The Immunonephrology Working Group (IWG) of the ERA was funded and officially recognised by the ERA in 2009 to encourage research, teaching, communication and education in the field of immune system dysregulation.
Its area of interest includes:
– Glomerular, tubular, vascular immuno-mediated renal diseases;
– Immune mechanisms in pathogenesis and progression of renal damage;
– Immune-mediated damage in kidney transplantation.
The Immunonephrology Working Group’s mission is
• To promote and organise research in the field of Immunonephrology.
• To foster communication among members with similar research interests, with other Working Groups and Committees of the ERA.
• To collaborate to the organisation of educational activities and to promote scientific networking
Annette Bruchfeld (Sweden) – Chair
Hans Joachim Anders (Germany) – Vice Chair
Gema Maria Fernandez Juarez (Spain)
Juergen Floege (Germany)
Eleni Frangou (Cyprus)
Dimitrios Goumenos (Greece)
Kate Stevens (United Kingdom)
Andreas Kronblicher (Austria)
Kultigin Turkmen (Turkey)
Cees van Kooten (Netherlands)
HOW TO JOIN THE WORKING GROUP
Being a ordinary member of the Immunonephrology Working Group means being part of a network which facilitates exchanges of ideas on basic science research and new treatment protocols.
Becoming an ordinary member of the Immunonephrology Working Group is FREE OF CHARGE (ERA Membership is not mandatory) and is also open to non-nephrologists.
By joining the Immunonephrology Working Group you will receive constant updates on the Working Group initiatives be included in the Directory of Immunonephrology Working Groups’ ordinary members and start networking with colleagues from all over the world.
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.
RITERM (Rituximab and the assessment of InfecTions, Eosinophil counts, long-term Remission and Malignancy risk in idiopathic nephrotic syndrome) – Paucity exists regarding essential unanswered questions related to long-term efficacy of rituximab in the management of nephrotic syndrome, the respective side effect profile of B-cell depletion in this indication (namely infections and malignancies) and the role of peripheral blood eosinophils in the pathogenesis of nephrotic syndrome and its potential relevance to predict relapse or the disease course. In order to address these questions, we propose an international, multicenter study which should lead to further understanding of these rare diseases. We acknowledge that not all variables are present during different time points, but would like to receive an almost complete database to evaluate these questions appropriately. Long-term remission will use the oncologic approach for remission (5 years).
Among the inclusion criteria, patients should have received at least one rituximab application (indication: minimal change disease, membranous nephropathy or focal segmental glomerulosclerosis), age > 18 at the time of first rituximab and a minimum follow-up time of 36 months. The key exclusion criteria are chronic infectious diseases, secondary causes of nephrotic syndrome and patients with a kidney allograft.
Click here to get in contact with the Principal Investigators.
Identification of prognostic factors for patients with ANCA associated vasculitis – This project is performed in collaboration with European Vasculitis Society ‘EUVAS and DESCARTES Working Group of the ERA. The project aims at identifying prognostic factors present at time of diagnosis regarding relapses, patient and renal survival, risk for cardiovascular disease and malignancy. Secondary aims include the validation of prognostic factors and the development of a cohort with long term outcomes to permit a genomic approach to prognosis. Integration of predictive factors to develop prognostic tools that might also aid treatment selection.
European VALIdation Study of the Oxford Classification of IGA Nephropathy (VALIGA) – IgA nephropathy (IgAN), the most common glomerular disease worldwide, is potentially progressive to renal failure. In individual patients its course is unpredictable before development of severe proteinuria, hypertension, reduced glomerular filtration rate and renal fibrosis. There is a need to detect progressive cases in early stages, when a therapeutic intervention is more likely to be effective. A breakthrough report just published from an International Consensus -based on a retrospective analysis of 265 adults and children with IgAN from four continents -focuses on prognostic information provided by renal biopsy. According to this Oxford Classification of IgAN, four pathological features (mesangial hypercellularity, segmental glomerulosclerosis, endocapillary hypercellularity, and tubular atrophy/interstitial fibrosis) predict renal outcome independently from all clinicalindicators at the time of biopsy and during follow up (Kidney International 2009;76:534-45; and Kidney International 2009;76:546-56). The limited number of patients and their heterogeneous origin indicate a need for validation studies involving large cohorts of patients. The proposed study will investigate European patients and the results will be complementary to those from similar studies in North America and Asia, allowing a global perspective on the value of these predictive factors Biopsy-proven IgAN with long follow-up or rapidly progressive course (about 500 cases) will be enrolled by 26 Centers of Nephrology and Renal Pathology from 9 Countries. Renal biopsies will be scored by the local pathologist and centrally reviewed in Oxford. Clinical data at renal biopsy and during the follow-up will be provided by local Nephrologists to the Coordinating Center. Statistical analysis will be performed by Canadian experts. This multicenter, multinational study supported by the ERA Working Group of Immunonephrology provides with information beyond the validation of the Oxford classification of IgAN, aiming at detecting for each lesion the most effective treatment and the “point of no return” when no treatment is effective.
IgA nephropathy in Europe and Japan IWG – Background: In studies published in Japan and in Europe there are usually substantial differences in demographics and clinical features. However, these differences have never addressed in a study using similar method to identify cases. Method: An online survey was created consisting of a large number of questions where data of individual patients could be entered on-line. A call was opened and advertised in Europe through the IWG newsletter and homepage and in a similar fashion in Japan. Nephrologists were encourage to complete data on an unspecified number of consecutive patients with biopsy proven IgAN. Results: Data from more than 400 European IgAN and more than 200 Japanese patients have been entered into the database. Preliminary results were presented at the IWG-JSN business meeting in Budapest. There were not so big differences when it comes to severity (eGFR and U-alb), but there were huge differences regarding sex distribution and with regard to respiratory versus gastrointestinal co-morbidities.
The acute/subacute nephritic syndrome in Europe and Japan – Background: The epidemiology of glomerulonephritis is difficult to compare between countries due to the huge impact of how biopsy indications are applied. A way to reduce the variability is to limit the comparisons clinical situations where there is less disagreement on whether a biopsy should be performed or not. Method: Renal biopsy registries across Europe was contacted through the IWG newsletter or directly and invited to deliver data if they could provide data on the subset of patients having undergone a biopsy on the indication of acute/subacute nephritic syndrome (ANS). This was defined as the combination of hematuria, proteinuria and a rising creatinine in the absence of known chronic renal failure. Results: Data has now been delivered from Japan, Sweden, Scotland, Croatia and Austria. We are still waiting for data from Norway, Italy and Turkey. A poster has been recently accepted at the 57th ERA-EDTA Virtual Congress. Click here to view the poster.
Athens Winter School in Nephrology – Focus in Glomerular Diseases February 27-29, 2020 – Athens, Greece
Join the Athens Winter meeting 2020, an educational event organised by the Immunonephrology Working Group (IWG) of the ERA and Mayo Clinic (Rochester USA) in collaboration with Hellenic Society of Nephrology. The meeting is mainly focused on glomerular diseases but also covers a wide spectrum of topics in the field of nephrology such as kidney transplantation, chronic kidney diseases and the relation between pregnancy and the kidneys. Read more
In 2019 the ERA organised the Scientific and Educational Interaction Day (SEID) on October 25-26, 2019 in Vienna (Austria). IWG contributed in the creation of the Scientific Programme with the educational session on ‘Systemic diseases affecting the kidney‘