Glomerular complement activation has been recognized as a hallmark of IgAN, and deposition of C4d was previously demonstrated to identify patients with more severe disease and worse prognisis. Narsoplimab (OMS721) is a human monoclonal antibody directed against mannan binding lectin-associated serine protease 2 (MASP-2), an initiator of the lectin pathway of complement. Lafayette (Lafayette et al (2020) Kidney Int Rep) reported on the staged phase 2 study, with 2 sub-studies, assessing safety and effectiveness in high-risk patients with IgA nephropathy (IgAN).
The 4 patients who were enrolled in the single arm study with 12 weekly infusions, had reductions in 24-hour urine protein excretion (UPE) at week 18, ranging from 54% to 95% compared with baseline. However, in the 1:1 randomized sub-study, the vehicle- and narsoplimab-treated groups had similar proteinuria reductions at week 18. No treatment-related serous AEs were reported. Therefore, complement inhibition appears safe, but the effectiveness in reduction of proteinuria and stability of sGFR remains to be established. It should be noted that the C4d positivity of the renal biopsy, which has been observed in 30% of patients, was not evaluated for patients included in the study.
Results of the DAPA study have demonstrated the beneficial effect of inhibition of the sodium–glucose transporter-2 (SGLT2) with dapagliflozin in a large population of patients with CKD, both with and without diabetes (Heerspink et al (2020) NEJM). Although not specifically designed for patients with glomerulonephritis, these patients represented a significant amount of patients in the non-diabetic group. The results of this trial will directly impact the design of future studies and will also affect the standard therapy of patients with various forms of GN and proteinuria (Anders et al (2020) NDT). In line with this, also the results of the study showing that finerenone reduces the risk for CKD development in patients with type-2 diabetes, will be of broader interest (Bakris et al (2020) NEJM).
Various B cell-directed therapies have been investigated in patients with SLE and lupus nephritis. The BLISS-LN study is a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled trial in adult patients with biopsy-proven, active lupus nephritis (Furie et al (2020) NEJM). A total of 448 patients underwent 1:1 randomization to receive intravenous belimumab (at a dose of 10 mg per kilogram of body weight) or matching placebo, in addition to standard therapy. At week 104, significantly more patients in the belimumab group than in the placebo group had a primary efficacy renal response (43% vs. 32%; odds ratio, 1.6; 95% confidence interval [CI], 1.0 to 2.3; P = 0.03) and a complete renal response (30% vs. 20%; odds ratio, 1.7; 95% CI, 1.1 to 2.7; P = 0.02). The risk of a renal-related event or death was lower among patients who received belimumab than among those who received placebo (hazard ratio, 0.51; 95% CI, 0.34 to 0.77; P = 0.001). The safety profile of belimumab was consistent with that in previous trials and mostly related to infectious complications.
One of the hypotheses is that belimumab will also target plasma cells, the antibody producing cells, that are mostly CD20 negative and therefore not recognized by rituximab. Daratumumab is a human monoclonal antibody that targets CD38, depletes plasma cells and is approved for the treatment of multiple myeloma. The use of daratumumab has now been reported two patients with life-threatening lupus (Ostendorf et al (2020) NEJM). Significant depletion of long-lived plasma cells was seen associated with a substantial clinical response upon daratumumab treatment, followed by belimumab maintenance therapy. Both patients were extensively characterized by immune monitoring and single-cell RNA sequencing, showing a reduction of interferon type I activity, and down-regulation of T-cell transcripts associated with chronic inflammation.
The cellular origin of interferon-stimulated genes (ISG) in SLE was investigated using single-cell RNA sequencing of ~276,000 peripheral blood mononuclear cells from 33 children with SLE with different degrees of disease activity and 11 matched controls (Nehar-Belaid et al (2020) Nat Immunol). The high ISG expression signature (ISGhi), observed in the SLE patients, was derived from a small number of transcriptionally defined subpopulations within all major cell types. Expansion of unique subpopulations enriched in ISGs and/or in monogenic lupus-associated genes classified patients with the highest disease activity. Profiling of ~82,000 single peripheral blood mononuclear cells from adults with SLE confirmed the expansion of similar subpopulations in patients with the highest disease activity. This study lays the groundwork for resolving the origin of the SLE transcriptional signatures and the disease heterogeneity towards precision medicine applications.
The controversy regarding the use of plasma exchange in ANCA associated vasculitis AAV continues. The IWG Board members believe it is too early to discontinue use of this treatment in all patients with AAV. Proper meta-analysis and histological evaluation of the PEXIVAS cohorts are still awaiting. Their views were presented in a recent pro-con debate published in the NDT (Kronbichler et al (2021) NDT). Their views were rebuked by Specks at al. who supported their arguments in a recently published retrospective cohort study (Casal Moura et al (2020) JASN). Patients receiving cyclophosphamide (CYC; n=161) or rituximab (RTX; n=64) for remission-induction, including 51 who were also treated with plasma exchange (PLEX) were compared. This observational study did not find statistically significant differences between RTX and CYC for remission-induction therapy and no apparent benefit from the addition of plasma exchange (PLEX) to standard remission-induction therapy for patients with AAV and severe renal involvement. They conclude that the apparent benefits and risks of using CYC or RTX for the treatment of patients with AAV and severe kidney disease are balanced. A randomized controlled trial is the only satisfactory means to evaluate efficacy of remission-induction treatments in AAV with severe renal involvement.
The results of the STARMEN trial have been published, comparing tacrolimus rituximab to cyclical alternating treatment with corticosteroids and cyclophosphamide in inducing persistent remission in patients with primary MN (Fernández-Juárez et al (2020) Kidney Int). This randomized, open-label controlled trial included 86 patients with primary membranous nephropathy and persistent nephrotic syndrome after six months observation. The primary outcome of complete or partial remission of nephrotic syndrome at 24 months occurred in 36 patients (83.7%) in the corticosteroid-cyclophosphamide group and in 25 patients (58.1%) in the tacrolimus-rituximab group (relative risk 1.44; 95% confidence interval 1.08 to 1.92). Relapses occurred in one patient in the corticosteroid-cyclophosphamide group, and three patients in the tacrolimus-rituximab group. Serious adverse events were similar in both groups. Thus, treatment with corticosteroid-cyclophosphamide induced remission in a significantly greater number of patients with primary membranous nephropathy than tacrolimus-rituximab.