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

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

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

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

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

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

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: , 2007

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

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

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

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)

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

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

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

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

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

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

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

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

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 G Serino,…and F.P.Schena, ASN, 2012

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

Study design

Training cohorts

Validation cohorts

Test cohorts

Effects of corticosteroid therapy on the serum levels of combined miRNA

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)

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 POTENTIAL ONSET DISEASE DEVELOPMENT RENAL PROGRESSION 4

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