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 literatureADULTS (Incidence)
IgA Nephropathy
25 new cases/pmp/year
Membranous glomerulopathy
12 new cases/pmp/year
A.McGrogan et al NDT 26, 414, 2011
IgA NEPHROPATHY
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
Different distribution in the world
•
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
RESEARCH GROUP ON PROGRESSIVE CHRONIC RENAL
DISEASE LONG-TERM SURVIVAL OF PRIMARY
GLOMERULONEPHRITIS IN JAPAN (1850 RB)
Nephron 82, 205, 1999
RESEARCH GROUP ON PROGRESSIVE
CHRONIC RENAL DISEASE
IgAN renal survival from the apparent onset of the
disease or earliest known renal abnormalities in
Japan
After 5 years
10
15
20
96%
85%
75%
61%
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: 763-775, 2007
KIDNEY BIOPSY REGISTRY. KAPLAN-MEIER PLOTS OF EXPECTED
VERSUS OBSERVED MORTALITY IN NORWEGIAN IgAN PATIENTS.
T.Knoop,…….. and R.Bjømeklett, AJKD, 2013
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
FREQUENCY OF URINARY ABNORMALITIES
IN 269 RELATIVES FROM 48 FAMILIES OF
IgAN PATIENTS AND IN 8255 STUDENTS
MH
15.6%
P
3%
MH+P
4%
77.4%
IgAN Families
MH
2%
P
2%
MH+P
0.3%
95.7%
Normal population
F.P.Schena Kidney Int. 48, 1998, 1995
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
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
IgA NEPHROPATHY
F.P. Schena et al. Malattie dei Reni e delle Vie Urinarie, 4° Edizione, Mc Graw-Hill, 2008
IgA1
Fab
Hinge
region
GALNT2
Ser/Thr
O
GalNAc
C1GALT1
+Cosmc
ST6GalNAc II
NeuAc
Fc
ST3Gal
Gal
NeuAc
ABERRANT IgA1 GLYCOSYLATION IS INHERITED
IN FAMILIAL IgAN
Gharavi A.G. et al. JASN. 19: 1008-1014 2008
ABERRANT IgA1 GLYCOSYLATION IS INHERITED
IN RELATIVES OF SPORADIC IgAN
Gharavi A.G. et al. JASN. 19: 1008-1014 2008
IgA1
Fab
let-7b
Hinge
region
GALNT2
Ser/Thr
O
miR-148b
C1GALT1 + Cosmc
GalNAc
ST6GalNAc II
NeuAc
Fc
Gal
ST3Gal
NeuAc
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.
0.0.1.0.
0.1.1.1.
1.1.1.2.
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
3
Renal Biopsy
2
Deglycosylated IgA1
miR148b+Let7b
Preventive
POTENTIAL
ONSET
4
1
Probable
Definite
DISEASE
DEVELOPMENT
Progression
RENAL
PROGRESSION
G.De Palma, G.Serino,
SN.Cox, F.P.Schena, F.Sallustio, C.Curci, F.Pesce