Kidney International, Vol. 55, Suppl. 70 (1999), pp. S-41–S-46
Management of membranoproliferative glomerulonephritis:
Evidence-based recommendations
ADEERA LEVIN
Division of Nephrology, University of British Columbia, St. Paul’s Hospital, Vancouver, British Columbia, Canada
Management of membranoproliferative glomerulonephritis:
Evidence-based recommendations. Idiopathic membranoproliferative glomerulonephritis (MPGN) is one of the least common types of GN. This article critically evaluates the literature
and generates evidence-based recommendations for the management of idiopathic MPGN. For all age groups, for idiopathic
MPGN with normal renal function and asymptomatic nonnephrotic range proteinuria, no specific therapy is necessary
(grades B and C). Close follow-up every three to four months,
with specific attention to renal function, proteinuria, and blood
pressure control, is recommended. In children with MPGN and
nephrotic syndrome and/or impaired renal function, a trial of
steroids is warranted (grade A). The best data suggest highdose, alternate-day steroids for a period of 6 to 12 months (40
mg/m2 on alternate days). If no benefit is seen, discontinuation
with close follow-up and attention to conservative treatment
(that is, blood pressure control, use of agents to reduce proteinuria, and correction of metabolic abnormalities) is recommended. In adults with MPGN, impaired renal function, and/
or nephrotic-range proteinuria, a trial of aspirin (325 mg daily),
dipyridamole (75 to 100 mg tid), or a combination of the two
for 12 months is reasonable (grade B). Again, if no benefits are
seen, the treatment should be stopped. Attention to factors
known to delay the progression of renal decline and close followup should be part of the treatment plan (grades B and C).
Among all of the glomerulonephritides, membranoproliferative glomerulonephritis (MPGN) is one of the
least common. It primarily affects children and young
adults, with the mean age of onset ranging between 8
and 30 years. Conventionally, it has been classified as
idiopathic or secondary, with idiopathic MPGN further
subdivided into types I through III based on morphological pattern. This disease has had many different names
over the years, including lobular, hypocomplementemic,
and mesangiocapillary GN. There has been a decline in
the incidence of primary MPGN over the two decades [1].
The diagnosis of MPGN requires the exclusion of all
secondary causes such as hepatitis B or C, HIV, other
infections, or collagen vascular disease (grade B). HepaKey words: idiopathic MPGN, secondary MPGN, hepatitis C, nephrotic syndrome, interstitial disease.
 1999 by the International Society of Nephrology
titis C has been increasingly implicated as a cause of
MPGN over the last five years [2–4], and the association
of MPGN with HIV disease has also been described [5].
Given the rising prevalence of these diseases, appropriate serology must be obtained in patients presenting
with apparently idiopathic MPGN. Because there are a
number of other noninfectious secondary causes with
different treatment regimens and outcomes [2–8], it is
important to conduct a thorough and focused search for
secondary causes.
The pathogenesis of MPGN has been well studied,
and improved understanding has led to the search for
agents that will modify the intense cellular proliferation
and immune deposition that occurs. Immune-modulating
therapy and therapy that interferes with the biological
processes (for example, platelet activation) proposed to
be central in the pathogenesis of the MPGN lesion have
been evaluated in human trials [2].
The focus of this article is to review the clinical studies
or trials in treatment of patients with idiopathic MPGN
and to critically evaluate the quality of that data in order
to make evidence-based recommendations for treatment.
METHODS
Human clinical trials, including adults and children,
were reviewed from the English language literature from
1927 to 1997. Twenty-one studies were selected for review after an extensive MEDLINE search using the key
words mesangiocapillary, membranoproliferative and
lobular GN, clinical trials, and therapies. The articles
selected include over 1100 patients with MPGN (all subtypes and age groups).
Studies were evaluated based on the levels of evidence,
graded 1 through 6 using the study design, size, power,
and end points as criteria for evaluation. Recommendations were then graded based on the level of evidence
of the supporting studies. Grades A through D are based
on the number, type, and strength of studies available
[9–12].
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Levin: Membranoproliferative GN
Table 1. Immune modulating therapy: Steroids, cyclophosphamide
Level of
evidence
Author [Ref]
Design
N(Rx/C)
Rx (dose)
Duration
2
1
Tarshish [18]
RCT
8(47/33)
Prednisone (40 mg/m ) vs.
placebo
130 months (mean)
1
Cattran [20]
RCT
59(27/
32)
Cyclophosphamide,
dypridamole and ASA
vs. no therapy
18 months
3
Strife [26]
UTC
17(16/1)
Prednisone 2 mg/kg alt day
2 years
3
Davis [27]
CT
27(19/8)
3
Orlowski [24]
UCT
50
Prednisone and
immunosuppressives
(NS)
P/Aza/CP/chlorambucil in
combinations
3
Ford [23]
UCT
19
Oral/i.v. Pred (2 mg/kg) 1
ACEI
3
Faedda [28]
UCT
19
3
Bergstein [29]
UCT
16
i.v./p.o. Cyclo and P (in
different combinations)
6 3 alt day i.v. MP, then
p.o. prednisone alt day
4
Habib [25]
UCT
4
McEnery [22]
CS
97(28/
69)
6
4
Arslap [30]
CS
4
Emre [31]
4
4
—
79 months
8–10 week initial
therapy, then 3
2–3 years
tapered dose
10 months
Mean duration 37
months therapy
Prednisone vs. placebo
—
Prednisone alt day
14 years
96
Prednisone or Cyclo 6 i.v.
MP
10 year follow-up
CS
15
Mean 27 months
(6–84)
Takeda [32]
CS
18
i.v. Pulse MP 30 mg/kg alt
days 3 9–15 days; then
oral Pred 1 mg/kg 3 1
month, tapered off 3 1
month
i.v. MP, Dp and oral Pred
Itaka [33]
CS
41
3 therapies: low dose Pred,
low dose followed by
high dose alt day Pred,
high dose alt day Pred
alone
Median 6 years
(3–15.5 years)
8 years
Results/comments
Children only,
predominantly MPGN I
stable renal function 61%
(Rx) vs. 12% (C)
No difference found, mixed
MPGN I . II
MPGN III only. Nephrotic
range did worse, 3/16
developed RF
No effect
10 year follow-up, reduce
urine protein with triple
drug therapy
Children; 6.5 year follow-up,
early therapy, shorter
course, reduce glomerular
proliferation
15/19 clinical remission, 7
year follow-up
Mean follow-up 5 57 months,
children, type I, all
parameters of renal
function, proteinuria
improved after 3 months.
Repeat kidney bx
improved acute but worse
chronic changes
No effect
Type II, children, serial renal
bx: reduce proliferative
changes 37% remission,
89% 10 year renal survival
If Pred failed, then Cyclo 6
i.v. MP given with 25 and
50% remission; 10 year
survival 61–81%
9/15 responsive, children
significant reduction
proteinuria
Children, 94% renal survival
at 4–10 years post-clinical
onset; variable group: mild
urinary abnormalities
(12/18), heavy proteinuria
(3/18), mild renal
insufficiency (3/18)
Children, identified by school
screening 32 Type 1, 2
Type II, 7 type III; best
outcomes 5 those with
high dose alt day Pred;
1/41 ESRD? utility of early
screening and therapy
Abbreviations are: RCT, randomized control trial; CT, controlled trial; UCT, uncontrolled trial; CS, case series; DS, descriptive study; Rx, treatment group;
C, control group; fn, function; NS, nonsignificant; N, number in study; P, prednisone; MP, methylprednisolone; i.v., intravenous; p.o., oral; alt day, alternative
day; ASA, asprin; Dp, dipyridamole; Chlor, Chlorambucil; CP, cyclophosphamide; sign diff, significant difference; AZA, azathioprine.
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Levin: Membranoproliferative GN
Table 2. Non-immune modulating therapy: ASA, dipyridamole
Level of
evidence
Author [Reference]
Design
N (Rx/C)
1
Donadio [19]
RCT
40 (21/19)
1
Zimmerman [17]
RCT,
cross
over
18 (8/10)
1
Zauner [21]
RCT
18 (9/9)
Rx (dose)
Duration
Dipyridamole (275 mg/day
and ASA (975 mg/day vs.
placebo
Warfarin (target INR 1.5–2)
dipyridamole (75–100 mg
qid) vs. placebo
Results/comments
1
12 months
12 months
(2 year study)
ASA (500 mg/day) and dipyridamole (75 mg/day)
(both got protein restriction and HTN control)
36 months
t ⁄2 platelets and renal function. Rapid
decline in control group, sign diff
at 3–5 year, NS 10 year renal fn
Protein restriction and HTN control
standardized. Significant reduction
in proteinuria, ns difference in renal function
Significant reduction in proteinuria
Rx group (1 g Uprotein vs. 8 g Uprotein
control group P , 0.5)
Abbreviations are in Table 1.
Table 3. Natural history studies
Level of
evidence
Author reference
Design
N
Treatment
Duration Rx/Fup
Results/comments
3
3
Schmitt [6]
Confalonerri [7]
DS
DS
220
294
—
—
59 month mean follow-up
60 month mean follow-up
4
Bennett [8]
DS
27
—
—
4
Cameron [9]
DS
104
—
65% 10 year survival
60% 10 year survival
MPGN II, progressive disease 5 nephrotic syndrome and TI changes; C3
? predictive
Adults and children, Types I and II/
nephrotic
Recommendations
Recommendation 1. Treatment in adults and children
with idiopathic MPGN is reserved for those patients with
proteinuria of greater than 3 g/day, interstitial disease
on biopsy, or impaired renal function (grades B and C).
Evidence. The natural history of MPGN has been
studied in a number of large European studies, which
have shown a 60% 10-year renal survival for idiopathic
MPGN. The level 4 natural history studies of Schmitt et
al [6] and Confaloneiri et al [7], with over 500 patients
followed, confirmed earlier findings that the 10-year renal survival of MPGN is approximately 60 to 65%. These
historical reviews describe a large number of patients
followed in Italy, Germany, United Kingdom, and Australia in an attempt to define adverse prognostic factors
in patients with MPGN [13–16]. Nephrotic syndrome
(heavy proteinuria) and the presence of interstitial disease are the main adverse prognostic signs [14, 15].
Recommendation 2. Children with idiopathic MPGN,
proteinuria (more than 3 g/day), or impaired renal function may respond to high-dose steroid therapy, which
should be maintained for 6 to 12 months (grade A).
Recommendation 3. Adults with idiopathic MPGN,
proteinuria (more than 3 g/day), or impaired renal function should undergo a trial of therapy with dipyridamole
or aspirin (grade B).
Evidence. Treatment studies have compared antiplatelet agents, coumadin, steroids, and other immuno-
8 years mean follow-up
suppressive agents. They are varied in study design, duration of follow-up, and inclusion of patients with different
types of MPGN. Furthermore, the studies vary in definition of successful treatment (reduction in proteinuria,
renal survival, and regression of lesions on biopsy), often
making comparisons difficult. However, specific therapy
can be recommended in certain instances (Figure 1).
Of the 13 treatment trials available in the literature,
eight used steroids either alone or in combination with
other treatment. Regimens included alternate-day steroids, intravenous boluses of steroids, and a combination
of intravenous and oral therapy. Duration of treatment
was variable, ranging from less than 6 months to over
130 months. This review considered changes in renal
function, as well as reduction in proteinuria as objective
and clinically meaningful end points.
Only five randomized clinical trials have been published with sufficient power to determine the benefits of
therapy in this rare disease (level 1 data) [17–21]. Tables
1, 2, and 3 provide an overview of the studies included,
grouped according to type of therapy, and subgrouped
according to the level of evidence.
One of these five trials exclusively studied children
and showed that prednisone (40 mg/m2 alternate days)
when compared with placebo was of benefit in slowing
the change in glomerular filtration rate (GFR) over time
and stabilizing renal function in children with MPGN.
Eighty children, predominantly with MPGN type 1, were
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Levin: Membranoproliferative GN
Fig. 1. Algorithm for the treatment and follow-up of mesangial proliferative glomerulonephritis (MPGN).
enrolled in the study, with a mean duration of treatment
of 130 months: 61% of the treatment group versus 12%
of the placebo group had stable renal function at the
end of the study period (level 1 evidence) [18]. Other
less well-designed studies have corroborated the finding
that steroids are useful in the treatment of MPGN in
children (level 3 to 4 evidence) [22–25].
The other four randomized, controlled studies were
smaller, enrolled more heterogeneous groups of patients,
including both children and adults, and had different
end points (proteinuria, renal function measured using
variable techniques, etc.). These randomized controlled
trials are offered as level 1 and 2 evidence for the use
of antiplatelet agents in adults.
Donadio et al’s randomized 40 patients to examine
the effect of dipyridamole and aspirin on renal outcome
and the t1/2 of platelets. Both measures were improved
by the antiplatelet therapy compared with placebo [19].
However, in the control group, the rate of renal deterioration was quite rapid and has led to concerns about the
representativeness of the control group. Zauner et al’s
1994 study of 18 people, also treated with aspirin (ASA)
and dipyridamole, compared therapy with no therapy
over a 36 month follow-up. Both groups received similar
protein restriction and antihypertensive regimens. The
study demonstrated a clinically significant effect of reduction in proteinuria in the treatment group, but no
change in GFR [21].
Levin: Membranoproliferative GN
Another prospective study involved 18 patients over
two study years (placebo and treatment), comparing warfarin and dipyridamole against placebo. The active treatment group showed reduced proteinuria but very little
impact on GFR. An increased incidence of bleeding was
noted in the treatment groups [17].
Cattran et al studied the effect of cyclophosphamide
and coumadin and dipyridamole therapy in patients with
MPGN in 59 patients. Therapy was continued for 18
months. These investigators were unable to show a difference between control and treatment groups after this
length of time. They were also unable to define any
predictors of renal decline, perhaps in part because all
had nephrotic range proteinuria as part of the entry
criteria to the study. The authors were careful to state
that their study was able to address treatment issues
clearly in only patients with MPGN type I, and did not
have sufficient power to offer any conclusions for those
with type II disease [20].
Thus, in 215 patients involved in robust randomized
controlled trial (RCT) study designs (level 1 to 2 evidence), little benefit has been found in adults with any
immunosuppressive therapy, but the data do suggest a
possible benefit of antiplatelet therapy. Reduction of
proteinuria has been used as a surrogate measure of
success and may be an important clinical outcome in
this patient group. Rigorous studies comparing high-dose
steroids (the effective regimen for children) with ASA
and dipyridamole in high-risk adult patients have not
been performed.
The remaining studies include uncontrolled trials, case
series, and descriptive or comparative studies [22–33].
These studies suffer from weaknesses, which include
variability in the different therapies used, the end points
measured, and duration of therapy (Tables 1, 2, and 3).
Of note, more recent studies in children with both mild
urinary abnormalities and in those with nephrotic range
proteinuria demonstrate that early high-dose immunosuppressive therapy (prednisone) appears to be effective
in attenuating the course of renal disease, and argue for
early aggressive therapy. These observations need to be
validated in properly conducted, randomized controlled
trials.
As in other glomerular disease, the concomitant cellmediated interstitial infiltrate, which often occurs secondarily to the glomerular injury or is triggered by it, is
probably responsible for ongoing renal decline. Thus,
the prognosis for MPGN is adversely affected by the
presence of heavy proteinuria, the presence of tubulointerstitial disease on biopsy, and hypertension [7].
In deciding who and when to treat, the clinician must
consider the expected duration and outcome of the disease, as well as the risks and benefits of treatment of
renal disease, and comorbidity that arises both from progressive renal dysfunction, and potentially from drug
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therapy. No study has addressed these particular issues
in an objective format.
SUMMARY
The recommendations offered here are based on the
best level of evidence in an attempt to rationalize the
current therapy for idiopathic MPGN. Steroid therapy
has been proven effective for children but not for adults.
This situation is similar to that previously existing in
the focal segmental glomerulosclerosis (FSGS) literature
[30]. A number of unanswered general questions in this
disease remain, which include the optimal proactive
management of steroid complications, the proper dosing
and tapering of medications, and the projected duration
of the study that would be needed to revise the current
therapeutic recommendations.
A number of logistical problems are inherent in the
study of a rare GN, especially one with a long natural
history. Despite this, patients and their physicians do
require guidance, and the review of evidence is important
to guide practice and follow-up. These recommendations
attempt to address those needs. Future studies will need
to address shortcomings of previous data and will require
collaborative efforts.
Reprint requests to Adeera Levin, M.D., St. Paul’s Hospital, 1081
Burrard Street, Room 6010 A Providence Wing, Vancouver, BC V6Z
1Y6, Canada.
E-mail: [email protected]
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