Classification and Pathology of Nephrotic Syndrome
Definition and Diagnostic Criteria
Nephrotic syndrome is defined by heavy proteinuria (≥3.5 g/day in adults; ≥1.0 g/m²/day in children), hypoalbuminemia (<3.0 g/dL in adults; <2.5 g/dL in children), and edema, often accompanied by hyperlipidemia. 1, 2
- Nephrotic-range proteinuria can be confirmed with urine protein:creatinine ratio (PCR) >300-350 mg/mmol 3
- Patients typically present with periorbital edema (most noticeable in the morning) or dependent pitting edema (later in the day) 3
Classification Systems
Primary (Idiopathic) Nephrotic Syndrome
The classification of nephrotic syndrome divides cases into primary (idiopathic) and secondary forms, with primary cases representing the majority and requiring histopathologic subclassification. 1, 4
Minimal Change Disease (MCD)
- Characterized by normal-appearing glomeruli on light microscopy but diffuse podocyte foot process effacement on electron microscopy 2
- Most common cause in children and accounts for the majority of idiopathic nephrotic syndrome 5, 6
- Typically presents with selective proteinuria, absence of hematuria, and excellent response to steroids 5
- Long-term kidney survival is excellent in patients who respond to glucocorticoids 1
Focal Segmental Glomerulosclerosis (FSGS)
FSGS requires a novel four-category classification system that fundamentally changes diagnostic and treatment approaches: 1
Primary FSGS: Immunologically mediated, responsive to immunosuppression, characterized by proteinuria >3.5 g/day, serum albumin <3.0 g/dL, and diffuse podocyte foot-process effacement 1
Genetic FSGS: Includes familial, syndromic, and sporadic forms with disease-causing variants in type IV collagen or podocyte genes (found in 11-24% of steroid-resistant cases) 1
Secondary FSGS: Mediated by viral injury, medication-related injury, or adaptive changes (including reduced nephron number from prematurity) 1
FSGS of Undetermined Cause (FSGS-UC): Segmental foot process effacement with proteinuria but without nephrotic syndrome features or evidence of secondary causes 1, 2
- Workup for secondary causes should occur in patients with non-nephrotic-range proteinuria (<3.5 g/day) or with nephrotic-range proteinuria but albumin >3.0 g/dL 1
Membranous Nephropathy
- Most common cause of nephrotic syndrome in white adults 3, 4
- Has unequivocal proof of autoimmune mechanism with pathogenic autoantibodies targeting podocyte antigens 2
Secondary Nephrotic Syndrome
Secondary causes must be systematically excluded through patient history and targeted diagnostic studies: 4
- Diabetic nephropathy (most common multisystem disease causing nephrotic syndrome) 3
- Systemic lupus erythematosus 4
- Medication adverse effects 4
- Infections (hepatitis C, HIV) 1
- Amyloidosis 3
Congenital/Genetic Forms
- Caused by genetic defects in podocytes with common mutations including NPHS1, NPHS2, WT1, and PLCE1 2
- Includes congenital nephrotic syndrome of Finnish type and infantile mesangial sclerosis 5
Pathophysiology
Molecular Mechanisms
The primary pathophysiological mechanism involves increased glomerular permeability to proteins due to podocyte dysfunction. 2
- A T-cell-driven circulating "glomerular permeability factor" interferes with glomerular permselectivity to albumin in MCD and FSGS 2, 6
- Loss of albumin leads to decreased oncotic pressure, causing fluid shift from intravascular to interstitial spaces, resulting in edema 2
- Hyperlipidemia occurs as a compensatory mechanism for plasma protein loss 2
Pattern-Based Pathologic Classification
The Mayo Clinic/Renal Pathology Society consensus provides a standardized reporting format: 1
- Primary diagnosis: Specific glomerular disease entity
- Pattern of injury: Descriptive pattern (e.g., membranoproliferative, necrotizing and crescentic, mesangial proliferative) 1
- Score/grade: Disease-specific classification systems (e.g., Oxford classification for IgA nephropathy, ISN/RPS for lupus) 1
- Additional features: Global glomerulosclerosis percentage, tubular atrophy, interstitial fibrosis, vascular changes 1
Clinical Implications and Prognosis
Risk Stratification
Patients with nephrotic-range proteinuria >3.8 g/day have a 35% risk of end-stage renal disease within 2 years. 2
- Remission of proteinuria is the most significant predictor of renal survival in FSGS 2
- Steroid-responsiveness is of greater prognostic value than renal histology 6
Complications
Nephrotic syndrome carries significant thrombotic risk with 29% incidence of renal vein thrombosis and 17-28% incidence of pulmonary embolism due to loss of anticoagulant proteins. 2
- Increased susceptibility to infections due to loss of immunoglobulins and complement factors 2
- Acute kidney injury can occur as a complication 4
Diagnostic Algorithm
When to Perform Renal Biopsy
Renal biopsy should be performed in two specific circumstances: 5
When clinical symptoms suggest diffuse glomerular lesions (acute nephritic onset, moderate nephrotic syndrome, macroscopic hematuria, marked hypertension/renal insufficiency, poorly selective proteinuria, decreased plasma C3 levels) 5
When steroid resistance has been demonstrated 5
- In children up to 8 years with typical steroid-sensitive features, biopsy may be deferred as MCNS is most common 5
- Adults with nephrotic syndrome require biopsy confirmation as FSGS and membranous nephropathy are more common 1
Genetic Testing Indications
Genetic testing should be performed in: 1
- Patients with familial kidney disease or syndromic features 1
- Steroid-resistant FSGS cases 1
- Early-onset cases or those with family history 2
Clinical utility of genetic testing includes: 1
- Sparing patients from potentially toxic immunosuppression (genetic FSGS much less likely to respond) 1
- Predicting lower risk of disease recurrence after kidney transplantation 1
- Guiding enrollment in clinical trials for novel molecular therapies 1
- Identifying at-risk family members for early diagnosis and treatment 1