No abstract

Patients with membranous nephropathy (MN) and persistent nephrotic syndrome (NS) are at increased risk of ­progression to end-stage renal disease. The discovery of ­autoantibodies against the podocyte-expressed M-type phospholipase A₂ receptor (PLA₂R) provided a clear pathophysiological rationale for interventions targeting the B-cell lineage to prevent antibody production and subepithelial immune-complex deposition. The anti-CD20 monoclonal antibodies, rituximab and ofatumumab, are safe and achieve remission of NS in approximately two-thirds of patients with MN. In patients with PLA₂R-related MN, remission can be predicted by anti-PLA₂R antibody depletion, and faster depletion is associated with earlier reduction of proteinuria and improved nephroprotection. Selective apheresis methods, such as double-filtration plasmapheresis (DFPP), may accelerate the clearance of autoreactive antibodies and at the same time avoid the side effects of plasma-exchange. In this preliminary, explorative, proof-of-concept study, we observed that in patients with PLA₂R-related MN, NS and high antibody levels, ofatumumab-induced B-cell depletion followed by DFPP accelerated anti-PLA₂R depletion compared to anti-CD20 monotherapy. This therapeutic regimen was safe and well tolerated. These observations may provide the background for controlled trials aimed at formally testing whether the addition of DFPP to anti-CD20 therapy could offer a novel therapeutic option, especially for patients with more severe MN.

Dual induction with low doses of rabbit anti-human thymoglobulin (RATG) and basiliximab effectively and safely prevented allograft rejection in high-risk renal transplant recipients. To assess whether treatment timing affects efficacy and tolerability, in this single-center, matched-cohort study, we compared posttransplant outcomes in 25 patients and 50 gender-, age-, and treatment-matched reference patients induced with the same course of 7 daily RATG infusions (0.5 mg/kg/day) started before or after engraftment, respectively. All subjects received basiliximab (20 mg) before and 4 days after transplantation, withdrew steroids within 6 days after surgery, and were maintained on steroid-free immunosuppression with cyclosporine and mycophenolate mofetil or azathioprine. Over 12 months after transplant, 1 patient (4%) and 13 reference patients (26%) had acute rejection episodes. One patient and 5 reference-patients required dialysis therapy because of delayed graft function. In all patients circulating CD4+ and CD8+ T lymphocytes were fully depleted before engraftment. Both treatments were well tolerated. In kidney transplantation, perioperative RATG infusion enhances the protective effect of low-dose RATG and basiliximab induction against graft rejection and delayed function, possibly because of more effective inhibition of early interactions between circulating T cells and graft antigens.

Background/Aims: In renal transplantation, peri-operative low-dose rabbit-antithymocyte-globulin (RATG) plus basiliximab induction prevented acute allograft rejection more effectively than post-operative RATG plus basiliximab induction. We investigated the specific antirejection contribution of basiliximab in this context. Methods: This single-center, observational, matched-cohort study evaluated allograft rejections (primary outcome), steroid exposure and side effects, GFR (iohexol plasma clearance) and treatment costs in 16 deceased-donor renal transplant recipients induced with RATG (0.5 mg/kg/day) and 32 age-, gender- and treatment-matched reference-patients given RATG plus basiliximab (20 mg on days 0 and 4). Results: Induction was well tolerated. At 18 months, 8 patients (50%) vs. 3 reference-patients (9.4%) rejected the graft [HR (95% CI): 6.53 (1.73-24.70), p = 0.006]. Difference was significant (p < 0.01) even after adjusting for recipient/donor age and gender, cold ischemia time and HLA mismatches. There were 1 antibody-mediated rejection and 2 moderate cellular rejections in patients vs. none in reference-patients (p = 0.032). The median (interquartile range) prednisone cumulative dose was remarkably higher in patients than reference-patients [4.78 (1.12-6.10) vs. 0.19 (0.18-3.81) grams, p = 0.002]. Three patients vs. 24 reference-patients were off-steroid at study end (p < 0.001). Three patients vs. no reference-patient developed new-onset diabetes (p = 0.003). Both inductions similarly depleted B-cells. Outcomes of AZA- vs. MMF-treated participants were similar. GFR was similar in all groups. Compared to MMF, AZA therapy saved ≈ EUR 2,500/year and by month 14.3 post-transplant compensated basiliximab costs. Conclusion: In renal transplantation, basiliximab plus peri-operative low-dose RATG more efficiently prevented allograft rejection than RATG monotherapy, and minimized steroid exposure and toxicity. AZA- vs MMF-based maintenance immunosuppression largely compensated the extra costs of basiliximab.

Background and Aims Rituximab is the first-line treatment for patients with primary membranous nephropathy (MN) and nephrotic syndrome (NS) at high risk of progression to end-stage kidney disease. However, this drug is effective only in approximately two thirds of treated patients, and repeated rituximab infusions may be complicated by hypersensitivity reactions, which contraindicate retreatment. Ofatumumab, a fully human anti-CD20 antibody, could overcome these limitations. Method We retrospectively evaluated the response to a single 50–300 mg dose of intravenous ofatumumab in 17 MN patients referred to our institution who either experienced hypersensitivity reactions (rituximab-intolerant, n = 5) or failed to achieve NS remission after rituximab infusion (rituximab-resistant, n = 12). Results Over a median [IQR] follow-up of 5.0 [3.0-9.8] months, ten (58.8%) patients—five rituximab-resistant (41.7%) and all five rituximab-intolerant—achieved complete or partial NS remission, defined as proteinuria &lt;0.3 g/day or proteinuria &lt;3.5 g/day with ≥50% reduction from baseline, respectively. Ofatumumab infusion induced a progressive reduction in 24-hour urinary protein and IgG excretion, and a sharp increase in serum albumin and IgG levels. Peripheral B cells were depleted in all patients and started reconstituting by 3 months from baseline. Seven of the 12 subjects with PLA2R-related disease (i.e. with baseline anti-PLA2R antibody levels &gt;2.7 RU/mL by ELISA) achieved antibody depletion during the follow-up (half of rituximab-resistant and all rituximab-intolerant). There were 14 non-serious infusion-related adverse events in nine patients, all of which completely resolved with temporary interruption of ofatumumab infusion. Conclusion Ofatumumab may be an effective and safe treatment option for all rituximab-intolerant and a substantial proportion of rituximab-resistant MN patients.