Lupus
For the general nephrologist | 2024
1 / 27

Overview

lower your expectations
top tips
lupus biopsy
three cases
( guidelines & practice points )

slides at: https://www.kidneyfish.net/talks/

2 / 27

Top tips (1)

renal lupus is bad lupus
play a long game (slow tempo, lifelong)
good problem list
uPCR, dsDNA, C3, C4, plts, Lcytes every clinic
screen for aPS at diagnosis and transplant work-up
if in doubt, biopsy (diagnosis, pattern of injury, prognosis, response to therapy)...
...but know why you are biopsying

3 / 27

Top tips (2)

start with guidelines but usually deviate
body weight and ethnicity
adherence
reproductive health
CVS risk, bone...
judicious engagement with other specialties

4 / 27

Commoner and more severe in Black, Hispanic, Asian (susceptibility genes protect against malaria).

Ask about clots, pregnancies and send LAC and aCL.

TMA presents as proteinuria and HTN.

Classic lupus biopsy5 / 27

6 / 27

class II = granuluar mesangial "full-house" IF; mesangial hypercellularity
class III (focal <50% gloms)
class IV (diffuse >50% gloms) = granular capillary IF; endocapillary hypercellularity; fibrinoid necrosis; crescents; subendothelial deposits (= double-contour GBM); MPGN pattern
class V = granular glomerular "full-house" IF; subepithlial deposits; spikes and holes
class VI = sclerosis in 90% gloms

In SLE, IgG usually dominant or co-dominant.

'Full-house' also seen in IgAN, C1qN, infection-related GN, primary membranous, primary MPGN, cryo... ...or in the entity, 'non-lupus full house nephropathy'.

10 other things you might see on a lupus biopsy?7 / 27

10 biopsy findings

TMA / APS nephropathy
interstitial disease
lupus vasculopathy
scarring
endothelial TRIs

8 / 27

10 biopsy findings

TMA / APS nephropathy
interstitial disease
lupus vasculopathy
scarring
endothelial TRIs

"tissue ANA" (nuclear IgG)
podocytopathy
HCQ nephropathy
small vessel vasculitis
TB...

8 / 27

If lots of necrosis consider if concomitant ANCA.
TRIs ~ pathognomonic.

Cases9 / 27

Case 1

Case of class V LN with haemolytic anaemia.

Details redacted for online slides.

10 / 27

Case 1: learning points

for class V: HCQ and RASi
I/S if nephrotic proteinuria or extra-renal features
risk of PRESS
for anaemia: G6PD, haemolysis screen, film
I/S for extra-renal disease
contraception in lupus (oestrogens okay except if VTE risk high)

11 / 27

Case 2

Case of class IV LN, refactory to treatment.

Details redacted for online slides.

12 / 27

Case 2: learning points

'auto-immunosuppression' at diagnosis
angiooedema in lupus: steroids and anti-histamines
recent guidelines: option for triple Rx upfront
aspirin primary prophylaxis in high-risk aPS profile
target uPCR 0.7 - 0.8 (PERR)
for refractory disease: adherence?, CYC, RTX, CNI, belimumab
fertility preservation: ovarian cryopreservation, GnRH agonists
deranged LFTs in lupus: disease. drugs, weight gain, infections
RTX resistance common; CD19 monitoring; obinutuzumab?

13 / 27

See notes in guidelines for rationale for using PERR threshold.

Ovarian cryopreservation offered if >50% chance of infertility with chemoRx - therefore in practice not likely to be relevant but worth discussing. GnRH have short-term endocrine outcomes in breast cancer but no longer-term fertility data.

Case 3

Case of class IV LN and PML.

Details redacted from online slides.

14 / 27

Case 3: learning points

usually treat for at least 3 yrs; but longer often appropriate
tailor drug doses to body weight / age / ethnicity
DD of brain disease: cerebral lupus, PRESS, stroke, infections including PML, lymphoma...
know when to ask for help (locally and beyond)

15 / 27

GuidelinesEULAR 2023 | KDIGO 202316 / 27

Guidelines (1)

HCQ for all (5 mg/kg/day)
LN I-II: no I/S unless for lupus podocytopathy or extra-renal disease
LN III-IV: pred + MMF / Eurolupus CYC...
LN III-IV: ...or consider triple Rx up-front (+/- belimumab or CNI)
LN III-IV: MMF for maintenance (or aza if contemplating pregnancy)
LN V with low uPCR: RASi, ABP control, HCQ
LN V with nephrotic uPCR: add pred plus MMF, CNI, RTX or CYC
for APS and clot: VKA; for high-risk aPL but no clot: asa

17 / 27

Evidence for HQC from observational data. Canadian trial was n = 47.

Option for triple-therapy up-front new in recent guidelines. Rationale is that only ~25% patients achieve CR at 1 - 2 yrs on current SOC (from AURORA00578-X) and BLISS-LN trials).

High-risk aPL = LAC or more than one aCL / b2GP Abs.

Guidelines (2)

treat for at least 3 years after renal response
aim for complete response by 6 - 12 months
complete response = uPCR < 50 mg/mmol from 24 hr collection
primary efficacy renal response = uPER 0.7 - 0.8 g/day by 12 months
partial response = uPCR by 50% and to < 300 mg/mmol
withdraw steroids 12 months after complete renal response

18 / 27

PERR associated with prognosis (and therefore primary endpoint in BLISS-LN for example). This uPER threshold determined as the sweet-spot on ROC curves from European trials (Eurolupus and the follow-on MAINTAIN trial). Around 30% of patients achieved this at 2 yrs in the control arm of BLISS-LN. PPV of uPER < 0.7 for good long-term renal outcome (SCr < 88 mcM at 7 yrs) = 95%; NPV = 30% in a European population with first episode of LN.

Guidelines (3)

prefer CYC if problems with oral compliance
prefer MMF if high risk of infertility
+ CNI if preserved eGFR (45) and nephrotic proteinuria
+ belimumab if repeated renal flares / high risk of renal progression
consider RTX if not responding to standard of care
consider NIH CYC with IVMP if high risk of kidney failure

19 / 27

Guidelines (4)

uPER > 0.7 - 0.8 g/day after 12m (or rising SCr) = refractory LN
consider: adherence / drug levels / re-biopsy
consider: switching to alternative regimen
consider: adding RTX, enrolling in RCT

20 / 27

21 / 27

22 / 27

Practice points

HCQ: measure G6PD; eye monitoring at 5 yrs or 1 yr if RFs (eGFR < 60, HCQ > 5 mg/kg/day)
pred: low-dose = 0.5 mg/kg/day tapering to 10 mg by week 8 and 5 mg by week 12; 5 mg for maintenance and aim for withdrawal
MMF: 2 - 3 g per day for induction (at least 6 months) then 1 - 2 g per day
RTX: CD19 counts; consider obinutuzumab

23 / 27

Supplemental slides24 / 27

25 / 27

11 treatment options for LN?26 / 27

11 Rx options

HCQ
steroids
MMF, aza
cyclophosphamide
CNIs

27 / 27

11 Rx options

HCQ
steroids
MMF, aza
cyclophosphamide
CNIs

B-cell depletion (Rituximab, Obinutuzumab)
B-cell modulation (belimumab...)
PLEX
anifrolimab
CAR-T
immunoablation and allogeneic BMT

27 / 27

Lupus
For the general nephrologist | 2024
1 / 27

Overview

lower your expectations
top tips
lupus biopsy
three cases
( guidelines & practice points )

slides at: https://www.kidneyfish.net/talks/

2 / 27

Top tips (1)

renal lupus is bad lupus
play a long game (slow tempo, lifelong)
good problem list
uPCR, dsDNA, C3, C4, plts, Lcytes every clinic
screen for aPS at diagnosis and transplant work-up
if in doubt, biopsy (diagnosis, pattern of injury, prognosis, response to therapy)...
...but know why you are biopsying

3 / 27

Top tips (2)

start with guidelines but usually deviate
body weight and ethnicity
adherence
reproductive health
CVS risk, bone...
judicious engagement with other specialties

4 / 27

Commoner and more severe in Black, Hispanic, Asian (susceptibility genes protect against malaria).

Ask about clots, pregnancies and send LAC and aCL.

TMA presents as proteinuria and HTN.

Classic lupus biopsy5 / 27

6 / 27

class II = granuluar mesangial "full-house" IF; mesangial hypercellularity
class III (focal <50% gloms)
class IV (diffuse >50% gloms) = granular capillary IF; endocapillary hypercellularity; fibrinoid necrosis; crescents; subendothelial deposits (= double-contour GBM); MPGN pattern
class V = granular glomerular "full-house" IF; subepithlial deposits; spikes and holes
class VI = sclerosis in 90% gloms

In SLE, IgG usually dominant or co-dominant.

'Full-house' also seen in IgAN, C1qN, infection-related GN, primary membranous, primary MPGN, cryo... ...or in the entity, 'non-lupus full house nephropathy'.

10 other things you might see on a lupus biopsy?7 / 27

10 biopsy findings

TMA / APS nephropathy
interstitial disease
lupus vasculopathy
scarring
endothelial TRIs

8 / 27

10 biopsy findings

TMA / APS nephropathy
interstitial disease
lupus vasculopathy
scarring
endothelial TRIs

"tissue ANA" (nuclear IgG)
podocytopathy
HCQ nephropathy
small vessel vasculitis
TB...

8 / 27

If lots of necrosis consider if concomitant ANCA.
TRIs ~ pathognomonic.

Cases9 / 27

Case 1

Case of class V LN with haemolytic anaemia.

Details redacted for online slides.

10 / 27

Case 1: learning points

for class V: HCQ and RASi
I/S if nephrotic proteinuria or extra-renal features
risk of PRESS
for anaemia: G6PD, haemolysis screen, film
I/S for extra-renal disease
contraception in lupus (oestrogens okay except if VTE risk high)

11 / 27

Case 2

Case of class IV LN, refactory to treatment.

Details redacted for online slides.

12 / 27

Case 2: learning points

'auto-immunosuppression' at diagnosis
angiooedema in lupus: steroids and anti-histamines
recent guidelines: option for triple Rx upfront
aspirin primary prophylaxis in high-risk aPS profile
target uPCR 0.7 - 0.8 (PERR)
for refractory disease: adherence?, CYC, RTX, CNI, belimumab
fertility preservation: ovarian cryopreservation, GnRH agonists
deranged LFTs in lupus: disease. drugs, weight gain, infections
RTX resistance common; CD19 monitoring; obinutuzumab?

13 / 27

See notes in guidelines for rationale for using PERR threshold.

Case 3

Case of class IV LN and PML.

Details redacted from online slides.

14 / 27

Case 3: learning points

usually treat for at least 3 yrs; but longer often appropriate
tailor drug doses to body weight / age / ethnicity
DD of brain disease: cerebral lupus, PRESS, stroke, infections including PML, lymphoma...
know when to ask for help (locally and beyond)

15 / 27

GuidelinesEULAR 2023 | KDIGO 202316 / 27

Guidelines (1)

HCQ for all (5 mg/kg/day)
LN I-II: no I/S unless for lupus podocytopathy or extra-renal disease
LN III-IV: pred + MMF / Eurolupus CYC...
LN III-IV: ...or consider triple Rx up-front (+/- belimumab or CNI)
LN III-IV: MMF for maintenance (or aza if contemplating pregnancy)
LN V with low uPCR: RASi, ABP control, HCQ
LN V with nephrotic uPCR: add pred plus MMF, CNI, RTX or CYC
for APS and clot: VKA; for high-risk aPL but no clot: asa

17 / 27

Evidence for HQC from observational data. Canadian trial was n = 47.

Option for triple-therapy up-front new in recent guidelines. Rationale is that only ~25% patients achieve CR at 1 - 2 yrs on current SOC (from AURORA00578-X) and BLISS-LN trials).

High-risk aPL = LAC or more than one aCL / b2GP Abs.

Guidelines (2)

treat for at least 3 years after renal response
aim for complete response by 6 - 12 months
complete response = uPCR < 50 mg/mmol from 24 hr collection
primary efficacy renal response = uPER 0.7 - 0.8 g/day by 12 months
partial response = uPCR by 50% and to < 300 mg/mmol
withdraw steroids 12 months after complete renal response

18 / 27

Guidelines (3)

prefer CYC if problems with oral compliance
prefer MMF if high risk of infertility
+ CNI if preserved eGFR (45) and nephrotic proteinuria
+ belimumab if repeated renal flares / high risk of renal progression
consider RTX if not responding to standard of care
consider NIH CYC with IVMP if high risk of kidney failure

19 / 27

Guidelines (4)

uPER > 0.7 - 0.8 g/day after 12m (or rising SCr) = refractory LN
consider: adherence / drug levels / re-biopsy
consider: switching to alternative regimen
consider: adding RTX, enrolling in RCT

20 / 27

21 / 27

22 / 27

Practice points

HCQ: measure G6PD; eye monitoring at 5 yrs or 1 yr if RFs (eGFR < 60, HCQ > 5 mg/kg/day)
pred: low-dose = 0.5 mg/kg/day tapering to 10 mg by week 8 and 5 mg by week 12; 5 mg for maintenance and aim for withdrawal
MMF: 2 - 3 g per day for induction (at least 6 months) then 1 - 2 g per day
RTX: CD19 counts; consider obinutuzumab

23 / 27

Supplemental slides24 / 27

25 / 27

11 treatment options for LN?26 / 27

11 Rx options

HCQ
steroids
MMF, aza
cyclophosphamide
CNIs

27 / 27

11 Rx options

HCQ
steroids
MMF, aza
cyclophosphamide
CNIs

B-cell depletion (Rituximab, Obinutuzumab)
B-cell modulation (belimumab...)
PLEX
anifrolimab
CAR-T
immunoablation and allogeneic BMT

27 / 27

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Lupus

For the general nephrologist | 2024

Overview

Top tips (1)

Top tips (2)

Classic lupus biopsy

10 other things you might see on a lupus biopsy?

10 biopsy findings

10 biopsy findings

Cases

Case 1

Case 1: learning points

Case 2

Case 2: learning points

Case 3

Case 3: learning points

Guidelines

EULAR 2023 | KDIGO 2023

Guidelines (1)

Guidelines (2)

Guidelines (3)

Guidelines (4)

Practice points

Supplemental slides

11 treatment options for LN?

11 Rx options

11 Rx options

Overview

Help

Lupus

Lupus

For the general nephrologist | 2024

Overview

Top tips (1)

Top tips (2)

Classic lupus biopsy

10 other things you might see on a lupus biopsy?

10 biopsy findings

10 biopsy findings

Cases

Case 1

Case 1: learning points

Case 2

Case 2: learning points

Case 3

Case 3: learning points

Guidelines

EULAR 2023 | KDIGO 2023

Guidelines (1)

Guidelines (2)

Guidelines (3)

Guidelines (4)

Practice points

Supplemental slides

11 treatment options for LN?

11 Rx options

11 Rx options