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1. IgA Nephropathy
KDIGO 2021 Clinical Practice Guideline for the
Management of Glomerular Diseases
Mohammed Abdel Gawad MD Neph, ESENeph
Lecturer of Nephrology, School of Medicine, NewGiza University
Nephrology Consultant, Alexandria
Founder of NephroTube.com
Co-chair of AFRAN Web/Media Committee
ISN Education SoMe Team Member
drgawad@gmail.com
@Gawad_Nephro
29, June, 2022

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5. Talk Outline – IgA Nephropathy
• Pathogenesis
• Clinical Presentation
• Pathology
• Treatment

6. Talk Outline – IgA Nephropathy
• Pathogenesis
• Clinical Presentation
• Pathology
• Treatment

7. 7
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

8. • Immunoglobulin A (IgA) is an antibody that plays a critical role
in mucosal immunity
Normal IgA Formation & Function
8
S Fagarasan and T Honjo (2003). "Intestinal IgA Synthesis: Regulation of Front-line Body Defenses". Nat. Rev. Immunology 3 (1):
63–72

9. 9
Polymeric & Secretory IgA
Normal IgA Formation & Function

10. 10
Andrea Cerutti, Maria Rescigno, Immunity, volume 28, Issue 6, 13 June 2008, Pages 740–750
Normal IgA Formation & Function
Polymeric & Secretory IgA

11. IgA Clearance
• Circulating IgA1 is cleared by the liver through hepatocyte
asialoglycoprotein receptors and Kupffer cell Fcα receptors.
11
Normal IgA Formation & Function
Comprehensive Clinical Nephrology, 4th edition, Chapter 22, Page 270, 271

12. Normal IgA1 Structure
12
Normal IgA Formation & Function
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.

13. • 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. *
13
Pathogenesis – Abnormal Glycosylation
* Current Diagnosis & Treatment, Nephrology & Hypertension, Chapter 27, Page 243

14. • Hepatic clearance of IgA is reduced, possibly as a
consequence of the altered molecular characteristics
of IgA.
14
Pathogenesis – Hepatic Clearance
Comprehensive Clinical Nephrology, 4th edition, Chapter 22, Page 270, 271

16. Talk Outline – IgA Nephropathy
• Pathogenesis
• Clinical Presentation
• Pathology
• Treatment

17. 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
17
Floege J, Feehally J. IgA nephropathy: recent developments. J Am Soc Nephrol2000;11:2395-2403

18. Talk Outline – IgA Nephropathy
• Pathogenesis
• Clinical Presentation
• Pathology
• Treatment

19. 19
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

20. 20
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
Fundamental of Renal Pathology, Section III, Chapter 6, Page 63

21. 21
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.
Comprehensive Clinical Nephrology, 4th edition, Chapter 22, Page 275
Pathology - LM

22. 22
Mesangial Deposits % of cases
Diffuse IgA deposits Hallmark
C3 90%
IgG 40%
IgM 40%
Kappa & lambda chain May be present
Pathology - IF
Comprehensive Clinical Nephrology, 4th edition, Chapter 22, Page 275

23. 23
Comprehensive Clinical Nephrology, 4th edition, Chapter 22, Page 275
Diffuse mesangial IgA. (Indirect immunofluorescence with fluorescein isothiocyanate–anti-IgA;
magnification × 3300.)
Pathology - IF

24. 24
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

25. 25
Electron microscopy: mesangial electron-dense deposits. The deposits are shown by arrows. (Electron
micrograph; magnification ×316,000.)
Comprehensive Clinical Nephrology, 4th edition, Chapter 22, Page 275
Pathology - EM

26. 26
Fundamental of Renal Pathology, Section III, Chapter 6, Page 63
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

27. Talk Outline – IgA Nephropathy
• Pathogenesis
• Clinical Presentation
• Pathology
• Treatment

28. IGAN - TREATMENT
Practice Point 2.3.2: Algorithm for the initial assessment
and management of the patient with IgAN

29. IGAN - TREATMENT
Practice Point 2.3.2: Algorithm for the initial assessment
and management of the patient with IgAN

30. Treat to nationally agreed-upon blood pressure targets. KDIGO
suggests treating to an SBP target of <120 mm Hg measured
using standardized office blood pressure measurement.

31. The patients enrolled in the only large
RCT suggesting benefit of
immunosuppression had an average
of 2.4 g/d of proteinuria.

32. Where appropriate, treatment
with glucocorticoid (prednisone
equivalent ≥0.5 mg/kg/d) should
incorporate prophylaxis against
Pneumocystis pneumonia along
with gastroprotection and bone
protection, according to local
guidelines.

34. Tonsillectomy
should not be
performed as a
treatment for IgAN
in Caucasian
patients.

37. A number of new therapies for high-risk IgAN patients are currently
being evaluated:
• including drugs that may augment the supportive care approach:
sparsentan,
atrasentan,
hydroxychloroquine
• or more specific approaches
enteric-coated budesonide,
 various complement inhibitors,
therapies targeting B-cell development

38. IGAN – TREATMENT OF PATIENTS WITH IGAN WHO ARE
AT HIGH RISK OF PROGRESSIVE CKD DESPITE MAXIMAL
SUPPORTIVE CARE
Practice Point 2.3.1.5: Other pharmacologic
therapies evaluated in IgAN

39. A kidney biopsy is essential in these cases and will commonly demonstrate
mesangial and endocapillary hypercellularity, and a high proportion of glomeruli
affected by crescents with areas of focal necrosis.
Extensive crescent formation (usually >50% of glomeruli), commonly in the
absence of visible hematuria.
Importantly, the presence of crescents in a kidney biopsy in the absence
of a concomitant change in GFR does not constitute rapidly
progressive IgAN; however, these patients require close follow-up to
ensure prompt detection of any GFR decline.
Rapidly progressive IgAN is defined as a ≥50% decline in eGFR over ≤3 months,
where other causes of an RPGN (e.g., AAV, anti-GBM disease) and reversible
causes (e.g., drug toxicity, common pre- and post-kidney causes) have been
excluded.

40. A repeat kidney biopsy should be considered in patients
who fail to show improvement in kidney function within 2
weeks following cessation of the hematuria

41. Nephrotic range proteinuria without NS may be seen
in IgAN, and this commonly reflects coexistent secondary
focal segmental glomerulosclerosis (FSGS) (e.g., obesity,
uncontrolled hypertension) or development
of extensive glomerulosclerosis and tubulointerstitial
fibrosis.

42. Adult patients with IgAV should be assessed for secondary causes and for
malignancy with age- and sex-appropriate screening tests.
IgAV with RPGN as well as other IgAVN may also be associated with significant
extrarenal involvement (e.g., pulmonary, gastrointestinal, and skin), which may
dictate alternative immunosuppressive strategies.
Uncontrolled case series describe the potential role for the addition of plasma
exchange to glucocorticoid therapy to accelerate recovery in
patients with life- or organ-threatening extrarenal
complications of IgAV

43. IGAN – SPECIAL SITUATIONS
Practice Point 2.4.4: IgAN and pregnancy planning:
• IgAN is a disease predominantly of young adults, and all women of childbearing
potential should be offered preconception counseling when appropriate.
• Preconception counseling should include a discussion on cessation of renin–angiotensin
system (RAS) blockade. Blood pressure control should be optimized with alternative
antihypertensive medications prior to conception.
• In those women at high risk of progressive CKD (Recommendation 2.3.1.1) despite
maximal supportive care, a trial of immunosuppression to optimize immunologic activity
and reduce proteinuria prior to conception may be preferable to emergent initiation of
immunosuppression during pregnancy