Lupus nephritis. Dr Maria José Cuadrado Lupus Research Unit St. Thomas Hospital

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1 Lupus nephritis Dr Maria José Cuadrado Lupus Research Unit St. Thomas Hospital

2 Lupus nephritis: Presentation Proteinuria Haematuria Hypertension Acute renal failure Chronic renal failure End-stage renal failure

3 Aims of care in lupus nephritis Overall reduction of mortality and morbidity

4 Aims of care in lupus nephritis Obtain a complete remission Maintenance of renal function Reduction of renal flares Control of proteinuria

5 Biopsy: ISN / RPS (2003) Class I Minimal mesangial Class II Mesangial proliferative Class III Focal lupus nephritis Class IV Diffuse segmental (IV-S) or global (IV-G) Class V Membranous Class VI Advanced sclerosing Identification of APS nephropathy

6 Pathogenesis of lupus nephritis Immune complexes Anti-dsDNA antibodies Anti-nucleosomal antibodies Histone bridge - -ve heparan sulfate Anti-C1q antibodies Anti-actinin antibodies Role of B-cells

7 Choice of induction agent Likely compliance Future plans for pregnancy Race Cost Availability

8 Oral (rarely) Cyclophosphamide NIH regimen -750 mg to 1 g cyclophosphamide i/v at monthly intervals for 6 months, then every 3 months for 2 years St Thomas Hospital regimen -6 x 500mg pulses 2-weekly Toxicity:bladder, cytopenia, infection, ovarian, hair loss

9 CYP meta-analysis Cyclophosphamide plus steroids reduced risk for doubling of serum creatinine level (4 RCTs, 228 patients; RR, 0.59; 95% CI, 0.40 to 0.88) compared with steroids alone No impact on overall mortality(5 RCTs, 226 patients; RR, 0.98; 95% CI, 0.53 to 1.82) Risk for ovarian failure increased (3 RCTs, 147 patients RR, 2.18; 95% CI, 1.10 to 4.34) Flanc et al, 2004

10 Mycophenolate Mofetil Original use in transplantation Doses used 2-3g/day Toxicity: gastrointestinal, cytopenias, infection, neoplasia Contraindicated in pregnancy Does not cause ovarian toxicity

11 Mycophenolate Mofetil Data to support use of MMF Induction: Chan et al, 2000 Ginzler et al, 2005 ALMS study Maintenance: Contreras et al, 2004

12 ALMS Aspreva Lupus Management Study Multinational trial Induction phase followed by maintenance phase Powered for superiority of MMF over CYP 24-week randomisation for remissioninduction

13 ALMS 104/185 (56.2%) MMF response rate 98/185 (53.0%) CYP response rate (p=0.575) The study did not meet its primary objective of showing a superior response rate with MMF MMF & CYP arms showed comparable efficacy

14 ALMS Race MMF (% response) CYP (% response) p All Caucasian Asian Other (Black/mix ed race)

15 ALMS (3) More hispanic patients responded to MMF 60.9% vs 38.8% p=0.011 Latin America 60.7% vs 30% p=0.003 No difference in Asia, N America, or rest of the world

16 Aims of care in lupus nephritis Obtain a complete remission Reduction of renal flares Maintenance of renal function Control of proteinuria

17 Maintenance Survival rate was higher in MMF and AZA groups than in CYP group (P=0.05 and P=0.009) Rate of relapse-free survival was higher in the MMF group than in the CYP group (P=0.02) Incidence of hospitalization, amenorrhea, infections, vomiting was significantly lower in MMF and AZA groups than in CYP group Contreras et al, 2004

18 Maintenance trials MAINTAIN study Randomised to AZA or MMF Recruitment (90) completed ALMS study Randomisation of patients who entered remission in induction phase of trial Randomised to AZA or MMF

19 Rituximab (1) Lupus Meeting 26 patients, mean f/u 34.5 mths 9 response in LN (4 complete 5 partial) 7 relapsed without B-cell return 15 re-treated for relapse 14/15 remission after re-treatment Time to second relapse 1 year Catapano et al, Cambridge

20 Rituximab (2) Lupus Meeting Toxicity 10/26 mild-moderate infusion reactions 4/26 severe infusion reactions 8 patients had 11 severe infections 6 were on immunosuppressives, 1 neutropenic Catapano et al, Cambridge

21 Aims of care in lupus nephritis Obtain a complete remission Reduction of renal flares Maintenance of renal function Control of proteinuria

22 Maintenance of renal function Reduction of proteinuria: -ACE-inhibitor -ARB Control of blood pressure Control of vascular risk factors Minimisation of treatment-related toxicity

23 Why monitor in lupus nephritis? Early detection of renal flare in known LN Distinction between flare and chronic damage Detection of treatment-related toxicity

24 How to monitor LN? Urinalysis & microscopy: dipstick, sediment Renal function: serum creatinine, GFR Proteinuria: -protein-creatinine ratio, -24-hr urine protein Antibodies: -anti-dsdna -anti-c1q C3, C4 Repeat renal biopsy: Histological class, AI, CI, changes of APSN Novel urine markers: MCP-1, TWEAK, lipocalin- 2, proteomics, urine C3d

25 Risk factors for the progression of lupus nephritis Racial origin Afro-Caribbean Socio-economic status Delay between onset of nephritis and renal biopsy Elevated serum creatinine Failure to achieve remission Histological features

26 Assessment of compliance Communication with patients Agreement on treatment risk of drug interaction Never-ending list of medications Compliance not perfect