Low birth weight, but not postnatal weight gain ... - Thai Wonders

Pediatr Nephrol (2007) 22:1881–1889
DOI 10.1007/s00467-007-0597-9
ORIGINAL ARTICLE
Low birth weight, but not postnatal weight gain, aggravates
the course of nephrotic syndrome
Christian Plank & Iris Östreicher & Katalin Dittrich &
Rüdiger Waldherr & Manfred Voigt & Kerstin Amann &
Wolfgang Rascher & Jörg Dötsch
Received: 12 February 2007 /Revised: 16 July 2007 /Accepted: 16 July 2007 / Published online: 14 September 2007
# IPNA 2007
Abstract Clinical and animal studies have shown a higher
risk of an aggravated course of renal disease in childhood
after birth for babies small for gestational age (SGA). In
addition relative “supernutrition” and fast weight gain in
early infancy seem to support the development of later
disease. In a retrospective analysis of 62 cases of idiopathic
nephrotic syndrome treated between 1994 and 2004 at a
university centre for paediatric nephrology, we related the
course of disease to birth weight and to the weight gain in
the first 2 years of life. Six children were born SGA (birth
weight

1882 Pediatr Nephrol (2007) 22:1881–1889
neonatal hypotrophy show, in addition, a higher risk for
renal insufficiency in adult life, which is difficult to
separate from the risk of metabolic diseases in these
populations [5–7]. Another aspect in perinatal programming
of later diseases is postnatal growth and weight gain.
It is postulated that catch-up growth until the age of 2 years
restores the infant’s size back to the genetic growth
trajectory [8]. Up to 90% of children born small for
gestational age (SGA) show catch-up growth [9]. Barker
et al. studied the influence of postnatal growth on
cardiovascular events in later life and showed that adults
who had suffered coronary events were smaller at birth, thin
at 2 years and had showed rapid weight gain thereafter.
Other groups have shown negative consequences of catchup
growth on blood pressure, death from cardiovascular
diseases and occurrence of type 2 diabetes [10]. In a cohort
study Ong et al. showed an association between children’s
catch-up growth in the first 2 years of life and their fatness
at the age of 5 years. Of the children studied, 30.7% had a
weight gain of 0.67 standard deviation score (SDS).
Interestingly, these children had lower birth weights,
lengths and ponderal indices [11]. Data from the US
Collaborative Perinatal Project (1959–1974) looked at
blood pressure elevation at the age of 7 years. This study
did not show an elevated risk for SGA children but
demonstrated a higher risk in children who crossed weight
percentiles during early childhood [12]. A smaller Korean
study showed a connection between weight gain in the first
3 years of life and increased systolic blood pressure at the
age of 3 years [13]. In conclusion, infant weight gain could
be a risk factor for the course of later diseases independently
from SGA or intrauterine growth restriction (IUGR).
To date, three studies on children have looked for SGA
as a risk factor for an aggravated course of idiopathic
nephrotic syndrome. Two of these studies were performed
in an Asian population [14, 15] and one was done in
Slovenian children [16]. They all showed an unfavourable
course of nephrotic syndrome in SGA children. However,
there are no studies that examine the influence of early
postnatal growth on the course of kidney diseases. Two of
the studies were limited to children with clinical diagnoses
of idiopathic nephrotic syndrome or minimal change
disease [14, 16]. Therefore, we investigated our complete
cohort of children with idiopathic nephrotic syndrome due
to MCGN or FSGS to test the hypothesis that low birth
weight and early weight gain are risk factors for an
aggravated course of idiopathic nephrotic syndrome.
Methods
We retrospectively investigated every treated case of
idiopathic nephrotic syndrome between 1994 and 2004 in
a university centre for paediatric nephrology. In a first step,
all patients treated because of nephrotic syndrome, MCGN
or FSGS were identified by the diagnostic codes 580.-,
581.-, 582.-, 583.- (ICD 9) or N00., N01., N04., N05.,
N06., and N08.8 (ICD 10) in a patients’ database. Then, we
selected all patients with the clinical diagnosis of idiopathic
nephrotic syndrome or the histological diagnosis MCGN or
FSGS. Patients were 1–18 years old when nephrotic
syndrome was diagnosed. Patients with chromosomal
aberrations, congenital syndromes and congenital infections
were excluded. The selected families were contacted.
Informed consent of the parents and as far as possible
assent of the patients were obtained. Copies were drawn
from the patients’ prevention record with auxiology data at
birth, days 3–10, weeks 4–6, months 3–4, months 6–7,
months 10–12 and months 21–24, according to the German
national child prevention program. Parents answered a
questionnaire about parental auxiology, pregnancy and risk
factors during pregnancy. Patient records were analysed for
data on diagnosis, clinical course and therapy.
The study protocol was approved by the ethics committee
of the medical faculty of the University of Erlangen-
Nuremberg. The study was conducted according to the
Declaration of Helsinki and German national laws.
The definition of small for gestational age is very
arbitrary, ranging from the 2.5th percentile to the 25th
percentile [17]. Therefore, to distinguish between patients
that were small for gestational age and those that were
appropriate for gestational age, we used a birth-weight
standard deviation score (SDS) ≤−1.5 (equivalent to the 7th
percentile). SDS was calculated according to birth weight,
gestational age and gender, using the percentiles of M.
Voigt for German newborns between 1995–1997 [18]. The
same references were used for calculation of the SDSs for
head circumference and birth length. The ponderal index
was calculated according to the formula: body weight (g)/
[body length (cm)] 3 .
In fact, not only patients with a birth weight below the
10th percentile or the

Pediatr Nephrol (2007) 22:1881–1889 1883
Independent of birth weight, postnatal alimentation and
weight gain in early childhood might influence the later
course of kidney diseases. As a proxy for postnatal weight
gain we analysed the difference between body weight SDSs
at birth and at 24 months of age [11]. Percentile-crossing
weight gain or loss can be shown as gain or loss of SDSs
[12]. For example, a patient with a birth weight at the 2.3th
percentile and weight at the 15.9th percentile at the age of
2 years would present with a gain of SDS of 1.0, indicating
catch-up growth. In contrast, a SDS difference 1.0).
SDSs were calculated on the basis of dry weight.
As characteristics of the clinical course we used age at
manifestation, necessity of renal biopsy, histological diagnosis,
rate of primary and secondary steroid resistance, rate
of primary and secondary steroid dependence, use of
cyclophosphamide or cyclosporin A, rate of arterial hypertension
in the course of disease, number of antihypertensive
or antiproteinuric drugs, and number of relapses per year of
follow-up. At last follow-up, number of patients with endstage
renal failure, creatinine clearance according to
Schwartz [22], number of antihypertensive or antiproteinuric
drugs and immunosuppressive drugs were determined.
Ambulatory blood pressure measurements are given as
SDSs. SDSs were calculated on the basis of the data by de Man
[23]. Formulae were provided by Elke Wühl, Department of
Pediatrics, University of Heidelberg, Germany.
For the scoring of antihypertensive therapy, the following
drugs were considered: captopril, enalapril, atenolol, propranolol,
nifedipin, amlodipin, prazosin and dihydralazin.
The use of each class of antihypertensive or antiproteinuric
drug during the course of the disease was given one score
point, with a maximum score of 4.
Further definitions
Nephrotic syndrome was defined as proteinuria [urinary
protein excretion >40 mg/m 2 per hour (=1 g/m 2 per
24 hours)], oedema, and hypoalbuminaemia (serum albumin
level 40 mg/m 2 per
hour (1 g/m 2 per day) or as protein excretion >100 mg/dl in
three successive analyses of morning spot urine. Therapy
for relapses followed the APN standard, with 60 mg/m 2
BSA PRD divided into three single doses and the largest
dose in the morning (maximum dose 80 mg/day) until
morning spot urine showed protein excretion

1884 Pediatr Nephrol (2007) 22:1881–1889
nephritis, and another patient had nephronophtisis. All
these patients were excluded from further analysis. Six
children were identified as SGA, 56 as AGA (Table 1). In
SGA und AGA children median gestational age was
similar. Both groups differed significantly in birth weight,
birth length and head circumference. Birth weight SDS,
birth length SDS and head circumference differed significantly
after correction for gestational age and gender.
Auxiology after birth in SGA children
In the SGA group birth weight SDS was between −3.91 and
−1.51. To describe catch up growth in the SGA group we
analysed weight development and growth during the first
2 years of life. In one patient auxiology data from birth
until the age of 2 years was completely missing.
There was no body weight catch-up in three patients; the
other two patients increased their body weight at least by
0.5 SDS. No patient reached a body weight SDS over 1.2 at
24 months of age.
One patient did not attain a normal body length
according to SDS till the age of 24 months. Two patients
showed an increase in length SDS>1.5. Another two
patients showed a normal height SDS (>−2.0) at 24 months,
but catch-up details regarding height SDS between birth
and 24 months were missing. Because of the small number
of SGA patients, further analysis on the influence of catchup
growth after SGA was omitted.
Table 1 Patients’ characteristics at birth. Data are given as median
and range
Characteristic SGA (n=6) AGA (n=56)
Gestational age (weeks) 39.5 (37–41) 40 (29–42)
Gender (male/female) 3/3 32/24
Birth weight (g) 2,735 (1,280– 3,400 (1,320–
2,950)
4,380) a
Birth weight (SDS) −1.84 (−3.91– −0.28 (−1.45–
−1.51)
+1.72) b
Birth length (cm) 49.5 (36.0–50.0) 51.5 (39.0–58.0) b
Birth length (SDS) −1.21 (−5.67– −0.08 (−1.88–
−0.79)
2.37) a
Ponderal index 2.38 (2.09–2.74) 2.41 (2.1–2.93)
Head circumference at birth
(cm)
33.2 (32.8–35.0) 35.0 (29.0–38.0) b
Head circumference at birth −1.29 (−1.72– −0.04 (−1.93–
(SDS)
−0.42)
1.86) b
Differences between both groups are tested with unpaired Mann–
Whitney t-test
a P

Pediatr Nephrol (2007) 22:1881–1889 1885
Table 3 Clinical course of idiopathic nephrotic syndrome in SGA and
AGA children. Data are given as median and range
Parameter SGA (n=6) AGA (n=56)
Age at manifestation (years) 6.4 (1.9–15.3) 3.7 (1.2–15.5)
Follow-up period (years) 6.2 (2.2–17.2) 5.4 (0.2–15.7)
Cyclophosphamide therapy
required
5/6 (83.3%) 30/56 (53.6%)
Cyclosporin A therapy required 5/6 (83.3%) 23/56 (41.1%)
Steroid dependence 2/6 (33.3%) 20/56 (35.5%)
Steroid resistance 4/6 (66.6%) 12/56 (21.4%) a
Relapses per patient/year 0.69 (0–2.41) 0.65 (0–3.0)
Renal biopsy performed 6/6 (100%) 31/56 (55%)
Minimal change glomerulopathy
(MCGN)
5/6 (83.3%) 23/31 (74.1%)
Focal segmental
glomerulosclerosis (FSGS)
1/6 (16.6%) 8/31 (25.8%)
Differences between both groups were tested with unpaired Mann–
Whitney t-test and Fisher’s exact test
a P

1886 Pediatr Nephrol (2007) 22:1881–1889
nosis, or use of immunosuppressive substances; neither was
need for antihypertensive treatment, blood pressure at last
follow-up, or use of antihypertensive drugs different
between the four groups. Median number of relapses per
patient year was not different, but interestingly, patients in
the birth SDS group 0–1.0 had a bigger chance of facing a
relapse-free remission (P

Pediatr Nephrol (2007) 22:1881–1889 1887
Table 6 Clinical course of idiopathic nephrotic syndrome in relation to weight gain in the first 24 months of life. Data are given as median and
range
Parameter Weight gain
Weight gain
Weight gain
Weight gain
month 0–24
month 0–24
month 0–24
month 0–24
1.0 SDS (n=13)
Age at manifestation (years) 4.5 (1.2–8.0) 3.9 (1.6–7.2) 3.9 (2.1–15.3) 2.9 (1.5–14.8)
Follow-up period (years) 5.4 (4.2–17.25) 4.96 (1.7–11.7) 4.8 (0.9–14.2) 5.3 (0.2–15.2)
Cyclophosphamide therapy required 5/7 (71.4%) 6/14 (42.8%) 8/19 (42.1%) 9/13 (69.2%)
Cyclosporin A therapy required 4/7 (57.5%) 6/14 (42.8%) 4/19 (21.0%) 6/13 (46.1%)
Steroid resistance 4/7 (57.1%) 3/14 (21.4%) 3/19 (15.8%) 4/13 (30.7%)
Steroid dependence 3/7 (42.9%) 5/14 (35.7%) 4/19 (21.0%) 3/13 (23.0%)
Relapses per patient per year 1.0 (0–2.4) 0.56 (0–2.2) 0.57 (0–3.0) 0.7 (0–1.8)
Renal biopsy performed 4/7 (57.1%) 9/14 (64.2%) 7/19 (36.0%) 9/13 (69.2%)
Minimal change glomerulopathy
(MCGN)
2/4 8/9 5/7 6/9
Focal segmental glomerulosclerosis
(FSGS)
2/4 1/9 2/7 3/9
Differences between both groups were tested with one-way analysis of variance (ANOVA) and chi-square test
clinically suspected or proven by biopsy, the authors
identified five children who had been SGA. In the SGA
group, a higher number of relapses, a higher rate of steroid
dependency, use of cytotoxic drugs, and a higher rate of
renal biopsy could be observed. Sheu and Chen [14]
studied 50 Taiwanese children (1–13 years) with nephrotic
syndrome, half of them with biopsy proven MCGN. Eight
children were identified as having been SGA (birth weight
below 10th percentile). A higher rate of renal biopsy, higher
serum lipids at first manifestation, more steroid dependence,
higher number of relapses and a high proportion of
hypertension in SGA children were shown. In a third paper
Na and co-workers [15] analysed the records of 56 Korean
children with nephrotic syndrome. In their study steroid
resistance was seen significantly more often in the SGA
group. Zidar et al. and Na et al. investigated only MCGN
patients, Sheu and Chen identified at least one patient with
FSGS in their SGA cohort by renal biopsy. We were able to
confirm a high rate of renal biopsies in SGA children. In
contrast to those studies, we tried to investigate all our
patients with the clinical diagnosis of idiopathic nephrotic
syndrome and we included patients with FSGS as well.
Twenty-eight patients had a biopsy proven MCGN, and
nine patients out of 62 (14.5%) had FSGS. The FSGS rate
was higher than that reported in the International Study of
Kidney Disease in Children (ISKDC), with an FSGS rate of
7.9% [28]. This may explain the high rate of primary and
secondary steroid resistance (25%) in our cohort. Nevertheless,
the rate of steroid resistance was higher in the SGA
cohort. This is in line with our finding that the age at
manifestation was higher in the SGA group but did not
reach statistical significance. A median age of 2.5 years is
typical for steroid-responsive patients; patients with primary
steroid resistance present at a median age of 6 years [29].
Newer studies observe increasing rates of steroid resistance
in childhood nephrotic syndrome [30]. Steroid responsiveness
is an important prognostic parameter of idiopathic
nephrotic syndrome [31]. Nevertheless, we could not find
patients with renal failure in our study, which can be
expected in FSGS patients. A sampling error because the
data had been collected at a paediatric nephrology referral
centre, and the short observation period, may be explanations
for the difference in steroid resistance and renal survival.
In contrast to the published studies, we tried to analyse
the influence of postnatal weight gain on the later course of
disease. In our small SGA cohort we could not find a clear
pattern of catch-up growth, and, therefore, we could not
address the influence of catch-up growth of SGA children
on the course of nephrotic syndrome in later life in this
study. To find a connection between postnatal weight gain
and the course of disease independent of birth weight, we
tried to analyse the clinical course of nephrotic syndrome in
relation to the weight gain shown as SDS difference
between birth and 24 months of age. Between the four
groups with an SDS difference 1.0, there was no difference in the main aspects of clinical
course of nephrotic syndrome. Even though the number of
patients was too low for multiple regression analysis, the
comparison of the different groups may give an approximation
for the missing influence of postnatal percentile-crossing
weight gain. This question should be further pursued in a
bigger and, as far as possible, prospective study.
Another interesting feature of our study and the cited
papers on nephrotic syndrome in former SGA children is the
higher rate of hypertension in the SGA cohort. The high rate
of hypertension and the need for hypertensive treatment may
be confounded by the use of cyclosporine A and recurrent
prednisone treatment. Nevertheless, for long-term treatment

1888 Pediatr Nephrol (2007) 22:1881–1889
with cyclosporin A, the rate of hypertension is 10% [32] or
even below [33]. Development of elevated blood pressure is
one of the key features of perinatal programming by IUGR
[4], even though a meta-analysis of epidemiological studies
saw a weaker association between birth weight and later
hypertension [34] than initially suspected. Animal studies
analysed potential mechanisms of perinatal programming.
The main renal phenotype of IUGR is nephron reduction,
which could be demonstrated in different animal models of
IUGR and SGA [7, 35]. Autopsy studies confirmed the
inverse correlation between birth weight and nephron
number in humans [36]. Nephron reduction itself is seen as
a possible risk factor for the later development of hypertension
[37]. Studies in IUGR animals revealed further
influences on the development of hypertension, such as salt
intake [38, 39] or postnatal nutrition [40]. Nephron deficit,
perhaps in combination with other postnatal factors, is a risk
for the progression of secondary renal diseases. Zimanyi et
al. demonstrated an increased susceptibility to secondary
renal injury due to advanced gylcation products in a low
protein model of IUGR [41]. Our group showed increased
renal damage in anti-Thy1 nephritis as a model of
mesangioproliferative glomerulonephritis in a similar IUGR
model [42]. Even though studies on possible mechanisms in
nephrotic children are still missing, these animal studies
support the hypothesis that IUGR is a risk factor for the
progression of secondary renal injury such as idiopathic
nephrotic syndrome. Therefore, rather than nephron number,
altered glomerular inflammatory reaction might be involved
in the pathogenesis of nephrotic syndrome.
Analyses of genetic forms of nephrotic syndrome have
provided huge knowledge on the structure and function of
the slit diaphragma [1, 43]. The pathogenesis of idiopathic
nephrotic syndrome is still unclear, although studies of FSGS
have suggested the existence of a putative permeability
factor [44–46] probably derived from T cells [47]. The
relationship between MCGN and primary allergic reaction is
still under discussion [1]. More interesting are differences in
the phenotype, cytokine profiles and function of lymphocytes
of nephrotic patients during relapse in remission [48–51]. In
immunological studies of SGA cohorts, a reduced number of
T cells, a higher number of CD8-positive cells and delayed
hypersensitivity reaction were detectable [52, 53]. Knowledge
of the immunological consequences of IUGR is limited
at the moment. Therefore, since idiopathic nephrotic syndrome
is, at least partly, mediated by T cells, one might
speculate that an alteration in T cell response might be
involved in the pathogenesis of more severe nephrotic
syndrome in children with low birth weight.
In conclusion, we were able to find further evidence for the
influence of low birth weight, but not for postnatal weight
gain, on the clinical course of secondary renal injury in a
cohort of children with idiopathic nephrotic syndrome. The
mechanisms involved are not well understood. Perinatal
programming as an additional pathogenic principal in renal
disease needs further investigation. Investigation of the role of
early catch-up growth should be included in further studies.
Acknowledgements This study was supported by a grant from the
Deutsche Forschungsgemeinschaft, Bonn, Germany; SFB 423,
Collaborative Research Centre of the German Research Foundation
Kidney Injury: Pathogenesis and Regenerative Mechanisms, project
B13, to Wolfgang Rascher and Jörg Dötsch, and project Z2 to Kerstin
Amann. We thank Elke Wühl for the data for SDS calculation of
spontaneous blood pressure measurement in children. We gratefully
appreciate the support of Melek Düz in conducting this study.
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