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