Turkish pediatric atypical hemolytic uremic syndrome registry: Initial analysis of 146 patients

Abstract

Background
Atypical hemolytic uremic syndrome (aHUS) is a devastating disease with significant morbidity and mortality. Its genetic heterogeneity impacts its clinical presentation, progress, and outcome, and there is no consensus on its clinical management.

Methods
To identify the characteristics of aHUS in Turkish children, an industry-independent registry was established for data collection that includes both retrospective and prospective patients.

Results
In total, 146 patients (62 boys, 84 girls) were enrolled; 53 patients (36.3%) were less than 2 years old at initial presentation. Among the 42 patients (37.1%) whose mutation screening was complete for CFH, CFI, MCP, CFB, C3, DGKE, and CHFR5 genes, underlying genetic abnormalities were uncovered in 34 patients (80.9%). Sixty-one patients (41.7%) had extrarenal involvement. During the acute stage, 33 patients (22.6%) received plasma therapy alone, among them 17 patients (51.5%) required dialysis, and 4 patients (12.1%) were still on dialysis at the time of discharge. In total, 103 patients (70.5%) received eculizumab therapy, 16 of whom (15.5%) received eculizumab as a first-line therapy. Plasma therapy was administered to 84.5% of the patients prior to eculizumab. In this group, renal replacement therapy was administered to 80 patients (77.7%) during the acute period. A total of 3 patients died during the acute stage. A total of 101 patients (77.7%) had a glomerular filtration rate >90 mL/min/1.73 m² at the 2-year follow-up.

Conclusions
The Turkish aHUS registry will increase our knowledge of patients with aHUS who have different genetic backgrounds and will enable evaluation of the different treatment options and outcomes.

Full text

R E S E A R C H A R T I C L E Open Access
Turkish pediatric atypical hemolytic uremic
syndrome registry: initial analysis of 146
patients
Nesrin Besbas
1
, Bora Gulhan
1
, Oguz Soylemezoglu
2
, Z. Birsin Ozcakar
3
, Emine Korkmaz
1
, Mutlu Hayran
4
and Fatih Ozaltin
1*
Abstract
Background: Atypical hemolytic uremic syndrome (aHUS) is a devastating disease with significant morbidity and
mortality. Its genetic heterogeneity impacts its clinical presentation, progress, and outcome, and there is no
consensus on its clinical management.
Methods: To identify the characteristics of aHUS in Turkish children, an industry-independent registry was
established for data collection that includes both retrospective and prospective patients.
Results: In total, 146 patients (62 boys, 84 girls) were enrolled; 53 patients (36.3%) were less than 2 years old at
initial presentation. Among the 42 patients (37.1%) whose mutation screening was complete for CFH,CFI,MCP,CFB,
C3,DGKE, and CHFR5 genes, underlying genetic abnormalities were uncovered in 34 patients (80.9%). Sixty-one
patients (41.7%) had extrarenal involvement. During the acute stage, 33 patients (22.6%) received plasma therapy
alone, among them 17 patients (51.5%) required dialysis, and 4 patients (12.1%) were still on dialysis at the time of
discharge. In total, 103 patients (70.5%) received eculizumab therapy, 16 of whom (15.5%) received eculizumab as a
first-line therapy. Plasma therapy was administered to 84.5% of the patients prior to eculizumab. In this group, renal
replacement therapy was administered to 80 patients (77.7%) during the acute period. A total of 3 patients died
during the acute stage. A total of 101 patients (77.7%) had a glomerular filtration rate >90 mL/min/1.73 m
2
at the
2-year follow-up.
Conclusions: The Turkish aHUS registry will increase our knowledge of patients with aHUS who have different
genetic backgrounds and will enable evaluation of the different treatment options and outcomes.
Keywords: Atypical hemolytic uremic syndrome, Turkish registry, Treatment, Outcome, Prognosis
Background
Atypical hemolytic uremic syndrome (aHUS) is a life-
threatening systemic disease associated with the dysreg-
ulation of the complement system [1]. It has been
reported that mortality was higher in children when
compared to adults whereas progression to end stage
renal disease after the first episodes was higher in adults
[2]. Mutations in the genes encoding complement
regulatory proteins (i.e. CFH,CFI,MCP (CD46),or
CFH-CFHR genomic rearrangements) and components
of the alternative pathway C3 convertase (i.e. C3 and
CFB) or anti-complement factor H autoantibodies are
identified in 60–70% of patients with aHUS [2–7].
Recent studies have also identified mutations in diacyl-
glycerol kinase-ε(DGKE), thrombomodulin (THBD,
CD141) in thrombotic microangiopathies (TMAs) in-
cluding aHUS [8–13]. For years, plasma therapy was the
mainstay of treatment for aHUS [11, 12]. Eculizumab, a
monoclonal antibody that blocks the terminal part of the
complement system, has revolutionized the prognosis of
aHUS and is currently recommended as first-line ther-
apy in children with aHUS, whenever possible [11]. Sev-
eral retrospective and prospective studies involving both
pediatric and adult patients have demonstrated the
* Correspondence: fozaltin@hacettepe.edu.tr
1
Department of Pediatric Nephrology, Nephrogenetics Laboratory, Hacettepe
University Faculty of Medicine, Sihhiye 06100, Ankara, Turkey
Full list of author information is available at the end of the article
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Besbas et al. BMC Nephrology (2017) 18:6
DOI 10.1186/s12882-016-0420-6
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

efficacy and safety of eculizumab [11, 14, 15]. However,
exact duration of therapy and dose intervals are still a
matter of debate.
Owing to the low incidence of aHUS, large patient
registries are required to adequately address such ques-
tions and to evaluate the natural history and progression
of the disease, and the prognosis of patients from differ-
ent ethnic backgrounds. One of the largest aHUS regis-
tries, the global aHUS registry, was established in 2012
with industry support; it includes multiple participating
centers from 16 countries, not including Turkey. This
registry prospectively collects information on patient
demographics, disease characteristics, and treatment
modalities [16]. In addition, there are a few registries of
patients from different ethnic backgrounds [2, 17, 18].
However, investigators are aware that underlying genetic
abnormalities of patients from different ethnic back-
grounds differ and that the characteristics of aHUS may
vary among different patient populations. In Turkey, an
industry-independent aHUS registry was established to
collect data on pediatric patients with aHUS who were
treated in the 26 pediatric nephrology centers. This
registry not only collects information on the demo-
graphic, clinical, laboratory, and genetic features of
Turkish pediatric patients with aHUS, but also affords
researchers a unique opportunity to evaluate the treat-
ment strategies used at the different centers and to as-
sess their impact on the long-term prognosis of the
patients. This study aimed to introduce the registry and
to provide a general perspective about its initial findings.
Specific analyses addressing specific questions (i.e. genet-
ics, long-term prognosis etc.) will be conducted in our
subsequent studies.
Methods
Definitions
Pediatric aHUS was defined as a triad of Coombs-negative
microangiopathic hemolytic anemia, thrombocytopenia,
and acute renal failure in patients younger the age of
18 years. No adult patient, even if the first episode was ob-
served during the childhood period, was included. Shiga
toxin-producing E. coli (STEC) was investigated in a na-
tional centralized reference laboratory and STEC positive
patients were excluded. Patients with depressed
ADAMTS13 levels (i.e. ≤5%), other specific infections, co-
existing diseases or those with drug-related HUS were also
excluded [11].
Hematologic remission was defined as platelet count
≥150,000/mm
3
and lactate dehydrogenase levels ≤upper
limits of normal for ≥2 consecutive measurements taken
≥4 weeks apart, and cessation of hemolysis [11].
Renal remission was defined as estimated glomerular
filtration rate (eGFR) >90 mL/min/1.73 m
2
.
Data collection
Beginning year 2013, all retrospective and prospective
pediatric patients with aHUS from 26 pediatric nephrol-
ogy centers have been registered in the database at
www.ahusnet.org, a web-based national registry system
(NRS). A pediatric nephrology specialist from each par-
ticipating center is responsible for entering patients into
the registry. The objectives of the NRS are to assess the
clinical and genetic characteristics, treatment modalities,
associated extrarenal findings, and clinical outcomes of
patients with aHUS during their initial hospital admis-
sion, and to evaluate their long-term prognosis accord-
ing to disease management strategies.
Responsible specialists from each center registered
both retrospective and prospective patients in the secure
NRS and were able to access the website at any time to
enter and edit data. During patient registration, the fol-
lowing data were entered into the system: demographics,
medical and disease history, clinical characteristics at
disease onset (i.e. physical examination findings and la-
boratory data), genetic results (if available), all therapies
implemented during the acute stage (i.e. plasma therapy
including plasma infusions and/or plasma exchange,
eculizumab, rituximab, corticosteroid, antihypertensive,
hemodialysis, peritoneal dialysis, and continuous renal
replacement therapies), and the renal/hematologic status
(i.e. proteinuria, hypertension, serum creatinine level,
hemoglobin level, and platelet count) of the patient at
discharge. The side effects related to any of the treat-
ment medications were also recorded in the NRS.
Follow-up data, including the hematologic and renal pa-
rameters of the patient, current therapies, and relapses
(if any, since the last visit), were entered into the NRS
every 3 months. All patients in the NRS were evaluated
annually by the joint committee, which comprised
pediatric nephrology experts. Any patient who did not
meet the criteria for aHUS, as determined by the joint
committee, was removed from the registry.
Genetic analyses and ELISA
Genetic testing was not a prerequisite for patient regis-
tration. However, if individual genetic data was available,
their registration was also requested. DNA sample was
available in 113 patients. Mutation analyses via Sanger
sequencing of the coding regions of all of the following
genes were performed in 42 patients (37.1%) at the
Nephrogenetics Laboratory of Hacettepe University:
CFH,CFI,MCP,CFB, C3,DGKE,andCHFR5. Where
applicable, in slico analyses, using Sorting Tolerant From
Intolerant (SIFT) (http://sift.jcvi.org), Polymorphism
Phenotyping v2 (PolyPhen2) (http://genetics.bwh.harvar-
d.edu/pph2/index.shtml), Mutation taster (http://
www.mutationtaster.org), and Human Splicing Finder
(http://www.umd.be/HSF3/index.html) softwares were
Besbas et al. BMC Nephrology (2017) 18:6 Page 2 of 10
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applied for predicting likely effects of the variations.
aHUS mutation database (http://www.fh-hus.org), The
Human Gene Mutation Database Professional (http://
www.hgmd.cf.ac.uk/ac/index.php) and dbSNP database
(https://www.ncbi.nlm.nih.gov/snp) were used to check
whether identified variations had been reported previ-
ously. CFHR1-3 deletion in patients with anti-CFH
autoantibodies was evaluated by multiplex ligation-
dependent probe amplification (MLPA) analyses. Anti-
complement Factor H autoantibody was searched in 44
patients using the CFH IgG ELISA Kit (Abnova™), ac-
cording to the manufacturer’s recommendations, with a
detection limit of 0.6 AU/mL. ADAMTS13 activity was
detected using the ADAMTS-13 Activity Kit (Technozym™)
according to the manufacturer’s recommendations,
with a detection limit of 0.2% and an assay range of
0.3–105%.
The study was approved by the ethics committee of
Hacettepe University (FON10/03-22). Written informed
consent was obtained from the parents of all the
patients.
Statistical analysis
Descriptive statistical analysis methods were used to
evaluate the demographics and clinical data. The mean,
median, standard deviation, and interquartile range
(IQR) were calculated for the numeric variables. Fre-
quency tables were used to describe the categorical data.
Mann Whitney Utest was used to compare 2 independ-
ent samples. Data were analyzed using SPSS v.21 (SPSS
Inc., Chicago, IL, USA).
Results
Patient characteristics
As of March 30, 2016, 146 patients (62 boys, 84 girls)
from 26 pediatric nephrology centers were enrolled in
the NRS. The demographic and clinical characteristics of
the patients are presented in Table 1. A total of 69 pa-
tients (47.6%) had diarrhea prior to their initial presenta-
tion, and 35 patients (24.1%) had preceding upper
respiratory tract infection. Notably, 53 of the 146 pa-
tients (36.3%) were aged less than 2 years at the first
presentation, and 29 of the patients (19.8%) were aged
less than 1 year. A total of 61 patients (41.7%) showed
extra-renal involvement; the most common site of extra-
renal manifestation was the neurologic system (n= 41;
28.1%). Hemiparesis, loss of vision, unconsciousness,
headache, hallucination, encephalopathy were the main
symptoms for the neurological involvement. In 8 of
these patients, another system was also involved. Brain
imaging was performed in 27 patients, 15 of whom
showed abnormal radiological findings. Cardiac compli-
cations were identified in 9 patients (6.1%); 2 patients
had hypertrophic cardiomyopathy, and the other cardiac
manifestations included dilated cardiomyopathy, intra-
cardiac thrombus, elevated creatine kinase (CK)-MB
levels, mitral and tricuspid insufficiency, aortic valve
insufficiency, left ventricular hypertrophy, and tachycar-
dia. Involvement of the gastrointestinal system was
observed in 16 children (10.9%) and pancreatitis, ele-
vated liver enzymes, invagination, ischemic hepatitis,
cholelithiasis, vomiting were the main symptoms. GI
bleeding and pancreatitis were the most common
Table 1 Demographic and clinical characteristics of 146
patients with aHUS
Male (%) / Female (%) 62 (42.4) / 84
(57.6)
Current age, years
Mean (SD) 7.98 (5.0)
Median (IQR) 6.53 (3.8–11)
Age at diagnosis, years
Mean (SD) 4.82 (4.4)
Median (IQR) 3.5 (1.2–7.4)
Age category (years) at the time of diagnosis, n (%)
<2 53 (36.3)
2 to <5 40 (27.4)
5 to <12 38 (26)
≥12 15 (10.3)
Duration of follow-up (years)
Mean (SD) 2.9 (2.5)
Median (IQR) 2.1 (1.2–3.8)
Consanguinity (%) 42 (28.8)
Family history of aHUS (%) 7 (4.8)
Anuria (%) /oliguria at admission (%) 41 (28) / 67
(45.8)
Duration of anuria at admission (days)
Mean (SD) 6.3 (4.5)
Median (IQR) 5 (2–10)
Duration of oliguria at admission (days)
Mean (SD) 6 (6.8)
Median (IQR) 3 (2–7)
Extrarenal involvement, n (%) 61 (41.7)
Central nervous system 41 (28.1)
Gastrointestinal system 16 (10.9)
Cardiac 9 (6.1)
Respiratory system 10 (6.8)
Patients with GFR <90 mL/min/1.73 m
2
at admission,
n (%)
139 (95.2)
Hypocomplementemia (%)
a
66 (48.5)
Renal biopsy at admission (%) 44 (30.1%)
SD: standard deviation; IQR: interquartile range; aHUS: atypical hemolytic
uremic syndrome; GFR: glomerular filtration rate.
a
Data is available for
136 patients
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findings, which were observed in 4 and 3 patients, re-
spectively. Respiratory involvement was observed in 10
patients (6.8%), while 16 patients (10.9%) showed multi-
system involvement. Kidney biopsies were performed in
44 patients. The biopsies were performed to confirm the
diagnosis (in 29 patients), before initiation of eculizumab
therapy (in 7 patients), to assess patients with nephrotic-
range proteinuria (in 6 patients), and to evaluate patients
who exhibited a poor response to plasma therapy or ecu-
lizumab (in 2 patients).
Genetics
Number of mutation analyses performed in individual
genes are as follows in 113 patients whose DNA sample
was available: CFH (n= 64, 56.6%), CF1 (n= 69, 61.0%),
MCP (n= 49, 43.3%), CFB (n= 62, 54.8%), C3 (n= 35,
30.9%), DGKE (n= 67, 59.2%). Mutation screening was
complete for all of the corresponding genes in 42 pa-
tients (37.1%), and underlying genetic abnormalities
were uncovered in 34 of these patients (80.9%). These
include isolated abnormality in MCP (n= 7, 16.3%), in
DGKE (n= 6, 8.9%), in C3 (n= 4, 11.4%), in CFH (n=5,
7.8%), in CFB (n= 1, 1.6%), and in CFI (n= 1, 1.4%). In 4
patients, combined genetic abnormalities were detected:
CFH/CFB mutation (n= 1), CFB mutation/CFHR1-3 de-
letion (n =1), CFB mutation/CFHR1-3 deletion/anti-CFH
autoantibody (n= 1), and CFHR5 mutation/CFHR1-3 de-
letion/anti-CFH autoantibody (n= 1). In addition, 1 pa-
tient was diagnosed with cobalamin deficiency. The anti-
CFH autoantibody was detected in 5 out of 44 patients
who had been studied for anti-CFH autoantibody
(11.3%). All of these 5 patients had homozygous CFHR1-
3deletion. To our best of knowledge, 17 novel variations
have been identified in this study (Table 2).
Treatment
Remission was achieved with supportive therapy in 5 pa-
tients and by cobalamin administration, in 1 patient.
Four patients were diagnosed with ESKD at the time of
admission and, therefore, did not receive specific ther-
apy. During the acute stage, 33 patients (22.6%; M/F 13/
20) were treated with plasma therapy alone (i.e. plasma
infusion and/or plasma exchange). Of these, 15 patients
received plasma infusions, 14 patients underwent plasma
exchanges, and 4 patients received both therapies. The
median age at diagnosis in this group of patients was 3.9
(IQR 1.8–8.3) years. In total, 17 patients (51.5%) re-
quired dialysis; 2 patients (6%) died during the acute
stage. At the time of discharge, 4 patients (12.1%) were
on dialysis, 26 patients (78.7%) did not require dialysis,
and data on 1 patient were not available. The median
follow-up time for this group of patients was 1.7 (IQR
1.1–5.3) years. None of the patients required plasma
therapy after discharge. At the last follow-up, 1 patient
was still on dialysis and 1 patient had undergone renal
transplantation; no other renal replacement therapies
were recorded for the remaining patients. At the last
follow-up visit, the GFR of 23 of the patients (69.6%)
was >90 mL/min/1.73 m
2
.
In this registry population, 103 patients (70.5%)
received eculizumab therapy (45 males, 58 females). The
median age at diagnosis in this group of patients was 3.4
(IQR 1.2–7) years, and the median follow-up duration
was 2.05 (IQR 1.1–3.2) years. Eighty patients (77.7%)
underwent renal replacement therapy during the acute
period. Plasma therapy was administered to 84.5% of the
patients prior to the initiation of eculizumab, and 16 pa-
tients (15.5%) received eculizumab as a first-line therapy.
Complete hematologic and renal remission was achieved
in 82.2% and 76.3% of the patients, respectively. Median
follow up duration was 2.05 years (IQR 1.1-3.2 years) for
this group. During the follow-up period, eculizumab
treatment was discontinued in 52 patients (51.5%) for
various reasons (drug unavailability, genetic background
of the patient, choice of the patient’s family, or the clini-
cian’s decision). Five patients (4.8%) with severe renal
disease did not respond to therapy and progressed to
ESKD. The initial median eGFR of these patients was
significantly low when compared with the eGFRs of the
rest of the patients (7.6 mL/min/1.73 m
2
[range, 5.9–
18.3 mL/min/1.73 m
2
] vs. 18.6 mL/min/1.73 m
2
[range,
0.3–166 mL/min/1.73 m
2
]; P= 0.019). At the last follow-
up visit, the GFR of 68 of the patients (66%) was
>90 mL/min/1.73 m
2
. Eculizumab-related side effects
were reported in 2 patients: an allergic reaction in 1 pa-
tient, and convulsions and sepsis after eculizumab ad-
ministration in 1 patient. No patient relapsed while
receiving eculizumab therapy.
Follow-up
A total of 3 patients died during the acute stage. The
causes of death included sepsis (n= 1), intractable sei-
zures (n= 1), and multisystem involvement (n= 1).
Three patients died during the follow-up period. A total
of 10 patients were lost to follow-up, and outcome data
were available for the remaining 130 patients (56 males,
74 females). At their last follow-up visit, 13 patients had
undergone treatment for ESKD (hemodialysis [n= 5],
peritoneal dialysis [n= 3], and renal transplantation [n=
5]). More than 75% of the patients had a GFR >90 mL/
min/1.73 m
2
(Table 3).
Discussion
Here, we introduce one of the largest pediatric aHUS
registries in the world. However, it is very well known
that registries have its own limitations. In aHUS, many
factors such as STEC, genetics, anti-factor H antibodies
and follow-up data of the patients have to be taken into
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Table 2 Genetic results of the patients
Gene Screened
n (%)
a
Variation n
(%)
b
Variant (dbSNP
database)
Predicted
aminoacid change
Zygosity MAF_1000G MAF_ESP
6500
SIFT prediction
c
(score)
PolyPhen
prediction
d
(score)
Mutation Taster
prediction
e
(score)
HSF prediction
f
Ref
CFH (NM_000186.3)
64 (56.6) 5 (7.8)
c.3530A>G p.Tyr1177Cys Hom NR NR Tolarated (0.19) Probably damaging
(0.996)
Polymorphism (0.99) NA [22]
c.2850G>T
(rs149474608)
p.Gln950His Het <0.01 <0.01 Deleterious
(0.049)
Probably damaging
(0.96)
Polymorphism (0.99) NA [26]
c.2127_2129del p.Tyr711del Het NR NR NA NA Disease causing (0.54) NA Novel
c.3148A>T
(rs35274867)
p.Asn1050Tyr Het 0.01 0.01 Tolarated (0.08) Benign (0.016) Polymorphism (0.99) NA [27]
c.3133+1G>A Splice site Het NR NR NA NA N/A Broken WT
Donor Site
Novel
CFI (NM_000204.3)
69 (61.0) 1 (1.4)
c.608C>T
(rs138346388)
p.Thr203Ile Het <0.01 <0.01 Tolarated (0.16) Benign (0.051) Polymorphism (0.99) NA [28]
MCP (NM_002389)
49 (43.3) 7 (14.2)
c.535G>C
(rs779174212)
p.Glu179Gln Hom <0.01 <0.01 Tolarated (0.33) Benign (0.023) Polymorphism (0.99) NA [29]
c.841C>T p.Pro281Ser Hom NR NR Damaging (0) Probably damaging
(0.99)
Disease causing (0.85) NA Novel
c.841C>T p.Pro281Ser Het NR NR Damaging (0) Probably damaging
(0.99)
Disease causing (0.85) NA Novel
c.476-2A>G Splice site Hom NR NR NA NA NA Broken WT
Acceptor Site
Novel
c.476-2A>G Splice site Hom NR NR NA NA NA Broken WT
Acceptor Site
Novel
c.286+2T>G Splice site Hom NR NR NA NA NA Broken WT
Donor Site
[30]
c.1027+5G>T Splice site Hom NR NR NA NA NA Broken WT
Donor Site
[31]
CFB (NM_001710)
62 (54.8) 1 (1.6)
c.125T>C p.Val42Ala Het NR NR Tolarated (0.19) Benign (0.12) Disease causing (0.94) NA Novel
C3 (NM_000064)
35 (30.9) 4 (11.4)
c.537_539del p.Leu180del Het NR NR NA NA Polymorphism (0.99) NA Novel
c.3125G>T p.Arg1042Leu Het NR NR Damaging
(0.03)
Probably damaging
(0.99)
Disease causing (0.99) NA [17]
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Table 2 Genetic results of the patients (Continued)
c.4148C>A
(rs139100972)
p.Thr1383Asn Het NR <0.01 Tolarated (0.5) Benign (0.36) Polymorphism (0.99) NA [3]
c.1976-6C>T Splice site Het NR NR NA NA NA Probably no
impact
Novel
DGKE(NM_003647)
67 (59.2) 6 (8.9)
c. 1009C>T
(rs762576212)
p.Arg337Stop Hom NR <0.01 NA NA Disease causing (1) NA in
dbSNP
c.118_121dup p.Ser41Metfs*2 Hom NR NR NA NA Disease causing (1) NA Novel
c.607_610del p.Lys203Glnfs*6 Hom NR NR NA NA Disease causing (1) NA Novel
c.263_264insGGG p.Asp88Glufs*84 C-Het NR NR NA NA Disease causing NA Novel
CGCCA/c.76del p.Thr26Argfs*143 NR NR NA NA Disease causing
(1)
Novel
c. 427C>T p.Gln143Stop C-Het NR NR NA NA Disease causing NA Novel
c.1133C>G p.Pro378Arg NR <0.01 Damaging (0) Possibly damaging
(0.93)
Disease causing (1) Novel
c.793A>C p.Thr265Pro Het NR NR Tolarated (0.08) Benign (0.43) Disease causing (0.99) NA Novel
Combined genetic abnormalities
CFH c.3644G>A
(rs121913051)
p.Arg1215Gln Het NR NR Tolarated (0.19) Probably damaging
(0.99)
Polymorphism (0.99) NA [32]
CFB c.1135C>T p.Arg379Cys Het NR NR Damaging
(0.01)
Probably damaging
(0.99)
Polymorphism (0.97) NA Novel
CFB c.1050G>T p.Lys350Asn C-Het NR NR T olarated
(0.14)
Probably damaging
(0.99)
Polymorphism (0.81) NA [33]
c.1697A>C
(rs45484591)
p.Glu566Ala 0.01 0 . 0 1 Tolarated (0.73) Benign (0) Polymorphism (0.99) NA [34]
Heterozygous CFHR1-3 deletion
CFB c.397G>A p.Asp133Asn Het NR NR Damaging
(0.05)
Benign (0.014) Polymorphism (0.7) NA Novel
Anti-CFH antibody associated with homozygous CFHR1-3 deletion
CFHR5
(NM_030787)
c.53dup p.Glu19Argfs*6 Het NR NR NA NA Disease causing (1) NA Novel
Anti-CFH antibody associated with homozygous CFHR1-3 deletion
a
of the 113 patients whose DNA samples were avaliable,
b
of the analyses that were performed
c
Sorting Tolerant From Intolerant (SIFT) (http://sift.jcvi.org);
d
Polymorphism Phenotyping v2 (http://genetics.bwh.harvard.edu/pph2/index.shtml);
e
Mutation taster (http://www.mutationtaster.org);
f
Human Splicing Finder (http://www.umd.be/HSF3/index.html)
Variations and predicted aminoacid changes have been named according to the guidelines of the Human Genome Variation Society using Mutalyzer software (https://mutalyzer.nl)
C-Het, compound heterozygous; Het, heterozygous; Hom, homozygous; NA, not applicable; NR, not reported; WT, wild-type
MAF-1000G, minor allele frequency based on 1000 Genomes Project
MAF-6500, minor allele frequency based on 6503 samples collected at NHLBI Exome Sequencing Project and data from 60.706 individuals aggregated by the Exome Aggregation
Consortium (ExAC; http://exac.broadinstitute.org); (accessed October 2016)
Besbas et al. BMC Nephrology (2017) 18:6 Page 6 of 10
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

consideration to draw a certain conclusion. In this study,
we performed longitudinal follow-ups of pediatric
patients with aHUS to evaluate their clinical and genetic
characteristics in order to better understand the diversity
of this rare disease in the Turkish population. Owing to
the low incidence of aHUS, majority of the previous
series on aHUS have included both adult and pediatric
patients [2, 16–18] However, pediatric aHUS cases have
different disease characteristics than those of adult cases.
A study by Fremeaux-Bacchi et al. consisted of 214 pa-
tients, 89 of whom were pediatric patients. In this study,
the characteristics of adult and pediatric patients were
compared [2]. Another analysis of aHUS was from the
global aHUS registry, which was supported by an indus-
try sponsor. In that study, the baseline demographic and
clinical characteristics of 516 patients with aHUS from
195 clinical centers in 16 countries were described. In
that series, 201 patients were in the pediatric age group
[16]. When compared with other established series, the
Turkish aHUS registry has several distinctive features,
namely its homogenous nature (i.e. it involves only
Turkish patients with aHUS); availability of detailed data
on patient demographics, initial clinical presentation,
and the different treatments employed at the clinical
centers; and availability of long-term follow-up and out-
come data.
In our study, there were more female patients than
male patients. While the mean patient age at diagnosis
was comparable to the mean age of the population of
the global aHUS registry, it was higher than the mean
age of the population in the French registry (4.8 years vs.
1.5 years). Patients aged younger than 2 years accounted
for 36.3% of the population in our study, which was
significantly lower than the corresponding percentages
reported in the global and French registries (43.9% and
56%, respectively) [2, 16]. A total of 28 patients (19.1%)
in our study were aged under 1 year; the corresponding
data are not available in the other registries. In our
study, patients aged older than 12 years constituted
10.3% of all patients, whereas this figure was 6.5% in the
global registry. All these discrepancies could be attrib-
uted to the different genetic abnormalities and/or envir-
onmental factors that the patients in the different
populations were exposed to. It is well known that some
genetic abnormalities are associated with early-onset
aHUS whereas others can cause adolescent- or even
adult-onset aHUS. One of the most striking findings in
our study was the rather low percentage of patients with
a family history of aHUS when compared to the global
registry (4.8% vs 20.4%) despite a high rate of consan-
guinity in the Turkish population [16]. This was an
unexpected finding and may be due to the fact that fam-
ily history was not examined thoroughly by the reporting
clinicians in our study. Alternatively, since the diagnosis
of aHUS requires specific knowledge and expertise,
aHUS among family members of the Turkish registry
patients may not have been recognized if they did not
undergo a specialist evaluation.
Extra-renal involvement in aHUS can significantly im-
pact patient prognosis. Neurologic involvement is the
most frequent complication, which can occur in 8–30%
of the patients [10]. In our study, neurologic involve-
ment was observed in 28.1% of the patients, which is
consistent with the literature. The involvement of other
organ systems is reported to be much lower than that of
the central nervous system. Johnson et al. reported that
the most common gastrointestinal manifestations were
pancreatitis/pancreatic insufficiency and elevated trans-
aminases, and they observed respiratory and cardiac
involvement (i.e. heart failure/cardiomyopathy and peri-
cardial effusion) in 21% and 5.6% of pediatric patients
with aHUS, respectively [12]. In the current study, we
observed that pancreatitis was one of the most common
gastrointestinal system complications and that cardiac
involvement occurred at a similar rate (6.1%), whereas
respiratory involvement was slightly lower (6.8%).
Although we have limited data on genetics, the results
of our study might provide a general idea of the under-
lying genetic abnormalities in Turkish patients with
aHUS. It has recently been reported that 60–70% of
patients with aHUS carry identifiable mutations in com-
plement genes or anti-CFH antibodies, which result in
TMA lesions [11]. In a multicenter audit analysis com-
prising 71 patients, 61% of the patients with results
available for both complement genetic testing and anti
CFH-autoantibody testing had evidence of alternative
complement pathway dysregulation [12]. In our study
population, genetic analyses were completed for the cor-
responding genes in 42 patients (37.1%). In this subset
Table 3 Follow-up characteristics of patients (n= 130)
Age at diagnosis, years
Mean (SD) 4.8 (4.4)
Median (IQR) 3.5 (1.2–7.1)
Duration of follow-up (years)
Mean (SD) 2.8 (2.3)
Median (IQR) 2.1 (1.2–3.7)
Renal replacement therapy
a
, n (%) 13 (10)
GFR (mL/min/1.73 m
2
) at the last visit, n (%)
>90 101 (77.7)
60–89 14 (10.8)
30–59 6 (4.6)
15–29 3 (2.3)
0–14 6 (4.6)
SD standard deviation, IQR interquartile range, GFR glomerular filtration rate
a
Includes hemodialysis, peritoneal dialysis, and renal transplantation
Besbas et al. BMC Nephrology (2017) 18:6 Page 7 of 10
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

of patients, disease-causing mutations, 17 of which were
novel, were identified in 34 patients (80.9%). This figure
might indicate that the probability of detecting any mu-
tation in already known genes is high in Turkish patients
and, thereby, justifies the necessity of genetic screening
for a long-term therapeutic plan. In previous studies,
CFH mutations were the most commonly identified
abnormalities [2, 18]. In contrast, we found that MCP
mutations and C3 mutations were the most common
genetic abnormalities whereas CFH mutations were
detected in less than 10% of the genetically studied
population. These initial results may confirm the racial
differences between Turks and other populations. One
of the limitations of our study was that we did not
screen for thrombomodulin mutations, which have a
minor role in aHUS [11].
Before the introduction of eculizumab, plasma therapy
was the mainstay of treatment for aHUS, based on the
premise that it was beneficial by supplying normal com-
plement proteins and/or removing mutant proteins or
autoantibodies [11, 12]. After the study published by Bell
et al. in 1991, plasma-based therapies became the initial
treatment for most patients with aHUS [19]. Noris et al.
reported that two-third of adult patients with aHUS had
a poor outcome after 3 years of follow-up [3]. In a study
by Johnson et al. on aHUS treatment outcomes in 71 pa-
tients, 59 patients received plasma therapy and the other
12 patients received other types of treatment. Their re-
sults revealed that 17% of the patients remained
dependent on dialysis and 80.3% of the patients had per-
sistent renal sequelae at day 33 of treatment. The long-
term results of plasma therapy were unavailable [12]. In
our study, 12.1% of the patients were on dialysis at the
time of discharge; after a median follow-up period of
1.7 years, 1 patient was still on dialysis and 1 patient had
undergone renal transplantation. These differences in
findings between our study and other studies may be at-
tributed to the different genetic backgrounds of the
studied populations. Plasma therapy (i.e. plasma infu-
sions and/or plasma exchange) still appears to be a valid
therapeutic option for Turkish patients with aHUS.
The introduction of eculizumab has profoundly
changed the management of aHUS. The efficacy of
eculizumab has been demonstrated in three prospect-
ive clinical trials performed primarily in adult patients
with TMA [14, 20, 21]. In these trials, it was demon-
strated that eculizumab resulted in a time-dependent
improvement in patients with aHUS, and the benefi-
cial effects were maintained after 2 years of follow-
up. In children, the evidence for the efficacy of eculi-
zumab came from case reports and retrospective
studies [11, 22, 23]. Recently, Greenbaum et al. pub-
lished the first pediatric prospective study that
assessed the efficacy and safety of eculizumab in
patients with aHUS who were aged <18 years. Muta-
tions in the genes of the alternative complement
pathway were identified in 50% of the patients [15].
MCP mutations were the most common; the mean
duration of eculizumab treatment was 5.5 months,
and hematological remission occurred in 82% of the
patients. The authors reported that the mean im-
provement in eGFR from baseline to week 27 was
64 mL/min/1.73 m
2
, and discontinuation of dialysis
was possible in 82% of the patients who initially re-
quired renal replacement therapy [15]. In our study,
16 patients (15.5%) received eculizumab as a first-line
therapy. Complete hematologic and renal remission
was achieved in 82.2% and 76.3% of the patients, re-
spectively. Our study as well as the study by Green-
baum et al. supported the efficacy of eculizumab in
the acute period. However, there is ongoing debate on
the appropriate duration and intervals for eculizumab
treatment. Ardissino et al. reported findings from 10
patients who received eculizumab treatment, which
was discontinued later. All of these patients had com-
plement system dysregulation, and showed beneficial
effects after being treated with eculizumab. After the
eculizumab treatment was stopped, 3 patients relapsed
within 6 weeks [24]. Later, the authors published results
from a longer follow-up period. During a cumulative time
off treatment of 243 months, 5 of the patients experienced
relapse within 6 months of their last eculizumab dose
[25]. In our patient cohort, eculizumab was discontinued
in 52 patients for various reasons. The analyses of the gen-
etic backgrounds and clinical outcomes of the patients are
still underway and will be reported in detail in another
manuscript.
Another noteworthy feature of our study is that we
completed almost 2 years of patient follow-up. It has
been previously reported that the mortality rate in chil-
dren with aHUS was higher than that in adults, but the
renal outcomes were worse in adults than in children
[2]. In our study on pediatric patients, the mortality rate
was 2% (3 out of 146 patients) during the acute stage,
and 77.7% of the patients had a GFR >90 mL/min/
1.73 m
2
during the follow-up period. Our results suggest
that aHUS is a treatable disease and that progression to
ESKD can be prevented with early diagnosis, and me-
ticulous treatment and follow-up. However, it should be
noted that in our patient cohort, high frequency of MCP
mutations, lack of information on completed genetic
data and early initiation of treatment may explain favor-
able outcome.
Conclusions
We have established a unique Turkish aHUS registry
that will increase our knowledge of patients with aHUS
who have different genetic backgrounds, and enable the
Besbas et al. BMC Nephrology (2017) 18:6 Page 8 of 10
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

evaluation of different treatment options and patient
outcomes. This registry is now open to adult patients.
The collection of data on adult patients with aHUS will
help researchers to better characterize the spectrum of
adult aHUS in the country and will enable comparisons
with pediatric cases.
Abbreviations
aHUS: Atypical hemolytic uremic syndrome; C3: Complement factor 3;
CFB: Complement factor B; CFH: Complement factor H; CFI: Complement
factor I; CK: Creatine kinase; CFH-CFHR: Complement factor H-complement
factor H related proteins; DGKE: Diacylglycerol kinase-ε; eGFR: Estimated
glomerular filtration rate; ESKD: End-stage kidney disease; GI: Gastrointestinal;
IQR: Interquartile range; MCP (CD46): Membrane cofactor protein;
MLPA: Multiplex ligation-dependent probe amplification; NRS: National
registry system; SD: Standard deviation; STEC: Shiga toxin-producing E. coli;
THBD: Thrombomodulin; TMA: Thrombotic microangiopathy
Acknowledgements
The authors acknowledge the enrolling clinicians, data coordinators at
individual enrolling centers including Banu Çelikel Acar, Harika Alpay, Özlem
Aydoğ, Esra Baskın, Aysun Karabay Bayazıt, Nur Canpolat, Nilgün Çakar, Ali
Delibaş, Zelal Ekinci, Kibriya Fidan, Gürkan Genç, Nilufer Göknar, Can Hüzmeli,
Beltinge Demircioğlu Kılıç, Mustafa Koyun, Engin Melek, Aytül Noyan, Elif
Bahat Özdoğan, Sare Gülfem Özlü, Alper Soylu, Mehmet Taşdemir, Emel
Ünsür, Lokman Üstyol, Bilal Yıldız, Alev Yılmaz, Selçuk Yüksel, FatoşYalçınkaya.
Funding
This study was supported by Hacettepe University Scientific Research and
Development Office (Grant No: 010A101009). Article processing charge of
this manuscript has been granted by the Alexion Pharmaceuticals, Inc.
Availability of data and materials
The datasets during and/or analysed during the current study available from
the corresponding author on reasonable request.
Authors’contributions
NB conceived the study, and participated in its design. BG participated in the
collection of data, contributed to the statistical analysis and drafted the
manuscript. OS participated in designing of the study and in coordination of
the clinical centers. ZBO participated in designing of the study and collection
of data. EK carried out the molecular genetic studies. MH performed
statistical analyses. FO conceived the study, participated in its design and
coordination, evaluated genetic results, participated in analysis of data and
wrote the manuscript. All authors have also contributed to manuscript
development and review, and have read and approved the final manuscript.
Competing interests
Fatih Ozaltin and Oguz Soylemezoglu have received lecture and consultancy
honoraria from the Alexion Pharmaceuticals, Inc.
Ethics approval and consent to participate
The study was approved by the ethics committee of Hacettepe University
(FON10/03-22). Written informed consent was obtained from the parents of
all the patients.
Statement of prior presentation
Aspects of these data were presented at the following congresses:
Besbas N, Soylemezoglu O, Gulhan B, Ozcakar ZB, Korkmaz E, Ozaltin F.
Turkish atypical haemolytic uremic syndrome registry: initial pediatric
results. J Am Soc Nephrol 2015;26:457A. Presented at the American
Society of Nephrology Kidney Week 2015, November 3–8, 2015, San
Diego, CA, USA.
N. Besbas, O. Soylemezoglu, B.Gulhan, ZB. Ozcakar, E. Korkmaz, M.
Hayran, F. Ozaltin. Turkish Atypical Hemolytic Uremic Syndrome
Registry: Evaluation of 146 Patients. Pediatr Nephrol 2016; 31:1884,
PO-374. Presented at the 17th Congress of the International Pediatric
Nephrology Association, September 20–24, 2016, Iguaçu, Brazil.
Author details
1
Department of Pediatric Nephrology, Nephrogenetics Laboratory, Hacettepe
University Faculty of Medicine, Sihhiye 06100, Ankara, Turkey.
2
Department of
Pediatric Nephrology, Gazi University Faculty of Medicine, Ankara, Turkey.
3
Department of Pediatric Nephrology, Ankara University Faculty of Medicine,
Ankara, Turkey.
4
Department of Preventive Oncology, Hacettepe University,
Ankara, Turkey.
Received: 21 September 2016 Accepted: 17 December 2016
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