Proteinuria

Jonathan Stein, MD

MSH AIMGP Seminar Series

Objectives

Cases Dipstick analysis Mechanisms of proteinuria Transient vs. persistent proteinuria Benign orthostatic proteinuria Non-proliferative causes Proliferative

Case study #1

22M, routine annual check up, found to have 2+ proteinuria on dipstick

No Pmhx, otherwise healthy What workup is necessary?

Case study #2

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

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

typically picked up by urine dipstick typically picked up by urine dipstick testingtesting

Dipstick: reaction specific forDipstick: reaction specific for albuminalbumin

JUG

24 hour urine: measures all protein24 hour urine: measures all proteinexcreted (albumin and nonalbumin)excreted (albumin and nonalbumin)

Limitations of Dipstick

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

1.1. ““Leaky” glomerular capillary barrierLeaky” glomerular capillary barrier• allows albumin (and sometimes globulin) to allows albumin (and sometimes globulin) to

cross into Bowman’s spacecross into Bowman’s space• this is what occurs in many forms of this is what occurs in many forms of

glomerulonephritisglomerulonephritis

Glomerular barrier

tubule

• Normally, the larger proteins are excluded at the glomerular barrier

• Smaller proteins can pass, but are mostly reabsorbed

tubule

•Large proteins are able to pass by the abnormal glomerular barrier

Leaky Glomerular barrier

Proteinuria – 3 mechanisms

2. Malfunctioning tubular reabsorption of smaller proteins

• albumin excluded at (normal) glomerular barrier

• sick tubules unable to reabsorb the normally-filtered smaller proteins

• “tubular” proteinuria• eg., tubulointerstitial nephropathy

tubule

Malfunctioning tubules unable to reabsorb the smaller proteins filtered at the glomerulus

Tubular Reabsorption Malfunctioning

Proteinuria – 3 mechanisms

3. “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

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

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

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

Split urine collection 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

normalConfirmation: < 50 mg of protein in the supine

collection rest of protein in the upright collection

Benign orthostatic proteinuria

Benign orthostatic proteinuria

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 & Secondary2o 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

Edema Hypoalbuminemia Hyperlipidemia (Cholesterolemia) Hypercoaguability – loss of AT III, protein S,C IgG deficiency – decreased immunity

Diagnostic Work Up 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, thinkabout:1) Diabetes2) Malignancy3) Multiple myeloma

Membranoproliferative Glomerulonephropathy

Type I: subendothelial and mesangial deposits on EM that contain C3 and IgG Nephrotic proteinuria, active sediment, low C3, immune complex disease Associated with: chronic infections, systemic disease, malignancy, others (sarcoid, heroin)

Type II: Can present as nephritic syndrome Autoimmune disease IgG antibody (nephritic factor)

Nephritic Syndrome

Definition: Proliferative GN, RBC casts, hematuria, HTN, mild proteinuria, edema

Focal proliferative Diffuse proliferative Rapidly progressive (T1, T2, T3) Membranoproliferative

Summary 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 !