3. 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
4. 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
5. 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.
Brenner&Rector’s: The Kidney 9th Edition
6. Type I : Subendothelial
deposits
Type II : Dense
deposits in Lamina
densa of GBM
Type III : Subendothelial
&Subepithelial deposits
7. 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.
Brenner&Rector’s: The Kidney 9th Edition
8. 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.
Brenner&Rector’s: The Kidney 9th Edition
12. Pathology of MPGN Type I
LM
Mesagial proliferation
Endocapillary proliferation
Diffuse global capillary wall
thickening
“Lobular glomerulonephritis”
Brenner&Rector’s: The Kidney 9th Edition
13. Pathology of MPGN Type I
LM
Mesangial interposition
Doubing or replication of
GBM
Brenner&Rector’s: The Kidney 9th Edition
14. Pathology of MPGN Type I
IF
Granular staining for
complement, especially
C3, and usually
immunoglobulins
(IgG or IGM)
GBM,Mesangial
Few at TBM
Brenner&Rector’s: The Kidney 9th Edition
15. Pathology of MPGN Type I
EM
The ultrastructural
hallmark of type I
Subendothelial Electron-
dense -deposits
Mesangial interposition
Brenner&Rector’s: The Kidney 9th Edition
17. 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
Brenner&Rector’s: The Kidney 9th Edition
18. 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
Brenner&Rector’s: The Kidney 9th Edition
19. 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
Brenner&Rector’s: The Kidney 9th Edition
20. Peter F. Zipfel*‡ and Christine Skerka*
NATuRe RevIeWs Immunology vOLuMe 9 | OCTObeR 2009
22. 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.
Brenner&Rector’s: The Kidney 9th Edition
24. 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.
25. 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.
30. 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.
Brenner&Rector’s: The Kidney 9th Edition
31. Clinical Features :MPGN type II (DDD)
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
32. Clinical Features :MPGN type II (DDD)
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
33. 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.
Brenner&Rector’s: The Kidney 9th Edition
36. 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
37. 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.
39. Double-blinded RCT.
Compare altermate day prednisolone VS placebo
Between February 1970 and October 1980
Pediatr Nephrol(1992)6:123-130
40. 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.
Pediatr Nephrol(1992)6:123-130
41. 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
Pediatr Nephrol(1992)6:123-130
42.
43. 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.
44. 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
46. 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
47. 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
51. Retrospective analysis
Treatment group
MMF started 500 mg/daymaximum 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
52.
53. Change in proteinuria over time
in control and MMF treated patients
P=0.03
control
MMF
54. Change in creatinine clearance over time
in control and MMF treated patients.
MMF
P=0.06
control
55. 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
56. 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)
57. Treatment
Dipyridamole 75 mg
Aspirin 325 mg
12 months
Outcome
Treatment failure: decline of 25% Iotalamate clearance from
pre treatment.
James V.Donadio,JR.Nejm1984;vol310(22)
60. 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
James V.Donadio,JR.Nejm1984;vol310(22)
62. 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
James V.Donadio,JR.Nejm1984;vol310(22)
64. 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
65. 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
Adeera Levin., Mx of MPGN; Evidence based recommendations; KI 1999; 55: S41-S46
66. 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
Adeera Levin., Mx of MPGN; Evidence based recommendations; KI 1999; 55: S41-S46
70. 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.
71. 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
72. 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
