Membranous Nephropathy: The clinical syndrome and risk...

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Membranous Nephropathy:

The clinical syndrome and risk markers of progression

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Membranous nephropathy: key notes

• Most common cause of the nephrotic syndrome

• Idiopathic vs secondary MN– Malignancy a cause in the elderly

• Natural history– Unchanged despite more aggressive conservative therapy

– Progressive renal failure in 40-50% of patients

• Immunosuppressive therapy– Improves outcome

• Risk markers– Allow accurate prediction of prognosis

• MN may recur after Renal Transplantation– Recurrences more likely in LRD transplantation

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incidence of primary glomerulopathies

0

5

10

15

20

25

30

France Spain Italy Netherlands

inci

denc

e (N

/mill

ion)

IgAN

MGN

FSGS

Membranous nephropathy: incidence

Deegens et al 2006

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0

10

20

30

40

MGN FSGS MCN IgA Amyloid MPGN SLE

Pat

ient

s(%

)

van Paassen 2004

Membranous nephropathy: most common cause of nephrotic syndrome in a caucasian population

Epidemiology of non-nephrotic MN? biopsy bias, never nephrotic good prognosis

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idiopathic SLE Drugs (gold, NSAIDpenicillamine)

malignancy other

Membranous Nephropathy: secondary causes

80.9% 6.1% 7.8% 3% 3.1%

N = 658Noël 1979

Donadio 1988

McTier 1986

Hay 1992

Murphy 1988

Stirling 1998

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Membranous nephropathy: increased risk of malignancy

Adapted from Lefaucheur 2006

Malignancies in MN

05

101520253035

18-54 55-64 >65

Age group

Mal

igna

ncie

s(%

)

Men

Women

Malignancies in MN

02468

101214

18-54 55-64 >65

Age group

Sta

ndar

dize

d in

cide

nce

ratio

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How to recognize malignancy-associated MN?

Pathology?

• IgG1 IgG4 staining

• glomerular mononuclear cell count

Evaluation of patient?

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Clinical syndrome

• Inborn error age 50 yrs• Auto-immunity men

innate no other AIDinduced remitting-relapsing

early relapse after Tx• Planted antigen early relapse after Tx

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Renal Function Deterioration (%, corrected)

010203040506070

Davison

McTier

Donadio

Cattran

CameronPon

ticell

iSch

iepatti

Zuche

lliPon

ticell

i

Durin

Nephrotic MN: natural history in 1980 - 1995

Adapted from DuBuf et al 2005

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7 (10%)Severely nephrotic

27 (38%)Renal failure

35 (51%)Stable renal function:

Overall course in 69 patients

membranous nephropathy: no improvement in natural history in the last decade

P. DuBuf et al QJM 2004;97:353

P.DuBuf et al AmJKD 2005;46:1012

ACE-inhibition does not improve outcome

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Membranous nephropathy

High risk patients can be identified with reasonable accuracy

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• Genetic factors• Age• Histology• Hypertension • Renal function > ��• Proteinuria: duration and severity• Urinary excretion of IgG• Urinary excretion of ß2-microglobulin

membranous nephropathyidentification of high risk patients

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Uß2m2

UIgG

Combined

Proteinuria1

Uα1m

Specificity

88 %

82 %

94 %

88 %

88 %

Sensitivity

83 %

84 %

79 %

66 %

84 %1. Data from Cattran 2. Threshold values:

Uß2m > 500 ng/min. UIgG > 230 mg/day. Uα1m > 40 µg/min Combined = Uß2m > 500 ng/min and UIgG > 230 mg/day

Membranous nephropathy:risk prediction

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Branten et al 2005

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100

100

80

60

40

20

0

Ren

al S

urvi

val (

%)

Follow Up (months) 80604020

UIgG < 230 mg / Day

UIgG > 230 mg / Day


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Membranous nephropathy: recurrence after transplantation

��

120

108

96

84

72

60

48

36

24

12

0

��

1,0

,8

,6

,4

,2

0,0

LRD: 61%

Cadaveric 23%

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Recurrent MGN << de novo MGN

Recurrence rate: 32%

Onset of recurrence: 12 months

(range 3 –38 months)

Risk factors: LRD transplantation

(5/8 vs 2/13)

Graft failure due to recurrence:

20-40%

Treatment??

no evidence

UMC Nijmegen 2003

Membranous nephropathy: recurrence after transplantation

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Can we make a difference?

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••••nijmegen

MGN as cause of ESRD

0

20

40

60

80

100

120

140

160

1991-1995 1996-2000 2001-2005

Pat

iënt

s (%

)

Nijmegen

Netherlands

Treatment guidelines affect the incidence of ESRD

1991: introduction of treatment guidelines in the Nijmegen area

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Thank you for your attention

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Natural history

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Chlorambucil is effective in MN..

Ponticelli et al Kidney Int 1995

RENAL SURVIVAL IN TREATED AND UNTREATED PATIENTS

TREATED

UNTREATED

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..also when used in high-risk patients

Torres et al Kidney Int 2002:61: 219-227

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Ren

al s

urvi

val (

%)

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0 20 40 60 80 100 120 1400

20

40

60

80

100

Treatment Group

Historic Controls

Time (months)

Aliv

e w

ithou

t dia

lysi

s (%

)

Cyclophosphamide is also effective..

P. DuBuf et al NDT 2004:19: 1142-1148

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cyclophosphamide is more effective than chlorambucil

39(43%)

52(57%)

91Chlorambucil

17(17%)

85(83%

102Cyclophosphamide

Renal functionstable/improved deteriorated

Patients (N)

DuBuf et al AJKD 2005; 46:1012-1029Cyclophosphamide vs chlorambucil in patients with MN and CRF

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Alternative immunosuppressive agents in MN..

Ciclosporin

Tacrolimus

Mycophenolate

Rituximab

ACTH

Have been used, with short-term efficacy, few long-term data..

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Conclusion: efficacy of MMF may depend on dose and concomitant use of prednisone

Mycophenolate in membranous nephropathy

DuBuf et al AJKD 2005; 46:1012-1029

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Treatment of Membranous Nephropathy

Q: which is the preferred regimen/cytotoxic drug?

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Treatment of membranous nephropathyChlorambucil vs cyclophosphamide

Ponticellli etal JASN 1998

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Time (months)

Cum

ulat

ive

inci

denc

e of

rem

issi

on (

%)

0 10 20 30 40 50 600

25

50

75

100 cyclophosphamide

chlorambucil

p<0.02

Branten et al QJM 1998; 91: 359 - 366


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0 20 40 60 80 100 120 1400

20

40

60

80

100

partial and complete remissions

complete remissions

Time (months)

Rem

issi

ons

(%)

P. DuBuf et al NDT 2004:19: 1142-1148

Cyclophosphamide in membranous nephropathy

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15 (18%)

9 (11%)

82Chlorambucil

43 (41%)

25(25%)

102Cyclophosphamide

Remissionscomplete partial

Patients (N)

DuBuf et al AJKD 2005; 46:1012-1029Cyclophosphamide vs chlorambucil in patients with MN and CRF

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Membranous nephropathy recurrence aftertransplantation

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Prognostic factors in membranous nephropathy

Proteinuria Progressive Stable Odds Sens Spec

> 8 g/d > 6 months

31 16 13.7 66 88

< 8 g/d < 6 months

17 120

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Incidence

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Chlorambucil in membranous nephropathy

Cumulative incidence of remissions of proteinuria in treated and untreated patients

Ponticelli et al Kidney Int 1995

TREATED

UNTREATED

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Membranous nephropathy and malignancy

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Age (yrs) Male patients Female patients

Malignancy(%)

SIR Malignancy(%)

SIR

18 – 54 2.3 10.2 2.1 9.5

55 – 64 9.5 8.6 9.1 13

>= 65 28.9 10 17.9 13.2

Membranous nephropathy: increased risk of malignancy

SIR = standardized incidence ratio; data from Lefaucheur 2006

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••••••••

••••••••••••••••

••••nijmegen

MGN as cause of ESRD

0

20

40

60

80

100

120

140

160

1991-1995 1996-2000 2001-2005

Pat

iënt

s (%

)

Nijmegen

Netherlands

Cyclophosphamide decreases the incidence of ESRD

1991: introduction of cyclophosphamide in the treatment of MGN in the Nijmegen area

Limited use of immunosuppressive therapy in other parts of the Netherlands

Membranous Nephropathy: The clinical syndrome and risk...

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