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