Lupus Nephritis Management (The Soft Evidence) - Dr. Gawad

Lupus Nephritis Management
Mohammed Abdel Gawad
Nephrology Specialist
Kidney & Urology Center (KUC)
Alexandria
The Soft Evidence

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What is Evidence
Based Medicine?

Evidence vs Logic
Logically both of us may be right,
BUT
What is the EVIDENCE for what will be better for us?

Should We Follow
the Evidence
Blindly?
NO

Think Critically
To Evaluate The Available Evidence

Dose available evidence fit all patients?

For every treatment protocol in this
lecture, I will:
• Mention its evidence.
• Appraise it.
• When you appraise a study about LN you have to consider
the following points:
• Nnumber of patients.
• Ethnicity.
• Severity of the LN in study.
• Duration of the study.
• Remmision & relapse.
• Side effects.

Nomenclature and Description for Rating
Guideline Recommendations

Lupus Nephritis ISN/RPS Classification

Class I LN is not associated with long-
term impairment of kidney function.
At present, there are no data to suggest that
every patient with lupus requires a kidney
biopsy, or that treatment of class I LN is
clinically necessary.

There are no evidence-based data
on the treatment of class II LN.
While there have been no
prospective studies of the
treatment of nephrotic-range
proteinuria in class II LN, it is
reasonable to treat such
patients as for MCD/FSGS in
case of nephrotic syndrome,
or if proteinuria cannot be
controlled using RAS blockade.

Class III & IV Management
Overview
Initial
Therapy
Maintenance
Therapy
The objective is to rapidly
decrease kidney
inflammation by initial
intensive treatment,
and then
consolidate treatment
over a longer time.
At the end of initial
therapy, remission may
not be achieved.
Remissions continue to
occur well into the
maintenance phase.
The evolution of initial therapy in proliferative
LN has been to reduce toxicity while
maintaining efficacy.

Treatment Regimens
Initial Therapy - Class III & IV
Widely used regimens Other regimens
NIH
(IV high dose Cyclophosphamide)
Azathioprine
Euro-Lupus
(IV low dose Cyclophosphamide)
Cyclosporine
Oral Cyclophosphamide
Combination of Tacrolimus and MMF
(‘‘multitarget’’ therapy).
MMF Protocol
All the above regimens are in addition of Corticosteroids.

Widely used regimens
The dosing and duration of corticosteroids has
never been subject to evaluation by RCTs.

(A) NHI Regimen
Austin III HA et al. N Engl J Med 1986; 314: 614–619.

(A) NHI Regimen
With low dose prednisone

(A) NHI Regimen
Trials supporting Cyclophosphamide for initial
therapy
• Boumpas DT, Austin III HA, Vaughn EM et al. Controlled trial of pulse
methylprednisolone versus two regimens of pulse
cyclophosphamide in severe lupus nephritis. Lancet 1992; 340:
741–745.
• Donadio Jr JV, Holley KE, Ferguson RH et al. Treatment of diffuse
proliferative lupus nephritis with prednisone and combined
prednisone and cyclophosphamide. N Engl J Med 1978; 299: 1151–
1155.
• Gourley MF, Austin III HA, Scott D et al. Methylprednisolone and
cyclophosphamide, alone or in combination, in patients with lupus
nephritis. A randomized, controlled trial. Ann Intern Med 1996; 125:
549–557.

(B) Euro-Lupus Regimen
Houssiau FA et al. Arthritis Rheum 2002; 46: 2121–2131

Houssiau FA et al. Ann Rheum Dis 2010; 69: 61–64

Dose it fit all patients?
• Mild to moderate kidney disease. Few patients
in the Euro-Lupus trial had severe kidney
disease (defined as rapidly progressive kidney failure and
typically with widespread (>50%) segmental glomerular
necrosis or crescents).
• RCT in Caucasians.
Therefore, it is not certain whether this
protocol will be effective in patients of other
ancestry, or in patients with more severe class
III/IV LN.

NIH vs Euro-Lupus

(C) Oral Cyclophosphamide Regimen

• Oral CYC vs IV CYC
• Oral CYC vs MMF

• Oral CYC vs IV CYC

vs IV Cyclophosphamide
• It has equivalent efficacy to i.v. cyclophosphamide in
prospective observational studies.
/

vs IV Cyclophosphamide
• It has equivalent efficacy to i.v. cyclophosphamide in
prospective observational studies.
Mok CC et al. Am J Kidney Dis 2001; 38: 256–264.

vs MMF
• It has also been shown equivalent to MMF in Chinese patients.
Chan TM et al. N Engl J Med 2000; 343:1156–1162

• More adverse effects have been reported with
oral compared to i.v. cyclophosphamide, but
this is not a consistent finding.

(D) MMF Regimen
• MMF vs Oral CYC
• MMF vs IV CYC

(D) Mycophenolate Regimen vs Oral CYC
• MMF (maximum 3 g/d) for 6 months has been tested in an RCT in a
Chinese population, and was equivalent in achieving remission to Regimen
C; patients with severe LN were excluded from this study.
Chan TM et al. J Am Soc Nephrol 2005; 16: 1076–1084

Appel GB et al. J Am Soc Nephrol 2009; 20: 1103–1112
(D) Mycophenolate Regimen vs IV CYC
ALMS Trial
•370 patients with class
III, IV, and V LN
•Randomized to IV CYC
pulses for 6 months or
MMF 3gm/d target dose
for 6 months

ALMS Trial
MMF had an
equivalent
response rate to
i.v.
cyclophosphamide
at 6 months

ALMS Trial
Similar incidence of
adverse events including
serious infections and
deaths.

ALMS Trial
Black,Hispanic,Mixed

El-Shafey EM, Abdou SH, Shareef MM. Clin Exp Nephrol 2010;14: 214–221.

Ginzler EM et al. N Engl J Med 2005; 353: 2219–2228.

Ginzler EM et al. N Engl J Med 2005; 353: 2219–2228.
In this 24-week trial,
mycophenolate mofetil
was more effective than
intravenous
cyclophosphamide in
inducing remission of
lupus nephritis and had a
more favorable safety
profile.

(D) Mycophenolate Regimen & LN
Severity
• The patients in studies of MMF vs.
cyclophosphamide generally had less severe
LN, assessed by level of proteinuria and kidney
function, than the patients in some of the
RCTs of cyclophosphamide.
• However, a subset of patients in the ALMS trial
did have severe LN and responded to MMF, so
more data are required (!!!!).

Choice of Initial Therapy
Class III & IV
• 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.

Choice of Initial Therapy
Class III & IV

Treatment Regimens

Does Rituximab have a role in initial
therapy of proliferative LN?
• Because the kidney response rate for class III and IV LN with any of
the initial therapies so far discussed is only about 60% at 6–12
months, an RCT adding rituximab or placebo to MMF plus
corticosteroids for initial LN therapy was undertaken to determine if
remission rates could be improved.
• At 12 months, there were no differences between the rituximab
and placebo groups in terms of complete or partial remissions.
Thus, rituximab cannot be recommended as adjunctive initial
therapy.
Rovin BH et al. J Am Soc Nephrol 2009; 20: 77A.

Does Rituximab have a role in initial
therapy of proliferative LN?
Rovin BH et al. J Am Soc Nephrol 2009; 20: 77A.

! ! ! ! ! ! ! ! ! ! ! ! ! ! ! !

Choice of Maintenance Therapy
Class III & IV
• MMF
• AZA
• Cyclosporine

Class III & IV
• A cohort of mainly black and Hispanic patients
• Class III/IV LN
• Treated with monthly i.v. cyclophosphamide for up to seven
cycles, followed by azathioprine or MMF,
• And compared to patients treated with 6-monthly
cyclophosphamide pulses followed by quarterly
cyclophosphamide pulses for 1 year beyond remission.
Contreras G et al. N Engl J Med 2004; 350: 971–980.

Class III & IV
Contreras G et al. N Engl J Med 2004; 350: 971–980.
Over 72 months, patients
treated with maintenance
azathioprine or MMF were
significantly less likely to
reach the composite end-
point of death or CKD than
the CTX maintenance group,
and to experience fewer
adverse effects.

Class III & IV - MMF vs AZA
• Compared MMF with AZA as maintenance therapy in a
predominantly Caucasian population after initial
treatment with low-dose (Regimen B) cyclophosphamide.
• The primary end-point was time to kidney relapse.
Houssiau FA et al. Ann Rheum Dis 2010; 69: 2083–2089.

After at least 3 years of
follow-up, this trial
found MMF and
azathioprine to be
equivalent.
Houssiau FA et al. Ann Rheum Dis 2010; 69: 2083–2089.

• ALMS trial extension phase.
• Compared MMF and AZA as maintenance therapies after
the 6-month initial treatment period (Regimen D).
• Patients entered this extension phase only if they achieved
a complete or partial remission after initial therapy.
Dooley et al. N Engl J Med 2011; 365: 1886–1895.

Dooley et al. N Engl J Med 2011; 365: 1886–1895.
Over 3 years, the
composite treatment
failure end-point (death,
ESRD, kidney flare,
sustained doubling of SCr,
or requirement for rescue
therapy) was reached in
16% of MMF-treated
patients compared to 32%
of azathioprine-treated
patients.

After at least 3 years of follow-up,
this trial found MMF and
azathioprine to be equivalent.
Over 3 years, the composite
treatment failure was reached
in 16% of MMF-treated
patients compared to 32% of
azathioprine-treated patients.

Class III & IV - Cyclosporine
Moroni G et al. Clin J Am Soc Nephrol 2006; 1: 925–932.
A pilot RCT in 69 patients with
class III/IV LN suggested that 2
years of cyclosporine may be as
effective as 2 years of azathioprine
for maintenance, after initial
treatment with prednisone and
oral cyclophosphamide, in terms
of relapse prevention and
reduction of proteinuria.

Duration of Therapy
• Few patients reach complete remission by 6 months, (and
kidney biopsies after 6 months of initial therapy have
shown that, while active inflammation tends to improve,
complete resolution of pathologic changes is unusual). (1)
• Consistent with this finding, clinical improvement in class
III/IV LN continues well beyond 6 months and into the
maintenance phase of therapy. (2)
• There is no evidence to help determine the duration of
maintenance therapy. The average duration of
immunosuppression was 3.5 years in seven RCTs. (3)
(1) Traitanon O et al. Lupus 2008; 17: 744–751.
(2) Grootscholten C et al. Kidney Int 2006; 70: 732–742.
(3) Houssiau FA et al. Ann Rheum Dis 2010; 69: 61–64.

Duration of Therapy
• We suggest that immunosuppressive therapy should
usually be slowly tapered after patients have been in
complete remission for a year.
• If a patient has a history of kidney relapses it may be
prudent to extend maintenance therapy.
• Immunosuppression should be continued for patients who
achieve only a partial remission. (However, 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).

• Decisions to alter therapy should not be based
on urine sediment alone. A repeat kidney
biopsy may be considered if kidney function is
deteriorating.
Duration of Therapy

Monitoring Therapy
• The progress of LN therapy is monitored with serial measurements of:
– proteinuria (In LN, as in other proteinuric GN, resolution of proteinuria is the
strongest predictor of kidney survival; thus, effective treatment is expected to
decrease proteinuria over time).
– SCr.
– Urine sediment (However, hematuria may persist for months even if therapy is
otherwise successful in improving proteinuria and kidney dysfunction).
– It is desirable to see serologic markers of lupus activity, such as complement
and double-stranded DNA antibody levels, normalize with treatment.
(However, C3 and C4, and anti–double-stranded DNA antibodies have low
sensitivity (49–79%) and specificity (51–74%) in relationship to LN activity).

There are no convincing data to treat
class V LN and subnephrotic proteinuria
with immunosuppression; however,
given the adverse effects of proteinuria
on the kidney, it is reasonable to treat
these patients with antiproteinuric and
antihypertensive medications

The justifications to treat class V LN and nephrotic proteinuria
with immunosuppression are as follows:
1. Decreased GFR occurs in about 20% of cases of class V LN, and ESRD in
about 8–12% after 7–12 years. (1)
2. One study reporting death or ESRD in 28% of patients at 10 years. (2)
3. Spontaneous remission of heavy proteinuria occurs in only a minority of
class V LN.(3)
4. The adverse effects of sustained, heavy proteinuria include
hyperlipidemia and atherosclerosis, contributing to cardiovascular
morbidity and mortality, (4) and hypercoagulability with arterial and
venous
(1) Mok CC et al. Lupus 2009; 18: 1091–1095.
(2) Sloan RP et al. J Am Soc Nephrol 1996; 7: 299–305.
(3) Gonzalez-Dettoni H, Tron F. Adv Nephrol Necker Hosp 1985; 14: 347–364.
(4) Wilmer WA et al. J Am Soc Nephrol 2003; 14: 3217–3232.
Class V – Nephrotic Range

Cyclosporine vs CYC
Austin III HA et al. J Am Soc Nephrol 2009; 20: 901–911.

Both cyclophosphamide and
cyclosporine significantly
increased response
Cyclosporine vs CYC

Relapse after stopping
therapy was much more likely
in those treated with
cyclosporine compared to
cyclophosphamide (no
relapse in 48 months).
Cyclosporine vs CYC

MMF & AZA
• There have been small uncontrolled retrospective, or
open-label, studies of MMF and azathioprine with or
without corticosteroids in class V LN.
• In general, these studies have shown complete
remission rates of 40–60% at 6–12 months.

MMF
Spetie DN et al. Kidney Int 2004; 66: 2411-2415.

Azathioprine
Spetie DN et al. Kidney Int 2004; 66: 2411-2415.

Tacrolimus
Szeto CC et al. Rheumatology (Oxford) 2008; 47: 1678–1681.

• A fall in levels of serum complement
components and a rise in anti–double
stranded DNA antibody titers also support a
diagnosis of relapse but will not necessarily be
present.
Relapse - Diagnosis

Relapse - Incidence
• In subjects with LN who had participated in RCTs (1):
– 40% of complete responders experienced a kidney
relapse within a median of 41 months after remission,
– 63% of partial responders had a kidney flare within a
median of 11.5 months after response.
• The strongest risk factor for relapse is failure to
achieve complete remission. (2)
(1) Illei GG et al. Arthritis Rheum 2002; 46: 995–1002.
(2) Chan TM et al. Lupus 2005; 14: 265–272.

There is low-quality evidence that hydroxychloroquine
may protect against the onset of LN, against relapses
of LN, ESRD, vascular thrombosis, and that it has a
favorable impact on lipid profiles.
Ruiz-Irastorza G et al. Ann Rheum Dis 2010; 69: 20–28.

Post card sent from Ed Lewis to Mel Schwrtz
while Ed Lewis was at the 1980 ISKDC Meeting

Anyone WHO ISN’t confused really doesn’t
understand the situation.
Edward R. Murrow

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Lupus Nephritis Management (The Soft Evidence) - Dr. Gawad

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