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Proteinuria
Andrew S. Allegretti, MD
image BASICS
DESCRIPTION
Urinary protein excretion of >150 mg/day
  • Nephrotic-range proteinuria: urinary protein excretion of >3.5 g/day; also called heavy proteinuria
  • Three pathologic types:
    • Glomerular proteinuria: increased permeability of proteins across glomerular capillary membrane
    • Tubular proteinuria: decreased proximal tubular reabsorption of proteins
    • Overflow proteinuria: increased production of low-molecular-weight proteins
Pediatric Considerations
  • Proteinuria: Normal is daily excretion of up to 100 mg/m2 (body surface area).
  • Nephrotic-range proteinuria: daily excretion of >1,000 mg/m2 (body surface area)
Pregnancy Considerations
  • Proteinuria in pregnancy beyond 20 weeks' gestation is a hallmark of preeclampsia/eclampsia and demands further workup.
  • Proteinuria in pregnancy before 20 weeks' gestation is suggestive of underlying renal disease.
ETIOLOGY AND PATHOPHYSIOLOGY
  • Glomerular proteinuria: increased filtration/larger proteins (albumin) due to the following:
    • Increased size of glomerular basement membrane pores and
    • Loss of proteoglycan negative charge barrier
  • Tubular proteinuria: Tubulointerstitial disease prevents proximal tubular reabsorption of smaller proteins (&bgr;2-microglobulin, immunoglobulin [Ig] light chains, retinol-binding protein, amino acids).
  • Overflow proteinuria: proximal tubular reabsorption overwhelmed by increased production of smaller proteins
  • Glomerular proteinuria
    • Primary glomerulonephropathy
      • Minimal-change disease
      • Idiopathic/primary membranous glomerulonephritis
      • Focal segmental glomerulonephritis
      • Membranoproliferative glomerulonephritis
      • IgA nephropathy
    • Secondary glomerulonephropathy
      • Diabetic nephropathy
      • Autoimmune/collagen vascular disorders (e.g., lupus nephritis, Goodpasture syndrome)
      • Amyloidosis
      • Preeclampsia
      • Infection (HIV, hepatitis B and C, poststreptococcal, endocarditis, syphilis, malaria)
      • Malignancy (GI, lung, lymphoma)
      • Renal transplant rejection
      • Structural (reflux nephropathy, polycystic kidney disease)
      • Drug-induced (NSAIDs, penicillamine, lithium, heavy metals, gold, heroin)
  • Tubular proteinuria
    • Hypertensive nephrosclerosis
    • Tubulointerstitial disease (uric acid nephropathy, hypersensitivity, interstitial nephritis, Fanconi syndrome, heavy metals, sickle cell disease, NSAIDs, antibiotics)
    • Acute tubular necrosis
  • Overflow proteinuria
    • Multiple myeloma (light chains; also tubulotoxic)
    • Hemoglobinuria
    • Myoglobinuria (in rhabdomyolysis)
    • Lysozyme (in acute monocytic leukemia)
  • Benign proteinuria
    • Functional (fever, exercise, cold exposure, stress, CHF)
    • Idiopathic transient
    • Orthostasis (postural)
RISK FACTORS
  • Hypertension
  • Diabetes
  • Obesity
  • Strenuous exercise
  • CHF
  • UTI
  • Fever
Genetics
No known genetic pattern
GENERAL PREVENTION
Control of weight, BP, and blood glucose reduces the risk of proteinuria.
COMMONLY ASSOCIATED CONDITIONS
  • Hypertension (common)
  • Diabetes mellitus (common)
  • Preeclampsia (common)
  • Multiple myeloma (rare)
image DIAGNOSIS
PHYSICAL EXAM
  • BP
  • Weight
  • Peripheral edema
  • Periorbital/facial edema
  • Ascites
  • Palpation of kidneys
  • Check lungs, heart for signs of CHF
DIFFERENTIAL DIAGNOSIS
Includes all causes listed under “Etiology and Pathophysiology”
DIAGNOSTIC TESTS & INTERPRETATION
Screening for proteinuria is not cost-effective unless directed at groups with hypertension/diabetes, older persons, and so forth.
Initial Tests (lab, imaging)
  • Urinalysis (UA) quantitatively estimates proteinuria:
    • Only sensitive to albumin; will not detect smaller proteins of overflow/tubular etiologies
    • False-positive finding if urine pH >7, highly concentrated (specific gravity [SG] >1.015), gross hematuria, mucus, semen, leukocytes, iodinated contrast agents, penicillin analogues, sulfonamide metabolites
    • False-negative finding if urine is dilute (SG 1.005), albumin excretion <20 to 30 mg/dL, protein is nonalbumin
    • Sensitivity, 32-46%; specificity, 97-100%
    • Also can perform sulfosalicylic acid test to detect nonalbumin protein
  • If UA positive, perform urine microscopy. Refer to nephrologist if positive for signs of glomerular disease.
  • If UA shows trace to 2+ protein, rule out transient proteinuria with repeat UA at another visit:
    • More common than persistent proteinuria
    • Causes include exercise, fever, CHF, UTI, and cold exposure
    • Reassure patient that transient proteinuria is benign and requires no further workup.
  • If initial UA shows 3+ to 4+ protein or repeat UA is positive, measure creatinine clearance and quantify proteinuria with 24-hour urine collection (gold standard) or spot urine protein-to-creatinine (P/C) ratio (acceptable practice) (1)[A]:
    • Numerical P/C ratios correlate with total protein excreted in grams per day (i.e., ratio of 0.2 correlates with 0.2 g during a 24-hour collection).
    • Patients age <30 years with 24-hour urine excretion of <2 g/day and normal creatinine clearance should be tested for orthostatic proteinuria:
      • Benign condition is present in 2-5% of adolescents.
      • Diagnosed with a normal urine P/C ratio in first morning void and an elevated urine P/C ratio in a second specimen taken after standing for several hours
  • If protein excretion >2 g/day, consider nephrology referral and begin workup for systemic/renal disease.
  • Patients with persistent proteinuria not explained by orthostatic changes should undergo renal ultrasound to rule out structural abnormalities (e.g., reflux nephropathy, polycystic kidney).
Follow-Up Tests & Special Considerations
Renal/systemic disease workup can include the following:
  • CBC, ferritin, ESR, serum iron
  • Electrolytes, LFTs
  • Lipid profile (ideally, fasting)
  • Prothrombin time/international normalized ratio
  • Anti-phospholipase A2 receptor antibody: positive in ˜70% of primary membranous nephropathy
  • Antinuclear antibodies: elevated in lupus
  • Antistreptolysin O titer: elevated after streptococcal glomerulonephritis
  • P.865

  • Complement C3/C4: low in most glomerulonephritis
  • HIV, syphilis, and hepatitis serologies: all associated with glomerular proteinuria
  • Serum and urine protein electrophoresis: abnormal in multiple myeloma
  • Blood glucose: elevated in diabetes
  • All patients with diabetes should be screened for microalbuminuria.
  • Patients with nephrotic-range proteinuria are at increased risk for hypercholesterolemia and thromboembolic events (˜25% of adult patients) with highest risk in membranous nephropathy. Optimal duration of prophylactic anticoagulation is unknown but may extend for the duration of the nephrotic state (2).
  • Proteinuric pregnant patients beyond 20 weeks' gestation should be examined for other signs/symptoms of preeclampsia (e.g., hypertension, thrombocytopenia, elevated liver transaminases).
image TREATMENT
  • BP goals for both diabetic and nondiabetic adults is ≤140/90 mm Hg (3)[C].
  • Proteinuria goal is <0.5 g/day (4)[A].
GENERAL MEASURES
  • Limit protein intake to 0.8 g/kg/day in adults with DM or without DM and glomerular filtration rate (GFR) <30 mL/min/1.73 m2. Soy protein may be renoprotective. Monitor protein intake with 24-hour urine urea excretion (4)[A].
  • Limit sodium chloride intake to <2 g/day to optimize antiproteinuric medications (3)[B]. Effect on BP is further protective (4)[A].
  • Limit fluid intake for urine output goal of <2 L/day. Larger urine volumes are associated with increased proteinuria and later GFR decline (4)[B].
  • Smoking cessation: Smoking is associated with increased proteinuria and faster kidney disease progression (4)[B].
  • Encourage supine posture (up to 50% reduction vs. upright) (4)[B].
  • Discourage severe exertion (4)[B].
  • Encourage weight loss (4)[B].
MEDICATION
First Line
  • ACE inhibitors: first choice; use maximally tolerated doses; use even if normotensive (4)[A]
  • Angiotensin receptor blockers (ARBs): proven antiproteinuric and renoprotective; ARBs are first choice if ACE inhibitors are not tolerated (4)[A].
  • Combination ACE inhibitor and ARB should not be used. Although shown to reduce proteinuria, combination does not reduce poor CV outcomes and does increase risk of adverse drug reactions (5)[A].
Second Line
  • &bgr;-Blockers: antiproteinuric and cardioprotective (4)[A]
  • Dihydropyridine calcium channel blockers (DHCCBs): should be avoided unless needed for BP control; not antiproteinuric (4)[A]
  • Non-DHCCB: antiproteinuric, may be renoprotective (4)[B]
  • Aldosterone antagonists: antiproteinuric independent of BP control (4)[B]
  • NSAIDs: antiproteinuric, but also nephrotoxic; generally should be avoided (4)[C]
ISSUES FOR REFERRAL
Consider nephrology referral for possible renal biopsy if
  • Impaired creatinine clearance
  • Nephrotic-range proteinuria
  • Unclear etiology of non-nephrotic-range proteinuria
  • Diabetics with microalbuminuria
COMPLEMENTARY & ALTERNATIVE MEDICINE
  • Corticosteroids: No proven benefit in mortality or need for renal replacement in adults with nephrotic syndrome, although steroids are recommended in some patients who do not respond to conservative treatment. Classically, children with nephrotic syndrome respond better than adults, especially those with minimal-change disease (6)[A].
  • Estrogen/progesterone replacement: may be renoprotective in premenopausal women but should be avoided in postmenopausal women (4)[B]
  • Antioxidant therapy: may be antiproteinuric in diabetic nephropathy (4)[C]
  • Sodium bicarbonate: not antiproteinuric but may block tubular injury caused by proteinuria; correcting metabolic acidosis may decrease protein catabolism (4)[C].
  • Avoid excessive caffeine consumption: antiproteinuric in diabetic rat models (4)[C]
  • Avoid iron overload (4)[C].
  • Pentoxifylline: prevents progression of renal disease by unclear mechanisms (4)[C]
  • Mycophenolate mofetil: antiproteinuric and renoprotective in animal models (4)[C]
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
All patients with persistent proteinuria should be followed with serial BP checks, UA, and renal function tests in the outpatient setting. Intervals depend on underlying etiology.
PROGNOSIS
  • Transient and orthostatic proteinuria are benign conditions that do not convey a poor prognosis.
  • Clinical significance of persistent proteinuria varies greatly and depends on underlying etiology.
  • Degree of proteinuria is associated with disease progression in chronic kidney disease.
  • Independent of GFR, higher levels of proteinuria likely convey an increased risk of mortality, myocardial infarction, and progression to kidney failure (7).
REFERENCES
1. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation classification, and stratification: guideline 5. Assessment of proteinuria. http://www2.kidney.org/professionals/KDOQI/guidelines_ckd/toc.htm.
2. Kerlin BA, Ayoob R, Smoyer WE. Epidemiology and pathophysiology of nephrotic syndrome-associated thromboembolic disease. Clin J Am Soc Nephrol. 2012;7(3):513-520.
3. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311(5):507-520.
4. Wilmer WA, Rovin BH, Hebert CJ, et al. Management of glomerular proteinuria: a commentary. J Am Soc Nephrol. 2003;14(12):3217-3232.
5. Fried LF, Emanuele N, Zhang JH, et al. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. 2013;369(20):1892-1903.
6. Kodner C. Nephrotic syndrome in adults: diagnosis and management. Am Fam Physician. 2009;80(10):1129-1134.
7. Tonelli M, Muntner P, Lloyd A, et al. Using proteinuria and estimated glomerular filtration rate to classify risk in patients with chronic kidney disease: a cohort study. Ann Intern Med. 2011;154(1):12-21.
Codes
&NA;
ICD10
  • R80.9 Proteinuria, unspecified
  • R80.2 Orthostatic proteinuria, unspecified
  • R80.1 Persistent proteinuria, unspecified
Clinical Pearls
&NA;
  • Transient and orthostatic proteinuria are benign conditions that do not convey a poor prognosis.
  • Proteinuria >2 g/day likely represents glomerular malfunction and warrants a nephrology consultation.
  • Clinical course varies greatly but, in general, the degree of proteinuria correlates with kidney disease progression.
  • First-line therapy for persistent proteinuric patients is a high-dose ACE inhibitor.