Cystatin C-estimated Glomerular Filtration Rate in Pediatric Autologous Hematopoietic Stem Cell Transplantation

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DOI: 10.1016/j.bbmt.2012.06.006 · Source: PubMed
Abstract
Formal evaluation of kidney function is essential to determine chemotherapy dosing based on established treatment protocols in children undergoing autologous stem cell transplantation. Cystatin C has been widely studied as a marker of the glomerular filtration rate (GFR), although data regarding its use in stem cell transplantation are limited. We evaluated the performance of cystatin C-based equations and determined their sensitivity to detect a nuclear GFR of <100 mL/min/1.73 m(2) in children undergoing autologous transplantation. We performed a retrospective cohort analysis in 16 children undergoing 26 transplantations using a modified Bland-Altman analysis to account for repeated measures. Cystatin C-based equations published by Hoek, Le Bricon, Rule, Filler, Zappitelli, Larsson, and Schwartz (the New Chronic Kidney Disease in Children formula, New CKiD formula) were evaluated and compared to the creatinine-based modified Schwartz equation. We found that cystatin C-based equations demonstrated improved sensitivity to detect a nuclear GFR of <100 mL/min/1.73 m(2) compared to the creatinine-based modified Schwartz equation, which significantly overestimated GFR. Most cystatin C-based equations, however, tended to underestimate the nuclear GFR. The New CKiD formula, combining cystatin C and creatinine, offered a sensitivity of 100% and a specificity of 95% for detecting a nuclear GFR <100 mL/min/1.73 m(2). Institutions using cystatin C-based GFR estimation should be aware of the specific prediction formula and GFR measurement techniques available at their center, as each method's performance can vary considerably. As more research becomes available, this easily measured marker should become a valuable component of GFR estimation, providing cost savings (a nuclear GFR is 5.5 times more costly than a cystatin C) and reducing radiation exposure.
Cystatin C-estimated Glomerular Filtration Rate
in Pediatric Autologous Hematopoietic
Stem Cell Transplantation
Benjamin L. Laskin,
1
Edward Nehus,
1
Jens Goebel,
1
Jane C. Khoury,
2
Stella M. Davies,
3
Sonata Jodele
3
Formal evaluation of kidney function is essential to determine chemotherapy dosing based on established
treatment protocols in children undergoing autologous stem cell transplantation. Cystatin C has been widely
studied as a marker of the glomerular filtration rate (GFR), although data regarding its use in stem cell trans-
plantation are limited. We evaluated the performance of cystatin C-based equations and determined their
sensitivity to detect a nuclear GFR of \100 mL/min/1.73 m
2
in children undergoing autologous transplanta-
tion. We performed a retrospective cohort analysis in 16 children undergoing 26 transplantations using
a modified Bland-Altman analysis to account for repeated measures. Cystatin C-based equations published
by Hoek, Le Bricon, Rule, Filler, Zappitelli, Larsson, and Schwartz (the New Chronic Kidney Disease in Chil-
dren formula, New CKiD formula) were evaluated and compared to the creatinine-based modified Schwartz
equation. We found that cystatin C-based equations demonstrated improved sensitivity to detect a nuclear
GFR of \100 mL/min/1.73 m
2
compared to the creatinine-based modified Schwartz equation, which signif-
icantly overestimated GFR. Most cystatin C-based equations, however, tended to underestimate the nuclear
GFR. The New CKiD formula, combining cystatin C and creatinine, offered a sensitivity of 100% and a spec-
ificity of 95% for detecting a nuclear GFR \100 mL/min/1.73 m
2
. Institutions using cystatin C-based GFR
estimation should be aware of the specific prediction formula and GFR measurement techniques available
at their center, as each method’s performance can vary considerably. As more research becomes available,
this easily measured marker should become a valuable component of GFR estimation, providing cost savings
(a nuclear GFR is 5.5 times more costly than a cystatin C) and reducing radiation exposure.
Biol Blood Marrow Transplant 18: 1745-1752 (2012) Ó 2012 American Society for Blood and Marrow Transplantation
KEY WORDS: Cystatin C, Kidney function, Autologous transplantation, Pediatrics
INTRODUCTION
Measuring the glomerular filtration rate (GFR) is
crucial for determining appropriate drug dosing,
monitoring the effects of therapeutic interventions,
and following the progression of chronic kidney
disease [1-3]. In pediatric autologous hematopoietic
stem cell transplantation (HSCT) treatment
protocols, chemotherapy dosing is commonly based
on renal function, as patients with a GFR \100 mL/
min/1.73 m
2
receive reduced dosages, which can
affect toxicity profiles and therapeutic benefit [4,5].
The current standard of care is to evaluate GFR
pretransplantation using formal assessments (ie,
nuclear isotope testing or inulin or iohexol clearance),
which are repeated before each autologous HSCT in
children undergoing more than one transplantation.
Each of these methods is considered a gold standard,
but they are time and labor intensive, invasive, more
costly than serum-based or urine-based creatinine
methods, and may require exposure to radiation [6,7].
Newer, le ss invasive biomarkers may provide an al-
ternative to formal GFR measurements [1,3,7].
Perhaps the most widely studied and most promising
is cystatin C, a small housekeeping protein produced
by all nucleated cells at a constant rate that can
be measured in a single peripheral blood sample [8,9].
In contrast to creatinine, serum cystatin C
concentrations are not significantly affected by age
(after 1 year) [7], gender, and most relevant to the
HSCT population, muscle mass [10,11]. However,
cystatin C concentrations may be influenced by other
From the
1
Division of Nephrology and Hypertension;
2
Biostatistics
and Epidemiology; and
3
Bone Marrow Transplantation and Im-
mune Deficiency, Cincinnati Children’s Hospital Medical Cen-
ter, Cincinnati, Ohio.
Financial disclosure: See Acknowledgment on page 1751.
Correspondence and reprint requests: Benjamin L. Laskin, MD,
Division of Nephrology and Hypertension, The Children’s
Hospital of Philadelphia, 34th Street and Civic Center Boule-
vard, Philadelphia, PA 19104 (e-mail: laskinb@email.chop.edu).
Received March 12, 2012; accepted June 9, 2012
Ó 2012 American Society for Blood and Marrow Transplantation
1083-8791/$36.00
http://dx.doi.org/10.1016/j.bbmt.2012.06.006
1745
factors, including steroid therapy, the WBC count, and
thyroid function [3,7].
Although cystatin C estimation of GFR has been
studied in those with chronic kidney disease, recipients
of liver and kidney transplantations, and pediatric and
adult oncology patients, limited data exist on its use in
patients undergoing HSCT [7,12-15].Multiple
cystatin C-based prediction equations have been
published, each with varied agreement with gold
standard methods depending on the patient group
studied and measurement techniques used [7,12].
Our primary objective was to evaluate the performance
of these estimating equations and determine their
sensitivity to detect a nuclear GFR of \100 mL/
min/1.73 m
2
in children undergoing autologous
transplantations, including multiple HSCTs. In
addition, we evaluated the association of demographic
and laboratory parameters with cystatin C, after
adjustment of GFR, in order to explore potential
covariates that may improve accuracy of cystatin
C-based equations. Demographic covariates included
age, gender, height, weight, and the height-to-
creatinine ratio, whereas laboratory covariates included
creatinine, blood urea nitrogen, and the WBC count.
MATERIALS AND METHODS
Study Population
We conducted a retrospective cohort analysis by
reviewing the records of all consecutive autologous
HSCTs performed at Cincinnati Children’s Hospital
Medical Center (CCH MC) over the last 5 years (end-
ing June 2011) to identify patients having both a cysta-
tin C and formal nuclear medicine GFR measurement
(using
99m
Tc-labeled diethylene triamine pentaacetic
acid [DTPA]). If these measurements were performed
on different days, we only included patients with stable
kidney func tion (defined as an intrapatient creatinine
SD of \0.1 mg/dL) and without intervening therapy
or events that would predispose to kidney injury.
The study was approved by the CCHMC Institution al
Review Board.
Laboratory Assessments and GFR Estimation
All patients at our institution receive nuclear GFR
measurements (DTPA) before autologous HSCT, in-
cluding each HSCT if multiple transplantations are
planned. Nuclear GFR was performed and calculated
using the methods described by Balachandran et al.
[16]. Specifically, GFR is determined using plasma
DTPA disappearance curves obtained from 4 sampling
time points (120, 150, 180, and 210 minutes) after a sin-
gle injection of a known amount of radioisotope for
each patient. Scintillation co unting allowed for the
creation of time activity curves to calculate GFR.
Cystatin C concentrations were measured using
particle-enhanced immunonephelometry (Siemens
Healthcare Diagnostics Products, 2008) in the
CCHMC Division of Nephrology clinical labora tory.
To determine the optimal prediction formula, we
estimated GFR using several equations published
over the past decade including Larsson [17], Filler
[18], Zappitelli [12],Hoek[19], Rule [20], and Le
Bricon [21]. We also assessed the accuracy of formulas
published by Zappitelli [12] and Schwartz [15] (the
New Chronic Kidney Disease in Children formula,
New CKiD), as these equations, including both
serum creatinine and cystatin C, have shown
improved precision and accuracy [12,15,22]. Finally,
as a comparison, GFR was estimated with serum
creatinine using the modified Sc hwartz formula, with
a constant of 0.413 [15]. All assessed GFR estimating
equations are shown in Table 1.
Transplantation Procedure
All patients had pediatric solid tumors and received
high-dose chemotherapy followed by autologous pe-
ripheral blood stem cell rescue according to national
or institutional protocols. Patients received uniform
prophylaxis and clinical monitoring, including nuclear
GFR to determine renal function for chemotherapy
dosing before each transplantation. Serum creatinine
was monitored daily duringinpatientstays and regularly
during outpatient follow-up between transplantations.
Statistical Analysis
Descriptive statistics for continuous variables were
reported as means and SDs and as medians and inter-
quartile rang es when there was significant departure
from normality. For those patients having more than
one serum creatinine or blood urea nitrogen value be-
tween cystatin C and nuclear GFR measurements, the
mean value was used in the analysis. Because
we included only patients with stable serum creatinine
values between GFR measurements, we assumed
any intrapatient differences between creatinine
Table 1. GFR Estimating Equations
Creatinine-based formula
Modified Schwartz
formula
0.413*height/SCr
Cystatin C-based formula
Filler 91.62*(cys C)
21.123
Zappitelli 75.94*(cys C)
21.17
Larsson* 77.24*(cys C)
21.2623
Hoek 24.32+(80.35/cys C)
Rule 66.8*(cys C)
21.30
Le Bricon (78/cys C) + 4
Formulas including both cystatin C and creatinine
Zappitelli 43.82*(cys C)
20.635
*SCr
20.547
*e
0.003*height
New CKiD 39.1(height (m)/SCr)
0.516
*(1.8/cys C)
0.294
*
(30/BUN)
0.169
*(1.099)
male
*(height (m)/1.4)
0.188
SCr indicates serum creatinine (mg/dL); BUN, blood urea nitrogen
(mg/dL); m, meters.
GFR in mL/min/1.73 m
2
unless indicated by *mL/min Cys C, Cystatin C
(mg/L).
1746 Biol Blood Marrow Transplant 18:1745-1752, 2012B. L. Laskin et al.
measurements would be random and normally distrib-
uted, favoring use of the mean. We included the WBC
count from the same day the cystatin C was perform ed.
To compare cystatin C-based equations (Table 1)
and the modified Schwartz equation [15] to nuclear
GFR estimation, mean bias and 95% limits of agree-
ment were calculated according to the methods of
Bland-Altman. Accounting for the repeated nature of
the measurements in patients having more than one au-
tologous HSCT, we used a modified Bland-Altman
analysis as previously described [23]. Briefly, mean
bias was calculated assuming that the true value of
GFR changed between measurements. The 95% limits
of agreement were calculated by partitioning the
variance of the difference into within-patient and
between-patientvarianceof differences,which were cal-
culated using one-way analysis of variance [23].We
computed each equation’s accuracy (the proportion of
the estimated GFR within 10% and 30% of the gold
standard value) and also reported the proportion of var-
iability (R
2
) for eachequation. In addition, we calculated
the sensitivity and specificity of each GFR estimating
equation for detecting a nuclear GFR of \100 mL/
min/1.73 m
2
(the cutoff most relevant to chemotherapy
dosing in the pediatric autologous HSCT population).
To evaluate the significance of covariates, we used
generalized linear modeling to correct for repeated
measures. Cystatin C was the main independent vari-
able, and nuclear GFR was the dependent variable; co-
variates were then added to the model. Because certain
covariates have been associated with cystatin C con-
centrations [24], we included age, gender, height,
weight, creatinine, blood urea nitrogen, the height-
to-creatinine ratio (as used in the Schwartz formula),
and the WBC count in the model. Cystatin C, creati-
nine, and nuclear GFR were log transformed to satisfy
the assumptions of linear regression modeling. There-
fore, the general model used to assess the significance
of covariates was as follows:
Log
DTPA GFR
mL=min=1:73 m
2

5
b
0
1b
1
log ðcystatin CÞ1b
2
ðXÞ1ε
where X represents covariates added to the model and
ε is the residual values under which the assumptions of
linear regression modeling have a normal distribution.
Partial F tests were used to assess the significance of
added covariates (assessed at a P value \.15). All anal-
yses were conducted using SAS statistical software
(version 9.2; SAS Institute, Cary, NC).
RESULTS
Subjects
Of 100 pediatric autologous HSCT performed in
the last 5 years, we identified 17 patients who had a cys-
tatin C measurement performed. One patient was ex-
cluded because the serum creatinine decreased by 0.2
mg/dL (SD of 0.14 mg/dL) between the cystatin C
and nuclear GFR measurements. The 16 included pa-
tients underwent a total of 33 autologous HSCTs (me-
dian of 2 transplantations per patient; range, 1-4
transplantations). Of these 33 transplantations, 26
had both a nuclear GFR and cystatin C perform ed
and were, therefore, included in the final analysis.
Clinical and laboratory inform ation for these 16 pa-
tients and 26 transplantations are shown in Table 2.
The mean cohort nuclear GFR was 128.1 6 45.7
mL/min/1.73 m
2
.
In 13 of the 26 transplantations (50%), patients
had a cystatin C and nuclear GFR performed on the
same day, whereas in the remaining 13 transplanta-
tions, patients had these measurements performed
a median of 6 days apart (range, 1-13 days). In these
13 transplantations, the serum creatinine was mea-
sured a median of 2 times (range, 2-8 times) between
the cystatin C and nuclear GFR measurements. In 7
of these 13 transplantations (54%), the creatinine
was unchanged between cystatin C and nuclear GFR
measurements, and in the remaining 6, the creatinine
Table 2. Clinical and Demographic Characteristics of the
Study Cohort (16 Patients and 26 Autologous HSCT)
Primary Disease
Neuroblastoma 6/16 (37%)
Medulloblastoma 6/16 (37%)
Atypical teratoid rhabdoid tumor 2/16 (12%)
Relapsed clear cell sarcoma 1/16 (6%)
Relapsed hepatoblastoma 1/16 (6%)
Age at time of HSCT (years) 3.7 [3.1-6.3] (1.8-30.5)
Male gender 9/16 (56%)
Race
White 15/16 (94%)
African American 1/16 (6%)
Height (cm) 99.9 [97.3-116.6] (79.5-170)
Weight (kg) 17.0 [14.0-22.2] (11.2-70.6)
No. of HSCT with cystatin C and nuclear
GFR on same day
13/26 (50%)
Days between cystatin C and nuclear
GFR (n 5 13 HSCTs)
6 [3-9] (1-13)
Serum creatinine (mg/dL)* 0.3 [0.2-0.4] (0.2-0.7)
Blood urea nitrogen (mg/dL)* 12 [8-14.5] (3.5-25)
WBC count (K/L) 4.1 [2.3-5.7] (1.3-17.8)
Cystatin C (mg/L) 0.7 [0.6-0.9] (0.5-1.2)
Steroid therapy at time of cystatin C 0/16 (0%)
Thyroid replacement therapy at time
of cystatin C
0/16 (0%)
Abnormal TSH 3/15 (20%)
Abnormal free thyroxine (T4) 1/13 (7%)
HSCT indicates hematopoietic stem cell transplantation; GFR, glomeru-
lar filtration rate; TSH, thyroid-stimulating hormone.
Data shown as median [interquartile range] (range) or number (%).
*For patients not having a cystatin C and nuclear GFR performed on the
same day (n 5 13 HSCT), the available serum creatinine and blood urea
nitrogen values between the cystatin C and nuclear GFR measurements
were averaged (median of 2 creatinine/blood urea nitrogen values per
HSCT; range, 2-8).
†One patient had a low TSH and elevated T4 and free T4 (hyperthyroid)
at the time of cystatin C measurement but 2 months later developed hy-
pothyroidism requiring replacement therapy.
Biol Blood Marrow Transplant 18:1745-1752, 2012
1747Cystatin C in Autologous Transplant
was stable, with an intrapatient creatinine SD of 0.05
to 0.07 mg/dL. Furthermore, betwee n GFR measure-
ments, all patients were outpatients and did not receive
any chemotherapy, antibiotics (other than stable acy-
clovir prophylaxis), or other nephrotoxic medications
that would predispose them to kidney injury.
At the time of assessment, no patient was pre-
scribed steroid therapy and no patient was receiving
thyroid hormone replacement. Fifteen of 16 patients
had thyroid function studies available, and 14 of 15
had this assessment performed before the autologous
HSCT that was included in the analysis. In the remain-
ing patient, thyroid studies were performed for the first
time 5 months after transplantation and on the same
day as the cystatin C measurement. Three of 15 pa-
tients (20%) had a low thyroid-stimulating hormone
(TSH) level, and the remaining 12 of 15 patients
(80%) had a normal TSH. Of these 3 patients with
a low TSH, 2 (67%) had a nor mal free thyroxine
(T4), whereas the remaining patient had a mildly ele-
vated free T4 level when thyroid studies were obtained
5 months after transplantation. However, 2 months
later, this same patient became hypothyroid and re-
quired levothyroxine therapy.
We assessed the association between changes in
nuclear GFR and cystatin C in the 8 patients undergo-
ing .1 HSCT during the study period (6 patients with
2 HSCTs, 2 patients with 3 HSCTs each). Overall, the
nuclear GFR decreased by a mean 11% (median 16%)
between transplantations in these patients, whereas the
cystatin C estimated GFR (Larsson formula currently
used in clinical care at CCHMC) decreased by a mean
5% (median 7%). In 6 of 8 of these patients, the nu-
clear GFR and cystatin C estimated GFR both de-
creased between the first 2 transplantations analyzed
(in the remaining 2 patients, the cystatin C and nuclear
GFR measurements moved in opposite directions). In
these 6 patients, the nuclear GFR decreased by a mean
20% (median 23%) between transplantations, whereas
the cystatin C GFR decreased by a mean 12% (median
8%). In 1 patient, 2 cystatin C measurements were
inadvertently obtained 11 days apart, before their 4th
autologous HSCT. In this patient, the L arsson esti-
mated cystatin C GFR decreased by 11% over the
11-day period, and the serum creatinine level rem ained
unchanged at 0.3 mg/dL.
Evaluation of Covariates
Specifically, the association between the nuclear
GFR and cystatin C concentration was independent
of patients’ age, gender, hei ght, weight, creatinine,
blood urea nitrogen, and the WBC count. However,
the height-to-creatinine ratio (as used in the Schwartz
formula [15]) was significantly associated (P 5 .06)
with the nuclear GFR when included in the model
with the cystatin C concentration.
Sensitivity and Specificity to Predict a GFR \100
mL/min/1.73 m
2
As shown in Tabl e 3, the sensitivity of each esti-
mating equation to detect a nuclear GFR \100 mL/
min/1.73 m
2
varied from 50% to 100%. The modified
Schwartz formula and the Zappitelli equation, includ-
ing both cystatin C and creatinine, performed the
worst with sensitivities of 50% and 66.7%, respec-
tively. Cystatin C formulas demonstrated improved
sensitivity with values ranging from 83% to 100%.
Overall, the New CKiD formula provided the best
combination of sensitivity (100%) and specificity
(95%). The Larsson formula, currently used for
GFR estimation at our institution, had a sensitivity
of 83.3% and a specificity of 85% for detecting a nu-
clear GFR \100 mL/min/1.73 m
2
. In our cohor t,
this meant that of 6 HSCTs with a nuclear GFR
\100 mL/min/1.73 m
2
, the Larsson formula correctly
detected this level of kidney function in 5 of 6 HSCTs
(83.3% sensitivity). In the remaining 20 HSCTs, the
Table 3. Overall Performance of GFR Estimating Equations
Formula Mean GFR (SD) Mean Bias (95% CI) 95% LOA Sensitivity (%) Specificity (%) R
2
30% Accuracy (%) 10% Accuracy (%)
Nuclear GFR 128.1 ± 45.7
Creatinine formula
New Schwartz 141.2 ± 38.2* 13.1 (1.5, 24.7) (243.9, 70.1) 50.0 100.0 0.61 73.1 34.6
Cystatin C formulas
Filler 139.0 ± 39.4 10.9 (20.3, 21.9) (243.4, 65.2) 83.3 95.0 0.65 73.1 30.8
Zappitelli 117.5 ± 34.6 210.6 (221.6, 0.3) (264.9, 43.7) 83.3 80.0 0.65 88.5 38.5
Larsson 124.1 ± 39.3 24.0 (215.0, 7.0) (258.6, 50.6) 83.3 85.0 0.65 76.9 34.6
Hoek 111.7 ± 29.4* 216.4 (227.7, 25.1) (272.3, 39.5) 83.3 80.0 0.65 84.6 26.9
Rule 109.0 ± 35.6* 219.1 (230.1, 28.1) (273.5, 35.3) 100.0 80.0 0.65 84.6 19.2
Le Bricon 116.7 ± 28.5* 211.5 (222.9, 20.1) (267.9, 44.9) 83.3 85.0 0.65 76.9 30.8
Combined cystatin C and creatinine formulas
Zappitelli 145.8 ± 44.1* 17.7 (7.2, 28.2) (234.4, 69.8) 66.7 95.0 0.69 73.1 30.8
New CKiD 118.4 ± 28.6 29.7 (221.2, 1.8) (267.0, 47.6) 100.0 95.0 0.64 80.8 38.5
GFR indicates glomerular filtration rate; CI, confidence interval; LOA, limits of agreement.
Sensitivity and specificity to detect a GFR <100 mL/min/1.73 m
2
.
*Significantly different from nuclear GFR (P < .05).
†Thirty percent accuracy is the percentage of estimated GFR values falling within 30% of the nuclear GFR, and 10% accuracy is the percentage of es-
timated GFR values falling within 10% of the nuclear GFR.
1748 Biol Blood Marrow Transplant 18:1745-1752, 2012B. L. Laskin et al.
Larsson formula correctly identified a GFR .100 mL/
min/1.73 m
2
in 17 of 20 HSCTs (85% specificity).
Conversely, the New CKiD formula correctly de-
tected a nuclear GFR \100 mL/min/1.73 m
2
in 6 of
6 HSCTs (100% sensitivity) and a GFR .100 mL/
min/1.73 m
2
in 19 of 20 HSCTs (95% specificity).
Performance of the GFR Estimating Equations
Table 3 summarizes the Bland-Altman analyses in
our cohort. In general, most cystatin C-only based for-
mulas (except the Filler equation) tended to underesti-
mate nuclear GFR, as evidenced by their negative
mean bias. However, based on the 95% confidence in-
tervals, this negative mean bias was statistically signif-
icant only for the Hoek (unde restimated true GFR by
16.4 mL/min/1.73 m
2
), the Rule (underestimated true
GFR by 19.1 mL/min/1.73 m
2
), and Le Bricon formu-
las (underestimated true GFR by 11.5 mL/min/1.73
m
2
). Conversely, the modified Schwartz (creatinine-
based) and Zappitelli (including both cystatin C and
creatinine) significantly overestimated GFR by 13.1
to 17.7 mL/min/1.73 m
2
. The remaining equations
shown in Table 3 (Filler, Larsson, cystatin C only Zap-
pitelli, and New CKiD) had a mean bias that was not
significantly different from the nuclear GFR.
All estimating equations predicted .73% of GFR
values within 30% of the nuclear GFR. This 30% accu-
racy was best for the cystatin C-only Zappitelli formula
(88.5% of values within 30% of the true GFR). All es-
timating equations predicted .19% of GFR values
within 10% of the gold standard, nuclear GFR. The
Zappitelli formula with only cystatin C and the New
CKiD formulas had the best accuracy at this level, pre-
dicting 38.5% of values within 10% of the true GFR.
The 95% limits of agreement are also shown in
Table 3, with narrower limits representing greater pre-
cision. All estimating equations demonstrated similar
precision, with the combined Zappitelli formula having
the narrowest limits (10 4.2) and the New CKiD for-
mula having the widest (114.6). Finally, all formulas
demonstrated similar R
2
values (proportion of the var-
iability in true GFR explained by each estimating equa-
tion) ranging from 0.61 (modified Schwartz formula) to
0.69 (combined Zapp itelli formula).
DISCUSSION
To the best of our knowledge, this is the largest
study estimating renal function with cystatin C in pe-
diatric autologous HSCT recipients. We evaluated
the sensitivity, specificity, and overall performance of
GFR prediction formulas. Most of our patients did
not have significant kidney disease, as shown by the co-
hort mean nuclear GFR of 128 mL/min/1.73 m
2
. The
New CKiD formula [15], including both cystatin C
and creatinine, performed well, with a sensitivity of
100% and a specificity of 95% for detecting a nuclear
GFR of \100 mL/min/1.73 m
2
. It offered the best ac-
curacy in predicting GFR within 10% of the true value
and a mean bias that was not significantly different
from zero. Overall, cystatin C-based equations dem-
onstrated improved sensitivity to detect a GFR of
\100 mL/min/1.73 m
2
compared to the creatinine-
based modified Schwartz formula. We found that
most cystatin C-only–based equations (except the
Filler equation) tended to underestimate GFR,
whereas the modified Schwartz formula overestimated
kidney function.
Serum creatinine is an established marker of kidney
function and is less than ideal, especially in patients with
chronic illnesses and with reduced muscle mass [25,26].
Current standard of care at our institution is to formally
measure GFR using a radioisotope study in children
undergoing autologous HSCT. The procedure is
invasive, time consuming, more costly than serum-
based methods, and requires repeated exposure to radi-
ation in multiple transplantations [3,6,7]. The costs of
running these tests vary by geographic location
(Table 4) [27-29]. The United States Medicare data
from 2012 show that a nuclear GFR is 5.5 times more
costly than a cystatin C, and a cystatin C is 2.7 times
more costly than a serum creatinine [27].
Accordingly, there is a need to develop novel
methods of GFR estimation that are reliable, less inva-
sive, and applicable to this patient population and
a wide range of others [1]. Cystatin C is perhaps the
most promising marker of kidney function in this con-
text, as several estimating equations have already been
developed, the assay is easy to perform, and it has been
studied in several disease states [12,15,17-22].
Other investigators have assessed the ability of cys-
tatin C to estimate kidney function in patients with
malignancy. Bakoush et al. [30] measured cystatin C
using an immunoturbidimetry assay in 147 adults
with newly diagnosed cancer. Using the cystatin C es-
timating equation publ ished by Grubb et al. [31], the
authors reported a reasonable correlation (R
2
5 0.57)
and mean bias of -5 mL/min/1.73 m
2
compared to io-
hexol GFR measurement. Conve rsely, the creatinine-
based equation overestimated GFR by 15 mL/min/
1.73 m
2
. Blufpand et al. [32] studied cystatin C
Table 4. Cost Estimates for Serum and Nuclear GFR Pre-
diction
Study (year)
Serum
Creatinine
Serum
Cystatin C
Nuclear
GFR
Bogota, Colombia (2006 US$) [28] $2.00 $27.00
Madrid, Spain (2006 US$) [28] $0.08 $3.00
United Kingdom (2003) [29] $0.15 $3.00
Belgium (2003) [29] $0.02 $2.00
United States Medicare (2012)* [27] $7.26 $19.25 $106.20
GFR indicates glomerular filtration rate.
*Non facility price National Payment Amount.
Biol Blood Marrow Transplant 18:1745-1752, 2012
1749Cystatin C in Autologous Transplant
(measured by nephelometry) in 68 children with cancer
up to 3 months postchemotherapy. Cystatin C GFR
calculated with the Filler equation was compared
with the modified Schwartz formula and inulin. Com-
pared to inulin, GFR estimation using the Filler equa-
tion and the modified Schwartz formula had a mean
bias of 27.3 mL/min/1.73 m
2
and 214.3 mL/min/
1.73 m
2
, respectively. Regarding accuracy, 82.4%
(Filler) and 72.1% (modified Schwartz) of values were
within 30% of inulin. Finally, Chew et al. [33] com-
pared cystatin C (measurement assay not reported) to
DTPA-measured GFR in adult oncology patients.
They reported that the Le Bricon, Hoek, and Rule for-
mulas showed no significant mean bias, and the Hoek
formula had the best accuracy at the 30% level (89%).
In contrast, fewer studies have measured cystatin C
in the HSCT population. Recently, Bacchetta et al.
[14] published a well-designed cross-sectional analysis
validating cystatin C-based equ ations in 252 children
at high risk of renal injury. However, only 7 of the chil-
dren in their cohort had an HSCT. Compared to inu-
lin, the authors assessed cystatin C (nephelome try)
estimating equations (Hoek, Le Bricon, Larsson,
Rule, Filler, Zappitelli, and Bouvet) and both the orig-
inal and modified Schwartz formulas. They were not
able to assess the New CKiD formula because they
did not have blood urea nitrogen values available. All
formulas performed well except for the Filler and orig-
inal Schwartz equations (which both overesti mated
GFR) and the Hoek and Bouvet formulas (which
underestimated GFR). The authors recommended us-
ing the Larsson formula (without correcting for body
surface area) or the Le Bricon equation in their study
population. Two other studies have assessed the Filler
equation to estimate GFR after HSCT. Hazar et al.
[34] prospectively analyzed 34 children after allogeneic
HSCT and compared nuclear (DTPA), creatinine, and
cystatin C-based GFR (nephelometry). Similar to our
findings, creatinine-based GFR formulas overesti-
mated DTPA GFR, whereas cystatin C did not. Inter-
estingly, creatinine-based GFR equations, which have
been shown to underestimate GFR in healthy adoles-
cents [35], overestimated GFR after HSCT. There-
fore, creatinine-based GFR estimation may not be
useful to detect decreased GFR after HSCT, possibly
due to the influence of decreased muscle mass in this
population. Finally, Aydin et al. [36] measured cystatin
C (nephelometry) and a 2-sample DTPA in 31 chil-
dren 1 month post-HSCT. Although the Filler equa-
tion had a low correlation with GFR (r 5 0.43), it
demonstrated reasonable mean bias (23 mL/min/
1.73 m
2
) and precision (95% limits of agreement
from 257.8 to 51.8).
Debate continues as to whether cystatin C GFR es-
timation is dependent on nonrenal factors such as ste-
roid use, malignancy, thyroid disease, or the WBC
count [3,13,24]. Some have reported that cystatin C is
disproportionally increased in patients with active
malignancy [37,38], whereas others have failed to
demonstrate this association [33]. Similar controver-
sies exist regarding the independent effect of steroid
therapy and the WBC count on cystatin C levels
[24,39,40]. We were unable to find an association
between the WBC count and cystatin C in our
cohort. As none of our patients were receiving steroid
therapy and most had normal thyroid function as
measured before autologous HSCT, we were unable
to generate conclusions ba sed on these covariates.
The strengths of our analysis include use of an es-
tablished methodology to compar e agreement using
repeated measures data, the inclusion of multiple
GFR estimating equations, a gold standard nuclear
medicine technique with 4 sampling time poin ts, and
cystatin C measurements with a nephelometric assay.
Nephelometry, as opposed to immunoturbidimetry,
has been shown to potentially result in more reliable
GFR estimation [3,8]. In contrast to most prior
studies in the HSCT population, we evaluated the
effect of several clinical and laboratory covariates on
cystatin C, including the WBC count.
Our analysis has several limitations. First, our co-
hort was relatively small. However, we did find bias,
precision, and accuracy results that were similar to
the published literature. Furthermore, a large propor-
tion (50%) of our cystatin C and nuc lear GFR measure-
ments were performed on different days. We believe
the effect of this was likely small because the patients
had stable creatinine values and no intervening nephro-
toxic therapy between measurement s. Finally, we were
unable to assess the influence of all potential covariates
previously reported to affect cystatin C GFR estima-
tion [3]. However, co mpared to a heterogeneous allo-
geneic HSCT population often receiving steroids,
our autologous HSCT cohort was relatively homoge-
nous, providing an opportunity to study GFR estimat-
ing equations in a uniform group of patients.
In conclusion, we demonstrate that cystatin C-
based equations performed better than creatinine in
identifying decreased GFR in pediatric patients who
undergo HSCT receiving multiple transplantations.
The New CKiD formula, combining cystatin C, creat-
inine, and blood urea nitrogen offered a sensitivity of
100% and a specificity of 95% for detecting a GFR
\100 mL/min/1.73 m
2
. Cystatin C-only based formu-
las demonstrated improved sensitivity to detect a GFR
\100 mL/min/1.73 m
2
compared to the modified
Schwartz equation, although most tended to underes-
timate GFR. Institutions using cystatin C-based GFR
estimation for clinical care should be aware of the
specific prediction formula available at their center,
as each equation’s performance can vary considerably.
Similarly, clinicians should be mindful of the various
creatinine, cystatin C, and gold standard (ie, nuclear
GFR) measurement techniques used at their
1750 Biol Blood Marrow Transplant 18:1745-1752, 2012B. L. Laskin et al.
institution, as differenc es between technique and
across hospitals can lead to variable estimation of kid-
ney function. As more research becomes available on
standardized cystatin C assays [41], and the impact of
additional covariates (such as steroids or thyroid dis-
ease), this easily measured marker should become a use-
ful alternative to formal GFR measurements, offering
cost savings and decreasing radiation exposure. A pre-
diction formula that combines cystatin C, creatinine,
and additional covariates will likely provide the greatest
agreement compared with those formulas only includ-
ing a single biological marker [3,15]. Importantly, the
ease of measurement of cystatin C in a single
peripheral blood sample means that this assay can
easily be used for serial assessment of GFR during the
course of transplantation in persons with high risk of
kidney injury. Future rese arch should aim to validate
these findings in larger, multicenter cohorts against
standardized measurements of kidney function.
ACKNOWLEDGMENT
Financial disclosure: No financial support was re-
ceived. The authors declare no conflicts of interest.
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    • There are several " renal " manifestations of TA-TMA, including decreased kidney function — as evidenced by a less-than-normal glomerular filtration rate (GFR), proteinuria, and hypertension[4,12,13]. It should be noted that, especially in children, serum creatinine and creatinine-based GFR estimates may not always be sensitive enough to detect renal dysfunction after HSCT because of the small body size and potentially low muscle mass of these patients[14][15][16]. In patients at risk for TA-TMA, kidney function should be monitored precisely and regularly.
    [Show abstract] [Hide abstract] ABSTRACT: Hematopoietic stem cell transplantation (HSCT)-associated thrombotic microangiopathy (TA-TMA) is now a well-recognized and potentially severe complication of HSCT that carries a high risk of death. In those who survive, TA-TMA may be associated with long-term morbidity and chronic organ injury. Recently, there have been new insights into the incidence, pathophysiology, and management of TA-TMA. Specifically, TA-TMA can manifest as a multi-system disease occurring after various triggers of small vessel endothelial injury, leading to subsequent tissue damage in different organs. While the kidney is most commonly affected, TA-TMA involving organs such as the lung, bowel, heart, and brain is now known to have specific clinical presentations. We now review the most up-to-date research on TA-TMA, focusing on the pathogenesis of endothelial injury, the diagnosis of TA-TMA affecting the kidney and other organs, and new clinical approaches to the management of this complication after HSCT. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Full-text · Article · Nov 2014
    • Future studies using muscle masseindependent methods to estimate kidney function may better define the degree of renal impairment after HSCT, both in those with and without BKV infection. One such method, serum cystatin C, is gaining more widespread use [26,27]. Importantly, our cohort consisted of only patients having PCR testing performed for a clinical indication, raising the possibility these were the sickest patients.
    [Show abstract] [Hide abstract] ABSTRACT: BK virus (BKV) infection is associated with hemorrhagic cystitis (HC) in hematopoietic stem cell transplant (HSCT) recipients and nephropathy after kidney transplant. We assessed the association between BKV and kidney and bladder complications in children developing HC by retrospectively reviewing 221 consecutive pediatric allogeneic HSCT recipients at the Children's Hospital of Philadelphia from 2005-2011. We included all patients with BKV PCR testing performed for clinical indication from day 0 until 1 year post-HSCT (N=68). We assessed the association of any BKV infection (urine and/or blood) or peak BK viremia ≥10,000 copies/ml (high viremia) with severe HC (defined as grade IV-bladder catheterization or surgical intervention), the need for dialysis, serum creatinine-estimated glomerular filtration rate (eGFR) at the time of BKV testing, day 100, and day 365, and death. Children with high viremia more likely developed severe HC compared to those with peak viremia <10,000 copies/mL (21% versus 2%; p=0.02). BKV infection of the blood or urine was not associated with the need for dialysis, change in eGFR, or mortality. BKV infection is common after pediatric allogeneic HSCT and plasma testing in those with HC may predict patients who will develop severe bladder injury.
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  • [Show abstract] [Hide abstract] ABSTRACT: Hematopoietic stem cell transplant (SCT) remains a curative option for a variety of malignant and non-malignant disorders in children. Following transplant a proportion of SCT recipients become critically ill and need intensive care. Critical illness may occur in the setting of transplant complications such as graft versus host disease (GVHD), idiopathic pneumonia syndrome (IPS), veno-occlusive disease (VOD) and transplant associated thrombotic microangiopathy (TA-TMA). Hence, familiarity with recent advances in the transplant process and complications is crucial for the intensivist. This article will highlight common complications encountered in the critically ill SCT recipient.
    Article · Jun 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Drug-induced kidney injury is a serious adverse event which needs to be monitored during aminoglycoside therapy. Urine cystatin C is considered an early and sensitive marker of nephrotoxicity. Cystatin C, a low-molecular-weight serum protein, and basic drugs have a common transport system expressed in the apical membrane of renal proximal tubular cells. The aim of this study was to investigate whether aminoglycoside antibiotics influenced cystatin C binding to the renal brush-border membrane. The binding study was performed using a rapid filtration technique and affinity column displacement method. Concentration-dependent inhibition of chicken cystatin binding to brush-border membranes by gentamicin was observed. The gentamicin interaction with brush-border membranes was of relatively low affinity (Ki = 32 μm) in comparison with the chicken cystatin affinity to the binding sites (Kd = 3.6 μm). Amikacin and gentamicin were only able to displace chicken cystatin from the chromatographic affinity column in concentrations several times higher than normally found in the tubular fluid during standard aminoglycoside therapy. Cystatin reabsorption in the proximal tubule cannot be significantly affected by aminoglycoside antibiotics because of their relatively low affinity to common binding sites on the brush-border membrane.
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  • [Show abstract] [Hide abstract] ABSTRACT: We recently observed that dysregulation of the complement system may be involved in the pathogenesis of hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA). These findings suggest that the complement inhibitor eculizumab could be a therapeutic option for this severe HSCT complication with high mortality. However, the efficacy of eculizumab in children with HSCT-TMA and its dosing requirements are not known. We treated six children with severe HSCT-TMA using eculizumab and adjusted the dose to achieve a therapeutic level of >99 μg/ml. HSCT-TMA resolved over time in four of six children after achieving therapeutic eculizumab levels and complete complement blockade, as measured by low total hemolytic complement activity (CH50). To achieve therapeutic drug levels and a clinical response, children with HSCT-TMA required higher doses or more frequent eculizumab infusions than currently recommended for children with atypical hemolytic uremic syndrome. Two critically ill patients failed to reach therapeutic eculizumab levels, even after dose escalation, and subsequently died. Our data indicate that eculizumab may be a therapeutic option for HSCT-TMA but HSCT patients appear to require higher medication dosing than recommended for other conditions. We also observed that a CH50 level ≤4 complement activity enzyme (CAE) units correlated with therapeutic eculizumab levels and clinical response, and therefore CH50 may be useful to guide eculizumab dosing in HSCT patients as drug level monitoring is not readily available.
    Full-text · Article · Dec 2013
  • [Show abstract] [Hide abstract] ABSTRACT: Hematopoietic stem cell transplantation (SCT) is a therapeutic option for patients with bone marrow failure, certain malignancies and inborn errors of metabolism. Complications requiring intensive care are frequent, and intensivists need to be familiar with the transplantation process and the disorders that are unique to these patients. The transplant process involves the use of high dose chemotherapy or radiation, followed by intravenous infusion of stem cells matched with the recipient at the human leukocyte antigen (HLA) loci. Full recovery of a normal immune system can take a year or more, so following transplantation, patients are exquisitely susceptible to infections. Moreover, complications such as graft versus host disease, idiopathic pneumonia syndrome, sinusoidal obstruction syndrome and transplant associated thrombotic microangiopathy are common in the first hundred days after stem cell infusion. Respiratory failure is a common presentation necessitating intensive care admission and may be due to infectious or non-infectious causes. Mechanical ventilation may be needed along with broad spectrum anti-microbial coverage; corticosteroids are commonly used if graft versus host disease is present. Acute graft versus host disease is most frequent in children receiving grafts from unrelated donors and results in significant morbidity. Increased immunosuppression is the cornerstone of therapy for graft versus host disease, and protection of the children from infection is essential to survival. Sinusoidal obstruction syndrome and transplant associated thrombotic microangiopathy may lead to multiple organ failure with limited therapeutic options, but both disorders can resolve with good supportive care during the period of organ failure. Outcomes for patients who develop multiple organ failure following SCT remain poor despite aggressive supportive care, however, children with failure of a single organ can do well. Integrated multi-disciplinary care between intensivists and transplant physicians, and other specialists such as nephrologists and pulmonologists leads to improved outcomes.
    Article · Feb 2014 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
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