IgA Nephropathy: Treatment Update

(and a tiny bit on pathogenesis)

Patrick H. Nachman, MD
Professor of Medicine
UNC Kidney Center
University 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

Ambruzs JM et al Clin J Am Soc Nephrol 2014;9: 265270

Ambruzs JM et al Clin J Am Soc Nephrol 2014;9: 265270

Genome Wide Association Study in IgAN

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

Genome Wide Association Study in IgAN

Locus / Gene

Role in intestinal mucosal immunity

ITGAM, ITGAX

Regulation of intestinal IgA-producing plasma cells in

Peyers patches.

CARD9

Association with risk of UC and Crohns dis.

VAV3

Required for colonic enterocyte differentiation and

prevention of spontaneous ulceration

DEFA1, -3, -4, -5, -6 Anti-microbial peptides.

Deficiency associated with Crohns dis.
Encodes B cell stimulating cytokine that promotes IgA class
switching. Induced by intestinal bacteria

TNFSF13

LIF, OSM,
IgAN risk allele is protective of Crohns dis, and associated
HORMAD2,MTMR3 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

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

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

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

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

IgAN : n= 99
Age-, sex matched controls n=96
Biopsy-proved Celiac dis: n= 30
Tests:
IgG and IgA Ab to gliadin, deamidated
gliadin
IgA Ab to Transglutaminase 2
-> Ab to Endomysial
-> HLA-DQ2 and DQ8

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

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

Pouria S et al. Semin Nephrol 2008;28:27-37

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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

DAmico G. Semin Nephrol 2004; 24:179-196

Risk Factors for Progression: Creatinine

5/6/2015

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

IgA N

MN

-15 -12 -9

-6

FSGS

-18

ml/min/1.73m2/year

Slope

-3

Interaction between time average proteinuria

and rate of renal function decline

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

Remission of Proteinuria and Prognosis

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

Serum C3
Serum IgA/C3
Renal C3 deposition

5/6/2015

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

21

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)

50% creatinine increase

1.0

0.8

Log Rank P=0.006

0.6

0.4

0.2
0.0
10

Combination
ACE inhibitor
20

30

40

50

Patient Not Reaching an End Point

Patient Not Reaching an End Point

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).
25% eGFR decrease
1.0

Log Rank P<0.001

0.8

0.6

0.4

0.2

Combination
ACE inhibitor

0.0
10

20

Combo

40

50

Time (month)

Time (month)
# at risk
ACE-I

30

30

29

28

10

29

28

10

33

32

30

14

32

30

16

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

Kaplan-Meier Analysis of Kidney Survival in

the Two Treatment Groups

Monotherapy represented by interrupted line; Combination therapy

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

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

Corticosteroids in IgA Nephropathy

Trial Profile

370 patients
screened

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

284 not
eligible
86 eligible patients
randomized
43 assigned
standard treatment

43 assigned
steroid treatment

43 completed
6-month trial

43 completed
6-month trial
5 withdrawn
3 dropped out
1 lost to follow up
1 protocol violation

7 withdrawn
1 dropped out
2 lost to follow up
4 protocol violation
43 assigned
standard
treatment

43 assigned
standard
treatment

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

VALIGA study

5/6/2015

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

30

VALIGA study

5/6/2015

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

31

VALIGA study
Outcome

RAS B

RASB + CS

P value

Rate of GFR decline

(ml/min/1.73m2 per year)

-3.28.3

-1.0 7.3

0.004

-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

0.003

Change in proteinuria (g/d)

5/6/2015

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

32

VALIGA study
UP < 1 g/d

UP 1 to <3 g/d

UP > 3 g/d

UP < 1 g/d

Response to
treatment based
on time-average
proteinuria before
treatment

UP > 1 g/d

Renal survival
based on
achieving
proteinuria < 1 g/d
in response to
treatment
5/6/2015

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

33

5/6/2015

34

Survival without 50% increase Cr

Azathioprine + Steroids vs Steroids alone

5/6/2015

Pozzi C et al J Am Soc Nephrol. 2010 ;10: 17831790.

35

Prednisone and Cytotoxics in IgA Nephropathy

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

Mean rate of decline

of renal function was
reduced > 4-fold in
the treatment group.
Ballardie FW, Roberts IS. J Am Soc Nephrol 2002; 13(1)142-8

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

proteinuria

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

Complete remission

Tonsillectomy + Steroids vs Steroids alone

5/6/2015

Kawamura T et al. Nephrol Dial Transplant (2014) 29: 15461553

38

PN3

Efficacy of Tonsillectomy on Long-Term

Survival in IgAN
118 IgAN biopsies 1973-1980 PN4
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

Slide 39
PN3

Patrick Nachman, 4/2/2015

PN4

change to RCT of tonsillectomy

Patrick Nachman, 4/2/2015

Crescentic IgA Nephropathy

205 patients; mean F/U 7.9 years [ 1 to 22 years] .
Group
1
2
3
4

5/6/2015

% Crescents
0
<25
25-50
>50

10-Yr Survival
100%
94.3%
82.8%
25.5%

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

Crescentic IgA Nephropathy

12 patients with crescentic (>10%) proliferative IgA N
Pulse methylpred x 3 days, then monthly IV
cyclophosphamide x 6 months
mean SCr decreased from 2.650.39 to 1.510.10 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 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 potentially
toxic therapy is to be avoided in patients
who will receive no benefit from treatment
DAmico et al (1993) raised concept and
proposed SCr of 3.0 mg/dL as PNR
Scholl et al (1999) concurred with DAmico
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 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 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)"

DAmico G et al. Contrib Nephrol

1993;104:6-13

5/6/2015

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

Schll U et al Clin Nephrol. 1999 Nov;52(5):285-92.

46

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 36 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

Patient

Clinical Features

Interventions

All patients

BP control < 130/80 mm Hg

Strongly consider ACEI or ARB
Consider statin
Consider tonsillectomy if recurrent tonsillitis
+/- fish oils per patient preference

Mild disease

Normal GFR
Proteinuria < 500 mg/d
Benign histology
Normal BP

Watchful waiting
Enrollment into prospective observational studies

Moderate/severe
disease

Proteinuria > 1 g/d or proteinuria 0.5-1 g/d with

other features suggesting risk of progression
Histologic 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 immunosuppression
Prepare for transplant or renal replacement therapy

Crescentic IgAN

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

Pulse + high-dose oral glucocorticoids

Consider cyclophosphamide

IgAN with minimal

change disease

Sudden-onset nephrotic syndrome

Mesangial IgA deposits on biopsy without
sufficient sclerosis to explain proteinuria

Glucocorticoids, akin to treatment of minimal change

disease

5/6/2015

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

48

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

Current Clinical Trials in IgA Nephropathy

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.

5/6/2015

50