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LA NEFROPATIA A DEPOSITI MESANGIALI DI IgA University of Bari C.A.R.S.O. Consortium Valenzano, Bari F.P. Schena

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ADULTS (Incidence) IgA Nephropathy 25 new cases/pmp/year Membranous glomerulopathy12 new cases/pmp/year INCIDENCE OF PRIMARY GLOMERULONEPHRITIS WORLDWIDE -Systematic review of the literature- A.McGrogan et al NDT 26, 414, 2011

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The most common primary glomerulonephritis in the world: 2.5 cases/y/100,000 adults >16% in the general population: -autopsy studies (Waldherr R. et al NDT 1989) -time 0 protocol RB (Suzuki K. et al. Kidney Int 2003) Prevalence should be 250 cases/pmp in adults IgA NEPHROPATHY

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High prevalence in East Asia - laws - preventive medicine Intermediate prevalence in North America and Europe - no preventive medicine - RB in patients with documented CRF (North America) Low prevalence in Africa - no preventive medicine - reduced use of immunofluorescence technique Different distribution in the world

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RESEARCH GROUP ON PROGRESSIVE CHRONIC RENAL DISEASE LONG-TERM SURVIVAL OF PRIMARY GLOMERULONEPHRITIS IN JAPAN (1850 RB) Nephron 82, 205, 1999

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After 5 years96% 1085% 1575% 2061% RESEARCH GROUP ON PROGRESSIVE CHRONIC RENAL DISEASE IgAN renal survival from the apparent onset of the disease or earliest known renal abnormalities in Japan Nephron 82, 205, 1999

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CUMULATIVE FAILURE ESTIMATED BY KAPLAN-MEIER METHODS AS A FUNCTION OF HISTOLOGICAL CLASS IN 473 IgAN PATIENTS. THE END POINT OUTCOME IS REPRESENTED BY ESRD REQUIRING DIALYSIS OR TRANSPLANTATION C.Manno,.. and F.P.Schena et al. AJKD, 49: 763-775, 2007

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T.Knoop,.. and R.Bjmeklett, AJKD, 2013 KIDNEY BIOPSY REGISTRY. KAPLAN-MEIER PLOTS OF EXPECTED VERSUS OBSERVED MORTALITY IN NORWEGIAN IgAN PATIENTS.

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DEFINITION OF PATIENTS WITH FAMILIAL AND SPORADIC IgAN The relatives of at least 3 generations of each IgAN patient are checked for urinalysis Sporadic IgAN. Negative urinalysis in all relatives Familial IgAN. At least two relatives with biopsy-proven IgAN Suspectable Familial IgAN. Relatives with persistent microscopic hematuria without renal biopsy

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MH 15.6% P 3% MH+P 4% 77.4% IgAN Families MH+P 0.3% P 2% MH 2% 95.7% Normal population F.P.Schena Kidney Int. 48, 1998, 1995 FREQUENCY OF URINARY ABNORMALITIES IN 269 RELATIVES FROM 48 FAMILIES OF IgAN PATIENTS AND IN 8255 STUDENTS

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Mucosal infections Immunological system (innate and adaptive immunity) Abnormal production of deglycosylated IgA1 Deposition of polymeric IgA1 and IgA1-IgG immunocomplexes at glomerular level PATHOGENESIS OF IMMUNOGLOBULIN A NEPHROPATHY (IgAN)

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B cells encounter the antigen at mucosal level. Then, they migrate to the bone marrow and become the major source of aberrantly glycosylated IgA1 production HYPOTHESIS: MUCOSAL IMMUNITY AND IgAN

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IgA NEPHROPATHY F.P. Schena et al. Malattie dei Reni e delle Vie Urinarie, 4 Edizione, Mc Graw-Hill, 2008

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NeuAc ST6GalNAc II NeuAc ST3Gal IgA1 Ser/Thr GalNAc O GALNT2 Gal C1GALT1 +Cosmc Fab Fc Hinge region

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Gharavi A.G. et al. JASN. 19: 1008-1014 2008 ABERRANT IgA1 GLYCOSYLATION IS INHERITED IN FAMILIAL IgAN

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Gharavi A.G. et al. JASN. 19: 1008-1014 2008 ABERRANT IgA1 GLYCOSYLATION IS INHERITED IN RELATIVES OF SPORADIC IgAN

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NeuAc ST6GalNAc II NeuAc ST3Gal IgA1 Ser/Thr GalNAc O GALNT2 Gal C1GALT1 + Cosmc Fab Fc Hinge region miR-148b let-7b

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SERUM LEVELS OF COMBINED BIOMARKER (miR-148b and let-7b) G Serino,and F.P.Schena, ASN, 2012

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SERUM LEVELS OF COMBINED BIOMARKER (miR-148b and let-7b) IN IgAN PATIENTS WITH NORMAL RENAL FUNCTION (NRF), DETERIORATED RENAL FUNCTION (DRF), HAEMODIALYSIS (HD) IgAN PATIENTS AND HEALTHY BLOOD DONORS G Serino,and F.P.Schena, ASN, 2012

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SERUM LEVELS OF COMBINED BIOMARKER (miR-148b and let-7b) IN IgAN PATIENTS WITH MILD(G1), MODERATE (G2) AND SEVERE (G3) HISTOLOGICAL RENAL DAMAGE, AND HEALTHY BLOOD DONORS (HBD) Oxford Classification M.E.S.T. 0.0.1.0. 0.1.1.1. 1.1.1.2. G Serino,and F.P.Schena, ASN, 2012

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SERUM LEVELS OF COMBINED BIOMARKER (miR-148b and let-7b) IN IgAN PATIENTS WITH HISTORY OF GROSS OR MICROSCOPIC HEMATURIA (MH), AND HEALTHY BLOOD DONORS (HBD) G Serino,and F.P.Schena, ASN, 2012

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Study design

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Training cohorts

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Validation cohorts

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Test cohorts

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Effects of corticosteroid therapy on the serum levels of combined miRNA

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CONCLUSIONS The combined miRNA biomarker (let-7b and miR-148b) appears to be the first robust non-invasive test for diagnosis of idiopathic IgAN without performing the renal biopsy. F.P.Schena et al (in preparation)

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PREDICTION MODEL OF CANDIDATE BIOMARKERS FOR DIAGNOSIS OF IgA NEPHROPATHY (Risk scale) Serum creatinine/GFR Proteinuria Blood pressure Renal Biopsy Deglycosylated IgA1 miR148b+Let7b PreventiveProbableDefiniteProgression 1 2 3 POTENTIAL ONSET DISEASE DEVELOPMENT RENAL PROGRESSION 4

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G.De Palma, G.Serino, SN.Cox, F.P.Schena, F.Sallustio, C.Curci, F.Pesce

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