1. Proteinuria
Anh Nguyen, MD, MPH

2. Objectives Define normal range of proteinuria
Define abnormal range of proteinuria
Learn to work-up for proteinuria

3. 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
Higher rates of protein excretion that persist beyond a single measurement should be evaluated, as they often imply an increase in glomerular permeability that allows the filtration of normally non-filtered macromolecules, such as albumin.
The majority view is that no more than about 2 to 4 g/day of albumin are filtered normally, but some investigators claim that as much as 200 g of albumin are filtered each day (with nearly all of the filtered albumin "reclaimed" in the early proximal tubule)

4. 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)
Previously, abnormal proteinuria was generally defined as the excretion of more than 150 mg of total protein per day. However, it is now clear that early renal disease is reflected by lesser degrees of proteinuria, particularly increased amounts of albuminuria.

5. 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

6. 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
The presence of proteinuria is discovered incidentally by use of a dipstick during routine analysis.
This benign presentation of isolated non-nephrotic proteinuria is different from that in patients with more prominent renal disease.

7. 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)
Glomerular proteinuria — Glomerular proteinuria is due to increased filtration of macromolecules (such as albumin) across the glomerular capillary wall. This is a sensitive marker for the presence of glomerular disease. The proteinuria associated with diabetic nephropathy and other glomerular diseases, as well as more benign causes, such as orthostatic or exercise-induced proteinuria, fall into this category. Most patients with benign causes of isolated proteinuria excrete less than 1 to 2 g/day.
Tubular proteinuria — Low-molecular-weight proteins, such as beta2-microglobulin, immunoglobulin light chains, retinol-binding protein, and polypeptides derived from the breakdown of albumin, have molecular weights that are generally under 25,000 Daltons in comparison to the 69,000 Dalton molecular weight of albumin. These smaller proteins can be filtered across the glomerulus and are then almost completely reabsorbed in the proximal tubule. Interference with proximal tubular reabsorption, due to a variety of tubulointerstitial diseases or even some primary glomerular diseases, can lead to increased excretion of these smaller proteins.
Tubular proteinuria is often not diagnosed clinically since the dipstick for protein is not highly sensitive for the detection of proteins other than albumin and because the quantity of non-albumin proteins excreted is relatively low. The increased excretion of immunoglobulin light chains (or Bence Jones proteins) in tubular proteinuria is mild, polyclonal (both kappa and lambda), and not injurious to the kidney. This is in contrast to the monoclonal and potentially nephrotoxic nature of the light chains in the overflow proteinuria seen in multiple myeloma.
Overflow proteinuria — Increased excretion of low-molecular-weight proteins can occur with marked overproduction of a particular protein, leading to increased glomerular filtration and excretion. This is almost always due to immunoglobulin light chains in multiple myeloma but may also be due to lysozyme (in acute myelomonocytic leukemia), myoglobin (in rhabdomyolysis), or free hemoglobin (in intravascular hemolysis) that is not bound to haptoglobin.
Post-renal proteinuria — Inflammation in the urinary tract, which can occur with urinary tract infection, can give rise to increases in urinary protein excretion. The excreted proteins are generally non-albumin (often IgA or IgG), and only small amounts are excreted. Leukocyturia is frequently present in such patients. Patients with nephrolithiasis or tumors of the urinary tract may also have proteinuria.

8. 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
The urine sediment should be examined for indicators of glomerular disease, such as hematuria with dysmorphic red blood cells, specifically acanthocytes; red blood cell casts; and white blood cells or white blood cell casts in the absence of infection. Lipiduria is seen in patients with nephrotic syndrome, which implies glomerular disease. The serum creatinine should be measured and the glomerular filtration rate (GFR) estimated by use of the CKD-EPI formula.
Transient proteinuria is diagnosed if a repeat qualitative test is no longer positive for proteinuria. These patients need no further evaluation and should be reassured that they do not have kidney disease. If proteinuria is present on subsequent examinations and is not associated with orthostatic proteinuria, then persistent isolated proteinuria is diagnosed.
Transient proteinuria can occur with fever and exercise, perhaps mediated by angiotensin II or norepinephrine-induced alterations in glomerular permeability, as well as with symptomatic urinary tract infection
With marked exercise, protein excretion can exceed 1.5 mg/min in normal subjects (which is the equivalent of more than 2 g/day if sustained). Exercise is also associated with hematuria and occasionally red blood cell casts, suggesting that the proteinuria is likely glomerular in origin.
Rule out orthostatic proteinuria — Orthostatic proteinuria is characterized by increased protein excretion in the upright position but normal protein excretion when the patient is supine. The mechanism by which orthostatic proteinuria occurs is unclear, but neurohumoral activation and altered glomerular hemodynamics may be important. Total protein excretion is generally less than 1 g/day in orthostatic proteinuria but may exceed 3 g/day in selected patients
Orthostatic proteinuria is a relatively common finding in adolescents (occurring in 2 to 5 percent) but an uncommon disorder in those over the age of 30 years

9. 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

10. 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)
UA on early morning sample before patient is involved in physical activities: rule out transient proteinuria or proteinuria associated with exercises
Split urine collection: daytime (7 AM to 11 PM ) and nighttime (11 PM to 7 AM): rule out orthostatic proteinuria

11. Case 1 (cont.)
Repeat UA in the morning before physical activites: negative
This patient has transient exercise-induced proteinuria.

12. 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

13. 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

14. 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

15. 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

16. 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)

17. 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

18. 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

19. 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