Glomerulonephritis (GN) is a common cause of end stage renal disease (ESRD). Some of these entities are responsive to immunosuppressive agents and other therapies. There have been recent advances in the treatment options, notably the benefit shown with the use of rituximab in some forms of GN. Moreover, the KDIGO guideline on the management of glomerulonephritis has recently been published which has consolidated the available evidence on the management of this heterogeneous group of disorders. Though there are significant risks and side-effects involved, the treatment of some of the forms of GN can be very gratifying while others progress relentlessly to ESRD. This review summarizes some of the key recommendations from the KDIGO guideline along with a brief discussion of the supporting evidence.

1. Anupdateonthetreatmentofglomerulonephritis

2. Review Article
An update on the treatment of glomerulonephritis
Vadamalai Vivek
Consultant Nephrologist, Apollo Hospital, Greams Lane, Off Greams Road, Chennai 600006, India
a r t i c l e i n f o
Article history:
Received 11 January 2013
Accepted 17 January 2013
Available online 23 January 2013
Keywords:
Glomerulonephritis
Treatment
Immunosuppression
Nephrotic syndrome
Proteinuria
a b s t r a c t
Glomerulonephritis (GN) is a common cause of end stage renal disease (ESRD). Some of
these entities are responsive to immunosuppressive agents and other therapies. There
have been recent advances in the treatment options, notably the benefit shown with the
use of rituximab in some forms of GN. Moreover, the KDIGO guideline on the management
of glomerulonephritis has recently been published which has consolidated the available
evidence on the management of this heterogeneous group of disorders. Though there are
significant risks and side-effects involved, the treatment of some of the forms of GN can be
very gratifying while others progress relentlessly to ESRD. This review summarizes some of
the key recommendations from the KDIGO guideline along with a brief discussion of the
supporting evidence.
Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
1. Introduction
Glomerulonephritis (GN) is the third most common cause of
end stage renal disease (ESRD). The incidence of some forms
of primary GN, like IgA nephropathy, is increasing worldwide.
Some of them respond well to treatment, hence avoiding the
morbidity and cost associated with dialysis or renal trans-
plantation. This article reviews the recent evidence for the
treatment of the common types of GN in adults. The Kidney
Disease Improving Global Outcomes (KDIGO) clinical practice
guideline for glomerulonephritis has recently been pub-
lished.1
Newer drugs such as rituximab are now available
which has increased the options available to treat this chal-
lenging group of disorders. Salient aspects of the KDIGO rec-
ommendations are highlighted and a brief discussion of the
supporting evidence follows the recommendations.
The grading of the recommendations stated and their
supporting evidence is according to the KDIGO clinical prac-
tice guideline for glomerulonephritis. The strength of
recommendation followed by the level of supporting evidence
is mentioned within parenthesis after each guidance.
The strength of recommendation is indicated as Level 1
(“recommend”), Level 2 (“suggest”), or Not Graded, and the
quality of the supporting evidence is shown as A, B, C, or D.
Grade Quality of
evidence
Meaning
A High We are confident that the true effect lies
close to that of the estimate of the effect.
B Moderate The true effect is likely to be close to the
estimate of the effect, but there is
a possibility that it is substantially
different.
C Low The true effect may be substantially
different from the estimate of the effect.
D Very low The estimate of effect is very uncertain,
and often will be far from the truth.
E-mail address: vadamalaivivek@gmail.com.
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/apme
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 7 e1 4
0976-0016/$ e see front matter Copyright ª 2013, Indraprastha Medical Corporation Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.apme.2013.01.011

3. 2. Minimal change disease (MCD)
2.1. Treatment of initial episode of adult MCD
Corticosteroids are recommended for the initial treatment of neph-
rotic syndrome (1C).
The following treatment measures are suggested:
Prednisolone as a daily single dose of 1 mg/kg (maximum 80 mg)
or alternate-day single dose of 2 mg/kg (maximum 120 mg) (2C).
The initial dose of prednisolone is to be maintained for a mini-
mum period of 4 weeks in those achieving complete remission, and
for a maximum period of 16 weeks in those that don’t achieve
complete remission (2C).
In patients who remit, taper steroids slowly over a period of up to
6 months (2D).
Cyclophosphamide or calcineurin inhibitors (CNIs) are to be
considered in patients with contraindications or intolerance to high-
dose corticosteroids (2D).
Up to 3 relapses a year can be treated with corticosteroids (2D).
There are no randomized controlled trials (RCTs) to guide
the therapy of relapse in adult MCD. But relapses can usually
be managed with a more rapid taper of corticosteroids. Much
of the recommendations for the treatment of adults with MCD
with steroids is based on extrapolation from studies in
children.2
A complete remission (CR) is a reduction in proteinuria to
300 mg/day. Glucocorticoid or steroid-resistance (SR) refers to
little or no reduction in proteinuria after 16 weeks of adequate
steroid therapy. Patients are considered frequent relapsers
(FR) if they have more than three relapses per year.
2.2. In the frequent relapser (FR)/steroid dependant (SD)
patient the following treatment measures are suggested
Oral cyclophosphamide 2e2.5 mg/kg/d for 8 weeks (2C).
CNI (cyclosporine 3e5 mg/kg/d or tacrolimus 0.05e0.1 mg/kg/
d in divided doses) for 1e2 years for patients with FR/SD MCD who
elapsed despite cyclophosphamide, or for those concerned about the
risk of infertility (2C).
Mycophenolate mofetil (MMF) 500e1000 mg twice daily for 1e2
years for patients intolerant of corticosteroids, cyclophosphamide,
and CNIs (2D).
Re-evaluate corticosteroid-resistant patients for other causes of
nephrotic syndrome (Not Graded).
Response to steroids is usually abrupt with response being
of the “all or none type”. More than half of adult MCD patients
will relapse and up to a third of them may be frequent re-
lapsers or corticosteroid-dependent. Corticosteroid therapy
leads to complete remission in over 80% of adults with MCD.
Adults with MCD take longer to respond compared to children,
with only 50% responding by 4 weeks.3
Many observational
studies have reported the efficacy of cyclosporine with
remission rates of 70e90%.4
Cyclosporine may have the
additional benefit of lower exposure to corticosteroids as it
permits earlier steroid withdrawal.5
Cyclosporine is a possible
alternative in patients who continue to relapse after an initial
course of cyclophosphamide, who are steroid-dependent, or
in whom avoidance of the toxicity of cyclophosphamide (eg,
gonadal toxicity) is important.6
70 and 90 percent of glucocorticoid-dependent or fre-
quently relapsing patients, respectively, could undergo com-
plete or partial remission when treated with cyclosporine at
a dose of 4e6 mg/kg per day in divided doses.7
Tacrolimus is
similar in efficacy to cyclosporine in inducing complete
remission.8
All patients in this study were able to discontinue
corticosteroids. Therapeutic levels for CNI’s have not been
defined in adult patients with MCD. CNI dose should be
gradually reduced to the lowest level that maintains
remission.
There is very scant evidence to recommend the use of MMF
in adults. Other agents that have shown anecdotal benefit in
MCD are levamisole, azathioprine and rituximab. In situations
of resource constraints, it is worthwhile remembering that
prednisone and cyclophosphamide are considerably less
expensive than CNIs and MMF.
3. Focal and segmental glomerulosclerosis
3.1. Initial treatment of FSGS
It is recommended that corticosteroid and immunosuppressive
therapy be used only in patients with idiopathic FSGS with the
nephrotic syndrome (1C).
The following measures have been suggested-
Prednisolone be given at a daily single dose of 1 mg/kg (max-
imum 80 mg) or alternate-day dose of 2 mg/kg (maximum 120 mg)
(2C).
The initial dose of steroids be given for a minimum of 4 weeks;
and continued up to a maximum of 16 weeks, if tolerated, or until
complete remission has been achieved, whichever is earlier (2D).
Corticosteroids are to be tapered slowly over a period of 6 months
after achieving complete remission (2D).
CNIs are to be considered as first-line therapy for patients with
relative contraindications or intolerance to high-dose corticosteroids
(e.g., uncontrolled diabetes, psychiatric conditions, severe osteopo-
rosis) (2D).
3.2. Treatment for relapse
Relapse of nephrotic syndrome is treated as per the recommendations
for relapsing MCD in adults (2D).
3.3. Treatment for steroid-resistant FSGS
The following measures have been suggested:
Cyclosporine use at 3e5 mg/kg/d in divided doses be given for at
least 4e6 months.
If there is a partial or complete remission, cyclosporine could be
continued for at least 12 months, followed by a slow taper (2D).
In patients with steroid-resistant FSGS, who do not tolerate
cyclosporine, a combination of mycophenolate mofetil and high-dose
dexamethasone could be tried (2C).
Partial remission refers to a reduction of proteinuria to
0.3e3.5 g/d (300e3500 mg/g [30e350 mg/mmol]), urine crea-
tinine and stable serum creatinine (change in creatinine <25%)
OR Reduction of proteinuria to 0.3e3.5 g/d (300e3500 mg/g
[30e350 mg/mmol]), urine creatinine and a decrease >50%
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 7 e1 48

4. from baseline, and stable serum creatinine (change in crea-
tinine <25%).
Focal and segmental glomerulosclerosis could occur with-
out an identifiable cause (“primary”) or as a response to glo-
merular injury or glomerular hypertension (“secondary”). No
randomized trial has compared prednisolone or other im-
munosuppressives for the initial therapy of primary FSGS.
In patients with patients with preserved GFR, prednisolone
has been shown to induce complete or partial remission in
40e80 percent. It is probably beneficial to use immunosup-
pressive therapy in patients who have nephrotic range pro-
teinuria. Prednisolone is administered for a minimum of
12e16 weeks.9
Its efficacy is less in patients with reduced
kidney function (Eg. GFR <25e35 mL/min per 1.73 m2
). The
response to immunosuppressive drugs is perhaps less for
those with reduced kidney function. In the one study, the rate
of remission was less in patients with a serum creatinine
>1.4 mg/dL (124 mmol/L).10
Overall course of treatment of at least six to eight months
is required.11
Shorter courses (two months) result in much
lower remission rates (20e30%) and may have led to the
view held earlier that this condition was not steroid
responsive.12
The following dosing recommendations are extrapolated
from doses used with apparent success in some of the
observational studies and in trials of other renal diseases:
Prednisolone, 1 mg/kg per day (maximum dose 80 mg/day)
OR 2 mg/kg every other day (maximum dose 120 mg/day).
Patients who are steroid responsive show some reduction
in protein excretion within the first 8e12 weeks of therapy.
Steroid-resistance (SR) is defined as little or no reduction in
protein excretion with 16 weeks of therapy. Predisposing
factors for SR, in addition to reduced GFR, include African
American race, patients with significant tubulointerstitial
change on renal biopsy, massive proteinuria and those with
mutations in genes that code for podocyte proteins (Eg.
NPHS2). Compliance with therapy should be ensured before
labelling a patient steroid-resistant. Steroid-dependence is
defined as the development of two relapses during or within 2
weeks of completing steroid therapy.
Tacrolimus has been shown to be effective in patients
with steroid resistant or dependant FSGS.13
Its superiority
over cyclosporine has not been established. MMF may have
a role in patients who have not responded to steroid or
cyclosporine treatment or who develop adverse effects due to
the use of high-dose steroids or cyclosporine. Though MMF
use may not achieve complete remission may in the majority
of patients, it has been shown to induce partial remission in
FSGS.14
Only small observational studies have addressed the use of
alkylating agents, sirolimus and rituximab in primary FSGS.
Though plasma exchange is of benefit in recurrent FSGS in the
renal allograft, its role in the treatment of primary FSGS is yet
to be established. Only one small uncontrolled study showed
some benefit with plasma exchange in addition to the use of
steroids and an alkylating agent.15
The role of the GVV-test for
the soluble permeability factor and that of LDL apheresis is yet
to be determined. One uncontrolled study has shown some
benefit with the use of the orally active antifibrotic agent,
pirfenidone.16
4. Idiopathic membranous nephropathy
(IMN)
4.1. When is initial therapy indicated?
It is recommended that initial therapy be started only in patients
with nephrotic syndrome AND when at least one of the following
conditions is met. These patients are at a high risk of progressive
decline in renal function:
Urinary protein excretion persistently 4 g/d AND remains
at over 50% of the baseline value, AND does not show pro-
gressive decline, during antihypertensive and antiproteinuric
therapy during an observation period of at least 6 months (1B).
The presence of severe, disabling, or life-threatening symptoms
related to the nephrotic syndrome (1C).
Serum creatinine has risen by 30% or more within 6 to 12 months
from the time of diagnosis but the eGFR is not less than 25e30 ml/
min/1.73 m2
(2C).
Treatment is usually commenced after 6 months of
observation as there is an up to 30% chance of spontaneous
remission.17
4.2. Initial therapy of IMN
Initial therapy consists of a 6-month course of alternating monthly
cycles of oral and i.v. corticosteroids, and oral alkylating agents (1B).
Cyclosporine or tacrolimus can be used for a period of at least 6
months in patients who meet the criteria for initial therapy, but who
refuse or have contraindications to the cyclical corticosteroid/
alkylating-agent regimen (1C).
The dosage of CNI be reduced at intervals of 4e8 weeks to a level
of about 50% of the starting dosage, if remission is maintained and
there is no CNI-related nephrotoxicity, and continued for at least 12
months (2C).
Remission can be induced either with the use of a 6 month
regime of alternating months of corticosteroids and an alky-
lating agent like chlorambucil or cyclophosphamide (“Ponti-
celli regime”). Both alkylating agents are equally effective.18
Many clinicians prefer cyclophosphamide because of its po-
tential for less bone marrow toxicity than chlorambucil. The
regime can be summarised as follows:
Months 1,3 5: i.v. methylprednisolone (1 g) daily for three
doses, then oral prednisolone (0.5 mg/kg/d) for 27 days
Month 2,4 6: Oral chlorambucil (0.15e0.2 mg/kg/d) or oral
cyclophosphamide (2.0 mg/kg/d) for 30 days
An alternative to the use of an alkylating agent is cyclo-
sporine. This agent should be the initial choice in patients
concerned about the risk to fertility and adverse effects of
corticosteroid use. Though the remission rates are similar to
the use of steroids and alkylating agents alternately, the
duration of therapy is longer with the risk of cyclosporine
nephrotoxicity.19
Moreover, cyclosporine is expensive, it re-
quires therapeutic drug level monitoring and there is a higher
risk of relapse on stopping this agent. Tacrolimus is associated
with less side effects, such as hirsutism or gingival hypertro-
phy than cyclosporine but has a higher risk of inducing
diabetes.
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 7 e1 4 9

5. 4.3. Treatment of IMN resistant to initial therapy
Patients with IMN resistant to alkylating agent/steroid-based initial
therapy can be treated with a CNI (2C).
Patients with IMN resistant to CNI-based initial therapy can be
treated with an alkylating agent/steroid-based therapy (2C).
4.4. Treatment for relapses of nephrotic syndrome in
adults with IMN
They can be treated by reinstitution of the same therapy that resulted
in the initial remission (2D).
The risk of renal and deep vein thrombosis seems higher in
IMN patients than those with other causes of the nephrotic
syndrome. The exact reason is unknown. A serum albumin
concentration 2.8 g/dL (28 g/L) seems to be the threshold
level for increased risk in membranous nephropathy.20
Anti-
coagulation may be considered if there is an additional risk
factor for thrombosis, eg. Recent surgery.
Great strides have been made in understanding the patho-
genesis of IMN. The most notable being the discovery of
Phospholipase A2 receptor (PLA2R) as the possible target anti-
gen in the development of this disorder. An assay has been
developed for the detection of the antibody directed against
PLA2R which could guide therapy.21
The clinical utility of using
the antibody assay for guiding therapy requires further study.
IMN usually progresses very slowly and once remission is
achieved, it can be maintained for a prolonged period with the
use of ACE inhibitors and/or angiotensin receptor blockers.
5. Idiopathic membranoproliferative
glomerulonephritis (MPGN)
5.1. Treatment of idiopathic MPGN
Adults with presumed idiopathic MPGN accompanied by nephrotic
syndrome AND progressive decline of kidney function could receive
oral cyclophosphamide or MMF plus low-dose alternate day or daily
corticosteroids with initial therapy limited to less than 6 months
(2D).
Type I MPGN is associated with subendothelial and
mesangial electron-dense deposits containing immunoglo-
bulin and/or C3, chronic hepatitis B or C infection are common
causes. Type II MPGN with electron-dense intramembranous
deposits containing numerous complement components, but
not immunoglobulin, now known as ‘‘dense-deposit disease’’.
Type III MPGN is characterized by the presence of sub-
epithelial as well as subendothelial electron-dense deposits. A
diagnosis of idiopathic MPGN necessitates that all underlying
causes of the MPGN pattern are excluded.
Long-term use of prednisolone has been shown to be of
benefit in children with MPGN.22
Pulsed intravenous methyl-
prednisolone may be better than oral steroids.23
There are no
randomized controlled trials of steroid use in adults with
MPGN.Inpatientswithsignificantproteinuria, a regimesimilar
to that used in focal and segmental glomerulosclerosis is used,
starting with oral prednisolone at 1 mg/kg for 12e16 weeks. If
the patient responds, prednisone is gradually tapered to
alternate day therapy over six to eight months. If there is an
inadequate response, steroids are tapered and stopped. Con-
vincing evidence does not exist to support the use of cytotoxic
agents, MMF, cyclosporine or oral anticoagulants.
Some studies have demonstrated a significant reduction in
proteinuria with the use of anti-platelet agents. Platelet con-
sumption has been shown to be increased in MPGN, suggest-
ing a possible role for platelets in causing glomerular injury. If
a combination of aspirin and dipyridamole is used, this has to
be continued for a prolonged period.24
Rituximab has been shown to be beneficial in patients with
MPGN and no underlying haematological disorder.25
It also
seems to help those with a monoclonal gammopathy.26
6. Immunoglobulin A nephropathy (IgAN)
6.1. Antiproteinuric and antihypertensive therapy
Long-term ACE-I or ARB treatment is recommended when protein-
uria is 1 g/d, with dose titration based on blood pressure (1B).
In IgAN, use blood pressure treatment goals of 130/80 mmHg in
patients with proteinuria 1 g/d, and 125/75 mmHg when initial
proteinuria is 1 g/d (Not Graded).
6.2. Corticosteroids
Patients with persistent proteinuria 1 g/d, despite 3e6 months of
optimized supportive care (including ACE-I or ARBs and blood
pressure control), and GFR 50 ml/min per 1.73 m2
, could receive
a 6-month course of corticosteroid therapy (2C).
Two options exist for the use of steroids:
i.v. bolus injections of 1 g methylprednisolone for 3 days
each at months 1, 3, and 5, followed by oral steroid 0.5 mg/kg
prednisone on alternate days for 6 months.27
6-month regime of oral prednisolone starting with
0.8e1 mg/kg/d for 2 months and then reduced by 0.2 mg/kg/
d per month for the next 4 months.28
6.3. Fish oil treatment
Fish oil is suggested in the treatment of IgAN in patients with per-
sistent proteinuria 1 g/d, despite 3e6 months of optimized sup-
portivecare(includingACE-IorARBsandbloodpressurecontrol)(2D).
Low quality evidence supports its use in patients with
significant proteinuria.29
A dose of 3.3 g/d can be used in pa-
tients who have proteinuria 1 g/d despite ACE-I or ARB use.
6.4. MCD with mesangial IgA deposits
Treatment is as for MCD in nephrotic patients showing pathological
findings of MCD with mesangial IgA deposits on kidney biopsy (2B).
6.5. Crescentic IgAN
Define crescentic IgAN as IgAN with crescents in more than 50% of
glomeruli in the renal biopsy with rapidly progressive renal deteri-
oration (Not Graded).
The use of steroids and cyclophosphamide is suggested in pa-
tients with IgAN and rapidly progressive crescentic IgAN, analogous
to the treatment of ANCA vasculitis (2D).
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 7 e1 410

6. This entity could result in rapid deterioration of renal
function and is likely to respond to immunosuppression.
Though there are no randomized controlled trials, observa-
tional studies have shown benefit with the use of steroids and
cyclophosphamide.30
The ideal maintenance regime and
duration of therapy is unclear. Only poor quality evidence
supports the use of plasma exchange in crescentic IgAN.
There is no convincing evidence supporting the use of anti-
platelet agents or tonsillectomy in patients with IgA
nephropathy.
Henoch-Schonlein nephritis is treated similar to IgA
nephropathy.
7. Lupus nephritis
7.1. Class I LN (minimal-mesangial LN) Class II LN
(mesangial-proliferative LN)
It has been suggested that these patients be treated as dictated by the
extrarenal clinical manifestations of lupus. (2D) Patients with class II
LN with proteinuria 3 g/d could be treated with corticosteroids or
CNIs as described for MCD (2D).
7.2. Class III LN (focal LN) and Class IV LN (diffuse LN)
7.2.1. Initial therapy
It is recommend that corticosteroids (1A) be combined with either
cyclophosphamide (1B) or MMF (1B).
Prednisolone is usually initiated at a dose of 1 mg/kg/
d which is tapered over 6 months. Four options are available
for the initial treatment, along with steroids:
The NIH regime e i.v. cyclophosphamide 0.5e1 g/m2
;
monthly for 6 months.31
Euro-Lupus regime e i.v. cyclophosphamide 500 mg; every
2 weeks for 3 months.32
Oral cyclophosphamide e 1.0e1.5 mg/kg/d (maximum
dose 150 mg/d) for 2e4 months.33
MMF e up to 3 g/d for 6 months.34
Mycophenolate has been shown to be equivalent to
cyclophosphamide in inducing remission in LN.35
Combina-
tion therapy with steroids, tacrolimus and mycophenolate has
been shown to be superior to steroids and cyclophosphamide
in one study.36
This strategy needs further study in different
patient populations. Cyclosporine and azathioprine have been
shown to be effective in only small studies and their use is not
recommended as initial treatment of LN.
7.2.2. Maintenance therapy
After initial therapy is complete, patients with class III and IV LN
should receive maintenance therapy with azathioprine (1.5e2.5 mg/
kg/d) or MMF (1e2 g/d in divided doses), and low-dose oral corti-
costeroids (10 mg/d prednisolone equivalent) (1B).
CNIs with low-dose corticosteroids can be used for in patients
who are intolerant of MMF and azathioprine (2C).
After complete remission is achieved, maintenance therapy be
continued for at least 1 year before consideration is given to tapering
the immunosuppression (2D).
The MAINTAIN Nephritis trial found that MMF was
equivalent to azathioprine in maintaining remission in LN
after an initial induction regime of 6 months of IV cyclo-
phosphamide.37
The ALMS study extension phase found that
MMF was superior to azathioprine at maintaining remission
after an initial induction regime of 6 months of MMF.38
The
duration of maintenance treatment is not clearly defined. A
minimum duration of 1 year is recommended after complete
remission has been achieved.
7.3. Class V LN (membranous LN)
It is recommended that patients with class V LN, normal kidney
function, and sub-nephrotic range proteinuria be treated with anti-
proteinuric and antihypertensive medications, and only receive cor-
ticosteroids and immunosuppressives as dictated by the extrarenal
manifestations of systemic lupus (2D).
Patients with pure class V LN and persistent nephrotic protein-
uria could be treated with corticosteroids plus an additional immu-
nosuppressive agent: cyclophosphamide (2C), or CNI (2C), or MMF
(2D), or azathioprine (2D).
Only one small study compared cyclophosphamide with
cyclosporine in the treatment of patients with class V LN and
nephrotic range proteinuria. They were both equivalent in
efficacy with a higher risk of relapse associated with cyclo-
sporine use.39
Small studies have shown benefit with the use
of MMF, azathioprine and tacrolimus.
7.4. General treatment of LN
It has been suggested that all patients with LN of any class are
treated with hydroxychloroquine (maximum daily dose of 6e6.5 mg/
kg ideal body weight), unless there is a specific contraindication (2C).
7.5. Class VI LN (advanced sclerosis LN)
Patients with class VI LN could be treated with corticosteroids and
immunosuppressives only as dictated by the extrarenal manifesta-
tions of systemic lupus (2D).
7.6. Relapse of LN
It has been suggested that a relapse of LN after complete or partial
remission be treated with the same regime as that which achieved
the initial response (2B).
If resuming the original therapy would put the patient at risk for
excessive lifetime cyclophosphamide exposure, then a non-
cyclophosphamide-based initial regimen can be used (2B).
7.7. Treatment of resistant disease
Treat patients with worsening serum creatinine and/or proteinuria
who continue to have active LN on biopsy with one of the alternative
initial treatment regimens (Not Graded).
Non-responders who have failed more than one of the recom-
mended initial regimens may be considered for treatment with rit-
uximab, i.v. immunoglobulin, or CNIs (2D).
Rituximab has been shown to be beneficial in refractory LN
only in small open-label studies.40
Very limited evidence
supports the use of i.v immunoglobulin and cyclosporine in
this situation. Plasma exchange could be considered, espe-
cially with other organ involvement eg. CNS.
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 7 e1 4 11

7. 7.8. Systemic lupus and thrombotic microangiopathy
Antiphospholipid antibody syndrome (APS) involving the kidney in
systemic lupus patients, with or without LN, can be treated by
anticoagulation (target international normalized ratio [INR] 2e3)
(2D).
Patients with systemic lupus and thrombotic thrombocytopenic
purpura (TTP) could receive plasma exchange as for patients with
TTP without systemic lupus (2D).
8. Pauci-immune focal and segmental
necrotizing glomerulonephritis
8.1. Initial treatment of pauci-immune focal and
segmental necrotizing GN
It is recommended that cyclophosphamide and corticosteroids be
used as initial treatment (1A).
Rituximab and corticosteroids are recommended as an alter-
native initial treatment in patients without severe disease or in
whom cyclophosphamide is contraindicated (1B).
Both i.v and oral cyclophosphamide are equally effective in
inducing remission but for the same duration of therapy, pa-
tients in the i.v. pulse arm received about half the cumulative
amount of cyclophosphamide as in the daily oral arm.41
The
consequence is a lower risk of leucopoenia and infections but
a higher relapse rate in patients treated with i.v cyclo-
phosphamide.42
There is no convincing evidence supporting
the use of i.v pulsed methylprednisolone which is widely used
because of the rapidity of action. A dose of 500 mg daily for 3
days is probably as effective as the 1 g dose and associated
with less side effects.
Two randomized controlled studies, RITUXVAS and RAVE,
have shown rituximab to be as effective as cyclophosphamide
in inducing remission.43
Both trials used a dosage of 375 mg/
m2
weekly for 4 weeks. The long-term adverse effect profile of
rituximab is unknown. Its expense may also limit its use.
8.2. Special patient populations
The addition of plasmapheresis is recommended for patients
requiring dialysis or with rapidly increasing SCr. (1C) It can also be
used in diffuse pulmonary haemorrhage. (2C), combined ANCA
vasculitis and anti-GBM GN (2D).
Discontinue cyclophosphamide therapy after 3 months in pa-
tients who remain dialysis dependent and who do not have any
extrarenal manifestations of disease (2C).
Plasma exchange should be considered as an adjunct to
conventional agents in inducing remission in patients with
severe renal disease (creatinine 5.66 mg/dL) or alveolar
haemorrhage.44
Plasma exchange may have a role in those
with ANCA and Anti-GBM antibody positivity. There is insuf-
ficient evidence to recommend MMF as initial therapy of
vasculitis.
8.3. Maintenance therapy
Maintenance therapy is recommended in patients who have achieved
remission (1B).
Maintenance therapy could be continued for at least 18 months in
patients who remain in complete remission (2D).
Maintenance therapy is not to administered in patients who are
dialysis-dependent and have no extrarenal manifestations of disease
(1C).
8.4. Choice of agent for maintenance therapy
Azathioprine 1e2 mg/kg/d orally is recommended as maintenance
therapy (1B).
MMF, up to 1 g twice daily, can be used in patients who are
allergic to, or intolerant of, azathioprine (2C).
It has been suggested that trimethoprim-sulfamethoxazole be
used as an adjunct to maintenance therapy in patients with upper
respiratory tract disease (2B).
Methotrexate (initially 0.3 mg/kg/wk, maximum 25 mg/wk)
could be used for maintenance therapy in patients intolerant of aza-
thioprine and MMF, but not if GFR is 60 ml/min per 1.73 m2
(1C).
Maintenance therapy with azathioprine (2 mg/kg/d) has
been clearly shown to be superior to mycophenolate.45
Eta-
nercept is not recommended as maintenance therapy.
8.5. Treatment of relapse
Treat patients with severe relapse of ANCA vasculitis (life- or organ-
threatening) according to the same guidelines as for the initial
therapy (1C).
Other relapses could be treated by reinstituting immunosup-
pressive therapy or increasing its intensity with agents other than
cyclophosphamide, including instituting or increasing dose of corti-
costeroids, with or without azathioprine or MMF (2C).
It is probably unsafe to exceed a cumulative dose of 36 g of
cyclophosphamide to avoid the risk of malignancies.46
Rituximab-based regimes may be safer in patients who have
been exposed to significant doses of cyclophosphamide in the
past.
8.6. Treatment of resistant disease
In ANCA GN resistant to induction therapy with cyclophosphamide
and corticosteroids, the addition of rituximab (1C) is recommended.
i.v. immunoglobulin (2C) or plasmapheresis (2D) have been sug-
gested as alternatives.
In patients with resistant disease adjunctive therapy with
i.v. immunoglobulin (single course of a total of 2 g/kg) was
effective in an RCT.47
Several small studies have demon-
strated a possible role for rituximab (375 mg/m2
i.v. weekly x 4,
or 500 mg i.v. weekly x 4 fixed doses) in this scenario. Plasma
exchange may also be beneficial.
9. General measures in the management of
all patients with glomerulonephritis
Measures to manage symptoms and those to retard the pro-
gression to ESRD should be instituted along with the specific
management of the GN. Patients with significant oedema will
require dietary salt and fluid restriction and perhaps the use of
diuretics. Moreover, the antiproteinuric effect of ACE inhibitor
is potentiated by dietary salt restriction.48
Adequate dietary
a p o l l o m e d i c i n e 1 0 ( 2 0 1 3 ) 7 e1 412

8. protein (0.8e1.0 g/kg daily) should be ensured. The nephrotic
state results in complications such as coagulopathy and
hyperlipidemia which may necessitate the use of anticoagu-
lants and lipid lowering medication. Treatment of hyper-
lipidemia should be in accordance with the guidelines for those
at high risk for the development of cardiovascular disease.
Statins(HMG CoAreductase inhibitors)aretheagentsofchoice.
The major predictors of progression of nephropathy are
proteinuria and hypertension. The target blood pressure in
proteinuric patients should be 125/75 mm Hg and 130/80 in
those with proteinuria 1 g/d49
ACE inhibitors (ACEI) and/or angiotensin receptor blockers
(ARB) are the drugs of choice.50
Some patients may not toler-
ate higher doses of ACEI and/or ARB due to hypotension,
hyperkalaemia or worsening azotemia (30% above baseline).
Although these agents can be used at any level of GFR, caution
should be exercised in patients with advanced renal insuffi-
ciency. In patients with normal renal function NSAID’s or
spironolactone may be added as additional anti-proteinuric
agents with close monitoring of renal function and serum
potassium levels.
Conflicts of interest
The author has none to declare.
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