IWG Newsletter
n. 8, February 2018
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Dear Friends,

In this eighth newsletter of Immunonephrology Working Group (IWG), you will find updates on recently published articles and late-breaking clinical trials on immune mediated renal diseases. We would like to draw your attention to the upcoming CME course of the Immunonephrology Working Group (IWG) that will be held at the 55th ERA-EDTA Congress organized in Copenhagen, Denmark on May 24-27, 2018.

We would also like to invite you to kindly encourage your colleagues interested in research, teaching, communication and education in the field of immuno-mediated renal diseases to become an IWG Ordinary Member. Click here to become one.

With kind regards,

Vladimir Tesar,  Chairman
Mårten Segelmark, Vice Chair

Cees van Kooten, newsletter Co-Editor
Yasar Caliskan, newsletter Co-Editor

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INSTITUTIONAL

New Board Member Election
In 2018, the Board Members Rosanna Coppo (Italy), Mohamed R. Daha (The Netherlands), Renato Monteiro (France), Jack Wetzels (The Netherlands) and Yasar Caliskan (Turkey) will end their term as IWG Board members. The Open Call for candidates to become an IWG Board Member will be announced on the IWG webpage. There will be three open vacancies for new Board members.
We encourage all ordinary IWG members to submit their candidacy by April 28, 2018.

Click here for more information.

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EDUCATION

IWG CME course at the 55th ERA-EDTA Congress, Copenhagen (Denmark) on May 24, 2018
It is a great pleasure and honour for us to invite you to the 55th ERA-EDTA Congress, Copenhagen (Denmark) and to attend the IWG CME course focusing on two main topics:  “Cyclophosphamide in glomerular disease: is this old drug still to be used or does it have to be dismissed?” and “Renal involvement in rare inflammatory diseases.”

Click here for more information.

Do not miss the joint YNP/IWG/WGIKD CME course to be held on October 8-9, 2018 in Belgrade (Serbia) and focusing on Nephrogenetics.

Click here for more information.

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IWG warmly suggests the following educational event:

IIgANN2018 – International Symposium on IgANephropathy
Buenos Aires (Argentina)
September 27-29, 2018

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RESEARCH

Updates from recent ASN Kidney Week 2017
We would like to draw your attention to the results of high-impact clinical trials presented at ASN Kidney Week on October 31-November 5, 2017 in New Orleans (USA) that could affect kidney-related medical care.

MENTOR Trial “A Multi-Center Randomised Controlled Trial of Rituximab versus Cyclosporine in the Treatment of Idiopathic Membranous Nephropathy (MENTOR)” by Fernando C. Fervenza et al.
Preliminary results from the MENTOR trial suggested that B-cell targeting with rituximab (RTX) in membranous nephropathy (MN) was as effective as oral cyclosporine in inducing remission of proteinuria during a year of treatment. Investigators randomised patients with MN from 25 participating institutions to receive cyclosporine (n=63) or RTX (n=64) for a year, followed by a year of follow-up visits. Patients with an active infection, a secondary cause of idiopathic MN, or type 1 or 2 diabetes had not been included in the trail. Patients who received cyclosporine had a higher rate of treatment failure at 24 months compared with those who received RTX (79.4% versus 37.5%), and complete or partial remission occurred in 62.5% of the RTX cohort compared with 20.6% of those who received cyclosporine (odds ratio 6.0, 95% CI 2.7-13.2, p<0.0001).
Several studies presented at the ASN Kidney Week 2017 suggested that in the steroid resistant nephrotic syndrome families analysed with next generation sequencing methods, COL4A3-4-5 gene mutations were the more frequent identified mutations (FR-OR032, SA-PO588, SA-PO604).

IgA Nephropathy (IgAN)

TESTING Study
Immunosuppression therapy in IgAN still remains debatable despite recent evidence based on randomised controlled trials. The Therapeutic Evaluation of Steroids in IgA Nephropathy Global (TESTING) study, which is a multicentre, double-blind, randomised clinical trial including 750 participants (proteinuria greater than 1 g/d and eGFR of 20 to 120 mL/min/1.73 m2) evaluated the efficacy and safety of corticosteroids in patients with IgAN at risk of progression. After the randomisation of 262 participants and 2.1 years' median follow-up, recruitment was discontinued because of excess serious adverse events (14.7%) in the methylprednisolone group vs (3.2%) placebo group (p = .001), mostly due to excess serious infections, including 2 deaths. The primary renal outcome occurred in 8 participants (5.9%) in the methylprednisolone group vs 20 (15.9%) in the placebo group (p = .02). The authors concluded that steroid use in IgAN patients with proteinuria more than 1g/d was potentially beneficial for the kidney, but also predisposed to increased risk of predominantly serious adverse effects. However, definite conclusions regarding renal benefits could not be conclusively drawn due to premature termination of the trial (Lv et al, JAMA, 2017 Aug).

STOP-IgAN Trial
Another important study by Floege et al evaluated the results of secondary intention to treat analysis of the STOP-IgAN Trial. In this paper they separately analysed data from each immunosuppression subgroup and the corresponding patients on supportive care. Full clinical remission occurred in 11 (20%) patients receiving corticosteroid monotherapy and three (6%) patients on supportive care (odds ratio, 5.31; 95% confidence interval, 1.07 to 26.36; p=0.02), but the rate did not differ between patients receiving immunosuppressive combination and controls on supportive care (11% vs 4%, respectively; P=0.30). The end point of GFR loss ≥15 ml/min per 1.73 m2 did not differ between groups. Only corticosteroid monotherapy transiently reduced proteinuria at 12 months. Severe infections, impaired glucose tolerance, and/or weight gain in the first year were more frequent with either immunosuppressive regimen than with supportive care. They concluded that potential benefits from corticosteroid monotherapy in IgAN have to be balanced against the significant increase in adverse events, which stresses that novel, alternative therapeutic approaches to IgAN are urgently needed (Rauen et al, J Am Soc Nephrol, 2017 Oct).

B-cell depletion treatment in IgAN
A candidate therapy in IgAN is B-cell depletion using RTX. However, a small randomised controlled trial in patients at risk of progressive IgAN reports the failure of this therapy in reducing proteinuria over 1 year and more adverse events per patient were reported. Lafayette et al conducted an open label, multicentre, randomised study with 34 adult IgAN patients with proteinuria >1 g/d, maintained on RAS blockers that received standard therapy or RTX with standard therapy. eGFR did not change in either group. RTX did not significantly improve renal function or proteinuria assessed over 1 year. Although RTX effectively depleted B cells, it failed to reduce serum levels of galactose-deficient IgA1 and antigalactose-deficient IgA1 antibodies. (Lafayette et al, J Am Soc Nephrol, 2017 April).

Mycophenolate mofetil (MMF)  treatment in IgAN
An uncertain issue in the treatment of IgAN is the application of mycophenolate mofetil (MMF). Du B et al performed an meta-analysis where they evaluated a total of 297 publications. The quality of included studies was critically evaluated and only eight articles were finally included. Pooled results suggested that IgAN patients in MMF group had a higher remission rate than that in control groups of placebo or corticosteroid monotherapy. Compared to corticosteroid plus other immunosuppressive agent therapy, corticosteroid plus MMF therapy had a higher remission rate, lower serum creatinine doubling rate, progression to ESRD rate and side effects rate. They concluded that MMF has a potential role in treatment of IgAN, especially for Asians. (Du et al. BMC Nephrology, 2017 July).

Focal Segmental Glomerulosclerosis (FSGS)

SGLT2 inhibitors in FSGS
Sodium glucose cotransporter-2 inhibition (SGLT2i) therapy attenuates the progression of nephropathy. It is unclear whether SGLT2i provides renoprotection in non-diabetic kidney diseases such as FSGS. Rajasekeran et al evaluated the effect of 8 weeks of dapagliflozin on GFR in 10 patients with FSGS and in insubtotally nephrectomised (SNx) rats. In response to dapagliflozin, changes in GFR, renal plasma flow and 24-hour urine protein excretion were not statistically significant in humans or rats. The authors concluded that short-term treatment with the SGLT2i dapagliflozin did not modify renal hemodynamic function or attenuate proteinuria in humans or in experimental FSGS, which may be related to downregulation of renal SGLT2 expression (Rajasekeran et al, Am J Physiol Renal Physiol, 2017 Nov).

Rituximab treatment in FSGS
Roccatello et al investigated the use of RTX in 8 adult patients with idiopathic FSGS. RTX failed to improve proteinuria in 7 out of 8 patients, who had persistent nephrotic proteinuria. In one case, a rapidly deteriorating renal function was also observed. Only one patient showed an improvement in renal function and a remarkable reduction in proteinuria. They concluded that high-dose RT is ineffective for FSGS (Roccatello et al, Am J Nephrol 2017, July).

Membranous Nephropathy (MN)

Epitope spreading and the prognosis of MN
Several phospholipase A2 receptor (PLA2R1) epitopes have been characterised in MN and recently Seitz-Polski et al analysed the predictive value of PLA2R1-Ab titers and epitope spreading in a prospective cohort randomly allocated to RTX (n=29) or antiproteinuric therapy alone (n=29). At their baseline evaluation, the epitope profile did not correlate with age, sex, time from diagnosis, proteinuria, or serum albumin, but epitope spreading strongly correlated with PLA2R1-Ab titer. In adjusted analysis, epitope spreading at baseline was associated with a decreased remission rate at month 6 and last follow-up (Seitz-Polski et al, J Am Soc Nephrol, 2017 Nov).

Rituximab treatment  in MN
Wang et al recently showed that RTX could induce remission of proteinuria and stabilisation of renal function in resistant idiopathic MN patients, even in those with damaged renal function. They evaluated 36 MN patients who were non-responsive to prior immunosuppression. Fifteen (41.7%) patients achieved partial (n = 13) or complete (n = 2) response to the RTX treatment. Two of the 15 patients relapsed during the follow-up period with anti-PLA2R antibody reoccurrence and B-cell reconstitution. The second course of rituximab combined with tacrolimus induced a faster partial response again in one patient (Wang et al. Nephrol Dial Transplan 2017, Nov).

C3 Glomerulopathy (C3G)

Immunosuppressive treatment in C3G

The treatment of C3 glomerulopathy is still unclear and no therapeutic standard is defined with which novel strategies aimed at complement activation could be compared. Caliskan et al in their retrospective analysis compared the outcomes of 66 patients with C3 glomerulopathy who were treated with mycophenolate mofetil, with cyclophosphamide-based treatment, or by adopting conservative treatment methods. The primary outcome (CKD stage 5 or decrease of eGFR by more than 50%) was not significantly different between the groups with 25.8% of patients achieving the primary outcome within the median follow-up of 28 months. Although patients receiving immunosuppressive treatments had higher proteinuria and lower serum albumin at baseline, numerically the percentage of patients achieving the primary outcome was similar among mycophenolate-treated patients and patients on conservative treatment (29.6 vs. 31.3%, respectively). (Caliskan et al Am J Nephrol , 2017 July).

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55th ERA-EDTA Congress
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