treatment of idiopathic membranous nephropathy...antigen in idiopathic membranous nephropathy beck...

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Treatment of Idiopathic Treatment of Idiopathic Membranous Membranous NephropathyNephropathyNephrology Grand RoundsNephrology Grand Rounds

PathophysiologyPathophysiology

MM‐‐Type Phospholipase A2 Receptor as Target Type Phospholipase A2 Receptor as Target Antigen in Idiopathic Membranous NephropathyAntigen in Idiopathic Membranous Nephropathy

Beck et al. N Engl J Med 2009;361:11‐21

• PlA2R is a major target antigen in IMN.

• 70% of patients with biopsy proven IMN had IgG antibodies that reacted

with a reduction sensitive epitope present on PLA2R

• IgG is subtype 4

• PLA2R is located on podocytes

• It is possible presence of PLA2R corresponds to disease activity

• Antibody most likely the cause of podocyte injury and proteinuria

Results of Western Blotting of Glomerular Proteins with SerumResults of Western Blotting of Glomerular Proteins with Serum

from Patients with Idiopathic Membranous Nephropathy.from Patients with Idiopathic Membranous Nephropathy.


Expression of the MExpression of the M‐‐Type Phospholipase A2 Receptor (PLA2R) in Normal Kidney Type Phospholipase A2 Receptor (PLA2R) in Normal Kidney

Tissue and Glomeruli.Tissue and Glomeruli.

Colocalization of the MColocalization of the M‐‐Type Phospholipase A2 Receptor (PLA2R) Type Phospholipase A2 Receptor (PLA2R)

and IgG4 and Reactivity of Eluted IgG4.and IgG4 and Reactivity of Eluted IgG4.


Richert et al., Am J Kidney Dis. 1998;31(1):1.Richert et al., Am J Kidney Dis. 1998;31(1):1.

Causes of MN

‐‐Spontaneous Complete remission in 5Spontaneous Complete remission in 5‐‐30% of patients at 5yrs 30% of patients at 5yrs

‐‐Spontaneous Partial remission in 25Spontaneous Partial remission in 25‐‐40% of patients at 5 yrs40% of patients at 5 yrs

‐‐ESRD in 14 % at 5yrs, 35% at 10 yrs, and 41% at 15 yrsESRD in 14 % at 5yrs, 35% at 10 yrs, and 41% at 15 yrs

Natural historyNatural history

Prospective study following 100 patients over 5 yrsProspective study following 100 patients over 5 yrs

CR<0.2g, PR: 0.2CR<0.2g, PR: 0.2‐‐2.0, ESRD=CrCl<102.0, ESRD=CrCl<10

Results: 24/37(65%) with CR or PR at 5 yrs, 6/37(16%) with ESRDResults: 24/37(65%) with CR or PR at 5 yrs, 6/37(16%) with ESRD

at 5 yrs.at 5 yrs.

Schieppati et al, N Engl J Med 1993; 329:85Schieppati et al, N Engl J Med 1993; 329:85

Schieppati el alSchieppati el al

Schieppati et al, N Engl J Med 1993; 329:85

vv


Retrospective study of 949 patients in JapanRetrospective study of 949 patients in Japan

Results: Renal survival rates were 95.8%, 90.3% 81.1% and 60.5% Results: Renal survival rates were 95.8%, 90.3% 81.1% and 60.5% at 5, 10, at 5, 10,

15, and 20 yrs respectively.15, and 20 yrs respectively.

Risk factors affecting renal survival were Cr>1.5, Male >60yrs, Risk factors affecting renal survival were Cr>1.5, Male >60yrs,

Tubulointerstitial lesions>20%.Tubulointerstitial lesions>20%.

Shiiki et al, Prognosis and risk factors for idiopathic Shiiki et al, Prognosis and risk factors for idiopathic membranous nephropathy with nephrotic syndrome in membranous nephropathy with nephrotic syndrome in

Japan.Japan.

Shiiki et al, Kidney International 2004;65: 1400Shiiki et al, Kidney International 2004;65: 1400––14071407

Shiiki et al, Kidney International 2004;65: 1400–1407

Prospective study of 108 patients with subnephrotic proteinuria Prospective study of 108 patients with subnephrotic proteinuria at at

presentationpresentation

Results: 40% remained subnephrotic within 12 months, patients whResults: 40% remained subnephrotic within 12 months, patients who o

subsequently developed proteinuria had 4x rate of decline in CrCsubsequently developed proteinuria had 4x rate of decline in CrCl as l as

compared to patient who remained subnephrotic compared to patient who remained subnephrotic

Majority of patients who developed nephrotic range proteinuria dMajority of patients who developed nephrotic range proteinuria did so in id so in

the first year the first year

Hladunewich et al, The natural history of the nonHladunewich et al, The natural history of the non‐‐ nephrotic membranous nephropathy patientnephrotic membranous nephropathy patient..

Hladunewich et al. Clin J Am Soc Nephrol 2009;4: 1417Hladunewich et al. Clin J Am Soc Nephrol 2009;4: 1417––14221422

Group 1: never

nephrotic

Group 2:

nephrotic post

presentation

Group3:

nephrotic at

presentation

Hladunewich et al. Clin J Am Soc Nephrol 2009;4: 1417Hladunewich et al. Clin J Am Soc Nephrol 2009;4: 1417––14221422

{{Non immunosuppressive therapyNon immunosuppressive therapy

‐‐

Angiotensin inhibitorsAngiotensin inhibitors‐‐

BP controlBP control‐‐

Lipid loweringLipid lowering‐‐

AnticoagulationAnticoagulation

Recommended in all patients with proteinuriaRecommended in all patients with proteinuria

Goal : 60 % reduction of proteinuria from baseline value and optGoal : 60 % reduction of proteinuria from baseline value and optimally imally

less than 500 to 1000mg/dayless than 500 to 1000mg/day

May significantly reduce the rate of disease progressionMay significantly reduce the rate of disease progression

ACE/ARBACE/ARB

Polanco et al, J Am Soc Nephrol 2010;21: 697Polanco et al, J Am Soc Nephrol 2010;21: 697––704704

Remission more frequent with lower baseline proteinuriaRemission more frequent with lower baseline proteinuria

Rate of remission are higher among patients treated with ACE/ARRate of remission are higher among patients treated with ACE/ARB, B,

results only significant if proteinuria <8gresults only significant if proteinuria <8g

Independent predictors for remission: baseline Cr, baseline protIndependent predictors for remission: baseline Cr, baseline protein ein

excretion, and >50 percent reduction in protein excretion at oneexcretion, and >50 percent reduction in protein excretion at one

year.year.

ACE/ARBACE/ARB

Risk stratification to low, moderate and high risk for progressiRisk stratification to low, moderate and high risk for progression to on to

ESRDESRD

Measure 24 hr collection for protein, GFR as estimated from creMeasure 24 hr collection for protein, GFR as estimated from creatinine atinine

clearance clearance

Random Uptn/Ucr should not be used for initial decision for treaRandom Uptn/Ucr should not be used for initial decision for treatment tment

but can be used for follow upbut can be used for follow up

Goal to obtain complete remissionGoal to obtain complete remission

Immunosuppressive therapyImmunosuppressive therapy

Low risk: Proteinuria remains less than 4g/day Low risk: Proteinuria remains less than 4g/day andand

CrCl remains nl for 6 CrCl remains nl for 6

months follow up period. Less than 8% risk of developing CRI in months follow up period. Less than 8% risk of developing CRI in 5 yrs.5 yrs.

Moderate risk: Proteinuria is between 4Moderate risk: Proteinuria is between 4‐‐8g/day and persists for more 8g/day and persists for more

than 6 months. CrCl is normal or near nl and remains stable for than 6 months. CrCl is normal or near nl and remains stable for more more

than 6 months. Those patients have 50% risk of progression to CRthan 6 months. Those patients have 50% risk of progression to CRI in 5 I in 5

yrs.yrs.

High risk: proteinuria is > 8g/day and persists for 3 months andHigh risk: proteinuria is > 8g/day and persists for 3 months and/or renal /or renal

function that is either below normal or decreases during observafunction that is either below normal or decreases during observation tion

period. Those patients have 75% risk of progression to CRI in 5 period. Those patients have 75% risk of progression to CRI in 5 yrs.yrs.

Risk stratification:Risk stratification:

Cattran, J Am Soc Nephrol 2005; 16: 1188–1194

Prospective controlled study of 81 patients followed for 10 yrsProspective controlled study of 81 patients followed for 10 yrs

Study group received Study group received methyplrednisolone and chlorambucil methyplrednisolone and chlorambucil for 6 for 6

months and control group received symptomatic therapymonths and control group received symptomatic therapy

The probability of surviving without developing endThe probability of surviving without developing end‐‐stage renal disease stage renal disease

at 10 years was 92% in patients given methylprednisolone and at 10 years was 92% in patients given methylprednisolone and

chlorambucil versus 60% in controls (P = 0.0038). chlorambucil versus 60% in controls (P = 0.0038).

Ponticelli et al., Kidney International Ponticelli et al., Kidney International 1995;48:16001995;48:1600‐‐16041604

Ponticelli et al., Kidney International 1995;48:1600Ponticelli et al., Kidney International 1995;48:1600‐‐16041604

‐‐‐‐treatment group___control group

Ponticelli et al., Kidney International 1995;48:1600Ponticelli et al., Kidney International 1995;48:1600‐‐16041604

Randomized controlled trial, 87 patients followed for at least Randomized controlled trial, 87 patients followed for at least 1 yr1 yr

Compared two regimens based on a 6Compared two regimens based on a 6‐‐mo treatment, alternating every mo treatment, alternating every

other month other month methylprednisolone with chlorambucil or or

methylprednisolone with cyclophosphamidemethylprednisolone with cyclophosphamide..

Results: 36 of 44 (82%)assigned to methylprednisolone and chloraResults: 36 of 44 (82%)assigned to methylprednisolone and chlorambucil mbucil

entered complete or partial remission of the nephrotic syndrome,entered complete or partial remission of the nephrotic syndrome,

versus versus

40 of 43 (93%)assigned to methylprednisolone and cyclophosphamid40 of 43 (93%)assigned to methylprednisolone and cyclophosphamide (P e (P

= 0.116).= 0.116).

Ponticelli et al, J Am Soc Nephrol. 1998;9(3):444 Ponticelli et al, J Am Soc Nephrol. 1998;9(3):444

Ponticelli et al, J Am Soc Nephrol. 1998;9(3):444 Ponticelli et al, J Am Soc Nephrol. 1998;9(3):444

Randomized controlled trial, 93 patients followed for 10 yrsRandomized controlled trial, 93 patients followed for 10 yrs

Compared the effect of a 6Compared the effect of a 6‐‐mo course of alternating mo course of alternating prednisolone and prednisolone and

cyclophosphamidecyclophosphamide

with supportive treatment in adults with IMN.with supportive treatment in adults with IMN.

End points: doubling of serum creatinine, development of ESRD, aEnd points: doubling of serum creatinine, development of ESRD, and nd

quality of lifequality of life

In tx group 34/43 achieved remission (15 CR, 19 PR), In tx group 34/43 achieved remission (15 CR, 19 PR),

In control group 16/42 achieved remission (5 CR, 11 PR) (P<0.000In control group 16/42 achieved remission (5 CR, 11 PR) (P<0.0001). 1).

1010‐‐yr dialysisyr dialysis‐‐free survival was 89 and 65% (P = 0.016)free survival was 89 and 65% (P = 0.016)

the likelihood of survival without death, dialysis, and doublinthe likelihood of survival without death, dialysis, and doubling of serum g of serum

creatinine were 79 and 44% (P = 0.0006) in the two groups.creatinine were 79 and 44% (P = 0.0006) in the two groups.

Jha et al, , J Am Soc Nephrol 18: 1899Jha et al, , J Am Soc Nephrol 18: 1899––1904, 2007 1904, 2007

Jha et al, J Am Soc Nephrol 18: 1899Jha et al, J Am Soc Nephrol 18: 1899––1904, 20071904, 2007

___ treatment group

‐‐‐‐‐‐‐

Control group

Jha et al, J Am Soc Nephrol 18: 1899Jha et al, J Am Soc Nephrol 18: 1899––1904, 20071904, 2007

Randomized trial in 51 patients with idiopathic MGN with nephrotRandomized trial in 51 patients with idiopathic MGN with nephroticic‐‐

range proteinuriarange proteinuria

Comparing 26 weeks of Comparing 26 weeks of cyclosporine cyclosporine treatment plus lowtreatment plus low‐‐dose dose

prednisone to placebo plus prednisone. prednisone to placebo plus prednisone.

Patients were followed for an average of 78 weeksPatients were followed for an average of 78 weeks

Results: 75% percent of the treatment group vs 22% of the contrResults: 75% percent of the treatment group vs 22% of the control group ol group

(P<0.001) had a partial or complete remission of their proteinur(P<0.001) had a partial or complete remission of their proteinuria by 26 ia by 26

weeks. weeks.

Relapse occurred in 43% (N = 9) of the cyclosporine remission grRelapse occurred in 43% (N = 9) of the cyclosporine remission group and oup and

40% (N = 2) of the placebo group by week 52.40% (N = 2) of the placebo group by week 52.

Cattran et al., Kidney Int. 2001;59(4):1484Cattran et al., Kidney Int. 2001;59(4):1484

Cattran et al., Kidney Int. 2001;59(4):1484Cattran et al., Kidney Int. 2001;59(4):1484

P=0.001

P=0.004P=0.007

Prospective randomized trial following 48 patients Prospective randomized trial following 48 patients

To evaluate To evaluate monotherapy with tacrolimus monotherapy with tacrolimus (12 months then 6 months (12 months then 6 months

taper) vs placebotaper) vs placebo

The probability of remission in the treatment group was 58, 82, The probability of remission in the treatment group was 58, 82, and 94% and 94%

after 6, 12, and 18 months but only 10, 24, and 35%, respectivelafter 6, 12, and 18 months but only 10, 24, and 35%, respectively in the y in the

control group. control group.

Nephrotic syndrome reappeared in almost half of the patients whoNephrotic syndrome reappeared in almost half of the patients who

were were

in remission by the 18th month after tacrolimus withdrawal.in remission by the 18th month after tacrolimus withdrawal.

Praga et al. Kidney Int. 2007;71(9):924Praga et al. Kidney Int. 2007;71(9):924

Praga et al. Kidney Int. 2007;71(9):924Praga et al. Kidney Int. 2007;71(9):924

Clinical trial with historic controls, median Clinical trial with historic controls, median f/uf/u

23 months, 32 cases and 32 23 months, 32 cases and 32

controlscontrols

MMFMMF, 1 g twice daily, for 12 months versus , 1 g twice daily, for 12 months versus cyclophosphamidecyclophosphamide, 1.5 mg/kg/d, , 1.5 mg/kg/d,

for 12 months. Both groups also received intermittent for 12 months. Both groups also received intermittent methylprednisolonemethylprednisolone

and alternateand alternate‐‐day prednisone.day prednisone.

Cumulative incidences of remission of Cumulative incidences of remission of proteinuriaproteinuria

at 12 months were 66% in at 12 months were 66% in

the MMF group versus 72% in the the MMF group versus 72% in the cyclophosphamidecyclophosphamide

group (P = 0.3).group (P = 0.3).

5 patients (16%) in the MMF group 5 patients (16%) in the MMF group vsvs

none in the none in the cyclophosphamidecyclophosphamide

group group

had disease that did not respond to therapy (P = 0.05). had disease that did not respond to therapy (P = 0.05).

12 pts (38%) experienced a relapse and 9 pts (31%) were re12 pts (38%) experienced a relapse and 9 pts (31%) were re‐‐treated in the treated in the

MMF group compared with 4 (13%) and 2 pts (6%) in the MMF group compared with 4 (13%) and 2 pts (6%) in the cyclophosphamidecyclophosphamide

group (P<0.01 and P = 0.024, respectively).group (P<0.01 and P = 0.024, respectively).

BrantenBranten

et al. Am J Kidney Dis. et al. Am J Kidney Dis. 2007;50(2):2482007;50(2):248

Thank youThank you

treatment of idiopathic membranous nephropathy...antigen in idiopathic membranous nephropathy beck...

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