Review treatment of mn - tsgh.ndmctsgh.edu.tw

REVIEW TREATMENT

OF MN

Supervisor VS 許育瑞

Speaker PGY2 邱俊樺

2020.01.07

1

Pretreatment considerations

Likelihood of spontaneous remission

– Spontaneous complete remission of proteinuria occurs in

5~30 % at 5 years

– Spontaneous partial remission (proteinuria ≤2 g/day) occurs

in 25~40 % at 5 years

– End-stage kidney disease (ESKD)

■ Untreated patients with nephrotic syndrome 14 % at 5

yrs, 41 % at 15 yrs

■ Untreated patients remain non-nephrotic 2% at 10 yrs

2 Prognosis of untreated patients with idiopathic membranous nephropathy. N Engl J Med 1993;329(2):85.

■ Indolent clinical course

■ Toxicity of available therapies

■ Immunosuppressive agents should be considered

– In patients with primary MN

– Most at risk for progressive disease

– Have severe symptomatic nephrotic syndrome

– At risk for or have complications of nephrotic syndrome

4

Pretreatment considerations – features of MN

RISKS ?

5

Clinical features higher progression risk of developing ESKD

6

Older age at onset (>60 y/o) Male sex

Nephrotic-range proteinuria

(protein excretion >8~10 g/day)

Increased serum Cr

Biomarker higher progression risk

■ Serum anti-phospholipase A2 receptor (PLA2R) antibody

– High level of anti-PLA2R antibody high(223↑)low(53↓) Anti-PLA2R Antibodies as a Prognostic Factor in PLA2R-Related Membranous Nephropathy, Am J Nephrol. 2015;42(1):70. Epub 2015 Sep 5.

■ Increased risk for progressive loss of kidney function

■ Lower risk of spontaneous remission

■ Serum anti-thrombospondin type-1 domain-containing 7A (THSD7A) antibody correlate with disease activity

An Indirect Immunofluorescence Method Facilitates Detection of Thrombospondin Type 1 Domain-Containing 7A-Specific Antibodies in Membranous Nephropathy, J Am Soc Nephrol. 2017;28(2):520. Epub 2016 Jul 19.

■ Urine low-molecular-weight proteins correlate with disease progression

Urinary excretion of beta2-microglobulin and IgG predict prognosis in idiopathic membranous nephropathy: a validation study, J Am Soc Nephrol. 2005;16(1):169. Epub 2004 Nov 24.

7

WHICH PATIENTS NEED TREATMENT ?

9

Which patients need treatment – progression risk

■ 2 or more of the following features to be at very high risk for progressive disease

– Serum creatinine ≥1.5 mg/dL considered to be due to active MN

– Progressive decline in kidney function (eGFR ↓ ≥25 % from baseline over prior 2 years) considered due to active MN

– Severe, disabling, or life-threatening nephrotic syndrome

■ Serum albumin <2.5 g/dL and refractory edema/thromboembolic event

■ Treatment with immunosuppressive therapy, should not be delayed unless contraindicated

10 KDIGO CLINICAL PRACTICE GUIDELINE ON GLOMERULAR DISEASES p.138

Progression risk

■ Primary MN with normal kidney function without nephrotic syndrome

■ treating with general supportive measures for 3-6 months for observation


High risk

■ Decrease in eGFR of ≥25 %, not explained by other causes

■ Proteinuria >8 g/day at the end of the observation, or persistent nephrotic syndrome (proteinuria >3.5 g/day and serum albumin <3.5 g/dL)

■ If anti-PLA2R antibody positive serial anti-PLA2R antibody titers are high (≥150 RU/mL by the ELISA method) and not declining

■ Immunosuppressive therapy without further delay, unless contraindicated


Moderate risk

■ Normal or stable eGFR over the 3~6 months period

■ Proteinuria persistently between 4~8 g/day

■ If anti-PLA2R antibody positive serial anti-PLA2R antibody titers are <150 RU/mL and stable or increasing by <25 %

■ Immunosuppressive therapy based upon clinical condition


Low risk

■ Normal or stable eGFR over the 3~6 months period

■ Proteinuria <4 g/day at the end of the observation period

■ Anti-PLA2R antibody titers are low (defined as <50 RU/mL)

or decreasing by ≥25 % at 3~6 months

■ Do not require immunosuppressive therapy and can

generally be managed with supportive measures only.


■ Immunosuppressive therapy is contraindicated to patients if they have evidence of severe and irreversible kidney damage

– CKD with a serum creatinine >3.5 mg/dL

– eGFR <30 mL/min/1.73 m2 for >3 months

– Kidney size < 8 cm on kidney ultrasound

– Severe interstitial fibrosis

– Tubular atrophy

– Glomerulosclerosis on kidney biopsy

■ Also contraindicated to concomitant severe or potentially life-threatening infections

15

Contraindication of immunotherapy

Therapy of high/very high risk of progression

■ Abnormal or declining kidney function

■ Rapidly declining kidney function due to MN

– Combination treatment with

glucocorticoids and a cytotoxic agent

(prefer cyclophosphamide) rather

than rituximab or other therapies

– Cytotoxic therapy best protection

against progressive kidney disease


Therapy of high/very high risk of progression

■ Stable kidney function

■ Rituximab rather than cytotoxic therapy or other therapies

■ Rituximab less treatment-related toxicity

■ Prefer rituximab to a calcineurin inhibitor (cyclosporine or tacrolimus)

– More prolonged remission

– Higher relapse rate of calcineurin inhibitor

■ There are no randomized trials that have directly compared rituximab

with cytotoxic therapy in high-risk patients with primary MN

17 Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy. N Engl J Med.

2019;381(1):36.

Membranous Nephropathy Trial of Rituximab – MENTOR trial

■ 2019 NEJM, open-label, multicenter

■ Included patients with primary MN who had heavy

proteinuria but mostly preserved kidney function

■ Result rituximab was more effective than cyclosporine at

maintaining complete or partial remission of proteinuria at

24 months

18 Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy. N Engl J Med.

2019;381(1):36.

■ 130 patients with proteinuria ≥ 5 g/day and 24-hour creatinine

clearance ≥40 mL/min/1.73 m2

■ At least three months of supportive care

■ Randomly assigned

– Rituximab (1 g *2 administered 14 days apart, repeated at six

months in case of partial response)

– Cyclosporine (starting at a dose of 3.5 mg/kg/day for 12 months)

19


Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy. N Engl J Med.

2019;381(1):36.

20


Patients

were considered to have

treatment failure if they had

reduction in proteinuria

of less than 25% from

baseline at 6 months


2019;381(1):36.

21



2019;381(1):36.

■ Result

– Mean creatinine clearance was higher in the rituximab group

than in the cyclosporine group (100:87)

– Anti-PLA2R antibody-positive patients ↓anti-PLA2R level,

rituximab > cyclosporin

– Serious adverse events rituximab < cyclosporin 17% / 31%

– Higher anti-PLA2R antibody levels at baseline patients are likely

to poor respond to rituximab

22



2019;381(1):36.

United Kingdom Membranous Trial

■ 2013 LANCET

■ Specifically enrolled patients with primary MN who had deteriorating kidney function

– At least 20 % decrease of eGFR during the preceding two years

– Baseline serum creatinine < 3.4 mg/dL

– Mean eGFR (50 mL/min/1.73 m2)/mean protein excretion of (8.5 g/day)

■ Glucocorticoids + cytotoxic therapy > cyclosporine

■ Glucocorticoids + cytotoxic therapy > supportive therapy alone

– preventing further loss of kidney function

24 Immunosuppression for progressive membranous nephropathy: a UK randomised controlled

trial, Lancet 2013; 381: 744–51

■ Assigned groups

– Supportive treatment plus glucocorticoids and cyclical cytotoxic therapy for six months

25


1m 2m 3m 4m 5m 6m 0m

methylprednisolone

(1 g/day for 3 days) methylprednisolone methylprednisolone

prednisolone (0.5 mg/kg

per day for 28 days)

prednisolone prednisolone

chlorambucil (0.15 mg/kg per

day throughout the month)

chlorambucil chlorambucil

Immunosuppression for progressive membranous nephropathy: a UK randomised controlled

trial, Lancet 2013; 381: 744–51

■ Assigned group

– Supportive treatment plus cyclosporine for 12 months

■ The initial dose of cyclosporine was 5 mg/kg/day

■ Adjusted to achieve a plasma concentration of 100 to 200 mcg/L.

– Supportive treatment alone.

26



trial, Lancet 2013; 381: 744–51

UNITED KINGDOM MEMBRANOUS TRIAL

27 Immunosuppression for progressive membranous nephropathy: a UK randomised controlled

trial, Lancet 2013; 381: 744–51

■ Result

– The primary endpoint (↓eGFR of at least 20 percent)

– Glucocorticoids and chlorambucil < supportive treatment alone

(58 versus 84 percent)

– Cyclosporin therapy did not reduce the incidence of kidney

function loss as compared with supportive treatment

– No difference in mortality among the three groups

28



trial, Lancet 2013; 381: 744–51

■ Limitations

– Patients with declining GFR due to MN generally

comprise a small fraction of all patients with primary

MN

– Cyclosporine dose escalation in this trial was faster than

common practice produce an acute reversible

reduction in GFR

29



trial, Lancet 2013; 381: 744–51

Moderate risk of progression

■ Initial therapy depending upon the course of disease during an initial 3~6 months observation period

■ Progressive increase in proteinuria over the observation period

– Recommend immunosuppressive therapy

■ Stable proteinuria over the observation period

– Suggest immunosuppressive therapy

– Some clinicians withhold beyond six months

■ Serum albumin↑

■ Anti-PLA2R antibody levels↓

■ High risk of adverse event with immunosuppressive therapy

30

■ Show a progressive decline in proteinuria

– Withhold immunosuppression

■ Preferred first-line immunosuppressive therapies

– Rituximab

– Combination therapy with glucocorticoids and cytotoxic agent

(preferably cyclophosphamide

– Calcineurin inhibitor (cyclosporine or tacrolimus)

31


■ In most moderate-risk patients who require immunosuppressive therapy, we

suggest rituximab

■ Anti-CD20 monoclonal antibody that depletes CD20-positive B cells

■ Standard regimen 1 g initially followed 14 days later by another 1 g dose

■ Alternative regimen

– 375 mg/m2 weekly for 4 weeks

– Second dose of 375 mg/m2 is given if ≥5 circulating B cells/microL are

detected by flow cytometry one week after treatment

32



2019;381(1):36.

■ Why use Rituximab for first line?

– Well tolerated

– Short-term adverse events

– Less opportunistic infections

– Rarely anaphylaxis

– Compare with cytotoxic comparable short-term outcomes with

better safety profile

– Compare with Calcineurin inhibitor MENTOR trial

33



2019;381(1):36.

■ 75 patients with persistent proteinuria greater than 3.5 g/day after six months of (general supportive measures)

■ Assigned to rituximab or no rituximab

■ 2 infusions of 375 mg/m2 administered 1 week apart

■ Result

– Complete or partial remission, Proteinuria, serum creatinine, and eGFR similar (6 months)

– Serum albumin levels were higher in rituximab group

– Rate of complete or partial remission was higher (12 months)

34

Evaluate Rituximab Treatment for Idiopathic Membranous Nephropathy (GEMRITUX) trial

Rituximab for Severe Membranous Nephropathy: A 6-Month Trial with Extended Follow-Up. Am

Soc Nephrol. 2017;28(1):348. Epub 2016 Jun 27.


■ If rituximab is unavailable

– Glucocorticoids plus a cytotoxic agent

– Calcineurin inhibitor monotherapy

■ Cytotoxic therapy

– Short-term efficacy

■ Calcineurin inhibitors

– Higher relapse rates

– Potential for nephrotoxicity

– Evidence of disease progression

35

Cytotoxic therapy plus glucocorticoids

■ We prefer cyclophosphamide since chlorambucil has more side

effects

36

1m 2m 3m 4m 5m 6m 0m

methylprednisolone

(1 g/day for 3 days) methylprednisolone methylprednisolone

prednisolone (0.5 mg/kg

per day for 28 days)

prednisolone prednisolone

oral cyclophosphamide

(2.0 mg/kg per day) cyclophosphamide

cyclophosphamide

A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome

caused by idiopathic membranous nephropathy. J Am Soc Nephrol. 2007;18(6):1899. Epub 2007 May 9.

■ Most studies evaluating cytotoxic therapy have included prednisone clinical impression of many clinicians of less beneficial without prednisone

■ Significant risk for infertility

■ Significant toxicity

– Hematologic toxicity

– Infection

– Gonadal toxicity

– Malignancy

37

Cytotoxic therapy plus glucocorticoids

A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome

caused by idiopathic membranous nephropathy. J Am Soc Nephrol. 2007;18(6):1899. Epub 2007 May 9.

Calcineurin inhibitors

■ Both cyclosporine and tacrolimus have proven short-term efficacy in

patients with primary MN

■ Cyclosporine-based regimen

– At least 6 months

– Dose of 3 to 5 mg/kg/day

– 2 divided doses

– Maintain whole blood trough levels of 120 to 200 ng/mL

– Some clinicians may add prednisone

38 Cyclosporine in patients with steroid-resistant membranous nephropathy: a randomized trial.

Kidney Int. 2001;59(4):1484.


■ Tacrolimus-based regimen

– 0.05 to 0.1 mg/kg per day

– At least 6 months

– Two divided doses

– Whole blood trough levels between 3

and 5 ng/mL

– May titrate to 5 and 8 ng/mL if no

reduction in proteinuria by two months

Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial. Kidney Int. 2007;71(9):924. Epub 2007 Mar 21.

39


■ If partial remission continue for additional 6 months

– Cyclosporine reduce the dose to 1.5 to 2.5 mg/kg/day

– Tacrolimus reduce the dose by 25 to 50 percent

■ Some clinicians may choose to withdraw therapy

– Achieve a disappearance of anti-PLA2R antibodies

– Complete clinical remission (protein excretion ≤300 mg/day)

40

Cyclosporine in patients with steroid-resistant membranous nephropathy: a randomized trial.

Kidney Int. 2001;59(4):1484.

Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial. Kidney

Int. 2007;71(9):924. Epub 2007 Mar 21.

Low risk of progression

■ Continued observation with general supportive measures

■ Generally have excellent long-term prognosis

■ Often undergo spontaneous partial or complete remission

■ Monitored periodically every three months for two years and twice

yearly thereafter

– Serum creatinine

– 24-hour urine protein excretion

– Anti-PLA2R antibody levels

41 Prognosis of untreated patients with idiopathic membranous nephropathy. N Engl J Med.

1993;329(2):85.

42

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Review treatment of mn - tsgh.ndmctsgh.edu.tw