Introduction

• Immune mediated renal damage can occur due to
  • Direct immune-mediated processes (anti GBM, FSGS, etc)
  • Systemic inflammatory/immune disorders
• Systemic autoantibody mediated injury
  • Circulating immune complex deposition
  • Monoclonal Ig deposition
  • Alternative complement pathway dysregulation

Classes of Immunosuppressive Drugs in Kidney Care

Alkylating Agents

• Cyclophosphamide (CYC) is the most commonly used alkylating agent in glomerular disease
• MOA: crosslinkage of DNA in active and inactive cells (especially T and B cells), leading to reductions in antibody production.
• Pharmacology:
  • Inactive prodrug
  • Oral formulations are well absorbed with >75% oral bioavailability
  • P450  metabolism to active metabolites
• Indicated in:
  • MCD
  • MN
  • ANCA associated vasculitis
  • Anti-GBM disease
  • Lupus nephritis
• Major adverse effects:
  • 
  • Malignancy: leukemia, bladder cancer

Anti-CD20 Therapy

• Rituximab (RTX) is the prototype here.
  • Monoclonal, chimeric IgG1 antibody
  • Leads to profound and prolonged elimination of peripheral B cells
  • Effects last 6-12 months typically
• Pharm:
  • Elimination half life of 3 weeks and persists in the circulation for 3-6 months
  • Not removed by dialysis, but yes with PLEX
• Note: suspect formation of human antichimeric Ab in patients with rapid B cell reconstitution or failure of depletion (more common in lupus)
• Indications: AAV. Off-lable: MN, MCD, Lupus nephritis, cryoglobulinemia
• Adverse effects:
  • Infusion reactions (hypersensitivity)
  • Late-onset neutropenia (neutrophils < 1 more than 1 month post last infusion with spontaneous recovery). Consider G-CSF if at high risk.
  • Hypogammaglobulinemia - 30% - associated with severe infections
  • Infections - mostly in the first year of therapy
    • PJP - particularly + risk
    • HBV reactivation - black box indication - patients need screening - ARV ppx 7 days prior initiation if HbSAg+ or HBCAb+. Avoid in active HBV infection. PPx duration is 1 year after cessation of RTX
    • PML - reactivation of JCV. Progressive neurologic deficits, unsteady gait, cognitive decline. MRI diagnosed.

Antimetabolites

• These lead to inhibition of nucleotide synthesis. Lymphocytes are particularly sensitive to these drugs given their dependence on de novo DNA synthesis for proliferation.
• MMF
  • Derived from Penicilliulm stoloniferum. Prodrug, converted to active mycophenolic acid. Oral bioavailability is 94%, half life is 18 hours. Hepatic hydrolytic metabolism.
  • Indications: lupus nephritis, MCD, FSGS, C3 glomerulopathies.
  • Monitoring: CBC 1-2 weeks post, and every 6-8 weeks
• AZA
  • Analogue of 6-MP. Purine analogue and interrupts the cell cycle, reduces IL2 secretion.
  • 16-50% bioavailability. Elimination half life is 2 hours, urinary mostly. Needs TPMT testing.
  • Avoid XOIs (allopurinol, febuxostat) with AZA. Increases accumulation of 6-MP.

Calcineurin Inhibitors

• CNIs bind CN-dependent signalling proteins and lead to T-cell inhibition. Both have immunosuppressive effects as well as podocyte stabilization effects.
• Both drugs have poor intestinal absorption, partial enzymatic metabolism in GI mucosa, and first-past hepatic metabolism. Both are metabolized via CYP3A system and have biliary excretion.
• Tacrolimus
  • Bioavailability variable (7-27%) with half-life 23 to 46 hours.
  • IR form - monitor with 12-hour trough level.
  • Dose changes are reflected in 2-3 days. Range of dose adjustment should be 0.5-1 mg per dose depending on trough.
• Cyclosporine
  • Bioavailability is 30-68%, half life 5-18 hours
  • Monitor with 12-hour trough level.
  • Dose changes are reflected in 2-3 days. Range of dose adjustment should be 23-50 mg per dose depending on trough.

Complement Inhibitors

• C5 inhibitors prevent the formation of the C5b-C9 MAC
• Eculizumab (C5 inhibitor)
• Ravulizumab (C5 inhibitor) has a 4x longer half-life then eculizumab.
• Adverse effects
  • Life-threatening meningococcal infections
  • Encapsulated organisms: Strep pneumo, N meningitis, HIB. Need vaccinations and prophylactic antibiotics against meningococcus.

References

1. Kant S, Kronbichler A, Geetha D. Principles of Immunosuppression in the Management of Kidney Disease: Core Curriculum 2022. American Journal of Kidney Diseases. 2022;80(3):393-405. doi:10.1053/j.ajkd.2021.12.011