Nephrol Dial Transplant (2011) 26: 178–184
doi: 10.1093/ndt/gfq405
Advance Access publication 7 July 2010
Long-term effects of cyclophosphamide therapy in steroid-dependent
or frequently relapsing idiopathic nephrotic syndrome
Benoît Cammas1,4,*, Jérôme Harambat1,*, Aurélia Bertholet-Thomas2, François Bouissou3,
Denis Morin4, Vincent Guigonis5, Salih Bendeddouche6, Nawel Afroukh-Hacini7, Pierre Cochat2,
Brigitte Llanas1, Stéphane Decramer3 and Bruno Ranchin2
1
Centre Hospitalier Universitaire de Bordeaux, Service de Pédiatrie, Centre de référence Maladies Rénales Rares du Sud Ouest,
Bordeaux, France, 2Hospices Civils de Lyon, Service de Néphrologie et Rhumatologie Pédiatriques, Centre de référence Maladies
Rénales Rares, Bron, France, 3Centre Hospitalier Universitaire de Toulouse, Service de Pédiatrie, Centre de référence Maladies
Rénales Rares du Sud Ouest, Toulouse, France, 4Centre Hospitalier Universitaire de Montpellier, Service de Pédiatrie, Centre de
référence Maladies Rénales Rares du Sud Ouest, Montpellier, France, 5Centre Hospitalier Universitaire de Limoges, Service de
Pédiatrie, Centre de référence Maladies Rénales Rares du Sud Ouest, Limoges, France, 6Centre Hospitalier Universitaire de Tlemcen,
Service de Pédiatrie, Tlemcen, Algeria and 7Centre Hospitalier de Valence, Service de Pédiatrie, Valence, France
Correspondence and offprint requests to: Jérôme Harambat; E-mail: [email protected]
*
BC and JH contributed equally to this work.
Abstract
Background. It has been demonstrated that alkylating
agents such as cyclophosphamide (CYP) are effective in
reducing the risk of relapse in frequently relapsing (FRNS)
and steroid-dependent nephrotic syndrome (SDNS). Little
is known about prognostic factors in SDNS and FRNS
treated by CYP. The objectives of this study are to determine long-term outcomes and factors associated with sustained remission in these patients.
Methods. We retrospectively studied the data from 143
children (104 boys) with SDNS and FRNS treated with
CYP in six centres over 15 years. Relapse-free survival
was estimated by Kaplan–Meier method. The determinants of long-term remission were assessed by univariate
and multivariate analyses using Cox proportional hazard
models.
Results. Median age at diagnosis was 3.7 years (interquartile range: IQR 2.3–5.9), and median follow-up was
7.8 years (IQR 4.0–11.8). CYP treatment was introduced
after a median time of 1.7 years (IQR 0.7–5.9) after diagnosis. Patients received a median cumulative dose of
168 mg/kg (IQR 157–197) body weight. Relapse-free survival was 65%, 44%, 27% and 13% after 6 months, 1 year,
2 years and 5 years, respectively. In multivariate analysis,
sustained remission >2 years was associated with age at
treatment >5 years (P = 0.02) and cumulative dose of
CYP >170 mg/kg (P = 0.02). Frequently relapsing versus
steroid-dependent status and female gender were predictors of borderline significance. Height and body mass
index standard deviation score were significantly influenced by CYP treatment.
Conclusion. In our study, long-term efficacy of cyclophosphamide in steroid-responsive nephrotic syndrome is dis-
appointing. Further well-designed trials are required to
evaluate the efficacy of other steroid-sparing agents.
Keywords: cyclophosphamide; growth; idiopathic nephrotic syndrome;
steroids
Introduction
Idiopathic nephrotic syndrome (NS) is the most frequent
glomerular disease in childhood, with reported incidence
varying from two to seven cases per 100,000 children [1].
Most patients are steroid responsive, achieving complete
remission, but about 70% will relapse [2]. Of those, 60%
relapse frequently or become steroid-dependent [2]. In
patients with frequently relapsing nephrotic syndrome
(FRNS) or steroid-dependent nephrotic syndrome (SDNS),
side effects of steroids can occur, including growth failure,
obesity, hypertension, osteoporosis and ocular complications. To reduce the degree of steroid dependency and avoid
steroid toxicity, several non-steroid immunosuppressive
agents have been proposed to treat these children [3].
Cyclophosphamide (CYP) has been used since the early
1970s in the treatment of NS [4], especially in individuals
with marked steroid side effects. CYP has been known to
reduce relapse frequency and to induce long-term remission. According to a meta-analysis including 102 children
from three trials performed in children with relapsing
steroid-sensitive NS, CYP in comparison with prednisone
alone results in a significant decreased risk of relapse at
6–12 months (relative risk 0.44, CI 0.26–0.73) [5]. However, the use of daily CYP treatment has been associated
with bone marrow depression, increased susceptibility to in-
© The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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Long-term effects of CYP therapy in SDNS or FRNS
179
Table 1. Population characteristics
Table 2. Therapeutic strategies used in the population
Variables
S1
Median (IQR) age at diagnosis, years
Male, n (%)
Renal pathology, n (%)
MCD
FSGS
DMP
Median (IQR) time to first
relapse from diagnosis, months
Median (IQR) total number of
relapse before CYP
Median (IQR) dose of prednisone
before CYP, mg/kg/day
Indication of treatment by CYP, n (%)
Steroid dependency
Adverse steroid effects
Frequent relapses
Median (IQR) time to CYP from
diagnosis, years
Median (IQR) age at start of CYP, years
Median (IQR) cumulative
dose of CYP, mg/kg
Patient without relapse after CYP, n (%)
Median (IQR) follow-up duration, years
Median (IQR) age at last follow-up, years
3.7
104
81
66
12
3
4.0
4
(2.3–5.9)
(73%)
(81%)
(15%)
(4%)
(2.2–7.0)
(3–8)
0.7
(0.4–1.0)
143
86
36
21
1.7
(60%)
(25%)
(15%)
(0.7–5.9)
7.9
168
(4.6–11.2)
(157–197)
29
7.8
12.8
(20%)
(4.0–11.8)
(9.1–16.3)
CYP alone
IS before CYP
Lev
Lev
Lev
CsA
CsA
Others
IS after CYP
CYP
CYP
CYP
CYP
Others
S2
CYP
CYP
CYP
CYP
CYP
Lev
MMF
CsA
CsA
S3
MMF
CsA
MMF
MMF
S4
MMF
n
%
55
38
9
4
4
3
10
8
50
5
15
13
12
5
38
27
35
S1, step 1; S2, step 2; S3, step 3; S4, step 4; CYP, cyclophosphamide;
CsA, cyclosporine A; IS, immunosuppressive agent; Lev, levamisole;
MMF, mycophenolate mofetil.
Definitions
CYP, cyclophosphamide; IQR, interquartile range; MCD, minimal change
disease; FSGS, focal segmental glomerulosclerosis; DMP, diffuse mesangial proliferation.
fections, haemorrhagic cystitis, alopecia and, in long term,
sterility or increased risk of malignancy [6]. These side effects of CYP have led to the use of other steroid-sparing
agents such as levamisole (Lev) [7], cyclosporine (CsA)
[8,9], mycophenolate mofetil (MMF) [10,11] and, more recently, rituximab [12]. Due to the potential nephrotoxicity
of CsA and the lack of evidence for efficacy of Lev, MMF
and rituximab, CYP is still commonly used as the first-line
non-steroid agent in SDNS and FRNS. In a meta-analysis,
the remission rate of NS at 5 years after CYP was found to
be rather low, ranging from 24% to 36% [6]. Some potential determinants like steroid dependency, age <5.5 years at
diagnosis, male sex and absence of leukopaenia during
treatment have been associated with a lower efficacy of
CYP [13]. However, limited data exist about its long-term
efficacy, and identification of a target population who may
benefit from CYP treatment remains a challenge for paediatric nephrologists. The objectives of this study are to
evaluate the long-term results of CYP treatment and to
identify parameters that might predict CYP efficacy.
Materials and methods
Study population
We performed a retrospective multicentre cohort study, including 143
children with idiopathic nephrotic syndrome according to the criteria of
the International Study of Kidney Diseases in Children [1]. Patients were
followed in six different French-speaking centres (Bordeaux, Limoges,
Lyon, Montpellier, Tlemcen and Toulouse) and have been treated by
CYP in the period 1993–2008. The recommended dose of CYP was 2
to 2.5 mg/kg/day of oral CYP over 10 to 12 weeks. The goal of the treatment was to stop corticosteroids within 2 months following the end of
CYP therapy. Patients treated with another alkylating agent prior CYP
treatment were excluded from the study.
All patients were steroid responsive at initial presentation and were treated
according to the guidelines of the French Society for Pediatric Nephrology [14]. Relapses were treated with prednisone 60 mg/m2/day until urinary remission, followed by alternate-day prednisone for 4 months. Steroid
dependency was defined as at least two relapses during alternate-day
treatment with prednisone or within 14 days after stopping this treatment
[14]. Frequent relapses were defined as two relapses during 6 months or
three relapses in 1 year. Clinical remission was defined as zero to trace
albuminuria on dipstick on five consecutive days. For the analysis, we
defined a sustained remission as a relapse-free period for 2 years or more
since CYP treatment.
Data collection
Age at onset of disease, clinical characteristics of initial episode of NS,
renal histology, time of relapses, use of other immunosuppressive treatments (Lev, MMF, CsA) and dose of prednisone before CYP introduction
were recorded. Treatment duration and cumulative dose of CYP were calculated. The cumulative dose of CYP and the dose of prednisone at CYP
introduction were transformed into binary variables according to the median values (i.e. 170 mg/kg and 0.75 mg/kg/day, respectively). Height and
body mass index (BMI) were recorded at diagnosis, at start of CYP, at the
first relapse after CYP and at last follow-up. Height and BMI were transformed into standard deviation score (SDS) according to national reference curves [15,16].
Statistical analyses
Data are presented as mean ± SD (standard deviation) or median and
interquartile range (IQR) for continuous variables and percentages for categorical variables. Kaplan–Meier analysis was performed to estimate the
relapse-free survival since the start of CYP. The end point was the time of
first relapse after CYP censored at last available follow-up. Comparisons
between subgroups were done using a logrank test. In order to evaluate
factors associated with a sustained remission after CYP treatment, a Cox
proportional hazard model was established using a backward stepwise
procedure. The Wilcoxon rank sum test was used to compare the height
and BMI SDS variations before and after CYP. Statistical analysis was
performed using the SAS 8.2 software (SAS Institute, Carry, USA).
Results
Population characteristics
Data from 143 patients (104 boys and 39 girls) with FRNS
or SDNS treated with CYP have been analysed. Median
relapse-free survival
180
B. Cammas et al.
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
6
12
18
24
30
36
42
48
54
60
48
54
60
follow-up after CYP (months)
relapse-free survival
Fig. 1. Relapse-free survival after cyclophosphamide treatment.
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
6
12
18
24
30
36
42
follow-up after CYP (months)
age at CYP > 5 years
age at CYP < 5 years
Fig. 2. Relapse-free survival according to age at cyclophosphamide treatment (P = 0.01).
duration of follow-up was 7.8 years (4.0–11.8). Diagnosis
was made at a median age of 3.7 years (IQR 2.3–5.9).
When a renal biopsy was performed (n = 81), histological
analysis showed minimal change disease, focal and segmental glomerulosclerosis and diffuse mesangial proliferation in 81%, 15% and 4% of cases, respectively. CYP was
introduced after a median total number of four relapses
(IQR 3–8) and a median time of 1.7 years (IQR 0.7–5.9).
The median cumulative dose of CYP was 168 mg/kg (IQR
157–197). The main indication reported for CYP treatment
was steroid dependency or frequent relapses in 75% of
patients and steroid toxicity in 25%. Patients’ characteristics
are summarized in Table 1. In 88 patients (62%), another
immunosuppressive agent was used before (43%) or after
(57%) treatment by CYP. CsA (n = 54) was introduced after
a median time of 1.1 years (IQR 0.5–3.2) after diagnosis,
whereas MMF (n = 54) was started 5.8 years (3.3–10.4)
after diagnosis. Table 2 summarizes the different treatment
strategies.
Relapse-free survival and factors associated with sustained
remission
Median time to steroid withdrawal since CYP treatment
(n = 132) was 10 months (IQR 3–34). In the subgroup
of patients who had just received CYP and no other immunosuppressive drugs (n = 55), the median time to steroid
withdrawal was 5 months (range 1–48). Ongoing remission
after CYP was obtained in 29 of 143 patients (20.5%) after
a median follow-up of 1.9 years (range 3 months to 7 years).
According to Kaplan–Meier estimator, the cumulative relapse-free survival was 65% (CI 58–71), 45% (CI 35–55),
28% (CI 15–41), 13% (CI 0–26) and 11% (CI 0–22) at
6 months, 1 year, 2 years, 5 years and 10 years after treatment with CYP, respectively (Figure 1). The median survival between start of CYP treatment and first relapse
post CYP was 10 months (Figure 1).
In univariate analysis, the occurrence of sustained remission after CYP was not influenced by age at diagnosis
(P = 0.32). Nevertheless, age <5 years at the introduction
of CYP treatment was highly correlated with an increased
risk of relapse (P = 0.01) (Figure 2). The cumulative rate
of remission was lower in boys than girls although not
significantly (P = 0.13). Children with biopsy-proven
minimal change disease had a significantly higher relapse-free survival (P = 0.02) than children with another
underlying pathology. Children who were treated by CYP
beyond the first year after disease onset were more likely
to remain relapse-free (P = 0.02), as were children who received a cumulative dose of CYP >170 mg/kg (P = 0.02)
and those with a low degree of steroid dependency (prednisone dose <0.75 mg/kg/day at time of CYP) (P = 0.02)
(Figure 3). Moreover, the median time without relapse after
CYP treatment was 15 months in FRNS vs 8 months in
relapse-free survival
Long-term effects of CYP therapy in SDNS or FRNS
181
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
6
12
18
24
30
36
42
48
54
60
follow-up after CYP (months)
prednisone < 0.75 mg/kg/day
prednisone > 0.75 mgg/kg/day
relapse-free survival
Fig. 3. Relapse-free survival according to prednisone dose at cyclophosphamide treatment (P = 0.02).
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
6
12
18
24
30
36
42
48
54
60
follow-up after CYP (months)
FRNS
SDNS
Fig. 4. Relapse-free survival according to steroid-dependent or frequently relapsing nephrotic syndrome status (P = 0.10).
SDNS (P = 0.10) (Figure 4). The order of CYP introduction
before or after use of other immunosuppressive agents was
not a predictor of sustained remission (P = 0.25).
As the exposure variables prednisone dose at CYP
introduction and frequently relapsing vs steroid-dependent
status were highly collinear, we decided to choose the
variable FRNS vs SDNS for inclusion in the multivariable model because of its clinical relevance. In the final
Cox multiple regression model (Table 3), factors which
remained significantly associated with sustained remission after treatment were cumulative dose of CYP
>170 mg/kg (P = 0.02) and age at CYP treatment
>5 years (P = 0.03). FRNS vs SDNS (P = 0.05) and female sex (P = 0.06) were predictors of sustained remission
of borderline significance.
Table 3. Factors associated with sustained remission after cyclophosphamide treatment in a Cox regression multivariate analysis
Variables
P
HR
CI 95%
Female gender
Age at treatment >5 years
FRNS vs SDNS
Cumulative dose of CYP >170 mg/kg
0.06
0.03
0.05
0.02
1.60
1.58
1.72
1.63
[0.97–2.61]
[1.03–2.44]
[0.99–2.98]
[1.08–2.49]
CI, confidence interval; CYP, cyclophosphamide; HR, hazard ratio.
Evolution of height and body weight
Linear growth showed a significant decrease between diagnosis of nephrotic syndrome and CYP introduction, with a
median decrease from 0.2 to −0.5 SDS (P < 0.01) over a
median duration of 20 months (Figure 5). From start of
CYP treatment to the first relapse after CYP, median
height increased significantly from −0.5 to −0.1 SDS
(P < 0.01) over a median duration of 11 months. However, height SDS at last follow-up was not significantly
different from height SDS at time of CYP (Figure 5).
Median BMI increased significantly from 0.9 to 1.6 SDS
(P < 0.01) between diagnosis and CYP introduction.
After using CYP treatment, BMI decreased significantly
to 0.9 SDS (P < 0.01) and remained stable afterwards
(Figure 6).
Discussion
We conducted a retrospective multicentre study describing
the long-term clinical course of a large cohort of patients
with NS treated with oral CYP. More than half of children
experienced relapse during the first 12 months following
the CYP course, and only 20% of children achieved a prolonged remission. The overall long-term success rate after
CYP treatment in our study is disappointing and globally
182
B. Cammas et al.
P < 0.05
NS
4
3
2
Height SDS
1
0
-1
-2
-3
-4
-5
Diagnosis
First relapse after CYP
Start of CYP
Time
Median age, years (IQR)
Diagnosis
Start of CYP
Last follow-up
First relapse after CYP Last follow-up
3.7 (2.3 ; 5.9)
7.9 (4.6 ; 11.2)
9.4 (5.6 ; 12.9)
12.8 (9.1 ; 16.3)
Median height, SDS (IQR) 0.2 (- 0.5 ; 1.2)
- 0.5 (-1.3 ; 0.4)
- 0.1 (- 1.0 ; 0.7)
- 0.4 (- 1.4 ; 0.4)
Fig. 5. Evolution of height SDS before and after start of cyclophosphamide.
worse than reported in other studies [12,17]. Vester et al.
have reported a relapse-free survival of 44%, 34% and
24% at 1, 2 and 10 years after CYP in a cohort of 94 children with biopsy-proven minimal change disease [12]. In a
cohort of 93 Dutch patients with biopsy-proven minimal
change disease, 33 (35%) never experienced relapse after
the first course of CYP [17]. It cannot be assessed, however, whether these populations and ours are comparable
in terms of disease severity before CYP course. Given the
potential adverse effects of CYP, more data on predictors
of remission are needed to identify early those children
who might benefit from this treatment. We identified several factors associated with a sustained remission. The
negative impact of male gender has already been reported
by others [6]. We found, as expected, that the risk of relapse was higher in the group of patients with SDNS
compared with patients with FRNS before CYP course.
Moreover, the use of CYP before 5 years of age was associated with a considerable risk of relapse. The relapse-free
survival in this subgroup was 50% at 6 months and only
29% at 12 months after CYP, and this result remained significant after adjusting for potential confounding variables
(sex, SDNS vs FRNS, cumulative dose of CYP and timing
of CYP introduction). This finding suggests that CYP is of
limited interest in the early years of NS when the disease
activity is higher. The rate of remission was also significantly associated with a cumulative dose of CYP
of >170 mg/kg. This is in contrast with a previous study
showing that cumulative dose of CYP per body surface area
but no per body weight was a predictor of sustained remission [13]. Yet, the dose-dependent effect of CYP does not
prompt to use a high dose because of the inverse correlation
between cumulative dose and spermatogenesis [18], and
the risk of definitive sterility over 200 mg/kg [5]. The systematic review of Latta et al. suggests that single courses of
CYP exceeding 2 mg/kg/day during 12 weeks and repeated
courses should be avoided [6]. We did not find a relationship
between patient age at initial presentation and incidence of
remission, whereas previous studies had suggested that
early onset of disease predisposes to a lengthy [17,19] or a
more frequently relapsing course [13,20]. Lastly, the use of
another non-steroid agent before CYP treatment did not
contribute to a better efficacy of CYP.
Severe growth retardation related to corticosteroids
effects has been widely reported in children with SDNS
and FRNS [21,22]. Catch-up growth after cessation of
steroid treatment may not be constant [23]. A major indication for using immunosuppressive treatments in NS
is the growth impairment associated with long-term steroid treatment. However, studies specifically investigating
the effect of one immunosuppressive agent on growth
and body weight in patients with SDNS or FRNS are
rare [24,25]. In a single-centre study including 60 children, CYP treatment was associated with an increase in
height SDS from −0.84 ± 0.4 to −0.28 ± 0.3 [25]. In our
study, the use of CYP had a mild but significant impact on
growth with an increase of median height SDS from −0.5
at the start of CYP treatment to −0.1 at the first relapse
Long-term effects of CYP therapy in SDNS or FRNS
183
P < 0.05
5
4
BMI Z-score
3
2
1
0
-1
-2
-3
-4
Diagnosis
First relapse after CYP
Start of CYP
Time
Diagnosis
Start of CYP
Last follow-up
First relapse after CYP Last follow-up
Median age, years (IQR) 3.7 (2.3 ; 5.9)
7.9 (4.6 ; 11.2)
9.4 (5.6 ; 12.9)
12.8 (9.1 ; 16.3)
Median BMI, SDS (IQR) 0.9 (- 0.3 ; 1.9)
1.6 (0.9 ; 2.6)
0.9 (0.3 ; 2.2)
0.9 (- 0.3 ; 1.9)
Fig. 6. Evolution of BMI SDS before and after start of cyclophosphamide.
after CYP. Moreover, we also observed an improvement of
BMI, with a significant decrease of BMI SDS from +1.6 at
the start of CYP treatment to +0.9 at the first relapse after
CYP. However, the long-term risk of obesity is high with
25% of patients having a BMI over +2 SDS at last followup. Since the decrease of prednisone dose after CYP treatment has not been systematically recorded in our study, it
must be assumed that the beneficial effect of CYP on
growth and BMI was due to the reduction of corticosteroids. In our study, steroids should have been withdrawn
within 2 months of completion of CYP. However, steroids
were stopped after a median time of 10 months after start of
CYP. Indeed, steroid withdrawal was achieved according to
protocol in about one-third of patients; relapse occurred
during CYP course or steroid decrease in one-third of patients; and steroids were not discontinued within 2 months
after the end of CYP course despite no relapse in one-third
of patients. This was likely to have an impact on post CYP
growth, as those with early steroid withdrawal experienced
better growth.
Many children with SDNS or FRNS have a long-term disease course and usually receive more than one immunosuppressive agent so that exact long-term efficacy of CYP is
difficult to appreciate. In that setting, determining the place
of CYP among the different options for the management of
steroid-sensitive nephrotic syndrome remains difficult.
However, we believe that the efficacy of CYP to obtain a
long-term remission might be limited, particularly in boys,
aged <5 years old, with a high degree of steroid dependency.
This study has some limitations. It is a retrospective multicentre study with a risk of changes in treatment modalities
during time and between centres. Moreover, the patients
have been identified from the units’databases so that the exhaustiveness cannot be ascertained. Thus, there is a possibility that the outcome may have been made to look worse than
it actually was, as some of the most favourable cases might
have been lost to follow-up. Nevertheless, we believe that
this study gives important information for clinicians with
its long-term follow-up and its large number of patients.
In conclusion, this study suggests that long-term efficacy of cyclophosphamide in steroid-responsive nephrotic
syndrome is rather disappointing. Cyclophosphamide
might not be the first-line non-steroid agent for children
with frequently relapsing or steroid-dependent nephrotic
syndrome. Further well-designed trials are required to
evaluate the efficacy of other steroid-sparing agents.
Conflict of interest statement. None declared.
References
1. Nephrotic syndrome in children: prediction of histopathology from
clinical and laboratory characteristics at time of diagnosis. A report
of the International Study of Kidney Disease in Children. Kidney Int
1978; 13: 159–165
2. Niaudet P. Steroid-sensitive nephrotic syndrome in children. In: Avner
ED, Harmon WE, Niaudet P (eds). Pediatric Nephrology. Philadelphia:
Lippincott Williams and Wilkins, 2004; 543–556
184
3. Hodson EM, Craig JC, Willis NS. Evidence-based management of
steroid-sensitive nephrotic syndrome. Pediatr Nephrol 2005; 20:
1523–1530
4. Barratt TM, Soothill JF. Controlled trial of cyclophosphamide in steroidsensitive relapsing nephrotic syndrome of childhood. Lancet 1970; 2:
479–482
5. Hodson EM, Willis NS, Craig JC. Non-corticosteroid treatment for
nephrotic syndrome in children. Cochrane Database Syst Rev 2008;
1: CD002290
6. Latta K, von Schnakenburg C, Ehrich JH. A meta-analysis of cytotoxic
treatment for frequently relapsing nephrotic syndrome in children.
Pediatr Nephrol 2001; 16: 271–282
7. British Association for Paediatric Nephrology Levamisole for
corticosteroid-dependent nephrotic syndrome in childhood. Lancet
1991; 337: 1555–1557
8. Ponticelli C, Edefonti A, Ghio L et al. Cyclosporin versus cyclophosphamide for patients with steroid-dependent and frequently relapsing
idiopathic nephrotic syndrome: a multicentre randomized controlled
trial. Nephrol Dial Transplant 1993; 3: 1326–1333
9. Ishikura K, Ikeda M, Hattori S et al. Effective and safe treatment with
cyclosporine in nephrotic children: a prospective, randomized multicenter trial. Kidney Int 2008; 73: 1167–1173
10. Dorresteijn EM, Kist-van Holthe JE, Levtchenko EN et al. Mycophenolate mofetil versus cyclosporine for remission maintenance in
nephrotic syndrome. Pediatr Nephrol 2008; 23: 2013–2020
11. Gellermann J, Querfeld U. Frequently relapsing nephrotic syndrome:
treatment with mycophenolate mofetil. Pediatr Nephrol 2004; 19:
101–104
12. Guigonis V, Dallocchio A, Baudouin V et al. Rituximab treatment for
severe steroid- or cyclosporine-dependent nephrotic syndrome: a
multicentric series of 22 cases. Pediatr Nephrol 2008; 23: 1269–1279
13. Vester U, Kranz B, Zimmermann S et al. Cyclophosphamide in
steroid-sensitive nephrotic syndrome: outcome and outlook. Pediatr
Nephrol 2003; 18: 661–664
14. Bérard E, Broyer M, Dehennault M et al. Pediatric Society of
Nephrology. Corticosensitive nephrotic syndrome (or nephrosis) in
J.J. Carrero et al.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
children. Therapeutic guideline proposed by the Pediatric Society of
Nephrology. Nephrol Ther 2005; 1: 150–156
Sempé M, Pédron G, Roy-Pernot MP. Auxologie méthode et
séquences. Théraplix Paris 1979
Rolland-Cachera MF, Cole TJ, Sempé M et al. Body mass index
variations: centiles from birth to 87 years. Eur J Clin Nutr 1991; 45:
13–21
Kyrieleis HA, Levtchenko EN, Wetzels JF. Long-term outcome after
cyclophosphamide treatment in children with steroid-dependent and
frequently relapsing minimal change nephrotic syndrome. Am J
Kidney Dis 2007; 49: 592–597
Watson AR, Rance CP, Bain J. Long term effects of cyclophosphamide on testicular function. Br Med J (Clin Res Ed) 1985; 291:
1457–1460
Fakhouri F, Bocquet N, Taupin P et al. Steroid-sensitive nephrotic
syndrome: from childhood to adulthood. Am J Kidney Dis 2003;
41: 550–557
Kabuki N, Okugawa T, Hayakawa H et al. Influence of age at onset
on the outcome of steroid-sensitive nephrotic syndrome. Pediatr
Nephrol 1998; 12: 467–470
Emma F, Sesto A, Rizzoni G et al. Long-term linear growth of children
with severe steroid-responsive nephrotic syndrome. Pediatr Nephrol
2003; 18: 783–788
Foote KD, Brocklebank JT, Meadow SR. Height attainment in children
with steroid-responsive nephrotic syndrome. Lancet 1985; 2: 917–919
Lam CN, Arneil GC. Long-term dwarfing effects of corticosteroid
treatment for childhood nephrosis. Arch Dis Child 1968; 43: 589–594
Kano K, Nishikura K, Hoshi M. Linear growth of low-dose cyclosporin
A therapy in children with steroid-dependent nephrotic syndrome.
Nephron 2001; 87: 293–294
Berns JS, Gaudio KM, Krassner LS et al. Steroid-responsive nephrotic syndrome of childhood: a long-term study of clinical course,
histopathology, efficacy of cyclophosphamide therapy, and effects
on growth. Am J Kidney Dis 1987; 9: 108–114
Received for publication: 30.11.09; Accepted in revised form: 15.6.10
Nephrol Dial Transplant (2011) 26: 184–190
doi: 10.1093/ndt/gfq397
Advance Access publication 11 July 2010
Prevalence and clinical implications of testosterone deficiency in men
with end-stage renal disease
Juan Jesús Carrero1,2,3,*, Abdul Rashid Qureshi1,*, Ayumu Nakashima1, Stefan Arver4, Paolo Parini5,
Bengt Lindholm1, Peter Bárány1, Olof Heimbürger1 and Peter Stenvinkel1
1
Divisions of Renal Medicine and Baxter Novum, 2Centre for Molecular Medicine, 3Centre for Gender Medicine, 4Centre for
Andrology and Sexual Medicine and 5Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
Correspondence and offprint requests to: Juan Jesús Carrero; E-mail: [email protected]
*Both authors contributed equally to this work.
Abstract
Background. Abnormally low serum testosterone levels
were recently associated with an increased mortality risk
in male dialysis patients. However, the prevalence of tes-
tosterone deficiency in end-stage renal disease (ESRD) is
not well defined. We hereby explore the prevalence and
correlates of clinical testosterone deficiency in a large cohort of ESRD male patients.
© The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.
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