Ig A nephropathy

1. IgA NEPHROPATHY
presented by Dr Shami kumar
(PG1458)
WEDNESDAY 13 DEC, 2017

2. Definition
•Immunoglobulin A (IgA) nephropathy is characterized by predominant
IgA deposition in the glomerular mesangium.
•It is the most common cause of glomerulonephritis in the world.
•IgA nephropathy was first described by Berger and Hinglais in 1968,
and is also known as Berger disease.
•Lupus GN which may have IgA dominant or co-dominant deposits, is
excluded from this diagnostic category.

3. Classification of Immunoglobulin A (IgA) Nephropathy
Primary IgA Nephropathy (idiopathic)
Secondary IgA Nephropathy
AssociatedDisorders
Henoch-Schönlein purpura
Human immunodeficiency virus
infection
Toxoplasmosis
Seronegative spondyloarthropathy
Celiac disease
Dermatitis herpetiformis
Crohn’s disease
Liver disease
Alcoholic cirrhosis
Neoplasia
•Mycosi fungoides
•Lung carcinoma
•Mucin-secreting carcinoma
Cyclic neutropenia
Sicca syndrome
Mastitis
Leprosy
Ankylosing spondylitis
Reiter’s syndrome
Familial IgA Nephropathy

4. Diseases reported in association with IgA nephropathy: common, reported, and rare. Rare associations have
been made in one or two reported cases only. In a disease as common as IgA nephropathy, it is therefore
uncertain whether these are truly related. HIV, Human immunodeficiency virus. *Behçet syndrome: systemic
vasculitis typified by orogenital ulceration and chronic uveitis. †Takayasu arteritis: systemic vasculitis involving the
aorta and its major branches, most often found in young women. ‡Wiskott-Aldrich syndrome: X-linked disorder in
which increased serum IgA is associated with the triad of recurrent pyogenic infection, eczema, and
thrombocytopenia.

5. Primary IgA nephropathy occurs at any age, most commonly with
clinical onset in second and third decade of life.
In populations of caucasian decent, it is more common in males
than in females by a ratio of 3:1, wheras the ratio approaches 1:1
in most asian populations
Age & Sex

6. •Unknown
• predisposition factors include
a) Infections
b) Genetic characteristics
c) food antigens
IgA nephropathy results from dysregulation of mucosal-type IgA
immune responses. As a result, any mucosal infection or food
antigen may drive the production and release of pathogenic IgA
into the circulation where it has the propensity to deposit within the
mesangium and trigger glomerular injury.
Etiology/Pathogenesi
s

7. Immunoglobulin A nephropathy probably can result from different
etiologies and pathogenic processes such as:
a) Abnormal structure and function of IgA molecules.
b) Reduced clearance of circulating IgA complexes.
c) Increased affinity for or reduced clearance of IgA deposits from
the glomerular mesangium.
d) Excessive IgA antibody production in response to mucosal
antigen exposure.
e) Increased permeability of mucosa to antigen.
f) Combinations of these factors.
Etiology/Pathogenesi
s

8. Some secondary forms of IgA nephropathy appear to be
caused by either decreased clearance of IgA from the
circulation (e.g, reduced hepatic clearance caused by cirrhosis)
or increased entry of IgA complexes into the circulation (e.g,
caused by increased synthesis and greater access to the
circulation in inflammatory bowel disease)
Impaired IgA clearance
Impaired systemic clearance of IgA promotes IgA deposition in
the mesangium . Persistent mesangial IgA accumulation occurs
by one or both of two mechanisms: the rate of IgA deposition
exceeds the mesangial clearnce capacity ; or the deposited IgA
is resistant to mesangial clearance.
Etiology/Pathogenesi
s

9. Systemic clearance
Alterations in systemic IgA and IgA-immune comlex clearance
mechanisms will facilitate their persistence in the serum. The liver
play an important role in IgA clearance from the circulation and
radiolabelled IgA clearnce studies suggest reduced hepatic
clearance in IgA nephropathy.
A second route of IgA clearance is through CD89 which is the Fc
receptor for IgA. IgAN is associated with downregulated CD89
expression on myeloid celss and decreased IgA binding to CD89.
Etiology/Pathogenesi
s

10. Pathogenesis of IgA Nephropathy
Pathogenesis of IgA
nephropathy.
Proposed
mechanisms leading
to mesangial
deposition of
abnormally
glycosylated IgA1
and mesangial
injury. Not shown in
this scheme is the
role of generic
progression factors
(e.g., primary
hypertension,
smoking, obesity).

11. Induction of Glomerular and Tubulointerstitial
Injury by Pathogenic IgA1-Containing Immune
Complexes.
•Galactose-deficient IgA1 may accumulate in the
glomerular mesangium by either of two routes:
galactose deficient IgA1 is bound by glycan-
specific antibodies in circulating immune
complexes that pass through large fenestrae in
the glomerular capillary network,
•or uncomplexed galactose-deficient IgA1
passes through glomerular capillary fenestrae to
be “planted” in the Mesangium and
subsequently, targeted by circulating anti-glycan
antibodies of the IgG or IgA1 isotype.
•Attachment of galactose-deficient IgA1 in
immune complexes to mesangial cells
stimulates the cells to proliferate; secrete
various proinflammatory and profibrotic
cytokines, components of the extracellular
matrix, and growth factors; activate the
alternative and lectin complement pathways;
and release reactive oxygen species. These
mediators activate neighboring mesangial cells
and also enter the urinary space, damaging
podocytes and proximal tubular epithelial cells
(PTECs). Injury to podocytes compromises the
filtration-barrier function of the glomerular
basement membrane,
Allowing circulating proteins and IgA1-containing immune complexes to enter the urinary space, and leads to
sclerosis of the glomerular tuft. Injury to PTECs causes tubular atrophy and interstitial fibrosis, which is the
component of the MEST (mesangial hypercellularity, endocapillary proliferation, segmental glomerulosclerosis or
adhesion, and tubular atrophy and interstitial Fibrosis) score that is most strongly associated with renal-function
outcome.

13. IgA nephropathy appears to result from an ordered sequence of events,
starting with galactose-deficient IgA1, which contains less than a full
complement of galactose residues on the O-glycans in the hinge region of
the heavy chains. .These may act as auto-antigens that trigger the
production of glycan-specific autoantibodies and the formation of
circulating immune complexes that are deposited in renal mesangium.
These then induce glomerular injury through pro-inflammatory cytokine
release, chemokine secretion, and the resultant migration of
macrophages into the kidney.
Deposited IgA is predominantly polymeric IgA1, which is mainly derived
from the mucosal immune system.
Pathophysiology

14. Presentation % of IgA cases
Macroscopic Hematuria 40-50% of cases
Asymptomatic Hematuria
±Proteinuria (<2g/d)
30-40% of cases
Nephrotic Syndrome 5% of cases
AKI : a) Cresentric IgAN
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

15. Age in clinical presentation of IgA nephropathy and Henoch-Schönlein purpura. HSP is most common in
childhood but may occur at any age. Macrohematuria is very uncommon after age 40. The importance of
asymptomatic urine abnormality as the presentation of IgAN will depend on attitudes to routine urine
testing and renal biopsy. It is uncertain whether patients presenting late with chronic renal impairment have
a disease distinct from that of those presenting younger with macrohematuria.

16. Gross Hematuria (40-50%)
Occur concurrent with URTI.
Occur within 1-2 days after onset of infectious symptoms
so called synpharngitic hematuria.
Loin pain, malaise, fever may be present.
HTN & Peripheral edema are rare.
Clinical Presentation

17. Asymptomatic Hematuria (30-40%)
Accidentally discovered on routine exam.
Proteinuria is variable but less than 2 gm/d.
Nephrotic Syndrome (10%)
Rare for proteinuria to occur without microscopic
hematuria.
Presented with advance glomerular disease and
uncontrolled HTN.
Clinical Presentation

18. Acute Kidney Injury
Although uncommon.
Mostly seen in age >65yrs (27% of cases)
-mechanisms:
-Acute severe immune & inflammatory injury & necrotising
GN & cresent formation.
-AKI can occur with mild glomerular injury when heavy
glomerular hematuria leads to tubular occlusion by RBCs
Chronic rena;l failure with HTN
Clinical Presentation

19. In case of HSP
Seasonal variation more on spring and autumn
Joint: Joint swelling which is non migratory and non
damaging.
Intestinal tract: Severe abdominal pain, vomiting and
melena.
Skin: Purpuric eruption on lower trunk and legs
Clinical Presentation

20. Diagnosis
Often suspected on the basis of clinical history, but can be
confirmed only by kidney biopsy.
A kidney biopsy is usually performed for the evaluation of
suspected IgAN only if there are signs suggestive of more
severe or progressive disease such as protein excretion
above 0.5-1g/d, elevated sr. Creatinine conc, or HTN.

21. PATHOLOGIC FINDINGS
LIGHT MICROSCOPY
A variety of classification systems have been used to
categorise the light microscopic phenotypes of IgAN such
as those proposed by Kurt Lee et al and by Mark Haas.
Another approach is to use the same descriptive
terminology that is in the WHO lupus classification
system to categorise IgAN as well as other forms of
Immune complex GN.

22. Lee System Haas System WHO lupus terminology
I: Focal
Mesangioproliferative
I: Focal
Mesangioproliferative
I: Normal by light
II: Moderate focal
proliferative
II: Focal proliferative II: Focal
Mesangioproliferative
III: Mild Diffuse
Proliferative
III: Focal Sclerosing III: Focal proliferative
IV: Moderate diffuse
proliferative
IV: Diffuse proliferative IV: Focal Sclerosing
V: Severe diffuse
proliferative
V: Chronic Sclerosing V: Diffuse proliferative
VI: Chronic Sclerosing
Lee And Haas System were specifically designed for IgA Nephropathy, whereas
terminology for the WHO system was designed for lupus GN but can be used to
describe the pathology of IgAN.

23. As the disease progresses, several features may be seen (all contribute towards a
poorer prognosis- collectively known as Oxford classification)

24. Diffuse mesangial hypercellularity
(M1, Oxford classification).
Endocapillary hypercellularity (E1).

25. Segmental sclerosis (S1).
Mesangial electron-dense deposits
(arrows)

26. Acute kidney injury in IgA nephropathy. Tubular
occlusion by red blood cells. This appearance may be
associated with only minor glomerular changes.

27. IMMUNOFLUORESCENCE MICROSCOPY
Immunological detection of dominant or co-dominant staining for IgA in
the glomerular mesangium. Staining for IgA should be atleast 1+ on a
scale of 1-4+ or 1-3+. Trace amounts of IgA are not definitive evidence of
IgAN. The IgA is predominanly IgA1 rather than IgA2 & predominance of
staining for lambda over kappa light chains.
Rare patients have IgA nephropathy concurrent with membranous
glomerulopathy, and thus their specimens show granular capillary wall
IgG staining and mesangial IgA dominant staining.
Staining for IgG & IgM often present but at low intensity compared to IgA.
C3 staining is almost always present and usually bright. However staining
for C1q is uncommon, when present is typically of low intensity. Presence
of substantial C1q should raise ther possibility of lupus nephritis with
conspicuous IgA deposition
In case of HSP, Skin biopsy of the purpuric skin shows a leucocytoclastic
vasculitis with IgA and C3 in the wall of dermal capilllaries.

28. Diffuse mesangial IgAN seen on indirect
immunofluorescence with fluorescein
isothiocyanate–antiIgA

29. Differential Diagnosis of IgA Nephropathy:
Conditions Associated with Mesangial lgA Deposition
•IgA nephropathy
•Henoch-Schönlein nephritis
•Lupus nephritis*
•Alcoholic liver disease
•IgA monoclonal gammopathy
•Schistosomal nephropathy
•IgA-dominant postinfectious glomerulonephritis (usually induced by
Staphylococcus aureus)
Differential diagnosis of IgA nephropathy: conditions associated with mesangial IgA deposition.
*Distinguishing lupus nephritis (especially International Society of Nephrology/Renal Pathology Society
classes II and III) may cause difficulty. The finding of C1q deposition is useful. It indicates classical pathway
involvement found in lupus nephritis but not
in IgAN.

30. ELECTRON MICROSCOPY
Typical ultrastructural finding is immune complex type electron dense
deposits in the mesangium.
Dense deposits most often are found immediately beneath the
paramesangial glomerular basement membrane. The amount of deposits
varies substantially, with ocasional specimens having massive
replacement of the matrix by the dense material.

31. Treatment Recommendations for IgA Nephropathy
Treatment recommendations for IgA nephropathy.
AKI, Acute kidney injury; GFR, glomerular filtration
rate; RPGN, rapidly progressive glomerulonephritis.

32. Treatment Recommendation for IgA Nephropathy
Recurrent Macroscopic hematuria (preserved renal function)
Aggressive hydration (no role for antibiotics or tonsillectomy)
Macroscopic hematuria with AKI
Renal biopsy mandatory if persistent acute kidney injury
ATN : Supportive measures only
Cresentric IgAN
Induction: Prednisolone 0.5-1mg/kg/d for upto 8 weeks
cyclophosphamide 2mg/kg/d for upto 8 weeks
Maintainence: Prednisolone in reducing dosage
Azathioprine 2.5 mg/kg/daily
Proteinuria <1g/24h (±microscopic hematuria) : No specific treatment
Nephrotic Syndrome with minimal change on light microscopy
Prednisolone 0.5-1mg/kg/d (children 60mg/m2/d) for upto 8 weeks then taper.
Non-Nephrotic Proteinuria >1g/24 h (±microscopic hematuria)
ACE inhibitor and/or ARB (maximise dosage to achieve target blood pressure and proteinuria
<0.5g/d)
If proteinuria still >1g/24h on maximal supportive therapy and GFR <70ml/min, consider fish oil-
12g/d for 6 mo. If further progression of renal failure, consider prednisolone (40mg/d decreasing to
10 mg by 2 years.
HTN
ACE/ARBs are agents of choice – target BP 130/80mmHg if proteinuria <1g/24h; 125/75 mmHg if
proteinuria >1g/24h
Transplantation

33. Treatment of IgA Nephropathy, According to KDIGO Guidelines.*
Recommendation
ACE inhibitor or ARB for urinary protein excretion of >1 g/day; increase dose depending
on blood pressure
Suggestions
Proteinuria
ACE inhibitor or ARB if urinary protein excretion of 0.5 to 1.0 g/day; increase dose to the
extent that adverse events are acceptable to achieve urinary protein excretion of <1
g/day
6-mo glucocorticoid therapy if urinary protein excretion of >1 g/day continues after 3 to 6
mo of proper supportive therapy (ACE inhibitor or ARB and blood-pressure control) and
an eGFR of >50ml/min/1.73m2
Fish oil if urinary protein excretion of >1 g/day continues after 3 to 6 mo of proper
Supportive therapy
Blood pressure: target is <130/80 mm Hg if urinary protein excretion is <1 g/day but
<125/75mm Hg if initial protein excretion is >1 g/day
Rapidly declining eGFR
Glucocorticoids and cyclophosphamide for crescentic IgA nephropathy (>50% glomeruli
with crescents) with rapid deterioration in eGFR
Supportive care if kidney biopsy shows acute tubular injury and intratubular erythrocyte

34. Treatments without proven benefit
Glucocorticoids with cyclophosphamide or azathioprine, unless crescentic IgA
nephropathy with rapid deterioration in eGFR
Immunosuppressive therapy with an eGFR of <30 ml/min/1.73 m2, unless
crescentic IgA nephropathy with rapid deterioration in eGFR
Mycophenolate mofetil
Antiplatelet agents
Tonsillectomy

35. Prognostic Markers at Presentation in IgA
Nephropathy
Clinical
Poor Prognosis
Histopathologic
Hypertension
Renal impairment
Severity of proteinuria
Smoking
Hyperuricemia
Gross obesity
Long duration of preceding symptoms
Increasing age
Mesangial hypercellularity
Endocapillary proliferation
Segmental glomerulosclerosis
Tubular atrophy
Interstitial fibrosis
Capillary loop IgA deposits
Crescents (controversial)
Good Prognosis
Recurrent macroscopic hematuria
No Impact on Prognosis
Gender
Serum IgA level
Intensity of IgA deposits
Prognostic markers at presentation in IgA nephropathy.
None of the clinical or histopathologic adverse features, except capillary loop.
IgA deposits, is specific to IgA nephropathy.