Immunoglobulin A (IgA) Nephropathy

Current Updates

Dr. Om Kumar
 Epidemiology

Most common cause of 7 – 10%

primary glomerulonephritis 1995
in most developed countries
Delhi

Peak incidence in 2nd to 3rd

decade of life

2:1 male to female ratio

Most common in Asians &

Caucasians

Available evidence 12-15%

2009 4.2%
suggests an increasing 1987
incidence in India!
u
ad
Ker

il N
Tam
ala

Chandrika BK. IgA nephropathy in Kerala, India: A retrospective study. Indian J Pathol
IgA Nephropathy Microbiol 2009;52:14-6 2
 Clinical Features

40- 50% present with gross hematuria, usually following an

upper respiratory infection

30- 40% present with microscopic hematuria and non-

nephrotic proteinuria

<10% present with nephrotic syndrome or acute RPGN

Rarely presents with malignant HTN or AKI

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 Clinical Associations

Hepatic Cirrhosis Membranous Nephropathy

Gluten Enteropathy Wegener’s

HIV Dermatitis Herpetiformis

Minimal Change Seronegative Arthritis

Small Cell Carcinoma

Disseminated TB

Mycosis Fungoides

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 Diagnosis

Gold standard for diagnosis is Biopsy

IgA- fibronectin not used any longer
– Assays cannot reliably distinguish between free IgA and IgA-
fibronectin complexes

Skin biopsy is not predictive of IgA nephropathy

Serum IgA levels are not reliable

IgA Nephropathy 5
 Pathology- Light Microscopy

Most common
appearance is
mesangial
hypercellularity

Crescents and tubular

sloughing are not
uncommon with gross
hematuria and renal
insufficiency

IgA Nephropathy 6
 Pathology- Immunofluorescence

Pathognomonic finding
is prominent, globular
deposits of IgA in the
mesangium

Dominant form is
polymeric IgA1

Minimal staining for C1q

or its absence
distinguishes IgAN from
lupus nephritis

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 Pathology- Electron Microscopy

Electron dense deposits

primarily in the
mesangium

May have focal thinning

of basement membrane

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 Pathogenesis

Inciting event in the pathogenesis is mesangial deposition of

IgA

Three key elements contribute to development of IgA

nephopathy:

1. Persistence of characteristic pIgA1

2. “Reactivity” of glomerular mesangium

3. How the kidney responds

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IgA Nephropathy 10
 IgA

Tetramer consisting of two identical light chains and two

heavy chains
Two isotypes: IgA1 and IgA2
Two “compartments” of IgA: the mucosa associated
lymphoepithelial tissue (MALT) and the bone marrow-plasma
compartment
Circulating IgA contains 90% IgA1; 10% IgA2

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 IgA

IgA Nephropathy 12
 IgA

IgA Nephropathy 13
 Characteristics of IgA in IgAN

No single pathogenic
antigen yet identified

Elevated IgA level by

itself does not cause
IgA nephropathy

Thought that
abnormal
glycosylation plays a
role

IgA Nephropathy 14
 IgA Production and Clearance in IgAN

Associated with upper respiratory tract infections, so

thought that the mucosa was the site of IgA production

Studies have shown that abnormal pIgA1 comes from bone

marrow rather than mucosal sites

In IgAN, have decreased hepatic clearance as well as

decreased myeloid clearance, further leading to elevated
pathogenic IgA levels

IgA Nephropathy 15
 IgA and the Mesangium

In IgAN, rate of IgA deposition either exceeds mesangial

clearance capacity or is somehow resistant to clearance

Not all IgA deposition is is associated with inflammation, and

IgA deposition is not necessarily irreversible

Deposition may be enhanced by abnormal glycosolation

IgA Nephropathy 16
 IgA and the Mesangium

May have abnormal clearance because have impaired

binding of IgA to mesangial cell receptors, leading to
accumulation

Once mesangial cells bind to IgA, triggers a proinflammatory

and profibrotic responsehave increased expression of TGF-
beta and components of renin-angiotensin sytem

IgA Nephropathy 17
Treatment - Nonimmunosuppressive Therapy

ANGIOTENSIN INHIBITION
– Reduce proteinuria by reducing intra- glomerular pressure and
improving size-selective properties of the glomerular wall
– Used in patients with >500mg/day or if hypertensive

– No randomized controlled trial shows benefit of ACE-I and/or ARB,

with most being underpowered

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Treatment- Nonimmunosuppressive Therapy

FISH OIL
– Mechanism unclear, but likely due to anti-inflammatory properties

– Use limited by taste and patient compliance

– No consensus among studies on outcome with fish oil

IgA Nephropathy 19
Treatment- Immunosuppressive Therapy

Available studies have been small with limited follow-up, so

most studies are inconclusive

Reserved for those with evidence of active inflammation

IgA Nephropathy 20
 Treatment- Immunosuppressive Therapy

GLUCOCORTICOIDS
– SW Pediatric Nephrology Study Group randomized 96 patients to
omega-3 fatty acids (4g/day); alternate day prednisone; or placebo
– Primary end point: reduction in GFR to below 60% of baseline

– At 3 years, primary outcome was seen more frequently in fish-oil

group (19%) than in prednisone (9%) or placebo (9%)

IgA Nephropathy 21
Treatment- Immunosuppressive Therapy

COMBINATION THERAPY
– Lv et al randomized 63 patients to either ACE-I (Cilazapril) or ACE-I
and prednisone (0.8mg/kg/day x 8 weeks, then tapered by 5-10mg
every 2 weeks
– Primary end point: 50% increase in serum creatinine

– Secondary end point: 50% reduction in proteinuria

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 Treatment- Immunosuppressive Therapy

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 Treatment- Summary

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 Treatment- Other Interventions

TONSILLECTOMY
– No randomized trials showing a benefit

– One nonrandomized trial of 55 patients compared steroids alone vs

steroids with tonsillectomy
– Those who received combination therapy had remission of
proteinuria and hematuria at 2 years, as well as decreased mesangial
proliferation and IgA deposition

IgA Nephropathy 25
 Treatment- Other Interventions

IVIG
– Small studies show that may have reduction in proteinuria and
stabilization of renal function

VITAMIN D
– Small, uncontrolled, short-term study decrease in proteinuria as
measured by spot protein / creatinine

IgA Nephropathy 26
 Prognosis

<10% of patients have complete resolution of urinary

abnormalities

1.5% of patients with IgA nephropathy reach ESRD per year

15-25% of any published cohort will require renal

replacement therapy within 10 years of presentation; 20-30%
at 20 years

IgA Nephropathy 27
 Clinical Prognostic Markers

Poor Prognosis: Good Prognosis:

Severity of proteinuria Recurrent macroscopic

hematuria
HTN

Renal impairment No Impact on

Prognosis:
Increasing age
–Gender
Duration of preceding
–Ethnicity
symptoms
–Serum IgA level
Increased BMI

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 Histopathologic Prognostic Markers
Poor Prognosis Good Prognosis:
Light Microscopy:
–Capsular adhesions & Minimal light microscopic
crescents abnormalities
–Glomerular sclerosis
–Tubule atrophy
–Interstitial fibrosis No Impact on Prognosis:
–Vascular wall thickening Intensity of IgA deposits
Immunofluorescence:
–Capillary-loop IgA deposits Co-deposition of mesangial
IgG, IgM, or C3
Ultrastructure:
–Mesangiolysis
–GMB abnormalities

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 Transplantation

Frequency of histologic or clinically significant

recurrence varies in the literature

Similar graft survival as those patients with

non-IgA glomerular disease and non-glomerular
disease

Large retrospective analysis from Australia

showed an estimated 10-year incidence of
graft loss due to recurrent disease of 9.7%

However, it is a very suitable alternative for patients

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 Transplantation

Likelihood of recurrence does not appear to be affected by

the type of induction or maintenance immunosuppression
used

Angiotensin inhibition may delay progression of recurrent

disease

No clear evidence that graft survival is improved by using

angiotensin inhibition once disease recurs

Case reports of fish oil have a favorable effect in recurrent

IgA nephropathy, but no studies support this
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 IgA
Challenges & Opportunities!
Challenges
 Current Facts !

1 IgA Nephropathy is a significant contributor to the

incidence of ESRD in many countries

2 IgA Nephropathy poses many challenges in its Etiology,

Pathogenesis, Prevention & Treatment

3 Opportunities available for new tests & treatments that

may eventually lead to control of this chronic form of
kidney disease

IgA Nephropathy 34
 Diagnostic & Prognostic Challenges
1
Can IgA nephropathy be diagnosed without a renal biopsy?

Renal Biopsy remain the ‘Gold Standard’for diagnosis !

New, sensitive & reasonably noninvasive tests are emerging

– Test for Abnormally glycosylated IgA subclass I (IgA1)

– Such tests offer great promise for use in genetic & epidemiology
studies, in which renal routine biopsy is impractical

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 Diagnostic & Prognostic Challenges
1
Can IgA nephropathy be diagnosed without a renal biopsy?

Renal Biopsy remain the ‘Gold Standard’ for diagnosis !

New, sensitive & reasonably noninvasive tests are emerging

– Test for Abnormally glycosylated IgA subclass I (IgA1)

– Such tests offer great promise for use in genetic & epidemiology
studies, in which renal routine biopsy is impractical

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 Diagnostic & Prognostic Challenges
2
Signs & Symptoms are non-specific!

Most common clinical presentation – Macroscopic

hematuria ± proteinuria

Similar presentation in thin basement membrane

nephropathy, Alport syndrome and membranoproliferative
glomerulonephritis
– IgA nephropathy can be reliably distinguished ONLY
by renal biopsy and electron microscopy

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 Diagnostic & Prognostic Challenges
3
Can we better predict which patients with IgA
nephropathy will develop renal failure?

Several factors, if present at the time of discovery or

developing within a relatively short time thereafter (usually
6 months to 1 year), appear to predict a progressive course
and, eventually ESRD

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 Diagnostic & Prognostic Challenges
4
Are clinical risk factors more useful than pathological risk
factors in IgA nephropathy?

Clinical factors appear to have greater

predictive power than pathologic
factors for long-term outcome

If we can find new risk factors that

can predict progressive disease earlier,
the knowledge will help us in designing
future clinical trials, which will be vital if
progress is to be made towards controlling
IgA nephropathy

IgA Nephropathy 39
 Diagnostic & Prognostic Challenges
5 How can IgA nephropathy be diagnosed and treated before the ‘point of
no return’?

IgAN progresses silently, and many patients do not receive

the diagnosis until late in its course
The “point of no return” appears to be an estimated GFR
of about 30 mL/min/1.73 m2 (stage 4 chronic kidney
disease)
The need is for early diagnosis and treatment based on
factors that can accurately predict an unfavorable outcome
The challenge is to translate these findings into rational,
safe, and effective therapies applicable across
a broad spectrum of disease

IgA Nephropathy 40
 Diagnostic & Prognostic Challenges
5
How can IgA nephropathy be diagnosed and treated before
the ‘point of no return’?

For patients at risk of developing ESRD,

the two most critical goals are:
– Control blood pressure rigorously, preferably
with ACE inhibitor, an ARB, or both &
– Reduce proteinuria to less than 500 mg/ day

If these two goals can be met without undue

side effects and patient compliance, many
patients can avoid ESRD

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 Opportunities
Genetics, Proteomics, New Tests & Treatments
 Opportunities - Genetics
1 Genetic studies may lead to novel treatments for IgA
nephropathy!
At present, genetic testing based on genomic or transcriptosomic analysis does
not have much diagnostic value

Most current genetic studies actually examine susceptibility to the clinical

expression of disease rather than susceptibility to the mesangial IgA deposition
that underlies the disease

The opportunity that lies ahead in genetic testing of IgA nephropathy (including
haplotype analysis) appears to be primarily in the elucidation of potential
pathogenetic pathways, in the refinement of prognosis and the definition of
treatment responsiveness (pharmacogenomics)

If a gene (or group of genes) can be identified that is strongly and consistently
associated with IgA nephropathy across diverse populations, then a new era in
targeted therapy of IgA nephropathy will be unleashed!

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 Opportunities - Proteomics
2
Proteomics may prove useful in diagnosis and
prognosis of IgA nephropathy!
– Preliminary studies have shown that this technique may provide a
novel noninvasive means of diagnosing IgA nephropathy, and
– It may have additional value as a prognostic tool

IgA Nephropathy 44
 Opportunities - IgA1 testing
3
IgA1 testing may help detect IgA nephropathy early in its
course

– Abnormally undergalactosylated and oversialyted

epitopes at the hinge region of the IgA1 molecule
play a critical role in the pathogenesis of sporadic
IgA nephropathy
– This discovery provides a great opportunity for profiling
patients suspected of having IgA nephropathy on the
basis of sensitive determination of the serum level of
abnormal IgA1 molecules

IgA Nephropathy 45
 Opportunities - IgA1 testing
3
IgA1 testing may help detect IgA nephropathy early in its
course

– Abnormally undergalactosylated and oversialyted

epitopes at the hinge region of the IgA1 molecule
play a critical role in the pathogenesis of sporadic
IgA nephropathy
– This discovery provides a great opportunity for profiling
patients suspected of having IgA nephropathy on the
basis of sensitive determination of the serum level of
abnormal IgA1 molecules

IgA Nephropathy 46
 Opportunities - IgA1 testing
3
IgA1 testing may help detect IgA nephropathy early in its
course

IgA Nephropathy 47
Opportunities - Knowledge of secondary mediators

4
Knowledge of secondary mediators may also lead to new
treatments for IgA nephropathy!
– Detailed knowledge of the participation of specific
cell types and the “cytokine milieu” (eg, interleukin 4,
interferon) in directing the abnormality toward
defective glycosylation would also be very important
in designing new approaches to diagnosis and therapy
– Lack of a suitable animal model of IgA nephropathy that
mimics all aspects of the human condition

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Opportunities - Knowledge of secondary mediators

5
Prognostic biopsy analysis may be improved in IgA
nephropathy!
– Great opportunities lie in refining the value of renal biopsy in
prognostication
– Much better clinico-pathological correlations, especially with
respect to outcomes, among well-characterized patient with IgA
nephropathy are greatly needed.
– New nonconventional markers of progression, such as “tubulitis,”
deposition of fibroblastspecific proteins, and the proteome of the
deposited immunoglobulins and complemen show much promise!

IgA Nephropathy 49
Opportunities – Addition of Immunosuppresors

6
Immunosuppressive therapy could be added to ACE
inhibitors or ARBs in IgA nephropathy!

The clinical trials performed have a number of limitations:

– the numbers of patients were relatively small, follow-up was
relatively short, and the findings may not apply to the IgA
nephropathy population at large or to specific patients having
features that diverge from those in the patients enrolled in the
studies.
– The value of initial therapy with an ACE inhibitor, an ARB, or both in
combination appears well established
– Many opportunities for combining Angiotensin II inhibition and
immunosuppressive therapy are being explored!

IgA Nephropathy 50
Much Work Needs to be done !
 Summary

Much work needs to be done in the field of therapeutics in IgA

nephropathy.

At present, the prospects for the development of a safe and effective

novel therapy for IgA nephropathy (eg, approvable by the US Food and
Drug Administration) appear great!

The nature of the disease mandates long-term observation, agents that

are very safe (with low rates of ESRD, death, and transplantation), and
dependency on surrogate markers of efficacy.

Well designed and executed studies are the need of the hour!

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IgA Nephropathy 53
Additional Slides
Treatment- Nonimmunosuppressive Therapy
ANGIOTENSIN INHIBITION
– HKVIN trial randomized 109 Chinese patients to either valsartan or
placebo
– Valsartan group had lower baseline proteinuria and achieved target
BP
– Primary end point: doubling of serum creatinine or ESRD

– Fewer patients in valsartan group (1) reached primary endpoint than

in placebo (4)

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Treatment- Nonimmunosuppressive Therapy
ANGIOTENSIN INHIBITION
– IgACE trial randomized 65 patients to either benazepril or placebo

– Primary end point: >30% decrease in renal function

– Secondary composite end point: worsening or proteinuria or >30%

decrease in renal function
– Fewer patients reached primary end point in benazepril group (1)
than in the placebo group (5)

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Treatment- Nonimmunosuppressive Therapy
ANGIOTENSIN INHIBITION
– Maschio et al randomized 44 patients to enalapril or other non-
ACE/ARB antihypertensive
– Patients had >.5g/day proteinuria and Cr<1.6

– At six years, renal survival more likely in ACE-I group (92%) than in
control (55%)
– Only enalapril group showed significant decrease in proteinuria

IgA Nephropathy 57
Treatment- Nonimmunosuppressive Therapy
FISH OIL
– Denadio et al in 1994 published in NEJM a study that randomized 104
patients to fish oil 12g daily vs placebo with olive oil
– Primary end point: 50% increase in serum creatinine

– At four years of follow-up, fish oil group had lower incidence of

primary end point (6% vs 33%) and lower incidence of death or ESRD
(10% vs 40%)
– Benefits continued at six years of follow up

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Treatment- Nonimmunosuppressive Therapy
FISH OIL
– SW Pediatric Nephrology Study Group randomized 96 patients to
omega-3 fatty acids (4g/day); alternate day prednisone; or placebo
– Primary end point: reduction in GFR to below 60% of baseline

– At 3 years, primary outcome was seen more frequently in fish-oil

group (19%) than in prednisone (9%) or placebo (9%)

IgA Nephropathy 59
 Treatment- Immunosuppressive Therapy
COMBINATION THERAPY
– Ballardie et al performed a single center study of 38 patients with
IgAN with impaired renal function
– Randomized to no therapy or prednisone, cyclophosphamide, and
azathioprine
– Those with combination therapy had significant reduction in
proteinuria during the first 6 months (1.8g/day vs 4.4g/day) and
higher renal survival at 2 years (82% vs 68%) and at 5 years (72% vs
6%)

IgA Nephropathy 60
References

Barratt J, Feehally J: IgA Nephropathy. J Am Soc Nephrol 16: 2088-2097, 2005

Donadio JV, Grande JP: A controlled trial of fish oil in IgA nephropathy. N Engl J
Med 1994; 331:1194.

Li PK, Leung CB, Chow KM, et al: Hong Kong study using valsartan in IgA
nephropathy (HKVIN): a double-blind, randomized, placebo-controlled study. Am
J Kidney Dis 2006; 47:751.

Lv J, Zhang H, Chen Y, et al: Combination therapy of prednisone and ACE inhibitor

vs. ACE inhibitor alone in patients with IgA nephropathy: a randomized controlled
trial. Am J Kidney Dis 2009; 53:26.

Pozzi C, Bolasco PG, Fogazzi GB, et al: Corticosteroids in IgA nephropathy: A

randomized controlled trial. Lancet 1999; 353:883.

Van der Boog PJM, van Kooten C, de Fitjer JW, Daha MW: Role of macromolecular
IgA in IgA nephropathy. Kidney International 67: 813-21, 2005

IgA Nephropathy 61