Lupus Nephritis LN: Insight in New Classification

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Lupus Nephritis LN Insight in New
Classification?

• By
• Ahmed Gaber Adam, MD
• Professor of Internal Renal Medicine
• Alexandria Egypt

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CS
I
Oral
Pulse
CYP
Type
II
MMF
Dose / Cr
III
AZA
G
S
IV
CsA
A ?/24
C ?/12
Rituximab
V
PP
VI
???
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Agenda

• Questions need answers.
• Definition
• Molecular Basis
• Pathogenesis
• Pathology
• Diagnosis based Therapy Next Episode?

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LUPUS NEPHRITIS

• Definition
• Incidence Prevalence
• Pathophysiology
• Investigation
• Pathology
• Clinical / Clinico-Pathological Correlations
• Treatment

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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

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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?

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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

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EPIDEMIOLOGY OF SLE

• Prevalence gt 10/100,000 FM 91 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 Kleinfelters syndrome
• Associated with partial Complement deficiency
  states Especially C2
• May be drug induced hydralazine, procainamide

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• 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

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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.

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The active inflammatory infiltrate is generally
composed of mainly lymphocytes, plasma cells,
histiocytes and a few polymorphs, with focal
tubulitis accompanied by interstitial edema and
focal tubular cell degenerative changes.
Chronic tubulo-interstitial changes showing
tubular atrophy, interstitial fibrosis contribute
towards progression of the renal parenchymal
disease and the extent correlates with the degree
of decline in renal function.
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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.

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Autoantigens in SLE

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

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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.

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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).

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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.

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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.

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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

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Do we really need classifications?

• Reliability of communicating information
• Simplify interpretation of pathological findings
• Facilitate clinicopathological studies
• Guide treatment and prognosis

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

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ISN/RPS Working Group on the Classification of
Lupus Glomerulonephritis

• PATHOLOGISTS
• Charles Alpers, U.S.A.
• Jan Bruijn, Netherlands
• Terence Cook, England
• Vivette DAgati, 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

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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 lt50 of
  glomeruli)
• Class IV Diffuse LGN (involving 50 or gt
  glomeruli)
• Class V Membranous LGN
• Class VI Advanced sclerotic LGN (gt90 sclerotic
  glomeruli)

for classes III and IV, the diagnosis should
include one of the following with active
lesions/with active and chronic lesions/ inactive
with scars for classes III and IV, the
diagnosis should include the percentage of
glomeruli with fibrinoid necrosis or cellular
crescents when present for class IV, the
diagnosis should include one of the following
predominantly segmental (IV-S)/predominantly
global (IV-G) class V may occur in combination
with III or IV in which case both will be
diagnosed
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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.

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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.

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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

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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 gt50 of the involved
  glomeruli have segmental lesions, and diffuse
  global (IV-G) when gt50 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

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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.

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2002 ISN/RPS Consensus Conference on the
Classification of Lupus Nephritis

• Class VI Advanced sclerotic lupus
  glomerulonephritis
• 90 or gt glomeruli globally sclerosed without
  residual activity

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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 lt50 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 (gt90 sclerotic
  glomeruli)

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