What is the cause of gross hematuria in a patient with no evidence of kidney stones, casts, hydronephrosis, or hydroureter?

Gross Hematuria Without Stones, Casts, or Obstruction: Malignancy Until Proven Otherwise

In a patient with gross hematuria and no evidence of stones, casts, hydronephrosis, or hydroureter, the most critical cause to exclude is urologic malignancy—particularly bladder cancer, renal cell carcinoma, or upper tract urothelial carcinoma—which accounts for 30-40% of gross hematuria cases and requires urgent urologic evaluation with cystoscopy and CT urography regardless of whether bleeding is self-limited. 1, 2

Why Malignancy Must Be Your Primary Concern

The absence of stones (no crystals, no hydronephrosis/hydroureter) and casts (suggesting no active glomerulonephritis) significantly narrows your differential and elevates malignancy risk:

• Gross hematuria carries a 30-40% malignancy risk in adults, with bladder cancer being the most frequently diagnosed malignancy in hematuria cases 1, 2
• Painless gross hematuria has a stronger association with cancer than symptomatic hematuria with flank pain (which typically indicates stone disease—already excluded in your patient) 1
• The American College of Physicians explicitly states that any episode of gross hematuria in an adult warrants urgent urologic evaluation, even if self-limited 1

Differential Diagnosis in Order of Clinical Priority

1. Urologic Malignancies (30-40% of gross hematuria)

• Bladder cancer (transitional cell carcinoma) is the most common malignancy causing hematuria 2, 3
• Renal cell carcinoma can present with painless gross hematuria 2
• Upper tract urothelial carcinoma (renal pelvis/ureter) must be excluded 3
• Risk factors that increase malignancy probability: age >35-40 years, male gender, smoking history (especially >30 pack-years), occupational exposure to chemicals/dyes (benzenes, aromatic amines) 2, 3, 4

2. Benign Prostatic Hyperplasia (in men >50 years)

• BPH is the most common benign urologic cause of hematuria specifically in men 2
• However, BPH does not exclude concurrent malignancy, and gross hematuria from BPH must be proven through appropriate evaluation—never assume BPH is the cause without complete workup 4

3. Urinary Tract Infection

• UTI commonly causes both microscopic and gross hematuria, presenting with pyuria, bacteriuria, and typically dysuria/urgency/frequency 2, 3
• However, persistent hematuria despite appropriate antibiotic therapy effectively rules out simple UTI and strongly suggests malignancy 4

4. Trauma

• Even minor trauma can cause gross hematuria, particularly if there's an underlying anatomic abnormality 4
• History of recent trauma (including vigorous exercise or urologic instrumentation) should be elicited 2

5. Glomerular Disease (Less Likely Given No Casts)

• The absence of casts makes active glomerulonephritis less likely, but you should still assess for glomerular indicators 2, 3
• Look for: tea-colored urine, significant proteinuria (>500 mg/24h), dysmorphic RBCs >80% on microscopy 2, 3, 4
• If glomerular features are present, nephrology referral is needed in addition to completing urologic evaluation—not instead of it 4

Mandatory Immediate Workup

Urgent Urologic Referral for:

1. Cystoscopy (flexible preferred—less painful, equivalent diagnostic accuracy) to visualize bladder mucosa, urethra, and ureteral orifices 1, 4
2. Multiphasic CT urography (unenhanced, nephrographic, and excretory phases) to detect renal cell carcinoma, transitional cell carcinoma, and evaluate entire urinary tract 2, 3, 4

Laboratory Evaluation:

• Microscopic urinalysis to confirm ≥3 RBCs/HPF and assess for dysmorphic RBCs, casts, proteinuria 2, 4
• Urine culture if infection suspected (preferably before antibiotics) 2, 4
• Serum creatinine, BUN, complete metabolic panel to assess renal function 3, 4
• Complete blood count with platelets to evaluate for anemia from blood loss and coagulopathy 2, 4
• Voided urine cytology in high-risk patients (though not recommended in initial evaluation per ACP guidelines, it's useful for detecting high-grade urothelial carcinomas) 1, 4

Critical Clinical Pearls and Pitfalls

Never Defer Evaluation For:

• Anticoagulation or antiplatelet therapy—these medications may unmask underlying pathology but do not cause hematuria themselves 1, 3, 4
• Self-limited bleeding—even if hematuria resolves, the 30-40% malignancy risk mandates complete evaluation 1, 2
• Presumed benign cause (like BPH)—complete workup is still required to exclude concurrent malignancy 4

Red Flags for Malignancy:

• Age >60 years (males) or >60 years (females) 2, 4
• Smoking history >30 pack-years 2, 4
• Occupational exposure to chemicals/dyes 2, 3, 4
• Irritative voiding symptoms without infection (urgency, frequency, nocturia) 4
• History of prior gross hematuria 4

Monitor Hemoglobin/Hematocrit:

• In patients with gross hematuria, check H&H at presentation, then monitor frequently (every 1-2 days initially) until bleeding stabilizes 2
• H&H monitoring is more reliable than visual assessment of urine color for gauging bleeding severity 2
• Even modest drops in hemoglobin can have significant clinical impact in elderly patients with comorbidities 2

If Initial Workup Is Negative

• Repeat urinalysis, urine cytology, and blood pressure at 6,12,24, and 36 months 3, 4
• Immediate re-evaluation warranted if: recurrent gross hematuria, significant increase in microscopic hematuria, new urologic symptoms, or development of hypertension/proteinuria 4
• Hematuria can precede bladder cancer diagnosis by many years, making long-term surveillance essential in high-risk patients 4