A 40-year-old male patient with a pretransplant calculated panel reactive antibody of 0 and no prior sensitizing events developed mixed active antibody-mediated rejection and acute cellular rejection (Banff grade 1A) 1.5 years posttransplant. Testing for donor-specific antibody or non-human leukocyte antigen antibody (major histocompatibility complex class I chain-related antigen A/angiotensin II type I receptor) was negative. Biopsy demonstrated diffuse C4d staining in peritubular capillaries. The patient was treated with standard of care, including plasmapheresis and intravenous immunoglobulin along with steroids, with return of renal function to baseline. However, 1 year after treatment, he developed chronic active antibody-mediated rejection without any donor-specific antibodies. We believe he did have smoldering antibody-mediated rejection that had progressed to a more chronic state over time. He was then treated with tocilizumab and had a successful return of serum creatinine to baseline. One year after treatment, he still has stable renal function, suggesting a role of tocilizumab in stabilizing renal function in patients with chronic active antibody-mediated rejection for which there is no Food and Drug Administration-approved treatment.
Key words : AlloSure, Anti-interleukin-6 receptor antibody, Tocilizumab
A 40-year-old male with end-stage renal disease secondary to Fabry’s disease received a deceased donor kidney transplant in January 2017. His pretransplant calculated panel reactive antibody was 0, and he received a 5-antigen mismatch kidney. T-cell and B-cell crossmatch was negative. He had no previous sensitizing events. Transplant was uneventful, and he achieved a posttransplant baseline serum creatinine level of 1.1 mg/dL. He developed cytomegalovirus (CMV) viremia in the first year posttransplant, which was treated with valganciclovir and resolved without complications. In June 2018, 1.5 years after transplant, he had an elevation of serum creatinine to 1.4 mg/dL, which prompted donor-derived cell-free DNA (AlloSure, CareDx) testing, which was 9.4%. Renal allograft biopsy was then performed, which demonstrated active antibody-mediated rejection (AMR) with glomerulitis, peritubular capillaritis, and diffuse C4d staining in peritubular capillaries, along with acute cell-mediated rejection, tubulointerstitial type, Banff grade 1A (Figure 1). Donor-specific antibody (DSA) testing was negative, and non-human leukocyte antigen (HLA), major histocompatibility complex class I chain-related antigens A (MICA), and angiotensin II type I receptor (AT1R) antibodies were negative as well. He was treated with standard of care including intravenous immunoglobulin (IVIG) 1.5 g/kg, plasmapheresis (therapeutic plasma exchange [TPE]) ×5 cycles, and solumedrol 1 g. Four weeks after treatment, serum creatinine level returned to a baseline value of 1.1 mg/dL.
In July 2019, 1 year after treatment of the initial episode of AMR, serum creatinine level went up again to 1.4 mg/dL. Allograft biopsy was performed, which revealed focal glomerulitis, peritubular capillaritis, early transplant glomerulopathy, and chronic transplant arteriopathy; C4d staining was negative in peritubular capillaries (Figure 2). The biopsy was diagnostic for chronic AMR and highly suspicious for active AMR but did not meet Banff criteria for active disease due to negative results for DSA, MICA, and AT1R antibody testing. He was treated with IVIG 1.5 g/kg, TPE ×5 cycles, and tocilizumab 8 mg/kg (5 doses intravenously) at 1-month intervals. Tocilizumab was discontinued following the fifth dose due to hyperbilirubinemia that subsequently resolved. Four weeks after treatment, serum creatinine level was down to 1.2 mg/dL.
He is now 3.5 years posttransplant and has stable renal function with a serum creatinine level of 1.0 mg/dL.
Antibody-mediated rejection is now recognized as the leading cause of late allograft failure in kidney transplantation.1 Currently, there is no Food and Drug Administration (FDA)-approved treatment for AMR. The current standard of care, derived from expert consensus, involves IVIG, TPE with or without rituximab, or bortezomib, with varying treatment results.2 Both rituximab (anti-CD20 monoclonal antibody) and bortezomib (proteasome inhibitor) have failed to demonstrate clinical benefit in clinical trials.3,4
Interleukin 6 (IL-6) is a proinflammatory cytokine that promotes maturation of B cells into plasma cells that produce DSAs, which can cause allograft injury by complement-dependent or complement-independent pathways. Interleukin 6 also promotes Th1, Th2, Th follicular, and Th17 cells while inhibiting regulatory T cells.5 Tocilizumab is the first-in-class drug developed to treat diseases mediated by IL-6. Data are emerging from animal and human studies indicating a critical role for IL-6 in mediation of cell-mediated rejection, antibody-mediated rejection, and chronic allograft vasculopathy. This suggests that anti-IL-6/IL-6 receptor blockade could be effective in modifying T-cell and B-cell responses to allografts.5
Choi and colleagues studied 36 patients with refractory chronic active AMR treated with tocilizumab (a monoclonal IL-6 receptor antibody) and demonstrated graft survival and patient survival rates of 80% and 91% at 6 years, respectively, along with significant reductions in DSAs and stabilization of renal function at 2 years.6 Adverse infectious events were noted in their study, which included 5 patients with CMV infection, 2 with BK virus infection, and 1 with trichodysplasia spinulosa, which resolved following tocilizumab discontinuation. Seven patients with bacterial infections resolved with treatment without tocilizumab discontinuation. More recently, Pottebaum and colleagues7 reported treating 7 patients with acute active AMR with tocilizumab and found a 50% reduction in immunodominant DSA in 4 patients, with DSA stabilized in all other patients. Renal function improved or stabilized in all patients throughout the duration of therapy.7 Infectious adverse events were reported in their case series, as well, where 1 patient with a prior history of CMV viremia developed CMV esophagitis following tocilizumab treatment.
Outside these 2 studies, there in not much more published in the literature. There is a large multicenter, randomized, double-blind, parallel-group, placebo-controlled phase 3 trial ongoing to investigate whether clazakizumab (anti-IL-6 monoclonal antibody) may be beneficial for the treatment of chronic active AMR in kidney transplant recipients. This trial is currently recruiting patients (ClinicalTrials.gov identifier: NCT03744910).
We believe our patient had smoldering disease that progressed from active AMR to chronic active AMR. We decided to use tocilizumab since he did not have DSA or other non-HLA antibodies and had developed transplant glomerulopathy. Although we could not complete the desired 6 doses of tocilizumab due to hyperbilirubinemia, renal function stabilized after tocilizumab treatment at 1 year follow-up, suggesting a role of tocilizumab in stabilizing renal function and prolonging patient and graft survival in chronic active AMR, where there is no FDA-approved treatment yet. However, careful monitoring for infectious adverse events is strongly recommended.
DOI : 10.6002/ect.2020.0389
From the 1University of Nevada, Las Vegas School of Medicine, Las Vegas, Nevada;
the 2Kidney Specialists of Southern Nevada, Las Vegas, Nevada; and the
3Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, California,
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Rajeev Sharma, University of Nevada, Las Vegas School of Medicine, 1701 W Charleston Blvd, Ste 490, Las Vegas, NV 89102, USA
Phone: +1 313 745 8772
Figure 1. 2018 Kidney Biopsy Showing Active Antibody-Mediated Rejection and Acute Cell-Mediated Rejection Banff Grade 1A
Figure 2. 2019 Biopsy Showing Chronic Antibody-Mediated Rejection With Features Suspicious for Chronic Active Antibody-Mediated Rejection