Efficacy and safety of angiotensin II receptor type 1 antagonists in children and
adolescents
Siegtraut Dorothea Herder1
and Hartmut Morck1
, Ernst Weber2, Almuth Winkemann3, Christoph Herder4
(1) Department of Pharmacy, Philipps University Marburg, Marburg, Germany
(2) Formerly: Department of Biostatistics, University Heidelberg, Heidelberg,
Germany
(3) General Practitioner in private practice, Siegen, Germany
(4) Pediatrician in private practice, Siegen, Germany
Our purpose was to evaluate the effects of angiotensin II receptor type 1 antagonists
(ARAs) in children and adolescents with hypertension or/and several kinds of
nephropathies on blood pressure (BP) and proteinuria and to evaluate related safety
issues. Data sources were Medline, Embase, The Cochrane Library, BIOSIS Previews,
contact with investigators and manufacturers, personal bibliography of the lead author,
and manual searches. We selected randomized controlled trials (RCTs), uncontrolled
trials, and case series investigating ARAs in children and adolescents, as well as case
reports about adverse events and the embryotoxic effects of ARAs in children. In four
RCTs with 698 individuals, mean systolic blood pressure (BP) decreased by
10.5 mmHg [95% confidence interval (CI) 9.8−11.2] and mean diastolic BP by
6.4 mmHg (95% CI 5.8−7.0). Proteinuria decreased by 30−64% (range) in two RCTs
and four case series. Safety data were comparable with adult safety data. ARAs can be
considered effective and safe in lowering BP and proteinuria in the pediatric age group.
The correlation between the surrogate parameters BP and proteinuria with clinical end
points is documented to a large degree. The evidence is based on RCTs and also on
lower evidence levels, such as case series. In some conditions, RCTs in children are not
feasible. Registers could provide more evidence in the future.
Proteinuria and events beyond the slit
Rikke Nielsen1 and Erik Ilsø Christensen1
(1) Department of Anatomy, Section of Cell Biology, Aarhus University, Building
1234, DK-8000 Aarhus C, Denmark
The origin of proteinuria is found in either the glomerular filtration device or the
proximal tubular reabsorption machinery. During equilibrium, small amounts of
predominantly low molecular weight proteins are filtered and reabsorbed by the
receptor complex megalin/cubilin/amnionless. This results in a protein-free filtrate
passing further down the tubule. During glomerular damage, the reabsorption
machinery in the proximal tubule is challenged due to elevated amounts of proteins
passing the glomerular filtration slits. Even though it is considered to be a high-capacity
system, several conditions result in proteinuria, thus exposing the cells in the rest of the
nephron to a protein-rich environment. The impact on cells in the more distal part of the
nephron is uncertain, but studies support an involvement in fibrosis development.
Protein accumulation in lysosomes of the proximal tubule, due to increased protein
internalization, is thought to mediate inflammation and fibrosis, eventually leading to
renal failure. In contrast, low molecular weight proteinuria develops when the endocytic
machinery is malfunctioning either by direct or indirect causes such as in Imerslund-
Gräsbeck syndrome (IGS) or Dent’s disease, respectively. This review discusses the
origin of proteinuria and describes the structural fundament for protein reabsorption in
the proximal tubule as well as conditions resulting in low molecular weight proteinuria.
Idiopathic immunoglobulin A nephropathy in children and adolescents
Ronald J. Hogg1
(1) Department of Pediatrics, The Children’s Hospital, Scott and White Memorial
Hospital and Clinic, and the Scott, Sherwood and Brindley Foundation and Texas
A&M College of Medicine, 2401 South 31st Street, Temple, Texas 76508, USA
Immunoglobulin A nephropathy is now recognized as the glomerular disease most often
associated with progressive renal failure in patients around the world. In many cases it
is not known when the disease starts to inflict glomerular injury, but recent studies that
have shown genetically determined abnormalities in glycosylation of the IgA molecule
suggest that this may begin in early life. This review focuses on recent advances in our
understanding of IgA nephropathy, with special emphasis on clinical aspects of the
disease when it presents in children and adolescents. In addition, the sections dealing
with therapeutic options for patients with IgA nephropathy concentrate on studies that
have been carried out on children. Whenever possible, data from randomized controlled
clinical trials have formed the basis for recommendations. Unfortunately, this is not
always possible, because of the lack of such trials in patients with IgA nephropathy.
Physiopathology and etiology of stone formation in the kidney and the urinary
tract
Andrew P. Evan1
(1) Department of Anatomy and Cell Biology, Indiana University School of Medicine,
635 Barnhill Drive, MS 5055, Indianapolis, IN 46220, USA
All stones share similar presenting symptoms, and urine supersaturation with respect to
the mineral phase of the stone is essential for stone formation. However, recent studies
using papillary biopsies of stone formers have provided a view of the histology of renal
crystal deposition which suggests that the early sequence of events leading to stone
formation differs greatly, depending on the type of stone and on the urine chemistry
leading to supersaturation. Three general pathways for kidney stone formation are seen:
(1) stones fixed to the surface of a renal papilla at sites of interstitial apatite plaque
(termed Randall’s plaque), as seen in idiopathic calcium oxalate stone formers; (2)
stones attached to plugs protruding from the openings of ducts of Bellini, as seen in
hyperoxaluria and distal tubular acidosis; and (3) stones forming in free solution in the
renal collection system, as in cystinuria. The presence of hydroxyapatite crystals in
either the interstitial or tubule compartment (and sometimes both) of the renal medulla
in stone formers is the rule and has implications for the initial steps of stone formation
and the potential for renal injury.
Fluid and electrolyte therapy: a primer
Aaron Friedman1
(1) Department of Pediatrics, University of Minnesota, 516 Delaware Street SE,
Minneapolis, MN 55455, USA
The prescription of fluid therapy in pediatrics is a common clinical event. The
foundations that underpin such therapy should be understood by all clinicians involved
in the short-term care of children. This article describes some important basic principles
of fluid management.
Toll-like receptors 2 and 4 in renal ischemia/reperfusion injury
Krisztina Rusai1, Daniel Sollinger1, Marcus Baumann1, Bettina Wagner1,
Matthias Strobl1, Christoph Schmaderer1, Marcel Roos1, Carsten Kirschning2,
Uwe Heemann1 and Jens Lutz1
(1) Department of Nephrology, Technical University Munich, Klinikum rechts der Isar,
Ismaninger Str. 22, 81576 Munich, Germany
(2) Institute of Microbiology, Immunology and Hygiene, Technical University Munich,
Klinikum rechts der Isar, Munich, Germany
Toll-like receptors (TLRs) are an evolutionarily conserved family of cell membrane
receptors that are part of the innate immunity system playing an important role as a first
response to tissue injury. TLR2 and TLR4 are constitutively expressed on renal
epithelium, and their expression is enhanced following renal ischemia/reperfusion (I/R)
injury. Genetic deletion of either TLR2 or TLR4 protects from renal I/R injury.
However, it is not known whether deletion of both combined protects the kidney more
than a deletion of either one alone. Therefore, we performed renal I/R injury in mice
lacking TLR2, TLR4, and TLR2/4, respectively. Our results demonstrate that there are
no significant differences regarding protection from renal I/R injury in TLR2/4(−/−)
compared with either TLR2(−/−) or TLR4(−/−) gene-targeted mice as determined by
histological evaluation and renal functional parameters. Furthermore, there was no
difference in the number of apoptotic tubular cells and in nuclear translocation of
nuclear factor kappa-B (NF-κB) between the TLR-gene-targeted groups. In parallel, in
vitro experiments did not demonstrate an additional effect of the double genetic deletion
compared with the single gene deletion with respect to tumor necrosis factor (TNF)alpha and interleukin (IL)-8 production in hypoxic isolated proximal tubular epithelial
cells of the respective animals. In conclusion, a double genetic deletion of TLR2 and
TLR4 confers a similar protection following renal I/R injury compared with single
deletions of TLR2 and TLR4.
Hypokalemic rhabdomyolysis in congenital tubular disorders: a case series and a
systematic review
Rodo O. von Vigier1, Maria Teresa Ortisi2, Angela La Manna3, Mario G. Bianchetti4
and Alberto Bettinelli5, 6
(1) Pediatric Nephrology, University Children’s Hospital Bern and University of Bern,
Bern, Switzerland
(2) Department of Pediatrics, Sant’Anna Hospital, Como, Italy
(3) Department of Pediatrics, Second University of Naples, Naples, Italy
(4) Department of Pediatrics, Bellinzona and Mendrisio, and University of Bern, Bern,
Switzerland
(5) Department of Pediatrics, San Leopoldo Mandic Hospital, Merate-Lecco, Italy
(6) Ospedale San Leopoldo Mandic, Largo Mandic 1, 23807 Merate, Italy
Hypokalemia is a recognized cause of rhabdomyolysis but very few reports document
its association with inborn renal tubular disorders. We report our experience with
hypokalemic rhabdomyolysis in 5 pediatric patients affected by inborn renal tubular
disorders and the results of a careful review of the literature disclosing 9 further cases
for a total of 14 patients (8 male and 6 female subjects, aged between 1.6 and 46,
median 16 years). The inborn renal tubular disorders underlying rhabdomyolysis were
classic distal renal tubular acidosis (n = 7), Gitelman syndrome (n = 5), classic Bartter
syndrome (n = 1), and antenatal Bartter syndrome (n = 1). In 8 patients rhabdomyolysis
followed an acute intestinal disease, an upper respiratory illness or the discontinuation
of regular medication. Five patients experienced two or more episodes of
rhabdomyolysis. In 10 patients the underlying renal tubular disorder was recognized
concurrently with the episode of rhabdomyolysis or some weeks later. In conclusion
some congenital renal tubular disorders predispose to hypokalemic rhabdomyolysis.
Prevention of discontinuation of regular medication and electrolyte repair in the context
of acute intercurrent illnesses might avoid the development of hypokalemic
rhabdomyolysis.
Changes in glomerular mesangium in kidneys with congenital nephrotic syndrome
of the Finnish type
Anne Kaukinen1
, Arvi-Matti Kuusniemi1, Heikki Helin2 and Hannu Jalanko1
(1) Children’s Hospital and Biomedicum Helsinki, University of Helsinki, P.O.Box 20,
00014 Helsinki, Finland
(2) Department of Pathology, University of Helsinki, Helsinki, Finland
Congenital nephrotic syndrome of the Finnish type (NPHS1, CNF) is an autosomal
recessive disease caused by mutations in a major podocyte protein, nephrin. NPHS1 is
associated with heavy proteinuria and the development of glomerular scarring. We
studied the cellular and molecular changes affecting the glomerular mesangium in
NPHS1 kidneys. Marked hyperplasia of mesangial cells (MC) was mainly responsible
for the early mesangial expansion in NPHS1 glomeruli. The levels of the proliferation
marker, mindbomb homolog 1 and the major MC mitogen, platelet-derived growth
factor, and its receptors, however, were quite normal. Only a small number of cells were
positive for CD68 (marker for phagocytic cells) and CD34 (marker for mesenchymal
precursor cells) in the NPHS1 mesangium. MCs strongly expressed α-smooth muscle
actin, indicating myofibloblast transformation. The expression levels of the profibrotic
mediators osteopontin and transforming growth factor β were up-regulated in NPHS1
glomeruli by 3.2 and 1.6-fold, respectively, compared to the controls. The synthesis by
MCs of the typical fibroblast products collagen I, fibronectin, and tenascin, however,
was low, and the extracellular matrix increase was caused by the accumulation of a
normal MC product, collagen IV. The results indicate that severe glomerular sclerosis
can develop without major qualitative cellular or molecular changes in the mesangium.
Combination therapy with steroids and mizoribine in juvenile SLE: a randomized
controlled trial
Yuriko Tanaka1 , Norishige Yoshikawa2, Shinzaburo Hattori3, Satoshi Sasaki4,
Takashi Ando5, Masahiro Ikeda6, Masataka Honda6 and for Japanese Study Group for
Renal Disease in Children
(1) Department of Pediatrics, Dokkyo Medical University Koshigaya Hospital, 2-1-50
Minamikoshigaya, Koshigaya City Saitama, Japan, 343-8555
(2) Department of Pediatrics, Wakayama Medical University, Wakayama, Japan
(3) Fundamental Medicine, Kumamoto Health Science University, Kumamoto, Japan
(4) Department of Pediatrics, Hokkaido University, Beijing, China
(5) Department of Economic History, School of Economics and Management, Lund
University, Lund, Sweden
(6) Department of Pediatric Nephrology, Tokyo Metropolitan Children’s Hospital,
Kiyose City, Tokyo, Japan
The initial treatment of childhood-onset systemic lupus erythematosus (SLE) is not
standardized. Although corticosteroids are the first-line therapy for SLE, long-term,
high-dose steroid therapy is associated with various side effects in children. The
Japanese Study Group for Renal Disease in Children (JSRDC) has carried out a multicenter, randomized, controlled trial to evaluate the efficacy and safety of corticosteroid
and mizoribine (MZB) therapy as an initial treatment for newly diagnosed juvenile SLE.
Twenty-eight patients were treated with a combination steroid and MZB (4–
5 mg/kg/day) (group S+M) drug therapeutic regimen, while 29 patients were treated
with steroid only (group S); both groups were followed up for 1 year. The time to the
first flare from treatment initiation was not significantly different between the two
groups (Kaplan–Meier method, p = 0.09). During the period when the steroid was given
daily (day 0–183), the time to the first flare from treatment initiation was significantly
longer in the patients of group S+M than in those of group S (log-rank test, p = 0.02). At
the end of the study period, there were no differences in the severity of proteinuria and
renal function impairment between the two groups. No patients dropped out of the trial
due to adverse events. In conclusion, our combined steroid and MZB drug therapeutic
regimen was not shown to be significantly better than the steroid-only therapy as initial
treatment for juvenile SLE. Whether MZB administered in a higher dose would be
therapeutically advantageous can only be answered by further studies.
Mycophenolate mofetil therapy for children with steroid-resistant nephrotic
syndrome
Zhihui Li1
Yan Yin1
, Cuirong Duan1, Jinhua He1, Tianhui Wu1, Mai Xun1, Yi Zhang1 and
(1) Department of Nephrology, Hunan Children’s Hospital, 82 Ziyuan Road, Changsha,
Hunan, 410007, People’s Republic of China
Treating children with steroid-resistant nephrotic syndrome (SRNS) has been a clinical
challenge for pediatricians. We recruited 24 children (18 boys and six girls) with
steroid-resistant idiopathic nephrotic syndrome (SRINS) who were <2 years. All
patients were administered prednisone 2 mg/kg per day prior to mycophenolate mofetil
(MMF). By the end of the eighth week, MMF was initiated at 25–30 mg/kg daily for
6− 12 months. Prednisone dose was reduced stepwise. Biochemical assays were
performed every 2 months. Complete remission was achieved in 15 patients, partial
remission in six, and no response to MMF was noted in three. With MMF treatment, the
levels of urinary protein and serum cholesterol decreased and that of serum albumin
increased in a time-dependant manner. We demonstrated the MMF could reduce
proteinuria in SRINS children <2 years. Our study suggests that MMF therapy might be
an effective strategy for treating SRINS in children <2 years.
Neutrophil gelatinase-associated lipocalin (NGAL): a new marker of cyclosporine
nephrotoxicity?
Anna Wasilewska1 , Walentyna Zoch-Zwierz1, Katarzyna Taranta-Janusz1 and
Joanna Michaluk-Skutnik1
(1) Department of Paediatrics and Nephrology, Medical University of Białystok, ul.
Waszyngtona 17, Białystok, 15-274, Poland
The aim of work was to investigate whether serum and urinary neutrophil gelatinaseassociated lipocalin (sNGAL and uNGAL, respectively) are potential biomarkers of
early cyclosporine A (CsA) nephrotoxicity in steroid-dependent nephrotic children
(SDNS). The study group (I) consisted of 19 children with SDNS aged 9.46 ± 5.52 years
treated with CsA. The children were examined four times: at proteinuria relapse, prior
to CsA treatment, then after 3, 6, and 12 months of CsA treatment. The control group
(II) consisted of 18 healthy children aged 3–15 years. A commercial enzyme-linked
immunosorbent assay method was used to measure NGAL concentration. The sNGAL
level in SDNS children prior to the administration of CsA was similar to that in the
healthy controls (p > 0.05), but it increased significantly during the course of treatment
(p < 0.01). The uNGAL/creatinine (cr) ratio in SDNS patients was higher before the
withdrawal of CsA therapy (p < 0.05), and was also increased at the consecutive
examinations (p < 0.01). There was a positive correlation between both sNGAL and
uNGAL levels and CsA serum level. However, based on the serum and urinary
NGAL/cr receiver operating characteristic curve and area under the curve (AUC)
analysis, it remains uncertain whether uNGAL is a good predictor of cyclosporine
nephropathy. Both sNGAL and uNGAL concentrations increased during the course of
CsA treatment. Further studies in larger groups of patients are therefore necessary to
confirm our experimental data that increased NGAL levels may be a non-invasive
marker for the early detection of tubulointerstitial damage in CsA nephrotoxicity.
Intravenous methylprednisolone in idiopathic childhood nephrotic syndrome
Mohan Shenoy1, Nicholas D. Plant1, Malcolm A. Lewis1, Mark G. Bradbury1,
Rachel Lennon1 and Nicholas J. A. Webb1
(1) Department of Paediatric Nephrology, Royal Manchester Children’s Hospital,
Oxford Road, Manchester, M13 9WL, UK
The aim of our study was to determine the clinical course of children with idiopathic
childhood nephrotic syndrome (ICNS) who received intravenous methylprednisolone
(ivMP) following failure to achieve remission with standard oral prednisolone therapy.
This study was designed as a retrospective case record review from 1993 to 2007.
Sixteen children received ivMP over the 15-year study period, of whom ten responded,
achieving clinical remission. The remaining six children with steroid resistant nephrotic
syndrome (SRNS) underwent biopsy [four focal segmental glomerulosclerosis (FSGS),
two minimal change disease (MCD)]. Three responders developed late secondary
steroid resistance (two FSGS, one MCD). At the latest follow-up (mean 6.7 years), three
of the ten ivMP responders and none (0/6) of the children with SRNS had heavy
proteinuria and chronic kidney disease (CKD) stage 3-5. The remaining 13 children
demonstrated significant steroid dependency but had achieved stable remission
following cyclophosphamide and/or ciclosporin therapy. The majority of children with
ICNS who do not respond to 4 weeks of daily prednisolone therapy will enter remission
following three to five doses of ivMP, thus avoiding a renal biopsy at initial
presentation. These children are likely to develop steroid dependency, and the majority
will require treatment with alkylating agents and/or ciclosporin to maintain remission.
The requirement for ivMP in this setting appears to be associated with a risk of
developing CKD in the longer term.
Urinary levels of interleukin-6 and interleukin-8 in patients with vesicoureteral
reflux and renal parenchymal scar
Ibrahim Gokce1 , Harika Alpay1, Nese Biyikli1, Goksenin Unluguzel2, Fuat Dede3 and
Ahmet Topuzoglu4
(1) Pediatric Nephrology Department, Marmara University Medical Faculty,
Tophanelioglu street, No. 13/15, 34662 Altunizade, Istanbul, Turkey
(2) Department of Biochemistry, Marmara University Medical Faculty,
34662 Altunizade, Istanbul, Turkey
(3) Department of Nuclear Medicine, Marmara University Medical Faculty,
34662 Altunizade, Istanbul, Turkey
(4) Department of Public Health, Marmara University Medical Faculty,
34662 Altunizade, Istanbul, Turkey
The objective of this study was to assess the urine levels of interleukin-6 (IL-6) and
interleukin-8 (IL-8) as noninvasive markers of vesicoureteral reflux (VUR) and renal
parenchymal scarring (RPS) in children in the absence of a recent urinary tract infection
(UTI) episode. Urine concentrations of IL-6 and IL-8 in 114 children aged 1 month to
16 years were evaluated. The children were divided into four groups: group 1, 26
children with VUR and RPS; group 2, 27 children with VUR without RPS; group 3, 34
children with RPS without VUR, group 4, 27 children without VUR and RPS, as the
control group. After the first assessment, the children were divided into four larger
groups for comparison purposes: group A (groups 1+2), 53 children with VUR; group B
(groups 3+4), 61 children without VUR; group C (groups 1+3), 60 children with RPS;
group D (groups 2+4), 54 children without RPS. Urinary IL-6 and IL-8 concentrations
were determined. To avoid dilution effects and to the standardize samples, urinary
levels of IL-6 and IL-8 were expressed as the ratio of cytokine to urinary creatinine
(pg/mg). The median urine IL-6/creatinine was significantly higher in patients with
VUR than in those without VUR (5.72 vs. 3.73). In patients with VUR, there was a
significant but rather weak correlation between IL-6/creatinine concentrations and the
reflux grade (p < 0.05, R = 0.305). The median urine IL-8/creatinine was significantly
higher in patients with RPS than in those without RPS (43.12 vs. 16.36). In patients
with RPS, there was a significant but rather weak correlation between IL-8/creatinine
concentrations and the renal scar grade (p < 0.05, R = 0.251). The results of this study
provide preliminary evidence that children with VUR have a high urine IL-6
concentration, whereas children with RPS have a high urine IL-8 concentration.
Are renal volumes measured by magnetic resonance imaging and threedimensional ultrasound in the term neonate comparable?
Alison L. Kent1, 2 , Rajeev Jyoti3, Cameron Robertson3, Lisa Gonsalves3,
Sandra Meskell4, Bruce Shadbolt5, 2 and Michael C. Falk6
(1) Department of Neonatology, Canberra Hospital, PO Box 11, Woden, 2606, ACT,
Australia
(2) Australian National University Medical School, Canberra, ACT, Australia
(3) Department of Medical Imaging, Canberra Hospital, Woden, ACT, Australia
(4) Centre for Newborn Care, Canberra Hospital, Woden, ACT, Australia
(5) Clinical Epidemiology Unit, Canberra Hospital, Woden, ACT, Australia
(6) Department of Nephrology, Canberra Hospital, Woden, ACT, Australia
Renal volume, but not renal length, has been shown to be positively correlated with
renal function. Three-dimensional (3D) ultrasound and magnetic resonance imaging
(MRI) are two modalities used to assess renal volume. The aim of our study was to
determine whether 3D ultrasound measurements of renal volume in the neonate are
comparable to those of MRI measurements. Preterm and term neonates had an MRI and
3D ultrasound to determine renal volume at the same time as they had an MRI brain
scan for other clinical conditions. The preterm neonates were all term corrected age, and
the term neonates were 1–4 weeks of age. None of the kidneys examined were
abnormal. There were no significant differences in the weight or length of the preterm
and term infants at the time of their MRI scan. The left renal length was significantly
longer according to MRI measurements than according to 3D ultrasound measurements
(p = 0.02). Renal volumes of both the left and right kidney were greater when measured
by MRI than by 3D ultrasound (p < 0.0001, respectively). Total volumes of the kidneys
were greater when measured by MRI than by 3D ultrasound (p = 0.008). Renal volume
in neonates was significantly less when evaluated by 3D ultrasound than by MRI. These
results demonstrate that MRI and 3D ultrasound renal volumes are not comparable in
the neonatal population and, therefore, the same radiological modality should be used if
repeat volume measurements are to be performed.
Risk factors in community-acquired urinary tract infections caused by ESBLproducing bacteria in children
Rezan Topaloglu1 , Ilkay Er2, Bahar Guciz Dogan3, Yelda Bilginer1, Fatih Ozaltin1,
Nesrin Besbas1, Seza Ozen1, Aysin Bakkaloglu1 and Deniz Gur4
(1) Department of Pediatric Nephrology, Hacettepe University Faculty of Medicine,
Ankara, 06100, Turkey
(2) Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara,
Turkey
(3) Public Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey
(4) Microbiology Laboratory, Hacettepe University Children’s Hospital, Ankara,
Turkey
In this study, risk factors were investigated in children with community-acquired
urinary tract infections (UTI) caused by extended-spectrum beta-lactamases (ESBL)producing E. coli or Klebsiella spp. One hundred and fifty-five patients were diagnosed
with ESBL-positive UTI (case group) in the outpatient clinics of Hacettepe University
Children’s Hospital between 1 January 2004 and 31 December 2006. A control group,
155 out of 4,105 children, was matched by age and sex among children with ESBLnegative UTI. A total of 310 patients’ files were evaluated retrospectively. As regards
the symptoms of UTI, no statistical differences were seen between the two groups.
Although the most frequently isolated microorganism was E. coli in both groups,
Klebsiella spp. was found to be more frequent in those diagnosed with ESBL(+) UTI (p < 0.001). Having an underlying disease and hospitalization, infections, and use of
antibiotics within the last 3 months were found to be potential risk factors (p < 0.001).
With conditional logistic regression analysis, having an underlying disease and
hospitalization within the last 3 months were identified as independent risk factors for
ESBL(+) UTI. In conclusion, the recognition of risk factors for UTI, caused by
ESBL(+) bacteria in children, may aid in the identification of high-risk cases and may
enable proper management of these patients.
On the relationship between glomerular filtration rate and serum creatinine in
children
Hans Pottel1
, Felix M. Mottaghy2, 5, Zahur Zaman3 and Frank Martens4
(1) Interdisciplinary Research Center, Catholic University of Leuven, Kortrijk Campus,
Etienne Sabbelaan 53, 8500 Kortrijk, Belgium
(2) Department of Nuclear Medicine, University Hospital KU Leuven, Leuven,
Belgium
(3) Department of Laboratory Medicine, University Hospital KU Leuven, Leuven,
Belgium
(4) Department of Clinical Chemistry, AZ Groeninge Hospital, Kortrijk, Belgium
(5) Present address: Department of Nuclear Medicine, University Hospital Aachen,
Aachen, Germany
The Schwartz formula (eGFR = kL/Scr, with k = 0.55) to determine the estimated
glomerular filtration rate (eGFR) in children with chronic kidney disease (CKD), based
on length (L) and serum creatinine (Scr) has recently been updated for enzymatic serum
creatinine concentrations, resulting in k = 0.413. Based on a meta-analysis, we evaluated
the validity of this updated equation and other published equations for healthy children.
This is the first time that publicly available data for healthy children of uncorrected and
body surface area (BSA)-corrected median GFR have been combined with median
serum creatinine values and median lengths and weights from different sources in the
literature to evaluate several statistical models to estimate GFR in children. For
enzymatic serum creatinine, we show that the simple model for uncorrected GFR
(uGFR = k′L3/Scr, with k′ = 1.32 × 10−5) and the BSA-corrected GFR (cGFR = kL/Scr,
analogous to the Schwartz formula), with an important age-dependent adaptation for k
(
), correlate extremely well with chromium-51–
51
ethylenediamine tetra-acetic acid ( Cr-EDTA) data for children between 1 month and
14 years of age. With this age-dependent modification for k, presented here, the simple
bedside calculation tool derived by Schwartz can be used for screening all children for
CKD. When height information is not available, the Lund–Malmö equation is an
excellent alternative.
Clinical characteristics and outcomes of children with stage 3–5 chronic kidney
disease
Tran Thi Mong Hiep1 , Khalid Ismaili2, Frederic Collart3, Rita Van DammeLombaerts4, Nathalie Godefroid5, Marie-Sophie Ghuysen6, Koen Van Hoeck7,
Ann Raes8, Françoise Janssen2 and Annie Robert9
(1) Department of Pediatrics, Nhi Dong 2 Hospital-Grall, University Pham Ngoc
Thach, 86/2 Thanh Thai Quan 10, Ho Chi Minh City, Vietnam
(2) Department of Pediatric Nephrology, Hôpital Universitaire des Enfants–Reine
Fabiola, Université Libre de Bruxelles (ULB), Brussels, Belgium
(3) Department of Nephrology, Hôpital Universitaire Brugmann, Brussels, Belgium
(4) Department of Pediatric Nephrology and Organ Transplantation, UZ Gasthuiberg,
Leuven, Belgium
(5) Department of Nephrology, Université catholique de Louvain (UCL), Brussels,
Belgium
(6) Department of Pediatric Nephrology, Centre Hospitalier Chrétien et Centre
Hospitalier Universitaire de Liège, Liege, Belgium
(7) Department of Pediatric Nephrology, Universitair Ziekenhuis Antwerpen, Edegem,
Belgium
(8) Department of Pediatric Nephrology, Universitair Ziekenhuis Gent, Ghent, Belgium
(9) Department of Epidemiology and Biostatistics, Université catholique de Louvain
(UCL), Brussels, Belgium
(10) Hôpital Tivoli, La Louvière, Belgium
The aim of this study was to report on the clinical characteristics and outcomes of
Belgian children with chronic kidney disease (CKD). Between 2001 and 2005, we
followed 143 new successive patients younger than 20 years of age with a glomerular
filtration rate of <60 ml/min/1.73 m2 prospectively in a Belgian department of pediatric
nephrology. The incidence of diagnosed CKD was 11.9 per million child population
(pmcp), and the incidence of renal replacement therapy was 6.2 pmcp. There were 67%
patients in CKD stage 3, 19% in CKD stage 4 and 14% in CKD stage 5. Patients with
congenital anomalies of the kidney and urinary tract (CAKUTs), hereditary diseases and
glomerular diseases were diagnosed at a median age of 1, 2 and 10 years, respectively.
CAKUTs were the main causes of CKD, accounting for 59% of all cases. After 3, 4 and
5 years of follow-up, 27, 31 and 38% of patients treated conservatively, respectively,
reached end-stage renal failure (ESRF). The progression rate to ESRF was eightfold
higher in patients with CKD stage 4 than in those with CKD stage 3. Among our patient
group, hereditary diseases progressed more rapidly to ESRF than CAKUTs.
Transplantation was performed preemptively in 22% of these children. Infections and
cardiovascular diseases were the main causes of death.
Cutaneous warts in children before and after renal transplantation
Andy Lunn1, Jane Ravenscroft2 and Alan R. Watson1
(1) Children’s Renal and Urology Unit, Queens Medical Centre Campus, Nottingham
University Hospitals NHS Trust, Derby Road, Nottingham, NG7 2UH, UK
(2) Department of Dermatology, Nottingham University Hospitals NHS Trust,
Nottingham, UK
Cutaneous warts occur in 3.9–4.9% of children in the UK. The incidence is increased in
organ transplant recipients and may be increased in patients with chronic kidney disease
(CKD), since uraemia reduces the immune system’s function. We surveyed the records
from our CKD and renal transplant clinic to ensure patients with warts were identified
and appropriately treated. Data were collected by questionnaire. The presence of warts,
location, treatment, levels of pain and emotional upset were recorded. Nine of 49
(18.4%) pre-transplantation patients (33 male, median age 12.1 years) were currently
suffering from warts compared with 17 of 60 (28.3%) post-transplantation patients (34
male, median age 13.9 years). A further 14 pre-transplantation and 16 posttransplantation patients had previously suffered from warts which had resolved. Fortyone patients had sought treatment for warts, mainly from primary care. Five patients, all
having received transplants, were seen by a dermatologist. Self-rated levels of pain and
emotional upset were generally low, apart from those of four adolescent patients who
expressed significant emotional upset. We concluded that cutaneous warts are more
common among CKD patients. Appropriate information and treatment are required
before and after transplantation. The majority of warts can be treated in primary care,
but selected patients with extensive warts that cause distress need early referral for
dermatology opinion.
A novel mutation in the Complement Factor B gene (CFB) and atypical hemolytic
uremic syndrome
Hanan Tawadrous1 , Tara Maga2, Josefina Sharma1, Juan Kupferman3,
Richard J. H. Smith2 and Morris Schoeneman1
(1) Division of Pediatric Nephrology, SUNY Downstate Medical Center, 450 Clarkson
Avenue, Brooklyn, NY 11203, USA
(2) Interdepartmental Genetics PhD Program, Molecular Otolaryngology and Renal
Research Laboratories, University of Iowa, 200 Hawkins Drive, Iowa City,
IA 52242, USA
(3) Division of Pediatric Nephrology, Maimonides Medical Center, 49 Street and Fort
Hamilton Parkway, Brooklyn, NY 11245, USA
We report the case of an 8-year-old girl diagnosed with atypical hemolytic uremic
syndrome (aHUS) with a complement factor B (CFB) gene mutation. aHUS is a disease
of complement dysregulation. In approximately 50% of patients, mutations are
identified in genes encoding regulators of complement—complement factor H (CFH),
membrane cofactor protein or complement factor I (CFI)—or activators of
complement—complement factor B (CFB) or C3. The mutation in this patient was
identified in exon 12 of CFB and changes a lysine at amino acid position 533 to an
arginine (c.1598A>G p.Lys533Arg). The two other mutations previously reported in
CFB associated with aHUS are c.858C>G, p.F286L in exon 6 and c.967A>Gp.K323E
in exon 7.
Hypokalemic rhabdomyolysis in a child with Gitelman’s syndrome
Hideki Kumagai1
, Shizuko Matsumoto1 and Kandai Nozu2
(1) Department of Pediatrics, Hitachiomiya Saiseikai Hospital, 3033-3 Tagouchi-cho,
Hitachiomiya Ibaraki, 3192256, Japan
(2) Department of Pediatrics, Kobe University Graduate School of Medicine,
Kobe Hyogo, 6500017, Japan
Abstract
We report here the first published case of a pediatric patient with Gitelman’s syndrome
(GS) in whom hypokalemia-associated rhabdomyolysis developed. A 13-year-old girl
was admitted with weakness of the extremities, walking difficulty and calf pain.
Laboratory data showed a serum potassium level of 2.1 mmol/l and a serum creatinine
phosphokinase level of 1,248 IU/l plus myoglobinemia. The presence of
normomagnesemia was the basis for a genetic analysis of the thiazide-sensitive sodium
chloride cotransporter gene, which revealed compound heterozygous mutations in this
gene. Prompt fluid expansion and potassium supplementation led to regression of the
muscle symptoms. Hypokalemia can be a rare cause of rhabdomyolysis in patients with
GS, even in childhood. We emphasize that genetic analysis is advisable to determine
whether the suspicion of GS is warranted.
Successful treatment of collapsing focal segmental glomerulosclerosis with a
combination of rituximab, steroids and ciclosporin
Hiroshi Kaito1, 4 , Koichi Kamei1, Eriko Kikuchi1, Masao Ogura1, Kentaro Matsuoka2,
Michio Nagata3, Kazumoto Iijima4 and Shuichi Ito1
(1) Department of Nephrology, National Center for Child Health and Development,
Setagaya, Tokyo, Japan
(2) Department of Pathology, National Center for Child Health and Development,
Setagaya, Tokyo, Japan
(3) Department of Pathology, University of Tsukuba, Tsukuba, Ibaragi, Japan
(4) Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1,
Kusunoki-cho, Chuo-ku, Kobe Hyogo, 6500017, Japan
We report a case of a 2-year-old boy with steroid- and ciclosporin (CsA)-resistant
collapsing focal segmental glomerulosclerosis (FSGS) who went into complete
remission with a combination of IV rituximab and methylprednisolone pulse therapy
(MPT) while receiving oral CsA. He was initially treated with steroids including MPT,
CsA, and plasmapheresis, but his massive proteinuria and severe systemic edema
persisted. We treated him with four weekly doses of intravenous rituximab. After the
second administration of rituximab, his proteinuria and systemic edema were
dramatically improved, but hypoalbuminemia and proteinuria persisted. Eight months
after the onset, he was re-treated with two courses of MPT. Thereafter, he finally went
into complete remission 1 month after MPT. He continued in remission for 8 months
with CsA, but then relapsed. However, he went into complete remission again with
60 mg/m2 of oral prednisolone without rituximab and since then, he has been in
remission with CsA. This is the first report of the successful treatment of collapsing
FSGS with rituximab. Thus, rituximab emerges as a new therapeutic option against
refractory collapsing FSGS.
Idiopathic membranous nephropathy associated with polycystic kidney disease
Severin Kengne-Wafo1, Laura Massella1, Francesca Diomedi-Camassei2 and
Francesco Emma1, 3
(1) Division of Nephrology and Dialysis, Bambino Gesù Children’s Hospital and
Research Institute, Rome, Italy
(2) Division of Pathology, Bambino Gesù Children’s Hospital and Research Institute,
Rome, Italy
(3) Department of Nephrology and Urology, Division of Nephrology and Dialysis,
Ospedale Bambino Gesù–IRCCS, Piazza S. Onofrio, 4, 00165 Rome, Italy
Membranous nephropathy (MN) and polycystic kidney disease are both relatively rare
diseases in children. On rare exceptions, these two conditions have been associated in
adults. We report here the first case of a pediatric patient with this association. This 6year-old child presented with gross hematuria, nephrotic syndrome, and mild renal
failure. A renal ultrasound subsequently revealed that the patient also had polycystic
kidney disease.
Tacrolimus nephrotoxicity: beware of the association of diarrhea, drug interaction
and pharmacogenetics
Sandrine Leroy1, Arnaud Isapof1, Sonia Fargue2, 3, May Fakhoury4, Albert Bensman1,
Georges Deschênes5, Evelyne Jacqz-Aigrain4 and Tim Ulinski1, 6
(1) Department of Pediatric Nephrology, Armand-Trousseau Hospital, AP-HP and
University Paris VI, 26 Avenue du Docteur Arnold Netter, 75012 Paris, France
(2) Department of Biology, University College London, London, UK
(3) Department of Pediatric Nephrology—Reference Centre for Rare Renal Diseases,
Femme Mère Enfant Hospital, University of Lyon, Lyon, France
(4) Department of Pediatric Pharmacology—Pharmacogenetics and Clinical
Investigation Center—CIC9202, Robert-Debré Hospital, AP-HP, Paris, France
(5) Department of Pediatric Nephrology, Robert-Debré Hospital, AP-HP, Paris, France
(6) Inserm UMR S938, Université Pierre et Marie Curie, Paris, France
Tacrolimus is known to potentially lead to adverse events in recipients with diarrhoea
and/or calcium channel blocker (CCB) co-administration. We report a renal transplant
recipient who suffered from severe nephrotoxicity related to a toxic tacrolimus trough
concentration in both conditions, diarrhoea and CCB co-administration, and with
genotyped CYP3A system and P-glycoprotein (P-gp) polymorphisms. To our
knowledge, this is the first case to be investigated for such polymorphisms. Clinicians
should be reminded of the possibility of highly increased levels of tacrolimus in
situations of diarrhoea and/or co-administration of CCBs. It also highlights the key role
in tacrolimus pharmacokinetics of the CYP3A system and P-gp polymorphisms, and
their influence in high-risk situations when enzyme activity is already affected by
enterocyte damage due to diarrhoea and CCB competition.
Anti-erythropoietin antibodies followed by endogenous erythropoietin production
in a dialysis patient
Parnell Mattison1, Kiran Upadhyay1, Jennifer E. Wilcox1, Asha Moudgil1 and
Douglas M. Silverstein1
(1) Department of Nephrology, Children’s National Medical Center, 111 Michigan
Avenue NW, Washington, DC 20010, USA
We present a case of a young girl with end-stage renal disease secondary to antiglomerular basement membrane disease who was receiving maintenance peritoneal
dialysis and developed pure red cell aplasia secondary to anti-erythropoietin (EPO)
antibodies. This occurred 13 months after the initiation of EPO alfa therapy for anemia.
Initially, the patient required intermittent red blood cell transfusions. After
immunosuppressive therapy had been initiated with corticosteroids and cyclosporine,
the EPO antibody levels decreased precipitously, associated with an increased level of
endogenous EPO production. For the following 6 months, the patient maintained
adequate (>10 g/dL) hemoglobin levels and did not require red cell transfusions.
Co-existence of chronic renal failure, renal clear cell carcinoma, and Blau
syndrome
Ipek Akil1, 9 , Aykan Ozguven2, Ebru Canda3, Omer Yilmaz4, Nalan Nese5,
Mine Ozkol6, Sandra May7, Andre Franke7 and Sebahattin Cirak8
(1) Department of Pediatric Nephrology, Celal Bayar University, Manisa, 45040,
Turkey
(2) Department of Pediatric Oncology, Celal Bayar University, Manisa, Turkey
(3) Department of Pediatrics, Celal Bayar University, Manisa, Turkey
(4) Department of Pediatric Surgery, Celal Bayar University, Manisa, Turkey
(5) Department of Pathology, Celal Bayar University, Manisa, Turkey
(6) Department of Radiology, Celal Bayar University, Manisa, Turkey
(7) Institute for Clinical Molecular Biology, Christian-Albrechts-University, Kiel,
Germany
(8) Institute of Child Health, University College London, London, UK
Blau syndrome is a rare, multisystem, autosomal-dominant, and granulomatous disorder
caused by susceptibility variants in the NOD2 gene. We describe here a 14-year-old girl
with Blau syndrome with incidentally diagnosed renal carcinoma. The index case
presented with growth retardation and recurrent symmetric arthritis. Her clinical
symptoms included bilateral cataract due to recurrent uveitis, camptodactyly, and
persistent erythematous rash with ichthyosis. Her two sisters and her mother were
affected with combinations of these conditions—symmetric polyarthritis, uveitis, and
skin involvement—suggesting an autosomal dominant trait. The index case developed a
chronic renal insufficiency, and an abdominal computerized tomography scan revealed
a 2.5-cm mass in the left kidney. The histopathological examination showed renal clear
cell carcinoma, chronic tubulointerstitial nephritis, and giant cell granulomas in both the
tumor and non-neoplastic renal tissue. Granulomatous inflammation was observed in
the skin biopsy specimen. The patient was diagnosed with Blau syndrome based on her
family history, uveitis, granulomatous inflammation proved by skin biopsy, and
polyarthritis. Sequencing of the NOD2 gene showed a heterozygous p.R334Q mutation
in all affected family members. To the best of our knowledge, this is the first reported
case of a patient with Blau syndrome accompanied by chronic renal failure and renal
carcinoma.
Development of renal and iliac aneurysms in a child with generalized infantile
myofibromatosis
Benoit Brasseur1, 2, Christophe F. Chantrain1 , Nathalie Godefroid3,
Thierry Sluysmans4, Christine Anslot5, Renaud Menten6, Philippe Clapuyt6,
Sophie Dupont1, Christiane Vermylen1 and Bénédicte Brichard1
(1) Department of Pediatric Hematology and Oncology, Cliniques Universitaires SaintLuc, Université Catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels,
Belgium
(2) Department of Pediatrics, Cliniques Saint-Pierre, Avenue Reine Fabiola 9,
1340 Ottignies, Belgium
(3) Department of Pediatric Nephrology, Cliniques Universitaires Saint-Luc, Université
Catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium
(4) Department of Pediatric Cardiology, Cliniques Universitaires Saint-Luc, Université
Catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium
(5) Department of Pediatric Intensive Care, Cliniques Universitaires Saint-Luc,
Université Catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium
(6) Pediatric Radiology, Cliniques Universitaires Saint-Luc, Université Catholique de
Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium
Infantile myofibromatosis is a rare disorder characterized by the formation of tumors in
the skin, soft tissues, bone, and viscera. We report the case of a 3-week-old girl who
presented with severe hypertension due to generalized infantile myofibromatosis
including renal involvement. The infant was treated by chemotherapy and showed
progressive regression of the tumors. However, her evolution was marked by the
development of aneurismal dilations of the renal and iliac arteries as observed in
fibromuscular dysplasia. We discuss the possibility of a link between these two
mesenchymal disorders.