Approach to the Patient with Hematuria
Vishal N. Ratkalkar and Kevin R. Regner

Case 1

An 83-year-old man presents with painless gross hematuria. The patient’s history is notable for a 50 pack-year history of smoking. He is afebrile with a blood pressure of 128/64. Physical examination is notable for an enlarged prostate but shows no rash, edema, or abnormal abdominal findings. Serum creatinine is within normal limits. A dipstick urinalysis shows 3+ blood and trace proteinuria.

Case 2

A 38-year-old woman presents with new-onset lower extremity edema. One month ago, she was seen by her primary care physician with complaints of headache and fatigue. A dipstick urinalysis showed 2+ blood, and she was treated for a urinary tract infection. She subsequently developed new-onset lower extremity edema 1 week ago. On examination, she is afebrile with a blood pressure of 164/102. There is 2+ pretibial edema but no rash or abnormal abdominal findings. Her serum creatinine is 1.56 mg/dl. A dipstick urinalysis shows 3+ blood and 2+ protein.

Introduction

Hematuria is a common sign of genitourinary disease involving the kidneys, ureters, bladder, prostate, or urethra (Table 5.1). Patients can present with either “gross” hematuria that is visible to the naked eye or with hematuria detectable only under microscopic examination or by urinary dipstick analysis. Notably, 1 ml of blood/1 of urine is sufficient to produce gross hematuria. In most cases, gross hematuria is an indication for a detailed diagnostic evaluation. Microscopic hematuria has been defined as >3 red blood cells (RBCs) per high power field (HPF) upon examination of the urinary sediment from 2 of 3 prop­erly collected and centrifuged urine specimens [1]). In contrast to gross hematuria. the approach to asymptomatic microscopic hematuria remains controversial. However, the diagnostic approach to both types of hematuria requires consideration of both benign and malignant processes involving the kidneys and urinary tract.

     The prevalence of hematuria is variable and depends upon the characteristics of the patients screened and whether hematuria is detected by dipstick or by urine microscopy. Therefore, estimates of the prevalence of hematuria in adults range from 0.19 to 16.1% [1, 2]. In patients selected for referral to a hematuria clinic, the underlying etiology for hematuria could not be established in up to 60% of patients [3]. Urinary tract infection (13%), bladder cancer (11.9%), urolithiasis (3.6%), renal cancer (0.6%), prostate cancer (0.4% ), and urothelial cancer (0.1 % ) were the underlying urologic causes of hematuria in the remainder of cases. Renal parenchymal disease was identified in approximately 10% of cases [3]. The incidence of bladder cancer was four times higher in the setting of gross hematuria in comparison to microscopic hematuria. The American Urological Association Best Practice Policy outlined the following factors as high risk for urological malignancy in patients with hematuria: age >40 years; history of smoking; occupational exposure to chemicals or dyes (aromatic amines, benzenes); gross hematuria; history of urological disease, irritative voiding symptoms, or urinary tract infection; analgesic abuse; and prior pelvic irradiation [4]. Obviously, those patients falling into high-risk subsets would require a more aggressive diagnostic approach to exclude malignancy as the cause.

     Renal parenchymal causes of hematuria include glomerulonephritis (GN) and hereditary glomerular disease (Table5.1 ). Glomerulonephritis can be primary (no clear associated etiology) or secondary to a number of systemic diseases. The most common causes of GN presenting with hematuria include IgA nephropathy, necrotizing crescentic GN, lupus nephritis, post-infectious GN, and membranoproliferative GN [5]. Hereditary glomerular diseases include Alport’s syndrome and thin basement membrane nephropathy (TBMN). Alport’s syndrome is most commonly due to an X-linked mutation in the COL4A5 gene resulting in defective α5 chains of type IV collagen and subsequent alterations in the glomerular basement membrane [6]. Autosomal recessive and autosomal dominant Alport’s syndrome occurs less frequently. Both types of autosomal Alport’s syndrome can be due to mutations in either the COL4A3 or the COL4A4 gene which produce defects in the α3 or α4 chains of type IV collagen. Hematuria and sensorineural hearing loss are common presenting signs of Alport’s syndrome (6). TBMN is typically transmitted in an autosomal dominant pattern and presents with isolated hematuria [7].

Case 1

In this case, the patient’s age and history of cigarette smoking increase his risk for urologic malignancy. He has no signs or symptoms of a urinary tract infection or urolithiasis. There was no family history of hematuria or kidney disease. The absence of hypertension and renal dysfunction decreases the likelihood of an underlying renal parenchymal disease. Taken together, these findings should raise concern that malignancy is the most likely cause for hematuria. It is important to look at the urine under microscopy. Tbe absence of dysmorphic red blood cells or red blood cell casts increases the likelihood that the hematuria is not secondary to GN. Furthermore, the absence of significant proteinuria also argues against a glomerular source for the proteinuria.

Case 2

The patient, in this case, is <40 years old and has no significant risk factors for urologic malignancy and no current symptoms to suggest urinary tract infection or urolithiasis. Renal parenchymal disease should be strongly considered. especially in the context of hypertension, proteinuria, and elevated serum creatinine. Once again, the presence of dysmorphic red blood cells or red blood cell casts would argue that the source is the glomerulus in this case. There was no family history of hematuria or renal failure to suggest a hereditary glomerular disease. Therefore, glomerulonephritis should be strongly suspected. 

Diagnostic Approach

Initial Evaluation

The initial approach to hematuria involves a stepwise evaluation to confirm the presence of hematuria and to ascertain the most likely source of urinary tract bleeding (Fig. 5.1). First, a complete history and physical examination should be performed in all patients. Historical elements of particular importance include recent unintentional weight loss, fever, dysuria, flank or abdominal pain, hearing loss, or skin rash. The family history should be reviewed for documentation of Alport’s syndrome, TBMN, nephrolithiasis, polycystic kidney disease, or hematuria of undetermined etiology. Medications should be reviewed with particular attention to recent use of anticoagulants, aspirin. or nonsteroidal anti-inflammatory drugs (NSAIDS). Notable physical findings include costovertebral angle tenderness radiating to the groin in patients with nephrolithiasis, sensorineural hearing loss in Alport’s syndrome, flank masses in renal cancer, organomegaly in polycystic kidney disease, and palpable purpura in some types of glomerulonephritis. Hematuria is often initially detected by dipstick urinalysis. Dipstick reagent strips detect the heme peroxidase activity of RBC hemoglobin, free hemoglobin, and myoglobin. The sensitivity and specificity of dipstick tests for the detection of >5 RBCs/HPF range from 86 to 100% and 64 to 94%, respectively [8]. However, dipstick tests for hematuria should be interpreted with caution as a variety of factors can produce false positive and false negative results. Dipstick pseudohematuria is defined as a positive dipstick result for hematuria without the presence of RBCs on urine microscopy [10]. Myoglobin and free hemoglobin in the urine can both result in a pseudohematuria and require additional evaluation in the appropriate clinical contexts. Vigorous exercise and highly concentrated urine can also lead to pseudohematuria. In these cases, repeat testing after resting or hydration is indicated. Very dilute (specific gravity <1.007) urine can cause RBC lysis giving rise to false negative urine microscopy [1, 10]. Therefore, careful interpretation of the dipstick and microscopic urinalyses requires consideration of patient factors, urine specific gravity, and urine pH. In all cases, it is critical to view the urine sediment under the microscope. 

Urine Microscopy

Microscopic examination of the urine is performed to confirm the presence of RBCs in the urine and to determine the anatomical origin of the RBCs [1, 10]. A clean-catch midstream urine sample is collected, and 10 ml of urine is spun in a conical centrifuge tube for 5 min at 2,000 rpm. After centrifugation, the tube is inverted and cleared of the supernatant fluid and the pellet is carefully resuspended without excessive agitation. A drop of this specimen is placed onto a microscope slide with a pipette and should be sufficient in size such that the coverslip floats on the specimen. The urine sediment should then be examined under low-power magnification prior to moving on to high-power examination of individual fields. The presence of >3 RBCs/HPF is considered pathological [1].

Evaluate for Glomerular Hematuria

Urine RBC morphology can help distinguish glomerular causes of hematuria from non-glomerular causes. Non-glomerular hematuria is characterized by normal-appearing RBCs on urine microscopy. In contrast, glomerular hematuria is defined by the presence of dysmorphic RBCs and/or RBC casts. Urine RBC casts are pathognomonic of glomerulonephritis. Dysmorphic RBCs are differentiated from normal RBCs by the presence of cellular blebs or spicules. Greater than 80% dysmorphic RBCs has been shown to have high specificity but low sensitivity for glomerular disease [8]. Therefore, this cutoff value is most useful for ruling in a glomerular source of hematuria. Urine microscopy is operator dependent and not always readily available. Therefore, the urine albumin-to-total protein ratio has been proposed as a novel method of differentiating glomerular from non-glomerular hematuria. A urine albumin-to-total protein ratio of >0.59 mg albumin/ mg total protein was shown to be highly sensitive and specific for glomerular bleeding compared with phase contrast microscopy of the urinary sediment [11]. Of note, this test is not useful in patients with a urine total protein concentration of <5 mg/di. Other laboratory findings that are suggestive of a glomerular cause for hematuria include proteinuria (>300 mg/g creatinine) and/ or elevated serum creatinine. 

Nephrology Evaluation

Patients with glomerular hematuria, as determined by the presence of RBC casts or dysmorphic RBCs on microscopic urinalysis or elevated urine albumin-to-total protein ratio, should be referred to a nephrologist. Renal function should be assessed by measurement of serum creatinine and proteinuria quantified by 24-h urine collection or spot urine protein-to-creatinine ratio. Laboratory testing for lupus (antinuclear antibody, anti-double-stranded DNA antibodies, and serum complement C3 and C4), post-infectious GN (blood cultures, anti-streptolysin O titer, and serum C3 complement), small vessel vasculitis (anti-neutrophil cytoplasmic antibodies and antibodies to proteinase 3 and to myeloperoxidase), viral infections (serologic testing for hepatitis B and C viruses and human immunodeficiency virus), and Goodpasture’s syndrome (anti-glomerular basement membrane antibody) may assist in the diagnosis of GN. Patients with acute kidney injury in the setting of suspected GN should be emergently evaluated for rapidly progressive glomerulonephritis (see Chap. 6). Ultimately, a kidney biopsy may be necessary to establish the diagnosis in cases of glomerular hematuria. Kidney biopsies are typically performed by percutaneous approach under the guidance of real-time ultrasound [12]. The lower pole of the kidney is identified, and a 14-16-gauge biopsy needle is used to obtain 2–3 cores of tissue from the renal cortex and the tissue is examined with an operating microscope to confirm the presence of glomeruli. The specimens are then evaluated by a renal pathologist after staining and preparation for light, immunofluorescence, and electron microscopy. Common complications of kidney biopsy include perinephric hematoma formation (2.1%) and transient gross hematuria (3.1%). Major complications such as arteriovenous fistula formation and bleeding requiring invasive intervention occur in <1 % of native kidney biopsies [12].

Urology Evaluation

Patients with gross hematuria or persistent non-glomerular microscopic hematuria should be referred for urological evaluation (Fig. 5.2) [1]. A urine culture should be performed on a clean-catch midstream urine sample. If the urine culture is positive the patient should be treated with the appropriate antibiotics. A repeat urinalysis should then be performed to confirm resolution of the hematuria. In high-risk patients or patients with persistent hematuria, further examination of the urinary tract is warranted. Low-risk patients should first undergo radiologic imaging of the upper urinary tract followed by urine cytology and cystoscopy depending on the patient’s age and risk factors for malignancy [4]. The American Urological Association has recommended cystoscopy for evaluation of hematuria in all patients over the age of 40 and in patients <40 years old with risk factors for bladder cancer [4]. High-risk patients should be referred for complete evaluation of the urinary tract including upper tract radiologic imaging, urine cytology, and cystoscopy (Fig. 5.2) [4]. Radiologic imaging of the urinary tract is most useful for detecting urolithiasis, cysts, and tumors of the kidney and ureters. Cystoscopy is the preferred method for detection of bladder cancer [4]. Radiologic techniques for urinary tract imaging include intravenous urography (IVU), ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) [8]. Each of these modalities has unique advantages and disadvantages which need to be accounted for based on patient factors, local expertise, and clinical context. The major disadvantage of IVU is its inability to differentiate cystic lesions from solid masses; therefore, an indeterminate mass detected on IVU requires additional radiologic follow-up [4, 8]. US is less costly than IVU and is useful in the characterization of renal cysts but is less sensitive for solid lesions <3 cm [4, 8]. CT detects renal cysts and solid masses and is also useful for detection of urolithiasis and intra-abdominal pathology outside of the urinary tract [4, 8]. MRI can characterize small renal masses and differentiate solid from cystic masses and is advantageous when exposure to radiation and iodinated contrast is contraindicated [8, 9]. 

Case 1

Microscopic examination of the patient’s urine showed> 100 RBCs/HPF. No dysmorphic RBCs or RBC casts were found. He had no significant proteinuria. These findings were consistent with a non glomerular cause for hematuria. The patient was referred to a urologist and underwent a CT scan of the abdomen and pelvis which revealed an irregular bladder mass. A cystoscopy was performed which showed a 3 cm lesion over the posterior bladder wall. Biopsy of this lesion confirmed the diagnosis of high-grade invasive urothelial carcinoma.

Case 2

In this case, the patient was found to have a urine protein excretion of 1.3 g/day. Microscopic examination of the patient’s urine showed 26-50 RBCs/HPF with >80% dysmorphic RBCs and numerous RBC casts. These findings, in the setting of concurrent renal dysfunction, were strongly suggestive of a glomcrular cause for hematuria. The patient was referred to a nephrologist for further evaluation. At that time, serologic testing was notable for an elevated anti-streptolysin O titer and markedly decreased serum C3 concentration. A renal biopsy was performed which demonstrated a proliferative glomerulonephritis with diffuse endocapillary proliferation on light microscopy and glomerular deposition of IgG and C3 on immunofluorescence microscopy consistent with a final diagnosis of post-streptococcal GN.

Key Points

  1. Hematuria is a sign of a number of benign and malignant disorders involving the kidneys or the urinary tract.
  2. Patients with gross hematuria should undergo complete urologic evaluation. The approach to microscopic hematuria requires a stepwise evaluation of the kidneys and urinary tract.
  3. Urine microscopy should be performed to confirm the presence of urine RBCs in patients with dipstick hematuria.
  4. Patients with RBC casts or dysmorphic RBCs on urine microscopy should be evaluated for glomerular causes of hematuria. An elevated urine albumin/total protein ratio in the setting of hematuria is also suggestive of glomerular hematuria.
  5. Patients with non-glomerular hematuria should undergo a urologic evaluation which may include radiologic imaging of the upper urinary tract, urine cytology, and cystoscopy.

Prognosis

The prognosis of hematuria depends- upon the underlying cause. However, a large proportion of patients with hematuria have no readily identifiable cause despite an extensive urologic and renal evaluation. Urologic malignancy develops rarely (<1 %) in this situation [13]. However, the American Urological Association recommendations state that such patients be followed closely for 3 years with serial urinalysis, urine cytology, and screening for hypertension, proteinuria, and renal dysfunction [4]. Indications for reevaluation include positive urine cytology, gross hematuria, new-onset hypertension, proteinuria, or renal dysfunction.

References

  1. Grossfeld GD, Litwin MS, Wolf JS, Hricak H, Shuler CL, Agerter DC, Carroll PR. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy. Part I: Definition, detection, prevalence, and etiology. Urology. 2001;57:599-603.
  2. Woolhandler S, Pels RJ, Bor DH, Himmelstein DU, Lawrence RS. Dipstick urinalysis screening of asymptomatic adults for urinary tract disorders: I. Hematuria and proteinuria. J Am Med Assoc. 1989;262:1214 9.
  3. Khadra MH, Pickard RS, Charlton M, Powell PH, Neal DE. A prospective analysis of 1,930 patients with hematuria to evaluate current diagnostic practice. J Urol. 2000;163:524-7.
  4. Grossfeld GD, Litwin MS, Wolf JS, Hricalc H, Shuler CL, Agerter DC, Carroll PR. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy. Part II: Patient evaluation, cytology, voided markers, imaging, cystoscopy, nephrology evaluation, and follow-up. Urology. 2001;57:605-10.
  5. Swaminathan S, Leung N, Lager DJ, Melton 3rd LJ, Bergstralh EJ, Rohlinger A, Fervenza FC. Changing incidence of glomerular disease in Olmsted County, Minnesota: 30-year renal biopsy study. Clin J Am Soc Nephrol. 2006;1:483-74.
  6. Heidet L. Gubler M. The renal lesions of Alport syndrome. J Am Soc Nephrol. 2009;20:1210-5.
  7. Tryggvason K, Patrakka J. Thin basement membrane nephropathy. J Am Soc Nepbrol. 2006;17:813-22.
  8. Rodgers M, Nixon J, Hempel S, Aho T, Kelly J, Neal D, Duffy S, Kleijnen J, Westwood M. Diagnostic tests & algorithms used in the investigation of haematuria: systematic reviews & economic evaluation. Health Technol Assess. 2006;10:1-276.

Suggested Reading

Grossfeld GD, Litwin MS, Wolf JS, Hricak H. Shuler CL, Agerter DC, Carroll PR Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy. Part II: Patient evaluation, cytology, voided markers, imaging, cystoscopy, nephrology evaluation, and follow-up. Urology. 2001;57:605-10.

Rodgers M, Nixon J, Hempel S, Aho T, Kelly J, Neal D, Duffy S, Kleijnen J, Westwood M. Diagnostic tests & algorithms used in the investigation of haematuria: systematic reviews & economic evaluation. Health Technol Assess. 2006;10: 1-276.

Swaminathan S, Leung N, Lager DJ, Melton 3rd LJ, Bergstralh EJ, Rohlinger A, Fervenza FC. Changing incidence of glomerolar disease in Olmsted County, Minnesota: a 30-year renal biopsy study. Clin J Am Soc Nephrol. 2006;1:483-7.

Ohisa N, Yoshida K. Matsuki R. Suzuki H. Miura H, Ohisa Y, Murayama N, Kaku M, Sato H. Comparison of urinary albumin-total protein ratio to phase-contrast microscopic examination of urine sediment for differentiating glomerular and nonglomerular bleeding. Arn J Kidney Dis. 2008;52:235-41.