This document provides guidelines for screening, treating, and managing lupus nephritis (LN). It defines LN and its classification system. For classes I and II LN, treatment focuses on extrarenal symptoms. Classes III and IV are treated aggressively with glucocorticoids and immunosuppressants. Maintenance therapy includes azathioprine or mycophenolate mofetil with low-dose steroids. Relapse is treated with the initial regimen. The guidelines recommend treatments and monitoring for various LN classes and complications.

1. American College of
Rheumatology Guidelines for
Screening, Treatment, and
Management of Lupus Nephritis
Dr. Amit Agrawal

2. Disease Burden
• 35% of adults with SLE have clinical evidence of
nephritis at the time of diagnosis.
• 50–60% developing nephritis during the first 10
years of disease.
• Higher in men than in women.
• Survival with SLE - 95% at 5 years
• 92% at 10 years
• Lupus nephritis reduces survival 88% at 10 years

3. Case definition
• Persistent proteinuria 0.5 gm per day
• Or greater than 3+ by dipstick
And/or
• Cellular casts including red blood cells,
hemoglobin, granular, tubular, or mixed

4. • Spot urine protein/creatinine ratio of >0.5
Active Urinary Sediment:
• >5 RBCs/hpf
• >5WBCs/hpf in the absence of infection
• cellular casts limited to RBC or WBC casts

5. Renal Biopsy
• All patients with clinical evidence of active LN,
previously untreated, undergo renal biopsy
(unless strongly contraindicated) so that
glomerular disease can be classified by current
ISN/RPS classification
• Evaluated for activity and chronicity and for
tubular and vascular changes

8. Principles of treatment
• Class I and Class II- do not require
immunosuppressive treatment.
• Class III And Class IV aggressive therapy with
glucocorticoids and immunosuppressive agents
• Class V when combined with class III or IV should
be treated in the same manner as class III or IV
• Class VI requires preparation for renal
replacement therapy rather than
immunosuppression

9. • All SLE patients with nephritis be treated with
a background HCQ unless there is a
contraindication
Rationale:
• Lower rates of Flare
• Reduced renal damage
• Less clotting events

10. • LN patients with proteinuria >0.5 gm per 24
hours should have blockade of the renin–
angiotensin system, which drives
intraglomerular pressure
Rationale:
• Reduces proteinuria by 30%, and
• Significantly delays doubling of serum
creatinine
• Delays progression to end-stage renal disease

11. • Control of hypertension, with a target of
<130/80 mm Hg
• Statin therapy be introduced in patients with
low-density lipoprotein cholesterol >100
mg/dl

13. Class V Management

16. Class I LN (minimal-mesangial LN)
• Treatment as dictated by the extrarenal
clinical manifestations of lupus
RATIONALE:
• Class I LN has no clinical kidney
manifestations.
• Class I LN is not associated with long-term
impairment of kidney function

17. Class II LN (mesangial-proliferative LN)
• Treat patients with class II LN and proteinuria
<1 g/d as dictated by the extrarenal clinical
manifestations of lupus.
• Class II LN with proteinuria >3 g/d be treated with
corticosteroids or CNIs as described for MCD.
RATIONALE:
There are no evidence-based data on the
treatment of class II LN.

18. Class III LN (focal LN) and class IV LN
(diffuse LN)
• Initial therapy with corticosteroids , combined
with either cyclophosphamide or MMF
• 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

19. Regimens for initial therapy in class III/
class IV LN

21. Other Initial Regimens
• Azathioprine
• Cyclosporine
• Combination of tacrolimus and MMF
(sometimes called ‘‘multitarget’’ therapy).

22. Important considerations
• Lifetime maximum of 36 g cyclophosphamide
in patients with systemic lupus.
• The dose of cyclophosphamide should be
decreased by 20%(CrCl 25–50 ml/min) or 30%
(10–25 ml/min)

23. Choice of Initial Therapy
• In severe class III/IV LN, a cyclophosphamide-
containing protocol for initial therapy may be
preferred.
• In patients with less severe proliferative LN, an
initial regimen not containing
cyclophosphamide should be considered.

24. Class III LN and class IV LN
maintenance therapy
• Patients with class III and IV LN receive
maintenance therapy with
• Azathioprine (1.5–2.5 mg/kg/d) or
• MMF (1–2 g/d in divided doses), and
• low-dose oral corticosteroids

25. • CNIs with low-dose cortico-steroids be used
for maintenance therapy in patients who are
intolerant of MMF and azathioprine.
• After complete remission is achieved,
maintenance therapy be continued for at least
1 year before consideration is given to
tapering the immunosuppression.

26. • If complete remission 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.
• While maintenance therapy is being tapered, if
kidney function deteriorates and/or proteinuria
worsens, treatment be increased to the previous
level of immunosuppression that controlled the
LN.

27. Duration of Therapy
• There is no evidence to help determine the
duration of maintenance therapy.
• The average duration of immunosuppression
was 3.5 years in seven RCTs.
• Immunosuppressive therapy should usually be
slowly tapered after patients have been in
complete remission for a year.

28. • Immunosuppression should be continued for
patients who achieve only a partial remission.
• The strategy of trying to convert a partial
remission to a complete remission by
increasing corticosteroids or using alternative
immunosuppressive agents is not supported
by evidence.

29. Predictors of Response to Treatment of
Class III/IV LN
Predictors for not achieving remission:
• SCr at the start of treatment
• Magnitude of increase in SCr during relapse
• Delay in starting therapy for more than 3
months after a clinical diagnosis of LN.
• Severity of proteinuria
• Failure to achieve complete remission a major
risk factor for kidney relapse.

30. Monitoring Therapy of Class III/IV LN
• Proteinuria
• SCr
• Urine sediment
• C3 and C4,
• Anti–double-stranded DNA antibodies

31. Class V LN (membranous LN)
• Patients with class V LN,normal kidney
function, and non–nephrotic-range
proteinuria be treated with antiproteinuric
and antihypertensive medications, and only
receive corticosteroids and immunosup-
pressives as dictated by the extrarenal man-
ifestations of systemic lupus.

32. • Pure class V LN and persistent nephrotic
proteinuria be treated with corticosteroids
plus an additional immunosuppressive agent:
• cyclophosphamide
• CNI
• MMF
• Azathioprine

33. General treatment of LN
• All patients with LN of any class are treated
with hydroxychloroquine(maximum daily dose
of 6–6.5 mg/kg ideal body weight), unless
they have a specific contraindication to this
drug.

34. Class VI LN (advanced sclerosis LN)
• Treated with corticosteroids and immuno-
suppressives only as dictated by the extrarenal
manifestations of systemic lupus.

35. Relapse of LN
• Relapse of LN after complete or partial
remission be treated with the initial therapy
followed by the maintenance therapy that was
effective in inducing the original remission
• If resuming the original therapy would put
the patient at risk for excessive lifetime
cyclophosphamide exposure, then we suggest
a non cyclophosphamide based initial regimen
be used.

36. • Consider a repeat kidney biopsy during
relapse if there is suspicion that the histologic
class of LN has changed, or there is
uncertainty whether a rising SCr and/or
worsening proteinuria represents disease
activity or chronicity.

38. Treatment of resistant disease
• In patients with worsening SCr and/or protei-
nuria after completing one of the initial
treatment regimens, consider performing a
repeat kidney biopsy to distinguish active LN
from scarring.
• Treat patients with worsening SCr and/or
proteinuria who continue to have active LN on
biopsy with one of the alternative initial treat-
ment regimens.

39. • Nonresponders who have failed more than
one of the recommended initial regimens may
be considered for treatment with rituximab,
i.v.immunoglobulin, or CNIs.

40. Systemic lupus and thrombotic
microangiopathy
• The antiphospholipid anti-body syndrome
(APS) involving the kidney in systemic lupus
patients, with or without LN,be treated by
anticoagulation target INR 2–3.
• Patients with systemic lupus and thrombotic
thrombocytopenic purpura (TTP) receive
plasma exchange as for patients with TTP
without systemic lupus.