Treatment of Idiopathic Membranous Nephropathylouisville.edu/medicine/departments/medicine/divisions/nephrology/... · podocytes.1 Compelling work from Beck et al. suggests that the

BRIEF REVIEW www.jasn.org

Treatment of Idiopathic Membranous Nephropathy

Meryl Waldman and Howard A. Austin III

Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,Bethesda, Maryland

ABSTRACTExciting progress recently has been made in our understanding of idiopathicmembranous nephropathy, as well as treatment of this disease. Here, we reviewimportant advances regarding the pathogenesis of membranous nephropathy. Wewill also review the current approach to treatment and its limitations and willhighlight new therapies that are currently being explored for this disease includingRituximab, mycophenolate mofetil, and adrenocorticotropic hormone, with anemphasis on results of the most recent clinical trials.

J Am Soc Nephrol 23: 1617–1630, 2012. doi: 10.1681/ASN.2012010058

This is an especially exciting time in thehistory of idiopathic membranous ne-phropathy (IMN). Our understandingof its natural history and pathogeneticmechanisms has been slowly evolvingover several decades but has recentlygained more momentum. This, in con-junction with data from recent clinicaltrials, makes it an ideal time to revisitour approach to patients with IMN.

The recent identification of the M-type phospholipase A2 receptor (PLA2R)as the first major human antigenic targetin adult onset IMN represents a majormilestone in understanding of the path-ogenesis of this disease. In 2009, Becket al. reported that the majority of IMNpatients (70%) have circulating antibod-ies against PLA2R, a cell surface transmem-brane receptor expressed on the surface ofpodocytes.1 Compelling work from Becket al. suggests that the subepithelium-likedeposits, characteristic of IMN, areformed from in situ binding of circulat-ing anti-PLA2R autoantibodies to thePLA2R antigen. From a historical perspec-tive, the findings of Beck et al. come 50years after Heymann et al. first describedan experimental model of membranousdisease known as Heymann nephritis by

injecting rats with an antigenic prepara-tion of kidney extracts.2 Elegant workover several decades on this now wellestablished rat model shed light on theimmune events and molecular basis forpodocyte injury in membranous lesionsand generated hypotheses regarding theirrelevance in human disease.3–9 Indeed,the findings of Beck et al. are in agree-ment with a critical prediction of theHeymann model that circulating auto-antibodies directed against a podocytemoiety cause IMN.

The precise biologic function ofPLA2R in the kidney and the effect ofanti-PLA2R on podocytes are still un-known.10 However, the existing body ofevidence supports the following impor-tant concepts: autoantibodies reactive toPLA2R are both sensitive and specific forthe disease,11,12 autoantibodies seem todiscriminate between primary and sec-ondary forms of membranous disease,1

and there seems to be a relationship (inmost, but not all patients) between thetiter of circulating anti-PLA2R and clinicaldisease activity defined by proteinuria.13,14

Moreover, changes in titers of anti-PLA2Rantibody precede corresponding changesin proteinuria.13,14 These observations

strengthen the relevance of this antigen-autoantibody pair in IMN. However, it isimportant to note that causation has yetto be definitively proven.15

Additional podocyte autoantigens in-cluding SOD2,16 aldose reductase,16

a-enolase,17 and neutral endopeptidase18

are also implicated as targets for specificautoantibodies in some IMN patients.Antibodies to these targets may be rele-vant in patients who are negative forPLA2R antibody. Unlike the anti-PLA2Rantibody, correlation of antibody titersfor these antigens with disease activityhas not been reported to date.

What incites the immune responseand triggers the development of theseand other autoantibodies remain a mys-tery.19 Genetics may play a role. Resultsof a recent genome-wide associationstudy in a large European cohort suggestthat sequence variants within HLA-DQA1 and PLA2R1 alleles might conferan increased risk of membranous ne-phropathy in some populations.20

We have only touched the tip of theiceberg, and there is still somuch to learn.Nevertheless, what has been uncoveredthus far is certainly provocative and willadvance our approach to diagnosis, mon-itoring, and treatment of patients with

Published online ahead of print. Publication dateavailable at www.jasn.org.

Correspondence:Dr.Meryl Waldman, Kidney DiseaseSection, National Institute of Diabetes and Digestiveand Kidney Diseases, National Institutes of Health, 10Center Drive, CRC 5-5750, Bethesda, MD 20892.Email: [email protected]

Copyright © 2012 by the American Society ofNephrology

J Am Soc Nephrol 23: 1617–1630, 2012 ISSN : 1046-6673/2310-1617 1617

http://www.jasn.org

mailto:[email protected]

thisdisease in thenear future.Applicationof new technology is allowing for a muchfaster transition of these bench-side find-ings to the bedside, and progress hasalreadybeenmade indeveloping standard-ized immunoassays for anti-PLA2R foruse in clinical practice. One can envisionhow integrating information obtainedfrom genetic testing and antigen-antibodyprofiling might potentially be appliedfor individual patient management andin future clinical trials in that it may helpto better classify subsets of patients withdifferent prognoses or to predict re-sponse to treatment. Measurement ofcirculating anti-PLA2R and other anti-bodies may be used in conjunctionwith proteinuria to better assess diseaseactivity and provide a more informativedefinition of clinical remission. Such in-formation might provide insight as towhether persistent proteinuria in pa-tients is related to ongoing immunologicactivity, amenable to more immunosup-pression, or due to fixed structural dam-age to glomeruli or tubulointerstitium.Future clinical trials might use such in-formation to identify and enroll a morehomogenous population of patients athigher risk of disease progression whowould most benefit from immunosup-pression. In addition, comparison of effi-cacy of immunosuppressive agents intrials might involve evaluation of theireffect on immune activity, including thetiming and kinetics of autoantibodyclearance from the circulation.

NATURAL HISTORY OF IMN

As we move forward in our understand-ing of the pathogenesis of disease inIMN, two recent studies re-examinemorebasic concepts regarding the natural his-tory of IMN.21,22 These concepts werelargely derived from studies performed2–3 decades ago, when antiproteinuricstrategies and other supportive measureswere implemented inconsistently.23–26

Moreover, some of the older studies in-cluded patients with non-nephrotic–rangeproteinuria, a group with an invariablygood prognosis.25,27 In contrast, these con-temporary studies include only nephrotic

patients, make greater use of antiprotein-uric strategies, and serve as importantreferences to inform management deci-sions in these patients.

An impressive multicenter studyfrom the Spanish Group for the Studyof Glomerular Disease (GLOSEN) exam-ined the course of a large number ofnephrotic IMN patients (n=328) whowere diagnosed between 1975 and 2007and followed for an extended periodof time (approximately 6 years).21 Im-portantly, because of the possibility ofspontaneous remission, all patients wereinitially managed conservatively; immu-nosuppressive therapy was withheld untilcomplications arose or deterioration of re-nal function was evident, an approach thatprovides greater insight into the naturalevolution of this disease. Approximatelytwo-thirds of patients received angiotensin-converting enzyme (ACE) inhibitors orangiotensin receptor blockers (ARBs).Almost 32%ofpatients experienceda spon-taneous remission, most of which occurredwithin the first 2 years of diagnosis, compa-rable with several other studies.23,24,26,28

Two features regarding spontaneousremissions in the Spanish study21 deserveconsideration. First, among patients des-tined to experience a spontaneous re-mission, proteinuria tended to declinegradually. Moreover, a decrease in protein-uria during the first year of follow-up.50% of baseline (even if still nephrotic)significantly predicted spontaneous remis-sion. Second, spontaneous remissionswereobserved among some high-risk patients,including approximately 25% of thosewith severe proteinuria (.8 g/24 h) aswell as a number of patients with CKD,29

another subset considered unlikely toundergo spontaneous remission. Conse-quently, careful observation of somehigh-risk patients may be appropriatebefore starting immunosuppressive ther-apy, particularly if they are not experi-encing complications of the nephroticsyndrome or declining renal functionand if they are manifesting a gradual de-cline in proteinuria.

Concordant with previous reports,30

the long-term outcome and renal survivalof those with spontaneous remission(either complete or partial) is excellent,

with a 0% risk of ESRDand a 2%mortalityrate.21 In contrast, outcomes in patientswho have persistence of nephrotic-rangeproteinuria are less favorable, with a 11%mortality rate and a 19% risk of ESRD.

A second contemporary natural his-tory study from the United Kingdom byMcQuarrie et al. analyzed patients diag-nosed between 1997 and 2008.22 Almostall patients were treated with ACE inhib-itors and/or ARBs. Consistent with theabove data and previous reports,30 thisstudy showed that achieving any remis-sion (spontaneous or treatment-induced)independently associated with a reducedrisk of requiring renal replacement ther-apy (hazard ratio, 0.02; 95% confidenceinterval, 0.0–0.2; P=0.001) and reducedrisk of death (hazard ratio, 0.07; 95%confidence interval, 0.02–0.3; P=0.001).

Although these contemporary retro-spective analyses do have greater imple-mentation of ACE inhibitors or ARBs,they were not designed to formally eval-uate whether these drugs have significantbenefit on renal prognosis or reduction ofproteinuria in IMN. Some investigatorsnote that responsiveness to these agents isless impressive in IMN compared withother typesof glomerulardisorders,whichhas raised questions about their role in thisdisorder.31–33 In the GLOSEN study, theprobability of spontaneous remissionwas higher in patients taking ACE inhib-itors or ARBs than those not receivingthese agents (P=0.009).21 In the study byMcQuarrie et al. in which there was wide-spread use of ACE inhibitors/ARBs, the5-year actuarial rate for spontaneous par-tial remission was remarkably high at70%.22 These data hint, but do not prove,that ACE inhibitors and ARBs have favor-able effects on the disease. In contrast,other studies failed to demonstrate aneffect of ACE inhibitors on renal out-come in IMN.30,32,34,35 This issue can-not be definitively answered without acontrolled trial. For now, given that treat-ment with ACE inhibitors and ARBs hasproven benefits in other kidney diseasesand may result in some improvementin proteinuria, hypoalbuminemia, andhyperlipidemia, these agents should re-main as part of standard conservativetreatment for IMN.36–38

1618 Journal of the American Society of Nephrology J Am Soc Nephrol 23: 1617–1630, 2012


IMMUNOSUPPRESSION

Immunosuppressive therapies that havereceived the most attention for IMN in-clude alkylating agents such as cyclophos-phamide and chlorambucil, calcineurininhibitors (CNIs) such as cyclosporineand tacrolimus, mycophenolate mofetil(MMF), rituximab, and adrenocortico-tropic hormone (ACTH). Table 1 showsthe commonly used regimens, althoughmany variations exist. There is a lack ofwell powered, randomized, controlledtrials that formally compare therapies.The quality of the existing evidence forthese different regimens in IMN is vari-able. Comparisons among studies arehampered by differences in the risk pro-files28 of the patients and variable dura-tion of follow-up, among other factors.

Alkylating AgentsTable 2 depicts results of several studiesexamining the efficacy of two very dif-ferent approaches to cytotoxic drugtherapy for IMN. Ponticelli et al. andJha et al. used a 6-month regimen con-sisting of daily oral chlorambucil or cy-clophosphamide, alternating monthlywith corticosteroids.39–41 Their patients

had nephrotic-range proteinuria andnormal or near normal renal function.Conversely, investigators from the Neth-erlands have described outcomes of anextended course, typically 12 months(Table 1), of daily oral cyclophosphamideand corticosteroids in patients with ne-phrotic syndrome and deteriorating re-nal function.34,42

Both Ponticelli et al. and Jha et al.found that alternating monthly cycles ofcorticosteroids and an alkylating agentwere more effective than supportive ther-apy alone for inducing remissions of pro-teinuria and preserving renal function.40,41

Ponticelli et al. found that substitution ofcyclophosphamide for chlorambucil pro-vides similar efficacy with an improvedadverse event profile.43

Jha et al. permitted crossover to theimmunosuppressive treatment arm 24months after randomization to supportivetreatment.41 It is notable that remissionrates were lower among patients whoswitched to immunosuppression as rescuetherapy (47%) than among thosewhowereinitially randomized to immunosuppres-sion (72%), suggesting that delay in immu-nosuppressive therapy until evidence ofdisease progression diminishes efficacy.

Studies reported by du Buf-Vereijkenet al. and Hofstra et al. from the Nether-lands provide additional insights intothe effect of delaying cytotoxic drugtherapy for IMN until there is evidenceof renal function deterioration.34,42,44

These investigators favor this restrictivetreatment policy because it identifies pa-tients at highest risk of progression andavoids unnecessary immunosuppressionin patients with a more favorable prog-nosis. A beneficial effect of this approachin attenuating deterioration of renalfunctionwas shown in the case-controlledstudy of high-risk IMN patients reportedby du Buf-Vereijken et al.34 Renal out-comes of 65 patients treated for 1 yearwith oral cytoxan and steroids were com-pared with 24 historical matched controlpatients. Control patients received eitherno immunosuppression or treatmentsthat have subsequently proven to be inef-fective (prednisone monotherapy, intrave-nous cyclophosphamide, or both). Patientshad an impaired GFR at baseline (me-dian creatinine clearance of 42 ml/minper 1.73 m2) and high-grade proteinuria.Remission of proteinuria was achievedin 86% of 65 patients receiving immuno-suppressive therapy (Table 2). At 5 years, a

Table 1. Immunosuppressive regimens that have been used in treatment of IMN

ImmunosuppressionAgent

Regimen

Alkylating agents Italian Ponticelli protocolMonths 1, 3, and 5: 1 g/d intravenous methylprednisolone for 3 consecutive d, followed by oral prednisolone0.4 mg/kg daily or oral prednisone 0.5 mg/kg daily for 27 dMonths 2, 4, and 6: 0.2 mg/kg oral chlorambucil daily for 30 d

Modified Ponticelli protocolMonths 1, 3, and 5: 1 g/d intravenous methylprednisolone for 3 consecutive d, followed by oral prednisone0.5 mg/kg daily for 27 d

Months 2, 4, and 6: 2–2.5 mg/kg oral cyclophosphamide daily for 30 dDutch protocol34

1.5–2 mg/kg oral cyclophosphamide daily for 12 mo plus 0.5 mg/kg oral prednisone daily or every other day for6 months and then tapered, plus 1 g/d intravenous methylprednisolone for 3 consecutive days for months 1, 3, and 5

Cyclosporine,tacrolimus

3.5mg/kg cyclosporine daily, achieving levels of 125–200mg/L for aminimumof 6–12mo, then tapered to lowest possiblemaintenance dose (6 low-dose corticosteroids)

0.05 mg/kg tacrolimus daily achieving levels 7–9 for 6–12 mo, then tapered to lowest possible maintenance dose(6 low-dose corticosteroids)

MMF 2 g/d MMF for 1 yr 6 low-dose corticosteroidsRituximab 375 mg/m2 weekly for four doses

1 g on days 1 and 15375-mg/m2 single doses, titrated to the number of circulating B cells

ACTH 1 mg tetracosactrin injected intramuscularly twice weekly for 6–12 mo80 U corticotropin injected intramuscularly twice weekly for 6–12 mo

J Am Soc Nephrol 23: 1617–1630, 2012 Membranous Nephropathy 1619

www.jasn.org BRIEF REVIEW

Table

2.Se

lected

stud

iesof

alky

lating

agen

tsin

patientswithIM

N

Stud

yN

Treatment

Reg

imen

Follo

w-U

pInitialR

emissionRate

Relap

seRate

(Tim

ing)

Effec

tonRen

alSu

rvival

CR

PR

Total

Ponticellietal.(198

9an

d19

95)39,40

42Mon

ths1,

3,an

d5:

steroidsa;

mon

ths2,

4,an

d6:

0.2

mg/kgch

lorambuc

ildaily

Upto

10yr

57(24/42

)24

(10/42

)81

24(8/34)

Dialysis-free

10-yrs

urviva

l:92

39Noim

mun

osup

pression

18(7/39)

15(6/39)

3331

(4/13)

Dialysis-free

10-yrs

urviva

l:60

Ponticellietal.(199

8)43

44Mo1,

3,an

d5:

steroidsb;

mon

ths2,

4,an

d6:

0.2

mg/kgch

lorambuc

ildaily

Med

ian3yr

27(12/44

)55

(24/44

)82

31(11/36

)(betwee

n6

and30

mo)

1patient

(2%)rea

ched

ESRD

after4

2mo

43Mo1,

3,an

d5:

steroidsb;

mon

ths2,

4,an

d6:

2.5mg/kg

cyclop

hosp

hamidedaily

Med

ian3.5yr

37(16/43

)56

(24/43

)93

25(10/40

)(betwee

n6

and24

mo)

2patients(4%)rea

ched

ESRD

after3

6mo

Jhaetal.(200

7)41

47Mo1,

3,an

d5:

steroidsc;

mon

ths2,

4,an

d6:

2mg/kg

cyclop

hosp

hamidedaily

Med

ian11

yr32

(15/47

)40

(19/47

)72

24(8/34)

10-yrd

ialysis-

free

survival:8

9

46Noim

mun

osup

pression

Med

ian11

yr11

(5/46)

24(11/46

)35

25(4/16)

10-yrd

ialysis-free

survival:6

5duBuf-Vereijken

(200

4)34(not

rand

omized

;match

edhistorical

comparison

)

651.5–

2mg/kgoral

cyclop

hosp

hamidedaily

for

12moplussteroidsd

Med

ian4.3yr

26(17/65

)60

(39/65

)86

20(11/56

)5-yr

dialysis-

free

survival:8

6

24Notrea

tmen

tor

vario

usim

mun

osup

pressiveag

ents

subseque

ntlyco

nsidered

ineffective

NA

NA

NA

NA

5-yr

dialysis-free

survival:3

2

Hofstra

etal.(201

0)42

14Ea

rlystart.1

.5mg/kgoral

cyclop

hosp

hamidedaily

for1

2moplussteroidsc

Mea

n6yr

64(9/14)

29(4/14)

9323

(3/13)

(med

ian

36moafter

trea

tmen

t)

1patient

(7%)rea

ched

ESRD

12La

testart.1.5mg/kgoral

cyclop

hosp

hamidedaily

for1

2moplussteroidsc

Mea

n6yr

67e(8/12)

25(3/12)

9227

%(3/11)

(med

ian38

mo

aftertreatmen

t)

0patientsreac

hedES

RD

Dataareex

pressed

inperce

ntag

esun

less

othe

rwiseindicated

.CR,

complete

remission

;PR,

partia

lrem

ission

;NA,d

atano

tavailable.

a Dosages

atmonths

1,3,

and5:

1gintraven

ousmethy

lprednisolone

dailyfor3

days,follo

wed

by0.4mg/kgoral

prednisolone

dailyor

0.5mg/kgprednisone

dailyfor2

7d.D

osageat

mo2,

4,6:

0.2mg/kg

chlorambuc

ildaily.

bDos

ages

atmon

ths1,

3,an

d5:

1gintrav

enous

methy

lpredniso

lone

dailyfor3day

s,follo

wed

by0.4mg/kgoral

prednisolone

dailyfor2

7d.

c Dosages

atmon

ths1,

3,an

d5:

1gintraven

ousmethy

lprednisolone

dailyfor3

day

s,follo

wed

by0.5mg/kgoral

prednisolone

(orp

rednisone

)daily.

dDos

ages

atmon

ths1,

3,an

d5:

1gintrav

enous

methy

lpredniso

lone

dailyfor3day

s,follo

wed

by0.5mg/kgoral

prednisone

everyothe

rday

for6

moan

dthen

tapered

.eInclud

esfour

spontan

eous

remissions

that

occu

rred

duringtheob

servationperiod.



renal survival advantage was evident incytoxan-treated patients compared withcontrols (86%versus 32%;P,0.001). Therenal survival of these cytoxan-treatedpatients at 7 years was 74%, which issomewhat lower than the 10-year renalsurvival of patients with normal baselinerenal function treated with a cytotoxicdrug regimen by Ponticelli et al.40 (92%).

Hofstra et al. recently reported the re-sults of a small but well designed studycomparing early versus late initiation ofimmunosuppressive treatment.42 Patientswere randomized to receive oral cyclo-phosphamide for 12 months plus corti-costeroids early after diagnosis (n=14) orlater if renal function deteriorated(n=12), defined as an increase of serumcreatinine $25% reaching a level of$135 umol/L or an increase of serumcreatinine $50%. In the late treatmentarm, 67% of patients ultimately met cri-teria for immunosuppression after a me-dian of 14 months from randomization.Overall cumulative incidence of remis-sion was similar in both the early andlate treatment arms (93% versus 92%, re-spectively) but earlier treatment resultedin more rapid onset of remission. Relapserates were similar. At final follow-up(mean 72 months), there were no differ-ences in clinical status, proteinuria, orrenal function in either group, with thelatter observation indicating that immu-nosuppressive treatment led to an im-provement in renal function in the latetreatment arm (because those patientsstarted out with a lower average GFR).The good overall outcomes do provide re-assurance that delaying therapy is justifiedin some patients. By delaying treatment,33% of patients avoided unnecessary ex-posure to immunosuppression. How-ever, delayed treatment was associatedwith more frequent and severe side ef-fects and more hospitalizations. An indi-vidualized approach that considers age,pre-existing comorbidities, and risk oftreatment versus risk of complicationsof the nephrotic syndrome is criticalwhen deciding on therapy.

Despite the favorable results with alky-lating agents, there is reluctance toprescribethem due to the short-term and potentiallong-term adverse effects. Short-term

effects include myelosuppression, espe-cially leucopenia infections, hemorrhagiccystitis, and gastrointestinal problems suchas peptic ulcers, nausea, anorexia, and liverdysfunction. Risk of infertility remains aconcern for patients in childbearing years.Cancer risk remains a long-term worry,particularly since the cumulative dosageof cyclophosphamide increases if repeatcourses are needed after relapse. ThePonticelli regimen entails 3 months ofcyclophosphamide (2mg/kg daily), whichis a cumulative dose of approximately 13 gin a 70-kg patient. The 12-month regi-men34 (using 1.5mg/kg daily) represents acumulative dose of approximately 40 gin a 70-kg patient. Several studies havereported threshold values for cumulativedoses of cyclophosphamide, above whichis associated with increased risk of malig-nancies such as bladder cancer, skin cancer,and lymphoproliferative disorders. Olderstudies report an increased risk of malig-nancy with cumulative doses .50 g,45,46

whereas more recent studies suggest thatexposure to lower cumulative dosagesmay also pose an increased risk.47

CNIsCyclosporine is an established option fortreatment of IMN patients at moderateor high risk of disease progression.48

Tacrolimus, another CNI, is an alterna-tive.49,50 Cumulative data indicate thatCNIs are effective in inducing a remissionof proteinuria in up to 80% of patients(Table 3).49–52 CNIs show favorable re-sponses in patients who have been unre-sponsive to other immunosuppressants,including alkylating agents.51–54 In a recentrandomized controlled trial in which allpatients had previously failed the Ponticelliprotocol, treatment with cyclosporine for2 years (plus low-dose prednisone) led toremissions in 80% of patients and stabi-lization of renal function.52

The antiproteinuric effect of CNIs istypically evident early. Generally, if someresponse in proteinuria is not present by3months (provided adequate drug levelsare achieved), it is unlikely that a signif-icant response will occur later. However,time to maximum reduction of protein-uria takes longer. Although optimal dura-tion of therapy has not been established,

extended therapy for at least a year isrecommended for patients who show aninitial response to theseagents,because thenumber of remissions and proportion ofcomplete remissions increases with dura-tion of treatment.53

The majority of complete remissionswith CNIs occur after at least 6 monthsof therapy and the number increases astreatment continues for .12 months.This concept is supported by severalstudies.49,52,53,55 A prospective study byNaumovic et al. recently showed that aprolonged course of cyclosporine for 24months led to a steady increase in cumu-lative remission rates from 50% at 6months to 80% by 18 months, and com-plete remissions increased from 0 at 6months to 40% by 18 months.52 Meantime to partial remission was 9.7 months(range, 3–18 months), and mean timeto complete remission was 15 months(range, 9–18 months). These outcomesare consistent with the results of earlierstudies reported by Cattran et al.51 andPraga et al.49 (Table 3). Cattran et al.found that a 6-month course of cyclo-sporine led to complete remissions inonly 7% of his patients,51 whereas Pragaet al. observed complete remissionsin 32% of patients after 18 months oftacrolimus treatment.49

Relapse upon drug withdrawal is a wellrecognized problem with CNIs, occurringin 13% to almost 50% of patients within1 year of drugwithdrawal.49 In the above-mentioned study by Praga et al., 47% ofpatients randomized to tacrolimus re-lapsedwithin an average of 4months afterdiscontinuation of therapy such that byfinal follow-up, the number of remis-sions in the tacrolimus arm was notmarkedly different from the placeboarm.49 These data provide additionaljustification for long-term treatment.Maintenance therapy with low-dose cy-closporine (1.4–1.5 mg/kg daily; troughlevels .100 ng/ml), possibly in con-junction with low-dose steroids (0.1mg/kg daily), may help to reduce thelikelihood of relapses55; however, thispractice has not been formally tested inrandomized controlled trials.

The role of CNIs in attenuating a de-cline in renal function and the long-term



Table

3.Se

lected

rand

omized

controlle

dtrials

ofCNIs

inpatientswithIM

Nan

dev

olutionof

remission

sov

ertime

Stud

yn

Trea

tmen

t(TotalD

uration)

Follo

w-U

p(m

o)

Rem

issions

Relap

seRate(n)

[Tim

eto

Relap

se]

6mo

12mo

24mo

CR

PR

Total

CR

PR

Total

CR

PR

Total

Cattran

etal.

(200

1)51

283.5mg/kgcyclosporinedaily

(26wk);target

trou

gh12

5–22

5mg/m

lfor

26wk,

then

tapered

for4

wkplus0.15

mg/kg

predniso

nedaily

Upto

197(2/28)

68(19/28

)75

7(2/28)

39(11/28

)46

7(2/28)

a32

(9/28)

a39

a48

(10/21

)[with

in12

moof

drug

cessation]

23Plac

eboplus0.15

mg/kg

predniso

nedaily

4(1/23)

17(4/23)

214(1/23)

9(2/23)

134(1/23)

9(2/23)

1340

(2/5)

Nau

mov

iceta

l.(201

1)52

103mg/kgcyclosporinedaily

for

6mo,

then

adjusted

toachiev

etroug

hleve

lsof

80–10

0ng

/ml(24

mo)

plus

0.5mg/kgpredniso

nedaily

for8

wk,

then

tapered

360

50(5/10)

5010

(1/10)

40(4/10)

5040

(4/10)

40(4/10)

8013

(1/8)[with

in12

moof

drug

cessation]

131.5–

2mg/kgazathiop

rinedailyfor

6mo,

then

50mgdaily(24mo)

plus0.5mg/kgprednisone

daily

for8

wk,

then

tapered

7(1/13)

77(10/13

)84

092

(12/13

)92

31(4/13)

62(8/13)

9242

(5/12)

[with

in12

moof

drug

cessation]

Prag

aetal.

(200

7)49

250.05

mg/kgtacrolim

usdailyfor

12mo(trou

ghleve

l5–8ng

/ml),

then

tapered

over

6mo(18mo)

Upto

3012

(3/25)

44(11/25

)56

24(6/25)

48(12/25

)72

32(8/25)

a44

(11/25

)a76

a47

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effect on renal survival in IMNare less cleardue to lack of longitudinal studies.56,57

Cattran et al. reported reduced rates ofdeterioration of renal function with cy-closporine in one small study of high-riskpatients.56 In a study design similar tothat used by du Buf-Vereijken et al.,34,44

65 patients with IMN were initially fol-lowed conservatively for 12 months. Onlypatients with clear evidence of decliningrenal function and persistent nephrotic-range proteinuria during the observationperiod were randomized to receive treat-ment with cyclosporine for 12months orplacebo. Of 65 patients, 23 (36%) metcriteria for randomization. Comparedwith placebo, cyclosporine-treated pa-tients demonstrated significantly reducedproteinuria (halving of proteinuria in50% of treated patients versus no im-provement in placebo patients) andslower rates of decline in kidney functionas measured by change in the slope ofcreatinine clearance. These improvementswere sustained in 75% of the patients forup to 2 years post-treatment. Fewer pa-tients in the treated group progressed toend stage (11% versus 50%, respectively).In contrast, a controlled trial by the Cy-closporine in Membranous NephropathyStudy Group failed to demonstrate anylong-term benefits of cyclosporinewhen used in patients with deterioratingrenal function.58 In light of the nephro-toxic potential of calcineurin inhibitors,caution and close monitoring of blooddrug levels and renal function are advisedif CNIs are initiated in patients with animpaired GFR at the start of therapy and/or severe tubulointerstitial damage on re-nal biopsy.

No prospective randomized head-to-head comparisons of cyclosporine(or tacrolimus) to standard regimens ofalkylating agents have been conducted. Aretrospective study by Goumenos et al.attempted to address this issue by com-paring the outcomes of patients whowere treated with a 6-month Ponticelliprotocol (steroids plus chlorambucil orcyclophosphamide; n=31) with thosetreated with cyclosporine for 2 years plussteroids (n=46).59 The use of differenttherapeutic regimens in the two groups re-flects institutional treatment preferences

over a 10-year period. Baseline charac-teristics of the groups were similar.More remissions occurred among thecyclosporine-treated patients than amongthose receiving alkylating agents (85%versus 55%; P=0.004). Relapses tendedto occur more often in the cyclosporine-treated group but the differences were notsignificant (41% versus 29%, respec-tively). During a mean follow-up of48636 months there were no differencesin rates of doubling of serum creatininebetween treatment groups (26% versus23%, respectively) or requirement for re-nal replacement therapy. However thedesign and retrospective nature of thestudy preclude definitive comparisonsof these therapies for IMN.

A recent multicenter randomizedcontrolled trial from China comparedefficacy of tacrolimus with an abbrevi-ated course of cytoxan in 73 patients withIMN.50 Patients were randomized to re-ceive tacrolimus for 9 months or 4months of daily oral cytoxan (100 mg/d).Both groups received oral prednisone.Cumulative remission rates at 6 monthswere greater in the tacrolimus arm thanthe cytoxan arm (85% versus 65%,P,0.05); however, remission rates werecomparable by 12 months. Relapse ratesbetween the two groups were similar(18% versus 23%), leading the authorsto conclude that short-term efficacy oftacrolimus plus steroids might be betterthan cyclophosphamide plus steroids.Several issues limit the conclusions thatcan be drawn from this study. Tacrolimuswas not compared with one of the stan-dard cytoxan-containing regimens.Follow-up was very short, which mayunderestimate true relapse rates. Last, therewas inconsistent use of ACE inhibitorsand ARBs, which favored the tacrolimusgroup.

Currently, there is a three-arm ran-domized controlled trial in progress inthe United Kingdom that compares sup-portive therapy versus 12 months ofcyclosporine versus 6 months of alter-nating prednisolone/chlorambucil in pa-tients with progressive IMN. The resultsof this trial are eagerly awaited and shouldprovide information regarding this im-portant group of patients.

RituximabOf the newer agents being explored forIMN, rituximab has emerged as themostlikely candidate to be incorporated intotreatment guidelines. Although it has yetto be tested in randomized controlledtrials and there is a lack of longitudinaldata, important groundwork has beenlaid since its first reported use for IMN in2002.60 Most of the reported experienceswith rituximab are from uncontrolledpilot trials or case series from two centersin Bergamo, Italy, and theMayoClinic inthe United States.60–67

The following treatment protocolshave been tried for IMN (Table 1): fourweekly doses of 375mg/m2, which is stan-dard dosing for treatment of lymphoma;two 1000-mg doses given biweekly, whichis standard for rheumatoid arthritis;and a B cell–driven protocol in whichdosing is titrated to the number of cir-culating B cells.63 The pharmacokineticsof rituximab in nephrotic patients differfrom that in nonproteinuric patientstreated with identical protocols,65

prompting interesting questions aboutthe optimal dosing regimen for IMN.Compared with nonproteinuric patients,rituximab levels are lower and recoveryof CD20-expressing B cells typically oc-curs earlier in nephrotic patients. How-ever, among nephrotic patients withIMN, the four-dose lymphoma andtwo-dose arthritis regimens seem tohave similar efficacy despite faster B cellrecovery after the two-dose regimen.66

Consistent with these conclusions, a re-cent retrospective analysis of bankedserum samples showed no detectabledifferences in the progressive reductionof anti-PLA2R levels between the twodosing regimens.14

Regardless of the regimen adminis-tered, proteinuria tends to decline slowlyand remissions may occur up to 2 yearsafter treatment (Table 4). Interestingly,Beck et al. showed that after administra-tion of rituximab, the median time toreach undetectable anti-PLA2R levelswas 9 months (range, 1–18 months).14

Thismay explain the delay in remissions,because the reduction in antibody levelsseems to precede the decline in protein-uria by months.



It is interesting to note that remissionscontinue to occur well after the end oftherapy with rituximab or alkylatingagents; complete remissions can be seen.12months after the completion of theseinterventions. This is in contrast towhat isobserved after cyclosporine or tacrolimus,in which typically no additional remis-sions occur once treatment stops.

Relapse rates after rituximab therapyare difficult to estimate given the limitedlongitudinal data.There are twopublishedstudies (n=31) that followed patients forup to 24 months64,66 and relapses wereinfrequent (6% and 13%, respectively). Itis hoped that forthcoming studies withextended follow-up will provide muchneeded information. Such data may in-form decisions regarding role and timingof redosing.

Currently, there are no establishedguidelines regarding the issue of retreat-ment and investigators have taken dif-ferent approaches. Inone study, Fervenzaet al. retreated patients with rituximabafter 6 months, only if B cells recovered (Bcells $15/ml) and patients had nephrotic-range proteinuria.65 In another study fromthe same institution, all patients were re-treated 6 months after the first course ofrituximab, regardless of clinical status.66

Remuzzi et al. have redosed rituximab(with single doses of 375 mg/m2) whenthere is evidence of relapse of nephrotic-range proteinuria (rather than empiricalretreatment).63 Whether empirical re-dosing at 6 months, or other predefinedintervals, provides added benefit with re-spect to durability of remissions or num-ber of remissions is not clear. In light ofthe preliminary observation that re-emergence of anti-PLA2R antibody inthe circulation precedes recurrence ofdisease, serial measurements of the anti-body may help guide decisions regardingretreatment.

There are several advantages ofrituximab that add to its appeal. It appearseffectiveasmonotherapy,andthesideeffectprofile may be more favorable than withother agents (i.e., with no hypertension orpotential for nephrotoxicity). Conversely,the long delay in reduction of proteinuriamay be problematic in patients who sufferfrom severe complications of nephroticTa

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syndrome. Combining rituximab withan abbreviated course of another agentthat has a quicker onset of antiprotein-uric effects (CNIs) is an approach that weare currently investigating.

We do need to have a balanced per-spective regarding the toxicity profile ofrituximab. Although acute infusion re-actions are often mild and manageable(e.g., fever, chills, pruritus, and skinrash), more severe and potentially fatalreactions (e.g., acute respiratory distresssyndrome, bronchospasm, angioedema,shock and myocardial infarction) as wellas potentially fatal mucocutaneous reac-tions (e.g., Stevens–Johnson syndromeand toxic epidermal necrolysis) can oc-cur. Rare cases of the devastating demy-elinating central nervous system disease,progressive multifocal leukoencepha-lopathy, have also been reported, al-though typically when administered aspart of multidrug immunosuppressiveregimens. Finally, the long-term safetyprofile of rituximab in glomerular diseasesis largely unknown, particularly if repeatedcourses are needed.

Controlled prospective trials are neededto compare the efficacy and toxicity ofrituximab with CNIs and cytotoxic drugs.More data are needed to clarify the roleof rituximab in patients with impairedor declining renal function and the effectsof rituximab on hard endpoints such asdialysis and death. A randomized con-trolled trial comparing rituximab with

cyclosporine is underway and hopefullywill provide much needed answers.

MMFEncouraging results from early, uncon-trolled series published almost a decadeago indicated a potential role of MMFin the management of high-risk patientswith IMN.68–72 Subsequent studies haveproduced mixed results (Table 5).73–76 Amulticenter randomized controlled trialfrom France reported cumulative remis-sion rates after 1 year of MMF that wereno different from conservative therapy(approximately 40%).73 Two other stud-ies suggested that treatment with MMFhad similar efficacy as a regimen consist-ing of alkylating agents plus steroids.74,75

A multicenter trial from China by Chanet al. randomized 20 treatment-naïve,newly diagnosed nephrotic patients toundergo 6 months of treatment withMMF (2 g/d) plus prednisolone orwith a regimen of chlorambucil alternat-ing with corticosteroids.74 The treat-ment arms achieved similar remissionrates (approximately 65%) at 15 monthsand experienced few relapses. To note,the study was not powered to demon-strate equivalency or noninferiority,follow-up was too short to evaluate relapseor renal survival outcomes, and only pa-tients with a favorable risk profile wereenrolled. Furthermore, only Asian pa-tients were included. On the basis of stud-ies of other primary glomerulopathies,

Asian ethnicity may be associated with arelatively favorable prognosis and in-creased responsiveness to certain immu-nosuppressive regimens.77–79

A trial from the Netherlands com-pared outcomes of 32 IMN patientstreated with 1 year of MMF plus cortico-steroids with historicalmatched controlstreated with oral cyclophosphamide pluscorticosteroids for 1 year.75 Patients wereconsidered at high risk for progressivedisease with reduced GFR at baseline(median approximately 40 ml/min)and high-grade proteinuria. The twogroups achieved similar initial remissionrates (approximately 70%). Renal func-tion stabilized or improved in themajor-ity of patients during the year of therapywithMMF. However, the post-treatmentrelapse rate was considerably higher inthe MMF group such that by the end offollow-up (median 23 months), patientsin the MMF arm were less likely to be inremission than those in the cytoxan arm(44% versus 75%; P=0.02).

Post-treatment relapse is problem-atic. In the trial by Branten et al., 57%of patients relapsed within 2 years andsome relapses occurred during activetreatment.75 Of interest, relapse isalso a concern after treatment with therelated older antimetabolite, azathio-prine.80,81 A recent study showed that12 months of azathioprine induced re-missions in a large percentage of patientswho had previously been refractory to

Table 5. Selected studies using MMF in IMN

Study Study Type nTreatment Regimen

(Duration)Follow-Up

(mo)Remissions (Initial) Relapse Rate (n)

[Time to Relapse]CR PR Total

Chan et al. (2007)74 RCT 11 2 g/d MMF (6 mo) plusprednisone (0.8 mg/kgdaily tapered over 6 mo)

Up to 15 27 (3/11) 36 4/11 63 29 (2/7) [within 2–8mo after achievingremission]

9 Modified Ponticelliprotocola

33 (3/9) 33 3/9 66 17 (1/6)

Branten et al. (2007)75 Historicalmatchedcomparison

32 2 g/d MMF (12 mo) plussteroidsb

Median 23 NR 66 (21/32) 66 57 (12/21) [within 2 yr]

32 1.5mg/kgoral cytoxandaily(12 mo) plus steroidsb

NR 84 (27/32) 84 15 (4/27) [within 2 yr]

Dussol et al. (2008)73 RCT 19 2 g/d MMF (12 mo) Up to 12 5 (1/19) 32 (6/19) 37 NR17 Conservative 12 (2/17) 29 (5/17) 41 NR

Data are expressed in percentages unless otherwise indicated. CR, complete remission; PR, partial remission; RCT, randomized controlled trial. NR, not reported.aSteroid dosage during mo 1, 3, and 5: 1 g/d intravenous methylprednisolone for 3 d, 0.4 mg/kg oral prednisolone daily for 21 d, and then 0.2 mg/kg daily for 6 d;mo 2, 4, and 6: 0.2 mg/kg oral chlorambucil daily.bDosage of 0.5 mg/kg oral prednisone every other day for 6 mo and then tapered, plus intravenous methylprednisolone 1g/d for 3 days during months 1, 3, and 5.



the Ponticelli protocol.52 However,within 6 months of azathioprine with-drawal, 33% relapsed.

Although the initial enthusiasm re-garding MMF has quieted, a place forMMF in treatment of IMN cannot bediscounted at this point. However, untilmore data become available, it is difficultto recommendMMF as initial therapy. Itmaybea reasonableoption for patients inwhom toxicity of alkylating agents andhigh-dose steroids are a concern or whensignificant azotemia prohibits use ofCNIs (Figure 1). MMF has been usedwith some success as rescue therapy inpatients resistant to other immunosup-pression and has also been tried as ad-junctive or maintenance therapy toavoid prolonged exposure to CNIs71;however, the evidence is too limited torecommend routine use of MMF forthese indications. Extended duration of

treatment (.12 months), and possiblythe addition of oral corticosteroids,may be necessary to achieve greater anti-proteinuric effects or to prevent relapse.The optimal target dosing of MMF forIMN is not known because the kineticsofMMF inpatientswithhypoalbuminemiaand nephrotic syndrome are not welldefined. It is possible that higher drugdoses are needed to reach the therapeuticwindow.

ACTHACTH is one of the newer agents beingexplored for treatment of IMN but itcertainly is not a new drug. Historically,ACTH was used decades ago to treatnephrotic syndrome aswell as a variety ofinflammatory and autoimmunediseases.However, this parenterally administereddrug fell out of favor when the greaterclinical benefits of oral steroids were

recognized. Its usewas recently resurrectedafter Berg et al. in Sweden observed reduc-tion in proteinuria when ACTH was ad-ministered for lipid-lowering purposes inpatients with IMN.82

Initial experiences with ACTH havebeen inEuropeusingACTHtetracosactide, asynthetic,depotformulation(tetracosactrin;NovartisPharmaceuticals,Basel,Switzerland).The data are conflicting. Several smallcase series reported reduction of pro-teinuria in IMN patients, many ofwhom were refractory to other thera-pies.83–86 A smallmulticenter randomizedcontrol trial of 32 patients by Ponticelliet al. compared efficacy of 6 months ofalkylating agents alternating with corti-costeroids to tetracosactrin intramus-cular injections for 1 year (1 mg twiceweekly).87 There were no significant dif-ferences in cumulative remission ratesbetween the treatment arms initially

Figure 1. Current consensus guidelines for treatment of IMN, adapted from Cattran et al.48 Possible positions of MMF and rituximab intreatment scheme based on available data (but not currently in guidelines). SAE, severe adverse event.



(93% versus 87%, respectively) or at finalfollow-up of 21 months (75% total ver-sus 87%, respectively). However, it is no-table that these patients were treatmentnaïve, with preserved kidney functionand low to modest degrees of proteinuria(5–6 g/d)—all of which may lead to anoverly optimistic view of remission rates.Outcomeswere not as favorable in a recentprospective study from the Netherlandsin which tetracosactrin was adminis-tered to high-risk IMN patients.88 Pa-tients were considered at high risk forprogression based on elevated urinaryb2microglobulin levels and high-grade pro-teinuria. After 9 months of treatment,only 44% of patients achieved remissionand relapse rates were high (43%). Otherinvestigators have reported similarly highrelapse rates after drug discontinuation,particularly after short courses of ther-apy.82

A different formulation of ACTH, anatural highly purified gel, is available intheUnited States (corticotropin; QuestcorPharmaceuticals Inc, Anaheim Hills,CA). In a retrospective study of cortico-tropin in proteinuric glomerular diseases,9 of 11 (82%) patients with IMNachieveda remission (three complete; six partial).The complete remissions occurred inpatients with relatively low levels of base-line proteinuria (2.6–4.8 g/d). Interpreta-tions of the data are limited due to theuncontrolled nature of the study, the var-iable dosing regimens used, a possiblecarry-over effect from previously admin-istered immunosuppression, and shortfollow-up (beyond the active treatmentperiod).

The mechanisms by which ACTHexerts its antiproteinuric effect are notunderstood. Multiple mechanisms likelycontributeandmay involvebothimmune-mediated and immune-independentmechanisms.89 The effects are not thoughtto be mediated by induction of endoge-nous cortisol from the adrenal glands be-cause administration of corticosteroids asmonotherapy has not been effective inIMN. However, it is conceivable thatACTH-induced increases in endogenoussteroidsmight act differently than oral ste-roid preparations.84 More recently, atten-tion has focused on a possible direct

effect of ACTH on podocytes as expres-sion of one of the natural receptors forendogenous ACTH (melanocortin re-ceptor-1) has been identified in humankidney tissue, mainly in the podocyte.86

In support of this theory, experimentalevidence in a rat model of membranousdisease showed that treatment with anagonist of the melanocortin receptor-1reduced proteinuria and improved podo-cyte morphology compared with un-treated rats.86

The experience with ACTH, particu-larly in the United States, is far toopreliminary to consider using this treat-ment outside of clinical research studies.A trial is currently underway to moreformally evaluate the efficacy of ACTHgel as secondary therapy in patients whohave failed conventional therapy.

SUMMARY

Figure 1 summarizes two widely usedtreatment options for immunosuppres-sive drugs in patients with IMN at mod-erate to high-risk of renal deterioration.These options, CNIs and cytotoxic drugtherapy, have been incorporated intoconsensus recommendations48 on thebasis of the clinical studies discussed inthis review. Randomized controlled trialsare needed to compare the efficacy andtoxicity of rituximab with these reg-imens. Additional studies are needed toidentify the optimal rituximab regimenfor this condition. Consequently, at thepresent time, it would be ideal to refer pa-tients to ongoing clinical trials of rituximabin order to address these important is-sues. MMF is another relatively new im-munosuppressive agent that has beenused (but not extensively studied) forthe treatment of IMN. Therefore, it isdifficult to determine its role in the stan-dard approach to IMN. It would be sen-sible to consider MMF as an alternativetherapy when the risk profiles of CNIs orcytotoxic drugs are considered unaccept-able. Figure 1 reflects where rituximaband MMF might potentially fit into thetreatment scheme on the basis of theavailable data. As previously discussed,there is too litt le information to

recommend using ACTH outside of thecontext of a clinical research study. On-going studies of pathogenic mechanismsand innovative treatments will refine ourapproach to the treatment of membra-nous nephropathy.

ACKNOWLEDGMENT

This research was supported in part by the

Intramural Research Program of the National

Institute of Diabetes and Digestive and Kid-

ney Diseases, National Institutes of Health.

DISCLOSURESNone.

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