IgA Nephropathy_New Updates

Current UpdatesCurrent Updates

Immunoglobulin A (IgA) Nephropathy

Dr. Om Kumar

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Epidemiology

Most common cause of primary glomerulonephritis in most developed countries

Peak incidence in 2nd to 3rd decade of life

2:1 male to female ratio

Most common in Asians & Caucasians

Available evidence suggests an increasing incidence in India!

4.2% 1987

7 – 10% 1995

12-15% 2009

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

Tam

il Na

duKerala

Delhi

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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

Gluten Enteropathy

HIV

Minimal Change

Membranous Nephropathy

Wegener’s

Dermatitis Herpetiformis

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

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Pathology- Light Microscopy

Most common appearance is mesangial hypercellularity

Crescents and tubular sloughing are not uncommon with gross hematuria and renal insufficiency

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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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PathogenesisPathogenesis

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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IgAIgA

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

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IgA

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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

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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

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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

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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 responsehave increased expression of TGF-beta and components of renin-angiotensin sytem

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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

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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

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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%)

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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- 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

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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

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PrognosisPrognosis

<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

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Clinical Prognostic MarkersClinical Prognostic Markers

Poor Prognosis:

Severity of proteinuria

HTN

Renal impairment

Increasing age

Duration of preceding symptoms

Increased BMI

Good Prognosis:

Recurrent macroscopic hematuria

No Impact on Prognosis:

–Gender

–Ethnicity

–Serum IgA level

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Histopathologic Prognostic Histopathologic Prognostic MarkersMarkers

Poor PrognosisLight Microscopy:

–Capsular adhesions & crescents

–Glomerular sclerosis–Tubule atrophy–Interstitial fibrosis–Vascular wall thickening

Immunofluorescence:–Capillary-loop IgA deposits

Ultrastructure:–Mesangiolysis–GMB abnormalities

Good Prognosis:

Minimal light microscopic abnormalities

No Impact on Prognosis:

Intensity of IgA deposits

Co-deposition of mesangial IgG, IgM, or C3

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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

IgA Challenges &

Opportunities!

Challenges

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Opportunities available for new tests & treatments that may eventually lead to control of this chronic form of kidney disease

IgA Nephropathy poses many challenges in its Etiology, Pathogenesis, Prevention & Treatment

IgA Nephropathy is a significant contributor to the incidence of ESRD in many countries

Current Facts !

1

2

3

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Diagnostic & Prognostic Challenges

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

1

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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

1

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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

2

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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

3

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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

4

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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

5

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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

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Opportunities - Genetics

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!

1

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Opportunities - Proteomics

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

2

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Opportunities - IgA1 testing

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

3

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– 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

3

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3

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Opportunities - Knowledge of secondary mediators

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

4

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Opportunities - Knowledge of secondary mediators

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!

5

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Opportunities – Addition of Immunosuppresors

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!

6

Much Work Needs to be Much Work Needs to be done !done !

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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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Additional Slides

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– 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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– 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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– 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

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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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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%)

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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%)

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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_New Updates

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