Lupus Nephritis LN : Insight in New Classification

1. Lupus Nephritis �LN�: Insight in New Classification? By Ahmed Gaber Adam, MD Professor of Internal & Renal Medicine Alexandria Egypt

3. Agenda Questions need answers. Definition Molecular Basis Pathogenesis Pathology Diagnosis based Therapy � Next Episode?

4. LUPUS NEPHRITIS Definition Incidence & Prevalence Pathophysiology Investigation Pathology Clinical / Clinico-Pathological Correlations Treatment

5. Questions Need Answers? Do we need a new classification? Do we need even a classification? Moreover; do we need a kidney biopsy and / or a concrete pathological diagnosis to manage? Do we have a certain class that mandates a specific immunosuppressive protocol change that enforces us primarily to study a classification? Does all renal injury in SLE patient is LN? But furthermore; do we need a second kidney biopsy for the same patient? And lastly, What is the most prognostic factor in the management of lupus nephritis? �may be the pathology & classification

6. Questions Need Answers? It is better to hide some of your clinical data from your pathologist and / or clinical pathologist; hence not to direct his decision and kept him away from being biased. Do we need an undisputed solid tissue based Diagnosis to Manage? The answer is probably: YES; as a good management is based on diagnosis directed therapy. But; be aware that: a single pathological picture may be seen in more than one single disease, and A Single disease may have more than one single pathological picture Do we need a whole punch of un-planned investigations to diagnose?

8. Laboratory and Clinical Manifestations of Systemic Lupus Erythematosus 1. Antinuclear antibodies 2. LE-cells, anti-ds DNA, anti-Sm, false-positive VDRL 3. Non-erosive polyarthritis 4. Cutaneous rash 5. Photosensitivity 6. Oral ulcers 7. Anemia, leukopenia, thrombocytopenia 8. Psychosis, seizures 9. Pleurisy, pericarditis, myocarditis 10. Proteinuria, cellular casts, renal failure

9. EPIDEMIOLOGY OF SLE Prevalence > 10/100,000; F:M = 9:1 Higher incidence in AA, Asians, Latino Genetic factors play a major role High incidence in identical twins; DR3 B8 associated Sex hormones play a major role Female predominance; seen in Kleinfelter�s syndrome Associated with partial Complement deficiency states Especially C2 May be drug induced: hydralazine, procainamide

10. Impaired removal of apoptotic cells could play a major role in SLE, causing apoptotic material to accumulate in tissues and circulation leading to release of immunreactive proteins which can ultimately trigger autoantibody responses Phagocytosis of apoptotic cells is defective (intrinsic defect) Inflammation in the course of phagocytosis of apoptotic cells could enhance the immunogenicity of autoantigen and also trigerring massive TNF? release

12. Tubulo-interstitial disease Active/ proliferative lupus glomerulonephritis is often accompanied by varying degrees of tubulo-interstitial inflammation and tubular basement membrane and vascular immune complex deposits demonstrable by IF and EM.

14. Pathogenic Mechanisms Human prototype of Chronic Immune Complex Disease. Circulating immune complexes. Cryoglobulins (II & III mixed IgG & IgM). Some have Rheumatoid factor or anti-idiotypic activity with antigen specificity for ds-DNA, ss-DNA & ribonucleoproteins.

15. Autoantigens in SLE Intracellular (including nucleoproteins and cytoplasmic ribonuclear proteins). Nucleosomes in particular (histones & DNA). Cell surface e.g phosphatidylserine. Plasma proteins eg. C1q.

16. Autoantigens During apoptosis they become accessible on cell surface. Failure of clearance of apoptotic cells by normal binding of C1q. Aberrant apoptosis seems to be a key mechanism in lupus nephritis. Antigens on the surface of these cells may then be available for presentation to T cells leading to an autoimmune response.

17. Initiation of Nephritis Deposition of immune complexes. Mesangial, subendothelial or subepithelial. According to charge, size, affinity, concentration. Local subepithelial formation by planting antigens in membranous type (histones which are cationic). Cross reaction of antibodies with basement membrane antigens (heparan sulfate proteoglycan).

18. Initiation of Nephritis Activation of complement system by classical and alternate pathways. Release of C3a & C5a with attraction of leukocytes. Macrophages seem to play an important role. Damage of capillary wall by enzymes and ROS. Local formation of cytokines and growth factors.

19. Other factors are probably involved Pauci-immune glomerulonephritis. Tubulointerstitial nephritis. Immune complexes or secondary to glomerular lesions. Vascular lesions. Uncomplicated vascular immune deposits. Thrombotic microangiopathies. HUS/TTP. Antiphospholipid antibodies. Necrotizing PAN type vasculitis (?ANCA). ? Others.

22. Pathologic Classification of Lupus Glomerulonephritis The primary clinical purposes for a pathologic classification system are to: Facilitate communication: Between pathologists Between pathologists and clinicians Between clinicians In understanding the literature Facilitate clinical management: Guiding treatment Suggesting proposals Indicating an etiology or pathogenic mechanism

23. Do we really need classifications? Reliability of communicating information Simplify interpretation of pathological findings Facilitate clinicopathological studies Guide treatment and prognosis

24. Newest Classification of Lupus Nephritis (Weening et al. JASN 2004; KI 2004)

25. Proposal of the International Society of Nephrology and Renal Pathological Society Working Group on the Classification of Lupus Glomerulonephritis �The major objective is to standardize definitions, emphasize clinically relevant lesions, and encourage uniform and reproducible reporting between centers.�

26. ISN/RPS Working Group on the Classification of Lupus Glomerulonephritis PATHOLOGISTS: Charles Alpers, U.S.A. Jan Bruijn, Netherlands Terence Cook, England Vivette D�Agati, U.S.A. Franco Ferrario, Italy Agnes Fogo, U.S.A. Gary Hill, Paris Prue Hill, Australia Charles Jennette, U.S.A. Lai-Ming Looi, Malaysia Luiz Moura, Brazil Michio Nagata, Japan Melvin Schwartz, U.S.A. Surya Seshan, U.S.A. Jan J. Weening, The Netherlands CLINICIANS: Gerald Appel, U.S.A. James Balow, U.S.A. Ellen Ginzler, U.S.A. Lee Hebert, U.S.A. Norella Kong, Malaysia Phillipe Lesavre, France Michael Lockshin, U.S.A. Hirofumi Makino, Japan

27. 2002 ISN/RPS Consensus Conference on the Classification Lupus Nephritis Class I Minimal mesangial lupus glomerulonephritis (LGN) Class II Mesangial proliferative LGN Class III Focal LGN (involving <50% of glomeruli) Class IV Diffuse LGN (involving 50% or > glomeruli) Class V Membranous LGN Class VI Advanced sclerotic LGN (>90% sclerotic glomeruli)

28. 2002 ISN/RPS Consensus Conference on the Classification of Lupus Nephritis Class I Minimal mesangial lupus glomerulonephritis Normal glomeruli by LM, but mesangial immune deposits by IF or EM.

29. 2002 ISN/RPS Consensus Conference on the Classification of Lupus Nephritis Class II Mesangial proliferative lupus glomerulonephritis Purely mesangial hypercellularity of any degree or mesangial matrix expansion by LM with immune deposits, predominantly mesangial with none or few, isolated subepithelial or subendothelial deposits by IF or EM not visible by LM.

30. 2002 ISN/RPS Consensus Conference on the Classification of Lupus Nephritis Class III Focal lupus glomerulonephritis Active or inactive focal, segmental or global endo- or extracapillary GN, typically with focal, subendothelial immune deposits, with or without focal or diffuse mesangial alterations. III (A) Active focal proliferative LGN III (A/C) Active and sclerotic focal proliferative LGN III (C) Inactive sclerotic focal LGN * Indicate the poroportion of glomeruli with active and with sclerotic lesions * Indicate the proportion of glomeruli with fibrinoidnecrosis and/or cellular crescents

31. 2002 ISN/RPS Consensus Conference on the Classification of Lupus Nephritis Class IV Diffuse segmental (IV-S) or global (IV-G) LGN Active or incative diffuse (50% or more involved glomeruli), segmental or global endo- or extracapillary GN with diffuse subendothelial immune deposits, with or without mesangial alterations. This class is divided into diffuse segmental (IV-S) when >50% of the involved glomeruli have segmental lesions, and diffuse global (IV-G) when >50% of the involved glomeruli have global lesions. IV (A) Active diffuse segmental or global proliferative LGN IV (A/C) Diffuse segmental or global proliferative & sclerotic LGN IV (C) Diffuse segmental or global sclerotic LGN * Indicate the poroportion of glomeruli with active and with sclerotic lesions * Indicate the proportion of glomeruli with fibrinoid necrosis or crescents

32. 2002 ISN/RPS Consensus Conference on the Classification of Lupus Nephritis Class V Membranous lupus glomerulonephritis Numerous global or segmental subepithelial immune deposits or their morphologic sequelae by LM or IF or EM with or without mesangial alterations. May occur in comibnation with III or IV in which case both will be diagnosed.

33. 2002 ISN/RPS Consensus Conference on the Classification of Lupus Nephritis Class VI Advanced sclerotic lupus glomerulonephritis 90% or > glomeruli globally sclerosed without residual activity

34. 2002 ISN/RPS Consensus Conference on the Classification Lupus Nephritis Class I Minimal mesangial lupus glomerulonephritis (LGN) Class II Mesangial proliferative LGN Class III Focal LGN (involving <50% of glomeruli) Class IV Diffuse LGN (involving = 50% of glomeruli, subdivided into IV-S and IV-G) Class V Membranous LGN Class VI Advanced sclerotic LGN (>90% sclerotic glomeruli)