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Nephrotic Syndrome

BASICS

Description

  • Constellation of clinical/lab findings:
  • Massive proteinuria (>3.5 g/1.73 m²/24hr)
  • Hypoalbuminemia (<3 g/dL)
  • Severe hyperlipidemia (total cholesterol often >380 mg/dL)
  • Peripheral edema
  • Increased risk of thrombotic disease
  • Can be due to intrinsic renal disease or secondary to infections, diabetes, SLE, neoplasia, drugs
  • Associated with many kidney diseases

EPIDEMIOLOGY

  • Children:
  • Minimal change disease (MCD) most common (<10 yrs, 90%)
  • Adults:
  • Membranous nephropathy: most common primary (40%)
  • Focal segmental glomerulosclerosis (FSGS): 35%; common in African Americans
  • Amyloidosis: 4–17% of idiopathic cases
  • Lupus nephropathy: women > men (10:1)
  • Membranoproliferative GN: often in systemic viral or rheumatic illness
  • Incidence:
  • Adults: ~3/100,000/yr
  • Children: 2–7/100,000 (<18 yrs), higher in African American/Hispanic

ETIOLOGY AND PATHOPHYSIOLOGY

  • Mechanism:
  • Increased glomerular permeability → protein loss (esp. albumin)
  • Edema: renal salt retention + low plasma oncotic pressure
  • Hypercoagulability: loss of antithrombin III in urine
  • Types:
  • Primary (MCD, FSGS, MGN, IgA nephropathy)
  • Secondary (diabetic nephropathy, amyloidosis, paraproteinemia)
  • Genetics:
  • Podocyte gene mutations in familial nephrotic syndrome

RISK FACTORS

  • Drug addiction (heroin—FSGS)
  • Hepatitis B/C, HIV, CMV, parvovirus B19, toxoplasmosis
  • Nephrotoxic drugs (NSAIDs, lithium, gold, penicillamine, bisphosphonates)
  • Immunosuppression
  • Cancer (esp. MGN, MCD)
  • Chronic NSAID use
  • Diabetes mellitus
  • Preeclampsia

GENERAL PREVENTION

  • Avoid causative meds (NSAIDs, gold, penicillamine, captopril)
  • Avoid heroin abuse, high-risk sexual behaviors
  • Tight glycemic control

DIAGNOSIS

History

  • Edema, weight gain, abdominal/fluid shift, puffy eyelids, scrotal swelling, SOB
  • Foamy/frothy urine, oliguria
  • Joint/rash/systemic Sx (SLE), infections, fever
  • Drug history, prior venous thromboembolism

Physical Exam

  • Peripheral edema, ascites, pleural effusion
  • Pericardial rub, decreased breath sounds (pleural effusion)
  • 25% have arterial hypertension
  • Macroscopic hematuria rare; microscopic hematuria in 20%

Alert: Watch for thromboembolic disease (e.g., PE), a life-threatening complication.

Differential Diagnosis

  • Edema/proteinuria: see causes above
  • Edema only: CHF, cirrhosis, hypothyroid, hypoalbuminemia, protein-losing enteropathy

Diagnostic Tests

  • Initial:
  • Urine dipstick (3+ or 4+), 24-hr urine or spot urine protein:creatinine ratio
  • CBC, coagulation, renal function, glucose, albumin, lipid panel, LFTs
  • ANA/dsDNA (SLE), complement (C3/C4), SPEP/UPEP (paraproteinemia)
  • Hepatitis B/C, HIV, syphilis serology
  • Renal US (shape, size), CXR (effusion/infection), Doppler US (DVT if suspected)
  • Follow-up:
  • Genetic testing (NPHS1, NPHS2) in infants/steroid-resistant children
  • Other:
  • Renal biopsy (adults or atypical pediatric cases)
  • Contraindicated if: small kidneys, tumor/cysts, infection, severe HTN, bleeding, uncooperative
  • Interpretation:
  • Light microscopy: sclerosis (FSGS), diabetic nodules, mesangial hypercellularity (proliferative GN)
  • IF: mesangial IgA (IgA nephropathy/HSP), other specific patterns

TREATMENT

  • General:
  • Monitor weight, BP, urine output, height in children
  • Edema:
  • Salt restriction (<2–3 g/day Na)
  • Fluid restriction if hyponatremic (<1.5 L/day)
  • Salt-wasting diuretics (loop/thiazide)
  • Target weight loss: 0.5–1 kg/day (1–2 lb/day)
  • Hyperlipidemia:
  • Usually resolves with syndrome control
  • Statins improve endothelial function, reduce proteinuria (except rosuvastatin—can worsen proteinuria)
  • Proteinuria:
  • ACE inhibitor or ARB (reduce proteinuria/progression, control HTN)
  • Protein restriction (benefit unclear)
  • Steroids for responsive cases (MCD, FSGS—consult nephrology)
  • Second line:
  • Immunosuppressives (cyclophosphamide, MMF, chlorambucil, cyclosporine) for resistant/relapsing cases
  • Rituximab, abatacept (refractory cases)
  • Anticoagulation (heparin/warfarin) if persistent nephrotic-range proteinuria, high risk/previous thrombosis
  • Corticotropin injection (for steroid-resistant)
  • Vitamin D supplement for hypocalcemia

Other

  • Ambulation, range-of-motion to reduce DVT risk
  • Admission criteria: respiratory distress, sepsis, thrombosis, renal failure, hypertensive crisis

ONGOING CARE

  • Adjust diuretics/ACEi/ARB as per edema/proteinuria
  • Monitor for relapse, progression, toxicity
  • Routine immunizations: defer until remission/off immunosuppression x 3 months

Diet

  • Normal protein (1 g/kg/day), low fat/cholesterol, low sodium (<2 g/day), vitamin D/iron supplements
  • Fluid restriction if hyponatremic

Patient Education

PROGNOSIS

  • Children (MCD): self-limited, good prognosis
  • Treatable causes (infection, drug, malignancy): complete remission possible
  • Aggressive forms (diabetic GN, FSGS): risk of progression to dialysis
  • Relapsing/remitting course possible

COMPLICATIONS

  • DVT/PE, renal/central venous thrombosis
  • Pleural effusion, ascites
  • Hyperlipidemia, CVD
  • Acute or progressive renal failure
  • Protein malnutrition/muscle wasting

ICD-10 CODES

  • N04.0 Nephrotic syndrome with minor glomerular abnormality
  • N04 Nephrotic syndrome (unspecified)
  • N04.3 Nephrotic syndrome with diffuse mesangial proliferative GN

Clinical Pearls

  • Classic tetrad: >3.5 g/day proteinuria, hypoalbuminemia, hyperlipidemia, edema
  • Most pediatric cases respond to steroids and have a good prognosis
  • Nondiabetic adults: always require renal biopsy to determine cause
  • Maintain high suspicion for embolic events