What are the treatment options for chronic rejection in kidney transplant recipients with glomerular changes?

Treatment of Chronic Rejection with Glomerular Changes in Kidney Transplant Recipients

For chronic antibody-mediated rejection (ABMR) with transplant glomerulopathy, treatment should include plasmapheresis with or without immunoadsorption, high-dose intravenous immunoglobulin (IVIG), rituximab, bortezomib, or eculizumab, used individually or in combination, though robust evidence for efficacy remains limited. 1

Understanding Chronic Rejection with Glomerular Changes

Chronic rejection manifesting as transplant glomerulopathy represents a major cause of late allograft loss, characterized by double contouring or multi-layering of the glomerular basement membrane resulting from repeated endothelial injury. 2, 1 This pathology occurs in 5-20% of transplant recipients in most series, reaching up to 55% in high-risk cohorts, and is associated with significantly worse allograft outcomes. 1

Pathophysiology and Risk Factors

• Antibody-mediated mechanism: Transplant glomerulopathy primarily results from chronic active ABMR triggered by donor-specific antibodies (DSAs) interacting with microvascular endothelial cells. 2, 1
• C4d deposition: Glomerular C4d deposits are found in the majority of cases (10/11 biopsies in one study), strongly suggesting in situ humoral rejection as the underlying mechanism. 3
• Key risk factors: Presensitization (panel reactive antibodies at transplantation, RR 1.23 per 10% increase) and late acute rejection episodes (RR 7.6) are independently associated with development of chronic transplant glomerulopathy. 3
• C1q-fixing DSAs: Persistence of C1q-binding DSAs at 3 and/or 6 months after ABMR diagnosis is associated with more severe chronic glomerulopathy, greater C4d deposition, and allograft loss. 4

Treatment Approaches

Immunosuppressive Interventions

Primary treatment modalities (adapted from desensitization protocols): 1

• Plasmapheresis with or without immunoadsorption to remove circulating antibodies
• High-dose IVIG to modulate antibody production and complement activation
• Rituximab (anti-CD20 monoclonal antibody) to deplete B cells
• Bortezomib (proteasome inhibitor) to target plasma cells
• Eculizumab (complement C5 inhibitor) specifically for C1q-fixing DSAs 4

Evidence for Specific Agents

• Eculizumab: Specifically abrogates the histomolecular rejection phenotype associated with C1q-fixing DSAs and decreases 3-month rejection incidence in patients with C1q-fixing DSAs, but not in those without. 4
• Post-treatment DSA monitoring: Patients without post-treatment C1q-fixing DSA demonstrate significantly improved glomerular filtration rate with reduced glomerulitis, peritubular capillaritis, and C4d deposition compared to those with persistent C1q-fixing DSA. 4

Maintenance Immunosuppression

Standard triple therapy: 5

• Mycophenolate mofetil (1-1.5 g twice daily) combined with calcineurin inhibitors and corticosteroids
• Corticosteroids should be maintained at approximately 10 mg daily after the first 6 months post-transplant 6
• Belatacept may be considered as an alternative to calcineurin inhibitors in EBV-seropositive patients for prophylaxis of rejection 6

Monitoring and Prognostic Assessment

• DSA MFI monitoring: Changes in DSA mean fluorescence intensity after ABMR treatment are incorporated into prognostic scoring systems (iBox) to predict allograft loss and inform therapeutic decisions. 4
• Serial biopsies: Kidney allograft biopsy is recommended when serum creatinine has not returned to baseline after treatment of acute rejection. 4
• Proteinuria surveillance: Monitor for new onset or unexplained proteinuria >3.0 g per gram creatinine as an indicator of glomerular injury. 4

Critical Limitations and Caveats

Major treatment gap: Despite the prevalence and clinical significance of transplant glomerulopathy, robust clinical trials evaluating treatment efficacy are urgently needed. 1 Current treatment recommendations are largely extrapolated from desensitization protocols and acute ABMR management rather than from controlled trials specifically addressing chronic glomerulopathy.

Diagnostic considerations: 2

• Chronic active ABMR and chronic active T cell-mediated rejection share overlapping histological features, potentially causing diagnostic confusion
• Molecular phenotyping and gene expression analysis may improve diagnostic accuracy in the future

Alternative etiologies: While chronic ABMR is the primary cause, hepatitis C infection, thrombotic microangiopathy, or other factors may also contribute to transplant glomerulopathy development and should be excluded. 1

Management of Failed Allografts

When chronic rejection progresses to graft failure with symptomatic complications: 4

• High-dose corticosteroids are the mainstay for symptomatic rejection of failed allografts, though most patients ultimately require surgical intervention
• Transplant nephrectomy should be considered for hemorrhage, unrelenting pain, malignancy, or persistent sepsis
• Renal artery embolization is an alternative with lower mortality (0.1% vs 4%) and morbidity compared to nephrectomy, though 20% require subsequent nephrectomy 4
• Timing considerations: Prophylactic nephrectomy should occur relatively soon after dialysis initiation while on maintenance immunosuppression to avoid acute rejection and minimize sensitization for future transplantation 4