SLE
Up to 60% of SLE patients have lupus nephritis
the female-to-male ratio is highest at reproductive age, ranging
between 8:1 and 15:1
Black and Hispanic SLE patients develop LN earlier and have worse
outcomes than white patients with SLE, including death and ESRD
SLICC criteria for diagnosis of SLE = 10 point and positive
ANA
Proliferative lupus nephritis = 10 points! Membranous = 8 so one
other thing will get you there
Extra Renal Manifestation - Malar Rash - Alopecia - Arthralgia -
Fatigue - Thrombocytopaenia - Haemolytic anaemia - more rare :
Cardiomyopathy, cerebritis
Lupus Nephritis
Haematuria and proteinuria, AKI/Flare - > CKD -Most patients
with SLE who develop LN do so within 5 years of an SLE diagnosis and, in
many cases, LN is the presenting manifestation resulting in the
diagnosis of SLE -Within 10 years of an initial SLE diagnosis, 5–20% of
patients with LN develop end-stage kidney disease
Be Suss: Young women with an ANA or proliferative GN
Almost always have full house staining (although not
100%)
Remember that LN classification are not diagnostic guidelines
i.e. you can fulfil criteria but not actually LN
In LN patients with two risk alleles for APOL1 the odds ratio
(OR) for ESRD was 2.72 (95% confidence interval [95% CI], 1.76 to 4.19;
P<6.2×10−6).
An HLA-DR2 subtype (HLA-DRB181503), characteristic of black
populations, was linked to worsening proteinuria
Patients with LN also have a higher standardized mortality ratio
(6–6.8 versus 2.4) and die earlier than SLE patients without LN
10-year survival improves from 46% to 95% if disease remission
can be achieved
Extra renal manifestations usually become quiestcent after ESRD
onset @ ~6-12 months of RRT.
Serology
- ANA = very sensitive, non specific
- dsDNA & anti-Smith = less sensitive but more
specific
- C3,C4 = Can be useful for dx and tracking flares.
also low in skin manifestations and haemolytic anaemia
- Anti-histone = Suggests drug induced lupus which
very rarely affects kidneys
- Anti Ro/La = Sjogrens, associated with neonatal
heart block
- Anti-RNP = assoc with lupus cerebritis
- Anti phopholipid ab = anti cardiolipin, lupus anti
coagulant or b2 glycoportein 1 = TMA associations
APL syndrome
- repeated VTE / miscarriages & Strongly + tests
- weak + is a common false + (infection)
- aka hughes syndrome and lupus anticoagulant
- misnomer 1: lupus anticoagulant + doesnt mean you have lupus - about
50% of APL patients have SLE
- misnomer 2: anticoagulant effect is an in vitro phenomon, in vivo
youre pro thrombotic
Pathopysiology
- Auto-Immune deposits in kidney, unclear aeitiology - theories
include:
- Apoptotic cells release DNA/nucelosomes -> antibodies form and
create complexes -> inflammatory cytokines
- “planted antigen” - anti dsDNA ab reacts with DNA/nucleosome (neg
charged) trapped in GBM (pos charge)
- Cross reactivity between kidney antigens and anti dsDNA : a-actinin,
laminin, heparin sulphate
Full house – several variables: usage of frozen vs paraffin / scale
of intensity / note the location of the staining - highly variable
One definition – concurrent + IgA,G,M,C4,C1q, at least 1+ in
intensity and granular, along the capillary walls
Classification
Lupus
classification - ISN 2018
- 15-40% can evolve from one form to another and in an non-sequential
manner
- I know this is a bit obvious, but full house is called full house
because you have 3 of a kind and a pair.
Disease activity
Proliferative components result in poorer outcomes. Signs of
proliferative : / activity & chronicity:
Endocapillary hypercellularity /neutrophil extravasation ( loops
occluded)
Fibrinoid necrosis and crescent/fibrocellular formation are actie
leasions and obviously bad
Hyaline thrombi, wire loops ( due to sub endothelial immune
deposits)
Proposed modified NIH lupus nephritis activity and chronicity scoring
system
Endocapillary hypercellularity |
Endocapillary hypercellularity in <25% (1+), 25%–50% (2+), or
>50% (3+) of glomeruli |
0–3 |
Neutrophils/karyorrhexis |
Neutrophils and/or karyorrhexis in <25% (1+), 25%–50% (2+), or
>50% (3+) of glomeruli |
0–3 |
Fibrinoid necrosis |
Fibrinoid necrosis in <25% (1+), 25%–50% (2+), or >50% (3+) of
glomeruli |
(0–3) × 2 |
Hyaline deposits |
Wire loop lesions and/or hyaline thrombi in <25% (1+), 25%–50%
(2+), or >50% (3+) of glomeruli |
0–3 |
Cellular/fibrocellular crescents |
Cellular and/or fibrocellular crescents in <25% (1+), 25%–50%
(2+), or >50% (3+) of glomeruli |
(0–3) × 2 |
Interstitial Inflammation |
Interstitial leukocytes in <25% (1+), 25%–50% (2+), or >50%
(3+) in the cortex |
0–3 |
Total |
|
0–24 |
Modified NIH chronicity index |
Definition |
Score |
Total glomerulosclerosis score |
Global and/or segmental sclerosis in <25% (1+), 25%–50% (2+), or
>50% (3+) of glomeruli |
0–3 |
Fibrous crescents |
Fibrous crescents in <25% (1+), 25%–50% (2+), or >50% (3+) of
glomeruli |
0–3 |
Tubular atrophy |
Tubular atrophy in <25% (1+), 25%–50% (2+), or >50% (3+) of
the cortical tubules |
0–3 |
Interstitial fibrosis |
Interstitial fibrosis in <25% (1+), 25%–50% (2+), or >50% (3+)
in the cortex |
0–3 |
Total |
|
0–12 |
NIH, National Institutes of Health.
via Tiffany
Caza on Glomcon
In the recent ISN revision te group decided that the term
‘’endocapillary proliferation’’ is a misnomer that should be abandoned
and replaced by the term “endocapillary hypercellularity,” because most
of the hypercellularity in glomerular capillaries in lupus nephritis is
caused by influx of inflammatory cells rather than by actual cell
proliferation
Future revisions to the classification may remove class VI and
suggest approach to classify tubular and vascular lesions
Unclear value in even distinguising between class III and IV. Tricky
business.
I - Minimal Mesangial LN
- Normal Light microscopy
- Only demonstrable on IF
- Remember the easiest place for a complex to deposit is the mesangium
as theres no GBM as a barrier, so its the logical first place to find
early disease
II - Mesangio proliferative
- Now there are some LM findings
- Four or more nuclei fully surrounded by matrix in the mesangial area
not including the hilar region
- Mesangial cells unhappy and reacting - increase in mesangial cells
and matrix
III - Focal Proliferative
- 20-35% of patients
- focal global or segmental involvment ( i.e. invidiual gloms, either
partially or wholly)
- Proliferative GN - hypercellularity all types of cell, epithelial,
endothelial, mesangial
- Fibrinoid Necrosis and intracapillary thrombi
- Wire loop lesions possible on LM ( sub endothelial deposits lead to
homogenous thickening of cap walls)
IV - Diffuse Proliferative
- 35-60%
- ESRD risk may be as high as 44% over 15 years
- Also (hypercellularity) aka proliferative
- Involvement now hits >50% of the glom
- Bad prognosis
- Crescents possible (lesion containing extracapillary
hypercellularity and involving>10% the circumferance of bowmans
capsule)
- Cellular cresents are <25% fibrin
- Wire loop lesions possible
- As recently demonstrated in a meta-analysis by Haring et al. the
clinical importance of distinguishing between segmental and global
lesions in class IV as defined by the ISN/RPS classification system has
been questioned.
V - Membranous LN
10-15%
Membranous lupus (V) can occur concurrent with proliferative
disease (III/IV)
If its >50% sub epithelial electron dense deposits (
i.e. immunoglob complexs)
If its <50% then its not called as a membranous component by
pathologist
Primary membranous and membranous lupus can often look very
similar
Clues: full house IF ( i.e. 3 immunoglob heavy chains – IgG, IgA,
IgM, C3, C1q,)
C1q is reasonably specific for auto immune
Tubular basement membrane (granular) are not present in primary
membranous but present in lupus membranous
Often diffuse deposits by EM: Sub endo, epi and mesangial and
tubuloreticular inclusions on the sub endothelial surface of GBM
(interferon “footprints” – also seen in other interferon drive diseases
such as covid and HIV)
IgG subclasses – would reveal reaction of multiple subtypes –
primary is usually just IgG4 (and sometimes also with IgG1)
Membranous Antibodies & Antigens
EXT1/EXT2
EXT1/2 associated with MN – Dragon fruit appearance on EM,
younger (mean age 38) 80% female, associated with autoimmune disease –
80% had lupus in Mayo series ( in contrast to PLA2R which is
0.55%)
In Memb lupus in mayo – 33% were EXT1/2 +
EXT+ basically didn’t progress, despite proliferation! Minimal
proteinuria with baseline however
Good prognosis! If find an EXT1/2 ensure investigated lupus (
?treated - clarify)
Stain for EXT1 or 2 (both not required) in PLA2r neg and
autoimmune ( arkana suggestion)
?whats the antibody
NCAM1
NCAM1 associated with Membranous lupus
Can have concurrent proliferative component ( 25%
overall)
NCAM1 is up in CSF post seizures and reactive astrocytes – link
to neuropsychiatric lupus? - speculative
In arkana series (n=20), mean age 34, 40% had neuropsychiatric
symptoms ( 9% in non NCAM1 +)
? circulating ? on podocytes. Antibody titres unclear
value
cohort: Normal function, 6.7 g/protein/day
Frequency: arkana looked at 220 cases of memb lupus = 6.6% +,
MAYO looked at idiopathic MN 1-2%
TGFBR3
TGFBR3 associated with membranous lupus
Arkana cohort ( n=17)
50% proliferative component
16/17 Female, 8.4g/proteinuria day , 13/17 lupus
Expressed on podocytes - ? whats the antibody
CNTN1
CNTN1 associated MN – Chronic inflammatory demyelinating
polyneuropathy. Contactin 1
IgG4 dominant ( odd )
1500 patients with CIDP/acute polyneuritis – older males (67,
10:1 m). 11 antibodies – 5 developed MN (?ref - mayo?)
VI - Advanced Sclerosing LN
- over 90% fibrosis
- End stage disease
- Rarely seen, may be scrubbed in next revision of ISN
classification
Non immune complex GN
- Anti Phospholipid ab associated
- thrombotic microangiopathy 24% - can be renal limited
- Renal artery/vein thrombosis with infarction
- HTN
- Livedo reticularis
- Necrotising ANCA+ GN ( pauci immune GN in SLE patients, pANCA and
MPO+)
- TIN - watch for hyper and hyperkalaemia. quite rare, especially in
isolation.
- lupus podocytopathy (defined as nephrotic syndrome in SLE that on
kidney biopsy shows diffuse foot process effacement and no
subendothelial or subepithelial immune deposits) 1.3% . Can lie along
the MCD/FSGS spectrum
- hydoxycholoroquine induced - rare - proteinuria and CKD, Biopsy
reveals cytoplasmic inclusions within the podocytes, like Fabrys.
Treatment
Notes
- It may be time to move away from thinking of induction/maintenance
and acknowledge the continuous nature of the disease (per Rovin @
Glomcon)
- Lupus has underlying and ongoing autoimmune processes that
periodically erupt into clinical flares
- Needs long term attenuation long term to prevent flares and CKD
- Probably multi targeted B cells,T cells ,DC and cytokine
- When flare occurs – needs acute inflammation stopped rapidly to stop
scarring
- Intermittent therapy bursts are needed to attenuate
inflammation
- Currently best acute therapy is IV pulse corticosteroids be we need
to eliminate these due to toxicities
Based on ISN classification
Class 2 generally do not need specific therapy for their kidney
disease but may need immunosuppressive treatment for extrarenal SLE
manifestations.
Patients with mainly chronic injury (any class) or end stage
damage (class 6) also do not need immunosuppression for LN, but may
benefit from antiproteinuric, renoprotective measures.
The proliferative classes (3 and 4) are often treated with potent
immunosuppression, whereas nonproliferative
membranous LN (class 5) may be managed conservatively
(antiproteinuric therapy) if patients have subnephrotic proteinuria, or
with immunosuppression if patients have nephrotic range
proteinuria.
Excellent
CJASN overview
Natural history with standard of care based on complete renal
remission in placebo arms of notable trial
- LUNAR 28.5% (multi-ethnic)
- ELNT aka Eurolupus 40% (Caucasian)
- Dutch working Party on SLE 32.5% (Caucasian)
- BMS(CTLA4Ig) aka abatacept 15% (multi-ethnic)
Antimalarials
A good idea for most lupus patients
- 6mg/kg hydroxychloroquine
- Gladel et al - OR 0.38 for developing LN in SLE if on anti
malarial.
- Relesser et al - OR 0.58 for developing LN in SLE if on anti
malarial, Developing ERSD 0.23, complete response 1.61
- Eye toxicity – annual dilated eye examination
Induction
Severe proliferative
Methylpred: 0.5-1g/kg for 1-3 days, then oral pred
1mg/kg/day (ideal body weight) max 80mg taper over weeks
Plus CYC or MMF
- MMF 2-3g/day for 6 months
- IV CYC 500mg fortnightly for 3 months - 3 g total
(Eurolupus)
- IV CYC 0.5-1g/m2 q monthly * 6 (NIH protocol)
- PO CYC 1-1.5mg/kg/d, max 150mg/d for 2-4 months
Eurolupus
- Low dose vs NIH regime
- Follow up (5 years and 14 years)
- Equally well free of Renal flare/ ESRD
Criticism:
- mostly white northern European patients (however trials from SE asia
and abatacept trial had all patients on Eurolupus trial and no different
was observed suggesting this ethnicity isn’t a concern)
- MMF ( Dooley NEJM 2011) – suggests that MMF induction may be
inferior to CYC induction – slightly higher treatment failure ( but non
statistically significant)
Maintenance
Pred taper down to 5-10mg /day
- MMF 1-2g/day (first choice)
- AZA 1-2.5mg/kg/d (pregnancy / intolerant of MMF)
- CSA 2.5mg/kg/d/TAC (trough 4-6) if MMF/AZA not tolerated
ALMS maintenance trial NEJM 2011
Time to treatment failure | n=227 | MMF vs AZA | European mild-mod
disease
Maintain nephritis ANN Rheum disease 2010
Time to renal flare | n= | MMF vs AZA |
Emerging therapies
Bortezomib
Bortezomib – proteosome inhibitor
- Auto ab are made by plasma cells/ blasts
- As b cell lineage mature, it loses its CD20 molecule thus arnt
targeted by rituximab
- PI blocks NK-kb activation – remembering hat NK-kB is a bit of a
master pro inflammatory regulator
- Decreased type 1 IFN activity
- Decreased Dendritic cells
- Peripheral nervous system off target side effects
- Not currently being trialed in LN, bother other PI are
Tobias el al Ann rheum disease 2015
- 12 refractory LN patients, 8 with class IV LN, pathogenic ( and
vaccine!) ab reduced, drop in SLEDAI ( activity scale)
- C3 improved, Proteinuria declined
Obinutuzumab
Humanized type II anti-CD 20 ( ritux is a type 1 anti CD20)
Approved for CLL and follicular lymphoma
Vs ritux it has 100x ab-dependent cytotoxicity, greater cell death,
reduced internalization, less reliance on complement dependent
cytotoxicity
Superior B cell depletion in patients with RA
Nobility trial – phase 2
- 2 years | n=126 | Obinutuzumab & MMF vs placebo & MMF
- ~ half were dsDNA + , 10% black | CRR 35 vs 23 ( 1 year) and 40 vs
18% at week 76
- Complete response rate increases over time
- Much earlier and almost complete b cell depletion vs ritux ( in
historical LUNAR data – ritux peaks around week 12 at 87% and has
declined by week 24 to 52%)
- SAE 23 s 30%, infection 6 vs 18%, 1 vs 4 death.
Belimumab
Belimumab is approved in USA for non renal lupus
Antibody vs BLys ( survival factor for b cells)
ITN calibrate – phase 2, open label proliferative LN – steroids + cyc
(750) + ritux week 0,2 and placebo or belimumam at week 4 – Didn’t
suggest any additional benefit
Why? Killing b cells increased serum BLys
Reconsistuion of b cells in high BLyS environment fosters auto
reactive B cells
Thus anti BLyS treatment may help sustain a response and prevent
reconsistution
TBC – BLISS LN will be out shortly
Multitargeted therapy
Lower dose of steroids & MMF & CNI
Usually Chinese studies
Voclosporin phase 2 multi target trial ( novel calineurin inhibitor)
– added to 2g/day MMF and rapid taper of steroids - down to 2.5mg by
week 16 – pretty aggressive taper
Outcomes: low dose was more effective – but disproportionate death in
the low dose group
Pregnancy
SLE often develops or Flares during pregnanacy or first 8 weeks post
partum. Can mimic preeclampsia/HELLP
Idiopathic full house GN
Ingeborg Bajema
@ Leiden
Aka Non-lupus full house nephritis, Lupus-like nephritis, a frome
fruste of lupus nephritis, renal limited lupus nephritis.
Is this LN? Renal limited LN? How do we recognize it?
Usually a bx turns up with full house and “consistent” ( could be
anything) pictures in a patient with no clinical suspicion of
SLE
It could of course be that this is the first finding of
LN/SLE
Bajema et al (NDT 2017) | N= 149 LN -> 32 non-lupus full house
->20 idiopathic/12 atypical variants | Poor renal outcomes | Non
developed SLE |
Other case reports of idiopathic full house GN:
Membranous due to syphilis (BMJ 2021)
Drug induced (CJASN 2015)
Infection related (Clin Nephrology 2020)
Herbal Medication (BMC 2020)
HIV (Kidney Int 2005) – 13/17 endo cap hypercellularity, memb in
1
Can occur post tx
Rarely can proceed SLE by several years, in paediatric patients
usually tbh
Tubulo-reticular inclusions by EM are useful to differentiate and
identify true lupus (TR inclusions no exclusive to LN)
Check for cryoglobs (especially if MPGN) - of course you can get
cryoglobs with LN
?Might be sensible to treat severe looking histology as a severe LN
in the absence of reversible causes/infections - careful with diagnostic
anchoring to avoid accidently immunosuppression if infection is a
cause
Follow up closely
Repeat Renal Biopsy
- After completing 6–8 months of immunosuppressive therapy, 20%–50% of
complete clinical renal responders still had histologic evidence of
ongoing active inflammation, and 40%–60% of patients with no histologic
evidence of disease activity still had persistent, high-grade
proteinuria
- Even after several years of immunosuppressive treatment, histologic
activity was found in about 20% of patients who had been in sustained
clinical remission.
- Conversely, 40% of patients in complete histologic remission after
long-term treatment had persistent clinical findings
- probably most useful for patients with class 2 or 5 with a Flare as
this could suggest proliferative disease thus intensification of
immunosuppresion
NIH disease activty scores as prognosis:
10 years of follow-up, the probability of doubling serum creatinine
was about 56% for patients whose second biopsy had persistent activity
(an activity index >2), compared with 20% for patients who had an
activity index ≤2 (P<0.001). Similarly, 10-year renal survival was
>90% if the chronicity index of the repeat biopsy was <3, but 55%
if the chronicity index was >6 (P=0.10).