proteinuria as a surrogate in kidney disease
DESCRIPTION
Proteinuria as a Surrogate in Kidney Disease In primary GN membranous nephropathy and focal and segmental glomerulosclerosis assocciated with the nephrotic syndrome Daniel Cattran M.D. Can we quantitate the “benefits”. Observational studies Prospective gathered information - PowerPoint PPT PresentationTRANSCRIPT
Proteinuria as a Surrogate in Kidney Disease
In primary GN membranous nephropathy and focal and segmental glomerulosclerosis assocciated with
the nephrotic syndrome
Daniel Cattran M.D.
Can we quantitate the “benefits”Observational studies
• Prospective gathered information
• Timed urine collection (24 hrs)
• On review used protein /creatinine ratios to substantiate values and changes
Relationship to outcome (RCT)
Time to event Proteinuria• Complete remission < 0.3 g/d and normal
creatinine• Partial remission 0.3-3.5g/d and 50%
reduction from peak proteinuria and stable creatinine
Progression• Kidney survival• Doubling baseline creatinine• Rate of progression(slope of cr cl )
pp=12g/d, delta crcl (mls/mo) = –3, crcl ii= 96
X = 1.26 + (0.3 x 12) + (-0.3 x -3) + (-0.05 x 96)
ex = 2.6
p = 2.6 / 3.6= 72%
Patient B
0
2
4
6
8
10
12
14
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Time (months)
Pro
tein
uri
a (
g/d
)
0
10
20
30
40
50
60
70
80
90
100
Cr
Cl
(mL
/min
)Proteinuria
Cr Cl
Cattran…KI 1995
Predicting likelihood of developing CKD in MGN
Currently only validation tool that has undergone model fitting and independent data set validation
Toronto Finland ItalyChronic renal insufficiency 47/184(26%) 13/78(17%) 25/101(25%)Sensitivity Proteinuria >3,5 g/d 93% 100% 84% Model 89% 77% 60%
Specificity Proteinuria >3.5 g/day 38% 30% 17% Model 86% 89% 92%
Positive predictive value Proteinuria >3.5 g/day 34% 24% 25% Model 67% 59% 64%
Negative predictive value Proteinuria >3.5 g/day 94% 100% 76% Model 94% 95% 82%
Accuracy 52% 43% 34% Model 85% 87% 79%
Cattran…KI 1997
MGN Effect of long-term proteinuria reduction on rate of progression
Troyanov …Cattran KI 2004
No remission vs Partial Remission vs Complete Remission Changes odds re:ESRD from 1in 2 to 1in 10 with PR to
none with CR at 10 years
90%
50%
100%
Troyanov …Cattran KI 2004 (PR = 50% in proteinuria and <3.5g/d
On Renal Survival
Value of proteinuria reduction in MGN
Data to support relationship between proteinuria reduction
and long term outcome
IV MP 1gx3 + Pred 0.5mg/kg od alternating monthly with cyclophosamide 2.5 mg/kg over 6/12
Improves with cytotoxic/steroid therapy
RCT’S MGN
Repeat RCT Cytotoxic plus Prednisone
Jha Vet al JASN:18:2007
Jha Vet al JASN:18:2007
Cytotoxic plus PrednisoneEffect on proteinuriaCR and /or PR Treated vs Control
Jha Vet al JASN:18:2007
Effect on outcome Renal survival of decrease in proteinuria but delayed as expected
Treated 90%
Control 65%
Jha Vet al JASN:18:2007
And eGFR was improved (but >50% control treated later in study so likely blunted treatment effect)
20mls/min
And effect on progression rate(eGFR)
Cattran et al K. I., 2001
Other therapy similar resultsRCT CNI’SNephrotic syndrome (MGN)improved with 6 mos CSA 3-CSA 3-4mg/kg4mg/kg + 10 mg prednisone od x 6/12 (Cattran …KI 2001 )
RCT Tacrolimus monotherapy in Nephrotic MGN
Praga et al KI 71:2007 Alternate CNI
Praga et al KI 71:2007
Effect of 12 months tacrolimus monotherapy on protinuria in MGN
Praga et al KI 71:2007
Effect on slowing progression(50 % change in creatinine) Tac 5%versus control 25%
25%
5%
Primary FSGS - NATURAL HISTORYPrimary FSGS - NATURAL HISTORY COURSECOURSE
Spontaneous complete remissionSpontaneous complete remission - 5 - 10% - 5 - 10% Rapidly progressive renal failureRapidly progressive renal failure - - 10 - 10 - 15%15% Slowly progressive renal Slowly progressive renal failure - - 40 - 40 - 60%60% Persistent proteinuria Persistent proteinuria - - 20 - 20 - 30%30%
Baseline characteristics 281 nephrotic FSGS
Troyonov…Cattran JASN 2005
Effect of proteinuria reduction on rate of progression (slope of Cr Cl)
Effect of proteinuria reduction on survival (from ESRD)
FSGS Renal survival related to proteinuria remission: complete, partial and no remission
4
CR
PR
NR
100%
80%
40%
Data to support relationship between proteinuria reduction
and long term outcome
FSGS – PrednisoneAuthor/ Level) Treatment Results
Cattran1998(3)
n=93
P Rx for 2 - 50/12Response time 4/12
CR 42% PR 8%CRF 50% in NR/N Rxat 11/1
Rydel,1995(3)
n=81
P Rx 2 - 10/12Response time 6/12
CR 33%, PR 16%CRF 50% in NR/N RxNNS-ESRD 10%
Ponticelli1999(3)
n=53
P Rx 2 - 24/12Response time 6 4/12
CR 36%, PR 16%CRF 65% in NR at 7/1
`All Obsevational
Cyclosporine vs Placebo in Steroid Resistant FSGS
0
20
40
60
80
100
Time (weeks) CyA COMPLETE REMISSION
CyA PARTIAL REMISSION
PLACEBO PARTIAL REMISSION
12 26 52 78 104
% R
EM
ISS
ION
RCT 6 Mos Rx CNI vs Placebo)
Effect on proteinuria
01
02
03
04
05
06
0
0 20 40 60 80 100 120 140 160 180 200 220
Weeks
Pe
rce
nta
ge
wit
h 5
0%
de
clin
e in
C
rCl
23
26
22
25
19
18
18
15
12
7
Placebo (n)
Cyclosporine (n)
Placebo
Cyclosporine
p<0.05
CNI vs Placebo in Steroid Resistant FSGSEffect on Cr Cl