Pi is 0272638613015552

7/24/2019 Pi is 0272638613015552

1/15

CSN Commentary

Canadian Society of Nephrology Commentary on the 2012KDIGO Clinical Practice Guideline for Glomerulonephritis:

Management of Glomerulonephritis in Adults

Andrey V. Cybulsky, MD, FRCPC,1 Michael Walsh, MD, FRCPC,2

Greg Knoll, MD, FRCPC,3 Michelle Hladunewich, MSc, MD, FRCPC,4

Joanne Bargman, MD, FRCPC,4 Heather Reich, MD, FRCPC,4

Atul Humar, MD, FRCP,5 Susan Samuel, MD, FRCPC,6 Martin Bitzan,MD, FRCPC,7

Michael Zappitelli, MD, FRCPC,7 Allison Dart, MD, FRCPC,8

Cherry Mammen, MD, FRCPC,9 Maury Pinsk, MD, FRCPC,6 andNorman Muirhead, MD, FRCPC, FRCP (Ed)10

The KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guideline for management of

glomerulonephritis was recently released. The Canadian Society of Nephrology convened a working group to

review the recommendations and comment on their relevancy and applicability to the Canadian context. A

subgroup of adult nephrologists reviewed the guideline statements for management of glomerular disease in

adults and agreed with most of the guideline statements developed by KDIGO. This commentary highlights

areas for which there is lack of evidence and areas in need of translation of evidence into clinical practice.Areas of controversy or uncertainty, including the choice of second-line agents, are discussed in more detail.

Existing practice variation also is addressed. The relevance of treatment recommendations to the Canadian

practitioner is discussed.

Am J Kidney Dis. 63(3):363-377. 2014 by the National Kidney Foundation, Inc.

INDEX WORDS: Clinical practice guideline implementation; KDIGO (Kidney Disease: Improving Global

Outcomes); Canadian Society of Nephrology (CSN); nephrotic syndrome; glomerulonephritis.

The proliferation of clinical practice guidelines in a

wide range of disciplines, including nephrology,

speaks to a deep-rooted need for comprehensive

assessment of the medical literature and the synthesisof that information into a practical and meaningful

context for the practicing physician. Unfortunately, the

proliferation of clinical practice guidelines has led at

times to confusion or contradiction as national societies

in many countries feel a need to provide their own

comprehensive clinical practice guidelines. In this

context, KDIGO (Kidney Disease: Improving Global

Outcomes) was established in 2003 with the stated

mission to improve the care and outcomes of

kidney disease patients worldwide through promoting

coordination, collaboration, and integration of initia-

tives to develop and implement clinical practiceguidelines.1(pS1)

In the period since the formation of KDIGO,

comprehensive clinical practice guidelines have been

developed and published for chronic kidney disease

(CKD)mineral and bone disorder,1

renal trans-

plantation,2

blood pressure in CKD,3

acute kidney

injury,4

anemia in CKD,5

and hepatitis C virus (HCV)

infection in CKD.6

The KDIGO clinical practice

guideline for glomerulonephritis (GN)7

represents a

systematic review and synthesis of the literature

available on the topic as of January 2011, with addi-

tion of new data available as of November 2011.

The Canadian Society of Nephrology (CSN) is

supportive of the efforts of KDIGO to provide

comprehensive and broadly applicable clinical prac-

tice guidelines for the international nephrology com-munity. However, the CSN and other professional

groups such as KDOQI (Kidney Disease Outcomes

Quality Initiative) see a need to consider local factors

in using clinical practice guidelines to guide care. In

this context, the CSN therefore has established

From the 1Department of Medicine, McGill University,Montreal, Quebec; 2Division of Nephrology, Department ofMedicine, McMaster University, Hamilton; 3Division ofNephrology, Department of Medicine, University of Ottawa,Ottawa; 4Department of Medicine, University of Toronto,Toronto, Ontario; 5Transplant Infectious Diseases and 6Depart-

ment of Pediatrics, University of Alberta, Edmonton, Alberta;7Montreal Childrens Hospital, Montreal, Quebec; 8Departmentof Pediatrics and Child Health, University of Manitoba, Winnipeg,Manitoba; 9Department of Pediatrics, University of BritishColumbia, Vancouver, British Columbia; and 10Division ofNephrology, Department of Medicine, Western University,London, Ontario, Canada.

Originally published online January 13, 2014.Address correspondence to Norman Muirhead, MD, FRCPC,

FRCP (Ed), LHSC University Hospital, Western University, 339Windermere Rd, London ON N6A 5A5, Canada. E-mail:[email protected] by the National Kidney Foundation, Inc.0272-6386/$36.00http://dx.doi.org/10.1053/j.ajkd.2013.12.001

Am J Kidney Dis. 2014;63(3):363-377 363
mailto:[email protected]:[email protected]://dx.doi.org/10.1053/j.ajkd.2013.12.001http://dx.doi.org/10.1053/j.ajkd.2013.12.001mailto:[email protected]:[email protected]

7/24/2019 Pi is 0272638613015552

2/15

working groups to review KDIGO clinical practice

guidelines and provide a perspective on their applica-

bility in Canadian health care. This is particularly

important for newer and/or more expensive therapies

that may be affected by variable restrictions on use in

different jurisdictions in the country.

REVIEW AND APPROVAL PROCESS FOR CSN

COMMENTARIES

The CSN guidelines committee, having decided

that the KDIGO clinical practice guideline for GN

was a priority for comment, established working

groups in the summer of 2012 to develop 2 com-

mentaries, one on the guideline statements relevant to

adults and another regarding guideline statements

relevant to children (see Samuel et al8

). Individual

members of CSN were solicited and selected for the

working group based on their interest and expertise,

taking due note of potential conicts of interest. This

commentary, focused on management of GN in

adults, was developed during summer and fall of

2012, using the original KDIGO GN clinical practice

guideline7

and materials referenced in the report as

information sources. The working group conferred

regularly by teleconference and all authors approved

the nal submitted text. All efforts were made to

achieve consensus. When consensus was not possible,

all viewpoints are discussed. The nal document was

sent out by CSN for peer review and revised

according to the issues raised before nal ratication

by the CSN guidelines committee and CSN executive.

STRUCTURE OF THIS COMMENTARY

This commentary does not attempt to discuss all the

KDIGO recommendations for GN; rather, the focus is

on areas for which there is more comprehensive evi-

dence or an important clinical need. Implications for

Canadian health care are discussed when applicable

and important areas for future research also are

identied.

Individually, each of the GNs is relatively un-

common and frequently has a chronic course. These

features make studying the GNs, particularly the

conduct of adequately powered randomizedcontrolled trials (RCTs), challenging. However, GNs

collectively account for approximately one-quarter of

end-stage renal disease (ESRD). Given this, global

studies to determine optimal treatments are required

and represent an opportunity for the nephrology

community to work toward reducing a cause of ESRD

that is uniquely its domain. Although the current

KDIGO guideline represents a step forward in

collating the existing knowledge on treating GNs,

many chapters lack a research agenda. In order to

advance our understanding of GNs, improve treat-

ments, and reduce ESRD, the nephrology community

needs to establish clear research priorities and un-

dertake large collaborative studies of these diseases.

The endorsement of such an agenda by international

groups such as KDIGO followed by the broader

nephrology community will be a major advancement

in the study and treatment of GN.

In this commentary, numbered text within hori-zontal rules is quoted directly from the KDIGO

document, using the same numbering scheme as in

the original. All material is reproduced with permis-

sion of KDIGO.

GUIDELINE STATEMENTS AND COMMENTARY

Treating Minimal Change Disease in Adults

5.1.3: We suggest the initial high dose of corticoseroids, if

tolerated, be maintained for a minimum period of

4 weeks if complete remission is achieved, and for a

maximum period of 16 weeks if complete remission is

not achieved. (2C)

5.1.5: For patients with relative contraindications or intoler-ance to high-dose corticosteroids (e.g., uncontrolled

diabetes, psychiatric conditions, severe osteopo-

rosis), we suggest oral cyclophosphamide or CNIs as

discussed in frequently relapsing MCD. (2D)

5.1.6: We suggest using the same initial dose and duration

of corticosteroids for infrequent relapses as in

Recommendations 5.1.2, 5.1.3, and 5.1.4. (2D)

5.4.2: We suggest that, for the initial episode of nephrotic

syndrome associated with MCD, statins not be used

to treat hyperlipidemia, and ACE-I or ARBs not be

used in normotensive patients to lower proteinuria.

(2D)

CommentaryThe overall grade of evidence to guide the treat-

ment of minimal change disease (MCD) in adults is

poor and largely extrapolated from studies in children.

Nonetheless, due to a severe paucity of controlled trial

data, the CSN is in agreement with the general prin-

ciples of management proposed by the KDIGO

guideline. However, an understanding of the quality

of available evidence as it pertains to adults is

important for the practicing clinician who is balancing

treatment response against the potential for treatment-

related side effects.

A recent systematic review that searched theCochrane Central Register of Controlled Trials,

MEDLINE, EMBASE, reference articles, and ab-

stracts from conference proceedings for RCTs or

quasi-RCTs identied only 3 RCTs with 68 partici-

pants older than 18 years.9

These data proved inade-

quate to make any rm conclusions with respect to the

utility of prednisone therapy in adults. The guideline

notes that the response rate to steroid therapy is more

variable in adults, who often respond more slowly,

increasing the potential for signicant steroid-related

side effects, and make recommendations for use of

steroid-sparing agents. However, there are inadequate

Cybulsky et al

364 Am J Kidney Dis. 2014;63(3):363-377

7/24/2019 Pi is 0272638613015552

3/15

controlled data to draw rm conclusions on the

superiority of any of the steroid-sparing treatment

options. Finally, all available observational data come

from short-term studies, yet nephrotic syndrome often

is a remitting and relapsing chronic disease that

requires a long-term approach to therapy. Although it

may be reasonable to withhold blockade of the renin-angiotensin system (RAS) in acutely nephrotic pa-

tients with the propensity to develop acute kidney

injury, supportive therapy including statins should be

considered in some adult patients given the variable

response to therapy, the often prolonged time to

response to therapy, and the potential relapsing-

remitting nature of MCD in adults. As such, the

extrapolation of the pediatric literature to adults as

quoted in the guideline may be inappropriate, and cli-

nicians will need to exercise judgment given the sig-

nicant morbidity and mortality due to coronary artery

disease noted in patients with CKD. Overall, vigilant

monitoring for side effects is warranted, irrespective

of chosen therapy, with supportive care aimed at

limiting ancillary damage from both nephrotic syn-

drome and the immunosuppressive agents.

Implications Within Canadian Health Care

Steroid therapy is inexpensive, whereas other po-

tential therapeutic options are more costly, less

proven, and may not be covered by all provincial

health plans. Further controlled trials will be neces-

sary to ensure similar coverage across all Canadian

provinces. This may prove unrealistic.

Evaluation and Treatment of Focal SegmentalGlomerulosclerosis

6.2.3: We suggest the initial high dose of corticosteroids be

given for a minimum of 4 weeks; continue high-dose

corticosteroids up to a maximum of 16 weeks, as

tolerated, or until complete remission has been ach-

ieved, whichever is earlier. (2D)

6.2.4: We suggest corticosteroids be tapered slowly over a

period of 6 months after achieving complete remis-

sion. (2D)

6.3.1: We suggest that a relapse of nephrotic syndrome is

treated as per the recommendations for relapsing

MCD in adults (see Chapters 5.1 and 5.2). (2D)

Commentary

Focal segmental glomerulosclerosis (FSGS) is a

clinicopathologic syndrome associated with glomer-

ular injury that may be either idiopathic or secondary

to one of a number of other disorders that typically

result from decreased glomerular mass. As noted

in the guideline, these secondary causes should be

considered carefully because in these cases, the risks

of immunosuppression are more likely to outweigh

any potential benet. As such, the guideline recom-

mends immunosuppressive therapy only in cases of

nephrotic syndrome. Cardiovascular risk reduction

(ie, RAS blockade and statin therapy) is recommended

in patients presumed to have a secondary cause of

FSGS. However, it should be noted that there is no

absolute conrmatory test that can differentiate idio-

pathic from secondary FSGS. Consequently, clinicians

must carefully assess for potential clinical and patho-logic clues with respect to the cause of this disease

while watching patients closely for worsening of

proteinuria and kidney function so that the opportunity

to provide immunosuppressive therapy is not missed.

In patients with nephrotic syndrome, immunosup-

pression has been shown to improve proteinuria and

slow progression to ESRD, but side effects of the

current options, including high-dose prolonged corti-

costeroids and calcineurin inhibitors (CNIs), are sig-

nicant and rates of treatment failure and relapses are

common. Prednisone often is used as rst-line therapy

largely based on data from observational cohorts. The

dose and duration of therapy are not clear and there-

fore have varied. As noted in the guideline, both daily

regimens and alternate-day regimens have been used.

As in MCD, adult patients can take much longer to

respond, with poorer response rates compared with

children. Steroid resistance even to prolonged treat-

ment is present in .50% of adult patients. Further,

intolerance to steroid therapy tends to be more sig-

nicant, especially in the presence of advanced age

and other comorbid conditions, such as obesity and

diabetes. In patients with steroid resistance or intoler-

ance, CNIs therefore have emerged as the therapeutic

choice in many centers. In a multicenter prospectiveRCT, patients with steroid-resistant FSGS were ran-

domly assigned to continue on low-dose prednisone

either alone or in combination with cyclosporine. The

therapy was continued for 26 weeks and then tapered

over 4 weeks. The response rate in cyclosporine-

treated patients was .70%, but relapses upon discon-

tinuation of therapy were common, at .50%.10

As

such, prolonged therapy likely is necessary, yet

duration of therapy was not described in the current

guideline. In smaller studies, tacrolimus also has

demonstrated similar rates of complete and partial

remission in patients with steroid-resistant or steroid-dependent nephrotic syndrome and thus can be

considered an alternative CNI guided by the side-effect

prole. It should be noted that CNIs must be used with

caution in patients with signicant vascular or inter-

stitial disease on renal biopsy and in those who have

decreased estimated glomerularltration rate (eGFR).

Other therapeutic options include mycophenolate

mofetil (MMF), dexamethasone, and rituximab. A

recent RCT of children and adults with steroid-

resistant FSGS showed that the combination of a

12-month course of MMF and high-dose dexameth-

asone induced a 33% combined partial and complete

Canadian Perspective on KDIGO Glomerulonephritis CPGs

Am J Kidney Dis. 2014;63(3):363-377 365

7/24/2019 Pi is 0272638613015552

4/15

remission. Following discontinuation of the MMF

and dexamethasone, 18% experienced relapse.11

This

study demonstrated a very modest improvement with

prolonged dexamethasone exposure and MMF when

given in combination. To date, evidence that ritux-

imab might prove effective in patients with FSGS is

limited.An important research recommendation in FSGS is

the establishment of biomarkers of disease activity. It

is hypothesized that a large number of circulating

proteins have pro- or antiproteinuric effects on normal

glomeruli, and that changes in the relative ratio of

these circulating proteins could be a major determi-

nant of proteinuria in disease states. Recent insights

into podocyte biology have identied a urokinase

receptor (uPAR [urokinase plasminogen activator

receptor]) integral to the maintenance of the slit dia-

phragm through its ability to form signaling com-

plexes with other transmembrane proteins, including

lipid-dependent activation of avb3 integrin.12 Asoluble cleavage product (suPAR) is elevated in

FSGS,13

particularly with posttransplantation recur-

rence. These novel biomarkers may provide insights

into the pathogenesis of the disease and its activity,

predict remission more accurately, and may lead to

mechanism-based therapeutics. Moreover, the bio-

markers may dene the appropriate timing and dura-

tion of treatments.

Idiopathic Membranous Nephropathy

7.2.1: We recommend that initial therapy be started only in

patients with nephrotic syndrome ANDwhen at leastone of the following conditions is met:

Urinary protein excretion persistently exceeds

4 g/d AND remains at over 50% of the baseline

value, AND does not show progressive decline,

during antihypertensive and antiproteinuric therapy

(see Chapter 1) 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)

SCr has risen by 30% or more within 6 to 12

months from the time of diagnosis but the eGFR is

not less than 2530 ml/min/1.73 m2 AND this

change is not explained by superimposed compli-

cations. (2C)

7.3.1: We recommend that initial therapy consist of a 6-

month course of alternating monthly cycles of oral and

i.v. corticosteroids, and oral alkylating agents (see

Table 15). (1B)

7.3.3: We recommend patients be managed conservatively

for at least 6 months following the completion of this

regimen before being considered a treatment failure

if there is no remission, unless kidney function is

deteriorating or severe, disabling, or potentially life-

threatening symptoms related to the nephrotic syn-

drome are present (see also Recommendation 7.2.1).

(1C)

Commentary

In chapter 7 of the KDIGO guideline, there are

no grade 1A recommendations and only 3 grade 1B

recommendations. There are 15 grade 1C, 2B, 2C, or

2D recommendations. The relatively low quality of

evidence in this area reects the absence of adequate

idiopathic membranous nephropathy biomarkersand lack of established effectiveness of current treat-

ments. The recommendations for therapy primarily

involve cyclophosphamide/chlorambucil or CNI-

based immunosuppression protocols, whereas there

are no specic recommendations for newer agents,

such as rituximab, due to lack of robust evidence.

Nevertheless, a signicant understanding of idiopathic

membranous nephropathy pathogenesis has been

achieved recently, biomarker studies are ongoing,14

and newer agents presently are being tested in RCTs

(eg, rituximab vs cyclosporine; ClinicalTrials.gov

identi

er NCT01180036). These developments pro-vide reason for optimism that therapy of idiopathic

membranous nephropathy may undergo improvement

and become more mechanism directed in future years.

In guideline statement 7.2.1, it is recommended that

specic therapy be instituted only if urinary protein

excretion persistently is .4 g/d, remains at.50% of

the baseline value, and does not show progressive

decline during antihypertensive and antiproteinuric

therapy during an observation period of at least 6

months. The recommendation is based on an algo-

rithm developed at 6 months of observation.15

At the

same time, the guideline states that remission may

be delayed for as long as 18-24 months and thatthe mean time to remission was recently reported

as 14.76 11.4 months.16

Moreover, spontaneous

remission has been reported in .20% of patients with

proteinuria with protein excretion of 8-12 g/d and

even .12 g/d. Therefore, although the guideline

recommends an observation period of at least 6

months, a signicantly longer observation period

could be considered. A conservative approach should

be maintained in patients showing a progressive

decline in proteinuria during the rst year of follow-

up (including patients with massive proteinuria),

provided that renal function continues to be normal.By analogy, guideline statement 7.3.3 recommends

that patients be managed conservatively for at least 6

months following the completion of a specic treat-

ment regimen before being considered a treatment

failure if there is no remission; however, spontaneous

remission may involve a period as long as 12-18

months.16

A 6-month denition of treatment failure is

relatively arbitrary compared with a longer period.

We agree with research recommendations for further

study of antiphospholipase A2receptor antibodies and

other biomarkers of disease activity, which may assist

Cybulsky et al

366 Am J Kidney Dis. 2014;63(3):363-377
http://clinicaltrials.gov/http://clinicaltrials.gov/

7/24/2019 Pi is 0272638613015552

5/15

in dening remission more accurately, as well as the

appropriate periods of observation.14

In regard to the recommendation in guideline

statement 7.3.1 that initial therapy consist of a

6-month course of alternating monthly cycles of oral

and intravenous corticosteroids and oral alkylating

agents, the published evidence for the efcacy ofalkylation agents appears stronger compared with

CNIs. Studies of alkylation agents have a longer

duration of follow-up data, and treatment with CNIs,

while effective in inducing remission, is associated

with a high rate of relapse. However, the side effects

of alkylating agents are perceived to be more sub-

stantial.17

On balance, a CNI-based regimen may be

favored by some practitioners. It should be noted that

results of a recently published study that compares an

alkylating agent (chlorambucil) with cyclosporine and

supportive therapy alone in patients with idiopathic

membranous nephropathy and declining renal func-

tion are strongly in favor of the alkylating agent

over both CNIs and supportive therapy in reducing

renal functional decline.18

The trial involved patients

with at least a 20% decline in renal function, but a

serum creatinine (SCr) level , 300mmol/L. Baselineproteinuria in the 3 treatment groups ranged from

protein excretion of 6.8-10.1 g/24 h. Even in the

chlorambucil-treated group, renal function continued

to decline in w60% of patients over 3 years, but

overall, renal function was signicantly better pre-

served in this group. However, side effects were

greater in patients receiving the alkylating agent.18

Idiopathic Membranoproliferative GN

8.2.1: We suggest that adults or children with presumed

idiopathic MPGN accompanied by nephrotic syn-

drome ANDprogressive decline of kidney function

receive oral cyclophosphamide or MMF plus low-dose

alternate-day or daily corticosteroids with initial ther-

apy limited to less than 6 months. (2D)

Commentary

Membranoproliferative GN (MPGN) is ahistologic

pattern of injury and not a specic disease.19-23

The

term MPGN therefore is obsolete and should bereplaced with a mechanistic classication according

to the presence of immunoglobulins (Igs) and/or

complement, that is, Ig1

C31

and IgC31

. The former

can be subclassied into the presence of polyclonal

and/or monoclonal antibodies, and the latter, into

dense deposit disease and C3 nephropathy. The key

to optimal treatment of MPGN likely will depend on

identication of the underlying cause and may include

immunosuppression, chemotherapy of monoclonal

gammopathy disorders, or complement-regulatory

therapies directed at the C3 convertase or terminal

complement pathway.22,24


There are no specic implications at the present

time, but assuming complement-regulatory therapies

are approved for IgC31 nephropathies in the future,

the cost and coverage of these therapies will become

major considerations. The substantial costs of such

drugs, which are biologic reagents, presently arecovered to a variable extent by provincial health plans

and private insurers.

Infection-Related GN

9.2.1: For HCV-infected patients with CKD Stages 1 or 2

and GN, we suggest combined antiviral treatment

using pegylated interferon and ribavirin as in the

general population. (2C) [based on KDIGO HCV

Recommendation 2.2.1]

9.2.2: For HCV-infected patients with CKD Stages 3, 4, or 5

and GN not yet on dialysis, we suggest monotherapy

with pegylated interferon, with doses adjusted to the

level of kidney function. (2D) [based on KDIGO HCV

Recommendation 2.2.2]

9.3.1: We recommend that patients with HBV infection and

GN receive treatment with interferon-a or with nucle-oside analogues as recommended for the general

population by standard clinical practice guidelines for

HBV infection. (1C)

Commentary

The working group noted that the majority of the

suggestions in chapter 9 were based on low- or very

low-quality data. The working group agrees with

most of the recommendations presented in this section

of the KDIGO guideline. Most of the suggestionsand recommendations are common sense statements

directed at treatment of the underlying infection. The

only level 1 recommendations in this chapter were

made in reference to the treatment of hepatitis B virus

(HBV)-related GN. The guideline stated that patients

should receive treatment with interferon alfa or a

nucleoside analogue. Both treatments would be

acceptable, but in Canada, it would be much more

common for a patient to receive one of the nucleoside

analogues such as tenofovir or entecavir as initial

therapy based on safety prole and ease of adminis-

tration.

25

In contrast to potential cure with interferon,drug therapy with a nucleoside analogue would be

required for life.

Although the working group agreed with the rec-

ommendations for the treatment of HCV infection, it

was noted that the referenced KDIGO HCV guideline

was published in 2008. Since that time, protease

inhibitors such as boceprevir and telaprevir have

become available for the treatment of HCV infection.

International guidelines now recommend that one

of the protease inhibitors (boceprevir or telaprevir)

be added to pegylated interferon and ribavirin for

genotype I patients. These newer regimens increase


Am J Kidney Dis. 2014;63(3):363-377 367

7/24/2019 Pi is 0272638613015552

6/15

response rates from 40%-50% up to 70%-80%.26,27

However, there are no data for the use of the agents

in patients with CKD. Unfortunately, Canadian

guidelines on the treatment of HCV were last published

in 2007 andmake no reference to the novel protease

inhibitors.28

Drug coverage for protease inhibitors

is variable across Canada. HCV therapy overall isevolving rapidly due to the development of new agents.

The working group agrees that human immunode-

ciency virus (HIV)-associated nephropathy should

be treated with antiretroviral therapy. Because a wide

variety of treatment options are available, recent

Canadian recommendations should be used to select

the most appropriate regimen.29


1. In contrast to other chapters in this guideline,

several of the disorders discussed in this section

would occur rarely in the Canadian population.

Nonetheless, given increased immigration and inter-

national travel, Canadian physicians will need to be

aware of renal issues related to certain infections (eg,

schistosomiasis and lymphatic lariasis) discussed in

this chapter.

2. Therapies to treat infection-related GN for the

most part are available in Canada. The cost of med-

ications, especially potentially expensive agents such

as lifelong antiviral therapy, is covered by a mix of

government funding and private insurance. However,

the level of government funding is under provincial

jurisdiction and varies somewhat between the prov-

inces, especially for new HCV therapies. In addition,eligibility for funding based on clinical criteria (eg,

viral load and renal function) may vary in different

jurisdictions throughout the country.

IgA Nephropathy

10.1: Initial evaluation including assessment of risk of

progressive kidney disease

10.1.2: Assess the risk of progression in all cases by

evaluation of proteinuria, blood pressure, and

eGFR at the time of diagnosis and during follow-

up. (Not Graded)

10.1.3: Pathological features may be used to assess

prognosis. (Not Graded)10.2: Antiproteinuric and antihypertensive therapy

10.2.4: In IgAN, use blood pressure treatment goals

of ,130/80 mm Hg in patients with proteinuria

,1 g/d, and ,125/75 mm Hg when initial protein-

uria is .1 g/d (See Chapter 2). (Not Graded)

10.3: Corticosteroids

10.3.1: We suggest that patients with persistent

proteinuria $1 g/d, despite 36 months of opti-

mized supportive care (including ACE-I or ARBs

and blood pressure control), and GFR . 50 ml/min

per 1.73 m2, receive a 6-month course of cortico-

steroid therapy. (2C)

10.4: Immunosuppressive agents (cyclophosphamide,

azathioprine, MMF, cyclosporine)

10.4.1: We suggest not treating with corticosteroids com-

bined with cyclophosphamide or azathioprine in

IgAN patients (unless there is crescentic IgAN with

rapidly deteriorating kidney function; see Recom-

mendation 10.6.3). (2D)

10.4.3: We suggest not using MMF in IgAN. (2C)

10.5: Other treatments

10.5.1: Fish oil treatment10.5.1.1: We suggest using fish oil in the treatment of IgAN

with persistent proteinuria .1 g/d, despite 36

months of optimized supportive care (including

ACE-I or ARBs and blood pressure control). (2D)

10.6: Atypical forms of IgAN

10.6.1: MCD with mesangial IgA deposits

10.6.1.1: We recommend treatment as for MCD (see

Chapter 5) in nephrotic patients showing patho-

logical findings of MCD with mesangial IgA

deposits on kidney biopsy. (2B)

10.6.3: Crescentic IgAN

10.6.3.1: Define crescentic IgAN as IgAN with crescents in

more than 50% of glomeruli in the renal biopsy with

rapidly progressive renal deterioration. (Not

Graded)10.6.3.2: We suggest the use of steroids and cyclophospha-

mide in patients with IgAN and rapidly progressive

crescentic IgAN, analogous to the treatment of

ANCA vasculitis (see Chapter 13). (2D)

Commentary

Prognosis. Clinicians cannot fully account for thevariability in outcome based on clinical features

alone. The KDIGO guideline alludes to the fact that

the new Oxford MEST (mesangial hypercellularity,

endocapillary hypercellularity, segmental glomerulo-

sclerosis, and tubular atrophy/interstitial brosis)score adds independent prognostic information at

the time of diagnosis.30,31

This nding now has

been validated in independent pediatric and adult

populations.32-36

However, although information ob-

tained from the pathology score is statistically inde-

pendent of the usual prognostic markers, the

incremental value of pathologic ndings in predicting

outcome remains unknown. The impact of histologic

variant on therapeutic response also is not known.

Conservative therapy. Data suggest that reductionin proteinuria to protein excretion , 1 g/d is associ-

ated with a favorable outcome, whether this is ach-ieved through conservative or immunomodulatory

treatment strategies.37

The incorporation of protein-

uria into the target blood pressure goals reects a

trend toward improved outcomes in proteinuric

patients receiving more aggressive blood pressure

control in a recent meta-analysis,38

but there are no

RCTs to compare blood pressure targets. Therefore,

the targeting of 130/80 versus 125/75 mm Hg is

opinion based. The guideline does not address the risk

of cardiovascular complications in patients with IgA

nephropathy (IgAN). Subnephrotic-range proteinuria

now is a well-recognized risk factor for cardiovascular

Cybulsky et al

368 Am J Kidney Dis. 2014;63(3):363-377

7/24/2019 Pi is 0272638613015552

7/15

disease in the general population, independent of renal

function.39

It is not known whether the association

between low-grade proteinuria and cardiovascular risk

is consistent in young and otherwise healthy patients

with proteinuria due to primary kidney disease, and

this is an important area for future research. If there is a

higher risk of cardiovascular morbidity and mortalityin this population, blood pressure targets should take

into account prevention of cardiovascular complica-

tions and lipid-lowering agents may be an important

cornerstone of long-term care.

Immunotherapy. There are 2 RCTs referenced inthis recommendation that support the benet of

corticosteroids compared to conservative therapy with

angiotensin-converting enzyme (ACE) inhibitors or

angiotensin-receptor blockers (ARBs),40,41

and both

these studies included patients with relatively pre-

served renal function. A larger multicenter RCT

currently is underway in a population with a broad

range of renal function (GFR, 20-70 mL/min/1.73 m2)

to evaluate the benets of corticosteroids in patients

with persistent proteinuria with protein excretion

. 1 g/d despite optimal conservative therapy.42

As in

other forms of GN, the relative potential benets

of corticosteroids must be evaluated at the level of

the individual patient and relative contraindications

(eg, obesity, glucose intolerance, and poorly controlled

hypertension) to steroid therapy must be considered.

The duration of therapy recommended in this

guideline is 6 months. However, this does not mean

that a full 6-month trial of corticosteroids is required

prior to determining if the patient is likely torespondand benet from this medication.

It is worth noting that with time, proteinuria

frequentlyrecurs following cessation of corticosteroid

therapy.43

This is not addressed in the guideline. The

role of adjunctive steroid-sparing therapy for patients

with a relapse following a good antiproteinuric

response to corticosteroids remains unclear and re-

quires further investigation. Future work also should

include the evaluation of whether the histologic

pattern of IgAN may identify patients who are more

likely to benet from corticosteroids.

The addition of azathioprine to prednisone does notresult in a benet with respect to clinical outcomes

according to a well-designed randomized prospective

study.44

However, it has not been studied as a steroid-

sparing agent in patients who have a relapse following

withdrawal of corticosteroid therapy.

The guideline advises explicitly against the use of

MMF. Although it has been suggested that the lack of

effect of MMF reected the fact that the drug was

administered initially to patients with very advanced

disease,45

RCTs in patients withmore moderate disease

risk demonstrate conicting ndings.46,47

In addition,

observational studies in IgAN should remind us that

MMF is not without toxicity48

and is not necessarily a

superior therapy in all forms of proliferative GN.49

Fish oil. The recommendation to use sh oil forprevention of renal disease progression is acceptable

largely due to the lack of observed harm of this

intervention because study ndings regarding benet

are conicting. However, it must be recognizedthat 3 g/d of puried polyunsaturated fatty acid was

the lowest dose associated with benecial renal out-

comes compared with ACE inhibitors or ARBs

alone.50

Therefore, the composition of the sh oil

formulation is important, and it may be a challenge

for individual patients to meet and maintain this

target.

IgAN variants. The role for combination immu-nosuppression in crescentic (.50% of glomeruli)

IgAN accompanied by rapidly progressive renal

deterioration is supported by only low-grade evi-

dence, with retrospective data supporting potentially

improved outcome compared with historical con-

trols.51,52

Even less is known about the therapeutic

implications of crescents in the absence of rapidly

progressive changes in renal function. The lack of

inclusion of crescents in the Oxford MEST score

should not lead clinicians to conclude that they have

no clinical importance; the independent impact of

crescents on outcome (above information from clinical

parameters) simply is not known. There were insuf-

cient numbers of patients with crescents in the multi-

national Oxford studies to evaluate the independent

prognostic value of crescents or the percentage of

glomeruli with crescents associated with adverseprognosis. Further, a very rapidly progressive clinical

course would have precluded inclusion in the Oxford

cohort. Limited observational data suggest that.50%

crescents indicates high risk of progression, and more

guidance is required to guide therapeutic decisions in

patients with preserved renal function.

Henoch-Schnlein Purpura

11.4.1: We suggest that HSP nephritis in adults be treated

the same as in children. (2D)

Commentary

In Canada, immunosuppressant medication choices

appear to be center specic and a unanimous practice

algorithm does not exist. There is a preference to use

immunosuppressant therapy for Henoch-Schnlein

purpura (HSP) that combines steroid therapy with one

of azathioprine, cyclosporine, tacrolimus, or MMF/

mycophenolic acid. Cyclophosphamide is used less

frequently, particularly because there is no evidence

suggesting increased efcacy and due to side effects

of infertility and malignancy. Cost has a signicant

impact on the choice of immunosuppressant therapy.


Am J Kidney Dis. 2014;63(3):363-377 369

7/24/2019 Pi is 0272638613015552

8/15

Newer medications generally are not approved for use

in children by Health Canada or provincial formu-

laries and thus are not eligible for provincial drug

coverage programs. These practice patterns suggest

that the current state of knowledge for treatment of

HSP nephritis shows areas requiring active research

that include: (1) determination of the severity of his-tologic disease that requires therapy, and (2) whether

any immunosuppressive therapy alone or in combi-

nation is effective in inducing remission and preser-

ving kidney function. Although most clinicians would

consider performing a biopsy in the presence of

persistent proteinuria, hypertension, or azotemia,

there currently are no data to inform how long a pa-

tient should be observed for spontaneous remission

before intervening with therapy or biopsy.

Lupus Nephritis

12.3: Class III LN (focal LN) and class IV LN (diffuse LN)initial therapy

12.3.1: We recommend initial therapy with corticosteroids

(1A), combined with either cyclophosphamide (1B)

or MMF (1B).

12.3.2: We suggest that, if patients have worsening LN

(rising SCr, worsening proteinuria) during the first 3

months of treatment, a change be made to an

alternative recommended therapy, or a repeat kid-

ney biopsy be performed to guide further treatment.

(2D)

12.5.2: We suggest that patients with pure class V LN and

persistent nephrotic proteinuria be treated with

corticosteroids plus an additional immunosuppres-

sive agent: cyclophosphamide (2C), or CNI (2C), or

MMF (2D), or azathioprine (2D).12.8: Relapse of LN

12.8.1: We suggest that a relapse of LN after complete or

partial remission be treated with the initial therapy

followed by the maintenance therapy that was

effective in inducing the original remission. (2B)

12.9: Treatment of resistant disease

12.9.1: In patients with worsening SCr and/or proteinuria

after completing one of the initial treatment regi-

mens, consider performing a repeat kidney biopsy

to distinguish active LN from scarring. (Not Graded)

12.9.2: Treat patients with worsening SCr and/or protein-

uria who continue to have active LN on biopsy with

one of the alternative initial treatment regimens

(see Section 12.3). (Not Graded)

12.9.3: We suggest that nonresponders who have failedmore than one of the recommended initial regimens

may be considered for treatment with rituximab, i.v.

immunoglobulin, or CNIs. (2D)

12.11: Systemic lupus and pregnancy

12.11.1: We suggest that women be counseled to delay

pregnancy until a complete remission of LN has

been achieved. (2D)

12.11.3: We suggest that hydroxychloroquine be continued

during pregnancy. (2B)

12.11.4: We suggest that LN patients who become pregnant

while being treated with MMF be switched to

azathioprine. (1B)

Commentary

There are 6 recommendations in the chapter about

lupus nephritis: 2 concerning induction and mainte-

nance therapy for class III and IV lupus nephritis; 2

concerning avoidance of immunosuppression for

patients with either membranous lupus with sub

nephrotic-range proteinuria or sclerosing lesions; and2 recommendations that involve the management of

lupus nephritis in pregnancy.

When strong RCT evidence does not exist, the

KDIGO guideline provides expert opinion, to the

great potential benet of clinicians seeking practical

advice. Inappropriate immunosuppression in lupus

nephritis likely accounts for much of the morbidity

and perhaps mortality that is seen with this illness. It

thus is useful that the guideline statements for lupus

nephritis include advice regarding overtreatment of

patients with more benign disease (mesangial lupus

nephritis and membranous lupus nephritis with low-grade proteinuria) or in whom treatment is unlikely

to be of benet (sclerosing lupus nephritis).The

guideline also appropriately does not distinguish be-

tween focal proliferative and diffuse proliferative

disease because the difference between the classi-

cations often is arbitrary (,50% vs .50% involve-

ment).53

Advice to avoid escalation of therapy unless

there is evidence of deterioration rather than persis-

tence of urinary abnormalities alone is welcome,

particularly because problems such as microscopic

hematuria may persist for months or years after

attaining remission. Although one earlier study sug-

gested a poor outcome for patients with lupusnephritis who attained only a partial remission,

54

more recent data suggest that the long-term outcome

of these patients is excellent.55

The CSN working group believes it is important to

emphasize 2 aspects of therapy: the importance of

corticosteroid dose and duration in the management

of lupus nephritis, and second, nonadherence to

therapy as perhaps one of the most important causes

of treatment failure (12.9).

Dose and duration of corticosteroid. There is atendency in treating lupus nephritis to worry more

about choice of immunosuppressive (eg, cyclophos-phamide vs MMF) than the dose and duration of

corticosteroid therapy. The guideline appropriately

recommends high-dose corticosteroids during initial

therapy, but then tapering according to clinical

response over 6 to twelve months.Although there is

little evidence concerning what to do after the initial

high-dose corticosteroid therapy, a rapid steroid

taper, especially aiming to have the patient off corti-

costeroid therapy by 6 months, can increase the risk

for relapse.56

Similarly, although a maintenance

dose , 10 mg/d is suggested, some patients may

Cybulsky et al

370 Am J Kidney Dis. 2014;63(3):363-377

7/24/2019 Pi is 0272638613015552

9/15

require a higher dose to maintain remission. A recent

survey of practice patterns in the management of

lupus nephritis indicated that Canadian physicians

were more likely than their counterparts in the United

Kingdom or in recommended clinical practice

guidelines to reduce or eliminate steroids in most

patients with lupus nephritis.57

Nonadherence to therapy and resistantdisease.The proclivity of lupus is to affect young female pa-

tients. Corticosteroid side effects can be devastating

for this demographic cohort. It is understandable

that patients experiencing side effects may modify

or abandon therapy altogether. Therefore, in a patient

with resistant or quickly relapsing disease

(guideline statements 12.3.2 and 12.9), rather than

switching to alternative therapy, it is crucial to

explore adherence to the current prescription.

Nonadherence to oral therapy probably is the best

reason to choose a parenteral cyclophosphamide-

based regimen. Given the reduction in serious side

effects with the Euro Lupus regimen (500 mg intra-

venously every 2 weeks for 6 doses total),58

it is

recommended over the National Institutes of Health

(NIH) protocol,59

particularly if there is reduced GFR.

Induction regimens. The guideline suggests thatinduction studies using MMF included patients with

milderrenal disease compared with those in studies

of high-dose cyclophosphamide and conclude that

because MMF is unproven for more serious renal

involvement, perhaps cyclophosphamide in the NIH

protocol would be preferred. It is difcult to say

which studies had patients with more, rather thanless, severe renal involvement when these reports

span continents and decades in time. However, it is

worth noting that in the NIH report rst using intra-

venous pulse cyclophosphamide, median SCr level

was 1.0 mg/dL.59

There is no a priori reason to

believe that patients with more severe involvement

with lupus nephritis will respond better to a more

toxic regimen. Further, a subgroup analysis of pa-

tients with eGFR , 30 mL/min/1.73 m2

in the ALMS

(Aspreva Lupus Management Study) did not nd

evidence that MMF was inferior to intravenous pulse

cyclophosphamide.

60

Azathioprine also is given little attention in the

section on initial therapy, most likely because there is

little evidence for its efcacy in class III and IV lupus

nephritis. However, lack of evidence of efcacy is not

the same as evidence of lack of efcacy. The inter-

esting Dutch study and its follow-up reports are

quoted in this section. Purported to be a trial of

azathioprine versus intravenous cyclophosphamide,

azathioprine was used with pulse corticosteroid,

whereas the cyclophosphamide was used with daily

oral corticosteroid. Nonetheless, the azathioprine

induction group did well with fewer side effects.61

However, a follow-up report noted a higher relapse

rate and doubling of SCr level (and chronicity on

renal biopsy) with the azathioprine regimen.62

The

second renal biopsies were performed in only half the

original study cohort, and the most recent report from

this trial shows that at close to 10 years of follow-up,

the incidence of doubling of SCr level, ESRD, andmortality were not different between the 2 groups.

63

The authors themselves note that the biopsy data

from their previous report did not help predict dete-

rioration of renal function.63

Maintenance therapy. Most clinicians agree thatlong-term maintenance therapy with cyclophospha-

mide should be avoided and maintenance therapy

be with either MMF or azathioprine, combined with

low-dose corticosteroid (recommendation 12.4.1).

The CSN working group concurs that the recom-

mendation did not advocate too strongly for MMF

over azathioprine.

In a US study comparing therapy with intravenous

cyclophosphamide, azathioprine, and MMF, there

was a suggestion of fewer relapses with MMF

compared to azathioprine.64

However, by 6 years of

follow-up, the numbers were small. Two more recent

studies have compared maintenance treatment with

these 2 drugs. In the MAINTAIN Nephritis Euro

Lupus trial, the Euro Lupus patients were randomly

assigned to azathioprine versus MMF after 6 months.

The patients did not have to be in complete or partial

remission to enter this phase of the trial. After more

than 4 years follow-up, there was no difference

between the MMF and azathioprine groups withrespect to relapse or doubling of SCr level.

65The

second study was the maintenance study of ALMS.

In contrast to the MAINTAIN study, patients had to

be in complete or partial remission at the time of

randomization to azathioprine or MMF in doses

similar to those used in MAINTAIN. In this study, the

relapse rate in the MMF group was half as much as

those being maintained with azathioprine (16% vs

32%; P , 0.005).66 Potential benets of MMF overazathioprine need to be offset by consideration of

costs and the potential for pregnancy.

Membranous lupus nephritis. The CSN workinggroup agrees with the recommendations that patientswith subnephrotic proteinuria have a good long-term

prognosis and should be managed with antiproteinuric

therapy, such as renin-angiotensin-aldosterone system

(RAAS) inhibitors only. Membranous lupus with sus-

tained nephrotic-range proteinuria certainly carries

a better renal prognosis than focal or diffuse prolifera-

tive lupus nephritis. However, there is still a small

subset of patients with sustained heavy proteinuria

who may progress to CKD. Furthermore, there is

sizable morbidity associated with sustained nephrosis,

including hyperlipidemia and associated accelerated


Am J Kidney Dis. 2014;63(3):363-377 371

7/24/2019 Pi is 0272638613015552

10/15

vascular disease. Important also is the thrombotic risk

that can lead to signicant morbidity. There is only one

RCT comparing corticosteroid alone to corticosteroid

plus cyclophosphamide or cyclosporine. Furthermore,

that study took decades to complete.67

As in nonlupus

glomerular disease, cyclosporine led to complete or

partial remission only for as long as it was used;there was a high relapse rate upon its discontinuation.

However, the length of therapy was limited to only

11 months. Furthermore, the corticosteroids in this

trial were given in an alternate-day regimen, which

although sparing many side effects, has not been

commonly used since the publication of the Coggins

study of alternate-day steroids for idiopathic membra-

nous nephropathy.68

The addition of cyclophospha-

mide led to a more sustained remission. A recent

meta-analysis found that the response to steroids

alone was 60% compared to 81%with the addition of

another immunosuppressive agent.69

Although the guideline recommends a study of

steroid monotherapy for class V lupus nephritis, this

particular nephritis can take months to years to remit.

For example, one study showed that it took up to

3 years for these patients to enter remission.70

This

delay in response poses a number of challenges:

First, it makes a good trial very difcult to undertake,

particularly because lupus membranous is less

commonly encountered than the proliferative forms,

and the duration of the trial would pose numerous

problems.

Systemic lupus in pregnancy. As in all CKDs,

renal insufciency and chronic hypertension factortoward poor pregnancy outcomes, but lupus is unique

in that active nephritis predicts an especially poor

pregnancy outcome. Furthermore, pregnancy itself

has been shown to increase the potential of a disease

are during any trimester and in the early postpartum.71

As such, the guideline appropriately recommends

delaying pregnancy until a complete remission of

lupus nephritis has been achieved (guideline statement

12.11.1) and not to taper pregnancy-safe immunosup-

pression until at least 3 months postdelivery (guideline

statement 12.11.6) to prevent aare in pregnancy or

the early postpartum, when the risk is deemed to bethe highest. However, the guideline does not comment

on the appropriate timing of pregnancy, denition

of remission, and provides insufcient detail with

respect to the management of potentially teratogenic

medications.

Implications for Canadian Health Care

Given the relatively high rate of immigration from

Asia and the Caribbean, many centers in Canada are

now seeing sizable numbers of high-risk patients with

lupus and lupus nephritis. The universal access to

health care blurs some of the socioeconomic barriers

that these patients might encounter in other countries.

However, drug costs often are not covered by pro-

vincial health plans and so these must be taken into

consideration. Newer agents such as the biologics

remain prohibitively expensive, but for most patients

do not add much therapeutic benet over the con-

ventional drugs discussed in this chapter.Pauci-immune focal and segmental necrotizing GN

13.1: Initial treatment of pauci-immune focal and

segmental necrotizing GN

13.1.1: We recommend that cyclophosphamide and corti-

costeroids be used as initial treatment. (1A)

13.1.2: We recommend that rituximab and corticosteroids

be used as an alternative initial treatment in patients

without severe disease or in whom cyclophospha-

mide is contraindicated. (1B)

13.2: Special patient populations

13.2.1: We recommend the addition of plasmapheresis for

patients requiring dialysis or with rapidly increasing

SCr. (1C)13.2.2: We suggest the addition of plasmapheresis for

patients with diffuse pulmonary hemorrhage. (2C)

13.2.3: We suggest the addition of plasmapheresis for pa-

tients with overlap syndrome of ANCA vasculitis and

anti-GBM GN, according to proposed criteria and

regimen for anti-GBM GN (see Chapter 14). (2D)

13.3: Maintenance therapy

13.3.3: We recommend no maintenance therapy in patients

who are dialysis-dependent and have no extrarenal

manifestations of disease. (1C)

13.4: Choice of agent for maintenance therapy

13.4.1: We recommend azathioprine 12 mg/kg/d orally as

maintenance therapy. (1B)

13.4.2: We suggest that MMF, up to 1 g twice daily, be used

for maintenance therapy in patients who are allergicto, or intolerant of, azathioprine. (2C)

13.4.3: We suggest trimethoprim-sulfamethoxazole as an

adjunct to maintenance therapy in patients with

upper respiratory tract disease. (2B)

13.4.4: We suggest methotrexate (initially 0.3 mg/kg/wk,

maximum 25 mg/wk) for maintenance therapy in

patients intolerant of azathioprine and MMF, but not

if GFR is ,60 ml/min per 1.73 m2. (1C)

13.4.5: We recommend not using etanercept as adjunctive

therapy. (1A)

13.6: Treatment of resistant disease

13.6.1: In ANCA GN resistant to induction therapy with

cyclophosphamide and corticosteroids, we recom-

mend the addition of rituximab (1C), and suggest i.v.

immunoglobulin (2C) or plasmapheresis (2D) asalternatives.

13.8: Transplantation

13.8.1: We recommend delaying transplantation until pa-

tients are in complete extrarenal remission for 12

months. (1C)

Commentary

Guideline section 13.1 has 2 level-1 recommenda-

tions. Both deserve comment. Recommending only

cyclophosphamide or rituximab in addition to gluco-

corticoids may be overly restrictive. There is evidence

to suggest that early or limited cases of antineutrophil

Cybulsky et al

372 Am J Kidney Dis. 2014;63(3):363-377

7/24/2019 Pi is 0272638613015552

11/15

cytoplasmic antibody (ANCA)-associated vasculitis,

approximately one-third of which have some degree of

renal involvement, in which SCr level is,150mmol/Lmay be treated safely with methotrexate.

72However,

the risks and benets of alternative agents, as well

as optimal duration of use, vary when compared to

cyclophosphamide.73

Data supporting the use of rituximab as an alter-

native to cyclophosphamide largely come from 2

RCTs.74,75

These trials focus on early outcomes.

Although the data are encouraging, unresolved issues

remain regarding optimal treatment after induction

with rituximab (eg, ongoing use of an immunosup-

pressive for maintenance, redosing of rituximab)

that those prescribing rituximab for pauci-immune

GN must be aware of. Furthermore, although long-

term evidence from the lymphoma experience and

medium-term evidence from rheumatoid arthritis sug-

gest rituximab is safe in the longer term, there are

few data for the long-term safety of rituximab in

vasculitis or for patients with chronic repeated expo-

sures (such as happens when it is used for recurrent

disease or as maintenance therapy).

One level 1 recommendation and 3 level 2 sug-

gestions are made for management of specic sub-

populations. Three of these points pertain to the use of

plasmapheresis. There is insufcient evidence to

support a recommendation that plasmapheresis be

used in all patients with a rapidly increasing SCr level

or that require dialysis. A recent meta-analysis found

that the number of patients randomly assigned was

insufcient to make robust conclusions (ie, high riskof type I and type II errors) and that there was an

important discrepancy between the apparent risk

reduction in dialysis dependency and mortality.76

Specically, although the risk of ESRD appears to

decrease in plasmapheresis-treated patients, the risk of

death is unchanged. Furthermore, the estimated risk

reduction in ESRD appears implausibly large, sug-

gesting serious overestimation of effect.

The suggested use of plasmapheresis in all patients

with alveolar hemorrhage or overlap syndromes of

ANCA vasculitis and antiglomerular basement

membrane (anti-GBM) disease is based on uncon-trolled case series. Given the heterogeneity of pre-

sentations of alveolar hemorrhage, the potential

variability in prognostic signicance of different se-

verities of hemorrhage, and the unproven role of

plasmapheresis and its associated side effects and

cost, it is difcult to support its use uniformly.

Furthermore, the potential for plasmapheresis to

deplete immunoglobulins and clotting factors and

therefore potentially predispose patients to infection

and further hemorrhage require its prescription

and monitoring to be considered carefully. Further

evidence is required and may be available in the

near future with currently enrolling RCTs (eg,

ISRCTN07757494).

The guideline makes one recommendation and 2

suggestions regarding maintenance therapy. The sec-

ond suggestion bears comment because it is based

on relatively small numbers of patients in observa-

tional studies. Some caution must be taken thatdiagnosing extrarenal manifestations in dialysis-

dependent patients often is difcult. For example,

malaise, fevers, fatigue, or difcult-to-control hyper-

tension may be manifestations of either ESRD or

inadequately controlled vasculitis. The decision to

withdraw or reinstitute immunosuppression based on

extrarenal symptoms must be weighed against the

risk of infection and the potential benets of

immunosuppression.77

In general, we agree with these recommendations

and suggestions regarding choice of agent for main-

tenance therapy. However, the best studied starting

dose for azathioprine is 2 mg/kg to a maximum of

150 mg/d and reduced by 25 mg/d for patients

older than 60 years.78

Furthermore, despite suggesting

MMF over methotrexate, neither direct nor formal

indirect comparisons of the efcacy of methotrexate

compared to MMF exist. Given that one RCT

demonstrated that MMF is inferior to azathioprine and

another demonstrated similar results between azathi-

oprine and methotrexate, one might surmise that

methotrexate should be favored over MMF in patients

intolerant of azathioprine and with preserved renal

function.79,80

The guideline does not comment on glucocorti-coids. There are few data to guide the optimal use of

glucocorticoids in either initial or maintenance treat-

ment. Observational data suggest that discontinuation

of glucocorticoids within the rst 6-12 months may be

associated with an increased risk of relapse, butalso

may be associated with reduced adverse events.81,82

Note should be made that given the ubiquity and

heterogeneity of its use and its potential short- and

long-term consequences, optimal use of glucocorti-

coids should be a research priority.

The recommendation for treating resistant disease

merits 2 comments. First, resistant disease (ie, persis-tent or worsening disease activity despite adequate

immunosuppressive therapy) must be differentiated

from inadequately treated disease (which may be

amenable to optimized doses of initial therapy) and

manifestations of organ scarring (ie, damage from

vasculitis such as impaired GFR secondary to glomer-

ulosclerosis and brosis rather than ongoing necrosis)

or superimposed disease (eg, infections, prerenal

azotemia, or acute tubular necrosis). Only the rst

of these scenarios is likely to merit adjuvant therapy.

The second comment is regarding the recommenda-

tion for rituximab while suggesting intravenous


Am J Kidney Dis. 2014;63(3):363-377 373

7/24/2019 Pi is 0272638613015552

12/15

immunoglobulins (IVIgs) or plasma exchange. The role

of rituximab is based largely on small uncontrolled case

series with heterogeneous denitions of resistance.83

There is arguably better evidence for the addition

of IVIg. There also is evidence from uncontrolled

studies to support the use of agents such as deoxy-

spergualin or alemtuzumab for refractory cases.84,85

The recommendation to delay transplantation until

patients are free of extrarenal manifestations for 12

months deserves comment. This recommendation is

based on a single observational study that included

only 26 deaths in the analysis. However, there was no

association between timing of transplantation and

transplant outcomes. There is a signicant risk of

misestimating the association between duration of

remission and death given the limited sample size

and ability to adjust for important confounders in

this study design. Given the discrepancy in the rela-

tionship between death and transplant outcomes, the

uncertain causal mechanism underpinning the asso-

ciation, and the potential benets of not delaying

transplantation, further research is required to deter-

mine the relationship between clinical manifestations

of the disease and timing of transplantation.


The relative cost-effectiveness of rituximab is not

discussed, but in the Canadian health care system, the

cost of the drug and its coverage by regional programs

or insurance plans will be an important determinant of

its use. Cost also must be considered when MMF is

contemplated as a therapy. Reimbursement programsfor MMF are heterogeneous across the provinces and

across insurance programs. Mycophenolic acid may

be covered by in some provinces when MMF is not.

Extrapolating from the transplantation literature, there

is little suggestion that mycophenolic acid is inferior

to MMF and therefore may serve as a cost-effective

substitute. The use of adjuvant therapies such as

IVIg or plasmapheresis is expensive, but the cost is

borne by the health care/hospital system rather than

by the individual patient, and access to these therapies

also may be controlled by the hospital system.

Treatment of Anti-GBM GN14.1: Treatment of anti-GBM GN

14.1.1: We recommend initiating immunosuppression with

cyclophosphamide and corticosteroids plus plasma-

pheresis (see Table 31) in all patients with anti-GBM

GN except those who are dialysis-dependent at

presentation and have 100% crescents in an

adequate biopsy sample, and do not have pulmo-

nary hemorrhage. (1B)

Commentary

The recommendation to not initiate therapy in

patients who are dialysis dependent at presentation

and have 100% crescents merits discussion. This

recommendation is based on several small cohort

studies in which the natural history of anti-GBM

GN did not appear modied by aggressive therapy.

However, patients with anti-GBM GN often are

relatively young and therefore may be the most likely

to tolerate aggressive therapy and have the largestlong-term gains from even marginal preservation of

renal function. Although patients with advanced glo-

merulosclerosis and tubulointerstitial brosis seem

unlikely to recover, those with predominantly cellular

crescents have improved in other studies of immu-

nosuppression and plasma exchange.86

More data are

required to make rm recommendations, particularly

in the current era of improved availability of anti-

GBM diagnostic tests and physician awareness of

the disease, as well as increasing knowledge

regarding the safe use of immunosuppression.


Access to plasmapheresis is limited in Canada.

Given the probability that time to diagnosis is a major

determinant of both SCr level and the degree of glo-

merulosclerosis and tubulointerstitial brosis prior to

treatment (and therefore associated with the proba-

bility of effective treatment), patients with suspected

anti-GBM disease should have the time it will take to

access plasmapheresis factored into the expediency of

their diagnostic workup.

SUMMARY AND CONCLUSIONS

The KDIGO clinical practice guideline for GNrepresents an excellent summary of the current state

of knowledge regarding glomerular disease and as

such provides a useful framework for the practicing

physician seeking advice on management of these

often challenging patients. At the same time, the

guideline emphasizes the lack of concrete evidence

for many of the treatment and management decisions

that need to be made on a daily basis. This is not the

fault of the KDIGO review panel; rather, it serves to

emphasize how difcult it is to study relatively un-

common diseases for which the clinical course can

run a relapsing and remitting course over severaldecades before nally resulting in end-stage renal

failure.

For Canadian clinicians, the challenge will be

how to incorporate some of the management sug-

gestions into their everyday practice, given the

somewhat fragmented nature of our individual pro-

vincial health plans that leads to variable access,

particularly for newer agents or biologics, across the

country. Additionally, having an approved indication

for a medication does not always ensure ready access,

particularly for patients without a drug plan who

rely on access through provincial formularies. As an

Cybulsky et al

374 Am J Kidney Dis. 2014;63(3):363-377

7/24/2019 Pi is 0272638613015552

13/15

example, rituximab is approved for management of

ANCA vasculitis, but obtaining access to payment for

this drug in the public or private system can be

challenging.

The gaps in our knowledge regarding management

of GN are readily evident when reading the guideline.

What is less evident is how those knowledge gapscan be closed and in what time frame. Canadian

nephrologists will need to engage with colleagues

throughout the world in collaborative research ven-

tures if there is to be any hope of improving our state

of knowledge. In the past decade, considerable

progress has been made on understanding the mo-

lecular basis of some of the glomerular diseases that

are either more common or have a poorer prognosis.

These improvements of our understanding of the

pathogenesis of FSGS, membranous nephropathy,

and IgAN, as examples, should lead to therapies that

are more directed. It is hoped that future clinical trials

using targeted therapy might yield results more

rapidly and with a greater degree of precision.

ACKNOWLEDGEMENTS

Support:No nancial support was required for the developmentof this commentary.

Financial Disclosure: The authors declare that they have norelevantnancial interests.

REFERENCES

1. Kidney Disease: Improving Global Outcomes (KDIGO)

CKD-MBD Work Group. KDIGO Clinical Practice Guideline for

the Diagnosis, Evaluation, Prevention and Treatment of Chronic

Kidney Disease-Metabolic Bone Disorder (CKD-MBD). Kidney

Int Suppl. 2009;113:S1-S130.


Transplant Work Group. KDIGO Clinical Practice Guideline for

the Care of Renal Transplant Recipients. Am J Transplant.

2009;9(suppl 3):S1-S155.


Blood Pressure Work Group. KDIGO Clinical Practice Guideline

for the Management of Blood Pressure in Chronic Kidney Disease.

Kidney Int Suppl. 2012;2(5):337-414.


Acute Kidney Injury Work Group. KDIGO Clinical Practice

Guideline for Acute Kidney Injury.Kidney Int Suppl. 2012;2(1):1-

138.


Anemia Work Group. Clinical Practice Guideline for Anemia in

Chronic Kidney Disease. Kidney Int Suppl. 2012;2(4):279-335.

6. Kidney Disease: Improving Global Outcomes (KDIGO).

KDIGO Clinical Practice Guidelines for the Prevention, Diag-

nosis, Evaluation and Treatment of Hepatitis C in Chronic Kidney

Disease.Kidney Int Suppl. 2008;109:S1-S99.


Glomerulonephritis Work Group. KDIGO Clinical Practice

Guideline for Glomerulonephritis. Kidney Int Suppl. 2012;2(2):

139-274.

8. Samuel S, Bitzan M, Zappitelli M, et al. Canadian Society of

Nephrology Commentary on the 2012 KDIGO Clinical Practice

Guideline for Glomerulonephritis: management of nephrotic syn-

drome in children. Am J Kidney Dis. 2014;63(3):354-362.

9. Palmer SC, Nand K, Strippoli GF. Interventions for minimal

change disease in adults with nephrotic syndrome. Cochrane

Database Syst Rev. 2008;1:CD001537.

10. Cattran DC, Appel GB, Hebert LA, et al. A randomized

trial of cyclosporine in patients with steroid-resistant focal

segmental glomerulosclerosis. North America Nephrotic Syn-

drome Study Group. Kidney Int. 1999;56(6):2220-2226.

11. Gipson DS, Trachtman H, Kaskel FJ, et al. Clinical trial offocal segmental glomerulosclerosis in children and young adults.

Kidney Int. 2011;80(8):868-878.

12. McCarthy ET, Sharma M, Savin VJ. Circulating perme-

ability factors in idiopathic nephrotic syndrome and focal

segmental glomerulosclerosis. Clin J Am Soc Nephrol. 2010;5:

2115-2121.

13. Wei C, El Hindi S, Li J, et al. Circulating urokinase re-

ceptor as a cause of focal segmental glomerulosclerosis. Nat Med.

2011;17:952-960.

14. Ronco P, Debiec H. Pathogenesis of membranous

nephropathy: recent advances and future challenges. Nat Rev

Nephrol. 2012;8:203-213.

15. Cattran DC, Pei Y, Greenwood CM, Ponticelli C,

Passerini P, Honkanen E. Validation of a predictive model ofidiopathic membranous nephropathy: its clinical and research

implications. Kidney Int. 1997;51:901-907.

16. Polanco N, Gutierrez E, Covarsi A, et al; Grupo de Estudio

de las Enfermedades Glomerulares de la Sociedad Espanola de

Nefrologia (GLOSEN). Spontaneous remission of nephrotic syn-

drome in idiopathic membranous nephropathy. J Am Soc Nephrol.

2010;21:697-704.

17. McQuarrie EP, Stirling CM, Geddes CC. Idiopathic

membranous nephropathy and nephrotic syndrome: outcome in the

era of evidence-based therapy. Nephrol Dial Transplant. 2012;27:

235-242.

18. Howman A, Chapman TL, Langdon MM, et al. Immuno-

suppression for progressive membranous nephropathy: a UK

randomised controlled trial. Lancet. 2013;381(9868):744-751.

19. Sethi S, Fervenza FC. Membranoproliferative

glomerulonephritisa new look at an old entity. N Engl J Med.

2012;366:1119-1131.

20. Sethi S, Nester CM, Smith RJ. Membranoproliferative

glomerulonephritis and C3 glomerulopathy: resolving the confu-

sion. Kidney Int. 2012;81:434-441.

21. Appel GB, Cook HT, Hageman G, et al. Mem-

branoproliferative glomerulonephritis type II (dense deposit dis-

ease): an update. J Am Soc Nephrol. 2005;16:1392-1403.

22. Nasr SH, Satoskar A, Markowitz GS, et al. Proliferative

glomerulonephritis with monoclonal IgG deposits. J Am Soc

Nephrol. 2009;20:2055-2064.

23. Fakhouri F, Fremeaux-Bacchi V, Noel LH, Cook HT,

Pickering MC. C3 glomerulopathy: a new classication.Nat Rev

Nephrol. 2010;6:494-499.

24. Bomback AS, Smith RJ, Barile GR, et al. Eculizumab for

dense deposit disease and C3 glomerulonephritis. Clin J Am Soc

Nephrol. 2012;7:748-756.

25. Sherman M, Shafran S, Burak K, et al. Management of

chronic hepatitis B: consensus guidelines. Can J Gastroenterol.

2007;21(suppl C):5C-24C.

26. Ghany MG, Nelson DR, Strader DB, Thomas DL,

Seeff LB; American Association for Study of Liver Diseases. An

update on treatment of genotype 1 chronic hepatitis C virus

infection: 2011 practice guideline by the American Association for

the Study of Liver Diseases. Hepatology. 2011;54(4):1433-1444.

27. Ramachandran P, Fraser A, Agarwal K, et al. UK

consensus guidelines for the use of the protease inhibitors


Am J Kidney Dis. 2014;63(3):363-377 375
http://refhub.elsevier.com/S0272-6386(13)01555-2/sref1http://refhub.elsevier.com/S0272-6386(13)01555-2/sref1http://refhub.elsevier.com/S0272-6386(13)01555-2/sref1http://refhub.elsevier.com/S0272-6386(13)01555-2/sref1http://refhub.elsevier.com/S0272-6386(13)01555-2/sref1http://refhub.elsevier.com/S0272-6386(13)01555-2/sref1http://refhub.elsevier.com/S0272-6386(13)01555-2/sref1http://refhub.elsevier.com/S0272-6386(13)01555-2/sref2http://refhub.elsevier.com/S0272-6386(13)01555-2/sref2http://refhub.elsevier.com/S0272-6386(13)01555-2/sref2http://refhub.elsevier.com/S0272-6386(13)01555-2/sref2http://refhub.elsevier.com/S0272-6386(13)01555-2/sref2http://refhub.elsevier.com/S0272-6386(13)01555-2/sref2http://refhub.elsevier.com/S0272-6386(13)01555-2/sref3http://refhub.elsevier.com/S0272-6386(13)01555-2/sref3http://refhub.elsevier.com/S0272-6386(13)01555-2/sref3http://refhub.elsevier.com/S0272-6386(13)01555-2/sref3http://refhub.elsevier.com/S0272-6386(13)01555-2/sref3http://refhub.elsevier.com/S0272-6386(13)01555-2/sref4http://refhub.elsevier.com/S0272-6386(13)01555-2/sref4http://refhub.elsevier.com/S0272-6386(13)01555-2/sref4http://refhub.elsevier.com/S0272-6386(13)01555-2/sref4http://refhub.elsevier.com/S0272-6386(13)01555-2/sref4http://refhub.elsevier.com/S0272-6386(13)01555-2/sref4http://refhub.elsevier.com/S0272-6386(13)01555-2/sref5http://refhub.elsevier.com/S0272-6386(13)01555-2/sref5http://refhub.elsevier.com/S0272-6386(13)01555-2/sref5http://refhub.elsevier.com/S0272-6386(13)01555-2/sref5http://refhub.elsevier.com/S0272-6386(13)01555-2/sref5http://refhub.elsevier.com/S0272-6386(13)01555-2/sref6http://refhub.elsevier.com/S0272-6386(13)01555-2/sref6http://refhub.elsevier.com/S0272-6386(13)01555-2/sref6http://refhub.elsevier.com/S0272-6386(13)01555-2/sref6http://refhub.elsevier.com/S0272-6386(13)01555-2/sref6http://refhub.elsevier.com/S0272-6386(13)01555-2/sref6http://refhub.elsevier.com/S0272-6386(13)01555-2/sref7http://refhub.elsevier.com/S0272-6386(13)01555-2/sref7http://refhub.elsevier.com/S0272-6386(13)01555-2/sref7http://refhub.elsevier.com/S0272-6386(13)01555-2/sref7http://refhub.elsevier.com/S0272-6386(13)01555-2/sref7http://refhub.elsevier.com/S0272-6386(13)01555-2/sref7http://refhub.elsevier.com/S0272-6386(13)01555-2/sref8ahttp://refhub.elsevier.com/S0272-6386(13)01555-2/sref8ahttp://refhub.elsevier.com/S0272-6386(13)01555-2/sref8ahttp://refhub.elsevier.com/S0272-6386(13)01555-2/sref8ahttp://refhub.elsevier.com/S0272-6386(13)01555-2/sref8ahttp://refhub.elsevier.com/S0272-6386(13)01555-2/sref8ahttp://refhub.elsevier.com/S0272-6386(13)01555-2/sref8http://refhub.elsevier.com/S0272-6386(13)01555-2/sref8http://refhub.elsevier.com/S0272-6386(13)01555-2/sref8http://refhub.elsevier.com/S0272-6386(13)01555-2/sref8http://refhub.elsevier.com/S0272-6386(13)01555-2/sref8http://refhub.elsevier.com/S0272-6386(13)01555-2/sref9http://refhub.elsevier.com/S0272-6386(13)01555-2/sref9http://refhub.elsevier.com/S0272-6386(13)01555-2/sref9http://refhub.elsevier.com/S0272-6386(13)01555-2/sref9http://refhub.elsevier.com/S0272-6386(13)01555-2/sref9http://refhub.elsevier.com/S0272-6386(13)01555-2/sref9http://refhub.elsevier.com/S0272-6386(13)01555-2/sref10http://refhub.elsevier.com/S0272-6386(13)01555-2/sref10http://refhub.elsevier.com/S0272-6386(13)01555-2/sref10http://refhub.elsevier.com/S0272-6386(13)01555-2/sref10http://refhub.elsevier.com/S0272-6386(13)01555-2/sref11http://refhub.elsevier.com/S0272-6386(13)01555-2/sref11http://refhub.elsevier.com/S0272-6386(13)01555-2/sref11http://refhub.elsevier.com/S0272-6386(13)01555-2/sref11http://refhub.elsevier.com/S0272-6386(13)01555-2/sref11http://refhub.elsevier.com/S0272-6386(13)01555-2/sref11http://refhub.elsevier.com/S0272-6386(13)01555-2/sref12http://refhub.elsevier.com/S0272-6386(13)01555-2/sref12http://refhub.elsevier.com/S0272-6386(13)01555-2/sref12http://refhub.elsevier.com/S0272-6386(13)01555-2/sref12http://refhub.elsevier.com/S0272-6386(13)01555-2/sref12http://refhub.elsevier.com/S0272-6386(13)01555-2/sref13http://refhub.elsevier.com/S0272-6386(13)01555-2/sref13http://refhub.elsevier.com/S0272-6386(13)01555-2/sref13http://refhub.elsevier.com/S0272-6386(13)01555-2/sref13http://refhub.elsevier.com/S0272-6386(13)01555-2/sref13http://refhub.elsevier.com/S0272-6386(13)01555-2/sref14http://refhub.elsevier.com/S0272-6386(13)01555-2/sref14http://refhub.elsevier.com/S0272-6386(13)01555-2/sref14http://refhub.elsevier.com/S0272-6386(13)01555-2/sref14http://refhub.elsevier.com/S0272-6386(13)01555-2/sref14http://refhub.elsevier.com/S0272-6386(13)01555-2/sref14http://refhub.elsevier.com/S0272-6386(13)01555-2/sref15http://refhub.elsevier.com/S0272-6386(13)01555-2/sref15http://refhub.elsevier.com/S0272-6386(13)01555-2/sref15http://refhub.elsevier.com/S0272-6386(13)01555-2/sref15http://refhub.elsevier.com/S0272-6386(13)01555-2/sref15http://refhub.elsevier.com/S0272-6386(13)01555-2/sref15http://refhub.elsevier.com/S0272-6386(13)01555-2/sref15http://refhub.elsevier.com/S0272-6386(13)01555-2/sref16http://refhub.elsevier.com/S0272-6386(13)01555-2/sref16http://refhub.elsevier.com/S0272-6386(13)01555-2/sref16http://refhub.elsevier.com/S0272-6386(13)01555-2/sref16http://refhub.elsevier.com/S0272-6386(13)01555-2/sref16http://refhub.elsevier.com/S0272-6386(13)01555-2/sref16http://refhub.elsevier.com/S0272-6386(13)01555-2/sref17http://refhub.elsevier.com/S0272-6386(13)01555-2/sref17http://refhub.elsevier.com/S0272-6386(13)01555-2/sref17http://refhub.elsevier.com/S0272-6386(13)01555-2/sref17http://refhub.elsevier.com/S0272-6386(13)01555-2/sref17http://refhub.elsevier.com/S0272-6386(13)01555-2/sref18http://refhub.elsevier.com/S0272-6386(13)01555-2/sref18http://refhub.elsevier.com/S0272-6386(13)01555-2/sref18http://refhub.elsevier.com/S0272-6386(13)01555-2/sref18http://refhub.elsevier.com/S0272-6386(13)01555-2/sref18http://refhub.elsevier.com/S0272-6386(13)01555-2/sref18http://refhub.elsevier.com/S0272-6386(13)01555-2/sref18http://refhub.elsevier.com/S0272-6386(13)01555-2/sref19http://refhub.elsevier.com/S0272-6386(13)01555-2/sref19http://refhub.elsevier.com/S0272-6386(13)01555-2/sref19http://refhub.elsevier.com/S0272-6386(13)01555-2/sref19http://refhub.elsevier.com/S0272-6386(13)01555-2/sref19http://refhub.elsevier.com/S0272-6386(13)01555-2/sref20http://refhub.elsevier.com/S0272-6386(13)01555-2/sref20http://refhub.elsevier.com/S0272-6386(13)01555-2/sref20http://refhub.elsevier.com/S0272-6386(13)01555-2/sref20http://refhub.elsevier.com/S0272-6386(13)01555-2/sref20http://refhub.elsevier.com/S0272-6386(13)01555-2/sref21http://refhub.elsevier.com/S0272-6386(13)01555-2/sref21http://refhub.elsevier.com/S0272-6386(13)01555-2/sref21http://refhub.elsevier.com/S0272-6386(13)01555-2/sref21http://refhub.elsevier.com/S0272-6386(13)01555-2/sref21http://refhub.elsevier.com/S0272-6386(13)01555-2/sref22http://refhub.elsevier.com/S0272-6386(13)01555-2/sref22http://refhub.elsevier.com/S0272-6386(13)01555-2/sref22http://refhub.elsevier.com/S0272-6386(13)01555-2/sref22http://refhub.elsevier.com/S0272-6386(13)01555-2/sref22http://refhub.elsevier.com/S0272-6386(13)01555-2/sref22http://refhub.elsevier.com/S0272-6386(13)01555-2/sref22http://refhub.elsevier.com/S0272-6386(13)01555-2/sref23http://refhub.elsevier.com/S0272-6386(13)01555-2/sref23http://refhub.elsevier.com/S0272-6386(13)01555-2/sref23http://refhub.elsevier.com/S0272-6386(13)01555-2/sref23http://refhub.elsevier.com/S0272-6386(13)01555-2/sref23http://refhub.elsevier.com/S0272-6386(13)01555-2/sref24http://refhub.elsevier.com/S0272-6386(13)01555-2/sref24http://refhub.elsevier.com/S0272-6386(13)01555-2/sref24http://refhub.elsevier.com/S0272-6386(13)01555-2/sref24http://refhub.elsevier.com/S0272-6386(13)01555-2/sref24http://refhub.elsevier.com/S0272-6386(13)01555-2/sref25http://refhub.elsevier.com/S0272-6386(13)01555-2/sref25http://refhub.elsevier.com/S0272-6386(13)01555-2/sref25http://refhub.elsevier.com/S0272-6386(13)01555-2/sref25http://refhub.elsevier.com/S0272-6386(13)01555-2/sref25http://refhub.elsevier.com/S0272-6386(13)01555-2/sref25http://refhub.elsevier.com/S0272-6386(13)01555-2/sref25http://refhub.elsevier.com/S0272-6386(13)01555-2/sref26http://refhub.elsevier.com/S0272-6386(13)01555-2/sref26http://refhub.elsevier.com/S0272-6386(13)01555-2/sref26http://refhub.elsevier.com/S0272-6386(13)01555-2/sref26http://refhub.elsevier.com/S0272-6386(13)01555-2/sref25http://refhub.elsevier.com/S0272-6386(13)01555-2/sref25http://refhub.elsevier.com/S0272-6386(13)01555-2/sref25http://refhub.elsevier.com/S0272-6386(13)01555-2/sref25http://refhub.elsevier.com/S0272-6386(13)01555-2/sref25http://refhub.elsevier.com/S0272-6386(13)01555-2/sref24http://refhub.elsevier.com/S0272-6386(13)01555-2/sref24http://refhub.elsevier.com/S0272-6386(13)01555-2/sref24http://refhub.elsevier.com/S0272-6386(13)01555-2/sref23http://refhub.elsevier.com/S0272-6386(13)01555-2/sref23http://refhub.elsevier.com/S0272-6386(13)01555-2/sref23http://refhub.elsevier.com/S0272-6386(13)01555-2/sref22http://refhub.elsevier.com/S0272-6386(13)01555-2/sref22http://refhub.elsevier.com/S0272-6386(13)01555-2/sref22http://refhub.elsevier.com/S0272-6386(13)01555-2/sref21h

Date post:	21-Feb-2018
Category:	Documents
Upload:	jhohan-miguel-huaman-florian
View:	220 times
Download:	0 times

Pi is 0272638613015552

Documents