the role of calcineurin inhibitors in the treatment of...

The Role of CalcineurinThe Role of CalcineurinInhibitors in the TreatmentInhibitors in the Treatmentof Idiopathic Membranous of Idiopathic Membranous

NephropathyNephropathy

Membranous Nephropathy Membranous Nephropathy Conference, Conference,

March 30March 30--31, 2007, 31, 2007, Bergamo, ItalyBergamo, Italy

Fernando C. Fervenza, MDFernando C. Fervenza, MDAssociate Professor of MedicineAssociate Professor of Medicine

Division of Nephrology and HypertensionDivision of Nephrology and HypertensionMayo Clinic College of MedicineMayo Clinic College of Medicine

Rochester, MNRochester, MN

Cyclosporine in Progressive MNCyclosporine in Progressive MNPatients Characteristics at EntryPatients Characteristics at Entry

CP1134827-25Cattran et al: Kl 47:1130, 1995Cattran et al: Kl 47:1130, 1995

Cyclosporine Placebon=9 n=8

Age (range) 44 (22-59) 40 (20-61)Males (%) 8 (89) 6 (75)Creatinine (µµµµmol/L) 186±±±±65 204±±±±81Ccr (mL/min/1.73 m2) 51±±±±20 46±±±±16Proteinuria (g/day) 11.5 (9-18) 12.8 (4-21)Serum albumin (g/L) 29±±±±6.6 30±±±±9.2Systolic BP/mm Hg 141±±±±6 138±±±±16Diastolic BP (mm Hg) 82±±±±12 83±±±±7Ultra structural stage 2.2 (1-4) 2.0 (1-4)Interstitial fibrosis (0-4+) 0.9 (0-1) 0.4 (0-1)Tubular atrophy (0-4+) 0.7 (0-2) 0.3 (0-2)Observation period (mo)

Part 1 9.3 (6-13) 9.7 (7-12)Part 2 10.1 (4-13) 8.9 (4-13)Post-med 20 (0-41) 22 (6-56)Total 49 (17-75) 48 (25-88)

Cyclosporine Placebon=9 n=8

Age (range) 44 (22-59) 40 (20-61)Males (%) 8 (89) 6 (75)Creatinine (µµµµmol/L) 186±±±±65 204±±±±81Ccr (mL/min/1.73 m2) 51±±±±20 46±±±±16Proteinuria (g/day) 11.5 (9-18) 12.8 (4-21)Serum albumin (g/L) 29±±±±6.6 30±±±±9.2Systolic BP/mm Hg 141±±±±6 138±±±±16Diastolic BP (mm Hg) 82±±±±12 83±±±±7Ultra structural stage 2.2 (1-4) 2.0 (1-4)Interstitial fibrosis (0-4+) 0.9 (0-1) 0.4 (0-1)Tubular atrophy (0-4+) 0.7 (0-2) 0.3 (0-2)Observation period (mo)

Part 1 9.3 (6-13) 9.7 (7-12)Part 2 10.1 (4-13) 8.9 (4-13)Post-med 20 (0-41) 22 (6-56)Total 49 (17-75) 48 (25-88)

Improvement in Rate of Change in Creatinine ClearanceImprovement in Rate of Change in Creatinine Clearance

CP1134827-9Cattran D: Curr Op Nephrol Hypert 5:427, 1996Cattran D: Curr Op Nephrol Hypert 5:427, 1996

0102030405060708090

100110

-15 -10 -5 0 5 10 15 20 25 30 35 40

Creatinine clearance (mL/min)


Months from randomizationMonths from randomization



0102030405060708090

100110

CyclosporineCyclosporine

PlaceboPlaceboDeathDialysisDeathDialysis

--2.4 vs 2.4 vs --0.70.7

--2.2 vs 2.2 vs --2.12.1

CP1256850-7

Cyclosporine in Progressive IMNCyclosporine in Progressive IMNCyclomen Study, FollowCyclomen Study, Follow--Up 12 MonthsUp 12 Months

Before Final Before Final

Proteinuria 6.8±0.9 7.5±7.9 4.0±0.5 2.8±0.7(g/24 hr)

CCr 49.3±6.5 44.1±9.1 47.8±7.3 46±7.9(mL/min/1.73 m2)

Before Final Before Final

Proteinuria 6.8±0.9 7.5±7.9 4.0±0.5 2.8±0.7(g/24 hr)

CCr 49.3±6.5 44.1±9.1 47.8±7.3 46±7.9(mL/min/1.73 m2)

Pisoni et al: JASN, 2000 (abstract)Pisoni et al: JASN, 2000 (abstract)

Remissions 2 4

ESRD 3 1

Remissions 2 4

ESRD 3 1

CsAn=10CsAn=10

Conservativen=11

Conservativen=11

Cyclosporine in SteroidCyclosporine in Steroid--Resistant MNResistant MNBaseline Demographic and Laboratory Data Baseline Demographic and Laboratory Data

of 51 Randomized Patientsof 51 Randomized Patients

CP1134827-26

Data ±±±± SDCattran et al: Kl 59:1484, 2001Data ±±±± SDCattran et al: Kl 59:1484, 2001

Placebo CyclosporineInitial n=23 n=28Age range 49±±±±14 47±±±±11Gender (M:F) 16/7 26/2Blood pressure (mm Hg)

Systolic 138±±±±16 137±±±±18Diastolic 84±±±±9 84±±±±7

Racial group, No. (%)Caucasians 20 (87) 24 (86)African-American 0 (0) 1 (4)Other/mixed 3 (13) 2 (10)

Serum albumin (g/dL) 2.7±±±±0.6 2.8±±±±0.6Serum creatinine (mg/dL) 1.1±±±±0.3 1.3±±±±0.5Creatinine clearance 95±±±±37 90±±±±27(mL/min/1.73 m2)Proteinuria (g/day) 8.8±±±±4.7 9.7±±±±5.3Urine urea (g/day) 9.5±±±±3.6 10.3±±±±4.0

Placebo CyclosporineInitial n=23 n=28Age range 49±±±±14 47±±±±11Gender (M:F) 16/7 26/2Blood pressure (mm Hg)

Systolic 138±±±±16 137±±±±18Diastolic 84±±±±9 84±±±±7

Racial group, No. (%)Caucasians 20 (87) 24 (86)African-American 0 (0) 1 (4)Other/mixed 3 (13) 2 (10)

Serum albumin (g/dL) 2.7±±±±0.6 2.8±±±±0.6Serum creatinine (mg/dL) 1.1±±±±0.3 1.3±±±±0.5Creatinine clearance 95±±±±37 90±±±±27(mL/min/1.73 m2)Proteinuria (g/day) 8.8±±±±4.7 9.7±±±±5.3Urine urea (g/day) 9.5±±±±3.6 10.3±±±±4.0

Cyclosporine in MGNCyclosporine in MGN

CP1134827-24

Cattran et al: Kidney Int 59:1484, 2001Cattran et al: Kidney Int 59:1484, 2001

WeeksWeeks

78

52

26

0

CyclosporineCyclosporine PlaceboPlacebo

2828

2 CR2 CR 19 PR19 PR 7 NR7 NR

7 NR7 NR2 CR2 CR

2 CR2 CR 11 PR11 PR 8 R8 R

9 PR9 PR 10 R10 R

(1)(1)

(1)(1)

(1)(1)(8)(8)

(2)(2)(8)(8)

(1)(1)(2)(2)

(1)(1)

1 CR1 CR 2 PR2 PR 3 R3 R 17 NR17 NR

18 NR18 NR2 R2 R2 PR2 PR1 CR1 CR

1 CR1 CR 4 PR4 PR 18 NR18 NR

2323

CyA Treatment in Membranous NephropathyCyA Treatment in Membranous Nephropathy

CP1123327-6

Rate of complete remission

(%)

Rate of complete remission

(%)

Duration of treatment (months)Duration of treatment (months)

MCMGNCensored

MCMGNCensored

0

20

40

60

80

100

0 6 12 18 24

Merier, NDT 14: 1036, 1999Merier, NDT 14: 1036, 1999

CP1256850-14

Induction and longInduction and long--term treatmentterm treatmentInitial TreatmentInitial Treatment

I) Treatment groups• Pred + CsA 31 patients• CsA alone 20 patients

II) Treatment regimen• Pred 0.6 mg/kg/day with tapering• CsA 2-3 mg/kg/day

Target whole blood 12-hour trough levels100-200 ng/mL

III) Duration of treatment• 12 months

I) Treatment groups• Pred + CsA 31 patients• CsA alone 20 patients

II) Treatment regimen• Pred 0.6 mg/kg/day with tapering• CsA 2-3 mg/kg/day

Target whole blood 12-hour trough levels100-200 ng/mL

III) Duration of treatment• 12 months

AlexopoulosAlexopoulos et al. NDT 21: 3127et al. NDT 21: 3127--3132, 20063132, 2006

CP1256850-15

OutcomeOutcome

5

80

20

65

19

64

35

48

0

20

40

60

80

100

Complete Partial Complete Partial

Res

pons

e of

pro

tein

uria

(% o

f pat

ient

s)R

espo

nse

of p

rote

inur

ia(%

of p

atie

nts)

6 Months6 Months 12 Months12 Months

Alexopoulos et al. NDT 21: 3127-3132, 2006AlexopoulosAlexopoulos et al. NDT 21: 3127et al. NDT 21: 3127--3132, 20063132, 2006

CsAPred+CsACsAPred+CsA

No relapsesNo relapses

CP1256850-18

Long Term Treatment of IMNLong Term Treatment of IMN

I) Treatment groups

• Pred + CsA 26 patients (11 CR, 15 PR)

• CsA alone 17 patients (4 CR, 13 PR)

II) Treatment regimen

• Pred ~0.1 mg/kg/day

• CsA ~1.5/kg/day over 2 months

I) Treatment groups

• Pred + CsA 26 patients (11 CR, 15 PR)

• CsA alone 17 patients (4 CR, 13 PR)

II) Treatment regimen

• Pred ~0.1 mg/kg/day

• CsA ~1.5/kg/day over 2 months


Proteinuria (g/24 hr) 1.1±1.7 1.1±0.8CsA dose (mg/day) 105±25 (P+C) 111±40 (C)Follow-up (months) 26±16 18±7

CP1256850-20

Pred + CsA vs CsA in IMNPred + CsA vs CsA in IMNLongLong--Term TreatmentTerm Treatment

Pred + CsA CsA P

Relapses (no.) 4/26 (15%) 8/17 (47%) <0.05

Time to relapse 10±2 6±4 NS(months)

Pred + CsA CsA P

Relapses (no.) 4/26 (15%) 8/17 (47%) <0.05

Time to relapse 10±2 6±4 NS(months)


*≥≥≥≥ 50% increase in proteinuria*≥≥≥≥ 50% increase in proteinuria

Relapsers Non relapsers PI) CsA dose (mg/kg)Pred + CsA 1.0±0.3 1.4±0.5 <0.001CsA 1.1±0.2 1.5±0.4 <0.003II) CsA levels (Co) 72±48 194±80 <0.03(ng/mL)

CP1256850-22

Final OutcomeFinal Outcome

End of End ofRemission 12 months follow-up 12 months follow-up

Complete 11 10 4 4

Partial 15 16 13 13

SCr (mg/dL) 1.3±0.6 1.3±0.4 1.1±0.3 1.1±0.2

Proteinuria 1.1±1.7 1.0±1.4 1.1±0.8 1.0±0.7(g/24 hr)

End of End ofRemission 12 months follow-up 12 months follow-up

Complete 11 10 4 4

Partial 15 16 13 13

SCr (mg/dL) 1.3±0.6 1.3±0.4 1.1±0.3 1.1±0.2

Proteinuria 1.1±1.7 1.0±1.4 1.1±0.8 1.0±0.7(g/24 hr)

Pred+CsAn=26

Pred+CsAn=26

CsAN=17CsAN=17

Relapses treated by Relapses treated by �� CsA dose; in 2 patients CsA dose; in 2 patients �� prednisone doseprednisone doseResponse = to initial treatmentResponse = to initial treatment

Tacrolimus MonotherapyTacrolimus MonotherapyProtein ExcretionProtein Excretion

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

Entry Six Months Nine Months Fifteen Months

Time Point

Pro

tein

uria

(mg)

9097 ± 3566 g/day 5291 ± 5979 g/day

3407 ± 2046 g/day

2872 ± 1942 g/day

AmerAmer et al. ASN 2006 (abs)et al. ASN 2006 (abs)

CP1262145-6

0

5,000

10,000

15,000

56.0

67.0

78.0

89.0

100.0

mg/

24 h

rm

g/24

hr

mL/m

in/SA

mL/m

in/SA

31 Dec 04 31 Dec 05 31 Dec 06

Total proteinTotal protein

Creatinine clearanceCreatinine clearance


CP1262145-5

0

5,000

10,000

15,000

20,000

0.0

50.0

100.0

150.0

mg/

24 h

rm

g/24

hr

mL/m

in/SA

mL/m

in/SA

31 Dec 04 31 Dec 05 31 Dec 06

Total proteinTotal protein

Creatinine clearanceCreatinine clearance


Tacrolimus monotherapyTacrolimus monotherapyrandomized controlled trialrandomized controlled trial

0.05 mg/kg/day for 12 months; 6 months taper0.05 mg/kg/day for 12 months; 6 months taper

PragaPraga et al. Kidney Int. 2007 (in press)et al. Kidney Int. 2007 (in press)

Tacrolimus monotherapyTacrolimus monotherapyRandomized controlled trialRandomized controlled trial

PragaPraga et al. Kidney Int. 2007 (in press)et al. Kidney Int. 2007 (in press)

72%72%

22%22%

76%76%

30%30%

CP1256850-23

ConclusionsConclusions

• Both Cyclosporine (± steroids) and Tacrolimus are effective for inducing remission in most NS patients with IMN and normal or near normal renal function

• Both are well tolerated

• Prolonged treatment is needed in order to achieve maximal success

• Lower doses (CsA 1.4-1.5 mg/kg/day; TAC 0.05 mg/kg/day) are useful and may be safe for maintenance of remission provided.

• Relapses are more frequent in the monotherapy group, when dose is lower (1.0-1.1 mg/kg) or when CsA levels are below 100 mg/mL

• Both Cyclosporine (± steroids) and Tacrolimus are effective for inducing remission in most NS patients with IMN and normal or near normal renal function

• Both are well tolerated

• Prolonged treatment is needed in order to achieve maximal success

• Lower doses (CsA 1.4-1.5 mg/kg/day; TAC 0.05 mg/kg/day) are useful and may be safe for maintenance of remission provided.

• Relapses are more frequent in the monotherapy group, when dose is lower (1.0-1.1 mg/kg) or when CsA levels are below 100 mg/mL

CP1256850-8

Cyclosporine in IMNCyclosporine in IMNResponders vs Responders vs NonrespondersNonresponders

Responders Nonresponders P

Age (yr) 40±9 55±10 <0.01

Scr (mg/dL) 1.1±0.4 2.1±0.8 <0.005

Proteinuria (g/24 hr) 5.6±3.3 4.8±3.5 NS

Segmental scars (%) 15% 33% <0.005

Obsolete glom (%)* 7% 28% <0.01

TIN fibrosis* 18% 52% <0.005

Responders Nonresponders P

Age (yr) 40±9 55±10 <0.01

Scr (mg/dL) 1.1±0.4 2.1±0.8 <0.005

Proteinuria (g/24 hr) 5.6±3.3 4.8±3.5 NS

Segmental scars (%) 15% 33% <0.005

Obsolete glom (%)* 7% 28% <0.01

TIN fibrosis* 18% 52% <0.005

Alexopoulos et al: Nephrology, 2002Alexopoulos et al: Nephrology, 2002

*Important also in multivariate analysis*Important also in multivariate analysis

CP1256850-16

Outcome of Renal FunctionOutcome of Renal FunctionInitial Treatment, 12 MonthsInitial Treatment, 12 Months

Pred + CsA CsA

Pre 5.1±2.5 4.9±1.5

Proteinuria <0.0001 <0.0001(g/24 hr) Post 1.1±2.7 1.1±0.8

Pre 1.2±0.4 1.0±0.2

Creatinine NS NS(mg/dL) Post 1.3±0.6 1.1±0.3

Relapses 0 0

Pred + CsA CsA

Pre 5.1±2.5 4.9±1.5


Pre 1.2±0.4 1.0±0.2


Relapses 0 0


CP1256850-17

No. % No. % No. %

Hypertension 8 25 4 20 12 23(new/aggravated)

Increase in Scr 8 25 5 25 13 25

No. % No. % No. %

Hypertension 8 25 4 20 12 23(new/aggravated)

Increase in Scr 8 25 5 25 13 25

Pred + CsAPred + CsA CsACsA TotalTotal

AlexopoulosAlexopoulos et al. NDT 21: 3127et al. NDT 21: 3127--3132, 20063132, 2006

Pred + CsA CsA

Pre 5.1±2.5 4.9±1.5


Pre 1.2±0.4 1.0±0.2


Relapses 0 0

Pred + CsA CsA

Pre 5.1±2.5 4.9±1.5


Pre 1.2±0.4 1.0±0.2


Relapses 0 0

CP1256850-11

Relapses of Proteinuria After CSA TreatmentRelapses of Proteinuria After CSA Treatment

RelapseCyA dose Duration of CsA rate(mg/kg) treatment (mo) (%)

Zietse et al, 1989 4-5 3 100

Guasch et al, 1992 4-6 3 78

Cattran et al, 2001 3.5 6 43

Rostoker et al, 1993 4.5 15 30

RelapseCyA dose Duration of CsA rate(mg/kg) treatment (mo) (%)

Zietse et al, 1989 4-5 3 100

Guasch et al, 1992 4-6 3 78

Cattran et al, 2001 3.5 6 43

Rostoker et al, 1993 4.5 15 30

CP1256850-21

Relapses and CsA Dose/LevelsRelapses and CsA Dose/Levels

Relapsers Non relapsers P

I) CsA dose (mg/kg)

Pred + CsA 1.0±0.3 1.4±0.5 <0.001

CsA 1.1±0.2 1.5±0.4 <0.003

II) CsA levels (Co) 72±48 194±80 <0.03(ng/mL)

Relapsers Non relapsers P

I) CsA dose (mg/kg)

Pred + CsA 1.0±0.3 1.4±0.5 <0.001

CsA 1.1±0.2 1.5±0.4 <0.003

II) CsA levels (Co) 72±48 194±80 <0.03(ng/mL)


Measured Creatinine ClearanceMeasured Creatinine Clearance

020406080

100120140160180

Entry 6 Months 9 Months 15 Months

Time Point

Cr

Cl

ml/m

in/S

A

83 ± 1784 ± 32 76 ± 20 81 ± 28

p 0.95

p 0.0.19

SummarySummary

•• Treatment with Tacrolimus was associated Treatment with Tacrolimus was associated with a significant drop in proteinuria.with a significant drop in proteinuria.

•• At final follow up:At final follow up:•• One patient achieved complete One patient achieved complete

remissionremission•• Five had subFive had sub--nephrotic range nephrotic range

proteinuriaproteinuria•• Four continued to suffer from nephrotic Four continued to suffer from nephrotic

range proteinuria range proteinuria

•• It is possible that complete remission may It is possible that complete remission may be achieved with longer periods of therapybe achieved with longer periods of therapy

••

CP1256850-10

CSA treatment for nephrotic syndrome in MN:CSA treatment for nephrotic syndrome in MN:outcome in prospective studies correlated to duration of outcome in prospective studies correlated to duration of

treatmenttreatment

Duration of CR PR Rtreatment (mo) (%) (%) (%)

Guasch et al, 1992 3 0 71 78

Zietse et al, 1992 3 0 NA 100

Cattran et al, 2001 6 7 68 43

De Santo et al. > 6 4/5 (80%)

Alexopoulos et al, 2000 11 25 60

Fritsche et al, 1999 12 34 NA

Rostoker et al, 1993 15 27 46 30

Duration of CR PR Rtreatment (mo) (%) (%) (%)

Guasch et al, 1992 3 0 71 78

Zietse et al, 1992 3 0 NA 100

Cattran et al, 2001 6 7 68 43

De Santo et al. > 6 4/5 (80%)

Alexopoulos et al, 2000 11 25 60

Fritsche et al, 1999 12 34 NA

Rostoker et al, 1993 15 27 46 30NA: not availableNA: not available

70

80

90

100

110

120

130

0 2 4 6 8 10 12 14 16

CP1151810-40

LowLow--Dose CSA May Reduce NephrotoxicityDose CSA May Reduce Nephrotoxicity41 Uveitis Patients41 Uveitis Patients

Bagnis et al: JASN, 2002Bagnis et al: JASN, 2002YearsYears

Ser

um

crea

tinin

e (�

mol

/L)

Ser

um

crea

tinin

e (�

mol

/L)

P<0.003P<0.003

CSA >3 mg/kg/dCSA >3 mg/kg/d

CSA ≤≤≤≤3 mg/kg/dCSA ≤≤≤≤3 mg/kg/d

n=28n=28

n=13n=13

CP1256850-19

LongLong--Term Treatment with CsATerm Treatment with CsA

Pred+CsA CsAn=26 n=17

Proteinuria (g/24 hr) 1.1±1.7 1.1±0.8

Scr (mg/dL) 1.3±0.6 1.1±0.3

CsA dose (mg/kg) 1.3±0.4 1.4±0.5

CsA dose (mg/day) 105±25 111±40

Follow-up (months) 26±16 18±7

Pred+CsA CsAn=26 n=17

Proteinuria (g/24 hr) 1.1±1.7 1.1±0.8

Scr (mg/dL) 1.3±0.6 1.1±0.3

CsA dose (mg/kg) 1.3±0.4 1.4±0.5

CsA dose (mg/day) 105±25 111±40

Follow-up (months) 26±16 18±7


CP1256850-24

Calcineurin Inhibitors in IMNCalcineurin Inhibitors in IMNGuidelines and AlgorithmGuidelines and Algorithm

Who to treat• Medium- and high-risk patients with the NS• Treat for a minimum of 6 months

Targets of treatment• CR or PR• Maintenance of GFR vs Reduction in Proteinuria• Co=125-200 ng/mL, C2=400-600 ng/mL

When to stop treatment• If no reduction by 50% of proteinuria by the end of

6 months therapy• If CR occurs taper off over 3-4 months• If PR occurs continue for 1-2 years and then taper gradually

Who to treat• Medium- and high-risk patients with the NS• Treat for a minimum of 6 months

Targets of treatment• CR or PR• Maintenance of GFR vs Reduction in Proteinuria• Co=125-200 ng/mL, C2=400-600 ng/mL

When to stop treatment• If no reduction by 50% of proteinuria by the end of

6 months therapy• If CR occurs taper off over 3-4 months• If PR occurs continue for 1-2 years and then taper gradually

the role of calcineurin inhibitors in the treatment of...

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