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LA NEFROPATIA A DEPOSITI MESANGIALI DI IgA

LA NEFROPATIA A DEPOSITI MESANGIALI DI IgA. F.P. Schena. University of Bari C.A.R.S.O. Consortium – Valenzano, Bari. INCIDENCE OF PRIMARY GLOMERULONEPHRITIS WORLDWIDE -Systematic review of the literature-.

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LA NEFROPATIA A DEPOSITI MESANGIALI DI IgA

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

  2. INCIDENCE OF PRIMARY GLOMERULONEPHRITIS WORLDWIDE -Systematicreviewof the literature- ADULTS (Incidence)IgANephropathy 25 newcases/pmp/yearMembranousglomerulopathy 12 newcases/pmp/year A.McGrogan et al NDT 26, 414, 2011

  3. IgA NEPHROPATHY The most common primaryglomerulonephritis in the world: 2.5 cases/y/100,000 adults >16% in the general population: -autopsystudies (WaldherrR. et al NDT 1989) -time 0 protocol RB (Suzuki K. et al. KidneyInt 2003) Prevalenceshould be 250 cases/pmp in adults

  4. Differentdistribution in the world • Highprevalence in East Asia • - laws • - preventive medicine • Intermediateprevalence in North America and Europe • - no preventive medicine • - RB in patients with documented CRF (North America) • Lowprevalence in Africa • - no preventive medicine • - reduced use of immunofluorescencetechnique

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

  6. RESEARCH GROUP ON PROGRESSIVE CHRONIC RENAL DISEASEIgANrenalsurvival from the apparentonset of the disease or earliestknownrenalabnormalities in Japan After 5 years 96% 10 85% 15 75% 20 61% Nephron 82, 205, 1999

  7. 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.Schenaet al. AJKD, 49: 763-775, 2007

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

  9. 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

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

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

  12. HYPOTHESIS: MUCOSAL IMMUNITY AND 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

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

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

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

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

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

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

  19. 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

  20. 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. 0.1.1.1. 0.0.1.0. 1.1.1.2. G Serino,…and F.P.Schena, ASN, 2012

  21. 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

  22. Study design

  23. Training cohorts

  24. Validation cohorts

  25. Test cohorts

  26. Effects of corticosteroid therapy on the serum levels of combined miRNA

  27. CONCLUSIONS The combinedmiRNAbiomarker (let-7b and miR-148b) appears to be the first robust non-invasive test for diagnosis of idiopathicIgANwithoutperforming the renalbiopsy. F.P.Schena et al (in preparation)

  28. PREDICTION MODEL OF CANDIDATE BIOMARKERS FOR DIAGNOSIS OF IgA NEPHROPATHY (Risk scale) 4 3 2 1 POTENTIAL ONSET DISEASE DEVELOPMENT RENAL PROGRESSION

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

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