Lupus Nephritis

Jackie Nam
 Introduction
60 75% of pts with SLE
Probably the most serious complication
Differs in clinical pattern, severity ,
prognosis & treatment
 Pathogenesis
Autoimmune

MHC II on APC/ B cell

Costimulatory molecules
T cell Eg. CD 40/ 40L
B7/ CD 28
B7/ CTLA4

Polyclonal B cell activation

Formation of autoreactive antibodies vs nuclear Ag & other self Ag

Ab/ Ag complexes ( preformed or in situ)

C activation Recruitment of polys & Binding & damage to

mononuclear cells GBM
RENAL DAMAGE
 Pathology
GLOMERULUS Histologic class

Mesangial deposits II
Subendothelial & mesangial
III & IV
Subepithelial
Widespread scarring V
VI
Interstitium
Tubules
Vessels
 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
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

 Renal manifestations
Tend to appear within the 1st 2yrs of SLE
Almost have asymptomatic urine abnormalities
Proteinuria - dominant feature
Haematuria almost always present but not in isolation
Nephrotic
Severe nephritis
ARF occassionally
GFR in

Revised criteria for classification of SLE

Proteinuria >0,5g / day or 3+
Casts rbc/ granular/ tubular/ mixed
 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 untreated esp. with nephritis
APLA
In 1/3 to
Associated with renal arterial, venous & glomerular thrombosis
 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
 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
 Histology
1995 WHO Classification of Lupus Nephritis
> 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
 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
 Prognosis
Predictors of poor prognosis:
Black race
Male
Anaemia
creatinine
Nephrotic range proteinuria
Glomerular & tubulointerstitial scarring
Severe tubulointerstitial nephritis
Chroniciy index > 3
 Treatment aims
Recognise early renal involvement
Induce & maintain remission & decrease
risk of progression to ESRD
Minimise Rx related toxicity ( esp. during
maintenance phase )
 Treatment
Induction
Maintenance
short courses associated with relapses
 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 < 2-3/12 ( S/E s)
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
 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)
 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
 Mild mesangial LN
good prognosis
no specific therapy
more aggressive disease
oral CS
AZA if initial response is poor
 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
 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
 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
 Membranous GN
progression to ESRD
20 % in 10 yrs
Membranous GN with non nephrotic
proteinuria
No Rx
Monitor progression
 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
 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
 Chronic renal failure
Nonimmune mechanisms

BP control
Low protein diet
Low salt
Calcium & vitamin D
EPO
nephrotoxic drugs
 Prognosis
> 30 yrs ago
few pts with severe class IV nephritis survived > 1-2 yrs
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