(Figure 1).

As shown in Figure 1, this

study stopped with verification of
IGFBP-7 and NGAL. Additional verifi-
cation steps could take advantage of
systems biology approaches and data
available from independent studies.
These approaches help home in on
the most promising proteins. For exa-
mple, an enriched process of IGFBP-7 is
negative regulation of cell proliferation
and growth, and other related proteins
may be of interest. The Search Tool for
the Retrieval of Interacting Genes/
Proteins (STRING) database of
proteinprotein interactions demon-
strates that CXCL10 interacts with
IGFBP-7. CXCL10 is a previously dis-
covered marker of AKI.
11
Mechanistic
studies exploring the biology of IGFBP-
7 should be pursued. The relevant
questions to address include the
function of IGFBP-7 in AKI, and the
mechanism of its appearance in urine.
One might speculate that this protein
is secreted by tubular cells rather
than filtered, as it is a glycoprotein,
present at higher levels in urine of
patients with lower glomerular filtra-
tion rate. Nonetheless, this question
deserves further study. Ultimately, the
greatest clinical problem in AKI is defi-
ning novel therapeutic targets, and
IGFBP-7 and its interactors should
be studied in this context. For mar-
kers that pass qualification criteria,
validation studies are needed to eval-
uate their clinical utility. It remains to
be seen whether IGFBP-7 stands the
challenges of further inquiry into its
role in AKI.
DISCLOSURE
The author declared no competing interests.
ACKNOWLEDGMENTS
The author expresses gratitude to James W.
Scholey for his helpful suggestions and
mentoring.
REFERENCES
1. Konvalinka A, Scholey JW, Diamandis EP.
Searching for new biomarkers of renal
diseases through proteomics. Clin Chem
2012; 58: 353365.
2. Waikar SS, Sabbisetti VS, Bonventre JV.
Normalization of urinary biomarkers to
creatinine during changes in glomerular
filtration rate. Kidney Int 2010; 78: 486494.
3. Aregger F, Uehlinger DE, Witowski J et al.
Identification of IGFBP-7 by urinary
proteomics as a novel prognostic marker in
early acute kidney injury. Kidney Int 2014; 85:
909919.
4. Oh Y, Nagalla SR, Yamanaka Y et al. Synthesis
and characterization of insulin-like growth
factor-binding protein (IGFBP)-7.
Recombinant human mac25 protein
specifically binds IGF-I and -II. J Biol Chem
1996; 271: 3032230325.
5. Yang QH, Liu DW, Long Y et al. Acute renal
failure during sepsis: potential role of cell
cycle regulation. J Infect 2009; 58: 459464.
6. Witzgall R, Brown D, Schwarz C et al.
Localization of proliferating cell nuclear
antigen, vimentin, c-Fos, and clusterin in the
postischemic kidney. Evidence for a
heterogenous genetic response among
nephron segments, and a large pool of
mitotically active and dedifferentiated cells.
J Clin Invest 1994; 93: 21752188.
7. Kashani K, Al-Khafaji A, Ardiles T et al.
Discovery and validation of cell cycle arrest
biomarkers in human acute kidney injury. Crit
Care [online] 2013; 17: R25.
8. Haase M, Bellomo R, Devarajan P et al.
Accuracy of neutrophil gelatinase-associated
lipocalin (NGAL) in diagnosis and prognosis
in acute kidney injury: a systematic review
and meta-analysis. Am J Kidney Dis 2009; 54:
10121024.
9. Srisawat N, Wen X, Lee M et al. Urinary
biomarkers and renal recovery in critically ill
patients with renal support. Clin J Am Soc
Nephrol 2011; 6: 18151823.
10. Parikh CR, Abraham E, Ancukiewicz M et al.
Urine IL-18 is an early diagnostic marker for
acute kidney injury and predicts mortality in
the intensive care unit. J Am Soc Nephrol
2005; 16: 30463052.
11. Ho J, Lucy M, Krokhin O et al. Mass
spectrometry-based proteomic analysis of
urine in acute kidney injury following
cardiopulmonary bypass: a nested case-control
study. Am J Kidney Dis 2009; 53: 584595.
see clinical investigation on page 898
Estimation of fluid volumes in
hemodialysis patients: comparing
bioimpedance with isotopic and
dilution methods
Antonio Piccoli
1
Both single-frequency bioimpedance and multiple-frequency
spectroscopy are equally accurate in measuring total-body water and
intracellular fluid. Estimates are consistent at a population level but not
at the individual level, because of wide limits of agreement. There is no
real gold standard method providing estimates with absolute accuracy
(in liters). Bioelectrical impedance vector analysis allows comparison
of the actual body impedance with that of the reference population
(in X/m). Hemodialysis prescription can be optimized with the use of
this feedback.
Kidney International (2014) 85, 738741. doi:10.1038/ki.2013.434
CLASSIFICATION OF BIOIMPEDANCE
ANALYSIS
Use of a phase-sensitive instrument
(50 kHz) yields a Z vector that is a
combination of R, opposition to the
flow of an alternating current through
intra- and extracellular ionic solutions,
and Xc, the capacitative component of
tissue interfaces, cell membranes, and
organelles. Although impedance is an
electrical property of tissues that can
be directly used in body composition
analysis, it is commonly embedded in
predictive equations that are derived by
correlation with criterion measures of
body compartments.
Literature is divided along four
methods of body composition analysis
based on impedance. The first and the
1
Department of Medicine, University of Padova,
Padova, Italy
Correspondence: Antonio Piccoli, Policlinico IV
piano, Via Giustiniani 2, Padova 35135, Italy.
E-mail: apiccoli@unipd.it
738 Kidney International (2014) 85
comment ar y
most validated is prediction of total-
body water (TBW) with functions of
50 kHz single-frequency impedance
(either series measures or their parallel
equivalents, mostly neglecting the Xc
component).
1,2
The second is prediction
of extracellular fluid (ECF) and TBW
with functions of low-frequency (15kHz)
and high-frequency (100500 kHz) im-
pedance (dual- or multiple-frequency
bioimpedance analysis (BIA)), with the
intracellular fluid (ICF) calculated by
difference.
1,2
The third is use of many
impedance measurements (11000 kHz)
through bioimpedance spectroscopy
(BIS) following the Coles model
approach (that is, extrapolating
R values at limit frequencies) for pre-
diction of TBW, ECF, and ICF.
14
The
fourth is use of the direct impedance
vector measurement (both R and Xc
components normalized for the height,
R/H and Xc/H) at 50 kHz (bioelectrical
impedance vector analysis, BIVA) in a
probabilistic graph (the RXc graph,
Figure 1).
1,5,6
BIVA is a stand-alone
method of body composition analysis,
where the continuous, bivariate, random
vector of impedance is evaluated through
an ordinal scale (tolerance interval
percentiles, 50, 75, and 95%) of the
deviation from a reference population.
Point vectors can be classified (normal
versus abnormal impedance) and ranked
(more or less than before intervention).
Body composition is then evaluated
through patterns of vector distribu-
tion with respect to the reference
percentiles.
3,59
PREDICTION EQUATIONS
In the literature, a good prediction
equation estimating body fluid of
uremic patients represents the top of
the information that is demanded by
the clinician for dialysis prescription.
Good equations are validated against
gold standard methods in the hope to
increase the accuracy. But the predic-
tion error of BIA and BIS equations
is the sum of five errors, namely, the
impedance measurement error, the
regression error, the intrinsic error of
the reference method, the electric-
volume model error, and the biological
variability among subjects.
3
Ethnicity
increases the biological variability among
subjects
10
and may act as a confounder
because equations are typically valida-
ted against one or possibly two ethnic
groups.
1,2
In hemodialysis (HD), a
specific error may be created by fistula
or superior vena cava stenosis where
congested soft tissues may decrease the
whole-body impedance (two electrodes
on hand and two on foot of the same
side). With isotope dilution methods
that are developed for healthy subjects,
accuracy may decrease in patients with
inflammation and endothelial leak.
Raimann et al.
4
(this issue) now
publish an excellent study evaluating
the intrinsic error of the reference
methods that are used for estimating
body fluid volume.
The authors compared the precision
and accuracy of single-frequency BIA
(SF-BIA) and multi-frequency BIS
(MF-BIS) in 49 HD patients in the
steady state before an HD session.
4
The
results of direct estimation methods
(DEMs; dilutometry and isotopic refer-
ence methods) for TBW (deuterium
oxide dilution), ECF (bromide dilution),
and ICF (total-body-potassium count)
were compared with the results of indi-
rect estimation methods (IEMs), which
used the sum of, or the difference
between, the other two respective
direct estimates. The assumption was
that if each estimate were accurate, the
direct method and the sum (or differ-
ence) of the other two values (the IEM)
would provide the same value. At the
BlandAltman analysis, if the DEM and
the IEM were accurate and precise, the
bias should have been close to zero and
the limits of agreement should have
been narrow.
RESULTS OF COMPARISON
Both bioimpedance methods appear to
be equally accurate in measuring TBW
and ICF. Instead, there was a significant
bias between ECF and SF-BIA estimate.
Furthermore, a proportional error was
found for ICF with both impedance
measurements. The proportional error
of MF-BIS could be explained by the
Cole model, in which ICF is calculated
by the difference between TBW (high
frequency) and ECF (low frequency). In
this particular SF-BIA equation, ICF is
calculated with the assumption that the
intracellular potassium concentration
is stable at 152 mmol/l and TBW is
known.
4
The correlation coefficients between
TBW, ICF, and ECF versus IEMs, SF-
BIA, and MF-BIS were moderate and
in favor of SF-BIA, namely 0.40or
2
o0.76 for TBW, 0.40or
2
o0.80 for
SF-BIA, and 0.41or
2
o0.54 for MF-
BIS. At BlandAltman analysis, the bias
of SF-BIA and MF-BIS was equally
distributed with wide limits of agree-
ment that exceeded

10 liters for TBW

and

7.5 liters for ICF and ECF. These

results indicate that estimates are con-
sistent at a population level but not at
the level of individual subjects. Indeed,
even a very accurate estimate of TBW in
a dialysis patient who loses 3 liters after
a dialysis session is not useful if the
individual error is

7.5 liters.
While the authors cannot establish
the mechanism for this divergence at
this time, the difference in ECF results
between the two bioimpedance meth-
ods did not differ significantly from the
difference in ECF results between DEM
and IEM. Stratification by sex and class
of age (older and younger than the
median age of 54 years) did not change
the distribution of bias (Supplementary
Table S2 online). The authors conclude
that there is no real gold standard with
absolute accuracy and the errors in
precision and accuracy are evident but
are of comparable magnitude to errors
found between measurements of gold
standard techniques. Compared with
DEM this suggests slightly better accu-
racy and precision of MF-BIS over
SF-BIA (50 kHz) for ECF and of
SF-BIA over MF-BIS for ICF.
TARGETING THE OPTIMAL HYDRATION
WITH BIVA
BIVA is a simple methodology, based
on electrical properties of tissues, that
allows a direct monitoring of fluid status
without the need of a body weight
measurement. Only measurement error
and biological variability contribute to
the global error. The intersubject varia-
bility of Z is represented with the
bivariate normal distribution, that is,
Kidney International (2014) 85 739
comment ar y
with elliptical probability regions on
the RXc plane, which are confidence
(95%) and tolerance ellipses (50%, 75%,
95%) for mean and individual vectors,
respectively.
5,6
Analysis of changes of
impedance measurements in abnormal
BIVA trajectories allows a feedback
between actual body fluid volumes and
those of the reference population.
69
Figure 1 shows hourly vector mea-
surements that form trajectories span-
ning within (green circles) or out of
(blue circles) the 75% tolerance ellipses
during 34 h of ultrafiltration in repre-
sentative HD patients. Trajectories can
be classified into normal (within 75%)
versus abnormal (outside of 75%)
assuming that a normal hydration in
HD patients is the normal hydration of
the healthy population (as supported
by the impedance vector distribution of
the reference population).
6,7
The classi-
fication of vectors into normal versus
abnormal with respect to the reference
third quartile (75% tolerance ellipse) is
based on electrical properties of soft
tissues, independent of body weight of
patients. Vector distribution in asymp-
tomatic HD patients was close to that
of healthy subjects and peritoneal
dialysis patients in the same body
mass index range.
69
Two dynamic patterns of abnormal
vector trajectories are characteristic in
HD patients undergoing ultrafiltration.
The first and more frequent pattern is a
vector displacement parallel to the major
axis of the tolerance ellipses, leaving or
ending outside of the 75% tolerance
ellipse. Long vectors overshooting the
upper poles indicate dehydration (dry
vectors), and short vectors migrating
across the lower poles indicate fluid
overload (wet vectors). Vector trajec-
tories spanning on the left side versus
trajectories on the right side of ellipses
are from patients with more versus less
soft tissue mass, respectively. The second
pattern of ultrafiltration is a flat vector
migration to the right side, resulting from
an increase in R/H without a propor-
tional increase in Xc/H due to loss of cells
in soft tissue. This pattern is characteristic
of patients with severe malnutrition or
cachexia. It is never observed in vectors
lying on the left of the ellipses.
69
OPTIMAL CURRENT FREQUENCY
Although BIVA can be done on R and Xc
components at any current frequency, the
optimal performance of the method is
obtained with the standard, single-
frequency, 50-kHz current that allows
impedance measurements with the best
signal-to-noise ratio.
1,3
WHOLE-BODY VS. SEGMENTAL BIA
All equations produce estimates of TBW
and of its compartments with a 95%
prediction interval too large for clinical
purposes. In principle, segmental impe-
dance measurements might reduce the
model error component, but the method
cannot be validated with dilutometry.
1,2
BIVARIATE Z SCORES
After transformation of the R and Xc
components into bivariate Z scores, the
RXc-score graph can be used with any
analyzer in any population.
10
For
instance, with our reference popula-
tion, the values of R and Xc in Ohm/m
are transformed into bivariate Z scores,
that is, Z(R) and Z(Xc), using the mean
and the s.d. of the gender-specific
reference healthy population, Z(R)
(R/H mean R/H)/s.d. (that is, (R/H
371.9)/49 if female and (R/H 298.6)/
43.2 if male) and Z(Xc) (Xc/H mean
Xc/H)/s.d. (that is, (Xc/H 34.4)/7.7 if
female and (Xc/H 30.8)/7.2 if male),
therefore defining one set of tolerance
ellipses (50%, 75%, and 95%) indepen-
dent of gender.
10
CONCLUSIONS
Both bioimpedance methods appear to
be equally accurate in measuring TBW
and ICF. There was a significant bias
between ECF and SF-BIA estimate, and
a proportional error for ICF with both
impedance measurements. The correla-
tion between TBW, ICF, and ECF
measurements with IEMs, SF-BIA, and
MF-BIS was moderate and in favor of
SF-BIA. These results indicate that
estimates are consistent at a population
level but not at the individual level,
because of wide limits of agreement.
There is no real gold standard with
absolute accuracy. The discrepancies
between the results with bioimpedance
and the results with direct methods are
comparable to discrepancies between
the results of different specific direct
methods. Errors in precision and accu-
racy are of comparable magnitude to
errors found between measurements of
gold standard techniques. Analysis of
X
c
/
H

(

/
m
)
R/H (/m) R/H (/m)
60
50
40
30
20
10
0
60
50
40
30
20
10
0
0 100 200 300 400 500 0 100 200 300 400 500 600
Males Females
95% 95%
75%
75%
50%
50%
Figure 1 | Vector lengthening during a hemodialysis session. Hourly point vectors form
trajectories spanning within (green circles) or out of (blue circles) the 75% tolerance ellipses
during 34 h of ultrafiltration in representative hemodialysis (HD) patients. The classification of
vectors into normal versus abnormal with respect to the reference third quartile (75%
tolerance ellipse) is based on electrical properties of soft tissues, independent of body weight
of patients. Vectors can also be ranked (more or less than before intervention). Appropriate
HD prescriptions can bring vectors within the target ellipses. The vector distribution in
asymptomatic HD patients was close to that of healthy subjects in the same body mass index
range.
740 Kidney International (2014) 85
comment ar y
changes of impedance measurements in
abnormal BIVA trajectories, although
forfeiting prediction of absolute vo-
lumes, allows determination of whether
body fluid volumes are returning to
those of the reference population.
DISCLOSURE
The author declared no competing interests.
REFERENCES
1. Kyle UG, Bosaeus I, De Lorenzo AD et al.
Bioelectrical impedance analysispart I:
review of principles and methods. Clin Nutr
2004; 23: 12261243.
2. Kyle UG, Bosaeus I, De Lorenzo AD et al.
Bioelectrical impedance analysispart II:
utilization in clinical practice. Clin Nutr 2004;
23: 14301453.
3. Piccoli A, Pastori G, Guizzo M et al.
Equivalence of information from single
versus multiple frequency bioimpedance
vector analysis in hemodialysis. Kidney Int
2005; 67: 301313.
4. Raimann JG, Zhu F, Wang J et al. Comparison
of fluid volume estimates in chronic
hemodialysis patients by bioimpedance,
direct isotopic, and dilution methods. Kidney
Int 2014; 85: 898908.
5. Piccoli A, Rossi B, Pillon L et al. A new method
for monitoring body fluid variation by
bioimpedance analysis: the RXc graph. Kidney
Int 1994; 46: 534539.
6. Piccoli A, Nigrelli S, Caberlotto A et al. Bivariate
normal values of the bioelectrical impedance
vector in adult and elderly populations. Am J
Clin Nutr 1995; 61: 269270.
7. Piccoli A. Identification of operational clues
to dry weight prescription in hemodialysis
using bioimpedance vector analysis. Italian
HemodialysisBioelectrical Impedance
Analysis (HD-BIA) Study Group. Kidney Int
1998; 53: 10361043.
8. Piccoli A. Bioelectrical impedance vector
distribution in peritoneal dialysis patients
with different hydration status. Italian
Continuous Ambulatory Peritoneal
DialysisBioelectric Impedance Analysis Study
Group. Kidney Int 2004; 65: 10501063.
9. Piccoli A, Codognotto M. Bioimpedance
vector migration up to three days after the
hemodialysis session. Kidney Int 2004; 66:
20912092.
10. Piccoli A, Pillon L, Dumler F. Impedance
vector distribution by sex, race, body mass
index, and age in the United States: standard
reference intervals as bivariate Z scores.
Nutrition 2002; 18: 153167.
see clinical investigation on page 920
Selecting the optimal peritoneal
dialysis catheter
Kostas G. Stylianou
1
and Eugene K. Daphnis
1
As the incidence of end stage renal disease increases across the globe,
so too do the survival rates of peritoneal dialysis patients. It is notable
though, that peritoneal dialysis utilization does not follow at the same
pace, attributable into the high technique failure rates, mainly due to
peritoneal catheter dysfunction. A new systematic review and meta-
analysis by Hagen et al. reveals that the use of straight catheters may
improve outcomes and technique survival.
Kidney International (2014) 85, 741743. doi:10.1038/ki.2013.424
Peritoneal access failure remains a
source of frustration for all peritoneal
dialysis (PD) programs, and its causes
need in-depth analysis and research.
The standard response to the question
which catheter shall we implant in our
patient today would be the catheter we
are most acquainted with, thus keeping
in line with international guidelines.
Current evidence, however, suggests
that this may not be the correct answer.
The survival rates of PD patients
have significantly improved over the
past decade.
1,2
At the same time the
decreasing trend in the use of PD in
many countries is raising concern. The
improving patient survival indices may
reflect better management of patients
on PD, such as early diagnosis and
treatment of comorbid diseases and
improvements in PD as a renal replace-
ment therapy. In contrast, there have
been only modest changes in technique
survival, especially soon after PD
initiation.
1,3
The relatively high rates
of technique failure were always one of
the main reasons for PD lagging behind
hemodialysis (HD), despite increasing
incidence rates of end-stage renal
disease worldwide. If more patients
entered PD programs and the techni-
que failure rates remained unchanged
(as statistics currently reflect), then
more patients would eventually be tran-
sferred to HD. Additionally, the consis-
tently high rates of technique failure
due to peritoneal access complications,
in combination with decreasing
mortality in PD, lead to increasing
rates of dropout to HD, as depicted in
Figure 1.
In the Netherlands Cooperative
Study on the Adequacy of Dialysis
(NECOSAD), one of the main reasons
for early dropout from PD was related
to PD catheter dysfunction. Abdominal
and catheter complications accounted
for 40% of transfers to HD during the
first 3 months and fell to 25% after 2
years.
3
Peritoneal access failure is the
reason for approximately 2035% of
dropouts to HD.
4,5
It is thus clear that
there is an urgent need for analysis and
improvement of peritoneal access out-
comes if we are to maintain an active
role for the PD modality as a renal
replacement therapy. There are several
variations to the peritoneal catheter
design that claim superiority over the
others. The most usual variations con-
cern the number of cuffs (single or
double), the design of the subcutaneous
tunnel (swan neck or Tenckhoff), and
the shape of the intra-abdominal
portion (straight or coiled). Several
combinations of the above (and some
other) characteristics result in a great
variation of available PD catheter
configurations. A downward-directed
exit site was associated with lower
peritonitis rates in early studies. The
swan-neck catheterwith an inverted
1
Department of Nephrology, Heraklion University
Hospital, Heraklion, Crete, Greece
Correspondence: Kostas G. Stylianou,
Department of Nephrology, Heraklion University
Hospital, Voutes Heraklion, 71110 Crete, Greece.
E-mail: kstylianu@gmail.com
Kidney International (2014) 85 741
comment ar y