igm nephropathy - nyu langone health · pdf fileis igm nephropathy a distinct disease entity?...

IgM Nephropathy11/29/2011

Jun‐Ki Park

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First described by Cohen, Border et al. in 1978, in a series of 12

cases whose initial native renal biopsy specimens displayed:

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mild glomerular mesangial hypercellularity on light microscopy

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Diffuse granular mesangial IgM and C3 deposition on IF

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EM showed generalized foot‐process effacement; mesangial

electron‐

dense deposits were seen in ~50% of the patients.

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Excluded those that showed focal sclerosis, those with systemic

disease such as lupus or vasculitis.

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Critical distinction between IgM mesangial nephropathy and MCD is

poor response rate to steroid therapy.

Light microscopy usually indicates diffuse

proliferation of mesangial cells and

accumulation of extracellular mesangial matrix

Diffuse, granular, mesangial deposition of IgM,

often is associated with complement,

especially C3

EM shows generalized foot‐process

effacement and mesangial electron‐dense

deposits

•

Failure to identify IgM nephropathy as a distinct clinicopathological entity thus far may have resulted

from failure to adhere to strict pathological criteria.

•

Other series of patients with ‘IgM nephropathy’ have included patients with FSGS (O’Donoghue et al. QJM

1991)

and normal glomeruli by light microscopy (Myllymaeki et al. AJKD 2003) on initial biopsy.

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Its extreme forms resemble MCD and FSGS

Is IgM Nephropathy a distinct disease entity?Pro…

Border et al. KI 1988

Is IgM Nephropathy a distinct disease entity?Pro…•

Recurrent IgM nephropathy in renal allograft.

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Solomon et al. 1981: recurrence in 3 weeks after Tx

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Myllymaeki et al. 2003: included normal glomeruli by light microscopy

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Salmon et al. NDT 2004: Recurrent diffuse, granular mesangial deposition, with increased mesangial matrix and cellularity in the allograft, 4 yrs after Tx.

Is IgM Nephropathy a distinct disease entity?Contra…•

Many investigators report its presence in the context of MCD, MH

and FSGS, rather than as a distinct pathological entity(Vilches et al Lab Invest 1982; Ji‐Yun et al. KI 1984; Pardo et al. AJKD 1984; Lool et al. Pathology 1985..)

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Other cases show IgM on IF (often segmental rather than diffuse)

but no mesangial deposits on electron microscopy.

•

IgM deposition without accompanying glomerular abnormalities by

light microscopy is reported to occur in up to 60% or normal kidneys

donated for Tx. (Bloom et al. KI 1978)

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The International Study of Kidney Disease in Children (ISKDC) did not

differentiate MCD with IgM+ IF from MCD when it characterized

childhood nephrotic syndrome.

Is IgM Nephropathy a distinct disease entity?Contra…

•

Relationship of the IgM in areas of sclerosis to that in the

mesangium of non‐sclerotic glomeruli is unknown, sclerotic

lesions of many diseases demonstrate the presence of IgM

and C3.

(Velosa etal. Mayo Clin Proc 1975)

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In this setting, the IgM may be nonspecifically deposited onto

an abnormally permeable glomerular basement membrane or

trapped in an area of glomerulosclerosis.

Is IgM Nephropathy a distinct disease entity?Contra…

•

Experimental studies have demonstrated an increase in

uptake of macromolecules by the mesangium in

experimentally induced nephrotic syndrome whether induced

by aminonucleoside of puromycin or anti‐GBM antibody.

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The mechanism of increased uptake is not clear but may

reflect increased mesangial perfusion in nephrotic states. It is

possible that the deposition of IgM in the mesangium in INS

reflects a similar mechanism

Michael et al. KI 1980

Morphologic transition observed

The morphologic group and outcome

in patients with idiopathic nephrotic

syndrome who had more than one

biopsy; the presence (+) or absence

(—) of IgM in the glomerulus is

indicated.

Ji‐Yun et al. KI 1984

IgMN: clinical picture and long‐term prognosis

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Of 2217 biopsy specimens between 1977 –

1998, 110

specimen met criteria for IgM nephropathy. (included normal

glomeruli on LM)

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Excluded patients with systemic disease (SLE, RA, DM,

paraproteinemia)

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63 M/47F

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Mean age was 29yrs (range 1‐75yrs); 36 were younger than

16yrs

Myllymaeki et al. AJKD Feb 2003

IgMN: clinical picture and long‐term prognosis


Fig 2. Renal insufficiency and ESRD in patients with IgM

nephropathy at time of biopsy and in postbiopsyfollow‐up.


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The histologic and clinical criteria for diagnosing IgMN,

the effect of mesangial IgM on prognosis and response

to therapy, and the relation of IgMN to MCD are

questions that cannot be fully resolved until the genesis

of the IgM deposits is understood.

Pathogenesis•

The pathogenesis of IgM nephropathy remains

unclear, although abnormal T‐cell function or a disturbance in immunoaggregate clearance by

mesangial cells have been suggested.

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Many studies have reported increased serum IgM or IgM immunocomplex concentration in patients with IgM nephropathy.

In vitro B‐lymphocyte switch disturbance from IgM into IgG in IgMN

Lin et al. Pediatr Nephrol 1989

Fig. 1. Serum IgM levels in patients

with IgM mesangial nephropathy (●),

minimal change nephrotic syndrome

(MCNS) with hypercellularity (◌) and

MCNS with normal cellularity (□)

during the acute nephrotic phase.

The solid lines indicate values (mean

+ 2SD) from normal controls


Fig. 2. Relationship between serum IgM level and in vitro IgM production

during acute nephrotic phase in patients with IgMN (●), MCNS with

hypercellularity (◌) and normal cellularity (□)



suppressor T‐cells

activated suppressor T‐cells

suppressor T‐cell inducers

In vitro B‐lymphocyte switch disturbance from IgM into IgG in IgMNAuthors conclude:

•Previous B‐lymphocyte development study demonstrated T‐cell involvement in the

constant region of heavy chain (CH) isotype "switching".

•The abnormality of T‐cells may influence the isotype expression and even the Ig

production.

•Hyperfunction of the suppressor T‐cells in the IgMN and MCNS patients with

hypercellularity may play a role as a direct or indirect "switch

blocker" and cause a

high level of IgM production, a low level of IgG production, in these patients during

the acute nephrotic phase.

•The OKT8 cell levels were correlated both with in vitro IgM production and with in

vitro IL‐2 production. These results indicate that high Tac expressed, activated

suppressor T‐cells either directly cause hyperfunction of suppressor T‐cells or

secrete some factor(s) which block(s) the switch of immunoglobulin synthesis from

IgM to IgG, leading to high serum IgM and low serum IgG levels.

Circulating heavy IgM in IgMN

DiSciullo et al. Clin. Exp. Immunol 1988

Presence of heavy IgM



Circulating heavy IgM in IgMN

Presence of IgM‐C3 complex

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Fractions were collected and assayed for the presence of IgM

and IgM‐C3 complexes using enzyme immunoessays.

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Dissociation of this heavy IgM by KSCN and glycine HCL is

compatible with the hypothesis that the IgM is in the form of

circulating immune complexes. This is further supported by

the observation of acid dissociable C3‐IgM complexes.

Presence of IgM‐C3 complex

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May indicate abnormality in B cell differentiation d/t defect in

regulatory T cell function.

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May be secondary reduce clearance of circulating antigen IgM

antibody complexes. (e.g in liver dysfunction)

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Circulating IgM complexes have been detected in SLE, viral

hepatitis A and , IgAN, HSP, membranous GN and lupus

nephritis.

•

Increased IgM immuncomplexes may be compatible with

IgMN but not proof that IgMN is separate disease entity.

Swartz et al. Pediatr Nephrol 2009

Swartz et al. Pediatr

Nephrol

2009

In conclusion:

‐IgM

pos IF identified to be a marker of disease severity in children with

MCD, MH and FSGS

‐Children with steroid‐dependent or steroid‐resistant nephrotic

syndrome and MCD with IgM

pos IF have a relatively poor prognosis

and poor response to adjuvant therapy

‐Children with MCD with IgM

pos IF have a tendency to respond better

to cyclosporine therapy as initial adjuvant therapy when compared with

cyclophosphamide.

‐A prospective study is needed to verify the findings

Summary•

It remains controversial, if IgMN

is a separate disease

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Strict pathological criteria to define IgMN

needed

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Studies required to elucidate pathogenetic

role of IgM

deposits on

molecular level

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Presence of IgM

deposits in MCD signifies poorer prognosis, with

fewer than 50% steroid sensitivity

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Prospective studies required to identify favorable adjuvant therapy

Thank You!

igm nephropathy - nyu langone health · pdf fileis igm nephropathy a distinct disease entity?...

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