cystoscopy
COPY RIGHT: USMLEGalaxy, LLC
ANSWERS TO SELF ASSESSMENT QUESTIONS:
Reddish discolration of urine with a negative dipstick for blood suggests that this red color is not from either a pigment globin ( hemoglobin or myoglobin) or a Red blood cell ( Hematuria). Such red colored urine with negative dipstick can be seen with drugs such as Rifampin, foods such as beets and substances like porpyrins in urine.
This patient also has sensory as well as motor neuropathy in his lower extremities, a typical manifestation of Acute intermittent porpyria attacks. The presence of peripheral neuropathy in patients with history of recurrent abdominal pains should raise the suspicion of Acute Intermittent Porphyria ( AIP). This patient had several severe abdominal pain episodes which were misdaiagnosed as appendicitis and he even underwent a futile laparotomy. Patients are pain free between the attacks. Fasting and drugs like phenobarbital, alcohol can precipitate AIP attacks. Unlike other porphyrias, rash is not typically seen in AIP.
A. is not the answer because dipstick would be positive for blood in rhabdomyolyisis
B. is not the answer because dipstick would be positive in hemoglobinuria
D. is not the answer since the diagnosis of reddish urine here is not in favor of myoglobinuria.
E. a negative dipstick and negative microscopic urinalysis rules out gross hematuria as a cause of this red urine
F. Negative dipstick for blood, negative urine microscopy and absence of RBC casts rule out glomerulonephritis as a cause of this patient’s red urine
2. Ans. E.
The presence of red cell casts indicate glomerular origin of this patient’s hematuria. Etiologies include various glomerulonephritis and hence, a renal biopsy is warranted.
A. is not the answer because here a positive dipstick is also followed by a positive urinalysis indicating true hematuria. A myoglobinuria will have positive dipstick but no RBCs on urine microscopy.
B. is not the answer because it does not add anything to elucidate the cause of this patient’s hematuria. In view of concomitant presence of RBC casts, this patient’s acute onset protein in the urine may be secondary to glomerulonephritis rather than DM nephropathy.
C. Presence of RBC casts indicate glomerual cause of hematuria. So, the patient should be referred to a nephrologist rather than a urologist
D. Repeating urinalysis in 3 months is appropriate for a new microscopic hematuria with out any features suggesting kidney involvement. Here hematuria is clearly glomerular in origin and requires further work up as soon as possible.
F. Is incorrect because this patient has no evidence of UTI. The patient’s clinical features as well as urinalysis findings do not suggest a UTI. The patient has no fever or dysuria. Dipstick is negative for leucoesterase or nitrite. Urinalysis has no WBCs or WBC casts. Absence of all these make UTI an unlikely etiology of her hematuria.
3. Ans. D
This patient has significant microhematuria defines as 3 0r more RBCs/HPF established on two occassions. He also has high risk factors for having a bladder cancer or urological malignancy. So, both upper tract imaging in the form of CT urogram as well as bladder visualization in the form of cystoscopy are warranted in this patient.
A. is incorrect because the patient already had >3RBCs/HPF on two occassions already establishing the diagnosis of significant microhematuria.
B. is incorrect because this patients has no symptoms or lab findings suggesting UTI.
C. is incorrect because this patient is a high risk patient and requires both upper tract imaging as well as cystoscopy as an initial protocol. IVP is good for upper urinary tract imaging but does not adequately visualize the bladder. More over, recent recommendations favor CT urogram over IVP for upper tract imaging.
E. is incorrect. Rifampin causes red colored urine but does not cause positive dipstick or hematuria.
4. Ans. B
This patient’s clinical features as well as hematuria on urinalysis suggest renal colic from possible urolithiasis. Non Contrast CT is the best and first imaging test of choice in evaluating renal calculi ( do not choose plain x-rays or ultrasound. Ultrasound is optimal only in pregnant patients).
A. is not correct as this patient has no evidence of pyelonephritis or UTI ( absent wbc casts, absent wbcs or fever, no leucoesterase or nitrite on dipstick)
C. is incorrect because CT urogram involves administration of contrast after a initial non contrast study. A non contrast CT is sufficient in most cases to evaluate the presence of stones ( except Indinavir stones in HIV positive patients on HAART where a contrast CT is preferred). Cystoscopy is not needed as acute flank pain with hematuria in this patient favors renal calculus more than a bladder cancer
D. IVP is incorrect since non contrast CT is the best test to visualize the stones
E. is incorrect because Non contrast CT is better than ultrasound in visualizing the renal calculi
5. Ans. A – in a healthy young individual with only one episode of microscopic hematuria a repeat urinalysis must be obtained to see if this is significant before proceeding to evaluate this patient with expensive and invasive investigations. If the repeat urinalysis also reveals microhematuria, upper tract imaging ( CT urogram) must be performed first in this low risk patient before proceeding to cystoscopy. In high risk patients, both Upper tract imaging as well as Cystoscopy must be performed.
B. is incorrect as a repeat urinalysis should first be performed in this patient. Also, non contrast CT is not helpful in evaluating causes of painless microscopic hematuria.
C. is incorrect. If the repeat urinalysis also reveals microhematuria, upper tract imaging ( CT urogram) must be performed first in this low risk patient before proceeding to cystoscopy. In high risk patients, both Upper tract imaging as well as Cystoscopy must be performed.
D. is incorrect. If the repeat urinalysis also reveals microhematuria, upper tract imaging ( CT urogram) must be performed first in this low risk patient before proceeding to cystoscopy.
E. is incorrect. If the repeat urinalysis also reveals microhematuria, upper tract imaging ( CT urogram) must be performed first in this low risk patient before proceeding to cystoscopy. In high risk patients, both Upper tract imaging as well as Cystoscopy must be performed.