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Proteinuria
Jonathan Stein, MD
MSH AIMGP Seminar Series
Objectives
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Cases
Dipstick analysis
Mechanisms of proteinuria
Transient vs. persistent proteinuria
Benign orthostatic proteinuria
Non-proliferative causes
Proliferative
Case study #1
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22M, routine annual check up, found to have
2+ proteinuria on dipstick
No Pmhx, otherwise healthy
What workup is necessary?
Case study #2
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65F, vague abdominal pain x 2 months, found
to have 4+ proteinuria on dipstick
Pmhx: blood transfusion in 1985
Hx: weight loss 20 lbs over 6 months
What work up is necessary?
Proteinuria
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Normal protein in urine <150 mg/day
Approx 30 mg is albumin
Rest is secreted by tubules: Tamm Horsfall,
IgA, Haptoglobin, transferrin, B2
microglobulin
Urine dipstick measures negatively charged
proteins only = albumin
Proteinuria
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typically picked up by urine dipstick testing
Dipstick: reaction specific for
albumin
JUG
24 hour urine: measures all protein
excreted (albumin and nonalbumin)
Limitations of Dipstick
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False positives: concentrated urine, ph>7.0,
hematuria
False negatives: dilute urine, predominate
protein not albumin
 Adding sulfasalicylic acid will precipitate non
albumin proteins
Proteinuria – 3 mechanisms
“Leaky” glomerular capillary barrier
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allows albumin (and sometimes globulin) to
cross into Bowman’s space
this is what occurs in many forms of
glomerulonephritis
Glomerular barrier
tubule
• Normally, the larger proteins are excluded at
the glomerular barrier
• Smaller proteins can pass, but are mostly
reabsorbed
Leaky Glomerular barrier
tubule
•Large proteins are able to pass by the
abnormal glomerular barrier
Proteinuria – 3 mechanisms
Malfunctioning tubular reabsorption of
smaller proteins
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albumin excluded at (normal) glomerular
barrier
sick tubules unable to reabsorb the
normally-filtered smaller proteins
“tubular” proteinuria
eg., tubulointerstitial nephropathy
Tubular Reabsorption
Malfunctioning
tubule
Malfunctioning tubules unable to reabsorb the smaller
proteins filtered at the glomerulus
Proteinuria – 3 mechanisms
3.
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“Overflow” proteinuria
filtered load of proteins exceeds capacity of
tubules to reabsorb it all
“filtered load” = plasma concentration X GFR
increased plasma concentration:
ie: excess light chains
increased GFR: pregnancy, fever,
hyperglycemia
Overflow
Glomerular barrier
tubule
• Filtered load of proteins exceeds the tubular
reabsorption rate (similar to glucosuria in
hyperglycemia)
Approach to Proteinuria
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History: urinary symptoms, infections, rash,
risk factors for HIV and hepatitis
Pmhx: Cancer, CHF, HTN, CTD, DM, CTD
FHx: Alports, Fabry’s
Drugs: NSAIDS, Gold, Heroin
Physical exam: vitals, JVP, peripheral edema, ascites,
rash, joint swellings
Arsenal of Investigations
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Work up: Dipstick 1+ or greater
 Urinanalysis (protein, casts)
 Random urine: alb:creat ratio
 Overnight supine and daytime upright
 24 hour urine for protein
 Blood work (basic vs. extensive)
 Renal imaging U/S, CT
 Biopsy
Transient vs. Persistent
Proteinuria
Transient
 Fever
 CHF
 Post exercise
>>>> No further testing required
Persistent Proteinuria: Benign
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Benign orthostatic proteinuria
Usually <1-2 g/d
Mostly in young, otherwise well
Often disappears by adulthood
Investigations:
 Obtain overnight supine and daytime upright
urine collection
Benign Orthostatic Proteinuria
Split urine collection
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first morning urine is discarded
16 hour ambulatory collection
assume recumbent position 2h before start of
supine collection
overnight 8 hour supine collection
total protein and total creatinine in each
collection
Benign orthostatic proteinuria
Results:
 No blood or casts on urinalysis
 Renal function and blood pressure
normal
Confirmation:
 < 50 mg of protein in the supine collection
 rest of protein in the upright collection
Benign orthostatic proteinuria
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3 theories about the pathogenesis
 exaggeration
of the normal response of
transient increase in urine protein upon
taking the upright posture
 subtle glomerular abnormalities
 renal vein compression by aorta or superior
mesenteric artery
Non-proliferative
Causes of Proteinuria:
Nephrotic range proteinuria: >3.5 g/d
1. Minimal change: Primary & Secondary
(2o = Hodgkin's, NSAIDS, Rifampin)
2. FSGS: Primary & Secondary
(2o = HIV, DM, NSAIDS, heroin, chronic
pyelonephritis, reflux nephropathy)
Non-proliferative:
Nephrotic Syndrome
3. Membranous: Primary & Secondary
2o causes =
 vasculitis – SLE
 infections – hep B,C, syphilis, malaria,
toxoplasmosis
 others: SBE, cancer, drugs (gold, penicillin,
captopril), DM, sarcoid, sickle cell
4. Nodular: DM, amyloid
Complications of
Nephrotic Syndrome
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Edema
Hypoalbuminemia
Hyperlipidemia (Cholesterolemia)
Hypercoaguability – loss of AT III, protein S,C
IgG deficiency – decreased immunity
Diagnostic Work Up
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CBC, lytes, Ca, Phos
Serum creatinine, creatine clearance
Fasting blood sugar
Serum and urine protein electrophoresis
Serology: Hep B, Hep C
Antistreptolysin O titer
ANA, Rheum factor, C3/C4
HIV, VDRL
Abdominal U/S – rule out PCKD
CXR
Renal Biopsy
Rule of Thumb
Nephrotic range proteinuria in the elderly, think
about:
1) Diabetes
2) Malignancy
3) Multiple myeloma
Membranoproliferative
Glomerulonephropathy
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Type I: subendothelial and mesangial deposits
on EM that contain C3 and IgG
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Nephrotic proteinuria, active sediment, low C3,
immune complex disease
Associated with: chronic infections, systemic
disease, malignancy, others (sarcoid, heroin)
Type II:
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Can present as nephritic syndrome
Autoimmune disease IgG antibody (nephritic
factor)
Nephritic Syndrome
Definition: Proliferative GN, RBC casts,
hematuria, HTN, mild proteinuria, edema
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Focal proliferative
Diffuse proliferative
Rapidly progressive (T1, T2, T3)
Membranoproliferative
Summary
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Dipstick analysis – uses & limitations
3 mechanisms of proteinuria: glomerular,
tubular, overflow
Benign orthostatic proteinuria: <2g/d, split
urine collection
Nephrotic: Min change, FSGS, Membranous,
Nodular
Membranoproliferative and Nephritic
Work up – begins with 24 hour urine for
protein and albumin:creatinine
References
1. Practice guidelines for Chronic Kidney
Disease. 2003. Annals of Internal
medicine. Vol. 139 Number 2.
2. Approach to proteinuria. American
family physician. 2000. 62: 1333-40
Thank You !