Acute renal failure in paediatric systemic lupus erythematosus:

treatment and outcome

S. M. Benseler
1,2,3
, J. M. Bargman
4
, B. M. Feldman
1,2,3
, P. N. Tyrrell
1
, E. Harvey
5
, D. Hebert
5
and E. D. Silverman
1,6
Objective. To determine the outcome of paediatric SLE (pSLE) patients with nephritis who developed acute renal failure (ARF). Efficacy and
safety of treatment regimens were compared.
Methods. A total of 249 pSLE patients were diagnosed and prospectively followed at a single centre between July 1973 and July 2003; 127
children (51%) had lupus nephritis. ARF was defined as serum creatinine of >250mmol/l or >75% above baseline. Standardized
assessments included clinical data and medications, laboratory testing, disease activity and damage scores were obtained. Subsequent renal
flares were documented. Primary outcome: renal function at last follow-up. Secondary outcomes: treatment efficacy and safety. AZA- and
cyclophosphamide (CYCLO)-treated patients were compared. Propensity score methods were applied to balance covariates. An intention to
treat approach was chosen.
Results. The ARF study cohort included 50 patients; 13 boys and 37 girls with a median age of 13.2 yrs at diagnosis and a mean follow-up of
45 months. Renal histology: Class III nephritis in 16; Class IV in 34. Dialysis requirement and disease activity were similar in both groups.
Treatment: AZA in 33 patients, CYCLO in 9 and corticosteroids only in 8. Outcome: no statistically significant or clinically relevant differences
were found for any of the outcome measures including last serum creatinine, time to renal flare, overall renal survival, disease activity over
time, disease damage, mean annual corticosteroid dose and rate of infection.
Conclusion. The treatment of renal failure in this pSLE cohort was associated with an excellent outcome. AZA and CYCLO were equally
efficacious.
KEY WORDS: Adolescent rheumatology, Rheumatic diseases, Systematic lupus erythematosus, Autoimmunity, Rheumatic disease, Renal, Tissues,
Outcome measures, Health services and practice.
Introduction
Paediatric SLE (pSLE) accounts for 20% of all cases of SLE, with
nephritis occurring in 50% [1]. Renal disease in general, and the
development of acute renal failure (ARF) and end-stage renal
disease (ESRD) in particular, are important factors contributing
to disease morbidity and mortality [27]. Long-term follow-up
studies have demonstrated that ESRD may occur in up to 50% of
adult SLE patients and is most commonly associated with Class
III and Class IV lupus nephritis [3, 8]. Although very few
controlled studies have been performed, current management of
patients with Class III and Class IV nephritis includes corticoste-
roids and another immunosuppressive agent, most commonly
cyclophosphamide (CYCLO) [9]. pSLE nephritis is commonly
treated similarly to adults [10, 11] and CYCLO is usually
considered when children present with Class III and Class IV
nephritis. Elevated serum creatinine, histological evidence of
proliferative nephritis and disease onset during childhood have
been shown to be associated with a poor long-term outcomes [12].
We have previously reported that pSLE patients with Class III
and Class IV nephritis treated with a combination of AZA and
corticosteroids have a long-term renal survival similar to that
reported in adult patients treated with a combination of CYCLO
and corticosteroids [13]. However, the role of AZA vs CYCLO
for the treatment of the subset of patients with lupus nephritis
who present with renal failure remains highly controversial.
Moreover, studies examining cytotoxic agents have included
patients with only mild renal impairment 1417], which may
obscure conclusions drawn about their efficacy.
The aim of this study was to analyse and compare the outcome
of two different treatment protocols for paediatric patients with
lupus nephritis who experienced very significant renal impairment
in our centre over the last three decades and to report on the
outcome of these patients.
Patients and methods
Study design and patient search
A single centre cohort of consecutively followed children
diagnosed with pSLE and followed between July 1973 and July
2003was performed. Approval from the Research Ethics Board
at The Hospital for Sick Children, Toronto, was obtained (REB
file No.1000000966). All pSLE patients have been followed by a
single physician in the paediatric lupus clinic (E.D.S.) utilizing a
standardized assessment protocol since 1984. Data before 1984
were obtained from chart review.
Patients, cohorts and treatment regimens
A total of 249 consecutive pSLE patients were followed.
Lupus nephritis was seen in 127/249 children (51%). Fifty of the
127 patients with nephritis met the definition of ARF described
below and represented the inception cohort. Based on therapy
received, children were assigned to three different treatment
cohorts exclusively (i) AZA: 33 patients received daily oral AZA
(13 mg/kg/day). The target dose was 3 mg/kg/day (maximum
dose of 150 mg/day). Lower doses were used in the face of
leucopenia, to maintain total white blood cell 53000, or in case of
haepatotoxicty; (ii) CYCLO: nine patients received monthly
intravenous CYCLO (5001000 mg/m
2
) for seven courses. In 2/9
patients, this was followed by six courses of 3 monthly intravenous
CYCLO. In the other seven CYCLO-treated patients, the seven
courses were followed by AZA maintenance therapy for at least
1
Division of Rheumatology, Department of Paediatrics,
2
Child Health Evaluative
Sciences, Research Institute, The Hospital for Sick Children,
3
Department of
Health Policy, Management and Evaluation,
4
Division of Nephrology, Department
of Medicine, University Health Network, University of Toronto,
5
Division of
Nephrology, Department of Paediatrics, The Hospital for Sick Children and
6
Department of Immunology, University of Toronto, Toronto, Canada.
Submitted 31 August 2007; revised version accepted 7 November 2008.
Correspondence to: E. D. Silverman, Division of Rheumatology, Department of
Pediatrics, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario
M5G 1X8, Canada. E-mail: earl.silverman@sickkids.ca
Rheumatology 2009;48:176182 doi:10.1093/rheumatology/ken445
176
The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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18 months. (iii) STE: eight patients were treated with steroids only
and did not receive a second-line agent, but received oral
prednisone or equivalent (2 mg/kg/day). All AZA and CYCLO
patients received the same additional standardized corticosteroid-
treatment regime. Prednisone was started at 2 mg/kg for 6 weeks
and then slowly tapered over 9 months in 4-weekly intervals.
Low-dose corticosteroids were then continued on alternating
days. Anti-hypertensive therapy was implemented when required.
Choice of treatments varied by time. All patients treated with
steroids only were seen prior to 1985. The choice of CYCLO
varied by time and whether there was any severe CNS involve-
ment. Specifically, the nine patients treated with CYCLO received
this therapy for the following reason: (i) severe CNS involvement
for five patients; (ii) treated shortly after the publication of the
1986 NIH papertwo patients and (iii) two patients received
CYCLO during a time when one of the authors was on sabbatical.
All other patients received AZA. The only clinical characteristic
which increased the likelihood of receiving CYLCO rather than
AZA was the presence of severe CNS disease and not the degree of
azotaemia or the need for dialysis.
ARF study cohort
The ARF study cohort included all pSLE patients, who (i) were
diagnosed and followed at the study centre and (ii) had biopsy
confirmed lupus nephritis and ARF. The statistical analysis
specifically compares the outcome of patients who were treated
with either daily oral AZA or monthly intravenous CYCLO as a
second-line immunosuppressive agent for nephritis and ARF since
this reflects the current standard of care.
Definitions
Renal failure. Renal failure was defined as an increased serum
creatinine >75% above baseline value on at least two consecutive
occasions or repeated serum creatinine levels >250 mmol/l.
Baseline was defined as the stable creatinine value over the
preceding 6 months.
Renal flares. A renal flare was defined as increased renal disease
activity requiring a significant increase in steroid dosing of
>400% or an increased dose to the usual maximum dose of
60 mg/day.
Significant infections. Infections were considered significant if
the patient (i) required hospitalization and/or (ii) was commenced
on oral or intravenous anti-bacterial or anti-viral therapy.
Demographics, clinical data and follow-up
All patients were followed in the interdisciplinary paediatric lupus
clinic at our tertiary paediatric care centre. Patient characteristics
including sex, age at diagnosis of pSLE and ARF were recorded.
In addition, the time intervals from diagnosis of pSLE to ARF
and the follow-up intervals were determined. Measures of
nephritis and ARF including the WHO histological classification
of lupus nephritis, requirement for dialysis and the overall and
renal domains of the SLE disease activity tool and SLEDAI were
documented. Hypertension was defined as elevated blood pressure
compared with height- and age-adjusted controls and expressed in
z-scores [18]. Hypertension was noted when present before start of
therapy at the time of diagnosis of ARF. Significant pSLE-related
comorbidities including concurrent CNS disease were determined.
With each visit all systems were reviewed. A complete physical
examination assessed all organ systems potentially affected by
pSLE. Associated conditions and complications of both disease
and treatment were sought. Treatment protocols, changes in
medication dosing, adverse events and intolerance to treatment
were documented.
Study follow-up assessments were recorded at 0, 3, 6, 9, 12, 18
and 24 months and then yearly. Intervals were re-assigned when a
flare occurred. Patient follow-up assessments were then noted
analogous to the disease onset.
Disease activity and damage scores SLEDAI, ECLAM and
SLICC-Damage Index
For each visit disease activity was determined utilizing the
previously validated SLEDAI [19, 20], the modified version
SLEDAI-2K [20] and the ECLAM [21, 22]. Disease activity
over time was calculated as mean area under the curve (AUC
per time interval) [23]. Disease damage was scored starting at
6 months of disease using the SLICC-Damage Index (SLICC-DI)
[24, 25]. Individual SLICC-DI domains including all renal
domains (proteinuria >3.5 g/24 h and ESRD), bone damage,
cataracts, malignancies, insulin-dependent diabetes mellitus
(IDDM) and premature gonadal failure were analysed separately.
Laboratory test results
Standardized laboratory testing at each visit included: (i) renal
function: serum creatinine (CR), urea, albumin (ALB) and
urinalysis including dipstick for blood and albumin, microscopy,
spot urine for protein:creatinine ratio (P:CR) and protein in 24 h
urine collection (uPRO); (ii) inflammatory markers and haema-
tology tests: ESR, complete blood count (CBC)/differential
including polymorphs, lymphocytes (LYM), haemoglobin
(HGB), platelet count (PTL), C3 and C4 complement levels;
(iii) liver function: aspartate transaminase (AST) and alanine
transaminase (ALT); (iv) SLE serology including ANA, anti-
DNA, anti-Ro, anti-La, anti-Sm, anti-RNP and aCL antibodies
and (v) pro-thrombotic testing including LAC [thrombin time
(TTI), platelet neutralization procedure (PNP) and Russell viper
venom (RVV)] and PTT/international normalized ratio (INR)
when indicated. Abnormal test results were documented.
Infections were determined in viral and bacterial cultures, serology
from blood, urine or CSF, when suspected.
Imaging
Imaging including radiographs and MRI was performed for
disease manifestations and complications when indicated.
Outcomes
Treatment efficacy, damage and safety markers were determined
for the study population as well as for each treatment cohort
separately.
(i) Primary outcome
Renal function:
(1) overall renal survival at last follow-up (deaths, renal
transplants and ESRD);
(2) renal function parameters (creatinine and urine
protein) at last follow-up;
(3) renal flare rates during study interval; and
(4) time to renal flare.
(ii) Secondary outcomes
(a) Disease activity and treatment efficacy:
(1) inflammatory markers (ESR and complement) and
lupus serology in response to therapy over time;
(2) mean disease activity (SLEDAI) over time (AUC);
(3) disease activity (SLEDAI) at last follow-up; and
(4) mean annual corticosteroid dose.
(b) Disease damage:
Overall damage score (SLICC-DI) at last follow-up visit and
specific SLICC-DI domains including: (1) renal damage: percen-
tage of patients with evidence of SLICC-DI proteinuria 53.5 g/
24 h, reduced estimated glomerular filtration rate of <50% or end
Outcome of acute renal failure in pSLE 177

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stage renal disease; (2) bone damage: percentage of patients with
evidence of SLICC-DI osteoporosis with vertebral fractures,
avascular necrosis (AVN) or more than one episode of AVN
and (3) eye damage: percentage of patients with cataracts.
(c) Treatment safety
Percentage of patients with new onset of IDDM; gonadal
failure or malignancies. In addition, the rate of significant
infections, as defined earlier, was determined.
Analysis
All clinical, laboratory, radiographic and score data were entered
into a designated pSLE Access

database (Microsoft Cor-

poration, Seattle, WA, USA). Baseline demographic data were
compared using descriptive statistics. As current therapies of
Classes III and IV nephritis include the use of an immunosup-
pressive agent, statistical comparisons included patient data of the
AZA and CYCLO cohorts exclusively.
KaplanMeier survival analysis. Time to renal flare was
plotted for the AZA and CYCLO groups using KaplanMeier
curves. Both groups were compared in an unadjusted analysis
using the log-rank statistic. An adjusted analysis (comparing pairs
of patients matched by propensity score, N9 pairs) for time to
renal flare was performed using Cox proportional hazards
regression.
Propensity score matching. A propensity score was generated
in order to balance covariates and reduce unobserved selection
bias between AZA- and CYCLO-treatment cohorts. The method
adjusts for confounding by intent (which, if it occurred, might
have led to a group of more severely affected pSLE patients being
allocated preferentially to one of the treatment protocols). To
determine the propensity score (which is the probability, based on
baseline disease and demographic features, that any given patient
will be treated with CYCLO), we identified clinically and/or
statistically important baseline features that may have differed
between the treatment groups. The variables included in the final
propensity score equation were: (i) demographics and baseline
characteristics: age at pSLE diagnosis, gender, time to nephritis/
ARF, age at ARF pSLE diagnosis; (ii) comorbidities: CNS
lupus; (iii) renal function at diagnosis: dialysis requirement,
hypertension, creatinine (CRE), ALB, P:CR, uPRO; (iv) disease
activity: SLEDAI and ECLAM; (v) laboratory pSLE markers:
ESR, CRP, C3, C4, HGB, WBC and PTL; and (vi) SLE serology
ANA and dsDNA.
Using a logistic regression model with these variables as
predictors, we determined the predicted probability that any
individual patient would be treated with CYCLO (JMP 5.0.1.2,
2004 SAS Institute Inc. Cary, NC, USA). The logistic model
predicted well which treatment group a patient would be in (area
under the receiver operating curve of 0.89). Each patient who
received CYCLO was matched to the patient in the AZA group
with the closest propensity score. For all study outcomes an
intention to treat approach was chosen.
Results
Patients and treatment cohorts
The ARF cohort consisted of 50 patients, of whom 33 received
AZA plus corticosteroids (AZA cohort), 9 CYCLO plus
corticosteroids (CYCLO cohort) and 8 corticosteroids only
(STE cohort). There were 13 boys and 37 girls (1: 2.8). The
median age at diagnosis of pSLE was 13.4 yrs (range 3.119.3 yrs).
ARF and nephritis was present at the time of diagnosis of pSLE in
37 of the 50 patients (74%), 5 patients developed nephritis and
renal failure within the first year following diagnosis of pSLE
(total of 84% within the first year), another 7 patients (14%)
within 25 yrs and 1 patient after 11.7 yrs of disease. The median
follow-up time following renal failure for the total cohort was
4.5 yrs (Table 1).
Demographics and baseline characteristics
All 50 patients had a kidney biopsy performed, which revealed
Class IV lupus nephritis (diffuse proliferative lupus nephritis,
DPLN) in 68% and Class III lupus nephritis (focal proliferative
lupus nephritis, FPLN) in 32%. In the AZA cohort, 79% had
Class IV nephritis as compared with 89% of the CYCLO patients
(Table 1).
Comparison of other baseline demographic characteristics for
AZA vs CYCLO cohort revealed no significant differences except
for presence of CNS disease: 56% of the CYCLO cohort had
concurrent CNS disease as compared with 21% in the AZA
cohort (P0.02).
The AZA and CYCLO comparison revealed that both cohorts
had similar markers of disease activity and severity as measured
by SLEDAI score, rate of children requiring dialysis and
percentage of patients with hypertension prior to initiation of
treatment (Table 1). Overall, 12% of patients required dialysis at
the time of diagnosis of ARF. Hypertension was present in 34%
of the total ARF cohort prior to treatment (Table 1).
Laboratory parameters. At the diagnosis of ARF all patients
had a high ESR and low C3 complement levels. Anaemia was
found in 100%, leucopenia in 57% and thrombocytopenia in 22%
of patients at the time of diagnosis of ARF. Positive anti-DNA
antibodies were seen in 97%. There was no statistically significant
difference comparing the frequencies of all laboratory baseline
parameters between AZA and CYCLO cohorts (Fig. 1).
Outcomes
(i) Primary outcome
Renal function:
(1) overall renal survival: overall renal survival of
paediatric lupus nephritis patients with ARF was
excellent at 92% and similar for the AZA [97%, one
death, patient with ESRD] and CYCLO cohort
(89%, one patient with ESRD) (P0.38, NS). Two
patients (25%) developed ESRD in the STE cohort.
Six patients required dialysis at the time of
presentation with ARF (three in the AZA cohort,
one in the CYCLO cohort and two in the STE
cohort). Following treatment, all patients were able
to stop dialysis at a mean of 7.7 months (range 313
months).
(2) Renal function parameters: normal serum creatinine
at last follow-up visit was seen in 43 patients (86%)
overall. There was no statically significant differ-
ence between AZA patients (91%) and CYCLO
patients (78%, P0.28, NS). In addition, there was
no difference in time to response for all other renal
function markers. At 6 months, overall only 13
patients (26%) continued to demonstrate protei-
nuria (27% of AZA and 33% of CYCLO patients).
Comparison of renal function parameters is shown
in Fig. 1.
(3) Renal flares: identical flare rates of 45.4 and 44%
were seen for the AZA and CYCLO cohorts. All
patients in the STE cohort experienced a renal flare.
The median time to flare for the STE cohort was
12.2 months.
(4) Time to renal flare: there was no statistically
significant difference in time to flare analysis
comparing AZA vs CYCLO with the median time
to flare being 35.8 months for the AZA cohort and
178 S. M. Benseler et al.

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19.6 months for CYCLO (P0.15, NS) (Fig. 2).
Interestingly, one of the nine CYCLO patients
flared while still on treatment with CYCLO, three
patients were off CYCLO at the time of renal flare.
After adjusting for the potential confounding
variables using the propensity score, the matched
time to flare analysis suggested that AZA patients
were less likely to flare (risk ratio 0.27; 95% CI
0.038, 0.92; P0.03).
(ii) Secondary outcomes
(a) Disease activity:
(1) Inflammatory markers: comparison of change in
inflammatory markers and lupus serology did not
reveal a statistically significant difference between
AZA and CYCLO cohorts (Fig. 1). Inflammatory
markers improved in all treatment cohorts. At 6
months, the ESR remained elevated in 41% of AZA
and 44% of CYCLO patients. There was a trend for
faster improvement of C3 complement levels in
the AZA group. Anti-DNA antibodies remained
positive in 68% of AZA patients and 44% of
CYCLO patients at 6 months.
(2) Disease activity scores: the mean disease activity
over time, as measured by mean SLEDAI per day,
was similar for all cohorts: 4.0 for AZA, 3.9 for
CYCLO and 4.1 for STE. The SLEDAI disease
activity score at last follow-up was similar for AZA
and CYCLO cohorts at 2.0 and 1.4, respectively.
The STE cohort maintained a slightly higher mean
SLEDAI of 4.2.
(3) Corticosteroids: the mean annual prednisone doses
were not statistically significantly different between
the groups at 11.8 g for the AZA cohort and 10.8 g
for the CYCLO. However, patients in the STE
cohort received an average of 16.1 g of prednisone
per year. All results are summarized in Table 2.
(b) Disease damage
Overall disease-related damage, as measured by the SLICC-DI,
at last follow-up was similar in all cohorts (0.9 for AZA, 1.8 for
CYCLO and 1.5 for STE cohort).
(1) Overall renal damage including decreased glomer-
ular filtration rate <50%, increased proteinuria on
TABLE 1. Characteristics of pSLE patients presenting in ARF
ARF study cohort AZA cohort CYCLO cohort STE cohort
Number of patients 50 33 9 8
Sex; male : female 13 : 37 10: 23 2: 7 1: 7
Age at diagnosis of pSLE, median (range), yrs 13.4 (3.119.3) 13.0 (3.119.3) 15.1 (9.617.1) 11.9 (6.216.6)
Median age at presentation ARF, yrs 13.5 13.2 15.6 13.3
Interval pSLE diagnosis to RF, yrs 011.6 011.6 01.9 04.7
Mean follow-up, months 56.4 47.6 39.6 72.5
Biopsy Class III lupus nephritis
a
16 (32%) 9 (21%) 1 (11%) 6 (75%)
Biopsy Class IV lupus nephritis
a
34 (68%) 24 (79%) 8 (89%) 2 (25%)
CNS involvement 17 (34%) 7 (21%) 5 (56%) 5 (63%)
SLEDAI at time of RF (SLEDAI range) 20.8 (740) 17.5 (834) 22.9 (1240) 24.9 (734)
Dialysis, n (%) 6 (12) 3 (9) 1 (11) 2 (25)
Hypertension, n (%) 17 (34) 12 (35) 3 (33) 2 (25)
a
Histology according to WHO Lupus Nephritis Classification [34].
Months
followed
0 12 24 36 48 60 72 84 96
No. at risk 42 39 35 31 29 29 29 29 29
AZA 33 31 29 26 24 23 23 23 23
CYCLO 9 8 6 5 5 5 5 5 5
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FIG. 2. KaplanMeier survival analysis of time to renal flare of pSLE patients
presenting in renal failure: comparison of AZA vs CYCLO treatment cohorts. Flare-
free survival rate is shown on the y-axis and time (in months) on the x-axis. The
analysis, adjusted for potential unobserved bias after performing propensity score
methods, did not reveal any statistically significant difference in time to renal flare
between AZA and CYCLO treatment cohorts.
0
10
20
30
40
50
60
70
80
90
100
RF diagnosis 3 months 6 months last follow-up
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P=0.56
P=1.0
P=0.69
P=0.70
P=0.17
P=0.38
P=1.0
P=0.46
P=0.40
% patients with proteinuria AZA
% patients with proteinuria CYCLO
% patients with elevated ESR AZA
% patients with elevated ESR CYCLO
% patients with low C3 complement AZA
% patients with low C3 complement CYCLO
FIG. 1. Resolution of proteinuria, elevated ESR and C3 hypocomplementaemia in
the AZA and CYCLO cohorts. Time in months is shown on the x-axis and
percentage of patients on the y-axis. Similar response rates for resolution of
proteinuria, elevated ESR and C3 hypocomplementaemia were seen for AZA and
CYCLO cohorts.
Outcome of acute renal failure in pSLE 179

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24 h (53.5 g/24 h) or ESRD were seen in 11% of
CYCLO and 6% of AZA patients with one patient
each in the AZA and CYCLO cohort developing
ESRD. Only one patient in each cohort had severe
persistent proteinuria (>3.5 g/day).
(2) Bone damage was the most common SLICC-DI
item detected with AVN in 18% of the total cohort,
recurrent AVN in 10% and osteoporosis with
vertebral fracture in 12% of patients. The two
cohorts had similar rates for all three of these
markers of bone damage.
(3) Eye damage: cataracts were present in 29% of all of
the patients with similar rates of 26 and 33% for the
AZA and CYCLO cohorts, respectively (Table 3).
(c) Treatment safety
None of the patients developed IDDM, malignancies
or premature gonadal failure. Significant infections,
including herpes zoster and pnaeumonia, were seen
overall in nine patients. These were present in 12% of
AZA and 23% of CYCLO patients (difference between
the AZA and CYCLO cohort was not statistically
significant) and in 38% of STE patients (Table 3).
Discussion
This is the first comprehensive study analysing the outcome of
paediatric lupus patients in ARF. We found that the overall renal
survival is in fact excellent at 92%. When comparing CYCLO
pulse therapy and oral AZA treatment both therapies were equally
efficacious. The outcome of both cohorts was similar with regards
to renal survival, renal flare rate, control of disease activity over
time, cumulative steroid doses and damage.
The number of paediatric lupus nephritis studies is limited.
There is significantly more information available regarding adult
lupus nephritis treatment and outcome. However, one criticism of
reports to date is that the majority of patients enrolled in lupus
nephritis trials did not, on the whole, have significant impairment
of renal function [1417]. Our study has analysed and compared
the outcome of two different immunosuppressive treatments for
paediatric patients with Class III or IV lupus nephritis who
developed renal failure. We found that CYCLO pulse therapy and
oral AZA treatment were equally efficacious for treatment of
renal failure in pSLE. The outcome of both cohorts was equal
with regards to overall renal survival, renal flare rate, control of
disease activity over time, cumulative steroid doses and evidence
of damage. Comparison of treatment safety in both cohorts did
not reveal a statistically significant difference; however, overall
there was a trend for an increased rate of infection in the group
that received CYCLO.
The treatment of severe paediatric lupus nephritis is contro-
versial. Treatment decisions for lupus nephritis are generally
directed by the histological classification on the kidney biopsy, as
proliferative glomerulonephritis has been shown to be associated
with the highest risk of renal failure and ESRD [8, 12, 26]. Most
paediatric and adult centres have treated patients with Class III or
IV nephritis with a 3-yr course of intravenous pulse CYCLO
[10, 17]. Recent publications suggest that an induction/
maintenance protocol of CYCLO for 36 months followed by
AZA or mycophenolate mofetil for maintenance, lower doses of
intravenous CYCLO and mycophenolate mofetil initiation
therapy may all be as efficacious and safer than the long-term
cyclophosphamide protocol [9, 2628]. Both uncontrolled paedia-
tric studies and a recent meta-analysis have shown that AZA is
efficacious in the treatment of proliferative lupus nephritis [12, 13,
29, 30]. In our centre, corticosteroids and AZA have been the
preferred-treatment regimen for severe lupus nephritis with or
without renal failure, while CYCLO therapy is predominantly
used in children with concurrent CNS disease or AZA intolerance.
This practice explains the greater numbers of patients treated with
AZA compared with CYCLO in our study cohort. In order to be
able to compare both treatment regimens and to overcome the
TABLE 3. Damage and treatment utilizing the SLICC-DI and its domains
AZA cohort N33 CYCLO cohort N9 STE cohort N8 AZA vs CYCLO
Damage score SLICC DI at last follow-up, mean (range) 0.9 (04) 1.8 (05) 1.5 (03) NA
Renal damage
Patients with proteinuria, n (%) 1 (3) 1 (11) 1 (12.5) 0.38; NS
Patients with overall renal damage, n (%) 2 (6) 3 (33) 1 (12.5) 0.06; NS
Bone damage
Patients with AVN, n (%) 5 (15) 2 (22) 2 (25) 0.62; NS
Patients with more than one episode of AVN, n (%) 3 (9) 1 (11) 1 (12.5) 1.00, NS
Patients with osteoporosis and vertebral fracture, n (%) 3 (9) 1 (11) 2 (25) 1.00; NS
Other damage
Patients with cataracts, n (%) 9 (26) 3 (33) 3 (38) 0.69; NS
Patients with IDDM, malignancy or gonadal failure, n 0 0 0 NA
Treatment safety
Patients with significant infections, n (%) 4 (12) 2 (23) 3 (38) 0.59; NS
NA: not applicable; NS: not significant.
TABLE 2. Treatment efficacy utilizing the SLEDAI and its domains
AZA cohort N33 CYCO cohort N9 STE cohort N8 AZA vs CYCLO* P
Overall renal survival, n (%) 32 (97) 8 (89) 6 (75) 0.38; NS
Normal creatinine at last follow-up, n (%) 30 (91) 7 (78) 6 (75) 0.28; NS
Disease activity, AMS/day, mean (range) 4.0 (0.98.3) 3.9 (0.96.6) 4.1 (2.16.4) 0.89; NS
Patients with renal flares, n (%) 15 (45.4) 4 (44.0) 8 (100) 1.00; NS
Time RF to renal flare in months (range) 35.8 (7.6126.6) 19.6 (11.526.4) 12.2 (5.016.0) 0.15, NS
Disease activity (SLEDAI) at last follow-up (range) 2.0 (04) 1.4 (03) 4.2 (020) 0.36; NS
Annual steroid dose, g, mean (range) 11.8 (6.218.11) 10.7 (6.216.6) 16.1 (14.823.8) 0.62; NS
*Analysis: Students t-test for mean/median age at diagnosis and follow-up; Fishers exact test for gender, NS not significant.
180 S. M. Benseler et al.

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confounding by intent, the propensity score method was utilized.
After accounting for all potential differences including CNS
disease by propensity score analysis, the data suggest that pSLE
patients treated with AZA in fact were less likely to flare
compared with those treated with CYCLO. Apart from renal
flares, we did not find any clinically relevant or statistically
significant difference in the outcome of patients treated with AZA
as compared with those treated with CYCLO [31, 32].
The overall renal survival was excellent for patients treated
with AZA (97%) and for those treated with CYCLO (89%).
However, a significant number of patients flared. CYCLO and
AZA treatment regimens of pSLE nephritis and ARF had
identical renal flare rates of 45%. This flare rate was identical to
the flare rate of a large cohort of adult patients with lupus
nephritis treated with the standard regimen of intravenous pulse
CYCLO [16]. Comparison of the AZA and CYCLO groups
showed that disease activity was equally well controlled over time.
All patients who required dialysis at presentation of ARF were
able to discontinue dialysis and had a normalization of their renal
function. Cumulative annual steroid doses were similar in both
groups. These findings demonstrate that both treatment regimens
were equally effective for the SLE nephritis patients, who required
dialysis at time of renal failure presentation.
Both treatment regimens were associated with low rates of
severe renal damage. In addition, the rates of bone damage,
avascular necrosis and osteoporosis with vertebral fracture, and
cataracts were comparable in both cohorts. None of the patients
in either group developed diabetes mellitus, a malignancy or
premature gonadal failure.
The most important limitation of this study is the study design.
An observational study in contrast to a randomized controlled
trial design is commonly affected by various sources of bias
including ascertainment bias. However, as demonstrated by
DAgostino [33], propensity score methods are a valid and
efficacious way to adjusted for unobserved bias including all
patient and disease characteristics that could effect treatment
decisions. This technique allows the inclusion of all given
consecutive patients into the analysis and may therefore reflect
reality and diversity of patient care and reality of treatment
efficacy and safety. Propensity score analysis defined the
differences between the two treatment groups and adjusted the
outcome analysis for these differences. The robustness of our data
is supported by our finding of no difference between the treat-
ment groups using a standardized set of markers of disease
activity and damage. A second limitation of the study is the
unbalanced treatment groups as only 9 patients received CYCLO
while 33 received AZA. This shortcoming was unavoidable, as
the standard of care in our centre for proliferative lupus nephritis
is AZA rather than CYCLO. Again, propensity score analysis
helped overcome this potential problem. The last limitation is that
this is a single centre experience from a large tertiary referral
centre. However, it is very likely that all paediatric patients with
SLE and renal failure within our catchment area will be seen at
our centre.
The treatment of ARF in this paediatric lupus nephritis cohort
was associated with an excellent outcome. AZA and CYCLO in
addition to standard corticosteroid therapy were equally effica-
cious for the control of disease activity, overall renal outcome and
renal survival; prevention of renal flares and the cohorts had
similar disease damage scores. We therefore conclude that AZA
and CYCLO are effective in paediatric patients with proliferative
lupus nephritis complicated by significant acute renal insuffi-
ciency. Given the side-effect profiles of the two agents, risk
benefit analysis and the propensity score analysis suggest that
AZA should be strongly considered for the management of
patients with lupus nephritis, even in patients with significant
renal impairment requiring dialysis.
Disclosure statement: The authors have declared no conflicts of
interest.
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