Proteinuria

Anh Nguyen, MD, MPH

Objectives Define normal range of proteinuria

Define abnormal range of proteinuria

Learn to work-up for proteinuria

Normal urinary protein excretion

In normal adult, normal urinary protein excretion should be < 150 mg/day

Normal rate of albumin excretion is < 20 mg/day (15 mcg/min), increases with age and higher body weight

Abnormal proteinuria Previously, abnormal proteinuria was defined as excretion of

protein > 150 mg/day

However, early renal disease is reflected by lesser degrees of proteinuria

Persistent albumin excretion between 30 and 300 mg/day (20 to 200 mcg/min): high albuminemia (formerly called microalbuminuria)

Albumin excretion > 300 mg/day (200 mcg/min): overt proteinuria or very high albuminuria (formerly called macroalbuminuria)

Nephrotic Syndrome Massive proteinuria—at least 3.5 g/day Hypoalbuminemia (albumin < 3.5 mg/dL) Generalized edema Hyperlipidemia, hyperlipiduria Dysmorphic and red cell casts in urine

Isolated proteinuria (benign) Defined as proteinuria without hematuria or

reduction in glomerular filtration rate (GRF) In most cases, patient is asymptomatic Urine sediment is unremarkable: few than 3

erythrocytes/hpf and no casts) Protein excretion is less than 3 g/day (non-

nephrotic) Serologic markers of systemic disease are

absent

Types of proteinuria Glomerular proteinuria: increased filtration of macromolecules

(such as albumin) across the glomerular capillary wall.

Tubular proteinuria: excretion of low-molecular-weight proteins, such as beta2-microglobulin, immunoglobin light chains, retinol-binding protein and polypeptides derived from breakdown of albumin

Overflow proteinuria: increased excretion of low-molecular-weight proteins; almost always due to immunoglobin light chains in multiple myeloma, lysozymes in AML, or myoglobin in rhabdomyolysis

Post-renal proteinuria: inflammation in the urinary tract (UTI), excreted proteins are generally non-albumin (IgA or IgG)

Approach to the patient with proteinuria Careful medical history and physical exam Examine urine sediments A patient with isolated proteinuria (normal

urine sediment, normal kidney function), should rule out transient and orthostatic proteinuria

Case 1 20 year-old man with no significant PMH who

came to clinic for a physical for college football. No physical complaints. Vital signs, BP WNL. Physical exams WNL.

UA: no casts, +2 protein

Work-ups for proteinuria UA and microscopic examination for at least

3 separate occasions Spot Alb/Cr or Pro/Cr ratio UA on early morning sample before patient is

involved in physical activities or Split urine collection: daytime (7 AM to 11

PM) and nighttime (11 PM to 7 AM)

Case 1 (cont.) Repeat UA in the morning before physical

activites: negative

Case 2• 43 year-old woman with h/o HTN and anemia since age 12 presents

progressive shortness of breath, hematuria, abdominal pain, and recurrent epistaxis.

• Constitutional symptoms: subjective fever with night sweat, 30 lb weight loss, extreme fatigue and weakness, dry mouth and dry eyes

• Pleuritic chest pain, shortness of breath with walking 5 steps• Arthritis with morning stiffness• Abdominal pain with loose stool, more recently becoming black• Large lymph nodes in the neck• Epitaxis for one week• Fingers and toes are cold with tingling and had non-blanching petechiae• Excessive hair loss every morning on pillows over the past 6 months• Violaceous rash on from thighs to ankles, neck and chest

Case 2• 43 year-old woman with h/o HTN and anemia since age 12 presents

progressive shortness of breath, hematuria, abdominal pain, and recurrent epistaxis.

• Constitutional symptoms: subjective fever with night sweat, 30 lb weight loss, extreme fatigue and weakness, dry mouth and dry eyes

• Pleuritic chest pain, shortness of breath with walking 5 steps• Arthritis with morning stiffness• Abdominal pain with loose stool, more recently becoming black• Large lymph nodes in the neck• Epitaxis for one week• Fingers and toes are cold with tingling and had non-blanching petechiae• Excessive hair loss every morning on pillows over the past 6 months• Violaceous rash on from thighs to ankles, neck and chest

Case 2 Lab Studies: BMP: electrolytes WNL, BUN 10 Cr 0.8, Glu 97, Ca 7.8 CBC: WBC 3.3 Hgb 8.6 Hct 25.6 PLT 42 MCV 84.9 AST: 56 ALT: 13 Iron Panel: Iron plasma 32, TIBC 217, FeSat 50%, Ferritin

213 UA: 200 protein spot, RBC 182 24 hour urine protein: 5.7 g CRP 2.6 ESR 109

Work-ups for proteinuria 24-hour urine Pro/Cr Rule out secondary causes: HA1C, ANA,

ANCA, anti-dsDNA, C3, C4, SPEP/UPEP, HBV, HCV, HIV, RPR, phospholipase A2 receptor Ab

Renal biopsy

Case 2 (cont.) Work-ups for nephrotic-range proteinuria

showed: ANA Positive 1:320 Anti-dsDNA 1:640 Decreased C3 of 13.8 Decreased C4 of 2.0 Renal biopsy: Lupus Nephritis Class IV (capillary proliferation,

wire loop thickening and sub-endothelial deposits)

Take Home Messages In normal adult, normal urinary protein excretion should be < 150

mg/day

Persistent albumin excretion between 30 and 300 mg/day (20 to 200 mcg/min): high albuminemia (formerly called microalbuminuria)

Albumin excretion > 300 mg/day (200 mcg/min): overt proteinuria or very high albuminuria (formerly called macroalbuminuria)

Nephrotic syndrome: massive proteinuria—at least 3.5 g/day, hypoalbuminemia (albumin < 3.5 mg/dL), generalized edema, hyperlipidemia, hyperlipiduria

Take Home Messages (cont.) Work-ups for isolated proteinuria: repeat UA

in the morning or split urine collection

Work-ups for proteinuria with systemic disease symptoms: 24-hour urine Pro/Cr, rule out secondary causes, renal biopsy

References Rennke HG, Denker BM. Renal

Pathophysiology: The Essentials 2nd edition. Lippincott Williams & Wilkins, 2007.

Sabatine MS. Pocket Medicine, 4th edition. Wolters Kluwer Health/Lippincott Williams & Wilkins, 2011.

Rovin BH. The assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults. UpToDate