Universal Supportive Care (All Diseases)

Blood Pressure Control: - Target <130/80 mmHg for all patients with glomerular disease - More aggressive targets for significant proteinuria - Use RAAS blockers (ACE inhibitors or ARBs) as foundation

RAAS Blockade (Angiotensin System Inhibition): - First-line for virtually all glomerular diseases - Reduces proteinuria 30-50% through hemodynamic and anti-inflammatory mechanisms - Provides kidney protection through non-immunologic pathways - Maximize dose to highest tolerated level

Lifestyle Modifications: - Sodium restriction (<2 g/day) reduces edema and blood pressure - Protein restriction (0.8 g/kg/day) in CKD, modest reduction in primary GN - Lipid management with statins - Weight loss when overweight

Anticoagulation in Nephrotic Syndrome: - Risk of venous/arterial thromboembolism elevated - Membranous nephropathy and FSGS highest risk - Screen for clinical indicators; anticoagulate if risk substantial

Minimal Change Disease (MCD)

First-Line Therapy: - Corticosteroids (all patients) - Prednisone 1 mg/kg/day (maximum 80 mg) or 2 mg/kg every other day - Maintain high dose minimum 4 weeks, maximum 16 weeks - Taper slowly over 6+ months after complete remission achieved - Expected response: 85-95% complete remission rate

Frequently Relapsing/Steroid-Dependent MCD: - Cyclophosphamide (KDIGO first-line) - Oral 1-2 mg/kg/day for 8-12 weeks - Remission rate 80% with <10% relapse at 1 year - Alternative: CNI monotherapy often requires long-term therapy

• Calcineurin Inhibitors
  • Cyclosporine or tacrolimus as alternative to cyclophosphamide
  • Remission rates 70-80%
  • Relapse frequent during tapering
• Mycophenolate Mofetil (MMF)
  • Emerging option for patients with cyclophosphamide failure
  • 1,200 mg/m²/day divided doses
  • Effective even in cyclophosphamide-refractory disease
• Rituximab
  • Anti-B cell antibody
  • Steroid-sparing benefit in pediatric population
  • Increasingly used in adults

Focal Segmental Glomerulosclerosis (FSGS)

Primary FSGS - Initial Treatment: - Corticosteroids (first-line) - Prednisone 1 mg/kg/day (maximum 80 mg) - Duration 8-16 weeks to determine response - 40-50% achieve remission with steroids

Steroid-Resistant FSGS (KDIGO 2021):

• Calcineurin Inhibitors (first-line)
  • Cyclosporine: 5-10 mg/kg/day targeting trough 125-175 ng/mL
  • Tacrolimus: 0.1-0.2 mg/kg/day divided doses
  • Tacrolimus particularly effective: 81% complete remission in SRNS
  • CNI + low-dose steroid reduces corticosteroid exposure
• Mycophenolate Mofetil
  • Alternative for CNI-intolerant patients
  • Complete/partial remission reduction 67% in SRNS
  • Less effective than CNI monotherapy
• Sirolimus
  • mTOR inhibitor
  • Reduces proteinuria and glomerular pore size in SRNS
  • Limited experience; reserve for specific scenarios
• Rituximab
  • Emerging data for steroid-resistant FSGS
  • May be particularly effective for certain FSGS subtypes

Secondary FSGS: - Treat underlying cause (HIV, obesity, remove nephrotoxin) - Immunosuppression generally ineffective - RAAS blockade foundation of therapy

Membranous Nephropathy

Diagnosis and Risk Stratification: - Anti-PLA2R antibody testing: Positive in 70-80% of primary MN - Risk categories determine treatment intensity

Low-Risk Patients: - Normal eGFR, proteinuria <3.5 g/dL, albumin >30 g/L - Conservative therapy: RAAS blockade, lipid management - Monitor; 30% achieve spontaneous remission

Moderate-Risk Patients: - Can receive symptomatic therapy (RAAS blockade, edema control) - OR rituximab OR calcineurin inhibitors

High/Very High-Risk Patients: - Proteinuria >4 g/day, declining eGFR, high anti-PLA2R titers - Require immunosuppressive treatment

Treatment Options:

• Rituximab (KDIGO first-line)
  • Superior in maintaining remission (60% vs. 20% with cyclophosphamide at 24 months)
  • Fewer adverse events
  • Re-treatment if failing to attain immunological remission at 3 months
• Modified Ponticelli Regimen (Cyclophosphamide + Steroids)
  • Alternating months of IV methylprednisolone + oral cyclophosphamide
  • Proven effective over decades
  • Immunological response faster at 6 months but comparable by 24 months
• Calcineurin Inhibitors
  • Cyclosporine 3-5 mg/kg/day targeting trough 125-175 ng/mL
  • Higher relapse rates compared to other treatments

IgA Nephropathy

Proteinuria <0.5 g/day: - RAAS blockade alone

Proteinuria 0.5-1 g/day: - RAAS blockade + consider steroids

Proteinuria >1 g/day Despite RAAS Blockade: - TARPEYO (targeted-release budesonide) indicated - Delivers therapy to Peyer’s patches - 27% proteinuria reduction, 50% eGFR decline reduction

Progressive Disease or High-Risk Features: - Sparsentan (dual endothelin/ARB antagonist) - 49.8% vs. 15.1% proteinuria reduction vs. irbesartan - Indicated for high-risk patients

• Mycophenolate mofetil for rapid progression

• Cyclophosphamide reserved for rapidly progressive disease

ANCA-Associated Vasculitis (AAV)

Induction Therapy (Remission Induction):

Non-Severe Disease: - Rituximab or mycophenolate mofetil + corticosteroids

Severe/Organ-Threatening Disease: - Cyclophosphamide or rituximab + high-dose corticosteroids - IV methylprednisolone 0.5-1 g/day × 3 days - Oral prednisone 1 mg/kg/day tapered

Life-Threatening Disease (Pulmonary Hemorrhage): - Above therapy PLUS plasma exchange (7-14 days) - Cyclophosphamide dosing: IV 15 mg/kg every 2 weeks or daily oral 1.5-2 mg/kg

Avacopan (C5a Receptor Antagonist): - FDA approved 2021 for severe active ANCA-associated vasculitis - Complement C5a receptor antagonist - Used as adjunctive therapy with standard immunosuppression

Maintenance Therapy (≥18-24 months): - Azathioprine 2 mg/kg/day OR - Mycophenolate mofetil 1 g twice daily OR - Rituximab 500 mg every 6 months - Low-dose prednisone (goal <7.5 mg/day)

Lupus Nephritis

Class I-II: - Conservative management - Hydroxychloroquine (all patients)

Class III-IV (Proliferative):

Induction Therapy (3-6 months): - Option A (MMF-preferred): - Mycophenolate mofetil 1-3 g/day - Corticosteroids (tapered to lowest effective dose) - 50-60% remission rate

• Option B (Cyclophosphamide):
  • IV 500-1000 mg/m² × 6 pulses monthly
  • Indicated for crescentic or rapidly progressive disease
  • Proven effective but more toxicity than MMF
• Belimumab (Anti-BLyS):
  • Added to standard induction
  • First biologic approved for lupus nephritis
• Obinutuzumab (Anti-CD20):
  • Potent B-cell depletion
  • FDA approval pending; shows benefit especially in high-proteinuria patients

Maintenance (≥2-3 years): - Mycophenolate mofetil or azathioprine - Low-dose prednisone (goal <7.5 mg/day)

All patients: - Hydroxychloroquine 200-400 mg daily (reduces flares, mortality benefit)

Class V (Membranous): - Calcineurin inhibitors or mycophenolate mofetil - Low-dose steroids

Anti-GBM Disease (Goodpasture Syndrome)

Urgent Treatment (Medical Emergency):

• Plasma Exchange: 7-14 days or until anti-GBM antibodies undetectable
  • Essential for antibody removal
  • Most effective if initiated before serum Cr >5.7 mg/dL
• Immunosuppression:
  • IV methylprednisolone 1 g daily × 3 days
  • Oral prednisone 1 mg/kg/day
  • Cyclophosphamide 2 mg/kg/day (oral)

Prognosis: 90% patient survival with treatment; renal recovery depends on initial severity

Corticosteroids

Mechanism: - Glucocorticoid receptor-mediated gene transcription - Induces apoptosis through BIM expression - NF-κB inhibition - Anti-inflammatory cytokine effects

Dosing Principles: - Use lowest effective dose - Taper slowly after remission - Prolonged therapy increases infection risk, osteoporosis

Key Monitoring: - Blood glucose (hyperglycemia) - Bone density (osteoporosis prevention) - Infection risk - Psychological effects

Calcineurin Inhibitors (CNI)

Mechanism: - Bind calcineurin phosphatase - Prevent NFAT dephosphorylation - Block T-cell activation and IL-2 production

Specific Agents: - Cyclosporine: Monitor trough levels (125-175 ng/mL for GN) - Tacrolimus: Monitor trough levels (5-10 ng/mL for GN)

Key Advantages: - Rapid onset of action - Effective for steroid-resistant disease

Key Toxicities: - Nephrotoxicity (can worsen renal function) - Hypertension - Hyperglycemia - Drug interactions (CYP3A4) - Tremor, gingival hyperplasia (cyclosporine)

Antiproliferative Agents

Alkylating Agents

B-Cell Depleting Agents

Complement Inhibitors

Pregnancy

General Principles: - Avoid teratogenic agents: mycophenolate, calcineurin inhibitors (controversial), some biologics - Compatible agents: corticosteroids, azathioprine, rituximab, cyclophosphamide (with caution) - ACE-I/ARB contraindicated; switch at conception

Renal Impairment

Dose Adjustments: - Mycophenolate: Reduce in eGFR <25 - Cyclophosphamide: Reduce in significant renal impairment - CNI: Monitor levels closely, nephrotoxicity concern - Most biologics: No dose adjustment needed

Infection Risk Populations

• Baseline CD4 <200: Avoid intensive immunosuppression if possible
• Prior tuberculosis: Vigilant monitoring during anti-TNF therapy
• Hepatitis B: Risk of reactivation with B-cell depletion

Clinical Response Markers

Complete Remission: - Proteinuria <0.3 g/day (or <300 mg/day) - Normal serum creatinine

Partial Remission: - ≥50% reduction in proteinuria - Stable or improved serum creatinine

No Response: - <50% proteinuria reduction or increasing creatinine

Laboratory Monitoring Timeline

Baseline (Before Therapy): - 24-hour urine protein or UPCR - Serum creatinine, BUN, electrolytes - CBC, LFTs - Serologies as indicated

During Induction (First 3-6 months): - Monthly: Serum creatinine, CBC (if cyclophosphamide/MMF) - 3 months: 24-hour urine protein or UPCR - Drug levels (CNI if used)

Maintenance Phase: - 3-6 months: Creatinine, urine protein - Quarterly: CBC if on mycophenolate - Annual: Comprehensive metabolic panel, lipids

Related Student Handouts

• Nephritic and Nephrotic Syndromes
• Lupus Nephritis
• IgA Nephropathy
• FSGS
• Vasculitis and Complement-Mediated Diseases
• Immunosuppressive Therapy in Nephrology
• Kidney Biopsy Essentials

Clinical Content (01-Clinical-Medicine/Nephrology)

• Glomerular Diseases Hub
• Essential Renal Laboratory Tests

Butler-COM Resources

• Butler COM - Nephrology Deep Dive