What is Nephrotic Syndrome and How Does It Occur?
Nephrotic syndrome is a kidney disorder characterized 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, resulting from severe disruption of the glomerular filtration barrier that allows massive protein loss into the urine. 1, 2
Pathophysiological Mechanisms
The fundamental defect in nephrotic syndrome involves increased glomerular permeability to proteins due to podocyte dysfunction, which are the specialized cells that maintain the kidney's filtration barrier 2. The specific mechanisms vary by underlying cause:
Primary Mechanisms by Disease Type
In minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS), evidence suggests a T-cell-driven circulating "glomerular permeability factor" that disrupts the glomerular barrier's ability to retain albumin 1, 2. This represents an immune-mediated mechanism where lymphocytes produce substances that directly damage the filtration system 1.
In membranous nephropathy, there is definitive proof of an autoimmune mechanism where pathogenic autoantibodies target specific antigens on podocytes, directly attacking these critical cells 2.
In congenital nephrotic syndrome, genetic defects in podocytes are the primary cause, with common mutations including NPHS1, NPHS2, WT1, and PLCE1 2.
Cascade of Consequences
Once the glomerular barrier is compromised, a predictable sequence of events occurs:
- Massive albumin loss through the damaged filter leads to hypoalbuminemia 1, 3
- Decreased oncotic pressure causes fluid to shift from blood vessels into tissues, producing edema 2, 4
- Compensatory hyperlipidemia develops as the liver attempts to replace lost proteins by increasing synthesis of all proteins, including lipoproteins 1, 5
- Loss of other critical proteins including immunoglobulins, complement factors, anticoagulant proteins, and hormone-binding proteins creates vulnerability to multiple complications 2, 5
Clinical Presentation
Patients typically present with periorbital edema most noticeable in the morning or dependent pitting edema more common later in the day 4. The disease usually manifests suddenly, with edema being the major presenting symptom, though it may occasionally be discovered during routine urinalysis 6.
Age and Epidemiology
The disease may occur during the first year of life but usually starts between ages 2 and 7 years in children 6. Annual incidence is estimated at 1-4 per 100,000 children and 3 per 100,000 adults, varying with age, race, and geography 6, 5.
Histologic Variants
The three leading histologic variants are minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy, with relative frequencies varying considerably by age and ethnicity 1. In white adults, membranous nephropathy is most common, while in populations of African ancestry, FSGS predominates 4. In children, minimal change disease is the most common cause 4.
Serious Complications
Thromboembolism risk is markedly elevated, with 29% risk for renal vein thrombosis and 17-28% for pulmonary embolism due to loss of anticoagulant proteins 2. Patients are also at increased risk for infections, particularly pneumonia and peritonitis from Streptococcus pneumoniae, due to loss of immunoglobulins and complement factors 2, 6.
Patients with nephrotic-range proteinuria >3.8g/day have a 35% risk of progressing to end-stage renal disease within 2 years 2, making early recognition and treatment critical for preserving kidney function.
Additional Complications
Hypovolemia, deep-vein or arterial thromboses, acute kidney injury, and metabolic bone disease with micronutrient deficiencies can occur 6, 7. The liver's compensatory increase in protein synthesis is unselective, leading to abnormal levels of various binding proteins for ions, vitamins, hormones, and coagulation factors 5.
Common Pitfalls
Many agents and conditions have been associated with triggering nephrotic syndrome, including infectious diseases, drugs, allergies, vaccinations, and malignancies 6. Secondary causes like diabetic nephropathy (the most common multisystem disease causing nephrotic syndrome), systemic lupus erythematosus, and amyloidosis must be excluded 4.