Secondary Secondary IgAIgA

Nephropathy Nephropathy & &

HSPHSP

Anjali Gupta, MDAnjali Gupta, MD

1/11/111/11/11

AKI sec to Hematuria?

65 cases of ARF after an episode of macroscopic hematuria

have been reported in the literature in patients with GN.

The main histologcal

findings was ATN with the presence of red cell casts in the lumen of tubules and edema of the interstitial

tissue ,changes in the glomeruh

were disproportionately mild for the severity of the ARF

57 were suffering from IgA

nephropathy, 2 from focal GN, two from postinfectious

GN and 1 from HSP

Recovery in 2-3 months

Renal Failure, 21(1), 107-111 (1999)

Secondary IgA

Causes

Studied light Mx

and immunofloresence

of 100 cirrhotic patients. Autopsy done within 24 hours. 90 were sec to alcoholic hepatitis

61 cases had Ig

A deposit,58 only mesangial

in 3 had subendothelial

extension

18 had only Ig

A, 43 along with some IgG

and IgM. C3 in most cases.

Light Mx-

focal glomerular

changes in 3 cases, rest mesangial

widening

3 patients had significant proteinuria, in others clinical correlation not studied

Renal Biopsy in 11 patients with cirrhosis

5 had membranoproliferative

GN with mainly Ig

A deposition-

All had nephrotic

range proteniuria

and hematuria. Renal insufficiency in 3.

Others had lobular? GN, mesangial

proliferation, glomerulosclerosis

In another series of 23 patient, 3 were noted to have h/o

microscopic proteinuria

and hematuria

(Kawaguchi et al)

No clinical studies about the course /progression or treatment

Secondary IgA

In 1950-mesangial expansion seen in cirrhotics

was reffered

as Cirrhotic gloemrulosclerosis.

No specific histological difference between primary n secondary Ig

A

In 2 case series C3 deposit were absent on 20-40% of pt which is higher than primary Ig

A

Clinical Presentation-

Incidental findings? Most case series are based on autopsy and retrospective review of renal findings

Progression to ESRD is not commonly reported as c/w

primary

Having macroscopic hematuria

is uncommon

IgA

in Cirrhotics

Glomerular

changes has been reported in more than 50% of cirrhotics

approaches 75% in ESLD.

Some have suggested its coincidence of 2 common pathology.

No consistent evidence that improvement in hepatic disease improves renal disease. One case report of remession

following treatment of portal vein thromosis. World J Gastroenterol

2007 November 21; 13(43): 5783-5786

Animal models -?

No established treatment protocols

Pathogenesis (Hypothesis)

Increased pIgA

production-

dimished

mucosal integrity leading to exagerrated

response of normal IgA

system vs

some evidence of intrinsic hyperactivity of IgA

system

Production of abnormal IgA-

did nt

come across data referring to glycosylation

in heptatic

Ig

A

Decreaed

Ig

A clearance –

Fractional catabolism of IgA

is reduced.

-

Alteration in receptor/ receptor distribution. ASGPR is located in canaicular

area as c/w

sinusoidal area in healthy

-

Decreased FcR

recptor

expressions on monocytes

Nephrol-dialysis-transp (1999) 14:2279-2282

HSPHSP

HSP

1837-

Association between purpura

and arthritis described by Schonlien

1870-

Henoch

recognized GI renal involvement.

1900 it was known as anaphylactoid

purpura

1990 –ACR published diagnostic criterion

1)Palpable purpura

2) Age <20

3)Bowel pain

4)Wall granulocytes

Clinical Features

Systemic vasculits

characterized by Ig

A dominant immune complex deposits affecting small vessels

Mostly affects children <10 yrs, males and commonly caucasian

Arthritis and GI symptoms often preceded rash by 2-8 week

Frequency of renal involvement in adults is reported as 50-70% as c/w

30-40% in children.

Nephritis becomes chronic and mainly results in morbidity

Frequency of Histologic Lesions

I 8%II 29%III 43%IV 12%V 6% VI 3%

Diagnosis

Clinical features

Increased serum IgA

in 20-60% of patients

Normal complements in >90% of patients

Biopsy with IgA

immune complex deposition-

edge of fresh purpuric

lesions. Can be seen in other disease like IgA, liver disease.

Kidney International, Vol. 59 (2001), pp. 823–834

Outcome in children

Treatment In Children

Role of steroids is controversial. Mainly retrospective data.

Aggressive therapy with corticosteroids or cyclophosphamide/Azathioprine

has not been proven to be beneficial in reversing the renal disease except among patients with crescentic

nephritis.

Steroid course of 6 months for patients with the nephrotic

syndrome and those with a reduced GFR has been used

Role of plasamphresis? Rituximab?

Corticosteroid treatment and odds of cumulative (transient or persistent ) incidence of renal disease

A, Prospective; B, retrospective. The box sizes are proportional

to the inverse of the magnitude of the variance.

No overall OR is displayed ,because of the heterogeneity of the studies.

Corticosteroid treatment and odds of persistent renal disease. A, Prospective; B, retrospective.

An end point of 1 year was used for the Huber et al and Mollica

et al studies and 6 months for the Ronkainen

et al study.

Early corticosteroid treatment significantly reduced the odds of

developing persistent renal disease

Retrospective analysis of 250 adults with Biopsy proven HSP. Median follow up 14.8 years

Renal involvement in adults varies from 45 to 85%

The risk of progression to renal insufficiency, which ranges from 5% to 15% in children, seems to be approximately 30% in adults

Palpable purpura

was present in 96% , arthritis in 61%, GI in 48% and renal involvement in 32%

J Am Soc Nephrol 13: 1271–1278, 2002

Renal Manifestations

Renal maifestations

developed within 2 months of first clinical symptom.

The most frequent lesion in renal biopsies was proliferative endocapillary

glomerulonephritis

(class 3) (61%)

Outcomes

64 pt (26%) died. Commonest cause neoplasia(27%) followed by infection( 16%)

Median survival 15yrs (11-21)

27 pt (11%) developed ESRD

25 were dialyzed, and 12 received renal transplant None of these

lost their graft because of a relapse of HSP.

13% had severe renal failure, and 14% had moderate renal insufficiency. In all 38% had renal insufficency.

At the end of the follow-up, only 20% of the patients were in clinical remission.

Prognostic factors

Age, Class of biopsy or treatment were significant factors in univariate

but not in multivariate analysis.

High rate of ESRD as c/w

other study but it was a longer follow up

Retrospective analysis of 37 patients with HUS , single centre UK study

Cytotoxics

were used in 32%, with no clear effect on outcome. Of the 10 ESRD patients, 60% had received prednisolone

and cyclophosphamide.

Q J Med 2006; 99:253–265

Treatment of HSP in adults

Multi-center, prospective, open-label trial –

intention to treat

54 adults with biopsy-proven HSP with severe visceral manifestations of one organ randomized to steroids alone or steroids plus cytotaxan

Average follow up of 5 years.

Kidney International (2010) 78, 495–502

Baseline Renal Characteristics

Kidney International (2010) 78, 495–502

Kidney International (2010) 78, 495–502

Conclusions

Small number of patient.

Study does suggest addition of cyclophosphamide

may have no clinical benefit. This pt group seemed to have relatively good GFR

Ideally an arm with no steroids would have been helpful

Thank you Thank you

Pathogenesis: Characteristics of IgA

in IgAN