MANAGEMENT OF LUPUS NEPHRITIS

INTRODUCTION
• Lupus nephritis (LN) is kidney
inflammation due to complication of
systemic lupus erythematosus (SLE)
• Up to 50% of SLE patient shows clinically
evident kidney disease at presentation
• More common in females compared to
males
• Age of onset for LN can range from 20-40
years old
• In Malaysia, LN is more commonly seen in
Malays, followed by Chinese and Indians
• Symptoms:
a) Hematuria
b) Proteinuria
c) ‘Butterfly rash’ on the face
d) Weight gain
e) High blood pressure
 PATHOPHYSIOLOGY

Genetic
factor

Environmental
factors
 DIAGNOSIS OF LUPUS NEPHRITIS

Proteinuria • Serological or laboratory tests cannot

≥ 0.5g/day accurately predict histological findings

• Lower glomerular filtration rate (GFR)

is associated with chronic histological
lesions
RENAL
BIOPSY • If GFR <30ml/min, biopsy should be
decided based on normal kidney size
Glomerular
Cellular casts
and/or evidence of renal disease
haematuria
activity

• Biopsy should be performed within 1st

month after disease onset (preferably
before initiation of
immunosuppressive treatment)
 CLASSIFICATION OF LUPUS NEPHRITIS
• Based on International Society of Nephrology/Renal Pathology Society, 2003 (ISN/RPS)
• Class I: Minimal mesangial LN
 Normal glomeruli by light microscopy, mesangial immune deposits by IF

• Class II: Mesangial proliferative LN

 Mesangial hypercellularity or expansion of mesangial matrix by light microscopy, mesangial
immune deposits by IF

• Class III: Focal LN

 Endo- or exocapillary glomerulonephritis involving <50% of all glomeruli, with subendothelial
immune deposits
 Glomerular lesions can be active, chronic or both
• Class IV: Diffuse LN
 Endo- or exocapillary glomerulonephritis involving >50% of all glomeruli, with diffused
subendothelial immune deposits
 Glomerular lesions can be active, chronic or both
• Class V: Membranous LN
 Global or segmental sub-epithelial immune deposits by light microscopy and IF

• Class VI: Advanced sclerosing LN

 >90% of glomeruli sclerosed without residual activity
 MANAGEMENT OF LUPUS NEPHRITIS

1. Initiation treatment
KDIGO -
Glomerulonephritis 2. Failure to initiation treatment
(2012)
3. Maintenance treatment

EULAR/ERA-EDTA 4. Adjunctive treatment

Guidelines (2012) 5. LN in pregnancy
6. LN in paediatrics
ACR (2012) 7. Monitoring of LN

Goals of treatment
Preservation of renal function
Prevention of flares
Avoidance of treatment-related harms
Improved quality of life and survival
 INITIATION TREATMENT
KDIGO EULAR/ERA-EDTA ACR
CLASS I No immunosuppressive treatment
• Proteinuria (<1g/d): ACEi/ARB • Proteinuria >1g/d (with presence of
glomerular haematuria):
CLASS II • Nephrotic syndrome: corticosteroids Prednisone 0.24-0.5 mg/kg/day No recommendation stated
and/or
AZA 1-2 mg/kg/day
Corticosteroids • MMF (target dose: 3g/day for 6 MMF 2-3g/day for 6 months OR CYC
CLASS III (Oral prednisolone up to 1mg/kg) months) or MPA sodium 720mg +
+ or Pulse IV MP 500-1000mg/day for 3
CYC or MMF • Low dose IV CYC (total dose 3g over doses, then PO Prednisone
CLASS IV 3 months) + PO Prednisolone 0.5-1mg/kg/day tapered to lowest
0.5mg/kg/day effective dose
• Proteinuria (>3g/d): • Proteinuria (>3g/d): • Proteinuria (>3g/d):
Corticosteroid MMF MMF 2-3g/day
+ + +
CLASS V CYC, or CNI, or MMF, or AZA PO prednisolone 0.5mg/kg/day PO Prednisone 0.5mg/kg/day
• Alternative/non-responder:
• high dose IV CYC, CNI (ciclosporin or
tacrolimus)
• Corticosteroids & immunosuppressive • No recommendation stated • No recommendation stated
CLASS VI agents (only as dictated by extrarenal
manifestations)

CYC = cyclophosphamide; MMF = mycophenolate mofetil; CNI = calcineurin inhibitor; AZA = azathioprine; MP = methylprednisolone
MPA = mycophenolate acid
 MYCOPHENOLATE
CYCLOPHOSPHAMIDE MOFETIL AZATHIOPRINE

Pharmacological class Immunosuppressant; alkylating Immunosuppressant Immunosuppressant

agent

Prevents cross-linking of DNA Exhibits cytostatic effect on T Incorporate into replicating

Mechanism of action strands and B lymphocytes DNA and stops DNA
replication
Route of Intravenous Oral Oral
administration
Induction: Maintenance:
500-1000 mg/m once every
2 2-3g daily for 6 months in 2mg/kg/day
month for 6 doses or 6 months, combination with
Dose then every 3 months for a total glucocorticoids If pregnant - ≤2 mg/kg/day
of at least 2.5 years Maintenance:
0.5-3g daily
Haemorrhagic cystitis, alopecia, Headache, nausea, lower Nausea and vomiting,
Adverse effects amenorrhoea, nausea and immune system, skin rash diarrhoea
vomiting (dose-related)
CBC; monitor for CBC, signs and symptoms of CBC, signs and symptoms of
signs/symptoms of infections infections,
Monitoring parameters haemorrhagic cystitis, hepatic
toxicity; serum electrolytes,
serum creatinine
 FAILURE TO INITIATION TREATMENT

KDIGO EULAR/ERA-EDTA ACR

• Rituximab • If unresponsive to MPA or CYC: • If unresponsive to
• IV immunoglobulin (low switch MPA↔CYC glucocorticoid + MMF or CYC:
evidence) • Other alternatives: switch MMF↔CYC + pulse IV
• Sucrose-containing IV • Rituximab glucocorticoids for 3 days
immunoglobulin showed • Calcineurin inhibitors • If failed both MMF and CYC:
nephrotoxicity • IV immunoglobulin • Rituximab
 MAINTENANCE TREATMENT

Preferred Treatment(s)

KDIGO MMF

MPA (MMF or
MAINTENANCE
TREATMENT EULAR/ERA-EDTA mycophenolate sodium)
IV Cyclophosphamide

MMF
ACR
Azathioprine
 MAINTENANCE TREATMENT

• A randomised, open-label, controlled trial comparing three regimens of maintenance therapy:

• 0.5-1g IV CYC every 3 months, oral MMF 0.5-3g/day and oral azathioprine 1-3mg/kg/day
• Results:
 47% of patients in CYC group had renal relapse during maintenance therapy as compared to
azathioprine (35%) and MMF (18%) groups
 Higher number of major infections (pneumonia, sepsis and meningitis) was found in those assigned
to CYC group
 The rate of relapse-free survival was the highest in MMF group among the three groups (p=0.02)
• Conclusion:
• Maintenance therapy with MMF is associated with better efficacy and safety followed by azathioprine
and IV CYC
MAINTENANCE TREATMENT

• Randomised, double-blind, phase 3 study

comparing oral MMF 2g/day and oral azathioprine
2mg/kg/day
• Results:
 MMF was superior to azathioprine with respect
of time to treatment failure (p=0.003)
 Higher occurrence of renal flare in patients
taking azathioprine (23.4%) compared to only
12.9% in patients taking MMF
 Withdrawal of drugs due to adverse events
was higher with azathioprine (39.6%) than
MMF (25.2%) (p=0.02)
• Conclusion:
• MMF is more superior than azathioprine in
maintaining renal response to treatment and
preventing relapse in active lupus
 ADJUNCTIVE TREATMENT
Hydroxychloroquine is recommended as adjunct treatment

KDIGO EULAR/ERA-EDTA ACR

• ACEi or ARBs is preferred to
treat proteinuria or
hypertension (BP target
<130/80mmHg)
• Recommended to be
immunised with non-live
vaccines
• Patients with proteinuria
≥0.5g/day should be
treated with ACEi or ARBs
• Statin is recommended in
patients with LDL
cholesterol >100 mg/dl

• Find evidence: (EULAR/ERA-EDTA) – 97,98, 95, 90-92

• Find evidence: (ACR) – 18-19, 20-21, 25, 24 (ACEi & ARB better than CCB)
 LUPUS NEPHRITIS IN PREGNANCY

RECOMMENDED NOT RECOMMENDED

• Hydroxychloroquine to be continued during • CYC, MMF, ACEi and ARB are not be used due
pregnancy to teratogenicity
• LN patients who become pregnant while
being treated with MMF be switched to
azathioprine
• For clinically active LN, may prescribe
glucocorticoids to suppress LN activity.
• Aspirin is recommended to reduce risk for
pre-eclampsia
• Patients with APS should be considered for
low molecular weight heparin and/or aspirin
 MANAGEMENT OF LN IN PAEDIATRIC

Oral MMF 600

mg/m2/dose BID for 6
months
(max 3g/day)

Concomitant
IV CYC every 4 weeks administration of
for 6 months glucocorticoid

Management
of Paediatric
Lupus Nephritis
MANAGEMENT OF LN IN PAEDIATRIC
 MONITORING OF LUPUS NEPHRITIS

• Monitoring of blood pressure, serum creatinine, proteinuria, urinary sediment (microscopic evaluation), serum
C3/C4 and serum anti-dsDNA antibody levels are used to define activity and evaluate response to treatment
• Spot UPCR measured on first morning void urine sample is valid for measuring proteinuria
• Reappearance of urine casts is >80% sensitivity and specificity as predictor for renal flares
• Repeat renal biopsy may provide assistance in therapeutic decisions for patients with relapse of nephritis after
complete renal response or with refractory disease
 ROLES OF PHARMACIST
• Emphasized the importance of medications compliance in patients as non-compliance will lead to
relapse of lupus nephritis

• Advice patients to apply sunscreen protection with protection factor of 25 or greater and avoid long
exposure under sunlight

• In terms of family planning, oestrogen contraceptive pill at high dose should be avoided in patients
with lupus nephritis

• Other non-pharmacological measures that can help to reduce trigger of lupus nephritis, include
avoidance of stress, rest as appropriate and a low saturated fat, high fish oil containing diet
 CONCLUSION
• Renal biopsy should be done in SLE patients with lupus nephritis in order to decide the appropriate
treatment for them

• For Class III/IV proliferative lupus nephritis, physicians may prescribe either oral Mycophenolate mofetil or
IV Cyclophosphamide in combination with glucocorticoids as initiation therapy

• Alternative options for failure of initiation treatment include switching either mycophenolate mofetil or
cyclophosphamide depending which treatment is was initially started

• Maintenance treatment should be continued for at least 6 months or until complete remission occur in
patients

• Hydroxychloroquine should be used as adjunct treatment as it can reduce the occurrence of flares

• In pregnant women with lupus nephritis, low dose aspirin is recommended to reduce the risk of pre-
eclampsia
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