IWG newsletter

   
Dear Friends,

In this seventh newsletter of Immunonephrology Working Group (IWG), you will find updates from the recently published articles on the immune-mediated renal diseases. We would like to inform you of the upcoming CME course of IWG which will be held in Madrid on June 3, 2017 and also introduce you our new board member (see below). Moreover, we would like to inform you as per the upcoming joint CME course given in cooperation between IWG, The Swedish Society of Nephrology and the Mayo clinic which will be held in Malmö (Sweden) on in September 19-20, 2017.

We are looking forward to meeting you during our CME courses. 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.

With kind regards,

Vladimir Tesar,  Chairman
Mårten Segelmark, Vice Chair

Yasar Caliskan, newsletter editor

Immunonephrology Working Group Newsletter, No. 7, May 2017
1. Upcoming joint meetings and CME courses

IWG CME course at 54th ERA-EDTA Congress, Madrid (Spain) on June 3, 2017
It is a great pleasure and honor for us to invite you to 54th ERA-EDTA Congress, Madrid (Spain) to attend the CME course of IWG “News in the pathogenesis and treatment of glomerular diseases”.

CME Course 1    Hall 10.A    08:30 - 11:45

News in the pathogenesis and treatment of glomerular diseases


Part I - Complement mediated diseases: pathogenesis, new entities, upcoming treatments, how to handle expensive drugs
- Complement activation in immune-mediated glomerular disease
Mohamed R. Daha, Leiden, The Netherlands
- Complement staining in kidney biopsy (C3, C4, C5b-9)
Pablo Cannata-Ortiz, Madrid, Spain
- Complement in ANCA-associated Vasculitis - new therapeutic target?
Annette Bruchfeld, Stockholm, Sweden
- Complement activation in IgA nephropathy, membranous nephropathy and FSGS
Yasar Caliskan, Istanbul, Turkey
- Targeting complement in atypical hemolytic uremic syndrome and C3 glomerulopathy
Giuseppe Remuzzi, Bergamo, Italy

Part II - Individualized (personalized) treatment of glomerular disease – is it already possible?
- Personalized immunomonitoring and treatment in lupus nephritis
Hans-Joachim Anders, Munich, Germany
- Personalized monitoring and treatment in membranous nephropathy
Jack F.M. Wetzels, Nijmegen, The Netherlands
- Personalized approach to IgA nephropathy, is supportive care the response for most patients?
Renato Monteiro, Paris, France
- Personalized treatment in ANCA-associated vasculitis
Mårten Segelmark, Linköping, Sweden
- Hematuria in glomerular disease - is it important for the outcome of the patients? Jesus Egido, Madrid, Spain


CME course in Malmö (Sweden) on September 19-20, 2017

Renal Implications of Advances in Immunology and Inflammation

The CME course in Malmö is organized through IWG in collaboration with the Swedish Society of Nephrology (SNF) and the Mayo Clinic. There has been enormous progress in the fields of immunology and inflammation in recent years. Now there is chance to learn the clinical implications for nephrologists of these achievements. The course is primarily intended for young specialists in Nephrology, however, it is open to anyone who wants to attend. You can access the web page of this CME course online:
https://mkon.nu/cme

Topics and speakers:
Bacterial infections and the kidney Catharina Svanborg, Kianush Kashani
Inflammation and metabolism Deborah Clegg, Biff Palmer
Systemic Vasculitis Ulrich Specks, Kerstin Westman, Sophie Ohlsson
Lupus nephritis/ Membranous nephropathy / Anti-GBM disease / IgA nephropathy Vladimir Tesar Fernando Fervenza, Mårten Segelmark, Rosanna Coppo
Renal Transplantation Carrie Schinstock
Genetic disorders and crystal nephropathies Peter Harris, Dawn Miller
Complement and renal disease Seppo Meri, Sanjeev Sehti
Renal tissue repair Martin Johansson, Stephen Textor

ERA-EDTA Travel grants available at http://www.enp-era-edta.org/#/enp/cme/malmo

2. News from IWG Board

New Board Member Election
One of our Board Members Pablo Javier Cannata (Spain) will be ending their term in the IWG Board. We thank him for his great contribution and service for IWG!

The IWG board elected a new member from three candidates who submitted their intention to serve as board members of the IWG for the next three years.

The newly elected IWG board member is:

• Cees van Kooten (Leiden, The Netherlands)

We congratulate our new board member!

Collaboration with the Japanese Society of Nephrology (JSN)
The IWG has recently agreed to start research collaboration with JSN in four areas related to nephron-immunology: ANCA vasculitis, renal biopsy registries, Lupus nephritis and IgA nephropathy. A first pilot project will be launched during 2017 and concerns comparisons of renal biopsy registry data on patients who have undergone renal biopsy due to acute/subacute nephritic syndrome. We hereby invite all European renal biopsy registries who wants to provide data for such a study to contact the IWG through marten.segelmark@liu.se

NEW!  Meet the Chair and Vice Chair of IWG!
Prof. Tesar (Chair) and Prof. Segelmark (Vice Chair) will be happy to meet 54th ERA-EDTA Congress delegates at the ERA-EDTA booth (No. 7.005) in the exhibition area!
Should you be coming to Madrid, do not miss this opportunity!
Read More→

3. Updates from recent publications

IgA Nephropathy (IgAN)
Phase 2b trial of oral drug candidate targeted-release formulation budesonide in primary IgA nephropathy (IgAN) patients have been eventually published online in The Lancet. The NEFIGAN trial was randomized, double-blinded, and placebo-controlled in male and female patients (aged ≥18 years) with primary IgAN and overt proteinuria considered at risk of progressing to end-stage renal disease (ESRD). The trial was conducted at 62 sites across 10 European countries between November 2012 and June 2015. Data from 149 patients constituted the final analysis set, from a total of 249 patients screened. Following a 6-month run-in phase (to optimize RAS blockade treatment), patients underwent a 9-month treatment phase in which they were randomized in a 1:1:1 ratio to receive targeted-release formulation budesonide at 16 mg/day, 8 mg/day or placebo. Targeted-release formulation budesonide 16 mg/day, added to optimised RAS blockade, reduced proteinuria in patients with IgAN. This effect is indicative of a reduced risk of future progression to ESRD. In the paper, clinical data are presented that demonstrate the potential of a novel, targeted-release formulation of the corticosteroid budesonide, as a new treatment for patients with primary IgAN targeting intestinal mucosal immunity upstream of disease manifestation (Fellström et al, Lancet 2017 March).

The IgAN Classification Working Group has established a well-characterized dataset from a large cohort of adults and children with IgAN that will provide a substrate for further studies to refine risk prediction and clinical utility, including the MEST-C score and other factors. A recent manuscript by this working group entitled “Oxford Classification of IgA Nephropathy: an update from the IgA Nephropathy Classification Working Group”, addressed crescents (C) as a predictor of renal outcomes and recommend that C be added to the MEST score, and biopsy reporting should provide a MEST-C score. Inconsistencies in the reporting of M and endocapillary cellularity (E) lesions have been reported, so a web-based educational tool to assist pathologists has been developed (Kidney Int 2017 May).

Clinical trials of mycophenolate mofetil (MMF) in IgAN have been inconclusive and have been limited by a lack of specific histological inclusion and exclusion criteria when recruiting patients. Beckwith et al reviewed histological changes after MMF therapy in their recent paper “Mycophenolate mofetil therapy in immunoglobulin A nephropathy: histological changes after treatment” including a cohort of 18 IgAN patients with native renal biopsies before and after repeated MMF treatment. Following MMF treatment, repeat biopsy demonstrated statistically significant improvement in the mean percentage of glomeruli showing endocapillary hypercellularity and cellular/fibrocellular crescents. Mesangial IgA deposition was also significantly reduced. Histopathological improvement persisted after the cessation of MMF therapy, suggesting that 2 years of treatment is adequate for benefit. The median serum creatinine remained stable at 3 years follow-up at 104 µmol/L (IQR 79-147). The authors concluded that MMF treatment is associated with histopathological improvement in IgAN (Nephrol Dial Transplant 2017 Jan).

Focal Segmental Glomerulosclerosis (FSGS)
In their study entitled “Interstitial fibrosis scored on whole-slide digital imaging of kidney biopsies is a predictor of outcome in proteinuric glomerulopathies” Mariani et al studied 315 participants in the Nephrotic Syndrome Study Network (NEPTUNE) study, including biopsy-proven minimal change disease (MCD=98), focal segmental glomerulosclerosis (FSGS=121), membranous nephropathy (MN=59) and IgA nephropathy (IgAN=37). Cortical Interstitial fibrosis (IF), tubular atrophy (TA) and interstitial inflammation (II) were quantified (%) on digitized whole-slide biopsy images, by five pathologists with high inter-reader agreement (intra-class correlation coefficient >0.8). Tubulointerstitial messenger RNA expression was measured in a subset of patients. IF was strongly correlated with baseline eGFR (P < 0.001) and proteinuria (P = 0.002). After adjusting for clinical pathologic diagnosis, age, race, global glomerulosclerosis, baseline proteinuria, eGFR and medications, each 10% increase in IF was associated with a hazard ratio of 1.29 (P < 0.03) for ESRD/40% eGFR decline, but was not significantly associated with CR. A total of 981 genes were significantly correlated with IF (| r | > 0.4, false discovery rate (FDR) < 0.01), including upstream regulators such as tumor necrosis factor, interferon gamma (IFN-gamma), and transforming growth factor beta 1 (TGF-B1), and signaling pathways for antigen presentation and hepatic fibrosis. The authors concluded that the degree of IF is associated with risk of eGFR decline across different types of proteinuric glomerulopathy, correlates with inflammatory and fibrotic gene expression, and may have predictive value in assessing risk of progression (Nephrol Dial Transplant 2017 February).

Results of another important pediatric study “Mycophenolate mofetil is inferior to tacrolimus in sustaining remission in children with idiopathic steroid-resistant nephrotic syndrome” reported by Sinha et al in Kidney Int, showed that the incidence of relapses was significantly higher for patients treated with MMF than tacrolimus (mean difference: 1.05 relapses per person-year). While there was no difference in the proportion of patients with sustained remission, the risk of recurrence of steroid resistance was also significantly higher for patients receiving MMF compared to tacrolimus (mean difference: 20.7%). Compared to tacrolimus, patients receiving MMF had a significantly (71%) lower likelihood of a favorable outcome and significantly increased risk of treatment failure (frequent relapses, steroid resistance). Thus, the authors concluded that replacing tacrolimus with MMF after six months of tacrolimus therapy for steroid-resistant nephrotic syndrome in children is associated with significant risk of frequent relapses or recurrence of resistance (Kidney Int. 2017 March).

Membranous Nephropathy (MN)
As we mentioned in the previous newsletter, GEMRITUX Study Groupreported the positive effect of rituximab (375 mg/m2, on days 1 and 8) on proteinuria remission after 6 months and also suggest that PLA2R-Ab levels are early markers of rituximab effect. An important paper by Rosenzwajg M et al entitled  “B- and T-cell subpopulations in patients with severe idiopathic membranous nephropathy may predict an early response to rituximab” recently reported that the patients who clinically responded to rituximab had a significantly lower percentage of Tregs at baseline compared to non-responders and a significantly increased percentage at day eight. Tregs remained unchanged in non-responders and in patients treated with supportive therapy alone. Thus, the authors concluded that evaluation of Tregs might be useful for predicting early response to rituximab (Kidney Int. 2017 March).

Another important paper entitled “A Proposal for a Serology-Based Approach to Membranous Nephropathy” was published in J Am Soc Nephrol 2017 February. In this study, findings propose that an individualized serology–based approach to membranous nephropathy (MN), used to complement and refine the traditional proteinuria–driven approach, will improve the outcome in this disease. The presence or absence of anti-PLA2R and anti-THSD7A antibodies was suggested to add important information to clinical and immunopathologic data in discriminating between primary and secondary MN. Levels of anti-PLA2R antibodies and possibly, anti-THSD7A antibodies were found to be tightly correlated with disease activity. Low baseline and decreasing anti-PLA2R antibody levels strongly predict spontaneous remission, thus favoring conservative therapy. Conversely, high baseline or increasing anti-PLA2R antibody levels associate with nephrotic syndrome and progressive loss of kidney function, thereby encouraging prompt initiation of immunosuppressive therapy. Serum anti-PLA2R antibody profiles reliably predict response to therapy, and levels at completion of therapy may forecast long-term outcome. Re-emergence of or increase in antibody titers precedes a clinical relapse. Persistence or reappearance of anti-PLA2R antibodies after kidney transplant predicts development of recurrent disease.

C3 Glomerulopathy
The area of complement related glomerular diseases has been further addressed by the recently published paper from Goodship et al “Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference” in Kidney Int, 2017 March. The objective of this conference was to gather a global panel of multidisciplinary clinical and scientific expertise to identify key issues relevant to the optimal management of these 2 diseases and to propose a research agenda to resolve outstanding controversial issues. In this report, the authors have made recommendations pertinent to the diagnosis and treatment of patients with these 2 diseases based on current expert opinion practices. They mentioned that though these 2 diseases presented as distinct entities, it is clear that there is substantial overlap not only in the pathogenesis but also in the clinical presentation such that some patients may show features of both.

ANCA Associated Vasculitis (AAV)
In April 2017, the Journal of the American Society of Nephrology (JASN) published the clinical results from the Phase II CLEAR trial, which demonstrated that avacopan (CCX168) an orally-administered complement inhibitor, specifically targeting the C5a receptor (C5aR) provides rapid and effective control of AAV while eliminating the need for chronic high doses of steroids, which are associated with significant safety issues. In conclusion, C5a receptor inhibition with avacopan was effective in replacing high-dose glucocorticoids in treating vasculitis. The ADVOCATE Phase III trial of avacopan in AAV is now underway, a randomized, double-blind two arm multi-center study enrolling 300 patients (Jayne DR et al.J Am Soc Nephrol. 2017 April).

Lupus Nephritis
An important study sought to assess the risk of renal flares during pregnancy in women with previous lupus nephritis in partial or complete remission, particularly in those with antidouble-stranded DNA antibodies and low complement levels, and the risk of new-onset nephritis in patients with stable/mildly active SLE. They assessed active nephritis (renal flares and de novo kidney disease) and associated predictors during pregnancy in patients with lupus with urine protein ≤1000 mg and serum creatinine <1.2 mg/dl at baseline; 373 patients (52% ethnic/racial minorities) enrolled between 2003 and 2012 were prospectively followed in the Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus Study. The study results demonstrated that de novo kidney involvement in SLE, even in ethnic/racial minorities, is uncommon during pregnancy. Past kidney disease and low C4 at baseline independently associate with higher risk of developing active nephritis. Antibodies to dsDNA alone should not raise concern, even in patients with past kidney disease, if in remission (Buyon JP et alClin J Am Soc Nephrol. 2017 April) .

References

  • Fellström BC, Barratt J, Cook H et al; NEFIGAN Trial Investigators. Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial. Lancet. 2017 Mar 28. pii: S0140-6736(17)30550-0. doi: 10.1016/S0140-6736(17)30550-0. [Epub ahead of print]
  • Trimarchi H, Barratt J, Cattran DC et al ; IgAN Classification Working Group of the International IgA Nephropathy Network and the Renal Pathology Society; Conference Participants. Oxford Classification of IgA nephropathy 2016: an update from the IgA Nephropathy Classification Working Group. Kidney Int. 2017;91(5):1014-1021.

  • Beckwith H, Medjeral-Thomas N, Galliford J et al. Mycophenolate mofetil therapy in immunoglobulin A nephropathy: histological changes after treatment. Nephrol Dial Transplant. 2017;32(suppl_1):i123-i128. doi: 10.1093/ndt/gfw326.

  • Mariani LH, Martini S, Barisoni L et al. Interstitial fibrosis scored on whole-slide digital imaging of kidney biopsies is a predictor of outcome in proteinuric glomerulopathies. Nephrol Dial Transplant 2017. doi: 10.1093/ndt/gfw443. [Epub ahead of print]

  • Sinha A, Gupta A, Kalaivani M, Hari P, Dinda AK, Bagga A Mycophenolate mofetil is inferior to tacrolimus in sustaining remission in children with idiopathic steroid-resistant nephrotic syndrome. Kidney Int. 2017 Mar 15. pii: S0085-2538(17)30070-4. doi: 10.1016/j.kint.2017.01.019. [Epub ahead of print]

  • Dahan K, Debiec H, Plaisier E et al. GEMRITUX Study Group. Rituximab for Severe Membranous Nephropathy: A 6-Month Trial with Extended Follow-Up. J Am Soc Nephrol 2017;28(1):348-358. doi: 10.1681/ASN.2016040449.

  • Rosenzwajg M, Languille E, Debiec H et al. B- and T-cell subpopulations in patients with severe idiopathic membranous nephropathy may predict an early response to rituximab. Kidney Int. 2017 Mar 15. pii: S0085-2538(17)30039-X. doi: 10.1016/j.kint.2017.01.012. [Epub ahead of print]

  • De Vriese AS, Glassock RJ, Nath KA, Sethi S, Fervenza FC. A Proposal for a Serology-Based Approach to Membranous Nephropathy. J Am Soc Nephrol. 2017;28(2):421-430. doi: 10.1681/ASN.2016070776.

  • Goodship TH, Cook HT, Fakhouri F et al ; Conference Participants. Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference. Kidney Int. 2017;91(3):539-551. doi: 10.1016/j.kint.2016.10.005.

  • Jayne DR, Bruchfeld AN, Harper L et al ; CLEAR Study Group. Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis. J Am Soc Nephrol. 2017 Apr 11. pii: ASN.2016111179. doi: 10.1681/ASN.2016111179. [Epub ahead of print]

  • Buyon JP, Kim MY, Guerra MM et al.  Kidney Outcomes and Risk Factors for Nephritis (Flare/De Novo) in a Multiethnic Cohort of Pregnant Patients with Lupus. Clin J Am Soc Nephrol. 2017 Apr 11. pii: CJN.11431116. doi: 10.2215/CJN.11431116. [Epub ahead of print]
Report prepared by Yasar Caliskan, Co-editor of IWG Newsletter