What are the possible causes of hematuria and proteinuria in a patient, particularly in those with a history of kidney disease, diabetes, or hypertension, or in older adults?

Causes of Blood and Protein in Urine

The combination of hematuria and proteinuria most commonly indicates glomerular disease, particularly when proteinuria exceeds 1,000 mg per 24 hours or when accompanied by dysmorphic red blood cells (>80%) or red cell casts. 1, 2

Primary Glomerular Causes

Glomerulonephritis is the most frequent cause when both hematuria and significant proteinuria coexist, including:

• Post-infectious glomerulonephritis and IgA nephropathy are common primary glomerular diseases presenting with this combination 2
• Alport syndrome (hereditary nephritis with associated hearing loss) should be considered, especially with family history 2
• Lupus nephritis and vasculitis can cause both findings simultaneously 2
• Thin basement membrane nephropathy represents a common benign familial cause of persistent microscopic hematuria 2

Systemic Diseases Causing Both Findings

• Diabetes mellitus causes proteinuria through diabetic nephropathy and may have concurrent hematuria from other urologic causes 3
• Hypertension produces proteinuric kidney disease and increases cardiovascular risk when proteinuria is present 3, 4
• HIV-associated nephropathy (HIVAN) causes both proteinuria and hematuria, particularly in African American patients with advanced disease 3
• Hepatitis C coinfection increases risk for proteinuric renal disease 3

Urologic Causes of Hematuria (with Secondary Proteinuria)

Malignancy accounts for 30-40% of gross hematuria cases and includes:

• Bladder cancer (transitional cell carcinoma) is the most frequently diagnosed malignancy in hematuria evaluation 2
• Renal cell carcinoma and prostate cancer can cause hematuria 2
• Upper tract urothelial carcinoma should be considered in high-risk patients 2

Benign urologic conditions include:

• Urinary tract infection causes both microscopic and macroscopic hematuria with possible proteinuria 2
• Urolithiasis (kidney and ureteric stones) produces painful hematuria 2
• Benign prostatic hyperplasia is a common cause in older men 2
• Trauma to kidneys or lower urinary tract 2

Metabolic and Vascular Causes

• Hypercalciuria and hyperuricosuria cause microscopic hematuria, sometimes with mild proteinuria, potentially leading to nephrolithiasis 2
• Nutcracker syndrome (left renal vein compression) causes hematuria with variable proteinuria 2, 5

Distinguishing True Proteinuria from Hematuria-Induced False Positives

Critical diagnostic principle: Blood in urine causes dipstick proteinuria readings because the dipstick detects both albumin and hemoglobin, leading to false-positive results 1

• Total protein excretion >1,000 mg per 24 hours cannot be explained by hematuria alone and mandates thorough evaluation or nephrology referral 1
• Even proteinuria >500 mg per 24 hours warrants evaluation if persistent, increasing, or accompanied by other concerning features 1
• Quantify proteinuria with 24-hour urine collection or spot protein-to-creatinine ratio when hematuria is present to determine true protein levels 1, 6

Age-Specific and Population-Specific Considerations

In children:

• Glomerulonephritis and congenital anomalies are common causes 2
• Post-infectious glomerulonephritis should be considered with recent streptococcal infection 2

In adults >35-60 years:

• Malignancy becomes a significant risk factor requiring complete urologic evaluation 2, 6
• Males ≥60 years are classified as high-risk and require cystoscopy and CT urography 2

In patients with chronic kidney disease:

• African American persons, patients with diabetes, hypertension, or hepatitis C coinfection are at higher risk for proteinuria and poor renal outcomes 3
• HIV-infected patients with CD4+ counts <200 cells/mL or HIV RNA ≥14,000 copies/mL require annual screening 3

Diagnostic Approach Algorithm

Step 1: Confirm true hematuria and quantify proteinuria

• Verify ≥3 RBCs per high-power field on microscopic examination 1, 6
• Obtain 24-hour urine collection or spot protein-to-creatinine ratio 1, 6

Step 2: Examine urinary sediment

• Look for dysmorphic RBCs (>80% suggests glomerular origin) 1, 2
• Identify red cell casts (pathognomonic for glomerular disease) 1, 2

Step 3: Determine if proteinuria exceeds what hematuria could cause

• If proteinuria >1,000 mg/24 hours, refer to nephrology regardless of hematuria 1
• If proteinuria >500 mg/24 hours with concerning features, refer to nephrology 1

Step 4: Complete appropriate evaluation based on source

• Glomerular features present: Nephrology referral for serologic testing (complement levels, ANA, ANCA), renal ultrasound, and possible biopsy 3, 2
• Non-glomerular features or high-risk patient: Complete urologic evaluation with multiphasic CT urography and cystoscopy 2, 6

Common Pitfalls to Avoid

• Never attribute significant proteinuria solely to hematuria without quantification—dipstick readings are misleading and must be confirmed with 24-hour collection 1
• Do not dismiss the combination of hematuria and proteinuria as benign—this strongly suggests underlying glomerular disease requiring nephrology evaluation 1
• Anticoagulation or antiplatelet therapy does not cause hematuria—these medications may unmask underlying pathology but evaluation should proceed regardless 2, 6
• Gross hematuria requires urgent urologic referral even if self-limited due to 30-40% malignancy risk 2, 6
• The presence of glomerular features does not eliminate the need for urologic evaluation—malignancy can coexist with medical renal disease 2