Overview:
- Proteinuria: presence of proteins in urine (albumin, globulin, Bence-Jones protein, mucoprotein)
- Common finding in outpatient and inpatient settings
- Warrants investigation, especially with comorbidities
- Increasing prevalence due to rising diabetes rates
- Primary cause: disturbance in kidney filter
- Associated with early renal disease and benign conditions
- Used with eGFR in CKD classification
- Indicator of early renal disease
- Increased risk of renal damage, hypertension, and cardiovascular disease
- Degree of proteinuria correlates with disease progression
Pathophysiology of Proteinuria
Overview:
- Proteinuria results from:
- Glomerular dysfunction
- Tubulointerstitial disease
- Secretory proteinuria
- Overflow proteinuria
1) Glomerular Dysfunction:
Glomerular Dysfunction:
- Most Common Cause: Glomerular dysfunction is the primary cause of significant proteinuria.
- Mechanism: Damage to the glomerular filtration barrier, composed of the fenestrated endothelium, glomerular basement membrane, and podocytes, leads to altered permeability. This results in proteins like albumin and immunoglobulins leaking into the urine.
- Basement Membrane: Restricts protein filtration due to type 4 collagen, which acts as a size and weight barrier. The negative charge on the capillary wall prevents negatively charged proteins (e.g., albumin) from passing through.
- Barrier Dysfunction: Damage to the size and charge barriers, increased hydrostatic pressure, mesangial cell growth, extracellular matrix production, and inflammatory cell infiltration contribute to proteinuria.
- Podocyte Injury: Dysfunction in podocyte proteins (nephrin and podocin) and the involvement of TRPC protein, which affects calcium influx, can lead to proteinuria. Klotho protein may suppress TRPC, offering potential therapeutic benefits.
Causes of Glomerular Dysfunction:
- Diabetic Nephropathy: Most common cause
- Drug-Induced Nephropathy: NSAIDs, lithium, heavy metals, heroin
- Lymphoma and Infections: HIV, hepatitis B and C
- Primary Glomerulonephropathies, Amyloidosis, Malignancies
- Dyslipidemia, Reactive Oxygen Species, Inflammatory Cytokines
- Activation of the Renin-Angiotensin System (RAS)
- Connective Tissue Diseases: Such as systemic lupus erythematosus (SLE)
Chronic Proteinuric Glomerulopathy:
- Definition: Sustained or permanent loss of protein filtration selectivity of the glomerulus.
Nephritic Syndrome:
Characteristics:
- Proteinuria: Mild to moderate (typically less than 3.5 g/24 hours)
- Hematuria: Presence of blood in urine
- Hypertension
- Oliguria: Reduced urine output
- Edema
- Reduced Glomerular Filtration Rate (GFR)
Mechanism:
- Inflammatory processes damage the glomerular capillaries, leading to hematuria and moderate proteinuria.
Causes:
- Post-Infectious Glomerulonephritis
- IgA Nephropathy
- Lupus Nephritis
- Membranoproliferative Glomerulonephritis
Nephrotic Syndrome:
Characteristics:
- Proteinuria: Severe (typically more than 3.5 g/24 hours)
- Hypoalbuminemia: Low levels of albumin in the blood
- Severe Edema
- Hyperlipidemia: High levels of lipids in the blood
- Lipiduria: Presence of lipids in the urine
Mechanism:
- Significant damage to the glomerular filtration barrier leads to massive protein loss in the urine.
Causes:
- Minimal Change Disease
- Focal Segmental Glomerulosclerosis (FSGS)
- Membranous Nephropathy
- Diabetic Nephropathy
- Amyloidosis
Key Correlations:
Proteinuria Levels:
- Nephritic Syndrome: Mild to moderate proteinuria (< 3.5 g/24 hours)
- Nephrotic Syndrome: Severe proteinuria (> 3.5 g/24 hours)
- Both indicate glomerular disease but differ in severity and associated clinical features.
Clinical Presentation:
- Nephritic Syndrome: Prominent hematuria, hypertension, and reduced GFR, with moderate proteinuria.
- Nephrotic Syndrome: Dominated by severe proteinuria, leading to significant hypoalbuminemia, edema, and hyperlipidemia.
Pathophysiology:
- Nephritic Syndrome: Involves inflammation and proliferative changes within the glomeruli, causing capillary damage and leakage of blood and proteins.
- Nephrotic Syndrome: Involves non-inflammatory glomerular damage, leading to significant protein leakage without substantial hematuria.
2) Tubulointerstitial Dysfunction:
- Dysfunction at the proximal tubule impairs uptake of filtered proteins
- Leads to less severe proteinuria (< 2 grams/24-hour)
Mechanism:
- Smaller, positively charged proteins reabsorbed by tubular epithelial cells, primarily in the proximal convoluted tubules
- Transport maximum of reabsorption can be exceeded, resulting in proteinuria
Causes of Tubular Dysfunction:
- Hypertensive nephrosclerosis
- NSAIDs induced nephropathy
- Nephrotoxins
- Chronic tubulointerstitial disease
3) Secretory Proteinuria
- Oversecretion of specific proteins in the tubules (e.g., Tamm-Horsfall proteins in interstitial nephritis)
4) Overflow Proteinuria:
- Increased protein production saturates reabsorptive channels in proximal convoluted tubules
- Occurs when plasma concentration of low-molecular-weight proteins exceeds tubular reabsorption capacity
Causes of Overflow Proteinuria:
- Multiple myeloma
- Myoglobinuria
- Amyloidosis
Evaluation of Proteinuria
Initial Steps:
- Exclude urinary tract infection and diabetes mellitus
- Use urine dipsticks as the first screening test (semi-quantitative and qualitative)
- Consider urine concentration (specific gravity) when interpreting dipstick results
- False positives:
- dehydration, UTI
- hematuria
- alkaline urine (pH > 8)
- recent exercise
- False negatives:
- overhydration
- positively charged proteins (e.g., light chains)
Urine Dipstick Diagnostic Pad:
- Contains tetra bromophenol blue and citrate buffers
- Changes color from yellow to blue based on protein’s electronegativity
- Some proteins (e.g., immunoglobulins) not detected due to positive charge; use sulfosalicylic acid (SSA) for detection
Quantification Methods:
- 24-Hour Urine Collection:
- Accurate but cumbersome
- Abnormal if protein excretion > 150 mg/24 hours
- Spot Urine Protein to Creatinine Ratio (UPCR):
- Preferably use early morning urine sample
- UPCR > 15 mg/mmol warrants further investigation
Additional Tests:
- Serum electrolytes, urea, and creatinine
- For nephrotic range proteinuria (> 3.5 g/24-hour or UPCR > 350 mg/mmol):
- Check serum albumin and cholesterol levels
Renal Function Evaluation:
- Creatinine clearance more informative than serum creatinine levels
- Use equations like MDRD, CKD-EPI, and Cockcroft-Gault formula
Creatinine Clearance Calculation: Creatinine clearance (ml/min)=(140−age)×weight (kg)×𝐶serum creatinine (μmol/L)Creatinine clearance (ml/min)=serum creatinine (μmol/L)(140−age)×weight (kg)×C
- C = 1.23 for males, 1.04 for females
- Normal for healthy young adults: > 90 ml/min
- Consider age and muscle mass changes
Imaging and Other Diagnostic Tests:
- Renal ultrasonography
- Immunology screen (ANA, ANCA)
- Viral screen (hepatitis B and C)
Degrees of Proteinuria:
- Normal: < 150 mg/24 hour or < 15 mg/mmol
- Nephritic: 150-3000 mg/24 hour or 12-300 mg/mmol
- Nephrotic: > 3500 mg/24 hour or > 350 mg/mmol
Albuminuria (mg/day):
- Normal: < 30
- Microalbuminuria: 30-300
- Macroalbuminuria: > 300
Other Tests:
- Autoantibodies (e.g., antistreptolysin O, ANA, anti-DNA, complement levels, anti-phospholipase A1 receptor autoantibody, cryoglobulins)
- Hepatitis B and C, HIV serologies
- Urine and plasma protein electrophoresis for light chains
- Anti-GBM antibodies and ANCA
Imaging Studies:
- Renal ultrasonography (size and echogenicity of kidneys)
- Chest radiography or computed tomography (if indicated)
Benign Causes of Proteinuria
Proteinuria can sometimes occur in the absence of significant kidney disease or systemic illness. These benign causes of proteinuria are typically transient and do not indicate serious underlying pathology. Here are some common benign causes:
- Orthostatic (Postural) Proteinuria:
- Description: Proteinuria that occurs when a person is standing but disappears when lying down.
- Mechanism: Increased pressure in the renal veins when upright can lead to mild protein leakage.
- Population: Common in adolescents and young adults.
- Exercise-Induced Proteinuria:
- Description: Proteinuria that occurs after strenuous physical activity.
- Mechanism: Increased glomerular permeability due to physical stress and increased blood flow to the kidneys.
- Resolution: Typically resolves within a few hours after stopping exercise.
- Febrile Proteinuria:
- Description: Proteinuria associated with fever.
- Mechanism: Increased metabolic rate and stress on the kidneys during febrile illnesses can cause transient protein leakage.
- Resolution: Resolves with the resolution of the fever.
- Dehydration:
- Description: Proteinuria can occur during periods of dehydration.
- Mechanism: Reduced plasma volume and increased concentration of proteins in the urine.
- Resolution: Resolves with adequate hydration.
- Emotional Stress:
- Description: Proteinuria that occurs during periods of significant emotional stress or anxiety.
- Mechanism: Stress-induced changes in kidney function and increased permeability of the glomerular membrane.
- Resolution: Typically resolves once the stressor is removed.
- Cold Exposure:
- Description: Proteinuria can be induced by exposure to cold temperatures.
- Mechanism: Vasoconstriction and increased glomerular permeability due to cold stress.
- Resolution: Resolves once the individual is warmed.
- Menstrual Cycle:
- Description: Some women may experience transient proteinuria related to their menstrual cycle.
- Mechanism: Hormonal fluctuations can affect renal hemodynamics and glomerular permeability.
- Resolution: Typically resolves after the menstrual period.
- Transient Proteinuria in Healthy Individuals:
- Description: Occasional, unexplained proteinuria in otherwise healthy individuals.
- Mechanism: Unknown, but thought to be related to minor, temporary changes in renal function.
- Resolution: Typically resolves on repeat testing without any intervention.