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
5/6/2015 33
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
5/6/2015 34
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
crea
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] .
5/6/2015
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
5/6/2015 48
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.
5/6/2015 50
Current Clinical Trials in IgA Nephropathy