howitreatiganephropathy - unc kidney center...suppor8ve-care-• acei-or-arb-to-targetprotein-

HOW I TREAT IGA NEPHROPATHY

Michelle Hladunewich, MD Associate Professor of Medicine University of Toronto Director, Divisions of Nephrology & Obstetric Medicine Sunnybrook Health Sciences Centre Clinical Director of Research, Toronto GN Registry

Disclosures/My Interests

•  Canadian PI for the Tes8ng Study •  Site inves8gator for Bright Study

(blisibimod -‐Anthera) – opted not to run in Canada

•  Medical lead for Glomerulonephri8s and Specialty Clinics for the Ontario Renal Network.

Why is IgA my least Favorite GN?

•  Globally -‐ most common primary glomerular disease – Asians>Caucasians>Blacks •  10% (US AJKD 2016) – 45% (China KI 2004) •  Toronto GN registry ≈ 40%

•  Peak Incidence 2 and 3rd decade of life •  Up to 40% of pa8ents with biopsy-‐proven

IgAN will progress to ESRD (silent killer) •  Treatment op8ons are sparse, toxic and the

subject of much debate •  Complicates pregnancy

planning

IgA Nephropathy

•  Defined by predominant IgA deposi8on in the glomerular mesangium

•  Has a highly variable phenotype and clinical outcome

•  Asymptoma8c microscopic hematuria, proteinuria •  Synpharyngi8c gross hematuria •  RPGN •  With nephro8c syndrome and diffuse foot process

effacement •  Progressive CKD

Most Relevant Clinical Ques8ons

•  Iden8fica8on of those at highest risk for progression

•  Suppor8ve Care •  Steroids – To treat or not to treat •  STOP IgA versus Tes8ng Study

•  What else is there? •  Now •  On the Horizon

RISK FACTORS FOR PROGRESSION IN IGA NEPHROPATHY

Risk factors for Progression in IgAN

•  Clinical •  GFR •  Proteinuria •  Race •  Gender •  BMI

•  Histological •  MEST Score or the

Oxford criteria •  Crescents •  FSGS •  Immunoglobulin

staining

Clinical Risk Factors -‐ GFR

Zhang et al PLOS 2017

Clinical Risk Factors -‐ Proteinuria

•  542 pa8ents followed for 6.5 years

Reich et al. JASN 2007


•  Par8al remission improves outcome •  Worsening proteinuria hastens progression •  Irrespec8ve of baseline proteinuria


NS difference in outcome irrespec8ve of star8ng proteinuria in remiiers, but those who started low and worsened did worse

Clinical Risk Factors -‐ Race

•  202 Pacific Asian compared to 467 other •  Higher rate of progression by 1.62 ml/yr •  Increased risk for loss of ½ GFR

•  (HR 1.81; 95% CI1.25-‐2.62)

Barbour et al KI 2013

Clinical Risk Factors -‐ Gender

•  Women not afforded the usual protec8on

Cairan et al. NDT 2008

Clinical Risk Factors -‐ BMI

Baseline Normal BMI Overweight/Obese P Value

Urine Protein > 1g 22% 40% P=0.006

Hypertension 25% 53% P<0.001

eGFR 80 69 P=0.003

Follow-‐up

CKD ≥ Stage 3 21% 43% P=0.001

Berthoux NDT 2013

N=331

Histological Risk Factors •  Oxford Criteria •  Mul8na8onal review of 265 cases of IgA

•  ≥ 0.5 g/day protein, ≥ 30 ml/min GFR and median 5 years of follow-‐up

•  Iden8fied reproducible pathology criteria that had independent predic8ve value

Cairan et al KI 2009

Histological Risk Factors

•  Oxford Criteria

Cairan et al KI 2009

Histological Risk Factors •  VALIGA Valida8on •  1147 mostly Caucasian pa8ents from Europe

unrestricted criteria •  Full spectrum of IgA presenta8on and

treatment •  All lesions except E predicted renal func8on

decline •  Subgroup with <0.5 g/day – M and E predicted

progression to higher grade proteinuria •  Predic8ve value of the MEST was reduced by

immunosuppression

Coppo et al KI 2014

Histological Risk Factors Barbour et al KI 2016


Barbour et al KI 2016

Addi8on of the MEST score to clinical data at the 8me of biopsy was as accurate as 2 years of clinical FU data

Histological Risk Factors •  Crescents

•  C0 no crescents •  C1 crescents <¼: at risk of poor outcome without

immunosuppression •  C2 crescents >¼: at risk of poor outcome even with

immunosuppression •  FSGS lesions •  Tip lesions, hyalinosis & perihilar sclerosis •  Worse outcomes compared to S1 without •  Immunosuppression associated with beier renal

survival •  Immunostaining •  Glomerular IgG trend toward worse renal survival

Haas et al JASN 2017

Bellur et al KI 2017

Bellur et al NDT 2011


Trimarchi et al KI 2017

IGA NEPHROPATHY MANAGEMENT

KDIGO Treatment Recommenda8ons

Suppor8ve Care

•  ACEi or ARB to target protein < 1 g/d •  STOP-‐IgAN 106 of 309 did not qualify aver a 6 month run-‐in

period with protein <0.75 g •  Tes8ng Trial 128 of 523 screened did not qualify aver a 3 month

run-‐in period with protein <1.0 g Aggressive BP control with RAS blockade is cri8cal Dual agent blockade used less -‐ concerns about increased K

•  Sta8ns •  Small placebo controlled RCT demonstrated protein lowering •  STOP-‐IgAN also op8mized sta8n therapy

•  Fish oil > 1g/day •  EPA > 1800 mg and DHA > 1000 mg •  Meta analysis data may lower proteinuria

Buemi Clin Phamacol Ther 2000

Chou et al Nephron Clin Pract 2012

Suppor8ve Care

•  STOP-‐IgAN •  1st RCT to carefully op8mize conserva8ve

therapy •  BP Target was < 125/75 mmHg •  If proteinuria > 0.75 g RAS was further increased to max

approved dose or as tolerated •  Dietary counseling (BMI 27.9 ±5.3) •  Sta8n to lower cholesterol to < 200 mg/dl •  Counseled on smoking cessa8on and avoidance of

nephrotoxins (eg NSAIDs)

•  -‐1.6 ml/min/1.73m2 yearly

Rauen et al NEJM 2015

Suppor8ve Care

•  Weight loss not protein restric8on

Kixskulnam P et al J Ren Nutr 2014

Immunosuppressive Therapy

•  Pathogenesis supports immunosuppressive agents -  T and B cell involvement -  Cytokines (BAFF) -  Poorly galactosylated IgA1 (auto an8gen) -  IgG autoan8body -  Ac8va8on of the alternate complement pathway

Rodrigues et all CJASN 2017

Cor8costeroids

28

.01 1.0 10

Study Risk raKo (95% CI)

Risk raKo (95% CI)

Events/paKents Steroids control

1.09 (0.23,5.13) Katafuchi 2003 0.31 (0.04,2.74) Julian 1993 0.20 (0.02,1.64) Pozzi 2004 0.18 (0.01,3.65) Lv 2009 0.15 (0.02,1.14) Manno 2009

Lai 1986 (Excluded) Shoji 2000 (Excluded)

0.36 (0.15,0.91),p=0.03 (I -‐ square =0.0%,p=0.578) Overall (95% CI)

0/11

1/43

0/17

1/18

0/8

5/43

0/17

3/17

0/33 1/48

2/30 7/49

3/43 3/47

6/213 20/211

1.09 (0.23,5.13) Katafuchi 2003 0.31 (0.04,2.74) Julian 1993 0.08 (0.01,0.56) 0.18 (0.01,3.65) Lv 2009 0.15 (0.04,0.65) Manno 2009

Lai 1986 (Excluded) Shoji 2000 (Excluded)

0.26 (0.10,0.70),p=0.008 (I -‐ square=28.2%,p=0.234) Overall (95% CI)

0/11 0/17

0/8

1/43 13/43

3/43 3/47

0/17

1/18 3/17

2/48 13/49

7/213 34/211

0/33 2/30

Doubling of serum creaKnine or ESKD

ESKD

Figure 3: cor8costeroids therapy on the outcomes of doubling of serum Crea8nine or ESKD Favours cor8costeroids Favours control

Lv et al JASN 2012

Cor8costeroids

•  Most single centre, leading to uncertainty about the balance of benefits and risks when applied across mul8ple centres with varying exper8se in this area

•  Sover endpoints, leading to uncertainty about the clinical importance of the findings

•  Subop8mal quality •  Small sample size (each less than 100 par8cipants),making

them suscep8ble to type 1 errors •  Data regarding the poten8al harms of cor8costeroid therapy

were not collected in a systema8c and consistent fashion •  Suppor8ve therapies were oven sub-‐op8mally provided •  The par8cipants chosen were not necessarily those at highest

risk of progressive loss of kidney func8on and kidney failure

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STOP IgA Nephropathy

•  1st RCT with a careful run in period on conserva8ve therapy


Protein > 0.75 g; GFR 30-‐90 ml/min Excluded protein > 3.5 g


•  Immunosuppression


•  Conclusions •  Addi8on of immunosuppression did not have

meaningful impact on outcome at 3 years, but caused increased adverse effects

•  Limita8ons •  Powered for clinical remission and there was

a difference •  Mixed IS regimens limited power •  Short follow-‐up 8me of 3 years •  Pa8ents studied not high risk enough


•  Limita8ons •  Short follow-‐up 8me of 3 years



•  Limita8ons •  Pa8ents studied not high risk enough

Pozzi Ballardie STOP IgA

IS Con IS Con IS Con

Proteinuria 2.0 1.8 4.4 4.8 1.8 1.6

GFR 93 87 NA NA 61 57

Risk of 1° Outcome 5% 26% 28% 95% 5% 17%


•  Limita8ons •  Pa8ents studied not high risk enough and

they excluded >3.5 g Tesar JASN 2015

< 1g 1-‐3 g > 3 g

Aim: Long-‐term efficacy and safety of oral methylprednisolone on a background of RAS inhibitor therapy, in pa8ents with IgA nephropathy at a high risk of progression > 1 gram of urine protein

TESTING Trial Design

V1 (-‐4wks) Register

V2 V3 V4 (0m)

RandomizaKon

V5 (1 m)

V6 (3m)

V7 (6m)

V9 (12m)

V13 (24m)-‐final (every 12 month)

ACE inhibitors or ARBs to full dose* blood pressure control as guidelines

Placebo

Methylprednisolone/matching placebo 0.6-‐0.8mg/kg/d (maximal 48mg/d) 2 months tapered at 8mg daily/month

Stopped within 6-‐8 months

ACE inhibitors or ARBs to full dose blood pressure control as guidelines

Final visit-‐End of Trial

Screening and run-‐in phase 4 to 12 weeks

Steroids treatment 6-‐8 months

Follow up un8l 335 events observed Visit every 12 months

ACE inhibitors or ARBs to full dose blood pressure control as guidelines

Sample size: 750 par8cipants, or total 335 primary outcome events 90% power to detect a 30% rela8ve risk reduc8on for primary outcome Follow-‐up : 4-‐6 years

Hong Zh, ERA Congress Vienna 2016

Efficacy Outcomes

•  Primary end points: •  Composite of a persistent 40% decrease in eGFR, ESKD,

or death due to kidney disease

•  Secondary end points: •  40% decrease in eGFR, ESKD or all-‐cause death •  50% decrease in eGFR, ESKD or all-‐cause death •  Each of 40% decrease in eGFR, ESKD or all-‐cause death •  Annual rate of eGFR decline •  Proteinuria reduc8on

43

Safety outcomes Pre-‐specified

•  Serious infec8ons requiring hospitaliza8on •  New onset diabetes mellitus •  Clinically apparent gastrointes8nal haemorrhage

requiring hospitalisa8on •  Clinically evident fracture or osteonecrosis •  Cardiovascular events, defined as a composite of

myocardial infarc8on, stroke , heart failure requiring hospitaliza8on or death due to cardiovascular disease

44

IDMC Communica8on November, 2015

‘……….Concern over an imbalance in severe adverse events between the test and control treatment groups and airibu8on of the majority of the severe adverse events to the test medica8on, methylprednisolone, has led the DSMB to conclude that the trial should not con8nue in its current form………..’

45

Trial Profile 523 pa8ents screened

262 randomized

261(50%) excluded during run-‐in phase: 31 (12%) es8mated GFR <20 or >120ml/min/1.73m2

128 (49%) proteinuria <1g/day 3 (1%) HBsAG +ve 74 (28%) par8cipant decision 25 (10%) other reasons

136 assigned to methylprednisolone

126 assigned to placebo

2 lost follow-‐up 0 lost follow-‐up

134 primary outcome available 126 primary outcome available

From May 2012 to November 2015

CharacterisKcs Methylprednisolone (N=136)

Placebo (N=126)

Age -‐ yr 38.6 ±11.5 38.6±10.7 Female sex – no. (%) 50 (36.8%) 46 (36.5) Race – no. (%) Chinese 130 (95.6) 121(96.0) Caucasian 5 (3.7) 3 (2.4) South-‐East Asian 1 (0.7) 2(1.6) Smoker -‐ % 34 (25.0) 31 (24.6) Body-‐mass index 24.4 ± 4.5 23.4 ± 3.7 Hypertension-‐no.(%) 71 (52.2) 52 (41.3) Blood pressure -‐ mmHg systolic 123.9 (14.7) 124.3 (11.6) diastolic 79.3 (10.5) 79.8 (9.9) Urine protein excreKon – g/day 2.55 (2.45) 2.23 (1.11) Serum creaKnine – mg/dl 1.5 (0.6) 1.6 (0.6) EsKmated GFR – ml/min/1.73m2 59.6 (24.1) 58.5 (23.1) Total Cholesterol – mg/dl 188.9 (39.0) 191.8 (51.1) Oxford histological Score M1 lesion – no. (%) 76 (57.6) 75 (61.0) E1 lesion – no. (%) 43 (31.6) 30 (23.8) S1 lesion – no. (%) 94 (71.2) 89 (72.4) T0/T1/T2 lesion – no. (%) 51(38.6%)/58(43.9)/23(17.4) 43(35.0)/60(48.8)/20(16.3) *Plus–minus values are means ±SD †The esKmated glomerular filtraKon rate (GFR) was esKmated with the use of the Chronic Kidney Disease Epidemiology CollaboraKon CreaKnine EquaKon.

47

Baseline Characteris8cs

Effect on Proteinuria

48

Month Mean Δ p value 3 -‐0.83 <.0001 6 -‐1.00 <.0001 12 -‐1.20 <.0001 24 -‐1.03 <.0001 36 -‐0.93 0.0077

Time averaged proteinuria: 1.37 vs 2.36 g/day (42% lower)

P<0.001

0.5

1

1.5

2

2.5

3

0 10 20 30 Month

Methylprednisolone

Placebo

Effect on eGFR

49

Month Mean Δ p value 3 5.14 0.0019 6 6.74 <.0001 12 4.62 0.0091 24 5.43 0.0088 36 7.67 0.0092

*-‐ defined for each individual pa8ent using the slope from least squares linear regression of all eGFR es8mates over 8me

20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70

0 10 20 30

Placebo

Methylprednisolone

Annual eGFR slope*: -1.7 vs -6.8 ml/min/1.73m2/yr

P=0.031

-‐1.25

-‐4.42

Primary Outcome

50

composite of ESKD, renal death or 40% decrease in eGFR

HR 0.37 (0.17-0.85) p= 0.019

0 6 12 18 24 30 36 42 136 109 96 76 55 35 18 0 126 119 107 84 65 46 22 2

51

Subgroup Methylprednisolone group (N=136)

Placebo group (N=126)

P Value

Primary End Point

40% es8mated GFR decrease, ESKD or renal death – no. 8 20 0.019

Secondary End points

40% es8mated GFR decrease, ESKD or all death – no. 10 20 0.034

50% es8mated GFR decrease, ESKD or all death – no. 10 15 0.293

40% es8mated GFR decrease – no. 7 16 0.047

50% es8mated GFR decrease – no. 7 11 0.330

ESKD or renal death – no. 4 9 0.156

Death – no. 2 1 1.000

1Rate of es8mated GFR decline with method 1 -‐1.71 -‐6.78 0.031

2Rate of es8mated GFR decline with method 2 -‐1.25 -‐4.42 0.005

8me average proteinuria –g/day 1.37±1.08 2.36±1.67 p<0.001

1 Method 1: defined for each individual pa8ent using the slope from least squares linear regression of all eGFR es8mates over 8me 2 Method 2: defined as method 1, but excluding the treatment period with highest steroid exposure i.e. excluding eGFR values from month 1 and month 3

Rela8ve Effects of Steroids on Pre-‐Specified Primary and Secondary Outcomes

Serious Adverse Events

52

Hazard ratio 4.95 (95% CI 1.87-17.0), p=0.003

3.2% 14.7%

0 6 12 18 24 30 36 42 136 109 96 76 55 35 18 0 126 119 107 84 65 46 22 2

Time (months)

Outcome Methylprednisolone group (N=136)

Placebo group (N=126)

P Value

Total paKents with serious adverse events 20 4 0.001

Serious adverse events of infecKon 11 0 <.001

Fatal infec8on 2 0 NS

Pneumocys8s jirovecii pneumonia 3 0 NS

Other lung infec8on 2 0 NS

Sep8c arthri8s 1 0 NS

Perianal infec8on 1 0 NS

GastrointesKnal serious adverse events 3 1 NS

Bone disorders

Avascular necrosis 3 0 NS

Fracture 1 0 NS

New onset diabetes mellitus 2 3 NS Hong Zh, ERA Congress Vienna 2016

TESTING Safety

54

TESTING study STOP-‐IgAN study

Sample size 262 162

Race Asian 96.3% Caucasian 3.7% Caucasian

Age 38.6 44.5

Female (%) 36.7% 21.5%

Systolic (mmHg) 124.1 125.5

Diastolic (mmHg) 79.5 77.5

Proteinuria (g/d) 2.4 1.7

eGFR (ml/min/1.73m2) 59 59

Annual eGFR decline in supporKve group -‐4.4 -‐1.6

Annual eGFR decline in IS group -‐1.3 -‐1.5

TESTING vs. STOP-‐IgAN

55

Proteinuria during follow-up and GFR decline including TESTING and STOP-IgAN

TESTING vs. STOP-‐IgAN

•  TESTING study control arm •  Expected: -‐4.484ml/min/1.73m2 •  Actual : -‐4.420ml/min/1.73m2

•  STOP study control arm •  Expected: -‐3.23ml/min/1.73m2

•  Actual: -‐1.6ml/min/1.73m2

56

Safety

Immunosuppression arm comparison Outcome STOP IgAN TESTING SAEs 29 (35%) 20 (14.7%) Serious infec8ons 8 (9.8%) 11 (8.1%) Fatal infec8ons 1 (1.2%) 2 (1.5%)

57

TESTING Low Dose Study -‐ Therapeu8c Evalua8on of STeroids in IgA Nephropathy Global low dose study •  Low-‐dose cohort: oral methylprednisolone 0.4mg/

kg/day ini8ally, maximal dose of 32mg/day, minimum dose of 24mg/day and then reducing over 6-‐9 months

•  Compared to matching placebo (double-‐blind) •  All par8cipants will also receive standard guideline

based care •  ProphylacKc trimethoprim/sulfamethoxazole

(one single strength or half a double strength tablet daily or every other day) will be used during the first 3 months

58

Outcomes -‐combined cohort

Overall Primary outcomes •  Progressive kidney failure: 40% decrease in eGFR, ESKD, and death due

to kidney disease Overall Secondary outcomes for combined cohorts •  The composite of ESKD, 30% decrease in eGFR and all cause death •  The composite of ESKD, 40% decrease in eGFR and all cause death •  The composite of ESKD, 50% decrease in eGFR and all cause death •  Each of ESKD, death due to kidney disease and all cause death •  Annual eGFR decline rate •  Time averaged proteinuria post-‐randomiza8on

500 par8cipants in total will provide 90% power (α=0.05) to detect a 40% risk reduc8on aver an average follow-‐up of 4 years, and 80% power to detect a 35% RRR

59

Other Immunosuppressive Regimens

•  Rituximab – Failed •  MMF – Mixed results •  CNI’s – Limited Data with a adverse SE •  Azathioprine -‐ Failed •  New Therapies – Desperately Needed

Lafayette et al. JASN 2016

Rituximab

•  34 adults randomized •  Inclusion: Upro >1g/day despite RASB,

eGFR>90 •  Primary outcome: change in Upro, GFR

RTX Cont

Mycophenolate Mofe8l Tang et al KI 2005

Mycophenolate Mofe8l

Hogg et al AJKD 2015

Calcineurin Inhibitors

Song et al BMC Nephrol 2017

Azathioprine Pozzi JASN 2010

New on the Horizon

•  Oral Budesonide (Nefecon) •  Locally on mucosal Lymphoid Tissue •  Phase 2 RCT in pa8ents > 0.75 g and GFR > 40 ml/

min •  27% reduc8on on proteinuria while placebo group

had a 3% increase •  GFR change less in Budesonide group •  22% stopped due to adverse SE

•  Acthar Gel, a purified form of ACTH •  Bortezomib, a proteasome inhibitor •  Fostama8nib, an oral spleen tyrosine kinase

inhibitor

In Summary

•  IgA is a progressive disease in many pa8ents

•  We know who is at risk •  Treatment op8ons are not benign •  Steroids: equipoise for ongoing study

•  Collabora8ve studies to test novel agents are desperately needed

howitreatiganephropathy - unc kidney center...suppor8ve-care-• acei-or-arb-to-targetprotein-

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