The document discusses systemic lupus erythematosus (SLE) and its effects on the kidneys, known as lupus nephritis. It defines SLE as an autoimmune disease that causes organ and tissue damage mediated by autoantibodies and immune complexes. Around 90% of SLE patients are women of childbearing age. The document outlines the classification criteria for diagnosing SLE and describes the clinical manifestations and role of renal biopsy in diagnosing lupus nephritis. It discusses the pathologic findings of lupus nephritis under light microscopy, immunofluorescence, and electron microscopy and provides the 2003 classification system for lupus nephritis.
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Sle &; kidney
1. SLE & KIDNEY
Ayan Santra,
PGT, Dept. of Pathology
Burdwan Medical College
2. Definition
• Systemic lupus erythematosus (SLE) is an
• autoimmune disease in which organs,
tissues, and cells undergo damage mediated by
tissue-binding autoantibodies and immune
complexes.
• Ninety percent of patients are women of child-
bearing years;
• people of both genders, all ages, and all ethnic
groups are susceptible.
3. Classification Criteria for the
Diagnosis of SLE(≥4 criteria at any
point)
• Malar rash Fixed erythema, flat or raised, over the malar eminences
• Discoid rash Erythematous circular raised patches with adherent
keratotic scaling and follicular plugging; atrophic scarring may occur
• Photosensitivity Exposure to ultraviolet light causes rash
• Oral ulcers Includes oral and nasopharyngeal ulcers, observed by
physician
• Arthritis Nonerosive arthritis of two or more peripheral joints, with
tenderness, swelling, or effusion
• Serositis Pleuritis or pericarditis documented by ECG or rub or
evidence of effusion
4. Classification Criteria for the
Diagnosis of SLE(≥4 criteria at any
point)
• Renal disorder Proteinuria 0.5 g/d or ≥3+, or cellular casts
• Neurologic disorder Seizures or psychosis without other
causes
• Hematologic disorder Hemolytic anemia or leukopenia
(<4000/L) or lymphopenia (<1500/L) or thrombocytopenia
(<100,000/L) in the absence of offending drugs
• Immunologic disorder Anti-dsDNA, anti-Sm, and/or
antiphospholipid
• Antinuclear antibodies An abnormal titer of ANA by
immunofluorescence or an equivalent assay at any point in
time in the absence of drugs known to induce ANAs
5. Lupus Nephritis
• The renal manifestations of SLE is called lupus
nephritis.
• Clinical or morphologic involvement of the
kidney in SLE occurs in 50% to 80% of lupus
patients at any moment during the course of
their disease.
• Renal alterations are found in almost 90% of
lupus patients at autopsy
6. Clinical manifestations
• Onset of renal involvement is most common
within the first year
• Manifestations varies according to stage of
disease
• From asymptomatic to renal failure
• The nephritis has the ability to transform from
one morphologic pattern to another
spontaneously or after treatment
7. • In class I and II (mesangial) lupus nephritis,
microscopic hematuria is the leading
symptom. Proteinuria may be present, but it is
not severe or in the nephrotic range.
• In classes III and IV (proliferative) lupus
nephritis, nephritic syndrome, with or
without nephrotic-range proteinuria, and
frequently low complement levels are seen.
• In class V (membranous) lupus nephritis,
severe, usually nephrotic-range proteinuria
is the most significant symptom, with
microscopic hematuria.
• Class VI (chronic sclerosing) lupus nephritis is
characterized by chronic renal failure.
8. Role of Renal Biopsy
• It is instrumental in establishing a diagnosis of
SLE or lupus nephritis.
• Indications are:
• newly diagnosed SLE,
• newly appearing renal symptoms;
• follow up every 6 months or more after therapy
to gauge the efficacy of treatment and guide
further therapeutic management;
• sudden change in renal symptoms & findings
9. • The biopsy should contain a minimum of 10
glomeruli for light microscopy analysis
• H&E, methenamine-silver, trichrome, and PAS
• Immunofluorescence (IF) should include
staining for IgG, IgA, IgM, C3 and C1q
• It is possible to do an adequate and complete
classification of the lupus nephritis, without
electron microscopy (EM); In cases without IF,
EM is essential
10. Terminologies
• Focal-Involving <50% of glomeruli
• Diffuse-Involving 50% or more of glomeruli
• Segmental-Involving part of a glomerular tuft(<50%)
• Global-Involving all of a glomerular tuft(>50%)
• Karyorrhexis: presence of pyknotic and fragmented
nuclei
• Mesangial hypercellularity- three or more mesangial
cells in mesangial areas away from the vascular pole,
assessed in 3-micron-thick histologic sections
11. Terminologies
• Endocapillary hypercellularity- Increased cellularity
internal to the GBM composed of leukocytes, endothelial
cells and/or mesangial cells
• Extracapillary hypercellularity- Increased cellularity in
Bowman’s space, i.e. > one layer of parietal or visceral
epithelial cells, or monocytes/macrophages
• Fibrinoid necrosis- Lytic destruction of cells and matrix
with deposition of acidophilic fibrin-rich material
• Sclerosis- Increased collagenous extracellular matrix
that is expanding the mesangium, obliterating capillary
lumens or forming adhesions to Bowman’s capsule
• Hyaline-Glassy acidophilic extracellular material
14. Pathologic Findings
• Gross Pathology:
• Acute disease: enlarged, swollen kidneys with
petechial hemorrhages and focal, shallow,
superficial scars.
• With immunosuppressive therapy: a
combination of chronic and acute changes, with
a contracted or swollen appearance.
15. Light Microscopy
• Glomeruli:
• 1. Immune deposits: large and wide spread
• Hyaline and hyper eosinophilic in H&E stain
• The trichrome stain highlights the deposits as red
(or fuchsinophilic) against the blue-staining
glomerular matrix components
• When large enough to completely involve the
peripheral circumference of the glomerular
capillary, they are referred to as classic wire
loops, which produce a rigid, refractile thickening
of the glomerular capillary wall in hematoxylin-
eosin stained sections,
16. Lupus nephritis class IV.
Trichrome stain highlights the
presence of global subendothelial
fuchsinophilic deposits. (Masson's
trichrome, ×500.)
Lupus nephritis class IV. In
addition to wire-loop deposits,
there are segmental intraluminal
deposits forming hyaline
thrombi.•(H&E; ×320.)
17. • Active class III or IV lupus
nephritis have large
intracapillary immune
deposits forming hyaline
thrombi;
• Can be differentiated from
true fibrin thrombi by
special stains for fibrin
(modified Fraser Lendrum
stain and phosphotungstic
acid hematoxylin [PTAH]
stain) and by staining for
fibrin-related antigens by
immunofluorescence
Lupus nephritis class IV. The
hyaline thrombi stain red against
the blue-staining glomerular
capillary walls. (Masson's
trichrome, ×500
18. • 2. Glomerular
proliferations:
• May be: mesangial,
endocapillary, and
extracapillary
• Endocapillary
proliferation can be
defined as a proliferation
of endothelial cells and
mesangial cells together
with infiltrating
leukocytes (including
mononuclear or
polymorphonuclear
leukocytes) that
significantly narrows or
occludes the glomerular
capillary lumen.
Lupus nephritis class IV. There is
relatively uniform diffuse and
global endocapillary
proliferation. (H&E; ×100.)
19. • 3. Glomerular Necrosis:
feature of class III or IV lupus
nephritis ; never observed in
pure mesangial proliferative
(class II) or membranous (class
V) lupus nephritis.
• Consists of a focus of smudgy
fibrinoid obliteration of the
glomerular tuft, which is often
associated with any or all of the
following: deposition of
intracapillary fibrin,
glomerular basement
membrane rupture or gap
formation, and apoptosis of
infiltrating neutrophils
forming pyknotic or
karyorrhectic nuclear
debris
Lupus nephritis class III.
There is segmental fibrinoid
necrosis with neutrophil
infiltration and pyknosis.
(H&E; ×500.)
20. • 4. Hematoxylin Bodies:
they are rounded, smudgy,
lilac-staining structures,
seen as cells with
degenerated aspect;
probably they represent
degenerated nuclei and
correspond to LE cells
described in the blood of
patients with SLE.
• Only truly pathognomonic
lesion in lupus nephritis but
very uncommon(2%).
Lupus nephritis class IV.
Several glomerular
capillaries contain
hematoxylin bodies.
Another lobule contains
karyorrhectic nuclear
debris. (H&E; ×500.)
21. • 5. Cellular crescents: defined as aggregates
comprising two or more layers of
proliferating visceral and parietal
epithelial cells with infiltrating mononuclear
cells lining one fourth or more of the
interior circumference of Bowman's
capsule.(c.f. single layer of reactive
hyperplastic visceral epithelial cells commonly
encountered in glomeruli with membranous
features or undergoing sclerosis.)
• Encountered frequently in class III or IV lupus
nephritis.
22. • 6. Glomerular
Scarring: may be
focal ,segmental to
diffuse, global.
Lupus nephritis class IV. Despite aggressive
therapy, repeat renal biopsy two years later
shows progression to segmental and global
glomerulosclerosis with focal fibrous
crescents. There is marked reduction in the
degree of interstitial inflammation. (Jones
methenamine silver, ×80.)
23. Tubules and Interstitium
• In patients with nephrotic-range proteinuria,
proximal tubules are involved. There are
pesence of intracytoplasmic lipid
resorption droplets that appear as clear
vacuoles in hematoxylin-eosin preparations
because of removal of the lipid in the course of
tissue processing and protein resorption
droplets that appear eosinophilic and strongly
PAS-positive and usually trichrome red. The
latter change has been referred to as hyaline
degeneration•of the proximal tubules,
24. • Active lesion: interstitial inflammation and
edema
• Chronic lesion: tubular atrophy and interstitial
fibrosis.
• The interstitial infiltrates consist predominantly
of mononuclear leukocytes, including
lymphocytes, monocytes, and plasma cells.
• Tubulointerstitial immune deposits: seen in
diffuse proliferative lupus nephritis.
• They consist of granular, electron-dense
deposits that involve tubular basement
membranes, interstitial capillary basement
membranes, and interstitial collagen.
25. Lupus nephritis class IV.
High-power view shows a
lamellated network of
tubular basement
membrane splayed
around the tubular
basement membrane
deposits. (Electron
micrograph, ×4000.)
Lupus nephritis class IV.
The immunofluorescence
micrograph shows
abundant granular
deposits of IgG within the
tubular basement
membranes and
interstitium. (×200.)
26. • The severity of tubulointerstitial
inflammation correlates broadly with
glomerular proliferative lesions . It constitutes
one of the best morphologic correlates with the
degree of renal insufficiency and is an accurate
prognosticator of subsequent decline in renal
function.
• Tubular atrophy, at least in part the result of
interstitial inflammation, is one of the strongest
predictors of renal failure , as it is in many
other glomerular diseases
27. Vascular Lesions
Arteriosclerosis and arteriolosclerosis
Uncomplicated vascular immune deposits
Noninflammatory necrotizing vasculopathy (so-
called lupus vasculopathy)
Thrombotic microangiopathy
Associated with HUS/TTP syndrome
Associated with antiphospholipid antibodies
Associated with scleroderma/mixed connective
tissue disease
Necrotizing vasculitis (PAN type)
28. Uncomplicated Vascular Immune
Deposits.
• Most common renal vascular
lesion in SLE is immune complex
deposition in the walls of small
arteries and arterioles; deposition
occurs to a lesser extent in veins
• Diagnosis requires the
demonstration of granular
deposits of immunoglobulin (IgG,
IgM, and IgA in various
combinations), often associated
with C1q or C3.
Lupus nephritis class IV.
The fluorescence
micrograph shows
abundant granular staining
for IgG within the intima
and media of an
interlobular artery. (×
400.)
29. Noninflammatory Necrotizing
Vasculopathy
• Affects predominantly preglomerular arterioles
in the setting of severe active class IV lupus
nephritis.
• The affected vessels are severely narrowed and
sometimes occluded by abundant intimal and
luminal deposits of glassy eosinophilic material
that may extend into the media.
• This material is usually fuchsinophilic in
trichrome-stained preparations
30. Lupus
vasculopathy. A
double panel
shows occlusion of
preglomerular
arterioles by
eosinophilic
deposits (left) that
stain positive with
Lendrum stain for
fibrin (right). (×
500.)
31. Thrombotic Microangiopathy
• Most commonly affect preglomerular arterioles
and interlobular arteries
• By LM, the affected vessels are occasionally
narrowed or occluded by intraluminal fibrin
thrombi, which may be associated with
endothelial swelling and denudation
• By IFM, the affected vessels usually reveal
intense, dominant staining for fibrin-related
antigens, with variable positivity for IgM and C3.
32. Renal Vasculitis
• Least common vascular lesion
• There is leukocyte infiltration of vessel walls,
often accompanied by necrosis.
• IFM: strong staining for fibrin-related antigens
with weak and more variable staining for
immunoglobulin and complement;
• representing nonspecific trapping of plasma
proteins in areas of necrosis.
33. Immunofluorescence
• Immunostaining for IgG in more than 90% of
cases; there is IgA and IgM staining in 60-70%
of cases.
• The presence of the three immunoglobulins (Igs)
with C3 and C1q is well-known as “full house”
pattern, and it is very characteristic of lupus
nephritis.
34. Electron microscopy
• Electron dense deposits are demonstrated with a
distribution similar to the one of the immune
deposits detected by IF, according to the class.
35. Classification of Lupus Nephritis
• 2003 International Society of Nephrology/Renal
Pathology Society (ISN/RPS) classification of
lupus glomerulonephritis (LGN)
• Class I: minimal mesangial lupus nephritis
• Normal glomeruli by light microscopy (LM), but
mesangial immune deposits by immunofluorescence (IF)
and/or electron microscopy (EM)
• Class II: mesangial proliferative lupus nephritis
• Purely mesangial hypercellularity of any degree or
mesangial matrix expansion by LM with mesangial
immune deposits; may be a few isolated subepithelial
and/or subendothelial deposits by IF and/or EM, but not
visible by LM
36. Lupus nephritis class I. The
glomerulus is normal in
cellularity, and the glomerular
basement membranes are
unremarkable. (PAS; ×500.)
Lupus nephritis class II. There is
mild, global, mesangial
hypercellularity with thin capillary
loops. (H&E, ×500.)
37. • Class III: focal lupus nephritis
• Active or inactive focal, segmental or global endo- or
extracapillary glomerulonephritis involving <50% of
all glomeruli, typically with focal subendothelial
immune deposits,with or without mesangial
alterations
• III (A) Active lesions: focal proliferative LGN
• III (A/C) Active and chronic lesions: focal
proliferative and sclerosing LGN
• III (C) Chronic inactive lesions with glomerular
scars: focal sclerosing LGN
38. Lupus nephritis class III. A
low-power view shows the
focal and segmental
distribution of the
endocapillary proliferation,
with some overlying
crescents. Endocapillary
proliferation affected less
than 50% of the total
glomeruli in this biopsy.
(Jones methenamine silver
stain; ×40.)
Lupus nephritis class III. There is
segmental obliteration of
glomerular capillary lumina by
endocapillary proliferation,
including infiltrating leukocytes,
with associated fibrinoid necrosis.
The adjacent lobules display mild
mesangial hypercellularity. (H&E;
×400.)
39. • Class IV: diffuse lupus nephritis
• Active or inactive diffuse, segmental or global endo- or extracapillary
glomerulonephritis involving ≥50% of all glomeruli, typically with diffuse
subendothelial immune deposits, with or without mesangial alterations.
This class is divided into diffuse segmental (IVS) lupus nephritis when
≤50% of the involved glomeruli have segmental lesions, and diffuse global
(IV-G) lupus nephritis when ≥50% of the involved glomeruli have global
lesions.
• IV-S (A) Active lesions: diffuse segmental proliferative lupus nephritis
• IV-G (A) Active lesions: diffuse global proliferative lupus nephritis
• IV-S (A/C) Active and chronic lesions: diffuse segmental proliferative and
sclerosing lupus nephritis
• IV-G (A/C) Active and chronic lesions: diffuse global proliferative and
sclerosing lupus nephritis
• IV-S (C) Chronic inactive lesions with scars: diffuse segmental sclerosing
lupus nephritis
• IV-G (C) Chronic inactive lesions with scars: diffuse global sclerosing
lupus nephritis
40. Lupus nephritis class IV-G. There is
diffuse and global endocapillary
proliferation involving all the
glomeruli in this biopsy. (H&E, ×
180).
Lupus nephritis class IV. The low-
power immunofluorescence
micrograph shows intense, diffuse
staining for IgG in the glomerular
mesangium and peripheral capillary
loops, consistent with a
subendothelial distribution. (×120.)
41. Lupus nephritis class IV. This
example has diffuse wire-loop
deposits without appreciable
endocapillary proliferation.
(Masson's trichrome, ×600.)
Wire-loop deposit. By
immunofluorescence there is a
large subendothelial deposit that
conforms to the contour of the
glomerular basement membrane,
producing a smooth comma-
shaped outer contour. (×1000.)
42. • Class V: membranous lupus nephritis
• Global or segmental subepithelial immune deposits
or their morphologic sequelae by LM and by IF or
EM, with or without mesangial alterations
• Class V lupus nephritis may occur in combination
with class III or IV, in which case both will be
diagnosed
• Class V may show advanced sclerosis
• Class VI: advanced sclerosing lupus
nephritis
• >90% of glomeruli globally sclerosed without
residual activity
43. • Lupus nephritis class V . There
are heavy mesangial immune
deposits of IgG with more
delicate granular subepithelial
deposits.(Immunofluorescence
micrograph, ×600.)
Lupus nephritis class V . There is
regular thickening and rigidity of
the glomerular capillary walls
accompanied by global mesangial
hypercellularity. (H&E; ×500.)
44. • Indicate the proportion of glomeruli with active and
with sclerotic lesions in class III.
• Indicate the proportion of glomeruli with fibrinoid
necrosis and/or cellular crescents in class IV.
• Class V may occur in combination with class III or
IV, in which case both will bediagnosed.
• Note: Indicate the grade (mild, moderate, severe),
tubular atrophy, interstitial inflammation and
fibrosis, severity of arteriosclerosis, or other
vascular lesions
45. Lupus nephritis class VI. Extensive glomerular sclerosis shows
vestiges of fibrous crescents. The global sclerosis affected more
than 90% of glomeruli in this biopsy. Several glomeruli pictured
here are segmentally sclerotic. Atrophic tubules alternate with
groups of compensatorily hypertrophied tubules. (Masson's
trichrome, ×80.)
46.
47. Definition of active and chronic glomerular lesions
according to the
2003 ISN/RPS classification of lupus nephritis
• Active lesions(0-24)
• Endocapillary hypercellularity
(0-3 +)
• Leukocyte Infiltration (0-3 +).
Neutrophil exudation is defined
as more than two neutrophils
per glomerulus.
• Subendothelial hyaline deposits
(0-3 +)
• Fibrinoid necrosis/karyorrhexis
(0-3 +)×2
• Cellular crescents (0-3 +)×2
• Interstitial Inflammation (0-3
+)
• Chronic lesions(0-12)
• Glomerular sclerosis
(segmental, global)(0-3)
• Interstitial fibrosis(0-3)
• Tubular atrophy (0-3)
• Fibrous crescents(0-3)
0, absent;
1+, less than 25% of glomeruli
affected;
2+, 25% to 50% of glomeruli affected;
3+, more than 50% of glomeruli
affected
48. DIFFERENTIAL DIAGNOSIS
• Any immune complex GN
• IgA nephropathy
• HSP
• C1q nephropathy
• Idiopathic membranous GN(In lupus-associated
membranous GN, there are
mesangial,subendothelial deposit,TID and ANA.
IF characteristically shows a “full house”
pattern.)
49. Pathogenesis
• Three major mechanisms of immune deposition
in the kidney have been identified:
• (a) binding of autoantibodies to intrinsic
glomerular antigens,
• (b) binding of autoantibodies to nonglomerular
autoantigens that have been planted in the
glomerulus, and
• (c) deposition of preformed circulating immune
complexes.
50. • Role of Immunoglobulin :
• predominant immunoglobulin isotype in
glomerular deposits is IgG
• other immunoglobulin classes (IgM, IgA, and
IgE) may codeposit in glomeruli
51. • Role of Electric Charge of
Immunoglobulin:
• Charge characteristics Igs probably play a role in
the localization of immune deposits in lupus
nephritis, they are not the major determinant of
susceptibility to nephritis
52. • Autoantibody Specificity and Cross-
Reactivity for Glomerular Constituents:
• antibodies to nuclear constituents (i.e., anti-
ssDNA, dsDNA, histone, RNP, and
nucleosomes),
• cytoplasmic constituents (i.e., anti-Sm), and
• cell membrane antigens (i.e., APL and
antiendothelial antibodies).
53. • lupus autoantibodies bind in situ to normal
glomerular cellular or matrix components and
that these cross-reactivities may play a major
role in the development of nephritis
54. • Role of Binding of Autoantigens to
Glomerular Constituents:autoantigens may
first become planted within the glomerulus
through particular charge or other physical
interactions.
• Once planted in the glomerulus, they are then
free to interact with circulating autoantibody,
causing the formation of immune complexes in
situ
55. Antibodies to nucleosomes (DNA bound
to histones)
• During apoptosis, the organized cleavage of
chromatin leads to clustering of nucleosomes on the
surface of apoptotic cells
• Normally, these apoptotic bodies are efficiently
cleared by effector cells before nucleosomes can be
released into the circulation
• In SLE, there is evidence of increased or delayed
apoptosis or reduced clearance of apoptotic cells,
leading to increased exposure of immunogenic
nucleosomes to the immune system and the ensuing
formation of nucleosome-specific T cells and
antinucleosome autoantibodies
56.
57. • Role of Deposition of Preformed Immune
Complexes: the circulating immune complex
load may predispose the patient to particular
patterns of lupus nephritis
• Small amounts of intermediate-sized, high-
avidity complexes=mesangial pattern
• Larger quantities of intermediate-sized
complexes or large complexes =subendothelial
deposition
58. • Cellular and Coagulation Factors:
• Deposition of immune complex
activation of cytokine networks
leukocyte recruitment,
cellular proliferation,
matrix production, and
intravascular coagulation
GLOMERULAR INJURY
59. • Genetic Factors: several class I and class II
MHC genes are involved
• Epidemiologic Factors:
• Race: african american> caucasians
• Sex: F>M
• Klinefelter's syndrome> hyperestrogenic state>
increased bindining of anti-Ro and anti-La Ab
60. • B-Cell and T-Cell Abnormalities:
• Lupus have enhanced B-cell proliferation,
activation, and immunoglobulin production, and the
number of Ig-secreting B cells in the peripheral
blood is increased .
• Paradoxically, the number of total B lymphocytes in
the peripheral blood is often reduced
• B cells secrete IL-2,IL-6,IL-10, TGF, TNF,IFN.
• B cells specific for nuclear antigens may get second
signals from TLRs and may be activated, resulting in
increased production of antinuclear autoantibodies.
• Impaired T-cell response to mitogens, antigens, and
autologous or allogeneic class II MHC molecules
• CD8+ cells from patients with SLE are often unable
to downregulate polyclonal immunoglobulin
production and synthesis of autoantibodies
61. • Antibody Specificity:
• The production of autoantibodies, especially
ANA, is a defining feature of SLE and probably
an integral pathogenetic factor.
• Clinical manifestation of ANA is LE cell.
• The LE cell is a neutrophil or monocyte that has
phagocytosed a nucleus, producing a purplish
inclusion in a process that is mediated by
antibody to the nucleosomal
deoxyribonucleoprotein histone complex
• Antibodies to dsDNA are the most specific for
SLE
• Anti histone and anti DNP Abs(against
nucleosome) are most common in SLE.
62. • Complement Abnormalities:
• Commonly involve C1,C2 and C4. Due to null
allele.
• Low C1q levels have been associated with
proliferative lupus nephritis classes III and IV
and may predict the occurrence of renal flares.
63. Demonstration of LE cell
• Twenty millilitres of venous blood are
defibrinated by agitation in a universal (1-oz.
bottle) container holding a bent paper clip.
• The defibrinated blood is transferred to a
conical tube and centrifuged for five minutes
at 1,800 r.p.m.
• The upper cellular layer is transferred by a
Pasteur pipette to a Wintrobe tube, which is
again centrifuged at 1,800 r.p.m. for five
minutes.
• Smears are made from the buffy coat, and
stained by the Leishman method.
• The number of L.E. cells per 500 leucocytes is
then determined.
• The inclusions show varying grades of density
and of colour from deep blue to pink.
64. References
• Sternberg's Diagnostic Surgical Pathology, 5th
ed. 2010, Pg
• Heptinstall's Pathology of the Kidney (2-Volume
Set), 6th ed
• Fogo_Fundamental of Renal Pathology