Proteinuria as a Surrogate Outcome in IgA Nephropathy

Ron Hogg MD

Scott & White Medical Center

Temple, Texas

Goals of Presentation

Overview of condition Observational studies Relationship between proteinuria and renal impairment in

patients with IgA nephropathy Impact of various treatments (eg: ACEi, steroids, omega-3

fatty acids) on changes in proteinuria and progressive renal impairment

Relationship between early changes in proteinuria and subsequent fall in varying measures of GFR associated with these treatments

IgA Nephropathy: Background

Original description by Jean Berger in 1968 Initially referred to as “Berger’s Disease” Thought to have a benign outcome in ‘70s Condition now known to be most common glomerular

disease leading to ESRD worldwide

Definitions

Measures of Proteinuria Collection: 24 hour urine excretion rates Analyte: Total protein Analytical methods: Variable Early change: One year in most cases

Outcome measures Measures of kidney disease progression

Kidney failure/ESRD Decline in mGFR/eGFR 50% increase in serum creatinine (Scr)

Mean slopes mGFR/eGFR

Clinical trials

Obser-vational studies

Baseline UPEX vs. CKD progression X X

Early change in UPEX (6-12 months) vs. CKD progression

X X

Effect of treatment on CKD progression (comparison of randomized groups)

X NA

Analyses

IgA Nephropathy: Observational studies

1. Predicting Progression in IgA nephropathy.

Bartosik et al. Am J Kidney Dis. 2001

2. Early prediction of IgAN progression: Proteinuria and AOPP are strong prognostic markers.

Descamps-Latcha etal. Kidney Int. 2004

Predicting progression in IgAN Bartosik et al. AJKD: 2001

Retrospective evaluation of the association between rate of decline of renal function (CG-GFR) and multiple variables in 298 adult patients with IgAN

Age at presentation: 36+/-13 years (16-73 years) Follow-up from presentation: 70+/-46 months (range

12-231 months) Age at biopsy: 37+/- 13 years (range 16-74 years) Follow-up from renal biopsy: 57+/-44 months (range

12-227 months)

Bartosik et al. 2004 Baseline clinical and laboratory data

CG-GFR: 76+/-35 ml/min (range 13-225 ml/min)

Serum creatinine: 1.54+/-1.0 mg/dl (0.5-8.4 mg/dl)

MAP-B: 102+/-15 mmHg (70-162mmHg) UPEX-B: 2.3+/-2.3 g/day (0.1-21.6 g/day)

Bartosik et al. 2004Variables monitored during follow-up

Slope of CG - GFR was derived from 10 +/- 7 values of serum creatinine in 90% of patients

Rate of decline of CG - GFR was -4.8 +/- 7.5 ml/min/year (0.4ml/min/month)

Five year renal survival rate from time of presentation was 80%

Ten year renal survival from presentation was 65%

Bartosik et al. 2004 Univariate analysis of factors associated with GFR decline

Variable P value

Age, Race, Sex, MAP-B, Serum creatinine, CG-GFR at baseline

ns

MAP during follow-up 0.001

UPEX at baseline 0.001

UPEX during follow-up 0.001

Lee Classification of histology (G5) 0.001

Bartosik et al. 2004Multiple Linear Regression Analysis

Using only clinical and laboratory data, the only independent predictors of slope were MAP-FU and UPEX-FU. The overall model was highly significant (p<0.001)

MAP and mean UPEX over progressively longer periods of follow-up were significantly associated with rate of deterioration of CG-GFR

Descamps-Latscha. KI: 2004

Prospective cohort study of 120 adult patients identified between 1994 – 1997 and followed until the end of 2002 or start of dialysis

Primary end point defined as 50% reduction of CCr from baseline

Risk factors evaluated included CRP, UPEX and advanced oxidation protein products (AOPP)

51 patients reached the end point, including 30 patients who had to start dialysis

Baseline UPEX was 0.59 +/- 0.62 g/day in 69 patients who did not reach the end point versus 2.67 +/- 1.28 mg/day in the 51 patients who did reach the end point

Descamps-Latscha. KI: 2004

1. Univariate Cox regression analysis showed age, proteinuria, hypertension, ACEi, CCr and AOPP levels to be significantly associated with renal outcome

Proteinuria >1g/day HR (95% CI) = 16.41 (3.97-67.84, p=0.00001)2. Multivariate analysis confirmed UPEX to be

independent predictor of renal outcome a. With CCr included: HR = 7.78 (1.81-33.4, p=0.006) b. With CCr excluded: HR = 23.7 (5.35-104.8, p=0.0001)3. Angiotensin II inhibitors were protective HR = 0.19 (0.09-0.44, p=0.001)

ACE inhibitors for IgA nephropathy

Treatment of IgA nephropathy with ACE inhibitors: A randomized contolled trial

Praga et al. JASN: 2003

Praga et al: 2003

RCT in 44 Patients with UPEX > 0.5g/day on 3 consecutive measurements and SCr <1.5mg/dl

Enrollment lasted 5 years (9/90-9/95) 23 randomized to enalapril 5-40 mg/day 21 randomized to control group BP goal <140/90 mmHg in both groups Follow-up: 78 months (E) vs 74 months (C) Primary outcome: 50% increase in SCr

Praga et al: 2003

Rx group: 3 pts (13%) reached end point Controls: 12 pts (57%) reached end point, p<.05 Renal survival at 4 years: 100% in Rx group, 70% in

control group Renal survival at 7 years: 92% in Rx group, 55% in

control group, p<0.0 Significant effect of the reduction in UPEX after 1 year of

treatment was seen on renal survival

Odds ratio=0.98, 95%CI 0.96-0.99, p=0.025

Omega-3 fatty acids in IgAN

Proteinuria patterns and their association with subsequent end stage renal disease in IgA nephropathy

Donadio et al. Nephrol Dial Transplant: 2002

Donadio et al. 1992

Examined data from 2 trials in patients with IgA nephropathy that had been conducted by the Mayo Collaborative Group to identify which determinants of proteinuria might provide the best predictors of ESRD after 1 year of treatment with O-3FA or placebo

UPEX was measured on 24 hour urines at baseline, 6 weeks, 6 months and 1 year in all patients

Donadio et al. 2002

HR (CI)

One year UPEX vs ESRD 1.5 (1.2, 1.9)

There were 91 patients available for study after 1 year and 18 ESRD events after year one in Trial #1

There were 63 patients available for study after 1 year and 14 ESRD events after one year in Trial #2

Corticosteroids for IgA nephropathy

1. Steroid therapy during the early stage of progressive IgA nephropathy.

A 10 year follow-up study Kobayashi et al. Nephron: 19962. Corticosteroids in IgA nephropathy: A randomized

controlled trial. Pozzi et al. The Lancet: 19993. Steroid treatment for severe childhood IgA

nephropathy:A randomized controlled trial. Yoshikawa et al. Clin J Am Soc Nephrol: 2006

Kobayashi et al. 1996

Ten year + study of subset of patients (n=46) with UPEX 1-2 g/day, CCr >70ml/minute, severe renal histology

Original cohort of patients = 363 ( 90 with UPEX above). Previous report on these patients showed persistent UPEX > 1g/day to be associated with progressive renal impairment

Patients “allocated” to course of steroids or non-steroidal therapy, usually in order of renal bx

Steroids – 20 patients; “controls” – 26 patients

Kobayashi et al. 1996

Outcome (ESRD)

Treatment vs control 20% vs 64%

Baseline UPEX (g/day)

Treatment group baseline UPEX 1.4

Control group baseline UPEX 1.3

Follow-up UPEX (g/day)

Treatment group 0.8

Control group 1.5

Pozzi et al. 1999

RCT in 86 patients with IgAN who showed

UPEX 1- 3.5g/day, plasma creatinine < 1.5g/day Patients enrolled over 8 years (7/87-9/95) Rx: Pulse IV MP 1g/day x 3 consecutive days on months 1,

3, 5 plus PO pred 0.5mg/kg/QOD x 6m 43 patients randomized to the steroid group 43 patients randomized to the control group who received

supportive therapy (BP goal 140/90) Study conducted in 7 renal units in Italy

Pozzi et al. 1999

Baseline Participants

Number of Rx pts / Controls 43 / 43

UPEX (mg/day) (mean) 2.0 / 1.8

UPEX 6m, 1y, 2y, 3y, 4y, 5yr

Rx group 1, 0.8, 0.6(2), 0.5, 0.8

Control group 1.6, 1.2, 1.4, 1.3, 1.4, 0.8

Study End (5 years)

50% increase in SCr: Rx/C 21% / 33%

100% increase in SCr: Rx/C 2% / 21%

Pozzi et al. 1999

Risk of reaching the 50% increase in serum creatinine endpoint was 59% lower in steroid treated patients vs controls (relative risk 0.41, 95% CI 0.17-0.98, p=0.04)

When the reduction in UPEX from 0-6 months was added to the model, this covariate was selected as significant (RR 0.48, CI 0.34-0.69, p<0.0001), and the beneficial effect of steroid Rx was lost from the final model

Yoshikawa et al. 2006

RCT conducted by the Japanese Pediatric IgA Nephropathy Treatment study Group

83 children < 16 yrs of age enrolled in 20 centers - 50/83 pts ( 60%) detected by school screening

Rx group: pred, Imuran, warfarin, dipyridamole “Control” group: prednisone. Rx duration 2 yrs ACEi prohibited in both groups Primary end point: disappearance of proteinuria Secondary end point: percentage of sclerosed glomeruli

on follow up renal biopsies

Yoshikawa et al. 2006

Outcome – Remission of proteinuria

Treatment vs control (after 2 years) 92.3% vs 74.4%

Baseline UPEX (g/day)

Treatment group baseline UPEX/day 1.29g/m2

“Control” group baseline UPEX/day 1.16g/m2

Follow-up # glomeruli showing sclerosis

Treatment group 4.6%

Control group p=0.0003 14.6%

Conclusions

Severity of proteinuria is closely correlated with risk of progressive renal impairment in patients with IgA nephropathy

Reduction in proteinuria via multiple therapeutic interventions is associated with improvement in renal outcome

The impact of reducing proteinuria in this condition appears to be best attained when the lowering of proteinuria can be sustained