The Blood Urea Nitrogen to Creatinine Ratio Identifies

The Blood Urea Nitrogen to Creatinine Ratio Identifies a High Risk
but Potentially Reversible Form of Renal Dysfunction in Patients
with Decompensated Heart Failure
Brisco et al: BUN/Cr and Reversible Renal Dysfunction
Meredith A. Brisco, MD, MSCE*†; Steven G. Coca, DO‡; Jennifer Chen, MD§;
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
Anjali Tiku Owens, MD*; Brian D. McCauley, BS*; Stephen E. Kimmel, MD, MSCE, FAHA*†;
Jeffrey M. Testani, MD, MTR‡
*
Department of Medicine,
dicine,
dici
ine
ne, Ca
C
Cardiovascular
rdio
rd
ddii vascular
l Division,
Di i i n,
n, andd †Depa
Department
p rttme
m nt of Biostati
Biostatistics and
lman
lm
a School
Schoool of
of Medicine
Medicin
ne att the
thee University
Unniv
iver
e siity
er
y of
of Pennsylvania,
Pennsy
Pe
sylv
sy
vania
iaa, Philadelphia,
Epidemiology, Perelman
Pennsylvania. ‡Department
artment of Internal
Intern
nal
a Medicine
Meddiici
c ne
n aand
ndd P
Program
rroogr
gram
m ooff Applied Transl
Translational
l
Research,
Yale University, New
wH
Haven
Haven,
aven
av
en Co
Connecticut
C
Connecticut.
nnec
nn
ecti
ticu
ti
cutt §De
Department
D
part
pa
rttme
ment
nt of
of Internal
Inte
ntern
rnal
all Medicine,
M
Medicine
edi
dici
cine
ci
ne Duke
D
University
School of Medicine, Durham, North Carolina
Correspondence to
Jeffrey M. Testani, M.D, M.T.R.
Yale University School of Medicine
60 Temple Street, Suite 6C
New Haven, CT 06510
Tel: 203-737-6627
Fax: 203-764-8873
Email: [email protected]
DOI: 10.1161/CIRCHEARTFAILURE.112.968230
Journal Subject Codes: [10] Cardio-renal physiology/pathophysiology, [110] Congestive
2
Abstract
Background—Identifying reversible renal dysfunction (RD) in the setting of heart failure (HF) is
challenging. The goal of this study was to evaluate if an elevated admission blood urea nitrogen
to creatinine ratio (BUN/Cr) could identify decompensated HF patients likely to experience
improvement in renal function (IRF) with treatment.
Methods and Results—Consecutive hospitalizations with a discharge diagnosis of HF were
reviewed. IRF was defined as •20% increase and worsening renal function (WRF) •20%
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
decrease in estimated glomerular filtration rate (eGFR). IRF occurred in 31% of the 896 patients
ciated with in-hospital
in ho
h
meeting eligibility criteria. Higher admission BUN/Cr was associated
IRF
ion ppersisting
ersi
er
s st
si
stin
ingg aafter
in
f adjustment
(OR=1.5 per 10 increase, 95% CI: 1.3-1.8, p<0.001), an association
erisstics (OR=1.4,
er
(OR
OR=1
=1
1.4
.4,, 95%
95
5% CI:
C : 1.1-1.8,
CI
1 11.
1 1.8, p=0.004).
p=0
=0.0
004
0 ). However,
Hoowe
weve
ver,
ve
r, higher
hig
ighh admission
for baseline characteristics
s oci
sso
ciat
a ed with
at
witth post-discharge
postt-d
po
-dis
issch
char
arge
ar
ge WRF
WRF ((OR=
OR=
OR
= 1.4,
1 4,
1.
4 95%
95% CI:
CI:: 1.1-1.8,
1.11-1
BUN/Cr was also associated
p=0.011).
wit
ithh an elevated
ele
levvat
ated
ed admission
adm
dmis
issi
is
sion
si
on BUN/Cr,
BUN
UN/C
/Cr,
/C
r, the
the risk
ris
iskk of death
dea
eath
th associated
ass
ssoc
ocii
oc
Notably, in patients with
with RD
(eGFR<45) was substantial (HR=2.2, 95% CI: 1.6-3.1, p<0.001). However, in patients with a
normal admission BUN/Cr, RD was not associated with increased mortality (HR=1.2, 95% CI:
0.67-2.0, p=0.59, p interaction= 0.03).
Conclusions—An elevated admission BUN/Cr identifies decompensated HF patients likely to
experience IRF with treatment, providing proof of concept that reversible RD may be a
discernible entity. However, this improvement appears to be largely transient and RD in the
setting of an elevated BUN/Cr remains strongly associated with death. Further research is
warranted to develop strategies for the optimal detection and treatment of these high-risk patients.
Key Words: heart failure; cardio-renal syndrome; mortality
3
Renal dysfunction (RD) is a common finding in heart failure (HF) and has emerged as one of the
most potent prognostic indicators in these patients.1, 2 However, multiple different mechanisms
capable of initiating a reduction in glomerular filtration rate (GFR) exist in HF and the
mechanism underlying the reduction in GFR likely has important prognostic and therapeutic
implications.3-6 Unfortunately, limited progress has been made with respect to differentiation of
these potential mechanistic subtypes of RD.
The blood urea nitrogen to creatinine ratio (BUN/Cr) has been extensively used in
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
clinical medicine for the differentiation of “pre-renal” RD from intrinsic renal parenchymal
ntra renal mech
mechanisms
cha
ch
disease.7 The discriminative ability of BUN/Cr is based on the intra-renal
governing tubular urea handling. In the setting of a “pre-renal” stressor
tresso
s r su
so
such
ch aass ddehydration,
significant renal neurohormonal
sympathetic
nerve
uroh
ur
ohormo
ona
nall activation
acti
ac
tivvat
ti
atio
ionn (i.e.,
io
(i.e
(i
. .,, iincreases
nccreas
ases
as
ses inn va
vvasopressin,
sopr
so
p es
essi
sin,
si
n rrenal
enal
en
al sy
y
activity, and the renin-angiotensin-aldosterone
i an
in-an
angi
g ot
gi
o en
nsi
s nn--al
aldo
ostteron
ne ax
axis
axis)
iss) ca
causes
ausses a ddisproportionate
isp
spro
r po
port
rtio
rt
i na
io
nate
tee rreabsorption
e
of
8-11
11
urea compared to that
at of ccreatinine.
reat
re
atin
at
inin
in
inee.8-1
in
Similarly,
Simi
Si
mila
mi
larl
la
rly,
rl
y, HF-induced
HFF-in
indu
in
duce
du
cedd RD has
ce
has also
als
lsoo traditionally
trad
tr
adit
ad
itt
been
classified as a “pre-renal” form of RD, and renal neurohormonal activation is hypothesized to
represent a prominent mechanistic contributor to the genesis of this form of RD.12 As such, the
same physiology that allows BUN/Cr to differentiate chronic intrinsic kidney disease from
dehydration should also apply to differentiation of HF-induced RD. Notably, we have recently
reported that BUN/Cr can differentiate clinically important subgroups of RD as evidenced by the
finding that essentially all of the mortality risk attributable to RD is confined to patients with an
elevated BUN/Cr.4
Given that most “pre-renal” forms of RD are reversible if the appropriate treatment is
instituted, it is plausible that some forms of HF-induced RD will also be reversible. The fact that
improvement in renal function (IRF) appears to occur in up to 30% of acutely decompensated
4
HF patients with their return to compensation supports this possibility.13, 14 Given that an
elevated BUN/Cr is often associated with reversible “pre-renal” physiology, we hypothesized
that an elevated admission BUN/Cr would identify patients with reversible HF-induced RD that
would improve with treatment of their decompensated HF. However, given that IRF is transient
in the majority of patients, we additionally hypothesized that despite this potential reversibility
RD in the setting of an elevated BUN/Cr would still be associated with worsened survival.13, 14
The primary aim of this study was to determine if baseline BUN/Cr could identify patients with
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
reversible renal dysfunction and to validate, in the same population, our previous observations
wor
o
that RD in the setting of an elevated BUN/Cr is associated with substantially worsened
survival.
Methods
i ns ffrom
ions
ro
rom
om 20
2004
04 tto
04
o 20
2009
09 tto
o th
thee ca
card
rd
diol
olog
ogyy an
og
aand
d in
inte
tern
te
rnal
rn
a m
al
edi
d ci
ci services at
Consecutive admissions
cardiology
internal
medicine
U
Univ
iver
iv
ersi
er
sity
si
ty
y ooff Pe
Penn
nnsy
nn
syylv
lvan
ania
an
ia wi
with
th a pprimary
rima
ri
mary
ma
ry
y discharge
dis
isch
char
ch
arge
ar
g diagnosis
ge
diag
di
agno
ag
noss of congestive
no
the Hospital of the Un
University
Pennsylvania
heart failure were reviewed. Inclusion required an admission B-type natriuretic peptide (BNP)
level of > 100 pg/mL within 24 hours of admission, a length of stay of 3-14 days, and
availability of serum creatinine and BUN levels. There were 7 patients without admission serum
BUN levels available that met all other inclusion criteria, accounting for the slightly lower
number of patients in this cohort than the parent cohort from which it was derived.13 Patients on
renal replacement therapy or those admitted to interventional cardiology services (to avoid
confounding from contrast nephropathy) were excluded. In the event of multiple hospitalizations
for a single patient, the first admission was retained. Post-discharge renal function was
ascertained in the subset of patients with data available as previously described.13
5
Estimated glomerular filtration rate (eGFR) was calculated using the four variable
Modified Diet and Renal Disease equation.15 Unless otherwise noted, IRF was defined as a
•20% increase at any time during the hospitalization and post discharge worsening renal
function a •20% decrease in eGFR from the discharge to the outpatient value, consistent with
previously published studies of IRF and WRF.3, 5, 6, 13, 14, 16, 17 All-cause mortality was
determined via the Social Security Death Index.18 Loop diuretic doses were converted to
furosemide equivalents with 1 mg bumetanide = 20 mg torsemide = 80 mg furosemide for oral
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
diuretics, and 1 mg bumetanide = 20 mg torsemide = 40 mg furosemide for intravenous diuretics.
h University of
he
The study was approved by the Institutional Review Board of thee Hospital of tthe
Pennsylvania.
Statistical analysis
this analysis
ana
naly
ly
ysi
siss was
was to evaluate
eva
valu
luaate the
lu
the association
ass
ssoc
ocia
oc
iati
ia
tion
ti
on between
bet
etw
wee
eenn ad
admi
miss
mi
sss
The primary goal off this
admission
BUN/Cr and
IRF during treatment of acute decompensated HF. For the purposes of the primary analysis and
unless otherwise specified, BUN/Cr was treated as a continuous covariate. Values reported are
mean ± SD, median (25th – 75th percentile), and percentage. Independent Student’s t test or the
Wilcoxon Rank Sum test was used to compare continuous variables. The Pearson chi-square
was used to evaluate associations between categorical variables. Spearman’s correlation
coefficients were used to examine statistical dependence between two variables. To facilitate
interpretability of the descriptive statistics relating to BUN/Cr, this variable was dichotomized as
• 20 or < 20 (in accordance with common clinical practice) for these analyses. Multivariable
logistic regression analysis was performed to estimate the association between BUN/Cr and IRF
after adjusting for potential confounders. Candidate covariates for the multivariable models
6
were obtained by screening clinical characteristics for an association with IRF at p”0.2.13 Using
backward elimination, any covariate whose removal resulted in a change in the odds ratio for
BUN/Cr >10% was retained in the final model. Additionally, any candidate variable associated
with IRF with p<0.05 was retained in the model, regardless of its influence on the odds ratio.
Covariates that had a p>0.2 but a theoretical basis for potential confounding were manually
forced into and subsequently retained in the final model. Furthermore, covariates associated
with mortality at p” 0.2 were also manually forced into (and retained in) the final model to
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ensure the relationship between BUN/Cr and IRF was not driven by the greater disease severity
eree included in the
er
in patients with either IRF or an elevated BUN/Cr. A total of 24 covariates wer
were
fina
naal model.
mode
mo
del.
de
l Odds
l.
O
first step of model building, and 17 variables were retained in thee final
ratios were
0 in
increase
see iin
nB
UN/C
UN
/Cr.
/C
r. Pr
P
opor
op
o tion
onal
al hhazards
azar
az
aarrrds
dss m
odel
od
elin
el
ingg wa
in
wass uuse to evaluate
reported for every 10
BUN/Cr.
Proportional
modeling
attio
ions
ns with
ns
wit
ithh all-cause
allal
l-ca
c us
usee mortality.
mort
mo
rtaali
rt
lity
t . Candidate
ty
Can
andi
dida
di
date
da
te covariates
cov
ovar
arria
iate
tes entered
te
ente
en
teere
redd in the model
time-to-event associations
var
aria
iate
ia
te aassociations
ssoc
ss
ocia
oc
iattio
ia
ions
ns w
ithh al
it
alll-ca
lcaus
ca
usee mo
us
mort
rtal
rt
alit
al
ityy p ” 00.2
it
.2
2 aand
nd m
od
d building was
were those with univariate
with
all-cause
mortality
model
done analogously to that described above for the logistic regression models. Hazard ratios were
also reported as per 10 increase in BUN/Cr. To examine the effect of BUN/Cr on the association
between eGFR and mortality, Kaplan-Meier curves for death from any cause were plotted for the
4 combinations of groups between patients with and without an elevated BUN/Cr defined as a
BUN/Cr in the highest compared to the lowest quartile (in accordance with prior studies) and
those with and without significant RD (GFR < 45 ml/min/1.73 m2).4 Statistical significance was
determined with the log-rank test. Stratum-specific hazard ratios and 95% confidence intervals
were derived from proportional hazards modeling of the individual strata, and the significance of
the interactions was formally assessed in models incorporating terms for the main effect of renal
function, the main effect of BUN/Cr, and the interaction between these variables. Statistical
7
analyses were performed using Stata 12.0 (Statacorp, College Station, Texas) and statistical
significance was defined as a two-sided p-value <0.05 with the exception of tests of interaction
where significance was defined as a p-value <0.1.
Results
Overall, 896 patients met the inclusion criteria. Thirty-one percent of the population (n=278)
experienced IRF during hospitalization with a mean improvement in eGFR in these patients of
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
43.7 ± 27.2%. The remainder of the cohort experienced a mean improvement in eGFR from
eta
t
admission to the highest eGFR during hospitalization of only 5.3 ± 6.7%. A de
detailed
description
occiaate
t d wi
with
th IRF has
of baseline characteristics, influence of treatment and prognosis assoc
associated
cri
ribbed.133
previously been described.
a eli
ase
line
ne BUN/Cr
ne
BUN
UN/C
/C
Cr in
i the
the cohort
coh
ohor
oh
ortt was
or
w s 18.6
wa
18 6 ± 7.7
7.7
7 with
with
itth a median
medi
me
d an
di
n value
v
The mean baseline
of 17 and
an interquartile range
g of
ge
of 13.3
13.33 to
to 22.2.
22.2.
2 Baseline
Bas
asel
elin
el
inee BUN/Cr
in
BUN
UN/C
/Crr de
/C
demo
demonstrated
mons
mo
nstr
ns
trat
tr
ated
at
ed vvery
eryy we
er
weak
ak
k correlations
with both admission serum creatinine (r=0.071, p=0.03) and eGFR (r=0.18, p<0.001). Baseline
characteristics of patients with and without a BUN/Cr • 20 are shown in Table 1. Notably,
patients with an elevated BUN/Cr were more likely to be white, older, and to have an ischemic
cause for their heart failure. Markers of venous congestion were more prevalent in patients with
an elevated BUN/Cr, including an elevated jugular venous pressure and presence of peripheral
edema. Notably, the elevated BUN/Cr group had multiple baseline indices consistent with
greater heart failure disease severity including lower baseline eGFR, serum sodium, hemoglobin,
and systolic blood pressure, and a higher BNP.
The admission BUN/Cr was significantly associated with IRF (OR=1.5 per 10 increase in
BUN/Cr, 95% CI: 1.3-1.8, p<0.001) (Figure 1). The association between BUN/Cr and IRF was
8
linear across values of BUN/Cr as evaluated graphically with a lowess smoother.19 Patients with
higher BUN/Cr also had a significantly greater likelihood of continuing to meet criteria for IRF
at the time of discharge (OR=1.5, 95% CI: 1.2-1.8, p<0.001). The BUN/Cr remained associated
with IRF after adjustment for baseline eGFR (OR=1.4, 95% CI: 1.2-1.7, p<0.001) and baseline
factors associated with IRF (age, race, hypertension, diabetes, ischemic HF etiology, jugular
venous distention, ejection fraction, systolic blood pressure, loop diuretic dose, ACE or ARB use,
beta blocker use, spironolactone use, thiazide use, nitrate use, BNP level, serum sodium, and
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
serum hemoglobin) (OR=1.4, 95% CI: 1.1-1.8, p=0.004). Results were similar when comparing
ottom quartile,
e, the
t top BUN/Cr
BUN/Cr • 20 to BUN/Cr < 20, the top BUN/Cr quartile vs. the bottom
ian ffor
or bboth
othh th
ot
tthe adjusted and
tertile vs. the bottom tertile, and BUN/Cr above and below the medi
median
(T
2).. Admission
Admi
Ad
miss
mi
sssio
ionn BUN
BUN demonstrated
deemo
ons
nstr
tratted a significant
tr
s gn
si
gnif
ific
if
ican
ic
an
nt univariate
univ
un
iv
unadjusted analyses (Table
2).
F (OR=1.02,
(OR
OR=1
=1.0
02,
2 95%
95%
% CI:
CI:
I 1.01-1.02,
1.0
011-1.
1 02
02, p<
<0.
0 00
001)
1). W
1)
hen
he
en bo
both
h aadmission
dm
dmis
mis
association with IRF
p<0.001).
When
BUN and
i ed ttogether
ined
in
ogget
ethe
herr in a rregression
he
eg
gres
essi
sion
si
on m
odel
od
el aadjusted
djjus
uste
tedd fo
te
forr ad
admi
miss
mi
ssio
ss
ionn eG
io
G
BUN/Cr were examined
model
admission
eGFR,
only
BUN/Cr retained a significant relationship with IRF (BUN/Cr OR=1.4, 95% CI: 1.09-1.82,
p=0.01; BUN OR=1.0, 95% CI: 0.99-1.01, p=0.93).
In the overall population, BUN/Cr increased on average 16.6 ± 40.2% from admission to
discharge (p<0.001). Interestingly, there was not a significant difference in the degree of
increase in BUN/Cr between patients that met criteria for IRF at discharge compared to those
that did not (14.7 ± 39.5% vs. 17.0 ± 40.3% increase, p=0.50). This lack of difference appeared
to be predominantly driven by the fact that patients with IRF had a relatively larger improvement
in serum creatinine (25.0% improvement) compared to their improvement in BUN (13.8%
improvement) ultimately leading to a net worsening in the ratio.
9
Baseline BUN/Cr and post-discharge renal function
The incidence of post-discharge WRF (data available n=452, 50.4% of the population) was
39.2%. Importantly, there was no significant difference between baseline BUN/Cr (18.3 r 7.4 vs.
18.9 r 7.9, p=0.2) or IRF (30.4% vs. 31.5%, p=0.7) in those patients with and without postdischarge data available. Patients with higher baseline BUN/Cr were more likely to experience
post-discharge WRF (OR= 1.4 per 10 increase, 95% CI: 1.1-1.8, p=0.011). Notably, this
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
association was unchanged after adjustment for admission eGFR (OR= 1.4 per 10 increase, 95%
CI: 1.1-1.8, p=0.016), discharge eGFR (OR= 1.4 per 10 increase, 95% CI: 1.1-1.9, p=0.006), or
rea
ease
se in BUN/Cr,
BUN
UN/C
/Crr 95% CI: 1.1/C
the admission to discharge change in eGFR (OR= 1.4 per 10 increase
tren
tr
engt
en
gthh of
gt
o aassociation
1.8, p=0.020). Notably, there was not a significant difference in the sstrength
nd post-discharge
nd
post-di
disc
di
scha
sc
haarg
rgee WRF
WRF between
b tw
be
weenn pa
ati
tien
entss tthat
en
haat didd orr ddid
id
d nnot
ot eexperience in
between BUN/Cr and
patients
r tio
ract
ion=
n=0.96
n=
96).
96
) This
Thiss relationship
relati
re
tiion
onsh
shhip was
a not
as
not detectable
det
eteect
ctab
ble for
for ddischarge
isch
is
ch
h
hospital IRF (p interaction=0.96).
BUN/Cr
rease, 95
5% CI
CI:: 0.
0.99 1.
91 6,
6 pp=0.28),
=0
0.228)
8),, a fi
find
ndin
nd
ingg un
in
nch
chan
ange
an
gedd bby
ge
y adj
djuu
(OR= 1.1 per 10 increase,
95%
0.9-1.6,
finding
unchanged
adjustment
for
admission eGFR (p=0.33), discharge eGFR (p=0.22), or the change in eGFR (p=0.30).
Baseline BUN/Cr, RD, and mortality
Forty-four percent of the population died over a median follow-up of 2.6 years. Baseline
BUN/Cr was significantly associated with increased mortality in this population (HR=1.8 per 10
increase, 95% CI: 1.6-2.0, p<0.001), an association that persisted when adjusted for baseline
eGFR (Table 3). Adjusting for baseline characteristics, chronic medical conditions, medication
use, and admission laboratory data did not eliminate the independent association of increasing
BUN/Cr with mortality (Table 3). Admission eGFR was also significantly associated with
mortality (HR=1.1 per 10 ml/min/1.73 m2 decrease in eGFR, 95% CI: 1.1-1.2, p<0.001), an
10
association which persisted after adjustment for baseline BUN/Cr (HR=1.1 per 10 ml/min/1.73
m2 decrease in eGFR, 95% CI: 1.1-1.2, p<0.001) and baseline characteristics (HR=1.1 per 10
ml/min/1.73 m2 decrease in eGFR, 95% CI: 1.0-1.1, p=0.017). Consistent with our previously
published findings in other populations, there was significant effect modification by BUN/Cr on
the association between eGFR and mortality (p interaction for continuous variables=0.04).4
Notably, in patients with a BUN/Cr in the top quartile, the risk of death associated with
admission eGFR remained significant (HR=1.2, per 10 ml/min/1.73 m2 decrease in eGFR, 95%
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
CI: 1.1-1.3, p<0.001). However, in patients with a BUN/Cr in the bottom quartile, eGFR was no
crease in eGFR,
eGF
FR,
R 95% CI: 0.97longer associated with death (HR=1.0, per 10 ml/min/1.73 m2 decrease
1.1, p=0.25, p interaction=0.029). Consistent with our previously
y pu
published
ubl
blis
ishe
is
hedd fi
he
fin
findings,
nd
nd
this effect
modification was strengthened
for
baseline
characteristics
ren
ren
engthene
n d byy aadjustment
ne
djus
dj
ustm
us
tmen
tm
entt fo
en
or ba
aseli
line
li
ne cha
hara
ha
raact
cteris
isti
is
tiics iincluding
nclu
nc
ludi
lu
d n age, sex, race,
hypertension, coronary
a y aartery
ary
rter
rt
eryy di
er
dis
disease,
sea
ease
s , BN
BNP
BNP,
P, serum
ser
erum
um sodium,
sod
diu
ium
m, systolic
sys
ysto
to
tol
olic blood
blo
lood
od pressure,
preesssu heart rate,
loop diuretic dose, an
angiotensin
converting
a d an
and
angi
giot
gi
oten
ot
ensi
en
sinn co
si
conv
nver
nv
erti
er
ting
ti
ng
g iinhibitor
nhi
hibi
bito
bi
torr or aangiotensin
to
nggio
iote
tens
te
nsin
ns
in rreceptor
ecep
ec
epto
ep
torr bblocker use (p
to
interaction for continuous variables=0.016). Similar results were noted when eGFR was
dichotomized into patients with or without moderate to severe RD (eGFR ” 45 ml/min/1.73 m2)
where the risk associated with RD was substantial in those with a BUN/Cr in the top quartile
(HR=2.2, 95% CI: 1.6-3.1, p<0.001) and undetectable in those with a BUN/Cr in the bottom
quartile (HR=1.2, 95% CI: 0.67-2.0, p=0.59, p interaction=0.03) (Figure 2). Although the risk of
death associated with RD also differed between those with an admission BUN in the top vs.
bottom quartile (p interaction=0.08), when both the interaction between admission BUN and RD
as well as the interaction between admission BUN/Cr and RD were examined in the same model,
only the interaction between BUN/Cr and RD remained significantly associated with mortality (p
interaction BUN/Cr*RD=0.03; p interaction BUN*RD=0.26).
11
Discussion
The primary finding of this study is the strong association between an elevated admission
BUN/Cr and significant improvement in kidney function during the treatment of acute
decompensated HF. Even after adjustment for comorbidities known to impact renal function, as
well as medications that influence GFR, an elevated BUN/Cr at admission continued to be
strongly associated with IRF. However, the IRF observed following standard decompensated HF
treatment was frequently transient, and RD in the setting of an elevated BUN/Cr remained
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
strongly associated with reduced survival. These findings provide proof of concept that not only
ble
le, but this form of
may prospective identification of potentially reversible forms of RD be possib
possible,
ant ca
ccardio-renal
rdio
rd
io
o-r
-ren
enaal
en
al phenotype in HF.
RD appears to represent perhaps the most prognostically important
fundam
men
nta
tall an
andd di
dire
rect
re
ct rrole
olee in ffluid
ol
luid
id aand
nd ssodium
od
diu
i m ho
home
meos
me
osta
os
tasi
ta
s s processes
Urea plays a fu
fundamental
direct
homeostasis,
8 9,
9 20
20,
0 21
21
euro
eu
roho
ro
horm
ho
mon
onal
al sys
ysste
t ms.8,
Ass a re
A
result,
resu
sult
su
lt, during
lt
dduuri
ring
ng ttimes
im
mes
e ooff fluid and
tightly regulated by neu
neurohormonal
systems.
sodium avidity, suchh aass in
intr
intravascular
trav
tr
avas
av
ascu
as
cula
cu
larr volume
la
volu
vo
lume
lu
me ddepletion
epllet
ep
etio
ionn or HF,
io
HF, the
the rate
rat
atee of urea
ure
reaa ex
excretion
x
is
reduced out of proportion to the reduction in GFR, ultimately leading to an elevated BUN/Cr.10,
22
However, with intrinsic renal parenchymal disease, the primary defect leading to RD is
irreversible nephron loss rather than neurohormonal activation. As a result, the rate of urea
clearance is reduced in parallel to the GFR resulting in a normal BUN/Cr. This neurohormonally
mediated disassociation between urea reabsorption and glomerular filtration forms the basis for
the widespread clinical application of BUN/Cr for the differentiation of “pre-renal” RD from
intrinsic renal parenchymal disease. Given the key role for neurohormones in the pathogenesis
of both HF and reversible “pre-renal” forms of RD, this physiology may represent the common
thread linking the finding of reversibility and the increased risk for death.
12
We have previously reported that the majority of patients who experience IRF during the
treatment of decompensated HF actually suffer post-discharge recurrence of the RD.13, 14
Similarly, in the current analysis we found that an elevated admission BUN/Cr was also
associated with an increased incidence of post discharge WRF, independent of the discharge
eGFR or changes in eGFR during hospitalization. These observations allow some speculation as
to how BUN/Cr could identify a form of RD that is potentially reversible but also associated with
significantly increased mortality. Since currently available HF treatments are not capable of
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
increasing renal function to supra-normal levels, for improvement in kidney function to be
st likely etiology
etiolog
ogy being RD
og
possible, reversible RD must be present at baseline (with the most
ere likely
liike
kely
ly “sicker”
“ssic
icke
k r at baseline,
ke
induced by severe HF). Given that patients experiencing IRF were
nt in disease
nt
disea
ease
ea
see severity
sev
ever
eritty is largely
er
lar
a ge
gelly transient,
tran
tr
nsi
sien
ent,, it
en
it iss understandable
und
der
erst
stan
st
an
anda
nda
dabl
ble how an elevated
bl
and the improvement
n ial
nti
ally
ly be
be associated
a so
as
soci
ciiat
a ed with
with reversible
reve
re
vers
ve
rssib
ible
le RD
RD but
but al
also
so w
orseene
or
n d ssurvival.
u
BUN/Cr could potentially
worsened
lsoo pr
ls
prev
evio
ev
ious
io
usly
us
ly
y rreported
ep
por
orte
tedd th
te
that
at in
in the
the few
few patients
p ti
pa
tien
ents
en
ts who
who maintain
mai
aint
ntai
nt
ainn IRF long term,
ai
However, we have aalso
previously
there may actually be improved survival associated with the IRF.13 Although again speculative,
this observation raises the possibility that strategies aimed at inducing and maintaining IRF could
potentially lead to improved outcomes. Markers such as BUN/Cr may allow the prospective
identification of patients with the potential for IRF, facilitating interventional trials that can
actually prove or disprove causality for these highly complex associations.
Despite the above promising proof of concept findings, BUN/Cr is a less than ideal
measure of renal urea handling and is influenced by non-renal factors such as diet and protein
catabolism.23 Furthermore, creatinine based estimates of GFR also have significant limitations
secondary to factors such as the dependence of serum creatinine on muscle mass and tubular
secretion.24 Recently, several novel renal biomarkers such as neutrophil gelatinase-associated
13
lipocalin (NGAL), N-acetyl-beta-D-glucosaminidase (NAG), and kidney injury molecule 1
(KIM-1) have demonstrated high specificity in the detection of acute kidney injury.25
Furthermore, the now widely available filtration marker cystatin C offers the advantage of
limited influence from lean body mass and tubular secretion. It is reasonable to hypothesize that
given the strong signals demonstrable using a crude metric such as BUN/Cr, the aforementioned
renal biomarkers may provide superior discriminative ability.
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
Limitations
preting these rresults.
e
es
There are several limitations that must be considered when interpreting
First, given
tratte and
and re
resi
sidu
si
dua confounding
du
the retrospective study design, causality is impossible to demonstrate
residual
hysiciian
anss we
were
re nnot
ot bblinded
liind
ndeed to
om
easu
ea
sure
su
ress of rrenal
re
en
nal
a ffunction
unct
un
ctio
ct
ionn aand thus may
io
cannot be excluded. P
Physicians
measures
e t decisions
ent
dec
e issio
i ns in response
respo
p nse to these
po
the
h se data.
dat
ata.
a Furthermore,
Furt
Fu
rthe
rt
herm
he
rmor
rm
ore,
or
e ggiven
iven
iv
en
n tthat
h proven
have altered treatment
e t an
ect
ec
andd op
pti
tima
mall
ma
llyy tr
ll
trea
eatt re
ea
reve
vers
ve
rsib
rs
ible
ib
le R
D in tthis
hiss po
hi
ppopulation
p la
pu
lati
tioon wa
ti
wass uunavailable to the
methodology to detect
optimally
treat
reversible
RD
treating physicians, it is highly likely that some patients with reversible RD may have been
refractory to the treatment they received (or possibly received treatment that lead to no
improvement or worsening in renal function) and thus did not experience IRF. This possibility
may have lead to a substantial underestimation of the magnitude of the association between
BUN/Cr and reversible RD. Additionally, non-neurohormonal factors such as diet and protein
catabolism that influence urea reabsorption may have introduced potential uncontrolled
confounding. Given the slow equilibration time and non-renal factors that influence serum
creatinine, assessment of IRF based on creatinine-based eGFR may have also introduced bias.
The analysis of post-discharge renal function suffers from a large degree of missing data, which
is likely missing not at random, and thus may have significant bias inherent to the results. As a
14
result of the above limitations, our findings should be considered hypothesis-generating and
serve primarily to initiate further investigation.
Conclusion
In the setting of decompensated HF, an elevated BUN/Cr identifies patients likely to experience
IRF, providing proof of concept that reversible RD may be a discernible entity. However, the
improved kidney function observed following standard decompensated HF treatment appears to
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
be largely transient and, perhaps as a result, RD in the setting of an elevated BUN/Cr remains
method
od
do
strongly associated with worsened survival. Further research to develop methodology
for the
rant
nted
ed w
ithh th
it
thee goal of
optimal detection and treatment of these high risk patients is warranted
with
improve
veeme
m nt
ntss inn renal
ren
enal
al function
func
fu
n tion
nc
on and
and potentially
pot
oten
enti
en
tial
ti
a ly
y cclinical
lini
li
n ca
ni
call ou
ooutcomes.
utcc
facilitating sustainedd improvements
Soour
S
urce
cess off Funding
Fun
undi
ding
di
ng
Sources
National Institutes of Health grant numbers 5T32HL007891 and 5T32HL007843-15.
Disclosures
None.
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17
Table 1. Baseline characteristics and their association with the blood urea nitrogen to creatinine ratio
BUN/Cr • 20
Overall Cohort
Characteristic
(n=896)
No (n=571)
Yes (n=325)
p-value
62.8 ± 15.8
59.6 ± 16.0
68.5 ± 13.8
<0.001*
White race
33.9%
24.3%
50.8%
<0.001*
Male
54.5%
56.6%
50.8%
0.094
Hypertension
74.1%
75.4%
4%
72.0%
0.268
Diabetes
39.4%
37.3%
3%
43.2%
0.084
Coronary artery disease
sease
se
eas
ase
42.8%
38.7%
38.77%
50.5%
0.001*
Ischemic etiology
24.6%
2
4 6%
4.
%
21.7%
21..7%
%
29.5%
0.009*
Ejection fraction •40%
40%
35.1%
35.1
35
.1
1%
33.9%
33.9
33
. %
37.3%
0.304
Hyperlipidemia
32.2%
32
3
2 2%
29.8%
29
2
9 8%
36.5%
0.040*
Heart rate (beats/min)
89.8 ± 20.0
92.2 ± 20.7
85.5 ± 17.9
<0.001*
Systolic blood pressure (mm
139.1 ± 34.6
146.7 ± 34.7
125.7 ± 30.1
0.004*
Jugular venous distention
35.5%
32.6%
40.3%
0.025*
Moderate to severe edema
15.4%
13.3%
19.2%
0.020*
E-Blocker
67.0%
63.1%
73.9%
0.001*
ACE inhibitor or ARB
61.0%
59.9%
62.8%
0.397
Digoxin
22.5%
18.2%
30.1%
<0.001*
Demographics
Age (y)
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
Medical History
Admission Physical Exam
Hg)
Medications
18
Aldosterone antagonist
15.1%
11.6%
21.1%
<0.001*
Loop diuretic dose (mg)
40 (0, 80)
40 (0, 80)
80 (20, 120)
<0.001*
Thiazide diuretics
11.6%
7.94%
18.0%
<0.001*
Nitrates
16.5%
15.5%
18.3%
0.280
Calcium channel blockers
18.5%
19.2%
17.1%
0.428
Serum sodium (mEq/L)
138.6 ± 4.3
139.1 ± 3.8
137.7 ± 5.0
<0.001*
Hemoglobin (g/dL)
12.2 ± 2.1
12.3 ± 2.1
12.0 ± 2.0
0.032*
1299 (659.0, 2368)
1208 (637.2, 2849)
1479 (738.0, 2848)
0.004*
60.4 ± 28.6
63.2 ± 28.9
28..9
55.6
± 27.4
5
<0.001*
1.5
1.5 ± 1.11
1.5
1 5 ± 1.22
1.
1.5 ± 0.8
0.649
28.3
28.
8 3 ± 20.2
20.22
21.2
21.2
1.2 ± 12.9
1.
12
2.9
40.8
± 24.3
4
<0.001*
Laboratory Values (Baseline)
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
B-Type natriuretic peptide
(pg/mL)
eGFR (mL/min)
Serum creatinine (mg/dL)
mg/dL)
Blood urea nitrogenn (mg/dL)
(mg
mg/d
/d
dL)
L
* Significant p-value. ( ) Represent interquartile ranges. BUN/Cr: blood urea nitrogen to creatinine ratio,
ACE: angiotensin converting enzyme, ARB: angiotensin receptor blocker, eGFR: estimated glomerular
filtration rate.
19
Table 2. Unadjusted and adjusted associations of blood urea nitrogen to creatinine ratio with
IRF by varied definitions of BUN/Cr
Unadjusted
BUN/Cr Definition
Adjusted
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
OR (95% CI)
p-value
OR (95% CI)
p-value
BUN/Cr as a continuous parameter†
1.51 (1.26-1.81)
<0.001*
1.43 (1.12-1.83)
0.004*
BUN/Cr • 20 †
1.86 (1.39-2.49)
<0.001*
1.66 (1.15-2.41)
0.007*
BUN/Cr dichotomized as top quartile
1.72 (1.25-2.37)
<0.001*
1.54 (1.02-2.32)
0.038*
(1.40 2.50)
0
1.86 (1.40-2.50)
<0.001
<0.001*
1 73 (1.19-2.50)
(1 19 2.50
(1
(1.19
2 50
1.73
0.004*
70
0 (1.27-2.26)
(1.27
2 -2
27
2.2
26)
1.70
<0.
0 00
001*
<0.001*
1.4
47 (1.01-2.14)
(1.001-2.
2 14
4
1.47
0.044*
vs. remainder of population
d as topp tertile
BUN/Cr dichotomized
lattion
vs. remainder of population
d as ab
bove vs.
BUN/Cr dichotomized
above
below median
*Significant p-value. BUN/Cr: blood urea nitrogen to creatinine ratio. †OR reported for BUN/Cr as a
continuous covariate are for every 10 increase in BUN/Cr. Adjusted analyses included adjustment for age,
race, hypertension, diabetes, ischemic heart failure etiology, jugular venous distention, ejection fraction,
systolic blood pressure, loop diuretic dose, angiotensin converting enzyme inhibitor or angiotensin
receptor blocker use, ß-blocker use, spironolactone use, thiazide use, nitrate use, brain natriuretic peptide
level, serum sodium, and serum hemoglobin.
20
Table 3. Association between BUN/Cr and All-Cause Mortality
Association
HR (95% CI)
p-value
Unadjusted
1.8 (1.6-2.0)
<0.001
Adjusted for admission eGFR
1.7 (1.5-1.9)
<0.001
Adjusted for baseline characteristics*
1.3 (1.1-1.5)
0.001
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
BUN/Cr: blood urea nitrogen to creatinine ratio, HR: hazard ratio, CI: confidence inte
interval,
erv
r
eGFR:
estimated glomerular filtration rate. BUN/Cr was analyzed as a continuous
uous
us pparameter
aram
ar
am
meter
eterr aand HR are per 10
et
increase in BUN/Cr. *Adjusted
hypertension,
diabetes,
disease,
preserved
*Ad
Adjjusted
Ad
ed for
for age,
age
g , race, hy
ype
p rtenssion, diabet
etes
et
te , coronary
y artery
y di
i
ejection fraction, systolic
loop
diuretic
angiotensin-converting
enzyme
oli
oli
licc blood
d ppressure,
reessu
sure, he
hheart
arrt rate
rrate,
at , lo
oop
p diu
iureetiic ddose,
iu
osee, an
ngi
gioten
enssin
en
n-co
co
onv
v
i receptor blockers
in
rss, E
-blo
-b
lock
lo
cker
ck
errs, ddigoxin,
ig
gox
oxin
in,, th
in
thia
azi
zid
de and spironolacto
o use, serum
inhibitor or angiotensin
blockers,
E-blockers,
thiazide
spironolactone
sodium, hemoglobin, B-type
B t pe natriuretic
natri
n
attrii rretic
eti
tic peptide
pepti
tid
ti
de level
llee ell and
andd admission
ad
dmiission
i GFR.
G
GFR
FR
21
Figure Legends
Figure 1. Incidence of improvement in renal function during hospitalization with a
progressively higher baseline blood urea nitrogen to creatinine ratio (BUN/Cr). IRF:
improvement in renal function. BUN/Cr: blood urea nitrogen to creatinine ratio. IRF defined as
a •20% improvement in glomerular filtration rate. Test for trend p < 0.001.
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
Figure 2. Kaplan-Meier survival curves grouped by blood urea nitrogen
oge to
o ccreatinine
e
ratio
(BUN/Cr) and renal dysfunction. eGFR: estimated glomerular filtration
iltraati
tion rrate.
tion
ate.
at
e. BU
B
BUN/Cr:
U
blood
atin
at
inine ra
atio.
o BU
BUN/
N/Cr
N/
Cr ddichotomized
ichot
ch
hot
o om
mized
d aass th
thee to
op vs
s. bo
bbottom
tttom qquartile.
u
urea nitrogen to creatinine
ratio.
BUN/Cr
top
vs.
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
The Blood Urea Nitrogen to Creatinine Ratio Identifies a High Risk but Potentially Reversible
Form of Renal Dysfunction in Patients with Decompensated Heart Failure
Meredith A. Brisco, Steven G. Coca, Jennifer Chen, Anjali Tiku Owens, Brian D. McCauley, Stephen
E. Kimmel and Jeffrey M. Testani
Downloaded from http://circheartfailure.ahajournals.org/ by guest on November 18, 2016
Circ Heart Fail. published online January 16, 2013;
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