IWG – Immunonephrology Working Group

The Immunonephrology Working Group (IWG) of the ERA-EDTA was funded and officially recognised by the ERA-EDTA 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-EDTA.

• To collaborate to the organisation of educational activities and to promote scientific networking

Vladimir Tesar (Czech Republic) – Chair
Mårten Segelmark (Sweden) – Vice Chair
Hans Joachim Anders (Germany)
Annette Bruchfeld (Sweden)
Gema Maria Fernandez Juarez (Spain)
Juergen Floege (Germany)
Dimitrios Goumenos (Greece)
Andreas Kronblicher (Austria)
Kultigin Turkmen (Turkey)
Cees van Kooten (Netherlands)

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-EDTA 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.

Click here to join.

The ordinary membership application is subject to validation. Please allow some time for a quick administrative check before applying multiple times.

The switch from proteasome to immunoproteasome is increased in circulating cells of patients with fast progressive immunoglobulin A nephropathy and associated with defective CD46 expression
Nephrology Transplant Dialysis, June 2020 –  Click here to watch the related NDT Author Video

Recommendations for the management of patients with immune-mediated kidney disease during the severe acute respiratory syndrome coronavirus 2 pandemic
Nephrology Dialysis Transplantation, May 2020 – Click here to watch the related NDT Author Video

2019 Update of the Joint European League Against Rheumatism and European Renal Association–European Dialysis and Transplant Association (EULAR/ERA–EDTA) recommendations for the management of lupus nephritis
Annals of the Rheumatic Diseases,  March 2020

Is there long-term value of pathology scoring in immunoglobulin A nephropathy? A validation study of the Oxford Classification for IgA Nephropathy (VALIGA) update
Nephrology Dialysis Transplantation, November 2018

Patients double-seropositive for ANCA and anti-GBM antibodies have varied renal survival, frequency of relapse, and outcomes compared to single-seropositive patients
Kidney International, September 2017, Volume 92, Issue 3

Oxford Classification of IgA nephropathy 2016: an update from IgA Nephropathy Classification Working Group
Kidney International, May 2017, Volume 91, Issue 5

A Multicenter Sudy of the Predictive Value of Crescents in IgA Nephropathy
JASN February 2017

Risk factors for progression in children and young adults with IgA nephropathy: an analysis of 261 cases from the VALIGA European cohort
Paediatric Nephrology, January 2017, Volume 32, Issue 1

Renal biopsy in patients with diabetes: a pooled meta-analysis of 48 studies
Nephrology Dialysis Transplantion, January 2017

Toward Noninvasive Diagnosis of IgA Nephropathy: A Pilot Urinary Metabolomic and Proteomic Study
Disease Markers, Volume 2016 (2016)

EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis
Annals of the Rheumatic Diseases,  June 2016

Renal Biopsy in 2015 – From Epidemiology to Evidence-Based Indications
Am J Nephrol 2016;43:1-19

Corticosteroids in IgA Nephropathy: A Retrospective Analysis from the VALIGA Study
JASN, September 2015

Validation of the Oxford classification of IgA nephropathy in cohorts with different presentations and treatments
Kidney International, April 2014

The ERA-EDTA database on recurrent glomerulonephritis following renal transplantation
Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis
Nephrology Dialysis Transplantion, January 2014

The Kidney, a Victim and Culprit of Autoimmune and Alloimmune Responses
Nephron Clin Pract 2011;119:c200–c204, August 11, 2011

ERA-EDTA Immunonephrology working group
Nephrology Dialysis Transplantation, February 2010

Glomerular diseases and transplantation: similarities in pathogenetic mechanisms and treatment options
Nephrology Dialysis Transplantion, September 2010

IgAN/IgAV

The long term follow up (up to10 years) of patients who had been included in the STOP-IgAN trials has been reported (Rauen et al (2020) Kidney Int). Patients receiving immunosuppression on top of standard of care showed no long term benefit concerning renal endpoints of developing ESKD or loss of eGFR compared to standard of care alone. This is in line with the original observations of the STOP-IgAN study. Over the years, there have been many discussions whether there would still not be subgroups of patients who could profit from immunosuppressive therapy. Patients at high-risk of disease progression are mostly defined by the level of proteinuria (1g or more/day). To investigate if treatment decisions can be more accurately accomplished, the International IgAN Prediction Tool has been explored (Barbour et al (2020) Kidney Int). Allocation of a hypothetical immunosuppression therapy was simulated in a large international cohort of adults with IgAN. Treatment allocation using the Prediction Tool had a larger net benefit and a larger net reduction in treatment compared to the use of proteinuria; in other words, the proportion of patients appropriately allocated to receive or withhold immunosuppression, adjusted for the harm from inappropriate decisions. Therefore, at least at the moment of kidney biopsy, such tools might be helpful in treatment decision making.
Novel pathogenic insights have been obtained in the regulation of galactose-deficient IgA1 (Gd-IgA1), which plays a crucial role in the development of IgA nephropathy (IgAN) (Makita et al. (2020) Kidney Int). TLR9 activation results in overproduction of nephritogenic IgA in human IgA1-secreting cells. This was confirmed in IgAN-prone ddY mouse injected with the TLR9 ligand CpG. Through specific inhibition, it could be demonstrated that both APRIL and IL-6 were involved in this enhanced synthesis of Gd-IgA1.
Activation through TLR agonists was previously also shown to be involved in a switch from proteasome to immunoproteasome (iPS), directly impacting the generation of peptides required for MHC loading. In 157 IgAN patients enrolled through the multinational Validation Study of the Oxford Classification of IgAN (VALIGA) study, the relationships between iPS switch in peripheral blood cells and estimated glomerular filtration rate (eGFR) modifications from renal biopsy to sampling were investigated (Peruzzi et al (2020) NDT). The switch towards iPS was significantly associated with the rate of eGFR loss (P = 0.026), but not with eGFR at biopsy. Moreover, fast progressors were also associated with low levels of CD46 mRNA, a molecule not only involved in regulation of complement C3, but also a receptor expressed on T cells and involved in immune regulation.

SLE

Belimumab is a fully humanized IgG1 γ monoclonal antibody directed against solubre B lymphocyte stimulator (BLyS). Curretly It is indicated as an add-on therapy for the treatment of adult patients with active SLE, who are receiveing standard therapy. Recently, a clinical trial has assessed the role of belimumab in adults wiht biopsy-proven, active lupus nephritis on addition to standard therapy. A total of 448 patients underwent randomization (224 to the belimumab group and 224 to the placebo group). 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. (Fuire et at N Engl J Med 2020; 383:1117-1128)
Type I interferon has been recognized as a potential target in SLE, based on the prominent IFN-gene signatures, which have been observed both in peripheral blood and target organs. Although the phase 2 trials for anifrolumab, a human monoclonal antibody to type I interferon receptor, in lupus nephritis is still ongoing, the results of the phase 3 trial in SLE have been published (Morand et al (2020) NEJM). In this TULIP-2 trial, 362 patients were randomized to receive monthly administration of anifrolumab. This resulted in a higher percentage of patients with a response (as defined by a composite end point) at week 52 than did placebo, in contrast to the findings of a similar phase 3 trial involving patients with SLE that had a different primary end point. The frequency of herpes zoster was higher with anifrolumab than with placebo. Interestingly, this treatment effect appeared similar between patients with a high or low IFN-signature.
To understand the molecular heterogeneity of lupus nephritis and identify immunologic mechanism and pathways, patterns of 1000 urine protein biomarkers were investigated in 30 patients with active lupus nephritis (Fava et al (2020) JCI Insight). This was combined with single-cell transcriptomics of kidney biopsies, and identified kidney-infiltrating CD8+ T cells as the most important source of urinary chemokines.

AAV

In a previous newsletter, we have discussed the results of the PEXIVAS trial, investigating the place of plasma exchange in the treatment of patients with severe AAV. In the final publication (Walsh et al (2020) NEJM), it is concluded that the use of plasma exchange did not reduce the incidence of death or ESKD, with similar results in subgroup analyses and in analyses of secondary outcomes. It will be interesting to see to which level this will result in a change in clinical practice, since many clinicians still feel more confident to use plasma exchange under specific circumstances.

MN

A cyclical corticosteroid-cyclophosphamide regimen is recommended for patients with primary membranous nephropathy at high risk of progression. Rituximab monotherapy and calcineurin inhibitors have shown efficacy in inducing remission, but relapses are very common after discontinuation of calcineurin inhibitors. STARMEN was an European clinical trial designed to compare a 6-month cyclical treatment with corticosteroid and cyclophosphamide (N=43) or sequential treatment with tacrolimus (full-dose for 6 months and tapering for another 3 months) and rituximab (1 gram at month 6) (N=43). Complete o partial remission outcome occurred in 36 patients (83.7%) in the corticosteroid-cyclophosphamide group and in 25 patients (58.1%) in the tacrolimus-rituximab group (relative risk [RR] 1.44; 95% confidence interval [CI] 1.08 to 1.92). Immunological response (depletion of antibodies targeting the phospholipase A2 receptor) was faster in the corticosteroid-cyclophosphamide group and associated with remission at 24 months. Relapses occurred in one patient (2.7%) in the corticosteroid-cyclophosphamide group, and three patients (12%) in the tacrolimus-rituximab group. The rate of serious adverse events was similar in both groups. (Fernández-Juárez Kidney International 2020)

Even with the identification of PLA2R, THSD7A, and NELL-1 as autoantigens in membranous nephropathy, not all cases can be explained. It is now shown that also antibodies directed against Semaphorin 3B (Sethi et al (2020) Kidney Int) and against Protocadherin-7 can occur (Sethi et al 2020 ASN renal week). Both new antigens was identified by mass spectrometry, and was localized to granular deposits along the glomerular basement membrane in association with IgG. Eight of the 11 cases of Semaphorin 3B-associated membranous nephropathy were pediatric cases, thereby identifying a distinct disease type.
The same MS approach has been used to characterize the complement deposits in patients with primary and secondary MN (Ravindran et al (2020) KI Reports). In both types of MN, a wide variety of complement components could be identified, including regulatory proteins. This suggests local complement activation and might provide a rationale for complement directed therapies.

Based on the involvement of autoantibodies in MN, the use of rituximab (RTX) has emerged as a safe and efficient treatment for patients with PLA2R-associated membranous nephropathy. A retrospective analysis has now been performed on patients with stage 4 or 5 chronic kidney disease (Hanset et al (2020) KI Reports). It is concluded that RTX seems effective and reasonably safe in this patient population and that immunological remission is associated with a good clinical outcome.
As an alternative B cell-directed treatment, 14 patients with persistent nephrotic-range proteinuria have received up to 2 years belimumab monotherapy, in a prospective, open-label, study (Barrett et al (2020) NDT). Treatment resulted in a reduction in anti-PLA2R antibody titers, combined with partial (n = 8) or complete (n = 1) remission as determined by proteinuria levels.

The link to autoimmunity in MN is well illustrated by GWAS analysis, which has identified both the autoantigen PLA2R and specific HLA alleles as risk factors. In a new study, several cohorts of East Asian and European ancestries have been combined (total 3,782 cases and 9,038 controls)(Xie et al (2020) Nat Comm). Via this method two new loci were identified (NFKB1 and IRF4), as well as ancestry-specific HLA alleles. Interestingly, these genes collectively explained approximately 30% of the risk, and were able to correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test.

aHUS / C3G

Introduction of eculizumab as a complement-directed drug has dramatically changed the treatment possibilities in patients with aHUS. Now the results have been published on ravulizumab, a long-acting antibody against C5, engineered from eculizumab, with increased elimination half-life, allowing an extended dosing interval (Rondeau et al (2020) Kidney Int). In this global, phase 3, single arm study in complement inhibitor-naïve adults (18 years and older) who fulfilled diagnostic criteria for aHUS, enrolled patients received ravulizumab through a 26-week initial evaluation period. It is concluded that treatment with ravulizumab once every eight weeks resulted in rapidly improved hematologic and renal endpoints with no unexpected adverse events. It remains to be seen what will be the place of this drug next to eculizumab and other C5 inhibitors currently under development.

Whereas the role of C5 in aHUS is undisputed, this is less clear for other renal diseases. An interesting new method has been developed to visualize the C3/C5 at the level of the renal biopsy (Person et al (2020) KI Reports), comparing aHUS and SLE.
Involvement of complement has also been implicated in primary forms of MPGN. In a large GWAS study it was shown that there was no significant enrichment of rare variants in candidate complement genes in this population (Levine et al (2020) JASN). However, there was an associated with specific HLA genes, suggestive of an underlying autoimmune reaction.

Anti-GBM disease

Three patients with refractory anti-GBM nephritis, without pulmonary involvement, have been treated with the endopeptidase IdeS (Immunoglobulin G degrading enzyme of Streptococcus pyogenes) (imliflidase) on a compassionate basis (Soveri et al (2019) Kidney Int). Treatment with IdeS led to rapid clearance of circulating and kidney bound anti-GBM antibodies. However, none of the patients regained independent renal function. Therefore, the clinical utility, dosage and use for preserving renal function remain to be determined.

• Prognosis and outcome in patients with primary membranous nephropathy project, submitted by IWG, was selected to be one of the projects to be supported by the ERA-EDTA through the Long Term Fellowship Programme.

• 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-EDTA. 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-EDTA 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 EDTA 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-EDTA 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‘

Extrarenal involvement in SLE and its impact on the outcome of pts with LN
Vladimir Tesar, Prague, Czech Republic
Renal involvement in AAV and its treatment
Annette Bruchfeld, Stockholm, Sweden
Anti-GBM disease with and without lung hemorrhage
Marten Segelmark, Lund, Sweden

How to become your local expert in Nephrogenetics – October 8-9, 2018,  Belgrade, Serbia – In collaboration with YNP, WGIKD, ERA-EDTA Ethics Committee and ERKnet

Renal Implications of Advances in Immunology and Inflammation– September 19-20, 2017 Malmo, Sweden – In collaboration with the Nordic Society of Nephrology and Mayo Clinic –  click here to view the available educational materials.

Pathogenesis and Treatment of IgA Nephropathy –September 16, 2016  Tours, France –  click here to view the available educational materials.

Immunonephrology Working Group Newsletter No. 13, July 2020

Immunonephrology Working Group Newsletter No. 12, October 2019

Immunonephrology Working Group Newsletter No. 11, April 2019

Immunonephrology Working Group Newsletter No. 9, September 2018

Immunonephrology Working Group Newsletter No. 8, February 2018

Immunonephrology Working Group Newsletter No. 7, May 2017

Immunonephrology Working Group Newsletter No. 6, January 2017

Immunonephrology Working Group Newsletter, No. 5, May 2016

Immunonephrology Working Group Newsletter, No. 4, December 2015

Immunonephrology Working Group Newsletter, No. 3, April 2015 

Immunonephrology Working Group Newsletter, No. 2, January 2015

Immunonephrology Working Group Newsletter, No. 1, September 2014