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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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slide1

LA NEFROPATIA

A DEPOSITI MESANGIALI DI IgA

F.P. Schena

University of Bari

C.A.R.S.O. Consortium – Valenzano, Bari

slide2

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

slide3

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

slide4

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
slide5

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

Nephron 82, 205, 1999

slide6

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

slide7

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

slide8

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
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
slide10

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

slide11

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
slide12

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
IgA NEPHROPATHY

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

slide14

C1GALT1 +Cosmc

GALNT2

ST6GalNAc II

ST3Gal

O

Gal

NeuAc

GalNAc

NeuAc

IgA1

Fab

Hinge region

Ser/Thr

Fc

slide15

ABERRANT IgA1 GLYCOSYLATION IS INHERITED

IN FAMILIAL IgAN

Gharavi A.G. et al.JASN. 19: 1008-1014 2008

slide16

ABERRANT IgA1 GLYCOSYLATION IS INHERITED

IN RELATIVES OF SPORADIC IgAN

Gharavi A.G. et al.JASN. 19: 1008-1014 2008

slide17

C1GALT1 + Cosmc

GALNT2

ST6GalNAc II

ST3Gal

O

Gal

NeuAc

GalNAc

NeuAc

IgA1

Fab

let-7b

miR-148b

Hinge region

Ser/Thr

Fc

slide18

SERUM LEVELS OF COMBINED BIOMARKER

(miR-148b and let-7b)

G Serino,…and F.P.Schena, ASN, 2012

slide19

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

slide20

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

slide21

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

slide27

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)

slide28

PREDICTION MODEL OF CANDIDATE BIOMARKERS

FOR DIAGNOSIS OF IgA NEPHROPATHY

(Risk scale)

4

3

2

1

POTENTIAL

ONSET

DISEASE

DEVELOPMENT

RENAL

PROGRESSION

slide29

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