n. 11, April 2019

Dear colleagues,

 

In this 11th newsletter of the Immunonephrology Working Group (IWG), you will find some updates related to the 56th ERA-EDTA Congress to the held in Budapest (Hungary) and the new Scientific and Educational Interaction Day (SEID), an invitation to apply for IWG Board membership, the ERA-EDTA Fellowship programme and ongoing studies, as well as an update of recently published clinical results in the field of Immunonephrology.

 

Wishing you all the best.

 

With kind regards

 

Vladimir Tesar, Chairman

Marten Segelmark, Vice Chair

 

Cees van Kooten, newsletter co-editor

Gema Maria Fernandez Juarez, newsletter co-editor

Dimitrios Goumenos, newsletter co-editor

 

 

Call for candidates

 

We would like to remind you for the open Call for candidates to become an Immunonephrology Working Group (IWG) Board Member. In 2019 the Board composition must be partially renewed and 3 new members will be elected.

 

The deadline to apply is April 28, 2019. No candidatures sent after this date will be accepted; furthermore, candidatures not fulfilling all the above mentioned requirements, as per the Working Groups regulations, will not be taken into consideration.

 

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; ERA-EDTA Full members (exceptions to this last rule can only be made for non-nephrologists) in particular women and young members, are encouraged to actively participate in the election.

 

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 IWG secretariat will, indeed, collect the candidatures on behalf of the Working Group Vice Chair.

 

56th ERA-EDTA Congress (Budapest, Hungary) June 13-16, 2019

 

The 56th ERA-EDTA Congress will be held in Budapest (Hungary) on June 13-16, 2019.

We warmly suggest all IWG ordinary members not to miss the following Symposia:

 

ANCA-associated vasculitis - Friday, June 14 at 15.00-16.30

Primary glomerulonephritides - Friday, June 14 at 17.00-18.30

Complement mediated kidney injury - Saturday, June 15 at 11.45-13.15

 

In addition, on June 13 at 08.45 - 12.25 the Continuous Education and Professional Development (CEPD) course on ‘Primary and Secondary Glomerulonephritis, vasculitis and auto-immune diseases’ will be organised. The preliminary programme is outlined below:

 

Focal and segmental glomerulosclerosis (FSGS)

Claudio Ponticelli, Milan, Italy

Membranous Nephropathy

Jack Wetzels, Nijmegen, The Netherlands

IgA Nephropathy

Rosanna Coppo, Turin, Italy

New directions in the treatment of ANCA-associated nephritis

Marten Segelmark, Lund, Sweden

Lupus Nephritis

Vladimir Tesar, Prague, Czech Republic

 

We look forward to seeing you in Budapest!

Updates from recent publications

 

General

Floege et al (2019) Kidney Int 95:268-280; Rovin et al (2019) Kidney Int 95:281-295

Two reports have been published concerning the KDIGO Controversies Conference which was held in November 2018. It systematically presents outstanding consensus and controversies on pathogenesis, biomarkers and treatment in different glomerular diseases including IgAN, MN (part 1), LN, AAV and C3G (part 2).

 

Selewski et al (2018) KI Reports 3:1373-1384; Mariani et al (2019) AJKD 73:218-229

Cure Glomerulonephropathy (CureGN) is a multicenter (66 centers) prospective cohort study that will enroll 2,400 children and adults with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy/IgA vasculitis and a first diagnostic kidney biopsy within 5 years. Clinical data along with a digital archive of kidney biopsy images and blood and urine specimens at study visits aligned with clinical care 1 to 4 times per year will be collected. Patients are followed up for changes in estimated glomerular filtration rate, disease activity, ESKD, and death and for nonrenal complications of disease and treatment. The first baseline characteristics of 667 patients with IgAN/IgAV were published, highlighting clear clinical differences between these two disease entities.

 

IgAN/IgAV

Thompson et al (2019) cJASN 14:469-481

The aim of this Kidney Health Initiative project was to identify surrogate end points that could serve as reliable predictors of a treatment effects on long-term kidney outcomes in IgAN. The authors after systematic search of the literature obtained access to data from 13 randomized, controlled trials. Proteinuria was identified as the most widely recognized and well-studied risk factor for progression to ESKD in IgAN. These data support the use of proteinuria reduction as a reasonably likely surrogate end point for a treatment effects on the loss of kidney function and progression to ESKD in future trials enrolling a similar population.

 

Zewiger et al (2018) JASN 29:2722-2733

Urinary Dickkopf-3 (DKK3) has been identified as a potential biomarker for interstitial fibrosis and predictor for loss of renal function in patients with CKD. Urinary DKK3 was determined in 96 patients of the STOP-IgAN trial. A rise in urinary DKK3 levels (corrected for creatinine) was associated with a significant decline in eGFR within 6 months. In contrast, stable or decreasing urinary DKK3 indicated a more favourable course. Therefore, DKK3 measurements might be a tool to monitor CKD progression and assess effects of interventions.

 

Jarrick et al (2019) JASN 30: April 10, epub ahead of print

In a population-based cohort study in Sweden, involving patients with biopsy-verified IgAN diagnosed in 1974-2011 (3622 patients) were linked with 18,041 matched controls. Patients with IgAN showed a 1.53-fold increased risk for mortality (10.67 vs 7.45 per 1000 person-years) and a 6-year reduction in median life expectancy. Similar increases in risk were seen in comparisons with siblings and spouses.

 

SLE/LN

Rovin et al (2019) Kidney Int 95:219-231

The AURA-LV study investigated the effect of two doses of the calcineurin inhibitor voclosporin (23.7 mg or 39.5 mg, each twice daily) vs. placebo, added to standard-of-care induction therapy (mycophenolate mofetil (2 g/d) and rapidly tapered low-dose oral corticosteroids) for induction of remission lupus nephritis (LN). Two hundred sixty-five subjects from 79 centers in 20 countries were recruited and randomized to treatment for 48 weeks. Complete renal remission (CRR) at week 24 was achieved by 32.6%, 27,3% and 19,3% of subjects in the low-dose, high-dose and placebo group respectively (OR=2.03 for low-dose voclosporin versus placebo). The greater CRR rate in the low-dose voclosporin group persisted at 48 weeks. However, there were more serious adverse events in both voclosporin groups. Therefore, although the addition of low-dose voclosporin to mycophenolate mofetil and corticosteroids in active LN results in an improved renal response, this comes at the cost of higher rates of adverse events, including death.

 

Wilson et al (2019) Kidney Int 95:655-665

With the emergence of complement directed therapeutics, it is of increasing importance to have a close monitoring of complement activation products. In this study, 57 biopsies from patients with LN were stained for complement products, including the end-product of the complement cascade (C5b-9). Glomerular staining for C5b-9 was not able to discriminate between active and chronic disease (high in both conditions), whereas staining for C3c or the macrophage marker CD68 was associated with active disease. This limits the use of glomerular C5b-9 deposition as a biomarker to identify patients with LN and ongoing C5 activation.

 

AAV

Hogan et al (2019) KI reports 4:551-560

This study describes the Glomerular Disease Collaborative Network ANCA vasculitis inception cohort, comparing patients who completely stopped immunosuppressive therapy with those who continued for more than 2 years. From a cohort of 427 patients, 65% stopped therapy at a median time of 20 months from induction therapy. Stopping was more frequent in women and in patients who had received methylprednisolone, and was associated with fewer relapses.

 

MN

Bobart et al (2019) Kidney Int 95:429-438; Zaghrini et al (2019) Kidney Int 95:666-679

Autoantibodies against phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type 1 domain-containing 7A (THSD7A) are emerging as biomarkers to classify membranous nephropathy (MN) and to predict outcome or response to treatment. In a cohort of patients from the Mayo Clinic, positivity for PLA2R antibodies were correlated with biopsy findings and primary vs secondary causes of membranous nephropathy. It is concluded that in patients with preserved renal function and no indications for secondary causes, positivity for PLA2R antibodies is highly predictive for the tissue diagnosis of MN. A prospective study will be required to demonstrate the value of the antibodies as a non-invasive diagnostic tool (Bobart et al).

Until recently, anti-THSD7A autoantibodies had to be detected by Western blot or indirect immunofluorescence test (IIFT). Zaghiri et al now describe a sensitive enzyme-linked immunosorbent assay (ELISA) optimized for quantitative detection of anti-THSD7A autoantibodies. Among 1012 biopsy-proven MN patients from 6 cohorts, 28 THSD7A-positive patients were identified by ELISA, indicating a prevalence of 2.8%. By screening additional patients, mostly referred because of PLA2R1-unrelated MN, 21 more cases were identified, establishing a cohort of 49 THSD7A-positive patients. Anti-THSD7A autoantibodies were predominantly IgG4 in all patients, and eight patients were double positive for THSD7A and PLA2R1. Levels of anti-THSD7A autoantibodies correlated with disease activity and with response to treatment.

 

Seikrit et al (2018) N Eng J Med 379:2479-2481

Autoantibodies directed against the complement regulatory molecule factor-H are frequently observed in patients with aHUS. A case report of Seikrit et al describe a patient with PLA2R-positive MN, who developed anti-CFH autoantibodies and showed subsequent impaired renal function. Analysis of a larger cohort (92 patients) identified 2 additional patients with anti-CFH antibodies. Since anti-CFH antibodies can interfere with the regulatory function of factor-H, this adds a new dimension on the complement activation and glomerular C3 deposition, in a disease mainly driven by non-complement-fixing IgG4 autoantibodies.

 

FSGS

Trachtman et al (2018) JASN 29:2745-2754

In this randomized, double-blind, active-control Phase 2 study, the authors evaluated and compared the effects of sparsentan, a dual endothelin type A (ETA) and angiotensin II type 1 receptor antagonist, with those of the angiotensin II type 1 receptor antagonist irbesartan in patients with FSGS. The patients received sparsentan (200, 400, or 800 mg/d) or irbesartan (300 mg/d) for 8 weeks, followed by open-label sparsentan only. Of 109 patients randomized, 96 received study drugs. Sparsentan-treated patients had greater reductions in UP/C than irbesartan-treated patients did when all doses (45% versus 19%; P=0.006) or the 400 and 800 mg doses (47% versus 19%; P=0.01) were pooled for analysis. After 8 weeks of treatment, BP was reduced with sparsentan but not irbesartan, and eGFR was stable with both treatments. Overall, the incidence of adverse events was similar between groups. Patients with FSGS achieved significantly greater reductions in proteinuria after 8 weeks of sparsentan versus irbesartan. Sparsentan was safe and well tolerated. This clinical trial has been criticized whether the patients were truly primary FSGS or they are a mix of secondary and primary FSGS (most of the patients do not have nephrotic syndrome). In any case, Sparsentan-treated patients had greater reductions in UP/C than irbesartan-treated patients

 

Nephrotic Syndrome

Sinha et al (2019) Kidney Int 95:210-218

This single center open label trial enrolled 149 children with frequently relapsing or steroid-dependent Nephrotic Syndrome, comparing treatment with MMF or levamisole for 1 year. There were no significant differences in different clinical (remissions, relapse rates, steroid resistance or steroid toxicity) and immunological parameters between both treatment arms.

 

Remy et al (2018) Kidney Int 94:1217-1226

In this open label randomized trial, 116 adult patients with Minimal Change Nephrotic Syndrome were treated with either low dose steroids in combination with MMF or with standard oral corticosteroids. The primary endpoint of complete remission after 4 weeks was reached in 91% of cases. Also secondary outcomes, including remission at 24 weeks and relapses during 1 year follow up, was not different between groups.

 

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