Nephrotic and Nephritic Syndrome Mechanisms and Treatment
Pathophysiological Mechanisms
- The primary pathophysiological mechanism of nephrotic syndrome involves increased glomerular permeability to proteins due to podocyte dysfunction, as noted by the American College of Physicians 1
- A T-cell-driven circulating "glomerular permeability factor" that interferes with glomerular permselectivity to albumin has been proposed in minimal change disease and focal segmental glomerulosclerosis (FSGS), according to the Kidney International 2, 1
- In membranous nephropathy, there is unequivocal proof of an autoimmune mechanism with pathogenic autoantibodies targeting podocyte antigens, as reported by the Kidney International 3, 1
- The loss of albumin leads to decreased oncotic pressure, causing fluid to shift from intravascular to interstitial spaces, resulting in edema, as explained by the Praxis Medical Insights 4
- Hyperlipidemia in nephrotic syndrome occurs as a compensatory mechanism for the loss of plasma proteins, as stated by the American Journal of Kidney Diseases 5
Clinical Manifestations and Treatment Implications
- Nephrotic syndrome is associated with a higher risk of thromboembolism (29% for renal vein thrombosis, 17-28% for pulmonary embolism) due to loss of anticoagulant proteins, as noted by the Kidney International 2, 4
- Patients with nephrotic-range proteinuria >3.8g/day have a 35% risk of end-stage renal disease within 2 years, according to the Kidney International 2, 1
- Treatment of nephrotic syndrome often targets immune mechanisms, particularly T-cell dysfunction, using calcineurin inhibitors like cyclosporin, as reported by the Kidney International 2
- Both syndromes require supportive care, including management of hypertension and proteinuria with RAAS inhibitors, as recommended by the American Journal of Kidney Diseases 5
- Thromboprophylaxis is more commonly needed in nephrotic syndrome due to the higher risk of thromboembolism, as stated by the American Journal of Kidney Diseases 5, 4
Nephrotic Syndrome: Genetic Factors and Complications
Genetic Factors
- Congenital nephrotic syndrome is primarily caused by genetic defects in podocytes, with common genetic mutations including NPHS1, NPHS2, WT1, and PLCE1, according to the National Kidney Foundation 6
Complications
- Infections are a significant complication, with increased susceptibility due to loss of immunoglobulins and complement factors, as reported by the American Society of Nephrology 6
- Genetic disorders, particularly in congenital nephrotic syndrome, play a crucial role in the development of the disease, as stated by the National Institute of Diabetes and Digestive and Kidney Diseases 6
Nephrotic Syndrome Causes and Treatment
Definition and Clinical Features
- Nephrotic syndrome is 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 7
Primary Causes
- Minimal Change Disease (MCD) is characterized by normal-appearing glomeruli on light microscopy but diffuse foot process effacement on electron microscopy 7
- Focal Segmental Glomerulosclerosis (FSGS) can be classified into primary FSGS, genetic FSGS, secondary FSGS, and FSGS of undetermined cause 8
- Primary FSGS is characterized by diffuse foot process effacement and nephrotic syndrome, often with sudden onset 8
Treatment Approaches
- For Minimal Change Disease, consider cyclosporin as an alternative to high-dose corticosteroids 9
- For Focal Segmental Glomerulosclerosis (FSGS), first-line therapy is prednisone 1 mg/kg/day (maximum 80 mg) or alternate-day dose of 2 mg/kg (maximum 120 mg) 8, 10
- For FSGS, continue high-dose corticosteroids for a minimum of 4 weeks up to 16 weeks as tolerated or until complete remission 8, 10
- For FSGS, taper corticosteroids slowly over 6 months after achieving complete remission 8, 10
- Genetic testing should be considered in early-onset cases or those with family history 10
- Remission of proteinuria is the most significant predictor of renal survival in FSGS 9
Dapagliflozin Use in FSGS
Introduction to FSGS Treatment
- The American Journal of Kidney Diseases recommends calcineurin inhibitors, rituximab, or mycophenolate as second-line therapies for steroid-resistant or steroid-dependent FSGS 11
Adjunctive Therapy in Established CKD
- For FSGS patients with eGFR ≥20 mL/min/1.73 m² and UACR ≥200 mg/g, SGLT2 inhibitors are recommended for kidney protection as part of comprehensive CKD management 12
- SGLT2 inhibitors should be used on top of maximally tolerated RAS inhibition, not as a replacement for disease-specific therapy 12
- SGLT2 inhibitors should be used on top of maximally tolerated RAS inhibition, not as a replacement for disease-specific therapy 13
Safety Considerations for SGLT2 Inhibitors
- Monitor for initial eGFR dip of 3-5 mL/min/1.73 m² in first 4 weeks, which is reversible and not an indication to discontinue 12
- Monitor for initial eGFR dip of 3-5 mL/min/1.73 m² in first 4 weeks, which is reversible and not an indication to discontinue 13
- Implement sick day rules: hold SGLT2 inhibitors during acute illness with nausea, vomiting, or diarrhea to prevent ketoacidosis 12
- Counsel on genital hygiene to prevent mycotic infections 12
- Reduce diuretic doses in patients at risk for hypovolemia before initiating SGLT2 inhibitors 12
Nephrotic Syndrome Causes and Mechanisms
Primary Causes
- Focal Segmental Glomerulosclerosis (FSGS) is one of the most common primary causes in adults and can be classified into four subclasses, according to the American Journal of Kidney Diseases 14, 15, 16
- Genetic testing is now recommended for patients with familial kidney disease, syndromic features, or steroid-resistant FSGS, representing a significant change from prior guidelines, as suggested by the American Journal of Kidney Diseases 14, 15, 16
Secondary Causes
- Other viral infections can trigger secondary glomerular disease, as reported in the American Journal of Kidney Diseases 16
- Drug-induced glomerular injury can manifest as secondary FSGS or membranous nephropathy, according to the American Journal of Kidney Diseases 16
Genetic Causes
- In adults with steroid-resistant nephrotic syndrome and FSGS on biopsy, 11-24% will have disease-causing variants primarily in type IV collagen or podocyte genes, as found in the American Journal of Kidney Diseases 14
- History of prematurity should be considered as a potential etiology for secondary FSGS due to reduced nephron number, as suggested by the American Journal of Kidney Diseases 14, 15, 16
Clinical Implications
- Failing to distinguish primary from secondary causes has critical treatment implications, since immunosuppression should not be used in secondary FSGS, as noted in the American Journal of Kidney Diseases 14
- Patients with proteinuria >3.8 g/day have a 35% risk of end-stage renal disease within 2 years, regardless of underlying histology, as reported in Kidney International 17
Focal Segmental Glomerulosclerosis Characterization
Clinical Classification and Prognosis
- FSGS accounts for 7-20% of nephrotic syndrome cases in children and a significantly higher percentage in adults, with prevalence as high as 80% among nephrotic patients in Afro-Caribbean populations 18
- Patients with persistent nephrotic syndrome have more than 50% risk of progressing to end-stage renal disease within 5-10 years if untreated, according to the Kidney International guidelines 18, 19