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\begin{document}

\title{Extent of Hypertension and Renal Injury in Children Surviving Acute
Lymphoblastic Leukemia}



\author[1]{Reeti Kumar}%
\author[2]{John Mahan}%
\author[3]{Joseph Stanek}%
\author[2]{Suzanne Reed}%
\affil[1]{Duke University}%
\affil[2]{Nationwide Children's Hospital}%
\affil[3]{Nationwide Childrens Hospital}%


\vspace{-1em}



  
  \date{May 29, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: Childhood acute lymphoblastic leukemia (ALL) fortunately has
high survival rates, and understanding longer-term implications of
therapy is critical. In this study, we aimed to investigate kidney
health outcomes by assessing the prevalence of renal dysfunction and
hypertension (HTN) in children with ALL at one to five years after ALL
diagnosis. Methods: This was a single center, cross-sectional study of
children with ALL who were 1-5 years post diagnosis. GFR measurements
were calculated, and urine samples were collected to assess for
protein/creatinine and albumin/creatinine. Blood pressure (BP) was
determined by standard oscillometric technique, and children
\textgreater{}6 years of age were eligible for ambulatory blood pressure
monitoring (ABPM). Results: Forty-five patients enrolled in the study,
21 completed ABPMs. Fifteen patients (33\%, 95\% CI: 20-49\%) developed
AKI at least once. Thirteen (29\%, 95\% CI: 16-44\%) had
hyperfiltration, and 11 (24\%) had abnormal proteinuria and/or
albuminuria. Prevalence of HTN based on clinic measurements was 42\%. In
the 21 ABPM patients, 14 had abnormal results (67\%, 95\% CI: 43-85\%)
with the majority (11/21) demonstrating abnormal nocturnal dipping
pattern. . Conclusions: Among children with ALL, there is a high
prevalence of past AKI. The presence of hyperfiltration, proteinuria
and/or albuminuria at 1-5 years after ALL diagnosis suggest real risk of
developing CKD over time. There is a high prevalence of HTN on casual BP
readings and even higher prevalence of abnormal ABPM in this group. The
high prevalence of impaired nocturnal dipping by ABPM indicates an
increased risk for future cardiovascular or cerebral ischemic events.%
\end{abstract}%



\sloppy


\textbf{Extent of Hypertension and Renal Injury in Children Surviving
Acute Lymphoblastic Leukemia}

Reeti Kumar, MD\textsuperscript{1}, John D. Mahan,
MD\textsuperscript{2}, Joseph R. Stanek, MS\textsuperscript{3}, Suzanne
Reed, MD\textsuperscript{3}

\textbf{Affiliations} :

\textsuperscript{1}Department of Pediatrics, Division of Nephrology Duke
University Medical Center Durham, NC 27705 USA

\textsuperscript{2}Department of Pediatrics, Division of Nephrology
Nationwide Children's Hospital Columbus, Ohio 432015 USA

\textsuperscript{3}Department of Pediatrics, Division of
Hematology/Oncology/Bone Marrow Transplant Nationwide Children's
Hospital Columbus, Ohio 432015 USA

\textbf{Correspondence to:}

Suzanne Reed, MD

700 Children's Drive

Columbus OH

43205

Phone: 614-722-6349

Fax: 614-722-1753

Suzanne.reed@nationwidechildrens.org

\textbf{Word counts}

Abstract: 250

Manuscript: 3230

\textbf{\# of Tables:} 1

\textbf{\# of Figures:} 1

\textbf{Short title:} Hypertension and Renal Injury in Survivors of ALL

\textbf{List of key words} : Acute kidney injury, chronic kidney
disease, hypertension, Acute lymphoblastic leukemia

\textbf{Abbreviations:}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
ABPM & ambulatory blood pressure monitoring\tabularnewline
\midrule
\endhead
ALL & acute lymphoblastic leukemia\tabularnewline
BMT & bone marrow transplant\tabularnewline
BP & blood pressure\tabularnewline
CKD & chronic kidney disease\tabularnewline
COG & Children's Oncology Group\tabularnewline
DBP & diastolic blood pressure\tabularnewline
eGFR & estimated glomerular filtration rate\tabularnewline
GFR & glomerular filtration rate\tabularnewline
HTN & hypertension\tabularnewline
KDIGO & Kidney Disease: Improving Global Outcomes\tabularnewline
MAP & mean arterial pressure\tabularnewline
SBP & systolic blood pressure\tabularnewline
TLS & tumor lysis syndrome\tabularnewline
\bottomrule
\end{longtable}

\textbf{Abstract}

\textbf{Background:}

Childhood acute lymphoblastic leukemia (ALL) fortunately has high
survival rates, and understanding longer-term implications of therapy is
critical. In this study, we aimed to investigate kidney health outcomes
by assessing the prevalence of renal dysfunction and hypertension (HTN)
in children with ALL at one to five years after ALL diagnosis.

\textbf{Methods:}

This was a single center, cross-sectional study of children with ALL who
were 1-5 years post diagnosis. GFR measurements were calculated, and
urine samples were collected to assess for protein/creatinine and
albumin/creatinine. Blood pressure (BP) was determined by standard
oscillometric technique, and children \emph{\textgreater{}} 6 years of
age were eligible for ambulatory blood pressure monitoring (ABPM).

\textbf{Results:}

Forty-five patients enrolled in the study, 21 completed ABPMs. Fifteen
patients (33\%, 95\% CI: 20-49\%) developed AKI at least once. Thirteen
(29\%, 95\% CI: 16-44\%) had hyperfiltration, and 11 (24\%) had abnormal
proteinuria and/or albuminuria. Prevalence of HTN based on clinic
measurements was 42\%. In the 21 ABPM patients, 14 had abnormal results
(67\%, 95\% CI: 43-85\%) with the majority (11/21) demonstrating
abnormal nocturnal dipping pattern. .

\textbf{Conclusions} :

Among children with ALL, there is a high prevalence of past AKI. The
presence of hyperfiltration, proteinuria and/or albuminuria at 1-5 years
after ALL diagnosis suggest real risk of developing CKD over time. There
is a high prevalence of HTN on casual BP readings and even higher
prevalence of abnormal ABPM in this group. The high prevalence of
impaired nocturnal dipping by ABPM indicates an increased risk for
future cardiovascular or cerebral ischemic events.

\textbf{INTRODUCTION}

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer
with an annual incidence of 30 cases per million persons younger than 20
in the United States.\textsuperscript{1,2} The cure rate of ALL has
improved from less than 10\% in the 1960's to around 90\% in recent
decades with innovations in chemotherapy, bone marrow transplantation
(BMT), and better supportive care\textsuperscript{1,3}. However, with
improvement in cure rate, there has been increased emergence of
long-term therapy related complications such as musculoskeletal
morbidity, cardiac comorbidities (congestive heart failure, coronary
artery disease) and neurological comorbidities (cranial nerve palsy,
cognitive defects)\textsuperscript{3}. While there are several studies
that address the prevalence of renal dysfunction and hypertension in
children diagnosed and successfully treated for ALL, most of these
studies investigated subjects with onset of disease prior to
2010.\textsuperscript{4-15}

Children diagnosed with ALL are at risk for renal injury due to a number
of factors including 1) intrinsic renal injury, secondary to either
leukemic cell lysozyme induced direct tubular damage, leukemic
infiltration, tumor lysis syndrome, sepsis, and/or exposure to
nephrotoxic medications, 2) prerenal acute kidney injury from volume
depletion, secondary to poor oral intake, vomiting and diarrhea, and 3)
thrombotic microangiopathies. \textsuperscript{4,16} Studies from prior
decades reported that 10-30\% of survivors of childhood ALL have
persistent reduced glomerular filtration rates
(GFR).\textsuperscript{4,6,7}

To more thoroughly understand renal injury, beyond assessing kidney
function (GFR), presence of persistent proteinuria and albuminuria can
indicate glomerular and/or tubular injury, and persistent proteinuria
has been well documented as a major risk factor for the progression of
renal disease\textsuperscript{17}. To our knowledge, urine
protein/creatinine and urine microalbumin/creatinine have not been
previously reported in children with a history of ALL.

Hypertension (HTN), cardiovascular disease, and metabolic syndrome are
known complications in patients who are long-term survivors of
ALL.\textsuperscript{9,12,18,19} This has been attributed to multiple
factors, including renal leukemic infiltration, persistent reduced
glomerular filtration rate (GFR), chemotherapy, fluid overload, and
exposure to chronic increased sodium loads from intravenous fluids and
especially high dose steroids.\textsuperscript{10,11,20} Prior studies
from the 1990's and 2000's show wide variation in incidence of HTN in
children with ALL ranging from 5-65\%, depending on timing of blood
pressure (BP) measurement and definition of
HTN.\textsuperscript{5,10,15,20,21} The latest clinical practice
guideline for screening and management of high blood pressure in
children and adolescents recommends obtaining a 24-hour ambulatory BP
monitoring (ABPM) study in all children prior to establishing the
diagnosis of hypertension.\textsuperscript{22} ABPM studies can help
uncover ``white coat HTN'' (related to anxiety in clinical settings),
masked HTN (normal office BP readings with elevated 24 hour mean BP),
nocturnal HTN and abnormal nocturnal BP dipping (incomplete or absent
decrease in BP while sleeping compared to while awake). To date, there
has been only one study using ABPM in pediatric patients with ALL to
assess for HTN\textsuperscript{23}.

The aim of this study was to determine the prevalence of 1) persistent
renal dysfunction based on assessments of GFR, proteinuria, and
microalbuminuria and 2) HTN using in-clinic BP values and ABPM in
children with ALL, at one to five years after ALL diagnosis.

\textbf{METHODS}

\textbf{Study Population}

Our study was a single center cross-sectional study conducted at
Nationwide Children's Hospital from July 1, 2018 to February 28, 2019.
All patients with ALL between the ages of 2-21 years who were 1-5 years
post ALL diagnoses were eligible. There were no exclusion criteria.
Subjects received chemotherapy according to various Children's Oncology
Group (COG) protocols, including AALL0031, AALL0434, AALL0932, AALL1131,
and AALL1231. The Institutional Review Board at Nationwide Children's
Hospital approved this research study.

\textbf{Data Collection}

Demographic and clinical data were collected for each subject, including
age at diagnosis, gender, ALL risk category, number of nephrotoxic
agents received prior, number of hospitalizations, need for
vasopressors, need for radiation therapy, obesity, current steroid use,
history of AKI, and echocardiograms. Urine samples were collected at the
time of study enrollment to assess for protein to creatinine and albumin
to creatinine ratios. Serum creatinine obtained as standard of care at
multiple times throughout ALL treatment was recorded from time of ALL
diagnosis and then at three-month intervals up to time of study
enrollment. Serum creatinine was measured using enzymatic method.
Estimated glomerular filtration rate (eGFR) was calculated using bedside
Schwartz and CKD-EPI creatinine equations 2009, depending on age of the
subject\textsuperscript{24,25}.

BP was measured by standard oscillometric methods at each clinic visit.
Children 6 years and older were eligible for measurement of BP by ABPM.
If they consented/assented to ABPM, a manual BP was obtained in the
upper extremity and the appropriate size ABPM cuff and monitor were
placed. The ABPM automatically measured BP values (systolic blood
pressure (SBP), diastolic blood pressure (DBP) and mean arterial blood
pressure (MAP)) every 20-30 minutes for a 24-hour period. If the subject
was less than 6 years old or declined to wear an ABPM, a manual BP was
obtained in clinic. If the BP was \textgreater{}
90\textsuperscript{th}percentile two repeat BP measuring were obtained
at separate follow-up visits.

\textbf{Definitions}

AKI was defined according to the Kidney Disease: Improving Global
Outcomes (KDIGO), modified to include only serum
creatinine\textsuperscript{26}. CKD was defined as GFR \textless{}
90ml/min/1.73m\textsuperscript{2}, CKD stage 2 as GFR
60-89ml/min/1.73m\textsuperscript{2}, CKD stage 3 as GFR
30-59ml/min/1.73m\textsuperscript{2}, CKD stage 4 as GFR
15-29ml/min/1.73m\textsuperscript{2}, and CKD stage 5 (end stage renal
disease) as GFR \textless{} 15 ml/min/1.73m\textsuperscript{2} for
greater than 3 months respectively\textsuperscript{27}. Renal
hyperfiltration was defined as GFR \textgreater{} 2 SD above mean GFR
for age and gender\textsuperscript{28,29}. Proteinuria was defined as
urine protein/creatinine [?]0.2mg/mg and albuminuria as urine
microalbumin/creatinine \textgreater{} 30mg/g.

Based on clinic BP measurements, all resting BP values were averaged and
compared to age, sex, and height normal:\textsuperscript{22} normal BP
was defined as BP \textless{} 90th percentile, elevated BP as BP [?] 90th
percentile to \textless{}95th percentile, stage 1 hypertension as BP [?]
95th percentile to \textless{}95th percentile +12mmHg, and stage 2
hypertension as BP [?] 95th percentile +12mmHg.

In patients who completed ABPM, HTN was defined as either mean SBP
and/or mean DBP [?] 95\textsuperscript{th} percentile for age, gender, and
height.\textsuperscript{30} Night-day mean arterial pressure (MAP)
ratios were calculated and dipping pattern was defined as follows:
\textless{}0\% reverse dippers, [?]0 and \textless{}10\% non-dippers, [?]10
and \textless{} 20\% normal dippers, and [?] 20\% extreme
dippers.\textsuperscript{31}

ALL risk groups were defined using the subject's treatment protocol,
which is assigned early in treatment, based on a combination of several
factors: age at diagnosis, presenting white blood count, cytogenetics,
and response to therapy. Tumor lysis syndrome (TLS) was defined per
Cairo-Bishop definition of laboratory TLS.\textsuperscript{32}

\textbf{Statistical analysis}

All data were summarized using standard descriptive statistical methods.
Prevalence values were reported with corresponding exact binomial 95\%
confidence intervals (CI). Comparisons of qualitative variables between
patient groups were completed using chi-square tests, and comparisons
between quantitative variables between patient groups were completed
using either t-tests or, in the case of non-normality, Mann-Whitney U
tests. The comparison of SBP and DBP indices at diagnosis and 1-month
post-diagnosis was completed using paired t-tests. Logistic regression
models were used to assess risk factors for the occurrence of AKI, CKD,
and HTN. Variables assessed included age at diagnosis, gender, ALL risk
category, number of nephrotoxic agents, number of hospitalizations, need
for vasopressors, need for radiation, obesity, current steroid use,
history of AKI. All analyses were performed using SAS software, version
9.4 (SAS Institute, Cary, NC).

\textbf{RESULTS}

\textbf{Patient Characteristics}

A total of forty-five patients enrolled in the study, of which
twenty-one completed ABPMs. Baseline demographic data and specific
clinical characteristics are presented in Table 1. Demographics included
predominance of males (71\%), Caucasians (96\%), B-cell ALL (80\%), and
high-risk ALL (62\%). The median age at time of diagnosis was 4 years
and median age at time of study visit was 7 years. Four patients had
pre-existing renal disease prior to diagnosis of ALL. Twenty-nine
patients were receiving active ALL therapy at time of enrollment in the
study, and eighteen patients were receiving steroids at enrollment.

\textbf{Renal Dysfunction}

The overall prevalence of a history of AKI in our cohort was high, with
15 subjects (33\%, 95\% CI: 20-49\%) developing AKI at least once. The
majority of AKI occurred at time of diagnosis (10/15, 66.7\%). Of the 15
subjects with AKI, 13 (86.7\%) had KDIGO stage 1 AKI, 1 (6.7\%) had
KDIGO stage 2 AKI, and 1 (6.7\%) had KDIGO stage 3 AKI. In the 28
high-risk ALL patients, 13 had AKI (46\%), while in the 17 standard-risk
ALL patients, only 2 had AKI (11.8\%). Those treated with high-risk ALL
therapy were more likely to have AKI than those treated with
standard-risk ALL therapy (P = 0.017). In univariate analysis,
predictors for AKI included increasing age at time of diagnosis (median
age with AKI 9.5yr vs median age with no AKI 4.3yr, P = 0.006) and
high-risk ALL (P = 0.026). Interestingly, number of nephrotoxic agents,
number hospitalizations, and need for vasopressors were not found to be
significant risk factors for AKI.

No patients in this short period of follow-up demonstrated CKD. However,
13 of 45 patients (28.9\%, 95\% CI: 16.4-44.3\%) had hyperfiltration,
which represents a supraphysiologic elevation in GFR. Last recorded GFR
for patients are shown in figure 1. The mean last GFR was
146.1ml/min/1.73m\textsuperscript{2} (range 74-228
ml/min/1.73m\textsuperscript{2}). The median month that last GFR was
calculated was 30 months (range 15-60 months) post diagnosis. In the 28
high-risk ALL patients, 9 had hyperfiltration (32.1\%). In the 17
standard-risk ALL patients, 4 had hyperfiltration (23.5\%). In light of
the small sample size, no variable was identified as a risk factor for
developing hyperfiltration.

Urinalysis was completed in 41 patients, as 4 were unable to provide a
sample. Eleven of 41 patients (24\%) had abnormal urinalysis. One
patient (2\%) had proteinuria alone, 6 patients (15\%) had albuminuria
alone, and 3 patients (7\%) had combined proteinuria and albuminuria.
Univariate analysis in the proteinuria group was not performed due to
small sample size. Univariate analysis in the microalbuminuria group did
not result in identification of any significant risk factors.

\textbf{HTN}

The prevalence of HTN in all patients was high, with 19 of 45 having HTN
(42.2\%, 95\% CI: 22.0-63.6\%). In univariate analysis, no variable was
significant as a risk factor for HTN. In these 19 HTN patients, one had
left ventricular hypertrophy noted on previous echocardiogram. None of
the 26 non-HTN patients had LVH on previous echocardiograms. However,
these echocardiograms were obtained as part of standard of care prior to
initiation of ALL therapy rather than at time of enrollment in this
renal outcomes study. Eight of 24 patients were on chronic anti-HTN
treatment at some point in time and 2 of these patients were actively
taking anti-HTN medications at the time of study enrollment. All patient
who received chronic anti-HTN treatment were prescribed the calcium
channel blocker amlodipine.

In the 21 patients who completed an ABPM study, 14 had an abnormal
result (67\%, 95\% CI: 43-85\%). Of these 21 patients, 13 had normal
casual BP values and of this group, 7 (54\%) had abnormal ABPM readings,
therefore being designated as having abnormal BP by ABPM even though by
casual BP readings their BP was normal. On ABPM, one patient with known
HTN had well-controlled BP on chronic anti-HTN medication. One patient
was noted to have pre-HTN. One patient was noted to have nocturnal HTN.
Eleven patients had abnormal nocturnal dipping pattern: 10 patients were
non-dippers, with no physiologic decline in sleep BPs, and 1 patient was
an extreme dipper, with greater than 20\% decline in sleep MAP compared
to wake MAP. In univariate analysis, no variable was significant as a
risk factor for abnormal ABPM.

\textbf{DISCUSSION}

In this cross-sectional study, we found a high incidence of AKI in
children diagnosed with ALL, with 33\% of subjects having at least one
AKI episode and the majority of AKI episodes noted at time of ALL
diagnosis. Most patients had mild AKI (KDIGO stage 1). Patients with
high-risk ALL had a higher prevalence of AKI compared to patients with
standard-risk ALL. This may have been due to greater likelihood of
leukemic infiltration in the kidneys at diagnosis, greater risk of tumor
lysis syndrome with initial chemotherapy, and/or the more toxic
chemotherapy regimens used in high-risk ALL which can be directly
nephrotoxic and increase risk for complications such as sepsis.

No patients were found to have CKD in this early follow-up study, a
better short-term outcome than that reported by studies from previous
decades, and perhaps a reflection of better supportive care now
available for children with ALL.\textsuperscript{4,6,7} Almost a third
of patients were noted to have hyperfiltration, however, and in other
populations this identifies increased risk for subsequent renal injury
and progressive CKD.\textsuperscript{33,34} The mean last recorded GFR
of the overall group was supraphysiologic, worrisome for potential
future renal complications. Additionally, 24\% of patients who completed
a urinalysis were noted to have either proteinuria, albuminuria or both.

The low prevalence of CKD in our cohort is likely related to short
duration of follow-up time. In a recent Israeli study evaluating the
risk of ESRD in childhood cancer survivors with median follow-up time of
30 years, participants with history of malignancy in childhood had
adjusted HR of 3.2 of developing ESRD compared to participants without
no history of tumors/malignancy in childhood.\textsuperscript{35} In the
1990's, Krawczuk-Rybak et al. found 5/37 (13.5\%) childhood ALL
survivors had abnormal creatinine clearance when followed 3.9\selectlanguage{ngerman}±3.7 years
after completion of chemotherapy\textsuperscript{6}. Yetgin et al.
detected reduced GFR in 22/116 (19\%) of pediatric ALL patients treated
mostly in the 1990's who were assessed 18-96 months after completion of
chemotherapy\textsuperscript{4}. Yetgin also performed urinalysis on all
subjects post chemotherapy and found no evidence of proteinuria in these
patients. However, 7/116 (6\%) of patients had high urine
B\textsubscript{2}-Microglobulin, a marker of renal tubular proteinuria.
Hovi et al. reported GFR \textless{} 85ml/min/1.73m\textsuperscript{2}in
6/60 (10\%) of children with ALL followed 1-9 years after completion of
chemotherapy, but this study presents data from over 25 years
ago.\textsuperscript{7}

The high prevalence of hyperfiltration, proteinuria, and/or albuminuria
noted in our cohort suggests that these children with ALL, treated since
2015, are at risk of developing CKD in the long term. This phenomenon is
well-described in patients with diabetic nephropathy. Glomerular
hyperfiltration commonly occurs early in diabetes secondary to increased
glomerular capillary pressure. Over time, sustained elevated GFR can
result in mesangial and podocyte injury and eventually glomerular
scarring leading to CKD progression and ESRD.
\textsuperscript{33,34,36}The presence of albuminuria/proteinuria in
patients with diabetes or CKD has been strongly associated with
increased risk of subsequent renal function decline and measures that
are successful at reducing albuminuria/proteinuria have been shown to
slow the renal disease progression in these
populations.\textsuperscript{36,37}

Our study also found that children with ALL have a high prevalence of
HTN.

Almost half of our study patients (42\%) fulfilled criteria for
outpatient diagnosis of HTN based on clinic BP measurements, termed
casual BP readings. Our findings are consistent with prior ALL
survivorship research, which has reported incidences of HTN in children
with ALL ranging from 5-65\%, with variations likely affected by study
methodology and HTN definitions.\textsuperscript{5,10,15,20,21} The high
incidence of HTN is likely multifactorial, related to past or present
corticosteroid therapy, chemotherapy, prior AKI, and/or renal leukemic
infiltration. Prior studies have also proposed metabolic syndrome and
obesity as risk factors for developing chronic HTN in adults who survive
childhood leukemia.\textsuperscript{5,8,9,12-14}

In the 21 patients who completed an ABPM study, we found that the
percentage of individuals with HTN was much higher, since 67\% had an
abnormal high BP value. The majority of patients with abnormal ABPM had
abnormal nocturnal dipping pattern. Ociepa et al. is the only other
study to report ABPM results as a method to diagnose HTN in children
with ALL. This study detected a higher prevalence of childhood survivors
of ALL with HTN via ABPM (37\%, 30/81), although it is perhaps
noteworthy that their study had a longer mean time of follow-up (60
months) compared to our study (36 months). Similar to our study, Ociepa
et al. found that childhood survivors of ALL were more likely to have
abnormal nocturnal dipping pattern (non-dippers, reverse-dippers, and
extreme-dippers) compared to control population. In healthy children
during sleep, a 10-20\% physiologic decrease of BP is normally noted.
The lack of this physiologic decrease is termed non-dipping and BP
decrease in excess of 20\% is considered extreme dipping. Both
non-dipping and extreme dipping have been associated with increased risk
of cardiovascular or cerebral ischemic/hemorrhagic events in
adults.\textsuperscript{38-42} In pediatric subjects with systemic lupus
erythematosus, non-dipping has been associated with endothelial
dysfunction and atherosclerotic changes.\textsuperscript{43} Similarly,
in adolescents with diabetes, non-dipping pattern has been associated
with LVH and increased carotid intimal media
thickness\textsuperscript{44,45}. Further studies of these ABPM
abnormalities and outcomes in children with ALL will help understand the
prognostic implications and identify opportunities for useful
interventions in these children.

Limitations of this study include its single-center design with
relatively small sample size and short duration of follow-up. A
multi-center study with larger sample size could usefully confirm the
findings of this study and help determine distinct risk factors for
developing renal dysfunction and hypertension. It should also be noted
in this study that urine samples were collected at the time of clinic
appointment for convenience and were not first morning samples. Thus,
orthostatic proteinuria (a benign phenomenon occurring in up to 7\% of
children and adolescents) could account for some of the
proteinuria/albuminuria noted in our findings\textsuperscript{46}.

In conclusion, our study showed that, among children with ALL, there is
a high prevalence of HTN based on casual BP readings obtained in the
clinic setting and a high prevalence of impaired nocturnal dipping based
on ABPM. Both abnormalities are associated with increased risk of
cardiovascular disease and cerebrovascular events later in life. While
the prevalence of CKD is very low, children with ALL have a high
prevalence of hyperfiltration and/or proteinuria/albuminuria suggesting
increased risk of developing CKD in the future.

Interestingly, screening urinalysis has been removed from the Children's
Oncology Group long-term follow-up guidelines for children who survive
ALL.\textsuperscript{47} The value of a screening urinalysis in
detection of early evidence of renal disease is highlighted by the
Prevention of Renal and Vascular End-Stage Disease (PREVEND) study
conducted of over 40,000 adult participants which indicated the
usefulness of albuminuria in early detection of CKD. PREVEND found that
of individuals who required renal replacement therapy after 9-years
follow-up, 58\% had moderately increased albuminuria (\selectlanguage{english}[?]20mg/L) on early
screening urine sample. Increased albuminuria was an independent risk
factor for progression to ESRD independent of
GFR.\textsuperscript{48}Based on our findings and other recent
studies,\textsuperscript{3,7,20}we propose that children with ALL should
undergo regular (yearly) renal function testing, urinalysis and BP
measurements to screen for early signs of renal abnormalities. Longer
term and larger studies will be needed to confirm our findings and
define predictors for these adverse outcomes in children with ALL.

As the long-term cure rate of ALL has improved to greater than 90\%, the
challenge now extends to achieving the same cure rates with reduced
short-term and long-term toxicities for these children. One treatment
modality which shows promise in this goal is immunologic therapy. There
have been several recent trials demonstrating the safety and efficacy of
antibody-based and T cell-based therapies for
ALL.\textsuperscript{49,50} Our findings demonstrate that current
conventional therapies for childhood ALL are accompanied by concerning
frequencies of early renal dysfunction and hypertension. The shift
towards targeted immunologic therapies may mitigate some of these
long-term renal consequences of conventional therapy and provide better
quality of life in survivors of childhood ALL.

\textbf{Conflicts of Interest Statement:} The authors have no conflicts
of interest

\textbf{Acknowledgements:} This work was supported by an intramural
grant from Nationwide Children's Hospital

\textbf{References}

1. Hunger SP, Mullighan CG. Acute Lymphoblastic Leukemia in
Children.\emph{New England Journal of Medicine} 2015; \textbf{373} (16):
1541-52.

2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. \emph{CA: A
Cancer Journal for Clinicians} 2017; \textbf{67} (1): 7-30.

3. Mody R, Li S, Dover DC, et al. Twenty-five-year follow-up among
survivors of childhood acute lymphoblastic leukemia: a report from the
Childhood Cancer Survivor Study. \emph{Blood} 2008; \textbf{111} (12):
5515-23.

4. Yetgin S, Olgar \selectlanguage{polish}Ş, \selectlanguage{english}Aras T, et al. Evaluation of kidney damage in
patients with acute lymphoblastic leukemia in long-term follow-up: Value
of renal scan. \emph{American Journal of Hematology} 2004;\textbf{77}
(2): 132-

5. Chow EJ, Pihoker C, Hunt K, Wilkinson K, Friedman DL. Obesity and
hypertension among children after treatment for acute lymphoblastic
leukemia. \emph{Cancer} 2007; \textbf{110} (10): 2313-20.

6. Krawczuk-Rybak MM. Renal function during and after treatment for
acute lymphoblastic leukemia in children. \emph{Pediatric nephrology
(Berlin, West)} 2005; \textbf{20} (6): 782-5.

7. Hovi L. Risk of progressive kidney damage after acute
leukemia.\selectlanguage{ngerman}\emph{Acta pædiatrica Scandinavica} 1989; \textbf{78} (4):
608-14.

8. Veringa SJE, van Dulmen-den Broeder E, Kaspers GJL, Veening MA. Blood
pressure and body composition in long-term survivors of childhood acute
lymphoblastic leukemia. \emph{Pediatric Blood \& Cancer}
2012;\textbf{58} (2): 278-82.

9. Levy E, Samoilenko M, Morel S, et al. Cardiometabolic Risk Factors in
Childhood, Adolescent and Young Adult Survivors of Acute Lymphoblastic
Leukemia -- A Petale Cohort. \emph{Scientific Reports} 2017;\textbf{7}
(1): 17684.

10. Louis CUCU. High blood pressure and hypertension in children with
newly diagnosed acute leukemia and lymphoma. \emph{Pediatric nephrology
(Berlin, West)} 2008; \textbf{23} (4): 603-9.

11. Attard-Montalto SPS. High incidence of hypertension in children
presenting with acute lymphoblastic leukemia. \emph{Pediatric hematology
and oncology} 1994; \textbf{11} (5): 519-25.

12. Nottage KA, Ness KK, Li C, Srivastava D, Robison LL, Hudson MM.
Metabolic syndrome and cardiovascular risk among long-term survivors of
acute lymphoblastic leukaemia - From the St. Jude Lifetime
Cohort.\emph{British Journal of Haematology} 2014; \textbf{165} (3):
364-74.

13. Saultier P, Auquier P, Bertrand Y, et al. Metabolic syndrome in
long-term survivors of childhood acute leukemia treated without
hematopoietic stem cell transplantation: an L.E.A.
study.\emph{Haematologica} 2016; \textbf{101} (12): 1603-10.

14. Oudin C, Simeoni M-C, Sirvent N, et al. Prevalence and risk factors
of the metabolic syndrome in adult survivors of childhood
leukemia.\emph{Blood} 2011; \textbf{117} (17): 4442-8.

15. Bakk I, O'Brien S, Reed S, Koch T. Steroid-Induced Hypertension
during Induction Chemotherapy for Acute Lymphoblastic Leukemia in US
Children's Hospitals. \emph{Jour Pediatr Hematol Oncol.}
2014;\textbf{124} (21): 3651-.

16. Luciano RL, Brewster UC. Kidney Involvement in Leukemia and
Lymphoma. \emph{Advances in Chronic Kidney Disease} 2014;\textbf{21}
(1): 27-35.

17. Bakris GLGL. Slowing nephropathy progression: focus on proteinuria
reduction. \emph{Clinical journal of the American Society of
Nephrology}2008; \textbf{3 Suppl 1} (supplement 1): S3-S10.

18. Oeffinger KC. Cardiovascular risk factors in young adult survivors
of childhood acute lymphoblastic leukemia. \emph{Journal of pediatric
hematology/oncology} 2001; \textbf{23} (7): 424-30.

19. Talvensaari KK, Lanning M, Tapanainen P, Knip M. Long-term survivors
of childhood cancer have an increased risk of manifesting the metabolic
syndrome. \emph{The Journal of Clinical Endocrinology \&
Metabolism}1996; \textbf{81} (8): 3051-5.

20. Olgar SS. Can renal leukemic infiltration cause hypertension in
children? \emph{Journal of pediatric hematology/oncology}
2006;\textbf{28} (9): 579-84.

21. Essig S, Li Q, Chen Y, et al. Risk of late effects of treatment in
children newly diagnosed with standard-risk acute lymphoblastic
leukaemia: a report from the Childhood Cancer Survivor Study
cohort.\emph{The Lancet Oncology} 2014; \textbf{15} (8): 841-51.

22. Flynn JT, Kaelber DC, Baker-Smith CM, et al. Clinical Practice
Guideline for Screening and Management of High Blood Pressure in
Children and Adolescents. \emph{Pediatrics} 2017.

23. Ociepa T, Bartnik M, Zielezinska K, Urasinski T. Prevalence and Risk
Factors for Arterial Hypertension Development in Childhood Acute
Lymphoblastic Leukemia Survivors. \emph{Journal of Pediatric
Hematology/Oncology} 2019; \textbf{41} (3): 175-80.

24. Levey AS, Stevens LA. Estimating GFR using the CKD Epidemiology
Collaboration (CKD-EPI) creatinine equation: more accurate GFR
estimates, lower CKD prevalence estimates, and better risk
predictions.\emph{Am J Kidney Dis} 2010; \textbf{55} (4): 622-7.

25. Staples A, LeBlond R, Watkins S, Wong C, Brandt J. Validation of the
revised Schwartz estimating equation in a predominantly non-CKD
population. \emph{Pediatr Nephrol} 2010; \textbf{25} (11): 2321-6.

26. Group KDIGOAKIW. KDIGO clinical practice guideline for acute kidney
injury. \emph{Kidney Int Suppl} 2012; \textbf{2} (1): 1-138.

27. Inker LA, Astor BC, Fox CH, et al. KDOQI US Commentary on the 2012
KDIGO Clinical Practice Guideline for the Evaluation and Management of
CKD. \emph{American Journal of Kidney Diseases} ; \textbf{63} (5):
713-35.

28. Hogg RJ, Furth S, Lemley KV, et al. National Kidney Foundation's
Kidney Disease Outcomes Quality Initiative Clinical Practice Guidelines
for Chronic Kidney Disease in Children and Adolescents: Evaluation,
Classification, and Stratification. \emph{Pediatrics} 2003;\textbf{111}
(6): 1416-21.

29. Altay S, Onat A, Özpamuk-Karadeniz F, Karadeniz Y, Kemalo\selectlanguage{polish}ğ\selectlanguage{english}lu-\selectlanguage{ngerman}Öz T,
Can G. Renal ''hyperfiltrators'' are at elevated risk of death and
chronic diseases. \emph{BMC nephrology} 2014; \textbf{15} : 160-.

30. Flynn JT, Daniels SR, Hayman LL, et al. Update: Ambulatory Blood
Pressure Monitoring in Children and Adolescents. \emph{A Scientific
Statement From the American Heart Association} 2014; \textbf{63} (5):
1116-35.

31. Urbina E, Alpert B, Flynn J, et al. Ambulatory Blood Pressure
Monitoring in Children and Adolescents: Recommendations for Standard
Assessment. \emph{A Scientific Statement From the American Heart
Association Atherosclerosis, Hypertension, and Obesity in Youth
Committee of the Council on Cardiovascular Disease in the Young and the
Council for High Blood Pressure Research} 2008; \textbf{52} (3): 433-51.

32. Mirrakhimov AE, Voore P, Khan M, Ali AM. Tumor lysis syndrome: A
clinical review. \emph{World J Crit Care Med} 2015; \textbf{4} (2):
130-8.

33. Jerums G, Premaratne E, Panagiotopoulos S, MacIsaac RJ. The clinical
significance of hyperfiltration in diabetes. \emph{Diabetologia}
2010;\textbf{53} (10): 2093-104.

34. Magee GM, Bilous RW, Cardwell CR, Hunter SJ, Kee F, Fogarty DG. Is
hyperfiltration associated with the future risk of developing diabetic
nephropathy? A meta-analysis. \emph{Diabetologia} 2009; \textbf{52} (4):
691.

35. Calderon-Margalit R, Pleniceanu O, Tzur D, et al. Childhood Cancer
and the Risk of ESKD. \emph{Journal of the American Society of
Nephrology} 2020: ASN.2020071002.

36. Mogensen CE, Christensen CK. Predicting Diabetic Nephropathy in
Insulin-Dependent Patients. \emph{New England Journal of Medicine}
1984;\textbf{311} (2): 89-93.

37. Bakris GL. Slowing nephropathy progression: focus on proteinuria
reduction. \emph{Clinical journal of the American Society of Nephrology
: CJASN} 2008; \textbf{3 Suppl 1} (Suppl 1): S3-S10.

38. Phillips RA, Sheinart KF, Godbold JH, Mahboob R, Tuhrim S. The
association of blunted nocturnal blood pressure dip and stroke in a
multiethnic population. \emph{Am J Hypertens} 2000; \textbf{13} (12):
1250-5.

39. Fagard RH, Celis H, Thijs L, et al. Daytime and Nighttime Blood
Pressure as Predictors of Death and Cause-Specific Cardiovascular Events
in Hypertension. \emph{Hypertension} 2008; \textbf{51} (1): 55-61.

40. Ben-Dov IZ, Kark JD, Ben-Ishay D, Mekler J, Ben-Arie L, Bursztyn M.
Predictors of All-Cause Mortality in Clinical Ambulatory
Monitoring.\emph{Hypertension} 2007; \textbf{49} (6): 1235-41.

41. Boggia J, Li Y, Thijs L, et al. Prognostic accuracy of day versus
night ambulatory blood pressure: a cohort study. \emph{The Lancet}
2007;\textbf{370} (9594): 1219-29.

42. Kario K, Pickering Thomas G, Matsuo T, Hoshide S, Schwartz Joseph E,
Shimada K. Stroke Prognosis and Abnormal Nocturnal Blood Pressure Falls
in Older Hypertensives. \emph{Hypertension} 2001; \textbf{38} (4):
852-7.

43. Chang JC, Xiao R, Meyers KE, et al. Nocturnal blood pressure dipping
as a marker of endothelial function and subclinical atherosclerosis in
pediatric-onset systemic lupus erythematosus. \emph{Arthritis Research
\& Therapy} 2020; \textbf{22} (1): 129.

44. Karavanaki K, Kazianis G, Konstantopoulos I, Tsouvalas E, Karayianni
C. Early signs of left ventricular dysfunction in adolescents with type
1 diabetes mellitus: the importance of impaired circadian modulation of
blood pressure and heart rate. \emph{J Endocrinol Invest}
2008;\textbf{31} (4): 289-96.

45. Lee SH, Kim JH, Kang MJ, Lee YA, Won Yang S, Shin CH. Implications
of nocturnal hypertension in children and adolescents with type 1
diabetes. \emph{Diabetes Care} 2011; \textbf{34} (10): 2180-5.

46. Brandt JR, Jacobs A, Raissy HH, et al. Orthostatic proteinuria and
the spectrum of diurnal variability of urinary protein excretion in
healthy children. \emph{Pediatric Nephrology} 2010; \textbf{25} (6):
1131-7.

47. Group CsO. Long-Term Follow-up Guidelines for Survivors of
Childhood, Adolescent and Young Adult Cancerns. Monrovia, CA.

48. van der Velde M, Halbesma N, de Charro FT, et al. Screening for
Albuminuria Identifies Individuals at Increased Renal Risk.\emph{Journal
of the American Society of Nephrology} 2009;\textbf{20} (4): 852-62.

49. Hoelzer D. Chemotherapy-free Treatment --- A New Era in Acute
Lymphoblastic Leukemia? \emph{New England Journal of Medicine}
2020;\textbf{383} (17): 1673-4.

50. Inaba H, Pui CH. Immunotherapy in pediatric acute lymphoblastic
leukemia. \emph{Cancer Metastasis Rev} 2019; \textbf{38} (4): 595-610.

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