1. Lupus Nephritis
treatment-current
consensus
Dr. Vishal Golay
IPGME&R
FANA

2. Case Definition of Lupus
Nephritis
ACR definition:
– persistent proteinuria >0.5 g/d or >3+ by dipstick, and/or
– cellular casts including RBCs, Hb, granular, tubular, or mixed).
Additional recommendations by ACR:
– Urinary PCR >0.5
– “active urinary sediment” (>5 RBCs/hpf, >5 WBCs/hpf in the
absence of infection, or cellular casts limited to RBC or WBC
casts) can be substituted for cellular casts.
– Optimal would be a histological demonstration.
– ACR Core Executive Panel- diagnosis of LN should also be
considered valid if based on the opinion of a rheumatologist
or nephrologist.
Lupus 2004;13:857–60.

3. Indications of renal biopsy
• Low threshold.
• Any sign of renal involvement.
• Lowering of GFR (formulas like CG, MDRD, Schwartz are not
fully validated in SLE).
• Biopsy within 1 month of disease onset preferably
before immunosuppression.
• But, high dose GC should be given if there will be a
delay in HPE.

4. ACR Recommendations

5. • The importance of early biopsy and start of treatment
as a prognostic factor for LN has been shown in many
studies.
• Data show that clinicians tend to wait for HPE of severe
LN before initiating immunosuppression. This
treatment delay is critical for the prognosis of LN.
J Rheumatol2006;33:1563–9.

6. Renal Biopsy in LN
• ISN/RPS 2003 classification is uniformly accepted.
• At least 8 g should be examined by LM with
H&E, PAS, Masson’s Trichrome & Silver stains. IF for
IgG, IgA, IgM, κ and λ.
• EM can be used(if possible) for recognition of prolif and
membranous lesions.
• Chronicity and activity scoring to be done. Vascular lesions
s/o APLA should be looked for.

7. NIH Disease activity scoring system
Activity index (graded on a
scale of 0 to 3+ for each); Chronicity index (0 to 3+
total of 24 each, total of 12)
1. Endocapillary 1. Glomerulosclerosis,
proliferation,
2. Fibrous crescents,
2. Glomerular leukocyte
infiltration, 3. Tubular atrophy, and
3. Wire loop deposits, 4. Interstitial fibrosis
4. Fibrinoid necrosis and
karyorrhexis (X2),
5. Cellular crescents (X2)
6. Interstitial inflammation
AI >12 and CI >4 has poor 10 year renal survival

8. Goals of immunosuppressive
Rx
– Long-term preservation of renal function,
– Prevention of flares,
– Avoidance of treatment-related harms, and
– Improved quality of life and survival.
• Treatment must be based on a shared decision
between patient and doctor.
• Immunosuppressive treatment is generally not
indicated in classes I and VI LN, unless necessitated by
extra-renal lupus activity

9. Outcome definitions
Complete renal response:
proteinuria <0.5 g/d(uPCR) (common) and normal or near-
normal (within 10% of normal GFR if previously abnormal)
GFR(return of sCr to previous baseline)
Partial renal response:
≥50% reduction in proteinuria to subnephrotic levels (common)
and normal or near-normal GFR by 6-12 months (Stabilization
(±25%), or improvement of SCr, but not to normal)
Deterioration: A sustained 25% increase in SCr is widely used
but has not been validated.
EULAR/ERA-EDTA KDIGO

10. Outcome definitions
(Flares/relapse)
KDIGO
A fall in levels of serum complement components and a rise in anti–dsDNA antibody titers also
support a diagnosis of relapse.

11. Outcome definitions
(Flares/relapse)
EULAR/ERA-EDTA
Nephritic flares:
• reproducible increase of sCr by ≥30% (or, decrease in
GFR by≥10%) and
• active urine sediment with increase in glomerular
haematuria by ≥10 RBC/hpf, irrespective of changes in
proteinuria;
Proteinuric flares:
• Reproducible doubling of UPCR to >100 mg/mmol after
complete response or reproducible doubling of UPCR
to >200 mg/mmol after partial response.

12. Adjunctive therapies
Hydroxychloroquine:
• protects against the onset of LN, against relapses of
LN, ESRD, vascular thrombosis, and that it has a
favourable impact on lipid profiles.
• Dosage of 6.5mg/kg/d or 400mg/d (whichever is
lower) after ophthalmological exam.
• Dose modification for GFR <30ml/hr.
• Yearly ophthal exam after 5 yrs of use (earlier if
increased risk).

13. Adjunctive therapies
RAS blockade:
• Recommended in all patients with HTN or proteinuria
>0.5g/d with target BP of <130/80 mmHg
• Recommendation based on
– Evidence for their antiHTN, antiproteinuric and
renoprotective effect, and
– Lack of data on the comparative efficacy of other classes of
antiHTN agents in LN.
• The use of combination ACE inhibitors/ARB therapies is
controversial.

14. Adjunctive therapies
Statins (ACR, Level C evidence):
• statin therapy in patients with LDL>100 mg/dl.
• Those with GFR <60ml/min is a risk factor for acc.
atherosclerosis.
• SLE is itself a risk factor for acc. atherosclerosis.
Pre-pregnancy counseling in women of child bearing age
(ACR, Level C evidence).

15. Treatment of Lupus
Nephritis

16. Analyzing available data
• “Hard outcome measures”: doubling of serum
creatinine, ESRD death. Usually seen only in very long
term follow up.
• “Intermediate outcome measures”: renal response
and flares/relapses. Usually seen within 2 years and
has been found to correlate well with the hard
outcomes.
• However, correlation does not guarantee surrogacy.

17. Lupus Nephritis Class II
KDIGO 2012:
1. Treat patients with class II LN and proteinuria <1 g/d as
dictated by the extrarenal clinical manifestations of lupus.
(2D)
2. We suggest that class II LN with proteinuria >3g/d be
treated with corticosteroids or CNIs as described for
MCD. (2D)
• No prospective studies in this group of patients.
• If nephrotic-range proteinuria is found with class II
LN, this may be due to a concomitant podocytopathy.

18. Lupus Nephritis Class III/IV
(Initial therapy)

19. • There are differences between the various guidelines
regarding the choice of the initial therapy.
• This is predominantly due to the racial differences and
response rates seen according to the place of origin of
these guidelines.

20. Major differences
• The European guidelines recommend either MMF/low
dose “Euro lupus protocol” as the first choice.
• KDIGO guidelines however favour use of CYC (high
dose) in those with severe disease and MMF in those
with less severe disease/ favourable ethnicity (although
the levels of evidence for both is 1B).

21. Major differences
• EULAR/ERA-EDTA guidelines recommend a lower
starting dose of steriods @0.5mg/kg/d after an initial
pulse of 500-750mg iv for 3 days reducing to ≤10mg/d
by 4-6 months.
• Steroids are recommended at starting dose of
1mg/kg/d in the KDIGO guidelines, tapering over 6-12
months.

22. Some relevant trials on Prolif
Lupus
Euro-Lupus Nephritis Trial
Compared with the NIH trials, much lower proportions of patients in
the Euro-Lupus Nephritis Trial were Afro-Caribbean, had nephrotic
syndrome or impaired renal function. The mean serum creatinine of
the patients was only 1.15 ± 0.66mg/dl

23. Some relevant trials on Prolif
Lupus

24. CYC treatment advice
• Bladder toxicity found to be greater with oral CYC.
Lifetime maximum should be 36 g CYC in patients SLE.
• Dose of CYC decreased by 20% or 30% in patients with
CrCl 25–50 and 10–25 ml/min, respectively.
•
•
.

25. CYC treatment advice
• Take oral CYC in the morning, and drink extra fluid
at each meal and at bed time.
• Use of sodium-2-mercaptoethane (mesna) will
minimize the risk of hemorrhagic cystitis in those
on iv CYC.
• Fertility prophylaxis with leuprolide and
testosterone.
• Other options for fertility-Ovarian tissue
cryopreservation and sperm banking.

26. KDIGO 2012:
• We suggest that, if patients have worsening
LN (rising SCr, worsening proteinuria) during
the first 3 months of treatment, a change be
made to an alternative recommended initial
therapy, or a repeat kidney biopsy be
performed to guide further treatment. (2D)

27. Lupus Nephritis Class III/IV
(Maintenance therapy)
MAINTAIN Trial

28. MMF superior to Aza for
maintenance?
• A total of 227 patients across sites in the US, Western
Europe, China, Argentina, and Mexico, who improved after
6 months of either high-dose CYC or MMF were randomly
assigned to maintenance treatment (116 to MMF and 111
to Aza)
• Over 3 years of follow up, MMF was statistically better
than AZA in time to treatment failure (a composite
including death, end-stage renal disease, doubling of serum
creatinine, and renal flare), and in each element of the
composite score.
• Severe adverse events occurred in significantly more
patients receiving AZA than receiving MMF.
Dooley et al. NEJM 2011;365:1886–95.

29. • Thus, although maintenance therapy with Aza (1.5–
2.5 mg/kg/d) or MMF (1–2 g/d in divided doses), and
low-dose oral corticosteroids (≤10 mg/d prednisone
equivalent) are both given equal levels of
recommendation(1B) by KDIGO as well as the
ACR(Level A) & EULAR/ERA-EDTA(Level A), it seems
more prudent to choose MMF over Aza considering
the present literature specially if the initial therapy
was with higher dose MMF.
CNIs with low-dose corticosteroids can be used for
maintenance therapy in patients who are intolerant of
MMF and azathioprine. (2C-KDIGO)

30. Duration of maintenance
therapy
• There is a very low–quality evidence to guide the
duration of maintenance therapy after CR.
• The average duration of immunosuppression was 3.5
years in seven RCTs.
• KDIGO recommends (2D) that immunosuppression
should be tapered only after 1 year of achieving CR.
• Immunosuppression should be continued for patients
who achieve only a partial remission.
• EULAR/ERA-EDTA recommends a total duration of
Maintenance therapy of at least 3 years (Level C).

31. • KDIGO guidelines also state If CR has not been
achieved after 12 months of maintenance
therapy, consider performing a repeat kidney biopsy
before determining if a change in therapy is indicated.
(Not Graded)
• While maintenance therapy is being tapered, if kidney
function deteriorates and/or proteinuria worsens, it is
suggested that treatment be increased to the previous
level of immunosuppression that controlled the LN.
(2D)

32. Predictors of poor outcome
Factors that are found to have a role in predicting poor
remission rates are:
–
–
–
–
• failure to achieve complete remission is a major risk
factor for kidney relapse.
Resolution of proteinuria is the strongest predictor of
kidney survival.

33. Monitoring therapy
ACR Recommendations

34. Treatment of pure LN Class
V
• Very poor available literature (only 1 small RCT).
• In those with non-nephrotic proteinuria, with normal
renal function, KDIGO recommends antiproteinuric and
antiHTN medications with steroids and immunosupp
depending on the extrarenal manifestations.
• In those with nephrotic range proteinuria KDIGO
recommends corticosteroids plus an additional
immunosuppressive agent: cyclophosphamide (2C), or
CNI (2C), or MMF(2D), or azathioprine (2D).

35. Treatment of pure LN Class
V
• However, ACR and EULAR/ERA-EDTA recommends
MMF as the first line therapy and alternatives given are
CYC/CNIs/rituximab.

36. Treatment of Relapse
• KDIGO guidelines suggest that relapses should be
treated with the same treatment that was used for
initial and maintenance therapy which induced
remission previously. If there is a chance of cumulative
CYC toxicity, non-CYC Rx should be used.
• Renal biopsy can be considered if there is a suspicion of
class switch or if there is uncertainty on the
activity/chronicity contribution to the worsening.

37. Treatment of refractory
disease
There is no consensus definition for refractory LN.
•
• Biopsy should be done in these case to determine the
level of activity and chronicity.
• “Salvage therapies” that may be considered are
rituximab, i.v. immunoglobulin, or CNIs. (2D)

38. LN and pregnancy
• Pregnancy may be planned in patients with inactive
lupus and UPCR <50 mg/mmol for the preceding 6
months, with GFR that should preferably be >50
ml/min.
• They should be Rx with drugs recommended as
acceptable during prepregnancy counselling (HCQ,
prednisone, Aza).
• Immunosuppresants should not be tapered during
pregnancy or for at least 3 months postpartum.
• Low dose aspirin is beneficial.

39. THANK