Proteinuria DR. SANJAY PANDEYA MD. FRCPC.

Proteinuria DR. SANJAY PANDEYA MD. FRCPC.

Objectives Define normal and abnormal range(s) of proteinuria Evaluation of proteinuria Be aware of complications of proteinuria When to refer and when not to refer

Case 1 20 year-old man with no significant past medical history who came to clinic for a physical as part of evaluation while playing on the university football team. No physical complaints. Vital signs, BP WNL. Physical exams WNL. UA: no hematuria, 2+ protein

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, increases with age and higher body weight Previously, abnormal proteinuria was defined as excretion of protein > 150 mg/day

Abnormal Proteinuria Persistent albumin excretion between 30 and 300 mg/day: moderately increased albuminuria (=microalbuminuria) Albumin excretion > 300 mg/day: overt proteinuria or severely increased albuminuria (=macroalbuminuria) Nephrotic range proteinuria >= 3.0-3.5 g/day

Measurement 24 hour urine is gold standard Cumbersome Incorrectly done Random ACR or Pr/Cr ratio correlates well with 24-hour urine protein excretion on the population level influenced by the urine creatinine concentration Underestimate in those large muscle mass Overestimate in patients towards cachexia Urine protein excretion can vary throughout the day (especially resulting from exercise and posture) and from day to day

Protein-creatinine ratio to estimate protein excretion

Microalbuminuria Albumin excretion 30 300 mg/d Not detected by dipsticks ACR - 2.0 30 mg/mmol for men 2.0 30 mg/mmol for women Represent early DM nephropathy Indicator of CVD risk in at-risk populations

Microalbuminuria and CV Survival Cardiovascular survival (Kaplan-Meier) according to microalbuminuria status in a population-based cohort aged 50 to 70 yr.

Isolated Proteinuria Defined as proteinuria without hematuria or reduction in glomerular filtration rate (GFR) In most cases, patient is asymptomatic Urine sediment is unremarkable: few than 3 RBC/hpf and no casts) Protein excretion is less than 3 g/day (non-nephrotic) Findings including 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-molecularweight 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)

Cause of Proteinuria by Quantity Daily protein excretion Cause 0.15 to 2.0 g Mild glomerulopathies Tubular proteinuria Overflow proteinuria 2.0 to 4.0 g Usually glomerular >4.0 g Always glomerular

Approach Careful medical history and physical exam Examine urine sediment A patient with isolated proteinuria (normal urine sediment, normal kidney function), next step should be to rule out transient and orthostatic proteinuria

TRANSIENT PROTEINURIA Most common cause Can occur in association with fever, seizures, strenuous exercise, emotional stress, hypovolemia, extreme cold, abdominal surgery, or congestive heart failure Believed to be glomerular in origin, related to hemodynamic changes (decreased renal plasma flow) rather than altered permeability of capillary wall

ORTHOSTATIC PROTEINURIA Increase in protein excretion in the erect position compared with levels measured during recumbency 2-5% of adolescents Proteinuria usually does not exceed 1-1.5 gm/day Mechanism postulated to involve an increased permeability of the glomerular capillary wall and a decrease in renal plasma flow Long-term studies have documented the benign nature of this condition, with recorded normal renal function up to 50 years later

ORTHOSTATIC PROTEINURIA Perform Orthostatic Test CBC BUN Creatinine Electrolytes 24-hr urine excretion split collection

Instructions for Testing for Orthostatic Proteinuria (Spot Urine Specimens) 1. Patient voids at bedtime. Discard urine. No food or fluids after dinner until the next morning. 2. When patient awakes in the morning, urine specimen is collected prior to arising, or after as little ambulation as possible. Label specimen #1. 3. Patient should ambulate for the next 2 to 3 hours. Then collect specimen. Label specimen #2. 4. Both specimens should be for pr/cr ratio (normal<0.2mg/mmol) 5. If specimen #1 is free of protein and specimen #2 has protein, then the test is positive for orthostatic proteinuria. 6. If both specimens have protein, orthostatic proteinuria is unlikely and further evaluation is necessary. 7. This protocol should be repeated on at least 2 occasions to confirm the diagnosis.

Instructions for Testing for Orthostatic Proteinuria (24 hour urine) When you first get up, urinate and throw away this urine. For the rest of the day, collect all of the urine each time you go to the bathroom. Put this urine into the daytime urine jug. You can do your normal daily activities, but strenuous exercise should be avoided. In the evening, lie down two hours before you go to sleep. Just before sleeping, go to the bathroom for the last time and add this urine to the daytime jug. Lying down for two hours helps to avoid mixing urine made at night with urine made during the day. If you need to go to the bathroom during the night, be sure to collect this urine and put it in the nighttime urine jug.the next morning (approximately eight hours after going to sleep), collect the first morning urine and put in the nighttime urine jug. Take the two jugs to the laboratory. Your doctor or nurse's office will notify you when the results are available.

Diagnosis Orthostatic proteinuria is diagnosed if the urinary protein excretion rate is normal for the nighttime collection (for children <4 mg/m 2 per hour and for adults <50 mg over an eight-hour period) and exceeds the normal rate in the daytime collection

Orthostatic Proteinuria Prognosis Orthostatic proteinuria is a benign condition with no effect on renal function based on long-term data including six individuals who have been followed for as long as 40 to 50 years. In a follow-up study of 36 of 64 original patients diagnosed with proteinuria, proteinuria resolved spontaneously in most patients being present in 50 and 17 percent of individuals at 10- and 20-year follow-up. All patients had normal renal function including those with persistent orthostatic proteinuria.

PERSISTENT PROTEINURIA Present for long periods after initial detection Absence of both orthostatic proteinuria and clinical evidence of renal disease Clinical course may be benign May be secondary to parenchymal disease

FURTHER EVALUATION OF PERSISTENT PROTEINURIA Examination or urine sediment CBC Renal function tests (blood urea nitrogen and creatinine) Serum electrolytes Cholesterol Albumin and total protein

PERSISTENT PROTEINURIA If further work-up normal, urine dipstick should be repeated on at least two additional specimens. If these subsequent tests are negative for protein, the diagnosis is transient proteinuria. If the proteinuria persists or if any of the studies are abnormal, the patient may warrant Nephrology opinion Urinary protein excretion should be quantified by a timed collection

DIFFERENTIAL DIAGNOSES OF PERSISTENT PROTEINURIA Benign/idiopathic proteinuria Acute Glomerulonephritis Chronic Glomerulonephritis with possible complication features of nephrotic syndrome Chronic interstitial nephritis Congenital and acquired structural abnormalities of urinary tract

OTHER TESTS Renal ultrasound Serum complement levels (C3 and C4) ANA Streptozyme testing, Hepatitis B and C serology HIV testing

Nephrotic Syndrome l Triad of: - Proteinuria >3g/24hours l Or spot urine protein:creatinine ratio >300-350mg/mmol - Hypoalbuminemia - Edema l And often: - Hypercholesterolemia/dyslipidemia

Nephrotic - Presentation l l l l New-onset edema - Initially periorbital or peripheral - Later scrotal/genitalia, ascites, anasarca Frothy urine Generalised symptoms lethargy, fatigue, reduced appetite Venous thromboembolism

Nephritic Syndrome l Clinical syndrome defined by: - Hematuria/ red cell casts - Hypertension (mild) - Oliguria - Uremia - Proteinuria (<3g/24 hours) - Much overlap!!!

Causes of Nephrotic Syndrome l Primary glomerulonephritis - Minimal change disease (80% paeds cases) - Focal segmental glomerulosclerosis (most common cause in adults) - Membranous glomerulonephritis

Systemic Causes l Secondary glomerulonephritis - Diabetic nephropathy - Sarcoidosis - Autoimmune: SLE, Sjogrens - Infection: Syphilis, hepatitis B, HIV - Amyloidosis - Multiple myeloma - Vasculitis - Cancer - Drugs: gold, penicillamine, captopril, NSAIDs

Nephritic Causes l l l Post-infectious glomerulonephritis Primary - IgA Nephropathy (Berger's disease) - Rapidly progressive glomerulonephritis - Proliferative glomerulonephritis Secondary glomerulonephritis - Henoch-Schonlein purpura - Vasculitis

Management of Proteinuria and Edema l l Conservative - Monitor, BP, fluid balance, weight - Salt and fluid restriction - Leg elevation/compressive stocking Medical - BP control <140/90 (<130/80 in diabetics) - Diuretics - ACE-inhibitors/ARBs - Other agents to control blood pressure *** Treat Underlying Condition

Case 1 20 year-old man with no significant past medical history who came to clinic for a physical as part of evaluation while playing on the university football team. No physical complaints. Vital signs, BP WNL. Physical exams WNL. UA: no hematuria, 2+ protein

Work-up UA and microscopic examination for at least 3 separate occasions Spot 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) Or random sample as described Repeat UA in the morning before physical activites: negative

Case 2 43 year-old woman with h/o mild HTN and no other symptoms Proteinuria on urine dipstick >3g/l UACR > 350 24 hour urine confirms 6 g/d proteinuria

Case 2 Lab Studies: Electrolytes WNL, Urea 4.2, Cr 76

Management Refer to Nephrology Renal Biopsy All patients with proteinuria of more than 3.0 g/day (ie, nephrotic range) Non-nephrotic proteinuria is associated with an active urine sediment (ie, hematuria or cellular casts) or decreased GFR

Management Serology Quantitative IgA (IgG/IgM) Serum immunoelectrophoresis ANA, DNA Ab, ENA C3, C4 RF ANCA testing Cryoglobulins Hepatitis and HIV Serology VDRL

Case 2 (cont d) Serological work-up for nephrotic-range proteinuria showed: Normal Renal biopsy Advanced Primary Membranous Nephropathy Secondary causes ruled out

Complications l l l Increased susceptibility to infection - 20% in adult cases - Due to reduced serum IgG, reduced complement activity, reduced T cell function Thromboembolism - Upwards of 40% in adult cases - Partly due to altered clotting factors and platelet abnormalities Hyperlipidemia - due to hepatic lipoprotein synthesis to restore osmotic pressure

Take Home Messages In normal adult, normal urinary protein excretion should be < 150 mg/day Persistent albumin excretion between 30 and 300 mg/day: moderately increased albuminuria (=microalbuminuria) Albumin excretion > 300 mg/day (200 mcg/min): overt proteinuria or severely increased albuminuria (=macroalbuminuria) Nephrotic syndrome: massive proteinuria at least 3.0 g/day, hypoalbuminemia (albumin < 35 g/l), generalized edema, hyperlipidemia, hyperlipiduria

Take Home Messages (Approach) Rule out transient proteinuria Rule out orthostatic proteinuria Persistent proteinuria that is greater than 500 mg/day or UACR of 45-60 should be referred to a nephrologist for decisions regarding further evaluation and management (eg, kidney biopsy, discussed below)

When to Refer ACR >60 unless due to diabetes, then may be ACR >30 with hematuria Stage 4 or severe (egfr <30) with or without diabetes irrespective of level of proteinuria Stage 3 CKD depending on comfort and degree of proteinuria and co-morbidities Rapidly declining egfr 5 ml/min in 1 year or 10 ml/min within 5 years irrespective of level of proteinuria

When not to Refer Elevated microalbumin (not ACR) Lower grade proteinuria in diabetics Urine ACR <45-60? Items to focus on Hyperglycemia Hypertension Cholesterol Profile Overarching lifestyle modification for all Make sure isolated proteinuria (hematuria may indicate systemic disease)

Questions?