Failure to removede novodonor-specific HLA antibodies is influenced by antibody properties and identifies kidney recipients with late antibody-mediated rejection destined to graft loss - a retrospective study

Abstract

Current research is focusing on identifying bioclinical parameters for risk stratification of renal allograft loss, largely due to antibody-mediated rejection (AMR). We retrospectively investigated graft outcome predictors in 24 unsensitized pediatric kidney recipients developing HLA de novo donor-specific antibodies (dnDSAs), and treated for late AMR with plasmapheresis + low-dose IVIG + Rituximab or high-dose IVIG + Rituximab. Renal function and DSA properties were assessed before and longitudinally post treatment. The estimated GFR (eGFR) decline after treatment was dependent on a negative % eGFR variation in the year preceding treatment (P = 0.021) but not on eGFR at treatment (P = 0.74). At a median follow-up of 36 months from AMR diagnosis, 10 patients lost their graft. Altered eGFR (P < 0.001) and presence of C3d-binding DSAs (P = 0.005) at treatment, and failure to remove DSAs (P = 0.01) were negatively associated with graft survival in the univariable analysis. Given the relevance of DSA removal for therapeutic success, we analyzed antibody properties dictating resistance to anti-humoral treatment. In the multivariable analysis, C3d-binding ability (P < 0.05), but not C1q-binding, and high mean fluorescence intensity (P < 0.05) were independent factors characterizing DSAs scarcely susceptible to removal. The poor prognosis of late AMR is related to deterioration of graft function prior to treatment and failure to remove C3d binding and/or high-MFI DSAs.

Impact of de novo donor‐specific HLA antibodies on pediatric kidney transplant prognosis in patients with acute declined or stable allograft function

“…In consistence with the current literature, in our study, dnDSA strength, represented by MFI‐sum, was significantly higher in patients with AAD 9 . It seems that high MFI dnDSA are more resistant to anti‐humoral therapy, increasing the risk of AAD 27 …”

“…9 It seems that high MFI dnDSA are more resistant to antihumoral therapy, increasing the risk of AAD. 27 Moreover, we observed that dnDSA specificities >1 were associated with AAD and…”

Long term tolerability and clinical outcomes associated with tocilizumab in the treatment of refractory antibody mediated rejection (AMR) in pediatric renal transplant recipients

“…Chronic AMR, and independently, the development of HLA DSA are associated with premature graft loss, steeper annual decline in eGFR, and reduced patient survival 24–27 . Treatment options have focused on removal of circulating antibodies concurrent with reduction of their redevelopment through the use of plasmapheresis, anti CD20 (anti‐B cell) monoclonal antibodies (i.e., rituximab or ofatumumab), proteasome inhibitors (bortezomib), anti‐C5 antibody (eculizumab) and IVIg 28 .…”

A diagnostic ‘C’ saw: the ups and downs of C1q testing

“…In fact, some investigators advocate removing DSAs (independent of complement fixation) as soon as they are detected [41]. This approach is underscored in a recent study by Cioni et al [47] who desensitized 24 patients presenting with AMR after developing DSA. At a median follow-up of 36 months, 10 patients had lost their grafts, and all were in patients who had DSAs with high MFI values that fixed C3d (another split product in the complement cascade) compared to patients who retained their grafts.…”