Evaluation and Management of Hematuria and Proteinuria

Initial Evaluation

• The American Academy of Family Physicians recommends ruling out benign causes of transient proteinuria/hematuria, such as fever, intense exercise, dehydration, emotional stress, menstruation, sexual activity, viral illness, trauma, and contamination from vaginal secretions 1
• Quantify protein excretion using urine albumin-to-creatinine ratio (ACR), urine protein-to-creatinine ratio (PCR), or automated reagent strip urinalysis, in order of preference, as recommended by the Kidney International guidelines 2
• Initial evaluation of proteinuria should use a first morning void urine sample tested for albumin-to-creatinine ratio (ACR) as the preferred method, followed by confirmatory testing if positive, as recommended by the Kidney International guidelines 3, 4

Confirming Positive Findings

• Confirm reagent strip positives with quantitative laboratory measurement, and use early morning urine sample for confirmation, as recommended by the Kidney International guidelines 2
• Reagent strip urinalysis for albumin with automated reading and reagent strip urinalysis for total protein with automated reading are also acceptable methods, as stated in the Kidney International guidelines 3

Assessing for Non-Albumin Proteinuria

• Test for specific proteins, such as α1-microglobulin and monoclonal light chains, if non-albumin proteinuria is suspected, as recommended by the Kidney International guidelines 2
• Consider serum and urine protein electrophoresis if monoclonal gammopathy is suspected, as recommended by the American Journal of Kidney Diseases guidelines 5

• Several factors can affect urinary protein or albumin measurements, including:

  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

• Additional factors that may affect protein-to-creatinine ratio (PCR) interpretation include:

  Factor	Effect on PCR
  Concentrated urine	False positive
  Exercise	False positive
  Fever	False positive
  Infection	False positive

Microscopic Examination

• Perform microscopic examination to determine red blood cell morphology and presence of red cell casts, which can help differentiate glomerular from non-glomerular bleeding, as recommended by the American Academy of Family Physicians 1
• Urine cultures for bacterial or viral pathogens should be performed if infection is suspected, and renal sonogram is recommended if hematuria, infection, or renal insufficiency is present, as suggested by the Clinical Infectious Diseases society 7

Referral and Treatment

• Refer patients to nephrology for comprehensive evaluation, as recommended by the American Academy of Family Physicians 1
• Patients with persistent significant proteinuria, nephrotic-range proteinuria, proteinuria with hematuria, proteinuria with hypertension, proteinuria with reduced GFR, proteinuria with edema or hypoalbuminemia, recurrent urinary tract infections, electrolyte abnormalities, persistent metabolic acidosis, or elevated blood urea nitrogen or creatinine levels should be referred immediately, as recommended by the Clinical Infectious Diseases society 7
• A protein-to-creatinine ratio (PCR) >0.2 g/g (or >200 mg/g) is considered abnormal in children, indicating potential proteinuric nephropathy, according to the American Academy of Pediatrics 7
• The National Kidney Foundation recommends ACE inhibitors or ARBs as first-line therapy for proteinuric nephropathies in children, starting with a low dose and titrating upward as tolerated 8
• ACE inhibitors or ARBs are recommended as primary treatment for children with ADPKD who have proteinuria, according to the American Society of Nephrology 8
• The Kidney International guidelines recommend first-line therapy with ACE inhibitors or ARBs, starting with a low dose and titrating upward as tolerated, with a target of reducing proteinuria to <1 g/day, and monitoring serum creatinine and potassium 1-2 weeks after starting treatment 4, 9
• Target blood pressure <130/80 mmHg in patients with proteinuria <1 g/day, and <125/75 mmHg when proteinuria is >1 g/day, as recommended by the Kidney International guidelines 9
• Iron supplementation is recommended for iron deficiency anemia, as stated by the Nature Reviews Nephrology society 10
• Treatment of post-transplant proteinuria may include plasmapheresis and immunosuppressive drugs, according to the Nature Reviews Nephrology society 10

Monitoring and Follow-up

• Assess GFR and albuminuria at least annually in people with confirmed kidney disease, and more frequently in those at higher risk of progression, as recommended by the Kidney International guidelines 2
• Regular assessment of total protein, albumin, and specific protein fractions based on underlying condition is recommended, with adjustments to treatment based on clinical response 11, 12
• Monitor for complications of protein abnormalities (edema, ascites, hyperviscosity) and adjust treatment accordingly 13, 12
• The KDIGO guidelines recommend kidney biopsy for new onset of proteinuria (2C) and unexplained proteinuria >3.0 g per gram creatinine (2C) 12

Definition of Progression

• Define progression based on decline in GFR category, 25% or greater drop in eGFR from baseline, or sustained decline in eGFR of >5 ml/min/1.73 m²/year, as recommended by the Kidney International guidelines 2

Common Pitfalls

• Failing to repeat abnormal findings to confirm persistence, as warned by the Kidney International guidelines 2
• Missing significant non-albumin proteinuria, such as light chains in multiple myeloma, as warned by the Journal of the National Comprehensive Cancer Network and Kidney International guidelines 2, 14
• Overlooking red cell morphology, which can help differentiate glomerular from non-glomerular bleeding, as warned by the American Academy of Family Physicians 1
• Common pitfalls in proteinuria evaluation and management include relying on dipstick testing alone, using 24-hour collections unnecessarily, ignoring factors affecting interpretation, failing to confirm initial positive results, and not considering preanalytical variables, which can lead to inaccurate or misleading results, as noted by the Kidney International guidelines 4