IgA NEPHROPATHY (CLOSING THE LOOP) - Dr. Gawad

IgA NEPHROPATHY
(CLOSING THE LOOP)
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m
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Pathogenesis & Clinical guide
Mohammed Abdel Gawad

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Historical View
3
It was described in 1968 by Jean Berger (it has
also been called Berger’s disease).

 Normal IgA formation & function
 Pathogenesis of IgAN
 Epidemiology
 Is IgA a familial disease?
 Age & Sex
 Clinical presentation
 Associations
 Investigations
 Would you biopsy?
 Pathology
 Prognostic markers
OBJECTIVES
4

 Epidemiology
 Age & Sex
 Associations
 Investigations
 Pathology
OBJECTIVES
5

6
Mestecky J, Russell MW, Jackson S, Brown TA. The human IgA system: a reassessment.Clin Immunol
Immunopathol 1986;40:105-114
Normal IgA Formation & Function
Humans produce two subclasses of IgA
by plasma cells
Plasma cells in
GIT and respiratory tract
IgA 1 &
IgA 2
Plasma cells in
bone marrow, lymph nodes, and
spleen
IgA 1

 Immunoglobulin A (IgA) is an antibody that plays a
critical role in mucosal immunity
7
S Fagarasan and T Honjo (2003). "Intestinal IgA Synthesis: Regulation of Front-line Body Defenses". Nat. Rev.
Immunology 3 (1): 63–72

Polymeric & Secretory IgA
 Mucosal antigen challenge provokes polymeric IgA
(pIgA) production by plasma cells of the mucosa-
associated lymphoid tissue; the pIgA is then transported
across epithelium into mucosal fluids, where it is
released after coupling to secretory component as
secretory IgA (sIgA).
8
Comprehensive Clinical Nephrology, 4th edition, Chapter 22, Page 270, 271

9

10
Andrea Cerutti, Maria Rescigno, Immunity, volume 28, Issue 6, 13 June 2008, Pages 740–750

IgA Clearance
 Circulating IgA1 is cleared by the liver through
hepatocyte asialoglycoprotein receptors and Kupffer cell
Fcα receptors.
11

Normal IgA1 Structure
12
Panel A:
The Structure of a Normal IgA1
Molecule
Panel B:
the Structure of Carbohydrates
O-Linked to Serine or Threonine
residues within the Hinge Region
of Normal IgA1
Donadio JV, Grande JP. N Engl J Med 2002;347:738-748.

Normal IgA2 Structure
IgA2 has no hinge and carries no such sugars.
13
Barratt J, Feehally J, Smith AC. Pathogenesis of IgA nephropathy. Semin Nephrol. 2004;24:197-217.

 Epidemiology
 Age & Sex
 Associations
 Investigations
 Pathology
OBJECTIVES
14

 The pathogenesis of IgA nephropathy remains
incompletely understood *
 Pathogenesis in one word = ABNORMAL
GALACTOSYLATED IgA
Pathogenesis
15
* Hahn WH, Suh JS, Cho BS, Kim SD. The enabled homolog gene polymorphisms are associated with
susceptibility and progression of childhood IgA nephropathy. Exp Mol Med. Nov 30 2009;41(11):793-801.

 Hinge region of the IgA1 molecule in patients with IgAN is often abnormal
with reduced galactose and/or sialic acid content. *
 The mechanisms responsible for this underglycosylation are unclear, but
reduced function of the enzyme responsible for performing this
glycosylation may be involved. *
16
Pathogenesis – Abnormal Glycosylation
* Current Diagnosis & Treatment, Nephrology & Hypertension, Chapter 27, Page 243

 Hepatic clearance of IgA is reduced, possibly
as a consequence of the altered molecular
characteristics of IgA.
17
Pathogenesis – Hepatic Clearance

18
Pathogenesis

19
Pathogenesis

 Studies of renal biopsy
specimens in human IgAN
also support a role for
PDGF and TGF-β.*
 These mechanisms are not
unique to IgAN but are likely
to be involved in all forms of
mesangial proliferative GN,
including those without IgA
deposition.*
20
* Floege J, Eitner F, Alpers CE. A new look at platelet-derived growth factor in renal disease. J Am Soc Nephrol.
2008;19:12-23.
Pathogenesis – Growth Factors

 Analysis of kidney tissue from patients with IgAN reveals
that the glomerular deposits are almost exclusively
polymeric IgA1.
21
Pathogenesis – IgA Type
Current Diagnosis & Treatment, Nephrology & Hypertension, Chapter 27, Page 243

22
IgA Court
Case 1:
Is the mucosal IgA accused ?!
 The onset of IgA nephropathy may be associated with infections in the upper
respiratory tract. It has therefore been proposed that IgA nephropathy results
from hyperactivity of the mucosal immune system.
Bene MC, Faure GC. Mesangial IgA in IgA nephropathy arises from the mucosa. Am J Kidney Dis 1988;12:406-409

 The onset of IgA nephropathy may be associated with
infections in the upper respiratory tract. It has therefore
been proposed that IgA nephropathy results from
hyperactivity of the mucosal immune system.[1]
 However, evidence suggests that mucosal immunity,
which is in part directed by IgA, is decreased in patients
with IgA nephropathy.[2]
 In some patients with IgA nephropathy, production of IgA1 in the
bone marrow is increased and may be responsible for the observed
increase in serum IgA1 levels.[3]
IgA Court
23
[1] Bene MC, Faure GC. Mesangial IgA in IgA nephropathy arises from the mucosa. Am J Kidney Dis 1988;12:406-409
[2] Feehally J, Allen AC. Pathogenesis of IgA nephropathy. Ann Med Interne (Paris)1999;150:91-98
[3] Harper SJ, Pringle JH, Wicks AC, et al. Expression of J chain mRNA in duodenal IgA plasma cells in IgA
nephropathy. Kidney Int1994;45:836-844
Case 1:
Is the mucosal IgA accused ?!

 Serum IgA levels are increased in 50% of
patients with IgAN.
 High serum IgA per se is not, however, sufficient
to cause IgAN; What is the evidence??
 High circulating levels of monoclonal IgA (in
myeloma) or polyclonal IgA (in AIDS) only
infrequently provoke mesangial IgA deposition.
IgA Court
24
Case 2:
Is elevated serum IgA accused ?!
Bene MC, Canton P, Amiel C, May T, Faure G. Absence of mesangial IgA in AIDS: a postmortem
study. Nephron 1991;58:240-241

IgA Court Verdict
25
 Studies have focused on
potential abnormalities of the
IgA molecule as a factor in
the pathogenesis of IgA
nephropathy not the level of
serum IgA.
Allen AC, Bailey EM, Brenchley PE, Buck KS,Barratt J, Feehally J. Mesangial IgA1 in IgA nephropathy exhibits
aberrant O-glycosylation: observations in three patients. Kidney Int2001;60:969-973

Tonsillar pIgA1 production is also increased,
although IgAN can occur after tonsillectomy,
and the tonsil is a very minor source of IgA
production compared with the mucosa or
marrow.
Note: Tonsils & IgA
26

IgAN is systemic disease
Evidence 1
 Histologic evidence of recurrent IgA
nephropathy is observed in over 35 percent of
patients who receive renal allografts as
treatment for end-stage renal disease due to
IgA nephropathy
Local or Systemic Disease?
27
Ponticelli C, Traversi L, Feliciani A, Cesana BM,Banfi G, Tarantino A. Kidney transplantation in patients with IgA
mesangial glomerulonephritis.Kidney Int 2001;60:1948-1954

IgAN is systemic disease
Evidence 2
 When a kidney obtained from a donor with
asymptomatic IgA nephropathy is transplanted
into a recipient with end-stage renal disease
due to a disease other than IgA nephropathy,
the deposits in the donor kidney rapidly
disappear.
Local or Systemic Disease?
28
Koselj M, Rott T, Kandus A, Vizjak A, Malovrh M. Donor-transmitted IgA nephropathy: long-term follow-up of
kidney donors and recipients.Transplant Proc 1997;29:3406-3407
IgA
IgA
IgA
IgA
IgA
IgA

No antigen has been consistently detected in
circulating immune complexes containing IgA
or in biopsy specimens from the kidneys of
patients with IgA nephropathy.
What is the Antigen ??
29
Russell MW, Mestecky J, Julian BA, Galla JH. IgA-associated renal diseases: antibodies to
environmental antigens in sera and deposition of immunoglobulins and antigens in glomeruli. J Clin
Immunol 1986;6:74-86

 Epidemiology
 Age & Sex
 Associations
 Investigations
 Pathology
OBJECTIVES
30

It is now generally known to be the most
common form of primary glomerulonephritis
throughout the world in most countries where
renal biopsy is widely used as an investigative
tool.
Epidemiology
31
Levy M, Berger J. Worldwide perspective of IgA nephropathy. Am J Kidney Dis1988;12:340-347

 Epidemiology
 Age & Sex
 Associations
 Investigations
 Pathology
OBJECTIVES
32

 Isolated cases of IgA nephropathy are common,
and the disease is not considered to be familial.[1]
 There have, however, been suggestions that there
may be immunogenetic factors that predispose
some persons to IgA nephropathy, and familial
clustering has been reported. [1]
 Many association studies have sought genes
associated with disease in sporadic IgAN, so far
without consistent findings. [2]
Genetic Basis of IgA Nephropathy
33
[1] Hsu SI, Ramirez SB, Winn MP, Bonventre JV,Owen WF. Evidence for genetic factors in the development and
progression of IgA nephropathy.Kidney Int 2000;57:1818-1835
[2] Hsu SI. Racial and genetic factors in IgA nephropathy. Semin Nephrol. 2008;28:48-57.

 Epidemiology
 Age & Sex
 Associations
 Investigations
 Pathology
OBJECTIVES
34

 Primary IgA nephropathy occurs at any age,
most commonly with clinical onset in the
second and third decades of life. [1]
 In populations of Caucasian descent, it is more
common in males than in females by a ratio of
3 : 1, whereas the ratio approaches 1 : 1 in
most Asian populations. [2]
Age & Sex
35
[1] Radford MG Jr, Donadio JV Jr, Bergstralh EJ,Grande JP. Predicting renal outcome in IgA
nephropathy. J Am Soc Nephrol 1997;8:199-207
[2] Comprehensive Clinical Nephrology, 4th edition, Chapter 22, Page 270, 271

 Epidemiology
 Age & Sex
 Associations
 Investigations
 Pathology
OBJECTIVES
36

Presentation % of IgA cases
Macroscopic Hematuria 40% to 50% of cases
Asymptomatic Hematuria ± Proteinuria (<2g/d) 30% to 40% of cases
Nephrotic Syndrome 5% of cases
Acute Kidney Injury:
a- Crescentic IgA nephropathy
b- ATN
- <5% of all cases
- 27% of those older than 65
years
Chronic Kidney Disease Older age with long years
undiagnosed IgA
Clinical Presentation
37
Floege J, Feehally J. IgA nephropathy: recent developments. J Am Soc Nephrol2000;11:2395-2403

Hematuria
38
 Synpharyngitic hematuria:
 Hematuria is usually visible within 24 hours of
the onset of the symptoms of infection (upper
respiratory tract or occasionally in the
gastrointestinal tract.
 Differentiating it from the 2 to 3 week delay
between infection and subsequent hematuria
in postinfectious (e.g., poststreptococcal) GN.
Comprehensive Clinical Nephrology, 4th edition, Chapter 22, Page 273

 Usually brown rather than red.
 Clots are unusual.
 The macroscopic hematuria resolves
spontaneously in the course of a few days.
 There is persistent microscopic hematuria
between attacks.
39
Hematuria

 Episodic gross hematuria, often in
association with upper respiratory
infections, may also be seen in familial
glomerular diseases such as thin
basement membrane disease or Alport’s
syndrome.
40
Hematuria

 It may be first presentation but very rare.
or
Alternatively, it may occur as a late manifestation
of advanced chronic glomerular scarring.
Nephrotic Syndrome
41

 This may be the first presentation of IgAN,
or
it may be superimposed on established, less
aggressive disease.
Crescentic IgA nephropathy
42

 Acute renal failure can occur with mild
glomerular injury when heavy glomerular
hematuria leads to tubule occlusion by red
cells
ATN
43

 May be first presentation.
 Usually old patients with long-standing disease
that remained undiagnosed because the
patient neither had frank hematuria nor
underwent routine urinalysis.
Chronic Kidney Disease
44

Clinical presentations in relation to age
45

 Epidemiology
 Age & Sex
 Associations
 Investigations
 Pathology
OBJECTIVES
46

Associations with IgA Nephropathy
47

48

 Epidemiology
 Age & Sex
 Associations
 Investigations
 Pathology
OBJECTIVES
49

 Serum IgA is increased in 50% of the cases
 Serum complement components are normal.
Neither finding, however, is reliable enough to
support the diagnosis without a renal biopsy.
Investigations
50

 Epidemiology
 Age & Sex
 Associations
 Investigations
 Pathology
OBJECTIVES
51

 Male
 34 years old
 Macroscopic hematuria
 History of upper respiratory tract infection
since 48 hours
 Normal serum complement level
 What is your DD
Would You Biopsy 1 ?!
52

 Male
 22 years old
 Macroscopic hematuria
 HTN
 History of upper respiratory tract infection
since 10 days
 Low C3, normal C4
Would You Biopsy 2 ?!
53

 Epidemiology
 Age & Sex
 Associations
 Investigations
 Pathology
OBJECTIVES
54

Pathology - LM
55
 Light microscopic findings are variable and can
reveal:
1. Mesangial cell proliferation, and increase in
mesangial matrix,*
2. Focal or diffuse proliferative glomerulonephritis, *
3. Crescentic glomerulonephritis, *
4. Chronic sclerosing glomerulonephritis,*
5. Membranoproliferative glomerulonephritis type I
pattern,*
6. A subset of nephrotic patients with normal appearing
glomeruli by light microscopy,*
7. Focal segmental GN *** Current Diagnosis & Treatment, Nephrology & Hypertension, Chapter 27, Page 243
* *Comprehensive Clinical Nephrology, 4th edition, Chapter 22, Page 275

 The preglomerular arterial vessels often
exhibit wall hyalinosis and subintimal fibrosis
even in cases of only mild arterial
hypertension.
56
Pathology - LM

57
Glomerulus from a patient with IgA nephropathy showing mild segmental mesangial hypercellularity in the upper
left quadrant of the glomerulus [periodic acid-Schiff (PAS) stain].
Pathology - LM
Fundamental of Renal Pathology, Section III, Chapter 6, Page 62

58
Glomerulus from a patient with IgA nephropathy showing moderate segmental mesangial hypercellularity and
increased mesangial matrix in the upper portion of the tuft (PAS stain).
Pathology - LM

59
Acute kidney injury in IgA nephropathy. Tubular occlusion by red cells. (Hematoxylin-eosin; magnification ×300.)
This appearance may be associated with only minor glomerular changes.
Pathology - LM

60
Mesangial Deposits % of cases
Diffuse IgA deposits Hallmark
C3 90%
IgG 40%
IgM 40%
Kappa & lambda chain May be present
Pathology - IF

61
Diffuse mesangial IgA. (Indirect immunofluorescence with fluorescein isothiocyanate–anti-IgA;
magnification × 3300.)
Pathology - IF

62
Immunofluorescence microscopy demonstrating glomerular mesangial staining for immunoglobulin
A (IgA) in a patient with IgA nephropathy. Fundamental of Renal Pathology, Section III, Chapter 6, Page 62
Pathology - IF

DD- IF - Mesangial Proliferative
63

64
Electron microscopy: mesangial electron-dense deposits. The deposits are shown by arrows.
(Electron micrograph; magnification ×316,000.)
Pathology - EM

65
Electron micrograph of a glomerulus from a patient with IgA nephropathy showing massive
electron-dense deposits within the mesangium. The mesangium is on the left of the image and a
portion of the capillary loop is on the right.
Pathology - EM

 Typically, electron dense deposits are confined
to mesangial and paramesangial areas, but, in
addition, subepithelial and subendothelial
deposits can also be seen.
 Up to one third of patients will have some focal
thinning of GBM. On occasion, there will be
extensive GBM thinning, suggesting a
coincident diagnosis of thin membrane
nephropathy
66
Pathology - EM

67
 A subset of nephrotic patients with normal
appearing glomeruli by light microscopy may
have only prominent visceral epithelial cell foot
process effacement on electron microscopy
and appear indistinguishable from patients
with minimal change disease.
Pathology - EM

 Epidemiology
 Age & Sex
 Associations
 Investigations
 Pathology
OBJECTIVES
69

Prognostic Markers
70

 Abnormal Glycosylated pIgA1
Pathogenesis
72

Highly suggestion of IgA
73
 Synpharyngitic hematuria within 24 hours of
the onset of the symptoms of infection in 2nd or
3rd decade of life with normal serum
complement

Other IgA presentations & Pathologies
74
 Other IgA presentations (nephrotic syndrome
& cresentic GN) & pathologies rather than
mesangial proliferation will be included in the
DD of these presentations

DD- IF - Mesangial Proliferative
75

Excepted IgA course
76
IgA (hematuria
or nephrotic
syndrome)
Untreated, loss
follow up
Chronic GN
AKI
ATN (with
heavy
hematuria)
Cresentic GN
Biopsy may be
mandatory to
DD

Prognostic Markers
77

78

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