Blood Cells, Molecules and Diseases 91 (2021) 102590

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Blood Cells, Molecules and Diseases

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Short Communication

Reliability of different estimated glomerular filtration rate as measures of

renal function in children with sickle cell disease
Baba Psalm Duniya Inusa, MD a, *, Ilaria Liguoro b, Bamidele Tayo c, Caroline Booth d,
Charles Turner e, Neil R. Dalton e
a
Paediatric Haematology, Evelina London Children's Hospital, Guy's & St Thomas' NHS Foundation Trust, London, UK
b
Department of Medicine, Division of Pediatrics, University of Udine, Italy
c
Department of Public Health Sciences, Parkinson School of Health Sciences and Public Health, Loyola University Chicago, Maywood, USA
d
Department of Nephrology, Evelina London Children's Hospital, Guy's and St Thomas NHS Foundation Trust, United Kingdom
e
WellChild Laboratory, Evelina London Children's Hospital, Guy's and St Thomas NHS Foundation Trust, United Kingdom

A R T I C L E I N F O A B S T R A C T

Keywords: Background: There is no reliable marker for detecting early renal disease in early children with sickle cell disease
Sickle cell disease (SCD). Estimation of glomerular filtration rate (eGFR) as derived from the height/plasma creatinine formula is
Sickle cell nephropathy dependent on the accuracy of the creatinine analytical method used. The aim of this study was to evaluate
Albuminuria
different equations for eGFR.
Glomerular filtration rate
Mass spectrometry
Methods: Children aged 5–16 years recruited. mGFR was obtained using plasma disappearance of Inutest/
Creatinine Iohexol, serum creatinine (SCr) was measured either by standard laboratory method or by tandem mass spec­
trometry (MSMS). Estimated GFR was then calculated either by “Bedside Schwartz method” or by the full-age
spectrum (FAS) equation.
Findings: A total of 79 patients (mean age 9.8 ± 4.0 years). A revised eGFR constant was calculated for Schwartz
equation from the slope of the plot of height/plasma creatinine versus mGFR. Mean values for mGFR (132.7 ±
32.1 ml/min/1.73m2) and eGFR methods compared: eGFR from standard SCr was significantly higher (144.2 ±
37.3 ml/min/1.73m2, p = 0.008). The MSMS eGFR showed the lowest SD (SD = 27.5), while both FAS eGFR and
FAS-height eGFR showed the highest correlation coefficient (r = 0.67).
Interpretation: eGFR calculation based on height and SCr determined with MSMS traceable creatinine is more
reliable than Schwartz formula using jaffe/enzymatic methods in SCD children.

1. Introduction
Sickle Cell Disease (SCD) is an inherited blood disorder caused by a
single base pair substitution of glutamic acid by valine at position 6 of
the β-chain of haemoglobin, resulting in Haemoglobin S (Hb S) [1]. SCD
is one of the world's leading disorders in childhood, with over 300,000
new births annually [2]. Even though the majority (over 75%) of the
births are in sub-Saharan Africa, there has been increasing prevalence in
high income settings, and the UK is reported to have over 14,000; 80% of
whom live in greater London [3].
SCD is characterised by acute and chronic manifestations, with
progressive organ damage and vasculopathy [4]. In as the deoxygen­
ation state, HbS undergoes polymerisation leading to para-crystal for­
mation and distortion of the red blood cells (RBCs) into ‘sickle’ forms
[5]. The sickled RBCs may cause microvascular obstruction, tissue
infarction, endothelial and reperfusion injury [6]. SCD is therefore
characterised by multi-organ involvement such as stroke, pulmonary
hypertension, renal impairment and premature death [7–9].
Renal complications, otherwise referred to as sickle cell nephropathy
(SCN), occur throughout the life of a patient with SCD. This usually
starts with hyperfiltration and impaired urinary concentration in early
childhood, followed by albuminuria, haematuria. Acute kidney injury
may occur at any point especially during episodes of vaso-occlusive
events and may ensue in chronic kidney disease (CKD)/end stage kid­
ney disease (ESKD) with advancing age [10,11]. As patients with SCD
survive longer, the risk of progressive end-organ damage rises. The
prevalence of ESKD by age 37 years has been estimated 12% [12], and
may rise in patients over 40 to 50% [13]. The median survival from the

* Corresponding author at: Evelina London Children's Hospital, Guy's and St Thomas NHS Foundation Trust, London SE17EH, USA.
E-mail address: Baba.inusa@gstt.nhs.uk (B.P.D. Inusa).

https://doi.org/10.1016/j.bcmd.2021.102590
Received 4 May 2021; Received in revised form 12 June 2021; Accepted 24 June 2021
Available online 7 July 2021
1079-9796/© 2021 Elsevier Inc. All rights reserved.
B.P.D. Inusa et al.
development of ESKD is 4 years irrespective of mode of renal replace­
ment therapy [14]. Furthermore, SCN is reported to accounts for about
16-18% of all deaths due to SCD.
Standard methods to directly measure glomerular filtration rate
(GFR) are represented by urinary inulin and plasma iohexol clearance.
Inulin is an exogenous polysaccharide that is not protein bound and is
freely filtered through the glomerulus and neither secreted nor reab­
sorbed in the renal tubules, and its urinary clearance has therefore been
regarded as the gold standard for measuring GFR [15], but its applica­
tion in clinical practice is limited by cost and the practical difficulty of
collecting accurately timed urine samples. Iohexol is a non-ionic
contrast medium that has been used intravenously in radiological pro­
cedures even in the presence of renal disease. It is not metabolized and is
excreted completely in the urine. Close agreement has been demon­
strated between iohexol clearance and inulin clearance for the mea­
surement of GFR [16–19]. Plasma clearance is usually performed with a
single-bolus injection followed by subsequent repeated blood sampling,
over the 4 h. The GFR is then calculated from the slope of plasma con­
centrations, and it has been shown to be sufficiently accurate as an
alternative to inulin [20].
However, both these techniques are time-consuming and cannot be
easily applied to a pediatric population as a routine screening exam.
Estimation of GFR (eGFR) in children is primarily derived from the
height and plasma creatinine, and it is therefore dependent upon the
accuracy of the creatinine analytical method used [21]. Currently, there
is no reliable marker for detecting early renal disease in patients with
SCD, especially in childhood during the period of hyperfiltration and
increased renal blood flow [10]. The Schwartz method was set up for
subjects with low to normal GFR, so it is not just the change in creatinine
methodology but the different study population that may lead to
possible discrepancy with the standard equation. The methods have not
been validated in people of African ancestry or SCD. This may signifi­
cantly compromise the design of appropriate clinical trials to identify
potential preventive therapy.
Recently, a new equation for estimating GFR was developed [22], the
full age spectrum (FAS) equation. This formula is based on normalized
serum creatinine (SCr/Q), where Q are the mean or median SCr value for
age-/sex-specific healthy populations [23–25]. The FAS equation
resulted less biased and more accurate than the Schwartz equation for
children and adolescents [22], but it has not been validated in SCD
population yet.
The aim of this study was to evaluate the application of different
equations for estimating GFR using clinical and demographic variables
and markers of renal function based on different biomarkers, correlating
them with gold standard methods of measuring GFR in children with
SCD.
2. Methods
This pilot study was carried out at the Evelina Children's Hospital,
Guy's and St Thomas NHS Foundation Trust, one of the largest tertiary
level health care facility in London, UK with over 400 children 0-16 with
SCD and total over 1000 patients across the Trust.
The study was initially approved by the local Institutional Review
Board Rec reference 06/Q0704/14 and then national REC Ref 10/
H0803/150. An informed consent form was obtained from all
participants.
Age appropriate information sheets were provided: 5-10 years, 11-
16 years and > 16 years. Parental information sheets for children under
16 years old were also provided.
2.1. Patients
Children aged 5-16 years followed for SCA (homozygous HbSS and
HbSβ0) were prospectively recruited. Clinical data were obtained from
medical records and included age, gender and growth parameters
2
Blood Cells, Molecules and Diseases 91 (2021) 102590
(height, weight).
Patients were enrolled irrespective of baseline treatment (chronic
transfusion regimen, hydroxycarbamide, or folic acid). Exclusion
criteria were the presence of any co-existing clinical condition likely to
complicate the interpretation of clinical and laboratory results (HIV,
viral hepatitis, CKD- stage 3 liver disease, diabetes mellitus,).
2.2. Blood and urine analysis
Routine blood and urine analysis were performed as part of normal
clinical care, including full blood count (FBC), reticulocyte count (RC),
liver function tests, lactate dehydrogenase (LDH), Foetal Haemoglobin
(HbF) quantitation. In addition, specific renal biomarkers were
measured: formally measured GFR (mGFR) was obtained using plasma
disappearance of Inutest/Iohexol, SCr was measured either by standard
laboratory method and tandem mass spectrometry (MSMS). Estimated
GFR was calculated by using the “Bedside Schwartz method” [26,27]
with the formula: eGFR = 0.413 * height (cm) / creatinine (mg/dl) or
eGFR = 36.5 * height (cm)/creatinine (μmol/l). The FAS equation
(107.3/(SCr/Q) for patients aged ≥2 and ≤ 40 years) was also applied in
two different ways: the same Q-values derived from a previous paper
[22] were matched according to age (FAS eGFR) and height (FAS-height
eGFR).
Glomerular hyperfiltration was defined as GFR > 140 ml/min/m2.
2.3. Statistics
Continuous variables were expressed as mean (SD) or median (range)
as appropriate, while categorical variables were expressed as percent­
ages or frequencies.
The eGFR calculated with different equations were compared to
mGFR values. For the agreement analyses between mGFR and eGFR,
mean bias (95% CI of agreement), that defines the accuracy, and the SD
of bias (i.e., the precision) were calculated using Bland-Altman methods
assuming constant variance. Correlations between the measures were
tested by Pearson's coefficient and differences between the eGFR and
mGFR were evaluated by paired t-test. p-values ≤0.05 were considered
as statistically significant. The percentage difference between eGFR and
mGFR and the percentage of values within ±10% (P10[%]) and ± 30%
(P30[%]) are also presented. The statistical analyses were performed
using SAS 9.4 (SAS Institute Inc., Cary, NC, USA).
3. Results
3.1. Baseline characteristics
A total of 79 children with SCD (HbSS and HbSβ0/β+) (39 males,
mean age 9.8 ± 4.0 years) were enrolled. Mean anthropometric mea­
sures were collected and summarized in Table 1.
Routine blood results were also collected at steady-state and
described in Table 2.
3.2. Renal measurements
Standard renal measurements were available for all patients. Mean
values for mGFR and SCr were 132.7 ± 32.1 ml/min/1.73m2 and 38.5 ±
Table 1
Baseline characteristics of 79 children with sickle cell disease.
N = 79
Males, n/N (%) 39/79 (49)
Mean age ± SD, years 9.8 ± 4.0
Mean height ± SD, cm 135.4 ± 20.9
Mean weight ± SD, kg 34 ± 15
Mean body surface area ± SD, m2 1.1 ± 0.3
B.P.D. Inusa et al. Blood Cells, Molecules and Diseases 91 (2021) 102590

Table 2 Table 4
Steady-state blood exams of 79 children with sickle cell disease. Bias, precision, agreement and accuracy of the estimated compared to measured
N = 79
glomerular filtration rate (eGFR vs mGFR) in children with sickle cell disease.
3 eGFR N Bias (95%CI SD Correlation P10 P30
Mean WBC ± SD (*10 /mmc) 11.9 ± 3.9
equation agreement bias coefficient
Mean Hb ± SD (g/dl) 9.2 ± 1.9
mGFR-eGFR)
Mean HbF ± SD (%) 4.8 ± 4.4
Mean RC ± SD (*103/mmc) 236.8 ± 107.7 eGFR 65 10.5 (-50⋅8 to 31.3 r = 0.62* 33.8% 77%
Mean LDH ± SD (U/l) 964.7 ± 499.6 (Schwartz 71.8)
Mean AST ± SD (U/l) 65.6 ± 55.2 2009)
[26,27]
MSMS eGFR 44 -4.9 (-58.8 to 27.5 r = 0.65* 47.7% 86.4%
17.8 μmol/l, respectively. Thirty-four children (43%) showed glomer­ 48.9)
ular hyperfiltration with mGFR >140 ml/min/1.73m2. Applying the FAS [22] 65 7.1 (-50.5 to 29.4 r = 0.67* 40% 83%
64.7)
Schwartz formula (=36.5 * height (cm)/creatinine (μmol/l)), the mean
FAS-height 65 4.3 (-50.7 to 28 r = 0.67* 50.7% 90.7%
value for eGFR derived from standard SCr was 144.2 ± 37.3 ml/min, [22] 59.2)
with significant difference in comparison to mGFR (paired t-test, p =
mGFR, measured glomerular filtration rate; eGFR, estimated glomerular filtra­
0.008) (Table 3).
tion rate; MSMS eGFR, tandem mass spectrometry -creatinine estimated
MSMS creatinine was also available for 44 children (39.1 ± 18.7
glomerular filtration rate, FAS eGFR, full-age spectrum estimated glomerular
μmol/l). Height/MSMS creatinine ratios were performed: significant filtration rate (creatinine/Q22); P10%: percentage of eGFR values within ±10%
correlation with mGFR was found, (r = 0.65; p < 0.001). A revised eGFR of GFR; P30%: percentage of eGFR values within ±30%.
constant was then calculated for Schwartz equation from the slope of the *
p < 0.05.
plot of height/MSMS creatinine vs mGFR forced through zero. The new
constant was determined as 31.44 or 31 for convenience. MSMS creat­ isolated glomerular hypertrophy) [28]. In a recently published study,
inine derived eGFR values were obtained with the new constant, similar patterns were found also in a cohort of children with SCD who
resulting with a mean of 120.5 ± 34.4 ml/min, and there was no sig­ underwent renal biopsy due to persistent proteinuria [29]. However,
nificant difference in comparison to mGFR (paired t-test, p = 0.239) despite pharmacological post-biopsy interventions, overall outcomes
(Table 3). were poor, as stated by authors [29]. Therefore, the detection of pro­
Mean FAS eGFR and FAS-height eGFR were calculated and compared teinuria may be a late sign of SCN even in children.
to mGFR, showing no significant difference (p = 0.055 and p = 0.224 An expert panel of clinicians, investigators and patients convened by
respectively). the American Society of Hematology along with US Food and Drug
Bias, precision and agreement of different eGFR compared to mGFR Agency to develop consensus recommendations for clinical trials end
were performed as reported in Table 4. The MSMS eGFR had the lowest points, undertook thorough literature review in 2019. The panel iden­
SD (SD = 27.5), while both FAS eGFR and FAS-height eGFR showed the tified multiple renal morbidities in SCD including albuminuria, hypo­
highest correlation coefficient (r = 0.67). We also compared the bias of sthenuria, CKD and AKI [30].
the eGFR equations: the eGFR obtained from the classical Schwartz The plasma clearance of inulin represents the gold standard to assess
formula had the highest bias (10.5), and it was significantly higher than renal function [15]. It can be measured after either a continuous intra­
the FAS-height eGFR (4.3; p < 0.001) and the MSMS eGFR (-4.9; p = venous infusion or a single bolus injection [31]. The continuous infusion
0.02). FAS-height eGFR and MSMS eGFR showed the highest P10 and method is based on the concept that when the plasma concentration of
P30 (50.7% and 90%; 47.7% and 86.4% respectively). the marker is constant (steady state concentration) and the volume of
Differences and correlations plots of mGFR vs eGFR derived from the distribution is saturated with the marker (state of equilibrium), the rate
studied equations are depicted in Figs. 1 and 2. of excretion equals the rate of infusion [15]. However, this is an inva­
sive, and expensive method to evaluate GFR that cannot be easily
4. Discussion applied to a pediatric population. Iohexol clearance has been proposed
as a valid alternative [32] and a possible routine screening exam, but it
These preliminary data suggest that eGFR may prove valuable in remains time-consuming and not suitable for practical use [33].
monitoring renal function in children with SCD, even during the earliest Estimated GFR calculated using SCr based formulae has always been
phase of hyperfiltration, providing the constant is appropriately dependent on the method used for measuring plasma creatinine and of
adjusted for the analytical method of creatinine. some constitutional factors. Creatinine-only based equations may over-
Evidence for the SCN is derived from adult studies: glomerular le­ estimate GFR in patients with SCD, and none have been formally vali­
sions found in adult patients with SCD include focal segmental glo­ dated in GFRs >100 ml/min/1.73m [2] [11,34,35]. Some effort has
merulosclerosis, membranoproliferative glomerulonephritis, been made to determine agreement of certain predictive equations with
thrombotic microangiopathy and SCD glomerulopathy (the presence of mGFR in SCD patients. The Baby HUG investigators found poor corre­
lation of 99‑technetium diethylenetriaminepentaacetate (99mTc-DTPA)
Table 3 measurements with the Schwartz formula36, and fair correlation with
Baseline characteristics of children with sickle cell disease. the CKid-Schwartz (Chronic Kidney Disease in Children) formula37.
N Mean ± SD p-Value (vs mGFR) Similarly, Aygun et al.38 compared GFR measured using 99mTc-DTPA to
various creatinine and Cystatin C based estimates and found them all to
mGFR (ml/min/1.73m2) 79 132.7 ± 32.1
eGFR (ml/min/1.73m2) 65 144.2 ± 37.3 0.008* be fairly lacking.
MSMS eGFR (ml/min/1.73m2) 44 120.5 ± 34.4 0.239 In our population, significant discrepancies were found between
FAS eGFR (ml/min/1.73m2) 65 140.7 ± 37 0.055 mGFR and eGFR obtained from Schwartz equation. Serum creatinine
FAS-height eGFR (ml/min/1.73m2) 65 138 ± 34.4 0.224
tends to be lower in children with HbSS in comparison to healthy pop­
mGFR, measured glomerular filtration rate; eGFR, estimated glomerular filtra­ ulation, as demonstrated by previous studies38,39. In addition, eGFR
tion rate (=36.5 * height (cm)/creatinine); MSMS eGFR, tandem mass spec­ formulas are usually based on the assumption that creatinine is fully
trometry -creatinine estimated glomerular filtration rate (=31 * height (cm)/ excreted through filtration at the glomerular level, while in children
MSMS-creatinine), FAS eGFR, full-age spectrum estimated glomerular filtration with SCD the increased renal blood flow leads to supra-normal proximal
rate (creatinine/Q22). tubular function resulting either in tubular secretion of creatinine and
*
Statistically significant.

3
B.P.D. Inusa et al. Blood Cells, Molecules and Diseases 91 (2021) 102590

Fig. 1. Differences plots of measured glomerular filtration rate (mGFR) values vs estimated GFR (eGFR) calculated according to the classical Schwartz equation (A),
the full-age spectrum equation (FAS-age) (B), the FAS-adjusted for height equation (C) and tandem mass spectrometry (MSMS) creatinine derived equation (D).

Fig. 2. Correlation plots of measured glomerular filtration rate (mGFR) values vs estimated GFR (eGFR) calculated according to the classical Schwartz equation (A),
the full-age spectrum equation (FAS-age) (B), the FAS-adjusted for height equation (C) and tandem mass spectrometry (MSMS) creatinine derived equation (D).

glomerular filtration40. Correction factors accounting for age, gender
and muscle bulk may be applied to these formulas, but it is not un­
common for individuals with SCD to experience growth and weight
patterns below the mean percentile for their age41.
Standard classical technique to measure SCr use a colorimetric
method (Jaffe), that is vulnerable to interference with some chromo­
gens, including bilirubin or other proteins42. Isotope dilution-mass
spectrometry (ID-MS) traceable methods have been developed to
address these interferences and reduce the bias43, but pitfalls in creati­
nine measurement could not be completely overwhelmed. MSMS SCr
measurements showed a more accurate and specific profile44.
Based on these premises, we decided to develop a revised constant
for the Schwartz formula using a MSMS methodology to measure SCr.
Mean MSMS eGFR showed no difference and good correlation with
mGFR values, as well as low bias and SD values (i.e. high accuracy and
precision), significantly lower than classical Schwartz derived eGFR.
This is the first study in which this methodology was applied to children
with SCD, but it has already be proven highly sensitive and specific, in
particular in patients with levels <0.5 mg/dl, such as pediatric or
pregnant population44. The identification of a tailored equation for
children with SCD may therefore change the approach to the evaluation
of renal function.
To make this methods generalisable, laboratory analysers, whether
based on enzymatic or Jaffe chemistry, are calibrated against mass spec
reference methods. Measuring creatinine using MSMS at the same time
as iohexol for GFR measurement, therefore reference method level re­
sults were available for this study. The results should be transferable to
any modern, accredited, creatinine method. There are some differences
in specificity between commercial methods45. Specificity Characteristics
of 7 Commercial Creatinine Measurement Procedures by Enzymatic and

4
B.P.D. Inusa et al.
Jaffe Method Principles45. so the use of mass spec makes this study
“manufacturer neutral”.
Our findings also show that FAS equations may have a very good
accuracy profile in estimating renal function, with the highest correla­
tion coefficient and P10/P30 values. The FAS formula has been exter­
nally validated in a large study as the most unbiased equation showing
better performance than the Schwartz and CKD-EPI equations22. This is
a reasonable alternative to classical eGFR equations for children and
adults, as the FAS equation is valid across the full age-spectrum. More­
over, the FAS equation does not require further correction for age or sex,
and probably not for other ethnicities, although Q-values specific for
other ethnicities still need to be obtained45. However, as the FAS
equation has been designed on the healthy population, it may be ex­
pected that it would perform better in the healthy people than in pa­
tients with nephropathy. The FAS formula has been externally validated
in a large study as the most unbiased equation showing better perfor­
mance than the Schwartz and CKD-EPI equations. This is a reasonable
alternative to classical eGFR equations for children and adults, as the
FAS equation is valid across the full age-spectrum. Moreover, the FAS
equation does not require further correction for age or sex, and probably
not for other ethnicities. Therefore, this formula is becoming widely
accepted throughout Europe, particularly in children. One of the ob­
jectives of this study was to see how this formula performs in children
with SCD, a population in which there are no previous data on this
formula, and in hyperfiltration.
One of the main limitations of this study is represented by the small
sample size, and this prevented us to control results for specific vari­
ables, such as the presence of a baseline treatment (HU or chronic
transfusion regimen). However, the renal function of our patients was
fully assessed, and to our knowledge this is also the first study evaluating
mGFR of a cohort of children with SCD.
5. Conclusions
In conclusion, the use of existing SCr based equations to estimate
GFR in clinical practice may not be very accurate in children with SCD.
Our results showed that FAS formula and a new creatinine-based
equation to calculate eGFR by introducing the constant = 31 when
using a MSMS method to measure SCr have good accuracy and precision
profiles. Both these equations may provide a more reliable estimation of
renal function in a hyperfiltration state in SCD. A larger cross-sectional
cohort of patients is planned in order to establish longitudinal data
collection.
Data sharing statement
All data relevant to the study are included in the article or uploaded
as online supplementary information. Deidentified participant data may
be available upon reasonable request from IL.
Funding source
No funding.
Research in context
Evidence before this study
Renal complications may occur early in the life of a patient with
sickle cell disease (SCD). Currently, there is no reliable marker for
detecting early renal disease in these patients, especially in childhood
during the period of hyperfiltration and increased renal blood flow.
Standard methods to directly measure glomerular filtration rate (GFR)
are time-consuming and cannot be routinely applied to children, while
equations to estimate GFR have not been validated in this population.
5
Blood Cells, Molecules and Diseases 91 (2021) 102590
Added value of this study
This study evaluates the application of different equations for esti­
mating GFR using clinical and demographic variables and markers of
renal function in children with SCD. Findings showed that formulae
based on height and serum creatinine determined by tandem mass
spectrometry provide a reliable estimation of renal function in com­
parison to standard Schwartz formula.
Implications of all the available evidence
These preliminary data suggest that estimated GFR may prove
valuable in monitoring renal function in children with SCD, even during
the earliest phase of hyperfiltration. The identification of a tailored
equation for children with SCD may therefore change the approach to
the evaluation of renal function.
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