Renal Failure

ISSN: 0886-022X (Print) 1525-6049 (Online) Journal homepage: https://www.tandfonline.com/loi/irnf20

Mycophenolate Mofetil versus Azathioprine in the

Maintenance Therapy of Lupus Nephritis

Gulizar Manga Sahin, Sevgi Sahin, Safak Kiziltas, Seval Masatlioglu, Fusun
Oguz & Hulya Ergin

To cite this article: Gulizar Manga Sahin, Sevgi Sahin, Safak Kiziltas, Seval Masatlioglu, Fusun
Oguz & Hulya Ergin (2008) Mycophenolate Mofetil versus Azathioprine in the Maintenance
Therapy of Lupus Nephritis, Renal Failure, 30:9, 865-869, DOI: 10.1080/08860220802353843

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Renal Failure, 30:865–869, 2008
Copyright © Informa Healthcare USA, Inc.
ISSN: 0886-022X print / 1525-6049 online
DOI: 10.1080/08860220802353843

CLINICAL STUDY
LRNF

Mycophenolate Mofetil versus Azathioprine in the Maintenance Therapy

of Lupus Nephritis

Gulizar Manga Sahin, Sevgi Sahin, Safak Kiziltas, Seval Masatlioglu, Fusun Oguz, and Hulya Ergin
MMF vs. AZA in the Maintenance Therapy of Lupus Nephritis

Goztepe Research and Training Hospital, Istanbul, Turkey

to end-stage renal failure, relapses, and documented side effects,

Background. Renal involvement is one of the major
determinants of the outcome in patients with systemic lupus
erythematosus. Renal involvement contributes to both morbidity
and mortality of the patients as well as indirectly through side
effects of therapy directed at the renal lesions. The aim of the
study was to evaluate the efficacy of mycophenolate mofetil
(MMF) and azathioprine (AZA) in the maintenance therapy of
lupus nephritis. Methods. Thirty-two patients from our center
with diagnosed lupus nephritis World Health Organization Class
III, IV, V were treated with IVC (0.75–1g/month) for six months
in addition to steroid therapy, and then with AZA (n = 15) or
MMF (n = 17) as a maintenance therapy. The efficacy of two
drugs was compared with changes in serum creatinine, creatinine
clearance, 24 hour urine protein excretion, cholesterol, anti-dsDNA
antibody, and urine sediment. Results. Mean follow-up time was
41.5 + 7 months. The total remission occurred in 84% of patients
(82% with MMF and 87% with AZA), with a complete remission
rate of 59.3% (58% with MMF and 60% with AZA) and a partial
remission rate of 25% (22% with MMF and 27% with AZA). The
urinary protein excretion before MMF treatment was 1.9 + 1 g/dL
and decreased significantly to 0.91 + 0.6 g/dL (p = 0.028) after
treatment, and decreased from 1.58 + 0.7g/dL to 0.4 + 0.23g/dL
in the AZA group (p = 0.04). The serum creatinine level
decreased from 1.32 + 0.7 mg/dL to 1.12 + 0.68 mg/dL in the
MMF group (p = 0.23), and decreased from 0.91 + 0.23mg/dL
to 0.88 + 0.23 mg/dL in the AZA group (p = 0.49). There was no
significant change between two groups (p = 0.1). The serum
cholesterol decreased from 229 + 57 mg/dL to 171 + 9 mg/dL
(p = 0.002), and serum triglyceride level decreased from
228 + 116 mg/dL to 98 + 35 mg/dL (p = 0.004) in the MMF
treatment, but no significant change was seen in AZA group.
There was no significant difference between the two groups con-
sidering the rates of doubling of serum creatinine, progression
Received 21 April 2008; revised 14 June 2008; accepted 15 July
2008.
Address correspondence to Prof. Gulizar Manga Sahin,
Division of Nephrology, Goztepe Research and Training Hospital,
Istanbul, Turkey; E-mail: gulimanga@yahoo.com
as well. Conclusion. Both therapeutic approaches with MMF
or AZA, in combination with corticosteroids, are effective as a
maintenance therapy for lupus nephritis.
Keywords lupus nephritis, mycophenolate mofetil, azathioprine,
maintanence
INTRODUCTION
Renal involvement is one of the major determinants
of the outcome in patients with systemic lupus erythema-
tosus (SLE). Renal involvement contributes both directly
to morbidity and mortality of the patients, as well as
indirectly through drug-related severe adverse effects and
toxicities.
Patient and renal survival of SLE patients has
improved considerably over the past few decades, due in
part to earlier recognition of renal disease, aggressive
immunosuppression, and the prevention of complications
of therapies.[13] Although long-term cyclophosphamide
(CY) regimens are efficacious in the treatment of prolifer-
ative lupus nephritis and has improved the prognosis of
disease in these patients, the safety of the regimen still
limits the success of therapy. There has been increasing
attention on developing alternate therapies that promptly
and effectively induce remission, prevent relapse, and
maximize patient and renal survival while incurring the
least toxicity. Nephrologists are now focusing on the
concept of induction treatment with vigorous initial
therapies, followed by maintenance treatment with lower
doses of less toxic regimens.
In the last decade, sequential regimens of short-term
CY induction followed by either mycophenolate mofetil
(MMF) or azathioprine (AZA) maintenance have shown to
be efficacious and safe in terms of reducing the long-term
exposure to CY.

865
866 G. M. Sahin et al.
Azathioprine is a safe drug, and many argued that it was
safer than and probably as effective as cyclophosphamide
in the management of lupus nephritis. A randomized con-
trolled trial comparing prednisolone, azathioprine with
prednisolone, and intravenous cyclophosphamide in patients
with mostly proliferative lupus nephritis observed that
cyclophosphamide treatment is more effective in main-
taining remission than azathioprine.[4]
Recently, MMF has emerged as a promising alternative
therapy for both induction and maintenance treatment for
lupus nephritis (LN). Extensively used in organ transplan-
tation, MMF has also been used in a variety of immune-
and non-immune-mediated renal diseases. Mycophenolic
acid (MPA), the active metabolite of MMF, is an inhibitor
of the crucial enzyme involved in the de novo synthesis of
guanosine nucleotides.[5,6] As lymphocytes do not possess
a salvage pathway for the generation of these nucleotides,
MMF results in selective blockade of B- and T-cell prolif-
eration. Unlike CYC, MPA has little impact on other
tissues with high proliferative activity, which possess a
salvage pathway for nucleotide synthesis. This accounts
for its more favorable toxicity profile. In addition, MMF
appears to have a variety of anti-inflammatory actions that
are independent of its effect on cell-mediated immunity.[7–11]
Despite the successful induction of proliferative GN,
relapses are common, ranging from 10 to 65%.[12,13] Con-
tinued renal damage can adversely affect long-term renal
survival with each relapse,[14] and the treatment of these
relapses is burdened by the toxicity. Consequently, opti-
mal treatment and duration of maintenance therapy
remains a challenge. The aim of the study was to evaluate
the efficacy of MMF and AZA in the maintenance therapy
of lupus nephritis
METHODS
In this retrospective study, we analyzed the patients
with biopsy-proven lupus nephritis followed at our center
from January 1999 to October 2006. The patients, who
were equal to or older than 16 years of age and had a
creatinine clearance >25 mL/min, were enrolled this retro-
spective clinical observation. All patients underwent renal
biopsies and had biopsy-proven lupus nephritis conducted
in immunofluorescence and light microscopic examina-
tions within the previous year.
Thirty-two patients with diagnosed lupus nephritis
World Health Organization class III, IV, V were treated with
IVC (0.75–1 g/month) for six months in addition to steroid
therapy, and then with AZA (2 mg/kg/day, n = 15) or
MMF (1500–2000 mg/day, n = 17) as a maintenance ther-
apy. All patients received either angiotensin-converting
enzyme inhibitor (ACEI) and/or angiotensin II receptor
blocker (ARB) therapy, and patients were advised regard-
ing dietary restriction, including low sodium (2 g/day) and
0.8 g/kg protein-restricted diet. For proteinuria, a complete
remission was defined as a reduction in proteinuria to <0.2g
per day with normal serum creatinine; partial remission
was defined as a reduction of proteinuria from a nephrotic
range to a range between 0.21 and 2 g per day with normal
serum creatinine. Treatment failure was evaluated at week 12
and was defined as doubling the baseline serum creatinine.
A relapse could occur after week 12 and was defined
as doubling the lowest obtained serum creatinine so far
and/or development of either a nephrotic syndrome
(proteinuria >3.5 g/day and serum albumin <30 g/L), while
the lowest protein excretion so far had been ≤ 2.0 g/day
repeatedly, or proteinuria >1.5 g/day without other causes,
in a previously non-proteinuric patient.
The efficacy of two drugs was compared with changes
in serum creatinine, 24 hr urine protein excretion rate,
serum cholesterol level, anti-dsDNA antibody titers, and
urine sediment.
Wilcoxon signed-ranks test was used as appropriate to
compare data from the start and end of the treatment
period. In all analyses, a two-tailed type error rate of 0.05
was used. Analysis was performed using SPSS Base 7.5
(SPSS, Inc, Cary, North Carolina, USA).
RESULTS
The baseline characteristics of the 32 patients are
shown in Table 1. Seventeen of the patients were included
in the MMF group and 15 in the AZA group. Of the
32 patients, 15 (47%) presented with renal impairment
(estimated creatinine clearance according to MDRD
<60 mL/min), 13 (41%) were nephrotic (proteinuria
>3.5 g/24 h), and in 19 patients (59%), nephritis was the
presenting symptom of SLE. The baseline parameters
between the two treatment arms were similar except for
higher creatinine level in the MMF group.
The total remission occurred in 84% of patients
(82% with MMF and 87% with AZA), complete remission
rate of 59.3% (58% with MMF and 60% with AZA), and a
partial remission rate of 25% (22% with MMF and
27% with AZA) over 41.5 + 7 months.
The urinary protein before MMF treatment was
1.9 + 1 g/dL and decreased significantly to 0.91+0.6g/dL
(p = 0.028), and decreased from 1.58 + 0.7g/dL to
0.4 + 0.23g/dL in AZA group (p = 0.04). The serum
creatinine level decreased from 1.32 + 0.7 mg/dL to
1.12 + 0.68 mg/dL in the MMF group (p = 0.23) and
decreased from 0.91 + 0.23mg/dL to 0.88 + 0.23 mg/dL in
the AZA group (p = 0.49).The comparison between two
groups in changes of serum creatinine levels and protein
 MMF vs. AZA in the Maintenance Therapy of Lupus Nephritis 867

Table 1 Table 3
Baseline characteristics of patients with lupus nephritis Last laboratory parameters (MMF group)

MMF n = 7 AZA n = 15 Pre-MMF Post-MMF p

Female gender (%) 13 (78%) 12 (80%) Urinary protein (g/day) 1.9 + 1 0.91 + 0.6 0.028
Age (years) 29 (21–55) 35 (25–57) Serum cholesterol (mg/dL) 229 + 57 171 + 9 0.002
Presence of hypertension 8 (47%) 8 (53%) Triglyceride (mg/dL) 228 + 116 98 + 35 0.004
WHO, class III 2 (12%) 2 (13%) Creatinine (mg/dL) 1.32 + 0.7 1.12 + 0.68 0.23
WHO, class IV 9 (53%) 8 (54%)
WHO, class V 6 (35%) 5 (33%)
Activity index 8.7 9.2
Table 4
Chronicity index 3.1 2.9
Last laboratory parameters (AZA group)
Laboratory parameters
Pre-AZA Post-AZA p
Serum creatinine (mg/dL) 1.32 + 0.7 0.91 + 0.23
Creatinine clearance (mL/min) 68 71 Urinary protein (g/day) 1.58 + 0.7 0.4 + 0.23 0.04
Hematuria (>5 RBC/hpf) 12 (76%) 12 (80%) Cholesterol (mg/dL) 184 + 42 189 + 44 0.6
Leukocyturia (>5 WBC/hpf) 11 (70%) 10 (73%) Triglyceride (mg/dL) 142 + 98 139 + 64 0.52
Proteinuria (g/24 h) 1.9 + 1 1.58 + 0.7 Serum creatinine (mg/dL) 0.91 + 0.23 0.88 + 0.23 0.1
Abbreviations: AZA = azathioprine, RBC = red blood cells,
hpf = high-power field, WBC = white blood cells, WHO = World
Health Organization. Table 5
Outcome at last follow-up

MMF n = 17 AZA n = 15
excretion rates were non-significant (p = 0.1). The creati- Follow-up (months) 39 + 14 43 + 18
nine clearance at 24 months was similar in both groups Treatment failure (n) 3 2
(MMF group: 79 mL/min, AZA group: 83 mL/min; Renal relapse rate 5.1 6.2
p = 0.4). The serum cholesterol levels decreased from 229 (relapse/100 patient years)
+ 57 mg/dL to 171 + 9 mg/dL (p = 0.002), and serum trig- Complete remission (n, %) 10, 58 9, 60
lyceride levels decreased from 228 + 116mg/dL to 98 + 35 Treatment failure (%) 18 13
mg/dL (p = 0.004) in the MMF treatment, but no Doubling of serum creatinine (n) 3 2
significant changes were seen in either in the AZA group ESRD (n) 2 1
(see Tables 2 and 3). There was no significant difference Death (n) 0 0
in the rates of doubling of serum creatinine, progression to
end-stage renal failure, and relapses (see Table 4). No
deaths were reported. serum transaminase levels) developed. Two patients with
In general, MMF and AZA were well tolerated (see MMF and four patients with AZA developed reversible
Table 5). Most of adverse events with MMF were gas- bone marrow suppression during the treatment. Complica-
trointestinal complications; in five patients diarrhea was seen, tions of therapy, including hospitalization, amenorrhea,
and in three patients hepatotoxicity (reversible increase in and infections, were similar with MMF and AZA.

Table 2 CONCLUSION
Baseline laboratory characteristics of the patients before the
maintenance treatment regimen Subsequent studies at the National Institutes of Health
Group 1 Group 2 proved that concomitant i.v. methylprednisolone with
(MMF), n =17 (AZA), n =15 monthly pulse i.v. CYC[15,16] was more effective in the
short term than either therapy alone. In longer follow-up
Serum creatinine (mg/dL) 1.32 + 0.7 0.91 + 0.23 of the same population, the combination regimen had no
Creatinine clearance (mL/min) 68 71
greater toxicity than CYC alone, but far superior renal
Hematuria (>5 RBC/hpf) 12 (76%) 12 (80%)
outcomes. Although clearly effective, this regimen is asso-
Leukocyturia (>5 WBC/hpf) 11 (70%) 10 (73%)
Proteinuria (g/24 h) 1.9 + 1 1.58 + 0.7
ciated with both short-term and long-term adverse effects,
including increased risk of severe infections, gonadal
868 G. M. Sahin et al.
damage,[16–18] and malignancy.[19] Many patients (up to
22%) fail to achieve remission with this regimen or relapse
after treatment, and some patients still progress to end-
stage renal disease.[20]
The aim of the present study was to demonstrate the
efficacy of mycophenolate mofetil (MMF) versus azathio-
prine (AZA) as a maintenance therapy for lupus nephritis.
In the present study we achieved a total remission rate
84% (82% with MMF and 87% with AZA), complete
remission rate of 59.3% (58% with MMF and 60% with
AZA), and a partial remission rate of 25% (22% with
MMF and 27% with AZA) over 41.5 + 7 months. There
has been no uniformly accepted definition of remission. In
most studies, remission is a composite of improvement in
proteinuria, using 50% reduction in proteinuria for partial
remission and proteinuria less than 0.5g/day for complete
remission.
The Euro-Lupus Nephritis Trial, a European-based
multi-center prospective trial, compared low-dose to
high-dose i.v. CYC for severe active LN.[21] The majority
of patients was white and had class IV diffuse prolifera-
tive lupus nephritis (DPLN). At 41 months, there were no
significant differences in the primary end point or
cumulative probability of treatment failure between the
high- and low-dose treatment arms (20 vs. 16%, respec-
tively). There were also no differences in renal remissions
(54 vs. 71%, respectively) or renal flares (29 vs. 27%,
respectively). The shorter regimen had less toxicity with
fewer and less severe infections. This study provides
good support for a shorter duration and lower total dose
of CYC for induction therapy for proliferative LN. The
Euro-Lupus trial includes a population with relatively
milder renal disease than in some other studies (mean
creatinine 1–1.3 mg/dL; mean proteinuria 2.5–3.5 g/day
for both groups). Moreover, almost 85% of the patients
were Caucasian. Nevertheless, the Euro-Lupus regimen is
an option for some patients with proliferative LN, particu-
larly Caucasians with less severe renal injury. In addition,
the study confirms that the sequential use of CYC and
AZA is a viable strategy to reduce toxicity without
compromising overall efficacy. In this cohort of patients
who were on high dose CYC and AZA maintenance
therapy, treatment failure rate was 13% and lower than
Euro-Lupus trial. Most patients had milder renal disease
(mean creatinine 0.91 + 0.23 mg/dL, mean proteinuria
1.58 + 0.7 g/day), like the Euro-Lupus trial, but fewer
patients (54%) were class IV DPLN as compared to
Euro-Lupus trial.
A recent trial by Contreras et al.[22] sheds light on the
relative efficacy of maintenance regimens using either
MMF, AZA, or continued i.v. CYC in severe LN. The
high-risk study population included 59 patients, predomi-
nantly African-Americans and Hispanics. The majority
had diffuse proliferative disease with mean Scr 1.6 mg/dL
and urine protein/creatinine ratio >5. Fewer patients
treated with AZA and MMF reached the primary end-
points of death and CRF compared to the CYC group.
Relapse-free survival was higher with MMF (78%) and
AZA (58%) compared to i.v. CYC (43%). Mortality was
increased with i.v. CYC compared to both oral agents.
They concluded that maintenance therapy with either
MMF or AZA was superior to i.v. CYC. In the present
study, we achieved a total remission rate 84% (82% with
MMF and 87% with AZA), complete remission rate of
59.3% (58% with MMF and 60% with AZA), and a partial
remission rate of 25% (22% with MMF and 27% with
AZA) over 41.5 + 7 months. In the Conteras study, some
patients did not achieve remission at the end of the induc-
tion phase with i.v. CYC, which may be attributable to the
large percentage of Hispanics and Blacks in the study.
Patients with rapidly progressive and crescentic disease
were excluded.
In the present study, all patients were Caucasian.
In comparison with the Conteras report, the lack of
racial differences of our study group could explain the
superiority of our total remission rate of AZA group
(87% vs. 58%).
In the present study, creatinine levels are higher in the
MMF group at the start, and proteinuria is higher after
treatment in the MMF group. As proteinuria after treat-
ment in the MMF group is higher compared to the AZA
group, it could be possible that the AZA group has favored
a better outcome for the AZA arm.
The adverse events experienced during our study
were mostly unremarkable and were not severe enough to
lead to the interruption of therapy. The patients’ compli-
ance to the therapy was similar in both groups. The
adverse events profile of MMF and AZA were similar in
our study patients. Most events were mild and reversible
with dose reduction. The incidence of diarrhea increased
with MMF. Complications of therapy, including hospital-
izations, amenorrhea, infections, and gastrointestinal prob-
lems, were similar with MMF and AZA.
This retrospective study confirms favorable results for
AZA and MMF in the maintenance treatment of lupus
nephritis. In conclusion, after induction treatment with
lower dosages CYC, AZA or MMF maintenance treatment
is effective for patients with moderate to severe lupus
nephritis.
DECLARATION OF INTEREST
The authors report no conflicts of interest. The
authors alone are responsible for the content and writing of
the paper.
 MMF vs. AZA in the Maintenance Therapy of Lupus Nephritis
REFERENCES
1. Fiehn C, Hajjar Y, Mueller K et al. Improved clinical
out-come of lupus nephritis during the past decade: Impor-
tance of early diagnosis and treatment. Ann Rheum Dis.
2003;62:435–439.
2. Bono L, Cameron JS, Hicks JA. The very long-term progno-
sis and complications of lupus nephritis and its treatment.
QJM. 1999;92:211–218.
3. Uramoto KM, Michet CJ Jr, Thumboo J, et al. Trends in the
incidence and mortality of systemic lupus erythematosus,
1950–1992. Arthritis Rheum. 1999;42:46–50.
4. Grootscholten C, Ligtenberg G, Hagen EC, et al.
Azathioprine/methylprednisolone versus cyclophosphamide
in proliferative lupus nephritis. A randomized controlled
trial. Kidney Int. 2006;70:732–742.
5. Allison AC, Eugui EM. Mycophenolate mofetil and its mech-
anisms of action. Immunopharmacology. 2000;47:85–118.
6. Eugui EM, Almquist SJ, Muller CD, et al. Lymphocyte-
selective cytostatic and immunosuppressive effects of myco-
phenolic acid in vitro: role of deoxyguanosine nucleotide
depletion. Scand J Immunol. 1991;33:161–173.
7. Hauser IA, Renders L, Radeke HH et al. Mycophenolate
mofetil inhibits rat and human mesangial cell proliferation by
guanosine depletion. Nephrol Dial Transplant. 1999;14:58–63.
8. Badid C, Vincent M, McGregor B, et al. Mycophenolate
mofetil reduces myofibroblast infiltration and collagen III
deposition in rat remnant kidney. Kidney Int. 2000;58:51–61.
9. Blaheta RA, Leckel K, Wittig B, et al. Mycophenolate
mofetil impairs transendothelial migration of allogeneic CD4
and CD8 T-cells. Transplant Proc. 1999;31:1250–1252.
10. Heemann U, Azuma H, Schmid C, et al. Effects of mycophe-
nolic acid mofetil on acute rejection of kidney allografts in
rats. Clin Nephrol. 1996;45:355–357.
11. Lui SL, Tsang R, Wong D, et al. Effect of mycophenolate
mofetil on severity of nephritis and nitric oxide production in
lupus-prone MRL/Lpr mice. Lupus. 2002;11:411–418.
12. Ponticelli C, Moroni G. Flares in lupus nephritis: Incidence,
impact on renal survival and management. Lupus.
1998;7:635–638.
869
13. El Hachmi M, Jadoul M, Lefebvre C, et al. Relapses of lupus
nephritis: Incidence, risk factors, serology and impact on
outcome. Lupus. 2003;12:692–696.
14. Moroni G, Quaglini S, Maccario M, et al. “Nephritic flares”
are predictors of bad long-term renal outcome in lupus
nephritis. Kidney Int. 1996;50:2047–2053.
15. Gourley MF, Austin HA III, Scott D, et al. Methylpredniso-
lone and cyclophosphamide, alone or in combination, in
patients with lupus nephritis: A randomized, controlled trial.
Ann Intern Med. 1996;125:549–557.
16. Illei GG, Austin HA, Crane M, et al. Combination therapy
with pulse cyclophosphamide plus pulse methylprednisolone
improves long-term renal outcome without adding toxicity
in patients with lupus nephritis. Ann Intern Med.
2001;135:248–257.
17. Boumpas DT, Austin HA III, Vaughan EM, et al. Risk
for sustained amenorrhea in patients with systemic lupus
erythematosus receiving intermittent pulse cyclophospha-
mide therapy. Ann Intern Med. 1993;119:366–369.
18. Mok CC, Lau CS, Wong RW. Risk factors for ovarian
failure in patients with systemic lupus erythematosus
receiving cyclophosphamide therapy. Arthritis Rheum.
1998;41:831–837.
19. Radis CD, Kahl LE, Baker GL, et al. Effects of
cyclophosphamide on the development of malignancy and
on long-term survival of patients with rheumatoid
arthritis. A 20-year follow-up study. Arthritis Rheum.
1995;38:1120–1127.
20. Korbet SM, Lewis EJ, Schwartz MM, et al. Factors
predictive of outcome in severe lupus nephritis. Lupus
Nephritis Collaborative Study Group. Am J Kidney Dis.
2000;35:904–914.
21. Houssiau FA, Vasconcelos C, D’Cruz D, et al. Immunosup-
pressive therapy in lupus nephritis: The Euro-Lupus
Nephritis Trial, a randomized trial of low-dose versus high-
dose intravenous cyclophosphamide. Arthritis Rheum.
2002;46:2121–2131.
22. Contreras G, Pardo V, Leclercq B, et al. Sequential thera-
pies for proliferative lupus nephritis. N Engl J Med.
2004;350:971–980.