LA NEFROPATIA A DEPOSITI MESANGIALI DI IgA University of Bari
C.A.R.S.O. Consortium Valenzano, Bari F.P. Schena
Slide 2
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
Slide 3
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
Slide 4
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
Slide 5
RESEARCH GROUP ON PROGRESSIVE CHRONIC RENAL DISEASE LONG-TERM
SURVIVAL OF PRIMARY GLOMERULONEPHRITIS IN JAPAN (1850 RB) Nephron
82, 205, 1999
Slide 6
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
Slide 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.Schena et al. AJKD, 49: 763-775,
2007
Slide 8
T.Knoop,.. and R.Bjmeklett, AJKD, 2013 KIDNEY BIOPSY REGISTRY.
KAPLAN-MEIER PLOTS OF EXPECTED VERSUS OBSERVED MORTALITY IN
NORWEGIAN IgAN PATIENTS.
Slide 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
Slide 10
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
Slide 11
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)
Slide 12
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
Slide 13
IgA NEPHROPATHY F.P. Schena et al. Malattie dei Reni e delle
Vie Urinarie, 4 Edizione, Mc Graw-Hill, 2008
Slide 14
NeuAc ST6GalNAc II NeuAc ST3Gal IgA1 Ser/Thr GalNAc O GALNT2
Gal C1GALT1 +Cosmc Fab Fc Hinge region
Slide 15
Gharavi A.G. et al. JASN. 19: 1008-1014 2008 ABERRANT IgA1
GLYCOSYLATION IS INHERITED IN FAMILIAL IgAN
Slide 16
Gharavi A.G. et al. JASN. 19: 1008-1014 2008 ABERRANT IgA1
GLYCOSYLATION IS INHERITED IN RELATIVES OF SPORADIC IgAN
Slide 17
NeuAc ST6GalNAc II NeuAc ST3Gal IgA1 Ser/Thr GalNAc O GALNT2
Gal C1GALT1 + Cosmc Fab Fc Hinge region miR-148b let-7b
Slide 18
SERUM LEVELS OF COMBINED BIOMARKER (miR-148b and let-7b) G
Serino,and F.P.Schena, ASN, 2012
Slide 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
Slide 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. 0.0.1.0. 0.1.1.1. 1.1.1.2. G Serino,and
F.P.Schena, ASN, 2012
Slide 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
Slide 22
Study design
Slide 23
Training cohorts
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Validation cohorts
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Test cohorts
Slide 26
Effects of corticosteroid therapy on the serum levels of
combined miRNA
Slide 27
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)
Slide 28
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