21: Hematuria

Red urine is not always caused by hematuria. A variety of medications, food dyes, and metabolites can cause heme-negative red urine, or pigmenturia (Table 21-1). Furthermore, not all dipstick tests positive for blood are due to hematuria. In addition to detecting heme in intact red blood cells (RBCs), urine dipsticks detect free hemoglobin and myoglobin, hence leading to false-positive tests for hematuria.

Whenever the urine dipstick is positive for blood, and the microscopic exam of the urine does not show RBCs, myoglobinuria and hemoglobinuria should be considered.

True macroscopic (visible) hematuria is always pathologic. Microscopic (nonvisible) hematuria may be transient, spurious, or persistent. Transient causes of microscopic hematuria include urinary tract infections (UTIs) (which sometimes also cause macroscopic hematuria) and strenuous exercise; hematuria due to these causes would be expected to resolve on repeat testing after 48 hours of treatment or after discontinuing exercise for 72 hours. Spurious causes include urinary contamination from menstruation and sexual intercourse in women. This chapter will focus on persistent, true hematuria.

All patients with hematuria should have a urine culture performed, regardless of the likelihood of infection.

The differential diagnosis of hematuria is often divided into microscopic hematuria or macroscopic hematuria. Microscopic hematuria is present when microscopic inspection of at least 2 properly collected urine specimens show > 3 RBCs per high-powered field (hpf). Macroscopic hematuria is red or brown urine, sometimes with blood clots. However, there is considerable overlap in the causes of microscopic and macroscopic hematuria, and it may be more practical to first consider whether the hematuria is glomerular in origin. Pivotal points that help distinguish glomerular hematuria from nonglomerular hematuria include dysmorphic RBCs (acanthocytes), red cell casts, new or acutely worsening hypertension or proteinuria, and increased creatinine. While these abnormalities may also be seen in some of the interstitial and vascular causes of hematuria, they will not be found when hematuria is caused by a renal structural abnormality or an abnormality distal to the kidneys. Visible blood clots, which are never due to a glomerular cause, are another pivotal point, indicating a lower urinary tract source of the hematuria.

1. Renal

   1. Glomerular

      1. IgA nephropathy

      2. Alport disease and thin basement membrane nephropathy (TBMN)

      3. Other primary and secondary glomerulonephritides

         • (1) Postinfectious or infection-related

         • (2) Systemic lupus erythematosus

         • (3) Goodpasture syndrome

         • (4) Henoch-Schünlein purpura (HSP) and other small or medium vessel vasculitides

         • (5) Hemolytic uremic syndrome (HUS)

   2. Nonglomerular

      1. Neoplastic

         • (1) Renal cell or transitional cell carcinoma

         • (2) Benign renal mass

      2. Tubulointerstitial

         • (1) Nephrolithiasis

         • (2) Polycystic kidney disease or medullary sponge kidney

         • (3) Pyelonephritis

         • (4) Acute interstitial nephritis

         • (5) Papillary necrosis

      3. Vascular

         • (1) Arterial embolus or thrombosis

         • (2) Arteriovenous malformation or arteriovenous fistula

         • (3) Renal vein thrombosis

         • (4) Nutcracker syndrome (compression of left renal vein)

         • (5) Malignant hypertension

      4. Metabolic (hypercalciuria, hyperuricosuria)

2. Extrarenal

   1. Ureter

      1. Mass: benign polyp or malignancy

      2. Stone

      3. Stricture

   2. Bladder

      1. Transitional cell or squamous cell carcinoma

      2. Noninfectious cystitis (radiation or medication [cyclophosphamide])

      3. Infectious cystitis

      4. Stone

   3. Urethra

      1. Urethritis

      2. Urethral diverticulum

      3. Traumatic catheterization

      4. Urethral stricture

   4. Prostate

      1. Benign prostatic hypertrophy (BPH)

      2. Prostate cancer

      3. Post prostatic procedure

      4. Prostatitis

Figures 21-1 and 21-2 reorganize the differential diagnosis using pivotal points and outline the diagnostic approach to hematuria.

Mr. A does not have the pivotal urinalysis findings that suggest a glomerular source of the hematuria. Therefore, nonglomerular causes should be considered first. Given the patient’s sex (male), age (>40), and 35 pack year smoking history, all risk factors for malignancy, bleeding from a urothelial bladder cancer needs to move to the top of the differential diagnosis. Although he does not have abdominal or flank pain suggestive of renal colic, stone disease is common and should be considered. Prostate cancer, BPH, and prostatitis are also common, and men with prostatitis may have vague abdominal discomfort, as Mr. A does. Renal cell carcinoma (RCC) is rare but must always be considered in a patient with hematuria. The otherwise bland urinalysis makes interstitial causes and UTI unlikely. He has no history of radiation or chemotherapy to suggest an associated cystitis. Table 21-2 lists the differential diagnosis.

Leading Hypothesis: Bladder Cancer

Textbook Presentation

Bladder cancer classically presents as painless visible hematuria in an older male smoker. Microscopic hematuria occurs in nearly all patients with bladder cancer. Other symptoms include dysuria or obstructive symptoms.

Disease Highlights

1. Accounts for 90% of urothelial cancers

2. Visible painless hematuria, often intermittent, occurs in 85% of patients

3. Risk factors for bladder cancer

   1. Male sex and white race: white males are 3–4 times more likely to develop bladder cancer than African American males or white females

   2. Smoking: accounts for 60% of bladder cancers in males and 30% in females

   3. Age > 40: median age at diagnosis is 70

   4. Preexisting urothelial cancer (RCC, ureteral, prostate)

   5. History of pelvic radiation

   6. Chronic UTI

   7. Schistosomiasis (in Africa and the Middle East)

   8. Industrial chemical/toxin exposure

      1. Kidneys filter and concentrate metabolic toxins into the urine which pool in the bladder, promoting oncogenesis

      2. Accounts for about 20% of bladder cancers

      3. 10- to 20-year latency period between exposure and disease

      4. Compounds associated with bladder cancer include aromatic amines, aniline dyes, nitrates, nitrites, coal, and arsenic

      5. Occupations associated with a higher risk of bladder cancer include miners, bus drivers, rubber workers, motor mechanics, leather workers, blacksmiths, machine setters, hairdressers, and mechanics.

4. Prognosis: 10-year survival for muscle-invasive cancer still confined to the bladder is 65–72%.

Evidence-Based Diagnosis

1. The diagnostic approach is based on the estimated pretest probability of disease.

2. Prevalence of cancer in patients with hematuria

   1. Microscopic hematuria

      1. Up to 8.9% of patients had a malignancy in 1 series

      2. Another cohort found bladder cancer in 3.7%, RCC in 1%, and ureteral cancer in 0.2%.

      3. Malignancy was extremely rare in patients under the age of 40 with microscopic hematuria.

   2. Macroscopic hematuria: studies generally included older patients who presented to “hematuria clinics”

      1. Up to 30% had a malignancy

      2. 20–25% had bladder cancer

      3. 1.3–10% had prostate cancer

      4. 0.6–2% had RCC

      5. 21% had stones

      6. 12–13% had BPH

         Urothelial cancer is a must not miss diagnosis in patients with macroscopic hematuria not due to an infection.

3. White light flexible cystoscopy with biopsies is the gold standard for diagnosing bladder cancer; random biopsies of bladder tissue are taken to detect carcinoma in situ not visible to the naked eye.

4. Hexaminolevulinate fluorescence cystoscopy is also useful for detection of carcinoma in situ.

5. Multiphasic CT urography is done with and without contrast and includes imaging in the excretory phase.

   1. Has largely replaced other imaging modalities such as IV pyelogram, ultrasound, conventional CT, and retrograde pyelography to evaluate unexplained hematuria

   2. Comparatively higher sensitivity (92–100%) and specificity (94–97%) for the detection of renal masses, urinary tract stones, and genitourinary transitional cell carcinomas

   3. May improve the sensitivity of cystoscopy if done first

   4. Delivers a relatively high radiation dose; therefore, some guidelines recommend avoiding in low-risk patients

6. Ultrasound

   1. The sensitivity of ultrasound for bladder cancer is 63% and the specificity 99%.

   2. Ultrasound is less sensitive than CT for detecting renal tumors < 3 cm.

7. Urine cytology and biomarkers

   1. None of the many urine biomarkers investigated has adequate test characteristics.

   2. Urine cytology sensitivity is 7–17% for low-grade and 53–90% for high-grade cancers; specificity is 90–98%.

      Patients ≥ 40 years old, or with visible urinary blood clots, require cystoscopy even if the bleeding is glomerular.

Treatment

1. Superficial or minimally invasive tumors are treated with transurethral resection for both diagnostic confirmation and cure.

2. Intravesicular chemotherapy (most often with BCG) is given immediately after the operation.

3. Muscle-invasive tumors are treated with radical cystectomy and cisplatin-based chemotherapy.

Alternative Diagnosis: Nephrolithiasis

See Chapter 3, Abdominal Pain.

Alternative Diagnosis: Prostate Cancer

See Chapter 2, Screening & Health Maintenance.

Alternative Diagnosis: BPH

See Chapter 28, Acute Kidney Injury.

Alternative Diagnosis: Prostatitis

See Chapter 16, Dysuria.

Alternative Diagnosis: Renal Cell Carcinoma

Textbook Presentation

RCC classically presents with the triad of hematuria, flank pain, and a palpable abdominal mass but now is far more commonly detected incidentally as a renal mass seen on a radiographic examination done for other reasons.

Disease Highlights

1. Epidemiology

   1. Arises from the renal epithelium and accounts for over 80% of renal cancers, with a 1.6:1 male predominance and peak incidence between the sixth and eighth decades of life

   2. About 2% of cases are associated with inherited syndromes like von Hippel-Lindau disease

   3. Risk factors

      1. Smoking

      2. Obesity

      3. Hypertension

      4. Toxic exposures

      5. Acquired cystic kidney disease associated with end-stage renal disease (ESRD)

2. Etiology

   1. The most common histologic form is clear cell, which accounts for 75–85% of cases.

   2. Other histologies are papillary (10–15%) and chromophobe (5–10%).

   3. The pathogenesis is incompletely understood, but the von Hippel-Lindau (VHL) tumor suppressor gene is mutated in most sporadic cases of RCC.

3. Presentation

   1. Many patients with RCC are asymptomatic until the disease is advanced, with roughly 25% having distant metastases or locally advanced disease at time of presentation.

   2. Hematuria occurs with tumor invasion of the renal collecting system, ranging from microscopic to visible blood clots.

   3. An abdominal or flank mass, generally only palpable in thin individuals, is usually firm, homogenous, and nontender, moving with respiration.

   4. Nonspecific symptoms such as fatigue, weight loss, and anemia, are common.

4. Prognosis

   1. Stage I: 5-year survival > 90%

   2. Stage II: 75–95%

   3. Stage III who undergo nephrectomy: 59–70% 5-year survival

   4. Stage IV: median survival of 16–20 months; < 10% 5-year survival rate for patients with distant metastases

Evidence-Based Diagnosis

1. RCC appears as a solid renal lesion on abdominal imaging.

   1. On ultrasound, the mass does not meet criteria for a simple cyst.

   2. On CT, features of RCC include thickened irregular walls or septa and enhancement with IV contrast.

2. RCC can remain localized, invade surrounding fascia and adjacent organs, and/or metastasize.

   1. CT scan is used for staging.

      1. 78% sensitive and 96% specific for the detection of renal vein invasion

      2. 83% sensitive and 88% specific for the detection of metastatic adenopathy

      3. 46% sensitive and 98% specific for the detection of perinephric invasion

      4. 100% specific for detecting adjacent organ invasion

   2. Bone scan, CT chest, MRI, or PET scanning are used to detect distant metastases.

Treatment

1. For patients with isolated, solid renal masses, resection with either partial or complete nephrectomy is preferred to biopsy since it is both diagnostic and therapeutic; consultation with urology is essential to determine whether surgery or surveillance is indicated.

2. Deciding whether to perform a partial or complete (radical) nephrectomy depends on

   1. Stage and location of the tumor

   2. Baseline renal function

   3. Functional status

   4. Presence of other comorbidities

3. A reasonable alternative for individuals at high risk for complications from surgery is thermal ablation (eg, cryotherapy or radiofrequency ablation)

4. Consultation with oncology is indicated for patients with locally advanced or metastatic RCC.

Mr. S is asymptomatic with nonvisible (or microscopic) hematuria. Based on the 2 separate urinalyses, it is persistent. In young patients (under age 40) without risk factors, cancer is an uncommon cause of asymptomatic nonvisible hematuria; in the absence of lower urinary symptoms, a urologic cause is rare. Notably, the concomitant proteinuria and the dysmorphic RBCs are pivotal points for a glomerular source. The most common glomerular causes are IgA nephropathy and TBMN. Table 21-3 lists the differential diagnosis.

Leading Hypothesis: IgA Nephropathy

Textbook Presentation

IgA nephropathy (IgAN) most commonly presents with visible hematuria within 12–72 hours of a mucosal (typically an upper respiratory) infection. It can also be discovered upon detection of asymptomatic, nonvisible hematuria with or without proteinuria during routine medical screening.

Disease Highlights

1. The most common cause of primary glomerulonephritis worldwide.

   1. Peak incidence of IgAN is between the second and fourth decades of life, though it can present at any age.

   2. Occurs with greatest frequency in Asians and whites.

2. An important cause of progressive CKD, with up to 50% of patients developing ESRD within 25 years of diagnosis.

3. Etiology of IgAN

   1. Caused by glomerular deposition of A1 isotype of IgA in the mesangium.

   2. No evidence of a role for any specific antigen despite the relation between mucosal infections and episodes of visible hematuria.

   3. Most cases of IgAN are sporadic, although familial cases do occur and appear to be transmitted as an autosomal dominant trait with incomplete penetrance.

4. Clinical manifestations of IgAN

   1. One or more episodes of visible hematuria, usually associated with upper respiratory infection (often called synpharyngitic hematuria) and sometimes accompanied by flank pain and low-grade fever (present in 40–50% of patients).

   2. Nonvisible hematuria and typically mild proteinuria, detected incidentally on routine screening (present in 30–40% of patients).

   3. Advanced, progressive CKD, hypertension, and heavy proteinuria, in addition to hematuria (seen in small proportion of patients); nephrotic range proteinuria (present in ~5% of patients).

   4. IgAN rarely occurs secondary to other conditions like cirrhosis, celiac disease, and HIV infection, all of which are associated with a high frequency of IgA deposition.

Evidence-Based Diagnosis

1. Urine dipstick with microscopy and culture should be used to rule out infection, confirm the findings of hematuria, and evaluate for proteinuria.

2. A definitive diagnosis can only be made by renal biopsy with immunofluorescence or immunoperoxidase studies for IgA deposits.

   1. In the absence of proteinuria, hypertension, or decreased glomerular filtration rate (GFR), the clinical course (at least short-term) of patients with IgAN is generally benign and renal biopsy is usually not indicated; periodic monitoring is recommended in these cases.

   2. Proteinuria (> 500–1000 mg/day), elevated serum creatinine, or hypertension suggests more severe or progressive disease and are indications for renal biopsy to establish the diagnosis.

3. The pathognomonic biopsy finding of IgAN is prominent, globular deposits of IgA in the mesangium on immunofluorescence microscopy.

Treatment

1. Patients with isolated hematuria, normal GFR, and no significant proteinuria should be monitored every 6–12 months for signs of progression (worsening proteinuria, BP, and GFR).

2. Clinical predictors of progression of IgAN, including proteinuria > 500–1000 mg/day, decreased GFR, and hypertension often signal the need for treatment.

3. Treatment is primarily aimed at reducing proteinuria and optimizing BP to minimize risk of progression.

4. Treatment of progressive IgAN

   1. Angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB) therapy slows progression by optimizing BP control and reducing proteinuria.

   2. Fish oil has also been used in IgAN patients with > 1000 mg/day of proteinuria despite 3–6 months of ACE inhibitor or ARB therapy.

   3. Some patients with IgAN with signs of more severe inflammatory disease on biopsy may require immunosuppressive therapy.

   4. Renal transplantation is an option for patients with IgAN who have had progression to ESRD, but recurrence is common.

Alternative Diagnosis: Thin Basement Membrane Nephropathy

Textbook Presentation

Most individuals with TBMN have isolated hematuria with normal renal function, no or minimal proteinuria, and a uniformly thinned glomerular basement membrane (GBM) on electron microscopy analysis of biopsy specimen.

Disease Highlights

1. The most common cause of persistent hematuria in children and adults

   1. Occurs in at least 1% of the general population and is often familial

   2. A family history of hematuria is present in 30–50% of TBMN cases.

2. Characteristically presents with persistent or intermittent hematuria incidentally discovered on routine urinalysis.

   1. Most patients have isolated hematuria, which can present at virtually any age, without proteinuria or renal impairment.

   2. Dysmorphic RBCs are commonly seen, and RBC casts may occur.

   3. Episodes of visible hematuria may occur in a small percentage of individuals with TBMN (12%) but are far more common in Alport syndrome (33%) and IgA nephropathy (88%).

   4. Proteinuria is rarely seen in children with TBMN, but mild proteinuria (up to 1 g/day) may be seen in a minority of adult patients.

3. TBMN is caused by defects in type IV collagen genes, which leads to a diffuse thinning of the GBM seen on electron microscopy.

4. The long-term prognosis in most patients with true TBMN is excellent.

Evidence-Based Diagnosis

1. The only way to definitively diagnose TBMN is by renal biopsy and electron microscopy.

   1. Renal biopsy is usually not performed in patients with isolated hematuria, normal renal function, and no or minimal proteinuria. The diagnosis is often inferred in these patients with positive family history of hematuria and negative family history of CKD.

   2. Renal biopsy is more commonly performed in patients with suspected TBMN who also have proteinuria (> 200–300 mg/day).

2. Biopsy reveals diffuse, uniform thinning of the GBM on electron microscopy, and the absence of other significant glomerular pathology.

3. Immunohistochemical evaluation of the type IV collagen alpha-3 to alpha-5 chains is useful in helping distinguish between TBMN and early Alport syndrome (with microscopic hematuria and thin GBM), as these chains are usually absent or abnormally distributed in Alport syndrome.

Treatment

1. Progressive CKD with TBMN is rare, but regular follow-up and monitoring is important.

2. While there are no proven therapies for TBMN, a goal BP of < 130/80 mm Hg and ACE inhibition is recommended for patients with TBMN and proteinuria > 1 g/day.

Alternative Diagnosis: Infection-Related Glomerulonephritis

Textbook Presentation

The classic presentation of infection-related glomerulonephritis (IRGN) is new onset of hematuria, proteinuria, and edema, often with hypertension and mild acute kidney injury, following or concurrent with an infection.

Disease Highlights

1. Epidemiology

   1. In the developing world, IRGN (especially poststreptococcal glomerulonephritis [GN]) occurs primarily in children (ages 6–10) and young adults, with a male predominance (2–3:1).

   2. In the developed world, IRGN affects mostly adults, especially those with immunocompromising comorbidities such as diabetes mellitus and alcoholism.

2. Etiology

   1. Upper respiratory and skin infections are the 2 most common sites of infection leading to IRGN, although multiple other sites have also been implicated.

   2. Historically, most cases have been attributed to group A streptococci, specifically Streptococcus pyogenes.

   3. More recently, it has become clear that other strains of streptococci (groups C and G), staphylococci, gram-negative bacilli, mycobacteria, parasites, fungi, and viruses can also cause IRGN.

   4. One-third to one-half of cases of IRGN in developed countries are associated with infections of gram-negative bacilli.

3. Clinical manifestations

   1. Acute nephritic syndrome (poststreptococcal GN is the prototypical form)

      1. Presents with hematuria, proteinuria, and edema, often accompanied by hypertension and mild acute kidney injury

      2. Urinary output usually improves after 5–7 days, followed rapidly by resolution of edema and normalization of BP

   2. Rapidly progressive nephritic syndrome

      1. Rarely, acute postinfectious GN (usually poststreptococcal) is complicated by rapidly worsening GFR

      2. Crescent formation often present on biopsy but tends to be limited

   3. Subclinical or asymptomatic GN

      1. Present in many patients with mild, self-limited streptococcal infections

      2. Characterized by low-grade proteinuria (< 1 g/day), pyuria, and nonvisible (microscopic) hematuria; often goes undetected

Evidence-Based Diagnosis

1. In children, nephritis typically follows pharyngitis by 1–2 weeks and skin infection by 2–4 weeks.

   1. During this time asymptomatic nonvisible (microscopic) hematuria and proteinuria is often present.

   2. Upon symptomatic presentation (eyelid and diffuse edema, smoky colored urine), a urinalysis shows proteinuria (mild to nephrotic range), pyuria (97%), and often hematuria (30–37%) with RBC casts.

   3. Acute kidney injury and hypertension are also common (60–80%).

   4. Hypocomplementemia is present in 90% of children with poststreptococcal GN and 35–80% of adults with IRGN.

      1. C3 is typically low while C4 is normal.

      2. One-third of patients with IRGN will have both low C3 and low C4.

   5. Serologies for recent streptococcal infection (ASO, DNase B, streptokinase, hyaluronidase, anti-NAD) are often positive, even when patients do not report recent respiratory or skin infection.

      1. The streptozyme test measures all 5 of these streptococcal antibodies and performs better than any individual antibody measurement alone.

      2. It has a sensitivity of 95% in patients with recent group A streptococcal pharyngitis and 80% in those with streptococcal skin infections.

   6. Biopsy is usually not recommended in children.

2. In a significant proportion (45%) of adults, the precipitating infection is still present and only discovered at the time IRGN is diagnosed.

   1. Adults present with gross hematuria and diffuse edema; proteinuria can lead to foamy urine and hypertension can cause headaches.

   2. Exam may reveal signs of infection, such as pharyngitis, pneumonia, cellulitis/abscess, endocarditis, or urethral/vaginal discharge.

   3. Older adults (25%) may have additional signs of volume overload (increased jugular venous pressure, S₃ gallop, pulmonary crackles, lower extremity edema) stemming from acute volume overload precipitated by the acute kidney injury.

   4. Urinalysis shows at least nonvisible (microscopic) hematuria, although gross hematuria is often already present.

   5. Proteinuria (mild to nephrotic range) is usually present, and RBC casts may be seen on microscopy.

   6. Biopsy is usually recommended in adults to confirm diagnosis and rule out glomerulonephritides that require immediate immunosuppressive therapy.

Treatment

1. Children should be treated with supportive therapy.

2. Adults

   1. Treat underlying infection, which is often ongoing at the time of diagnosis.

   2. Manage complications of nephritis.

      1. Antihypertensives, specifically ACE inhibitor if moderate to heavy proteinuria

      2. Diuretics and sodium restriction

   3. Immunosuppressive therapy is not recommended.

3. Prognosis

   1. Complete recovery occurs in almost all children, although potentially with increased likelihood of CKD and hypertension later in life.

   2. Adults with IRGN have a poorer prognosis.

      1. Up to 50% have persistent renal dysfunction, and up to 33% progress to ESRD.

      2. Elderly and diabetic patients have the highest risk of persistent CKD and ESRD.