What is the approach to evaluate and manage proteinuria?

Evaluation and Management of Proteinuria

For initial evaluation of proteinuria, a first morning void urine sample should be tested for albumin-to-creatinine ratio (ACR) as the preferred method, followed by confirmatory testing if positive. 1

Initial Assessment of Proteinuria

Preferred Testing Methods (in order of preference)

1. For albumin measurement:

   • Urine albumin-to-creatinine ratio (ACR)
   • Reagent strip urinalysis for albumin with automated reading

2. For total protein measurement:

   • Urine protein-to-creatinine ratio (PCR)
   • Reagent strip urinalysis for total protein with automated reading
   • Reagent strip urinalysis for total protein with manual reading 1

Sample Collection

• First morning void midstream urine sample is preferred for all testing
• For children: obtain first morning urine sample and test both PCR and ACR 1

Confirmation of Proteinuria

When initial screening is positive:

1. Confirm reagent strip positive results with quantitative laboratory measurement
2. Express results as a ratio to urine creatinine (ACR or PCR)
3. Confirm ACR ≥30 mg/g (≥3 mg/mmol) on a random sample with a subsequent first morning void sample 1

Interpretation of Results

Classification of Proteinuria

• Normal: ACR <30 mg/g (<3 mg/mmol) or PCR <0.2 mg/mg 2
• Moderate: ACR 30-300 mg/g (3-30 mg/mmol)
• Severe: ACR >300 mg/g (>30 mg/mmol)
• Nephrotic range: PCR >3.5 mg/mg or >3000-3500 mg/g 3, 2

Pathophysiologic Mechanisms

• Glomerular proteinuria: Most common, usually >2 g/24 hours 3, 4
• Tubular proteinuria: Characterized by low-molecular-weight proteins
• Overflow proteinuria: Due to increased production of proteins (e.g., multiple myeloma)

Factors Affecting Interpretation

Several factors can affect urinary protein or albumin measurements:

Factor	Effect
Hematuria	Falsely elevates ACR/PCR
Exercise	Increases albumin and protein in urine
Infection	Increases albumin and protein in urine
Upright posture	Can cause orthostatic proteinuria
Menstruation	Blood contamination affects results
Sex differences	Females have lower urinary creatinine, thus higher ACR/PCR
Weight/muscle mass	Affects creatinine excretion and ratio values
Acute kidney injury	Lower urinary creatinine excretion

1

Management Approach

For All Patients with Confirmed Proteinuria

1. Assess kidney function:

   • Measure serum creatinine and estimate GFR
   • Assess albuminuria/proteinuria at least annually in people with CKD
   • Monitor more frequently for those at higher risk of progression 1

2. Risk stratification:

   • Use validated risk equations to estimate absolute risk of kidney failure in CKD G3-G5
   • A 5-year kidney failure risk of 3-5% can guide nephrology referral decisions 1

3. Initiate treatment:

   • First-line therapy: ACE inhibitors or ARBs
   • Start with low dose and titrate upward as tolerated
   • Target: reducing proteinuria to <1 g/day 3
   • Target blood pressure: <130/80 mmHg for proteinuria <1 g/day; <125/75 mmHg for proteinuria >1 g/day 3

Referral Criteria

• Proteinuria >1 g/day (PCR >1000 mg/g)
• Proteinuria with hematuria
• Proteinuria with hypertension
• Proteinuria with reduced GFR
• Nephrotic range proteinuria (PCR >3.5 mg/mg)
• Children with PCR >2000 mg/g 3

Monitoring

• Monitor serum creatinine and potassium 1-2 weeks after starting ACE inhibitors or ARBs
• Assess albuminuria and GFR at least annually in people with CKD
• For CKD patients, a change in eGFR of >20% warrants evaluation
• For albuminuria monitoring, a doubling of ACR warrants evaluation 1

Special Considerations

Pediatric Patients

• Use both urine PCR and ACR for initial testing
• Consider enzymatic creatinine assays due to higher non-creatinine chromogens with Jaffe assay
• Flag eGFRcr <90 ml/min/1.73 m² as "low" in children over age 2 years 1

Point-of-Care Testing

• May be used where laboratory access is limited
• Ensure same quality criteria as laboratory testing
• Generate eGFR when using creatinine testing devices
• For albuminuria testing, devices should detect 85% of significant albuminuria cases 1

Common Pitfalls to Avoid

1. Relying on dipstick testing alone: Confirm positive dipstick results with quantitative measurements
2. Using 24-hour collections unnecessarily: Random urine PCR or ACR is more convenient and often more accurate
3. Ignoring factors affecting interpretation: Consider biological and analytical factors that may cause false results
4. Failing to confirm initial positive results: Always confirm with more accurate methods
5. Not considering preanalytical variables: Sample collection, storage, and handling can affect results

By following this structured approach to proteinuria evaluation and management, clinicians can effectively diagnose underlying kidney disease, monitor progression, and implement appropriate interventions to reduce morbidity and mortality associated with kidney disease.