Current concepts of IgA Nephropathy

1. IgA
Nephropathy

2. Definition
• IgAN is a mesangial proliferative glomerulonephritis characterized
by diffuse mesangial deposition of IgA.
• IgAN is unique among glomerular diseases in being defined by the
presence of an immune reactant rather than by any other
morphologic feature on renal biopsy, and the light microscopy
changes are variable.
• IgAN is the most prevalent pattern of glomerular disease seen in
most Western and Asian countries where renal biopsy is widely
practiced.
• It is likely that IgAN is not a single entity but rather a common
response to various injurious mechanisms.

3. Etiology
and
Pathogenesis

4. IgA immune system

6. Epidemiology
• IgA nephropathy is the most prevalent pattern of glomerular
disease in most countries where renal biopsy is widely used as an
investigative tool.
• Its estimated frequency is at least 2.5 cases per year per 100,000
adults.
• However, the striking geographical variation has been associated
with the presence of particular gene alleles that protect from IgAN
IgAN will be identified only if renal biopsy
is performed

7. Clinical Features
The wide range of clinical presentations of IgAN varies
in frequency with age.
No clinical pattern is pathognomonic of IgAN

9. Microscopic Hematuria
• In 40% to 50% of patients with IgAN, the clinical presentation is episodic
macroscopic hematuria, most frequently in the second decade of life.
• The urine is usually brown rather than red, and clots are unusual.
• There may be loin pain caused by renal capsular swelling.
• Hematuria usually follows intercurrent mucosal infection, typically in the upper
respiratory tract (synpharyngitic hematuria) or occasionally in the GI tract.
• Hematuria is usually visible within 24 hours of the onset of the symptoms of
infection, differentiating it from the 2- to 3-week delay in postinfectious GN.
• The macroscopic hematuria resolves spontaneously over a few days.
• Microscopic hematuria persists between attacks.
• Such episodes may be associated with acute kidney injury (AKI) characterized by
tubular injury that is usually reversible.

10. Asymptomatic Hematuria and
Proteinuria
• As many as 30% to 40% of cases of IgAN are identified during
routine testing of urine of asymptomatic individuals.
• Microhematuria with or without proteinuria (usually <2 g/24 h) is
noted.
• Most patients with IgAN are asymptomatic and would be identified
only when the urine is tested.

11. Proteinuria and nephrotic syndrome
• It is rare for proteinuria to occur without microscopic hematuria.
• nephrotic-range proteinuria may occur, in particular in the
presence of uncontrolled hypertension,
• Nephrotic syndrome may occur early in the course of the disease,
with minimal glomerular change (in such cases IgAN may coexist
with MCD) or with active mesangial proliferative GN.
• Alternatively, it may occur as a late manifestation of advanced
chronic glomerular scarring.

12. Acute kidney injury
• AKI is uncommon in IgAN (<5% of all cases),
• AKI develops by three distinct mechanisms.
• There may be acute severe immune and inflammatory injury with necrotizing
GN and crescent formation (crescentic IgAN); Rapid deterioration in IgAN in
pregnancy may be caused by crescentic transformation.
• Alternatively, AKI can occur with mild glomerular injury when heavy
glomerular hematuria leads to tubule occlusion by red blood cells (RBCs).
• Third, especially in elderly patients, chronic IgAN will predispose to AKI from
a variety of incidental renal insults

13. Chronic kidney disease
• Some patients already have renal impairment and hypertension
when they are first diagnosed with IgAN.
• These patients tend to be older, and they probably have long-
standing disease that previously remained undiagnosed because
the patient did not have frank hematuria or undergo routine
urinalysis.
• Hypertension is common

14. Clinical associations
• Mesangial IgA deposition, which does not necessarily equal IgAN, is
a frequent finding in autopsy studies in chronic liver disease.
• A number of case reports have associated IgAN with HIV infection
and AIDS.
• There are case reports associating IgAN with many other
conditions, particularly with a number of immune and
inflammatory diseases
• Celiac disease
• Dermatitis herpetiformis
• Sarcoid
• Ankylosing spondylitis
• RA

15. Pathology

16. Immune deposits
• Diffuse mesangial IgA is the
defining hallmark of IgAN.
• C3 is co-deposited in up to
90% of cases.
• IgG in 40% and IgM in 40% of
cases.
• IgA also may deposit along
capillary loops, a pattern more
common in IgAV; in IgAN, this
pattern is associated with a
worse prognosis.
Diffuse mesangial IgAN seen on indirect
immunofluorescence
with fluorescein isothiocyanate–anti-IgA

17. Light microscopy

18. Light microscopy
• The clinical significance of the individual MEST-C features is as
follows:
• M1- Worse outcomes than M0
• E1- Worse renal survival in patients not on immunosuppression and
improved renal survival with immunosuppression
• S1- Predictive of worse outcomes
• T- Strongest predictor of worse outcomes
• C1 - Predictive of worse outcomes if no immunosuppression is given, but not
if immunosuppression is used; C2 is predictive of worse outcomes regardless
of Immunosuppression

19. B. Diffuse mesangial
hypercellularity
(M1).
C. Endocapillary
hypercellularity (E1).
D. Segmental sclerosis
(S1).
E. Mesangial electron-
dense deposits (arrows)

20. Electron microscopy
• Electron-dense deposits correspond to the mesangial (or capillary
loop) IgA
• Typically, electron-dense deposits are confined to mesangial and
para-mesangial areas, although subepithelial and subendothelial
deposits also can be seen.

21. Differential diagnosis – condition
associated with Mesangial IgA deposition

22. Prognosis
• Clinical and histologic data at the time
of biopsy can be used to risk assess the
patient using the International IgAN
Prediction Tool.
• Available at: Calculate by QxMD
• The International IgAN Prediction Tool
cannot be used to determine the likely
impact of any particular treatment
regimen.
• There are no validated prognostic serum
or urine biomarkers for IgAN other
than eGFR and proteinuria.

23. Prognostic markers at presentation of
IgAN

24. Recurrent IgAN after transplantation
• Mesangial IgA deposits recur in the donor transplant kidney in up to 60%
of patients with IgAN.
• In pooled series, recurrent IgAN is 30% in living related transplants
versus 23% in cadaveric grafts, but this does affect graft survival only
beyond 10 years after transplantation.
• Any urinary abnormality in a potential related donor requires thorough
evaluation, including, if necessary, a renal biopsy.
• Recurrence of crescentic IgAN with rapid graft failure occurs infrequently
and is generally resistant to treatment.
• In a few unwitting experiments, cadaver kidneys with IgA deposits have
been transplanted into recipients without IgAN. In all cases, the IgA
rapidly disappeared, supporting the concept that abnormalities in IgAN
lie in the IgA immune system and not in the kidney.

25. Treatment
The balance of risk against benefit for immunosuppressive
therapy is often unfavorable in patients with IgAN, except in the
unusual circumstance of crescentic IgAN.

27. Supportive treatment
• Considerations for treatment of all patients with IgAN who do not
have a variant form of primary IgAN:
• The primary focus of management should be optimized supportive care.
• Assess cardiovascular risk and commence appropriate interventions as
necessary.
• Give lifestyle advice, including information on dietary sodium restriction,
smoking cessation, weight control, and exercise as appropriate.
• Other than dietary sodium restriction, no specific dietary intervention has
been shown to alter outcomes in IgAN.
• Variant forms of IgAN: IgA deposition with minimal change disease (MCD);
IgAN with acute kidney injury (AKI) and IgAN with rapidly progressive
glomerulonephritis may require specific immediate treatment.

28. Treatment of hypertension and
proteinuria
• ACE inhibitors in patients with IgAN as first-choice hypotensive
agents to lower BP.
• Risk for progression in IgAN decreases significantly if proteinuria
can be reduced to less than 1 g/d by any therapeutic maneuver
• ACE inhibitors or ARB are more effective than any other therapy in
reducing proteinuria so it is recommended that all patients with
proteinuria >0.5 g/24h, irrespective of whether they have
hypertension, are treated with either an ACEi or ARB

29. Rx of patients who are at high risk
• Considerations for treatment of patients with IgAN who are at high
risk of progressive CKD despite maximal supportive care.
• High risk of progression in IgAN is currently defined as proteinuria >1g/24h
despite at least 90 days of optimized supportive care.
• Immunosuppressive drugs should only be considered in patients with IgAN
who remain at high risk of progressive CKD despite maximal supportive care.
• All patients who remain at high risk of progressive CKD despite maximal
supportive care should be offered the opportunity to take part in a clinical
trial.
• In all patients in whom immunosuppression is being considered, a detailed
discussion of the risks and benefits of each drug should be undertaken with
the patient with a recognition that adverse treatment effects are more likely
in patients with an eGFR below 50 ml/min/1.73 m2.

30. Rx of patients who are at high risk
• There is insufficient evidence to support the use of the Oxford
MEST-C score in determining whether immunosuppression should
be commenced in IgAN.
• There is insufficient evidence to base treatment decisions on the
presence and number of crescents in the kidney biopsy.
• The International IgAN Prediction Tool cannot be used to determine
the likely impact of any particular treatment regimen.
• Dynamic assessment of patient risk over time should be performed
as decisions regarding immunosuppression may change
• Proteinuria reduction to under 1 g/d is a surrogate marker of
improved kidney outcome in IgAN.

31. Corticosteroids
• The previously mentioned recommendations have recently been
challenged by two large prospective trials of oral corticosteroids in
IgAN added to optimized supportive care
• STOP-IgAN and
• TESTING
• These two trials strongly emphasize the values of a comprehensive
optimization of supportive measures in high-risk patients with
IgAN.

32. In the German STOP-IgAN trial an extensive 6-month optimization of supportive measures
abolished any subsequent benefit from highdose corticosteroids in adult patients with IgAN with
an average baselin GFR of 60 ml/min and a baseline proteinuria around 1.7 g/d.

33. TESTING trial on high-dose corticosteroids in adults with a baseline GFR of 60 ml/min
and a baseline proteinuria of 2.4 g/d was terminated early after an excess of severe,
sometimes fatal infections was noted in the corticosteroid arm

34. Corticosteroids
• Clinical benefit of corticosteroids in IgAN is not established and
should be given with extreme caution or avoided entirely in the
following situations:
• eGFR < 30 ml/min/1.72m2
• Diabetes
• Obesity (BMI >30 kg/m2)
• Latent infection (e.g. viral hepatitis, TB
• Secondary causes (e.g. cirrhosis)
• Active peptic ulceration
• Uncontrolled psychiatric illness

35. IgAN with nephrotic syndrome
• In these cases, mesangial IgA deposition can be associated with
light, and EM features consistent otherwise with a podocytopathy
resembling MCD.
• It is unclear whether this is a specific podocytopathic variant of
IgAN or the existence of MCD in a patient with IgAN.
• Patients with a kidney biopsy demonstrating mesangial IgA
deposition and LM and EM features consistent otherwise with MCD
should be treated in accordance with the guidelines for MCD.
• Patients with nephrotic syndrome whose kidney biopsy has
coexistent features of a mesangioproliferative glomerulonephritis
should be managed in the same way as those patients at high risk
of progressive CKD despite maximal supportive care.

36. IgAN with AKI
• AKI can occur in patients with IgAN in the context of severe visible
hematuria, commonly in association with an URTI.
• A repeat kidney biopsy should be considered in patients who fail to
show improvement in kidney function within two weeks following
cessation of the hematuria.
• Immediate management of AKI with visible hematuria should focus
on supportive care for AKI.
• IgAN may also present with AKI either de novo or during its natural
history due to a RPGN with extensive crescent formation,
commonly in the absence of visible hematuria.
• In the absence of visible hematuria and when reversible causes
have been excluded (e.g., drug toxicity, common pre- and post-
kidney causes), a kidney biopsy should be performed as soon as
possible.

37. IgAN with RPGN
• Rapidly progressive IgAN is defined as a ≥50% decline in eGFR over
three months or less, where reversible causes have been excluded
(e.g., drug toxicity, common pre- and post-kidney causes).
• 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.
• The presence of crescents in a kidney biopsy in the absence of a
concomitant change in SCr does not constitute rapidly progressive
IgAN.
• Patients with rapidly progressive IgAN are treated with
cyclophosphamide and corticosteroids in accordance with the
guidelines for ANCA-associated vasculitis.
• There is insufficient evidence to support the use of rituximab for
the treatment of rapidly progressive IgAN.

38. IgAN with pregnancy planning
• IgAN is a disease predominantly of young adults, and all women of
child-bearing potential should be offered pre-conception counseling
where appropriate.
• Pre-conception counseling should include a discussion on
cessation of RAS blockade before conception. BP control should be
optimized with alternative antihypertensive medications prior to
conception.
• In those women at high risk of progressive CKD 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.

39. Other therapies
• Fish oil (omega-3 fatty acids)
• Causes reductions in eicosanoid and cytokine production, and reduced
proliferation of renal cells in response to PDGF.
• The evidence for a beneficial action of fish oil in IgAN is weak
• However, fish oil treatment does not have the drawbacks associated with
immunosuppressive treatment.
• MMF
• Opposite results in different trials
• Not recommended by KDIGO guidelines
• Cyclosporine
• showed a reversible decrease in proteinuria along with a decrease in
creatinine clearance,

40. Other therapies
• Rituximab
• Two infusions of 1 g failed to reduce levels of undergalactosylated IgA and
autoantibodies against this IgA in a small open label trial in adult patients
with high-risk IgAN and did not affect proteinuria over the course of 1 year.
• Pooled human immunoglobulin
• It has given encouraging preliminary results in patients with IgAN who have
an aggressive clinical course.
• Proteinuria was reduced, deterioration of GFR slowed, and histologic activity
lessened on repeated renal biopsies.
• No RCT is available for this approach.

41. Other therapeutic approaches
• Reduction of IgA production
• Tonsillectomy reduces the frequency of episodic hematuria when tonsillitis is
the provoking infection.
• In all other patients with IgAN, tonsillectomy is not routinely recommended
• there is no role for prophylactic antibiotics.
• Dietary gluten restriction, used to reduce mucosal antigen challenge, has not
been shown to preserve renal function.
• Transplant recurrence
• There is no evidence that newer immunosuppressive agents have modified
the frequency of recurrent IgA deposits or are of value in recurrent disease.
• There is, however, registry evidence that transplant outcome is improved if
corticosteroids are continued long term and if the immunosuppression
includes MMF

42. Thank you