This document discusses Lupus Nephritis (LN), a common complication of Systemic Lupus Erythematosus (SLE) that affects the kidneys. It covers the epidemiology and diagnostic criteria of SLE, outlines current treatment options for LN including steroids, immunosuppressants, and biologics, and discusses ongoing clinical trials. It also examines challenges in LN management such as variability in histological classification systems and lack of consensus on treatment protocols. Overall, the document provides an overview of LN as a complex condition with ongoing efforts to improve diagnosis and outcomes.

1. Lupus Nephritis
Dilemma
MOHSEN EL KOSSI
CONSULTANT RENAL PHYSICIAN
DONCASTER AND BASSETLAW TEACHING HOSPITALS

2. Epidemiology
SLE
 Prevalence:
 USA:150 in 100000
UK: 40/100000
Egypt: ????
 Incidence: 1/2000
 Females commoner than males
 Blacks commoner than whites
 Young commoner than old

3. Diagnostic Criteria of SLE

4. Diagnosis
Skin Rash
 1-Malar rash
 2-Discoid Lupus

5. 3-Photosensitivity
 Can precipitate flare

6. 4-Arthritis
 Non erosive non destructive arthritis.

7. 5-ANA
 98% sensitive
 >1:640 the higher the titre the more significant the
result
 Anti-centromere
 Does not follow disease activity

8. 6-DsDNA/Sm Antibody
 Specificity of 95% for both (former for Caucasians
and latter for afro-caribbean)
 Can follow disease activity (LN)

9. 7-Blood
 Cytopenias:
Leukopenia (<4000), lymphopenia (<1000),
thrombocytopenia (<100000) on X2 separate
occasions
 Haemolytic anaemia (not criteria but common)

10. 8-Mouth Sores
Painless

11. 9-Serositis
Pleurisy
Pericardial effusion
Abdominal pain

12. 10-Neurologic Disorders
Seizure
1
Psychosis
(elusion, delusion,
hallucination visual usually)
2
Cerebral haemorrhage
secondary to vasculitis
3

13. Phospholipid Antibody Syndrome
 30% of SLE patients.
 B2 Glycoprotein IgM or IgG antibody in concentration >1:40
 Venous or arterial thrombus
 Miscarriage in first trimester or X2 in the second trimester
 Thrombocytopenia
 Livedo reticularis
 Migraine, chorea, transverse myelitis, or depression.

14. 11-Renal
Lupus Nephritis
Proteinuria >500mg/24 hour urine collection
Urine dip stick +++ve proteinuria
Red cell cast
Impaired kidney function not due to any other
cause

15. Why Lupus Nephritis
 Affects 50% of SLE
 Carries poor prognosis
 90% happen in the first 5 years of SLE
 5 Years survival rate (1950 ) 0% after IV cyclophosphamide 5&10 years survival 85&73%
 Renal survival in a cohort of children 1& 10 years 90 & 65%
 1.5% of dialysis patients in the states secondary to LN

16. Current Management Options
 General Measures: blood pressure control, ACEI/ARBs, Statins
 Chloroquine
 Steroids
 MMF
 Cyclophosphamide: oral, NIH and Euro-Lupus
 Biologics
 Multitarget approach

17. Antimalarials in LN
 Probability of antimalarial prescribing by nephrologist is 0.5
 Chloroquine introduced in 1953, and hydroxychloroquine in 1955 &
both have better safety, tolerability and efficacy profiles compared to
quinacrine
 Antimalarial in SLE is associated with improved survival and reduced
disease activity
 Antimalarial in LN reduce steroid dose, prolong time to ESRD,
increased duration of renal remission
 Safety profile in pregnancy is good and reduce foetal cardiovascular
problems
 Dosing needs careful adjustment with renal impairment

18. Evidence for Antimalarials in
LN
 Canadian Hydroxychloroquine Study Group randomized withdrawal of
Hydroxychloroquine revealed 74% reduction in the risk of nephritic flares
 LUMINA study: hydroxychloroquine use in SLE reduced risk of developing
renal disease and those on it reduced risk of class IV LN
 Hopkins Lupus Cohort & Spanish long-term, observational, cohort and
GLADEL study reported positive impact of chloroquine on LN incidence and
outcome
 Risk of retinopathy increased with high daily doses (hydroxychloroquine
>400mg daily, or >6.5 mg/kg of lean body weight; chloroquine >250 mg
daily, or >3.0mg/kg of lean body weight) in normal kidney function
 Annual retinal screening is not required until after 5 years of cumulative
therapy
(Lee et al Nat. Rev. Nephrol 2011)

19. Steroids in LN,
How Much is Enough?
15 LN versus 30 patients mean with moderate versus high dose steroid 22mg/day) (49 mg/day)
cumulative steroid dose over 6 month of 1.7 g versus 4.5 g.
Cumulative cyclophosphamide dose 3 g versus 5 g at 6 month
At 6 month mean GFR nearly the same as well as proteinuria
At 12 month CR 47% versus 30%
Toxicity with steroids was observed in 1/15 (7%) vs. 20/30 (67%) patients
()
Ruiz-Irastorza et al; Autoimmun Rev,
2014

20. Steroid Free
Protocols in LN
 First trial 2012, which was
actually not steroid free
 Two different steroid regimen
with a mean of 1.5 g versus
3.3 g in 24 week, no
difference in outcome
(Fischer-Betz J Rheumatol et al 2012)
Dose >20 mg/day
Dose <20 mg/day
Long Term Renal Flares

21. Survival Benefit of IV
Cyclophosphamide
Bono et al QJM, 1999
5 Years survival pre steroids 17%
After steroids 55%
After cyclophophsphamide 80%

22. Euro-Lupus Vs NIH Regime
Houssiau et al Arthritis and Rheumatism 2002

23. Eurolupus versus Abatacept
ACCESS Trial

24. Eurolupus versus NIH regime
after 10 years
Houssiau et al Ann RheumDis ; 2010

25. MMF Vs Cyclophosphamide
Induction
Liu et al Drugs 2012

26. Complete & Partial Remission
Liu et al Drugs 2012

27. ESRD & Death Risk
Leukopenia, alopecia and amenorrhea were less with MMF but not diarrhoea
Liu et al Drugs 2012

28. Organizations Recommendations
For Induction
 ACR: MMF for 6 month (2-3 g) or Cyclo IV Euro-Lupus (preferable Euro-lupus for
Caucasians)
 EULAR/ERA-EDTA: recommends either MMF or low dose IV Cyclo
 Childhood Arthritis and Rheumatology Research Alliance: MMF (600 mg/m2 with a
maximum of 1500 mg twice daily) or i.v. CYC pulses (500 mg/m2 increasing to a
maximum of 1500 mg)
 Low dose Cyclo is economic, effective, less toxic, better compliance but alopecia &
amenorrhea more frequent
(Kallenberg NDT, 2016)

29. Biologics IN LN
Venuturupalli Lupus 2016

30. Rituximab
 LUNAR: -ve trial, primary end point not achieved (20% versus 11% in
combined CR+PR)
 56% (CR+PR) Rituximab arm versus 45% Placebo arm
 CR 26% Rituximab versus 30% Placebo
 PR 30% Rituximab versus 15% Placebo
 Arguments: small sample size (72 patients each arm, add on trial, not
powered for PR rather than combined, longer duration of follow up)
 18 month follow up remission rate has increased with > 50% reduction in
proteinuria
 RITUXILUP and CALIBRATE awaited results
Rovin et al Arthritis Rheum 2012

31. Abatacept
 Fusion molecule blocks T cell activation by APC
 ACCESS (Ascanas et al 2014): Abatacept versus EUROLUPUS
FAILED
 Furie et al 2014: Abatacept versus placebo on
background of MMF and steroids FAILED
 Re-analysis using LUNAR and ACCESS end points,
Abatacept found to have high remission rate?

32. Belimumab
 Monoclonal antibody inhibits BAFF
 BLISS-52 and BLISS-76 post hoc analysis was encouraging for mild lupus
nephritis patients
 Less renal flares, DsDNA and complement level improvement
 Did not include severe cases (Cr>2.5 mg/dl and daily urine protein >6 g
excluded) subset of patients with possible LN
 Unclear biopsy proven LN as the study was not powered for this end
point
 BLISS –LN is awaited

33. Other Potential Biologics
 Eculizumab: case reports mainly TMA or antiphospholipid +ve with or without biopsy
proven LN
 All patients with severe hypocomplementemia and renal impairment with one case with
biopsy proven severe LN and all normalized complement levels and renal function to
some extent (Sciascia et al Rheumatol Int 2017)
 Ocrelizumab: anti CD22 selectively depletes B cells. RCT for LN with 381 patients study
terminated early because of serious infections with MMF arm despite of 12%
improvement (Mysler et al Arthritis Rheum 2013)
 Atacicept: Fusion protein that blocks 2 B cell stimulation factors, serious low levels of IgG
terminated the study in 4 LN patients (Roschke et al J Immunol 2002)
 Sirukumab: anti IL-6 serious infections.
 Bortezomib and ixazomib: proteasome inhibitors of plasma cells small trial in LN
underway

34. Barriers Against Biologics
 The exact dose for this condition remains unclear
 Exact duration is also unclear to judge a response
 Most of the trials design is add on rather than single
agent with the problems of added toxicity particularly
serious infections
 Which subset of patients would benefit to be targeted

35. Multitarget Therapy
 RCT 24 week IV Cyclophsophamide versus Tac+MMF
 Overall response rate is higher 83% versus 63% without any difference in adverse events
Liu et al Annals of Int Med, 2015

36. Class V LN Treatment
 Unclear treatment strategy
 56 paediatrics pure MN all received steroids, mostly antimalarial, ACEI, MMF (70%) with
remission rate 74% in 2 years (Periera et al 2017)
 No single predictor of remission was identified and flares were high (50%)
 150 adults pure MN with 6% death, 5% ESRD, in 7 years and remission 65%
 predictors of poor renal outcome are males, hypertension, dyslipidaemia, high 24H proteinuria
at presentation, and high basal S Cr (Lucía Silva-Fernández et al 2017)
 Predictors of death, age, CCF, PVD, HD and not on MMF

37. Lupus Like Nephritis
 Histology consistent with lupus nephritis without clinical signs or autoantibodies
characteristic of SLE
 Negative autoantibodies but low complement explanation:
 Lack of lab techniques to detect too low levels of these autoantibodies
 Entrapment of these antibodies in the circulating immunocomplexes
 Development of different unidentified autoantibodies in these cases???
 Needs too long follow up interval
 Treated as LN cases
 Natural course is unclear
 Reviewed by Rijnink et al 2017 suggesting poor prognosis with more frequent ESRD
 Case reports: Maziad et al 2017; Touzot et al 2017; Jones and Magil 1982, Gianviti et
al 1999; Baskin et al 2007

38. Cardiovascular Risk In LN
 Cardiovascular risk factors were higher in patients with preserved
kidney function but with previous LN flare including high BP, Low
HDL-C, LVH, higher proteinuria and waist circumference (Todolí-Parra
JA et al 2018)
 Danish registry revealed high HR of MI, Stroke and CV mortality in
SLE patients compared to matched controls and LN patients
compared SLE
 Similar results were found for CV mortality (Hermansen et al 2017)

39. HR of CV Risk In LN Versus General Population

40. Renal Biopsy
 EULAR recommends renal biopsy to guide immunosuppression
 ACR leaves renal biopsy for the clinician discretion
 1/3 of patients with complete clinical remission has high histological index of activity
and 2/3 with complete histological remission they were still clinically active
 Chronic damage occurs rapidly even with complete clinical remission and correlates
well with long term renal outcome
 Re-biopsy was done in 11% of LN patients (Kajawo et al 2017)
 Indication of re-biopsy was worsening proteinuria (1/3 of cases) worsening Cr 13%
 Retrospective analysis of re-biopsy revealed management change in 85%
 Proliferative cases remained proliferative in re-biopsy
Malvar et al; NDT 2017

41. Re-Biopsy
 In a cohort of around 300 biopsy proven LN age<32years, +ve DsDNA,
musculoskleteal manifestations , new onset hypertension, S Cr>1.2, absence
of nephrotic range proteinuria are all risk factors for class III/IV (Mavragani
et al 2015)
 Histological transformation during flare is common (40-76%)
 Change from non proliferative into proliferative is high (class II at base line
to III,IV 78%) class V into III or IV 40%
 Proliferative cases at base line (III,IV mixed III&IV) 80% remained the same
leaving 20% non proliferative not requiring aggressive therapy
 Re-biopsy resulted in changing immunosuppression in 50% (intensifying)
with 5-30% reducing immunosuppression
 Diagnosing other causes of renal impairment other than LN such interstitial
nephritis and thrombotic microangiopathy
(Narvaez et al; Medicine 2017)

42. AI/CI Significance
 None of the available management guidelines linked to activity/chronicity indices
 Pitfalls of current histopathological classification:
 Mainly glomerular lesion
 Sclerotic lesions could be also age related or ischaemic
 LM and IF ignoring the value of EM
 Schwartz et al 1993 suggested that AI/CI too subjective to be used as therapeutic guides or as
prognosticators
 Interobserver agreement was poor for chronicity index (ICC 0.5) (Grootscholten et al 2008),
activity/chronicity (0.36) (Wilhelmus et al 2015)
 Rathi et al 2015 concluded: None of the histological indices better than S Cr to predict treatment
outcome or mortality

43. Correlation of AI/CI and
Clinical Parameters
Rathi et al Rheumatol Int 2015

44. Predictors of LN Outcome
(Dall’Era et al 2015)
 Proteinuria, urinary RBCs and serum Cr at 3,6 and 12 month for long term outcome (S
Cr < 1 mg/dl) ELNT
 Proteinuria <0.8 g/24H after 12 month is the best predictor of long term outcome
(sensitivity 81% and specificity 78%)
 Combining SCr and urinary RBCs reduced the predictive value of proteinuria

46. Pregnancy and LN
 Foetal loss due to LN has improved from 40% in 1960s to 17% in 2000s which is still
high
 Other complications include
 Premature delivery, intrauterine growth retardation, foetal cardiac problems
 Predictors of foetal outcome: lupus activity at conception and during pregnancy
(Moroni et al 2016)
 Biochemistry: low complement, high DsDNA in 2nd trimester and +ve PL antibody
 Predictors of renal outcome: Past history of partial or complete remission and low C4
carry high risk of flare (Odds ratio 21) and risk of de novo LN is not high during
pregnancy and low C4 is predictor of de novo LN (Buyon et al 2017)
 DsDNA and C3 did not carry negative predictor value on renal outcome????

47. Does Pregnancy Carry a Long Term Risk
of Nephritis Flare?
 After 10 years of F/U 32 LN pregnant women, number of SLE flares, significant increase in high BP
and reduced eGFR in control group (non pregnant)
Gianfreda et al J Autoimmunity 2017

48. eGFR After 10
Years Follow UP
 No significant
difference
 Kidney Function at
conception and
renal flares were
predictors of CKD
Malvar et al; NDT 2017

49. Pregnancy Advice
 Preconception counselling through multidisciplinary approach
 Severe renal insufficiency (serum creatinine > 2 mg/dl) a contraindication to pregnancy
(although should be taken case by case)
 SLE and lupus nephritis activity are predictors of adverse maternal & foetal outcome
 Patient should be in emission at least 6 months before conception
 Potential teratogenic drugs must be interrupted at least 3 months before conception
 High dose glucocorticoid is associated with Small birth weight and prematurity (5-10mg
maintenance dose is reasonable)
 Hdroxycloroquine should be continued during pregnancy, it reduces prematurity, growth
restriction and anti-Ro antibodies with anticipated cardiac complications
 Arterial hypertension should be optimized
 Aspirin is recommended to reduce preeclampsia risk and LMH for Anti PL
 Breast feeding is contraindicated with Azathioprine and cyclosporine
Moroni et al; J Autoimmunity 2016

50. Conclusions
 Renal biopsy is advisable with renal involvement and with renal flares to guide
treatment
 Steroids and HCL are essential components of treatment of LN
 Azathioprine maintenance is associated with high risk of LN flares
 In case there is no access to MMF, patient should be closely monitored for early signs
of flare
 Class V is preferably to be treated with MMF and steroids and in case failed CNI and
steroids
 In case there is no clinical or biochemical improvement in 4 month or no partial
response in 6 month or no complete response in 2 years think of alternative
 Those who are seeking relatively successful safe pregnancy, SLE should be quiescent
for at least 6 month prior to conception which should be planned with MDT
approach
 Minimum duration of immunosuppression js 3 years but not clear the maximum

51. THANKYOU