IWG newsletter
Newsletter 1, 2014

Dear Colleagues and Friends,

We are happy to share with you some recent advancements  in the field of immune-mediated renal diseases  of  the ERA-EDTA Immunonephrology Working Group (IWG).  We had the honor to be given the research support of  the first ERA-EDTA research grant in 2009 and we are proud to annonce that the ERA-EDTA supported project was very successful, establishing  a  true European network (VALIGA) , gathering more than 1000 patients with IgA nephropathy thoroughy investogated. The  results have been recently published  in Kidney International. From this VALIGA studies several collateral studies have been gererated, which are on the way . Moreover the IWG has launched an impulsion grant and awarded in 2014 some excellent proposals, which represent the future expansion of researches under the umbrella of this very active WG of the ERA-EDTA.

You are hearthly invited to join us!

Rosanna Coppo,  Chairman of Immunonephrology Working Group
Mohamed R.Daha, Secretary of the Immunonephrology Working Group

1. The largest cohort of patients with IgA nephropathy  reported in the literature (VALIGA) was aimed at  validating the Oxford classification of IgA nephropathy,  but has gathered much more information on this common renal disease

Oxford histologic classification of IgA nephropathy (1) was developed by the intenational consensus working group based on the retrospective analysis of clinical and histopathological data of 265 adults and children with a median follow-up of 5 years with the aim to find the histologic parameters which could contribute to the better prediction of the prognosis of the patients.  Four parameters:  1. mesangial hypercellularity (M), 2. segmental glomeruloclerosis (S), 3. endocapillary hypercellularity (E) and 4. tubular atrophy/interstitial fibrosis (T) were demonstrated to be independently related to the renal outcome.  However the original cohort of the patients was relatively small.
The recently published VALIGA study (2) launched  by ERA-EDTA IWG and supported by the first research grant of ERA-EDTA  in 2009 and aimed at validation of Oxford classification in a much larger retrospective cohort of 1147 patients from 13 European countries  and could also look at the interaction of treatment with histologic classification as 86% of patients received renin-angiotensin blockade and 42% of patients were treated by corticosteroids/ immunosuppressive drugs.  Mesangial hypercellularity (M), segmental glomerulosclerosis  (S) and tubular atrophy/interstitial fibrosis  (T) were confirmed as independent predictors of estimated glomerular filtration rate and poorer renal survival and their value was also assessed in patients not represented in the original Oxford cohort. In individuals with eGFR less than 30 ml/min per 1.73 m2, the M and T lesions independently predicted a poor survival. In those with proteinuria under 0.5 g/day, both M and E lesions were associated with a rise in proteinuria to 1 or 2 g/day or more. The addition of M, S, and T lesions to clinical variables significantly enhanced the ability to predict progression only in those who did not receive immunosuppression.
The VALIGA study thus provided a  validation of the Oxford classification in a large European cohort of IgAN patients covering  the whole spectrum of the disease.  Notably,  the independent predictive value of pathology MEST score was shown to be reduced by glucocorticoid/immunosuppressive therapy.

1.
Working Group of the International IgA nephropathy Network and the Renal Pathology Society et al.: The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Int., 2009, 76: 534 – 545.
2.
Coppo,R., Troyanov,S., Bellur,S., et al.: Validation of the Oxford classification of IgA nephropathy in cohorts with different presentations and treatments. Kidney Int., 2014 Apr 2. Doi: 10.1038/ki.2014.63 (epub ahead of print)

2. POST-VALIGA projects launched

Cooperation in the VALIGA project helped to establish international cooperation in the field of IgA nephropathy and  5 basic Post-VALIGA project were suggested  combining the available (and putatively further expanding) clinical database with use of the material (genetic samples, serum, urine) from existing biobanks and/or prospective collection of new blood, urinary, salivary and rectal samples.  Coordinators of each shortly described projects can be contacted by further physicians interested in the cooperation in the translational research in IgA nephropathy. 

1) A GENOME-WIDE ASSOCIATION STUDY (GWAS) FOR IGAN SEVERITY AND PROGRESSION
Coordinators:  Ali Gharavi and Krzysztof Kiryluk , New York, USA,  Rosanna Coppo, Torino, Italy
Aim of this project is to identify additional genetic variants which may influence the severity of disease at presentation and the risk of progression to end-stage renal failure performing a GWAS in the VALIGA cohort to identify variants linked to Oxford pathology scores ad baseline.

Kiryluk,K., Li,Y., Sanna-Cherchi,S., et al.: Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis.  PLoS Genet., 2012, 8: e1002765. doi: 10.1371/jounal.pgen.1002765.

2) INTERFERON REGULATED IMMUNOPROTEASOMES, GENETIC  CONDITIONING, EXPRESSION OF LYMPHOMONOCYTES AND CORRELATION WITH CLINICAL AND PATHOLOGY DATA AND  PROGRESSION
Coordinators: Rosanna Coppo, Turin, Italy, Ali Gharavi and  Krzysztof Kiryluk , New Your, USA
One of the five loci identified in recent GWAS to be associated with IgAN includes the PSMB8 and PSMB9 genes (Kiryluk et al., 2012), which encode immunoproteasome units previously found to be upregulated in peripheral blood mononuclear cells from individuals with IgAN (Coppo, et al., 2009). The hypothesis behind this project is that other IgAN risk loci are associated with additional sequential hits in the immune system that influence the development and progression of IgAN, e.g. a switch to an immuno-proteasome in peripheral blood mononuclear cells of patients with IgAN could result in increased efficiency of antigen processing and presentation, leading to increased production of immune complexes. 

Coppo,R., Camilla,R., Alfarano,A., et al.: Upregulation of the immunoproteasome in peripheral blood mononuclear cells of patients with IgA nephropathy. Kidney Int., 2009, 75: 536 – 541.

Kiryluk,K., Li,Y., Sanna-Cherchi,S., et al.: Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis.  PLoS Genet., 2012, 8: e1002765. doi: 10.1371/jounal.pgen.1002765.

3) THE ROLE OF COMPLEMENT SYSTEM IN DETERMINING OUTCOME OF IGA NEPHROPATHY
Coordinators: Jurgen Floege, Germany,  Mohamed Daha, Netherlands
Complement analyses such as C3, C4 or CH50 usually reveal no abnormalities in patients with IgAN, using very sensitive techniques, however,  systemic complement activation and activation  of the MBL-pathway in addition to the alternative pathway of complement  be demonstrated in IgAN. In this project C3, its catabolic fragments, C3a, C5a and C3d, complement H factor and its variants and MBL will be measured in the available samples from the STOP-IgAN study (Eitner et al.,  2008) and related to clinical data.  Potential newly identified markers will then be validated in independent population, e.g. VALIGA cohort.

Eitner,F., Ackermann,D., Hilgers,R.D., et al.: Supportive versus immunosuppressive therapy of progressive IgA nephropathy (STOP) IgAN trial: rationale and study protocol. J. Nephrol., 2008, 21: 284 – 289.

4) THE ROLE OF THE SALIVARY AND FECAL MICROBIOMA IN THE PATHOGENESIS OF PRIMARY IGA NEPHROPATHY
Coordinators: Loreto Gesualdo, Italy, Marco Gobbeti, Italy
Recently composition of the gut microbiota was shown to influence the immune system and disease development in nonmucosal organs (Chervonsky et al.,  2010) and may also play an important role in IgA nephropathy (De Angelis et al., 2014). The primary source of IgA contained in polymeric IgA-containing immunocomplexes deposited in the kidney of patients with IgAN was speculated to involve mucosal tissues, tonsils, and bone marrow. In IgAN commensal microbiota may participate in the breakdown of the normal mucosal barrier in the gut, stimulating IgA production and perturbation of B cell tolerance.
Salivary and fecal microbiota will be studied in different subgroups of patients with IgAN in relation to galactose-deficient IgA and circulating levels of BAFF and APRIL  with the aim to assess the potential role of microbiota in the progression of IgA nephropathy.

De Angelis,M., Montenumo,E., Piccolo,M., et al.: Microbiota and metabolome associated with immunoglobulin A nephropathy (IgAN). PLoS One, 2014, 12, 9: e99006.   doi: 10.1371/journal.pone.0099006.

Chervonsky,A.V.: Influence of microbial environment on autoimmunity. Nat. Immunol., 2010, 11: 28  - 35.

5) SOLUBLE TRANSFERRIN RECEPTOR IN URINE,  A NEW BIOMARKER FOR IGA NEPHROPATHY AND HENOCH-SCHOENLEIN PURPURA
Coordinator:  Marlijn Speeckaert,  Raymond Vanholder, Belgium
Upregulated soluble transferrin receptor (sTfR) might be excreted in urine and serve as a biomarker to monitor disease activity and therapeutic response in both IgAN and Henoch-Schoenlein purpura (HSPN). In the already published cross-sectional study urinary sTfR concentrations were markedly higher in patients with active IgAN or HSPN compared to other morphological types of glomerulonephritis  and higher in patients with active IgAN and HSPN compared to patients in remission (Delanghe et al., 2013). In the proposed study these results will be validated in VALIGA patients, histologically classified and with available data on progression and outcome.

Delanghe,S.E., Speeckaert,M.M., Segers,H., et al.: Soluble transferrin receptor in urine, a new biomarker for IgA nephropathy and Henoch-Schoenlein purpura nephritis. Clin. Biochem., 2013, 46: 591 – 597.

3. Impulsion grants of Immunonephrology working group

In 2013 Immunonephrology Working Group opened a call for impulsion grants, four projects which succeeded and are supported are shortly described

1)  EVALUATION OF THE CTGF - EGFR AXIS, AS A MODULATOR OF THE TH17 IMMUNE RESPONSE IN INFLAMMATION DRIVEN KIDNEY FIBROSIS

Principal investigator: Marta Ruiz Ortega, Spain

Suggested project will investigate if silencing connective tissued growth factor (CTGF) could reduce experimental inflammation driven kidney fibrosis and if this putative reduction is associated with impariment of EGFR and/or inhibition of the Th17 response.

2) URINARY EXOSOMES IN IGA NEPHROPATHY

Principal investigator: Harry Holthofer, Finnland

In this project exosome protein content will be studied in patients at different stages of IgA nephropathy with the aim to find out new, accurate, non-invasive and nonexpensive markers of IgAN, its activity and outcome.

3) A NOVEL APPROACH TO SEARCH FOR CIRCULATING FACTORS OF POST-TRANSPLANT RECURRENCE OF IDIOPATHIC NEPHROTIC SYNDROME

Principal investigators:  Mario Ollero, Djillali Sahali, France

The aim of the proposed study is to determine blood levels of these potential factors and their association with post-transplant INS recurrence and characterize their functional impact on glomerulus and podocyte.

4) CLASSIFICATION/GRADING OF HISTOPAHTOLOGICAL LESIONS IN RENAL AMYLOIDOSIS AL

Principal investigator:  Sandrine Florquin, Belgium

The aim of the study is to review the renal biopsies  of  patients with AL and categorize the localization and the degree of amyloid deposits and non-amyloid related histological lesions and finally  propose a classification of these histological lesions according to their clinical relevance.  

Report prepared by:  Vladimir Tesar, IWG Board Member