Anthony J. Tracey, MD, MPH
Raju Thomas, MD, MHA, FACS
BASICS
DESCRIPTION
• Persistent abnormal amounts or types of protein in the urine:
– May be 1st indication of renal disorders either primary (eg, proliferative glomerulonephritis) or secondary (eg, hypertension [HTN], lupus nephritis, diabetes [DM])
– Marker of overall cardiovascular health
• Healthy adult excretes 80–150 mg of protein per day in urine, consisting of 30% albumin, 30% serum globulins, and 40% tissue proteins.
• Dipstick urinalysis detects proteinuria only when protein excretion >300 mg/d:
– Microalbuminuria: 30 and 300 mg/d:
Earliest sign of diabetic nephropathy
Identifies those at risk of cardiovascular disease in both diabetic and nondiabetic populations (1)[2]
• Important to distinguish between benign (no long-term renal significance) and pathologic causes of proteinuria. Can often differentiate based on:
– Associated clinical findings (eg, known diabetes or HTN; edema and lipiduria in nephrotic syndromes)
– Persistency of proteinuria:
Transient or intermittent proteinuria is unlikely to be associated with significant renal pathology
Example etiologies: Exercise, emotional stress, fever, orthostatic proteinuria
Document proteinuria on >1 visit
– Degree of proteinuria:
500 mg/24 hr usually heralds significant glomerular disease
Proceed to quantitative measurement when dipstick is persistently positive
EPIDEMIOLOGY
Incidence
• In diabetic patients, progression to microalbuminuria 2% per year; from microalbuminuria to proteinuria 2.8% per year
• 1.7% of males and 0.9% of females
• Increases with age
• Higher in patients with DM:
– Microalbuminuria 24.9%; proteinuria 5.3%
Prevalence
• African Americans afflicted with higher levels of proteinuria due to increased risk of associated diseases
• Orthostatic proteinuria in 2–5% of adolescents:
– Uncommon in age >30 yr:
Increased protein excretion in the upright position. Resolves in supine position (2)[2]
No therapy required, often resolves with time
RISK FACTORS
• DM
• HTN
• Obesity (BMI >35 kg/m2), but progression to renal disease not proven
Genetics
Disease specific
PATHOPHYSIOLOGY
• Glomerular proteinuria:
– Results from increased glomerular capillary permeability to albumin
– Usually >1 g/24 hr
– When total protein >3 g/24 hr: Nephrotic syndrome (look for hypoalbuminemia, lipiduria, edema, ascites)
• Tubular proteinuria:
– Inability of proximal convoluted tubule to absorb low–molecular-weight proteins such as immunoglobulin light chains, β2-microglobulin, amino acids, and retinol-binding protein
– Proteinuria usually 2–3 g/24 hr
• Overflow proteinuria:
– No underlying renal disease
– Absorptive capacity of PCT is overwhelmed by overproduction and accumulation of immunoglobulins and low–molecular-weight proteins.
• Tissue proteinuria:
– Associated with acute inflammation of urinary tract due to cystitis, acute prostatitis, and urinary tract tumors
• Transient proteinuria:
– Glomerular permeability and decreased tubular reabsorption have both been proposed as possible mechanisms (2)
ASSOCIATED CONDITIONS
• See “Differential Diagnosis”
• Hypercoagulability, lipiduria, edema, and hypoalbuminemia (nephrotic syndrome)
DIAGNOSIS
HISTORY
• Presence of underlying systemic disease:
– DM, HTN, autoimmune disorders, cardiac disease, multiple myeloma
• Transient proteinuria triggered by:
– Exercise, emotional stress, fever, recent illness
• Medication-induced glomerular injury
• Associated symptoms that would suggest clinically significant proteinuria:
– Hematuria, bone pain (myeloma)
• Age <30 and healthy (orthostatic proteinuria) (1,2)
PHYSICAL EXAM
• BP measurement to rule out HTN
• Edema with nephrotic syndrome, heart failure
• Papilledema: Uncontrolled HTN
• Jugular venous pressure elevation, heart sounds (heart failure, HTN)
• Abdominal bruits: Renal artery stenosis
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Urine dipstick:
– Qualitative test only (1+ to 4+); detects protein concentration >20–30 mg/dL
– Cannot detect microalbuminuria; if persistently positive proceed to quantitative test (spot or 24-hr protein)
– False positive: Alkaline urine; concentrated urine; contamination with blood; recent IV contrast dye
– False negative: Dilute urine; dipstick only detects albumin and will miss other plasma proteins (eg, Bence Jones proteinuria in multiple myeloma)
• Urinalysis for associated hematuria, casts (glomerulonephritis)
• Serum creatinine to rule out renal insufficiency
• Blood glucose: DM
• Albumin-to-creatinine ratio or total protein-to-creatinine ratio in a random urinary sample:
– Quantitative test that is reliable and not dependent on concentration. Less cumbersome than 24-hr collection
– Corresponds to 24-hr albumin excretion in a linear manner (eg, ratio of 3 = 3 g/24 hr)
– Serial measurements monitor therapeutic response
– Preferred screening strategy for diabetic patients
– 2 out of 3 positive tests separated by 3–6 mo considered persistent proteinuria
• Albumin, cholesterol: Nephrotic syndrome
• 3% sulfosalicylic acid test:
– Detects all types of proteinuria
– Strongly consider in patients with acute renal failure and negative or trace protein on dipstick to rule out myeloma
• Split urine collection: Daytime (7 AM to 11 PM) and overnight (11 PM to 7 AM) to rule out orthostatic proteinuria
• Urine protein electrophoresis: To assess for light chain immunoglobulins/Bence Jones proteins associated with multiple myeloma
• Others as indicated: Hepatitis and/or HIV testing, autoantibodies (ANA, etc.) (2)
Imaging
• Renal US in cases of persistent proteinuria to rule out anatomic abnormality
• 3-phase CT if renal function sufficient and associated hematuria
• MRI urogram
Diagnostic Procedures/Surgery
• Tissue analysis:
– Renal biopsy strongly considered for:
Proteinuria with hematuria
Prolonged ARF of unknown etiology
Nephrotic proteinuria
Transplanted kidney (3)
• Cystoscopy if concurrent hematuria
• Cystoscopy with retrograde pyelogram if upper tract imaging indicated (hematuria, hydronephrosis) and unable to evaluate upper tracts with excretory phase imaging
Pathologic Findings
Depends on underlying etiology
DIFFERENTIAL DIAGNOSIS
• Glomerular proteinuria:
– IgA nephropathy
– Diabetic nephropathy
– Medications (eg, NSAIDs, captopril, lithium)
– Minimal change
– Primary glomerulonephritides
– Autoimmune (eg, SLE, amyloidosis)
• Tubular proteinuria:
– Obstructive uropathy
– Toxins and drugs
– Fanconi syndrome
• Overflow proteinuria:
– Multiple myeloma
– Monoclonal gammopathy of unknown significance
– Rhabdomyolysis causing myoglobinuria
– Any hemolytic state causing hemoglobinuria
• Transient proteinuria:
– Fever
– Strenuous exercise
– Emotional stress
– Pregnancy
– Cold exposure
– Orthostatic proteinuria
TREATMENT
GENERAL MEASURES
• Treat specific underlying etiology.
• All patients with persistent proteinuria should be referred to a nephrologist.
• Hematology–oncology evaluation for patients with Bence Jones protein for treatment of multiple myeloma
• Mild dietary protein restriction may prevent progression of chronic kidney disease.
• Strict glycemic and BP control in diabetics
• Salt/fluid restriction for edema associated with nephrotic syndrome
MEDICATION
First Line
• ACE inhibitors reduce proteinuria and can both prevent and slow deterioration of renal function in patients with diabetes or nondiabetic renal disease, independent of their antihypertensive effects (3)[A]:
– Can reduce protein excretion by 35–45%
– Lisinopril 2.5 mg/d PO; increase as tolerated
– Ramipril 2.5–5 mg/d PO, 20 mg/d max
– Captopril 12.5–25 mg PO BID/TID, 50 mg TID max
Second Line
• Angiotensin II receptor antagonists:
– Use if side effects such as cough and angioedema develop from ACE inhibitors
– Candesartan, eprosartan, irbesartan, losartan, valsartan
– Calcium channel blockers: May be better for HTN with less renal effect in the relatively ischemic kidney
SURGERY/OTHER PROCEDURES
N/A
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
N/A
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Isolated proteinuria; degree dependent:
– Nonnephrotic proteinuria has low risk of progressive kidney disease (3)[2]
– Nephrotic proteinuria (>3 g/d) associated with glomerular disease and high risk of progression to chronic kidney disease
– Japanese study of screened healthy patients; cumulative incidence of ESRD over 17 yr:
1.4% with 1+ proteinuria
7.1% with 2+ proteinuria
COMPLICATIONS
• Progression to renal failure
• Proteinuria is a marker for overall cardiovascular health (3)[2]
FOLLOW-UP
Patient Monitoring
• Transient proteinuria: Active monitoring unnecessary
• Nephrologist for any patient with large quantity of proteinuria and high-risk patients with microalbuminuria:
– Monitor urine albumin-to-creatinine ratio
– Monitor serum creatinine
Patient Resources
National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC). http://kidney.niddk.nih.gov/kudiseases/pubs/proteinuria/
REFERENCES
1. Ruiz J, Sánchez-Fructuoso A, Zárraga S. Management of proteinuria in clinical practice after kidney transplantation. Transplant Rev (Orlando). 2012;26:36–43.
2. Bello A, Thompson S, Lloyd A, et al; Alberta Kidney Disease Network. Multiple versus single and other estimates of baseline proteinuria status as predictors of adverse outcomes in the general population. Am J Kidney Dis. 2012;59:364–371.
3. Turin TC, Tonelli M, Manns BJ, et al. Proteinuria and life expectancy. Am J Kidney Dis. 2013;61:646–648.
ADDITIONAL READING
• American Diabetes Association. Standards of medical care in diabetes–2007. Diabetes Care. 2007;30:S4–S41.
• www.kidney.org/professionals/kdoqi/guidelines.cfm.
See Also (Topic, Algorithm, Media)
• Glomerulonephritis, Acute
• Glomerulonephritis, Chronic
• Proteinuria Algorithm 
• Renal Failure, Acute
• Renal Failure, Chronic
• Urinalysis and Urine Studies
CODES
ICD9
791.0 Proteinuria
ICD10
• R80.0 Isolated proteinuria
• R80.2 Orthostatic proteinuria, unspecified
• R80.9 Proteinuria, unspecified
CLINICAL/SURGICAL PEARLS
Proteinuria in excess of 500 mg/d likely represents significant glomerular disease.