Received: 15 May 2020 Revised: 14 June 2020 Accepted: 30 June 2020

DOI: 10.1111/cga.12384

ORIGINAL ARTICLE

Retrospective study of the renal function using estimated

glomerular filtration rate and congenital anomalies of the
kidney-urinary tract in pediatric Turner syndrome

Yukie Izumita1 | Satsuki Nishigaki2 | Mari Satoh3 | Noriyuki Takubo4 |

5 6
Chikahiko Numakura | Ikuko Takahashi | Shun Soneda | Yoshifusa Abe8 |
7

Hotaka Kamasaki9 | Yoshiaki Ohtsu10 | Junko Igaki11 | Yukihiro Hasegawa12 |

Keisuke Nagasaki13
1
Department of Pediatrics, Niigata City General Hospital, Niigata, Japan
2
Department of Pediatrics, Osaka City University Graduate School of Medicine, Osaka, Japan
3
Department of Pediatrics, Toho University Omori Medical Center, Tokyo, Japan
4
Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
5
Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Japan
6
Department of Pediatrics, Akita University Graduate School of Medicine, Akita, Japan
7
Department of Pediatrics, St. Marianna University School of Medicine, Kanagawa, Japan
8
Children Medical Center, Showa University Koto Toyosu Hospital, Tokyo, Japan
9
Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Japan
10
Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan
11
Department of Pediatric Endocrinology and Metabolism, Okinawa Prefectural Nanbu Medical Center & Children's Medical Center, Okinawa, Japan
12
Division of Endocrinology and Metabolism, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan
13
Division of Pediatrics, Department of Homeostatic Regulation and Development, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

Correspondence
Keisuke Nagasaki, MD, Division of Pediatrics,
Department of Homeostatic Regulation and
Development, Niigata University Graduate
School of Medical and Dental Sciences, 1-757
Asahimachi, Niigata 951-8510, Japan.
Email: nagasaki@med.niigata-u.ac.jp
Abstract
Although Turner syndrome (TS) is frequently associated with congenital anomalies of
the kidney-urinary tract (CAKUT), which is a major cause of pediatric chronic kidney
disease, renal function in TS is usually considered normal. The present study aimed to
analyze the frequency of renal dysfunction and CAKUT in pediatric patients with
TS. Our study included 122 patients with TS between the ages of 2 and 18 years
from 30 hospitals across Japan. Clinical data related to renal function and CAKUT
were retrospectively collected. The estimated glomerular filtration rate (eGFR) was
calculated using the serum creatinine-based formula recommended by the Japanese
Society for Pediatric Nephrology. An eGFR <90 mL/min/1.73 m2 for two consecutive
years was defined as renal dysfunction. Fifteen (13.5%) of 122 patients had CAKUT,
and four patients had renal dysfunction (3.2%, 95% confidence interval: 0%-6.7%).
Three of the four did not have CAKUT. Of the CAKUT manifestations, horseshoe kid-
ney, renal hypodysplasia, and multicystic dysplastic kidney were seen in nine, two,
and one patient, respectively. Eight of the nine patients with horseshoe kidney had a
normal renal function; however, the remaining patient with renal hypodysplasia had

Congenit Anom. 2020;1–5. wileyonlinelibrary.com/journal/cga © 2020 Japanese Teratology Society 1

2 IZUMITA ET AL.
renal dysfunction. A small percentage of patients with pediatric TS may had an eGFR
below 90 mL/min/1.73 m2 which was not necessarily associated with CAKUT.
KEYWORDS
CAKUT, horseshoe kidney, renal function, turner syndrome
1 | I N T RO DU CT I O N
Turner syndrome (TS) has an incidence of one in 2500 to 3000 live
female births.1 TS is caused by complete or partial monosomy of the
X chromosome and is characterized by various features including
short stature, ovarian failure, congenital heart disease, and other
1,2
minor stigmata. Furthermore, renal anomalies are present in up to
30 to 40% of patients with TS.1,2
Horseshoe kidney is the most common structural renal anomaly
observed in patients with TS and has a frequency of 7% to 14%.2-6 In
addition, duplex collecting system and unilateral renal agenesis are
known to occur in the syndrome.2-6 These anomalies are collectively
called congenital anomalies of the kidney-urinary tract (CAKUT),
which are a major cause of pediatric chronic kidney disease.8 Although
renal function in TS is considered normal,1 it has not been extensively
studied.
We hypothesized that renal function in patients with TS would be
lower than in healthy controls, possibly due to the high frequency of
CAKUT in TS. This study aimed to determine the frequency of renal
dysfunction and CAKUT in pediatric patients with TS in Japan.
2 | SUBJECTS AND METHODS
The present study was a multi-institutional, retrospective, semi-
longitudinal study. Data were collected from 30 different hospitals in
Japan from April 2016 to January 2017. The hospitals belonged to the
Trace the Turner Study Group (TTT-study group), an organization
formed by more than 30 institutions throughout Japan. The present
study was approved by the Ethics Committee of Niigata University
(No. 2399). The patients and/or their parents were informed of their
right to refuse the use of the patients' medical records in the study.
Patients with TS between the ages of 2 and 18 years from the
30 hospitals were included. TS was diagnosed by chromosomal analy-
sis of peripheral blood. The exclusion criteria were patients with oral
glucocorticoid therapy due to an autoimmune or other diseases, a his-
tory of radiotherapy or chemotherapy for malignancies, severe
chronic illness, and body weight <80% of the ideal body weight as cal-
culated by sex, age, and height according to the previously reported
method.9
Clinical data, including height, weight, serum creatinine (Cr), and
blood pressure were collected retrospectively. Serum Cr levels were
determined using the enzymatic method. Data on karyotype, perinatal
history, growth hormone (GH) therapy, congenital heart diseases, and
urological complications, such as CAKUT, hematuria and proteinuria,
and a history of urinary tract infection, were also obtained. Hematuria
and proteinuria were defined as consecutively positive red blood cells
(>5 cells)/high power field and >30 mg/dL, respectively, with no
improvement. The diagnosis of congenital heart diseases and CAKUT
was made using ultrasonography at each institution.
The glomerular filtration rate (GFR) was estimated using the follow-
ing Cr-based formula proposed by the Japanese Society for Pediatric
Nephrology10: estimated GFR (eGFR) (mL/min/1.73 m2) = 110.2 × (ref-
erence serum Cr [mg/dL]/patient serum Cr [mg/dL] + 2.93).
The reference serum Cr concentration (y) for males and females
was calculated using body length (x):
7
Males: y = − 1:259x5 + 7:815x4 −18:57x3 + 21:39x2 −11:71x + 2:628:
Females: y = −4:536x5 + 27:16x4 − 63:47x3 + 72:43x2 −40:06x + 8:778:
Renal dysfunction was defined as an eGFR <90 mL/min/1.73 m2
for two consecutive years and no improvement over 90 mL/
min/1.73 m2 until the last observation. Patients were classified as
having mild (60 mL/min/1.73 m2 ≤ eGFR <90 mL/min/1.73 m2), mod-
erate (30 mL/min/1.73 m2 ≤ eGFR <60 mL/min/1.73 m2), or severe
(eGFR <30 mL/min/1.73 m2) renal dysfunction.11
3 | RE SU LT S
Clinical information and detailed karyotypes are shown in Table 1.
The present study included 122 patients with TS, and the average
period of observation was 5.0 ± 2.8 (mean ± SD) years. In total,
27 patients (22.1%) had non-mosaic 45,X karyotype, 84 patients
(68.7%) had 45,X with mosaicism, and 11 patients (9.0%) had
X-structural abnormalities (Table 1). No patient had high blood pres-
sure, and 25 (20.5%) patients had congenital heart disease, such as an
atrial septal defect, bicuspid aortic valve, or aortic coarctation.
4 | CAKUT AND OTHER UROLOGICAL
COMP LIC A TI ONS
After excluding 11 patients lacking information about these complica-
tions, CAKUT were observed in 15 (13.5%) of 111 patients (Table 2).
Of these, nine had horseshoe kidney, three had hydronephrosis, and
two had hypodysplasia. Multicystic dysplastic kidney disease, renal
rotation abnormality, and duplicated ureter were diagnosed in one
patient each. Vesicoureteral reflux and hydronephrosis were observed
IZUMITA ET AL. 3

TABLE 1 Clinical information and karyotype Urinalysis data were available for 97 of the 122 patients. Eighteen

Mean (SD) of the 97 patients (18.6%) had microscopic hematuria, ten (10.3%)
Gestational age (weeks) 38.3 (1.6) had proteinuria, and five had both hematuria and proteinuria. The fre-
Birth weight (g) 2595.5 (575.9) quency of hematuria with and without CAKUT was 20% and 17%,
Karyotype Number (%) respectively. The difference was not statistically significant.
45,X 27 (22.1)
45,X mosaicism 84 (68.7)
45,X/46,r(X) or +mar 21 5 | RE N A L F UN CT ION
45,X/46,XX 20
Figure 1 shows four patients (3.2%) with renal dysfunction (one with
45,X/47,XXX or +mar 18
moderate, three with mild impairment (95% confidence interval: 0%-
45,X/46,X,idic(X) 12
6.7%). Patient A, who had horseshoe kidneys and hypodysplasia,
45,X/46,X,i(X) 6
showed mildly decreased renal function on her first visit at age
45,X/46,X,del(X) 4
6 years. Her karyotype was 45,X/46,X,r(X), and she previously
45,X/46,X,idic(Y) 2
received the diagnosis of horseshoe kidney and Hashimoto's disease.
45X/46,X,r(X)/46X,idic(X) 1 She also had isolated microscopic hematuria concomitant with a low
Structural X chromosome abnormality 11 (9.0) eGFR since the first visit, which was followed by a gradual decline in
46,Xdel(X) 6 subsequent years. A renal biopsy at age 10 years led to the diagnosis
46,X,i(X) 4 of renal hypodysplasia with fibrosis and cell infiltration, which were
46,Xr(X) 1 indicative of end-stage renal disease. The renal hypodysplasia was
Low birth weight infant (N = 110) 45 (40.9) likely to be associated with renal dysfunction. Her eGFR levels even-

Growth hormone treatment
Congenital heart disease
Hypertension
TABLE 2 CAKUT and other urological complications
Structural renal anomaliesa
110 (90.2) tually declined to 49.6 mL/min/1.73 m2 at age 13 years (Figure 1).
The eGFR of patients B, C, and D, who did not have CAKUT, appeared
25 (20.5)
to decline to mildly low (Figure 1). Patients B, C, and D had karyotypes
0 (0)
45,X/46,r(X), 45,X/47,XXX, and 45, X, respectively. Patients B and C
had no other complications, and patient D had coarctation of aorta.
Of the 15 patients with CAKUT, only one (6.6%) had renal dys-
function (Patient A). On the other hand, of 96 patients without
CAKUT, three (3.1%) had mild renal dysfunction (Patients B, C, and
Number Frequency (%) D). Table 3 shows the median, the 2.5 and 97.5 percentiles, and the
15 13.5 mean and SD of the eGFR values in each TS age group after excluding

Horseshoe kidney 9 8.1

the four patients with renal dysfunction. Notably, the average eGFR
in each age group did not decline with age.
Hydronephrosis 3 2.7
Renal hypodysplasia 2 1.8
Multicystic dysplastic kidney 1 0.9
6 | DI SCU SSION
Renal rotation anomaly 1 0.9
Duplicated renal pelvic ureter 1 0.9
In the present study, the four patients (3.2%) with pediatric TS had
Urinary tract infectious disease 0 0.0 renal dysfunction, which was moderate in one patient with horseshoe
Vesico-ureteric reflux 1 0.9 kidney and hypodysplasia and mild in the remaining three patients
Microscopic hematuriab 18 18.6 without CAKUT.
Proteinuriab 10 10.3 It is important to consider the possibility of a decline in GFR with
a age in TS patients, as suggested by our findings, for the management
Some patients had multiple structural renal anomalies. The total number
is shown. of these patients. To the best of our knowledge, only one study has
b
Data available for 97 patients, CAKUT, congenital anomalies of the evaluated renal function in TS patients. Hamza et al12 reported that
kidney-urinary tract. 44.44% of the patients (N = 90) in his research had renal dysfunction
as assessed Tc-99 m-DTPA scintigraphy, and that the total GFR
decreased with increasing age. They also showed that the frequency
in one and three patients, respectively. The frequency of CAKUT by of subnormal GFR was higher in patients with TS with renal anomalies
karyotype was 11.5%, 7.4%, and 25.0% in patients with 45,X mono- detected by ultrasonography than in those with normal kidneys.12
somy, 45,X with mosaicism, and X-structural abnormalities, respec- Another report described two adult patients with TS who received
tively. The 15 patients with CAKUT did not have a history of urinary the diagnosis of end-stage renal disease.13 One patient, in whom TS
tract infection. was associated with diabetes mellitus, began dialysis at age 44 years
4 IZUMITA ET AL.

F I G U R E 1 Time course of
estimated glomerular filtration rate
(eGFR) in patients with Turner
syndrome with renal dysfunction.
Patient A had mildly decreased renal
function at the first visit. Her eGFR
declined gradually every year, and by
the end of the observation period, her
eGFR was 49.6 mL/min/1.73 m2. The
eGFR in patients B, C, and D showed
mildly decreased renal function

TABLE 3 eGFR vs age in children with Turner syndorme

eGFR (mL/min/1.73 m2)

Age (years) na 2.5th percentile 50th percentile 97.5th percentile Mean SD Reference median16
2-4 42 95.2 124.3 159.1 124.4 22.1
5 27 79.0 112.1 160.5 113.6 21.4 109.6
6 33 85.7 117.4 183.4 119.1 25.8 116.5
7 37 79.9 111.2 171.6 114.2 23.5 113.6
8 38 83.9 114.7 165.7 117.0 22.1 109.7
9 37 84.8 111.9 162.7 116.3 20.6 109.9
10 45 93.0 117.1 145.6 115.6 15.6 113.1
11 49 90.8 115.8 151.2 117.4 16.6 123.1
12 52 93.8 121.6 149.7 119.6 15.3 110.4
13 50 89.3 118.7 163.6 118.5 18.9 115.6
14 47 83.7 118.4 166.2 123.2 21.3 106.6
15 42 94.7 120.0 154.7 121.5 15.5 112.2
16 40 90.3 116.6 153.5 118.2 15.4 108.4
17 34 83.4 111.1 138.7 109.6 15.9
18 28 94.1 115.7 150.4 116.2 14.2

Abbreviations: eGFR, estimated glomerular filtration rate; SD, standard deviation.

a
Except for four patients with impaired renal function.

while the other needed dialysis at age 42 years. There was no mention
of an association with CAKUT in these patients. These previous
reports indicated that the renal function of patients B, C, and D
required long-term monitoring.
It should be clarified how many patients with TS with CAKUT
may experience renal dysfunction at some point in their lives. CAKUT
generally predispose patients to renal dysfunction.8,14 For example,
adult patients with horseshoe kidneys are at risk of end-stage renal
disease, possibly due to the high prevalence of urinary tract infec-
15
tions. Careful, long-term follow-up of renal function is required in
patients with TS with horseshoe kidneys as for patients with other
CAKUT conditions.
The cause of the renal dysfunction in the three patients without
CAKUT is unknown. First, the patients may have had hypodysplasia.
However, they were not biopsied. Second, TS itself may be a risk fac-
tor of renal dysfunction even without CAKUT. Hamza et al12 reported
that 40% of patients with TS showed asymmetric renal function on
renal scintigraphy, which is the earliest indicator of future renal dys-
function even when the GFR is within the normal range. Third, minor
renal structural abnormalities, such as renal malrotation or mild
hydronephrosis, may have been overlooked by ultrasonography at
each hospital in the present study.
The present study is one of the first to evaluate the eGFR in a
large cohort of pediatric patients with TS. No other clinical research
IZUMITA ET AL.
has focused on CAKUT and semi-longitudinal renal function in
TS. However, this study has several limitations. First, this study was
retrospective. For example, blood pressure was not measured in a sys-
tematic fashion. Second, the eGFR calculation formula included body
length and has not been validated for use with patients with TS with
short stature. Third, the study cohort was small, as seen in the number
(N = 4) of the patients with renal dysfunction. Therefore, it remains to
be established whether the renal dysfunction observed was specific
to TS. Indeed, the 95% confidence interval for renal dysfunction in
the TS patients was 0% to 6.7%; Uemura et al16 reported that more
than 2.5% of healthy children have an eGFR <90 mL/min/1.73 m2.
In conclusion, a small percentage of patients with pediatric TS
had an eGFR <90 mL/min/1.73 m2 which was not necessarily associ-
ated with CAKUT.
ACKNOWLEDGMENTS
Permission has been obtained from the patient and the patient's par-
ents for presentation. We are grateful to Dr. Takeshi Yamada and
Dr. Masahiro Kaneko for their helpful input.
CONF LICT S OF INTE R ES T
The authors declare no conflict of interest.
ORCID
Keisuke Nagasaki https://orcid.org/0000-0002-5882-661X
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How to cite this article: Izumita Y, Nishigaki S, Satoh M, et al.
Retrospective study of the renal function using estimated
glomerular filtration rate and congenital anomalies of the
kidney-urinary tract in pediatric Turner syndrome. Congenit
Anom. 2020;1–5. https://doi.org/10.1111/cga.12384