Ig A nephropathy (Cresentric) by Dr. Shami (SKIMS)

1. Guide
Prof. Mohd Ashraf Bhat
Professor & Head
Department of Nephrology
Moderator
Prof. Iftikhar Bashir
Department of
Endocrinology
Presented
by
Dr. Shami Kumar
PG Medicine (PG3Y -1458)

2. Patient Profile
23 yrs male
Normotensive
Non-Diabetic
Presented with chief complaints of
Swelling of b/l lower limbs x 1 month.
Nausea x 1 week
H/o URTI 1 month back

3. No history of
1).Decreased urine output
2). Dysuria
3).Headache
4). Pain abdomen
5). Breathlessness
6). Arthralgia
7) . Loose stools / vomiting
8). Rash
9) . Trauma

4. GPE
• Patient was conscious/co-operative/oriented
• GC-Fair
• Pedal edema+
vitals
Pulse =76/ min
BP =120/80 mmHg
RR =16/min
sPO2 =96% on RA
Temp=98F

5. Systemic examination
CHEST – B/L AE+
CVS - S1 S2 +
P/A - Soft/ non-tender/ non-distended
No organomegaly

6. CNS – Neck free
B/L Pupils NSRTL
Cranial nerves - Normal
Sensations – Normal
Motor system – Bulk – Normal
Tone – Normal
Power – Grade 4+ in both
upper and lower limbs
Reflexes – 2+
Plantars – down

7. Investigations
Hb TLC DLC PLT MCV MCH HCT ESR
11.8 8.0 83/17 242 87 31 37.6 06
13.6 6.4 69/23 163 90 30 40
BIL ALT ALP T.PRO ALB PT INR APTT
0.31 14 104 5.8 2.67 13.2 1.16 36.2
0.76 36 73 5.62 2.86

8. UREA CREAT NA K PH PCO2 HCO3 LACT
246 15.2 128 5.4 7.27 29 9.2 0.5
188 11.53 129 4.6 7.39 24 14.5 1.7
KFT and Electrolytes
Other Serum chemistry
Ca2+ PO4- UA LDH CPK
8.27 4.0 4.2 333 16
8.41 4.33 4.7 286 47

9. R/U/E URINE
Pus Cells 30-32
RBCs 50-55
Albumin ++
Sugar nil
24 Hours urinary protein: 3.6 grams/24 hrs
ECG-NSR
CXR- WNL

10. Other
ANA Negative
Anti ds DNA Negative
HepB/C serology Negative
C-ANCA Negative
P-ANCA Negative
C3 & C4 levels Normal

11. USG abdomen
• Right kidney=10.4 x 4.6 cm
• Left kidney =10.6 x 4.8 cm
B/L raised echogenicity
Slightly altered CMD
• Mild ascites
• Rest unremarkable

12. Renal Biopsy
• Focal endocapillary & measangio-proliferative
crescentic IgA nephropathy associated with cellular
crescent formation in 5/8 glomeruli, Acute tuft
necrosis in one glomerulus and secondary segmental
sclerosis in several capillary tufts.
• Patchy acute tubular injury involving viable cortical
tubules, multifocal chronic tubulointerstitial
inflammation and mild increase in tubulointerstitial
chronicity are observed

13. Renal biopsy showing glomerular cellular crescent
(black arrow) with mesangial proliferation (red
arrow). Interstitium and tubules are preserved. (light
microscopy)
Renal Biopsy

14. MEST –C SCORE
M0 E1 S1 T0 C2
Mesangial hypercellularity(M score<50%) M0
Endocapillary cellularity(present) E1
Segmental sclerosis(present) S1
Tubular atrophy/ interstitial fibrosis(<25%) T0
Crescents(cellular/fibrocellular)(>25%) C2

15. Final Diagnosis
IgA
NEPHROPATHY
(CRESCENTIC)

16. Treatment in Hospital
Patient managed by multiple sessions of hemodialysis
Pulse methylprednisolone 1gm i.v. OD x 3 days
i.v. Monthly Cyclophosphamide 500mg/m2 bsa (x 6mo)
Discharged on :
Tab Prednisolone 1mg/kg body wt. OD
i.v. Monthly Cyclophosphamide 500mg/m2 bsa (x 6mo)
Pt doing well with recent Sr. Creat of 3.5 after 3 mo (not on RRT)

18. Introduction
• 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.

19. 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
Classification

20. Age and sex
• Primary igA nephropathy occurs at any age most
commonly with clinical onset at 2nd and third decade
of life
• In populations of caucasian descent it is more
common in males than females by a ratio of 3;1
whereas the ratio approaches 1;1 in most asian
populations.

21. Rheumatic &
autoimmune disease
•Ankylosing spondylitis
•RA
•Reiter syndrome
•Uveitis
GI disease
•Celiac disease (mc)
•UC
Hepatic disease
•Alcoholic liver disease
•Non-Alcoholic cirrhosis
•Schistosomal liver
disease
Lung disease
•Sarcoid
Skin disease
•Dermatitis
Herpetiformis
Malignancy
•IgA monoclonal
gammopathy
•Bronchial Ca
•Renal, laryngeal Ca
•Sezary syndrome
•Mycosis Fungoides
Infection
•HIV/ Hep B
•Brucellosis
•Leprosy
Miscellaneous
Wiscott-Aldrich
Syndrome
Disease
association
with Ig A
nephropathy

22. Pathogenesis
• 1) Aberrant glycosylation of IgA1
• 2) Synthesis of antibodies directed against galactose
deficient IgA1
• 3 )Binding of the galactose defecient IgA1 by the anti
glycan/glycopeptide anto-antibodies to form immune
complexes
• 4) Accumulation of these complexes in the glomerular
mesangium to initiate renal injury

23. Pathogenesis of IgA Nephropathy
Mesengial cell proliferation,
extracellular matrix overproduction
2nd Hit
Mesaengial deposition and/or in
situ formation of IgG-IgA1 O-
glycoforms
Ist hit
Presence of increased amount of
poorly galactosylated IgA1 O-
glycoforms in the circulation
Generation of auto-antibodies specific for
poorly galactosylated IgA1 O-glycoforms
IgAN
•Plasma cell O-glycosylation
defect
•Displacement of plasma cells
from mucosal to systemic
sites
•Molecular mimicry
trigerred by infections
•HLA polymorphisms

24. Presentation % of IgA cases
Macroscopic Hematuria 40-50% of cases
Asymptomatic Hematuria
±Proteinuria (<2g/d)
30-40% of cases
Nephrotic Syndrome 5-10% 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

25. 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

26. Asymptomatic Hematuria (30-40%)
Accidentally discovered on routine
exam.
Proteinuria is variable but less than 2
gm/d.
Nephrotic Syndrome (5-10%)
Rare for proteinuria to occur without
microscopic hematuria.
Presented with advance glomerular
disease and uncontrolled HTN.
Clinical Presentation

27. 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 casts.
Chronic rena;l failure with HTN
Clinical Presentation

28. Recurrent visible haematuria
Coincides with mucosal infection
Clinical presenations of IgA Nephropathy in relation
to age

29. Nephrotic syndrome
Clinical presenations of IgA Nephropathy in relation
to age

30. Asymptomatic
Haematuria / proteinuria
Clinical presenations of IgA Nephropathy in relation
to age

31. CKD
Proteinuria
Hypertension
Renal impairment
Clinical presenations of IgA Nephropathy in relation
to age

32. Diagnosis
Often suspected on the basis of clinical history, but
can be confirmed only by kidney biopsy.

33. Pathologic findings
LIGHT MICROSCOPY
A variety of classification systems have
been used to categorise the light
microscopic phenotypes of IgAN.

34. 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.

35. M
Mesangial
Hypercellulari
ty
E
Endo capillary
Hypercellularity
S
Segmental
Glomeruloscl
erosis
T
Tubular
atrophy/Inter
stitial fibrosis
C
Presence of
cresents
MEST-C
CRITERIA

36. Histological variable Definition Score
Mesangial
Hypercellularity
More than four mesangial cells
in any mesangial area of a
glomerulus
•M0: <50% of glomeruli
showing mesangial
hypercellularity
•M1: >50% of glomeruli
showing mesangial
hypercellularity
Endocapillary
Hypercellularity
Hypercellularity due to an
increased number of cells
within glomerular capillary
lumina
•E0: no endocapillary
hypercellularity
•E1: any glomeruli showing
endocapillary hypercellularity
Segmental
Glomerulosclerosis
Adhesion or sclerosis
(obliteration of capillary lumina
by matrix) in part but not the
whole glomerular tuft
•S0: absent
•S1: present in any glomeruli
Tubular
Atrophy/Interstitial
Fibrosis
Estimated percentage of
cortical area showing tubular
atrophy or interstitial fibrosis,
whichever is greater
•T0: 0–25% of cortical area
•T1: 26–50% of cortical area
•T2: >50% of cortical area
Cellular Or Fibrocellular
Crescents
Percentage of glomeruli with
cellular or fibrocellular
crescents
•C0: absent
•C1: 0–25% of glomeruli
•C2: ≥25% of glomeruli

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

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

39. 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.
C3 staining is almost always present and usually
bright. However staining for C1q is uncommon

40. 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.

41. Differential Dx. of IgA Nephropathy:
Conditions associated with mesangial IgA deposition

42. Management
• Initial evaluation including assessment of risk of
progressive kidney disease.
• Assess all patient with biopsy proven IgAN for
secondary causes.
• Assess the risk of progression in all cases by
evaluation of proteinuria, blood pressure,and eGFR
at the time of diagnosis and during followup.
• Pathological features may be used to assess
prognosis.

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

44. 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
casts

45. Crescentic IgAN
• IgAN with crescents in more than 50% of
glomeruli in the renal biopsy with rapidly
progressive renal deterioration
• Steroids and cyclophosphamide are to be used in
IgA nephropathy and rapidly progressive
crescentic IgAN.
• Intravenous pulse methylprednisonole f/by oral
prednisolone,intravenous or oral
cyclophosphasphamide and or plasmapharesis
can be used

46. •Gender
•Serum Ig A levels
•Intensity of Ig A
deposits
•Recurrent macroscopic
hematuria
•HTN
•Renal Impairment
•Severe Proteinuria
•Smoking
•Hyperuricemia
•Gross Obesity
•Increasing Age
•Long duration of
preceding symptoms
•Mesangial
Hypercellularity
•Endocapillary
proliferation
•Segmental
Glomerulosclerosis
•Tubular Atrophy
•Interstitial Fibrosis
•Capillary loop IgA
deposits
•Cresents
Prognostic factors
At Presentation
POOR
(CLINICAL)
POOR
(HPE)
GOOD
NO
IMPACT
Prognostic factors

47. Renal transplantation
There is a high rate of recurrence in the renal
allograft up to 60% by 10 yrs