1. Lupus Nephritis Update 2010
Review of recent treatment trials

2. 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 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.

4. 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.

5. 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

6. 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

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

11. 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

12. 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

18. 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

19. 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

21. 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

22. 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

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

24. 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

25. 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.

26. 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)

27. 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 years of follow-up; total of 61 patients

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

29. 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

34. 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 mg/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

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

36. 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%)

37. 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

38. 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

39. 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

42. 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

43. 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

44. 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

45. 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.

46. Treatment Induction Maintenance Relapse (no clinical trials)
-Cyclophosphamide 0.75g/m2 q month x 6 or
-MMF 500mg BID up to g/day
-Methylprednisolone mg 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

47. 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 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.

48. 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)