Lupus Nephritis

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Lupus Nephritis

• Dr Allister Williams
• Medical SpR (Renal)
• Glan Clwyd hospital

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Background

• GM (G036181)
• 51 year old
• Caucasian female
• Presented with nephrotic syndrome and
  hypertension in 2000

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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

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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

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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

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Over the next 6 years

• Ongoing proteinuria
• Stable creatinine- 90 micromol/l
• Ca breast in 2005 treated with lumpectomy and
  radiotherapy

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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

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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

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Admission October 2006

• Admitted on 25th 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

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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

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Treatment

• Refused IV cycloposphamide
• Treated with MMF and methyl prednisolone
• Creatinine peaked at 370
• Improved to 200 after 2 weeks

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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

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Diagnosis

• Clinical manifestations
• Immunological tests
• Renal biopsy

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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)
• 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

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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

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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

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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 treatmentIIIb-treated like DPLN

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Membranous lupus

• Renal prognosis variable (appel-1987Donadio-197
  7Sloan-1996)
• Natural history uncertain
• Clinical features associated with poor
  outcome-?plasma creat. at presentation,heavy
  proteinuria (Sloan-1996)

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Membranous lupus

• Optimal therapy uncertain
• Asymptomatic patients often not treatedthose
  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

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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/chloramb
  ucil
• 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

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Diffuse proliferative disease

• Aggressive therapy indicated (appel-1987Austin-
  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)

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Treatments available

• Steroids oral prednisolone/IV
  methylprednisolone
• Cyclophosphamide IV/oral
• Azathioprine
• Cyclosporin
• MMF
• Anti-CD20 monoclonal antibody

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Boumpas DT et al,Lancet.1992
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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/m2 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

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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

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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

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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

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Anti-CD20 monoclonal antibody(Rituximab)

• B cell depletion using monoclonal antibody
• Prolonged remissions achieved in lupus pts.
• Case reports in lupus nephritis
• RCTs needed

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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

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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

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Thank you

• Questions?