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IgA Nephropathy
IgA Nephropathy (IgAN) or
Berger's disease (MIM 161950) is a worldwide primary glomerulonephritis
characterized by recurrent episodes of macroscopic hematuria which usually
occur in concomitance with mucosal infections of upper respiratory tract or
other infections, or asymptomatic microscopic hematuria with or without
proteinuria (1).
It is characterized by
mesangial deposits of IgA in glomeruli and a wide range of lesions (from
minimal change lesions to glomerular extracapillary lesions and interstitial
lesions) in the renal biopsy. Thus, the histological classification identifies
three grades (G) of renal lesions: G1 (mild); G2 (moderate) and G3 (severe)
(2).
The incidence of the IgAN
ranges from 8.4 patients/pmp in Italy to 26 patients/pmp in France (3,4). The
disease is more frequent in the Eastern area of the world (Japan, Hong-Kong,
Singapore) than in the Western area (Europe and USA). However, IgAN remains in
prevalence at the first place among all primary glomerulonephritides worldwide.
The IgAN prevalence ranges from 20 to 40%. Incidence and prevalence of the
disease are mainly influenced by the policy in approaching the renal biopsy. In
some renal units patients with persistent microscopic hematuria undergo to a
renal biopsy more frequently than in other units (5). The difference in
prevalence is also due to the preventive medicine adopted by the various
countries (urinanalysis, is performed in schools in Japan or during military
service in Hong-Kong) (6,7).
The pathogenesis of this disease
is still unknown but immunological and genetic factors seem to be largely
involved.
For the first time Egido et
al distinguished a familial form, in which more than 2 relatives have
biopsy-proven IgAN, from a sporadic form in which only one family member is
affected by the disease (8). Many articles have described families with
different subjects affected by biopsy-proven IgAN and other subjects presenting
persistent microscopic hematuria (9). A recent epidemiological study showed an
increased risk to develop IgAN between first and second degree relatives (10).
Moreover, no increased risk of end stage renal disease was demonstrated in
familial IgAN (11).
Some investigators are
involved in the genetic dissection of IgAN using linkage-based, association-based,
and sequence-based approaches.
In a linkage study, the
genome wide scan of large multiplex families (to which more than one patient
belongs to) is performed to localize candidate chromosomal regions that could
contain disease susceptibility genes. A multi-center study demonstrated linkage
of IgAN to chromosome 6q22-23 (IGAN1) under a dominant model of transmission
with incomplete penetrance (12). Recently, another linkage analysis study, carried-out in 22 Italian IgAN
families, evidenced linkage of the disease to chromosome 4q26-31 (IGAN2) in 50%
of families and to chromosome 17q12-22 (IGAN3) in 65% of families (13). These
results provide further evidence for genetic heterogeneity among IgAN.
In association studies, genes
with a possible role in the pathogenesis of the disease have been analysed. The
premise is that a variation in the DNA sequence (polymorphism) of these genes
can alter either their expression or the structure of the proteins for which
they encode. Several association studies have been performed showing the role
of candidate gene polymorphisms on IgAN onset and progression. The following
Tables report the main obtained results.
Association
studies performed on genes of the Renin- Angiotensin System
y=yes, n=no
Association
studies performed on Interleukin and growth factor and Chemokine and genes
y=yes, n=no
Association studies performed on Immunoglobulin and their receptor genes
Association
studies performed on Adhesion Molecules and Proteins expressed within the
kidney
y=yes, n=no
Association
studies conducted on multifunctional Genes
y=yes, n=no
This website has been created
to disseminate scientific data on the genetic aspects of IgA nephropathy. The
discovery of gene(s) responsible for the hereditary transmission of the disease
may give more information on the aetiopathogenesis of the disease and may give
more specific and effective approaches to therapy.
References
1.
F.P. Schena: A retrospective analysis of the natural history of primary IgA
nephropathy worldwide. American Journal Medicine 89: 209-215; 1990.
2.
Churg J. Sobin L.H.: In Renal disease. Classification and atlas of glomerular
disease. Igaku-Shoin, Tokyo, New York, 1982.
3.
F.P. Schena and The Italian Group of Renal Immunopathology: Survey of the Italian
registry of renal biopsies. Frequency of the renal disease for 7 consecutive
years. Nephrology Dialysis Transplantation 12: 418-426; 1997.
4.
Simon P, Ramée M.P., Autuly V et al: Epidemiology of primary glomerular disease
in a French region. Variations according to period and age. Kidney
International 46: 1192-1198; 1994.
5.
Propper D.J., Power D.A., Simpson J.G., Edward N., Catto G.R.D.: Incidence of
IgA nephropathy in U.K. Lancet 1: 190; 1988. 6. Kitagawa T.: Screening for
asymptomatic hematuria and proteinuria in school children. Relationship between
clinical laboratory findings and glomerular pathology or prognosis. Acta
Paediatrics Japan 27: 366-373; 1985.
7.
Woo K.T., Edmondson R.P.S., Wu A.Y.T., Chiang G.S.C., Pwee H.S., Lim C.H.: The
natural history of IgA nephritis in Singapore. Clinical Nephrology 25: 15-21;
1986.
8.
Egido J., Garcia-Hoyo R., Lozano L., Gonzales-Cabrero J., de Nicolas R.,
Hernando L.: Immunological studies in familial and sporadic IgA nephropathy.
Seminars in Nephrology 7: 311-314; 1987.
9.
Scolari F. et al : Familial clustering of IgA nephropathy: further evidence in
an Italian population. American Journal of Kidney Disease 33: 857-865; 1999.
10.
Schena F.P., Cerullo G., Rossini M., Lanzilotta S.G., D'Altri C., Manno C.:
Increased risk of end stage renal disease in familial IgA nephropathy. J Am Soc
Nephrol 13: 453-460, 2002.
11.Izzi
C, Ravani P, Torres D, Prati E, Viola BF, Guerini S, Foramitti M, Frascà G,
Amoroso A, Ghiggeri GM, Schena FP, Scolari F: IgA nephropathy: the presence of
familial disease does not confer an increased risk of progression. American
Journal of Kidney Disease 47:761-769; 2006.
12.
Gharavi AG, Yan Y, Scolari F, Schena FP, Frascà GM, Ghiggeri GM, Cooper K,
Amoroso A, Viola BF, Battini G, Caridi G, Canova C, Farhi A, Subramanian V,
Nelson-Williams C, Woodford S, Julian BA, Wyatt RJ, Lifton RP: IgA nephropathy,
the most common cause of glomerulonephritis, is linked to 6q22-23. Nature Genet
26: 354-357, 2000.
13.
Bisceglia L, Cerullo G, Forabosco P, Torres DD, Scolari F, Di Perna M,
Foramitti M, Amoroso A, Bertok S, Floege J, Mertens PR, Zerres K, Alexopoulos
E, Kirmizis D, Mazzucco E, Zelante L, Schena FP on behalf of the European IgA
Nephropathy Consortium: Genetic Heterogeneity in Italian IgA nephropathy families:
Suggestive linkage for two novel IgAN loci. Am J Hum Genet (in press)
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