A slide of KDIGO CPG of Lupus Nephritis based on Glomerulonephritis CPG KDIGO

1. KDIGO CPG ON
LUPUS NEPHRITIS
REDZWAN ABDULLAH

2. background
 Lupus nephritis (LN) is a severe form of systemic lupus
 Incidence of ESRF caused by LN is about 4.5 cases in 1 million people
 The presence of LN should be suspected in lupus patient with:
 Impaired RP
 Proteinuria
 Hypertension
 Active urine sediments (hematuria, leukocyturia, RBC and WBC cast)
 LN must be confirmed by renal biopsy.
 LN has 5 classes.

3. Class I Lupus Nephritis
 Glomerulus is normal by light microscopy
 Presence of immune deposits restricted to mesangium, seen only by IF or
electron microscopy
 Class I has no clinical kidney manifestations, and not associated with long term
impairment of kidney.
 90% of Lupus patient without clinical manifestations of kidney impairment has LN
class I
 But, no indications for every lupus patient undergo renal biopsy, and clinical
treatment of LN Class I is not necessary.

4. Class II Lupus Nephritis
 Mesangial hypercellularity and matrix expansion in light microscopy
 Mesangial immune deposits by IF and electron microscopy
 Proteinuria and/or hematuria might be seen, but no nephrotic syndrome or
kidney impairment
 If proteinuria in nephrotic range (>3g/d), this maybe caused by podocytopathy
 Nephrotic syndrome in Class II should be treated as MCD/FSGS (Corticosteroids
or CNIs)
 If proteinuria cannot be controlled, to treat with RAS blockade

5. Class III and Class IV Lupus Nephritis
 Class III (<50% affected glomeruli) and class IV (>50% affected)
 Divided into active lesion or chronic lesion
 Active lesions: endocapillary with mesangial hypercellularity, crescents, necrosis,
wire loops and hyaline thrombi
 Chronic lessions: segmental and global glomerulosclerosis
 iF and electron microscope: significant subendothelial and mesangial immune
deposits
 Almost all patients have proteinuria/hematuria. Nephrotic syndrome and kidney
impairment are common
 If chronic, less overt clinical activity other than progressive kidney failure

6. Initial therapy of LN III and IV
 Corticosteroids combined with either cyclophosphamide or MMF
 If worsening LN (worsening proteinuria / rising SCr) during first 3 months:
 Change to alternative recommended treatment
 Repeat renal biopsy to guide further treatment
 Corticosteroid dosing:
 Initial oral prednisolone upto 1mg/kg, tapering according to response over 6 to 12
months
 IV methylprednisolone is widely used in the beginning for more severe disease.

9. Other regimens
 Corticosteroids with azathioprine
 Fewer adverse effects
 Higher rate of late relapse rate, higher rate of doubling SCr, more chronicity
 Corticosteroids with cyclosporine
 4-5mg/kg/day in first 9 months, then tapered over next 9 months
 Corticosteroids with Tacrolimus (4mg/day) and MMF (1g/day). ‘Multitarget
therapy’.
 Evaluated in Chinese ethnic group. 90% achieved complete or partial remissions.

10. CS + Cyclophosphamide Regime
 Reduced development of CKD, ESRF, LN relapses; and improved remission rate
compared to receiving CS only.
 No differences in outcome with IV vs Oral Cyclophosphamide, but oral
cyclophosphamide has risk of bladder toxicity.
 Cyclophosphamide may cause leukopenia due to bone marrow suppression.
 To protect fertility, female should be offered leuprolide and male should be
offered testosterones
 Regiment B (lower dose shorter duration CP) higher percentage of remission and
lower incidence of severe infections vs Regiment A

11. CS + MMF Regiment
 MMF equivalent to cyclophosphamide (Asian studies) or superior to IV
cyclophosphamide (USA study) in the first 6 months of study
 ALMS study: Oral CS with either daily MMF or 6-monthly IV pulses of
Cyclosporine (0.5-1g/kg). Equivalent in inducing response in 6 months and similar
adverse effects, serious infections, and death.
 However, in long term, cyclophosphamide shows more preservation of kidney
function; reduce relapses, prolonged proteinuria and persistent SCr > 177
 So, cannot state that initial therapy with MMF is equal to cyclophosphamide with
long term kidney function

12. Maintenance therapy of LN III and IV
 After initial therapy completed
 Maintenance with azathioprine (1.5-2.5mg/kg/day) or MMF (1-2g/day in divided doses)
and low dose of oral prednisolone (<10mg/day)
 Calcineurin inhibitors (CNIs) and low dose CS can be used if patient is not tolerating
Azathioprine/MMF
 After complete remission achieved, maintenance therapy should be given for at least 1
year before tapering down
 If complete remission cannot be achieved after 12 months of maintenance, consider
repeat renal biopsy
 If during tapering down , kidney function deteriorate / proteinuria worsen, to increase
treatment to the previous level

13. Duration of therapy
 Few patients have complete remission after 6 months of therapy
 Renal biopsy after 6 months of Rx shows active inflammation improving but
complete resolution of pathologic changes is unusual
 Average immunosuppression duration was 3.5 years
 Taper down only after one year of complete remission
 To continue maintenance therapy if only partial remission. No evidence of
increasing CS or alternative agent can convert partial remission to complete
remission

14. Monitoring therapy of LN III and IV
 Serial measurement of SCr and Proteinuria
 Effective treatment is expected to decrease proteinuria over time, and reduction
in elevated SCr
 Resolution of cellular cast can also be a indicator, however hematuria may persist
for months even after improved SCr and proteinuria
 C3, C4, anti-dsDNA has low sensitivity and specificity in relation to LN activity.

15. Class V (Membranous) LN
 Light microscopy: thickened glomerular basement membrane
 IF and electron microscopy show only subepithelial immune complexes.
 Class V LN accompanied by endocapillary hypercellularity and/or subendothelial
immune deposits, this adds LN Class III or IV to histopathologic diagnosis.
 Clinical findings in Class V is proteinuria often in nephrotic range (>3g/day) with
or without hematuria. Kidney function is usually normal. IF RP deranged, and
urine sediment is more active, class III or IV LN is also present

16.  Class V LN, with normal RP and non-nephrotic range proteinuria treated with
antiproteinuria and antihypertensive medications, and only received CS and
immunosuppressive as dictate by extrarenal maifestations of systemic lupus
 Pure class V LN with persistent nephrotic proteinuria be treated with CS plus
cyclophosphamide, or CNI, or MMF, or Azathioprine
 Patient with mixed Class V LN with Class III or IV LN should be treated similarly
with Class III or IV LN

17. General treatment of LN
 All patients with LN are treated with hydroxychloroquine (max 6-6.5mg/kg IBW
per day), unless contraindicated
 Those who had been on hydroxychloroquine before LN had lower frequency
developing ESRF, CV event and thrombotic event.
 Hydroxychloroquine also can retard kidney damage in LN.
 Prolonged used of hydroxychloroquie warrant yearly retinal toxicity check up,
especially after 5 years continuous use.

18. Class VI Lupus Nephritis
 90% of glomerular are sclerotic, usually globally along with interstitial fibrosis and
tubular atrophy with no sign of immunologic activity.
 Presented with severe kidney failure, accompanied by proteinuria and sometimes
hematuria.
 Only be treated with corticosteroid and/or immunosuppressant as dictated by
extrarenal manifestation of systemic lupus.
 Class VI is chronic injury, without immune mediated insult
 Antiproteinuric and antihypertensive are indicated to preserve residual kidney
function and delay ESRF

19. Relapses of LN

20.  Relapses should be treated with initial treatment followed by maintenance
therapy that was effective in inducing original remission
 If resuming original therapy put pt life n danger (excess lifetime cyclophosphamide),
MMF regiment can be used
 Consider repeat biopsy if suspicion that histologic class has changed or unsure
that worsening SCr/proteinuria due to chronicity or disease activity
 Relapses are associated with development of CKD
 The pathologic findings in LN may change with a relapse. LN class can transform
with relapse, mostly from class III to class IV
 Decrease in serum compliment, and increased in anti-dsDNA antibody titre may
support diagnosis of relapse

21. Resistant Disease
 In patient with worsening proteinuria or SCr after completing initial treatment,
consider repeat biopsy to distinguish active LN from scarring
 In those patient, patient with active LN should be treated with alternative initial
treatment regime (Azathioprine, Cyclosporin, Tacrolimus + MMF)
 Non responders who failed more than once of the recommended initial treatment
maybe considered for rituximab, IVIG or CNIs

22. Systemic Lupus and thrombotic
microangiopathy
 Antiphospholipid Ab Syndrome in systemic lupus patient with/without LN should
be treated with anticoagulant – INR 2.0-3.0
 APS occurs frequenty in Systemic Lupus. Failed to treat APS may cause CKD and ESRF
 Patient with Systemic Lupus and thrombotic thrombocytopenic purpura (TTP)
should receive plasma exchange therapy as for patient with TTP without SLE
 TTP in lupus associated with high mortality.

23. Systemic Lupus and Pregnancy
 Active LN or Partially Remission LN is associated with higher risk of fetal loss and
increased rate of kidney relapse during pregnancy
 To delay pregnancy until complete remission of LN
 Cyclophosphamide, MMF, ACEIs, and ARBs are teratogenic
 To stop using these agent during pregnancy
 Hydrochloroquine, azathioprine, and corticosteroids safe during pregnancy
 Hydrochloroquine should be continue, withdrawal can cause flares of lupus
 Previous use of MMF can be changed to azathioprine
 If pregnant women received CS or AZA, these drugs should not be tapered down for
atleast 3 months post partum
 Low dose aspirin may decrease rate of fetal loss

24. General Concusion of LN management
 LN Class I : No specific treatment
 LN Class II: With Corticosteroid or CNIs
 LN Class III and IV: Initial with CS + CPA/MMF, then maintenance
CS+MMF/Azathioprine
 LN Class V (without III and IV): Antiproteinuric and/or antihypertensive
 LN Class V (with LN III and IV): Same as LN III and IV
 LN Class VI: Antiproteinuric and antihypertensive. No immunosuppressant.
 Hydrochloroquine in all LN patient except contraindicated
 Relapses: restart initial treatment or repeat biopsy
 Resistant: Try alternative initial regime (Aza, Cyclosporine, Tacrolimus + MMF),
or rituximab, IVIGs or CNIs,

25. thank YOU!