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ORIGINAL ARTICLE
Best practice guidelines for idiopathic nephrotic syndrome:
recommendations versus reality
Andrea Pasini &Gabriella Aceto &Anita Ammenti &Gianluigi Ardissino &Vitalba Azzolina &
Alberto Bettinelli &Elena Cama &Sante Cantatore &Antonella Crisafi &Giovanni Conti &
Maria D’Agostino &Alessandra Dozza &Alberto Edefonti &Carmelo Fede &Elena Groppali &
Chiara Gualeni &Alessandra Lavacchini &Marta Lepore &Silvio Maringhini &
Paola Mariotti &Marco Materassi &Francesca Mencarelli &Giovanni Messina &Amata Negri &
Marina Piepoli &Fiammetta Ravaglia &Angela Simoni &Laura Spagnoletta &
Giovanni Montini &On behalf of the NefroKid Study Group
Received: 22 March 2014 /Revised: 2 June 2014 / Accepted: 30 June 2014
#The Author(s) 2014. This article is published with open access at Springerlink.com
Abstract
Background The optimal therapeutic regimen for manag-
ing childhood idiopathic nephrotic syndrome (INS) is
still under debate. We have evaluated the choice of
steroid regimen and of symptomatic treatment adopted
by pediatricians and pediatric nephrologists in a large
number of centers as the first step towards establishing
a shared protocol
Methods This was a multicenter, retrospective study. A
total of 231 children (132 admitted to pediatric units) aged
6 months to <15 years who presented with onset of nephrot-
ic syndrome to 54 pediatric units and six pediatric nephrol-
ogy units in Italy between 2007 and 2009 were eligible for
entry into the study.
Results Median steroid dosing was 55 (range 27–75) mg/m
2
/
day. The overall median cumulative dose regimen for the first
A complete list of NefroKid study group members is reported in the
Appendix.
A. Pasini :F. Mencarelli :G. Montini (*)
Nephrology and Dialysis Unit, Department of Pediatrics, Azienda
Ospedaliero Universitaria Sant’Orsola-Malpighi, Via Massarenti 11,
40138 Bologna, Italy
e-mail: giovanni.montini@aosp.bo.it
G. Aceto :G. Messina :L. Spagnoletta
Nephrology Unit, Giovanni XXIII Children’s Hospital, Bari, Italy
A. Ammenti
Department of Pediatrics, University of Parma, Parma, Italy
G. Ardissino :A. Edefonti :E. Groppali :M. Lepore
Pediatric Nephrology and Dialysis Unit, Fondazione Ca’Granda
IRCCS Ospedale Maggiore Policlinico Milano, Milan, Italy
V. A z z o l i na :S. Maringhini
Pediatric Nephrology Unit, Children’s Hospital ‘G. Di Cristina’,
A.R.N.A.S. ‘Civico’, Palermo, Italy
A. Bettinelli
Pediatric Unit, San Leopoldo Mandic Hospital, Merate, Italy
E. Cama
Department of Pediatrics and Neonatology, Desenzano del Garda,
Italy
S. Cantatore
Department of Pediatrics, Azienda Ospedaliera-University of
Modena, Modena, Italy
A. Crisafi
Pediatric Unit, Santa Maria Nuova Hospital, Reggio Emilia, Italy
G. Conti :C. Fede
Pediatric Nephrology and Dialysis, Azienda Ospedaliera
Universitaria Di Messina G. Martino, Messina, Italy
M. D’Agostino
Pediatric Unit, S. Giovanni XXIII Hospital, Bergamo, Italy
A. Dozza
Pediatric Unit, Ospedale Maggiore, Bologna, Italy
C. Gualeni
Pediatric Unit, Children’s Hospital, Brescia, Italy
A. Lavacchini
Pediatric Unit, Ospedale degli Infermi, Rimini, Italy
Pediatr Nephrol
DOI 10.1007/s00467-014-2903-7
episode was 3,440 (1,904–6,035) mg/m
2
, and the median
duration of the therapeutic regimen was 21 (9–48) weeks.
The total duration and cumulative steroid dose were signifi-
cantly higher in patients treated by pediatricians than in those
treated by pediatric nephrologists (p=0.001 and p=0.008).
Among the patient cohort, 55, 64 and 22 % received albumin
infusions, diuretics and acetyl salicylic acid treatment, respec-
tively, but the laboratory and clinical data did not differ
between children treated or not treated with symptomatic
drugs. Albumin and diuretic use did not vary between patients
in pediatric units and those in pediatric nephrology units.
Conclusions This study shows major differences in steroid
and symptomatic treatment of nephrotic syndrome by pedia-
tricians and pediatric nephrologists. As these differences can
influence the efficacy of the treatments and the appearance of
side-effects, shared guidelines and their implementation
through widespread educational activities are necessary.
Keywords Idiopathic nephrotic syndrome .Steroid regimen .
Albumin infusion .Thromboembolicprophylaxis .Guidelines
Introduction
Idiopathic nephrotic syndrome (INS) is a rare disease (2–7
cases/year per 100,000 children aged <14 years), character-
ized by edema, massive proteinuria and hypoalbuminemia
[1–3]. Its rarity makes the management of the disease cum-
bersome, especially in non-specialized centers. The current
mainstream therapy consists of corticosteroids, which induce
remission in 90–95 % of children; however, approximately
50 % of these frequently relapse and become steroid-
dependent [4,5]. The first therapeutic approach [4 weeks of
daily prednisone (PDN), followed by 4 weeks of PDN on 3
consecutive days per 7 days) was proposed in 1966, and since
then varying steroid regimens have been suggested, with the
aim of influencing the course of the disease [6–10]. In 2000, a
systematic review showed that the risk of relapse may be
reduced by longer treatment duration and a higher cumulative
steroid dose [5]. Various local, national and international
clinical practice guidelines have been published based on
currently available evidence [11–15], but in Italy, a shared
protocol has not yet been established.
In the early phase of the disease, symptomatic treatment is
also important as many severe complications can occur (in-
fections, thromboembolism, hypovolemia), which are either
directly related to the pathophysiology of the underlying NS
or to the steroid treatment itself. To date, very few studies—
most of which involve only a small number of patients—have
been published on the prophylaxis and treatment of these early
complications, while recommendations are either lacking or
conflicting [16–23]. Moreover, most of the published data
relates to cohorts of children treated at referral units.
For these reasons, the aim of this study was to retrospec-
tively evaluate the different therapeutic strategies adopted by
pediatricians and pediatric nephrologists in a large number of
centers, as the first step towards establishing a shared protocol.
Methods
Pediatricians from 114 pediatric units (PUs) and six pediatric
nephrology Units (PNUs) in nine Italian regions (Lombardy,
Emilia-Romagna, Tuscany, Apulia, Sicily, Marche, Trentino,
Friuli, Sardinia) were invited to participate in the study, after
obtaining approval from their respective Ethics Committees.
The participating pediatricians were asked to add the clinical,
epidemiological and laboratory data of their patients to an
online database (www.nefrokid.it) in a pseudonymized
manner.
The inclusion criteria were: (1) onset of INS between
January 2007 and December 2009, with INS defined as pro-
teinuria of >40 mg/m
2
/h or a urinary protein/creatinine ratio
(PrU/CrU) of >2 mg/mg, hypoalbuminemia (<2.5 g/dL) and
edema; (2) age at onset: ≥0.5 to<15 years (thus excluding
children with congenital forms of NS and including all late-
onset INS.
Subjects diagnosed with secondary NS, the presence of low
C3 and C4 levels, congenital NS or NS in association with
syndromes were excluded. All of the PNUs had patients who
met the inclusion criteria, whereas only 60/114 PUs had
suitable patients.
At diagnosis, height, weight, body mass index (BMI),
systolic (sBP) and diastolic blood pressure (dBP), expressed
as standard deviation scores (SDS), and laboratory data (blood
glucose, creatinine, urea, uric acid, total protein, albumin,
alpha-2globulin, gamma-globulin, total cholesterol, high-
density lipoprotein, low-density lipoprotein, triglycerides,
Na, K, Ca, P, complete blood count, prothrombin time-
partial thromboplastin time, fibrinogen, anti-thrombin III,
platelets, microscopic hematuria, proteinuria, urinary creati-
nine and diuresis) were collected. Days of hospitalization,
number of blood tests performed and blood tests/days of
P. Mariotti
Pediatric Unit, San Jacopo Hospital, Pistoia, Italy
M. Materassi:F. Ravaglia
Nephrology and Dialysis Unit, Meyer Children’s Hospital, Florence,
Italy
A. Negri
Pediatric Unit, Filippo Del Ponte Hospital, Varese, Italy
M. Piepoli
Pediatric Unit, Guglielmo da Saliceto Hospital, Piacenza, Italy
A. Simoni
Pediatric Unit, Ramazzini Hospital, Carpi, Italy
Pediatr Nephrol
hospitalization were compared among participating centers
and between PUs and PNUs.
Epidemiological data Morbidity rates were based on the data
from the Emilia Romagna region, where all of the PUs and
PNUs participated in the study. The incidence rate was calcu-
lated as the incidence per calendar year/100,000 age-related
population (≥0.5 to<15 years). The given incidence refers to
the data collected during the 3 years of the study (2007/2008/
2009). All of the regional units were contacted and asked to
search for patients registered with the code DRG 581-582-583
(for NS, chronic glomerulonephritis and chronic nephropa-
thies). The same codes were then crosschecked against the
regional database. The files of the patients identified were
evaluated to confirm the diagnosis of INS. The estimated
number of people “at risk”according to the morbidity analysis
was derived from the 2009 Census as 533,890.
Steroid regimens The different steroid regimens utilized were
evaluated.
Induction therapy was defined as the daily use (in single or
divided doses) of PDN at the highest fixed dose (mg/m
2
). We
looked for the implementation of the 4- and 6-week (±3 days)
induction regimens, as recommended by the International
Study of Kidney Disease in Children (ISKDC) [6] and the
Arbeitsgemeinschaft für Pädiatrische Nephrologie (APN)
[11], respectively.
Maintenance therapy was considered to be the use of a
stable dose of PDN given on alternate days and/or a tapered
dose.
The total length (induction and maintenance therapy) of the
steroid regimen and total PDN dose (mg/m
2
) were evaluated.
Data from PUs and PNUs were compared.
Remission was defined as the disappearance of proteinuria,
based on daily urinary dipstick results reported as “negative”
or “trace,”for at least 3 consecutive days. The time to remis-
sion was defined as the number of days between the first
steroid dose and the first day with a “negative”–“trace”dip-
stick result. Relapse was defined as a dipstick result of 3+ for
at least 3 consecutive days, or a PrU/CrU of >2.
Symptomatic therapy The number and dosage of albumin
infusions, diuretics, antihypertensive drugs, calcium-
containing medications, prophylactic anticoagulant therapy
and vitamin D were evaluated and then correlated with clinical
and laboratory parameters. Their possible influence on time to
remission was evaluated, and the different ways in which
pediatricians and pediatric nephrologists utilize symptomatic
therapies were compared. Data from PUs and PNUs were
compared.
Statistical analysis All data were analyzed using Stata9.2
(StataCorp, College Station, TX). Patient characteristics are
presented as the mean± standard deviation, median and range
or percentage. Differences in proportions in the categorical
data were tested using the chi-square test (Fisher test and
Pearson test), while differences for continuous outcome mea-
sures were tested using Student’sttest or the Kruskal–Wallis
test, as appropriate. The null hypothesis was rejected for all
tests with two-tailed alpha values <0.05. The differences
between treatments and the 95% confidence interval (CI) for
this difference were calculated. Risk factors were reported as
an odds ratio (OR) with 95 % CI.
Results
The patient cohort comprised 231 children who both satisfied
the inclusion criteria and received treatment at one of the six
PNUs or 60/114 PUs which submitted data to the online
database for further evaluation between January 2007 and
December 2009. All of the patients in our study were hospi-
talized at onset, with 60 % admitted to the PU and 40 % to the
PNU. The median duration of hospitalization was 10.7 (range
2–35) days, and there was a median of 0.5 (range 0.1–1.5)
blood samples per day of hospitalization, with no differences
between patients admitted to the PU and those admitted to the
PNU. Epidemiological, clinical and laboratory characteristics
at onset are shown in Table 1. The incidence rate (data from
the Emilia Romagna Region) was 3.5/100,000 age-related
population, and median age at diagnosis was 3.7 (0.7–14.9)
years. The median time of response to PDN treatment was 10
(range 2–81) days.
The flowchart of the 231 enrolled patients for the duration
of the study is shown in Fig. 1.
Steroid treatment
The steroid treatment regimens reported by the pediatricians at
the different participating PUs and PNUs differed in terms of
PDN dose and duration (Fig. 2; Table 2).
Induction treatment Prednisone was administered at a median
dose of 55.2 (range 27–75) mg/m
2
/day; however, cases of
underdosing and overdosing (from 27 to 75 mg/m
2
) were
noted. Comparison of the PDN dosing regimen used in the
PU and PNU revealed a significant difference (60 vs. 53.5 mg/
m
2
;p=0.01). PDN was administered for a period of 4 (3–11)
weeks with a cumulative dose of 1,800 (756–5,341) mg/m
2
.
Of the 199 steroid-sensitive (SS) children, 93 (46.7 %) follow-
ed a 4-week induction regimen, 53 (26.6 %) a 6-week induc-
tion regimen and 53 (26.6 %) either a shorter or longer
induction regimen.
Pediatr Nephrol
Maintenance treatment Median duration of the maintenance
treatment was 16 (3–44) weeks, and the PDN cumulative dose
was 1,410 (525–4,235) mg/m
2
.
Overall treatment The overall median duration of the
treatment regimen for the first episode was 21 (9–48)
weeks (Fig. 2a), and the median cumulative PDN dose
was 3,440 (1,904–6,035) mg/m
2
(Fig. 2b). No patient
was treated for less than 8 weeks, while 23 (17 %) and
eight (9 %) patients were treated for longer than
6monthsbythePUandPNU,respectively.Treatment
modalities adopted by pediatricians were significantly
different from those preferred by pediatric nephrologists
(Fig. 2c–e; Table 2).
Tabl e 1 Epidemiological, clinical and laboratory parameters of pediatric patients at onset of idiopathic nephrotic syndrome
Characteristics of
patient cohort
Number of patients for which
specific data were available
Total patient
cohort (n=231)
Pediatric
units (n=135)
a
Pediatric nephrology
units (n=96)
a
Age at diagnosis (year) 231 4.7 ±3.06 5.05±3.1 4.2± 2.6
Sex (male:female) 231 157:74 (68 %:32 %) 88:47 (65 %:35 %) 69:27 (72 %:28 %)
Race 231
Caucasian 196 106 90
Asian 6 5 1
African 16 12 4
Hispanic 7 7 0
Arabian 6 5 1
Season (autumn/winter vs. spring/summer 231 115:116 74:68 41:48
Clinical characteristics (SDS)
Height 231 −0.08±1.06 −0.01± 1.08 −0.2± 1
Weight 231 0.5±1.05 0.56±0,95 0.5±1.2
BMI 231 0.74±0.94 0.77±0.94 0.7± 0.9
Systolic blood pressure 197 1.05±1.1 8 1.17±1.04 0.9± 1.3
Diastolic blood pressure 196 1.23± 0.9 1.26±0.81 1.2± 1.1
Urine output (mL/kg/h) 1.4± 1.0 1.3±0.9 1.7±1.2
Laboratory data
Urea (mg/dL) 212 29.6±14 29.2±14.2 30.3±13.8
Creatinine (mg/dL) 212 0.35±0.15 0.35±0.15 0.4±0.2
Uricemia (mg/dL) 88 4.2± 1.1 4.45±1.0 4.0±1.1
Total proteins (g/dL) 212 4.2±0.7 4.2± 0.7 4.2± 0.7
Albumin (g/dL) 169 1.4± 0.4 1.4±0.4 1.4±0.4
Alpha-2- globulin (%) 112 29.8±12.5 30.2±12.8 29.8±12.4
Gamma-globulin (%) 141 7.3± 2.3 7.2±2.4 7.5±2.1
Total cholesterol (mg/dL) 208 401 ±100.3 414±103.8 381.3±92
Triglycerides (mg/dL) 183 211± 133 216± 144 205.5±117.3
Na (mmol/L) 206 136±3.2 136.1± 3.1 136.1± 3.6
K (mmol/L) 206 4.5± 0.5 4.5±0.5 4.6±0.6
Ca (mg/dL) 199 8.1 ±0.7 8.1± 0.6 8.3± 0.8
P (mg/dL) 149 5± 1 4.9± 1 5.2± 1.1
Fibrinogen (mg/dL) 143 659± 1,240 702,4±232,2 587.3±236.7
Antithrombin III (activity %) 66 69.5± 24.2 63,4±2.5 80 ±25.6
Platelets (×10
3
/μL) 207 432±131 412.2±137.1 463.3±116.8
PrU/CrU (mg/mg) 112 10.8± 7.55 10.5±7.1 11.3±8.2
Microhematuria (yes) 231 94 (41 %) 49 (36 %) 45 (47 %)
SDS, Standard deviation score; BMI, body mass index; PrU/CrU, urinary protein/creatinine ratio
Data in table are presented as the number of patients with the percentage in parenthesis, or as the mean ± standard deviation. All data refer to data
collected at initial admission
a
No differences were found between the two groups of patients [pediatric unit (PU) and pediatric nephrology unit (PNU)], apart from age at diagnosis
(p=0.042)
Pediatr Nephrol
Symptomatic therapy
Symptomatic therapy at onset is shown in Table 3.
Albumin infusions In total, 119 (54.5 %) patients received
albumin infusions (20 % solution), with no distinction seen
between SS and steroid-resistant (SR) children, at a mean dose
of 1 g/kg and a median number of infusions (range 1–16).
Albumin infusions were associated with furosemide treatment
in 94.1 % of cases. The overall percentage of infusions was
similar for both the PUs (52 %) and PNUs (58 %), but the use
of infusions varied considerably between individual centers,
ranging from 8.4 to 87.5 % in centers with at least ten subjects
enrolled in the study. Laboratory (serum albumin, proteins,
creatinine, urea, electrolytes, PrU/CrU) and clinical data
(BMI, sBP and dBP SDS, urine output) did not differ between
infused and non-infused subjects (Table 4), even when PU and
PNU behavior was compared. Patients who received albumin
infusions showed a significantly higher risk of remission at a
later date (11 vs. 8 days, respectively; OR 2.05, 95 % CI 1.11–
3.79).
Thromboembolic prophylaxis Prophylactic therapy with
acetylsalicylic acid was prescribed for 47 subjects (21.5 %).
Hematological risk factors of thromboembolism (albumin,
platelets, fibrinogen, antithrombin III, total cholesterol and
triglycerides) did not differ between treated and non-treated
subjects (Table 4), also when PU and PNU data were sepa-
rately examined. Pediatric nephrologists prescribed thrombo-
embolic prophylaxis more often than pediatricians (33.7 vs.
13.6 %, respectively; p<0.0001).
Diuretics Diuretic agents were used in 145/218 subjects
(66.5 %). Furosemide was the most widely used diruretic
agent, either alone (64.8 %) or in association with other
diuretics (26.2 %) (Table 5). Diuretic treatment was not asso-
ciated with a shorter time to remission. Urine output (1.6±1.1
vs. 1.0±0.7 mL/kg/h), serum albumin (1.37±0.04 vs. 1.46±
0.06 g/dL), electrolytes, protein, urea and clinical parameters
(weight-, BMI-, sBP- and dBP-SDS) did not differ between
treated and non-treated subjects. Pediatricians used furose-
mide alone more frequently than pediatric nephrologists
(45.4 vs. 39.5 %, respectively), while pediatric nephrologists
used a combination of two diuretics more often than pediatri-
cians (25.5 vs. 15.5 %, respectively).
Acute complications Of the 218 pediatric patients, 27
(12.4 %) developed infections, with 16 children (7.3 %) hav-
ing bacterial infections (8 pneumonia, 1 peritonitis, 1 cellulitis
and 1 otitis; 5 were not specified), ten having viral infections
(enteric or upper respiratory infections and 1 case of
chickenpox), and one having a fungal infection. Thromboem-
bolic complications were seen in two patients (pulmonary
embolism and cerebral venous thrombosis; one patient had
congenital dysfibrinogenemia).
Discussion
Our epidemiological data (3.5 new cases/100,000 age-related
population/year; male:female, 2:1) do not differ from those
reported by previous retrospective [1,2]orprospective[3,24,
25] studies, confirming that INS is a rare disease. Various
regional and national guidelines [12,13,26]havebeendevel-
oped, and the new Kidney Disease Improving Global Out-
comes (KDIGO) guidelines have recently been published
[14]. In Italy, shared treatment guidelines are lacking and,
consequently, the choice of steroid regimen and symptomatic
treatments still depends on the clinical expertise of each single
unit. The aim of our study was thus to establish a shared
protocol based on a retrospective evaluation of the different
therapeutic strategies adopted.
Steroid treatment
Our patients received a median PDN dose of 55.2 mg/m
2
/day.
However, cases of either underdosing or overdosing (from 27
to 75 mg/m
2
) were noted. Comparison of PDN dosing in the
PU and PNU revealed a significant difference (60 vs. 53.5 mg/
m
2
, respectively). The general pediatricians in our study
determined PDN doses using the body surface area
(BSA)-based formula (60 mg/m
2
/day) for two-thirds of
their patients, whereas they used the weight-based dosing
formula (2 mg/kg/day) for fewer than one-third of their
patients. In contrast, pediatric nephrologists utilized the
weight-based formula more often (2/3 of patients). If we
consider that the majority of children in the study cohort
weighed <30 kg, the nephrologists’preference for
weight-based dosing could explain why their daily doses
were lower than those of the general pediatricians, as
Fig. 1 Flowchart of the 231 enrolled pediatric patients
Pediatr Nephrol
mathematical models have demonstrated that weight-
based dosing can be less than BSA-based dosing in
smaller children [27].
Likewise, different steroid protocols were used. Overall, a
4-week induction therapy was the treatment of choice in one-
half of the subjects, whereas a 6-week induction therapy was
Total Total
AB
CD
EF
5
10
1520
2000 3000 4000 5000 6000
PDN mg/m2
10
20
30
0
14
28
42
0
14
28
42
Pediatric Units Pediatric Nephrology Units
n.
weeks
weeks
10
2030
2000 3000 4000 500 0 6000 2000 3000 4000 5000 6000
n.
PDN mg/m2
Pediatric Units Pediatric Nephrology Units
PDN mg/m2
5
10
15
20
014 28 42
weeks
Fig. 2 Treatment regimen for the
first episode. a,bDuration (a)
and total prednisone dose utilized
(b) for the total patient cohort. c–f
Comparison of the duration (c,d)
and total prednisone dose (e,f)of
the steroid regimen for the first
episode used by participating
pediatricians (c,e) and pediatric
nephrologists (d,f). Y-a x is shows
the number of patients. PDN
Prednisone
Pediatr Nephrol
the treatment of choice in one-quarter of patients, while the
remaining patients received either a much longer or much
shorter induction therapy. At the time of our study, the
Cochrane review suggesting the efficacy of longer treatment
duration and higher cumulative steroid dose in reducing the
risk of relapses had already been published [5], and the
ISKDC protocol, recommending a cumulative dose of
2,240 mg/m
2
, was still widely used, especially by pediatri-
cians. Concomitantly, extended protocols (APN protocol, total
cumulative dose 3,360 mg/m
2
)[11] were gaining popularity
among nephrologists. For this reason, the induction regimens
in our study were longer (and cumulative steroid doses higher)
in patients treated by nephrologists. We noted that pediatri-
cians were using modified ISKDC regimens, with longer
maintenance therapies, with progressive tapering to minimal
PDN doses for up to 9 months, which explains why the total
duration and cumulative PDN dose were significantly higher
in the pediatricians’group (24 weeks, 3,722 mg/m
2
)thanin
the pediatric nephrologists’group (20 weeks, 3,301 mg/m
2
).
When the new 2012 KDIGO recommendations [14,15]
were applied to this cohort, in a retrospective simulation, non-
adherence to the recommended range of PDN cumulative
dose and/or length of steroid regimen was noted in 62/118
subjects (52.5 %), with more patients being “overtreated”than
“undertreated”(37.2 vs. 15.2 %, respectively). The overall
rate of non-adherence to KDIGO guidelines was significantly
higher for patients treated by pediatricians (64.1 vs. 40.7 %,
respectively; p=0.01) than for those treated by pediatric ne-
phrologists. This means that the group of undertreated patients
from our cohort could have had a higher risk of relapse or
steroid dependency, while the overtreated subjects would have
been exposed to an increased risk of side-effects, probably
without beneficial effects for the clinical course of the disease.
More recently, a randomized controlled trial showed thatPDN
treatment (APN regimen) prolonged from 3 to 6 months with-
out any increase in the cumulative dose did not benefit clinical
outcome [28]. Applying this result to our cohort of patients,
there would have been no advantage for children who took a
cumulative dose equivalent to the APN protocol over a longer
period of time.
Similar practice variations have been documented in two
American and Canadian cohorts [29,30]: in both studies, data
Tabl e 2 Comparison of steroid regimens (induction, maintenance and total treatment) utilized by pediatricians and pediatric nephrologists
Variable Steroid regimen Children admitted to PU (n=132) ChildrenadmittedtoPNU(n=86) pvalue
Weeks Induction 5 (2.5–8) 6 (4–11) 0.0 001
Maintenance 20 (5–39.5) 14 (3–44) 0.0003
Tot al 24 (9 –45.5) 20 (10–48) 0.0014
PDN (mg/m
2
) Induction 1,887 (756–4,260) 2,117 (1,092–5,341) 0.012
Maintenance 1,883 (657–4,235) 1,259 (525–3,321) 0.0001
Total 3,722 (1,904–6,035) 3,301 (2,250–5,660) 0.008
PDN, Prednisone; PU, pediatric unit; PNU, pediatric nephrology unit
Values are presented as the median with the range given in parenthesis
Tabl e 3 Comparison of symptomatic therapy and hospitalization data at onset between the PUs and PNUs
Symptomatic therapy/hospitalization Total patient cohort (n=218) Pediatrics units (n= 132) Pediatric nephrology units (n=86) pvalue
Symptomatic therapy
Albumin infusions 119 (54.5) 69 (52) 50 (58) 0.72
Diuretics 139 (63.7) 82 (62.1) 57 (66.2) 0.13
Vitamin D 95 (43.6) 51 (38.6) 44 (51.2) 0.068
Proton pump inhibitors or H2 antagonists 98 (44.9) 49 (22.5) 49 (57) 0.016
ASA 47 (21.5) 18 (13.6) 29 (33.7) <0.0001
Calcium (carbonate or lactate) 14 (6.4) 9 (6.8) 5 (5.8) 0.34
Ca channel blockers, ACE inhibitors 9 (4.1) 4 (3) 5 (5.8) 0.30
Antibiotic prophylaxis 34 (15.6) 18 (13.6) 16 (18.6) 0.25
Hospitalization data
Hospitalization (days) 10.7 (2–35) 10.9 (2–35) 10.4 (2–29) 0.41
Blood samples/days of hospitalization 0.5 (0.1–1.5) 0.49 (0.1–1.2) 0.47 (0.1–1.5) 0.70
Data are presented as the mean with the percentage in parenthesis, or as the median with the range in parenthesis
ASA, Acetylsalicylic acid; ACE angiotensin converting enzyme
Pediatr Nephrol
were collected by means of a web-based survey completed by
pediatric nephrologists. Striking variations were found in the
number of daily steroid administrations (range 1–3) and in
daily and alternate-day regimen duration. The authors of these
studies expressed their hope of overcoming these discrepan-
cies by creating a standardized clinical pathway to promote
the uptake of the evidence published in the Guidelines into
daily clinical practice. This is what has clearly come to light
from the evaluation of our data—namely, guidelines do exist
yet they are not adhered to in a correct way, leading to a great
variation in the clinical management of INS.
Symptomatic therapy
Noted differences were evident in our data. However, it
must be acknowledged that guidelines are actually hard
to develop for the symptomatic treatment of patients
with NS due to the lack of trial data and the limitations
of observational data.
Albumin infusions Approximately one-half of our patients
(54.5 %) received albumin infusions. To our knowledge, no
epidemiological data have been published on the use of infu-
sions in nephrotic patients at onset in large cohorts of patients.
In nephrotic children, albumin may be essential when a circu-
latory volume depletion is present (underfilling hypothesis)
[31,32], while albumin infusion may be dangerous when the
circulatory volume is not depleted (overfilling hypothesis)
[33–36]. In the clinical setting, it is not easy to differentiate
circulatory volume contraction from volume expansion, and
various parameters, unfortunately not easily available in the
routine clinical setting, have been proposed as biomarkers,
such as the ratio urinary potassium (uK)/urinary sodium+ uK
(an index of aldosterone bioactivity) [37] or the inferior vena
cava diameter [18]. Kapur et al. showed that a simple tool, the
fractional excretion of sodium (FeNa), effectively differenti-
ates hypo- from hypervolemic edematous children and that the
use of diuretics without albumin is safe and beneficial in
hypervolemic patients [16]. While these authors report that
hypovolemia is present in about 30 % of nephrotic children,
albumin was administered to 55 % of the children in our study.
Unexpectedly, the serum chemistry and clinical data of the
patients who received infusions did not differ from the data
obtained from patients who were not treated with infusions.
Significantly different practices regarding the use of infusions
were noted between centers, confirming that the decision to
administer albumin is often based on the single-center expe-
rience. Moreover, the patients who received albumin went into
remission later than the untreated subjects (11 vs. 8 days,
respectively). A similar result was described by Yoshimura
et al. in a cohort of 27 adult patients with Ns, leading the
authors to speculate that morphological changes in the glo-
merulus might be aggravated when albumin is administered
[38]. Among our patients, 94 % were given albumin in
association with intravenous furosemide; however, the
efficacy of this combination therapy has been reported
to be low and transient, and it remains controversial
[19,23,36,39–41].
Diuretics In our study, two-thirds of the subjects were treated
with diuretics, mainly (91 %) furosemide. Published data
show that subjects with NS have an impaired natriuretic
response to loop diuretics: low plasma albumin binding allows
furosemide to leak out of the plasma into the interstitial space
and delivery to the peritubular space is diminished [35,42].
Thus, to achieve a good natriuretic response, it may be nec-
essary to use high doses of furosemide (however there are no
studies comparing different dosing levels) or add other di-
uretics to the treatment regimen [42,43]. In our study, only 29
% of the patients were prescribed two diuretics. Despite
Tabl e 4 Comparison of clinical and laboratory data of patients receiving or not receiving albumin infusions or thromboembolic prophylaxis
a
Clinical and laboratory data
Albumin infusion Albumin (g/dL) Serum Na (mmol/L) Urine output
(mL/kg/h)
sBP (SDS) dBP (SDS) BMI (SDS)
Yes 1.46 ±0.4 135.3±3.4 1.6 ±1.1 1.2±1.1 1.4±1.0 0.9 ±1.0
No 1.36±0.4 137.1±2.8 1.1 ±0.8 0.9±1.13 1.05± 0.8 0.6±1.0
pvalue NS NS NS NS NS NS
Thromboembolic
prophylaxis (ASA)
Albumin (g/dL) Platelets (×10
3
/μL) Antithrombin
III (%)
Fibrinogen
(mg/dL)
Cholesterol
(mg/dL)
Triglycerides
(mg/dL)
Yes 1.3 ±0.4 438±18.0 65±4.0 687±34 397± 12.2 196±15.0
No 1.4 ±0.4 430±10.9 71 ±4.1 651±25 402±8.5 217± 12.7
pvalue NS NS NS NS NS NS
sBP, Systolic blood pressure; dBP, diastolic blood pressure; NS, not significant
a
This analysis did not reveal any difference between the two group in terms of Albumin infusion and thromboembolic prophylaxis. No differences were
found when data were analyzed separately in children treated by pediatricians and pediatric nephrologists
Pediatr Nephrol
frequent reports about its effectiveness, amiloride was never
used [43,44].
Thromboembolic prophylaxis Only two cases of thromboem-
bolism were reported among our patient cohort. While the
incidence of thromboembolic complications in adults with NS
[15,45,46]rangesfrom10to42%,thatinchildrenranges
from only 1.8 to 5.3 % and is more likely associated with
congenital NS, membranous nephropathy or secondary NS
[46–48]. For this reason, there is no consensus on the role of
prophylactic anticoagulation [49]. Most clinicians do not ini-
tially prescribe prophylactic warfarin therapy [50]. Likewise,
for high-risk patients, low-dose aspirin or dipyridamole are
suggested by some guidelines [12] but not recommended by
others [13], although no controlled trials have demonstrated
their efficacy [17].
In our study, prophylactic therapy was performed in about
20 % of cases, exclusively with aspirin. Of note, laboratory
levels of risk factors for thromboembolism did not differ
between treated and non-treated subjects (Table 3). Prophy-
lactic treatment was prescribed more frequently by pediatric
nephrologists than by pediatricians (33.7 vs 13.6 %, respec-
tively), possibly because pediatric nephrologists usually treat
more complicated and severe forms of INS.
Strengths and weakness of the study
The main strength of our study is the large number of partici-
pating centers and, more importantly, the number of non-
specialized PUs involved, as most previous studies reported
series of patients from tertiary units only. Further strengths
include the rather short recruitment period and the evaluation
of clinical and laboratory parameters rarely evaluated in
previous studies. The major limitation of the study is its retro-
spective nature, especially in terms of the evaluation of clinical
parameters and the number of patients lost to follow-up.
Conclusions
This study has brought to light many inhomogeneities as
regards the steroid treatment of INS children at onset and a
lack of implementation of the current guidelines. Treatment
and prevention of the acute complications significantly varies
between centers and appears to be unrelated to any specific
clinical or laboratory parameters. Therefore, shared guidelines
for the symptomatic treatment and educational activities for
the proper implementation of current guidelines on steroid
treatment are necessary to avoid the above-mentioned unnec-
essary interventions.
A shared protocol for the treatment of the first episode of
INS, involving both pediatricians and pediatric nephrologists,
was implemented in the centers that took part in this study. To
evaluate the impact of this common protocol (in terms of
clinical results and socio-economic costs) an observational
prospective study on the treatment of INS was officially
initiated in 2011 (ClinicalTrials.gov Id.: NCT01386957).
Acknowledgments We thank all the members of Nefrokid Study
Group, whose collaboration was essential in order to perform the study.
We would also thank the charity organization “Il Sogno di Stefano”and
The Nando Peretti Foundation for their generous financial support.
Appendix
Members of the Nefrokid Study Group (all in Italy)
Andrea Pasini, Francesca Mencarelli, Chiara De Mutiis, Elena
Monti, GiovanniMontini Nephrology and Dialysis Unit, De-
partment of Pediatrics, Azienda OspedalieroUniversitaria
Sant'Orsola-Malpighi, Bologna; Gabriella Aceto, Giovanni
Messina, LauraSpagnoletta, Mario Giordano, Tommaso De
Palo Nephrology Division, Giovanni XXIIIChildren's Hospi-
tal, Bari; Alberto Edefonti, Luciana Ghio, Gianluigi
Ardissino, ElenaGroppali, Marta Lepore Pediatric Nephrolo-
gy and Dialysis Unit, Fondazione Ca’GrandaIRCCS
Ospedale Maggiore Policlinico, Milan; Silvio Maringhini,
Vitalba AzzolinaPediatric Nephrology Unit, Children's Hos-
pital ‘G. Di Cristina’, A.R.N.A.S. ‘Civico’, Palermo;Carmelo
Fede, Roberto Chimenz, Giovanni Conti Pediatric Nephrolo-
gy and Dialysis,AOU G.Martino, Messina; Marco Materassi,
Fiammetta Ravaglia Nephrology andDialysis Unit, Meyer
Children's Hospital, Florence; Maria D’Agostino Pediatric
Unit,S.Giovanni XXIII° Hospital,Bergam; Sante Cantatore
Tabl e 5 Diuretics utilized for the treatment of edema
Diuretic treatment Results
No diuretics 73 (33.5)
Diuretics utilized 145 (66.5)
Furosemide 94 (64.8)
Furosemide +spironolactone 31 (21.4)
Furosemide +spironolactone+hydrochlorothiazide 5 (3.4)
Furosemide +hydrochlorothiazide 2 (1.4)
Spironolactone 6 (4.1)
Spironolactone+hydrochlorothiazide 3 (2.1)
Hydrochlorothiazide 3 (2.1)
Total diuretics (alone or in association)
Furosemide 132 (91.0)
Spironolactone 46 (31.7)
Hydrochlorothiazide 13 (9.0)
Data are presented as the mean, with the percentage in parenthesis
Pediatr Nephrol
Department of Pediatrics, AziendaOspedaliera-University of
Modena, Modena; Anita Ammenti Department of
Pediatrics,University of Parma, Parma; Chiara Gualeni Pedi-
atric Unit, Children’s Hospital, Brescia;Elena Cama Depart-
ment of Pediatrics and Neonatology, Desenzano del Garda;
MariottiPaola Pediatric Unit, San Jacopo Hospital, Pistoia;
Amata Negri Pediatric Unit , FilippoDel Ponte Hospital, Va-
rese; Alberto Bettinelli Pediatric Unit, San Leopoldo
MandicHospital, Merate; Alessandra Lavacchini Pediatric
Unit, Ospedale degli Infermi, Rimini;Alessandra Dozza Pedi-
atric Unit, Ospedale Maggiore, Bologna; Angela Simoni
PediatricUnit, Ramazzini Hospital, Carpi; Marina Piepoli
Pediatric Unit, Guglielmo da SalicetoHospital, Piacenza,
Italy; Felice Sica Pediatric Unit, AOU Ospedali Riuniti,
Foggia;Gabriele Ripanti Pediatric Unit, San Salvatore
Hospital, Pesaro; Marina Milani PediatricUnit,
Fondazione MBBM, S. Gerardo Hospital, Monza; Paola
Tommasi Pediatric Unit,Vittore Buzzi Hospital, Milan;
Carla Romanello Pediatric Unit, S. Maria della
MisericordiaHospital, Udine; Manuela Pasini Pediatric
Unit, Maurizio Bufalini Hospital, Cesena; PaolaMastinu
Pediatric Unit, S.Chiara Hospital, Trento; Laura Luti
Pediatric Unit, AOU Pisa;Antonella Amendolea Pediat-
ric Unit, Cecina; Silvia Manfredi Pediatric Unit, Massa
eCarrara; Emanuela Lanfranchi Pediatric Unit, Fermo;
Maria Principi Pediatric Unit,Macerata; Agrippino
Reciputo Pediatric Unit, Cinisello Balsamo; Marialuisa
CascianaPediatric Unit, C. Poma Hospital, Mantova;
Antonio Pellegatta Pediatric Unit, BustoArsizio; Fiorella
Russo Pediatric Unit, Desio; Nicola Altamura Pediatric
Unit, Sesto SanGiovanni; Lorena Ruzza Pediatric Unit,
San Carlo Hospital, Milan; Stefano SardiniPediatric
Unit, Asola; Ines L'Erario Pediatric Unit, Burlo Garofalo
Hospital, Trieste;Claudio Ruberto, Antonella Crisafi Pe-
diatric Unit, Santa Maria Nuova Hospital, ReggioEmilia;
Andrea Zucchini Pediatric Unit, Faenza; Laura Serra
Pediatric Unit, Santa Mariadella Scaletta Hospital,
Imola; Peter Bertamini Pediatric Unit, Santa Maria del
CarmineHospital, Rovereto; Rita Bini Pediatric Unit,
Grosseto; Patrizia Cortesi Pediatric Unit,Pescia; Caterina
Balducci Pediatric Unit, Prato; Francesca Simoni Pedi-
atric Unit, Pianadi Lucca Hospital, Lucca; Patrizia
Fonduli, Franca Paola Zurrida Pediatric Unit,
BrotzuHospital, Cagliari; Laura De Petris Pediatric Unit,
Mazzoni Hospital, Ascoli Piceno;VinicioGoj Pediatric
Unit, Fatebenefratelli Hospital, Milan; Gian Luigi
Marsiglia Pediatric Unit,IRCCS Policlinico S Matteo,
Pavia; Patrizia Caruso Pediatric Unit, Cremona;
FilippoSalviniPediatric Unit, S. Paolo Hospital, Milano;
Paola Perotti Pediatric Unit, Voghera;Anna Bussolini
Pediatric Unit, Tradate; Stefano Poli, Barbara Balduzzi
Pediatric Unit,Esine; Barbara Roman Pediatric Unit,
Vimercate; Sergio Mariani, Laura CafarelliPediatric
Unit, Saronno; Vittorio Venturoli Pediatric Unit,
Morgagni-Pierantoni Hospital,Forlì; Andrea Corsini Pe-
diatric Unit, Bentivoglio; Luca Casadio, Fabrizio
PugliesePediatric Unit, Ravenna.
Open Access This article is distributed under the terms of the Creative
Commons Attribution License which permits any use, distribution, and
reproduction in any medium, provided the original author(s) and the
source are credited.
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