IWG newsletter

   
Dear Friends,

In this sixth newsletter of Immunonephrology Working Group (IWG), you will find updates from the recently published articles and late-breaking clinical trials on the immune-mediated renal diseases. Moreover, we would like to inform you of the upcoming CME course of IWG which will be held in Madrid on June 3, 2017 and the joint CME course held in cooperation between IWG, the Swedish Society of Nephrology and the Mayo Clinic which will be held in Malmö, Sweden on 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 Member.

Wishing you good health, happiness and success in 2017 and always.

With kind regards,

Vladimir Tesar,  Chairman
Mårten Segelmark, Secretary

Yasar Caliskan, newsletter editor

Immunonephrology Working Group Newsletter, No. 6, January 2017
   
1. Upcoming joint meetings and CME courses

IWG CME course, 54th ERA-EDTA Congress in Madrid (Spain) on June 3, 2017
It is a great pleasure and honour for us to invite you to 54th ERA-EDTA Congress, Madrid to attend the CME course of IWG “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 (Sweden) is organised by IWG in collaboration with the Swedish Society of Nephrology (SNF) and the Mayo Clinic. The course is primarily intended for young specialists in Nephrology who want to deepen their knowledge in Immunology and to understand how progress in this field can influence the care of patients with renal disease. The course is, however, open to anyone who wants to attend. You can access the web page of this CME course online:
www.malmokongressbyra.se/cme

2. News from IWG Board

One of our Board Members will end his term in the IWG in 2017. We encourage all IWG members to consider to candidate for the election of a new Board Member.
Before applying, please read the Working Groups regulations carefully and consider that to be eligible for the Board a member must have been an ordinary member of the WG for at least 2 years (or from its creation) or have a proven track record of relevant scientific expertise that would justify his/her being part of the Board; he/she must also be an active ERA-EDTA Full member: exceptions to this last rule can only be made for non-nephrologists. To download the Working Groups regulations, click here.

In order to apply, each candidate must send his/her application and CV (the use of this special template is mandatory) together with two supporting letters from two IWG members (Board or Ordinary members) to: immunonephrology@era-edta.org.

The deadline to apply is March 15, 2017

3. Updates from recent publications

IgA Nephropathy (IgAN)

Let us start with a study of B cells depleting therapy in IgAN entitled “A Randomized, Controlled Trial of Rituximab in IgA Nephropathy with Proteinuria and Renal Dysfunction” published in J Am Soc Nephrol, 2016 November. In their open label randomized multicenter study, Lafayette et al. assessed adding rituximab to standard treatment. Although rituximab effectively depleted B cells, rituximab did not significantly improve renal function or proteinuria assessed over 1 year. Rituximab treatment also failed to reduce serum levels of galactose-deficient IgA1 and antigalactose-deficient IgA1 antibodies.

In a large IgAN cohort pooled from four retrospective studies, Mark Haas et al. addressed crescents as a predictor of renal outcomes and determined whether the fraction of crescent-containing glomeruli associates with either a ≥50% decline in eGFR or ESRD (combined event) adjusting for covariates used in the original Oxford study. In this study entitled “A Multicenter Study of the Predictive Value of Crescents in IgA Nephropathy”, having crescents in at least one sixth or one fourth of glomeruli associated with a hazard ratio (95% CI) for a combined event of 1.63 (1.10 to 2.43) or 2.29 (1.35 to 3.91), respectively, in all 3096 patients. The authors propose adding the following crescent scores to the Oxford Classification: C0 (no crescents); C1 (crescents in less than one fourth of glomeruli), identifying patients at increased risk of poor outcome without immunosuppression; and C2 (crescents in over one fourth of glomeruli), identifying patients at even greater risk of progression, even with immunosuppression (J Am Soc Nephrol, 2016 September).

Focal Segmental Glomerulosclerosis (FSGS)

In their study entitled “Krüppel-Like Factor 15 (KLF15) Mediates Glucocorticoid-Induced Restoration of Podocyte Differentiation Markers” Mallipattu et al showed that in vitro treatment with dexamethasone induced a rapid increase of KLF15 expression in human and murine podocytes and enhanced the affinity of glucocorticoid receptor binding to the promoter region of KLF15. Importantly, the level of KLF15 expression in the podocytes and glomeruli from human biopsy specimens correlated with glucocorticoid responsiveness in 35 patients with minimal change disease or primary FSGS. (J Am Soc Nephrol, 2016 June).

Results of another important study “T Lymphocyte Activation Markers as Predictors of Responsiveness to Rituximab among Patients with FSGS” reported by Chan et al in Clin J Am Soc Nephrol, identified prognostic markers for responsiveness to Rituximab. In their FSGS cohort, they showed that activated CD154(+) CD4(+) CD3(+) <83.3% (AUC, 0.81; 95% CI, 0.61 to 1.00), IFN-γ(+) CD3(+)<2.5% (AUC, 0.90; 95% CI, 0.75 to 1.00), and IL-2(+) CD3(+) <0.3% (AUC, 0.78; 95% CI, 0.57 to 0.98) were good predictors of rituximab response (Clin J Am Soc Nephrol, 2016 August).

Membranous Nephropathy (MN)

In a recent paper “An Indirect Immunofluorescence Method Facilitates Detection of Thrombospondin Type 1 Domain-Containing 7A-Specific Antibodies in Membranous Nephropathy” published in J Am Soc Nephrol 2016 July, Hoxha et al screened serum samples of 1276 patients with MN from three different cohorts for the presence of THSD7A-Ab by Western blot analysis and a newly developed indirect immunofluorescence test (IFT). Patients with THSD7A-associated MN differ in their clinical characteristics from patients with PLA2R1-associated MN, and more intensive screening for the presence of malignancies seems to be warranted in those with THSD7A-associated MN.

Another important paper entitled “Rituximab for Severe Membranous Nephropathy: A 6-Month Trial with Extended Follow-Up” was published in J Am Soc Nephrol 2016 July. In this multicenter, randomized, controlled trial at 31 French hospitals, GEMRITUX Study Group reported the positive effect of rituximab (375 mg/m2, on days 1 and 8) on proteinuria remission after 6 months. Their data also suggest that PLA2R-Ab levels are early markers of rituximab effect and that addition of rituximab to nonimmunosuppressive antiproteinuric treatment does not affect safety.

ANCA Associated Vasculitis (AAV)

The 2009 European League Against Rheumatism (EULAR) recommendations for the management of ANCA-associated vasculitis (AAV) have in collaboration with the IWG ERA-EDTA been updated and published in Ann Rheum Dis, 2016 September. Fifteen recommendations were developed, covering general aspects, such as attaining remission and the need for shared decision making between clinicians and patients. More specificly For remission induction in life-threatening or organ-threatening AAV, cyclophosphamide and rituximab are considered to have similar efficacy; plasma exchange which is recommended, in the setting of rapidly progressive renal failure or severe diffuse pulmonary hemorrhage.

CCX168 is an orally-administered complement inhibitor, specifically targeting the C5a receptor (C5aR), which binds the complement fragment C5a. The European CLEAR trial was a 3-step randomized, double-blind, placebo-controlled Phase II trial designed to evaluate the safety and efficacy of CCX168 in patients with ANCA-associated vasculitis (AAV) on background cyclophosphamide or rituximab treatment. The study parameters included global vasculitis disease activity, as measured by Birmingham Vasculitis Activity Score, urinary albuminuria, estimated glomerular filtration rate (eGFR) based on serum creatinine, hematuria (based on microscopic RBC count), and urinary MCP-1:creatinine ratio. The results of this study are expecting to be published.

Lupus Nephritis

An important paper related to MAINTAIN trial is “Long-term follow-up of the MAINTAIN Nephritis Trial, comparing azathioprine and mycophenolate mofetil as maintenance therapy of lupus nephritis“ published in Ann Rheum Dis, 2016 March.The long-term follow-up data of the MAINTAIN Nephritis Trial do not demostrate that mycophenolate mofetil is superior to azathioprine as maintenance therapy in a Caucasian population suffering from proliferative lupus nephritis. Moreover, the study results demonstrated the prognostic importance and predictive value of an early proteinuria decrease for long-term renal outcomes.

4. Updates from late-breaking clinical trials (ASN Kidney Week 2016)

Furthermore we would like to draw your attention to the results (presented at ASN Kidney Week 2016, November 19 in Chicago, IL) of two high-impact clinical trials that could affect kidney-related medical care.

AURA-LV Trial “Successful Treatment of Active Lupus Nephritis with Voclosporin” by Pendergraft et al. This study enrolled 265 patients who were randomized to receive either 23.7 mg or 39.5 mg of voclosporin twice daily, or placebo. After 24 weeks of treatment, 32.6% of patients in the low-dose group and 27.3% of those in the high-dose group achieved complete remission, compared to 19.3% in the placebo group. Both voclosporin doses were also better than placebo in achieving partial remission, and in the time it took for patients to reach partial or complete remission.

The DUET Trial “Efficacy and Safety of Sparsentan, a Dual Angiotensin II (Ang II) and Endothelin (ET) Type A Receptor Antagonist, in Patients with Focal Segmental Glomerulosclerosis (FSGS): A Phase 2 Trial” by Howard Trachtman et al. The DUET study is a randomized, double-blind clinical trial in which investigators assigned 109 FSGS patients aged 8–71 years to receive daily oral doses of 200 mg, 400 mg, or 800 mg of sparsentan or 300 mg of irbesartan. After an 8-week treatment period, all patients were eligible to receive sparsentan as part of the study's open-label extension. After the 8-week treatment period, 28.1% of sparsentan recipients achieved the secondary endpoint of modified partial remission of proteinuria compared with 9.4% of irbesartan-treated patients, a significant difference between the medications. After 48 weeks of sparsentan treatment, 57.7% of patients achieved partial remission.

References

• Lafayette RA, Canetta PA, Rovin BH et al. A Randomized, Controlled Trial of Rituximab in IgA Nephropathy with Proteinuria and Renal Dysfunction. J Am Soc Nephrol 2016 Nov 7. pii: ASN.2016060640. [Epub ahead of print]

• Haas M, Verhave JC, Liu ZH et al. A Multicenter Study of the Predictive Value of Crescents in IgA Nephropathy. J Am Soc Nephrol 2016 Sep 9. pii: ASN.2016040433. [Epub ahead of print]

• Hogan MC, Reich HN, Nelson PJ et al. The relatively poor correlation between random and 24-hour urine protein excretion in patients with biopsy-proven glomerular diseases. Kidney Int 2016; 90(5) :1080-1089.

• Mallipattu SK, Guo Y, Revelo MP et al. Krüppel-Like Factor 15 Mediates Glucocorticoid-Induced Restoration of Podocyte Differentiation Markers. J Am Soc Nephrol 2016 Jun 10. pii: ASN.2015060672. [Epub ahead of print]

• Chan CY1, Liu ID1, Resontoc LP et al. T Lymphocyte Activation Markers as Predictors of Responsiveness to Rituximab among Patients with FSGS. Clin J Am Soc Nephrol 2016;11(8):1360-8.

• Hoxha E, Beck LH Jr, Wiech T et al. An Indirect Immunofluorescence Method Facilitates Detection of Thrombospondin Type 1 Domain-Containing 7A-Specific Antibodies in Membranous Nephropathy. J Am Soc Nephrol 2016 Jul 19. pii: ASN.2016010050. [Epub ahead of print]

• Dahan K, Debiec H, Plaisier E et al. Rituximab for Severe Membranous Nephropathy: A 6-Month Trial with Extended Follow-Up. J Am Soc Nephrol 2016 Jun 27. pii: ASN.2016040449. [Epub ahead of print]

• Damoiseaux J, Csernok E, Rasmussen N et al. Detection of antineutrophil cytoplasmic antibodies (ANCAs): a multicentre European Vasculitis Study Group (EUVAS) evaluation of the value of indirect immunofluorescence (IIF) versus antigen-specific immunoassays. Ann Rheum Dis 2016 Aug 1.

Report prepared by Yasar Caliskan, Co-editor of IWG Newsletter