Proteinuria Jonathan Stein, MD MSH AIMGP Seminar Series

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

Case study #1 n n 22M, routine annual check up, found to have 2+ proteinuria on dipstick n n No Pmhx, otherwise healthy n n What workup is necessary?

Case study #2 n n 65F, vague abdominal pain x 2 months, found to have 4+ proteinuria on dipstick n n Pmhx: blood transfusion in 1985 n n Hx: weight loss 20 lbs over 6 months n n What work up is necessary?

Proteinuria n n Normal protein in urine <150 mg/day n n Approx 30 mg is albumin n n Rest is secreted by tubules: Tamm Horsfall, IgA, Haptoglobin, transferrin, B2 microglobulin n n Urine dipstick measures negatively charged proteins only = albumin

Proteinuria n typically picked up by urine dipstick testing Dipstick: reaction specific for albumin albumin JUG 24 hour urine: measures all protein excreted (albumin and nonalbumin)

Limitations of Dipstick n n False positives: concentrated urine, ph>7.0, hematuria n n False negatives: dilute urine, predominate protein not albumin  Adding sulfasalicylic acid will precipitate non albumin proteins

Proteinuria – 3 mechanisms 1. “Leaky” glomerular capillary barrier allows albumin (and sometimes globulin) to cross into Bowman’s space allows albumin (and sometimes globulin) to cross into Bowman’s space this is what occurs in many forms of glomerulonephritis 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

tubule Large proteins are able to pass by the abnormal glomerular barrier Leaky Glomerular barrier

Proteinuria – 3 mechanisms 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 “Overflow” proteinuria n n filtered load of proteins exceeds capacity of tubules to reabsorb it all “filtered load” = plasma concentration X GFR n n increased plasma concentration: ie: excess light chains n n 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 n n History: urinary symptoms, infections, rash, risk factors for HIV and hepatitis n n Pmhx: Cancer, CHF, HTN, CTD, DM, CTD n n FHx: Alports, Fabry’s n n Drugs: NSAIDS, Gold, Heroin n n Physical exam : vitals, JVP, peripheral edema, ascites, rash, joint swellings

Arsenal of Investigations n n Work up: Dipstick 1+ or greater u u Urinanalysis (protein, casts) u u Random urine: alb:creat ratio u u Overnight supine and daytime upright u u 24 hour urine for protein u u Blood work (basic vs. extensive) u u Renal imaging U/S, CT u u Biopsy

Transient vs. Persistent Proteinuria Transient n n Fever n n CHF n n Post exercise >>>> No further testing required

Persistent Proteinuria: Benign n n Benign orthostatic proteinuria n n Usually <1-2 g/d n n Mostly in young, otherwise well n n Often disappears by adulthood Investigations: n n Obtain overnight supine and daytime upright urine collection

Split urine collection n n first morning urine is discarded n n 16 hour ambulatory collection n n assume recumbent position 2h before start of supine collection n n overnight 8 hour supine collection n n total protein and total creatinine in each collection Benign Orthostatic Proteinuria

Results: n n No blood or casts on urinalysis n n Renal function and blood pressure normal Confirmation: n n < 50 mg of protein in the supine collection n n rest of protein in the upright collection Benign orthostatic proteinuria

n n 3 theories about the pathogenesis u u exaggeration of the normal response of transient increase in urine protein upon taking the upright posture u u subtle glomerular abnormalities u u 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 (2 o = Hodgkin's, NSAIDS, Rifampin) 2. FSGS: Primary & Secondary (2 o = HIV, DM, NSAIDS, heroin, chronic pyelonephritis, reflux nephropathy)

Non-proliferative: Nephrotic Syndrome 3. Membranous: Primary & Secondary 2 o causes = n n vasculitis – SLE n n infections – hep B,C, syphilis, malaria, toxoplasmosis n n others: SBE, cancer, drugs (gold, penicillin, captopril), DM, sarcoid, sickle cell 4. Nodular: DM, amyloid

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

Diagnostic Work Up n n CBC, lytes, Ca, Phos n n Serum creatinine, creatine clearance n n Fasting blood sugar n n Serum and urine protein electrophoresis n n Serology: Hep B, Hep C n n Antistreptolysin O titer n n ANA, Rheum factor, C3/C4 n n HIV, VDRL n n Abdominal U/S – rule out PCKD n n CXR n n Renal Biopsy

Rule of Thumb Nephrotic range proteinuria in the elderly, think about: 1) Diabetes 2) Malignancy 3) Multiple myeloma

Membranoproliferative Glomerulonephropathy n n Type I: subendothelial and mesangial deposits on EM that contain C3 and IgG u u Nephrotic proteinuria, active sediment, low C3, immune complex disease u u Associated with: chronic infections, systemic disease, malignancy, others (sarcoid, heroin) n n Type II: u u Can present as nephritic syndrome u u Autoimmune disease IgG antibody (nephritic factor)

Nephritic Syndrome Definition: Proliferative GN, RBC casts, hematuria, HTN, mild proteinuria, edema n n Focal proliferative n n Diffuse proliferative n n Rapidly progressive (T1, T2, T3) n n Membranoproliferative

Summary n n Dipstick analysis – uses & limitations n n 3 mechanisms of proteinuria: glomerular, tubular, overflow n n Benign orthostatic proteinuria: <2g/d, split urine collection n n Nephrotic: Min change, FSGS, Membranous, Nodular n n Membranoproliferative and Nephritic n n Work up – begins with 24 hour urine for protein and albumin:creatinine

References 1.Practice guidelines for Chronic Kidney Disease Annals of Internal medicine. Vol. 139 Number 2. 2.Approach to proteinuria. American family physician :

Thank You !