Nephrotic Syndrome

Definition

1. Proteinuria >3.5 g/24 hours (nephrotic-range)
2. Hypoalbuminemia - serum albumin <3.5 g/dL (some sources use <2.5 g/dL as the threshold for clinically significant disease)
3. Hyperlipidemia - total cholesterol usually >180 mg/dL
4. Edema - often anasarca

Pathophysiology

Glomerular Filtration Barrier

• The glomerular basement membrane (GBM)
• Endothelial cells (fenestrated, covered by a glycocalyx)
• Epithelial cells (podocytes) - the foot processes with their slit diaphragms are the final barrier

Why Edema Develops - The Underfill vs. Overfill Debate

Etiology and Classification

Primary (Idiopathic) Causes

1. Minimal Change Disease (MCD)

• Epidemiology: Most common cause in children (70-90%); accounts for only ~15% of adult nephrotic syndrome
• Pathogenesis: Unknown, but T-cell-mediated dysfunction is suspected. Recent discovery of autoantibodies targeting the podocyte protein nephrin points to an autoimmune etiology in at least some cases. Associated with NSAIDs, lithium, thymoma, and Hodgkin lymphoma.
• Histology:
  • Light microscopy: No glomerular abnormalities ("minimal change"); tubules may show lipid droplet accumulation (hence the older term "lipoid nephrosis")
  • Immunofluorescence: No immune deposits
  • Electron microscopy: Diffuse, extensive foot process effacement across all capillary loops; no electron-dense deposits
• Treatment: Systemic corticosteroids (prednisone 1 mg/kg/day, max 80 mg, or alternate-day 2 mg/kg/day) with remission in >80% of adults. Relapses occur in ~40% by 1 year. Steroid-resistant or frequently relapsing cases: rituximab (1000 mg IV × 2), cyclosporine, tacrolimus, mycophenolate mofetil, or cyclophosphamide.
• Prognosis: Excellent. Most patients have relapses but maintain long-term kidney function. Progressive decline in kidney function should prompt re-biopsy to rule out FSGS. - Goldman-Cecil Medicine, p.1252

2. Focal Segmental Glomerulosclerosis (FSGS)

• Epidemiology: ~25% of adult nephrotic syndrome; most common cause of idiopathic nephrotic syndrome in Black Americans (APOL1 risk alleles increase susceptibility 10-20-fold)
• Classification: Primary (circulating podocyte permeability factor), Secondary (adaptive, drug/viral, maladaptive), Genetic (mutations in podocyte proteins: NPHS1/nephrin, NPHS2/podocin, ACTN4/α-actinin-4, TRPC6, INF2, collagen 4, APOL1)
• Secondary causes: HIV-associated nephropathy, parvovirus B19, COVID-19 (collapsing variant), heroin, pamidronate, sirolimus, obesity-related glomerulopathy, reduced nephron mass
• Histology:
  • Light microscopy: Focal (not all glomeruli) and segmental (not entire glomerulus) sclerosis. Five variants: cellular, tip, perihilar, collapsing, NOS
  • Electron microscopy: Varying degrees of foot process effacement - >80% diffuse effacement favors primary FSGS; <80% segmental effacement favors secondary FSGS
• Collapsing FSGS: Strongly associated with viral etiologies (HIV, SARS-CoV-2); presents with abrupt, severe nephrotic syndrome and rapid progression to ESKD
• Treatment: Primary FSGS - corticosteroids, calcineurin inhibitors, mycophenolate mofetil. Secondary FSGS - treat underlying cause; avoid unnecessary immunosuppression.
• Prognosis: Non-nephrotic-range proteinuria confers best outcomes. Persistent nephrotic syndrome or steroid resistance predicts progression to end-stage kidney disease (ESKD). - NKF Primer on Kidney Diseases, 8e, p.190-191

3. Membranous Nephropathy (MN)

• Epidemiology: Most common cause of adult nephrotic syndrome in whites; peak incidence in the 4th-5th decade; male:female ratio 2:1
• Pathogenesis: Autoantibody-mediated. Anti-phospholipase A2 receptor (PLA2R) antibodies are present in ~70% of primary MN. Other antigens include THSD7A (1-3%), NELL-1, EXT1/2, and Semaphorin 3B (Sema3B)
• Secondary causes: Autoimmunity (SLE), infections (hepatitis B), drugs (NSAIDs, penicillamine, gold), malignancies (typically solid tumors - colon, lung, breast cancer), paraproteinemias. EXT1/2-associated MN is linked to autoimmune disease.
• Histology:
  • Light microscopy: Thickened GBM with subepithelial "spikes" on methenamine silver stain (due to GBM growing around deposits)
  • Immunofluorescence: Granular deposition of IgG and C3 along capillary walls
  • Electron microscopy: Subepithelial and intramembranous electron-dense immune deposits; foot process effacement
• Treatment: One-third of patients undergo spontaneous remission, one-third partial remission. Immunosuppression (cyclophosphamide + steroids, rituximab, or calcineurin inhibitors) is indicated for persistent nephrotic syndrome or declining kidney function. PLA2R antibody titers guide response to therapy.
• Prognosis: The "rule of thirds" - 1/3 spontaneous remission, 1/3 persistent proteinuria, 1/3 progressive renal failure. Membranous nephropathy carries the highest thromboembolism risk among nephrotic causes. - NKF Primer on Kidney Diseases, 8e, p.192

Secondary Causes

Clinical Features

Symptoms

• Peripheral edema (often anasarca - generalized pitting edema), particularly periorbital on waking
• Fatigue
• Dyspnea (from pleural effusions or ascites)
• Foamy urine (due to proteinuria)

Physical Findings

• Hypertension
• Generalized dependent pitting edema
• Ascites
• Pleural effusions
• Muehrcke's lines: Paired white bands on fingernails due to hypoalbuminemia (transverse leukonychia)
• Eruptive xanthomata and xanthelasma (from hyperlipidemia)
• • Frameworks for Internal Medicine, p.464

Laboratory Investigations

Urine

• Proteinuria >3.5 g/24 hours (gold standard)
• Spot urine protein:creatinine ratio: A single untimed sample correlates with 24-hour protein excretion (value in g/g approximates g/day); practical and validated alternative
• Lipiduria: Oval fat bodies (tubular cells laden with lipid), free fat droplets, fatty casts with "Maltese cross" pattern under polarized light
• Microscopic hematuria may be present (especially in FSGS, MCD in adults)

Blood

• Hypoalbuminemia (<3.5 g/dL)
• Hyperlipidemia - elevated total cholesterol, LDL, VLDL, triglycerides (due to increased hepatic lipoprotein synthesis in response to low oncotic pressure)
• Serum creatinine: variable; may reflect intravascular volume depletion or true GFR reduction
• Complement levels (C3, C4): normal in primary nephrotic syndrome; reduced in SLE, MPGN, infection-related GN

Additional Work-Up

• ANA, anti-dsDNA (SLE)
• Anti-PLA2R antibody (membranous nephropathy - positive in ~70% of primary MN)
• Hepatitis B, C serologies
• HIV test
• Serum and urine protein electrophoresis (paraproteinemia/amyloidosis)
• Blood glucose/HbA1c (diabetic nephropathy)
• Renal biopsy - required for definitive diagnosis in adults (with exception of diabetic nephropathy with typical features and in children where MCD can be assumed and empirically treated)

Complications

1. Thromboembolism

• Loss in urine: Antithrombin III, proteins C and S, plasminogen (anticoagulant proteins)
• Increased hepatic production: Fibrinogen, factor V, factor VIII (procoagulant proteins)

2. Infection

• Loss of immunoglobulins (IgG) and opsonins in the urine → hypogammaglobulinemia → predisposition to bacterial infections (e.g., cellulitis, spontaneous bacterial peritonitis, pneumococcal infections)
• Loss of complement factor B may impair the alternate pathway
• Patients are particularly susceptible to encapsulated organisms (Streptococcus pneumoniae)

3. Acute Kidney Injury (AKI)

• Reduced effective circulating volume from hypoalbuminemia → prerenal AKI
• Interstitial edema compressing tubules
• Drug toxicity (nephrotoxic medications, diuretic-induced hypovolemia)

4. Hyperlipidemia

• Driven by increased hepatic synthesis of lipoproteins as a compensatory response to oncotic pressure loss
• Increased cardiovascular risk with prolonged nephrotic syndrome
• Urinary loss of HDL components accelerates atherogenesis

5. Nutritional Deficiencies

• Iron deficiency anemia: loss of transferrin in the urine
• Vitamin D deficiency: loss of vitamin D-binding protein → reduced 25-OH vitamin D → secondary hyperparathyroidism and bone disease
• Thyroid hormone loss: loss of thyroxine-binding globulin (may result in low total T4, but free T4 and TSH are usually normal)

Management

Non-Specific / Supportive Measures

• Low-salt diet to manage edema
• Protein-restricted diet (0.8-1 g/kg/day) - reduces proteinuria load but must balance against ongoing protein losses

• Loop diuretics (furosemide) are first-line; resistance is common in nephrotic syndrome because:
  • Furosemide is heavily protein-bound and its tubular secretion depends on albumin
  • Hypoalbuminemia reduces delivery of furosemide to its tubular site of action
  • A rational approach is to combine loop diuretics with ACE inhibitor/ARB to limit albuminuria
• Combination of IV albumin with furosemide may help in severe diuretic-resistant cases (though evidence is limited)

• ACE inhibitors or ARBs: Cornerstone of non-disease-specific management; reduce intraglomerular pressure, decrease proteinuria, and have additional benefits on coagulability, dyslipidemia, and progression of renal disease

• Statin therapy is recommended; reduces cardiovascular risk

• Anticoagulation (warfarin) for established thrombosis
• Prophylactic anticoagulation is recommended in membranous nephropathy with albumin <2.8 g/dL and low bleeding risk
• Data on direct oral anticoagulants (DOACs) in this setting are still insufficient - Goldman-Cecil Medicine, p.1252

• Pneumococcal vaccination
• Consider prophylactic penicillin in children with severe nephrotic syndrome

Disease-Specific Therapy

Nephrotic vs. Nephritic Syndrome (Key Distinction)

Prognosis

• MCD: Excellent; steroid-responsive in most cases; kidney function preserved long-term even with relapses
• FSGS: Variable; primary FSGS recurs post-transplant (supporting circulating factor hypothesis); secondary FSGS progresses slowly if underlying cause is addressed; collapsing FSGS has poor prognosis
• Membranous nephropathy: Rule of thirds (spontaneous remission, partial remission, progressive disease)
• Diabetic nephropathy: Progressive in absence of metabolic control; leading cause of ESKD

Summary

• National Kidneys Foundation Primer on Kidney Diseases, 8e - Chapters 16, 18, 19, 20
• Goldman-Cecil Medicine International Edition - Chapter 107
• Frameworks for Internal Medicine - Chapter 34
• Brenner and Rector's The Kidney, 2-Volume Set - Chapter 50