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

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

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

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

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

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

Value of CR or PR in Severe Lupus Nephritis LTFU of 86 pts from PE trial  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

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

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

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

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

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

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

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

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 mo: 87%  PPV: proteinuria  mo: 90%  Multivariate analysis of nl renal fcn:  Cr mo  Proteinuria <1 mo  Baseline variables did not contribute

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

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

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)

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

Boumpas. Lancet 1992

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

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

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