Transcript Document
Lupus Nephritis
Background
• GM (G036181) • 51 year old • Caucasian female • Presented with nephrotic syndrome and hypertension in 2000
Presented in 2000
• Urine protein +++, 24 hour protein 7 gms • Albumin 26, creatinine 90 • Creatinine clearance 95 ml/min • ANA, anti DNA, ANCA –ve, Complement normal • Myeloma screen negative
Renal Biopsy
• 15 glomeruli • Evidence of membranous nephritis • 2 sclerosed gloms, 3/15 crescents • Immuno-IgG, C3 positive, IgA, IgM negative • ?
Membranous lupus • No other features of lupus clinically
Course in 2000
• Started on 30 mg pred, 100 mg azathioprine • ACE added in, changed to ARB due to dry cough • Diarrhoea on aza, stopped after a month, resolved on stopping aza.
• Pred tapered over the next 2 months • 24 hr protein 5.7 gms, albumin 27
Over the next 6 years…
• Ongoing proteinuria • Stable creatinine- 90 micromol/l • Ca breast in 2005 treated with lumpectomy and radiotherapy
June 2006
• Admitted generally unwell • Worsening renal function • Creatinine 210 and climbing • ANA strongly positive, anti DNA –ve, complement normal, anti smith not tested • 24 hr urine protein 5.4 gms • Started on modified Ponticelli regime • Cycloposphamide 100 mg/day, pred 40 mg • Soon reduced to cyclo 50mg and pred 20 mg due to side effects
Over the next few weeks….
• Creatinine improved from 267 to 200 and stable • Abnormal LFTs thought to be due to statins, improved after stopping statins • Generalised weakness, stops cyclo in september • Desperate to cut down steroids, reduced and stopped over the next few weeks • Creatinine stable-200
Admission October 2006
• Admitted on 25 th oct for repeat biopsy • ? Transformation to proliferative lupus nephritis • Worsening renal function- creat 328 • No change in serum immunology • Post biopsy bleed, resolved without intervention
Renal biopsy October 2006
• 20 gloms-6 sclerosed • Membranous GN and some proliferative changes.
• No necrotising lesions, no crescents • Mild to moderate background damage • Full house immunology – IgG+++,IgA+, IgM++, C3++, C1q++ • EM- Numerous electron dense deposits with many subepithelial deposits • Class 5 + 4 lupus nephritis
Treatment
• Refused IV cycloposphamide • Treated with MMF and methyl prednisolone • Creatinine peaked at 370 • Improved to 200 after 2 weeks
Lupus nephritis
• Renal involvement common in idiopathic SLE • Abnormal urinalysis common finding – with or without renal impairment • • Proteinuria most frequently observed abnormality (80%) – (Rothfield- 1981) plasma creat 30% pts – evidence of decreased renal functions uncommon in first few years of diagnosis
Diagnosis
• Clinical manifestations • Immunological tests • Renal biopsy
Immune complex disease
Class I: normal glomeruli (~8% of biopsies) Class II: pure mesangial alterations (~40% of biopsies) Class III: focal glomerulonephritis (~15% of biopsies) a.
b.
Class IIIA: focal segmental glomerulonephritis (~12% of biopsies) Class IIIB: focal proliferative glomerulonephritis Class IV: diffuse glomerulonephritis (~25% of biopsies) Class V: diffuse membranous glomerulonephritis (~8% of biopsies) Class VI: advanced sclerosing glomerulonephritis
Immune complex disease
• Distinct histologic, clinical and prognostic characteristics • Substantial overlap – 15 to 50% evolve from one form to another – suggested in several studies • One pathological finding relatively specific to lupus is presence of
tubuloreticular structures
in glomerular endothelial cells
Immunological tests
• Pts. with SLE synthesize a variety of different autoantibodies – many react to well characterized nuclear antigens • Some antibodies also found in other CTD • 3 antinuclear antibodies diagnostically useful – anti-DNA; anti-Sm; and anti-RNP
Treatment of lupus nephritis
• Optimal treatment varies with type of disease • Mesangial disease – good renal prognosis – requires no treatment unless progression to more severe glomerular involvement • Focal proliferative disease – IIIa prognosis good-no treatment;IIIb-treated like DPLN
Membranous lupus
• Renal prognosis variable – (appel 1987;Donadio-1977;Sloan-1996) • Natural history uncertain • Clinical features associated with poor outcome plasma creat. at presentation,heavy proteinuria –(Sloan-1996)
Membranous lupus
• Optimal therapy uncertain • Asymptomatic patients often not treated;those with moderate disease may be treated with prednisolone • Those with worsening renal functions or marked NS treated with same regimen as DPLN • NIH study comparing cyclophosphamide or cyclosporin to prednisolone
Membranous lupus
• Combination therapy with steroids and chlorambucil may be beneficial • Retrospective study by Ponticelli group – 8 pts in the methypred and 11 pts in methylpred/chlorambucil • 7 of 8 pts in steroid alone group had flares and 3 had complete or partial remission after 114 months mean f/u • 1 of 11 in comination therapy group had flare and 10 had complete or partial remission after 83 mos mean f/u
Diffuse proliferative disease
• Aggressive therapy indicated – (appel-1987;Austin 2000) • Despite aggressive treatment,some pts. will progress to renal insufficiency • Severity of tubulointerstitial disease and crescent formation also correlate with long term prognosis (Austin-1994)
Treatments available
• Steroids – oral prednisolone/IV methylprednisolone • Cyclophosphamide – IV/oral • Azathioprine • Cyclosporin • MMF • Anti-CD20 monoclonal antibody
Boumpas DT et al,Lancet.1992
NIH study – Conteras et al
• 59 pts (12 in class III,46 in class IV,1 in class Vb) – seven monthly boluses of iv cyclophosphamide(0.5 to 1.0g/m 2 BSA) plus steroids • Randomly assigned to 1 of 3 maintanance therapies – quarterly iv cyclo/oral Aza(1 to 3 mg/kg/d)/oral MMF(500 to 3000mg/d) for 1 to 3 years
NIH study
• During maintanance – 5 pts died(4 in cyclo group/1 in MMF),CRF in 5(3 in cyclo/1 each in Aza and MMF) • 72 month event free survival rate for composite end point of death or CRF higher for MMF and Aza groups • Rate of relapse free survival higher in MMF group • Incidence of hospitalization, amenorrhoea, infections was significantly lower in MMF and Aza groups
More evidence for MMF
• Hong Kong group –
JASN,Feb 2005
• Extended long-term study, with median f/u of 63 mos • Role of MMF as continuous induction maintenance tretment for DPLN • 33 pts. in MMF arm and 31 pts. In cyclo/Aza arm both in combination with prednisolone
More evidence for MMF
• Complete or partial remission in 90% in each group • Improvement in serology and proteinuria comparable between both groups • Relapse- free survival and hazard ratio for relapse similar • Fewer infections with MMF • 4 pts in cyclo/Aza as compared to 1in MMF reached composite end point of death or CRF
Anti-CD20 monoclonal antibody(Rituximab)
• B cell depletion using monoclonal antibody • Prolonged remissions achieved in lupus pts.
• Case reports in lupus nephritis • RCTs needed
Conclusions 1
• Renal involvement common in lupus • Diagnosis of lupus nephritis based on a combination of renal bx and immunological tests • Anti-ds DNA most useful test for diagnosis and monitoring of disease activity
Conclusions 2
• Immunosuppressive treatment for class IIIb,IV and some cases of V • DPLN poorest prognosis • Cyclophosphamide and steroid based regimens traditionally • Very good latest evidence for MMF with less side-effect profile • Rituximab seems promising