Terapia de IgA 2015 2

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.

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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 IgANLocus / 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.

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 Crohns 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

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

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

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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

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IgA N

FSGS

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Interaction between time average proteinuria and rate of renal function decline

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

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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

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25% eGFR decrease

Combination

ACE inhibitor

Log Rank P

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



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:****


VALIGA study


VALIGA studyOutcome 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

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

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VALIGA studyUP < 1 g/d UP 1 to 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: 17831790.

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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

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n72 patientsProteinuria 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: 15461553

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

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 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 2.650.39 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 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

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

DAmico et al (1993) raised concept andproposed 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

PN2 need to review. acute vs chronic? treatment? what was adjusted for? endpoint is return to Cr

"Point of no return (PNR)"

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DAmico 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 46Schll 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

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

Terapia de IgA 2015 2

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