Received: 12 January 2017 Revised: 27 April 2017 Accepted: 6 May 2017

DOI: 10.1002/pbc.26665

Pediatric
RESEARCH ARTICLE Blood &
The American Society of
Cancer Pediatric Hematology/Oncology

Changes in urine albumin to creatinine ratio with the initiation

of hydroxyurea therapy among children and adolescents with
sickle cell disease

Sarah Tehseen1,2 Clinton H. Joiner1,2 Peter A. Lane1,2 Marianne E. Yee1,2

1 Aflac Cancer and Blood Disorders Center,

Children’s Healthcare of Atlanta, Atlanta, Abstract

Georgia
2 Department of Pediatrics, Division of Pediatric
Hematology/Oncology, Emory University,
Atlanta, Georgia
Correspondence
Sarah Tehseen, Aflac Cancer and Blood Disorders
Center, Children’s Healthcare of Atlanta, Atlanta,
GA.
Email: Sarah.Tehseen@BCW.edu;
stehseen@mcw.edu
Grant sponsor: National Center for Advancing
Translational Sciences of the National Institutes
of Health; Grant number: UL1TR000454. Grant
sponsor: Abraham J. & Phyllis Katz Foundation.
Background: Renal damage is a progressive complication of sickle cell disease (SCD) that begins in
childhood and may progress to renal failure and early mortality in 12% of adults with hemoglobin
SS (HbSS) SCD. Early sickle nephropathy is characterized by hyperfiltration and microalbuminuria;
therefore, urine albumin to creatinine ratio (ACR) is an effective screening tool for its detection.
Procedure: This study investigated the effect of hydroxyurea (HU) therapy on urine ACR levels
among children with SCD. A retrospective review was conducted to identify all patients with HbSS
or HbS𝛽 0 thalassemia of age 7–18 years who began HU therapy in 2011–2013; a control group of
patients not on HU were matched by age and baseline hemoglobin. All urine ACR measurements
≤24 months prior to and ≥24 months after HU initiation were recorded.
Results: There were 63 eligible patients on HU and 13 (25%) with albuminuria prior to HU initia-
tion. Among those with baseline albuminuria, the median ACR was 96 mg/g prior to HU, 39 mg/g at
1 year (P = 0.02), and 25 mg/g at 2 years (P = 0.03). Albuminuria normalized in 37.5% (6/16) after
1 year and 61% (8/13) after 2 years of HU therapy. Among those without albuminuria prior to HU,
13% (6/47) developed albuminuria during HU therapy. Sixteen percent (13/80) of control patients
had albuminuria in the beginning of study period, which normalized in 15% (two of 13) of patients
at 1-year follow up.

Conclusion: Introduction of HU is associated with significant decreases in urine ACR in children

with SCD and albuminuria.

KEYWORDS
albuminuria, hydroxyurea, nephropathy, sickle cell disease

1 INTRODUCTION adults with hemoglobin SS (HbSS).3–5 Ongoing glomerular injury leads

Advances in the management of sickle cell disease (SCD) have led
to improved survival into the third and fourth decades of life; how-
ever, adults with SCD face chronic complications related to ongoing
vaso-occlusive injury and hemolysis, including chronic kidney disease
(CKD).1 Although the underlying mechanisms associated with renal
damage in SCD are not fully elucidated, glomerular injury begins in
early childhood2 and is characterized by hyperfiltration and glomeru-
lar hypertrophy. Albuminuria, an early indicator of glomerular injury,
is observed in approximately 23% of children and in the majority of
Abbreviations: ACR, albumin to creatinine ratio; CBC, complete blood count; HU,
hydroxyurea; SCD, sickle cell disease
to glomerular sclerosis and renal insufficiency.6 Both proteinuria and
end-stage renal disease are independent predictors of early mortal-
ity in adults with SCD.7–10 Therefore, early identification of sickle
nephropathy and investigation of therapies to prevent or reverse renal
damage may have significant impact on long-term outcomes in adults
with SCD.
Standard methods for monitoring renal function such as creatinine-
based estimation of glomerular filtration rate are not reliable in SCD,
as serum creatinine remains low in SCD until the advanced stages of
renal damage.11,12 Albuminuria is an effective screening tool for iden-
tifying CKD and is the recommended test for screening pediatric and
adult SCD patients for early sickle nephropathy.13–15

Pediatr Blood Cancer. 2017;64:e26665. wileyonlinelibrary.com/journal/pbc 

c 2017 Wiley Periodicals, Inc. 1 of 6
https://doi.org/10.1002/pbc.26665
2 of 6
Therapeutic options for albuminuria in SCD remain an area of
insufficient evidence.15,16 Hydroxyurea (HU) therapy has proven to
be a cornerstone in the management of SCD and is associated with
improved survival and reduction of sickle complications in adults and
children.17–19 Although some studies have suggested that HU ther-
apy in children is associated with improvements in hyperfiltration,
urine concentration, and a lower prevalence of albuminuria, long-term
changes in albuminuria over time have not been well studied in children
with SCD on HU.3,20–22
This retrospective cohort study investigates the effect of introduc-
tion of HU therapy on urine albumin/creatinine ratio (ACR) levels over
a 2-year time period in children with SCD. We hypothesized that urine
ACR levels would decrease after 1 year or more of HU therapy. In order
to understand the natural history of albuminuria development and res-
olution in children with SCD, we also studied urine ACR values in a
matched group of children with SCD who were not on HU or other
SCD-modifying therapy.
2 METHODS
2.1 Study design and patient population
This was a retrospective cohort study of pediatric SCD patients who
began HU therapy between January 1, 2011 and December 31, 2013
and were followed longitudinally for up to 2 years on HU. The study
was approved by the Institutional Review Board of Children’s Health-
care of Atlanta (CHOA). Eligible patients were identified through the
SCD Clinical Database of CHOA, a prospectively gathered database
that tracks all patients with SCD with any encounter at CHOA since
2010 and includes laboratory-verified SCD genotype and dates of ini-
tiation of all SCD-specific treatments including HU, chronic transfu-
sion therapy, and bone marrow transplantation. Once eligible patients
were identified, electronic medical records were reviewed to iden-
tify patients who had urine ACR measurements both prior to and ≥3
months after starting HU. All patients followed institutional protocol
for HU therapy, with an initial dose of approximately 20 mg/kg/day,
with dose escalation every 8–12 weeks to achieve maximum tolerated
dose based on a goal absolute neutrophil count of ≥2,000/𝜇l.
2.2 Subject eligibility
2.2.1 HU subjects
Patients were included if they started HU between the ages of 7 and
18 years, had SCD genotypes of HbSS or HbS𝛽 0 thalassemia, and
had ≥1 ACR measurements in the 2 years prior to HU initiation and
≥1 ACR measurement at 6–24 months after HU initiation. Patients
were excluded if they had received chronic transfusion therapy within
12 months prior to starting HU, or had other medical conditions
associated with proteinuria or renal disease such as diabetes mellitus,
lupus, HIV, or pregnancy. Patients were also excluded if they were
on angiotensin converting enzyme inhibitor (ACE-I) or angiotensin
receptor blocker (ARB) medications before or during the study period,
TEHSEEN ET AL .
as these medications are known to decrease urine ACR and thus
would confound the assessment of the relationship between HU and
ACR.
2.2.2 Control subjects
In order to compare changes in ACR over time in children with SCD
without HU therapy, a control group of patients with HbSS or HbS𝛽0
thalassemia was matched by age (±1 year) and baseline hemoglobin
(±1 g/dl) to patients on HU therapy. Control patients were included
if they had two or more ACR measurements during the same time
period in which subjects on HU were studied. Control patients were
also excluded for chronic transfusion therapy, other disorders associ-
ated with renal impairment, or ACE-I/ARB treatment.
2.3 Study measurements
The main outcome variable was ACR, which was measured at ran-
dom time points on spot urine specimens. All urine ACR levels within
2 years prior to HU therapy initiation and from 6 months to 2 years
after HU initiation were recorded for patients on HU therapy. If more
than 1 ACR was measured prior to HU initiation, then the level clos-
est to the HU start date was recorded as the baseline level. Com-
plete blood counts (CBCs) including Hb and mean corpuscular volume
(MCV), reticulocyte counts, and fetal hemoglobin (HbF) were recorded
on the day of HU initiation (baseline) and at approximately 6 months,
1 year, and 2 years after starting HU. Albuminuria was defined as urine
ACR ≥ 30 mg/g on at least one spot urine specimen. Microalbuminuria
was defined as urine ACR level between 30 and 299 mg/g, and macroal-
buminuria was defined as urine ACR level ≥ 300 mg/g. Persistent albu-
minuria was defined as a urine ACR ≥ 30 mg/g on two or more consec-
utive urine specimens.
For SCD patients not on HU, all ACR values available over the 2-year
study period were recorded as well as CBC values.
2.4 Statistical analysis
Differences in urine ACR prior to HU initiation versus 1 year and
2 years after HU initiation were compared using Wilcoxon signed rank
test or paired t-test, as appropriate. Paired sample t-test was also used
to compare baseline CBC indices (Hb, MCV, reticulocyte count, and
HbF) to CBC indices after 12 months of HU therapy to assess hema-
tologic response to HU. Chi-square test or Fisher’s exact test was used
to determine change in proportion of patients with albuminuria before
and after HU initiation. Nonnormal variables including ACR were natu-
ral log transformed (ln). For multivariate analysis, a linear mixed effects
model was used to determine the effect of HU therapy on ACR over
time while adjusting for age, baseline hemoglobin, and baseline retic-
ulocyte count. Log transformed ACR was plotted against time from
HU therapy introduction and slope of the line was calculated using the
mixed effects model. Multivariable analysis included all ACR measure-
ments collected after HU initiation, including values beyond 2 years of
HU therapy, if available. A P-value of 0.05 was considered significant
for all comparisons. All analyses were conducted in SAS version 9.4.
TEHSEEN ET AL .
3 RESULTS
Review of the SCD Clinical Database of CHOA identified 166 patients
with HbSS or HbS𝛽 0 thalassemia of age 7–18 years who began HU
therapy during the 3-year study time period. Of these, 24 were
excluded for chronic transfusion therapy and five were excluded for
either ACE-I/ARB therapy or comorbid renal disorders. Of the remain-
ing 137 patients, 63 had a sufficient number of ACR measurements
both prior to and after initiation of HU to meet study inclusion. There
were 16 (25%) patients with albuminuria prior to initiation of HU ther-
apy (15 microalbuminuria and one macroalbuminuria), with a median
baseline ACR of 96 mg/g for the albuminuria group. All 63 patients
included had ACR measurements at ≥1 year after HU initiation, how-
ever 12 (19%) lacked ACR measurements at 2 years.
Table 1 shows baseline characteristics hematologic values and ACR
prior to HU initiation. Patients with albuminuria had significantly lower
hemoglobin (7.7 ± 2 vs. 8.6 ± 1 g/dl, P = 0.01) and higher MCV (91 ± 9
vs. 81.5 ± 14.2, P = 0.02) as compared to those without albuminuria
prior to HU. After 12 months of HU therapy, there were significant
increases in mean hemoglobin (8.3 ± 1.2 vs. 9.3 ± 1.5 g/dl, P = 0.02),
MCV (85 ± 12 vs. 95.4 ± 14 fl, P < 0.001), and HbF (9.4 ± 5 vs.
16.3 ± 8.7%, P = 0.001), and a significant decrease in absolute reticulo-
cyte count (331 ± 120 vs. 264 ± 104 × 109/l, P = 0.008) in all patients
as compared to baseline.
Among patients with albuminuria prior to HU initiation, there was
a significant decline in both median ACR level and in the proportion
of patients with ACR ≥ 30 mg/g at 1 year and 2 years of HU therapy
(Table 2). Normalization of urine ACR levels to < 30 mg/g occurred
in six (37.5%) patients by 1 year and eight (61%) by 2 years. Figure 1
shows lnACR levels before and after introduction of HU therapy, with a
decrease in lnACR levels after the introduction of HU at 1 and 2 years.
Changes in lnACR levels of individual patients with baseline albumin-
uria (n = 16) are shown in Figure 2.
Among patients with normal ACR levels prior to HU initiation
(n = 47), there was a nonsignificant decline in median ACR levels over
time (12 ± 24 at baseline, 10 ± 24 at 1 year, 7.5 ± 17 mg/g at 2 years,
P = n/s). There were six (13%) patients with baseline normal ACR who
then had ACR ≥ 30 mg/g at 1 year of HU therapy; of these, three had
normalized at 2 years, one remained persistently elevated at 2 years,
and two lacked repeat ACR measurements at 2 years. When compar-
ing CBC changes after HU initiation in those who developed elevated
ACR while on HU compared to those who did not, there were no sig-
nificant differences in hemoglobin, MCV, percent HbF, or reticulocyte
count that would suggest a difference in hematologic response to HU.
In mixed effects modeling, there was a significant negative asso-
ciation of HU therapy with lnACR while adjusting for the age of
HU initiation and for baseline hemoglobin and reticulocyte count
(P = 0.003, Supplementary Table S1). Older age at HU initiation also
was associated with significantly higher lnACR levels after starting HU
(P = 0.008).
Of the 16 patients with baseline albuminuria, 10 met the defini-
tion for persistent albuminuria (≥2 elevated ACR), while the remaining
six had only 1 ACR measurement prior to HU initiation. In this persis-
tent albuminuria group, seven patients (70%) were >10 years when HU
3 of 6
was initiated. For those with persistent albuminuria, median ACR levels
also showed a decline over 2 years of HU therapy, which was not statis-
tically significant (baseline ACR 96 ± 116 mg/g vs. 1-year ACR 67 ± 43
mg/g, and 2-year ACR 40.5 ± 492 mg/g; P = 0.2). None of the patients
with persistent albuminuria had normalization in urine ACR levels after
1 year of HU therapy, and three (37.5%) resolved after 2 years of HU
therapy (Table 2).
There were 80 matched control patients without HU or other SCD-
modifying therapy during the study period. At the initial ACR mea-
surement, 13 (16%) had ACR >30 mg/g, two of which normalized after
approximately 1 year without intervention while 11 remained persis-
tently high. Of the 67 patients with normal ACR at the initial measure-
ment, eight (12%) developed elevated ACR >30 mg/g at second mea-
surement, a frequency similar to the development of elevated ACR in
the patients on HU at 1 year.
4 DISCUSSION
This study demonstrates the long-term effects of HU therapy on
children who began the therapy unselected for baseline albuminuria
levels. Previous pediatric SCD studies have demonstrated a lower
prevalence of albuminuria in children on HU therapy, and obser-
vational studies have demonstrated normalization of urine ACR in
small numbers of patients with albuminuria.3,23,24 The prospective
Hydroxyurea Study of Long-Term Effects study showed no significant
change in albuminuria levels over 3 years of HU treatment; however
in that study only four of 23 patients had baseline albuminuria.20
Our study is the largest longitudinal study of ACR measurements in
children with SCD for up to 2 years after HU initiation, and provides
evidence that HU therapy is associated with a significant decrease in
ACR levels among children who have albuminuria prior to treatment.
The comparison of this HU cohort to a group of age, genotype, and
Hb-matched SCD patients not on HU therapy demonstrates that while
HU may help ameliorate albuminuria, it is not protective against the
development of elevated urinary ACR.
Our finding regarding HU’s role in the reduction of albuminuria
is similar to the recent prospective findings by Bartolucci et al., in
which 58 HbSS adults who initiated HU therapy were shown to have
a significant decrease in ACR at 6 months after HU, with the greatest
effect seen in those with albuminuria prior to HU initiation.25 Although
similar in its findings, our study is unique for its focus on pediatric
patients who are presumably in earlier stages of sickle nephropathy
as well as a longer time duration of study. Because sickle nephropathy
begins in childhood, with progressive damage during adulthood, it
is important to study the impact of interventions for albuminuria in
children, who typically have earlier stage nephropathy, as compared to
adults with SCD.
The mechanism by which HU therapy modulates sickle nephropathy
has not been well defined. Studies in pediatric and adult SCD groups
have shown an association of ACR levels with markers of hemoly-
sis, suggesting that endothelial damage related to chronic hemoly-
sis in SCD plays a role in the development of sickle nephropathy.3,26
Hemolysis leads to the release of heme and heme oxygenase 1 (HO-1).
4 of 6 TEHSEEN ET AL .

TA B L E 1 Baseline characteristics of patients with and without albuminuria prior to HU initiation

No albuminuria (n = 47) Albuminuria (n = 16) P-value

Age, mean ± SD (years) 11.8 ± 3 11.9 ± 4 0.83
Gender, female (%) 25 (53%) 9 (56%) 0.83
Hemoglobin, mean ± SD (g/dl) 8.6 ± 1.1 7.7 ± 1.3 0.01
MCV, mean ± SD (fl) 81.5 ± 14.2 91 ± 9 0.01
Reticulocyte count, mean ± SD (10 /l)
9
343.4 ± 137 337.3 ± 86 0.90
HbF, mean ± SD (%) 9.7 ± 4.6 8.3 ± 4.7 0.27
ACR, median ± IQR (mg/g) 10 ± 8 96 ± 120 <0.0001

ACR, albumin to creatinine ratio, HbF, fetal hemoglobin, MCV, mean corpuscular volume.

TA B L E 2 Change in ACR levels after the initiation of HU therapy among subjects with baseline albuminuria prior to HU

ACR prior to ACR at 1 year P-value ACR at 2 year P-value

HU initiation after HU after HU
initiation initiation
No. of patients (%) with albuminuria 16 (100) 10/16 (62.5) 0.02 5/13 (38.4) 0.003
No. of patients (%) with persistent albuminuria 10 10 (100) n/a 5/8 (62.5) 0.07
ACR, median ± IQR (mg/g) 96 ± 120 39 ± 55 0.02 25 ± 33 0.03

ACR, albumin to creatinine ratio, HU, hydroxyurea.

F I G U R E 1 Changes in mean lnACR (natural log transformed ACR) values with start of HU therapy (N = 16). There was a decline in natural log
transformed ACR values at 1 year (4.6 ± 1.17 vs. 3.7 ± 1.3 P-value: 0.01) and 2 years (3.7 ± 1.3; P-value: 0.2)

HO-1 causes vasodilatation and subsequent hyperfiltration, whereas
heme is proinflammatory and promotes vascular injury.27 Since HU
leads to decreased hemolysis, it could potentially lead to a decrease
in progressive reno-vascular damage, thus ameliorating ongoing kid-
ney damage. Another theoretical mechanism of action may be the
direct effect of HU on podocyte structure and function by destabiliza-
tion of proliferation markers like cyclin D1, thus preventing aberrant
podocyte proliferation that can prevent glomerular damage and devel-
opment of focal segmental glomerulosclerosis.28,29 Future studies are
needed to ascertain these effects.
Plasma-free Hb released by hemolysis may mediate proximal tubu-
lar dysfunction in SCD according to recent data gleaned from in vitro
models, thus inhibiting tubular reabsorption of albumin and further
contributing to albuminuria. Further studies of both glomerular and
tubular functions in sickle cell will contribute to the understanding
of the clinical finding of albuminuria and open avenues for further
treatment options.30
Limitations of this study include its retrospective design and a large
number of patients who were unable to be included due to lack of
consistent urine ACR measurements prior to and after HU initiation.
Additionally, due to the retrospective nature and limited number of
ACR measurements, albuminuria was defined by ACR ≥ 30 mg/g on a
single random urine sample (as is consistent with several other stud-
ies of albuminuria in SCD),3–5,13,20,24,25 while international consensus
guidelines define albuminuria as ACR ≥ 30 mg/g on at least two of
three separate random urine samples.14,15 Transient microalbuminuria
is known to occur in both SCD and non-SCD patients, and our study
did identify a small number of patients with transient albuminuria that
resolved without new intervention.31
To address this limitation, we attempted to analyze only the group
of patients on HU with persistent albuminuria. In this restricted group
of 10 patients with baseline albuminuria prior to HU therapy, ACR lev-
els did show a decreasing trend at 1 year and 2 years, however sta-
tistical significance was not achieved. We also sought to define the
prevalence of transient versus persistent albuminuria in an untreated
population of pediatric SCD patients in order to inform our analysis
of the patients on HU who had fewer than two ACR measurements
either prior to or after HU initiation. In the untreated control group,
we demonstrated that the majority of cases of elevated ACR at a
single time point (85%) were persistent on subsequent measurements
TEHSEEN ET AL .
FIGURE 2 Individual trajectories of natural log transformed (lnACR)
ACR levels among SCD patients with baseline albuminuria on HU ther-
apy (N = 16). The slope of regression line showed a decline in log trans-
formed ACR levels by 1.5 mg/g over 1–3 years of HU therapy (antilog
of −0.4)
at a year or later. This is in contrast to SCD patients who began HU
therapy, where normalization of ACR levels occurred in a large pro-
portion of patients with baseline elevated ACR. This constellation of
findings suggests a positive impact of HU therapy on reducing albumin-
uria. In order to conclusively address this limitation, future prospec-
tive studies would benefit from multiple urine ACR measurements to
define albuminuria as well as early morning urine measurements to
minimize detection of transient albuminuria or false positives.
A final limitation of this study is in the comparison of patients who
started HU therapy to those who were not on HU or other SCD-
modifying therapy, as there are potential differences in SCD sever-
ity and indications for HU therapy between the two groups, despite
attempts to match for age and baseline Hb value. Within the HU group
alone, however, the intrapatient pre-/postcomparison study design
helps to minimize potential confounding effect of the indication for HU
initiation on our results. Despite a limited sample size, we were able
to demonstrate a beneficial effect of HU on reducing urinary ACR val-
ues in pediatric patients with HbSS or HbS𝛽 0 thalassemia and baseline
albuminuria. This study also uncovered a similar frequency of new ele-
vations in ACR in SCD patients both on HU and not on HU, although
the exact proportion of transient versus persistent albuminuria was
not fully elucidated. Therefore, we conclude that HU, while clearly ben-
eficial in reducing baseline albuminuria, may not have strong protec-
tive benefits against albuminuria in all patients. Additionally, not all
patients had resolution of albuminuria after 2 years on HU therapy. In
patients with persistent albuminuria despite HU therapy, other ther-
apies such as ACE-I and ARB medications may be of benefit to treat
sickle nephropathy.32–35 Future prospective studies and longer longi-
tudinal follow-up will help determine the extent of HU’s role in the pre-
vention and amelioration of sickle cell nephropathy.
ACKNOWLEDGMENTS
The content is solely the responsibility of the authors and does not nec-
essarily represent the official views of the National Institutes of Health.
5 of 6
The authors wish to acknowledge Vaughn Barry, Ph.D. and Courtney
McCracken, Ph.D. for their statistical input.
CONFLICT OF INTEREST
The authors declare that there is no conflict of interest.
REFERENCES
1. Platt OS, et al. Mortality in sickle cell disease. Life expectancy
and risk factors for early death. N Engl J Med. 1994;330(23):1639–
1644.
2. Ataga KI, Derebail VK, Archer DR. The glomerulopathy of sickle cell
disease. Am J Hematol. 2014;89(9):907–914.
3. Lebensburger J, et al. Protective role of hemoglobin and fetal
hemoglobin in early kidney disease for children with sickle cell anemia.
Am J Hematol. 2011;86(5):430–432.
4. McPherson Yee M, et al. Chronic kidney disease and albumin-
uria in children with sickle cell disease. Clin J Am Soc Nephrol.
2011;6(11):2628–2633.
5. Guasch A, et al. Glomerular involvement in adults with sickle cell
hemoglobinopathies: prevalence and clinical correlates of progressive
renal failure. J Am Soc Nephrol. 2006;17(8):2228–2235.
6. da Silva GB, Jr., Liborio AB, Daher Ede F. New insights on pathophys-
iology, clinical manifestations, diagnosis, and treatment of sickle cell
nephropathy. Ann Hematol. 2011;90(12):1371–1379.
7. Elmariah H, et al. Factors associated with survival in a contemporary
adult sickle cell disease cohort. Am J Hematol. 2014;89(5):530–535.
8. McClellan AC, et al. High one year mortality in adults with sickle cell
disease and end-stage renal disease. Br J Haematol. 2012;159(3):360–
367.
9. Powars DR, et al. Outcome of sickle cell anemia: a 4-decade obser-
vational study of 1056 patients. Medicine (Baltimore). 2005;84(6):363–
376.
10. Powars DR, et al. Chronic renal failure in sickle cell disease: risk factors,
clinical course, and mortality. Ann Intern Med. 1991;115(8):614–620.
11. Asnani MR, Lynch O, Reid ME. Determining glomerular filtration rate in
homozygous sickle cell disease: utility of serum creatinine based esti-
mating equations. PLoS One. 2013;8(7):e69922.
12. Asnani MR, Reid ME. Renal function in adult Jamaicans with homozy-
gous sickle cell disease. Hematology. 2015;20(7):422–428.
13. Asnani MR, Reid ME. Diagnostic accuracy of spot and timed mea-
surements of urinary albumin concentration to determine microal-
buminuria in sickle cell disease. West Indian Med J. 2013;62(9):808–
816.
14. Levey AS, et al. Definition and classification of chronic kidney disease: a
position statement from Kidney Disease: Improving Global Outcomes
(KDIGO). Kidney Int. 2005;67(6):2089–2100.
15. Yawn BP, et al. Management of sickle cell disease: summary of
the 2014 evidence-based report by expert panel members. JAMA.
2014;312(10):1033–1048.
16. Savage WJ, et al. Evidence gaps in the management of sickle cell dis-
ease: a summary of needed research. Am J Hematol. 2015;90(4):273–
275.
17. Steinberg MH, et al. The risks and benefits of long-term use of hydrox-
yurea in sickle cell anemia: a 17.5 year follow-up. Am J Hematol.
2010;85(6):403–408.
18. Voskaridou E, et al. The effect of prolonged administration of hydrox-
yurea on morbidity and mortality in adult patients with sickle cell
6 of 6
syndromes: results of a 17-year, single-center trial (LaSHS). Blood.
2010;115(12):2354–2363.
19. Wang WC, et al. Hydroxycarbamide in very young children with sickle-
cell anaemia: a multicentre, randomised, controlled trial (BABY HUG).
Lancet. 2011;377(9778):1663–1672.
20. Aygun B, et al. Hydroxyurea treatment decreases glomerular
hyperfiltration in children with sickle cell anemia. Am J Hematol.
2013;88(2):116–119.
21. Fitzhugh CD, Wigfall DR, Ware RE. Enalapril and hydroxyurea
therapy for children with sickle nephropathy. Pediatr Blood Cancer.
2005;45(7):982–985.
22. Laurin LP, et al. Hydroxyurea is associated with lower prevalence of
albuminuria in adults with sickle cell disease. Nephrol Dial Transplant.
2014;29(6):1211–1218.
23. Alvarez O, et al. Early blood transfusions protect against microal-
buminuria in children with sickle cell disease. Pediatr Blood Cancer.
2006;47(1):71–76.
24. McKie KT, et al. Prevalence, prevention, and treatment of microalbu-
minuria and proteinuria in children with sickle cell disease. J Pediatr
Hematol Oncol. 2007;29(3):140–144.
25. Bartolucci P, et al. Six months of hydroxyurea reduces albuminuria in
patients with sickle cell disease. J Am Soc Nephrol. 2016;27(6):1847–
1853.
26. Haymann JP, et al. Glomerular hyperfiltration in adult sickle cell ane-
mia: a frequent hemolysis associated feature. Clin J Am Soc Nephrol.
2010;5(5):756–761.
27. Nath KA, Katusic ZS. Vasculature and kidney complications in sickle
cell disease. J Am Soc Nephrol. 2012;23(5):781–784.
28. Albaqumi M, Barisoni L. Current views on collapsing glomerulopathy. J
Am Soc Nephrol. 2008;19(7):1276–1281.
29. Mukherji A, Janbandhu VC, Kumar V. HBx protein modulates
PI3K/Akt pathway to overcome genotoxic stress-induced destabiliza-
tion of cyclin D1 and arrest of cell cycle. Indian J Biochem Biophys.
2009;46(1):37–44.
TEHSEEN ET AL .
30. Eschbach ML, Kaur A, Rbaibi Y, et al. Hemoglobin inhibits albumin
uptake by proximal tubule cells: implications for sickle cell disease. Am
J Physiol Cell Physiol. 2017.
31. Garg AX, et al. Albuminuria and renal insufficiency prevalence guides
population screening: results from the NHANES III. Kidney Int.
2002;61(6):2165–2175.
32. Yee ME, et al. Angiotensin Blockage with Losartan is Associated with
Decreased Albuminuria and Stable Renal Function in Adults and Children
with HbSS on Hydroxyurea, in American Society of Hematology. Orlando,
FL: American Society of Hematology; 2015.
33. Falk RJ, et al. Prevalence and pathologic features of sickle cell
nephropathy and response to inhibition of angiotensin-converting
enzyme. N Engl J Med. 1992;326(14):910–915.
34. Foucan L, et al. A randomized trial of captopril for microalbumin-
uria in normotensive adults with sickle cell anemia. Am J Med.
1998;104(4):339–342.
35. Sasongko TH, Nagalla S, Ballas SK. Angiotensin-converting enzyme
(ACE) inhibitors for proteinuria and microalbuminuria in people with
sickle cell disease. Cochrane Database Syst Rev. 2013;3:Cd009191.
SUPPORTING INFORMATION
Additional Supporting Information may be found online in the support-
ing information tab for this article.
How to cite this article: Tehseen S, Joiner CH, Lane PA, Yee
ME. Changes in urine albumin to creatinine ratio with the initi-
ation of Hydroxyurea therapy among children and adolescents
with sickle cell disease. Pediatr Blood Cancer. 2017;64:e26665.
https://doi.org/10.1002/pbc.26665