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Nigerian J Paediatrics 2018 vol 45 issue 2

Nigerian J Paediatrics 2018 vol 45 issue 2

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Renal abnormalities among children with sickle cell anaemia
Niger J Paediatr 2018; 45 (2):112 - 117
ORIGINAL
Olorukooba AA
CC – BY Renal abnormalities among
Akuse RM
Ogunrinde GO
children with sickle cell anaemia
Mamman AI
Yusuf R
Kajogbola G
DOI:http://dx.doi.org/10.4314/njp.v45i2.7
Accepted: 3rd May 2018
Abstract : Introduction: Sickle
Results: Eleven (10.3%) children
cell anaemia (SCA) is a non-
with SCA had haematuria while
Olorukooba AA (
)
communicable disease of public
6.5% had overt proteinuria. Chil-
Akuse RM, Ogunrinde GO
health significance. SCA is char-
dren with SCA who had proteinu-
Department of Paediatrics,
acterized by chronic red blood
ria were five times more likely, to
cell haemolysis and vaso-
develop haematuria than the con-
Mamman AI
occlusion which further compli-
trols with proteinuria (p = 0.03).
Department of Haematology and
cated by nitric oxide deficiency,
Microalbuminuria was found in
Blood transfusion services
causes oxidative damage to the
24.3% of children with SCA. The
body organs especially the kid-
mean estimated glomerular filtra-
Yusuf R
neys.
tion rate was normal for both sub-
Department of Chemical Pathology
Objectives: To document the
jects and controls. Only three
prevalence of renal function and
(2.8%) of the SCA subjects had
Kajogbola G
structural abnormalities in chil-
increased renal echogenicity all of
Department of Radiology,
dren with SCA in a teaching hos-
whom had microalbuminuria and
Ahmadu Bello University Teaching
pital in north western Nigeria.
were older than nine years.
Hospital, Zaria, Nigeria
Materials and Methods: One hun-
Conclusion and recommendations:
Email: abiolaira@yahoo.co.uk.
dred and ten subjects with SCA in
Renal abnormalities were found in
steady state without known renal
children with SCA occurring as
or cardiac abnormalities were
early as 4 years of age. Regular
enrolled and matched for age and
screening for renal disease in chil-
sex with controls (haemoglobin
dren with SCA is recommended to
AA).
Interviewer-administered
ensure management modalities are
questionnaires, clinical examina-
instituted early.
tion and renal ultrasound scans
were carried out. Urinalysis, spot
Key words: SCA, Renal abnor-
urine albumin creatinine ratio and
malities, haematuria, proteinuria,
serum creatinine were carried out
renal size, estimated glomerular
using
standardized
laboratory
filtration rate
methods.
Introduction
communicable disease of public health significance
world wide. Progression of CKD to end stage renal dis-
Sickle cell nephropathy encompasses the structural and
ease (ESRD) may be delayed or halted using various
functional abnormalities of the kidney seen in patients
modalities like lifestyle and dietary modifications and
with sickle cell haemoglobinopathy (an autosomal reces-
use of drugs like hydroxyurea and angiotensin convert-
sive genetic disorder ) in the absence of other secon-
1,2
ing enzyme inhibitors (ACEI) and receptor blockers
(ARB). Over the years, there have been advances in the
2
dary causes of kidney disease. Up to 1 in 5 people with
3
SCD develop renal abnormalities which may progress to
management of SCA, changes in lifestyle, diet, wide
chronic kidney disease (CKD). The haemodynamic
4
spread use of non-steroidal anti-inflammatory drugs
changes of chronic anaemia and the consequences of
(NSAID’s), herbs and substandard drugs all of which
may affect the kidney. The aforementioned, coupled
8
vaso-occlusion which are especially marked within the
renal medulla in SCA results in abnormalities in renal
with the increase in CKD noted worldwide prompted
structure and function that begin in childhood. Func-
5
this study to detect abnormalities in renal structure and
tional abnormalities include impaired urinary concentra-
function in children with SCA in the locality.
tion, causing hyposthenuria,
6
enuresis, proteinuria,
nephrotic syndrome, haematuria, hypertension, acute
This study therefore aimed to determine renal function
kidney injury, chronic kidney disease and end-stage re-
and ultrasonographic findings in children with sickle
nal disease. Chronic kidney disease is an emerging non
7
cell anaemia in a tertiary hospital north western Nigeria.
113
®
Materials and Methodology
ing Turbilatex a quantitative turbidimetric kit manufac-
tured by Labkit diagnostics limited. Microalbuminuria
A cross sectional study was carried out in the paediatric
was considered as an albumin creatinine ration (ACR) of
haematology and oncology clinic between August 2014
30-300mg/g.
to January 2015 following approval from the Human
Research and Ethics Committee
Abdominal ultrasound scan was carried out using the
Mindray
®
pro sound model ultrasonography machine
One hundred and ten subjects with SCA in steady state
with Doppler facilities using a convex (curved array)
without any prior known renal or cardiac abnormalities
transducer at 3.75MHz. The kidneys were evaluated in
were consecutively sampled, enrolled and matched for
the supine and prone positions. The longitudinal lengths
age and sex with controls (haemoglobin AA). A struc-
of the kidneys were measured and compared with paedi-
tured interviewer-administered questionnaire was ad-
atric normograms. The ultrasonographic appearance was
ministered and clinical examination carried out. Renal
described based on consensus between two ultrasono-
glomerular function was assessed using urinalysis, mi-
graphers (qualified radiologists) noting the presence of
cro-albuminuria a sensitive marker of renal disease and
increased parenchymal echogenicity, calyceal clubbing,
estimated glomerular filtration rate (eGFR). Renal struc-
renal scarring and other abnormalities. An increase in
ture was assessed using renal ultrasound scans.
reflectivity throughout the kidney and poor/loss cortico-
medullary differentiation was defined as diffusely in-
The first consecutive 10 children who met the inclusion
creased renal echogenicity.
criteria were enrolled for the study each clinic day. Sub-
jects were children with haemoglobin electrophoretic
diagnosis of SCA (Hb SS and Hb SS+F) aged two to 18
years old who were in their steady state. Steady state
Results
was defined as a child with SCA who has remained
symptom-free for the three weeks preceding enrolment
Of the 110 subjects enrolled, five of the subjects did not
into the study. Excluded from the study were subjects
report back following initial screening showing protein-
with known cardiac disease (congenital or acquired) or
uria despite efforts to get across to them (two control
hypertension and those with urinary tract infection (UTI)
and three subjects with sickle cell anaemia). Two urine
or symptoms suggestive of UTI. Urinary tract infection
samples for the controls were lost in the laboratory due
was considered present for this study in subjects with
to spillage. A final population consisting of 107 subjects
positive leucocyte esterase and/or nitrite on urinalysis
with haemoglobin SS and 106 controls with haemoglo-
and/or un-centrifuged urine microscopy of ≥1 leucocytes
bin phenotype AA following haemoglobin electrophore-
per high power field. Also excluded where children with
sis was used. The female: male ratio was 1:1.03. The
known congenital structural renal conditions (posterior
ages ranged from 2 to 17 years for the SCA subjects,
urethral valves, renal artery stenosis and children who
and 2.2 to 18 years for the controls. The mean age for
had been on antibiotics treatment in the last two weeks
the SCA group was 8.9 ± 4.0 years while that for the
preceding the study.
control was 8.2 ± 3.8 years ( p = 0.16).
A spot sample of 10 ml of urine was collected by clean
Thirty-three (30.8%) of the children with SCA had pro-
catch method in a universal specimen bottle for urinaly-
teinuria. These included 26 (24.3%) who had microalbu-
sis at the clinic; Urine was tested immediately with
minuria while the rest had overt proteinuria ( ≥1+). The
prevalence of proteinuria was significantly more ( χ =
2
Combi 11
®
dipstix. Only children with samples that
tested negative to nitrites and leucocyte esterase were
6.59, p = 0.01) than that in the control group who had an
recruited. In those with proteinuria (>+ 1 protein on dip-
overall prevalence of proteinuria of 16 (15.1%).
sticks) or haematuria (>+1 blood on dipsticks), urine
Microalbuminuria was significantly more in subjects
microscopy was carried out to rule out UTI. All samples
(24.3%) than controls ( p = 0.04). Table 1. Sickle cell
that tested negative for proteinuria, nitrite and leucocyte
anaemia subjects were 2.1 times more likely to have
esterase by dipstix and normal urine microscopy was
microalbuminuria than controls. There were 17 (31.5%)
stored at -20 C for quantification of micro-albuminuria
o
female subjects with SCA who had microalbuminuria,
using a semi-quantitative immunoturbidimetric assay.
they were not significantly more than the 9 (17.0%)
male subjects with SCA who had microalbuminuria ( χ =
2
Venous blood (2.5ml) was collected via a venepuncture
using a peripheral vein following swabbing of the skin
2.3, p = 0.1). Microalbuminuria apparently increased
with age but this was not statistically significant with χ
2
with 70% alcohol and povidone iodine and assayed for
creatinine. Serum creatinine was assayed using the Se-
for linear trend = 0.6, p = 0.4. Other biometric and labo-
lectra XL
®
automated chemistry analyser (ELITech
ratory parameters were not found to significantly affect
group, vital scientific Chicago, IL (USA)) which is
the occurrence of proteinuria in children with SCA in
based on the Jaffe’s reaction. Each assay was validated
this study.
using commercial quality control samples, standards and
previously assayed human sera. Laboratory reference
The overall mean estimated glomerular filtration rate
values for serum creatinine were used and the eGFR was
(eGFR) for subjects with SCA was not significantly
higher (101.4 ± 27.6 ml/min/1.73 m ) than that in the
2
calculated from the serum creatinine using the original
controls (98.9 ± 26.4 ml/min/1.73 m ; t -test = 0.68, p =
2
Schwartz formula. Micro-albuminuria was assayed us-
114
0.5). The mean eGFR, increased with age for the fe-
SCA = sickle cell anaemia, SD- standard deviation,
males and males in both the SCA and control groups.
*statistically significant
There was also no significant difference in the mean
eGFR of subjects and controls with proteinuria and
Fig 1: Ultrasound image of the right kidney showing increased
renal echogenicity in a nine-year old girl with sickle cell
those without proteinuria. Table 2
anaemia
Table 1: Prevalence of microalbuminuria in sickle cell anae-
mia and control subjects
Parameter
SCA
Control
Total
n (%)
n (%)
n (%)
Microalbuminuria
26 (24.3)
14 (13.2)
40 (18.8)
No microalbuminuria
81 (75.7)
92 (86.8)
164 (81.2)
Total
107 (100.0)
106 (100.0)
213 (100.0)
χ2 = 4.3, df = 1, p= 0.04, OR = 2.1, 95% C.I 1.0 - 4.3
Table2: Mean estimated glomerular filtration rates (eGFR) of
sickle cell anaemia and control subjects by age group and gen-
der
Mean eGFR ± SD (ml/
min/1.73 m2)
Discussion
Age
t-
p-
Gender
(years)
SCA
Control
test
value
The prevalence of proteinuria among sickle cell anaemia
0.19
subjects was 30.8% most of which was from microalbu-
Female
0-4
77.9 ± 13.7
76.3 ± 20.8
0.8
minuria and was significantly more than in the controls.
5-9
90.4 ± 20.4
88.3 ± 16.7
0.37
0.7
This study recorded a prevalence of overt proteinuria
107.9 ±
0.06
10-14
108.4 ± 39.8
23.1
0.9
using dipstix of 6.5% among children with sickle cell
anaemia, this was similar to finding by Ugwu et al in
9
15-19
127.2 ± 15.1
111.9 ± 9.8
1.94
0.09
Port Harcourt, Anigilage and Adedoyin
10
Male
0-4
80.1 ± 13.9
80.4 ± 29.2
0.03
0.9
in Ilorin, and
Wigfall et al
11
5-9
94.2 ± 20.8
89.8 ± 31.3
0.5
0.6
in the USA, who found a prevalence of
108.4 ±
0.12
7%, 6.7% and 6.2% respectively. However, while the
10-14
109.6 ± 20.3
20.6
0.9
finding of overt proteinuria among SCA subjects by
133.9 ±
0.17
Ugwu et al and Wigfall et al were significantly higher in
15-19
136.9 ± 18.8
23.1
0.8
subjects with SCA compared to controls, this was not
SCA = sickle cell anaemia, eGFR= estimated glomerular filtra-
found to be so in this study. The lack of significant dif-
tion
ference in the occurrence of overt proteinuria in subjects
with SCA when compared with controls may be as a
The mean kidney lengths and widths were significantly
result of the controls being drawn from the hospital set-
higher in the SCA groups compared with the controls.
ting and some may have had undocumented risk factors
Table 3. While the mean lengths and widths for the left
for proteinuria.
kidney were more than the right kidney in both SCA and
controls groups, the differences were not found to be
Microalbuminuria was significantly more in subjects
significant ( p >0.05). Three (2.8%) of the subjects with
with SCA compared with controls. SCA subjects were
SCA (two females and one male) had diffuse increased
found to be 2.5 times as likely to have microalbuminuria
renal echogenicity, a non-specific indication of renal
when compared to controls. This is similar to 26.5% of
parenchymal disease. All of the subjects with SCA with
SCA subjects with microalbuminuria recorded by
Dharnidharka et al
12
increased renal echogenicity were between 9 and 14
in a study in the United States of
years had microalbuminuria though none had proteinuria
America (USA) among 102 SCA subjects. These find-
or haematuria demonstrable on urine dipstix, raised
ings are however, higher than that recorded by Imuet-
inyan et al in Benin and Eke et al
13
14
blood pressure or abnormal estimated glomerular filtra-
at Enugu where
tion rates.
20.3% and 18.5% respectively of their SCA subjects had
microalbuminuria. In the studies by Dharnindakar,
12
Table 3: Mean renal lengths and widths in sickle cell anaemia
and Eke, microalbuminuria was signifi-
14
Imuetinyan
13
and controls
cantly higher in children with SCA than controls. The
Mean kidney
SCA
Control
t-test
p value
higher prevalence of micro-albuminuria in this study
measurement
n = 107
n= 106
and Dharnindakar et al
12
compared to the Benin and
mm (SD)
Enugu findings may be due to the difference in the
Right length
86.2 (13.0)
79.9 (11.1)
-3.76
<0.0001*
method of assay employed. Micral strips which are semi
Left length
87.1 (13.1)
80.2 (10.9)
-4.1
<0.0001*
Benin and
13
-quantitative
methods
were
used
in
Right width
36.7 (4.9)
34.0 (3.5)
-4.64
<0.0001*
Enugu whereas a quantitative method was used in this
14 ,
Left width
37.1 (5.0)
34.1 (3.9)
-4.86
<0.0001*
study and in the study by Dharnidharka et al . Preva-
12
lence of microalbuminuria from the study by Solarin et
al in Lagos using both semi quantitative micral strips
15
115
(38.8%) and quantitative methods (11.3%) varied. This
controls then studied in Zaria. Both studies like this
disparity is thought to be due to methodology.
15
The
study did not find a significant difference in the occur-
female preponderance of subjects with microalbuminu-
rence of haematuria between subjects with SCA and
ria in this study was also documented by Imuetinyan ,
13
HbAA controls. The higher prevalence of haematuria
12
Solarin and Dharnidhakar et al .
15
Microalbuminuria
found in this study compared to the studies by Konotey-
was found in children less than five years in this study,
Ahulu and Aikhionbare may be as a result of the long
26
27
similar to the study done by Imuetinyan et al in Benin
13
time that has elapsed between their studies and this
but in contrast with findings by Gusach et al
1 6
who
study allowing for other factors leading to increasing
documented that microalbuminuria was noted in those
prevalence of renal disease noted worldwide, such as
10 years or older and Dharnidharka et al in the USA
12
increased sensitivity of test materials and changes in
lifestyle. Ugwu et al in Port Harcourt reported a higher
9
who documented no microalbuminuria under the age of
prevalence of haematuria of 11.1%
9
seven years. The later occurrence of microalbuminuria
while Anigilaje et
al
28
may be as a result of possible effect of diagnosis of SCA
in Ilorin studied 75 subjects with SCA in their
at birth through routine screening in developed countries
steady states and reported prevalence of haematuria of
13.3%.
28
like the USA and England where screening for sickle
While dipstix method was used in Port Har-
court, Anigilaje et al
9
28
cell disease has been recommended for all infants, re-
used urine microscopy in addi-
gardless of ethnic origin. It was found in this study that
17
tion to urine diptix. The results obtained by Anigilaje et
al
28
there was a slight increase in prevalence of MA in those
were higher than what was recorded in this study
and in the study by Ugwu et al , as this may be as a re-
9
children who were older than 10 years but this apparent
increase of microalbuminuria was not significant. This
sult of the urine sediment microscopy method used in
increase with age was also noted in other studies
11 , 18 ,
the Ilorin study as against urine dipstix used in the latter
19
and may possibly be as a result of higher number of
two studies.
crisis in these children and disease progression over
time.
There was no significant sex predilection for haematuria
among subjects with SCA in this study though there was
The mean haemoglobin in subjects with SCA with pro-
a female preponderance. This was similar to the pattern
teinuria was significantly lower than controls with pro-
found in the controls in this study. Also, Anigilaje et
and Konotey-Ahulu found no significant sex
26
al ,
28
teinuria and lower than in subjects with SCA without
proteinuria. The lower levels of haemoglobin in sickle
predilections in their studies. Female preponderance
cell anaemia subjects may signify the increased severity
may be explained on the background of the anatomy of
of the disease due to resultant sickling which in turn
the female genitalia which predisposes the urethra to
triggers release of prostaglandins and nitric oxide which
trauma and ascending infections that may lead to tran-
sient occult haematuria. Studies have also shown the
13
cause oxidative damage to the glomerulus, renal vaso-
dilatation and raised glomerular filtration rate (GFR),
prevalence of renal papillary necrosis which is a cause
also anaemia will result in increased cardiac output.
20 , 21 ,
of haematuria was commoner in females.
29,30
This study
22 , 23
noted an apparent increase of haematuria with age simi-
lar to previous studies.
Weight and blood pressure were not associated with the
occurrence of proteinuria in subjects with SCA. How-
The estimated glomerular filtration rate eGFR increased
ever, weight was a factor in controls with proteinuria as
with age in both males and females in the SCA and con-
they had a significantly higher weight than those without
trol groups with no statistically significantly difference
between both groups. Wigfall et al in their study of
11
proteinuria.
Previous studies have linked proteinuria
with raised body mass index (BMI) and obesity
24,25
,
children aged 2 to 21 years recorded a higher than ex-
identifying obesity as a major risk factor to renal dis-
pected eGFR in the SCA group in the first decade which
ease. Eke et al found significantly raised BMI in the
25
14
declined toward normal in the second decade. This con-
control group with MA but BMI was not found to be
trasted with the findings of this study which found the
significant in SCA group with microalbuminuria. Micro-
eGFR was within low to normal limits in the first decade
albuminuria found in SCA, occurs independent of the
and steadily increased with age similar to findings in
other known factors influencing the prevalence of renal
controls as were also reported by Okoro and Onuwa-
meze
31
and Olowu et al .
32
disease in the control population.
The presence of urinary ab-
normalities did not significantly affect the mean eGFR,
and similar to the report by Alvarez et al .
33
Even though the study found twice as many children
with SCA having haematuria, the prevalence of haema-
turia in SCA subjects in this study may be clinically
The lengths of the right and left kidneys in sickle cell
significant and it is possible that increasing the sample
anaemia group were significantly longer than those in
size of subjects in this study will increase the power to
the control group. This increased renal size was also
documented by Odita et al in Nigeria unlike Ibinayie et
29
detect differences between the two groups. Some older
al who found 27% of subjects with SCA had shrunken
34
studies done decades ago showed lower prevalence of
kidney. This study and Odita et al looked at children,
29
Konotey-Ahulu
26
haematuria
26 ,27
recorded a prevalence
whereas the study by Ibinaiye et al
3 4
of 2.1% in sickle cell anaemia subjects with haematuria
involved mainly
adults up to 54 years who may have had continuous
34
at the Korle Bu hospital, Ghana. Aikhionbare et al did
27
not find haematuria in the 101 subjects with SCA or the
renal damage leading to shrunken kidneys. The mean
116
lengths for the kidneys for the SCA and control groups
within normal. Renal structural abnormalities occur in
where within normal range; this is similar to findings by
lower percentage children with sickle cell anaemia but
Yeboah and Rodrigues in Ghana.
35
its association with renal glomerular function needs to
be further explored.
Few (2.8%) of the SCA subjects had increased diffuse
echogenicity/loss cortico-medullary differentiation dem-
Authors’ contributions
onstrating structural abnormalities occurring in child-
Olorukooba AA: Conceptualization and design of study,
hood. All subjects with renal abnormalities on ultrasono-
literature search, acquisition of data, analysis and inter-
graphy were nine years or older and all microalbuminu-
pretation of data, drafting the manuscript and revising of
ria though none had proteinuria or haematuria demon-
intellectual content.
strable on urine dipstix, raised blood pressure or abnor-
Akuse RM, Ogunrinde GO, Mamman AI, Yusuf R: De-
mal estimated glomerular filtration rates. Other studies
sign of study, analysis and interpretation of data and
have shown increased prevalence of renal echogenicity
revision of manuscript.
in subjects with SCA this has been attributed to renal
Kajogbola G: Acquisition of data, interpretation of data
papillary necrosis, presence of high concentrations of
and revision of manuscript.
iron deposits within tubular epithelial cells, focal scaring
Conflict of interest: None.
and interstitial fibrosis in the vasa recta system, glome-
Funding: None
rular hypertrophy and renal sclerosis.
36, 37
Recommendation
Conclusion
The use of routine microalbuminuria assay needs to be
encouraged among children with sickle cell anaemia and
There were significant renal glomerular function abnor-
renal ultrasound evaluation should be included in follow
malities occurring in children as low as four years.
up of children with microalbuminuria.
Glomerular filtration rate however appears to remain
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