Lupus Nephritis

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 T cell Costimulatory molecules 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’ activationRecruitment of polys & mononuclear cells Binding & damage to GBM RENAL DAMAGE

Pathology GLOMERULUS –Mesangial deposits –Subendothelial & mesangial –Subepithelial –Widespread scarring Interstitium Tubules Vessels Histologic class –II –III & IV –V–V –VI

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 1 st 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

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

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 –> 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

NIH activity – Chronicity index 2 nd 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) )

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 ( 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 –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