1. Proteinuria Outcome Lupus Nephritis Classes of Lupus Nephritis I.Minimal II.Mesangial III.Focal proliferative* IV.Diffuse proliferative* V.Membranous** VI.Sclerosing Mixed membranous and proliferative* * Focus of clinical trials

2. Proteinuria Outcome Lupus Nephritis Lupus membranous nephropathy  Proteinuria is the practical outcome  Doubling Cr is very late outcome  Proteinuria associated with increased  Thromboembolic diathesis*  Cardiovascular events* * Because of effects on survival, multiple interventions are brought to bear, aside from ISD

3. Proteinuria Outcome Lupus Nephritis Proteinuria  Substantive issue in most, but not all, proliferative LN: eg, IV > III or II  Level of baseline proteinuria predicts prognosis in some, but not all, studies  Duration has impact, but is confounded by early interventions  Regression of proteinuria appears to be stronger predictor of prognosis -- appears to be a graded effect

4. Proteinuria Outcome Lupus Nephritis In SLE, more than 1 0 GN, proteinuria is a component of composite outcomes  Proteinuria reduction  Cr stable or improved  Improved urinary sediment  Clinical remission of extrarenal disease activity  Stable or improved lupus serologies

5. Proteinuria Outcome Range of Definitions Complete Remission (CR)  < 1 g/d or U Pr/Cr < 1  < 0.5  < 0.3  < 0.2

6. Proteinuria Outcome Range of Definitions Partial Remission (PR)  > 50% reduction  > 50% reduction and < 3.5  > 50% reduction and < 3.0  > 50% reduction and 50% reduction and < 2.0  > 50% reduction and < 1.5  > 50% reduction and < 1.0

7. Value of CR or PR in Severe Lupus Nephritis LTFU of 86 pts from PE trial 1981-88  CR: Cr <1.4; proteinuria <0.33 g/d (within 5 yr)  PR: Cr 50% reduction to <1.5 g/d (within 5 yr)  ESRD  Death Chen YE. Clin J Am Soc Nephrol 2008;3:46-53

8. Copyright ©2008 American Society of Nephrology Figure 1. Renal remission Chen, Y. E. et al. Clin J Am Soc Nephrol 2008;3:46-53 CR PR

9. Copyright ©2008 American Society of Nephrology Figure 2. Renal survival Chen, Y. E. et al. Clin J Am Soc Nephrol 2008;3:46-53 CR PR NR

10. Copyright ©2008 American Society of Nephrology Figure 3. Patient survival Chen, Y. E. et al. Clin J Am Soc Nephrol 2008;3:46-53 CR PR NR

11. Achievement of CR or PR Lupus Nephritis Dutch Trial 87 pts with PLN: AZ/MP vs CY Grootscholten. Kidney Int 2006; 70:732  CR: Cr <130%; proteinuria <0.5 g/d; RBC <10  PR: Cr stable or improved; proteinuria >50% reduction to <3 g/d

12. Grootscholten. Kidney Int 2006 AZ/MP vs IV-CY study

13. Renal Remission Lupus Nephritis Italian cohort 93 pts with proliferative LN Moroni. NDT 2007; 22:2531  Complete Remission:  Cr improved or not > 125% of baseline  Proteinuria <0.2 g/d

14. Copyright restrictions may apply. Probability of not doubling serum creatinine in patients who achieved or not complete remission

15. Predictors of Favorable Outcome Lupus Nephritis ELNT: 90 pts PLN (hi vs lo dose IV-CY) Houssiau. A&R 2004; 50:3934 LTFU: sustained normal renal function  PPV: proteinuria <1 g/d @6 mo: 87%  PPV: proteinuria  75% @6 mo: 90%  Multivariate analysis of nl renal fcn:  Cr decreased @6 mo  Proteinuria <1 g/d @6 mo  Baseline variables did not contribute

16. Change Proteinuria Lupus Nephritis MMF vs IV-CY induction trial  Inclusion: proteinuria >0.5 (44% NS)  Proteinuria at 6 mo: Not significantly different  MMF: 2.0 g/d (~50% decrease)  IV-CY: 1.5 g/d (~65% decrease) Ginzler. NEJM 2005; 353:2219

17. Copyright ©2005 American Society of Nephrology Chan TM. J Am Soc Nephrol 2005;16:1076-1084 CKD outcome Cr >3 MMF: 4/32 IV-CY: 0/30 ~80%  Asian population

18. Aspreva (ALMS) Trial MMF superiority trial: class III, IV, and V  MMF vs IV-CY induction (6 mo)  MMF vs AZ maintenance  370 patients randomized Caucasian 40%Hispanic35% Asian33%Non-Hispanic65% Other27% (Black 12%, mixed 10%) Appel, Ginzler et al (abstracts ASN, ACR 2007)

19. Aspreva (ALMS) Trial MMFIV-CY PR56%53% Deaths 9 5 (Superiority achieved in “Other race” cohort) Appel, Ginzler et al (abstracts ASN, ACR 2007)

20. Boumpas. Lancet 1992

21. CR, PR and NR and Doubling Cr Lupus Nephritis Treatment severe lupus nephritis -- Within 5 years: Doubling Cr NR: > 2 g/d14/1974% CR: < 0.5 g/d 1/22 5% PR:  50%, < 2 g/d 4/944% PR + CR 5/3116% Unpublished: LUPULSE cohort

22. Conclusions Lupus Nephritis  Baseline proteinuria controversial – generally poor predictor of CKD  No racial differences in baseline proteinuria or severity of LN  PR proteinuria ~75% at 1 yr  CR proteinuria ~50% at 1 yr  Blacks ~30% at 1 yr

23. Conclusions Lupus Nephritis  CR: predicts very low rate CKD  PR: intermediate predictor  NR: predicts high rate CKD  Current practice of combining CR and PR improves number of outcome events and may contribute to statistical significance but its weakness as a stand-alone outcome raises question about this practice