1. Lupus Nephritis Prof. Hafiz Ijaz Ahmad Department of Nephrology Allama Iqbal Medical College Lahore

2. Systemic Lupus Erythematosus Systemic Lupus Erythematosus (SLE) is a chronic inflammatory disease of unknown cause that can affect virtually any organ of the body. Immunologic abnormalities, especially the production of a number of antinuclear antibodies (ANA), are a prominent feature of the disease.

3. Prevalence in USA: 10-400 / 100,000 Blacks > Asians > whites F:M – 10:1 Multigenic Disease Highest in Black women, Lowest in white men OCP/hormone replacement: 1.2 – 2 fold↑ Environmental Stimuli: UV, EBV, Tobacco

4. Diagnostic Criteria for Systemic Lupus Erythematosus Malar Rash Discoid Rash Photosensitivity Oral ulcers Arthritis Serositis Renal disorder – Proteinuria, cellular casts Neurologic Disorder Hematologic Disorder Immunologic Disorder Antinuclear antibodies If ≥4 any time in Pt Hx

5. Clinical Manifestations Fever Fatigue Weight loss Malar Rash – Fixed erythema, flat/raised, over malar eminences Discoid Rash – Erythematous circular raised patches, scaling, scarring Photosensitivity – Exposure to UV light causes rash

6. Oral Ulcers – Oral/nasopharyngeal ulcers Arthritis – Non erosive, 2 or more peripheral joints, tenderness, swelling Serositis – Pleuritis, pericarditis (ECG / Rub) Renal Disorder – Proteinuria > 0.5 g/d or 3+, cellular casts Neurological disorder – Seizures / psychosis without other cause

7. Hematological disorder – Hemolytic anemia, leukopenia, lymphopenia, thrombocytopenia Immunologic disorder – Anti-dsDNA, anti-sm, and/or anti-phospholipid Antinuclear antibodies – ANA, IF or ther assay

9. Lupus Nephritis ACR Criteria Proteinuria > 0.5 g/d OR 3 + proteinuria Active urinary sediments: dysmorphic RBCs, RBC casts`

10. Renal Manifestations in patients with Lupus Proteinuria100% – Nephrotic syndrome45-65% Hematuria – Microhematuria80% – Macrohematuria1-2% Cellular casts30% Reduced renal function40-80% – RPGN10-20% – AKI1-2% Hypertension15-50% Tubular abnormalities60-80%

11. Histological Classification Minimal mesangial lupus nephritis (class I) Mesangial proliferative lupus nephritis (class II) Focal lupus nephritis (class III) Diffuse lupus nephritis (class IV) Membranous lupus nephritis (class V) Advanced sclerosing lupus nephritis (class VI)

15. Why renal biopsy is important Two Lesions: Membranous LN but may also have a proliferative GN Patients with less severe clinical disease but Biopsy shows severe Patients with more severe disease may have additional findings to alter the choice of therapy: diffuse proliferative LN & marked crescent formation In addition to its role in patients with established lupus, renal biopsy may aid the diagnosis in patients for whom the diagnosis of lupus is uncertain

16. Indications for renal biopsy ●Protein excretion greater than 500 mg/day. ●An active urinary sediment with hematuria (five or more red blood cells per high-power field, most of which are dysmorphic) and cellular casts. Red cells are dysmorphic. ●A rising serum creatinine that is not clearly attributable to another mechanism.

17. Treatment of Lupus Nephritis

19. Conclusions In this 24-week trial, mycophenolate mofetil was more effective than intravenous cyclophosphamide in inducing remission of lupus nephritis and had a more favorable safety profile.

20. Exclusion criteria creatinine clearance of less than 30 ml per minute serum creatinine on repeated testing greater than 3.0 mg per deciliter (265.2 µmol per liter) severe coexisting conditions precluding immunosuppressive therapy conditions requiring intravenous antibiotic therapy prior treatment with mycophenolate mofetil treatment with intravenous cyclophosphamide within the past 12 months monoclonal antibody therapy within the past 30 days pregnancy or lactation.

22. Conclusions a 36-month, randomized, double-blind, double- dummy, phase 3 study comparing oral mycophenolate mofetil (2 g/d) and oral azathioprine (2 mg/kg/d) Mycophenolate mofetil was superior to azathioprine in maintaining a renal response to treatment and in preventing relapse in patients with lupus nephritis who had a response to induction therapy. (N engl j med 365;20 nejm.org november 17, 2011)

25. Belimumab for Systemic Lupus Erythematosus (N Engl J Med 2013; 368:1528-1535) A 20-year-old woman with SLE presents with disease flares and receives belimumab, a monoclonal antibody that binds to B-cell activating factor, inhibiting B-cell stimulation. Belimumab is considered for patients who do not have a response or have adverse effects with first-line therapies.

27. Conclusions We used double immunostaining to evaluate pathway activation in the mammalian target of rapamycin complex (mTORC) and the nature of cell proliferation in the vessels of patients with primary or secondary antiphospholipid syndrome nephropathy. Our results suggest that the mTORC pathway is involved in the vascular lesions associated with the antiphospholipid syndrome.

28. Treatment of Lupus Nephritis Class I & II : No specific Therapy Class III & IV: – Induction Phase – Maintenance Phase Class V: – Nephrotic Syndrome – Subnephrotic Proteinuria Class VI

29. Treatment of Proliferative LN Induction Phase – Methylprednisolone1g IV X 3d or 1mg/kg oral – MMF 1-1.5 g bid or – IV cyclophosphamide or oral cyclophosphamide 3-6 Months

30. Treatment of Proliferative LN Maintenance Phase – Low dose steroids + MMF 0.5 -1 g bid – OR low dose steroids + AZA 1-2mg/kg Supportive Treatment ACE-I, ARBs, osteoporosis prophylaxis, CV prevention)

31. Prognosis A curable/managable disease with modern treatment Overall 5 year survival - >90% ESRD 8 – 15% Late improvement – termination of Dialysis LN - 1-2% of ESRD population

32. Prognosis Severe infections – Immuno-compromised status – Medicines AV fistula clotting Premature Myocardial Ischemia (APL)

33. Predictors of poor outcome Race – Black, South asians Male gender Younger age <24 Poor socio-economic status Higher baseline Creat. Higher baseline Proteinuria Severe anemia, throbocytopenia Hypocomplementemia Elevated anti dsDNA Delay in initiation of treatment Relapse of Nephritic syndrome

34. LN & Renal Transplant Outcome is the same as other patients False positive “cross match” Immunosuppression, rejection episodes, graft loss same Wait on dialysis ? Pre-amptive immunosuppression Disease recurrence 1-30%, graft loss rare

35. 772 adults with ESRD caused by lupus nephritis and 32,644 adults with ESRD caused by other causes who received a transplant between 1987 and 1994

36. Conclusions Graft and patient survival after first cadaveric and first living-related renal transplants are similar in patients with ESRD caused by lupus nephritis and patients with ESRD from other causes.

37. THANKS