MPGN Pam

Membranoproliferative
Glomerulonephritis

SUMANEE PRAKOBSUK

Scopes

 Classification

 Pathophysiology

 Pathology

 Clinical features

 Treatment

Overview

 Also termed mesangiocapillary glomerulonephritis.

 MPGN accounts for approximately 7 to 10% of all cases of
biopsy-confirmed glomerulonephritis.

Brenner&Rector’s: The Kidney 9th Edition

Classification
Idiopathic Secondary
Type I Infection
Hepatitis C and B
Type II Visceral abscess
Infectious endocarditis
Type III Shunt nephritis
Mycoplasma infection
Rheumatologic disease
SLE
Scleroderna
Sjogren syndrome
Mixed essential cryoglobulinemia with
or without hepatitis C infection
Malignancy
Carcinoma,Lymphoma,Leukemia

Brenner&Rectoer’s 9th Edition Complement deficiency
Hereditary C2,C4 deficiency

Classification

 Traditionally been classified into three subtypes
 MPGN types I

 MPGN types II

 MPGN types III

 The primary basis for this classification is histologic,
the appearance of the capillary wall by electron
microscopy and the location of electron-dense deposits.


Type I : Subendothelial
deposits

Type II : Dense
deposits in Lamina
densa of GBM

Type III : Subendothelial
&Subepithelial deposits

Membranoproliferative Glomerulonephritis Type I

 Epidemiology

 The majority of patients with MPGN are children
between the ages of 8 and 16 years.

 The proportions of males and females with the
disorder are nearly equal.


IMMUNE-COMPLEX-MEDIATED MPGN
Pathogenesis MPGN typeI

 Results from the deposition of immune complexs in
the glomeruli owing to persistent antigenemia.

 Type I MGPN often is secondary to recognizable
causes.


Secondary MPGN


Pathology of MPGN Type I

 LM
 Mesagial proliferation
 Endocapillary proliferation
 Diffuse global capillary wall
thickening

“Lobular glomerulonephritis”



 LM
 Mesangial interposition
 Doubing or replication of
GBM



IF
 Granular staining for
complement, especially
C3, and usually
immunoglobulins
(IgG or IGM)

 GBM,Mesangial
 Few at TBM



EM
 The ultrastructural
hallmark of type I

 Subendothelial Electron-
dense -deposits

 Mesangial interposition


Clinical Features of MPGN typeI

 Nephrotic syndrome 40-70%

 Acute nephritic syndrome 25 %

 Asymptomatic proteinuria and hematuria 25 %

 HT (not severe)

 Renal insufficiency 50%

Pediatr Nephrol.2010;25:1409-18.

Membranoproliferative
Membranoproliferative Glomerulonephritis Type III

 Type III MPGN occurs in a very small number of children
and young adults.

 Clinical features of disease quite similar to those of type I
MPGN.

 Regardless of the pathologic distinctions of MPGN type III
,few distinguishing clinical characteristics are noted in
these patients.

 EM: subendothelial and subepithelial EDD


Membranoproliferative Glomerulonephritis Type II

Dense Deposit Disease

 Epidemiology

 About 25% of MPGN in children but is much less common in
adults.
 The large majority of patients are children 8 - 16 years.
 2-3person/million.
 Female:male = 3:2

J Am Soc Nephrol 16: 1392–1404, 2005

Pathogenesis of MPGN type II (DDD)

 DDD is characterized by deposits of dense material
within the basement membranes of glomeruli,
Bowman’s capsule, and tubules.

 A porcine model of MPGN
 Massive deposition of C3 and the terminal C5b9 complement
complex (the membrane attack complex).
 No immune complex deposits were detected in renal tissue.

 Dysregulation of alternative pathway.
J Am Soc Nephrol 16: 1392–1404, 2005

Peter F. Zipfel*‡ and Christine Skerka*
NATuRe RevIeWs Immunology vOLuMe 9 | OCTObeR 2009

Pathogenesis of MPGN type II (DDD)

 Three distinct mechanisms result in uncontrolled
activation of C3 convertase.

1 .The development of an autoantibody, the C3
nephritic factor (C3NeF).
- Protects C3 convertase form factor H.
2. The absence of circulating factor H .
3. The presence of a circulating inhibitor of factorH.


Dysregulation of the alternative pathway

 To investigate causes for AP dysregulation
 32 patients with DDD (renal Bx C3+ and
intramembranous electron-dense deposits by EM)
 C3Nef detection assays
 Factor H antoantibodies(FHAA)
 Factor B autoantibodies (FBAA)
 Factor H Mutation screening.

Results

 C3Nef detection assays:
 25 patiests (78%)

 Factor H antoantibodies(FHAA)
 1 patients (3%)

 Factor B autoantibodies (FBAA)
 3 patiests (9%)

 Factor H Mutation screening.
 26 patiests(81%) carried at least one copy of the FH His402
polymorphism.

Pathology :MPGN II( DDD)

LM

5 distinct patterns:

(1) Membranoproliferative pattern
(2) Mesangioproliferative pattern
(3) Crescentic pattern
(4) Acute proliferative and
exudative pattern
(5) Unclassified dense deposit
disease.

Sibley RK, Kim Y. Dense intramembranous deposit disease: new
pathologic features. Kidney Int. 1984;25:660-670.


•Intense capillary wall linear to
bandlike staining for C3

•Little or no staining for Ig


A bandlike intramembranous dense deposit

Clinical Features :MPGN type II (DDD)

 ¾ of patients have all of the components of
nephrotic syndrome on presentation.
 ¼ of patients have acute nephritic syndrome.

 HT is typically mild, but may be severe in some
cases.
 Renal dysfunction occurs in at least half of cases and
is more common in adults han in children.



 May have deposits in the retina

There is no correlation between the
severity of kidney and ocular involvement.

J Am Soc Nephrol 16: 1392–1404, 2005


 DDD may be associated with the syndrome of

acquired partial lipodystrophy.

 About 80% of patients with this syndrome have low

C3 levels and C3NeF.

 About 20% of patients

develop MPGN

Prognosis:MPGN II (DDD)

 The prognosis for type II is worse than that for type I,

worse in adults than in children.

 Clinical remissions are rare,occurring in fewer than 5%

of children.

 Patients generally reach ESRD in 8 to 12 years from the

onset of disease.


Proposal for A new classification of MPGN

Proposal of a New classification

 Immune complex mediated MPGN.

 Complement mediated MPGN.

Sanjeev Sethi, Fernando C. Semin Nephrol 31:341-348 © 2011

Treatment

 Based on the heterogeneity of cause and pattern of
histologic injury of MPGN.

 All patients with MPGN must be thoroughly
evaluated for underlying diseases before classifying
as idiopathic MPGN, and before any specific
treatment decisions can be made.

 When there is a secondary MPGN, treatment should
be directed against that cause

Treatment

 Idiopathic MPGN is now an uncommon condition.

 The few RCTs of treatment of idiopathic MPGN in
children and adults have given inconsistent and
largely inconclusive results .

 Many of the reported trials have weak experimental
design or are underpowered, and the evidence base
underlying the recommendations for treatment of
“idiopathic” MPGN is very weak.

Treatment

 Immunosuppressive agent
 Prednisolone

 Cytotoxic agent
 Cyclophosphamide

 Mycophenolate

 Antiplatelet
 Non-specific Tx

 Double-blinded RCT.
 Compare altermate day prednisolone VS placebo
 Between February 1970 and October 1980

Pediatr Nephrol(1992)6:123-130

Treatment of mesangiocapillary
glomerulonephritis
with alternate-day prednisone

Inclusion criteria
Inclusion criteria
 1. Biopsy-prove MCGN
 2. GFR by crcl ≥ 70 ml/min per 1.73 m 2
 3. Heavy proteinuria ≥ 40 mg/h per m 2
 4. No evidence of SLE, HSP, nephritis accompanying
bacteremia (such as IE), or malaria,
 5. No treatment with corticosteroids during the year prior
to entry into the trial or with immunosuppressive agents
at any time.

Treatment of mesangiocapillary
glomerulonephritis
with alternate-day prednisone
• Prednisolone 40 mg/m2 alternate
days
Treatment • Maximum dose 60 mg
• 5 years

• Treatment failure: increase from baseline in
serum creatinine of 30% or more, or more than
0.4 mg/dl.
Outcome • Renal failure : cr ≥ 4 mg/dl
• Stable: no change or increase in S.Cr <0.4
mg/dl


61%

P=0.07
12%

Mean Tx 41 months Alternate- day prednisone therapy
Treatment failure improves the prognosis of
Treatment 40% patients with MCGN, when used at doses
control 54% of 40 mg/m2.

Prednisolone for Idiopathic MPGN

 There has been no systematic evaluation of
glucocorticoid therapy for idiopathic MPGN in
adults.

 Retrospective studies showed no clear benefit from
glucocorticoid therapy, but treatment was not as
prolonged in adults as it was in children.

Kidney International,Vol55(1999)pps41-s46

Cytotoxic Agent

 Cyclophosphamide

 Mycophenolate

 RCT
 Compare
 Combination
Cyclophosphamide 1.5-2.0 mg/dl
Coumadin keep PT 2-2.5 times
Dipyridamole start 25 mg qid  full dose 100
mg qid
 No specific therapy

Cyclo

Inclusion
MPGN type I &II ( no crescent)
Proteinuria > 2 g/day
Ccr < 80 mI/mm.
Ruled out Secondary causes of MPGN

Exclusion
Active infectin
Previous tuberculosis,
Hx PU
Uncontrolled HT

Outcome
Change of crcl from baseline at 18 months

Baseline
MPGN Type I Control(N =25) Treatmemt (N=22)

Age 33 (6-70) 38 (12-77)

Crcl (ml/min/1.73 m2) 64 (18-135) 65 (16-113)

Cr (mg/dl) 1.8 (0.7-7.0) 1.7 (0.7-5.9)

Proteinuria ( g/day) 5.2 (0.85-16.4) 3.6(0.4-8.3)

MPGN Type II
Control(N =7) Treatmemt (N=5)

Age 19(7-58) 17.5 (6-26)

Crcl (ml/min/1.73 m2) 87 (51-131) 63 (37-115)

Cr (mg/dl) 0.9 (0.3-1.2) 1.2 (0.7-2.1)

Proteinuria ( g/day) 4.3 (0.1-11.7) 6.8 (1.7-12.8)

Change in Crcl /18 months

MPGN Type I MPGN Type II

P=0.4 P=0.5

-1
0 -14
-8

Proteinuria ,g/day

No significant benefit could be observed over a period
of 18 months.

 Retrospective analysis
 Treatment group
 MMF started 500 mg/daymaximum 2 gm /day

 Oral Prednisolone 60 mg/day , tapering to 20mg within 2
months and withdrawn by 1 year.
 Control group
 Did not receive immunosuppressive therapy

Change in proteinuria over time
in control and MMF treated patients

P=0.03
control

MMF

Change in creatinine clearance over time
in control and MMF treated patients.

MMF

P=0.06
control

Antiplatelete

 Rationale

 Demonstrations of platelet activation and
deposition of platele antigen are invole in initiating
or contributing to glomerular injury .

Glomerular prostaglandin and thromboxane systesis in rat
nephrotoxic serum nephritis.J Clin Invest 1983;72:1439-48

 Randomized,double blind placebo-controlled trial .
 Renal biopsy prove MPGN TypeI
 1975-1981
 Only 2 were receiveing therapy with
prednisolone,with discontinued at the time of entry
 None had been treated with cytotoxic drugs.
 Excluded
 SLE,essential mixed cryoglobulinemia,PIGN,dialysis

James V.Donadio,JR.Nejm1984;vol310(22)

 Treatment
 Dipyridamole 75 mg

 Aspirin 325 mg

 12 months

 Outcome
 Treatment failure: decline of 25% Iotalamate clearance from
pre treatment.


Pretreatment Clinical manifestations
Treatment Placebo
N=21 N=19

Treatment failures(loss of renal function)

P<0.05


Change in Iothalamate clearance
-1.3 ml/min -19.6 ml/min

P<0.02

No differences between the groups
Proteinuria,Amount of RBC cast, C3,C4,CH50


Platelet Survival


 Follow up 7 years
 ESRD - 47 % in Placebo (33 months)
- 14 % in Treatment (62 months)

GFR and was better maintained, and progression to
ESRD occurred less often and over a longer period,in
the group treated with platelet-inhibitor drugs than
in the group given placebo


Plasmapheresis

Case report , improve renal function

 MPGN type II
 Rucurrent MPGN typeII post trasplant

Immunosuppressive drugs
Level of Author Design N Rx Duration Results/Comments
Evidence [Rx : C]

1
Tarshish RCT 80
[47/33]
Pred 40 mg/m2 130 mo Children only, predomly
MPGN I, stable renal fn
AD vs pcb
Pred 61% [Rx] vs 12% [C]

No difference found,

1
Cattran RCT 59 CY + coumadin 18 mo
[27/32] + dipyridamole mixed MPGN I > II

CY vs No Rx
1985
3 Strife UCT 17 Pred 2 mk AD 2y MPGN III only, nephrotic range
[16/1] did worse, 3/16 dvled RF

3 Davis CT 27 Pred+IS [NS] - No effect
[19/8]
3 Orlowski UCT 50 P/AZA/CP/chlorambucil 79 mo 10 y F/U, ↓ Uprot c triple drug
in combi Rx
3 Ford UCT 19 PO/IV pred 2 mk + 8-10 wk, Children; 6.5 y F/U, early Rx,
ACEI then x2-3 shorter course,
y tapered ↓ glom prolif
dose

3 Faedda UCT 19
IV/PO CY+P 10 mo 15/19 remission, 7 y F/U
1994 [different
combinations]

Adeera Levin., Mx of MPGN; Evidence based recommendations; KI 1999; 55: S41-S46

Antiplatelet
Level Author Design Rx Durati Results/Comments
of evi N [Rx : C] on

1
Donadio
1984
RCT Dipyridamole
75mg/d + ASA 325
12 mo -Tx : significantly delay
rate of GFR ↓
Prospective mg/d vs Pcb
[Sig difference at 7 y]
40 [21/19]
-No change in Uprot,
hematuria, Complement

-Mild bleeding complication
required discontinuation 15%

1
Zimmer
man
RCT Warfarin [INR 1.5-2]
+ dipyridamole [75-100
12 mo
[2 y
Prot restriction & HTN control
standardized.
Crossover mg qid] vs Pcb study] Sig reduction in proturia
18 [8/10]
NS diff in renal fn
Significantly ↓ Uprot
1
Zauner
1994
RCT ASA 500 mg/d +
dipyridamole 75
36 mo
[1 g Tx vs 8 g control] [Sig]
18 [9/9] mg/d
PR : Tx 7/10 vs Control
[I 15 + III [both : prot restriction 2/8
3] & HTN control]
-Comment : short F/U
SCr 1.8, Uprot 7 g/d


Evidence based recommendations : KI 1999
Idiopathic MPGN

24 h Uprot & CCr
<3 g >3 g

Normal renal function Abn renal function Normal renal function Abn renal fn

Grade C; Grade A; Grade B;
Child : trial of steroid x 3 Child : trial of Adult : trial of ASA
mo [AD; IV or PO 1 mk] steroids 40 mg/m2 325 mg/d &
Or AD x 6-12 mo Dipyridamole 75-100
Adult : no Rx, observe mg tid x 6-12 mo

F/U q 3 mo;
BP, Lipid monitoring
-No change : continued
F/U, ↓ frequency
- Increase cr or
proteinuria  Rx


Pediatr Nephrol (2010) 25:1409–1418

Recurrence in KT

 67-100% in MPGN II , graft loss 34-66%

 20-33% in MPGN I

 Related to severity of previous disease > type of

MPGN.

 The Mayo Clinic Transplant database.

 On examination of the records of 1321 patients following
kidney transplant over an 11-year period

 29 patients of MPGN

 Excluded MPGN type II, secondary MPGN

 Follow up Protocal Bx 0,4,12,24,60 months
Kidney International (2010) 77, 721–728

52 months of follow up
rMPGN 12 /29 patients (41.4%)

Recurrence occurred during
first 14 months( Median 3.3 months)

Kidney International (2010) 77, 721–728

MPGN Pam

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