commentary

homeostasis. The sustained FGF23

elevations observed in the study by
Zhang et al.10 may therefore be driven,
at least partly, by changes in calcium,
phosphate, and/or 1,25(OH)2D. In
addition, neither serum phosphate nor
circulating FGF23 levels decreased in
wild-type mice on the restricted diets, a
finding that is different from previously
published observations in mice11 and
our own experience.
Surprisingly, Col4a3/ mice on the
most severely restricted phosphate diet
showed significant variability in circulating FGF23 levels, much more than
their counterparts on control or moderately restricted diets or wild-type
littermates on the same diet. This
variability occurred despite an apparently uniform reduction in bone
production of FGF23, by both message
and protein levels. Renal function as
measured by creatinine, however, was
so heterogeneous in this group of mice
that it was not statistically different
from that in wild-type littermates on
the same diet. Does this finding
suggest that other, as-yet undefined
tissues start producing FGF23 in the
setting of CKD, or does variability in
renal pathology lead to changes in
glomerular filtration and/or tubular
degradation of FGF23, if, for example,
tubulointerstitial pathology affects
these processes? Clearance studies with
recombinant FGF23 injected into
Col4a3/ mice might help clarify
these questions. Alternatively, a CKD
model with a more homogeneous
reduction in kidney function may be
necessary to dissect the contributions
of kidney-dependent and -independent
factors to FGF23 synthesis and secretion.
The study by Zhang et al.10
highlights the challenges in attempting
to dissect the effect of dietary and
circulating phosphate on FGF23. To
further define the contribution of
dietary phosphate levels to FGF23 synthesis and secretion, it may be necessary
to use additional mouse models, rather
than a prolonged zero-phosphate diet,
which obviously leads to severe metabolic and physiological derangements.
For example, Col4a3/ mice could
be crossed into an osteocyte-specific
Kidney International (2013) 84

vitamin D receptor-null background to

eliminate the impact of 1,25(OH)2D on
FGF23 regulation. Likewise it may be
necessary to conduct studies in mice
that are null for both Col4a3 and PTH
to further explore the role of the latter
peptide in FGF23 synthesis. Thus, more
work still is required to determine
whether phosphate-reduced diets or
phosphate binders have only limited
or no effect on FGF23 synthesis and
secretion.

5.

6.

7.

8.

REFERENCES
1.

2.

3.

4.

Christov M, Juppner H. Insights from genetic

disorders of phosphate homeostasis. Semin
Nephrol 2013; 33: 143157.
Schiavi SC, Tang W, Bracken C et al. Npt2b
deletion attenuates hyperphosphatemia
associated with CKD. J Am Soc Nephrol 2012;
23: 16911700.
Vervloet MG, van Ittersum FJ, Buttler RM et al.
Effects of dietary phosphate and calcium
intake on fibroblast growth factor-23.
Clin J Am Soc Nephrol 2011; 6: 383389.
Bhattacharyya N, Wiench M, Dumitrescu C
et al. Mechanism of FGF23 processing in

9.

10.

11.

fibrous dysplasia. J Bone Miner Res 2012; 27:

11321141.
Yuan B, Feng JQ, Bowman S et al. Hexa-Darginine treatment increases 7B2*PC2 activity
in hyp-mouse osteoblasts and rescues the
HYP phenotype. J Bone Miner Res 2013; 28:
5672.
Christov M, Waikar SS, Pereira RC et al. Plasma
FGF23 levels increase rapidly after acute
kidney injury. Kidney Int 2013; 84: 776785.
Isakova T. Fibroblast growth factor 23 and
adverse clinical outcomes in chronic kidney
disease. Curr Opin Nephrol Hypertens 2012;
21: 334340.
Isakova T, Barchi-Chung A, Enfield G et al.
Effects of dietary phosphate restriction
and phosphate binders on FGF23 levels in
CKD. Clin J Am Soc Nephrol 2013; 8:
10091018.
Block GA, Wheeler DC, Persky MS et al. Effects
of phosphate binders in moderate CKD. J Am
Soc Nephrol 2012; 23: 14071415.
Zhang S, Gillihan R, He N et al. Dietary
phosphate restriction suppresses
phosphaturia but does not prevent FGF23
elevation in a mouse model of chronic kidney
disease. Kidney Int 2013; 84: 713721.
Stubbs JR, Liu S, Tang W et al. Role of
hyperphosphatemia and 1,25-dihydroxyvitamin D in vascular calcification and
mortality in fibroblastic growth factor 23 null
mice. J Am Soc Nephrol 2007; 18: 21162124.

see clinical investigation on page 795

Peri-dialytic hypertension and

hypotension: another U-shaped
BP-outcome association
Jula K. Inrig1,2
Park et al. performed a retrospective analysis of a large hemodialysis
cohort to describe the relationship between pre- to postdialysis
changes in BP and mortality. Their study demonstrated adverse
outcomes associated both with large decreases and with any increase in
blood pressure pre- to postdialysis. Although limitations exist in this
analysis, which lacked intradialytic blood pressure measurements, the
results support the ongoing concern about the potential adverse
hemodynamic stress associated with conventional three-times-weekly
hemodialysis.
Kidney International (2013) 84, 641644. doi:10.1038/ki.2013.247

1
Department of Medicine, Duke University,
Durham, North Carolina, USA and 2Quintiles
Global Clinical Research Institute, Morrisville,
North Carolina, USA
Correspondence: Jula K. Inrig, 14958 Vistaridge
Drive, Dallas, Texas 75248, USA.
E-mails: jula.inrig@duke.edu or
jula.inrig@quintiles.com

Among hemodialysis patients in the

United States, blood pressure (BP)
control is universally poor. Although
it is evident that BP control with more
frequent dialysis or longer dialysis
improves survival,1 these outcomes are
likely attributable to better salt and
641

commentary

water balance and improved hemodynamic stability with extended dialysis.

Unfortunately, there are no randomized
controlled trials among patients on conventional hemodialysis to help identify
goal BP targets. The available observational data, which are highly confounded,
suggest that lower (rather than higher)
BP associates with adverse outcomes.
Thus, much uncertainty remains regarding the ideal BP to improve outcomes
among patients on three-times-weekly
conventional hemodialysis.
One of the difficulties in identifying
goal BP targets relates to the inaccuracies surrounding the BP measurements
themselves. Agarwal et al. have clearly
shown that both pre- and post-dialysisunit BP measurements are inaccurate
reflections of BP burden, as measured
by ambulatory or home BP.2 Although
most agree that home BP measurements are useful clinically, many patients
are neither compliant nor willing to
measure home BP. Accordingly, hemodialysis-unit BP measurements remain
the main measurement used to direct BP
management. There is also increasing
evidence that conventional hemodialysis
causes hemodynamic stress and myocardial injury, which may contribute to
early cardiovascular death.3 Hence, there
is significant clinical interest regarding
the predictive utility of using intra- and
peridialytic BP measurements to identify
patients at a higher risk for adverse
outcomes.
Park et al.4 (this issue) performed a
retrospective analysis to describe the
relationship between pre- to postdialysis
changes in BP and mortality. The
authors hypothesized that both increases and decreases in BP from before to
after dialysis would be associated with
all-cause and cardiovascular mortality,
independent of predialysis BP levels.
The study cohort was inclusive of
113,255 US hemodialysis patients cared
for in a large dialysis organization
(DaVita) from 2001 to 2006. The
patients were fairly similar to incident
hemodialysis patients in the US Renal
Data System (USRDS): average age of
61 years, 32% African American, 58%
with diabetes, and a median dialysis
duration of 3 months. Overall mortality
642

was high, with 53,461 (47%) deaths

over the median 2.2-year follow-up.
In adjusted analyses, the authors
identified a U-shaped relationship
between pre- to postdialysis changes
in BP and all-cause and cardiovascular
mortality. Modest declines in systolic
BP (SBP) during hemodialysis ( 30 to
0 mm Hg) were associated with the best
survival, whereas a pre- to postdialysis
decline in SBP of less than  30 mm Hg
and any pre- to postdialysis increase in
SBP (40 mm Hg) were associated with
higher mortality. Results were similar
for diastolic BP. The greatest survival
was associated with a pre- to postdialysis
change in SBP of  14 mm Hg (hazard
ratio 0.92, 0.910.93). The authors also
compared outcomes across strata of
predialysis SBP, ultrafiltration rates, and
time on dialysis, none of which significantly modified the primary findings.
Although interesting associations
were identified, a number of important
limitations must be considered in interpreting the results of this study. No
information on intradialytic BP measurements, symptoms, medications, or
interventions was available. We do not
know whether those with large decreases
or increases in BP exhibited symptomatic intradialytic hypotension, received
intravenous saline, were treated with
thermoneutral or cooled dialysate, had
cessation of ultrafiltration, or altered
dialysis prescriptions. A number of small
crossover studies have demonstrated
improved intradialytic hemodynamic
stability with modifications such as
cooled dialysate or modification of the
ultrafiltration rate.5 Knowledge of such
factors is important in determining
whether the BP patterns are iatrogenic
or intrinsic and whether prescribed
treatments (or lack thereof) or
interventions could have contributed to
the exhibited BP patterns or the adverse
outcomes.
It is also imperative to note that the
analysis by Park et al.4 lacked information regarding metrics of euvolemia
or sodium balance. The authors found
that those with pre- to postdialysis
increases in BP had the lowest ultrafiltration (thus, the least sodium and water
removed). However, the study cannot

assess whether patients with pre- to

postdialysis increases or decreases in BP
achieved euvolemia or adequate sodium
removal at the end of treatment. It
would be informative if the authors
identified differences in predialysis
sodium or in the dialysate-to-serum
sodium gradient across groups to
provide more mechanistic information
regarding the different BP patterns. On
one end of the spectrum, we know that
intradialytic hypotension can be caused
by an initial drop in plasma osmolality
from intracellular shifts in fluid.6
Therefore, identification of a low prescribed dialysate sodium relative to
predialysis sodium could support the
idea that a decrease in osmolality due to
an initial drop in plasma sodium contributes to intradialytic hypotension. On
the other end of the spectrum, we have
demonstrated that patients with intradialytic hypertension have low predialysis serum sodium.7 A positive
dialysate-to-serum sodium gradient
raises the potential for diffusive transfer
of sodium into patients during dialysis.
In addition, raising plasma sodium can
impair the release of nitric oxide and
increase endothelin-1, which can raise
BP.8 Thus, if such differential sodium
gradients among patients with hypotension and hypertension during dialysis
were found, this could provide information about how potentially to individualize dialysate sodium to alter these
BP patterns. Thus, whether sodium
excess or changes in plasma sodium
during hemodialysis contribute to
adverse outcomes among these
patients remains unknown.
Finally, although the authors did
make adjustments for available comorbidities, these were only collected at
dialysis initiation as part of the USRDS
2728 form, which is inadequate to fully
capture comorbidities, overall functional status, and health. It is notable
that patients whose SBP increased by
more than 10 mm Hg before to after
dialysis (i.e., intradialytic hypertension)
were clearly a sicker group of patients,
with greater cardiac disease and higher
markers suggestive of malnutrition
inflammation complex. Undoubtedly,
residual confounding remains, and we
Kidney International (2013) 84

commentary

do not know whether the relationships

identified would persist if accurate
risk modifiers were available for
adjustment.
The findings of the study by Park
et al.4 are consistent with prior studies,
some of which had more detailed
information on intradialytic BP
measurements, interventions, and comorbidities. We have previously demonstrated that patients who exhibit a rise
in SBP during hemodialysis have a
more than twofold increase in nonaccess-related hospitalizations and
death and higher 2-year mortality.9,10
Similar to the current study which
identified higher comorbidity among
those with intradialytic hypertension,
we also identified that patients with
intradialytic hypertension have a higher
risk patient profile but that adjustment
for confounders does not modify the
adverse outcomes associated with
intradialytic hypertension. Intradialytic
hypotension (defined as a 40-mm-Hg
drop in BP during a single hemodialysis
session) has also been shown to be
associated with poor 2-year survival,11
although the data are from a Japanese
cohort of patients, and US data are
lacking. One of the strengths of the
study by Park et al.4 lies in its large
sample size, which gave higher statistical power to the identification of a
U-shaped association between pre- to
postdialysis changes in BP and outcomes. Future studies are required to
provide more granularity around
treatment-specific factors that contribute to the different BP patterns.
The question remains: are peridialytic BP changes modifiable risk factors
or purely surrogate markers of something else that hastens death? Another
recent study among hemodialysis
patients demonstrated that high BP
variability is associated with higher
all-cause and cardiovascular mortality.12 Although the study by Park
et al.4 did not show BP variability to
modify the relationship between preand postdialysis changes in BP and
death, the combination of these and
other studies suggests that large BP
changes with hemodialysis are important. A number of potential mechaniKidney International (2013) 84

Intradialytic
hypotension

Intradialytic
hypertension

Recurrent
myocardial stunning

Endothelial-cell
dysfunction

Myocardial fibrosis

Atherosclerosis

Arteriosclerosis

Systolic dysfunction

Ischemic
heart disease

Left ventricular
hypertrophy

Cardiovascular death

Cardiovascular death

Figure 1 | Potential mechanisms underlying adverse outcomes with intradialytic

hypotension and intradialytic hypertension.

sms would support both intradialytic

hypotension and hypertension as being
modifiable cardiovascular risk factors.
Intradialytic hypotension is associated
with myocardial stunning, which can
lead to myocardial fibrosis, systolic
dysfunction, and cardiovascular death
(Figure 1).3 Intradialytic hypertension
is associated with impaired endothelial
cell function, which can also lead to
early cardiovascular death (Figure 1).7
Mechanistic studies on dialysis-specific
factors contributing to both intradialytic hypertension and hypotension are
important to help determine the extent
to which these conditions could or
should be managed, if at all. However,
caution should be taken, as the study by
Park et al.4 provides no information on
intradialytic BP parameters.
Where do we go from here? How do
we better manage our patients with
large fluctuations in BP, assuming this
matters? We know that longer and
more frequent dialysis lowers BP and
improves survival. In the United States,
the payment structure for dialysis has
clearly narrowed the way we deliver
dialysis. There is no incentive for
achieving adequate sodium and water
balance, and in fact there is a financial
disincentive to prolong treatment
times. In addition, the Centers for
Medicare & Medicaid Services Quality
Incentive Program bases dialysis adequacy solely on urea removal. Factors
such as BP control, attainment of
euvolemia, and ensuring of isonatric

dialysis are not captured nor incentivized. A recent quality initiative by

three large dialysis organizations suggested that hospitalizations could be
reduced by close monitoring of volume
changes during hemodialysis.13 These
types of studies are commendable, and
more such studies are needed. Can we
improve the way we deliver dialysis in
the United States to improve outcomes?
Obviously, we have much to learn, and
the 2012 USRDS suggests, particularly
for incident hemodialysis patients, that
we still have significant room for
improvement.
DISCLOSURE

The author declared no competing interests.

REFERENCES
1.

2.

3.

4.

5.

6.

The FHN Trial Group. In-center hemodialysis

six times per week versus three times per
week. N Engl J Med 2010; 363: 22872300.
Agarwal R, Peixoto AJ, Santos SFF et al.
Pre- and postdialysis blood
pressures are imprecise estimates of
interdialytic ambulatory blood pressure.
Clin J Am Soc Nephrol 2006; 1:
389396.
McIntyre CW. Effects of hemodialysis
on cardiac function. Kidney Int 2009; 76:
371375.
Park J, Rhee CM, Sim JJ et al. A comparative
effectiveness research study of the change
in blood pressure during hemodialysis
treatment and survival. Kidney Int 2013;
84: 795802.
van der Sande FM, Wystrychowski G,
Kooman JP et al. Control of core temperature
and blood pressure stability during
hemodialysis. Clin J Am Soc Nephrol 2009; 4:
9398.
Henrich WL, Woodard TD, Blachley JD et al.
Role of osmolality in blood pressure stability

643

commentary

7.

8.

9.

10.

after dialysis and ultrafiltration. Kidney Int

1980; 18: 480488.
Inrig J, Van Buren P, Kim CM et al.
Intradialytic hypertension and its
association with endothelial cell
dysfunction. Clin J Am Soc Nephrol
2011; 6: 20162024.
Oberleithner H, Riethmuller C, Schillers H
et al. Plasma sodium stiffens vascular
endothelium and reduces nitric oxide release.
Proc Natl Acad Sci USA 2007; 104:
1628116286.
Inrig JK, Oddone EZ, Hasselblad V et al.
Association of intradialytic blood pressure
changes with hospitalization and mortality
rates in prevalent ESRD patients. Kidney Int
2007; 71: 454461.
Inrig JK, Patel UD, Toto RD et al. Association
of blood pressure increases during
hemodialysis with 2-year mortality in

11.

12.

13.

incident hemodialysis patients: a secondary

analysis of the Dialysis Morbidity and
Mortality Wave 2 Study. Am J Kidney Dis 2009;
54: 881890.
Shoji T, Tsubakihara Y, Fujii M et al.
Hemodialysis-associated hypotension as an
independent risk factor for two-year
mortality in hemodialysis patients. Kidney Int
2004; 66: 12121220.
Flythe JE, Inrig JK, Shafi T et al. Association of
intradialytic blood pressure variability with
increased all-cause and cardiovascular
mortality in patients treated with long-term
hemodialysis. Am J Kidney Dis 2013; 61:
966974.
Parker TF 3rd, Hakim R, Nissenson AR et al.
A quality initiative: reducing rates of
hospitalizations by objectively monitoring
volume removal. Nephrol News Issues 2013;
27: 3137.

see clinical investigation on page 786

Biomarkers and creatinine in AKI:

the trough of disillusionment or
the slope of enlightenment?
Zoltan H. Endre1,2 and John W. Pickering1
Assessment of acute kidney biomarkers against changes in plasma
creatinine is beset by issues of heterogeneity of study cohorts and
timing of sampling. Siew and colleagues attempt to minimize these
issues in a casecontrol study of three biomarkers in the intensive care
unit. The results highlight the inherent methodological difficulties and
the need to reference structural injury biomarkers against more
meaningful outcomes.
Kidney International (2013) 84, 644647. doi:10.1038/ki.2013.168

The discovery of new biomarkers of

kidney damage along with the rediscovery of enzymuria has reignited hope
for management of acute kidney injury
(AKI). The promise is earlier diagnosis
than with the current gold standards of
creatinine and urine output, raising the
possibility of early intervention in this
1
Christchurch Kidney Research Group,
Department of Medicine, University of
OtagoChristchurch, Christchurch, New Zealand
and 2Department of Nephrology, Prince of Wales
Clinical School, University of New South Wales,
Sydney, Australia
Correspondence: Zoltan H. Endre, Department
of Nephrology, Prince of Wales Hospital, High
Street, Randwick, Sydney, NSW 2031, Australia.
E-mail: z.endre@unsw.edu.au

644

critical syndrome. That said, the incorporation of any new biomarker

into clinical practice is far from easy.
Biomarker discovery appears to follow
the familiar path of a technology hype
cycle: disruptive technology, inflated
expectations, trough of disillusionment,
slope of enlightenment, and plateau of
productivity.
New technology, proteomics and
genomics, and new statistical insights
triggered a discovery phase, which
was rapidly followed by a peak of
inflated expectations as early reports
posted impressive areas under the
receiver operating characteristic curve
(AUCs).13 This first phase involves
careful selection of a discovery cohort

comprising an affected cohort and

matched unaffected controls, followed
by an equally carefully selected and very
homogenous initial validation cohort.
We are reassured that the biomarker
has clinical utility when the receiver
operating characteristic analysis yields
an AUC above 0.90. However, the
story gets more complex as soon
as the biomarker is applied to less
homogenous patient groups and to
those less carefully selected for the
differences mandated in the discovery
cohort. Subsequent validation studies
are in necessarily more heterogeneous
cohorts, so-called phase 3, and include
high-risk patients, not only affected
patients. Inclusion of intermediate-risk
patients necessarily reduces the AUC,
and many biomarker studies,4 including
that of Siew and colleagues5 (this issue),
have yielded AUCs barely greater
than 0.5, which questions our earlier
hopefulness.
Now that we have entered the hype
cycles trough of disillusionment, we
should pause to question our framework for discovery and validation.
Questions that need to be asked
include: Should the performance of
new biomarkers of damage be measured against the yardstick of functional
change? Are our measures of performance appropriate or relevant to the
process we are assessing? And is it
rational to attempt to diagnose a
complex syndrome with many causes
by any single measure? Sadly, the
answer to all these questions is a
resounding no. However, we must needs
walk on in the valley of the shadow until
we understand more about the complex
syndrome we are trying to treat as a
single disease process.
The study by Siew et al.5 both
reflects the sequence outlined above
and illustrates an attempt to avoid
some obvious pitfalls. They undertook
a retrospective nested case-controlled
study of 130 AKI patients and 250
controls. They looked at the early
detection and prognostic performance
of injury biomarkers in patients
assumed not to have elevated creatinine
on study entry. Because of the potential
for disparate mechanisms to contribute
Kidney International (2013) 84