Lupus Nephritis

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Lupus Nephritis

• Jackie Nam

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Introduction

• 60 75 of pts with SLE
• Probably the most serious complication
• Differs in clinical pattern, severity , prognosis
  treatment

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Pathogenesis

• Autoimmune

MHC II on APC/ B cell
Costimulatory molecules Eg. CD 40/ 40L B7/
CD 28 B7/ CTLA4
T cell
Polyclonal B cell activation
Formation of autoreactive antibodies vs nuclear
Ag other self Ag
Ab/ Ag complexes ( preformed or in situ)
Binding damage to GBM
C activation
Recruitment of polys mononuclear cells
RENAL DAMAGE
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Pathology

• GLOMERULUS
• Mesangial deposits
• Subendothelial mesangial
• Subepithelial
• Widespread scarring
• Interstitium
• Tubules
• Vessels

• Histologic class
• II
• III IV
• V
• VI

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WHO Classification of LN

• I. Normal glomeruli
• Normal by all techniques
• Normal on LM but deposits on immunohistology /
  or EM
• II. Pure mesangial alterations
• A. mesangial widening /or mild
  hypercellularity
• B. mesangial cell proliferation
• III. Focal segmental GN ( focal proliferative GN)
• A. active necrotising lesions
• B. active sclerosing lesions
• C. sclerosing lesions

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WHO Classification of LN ( cont.)

• IV. Diffuse proliferative GN
• ( severe mesangial/ mesangiocapillary with
  extensive subendothelial deposits. Mesangial
  deposits always present frequent subepithelial
  deposits)
• A. with segmental lesions
• B. With active necrotising lesions
• C. with active sclerosing lesions
• D. with sclerosing lesions
• V. Diffuse membranous GN
• A. Pure membranous GN
• B. associated with lesions of category II
• VI. Advances sclerosing GN

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Renal manifestations

• Tend to appear within the 1st 2yrs of SLE
• Almost ½ have asymptomatic urine abnormalities
• Proteinuria - dominant feature
• Haematuria almost always present but not in
  isolation
• Nephrotic
• Severe nephritis
• ARF occassionally
• ? GFR in ½
• Revised criteria for classification of SLE
• Proteinuria 0,5g / day or 3
• Casts rbc/ granular/ tubular/ mixed

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Lab investigations

• Monitoring with regular urinalysis serum
  creatinine
• Screen all pts with proteinuria for ANA
• Anti ds DNA
• In about 60 with SLE
• Levels often reflect disease activity
• ? with Rx ( ANA remains )
• If normal safe to ? Rx in chronic phase
• ? complement
• In ¾ untreated esp. with nephritis
• APLA
• In 1/3 to ½
• Associated with renal arterial, venous
  glomerular thrombosis

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Clinicopathologic correlates

• Many are asymptomatic insidiously progressive
• More severe histologic forms tend to have more
  severe clinical findings
• But histology cannot be predicted with certainty
• No clinical features - may have significant
  glomerular disease on biopsy
• ? BIOPSY NB

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Indications for renal biopsy

• Clinical lab features DPGN
• Biopsy may not be necessary prior to Rx
• Abnormal clinical lab features
• Lowgrade
• Compatible with more than one form of LN
• ?Biopsy may alter Rx

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Histology

• 1995 WHO Classification of Lupus Nephritis
• ½ Class III IV
• 10 15 class V
• Focus on glomerular lesions
• 50 of changes in interstitium
• In a few ATN occurs in absence of glomerular
  disease ? ARF
• Glomerular lesions not static
• May undergo transition with time eg from Class IV
  to V with Rx

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NIH activity Chronicity index

• 2nd classification
• Assessment of inflammation ( activity)
  permanent damage from scarring fibrosis
  (chronicity)
• Includes glomeruli TIN features
• Useful for prognosis, guide to Rx
• Chronicity worse outcome
• Helpful to monitor Rx response on repeat biopsies

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Prognosis

• Predictors of poor prognosis
• Black race
• Male
• Anaemia
• ? creatinine
• Nephrotic range proteinuria
• Glomerular tubulointerstitial scarring
• Severe tubulointerstitial nephritis
• Chroniciy index 3

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Treatment aims

• Recognise early renal involvement
• Induce maintain remission decrease risk of
  progression to ESRD
• Minimise Rx related toxicity ( esp. during
  maintenance phase )

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Treatment

• Induction
• Maintenance
• short courses associated with relapses

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Treatment options (1)

• Corticosteroids (CS)
• In all groups
• No trials of CS vs no CS
• Pulse medrol no formal studies impression of
  rapid control
• Cyclophosphamide ( CP)
• Intermittent pulse CP DOC in mod severe
  disease
• Oral CP used
• Infections, cervical dysplasia, gonadal toxicity
• Azathiaprine (Aza)
• Remarkably safe
• Leucopaenia, hepatotoxicity, marginal risk of
  malignancy
• Safe in pregnancy
• Primary Rx in mild forms in pts strongly
  oppposed to CP

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Treatment options (2)

• Mycophenolate mofetil (MMF)
• Toxicity of CP prompted a search for effective
  less toxic Rx for LN
• Inhibits de novo pathway of purine synthesis ?
  lymphocyte production
• Leukopaenia, nausea, diarrhoea, infections
• Shown to be effective but concern re relapse in
  severe disease
• Recent trial short term Rx with IVI CP
  followed by maintenance Rx with MMF or Aza more
  efficacious safer than long-term Rx with IVI
  CP.
• ( NEJM march 4, 2004 vol 350 (10) 971- 80)

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Treatment options (3)

• Cyclosporin A
• Evaluated in extrarenal manifestations few
  studies in LN
• Corticosteroid sparing effect in children
• flares of disease activity during Rx or when the
  drug is tapered
• may be used in combination with other
  immunosuppressives
• should not be used as monotherapy
• Low dose no permanent nephrotoxicity
• Monitor levels if higher doses used
• Monitor renal function
• Plasmapharesis
• no benefit

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Mild mesangial LN

• good prognosis
• no specific therapy
• more aggressive disease
• oral CS
• ? AZA if initial response is poor

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Proliferative GN (1)

• Immunosuppression most beneficial
• NIH Rx trials
• CS alone and CS AZA / oral CP/ AZA CP/ monthly
  IV CP.
• CP better than CS alone
• IV CP low dose prednisone better than high dose
  prednisone alone
• AZA had an intermediate response, but no
  significant difference between AZA CS

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Proliferative GN (2)

• Intial high dose CS (prednisone 1mg/kg/day)
  pulse IV CP (750-1000 mg/m2 BSA).
• pulse of CP is given at monthly interval x 6/12
• then every 3/12 x two years.
• CS gradually tapered
• Alternative to high dose oral steroids
• Pulse IV methylprednisolone, low dose oral
  prednisone (10-20 mg/day) to ?the incidence of
  steroid side-effects  
• Initial IV methylprednisolone, 12 weeks oral CP (
  1-3 mg/kg/day) followed by combined AZA and CS

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Proliferative GN (3)

• Euro-Lupus regimen.
• Induction limited course of low dose IV CP (6
  fortnightly pulses of 500 mg)
• followed by a safer cytotoxic drug, AZA, as a
  long-term maintenance Rx
• Data from the Euro-Lupus Nephritis Trial (ELNT)
  suggest that such a low cumulative dose of CP may
  achieve good clinical results, though important
  differences in patient populations between the
  ELNT and NIH studies, as well as in the dosing of
  CP, preclude extrapolation to other LN
  populations with different ethnic backgrounds or
  disease severity

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Membranous GN

• ? progression to ESRD
• 20 in 10 yrs
• Membranous GN with non nephrotic proteinuria
• No Rx
• Monitor progression

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Membranous GN

• Limited data on Rx
• Rx follows that of idiopathic membranous
  nephritis
• Steroids should not be used as sole therapy
• AZA is not associated with any significant
  benefits
• Alkylating agents, CP and chlorambucil - both
  effective
• for patients with clinical features that predict
  a high likelihood of progression to ESRD, such as
  severe or prolonged nephrosis, renal
  insufficiency or HT
• Cyclosporin
• -if alkylating agents are contraindicated or
  ineffective
• Limited experience suggests that most will
  experience a reduction in proteinuria.
• Early results from an NIH study of membranous LN
• prednisone alone vs prednisone CyA or CP
• more favourable response to CP
• frequency of relapse with CyA treatment may be
  significant

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Newer forms of Rx

• High dose immunoablative Rx
• For refractory cases
• CP, antithymocyte globulin methylprednisolone
  ? haematopoietic stem cell transplantation
• Long-term follow-up of reported cases
  randomized trials necessary
• Biological approaches
• Anti-CD40L and CTLA4Ig.
• Results of murine studies are encouraging
•  

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Chronic renal failure

• Nonimmune mechanisms
• BP control
• Low protein diet
• Low salt
• Calcium vitamin D
• EPO
• ? nephrotoxic drugs

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Prognosis

• 30 yrs ago
• few pts with severe class IV nephritis survived
  1-2 yrs
• ½ with less severe disease died within 5 yrs
• Marked improvement in Rx
• 10 15 progress to ESRF
• Sepsis major cause of death
• Transplant
• recurrence rare