Lupus Nephritis Update 2010 Review of recent treatment trials

Patient example 34 year-old unemployed, uninsured, poverty level income, African-American male diagnosed with SLE 1 yr ago and subsequently lost to follow-up. Has noticed swelling of the ankles about 6 mos. BP 145/95. Urinalysis: 4+ protein, 4+ blood. Red blood cell casts noted. Urine protein creatinine ratio 8. 24-hour urine with 8.6 g of protein. Serum creatinine 1.8 mg/dl. Hct 26 %. Positive double-stranded DNA. Very low C3 and C4.

Definitions of glomerular pathology Diffuse: more than 50% of sampled glomeruli are abnormal Focal: less than 50% of sampled glomeruli are abnormal Segmental: Only a portion of an individual glomerulus is abnormal Global: The entire individual glomerulus is abnormal.

Review of the biopsy specimen Glomerulus: Diffuse/focal. Segmental/global. Endothelium, glomerular basement membrane, podocyte, mesangium (cells and matrix), urinary space, Bowman’s capsule. Interstitium: Tubules, casts, fibrosis, inflammatory infiltrate, arterioles Light, immunofluorescence, and electron microscopy constitute a full biopsy

Pathogenesis Deposition of immune complexes is the key Mesangial and endothelial deposits have access to the vascular space. Leads to activation of complement, causing influx of leukocytes Subepithelial deposits do not attract inflammatory cells #1: where these deposits are found are responsible for the clinical presentation #2: because of this, they activate complement, which serves as a chemoattractant, causing influx of leukocytes. This leads to a GN with an active urine sediment and progressive renal failure #3: do not attract inflammatory cells because of GBM, even though they may activate complement. Pathology is on the epithelial side, so main manifestation is proteinuria

Mesangial electron dense deposits and increased mesangial matrix and cellularity in IgA nephropathy

Pathogenesis Site of the immune complex formation are related to characteristics of both the antigen and the antibody Anionic antigens are unable to cross the GBM, and therefore deposit in the mesangium and the subendothelial space Cationic antigen may bind to anionic GBM and incite in situ complex formation In situ complex formation is more damaging than circulating immune complex #1: site of the immune complex formation, either subepithelial or subendothelial #2: degree of deposition may determine if one develops mild mesangial disease or diffuse proliferative disease

Pathogenesis Key antibody in pathogenesis is anti-dsDNA, but not all anti-dsDNA are created equal Pathogenecity of anti-dsDNA may be due to IgG subclass. IgG1 and IgG3 fix complement more avidly than IgG 2 and IgG4 #1: some in clinical remission still have significantly elevated levels of anti-dsDNA #2: consistent with this is that IgG1 and IgG3 are more commonly associated with diffuse proliferative lesions

Treatment considerations Recognition of lupus nephritis: Physical examination, serum creatinine and eGFR, urine analysis. Approximately 50 to 60% of patients develop some form of lupus nephritis over the course of the disease Induction therapy is mandatory with immunosuppressive agents Long-term maintenance therapy must follow the induction therapy Relapses are common

Lab investigations APLA 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

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

Proteinuria Outcome Lupus Nephritis Classes of Lupus Nephritis Minimal Mesangial Focal proliferative* Diffuse proliferative* Membranous** Sclerosing Mixed membranous and proliferative* * Focus of clinical trials

Prognosis based on Classification Class I / II: excellent prognosis Class III Renal survival rates vary based on severity on biopsy, some as high as 15-20% Class IV: Poorest prognosis Class V 10 year survival rate may be as high as 90% Poor prognostic signs: black race; HTN; elevated creatinine; “heavy” proteinuria; mixed with III/IV Class VI: poor

Treatment considerations With currently available induction regimens, approximately 80% can be induced to a complete or partial remission. Remission is associated with better patient and renal survival (complete > partial). ~ 40 % of patients with remission will subsequently relapse.

NIH Trials Clinical trials in1970s and 1980s: Cyclophosphamide therapy it is superior to steroid therapy. No major response rate difference between oral and intravenous cyclophosphamide Standard of care has become monthly cyclophosphamide (0.5 – 1.0 mg/m2)

Induction Therapy—Cyclophosphamide NIH study published in 1986 Patients randomized to one of five groups: prednisone only; IV cytoxan; PO cytoxan; PO cytoxan AND azathioprine; or PO azathioprine Follow-up period was 20 years TITLE: this study published by the NIH looked at long-term data, with 10-12 years of follow-up; total of 61 patients

Induction Therapy—Cyclophosphamide Probability of avoiding renal failure was 90% with cytoxan; 60% with imuran; 20% with prednisone only

Lower dose cytoxan 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

Maintenance Therapy Contreras et al in 2004 published in NEJM a randomized controlled trial to determine optimal maintenance therapy 59 patients with class III; IV; or V lupus nephritis who received induction therapy with cyclophosphamide and steroids Randomized to IV cytoxan (.5-1.0g / m2 every 3 mo); azathioprine 1-3mg/kg/day; or MMF 500-3000mg/day Primary end point: patient and renal survival #2: excluded those with CrCl<20 #3: MMF dose titrated to GI side effects and to maintain WBC>2000 #3: all received maintenance steroids (prednisone up to .5mg/kd/day) #4: renal survival = not more than 2x increase in SCr from lowest point during induction or requiring RRT

Patient Survival For patient survival, higher for azathioprine (1 death) and MMF (1 death) than for CTX (5 deaths)

Event-Free Survival For primary event free survival (ie. Patient death or renal failure), significantly higher for MMF (90%) and AZA (80%) than for CTX (45%)

Relapse-Free Survival Renal Relapse: MMF had a total of 3; AZA had 6; CTX had 8 Renal replase defined as doubling of prot/Cr; increase in serum Cr of 50% for more than 1 month

ASPREVA trial International randomized controlled trial for induction therapy for lupus nephritis, stages 3/4/5. Randomized 370 subjects. Compares open label MMF(target dose 3 g/d ) to (IVC) intravenous cyclophosphamide (0.5 to 1.0 g /m2 in monthly pulses) in a 24 week induction study All patients received prednisone starting at 60 mg per day

ASPREVA Primary endpoint was a prescribed decrease in urine protein/creatinine ratio and stabilization or improvement in serum creatinine. Secondary in points included complete renal remission, systemic disease activity and damage, and safety

Results There was not significantly different response rate between the two groups: 56% of patients responded to MMF compared to 53% to cyclophosphamide. Secondary endpoints were also similar. 9 deaths in the MMF group and 5 in the IVC group. There were no significant differences with regard to adverse events, serious adverse events, or infections

ASPREVA Conclusion: Although most patients in both treatment groups experienced clinical improvement, the study did not meet its primary objective of showing that MMF is superior to IVC for lupus nephritis. Subgroup analysis: African-Americans responded better to MMF

Rituximab (LUNAR study) Randomized controlled trial, n=144 patients with stage 3/4 lupus nephritis with proteinuria. Induction treatment corticosteroids and MMF in all subjects Randomization: RTX or placebo Groups were well matched at baseline,most were nephrotic and mean creatinine 1.0 mg/dl

LUNAR study results Responders: 57% in RTX vs 46% placebo There were no statistically significant differences in the primary or clinical secondary endpoints. RTX had a greater effect on decreasing anti-double stranded DNA and increasing complement levels. Adverse events were similar between the groups.

Treatment Induction Maintenance Relapse (no clinical trials) -Cyclophosphamide 0.75g/m2 q month x 6 or -MMF 500mg BID up to 2.0-3.0g/day -Methylprednisolone 500-1000mg QD x3 or 6o mg qday Maintenance -Azathioprine 2mg/kg/day with prednisone OR -MMF 1-2g/day with prednisone Relapse (no clinical trials) Advantages of AZA: cheaper; fewer GI side effects; potential child-bearing Advantages of MMF: some small studies show that it may be better

Patient example 34 year-old unemployed, uninsured, poverty level income, African-American male diagnosed with lupus 1 yr ago and subsequently lost to follow-up. Has noticed swelling of the ankles about 6 mos. BP 145/95. Urinalysis: 4+ protein, 4+ blood. Red blood cell casts noted. Urine protein creatinine ratio 8. 24-hour urine with 8.6 g of protein. Serum creatinine 1.8 mg/dl. Hct 26 %. Positive double-stranded DNA. Very low C3 and C4.

Non-immunosuppressive therapies Blood pressure control, 130/80 mm Hg Renin angiotensin inhibitors (ACEI or ARB)to minimize proteinuria Statins for hypercholesterolemia Low-salt diet Antiplatelet therapy? Consider anticoagulation (particularly with antiphospholipid syndrome or known venous thrombosis)