IgA Nephropathy: Treatment Update(and a tiny bit on pathogenesis)

Patrick H. Nachman, MDProfessor of Medicine

UNC Kidney CenterUniversity of North Carolina

Chapel Hill, NC USA

Outline

• Pathogenesis:

» Association with GI disease

• Risk factors of progression

• Treatment:

» Major therapeutic options

» Crescentic IgAN

» Point of No Return

Association of IgAN with Gastrointestinal Disease

• Inflammatory Bowel Disease• Celiac Disease• Liver Disease.

5/6/2015 3

Ambruzs JM et al Clin J Am Soc Nephrol 2014;9: 265–270

Ambruzs JM et al Clin J Am Soc Nephrol 2014;9: 265–270

Genome Wide Association Study in IgAN

Kiryluk K et al Nature Genetics 2014;46:1187-1196

Genome Wide Association Study in IgANLocus / Gene Role in intestinal mucosal immunity

ITGAM, ITGAX Regulation of intestinal IgA-producing plasma cells in Peyer’s patches.

CARD9 Association with risk of UC and Crohn’s dis.

VAV3 Required for colonic enterocyte differentiation and prevention of spontaneous ulceration

DEFA1, -3, -4, -5, -6 Anti-microbial peptides.Deficiency associated with Crohn’s dis.

TNFSF13 Encodes B cell stimulating cytokine that promotes IgA class switching. Induced by intestinal bacteria

LIF, OSM, HORMAD2,MTMR3

IgAN risk allele is protective of Crohn’s dis, and associated with increased IgA levels

PSMB8, PSMB9, TAP1, TAP2

PSMB8 upregulated in tissue with active IBD lesions

HLA- DQA1, HLA-DQB1,HLA-DRB1

Associated with risk of celiac disease, and IgA deficiency

Risk allele protective for UC

Adapted from Kiryluk K et al Nature Genetics 2014;46:1187-1196

Welander A et al. J Clin Gastroenterol. 2013 Sep;47(8):678-83.

Is IgAN Associated with Celiac Disease?Population-based prospective study:• 27,160 individuals with biopsy proven Celiac disease, and no previous renal

disease. Individuals with IgAN identified by the 4 Swedish renal pathology centers.

• 133,949 age- and sex-matched reference individuals

Mapping Immunogenic Epitopes in IgAN• Sera from 22 patients with biopsy-proven IgAN, healthy

controls (n=10), and non-IgAN glomerular diseases (n=17)

• A protein microarray used for detection of IgAN-specific IgA autoantibodies across ~ 9000 human antigens:» 54 proteins mounted highly significant IgA antibody

responses in patients with IgAN• Anti-tissue transglutaminase IgA was significantly

elevated in IgAN (P<0.001), but was not correlated with the decline of eGFR.

5/6/2015 9Woo SH et al . Clin J Am Soc Nephrol. 2015 Mar 6;10(3):372-81.

Moeller, S et al. PLoS ONE 2014; 9(4): e94677

IgAN : n= 99Age-, sex matched controls n=96Biopsy-proved Celiac dis: n= 30

Tests:IgG and IgA Ab to gliadin, deamidated gliadinIgA Ab to Transglutaminase 2-> Ab to Endomysial-> HLA-DQ2 and DQ8

IgAN in Liver Disease• Likely related to decreased clearance of IgA by

hepatocytes (Asialoglycoprotein Receptor)• High prevalence of mesangial IgA deposits in patients with

alcoholic cirrhosis (30-90%)• Hepatic IgAN is often asymptomatic microscopic

hematuria• Risk of progression to CKD and ESKD is unknown; Not

correlated with severity of cirrhosis• No specific therapy• Prognosis likely depends on severity of liver disease

5/6/2015 11Pouria S et al. Semin Nephrol 2008;28:27-37

Patterns of Clinical Presentation

• Episodic macroscopic hematuria» Acute renal failure with gross hematuria

• Asymptomatic hematuria and proteinuria• Rapidly progressive glomerulonephritis• Chronic renal failure• Nephrotic syndrome

IgA Nephropathy is a Chronic Disease

• 1/3 clinical remission: resolution of proteinuria and hematuria

• 1/3 progressive decline in GFR to ESRD over 20 yr

• 1/3 benign chronic course of persistent hematuria and proteinuria (< 1 g/d)

Natural History of “Mild” IgA

• 72 consecutive patients with hematuria and

< 0.4 g proteinuria/day

• Normal renal function

• Hong Kong population

• Mean age 27; 78% female

Szeto CC et al. Am J Med 2001; 434

Natural History of “Mild” IgA

• Median follow up 7 years

• 44% adverse events

» 33% proteinuric

» 26% hypertensive

» 7% impaired renal function

• 42% persistently abnormal urinalysis

• Only 10 patients (14%) went into complete remission

Szeto CC et al. Am J Med 2001; 434

IgA Nephropathy “Traditional” Risk Factors for Progression

• Hypertension (SBP>DBP)

• Initial impairment of renal function

• Familial disease

• Magnitude, duration and qualitative aspects of proteinuria

D’Amico G. Semin Nephrol 2004; 24:179-196

5/6/2015

Risk Factors for Progression: Creatinine

Donadio J et al. Nephrol Dial Transplant 2002; 1197-1203

Risk Factors for Progression: Proteinuria

Donadio J et al. Nephrol Dial Transplant 2002; 1197-1203

Slo

pem

l/min

/1.7

3m2 /y

ear

IgA N

FSGS

MN

Interaction between time average proteinuria and rate of renal function decline

Adapted from Cattran DC et al. Nephrol Dial Transplant 2008;23:2247-53

-18

-1

5 -1

2 -9

-6

-3

0

Remission of Proteinuria and Prognosis

Reich HN et al J Am Soc Nephrol 2007;18:3177-3183

partial remission (1 g/d) associated with similar outcome regardless of peak.Peak proteinuria:

Group 1, 1- 2 g/d Group 2, 2- 3 g/d;Group 3, >3 g/d.

5/6/2015 21Canetta PA et al. Clin J Am Soc Nephrol 2014; 9:617-625

Serum C3Serum IgA/C3Renal C3 deposition

IgA Nephropathy: Therapy

• ACE inhibitors and/or ARB*• Fish-oils* (omega-3 fatty acids; Omacor) • Glucocorticoids* (daily, alternate-day,

cyclical IV pulse/oral)• Azathioprine (plus steroids)• Cyclophosphamide* (plus steroids)• Warfarin + dipyridamole*• Azathioprine, steroid, dipyridamole*,

warfarin • Mycophenolate mofetil* (plus steroids)• Leflunomide• Cyclosporine(* RCT performed)

The real question is:

what to add to RAS inhibition…

IgA Nephropathy: Therapy

• ACE inhibitors and/or ARB*• Fish-oils* (omega-3 fatty acids; Omacor) • Glucocorticoids* (daily, alternate-day,

cyclical IV pulse/oral)• Azathioprine* (plus steroids)• Cyclophosphamide* (plus steroids)• Warfarin + dipyridamole*• Azathioprine, steroid, dipyridamole*, warfarin • Mycophenolate mofetil* (plus steroids)• Leflunomide• Cyclosporine• Tonsillectomy*(* RCT performed)

Lv J et al. Am J Kidney Dis 2009; 53(1): 26-32

Kidney survival estimated based on an increase up to 50% greater than baseline serum creatinine level and a decrease of 25% in

estimated glomerular filtration rate (eGFR).

ACE-I 30 29 28 10 3 0 29 28 10 3 0

Combo 33 32 30 14 3 0 32 30 16 3 0

# at risk

10 20 30 40 50

1.0

0.8

0.6

0.4

0.2

0.0

25% eGFR decrease

Combination

ACE inhibitor

Log Rank P<0.001

Pat

ient

Not

Rea

chin

g an

End

Poi

nt

Time (month)

1.0

0.8

0.6

0.4

0.2

0.010 20 30 40 50

50% creatinine increase

Combination

ACE inhibitor

Log Rank P=0.006

Pat

ient

Not

Rea

chin

g an

End

Poi

nt

Time (month)

Kaplan-Meier Analysis of Kidney Survival in the Two Treatment Groups

Manno C et al. Nephrol Dial Transplant 24(12):3694-701, 2009

Monotherapy represented by interrupted line; Combination therapy represented by solid line

Corticosteroids in IgA Nephropathy

• 86 patients• 6-month course of steroid treatment• Either supportive therapy or steroid

treatment (IV methylprednisolone)• 9/43 patients in steroid group and 14/43

in control group reached endpoint (50% in plasma creatinine) by year 5

Pozzi C et al. Lancet 1999; 353(9156):883-887

370 patients screened

86 eligible patients randomized

284 not eligible

43 assigned standard treatment

43 assigned steroid treatment

43 completed 6-month trial

43 completed 6-month trial

43 assigned standard treatment

43 assigned standard treatment

5 withdrawn3 dropped out1 lost to follow up1 protocol violation

7 withdrawn1 dropped out2 lost to follow up4 protocol violation

Pozzi C et al. Lancet 1999; 353:883-887Trial Profile

Corticosteroids in IgA Nephropathy

Pozzi C et al. J Am Soc Nephrol 2004; 15(1):157-163

VALIGA study

5/6/2015 30Tesar V et al. J Am Soc Nephrol 2015;26:****

5/6/2015 31Tesar V et al. J Am Soc Nephrol 2015;26:****

VALIGA study

5/6/2015 32Tesar V et al. J Am Soc Nephrol 2015;26:****

VALIGA studyOutcome RAS B RASB + CS P value

Rate of GFR decline (ml/min/1.73m2 per year)

-3.2±8.3 -1.0 ± 7.3 0.004

Change in proteinuria (g/d) -0.3 (-1.1 to 0.3) -0.8(-1.6 to -0.2) <0.001

Reduction in proteinuria to <1g/d 54 84 <0.001

ESRD 20 7 0.003

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VALIGA studyUP < 1 g/d UP 1 to <3 g/d UP > 3 g/d

Tesar V et al. J Am Soc Nephrol 2015;26:****

UP < 1 g/d UP > 1 g/d

Response to treatment based on time-average proteinuria before treatment

Renal survival based on achieving proteinuria < 1 g/d in response to treatment

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Azathioprine + Steroids vs Steroids alone

5/6/2015 35Pozzi C et al J Am Soc Nephrol. 2010 ;10: 1783–1790.

Sur

viva

l with

out 5

0% in

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se C

r

Prednisone and Cytotoxics in IgA Nephropathy

Ballardie FW, Roberts IS. J Am Soc Nephrol 2002; 13(1)142-8

Mean rate of declineof renal function wasreduced > 4-fold inthe treatment group.

Kaplan-Meier survivalfunctions in treatmentand control groups.Preservation of function significant after 2 yr (p = 0.006, log rank; p = 0.035, Tarone-Ware)

MMF in the Treatment of IgA Nephropathy

• Chen et al., NMJC 2002» Benefit from MMF in GFR and UPEX in 31

patients vs. 31 controls (prednisone)• Maes et al., KI 2004

» No benefit from MMF in 21 patients vs. 13 controls

• Tang et al., KI 2005» Improvement in UPEX in 20 patients on

MMF vs. 20 controls• Frisch et al., NDT 2005

» No benefit from MMF in 17 patients with severe, chronic IgAN vs. 15 controls

Tonsillectomy + Steroids vs Steroids alone

5/6/2015 38

prot

einu

ria

Com

plet

e re

mis

sion72 patients

Proteinuria 1-3.5 g/d; Cr ≤ 1.5 mg/dlGp A: Tonsillectomy + pulse steroid (Pozzi)Gp B: pulse steroids

Kawamura T et al. Nephrol Dial Transplant (2014) 29: 1546–1553

Efficacy of Tonsillectomy on Long-Term Survival in IgAN

• 118 IgAN biopsies 1973-1980• 48 post-tonsillectomy; 70 without tonsillectomy• No difference in age, gender, UProt, SCr, SIgA,

BP, histology, treatment• Renal survival 90% with tonsillectomy vs. 64%

without at 240 months. • By MVA tonsillectomy has significant effect on

outcome.• Tonsillectomy has favorable effect on long-term

outcome IF performed early in the course.

Xie Y et al. Kidney Int 63:1861-1867, 2003

PN3

PN4

Slide 39

PN3 Patrick Nachman, 4/2/2015

PN4 change to RCT of tonsillectomyPatrick Nachman, 4/2/2015

Crescentic IgA Nephropathy

• 205 patients; mean F/U 7.9 years [ 1 to 22 years] .

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Group % Crescents 10-Yr Survival1 0 100%2 <25 94.3%3 25-50 82.8%4 >50 25.5%

Abe T et al. Clin Nephrol 1986;25:37-41

• 12 patients with crescentic (>10%) proliferative IgA N• Pulse methylpred x 3 days, then monthly IV

cyclophosphamide x 6 months• mean SCr decreased from 2.65±0.39 to 1.51±0.10 mg/dl

(P=0.03), • proteinuria decreased from 4.04 to 1.35 g/24 h (P=0.01).• Repeat kidney biopsy: elimination of endocapillary

proliferation, cellular crescents and karyorrhexis in all 12 patients after 6 months of therapy

JA Tumlin et al. Nephrol Dial Transplant 2003;18:1321-9

Crescentic IgA Nephropathy

Crescentic IgA N• 25 patients with diffuse crescentic IgA N (median 65%

crescentic glomeruli, range 50-95%)

• 88% with RPGN, creatinine 418 +/- 264 micromol/l. • 21 were treated with pulse methylpred + Cyclophos.

15 followed for more than 6 months (median 29.8 [range 8-92])» 10 did NOT reach ESRD, (4 with normal SCr, and

UP<1.5g/d) .» 5 reached ESRD at 0, 6 (x2) and 12 (x2) months

5/6/2015 Tang Z et al Am J Nephrol. 2002;22:480-6.

“Point of No Return (PNR)” in Patients with IgAN?

• Important controversial issue if potentiallytoxic therapy is to be avoided in patientswho will receive no benefit from treatment

• D’Amico et al (1993) raised concept andproposed SCr of 3.0 mg/dL as PNR

• Scholl et al (1999) concurred with D’Amico• Komatsu et al (2005) found SCr of 2.0

mg/dL to be PNR in Japanese patients

"Point of no return (PNR)" in progressive IgA nephropathy:

• Retrospective analysis the sequential data of patients with 1.2 <or= sCr <2.0 mg/dL at renal biopsy.

• 47 patients with moderate to severe histological lesions and whose 36-month follow-up did not require renal replacement therapy.

• None of the patients who exceeded sCr 2.0 mg/dL could return to <2.0 mg/dL ( F/U103.3 +/- 54.3 (36-237) months).

• Multivariate analysis: Risk factors of ESRD until sCrreached 2.0 mg/dl: » MBP: HR 2.56 (per 10 mmHg; (95% CI) 1.08-6.05) » UP: HR 4.37 (per 0.5 point; 95% CI 1.36-14.1).

Komatsu H et al. J Nephrol. 2005 Nov-Dec;18(6):690-5.

PN2

Slide 44

PN2 need to review. acute vs chronic? treatment? what was adjusted for? endpoint is return to Cr <2 vs ESRD? did treatment delay ESRD?Patrick Nachman, 4/2/2015

"Point of no return (PNR)"

5/6/2015

D’Amico G et al. Contrib Nephrol1993;104:6-13

Risk factors of ESRD until sCr reached 2.0 mg/dl:

MBP: HR 2.56 (per 10 mmHg; (95% CI) 1.08-6.05) UP: HR 4.37 (per 0.5 point; 95% CI 1.36-14.1).

Komatsu H et al. J Nephrol. 2005;18:690-5.

Point of No Return• 115 patients • 3 courses could be distinguished:

» a stable chronic course (91 patients), » early acute course followed by a rapid return to the normal

range. (only 2 patients)» a progressive course with increasing SCr (22 patients),

• After SCr exceeding 3 mg/dl no remissions were observed in the progressive cases.

• 16 patients showed a rapid, continuously progressive course until ESKD. SCr doubled from 3 to 6 mg/dl within an average of 10 months (range 2.5 to 21 months).

5/6/2015 46Schöll U et al Clin Nephrol. 1999 Nov;52(5):285-92.

Treatment According to KDIGO Guidelines• Recommendation

» ACE-I or ARB for urinary protein excretion of > 1 g/day; dose depending on BP (1B)

• Suggestions» Proteinuria

• ACE-I or ARB if urinary proteinuria 0.5-1.0 g/day; dose if adverse events are acceptable to achieve urinary protein excretion of < 1 g/day (2D)

• 6-mo glucocorticoid therapy if proteinuria > 1 g/day continues after 3-6 mos of ACEi or ARB, and GFR > 50 ml/min (2C)

• Fish oil of proteinuria > 1 g/day continues after 3 to 6 mos (2D)» Blood Pressure

• < 130/80 mm Hg if proteinuria is < 1 g/day, but < 125/75 mm Hg if initial proteinuria is > 1 g/day (not graded)

» Rapidly Declining eGFR• Glucocorticoids + cyclophosphamide for crescentic IgA (>50%

glomeruli with crescents) with rapid deterioration of eGFR (2D)Wyatt JR, Julian BA. N Engl J Med 2013; 368:2402-14

Approach to Treatment of IgA Nephropathy

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Patient Clinical Features InterventionsAll patients BP control < 130/80 mm Hg

Strongly consider ACEI or ARBConsider statinConsider tonsillectomy if recurrent tonsillitis+/- fish oils per patient preference

Mild disease Normal GFRProteinuria < 500 mg/dBenign histologyNormal BP

Watchful waitingEnrollment into prospective observational studies

Moderate/severe disease

Proteinuria > 1 g/d or proteinuria 0.5-1 g/d with other features suggesting risk of progressionHistologic signs suggesting risk of progression (mesangial hypercellularity, endocapillary proliferation, segmental sclerosis)

Glucocorticoids x 6 mos (trials showing benefits from steroid-treated patients with relatively preserved GFR and proteinuria > 1 g/d)Consider cytotoxics (i.e., cyclophosphamide)Enrollment into clinical trials

“Point of no return” Low GFR, typically < 30 ml/min/1.73 m2

Biopsy with severe global glomerulosclerosis and tubular atrophy/interstitial fibrosis

No immunosuppressionPrepare for transplant or renal replacement therapy

Crescentic IgAN Rapidly progressive GN> 30%-50% cellular or fibrocellular crescents on biopsy

Pulse + high-dose oral glucocorticoidsConsider cyclophosphamide

IgAN with minimal change disease

Sudden-onset nephrotic syndromeMesangial IgA deposits on biopsy without sufficient sclerosis to explain proteinuria

Glucocorticoids, akin to treatment of minimal change disease

Canetta PA et al. Clin J Am Soc Nephrol 2014; 9:617-625

Current Clinical Trials in IgA Nephropathy• Supportive Versus Immunosuppressive Therapy for the Treatment Of

Progressive IgA Nephropathy (STOP-IgAN) - NCT00554502, Phase 3» 148 patients» Group A: Supportive therapy with ACE-inhibitor/ ARB/ Statin» Group B: immunosuppressive treatment:

• GFR > or =60 ml/min: steroids• GFR <60 ml/min: steroids plus cyclophosphamide/azathioprine .

» Primary outcome measures: patients reaching full clinical remission of their disease at the end of 3-yr study period

» GFR loss of 15 ml/min or higher from baseline GFR at end of 3-yr study period

• Therapeutic Evaluation of Steroids in IgA Nephropathy Global Study (TESTING Study) NCT01560052

» 1300 patients» Oral methylprednisolone 0.8mg/kg/day (≤ 48mg/day)×2 months, taper by 8mg/day every

month to stop within 6-8 months; + ACE inhibitors or ARBs vs ACE inhibitors or ARBs

» Primary Outcome Measures: composite of a 50% decrease in eGFR, the development of ESKD or death from kidney disease.

49

• Pilot Open Label Study of C5aR inhibitor (CCX168)» 20 patients, Proteinuria > 1 g/d , Stable eGFR > 45 ml/min/1.73» Max tolerated RAAS blockade» 8 week run-in period, 12 week treatment, 8 week follow up.

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Current Clinical Trials in IgA Nephropathy