What is the appropriate work‑up for frothy urine suggestive of proteinuria?

Work-Up for Frothy Urine Suggestive of Proteinuria

Begin with a spot urine protein-to-creatinine ratio (UPCR) from a first-morning void to quantify proteinuria, then stratify risk and pursue additional testing based on the degree of protein excretion and clinical context. 1, 2

Initial Quantitative Confirmation

• Obtain a first-morning spot UPCR rather than relying on dipstick alone, as dipstick measures concentration (mg/dL) and is unreliable for quantification due to variability in urine concentration. 1, 2

• Normal UPCR is <200 mg/g (0.2 mg/mg); values ≥200 mg/g indicate pathological proteinuria requiring further evaluation. 1, 2

• For diabetic patients, use albumin-to-creatinine ratio (ACR) instead of UPCR, with abnormal defined as ≥30 mg/g. 1, 3

• Exclude transient causes before confirming persistence: rule out urinary tract infection, vigorous exercise within 24 hours, menstrual contamination, fever, marked hyperglycemia, severe hypertension, or congestive heart failure—all of which transiently elevate urinary protein. 1, 2

• Confirm persistence with repeat testing: obtain two positive UPCR results out of three separate samples collected over 3 months to establish chronic proteinuria, accounting for day-to-day biological variability. 1, 2

Baseline Assessment After Confirming Proteinuria

• Calculate estimated GFR (eGFR) using the CKD-EPI equation from serum creatinine, incorporating age, sex, and race to stage kidney function. 1, 2

• Perform urine sediment microscopy to detect dysmorphic red blood cells, red-cell casts, or white-cell casts, which indicate glomerular disease and warrant nephrology referral. 4, 1

• Measure blood pressure at every visit, as hypertension both causes and results from proteinuric kidney disease. 2

• Obtain serum albumin if UPCR is >1,000 mg/g to assess for nephrotic syndrome (albumin <3.0 g/dL). 2

Risk Stratification by Proteinuria Level

Low-Level Proteinuria (200–500 mg/g)

• Annual monitoring is sufficient if eGFR is normal and no other features of kidney disease are present. 1, 2

• Screen high-risk populations annually: patients with diabetes, hypertension, or family history of chronic kidney disease. 1, 3

Moderate Proteinuria (500–1,000 mg/g)

• Initiate ACE inhibitor or ARB therapy even if blood pressure is normal, as these agents reduce proteinuria independent of blood-pressure lowering. 1, 2

• Target blood pressure ≤130/80 mmHg using ACE-I/ARB as first-line therapy. 2

• Implement dietary sodium restriction (<2 g/day) and protein restriction (~0.8 g/kg/day). 2

• Repeat UPCR every 6 months after initiating therapy to assess treatment response. 2

• Refer to nephrology if proteinuria persists >1 g/day despite 3–6 months of conservative therapy, or if eGFR declines >20% acutely, or if active urinary sediment is present. 2

Nephrotic-Range Proteinuria (>3,500 mg/g or >3.5 g/day)

• Immediate nephrology referral is mandatory because nephrotic-range proteinuria carries high risk for progressive kidney disease, cardiovascular events, and thromboembolism. 1, 2

• Kidney biopsy is typically required to identify the underlying pathology and guide immunosuppressive therapy. 1, 2

• Consider 24-hour urine collection to confirm nephrotic syndrome (>3.5 g/day) for thromboprophylaxis decisions, as this diagnosis has critical implications for anticoagulation management. 2

Additional Testing Based on Clinical Context

In Children and Adolescents

• Use first-morning void exclusively to exclude orthostatic (postural) proteinuria, a common benign finding in school-age children that disappears when supine. 1, 5

• Do not order 24-hour collections routinely in children, as they are cumbersome and often inaccurate; spot UPCR is preferred. 1, 5

• Screen family members' urine if persistent unexplained microhematuria accompanies proteinuria, as benign familial hematuria (thin basement membrane nephropathy) is autosomal dominant. 4

In Patients >50 Years or With Unexplained Proteinuria

• Obtain serum protein electrophoresis and immunofixation to rule out multiple myeloma, especially if proteinuria is non-albumin predominant. 2

In Diabetic Patients

• Confirm microalbuminuria (ACR 30–299 mg/g) in 2 of 3 samples before diagnosing diabetic nephropathy. 1, 3

• Add SGLT2 inhibitor (e.g., dapagliflozin) if eGFR ≥30 mL/min/1.73 m² and ACR >300 mg/g to reduce composite risk of ≥50% eGFR decline, end-stage renal disease, or cardiovascular/renal death. 2

Safety Monitoring After Initiating ACE-I/ARB

• Check serum creatinine and potassium 1–2 weeks after starting therapy to detect hyperkalemia or acute kidney injury. 1, 2

• Do not discontinue ACE-I/ARB for modest creatinine rises <30% in the absence of volume depletion, as renal protective benefits outweigh small changes. 2

• Advise temporary discontinuation during acute illness with volume depletion (e.g., gastroenteritis), as all CKD patients have increased risk of acute kidney injury. 2

Common Pitfalls to Avoid

• Do not rely on a single dipstick reading to diagnose proteinuria; quantitative confirmation with UPCR is mandatory. 1, 2

• Do not interpret serum creatinine as "normal" without calculating eGFR, especially in elderly, women, or individuals with low muscle mass—a creatinine of 1.2 mg/dL often corresponds to eGFR 45–59 mL/min/1.73 m² in these populations. 2

• Do not order 24-hour urine collections routinely; spot UPCR is sufficient for most clinical scenarios except confirming nephrotic syndrome, establishing baseline before immunosuppression, or evaluating patients with extreme body habitus. 1, 2

• Do not combine ACE inhibitor with ARB routinely, as dual therapy increases risk of hyperkalemia and acute kidney injury without clear benefit. 2

• Do not dismiss postdonation proteinuria as benign; perform complete work-up as in the general population, as incidence of proteinuria is higher (~12%) in kidney donors than non-donors. 4