Pathophysiology/Etiology

• Classification by Mechanism:
  • Glomerular: Most common cause of pathologic proteinuria. Damage to the glomerular basement membrane (e.g., podocyte injury) increases permeability to proteins, especially albumin. Causes include diabetic nephropathy, glomerulonephritis (e.g., minimal change disease, FSGS, membranous nephropathy), and systemic diseases like SLE.
  • Tubular: Impaired reabsorption of normally filtered small proteins by damaged proximal tubules. Causes include acute tubular necrosis (ATN), interstitial nephritis, and drug toxicity (e.g., NSAIDs, aminoglycosides).
  • Overflow: Increased production of low-molecular-weight proteins overwhelms the reabsorptive capacity of the tubules. Classic example is Bence-Jones proteins in multiple myeloma.
• Classification by Duration:
  • Transient (Functional): Benign and temporary. Caused by stressors like fever, intense exercise, dehydration, seizures, or acute illness.
  • Orthostatic: Increased protein excretion when upright, which resolves when supine. Common in adolescents and benign.
  • Persistent: Present on repeated testing; indicates underlying pathology, most commonly glomerular disease.

Clinical Presentation

• Often asymptomatic and found incidentally on urinalysis.
• Frothy or foamy urine suggests significant proteinuria.
• Edema (periorbital, peripheral) due to hypoalbuminemia in nephrotic syndrome.
• Symptoms of underlying disease (e.g., rash in SLE, bone pain in multiple myeloma).
• Signs of Chronic Kidney Disease (CKD) in late stages (e.g., fatigue, HTN, nausea).

Diagnosis

• Urinalysis (Dipstick): Initial screening test; primarily detects albumin. Can have false positives (alkaline urine, gross hematuria) or negatives (dilute urine, non-albumin proteins).
• Urine Protein-to-Creatinine Ratio (UPCR) or Albumin-to-Creatinine Ratio (UACR): A spot urine test that estimates 24-hour protein excretion. Convenient and preferred for screening and monitoring. A UACR ≥30 mg/g is abnormal.
• 24-Hour Urine Collection: Gold standard for quantifying proteinuria but cumbersome.
  • Normal: <150 mg/day
  • Microalbuminuria (moderately increased): 30-300 mg/day.
  • Macroalbuminuria (severely increased/overt): >300 mg/day.
  • Nephrotic-range proteinuria: >3.5 g/day.
• Further Workup:
  • Microscopy: Look for cells, casts (e.g., muddy brown in ATN, RBC casts in glomerulonephritis), or oval fat bodies ("Maltese crosses") in nephrotic syndrome.
  • Blood tests: Serum creatinine/eGFR, albumin, lipids, glucose, electrolytes.
  • Serum/Urine Protein Electrophoresis (SPEP/UPEP): To detect monoclonal proteins (e.g., Bence-Jones) in suspected multiple myeloma.
  • Renal Biopsy: Considered for persistent, significant proteinuria (>1 g/day), especially with signs of active kidney disease, to determine specific etiology and guide therapy.

DDx (Differential Diagnosis)

• Transient Causes: Fever, exercise, dehydration, stress.
• Orthostatic Proteinuria: Especially in young, tall, thin individuals.
• Primary Renal Disease: Minimal change disease, FSGS, membranous nephropathy, IgA nephropathy.
• Systemic Disease with Renal Involvement: Diabetes mellitus (most common cause of CKD/proteinuria), HTN, SLE, amyloidosis, preeclampsia, vasculitis.
• Infections: UTI, HIV, Hepatitis B/C.
• Malignancy: Multiple myeloma, lymphoma.

Management/Treatment

• Treat the underlying cause: (e.g., glycemic control in DM, immunosuppressants for certain glomerulonephritides).
• Blood Pressure Control: Target BP is crucial, often <130/80 mmHg.
• RAAS Blockade: ACE inhibitors (e.g., lisinopril) or ARBs (e.g., losartan) are first-line agents to reduce proteinuria and slow CKD progression, even in normotensive patients. They decrease intraglomerular pressure.
• SGLT2 inhibitors (e.g., canagliflozin): Increasingly used in diabetic kidney disease and other CKDs to reduce proteinuria and protect the kidneys.
• Supportive Care for Nephrotic Syndrome:
  • Sodium and fluid restriction to manage edema.
  • Diuretics (loop diuretics like furosemide).
  • Statins for hyperlipidemia.

Key Associations/Complications

• Proteinuria is an independent risk factor for CKD progression and cardiovascular disease.
• Nephrotic Syndrome (>3.5g/day): Defined by massive proteinuria, hypoalbuminemia (<3.0 g/dL), edema, and hyperlipidemia.
• Complications of Nephrotic Syndrome:
  • Thromboembolism: Due to loss of anticoagulant proteins (e.g., Antithrombin III).
  • Infection: Due to loss of immunoglobulins.
  • Acute Kidney Injury (AKI).