Rituximab is a chimeric monoclonal antibody targeting the CD20 antigen. Rituximab administration was initially approved for the treatment of haematological and reumathological disease and results in naive and memory B cells depletion (15). Rituximab acts through the antibody-dependent and the complement-mediated cytotoxicity and through the induction of phagocytosis and apoptosis (16). In 2004, a young boy with SDNS secondary to MCD underwent proteinuria remission after receiving rituximab to treat supervened idiopathic thrombocytopenic purpura (17). After this initial case, other reports from patients receiving rituximab for post-transplant lymphoproliferative disorders (PTLD) indicated a potential benefit also on post- transplant FSGS recurrence (18, 19). Subsequently, there have been several randomised clinical trials reporting rituximab efficacy in SDNS (7).

On the other hand, the efficacy of rituximab in SRNS compared to common protocols, such as calcineurin inhibitors and plasma exchange, provided confounding results. Bagga et al. (20) treated with rituximab five SRNS children and and complete and partial remission were induced in three and two patients rispectively. After that, authors published a relevant case series reporting the treatment with rituximab of 33 SRNS paediatric patients: stable remission was achieved in around half of subjects at 12 months of follow-up (21).

In 2012, Magnasco et al. (22) proposed a randomised clinical study in 31 children with NS resistant to the combination of CNI and steroid. Authors compared the adding of two monthly infusions of rituximanb at the dose of 375mg/m² in the treated group versus the maintenance of CNI and steroid in the control group: adding of rituximab did not result superior in inducing NS remission ( Table 1 ).

Overall, observational studies suggested a complete remission rate of about 30% of cases treated with rituximab (36), but the limited controlled randomised studies did not support the superiority of rituximab compared to other treatments.

Similar results were described in the context of NS recurrence after KT. NS recurrence is reported in 35-60% of cases and represents a major risk factor for graft lost (37). Rituximab and plasmapheresis represented the corner-stones of treatment in NS recurrence, but remission was generally described in 40-55% of cases and directly correlates with better graft survival (38).

Rituximab administration in post KT recurrence was largely reported, but literature mostly consists of case reports and case series (39–42). Remission rate of subjects treated with rituximab for NS recurrence ranged from 50% to 100%. While other reports showed total failure of rituximab in inducing remission (43–45). Moreover, the dose of rituximab used to treat NS recurrence is variable according to the centers and represents a further confounding factor in interpreting previous reports: dose administered ranges from single infusion at low-dose of 100 mg to 2 monthly infusions of 1 gr, according to the centers’ protocols (46).

In 2017, Garrouste et al. (23), in a retrospective observational study, analysed the administration of rituximab in 19 patients with recurrent NS post KT. They reported 9/19 and 3/19 complete and partial remission respectively. Moreover, responsiveness to treatment correlated with a better renal function at 5 years of follow up. Of note, 14 patients reported severe infections in the first year of follow up. More recently, the same authors investigated the efficacy of rituximab in a large retrospective multicenter study on 148 KT recipients with FSGS recurrence, maintaining plasmapheresis as cornerstone of treatment (24). Overall, complete and partial remission were achieved in 47% and in 33%of patients, respectively ( Table 1 ). Of interest, the patients here reported where divided in two groups according to the time of administration of rituximab: the administration of rituximab for recurrence prevention at the day of transplantation did not correlate with higher incidence of remission or a decreased frequency of second relapse when compared to the administration of rituximab only in case of relapse.

Uffing et al. (38), in TANGO project (47), retrospectively screened for FSGS 11,742 KT recipients and reported that 176 had a diagnosis of native FSGS and 57 (32%) had recurrence after KT. Rituximab and plasmapheresis represented treatments of choice in 81% of cases, and overall, partial or complete remission was reported in 57% of patients, correlating with better survival of KT.

Regarding our experience, we revised the outcomes of 25 non-genetic SRNS who received KT at Gaslini Children’s Institute, Genoa, Italy, between 1988 and July 31, 2022. We here reported a recurrence rate of 45% (11/25). Patients were treated with plasmapheresis or plasmapheresis and rituximab, achieving a remission rate of 60% of recurrent cases. We did not report differences among who received or not rituxumab.

A meta-analysis recently evaluated the evidence of combining plasmapheresis with rituximab therapy. Authors considered eight observational studies including both adults and pediatrics age groups, and they found that the remission rate was 72.7%, 41% with complete and 32% with partial remission respectively (48).

Summarising, although there are no randomized control trials on the effectiveness of rituximab in treating post KT recurrent NS, the effectiveness of both rituximab and plasmapheresis is largely supported.

Rituximab is generally well tolerated. The infusion related reactions represent the most common complications and occur in 5–10% of the cases. In our recent clinical trial comparing efficacy and the safety of rituximab vs. ofatumumab, we demonstrated that infusion related reaction may be avoided with slow infusion and with pre-treatment based of steroid, antihistaminic, paracetamol and salbutamol.

In NS, serious adverse events in children receiving rituximab were reported in limited case reports, such as pulmonary fibrosis (49) fulminant myocarditis (50). Different complications, including leukoencephalopathy (51), do not seem related to rituximab, considering that also the administration of other immunosuppressive agents correlated with the JC virus reactivation (52). Moreover, previous findings largelly reported that chimeric nature of rituximab may be responsible of the development of anti-rituximab antibodies (53, 54). As consequence, anti-rituximab antibodies may limit the efficacy of subsequent infusions and may increase the infusion related reactions (55). We recently reported that, in our patients with SDNS, the development of anti-rituximab antibodies is limited and does not affect the efficacy of subsequent infusions, probably due to the low dose administered (single infusion 375mg/m²) compared to other protocols (56).

In a recent retrospective study, Bagga et al. (57) investigated the outcome of 250 patients with SDNS receiving two or more courses of rituximab. Authors reported that hypogammaglobulinemia was observed in around 35% of treated subjects. However that hypogammaglobulinemia may persist several months after the last rituximab infusion is commonly reported, but if the hypogammaglobulinemia would be related to a major risk of severe infections is still to be completely defined (58).

Ofatumumab is a fully human anti-CD20 monoclonal antibody. At development of the drug, ofatumumab presented different in vitro characteristics compared to rituximab, such as more extended binding site with consequent more affinity to the CD20 antigen and an higher efficient complement-dependent cytotoxicity (59). Such in vitro findigs raised the curiosity on the clinical administration with the aim to investigate possible superior clinical benefits.

In neprhrological context, ofatumumab was firstly administered in five children with SRNS

Not responding to rituximab at the dose of 300 mg/1.73m² followed by five weekly infu- sions (2 g/1.73m² per infusion). At 12 months of follow up, complete and partial remission were achieved in three and two subjects respectively (25). Such satisfactory results were not reported by further experiences (26). Vivarelli et al. (60) described the administration of ofatumumab in two cases of steroid and rituximab resistant NS, responding to a single dose. Wang et al. (27) treated with ofatumumab five patients with NS at dose of 300 mg/1.73m² for the first week, followed by four or five weekly infusions of 2 g/1.73m². One failed the treatment for severe infusion reactions. Three achieved complete remission, and one partial remission. In a more recent randomized controlled trial in children with multi-drug NS (MRNS), ofatumumab (single infusion at 1,5 g/1.73m²) was compared with placebo and failed to induce remission (28). Overall, ofatumumab induced NS remission in around 40% of treated children for SRNS (29) ( Table 1 ).

Based on single case reports and small series (61–65), ofatumumab was also proposed in the treatment of NS recurrence after KT. However, in the largest case series involving 6 children resistant to previous treatments, ofatumumab did not induce complete remission, partial remission was achieved in half of cases and no response at all in the remaining cases.

Antigen-presenting cells expressed on the surface a costimulatory ligand named B7-1 (CD80), fundamental for the binding with the T- cell receptors CD28 and Abatacept is an inhibitor of the B7-1 (66). Previous findings described the B7 expression on podocytes surface of subjects affect by proteinuric disease, such as lupus nephritis (67), membranous nephropathy (30) and diabetic nephropathy (68, 69). Therefore, such reports raised the hypothesis that B7 blockade may result in a podocyte-protective effect with consequent reduction of proteinuria. In a case report study, partial or complete remission was reported in 4 KT recipients with rituximab-resistant recurrent FSGS and treated with Abatacept and in one SRNS. Muhlbacher et al. (70) described a 19-years old boy with recurrent NS after KT and resistant to rituximab and plasmapheresis, who responded to abatacept and was mentained in remission with subsequent belatacept-based immunosuppression with a follow-up of over 4 years ( Table 1 ). Other studies reported confunding and not definitive results (31, 32).

More recently, Burke et al. (33) proposed the administration of abatacept, based on the B7-1 podocytes expression at kidney biopsy, in 12 subjects (median age 12 years old) with NS recurrence after KT and resistant to conventional treatments with plasmapheresis and rituximab. Nine subjects responded to treatment, of whom 7/9 had KT biopsy positive for B7-1, while 2/9 were without biopsy. Of note, of the 3 patients not responding to abatacept, one had KT biopsy positive for B7-1 ( Table 1 ). Based on these results, authors suggested that B7-1 podocytes staining may identify subject who can benefit of abatacept.

These evidence may support the need for confirmatory studies on podocyte B7-1 expression and randomized clinical trial to asses the response to abatacept in proteinuric kidney disease.

Adalimumab is a human monoclonal antibody anti-TNFa. It is approved for the rheumatoid and gastric disease, such as children affected by juvenile idiopathic arthritis, psoriasis Crohn’s disease and arthritis (71). TNFa was reported elevated in urine of subjects affected by FSGS (72, 73). Moreover, in vivo studies demonstrated that TNFa may induce endothelial cell injury and increased glomerular permeability (74). Therefore, based on these previous findings, adalimumab was supposed to be a promising treatment for proteinuric disease. In a Phase 1 clinical trial, adalimumab was effective in decreasing proteinuria in 4/10 subjects with FSGS (34)( Table 1 ).However, further clinical trials are missing and current data still do not support adalimumab use in FSGS.

In animal models of FSGS, regulation of C3 convertase in podocyte by decay-accelerating factor (CD55) is fundamental to enhance proteinuria and glomerular sclerosis. Recent studies showed that C3a/C3aR ligations on podocytes induce the podocytes to release active IL-1β that through the ligand with type 1 interleukin receptor (IL-1R1), with an autocrine loop, lead to the actin cytoskeleton rearrangement and podocyte loss. The loss of podocytes may be avoided preventing the binding IL-1β/IL-1R1, suggesting therefore a causal link (75, 76).

Since 1993, Anakinra, the receptor antagonist that blocks the activity of IL-1 binding the IL-1R1, represents the treatment of choice in several rheumatic disease (77). Of note, several previous studies reported the use of Anakinra in patients with familial Mediterranean fever and associated glomerular AA amyloidosis resulting with proteinuria: the administration of Anakinra remarkably reduced the amount of proteinuria (78). Such findings may be partially explained by the previous described mechanism correlating IL-1β production and the subsequent IL-1R signaling to the complement cascade during proteinuric disease.

Based on these findings, we recently administered Anakinra in 2 patients with multidrug-dependent/-resistant NS and 1 KT patient with FSGS recurrence. We induced a complete and two partial remission respectively. Therefore, our small case reports supported the hypothesis that IL-1R1 blockers may prevent the complement-mediated podocyte cytoskeleton rearrangement in glomerular diseases (35) ( Table 1 ).