RESEARCH ARTICLE
High plasma esis in associa es wi h se e e
acu e kidney inju y in Puumala han a i us
in ec ion
Paula S. Man ulaID
1
*, Tuula K. Ou inen
1
, Pia Jaa inen
2,3
, Ma i Ha
¨ma
¨la
¨inen
4
,
Heini Huh ala
5
, Ilkka H. Po
¨ s i
1,2
, An i Vahe i
6
, Jukka T. Mus onen
1,2
, Sa u M. Ma
¨kela
¨
1,2
1Tampe e Uni e si y Hospi al, Depa men o In e nal Medicine, Tampe e, Finland, 2Facul y o Medicine
and Li e Sciences, Uni e si y o Tampe e, Tampe e, Finland, 3Di ision o In e mal Medicine, Seina
¨joki
Cen al Hospi al, Seina
¨joki, Finland, 4The Immunopha macology G oup, Facul y o Medicine and Li e
Sciences, Uni e si y o Tampe e and Tampe e Uni e si y Hospi al, Tampe e, Finland, 5Facul y o Social
Sciences, Uni e si y o Tampe e, Tampe e, Finland, 6Depa men o Vi ology, Medicum, Uni e si y o
Helsinki, Helsinki, Finland
*paula.man [email protected]
Abs ac
Backg ound
Puumala han a i us (PUUV) in ec ed pa ien s ypically su e om acu e kidney inju y (AKI).
Adipokines ha e in lamma ion modula ing unc ions in acu e diseases including AKI. We
examined plasma le els o h ee adipokines ( esis in, lep in, and adiponec in) in acu e
PUUV in ec ion and hei associa ions wi h disease se e i y.
Me hods
This s udy included 79 pa ien s hospi alized due o acu e PUUV in ec ion. Plasma esis in,
lep in, adiponec in, as well as IL-6 and CRP, we e measu ed a he acu e phase, eco e y
phase and one yea a e hospi aliza ion.
Resul s
Plasma esis in le els we e signi ican ly highe in he acu e phase compa ed o he eco e y
phase and one yea a e (median esis in 28 pg/mL (11–107) s. 17 pg/mL (7–36) s. 14
pg/mL (7–31), p<0.001). Maximum esis in concen a ion co ela ed wi h maximum plasma
c ea inine le els ( = 0.63; p<0.001). The highe he amoun o albuminu ia in he u ine dip-
s ick es (0–1+, 2+ o 3+) a admission, he highe he median o maximum esis in (24.7 pg/
mL, 25.4 pg/mL and 39.6 pg/mL, espec i ely, p = 0.002). High esis in was also an indepen-
den isk ac o o se e e AKI (c ea inine �353.6μmol/L) (OR 1.08, 95% CI 1.02–1.14). Nei-
he plasma lep in no adiponec in le el had any co ela ion wi h c ea inine concen a ion o
he amoun o albuminu ia.
Conclusions
Plasma esis in independen ly associa es wi h he se e i y o AKI in acu e PUUV in ec ion.
The associa ion o esis in wi h he amoun o albuminu ia sugges s ha he le el o plasma
PLOS ONE | h ps://doi.o g/10.1371/jou nal.pone.0208017 Decembe 5, 2018 1 / 14
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OPEN ACCESS
Ci a ion: Man ula PS, Ou inen TK, Jaa inen P,
Ha¨ma¨la¨inen M, Huh ala H, Po¨ s i IH, e al. (2018)
High plasma esis in associa es wi h se e e acu e
kidney inju y in Puumala han a i us in ec ion. PLoS
ONE 13(12): e0208017. h ps://doi.o g/10.1371/
jou nal.pone.0208017
Edi o : Joe g La us, Robe Bosch K ankenhaus,
GERMANY
Recei ed: May 18, 2018
Accep ed: No embe 9, 2018
Published: Decembe 5, 2018
Copy igh : ©2018 Man ula e al. This is an open
access a icle dis ibu ed unde he e ms o he
C ea i e Commons A ibu ion License, which
pe mi s un es ic ed use, dis ibu ion, and
ep oduc ion in any medium, p o ided he o iginal
au ho and sou ce a e c edi ed.
Da a A ailabili y S a emen : All ele an da a a e
wi hin he manusc ip and i s Suppo ing
In o ma ion iles.
Funding: This s udy was inancially suppo ed by
he Compe i i e S a e Resea ch Financing o he
Expe Responsibili y A ea o Tampe e Uni e si y
Hospi al (JM and SM), Tampe e Tube culosis
Founda ion (JM), Sig id Juse
´lius Founda ion (JM),
Magnus Eh n oo h Founda ion (JM), and he
Finnish Kidney Founda ion (PM). The unde s had
no ole in s udy design, da a collec ion o analysis,
esis in is no only in luenced by enal clea ance bu could ha e some ole in he pa hogene-
sis o AKI du ing PUUV in ec ion.
In oduc ion
Puumala i us (PUUV) belongs o he amily o han a i uses and i is sp ead by he bank ole
(Myodes gla eolus). In humans, PUUV causes an illness known as Neph opa ia Epidemica
(NE) [1]. In Finland, housands o se ologically con i med diagnoses a e made annually and
he numbe o in ec ed humans pa allels he popula ion o he bank ole. The disease is ans-
mi ed by inhaling dus con amina ed by PUUV-in ec ed bank ole eces o u ine [2].
The cha ac e is ic mani es a ion o PUUV in ec ion is a mild o m o hemo hagic e e
wi h enal synd ome (HFRS) [3,4]. Al hough many o he diagnosed pa ien s need hospi al
ea men , he majo i y o he in ec ions a e asymp oma ic o cause only mild and ansien
symp oms and hus emain undiagnosed [5]. In a Finnish coho , 83% o hospi al- ea ed
pa ien s had acu e kidney inju y (AKI) [6]. This synd ome has a good p ognosis: kidney unc-
ion e u ns o no mal in p ac ically all pa ien s by suppo i e he apy and he mo ali y is low,
a ound 0,1% [6,7]. Se e al long- e m neph ological, ca dio ascula and endoc inological con-
sequences ha e, howe e , been desc ibed a e PUUV in ec ion [5].
P o einu ia and hema u ia a e ypical u ina y indings in he ea ly phase o he in ec ion.
P o einu ia is o en o neph o ic ange (>3g/day) and esol es apidly. I migh be a sign o
change in he ba ie unc ion o he glome ula ascula u e [7]. The his ological inding is
acu e ubuloin e s i ial neph i is while glome ula changes a e minimal [8]. Immunohis o-
chemical s udies e eal abno mali ies p e e en ially in he ubuli and pe i ubula a eas, whe e
in il a ing cells consis o plasma cells, monocy es/mac ophages, eosinophils and neu ophils.
A he same si e, he exp ession o umo nec osis ac o (TNF)-αas well as endo helial adhe-
sion molecules in e cellula adhesion molecule (ICAM)-1 and ascula cell adhesion molecule
(VCAM)-1 a e seen, as a sign o endo helial cell ac i a ion [9].
Fac o s a ec ing he se e i y o PUUV in ec ion emain mos ly unclea , bu hos gene ic
ac o s ha e an in luence [10]. In lamma o y ma ke s ha e been shown o inc ease du ing
acu e PUUV in ec ion, including plasma and u ina y in e leukins (ILs) IL-6, IL-1β, IL1
ecep o an agonis , TNF-α, and soluble u okinase- ype plasminogen ac i a o ecep o , as
well as plasma pen axin-3 and u ina y gela inase-associa ed lipocalin (NGAL) [11–15]. Pa -
icula ly u ina y IL-6 and u ina y NGAL [12,16] ha e been ound o associa e wi h he
se e i y o AKI. The associa ion o widely used C- eac i e p o ein (CRP) wi h se e e AKI in
PUUV in ec ion is less clea [17] [12]. We ha e p e iously ound ha he amoun o p o ein-
u ia and hema u ia in dips ick sample a he acu e phase is associa ed wi h he se e i y o
AKI in NE pa ien s [18,19]. The peak o p o einu ia seems o p ecede he mos se e e phase
o AKI [18].
Adipokines—also called adipocy okines—a e bioac i e molecules i s ound o be sec e ed
by adipose issue, and o egula e appe i e and ene gy me abolism. Mo e ecen ly, adipokines
ha e been disco e ed o be p oduced by many o he cell ypes, pa icula ly by in lamma o y
cells, and o egula e in lamma o y esponses [20]. In e es ingly, plasma esis in changes ha e
been epo ed in acu e in ec ions [21,22] and AKI [23].
In he p esen s udy, ou aim was o de e mine he adipokines adiponec in, lep in and esis-
in in PUUV in ec ion, and examine hei associa ions wi h he se e i y o acu e PUUV in ec-
ion and he concomi an AKI.
Resis in in Puumala han a i us induced acu e kidney inju y
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decision o publish, o he p epa a ion o he
manusc ip .
Compe ing in e es s: The au ho s ha e decla ed
ha no compe ing in e es s exis .
Ma e ials and me hods
The s udy coho o iginally consis ed o 86 consecu i e pa ien s wi h acu e, se ologically con-
i med PUUV in ec ion ea ed a he Tampe e Uni e si y Hospi al in Finland, du ing Jan
2005-No 2014. Plasma samples o adipokine measu emen s we e a ailable in 79 pa ien s and
hese pa ien s comp ised he inal s udy coho . De ailed medical his o y was ob ained and
physical examina ion was pe o med du ing he acu e phase o he disease. All pa ien s p o-
ided a w i en in o med consen and he s udy was app o ed by he E hics Commi ee o
Tampe e Uni e si y Hospi al (R04180, R09206).
Acu e PUUV in ec ion was con i med om a single se um sample by de ec ing he ypical
g anula s aining pa e n in immuno luo escence assay [24], and/o low a idi y o IgG an i-
bodies o PUUV [25], and/o by de ec ing PUUV IgM an ibodies by an ‘in-house’ enzyme-
linked immunoso ben assay (ELISA) based on a ecombinan an igen [26].
Plasma samples o he measu emen o esis in, lep in and adiponec in concen a ions as
well as CRP and IL-6 le els we e collec ed be ween 7:30–8:30 am, a median o 2 (1–5) imes
du ing he acu e phase. The highes o he lowes alues (as app op ia e) o he a ious a i-
ables measu ed du ing he hospi al s ay we e designa ed as he maximum o minimum alues.
The ollow-up samples we e ob ained a median o 15 ( ange 7–21) days a e discha ge om
hospi al in 74 pa ien s, and a one yea a e hospi aliza ion in 67 pa ien s. Plasma esis in, lep-
in, adiponec in, CRP and IL-6 concen a ions we e measu ed by an enzyme-linked immuno-
so ben assay (ELISA) using eagen s om R&D Sys ems Eu ope L d, Abingdon, UK ( esis in,
lep in, adiponec in and CRP) and om eBioscience Inc, San Diego, CA, USA (IL-6). The
de ec ion limi and in e assay coe icien o a ia ion we e 15.6 pg/mL and 8.5% o esis in,
15.6 pg/mL and 5.3% o lep in, 15.6 pg/mL and 6.0% o adiponec in, 3.9 pg/mL and 5.7% o
CRP, and 0.39 pg/mL and 4.8% o IL-6. Fo adiponec in, he es de ec s o al adiponec in.
Plasma c ea inine was measu ed daily du ing hospi aliza ion, median 5 (2–13) measu e-
men s pe pa ien , by a Cobas In eg a (F. Ho man- La Roche L d., Basel, Swi ze land). A u ine
dips ick es was pe o med on admission o hospi al. The u ine dips ick analysis was pe -
o med by au oma ed es s based on e ac ome y (Siemens Clini ec A las o Ad an us). The
sensi i i y o hese semi-quan i a i e dips ick es s o u ine albumin (1+) anges 0.15–0.3 g/l.
The dips ick esul 2+ indica es >1 g/l albumin, and he esul 3+ >3 g/l albumin. Assay o
hema u ia de ec s heme pseudope oxidase ac i i y and he e o e i de ec s ed cell cas s and
dysmo phic ed cells also. The sensi i i y o he assay is abou 10 x 10
6
cells/L (abou 3–5 cells
by high powe ield).
Se e e AKI was de ined as maximum plasma c ea inine le el �353.6 μmol/L du ing hospi-
aliza ion (s age 3, acco ding o KDIGO de ini ion) [22]. The amoun o hou ly u ine ou pu
was no eco ded. He e, shock is de ined by a all in sys olic blood p essu e unde 90 mmHg
wi h clinical symp oms o shock. Body mass index (BMI) was calcula ed as he a io o weigh
(kg) o squa ed heigh (m
2
).
S a is ical analyses
The da a is p esen ed as medians and anges o con inuous a iables and numbe s and pe -
cen ages o ca ego ical a iables. G oups we e compa ed using he Mann–Whi ney U es o
he K uskal-Wallis es , as app op ia e. Co ela ions we e calcula ed by he Spea man ank
co ela ion es . Rela ed samples we e compa ed using he Wilcoxon signed ank es o he
F iedman es , as app op ia e. A ecei e ope a ing cha as e is ic (ROC) cu es we e d awn in
o de o e alua e which o he maximum le els o a ious in lamma o y ma ke s could ac as
he bes indica o o se e e AKI (plasma c ea inine �353.6 μmol/L). A logis ic eg ession anal-
ysis was pe o med wi h age, sex, BMI, dips ick-albuminu ia class (0/1+,2+ and 3+) and
Resis in in Puumala han a i us induced acu e kidney inju y
PLOS ONE | h ps://doi.o g/10.1371/jou nal.pone.0208017 Decembe 5, 2018 3 / 14
maximum plasma esis in le el as independen ac o s o examine he associa ion o hese ac-
o s wi h se e e AKI. Adjus ed odds a ios (OR) and hei 95% con idence in e als (95% CI)
a e gi en. The goodness o i was assessed wi h Hosme Lemeshow s a is ic. All es s we e
wo-sided, and p- alues <0.05 we e conside ed s a is ically signi ican . The SPSS s a is ical
so wa e package (IBM SPSS S a is ics e sion 23.0 A monk, NY, USA) was used o all
analyses.
Resul s
The clinical cha ac e is ics and labo a o y indings o he pa ien s a e lis ed in Table 1. The
median leng h o hospi al s ay was 6 days. The median age was 41 yea s ( ange 21–74) and 48
(61%) o he pa ien s we e males. The ollowing diagnoses had been made be o e he acu e
PUUV in ec ion in 24 (30%) pa ien s: hype ension (n = 7), as hma/ch onic obs uc i e pul-
mona y disease (n = 4), gas i is/ e lux disease (n = 4), heuma oid a h i is (n = 3), co ona y
a e y disease (n = 2), ype 2 diabe es (n = 2), ype 1 diabe es (n = 1), and ansien ischemic
a ack (n = 1). Some o he pa ien s had mo e han one disease, bu none had a known kidney
disease o ch onic enal insu iciency.
The ele a ion o plasma c ea inine le el abo e 100 μmol/L was de ec ed in 56 (70%)
pa ien s. Se e e AKI (c ea inine �353.6 μmol/L) occu ed in 25 (32%) pa ien s. One pa ien
needed ansien dialysis ea men and wo pa ien s su e ed om a clinical shock on admis-
sion o hospi al. All o he pa ien s eco e ed. The median o he maximum plasma c ea inine
a he acu e phase was 186 μmol/L ( ange 51–1499) (Table 1). A he eco e y phase (15 days
a e hospi aliza ion) and one yea a e he acu e in ec ion, he median o c ea inine was
78 μmol/L ( ange 55–184) and 71 μmol/L ( ange 53–123) espec i ely.
The changes in plasma adipokine, IL-6 and CRP le els in he acu e phase o PUUV in ec-
ion, compa ed o he eco e y phase and one yea a e hospi aliza ion, a e p esen ed in
Table 2. and Fig 1. The median ime o he i s adipokine measu emen om he onse o
e e was 7 days ( ange 3–14). The esis in le els (Fig 1A) we e signi ican ly highe and lep in
Table 1. Clinical and labo a o y indings in 79 pa ien s hospi alized due o acu e Puumala han a i us in ec ion.
Finding Median Range
Age (yea s) 41 21–74
Body mass index, n = 72 (kg/m
2
) 26 18–37
Du a ion o e e (days) 8 4–15
Leng h o hospi al s ay (days) 6 2–14
Sys olic blood p essu e on admission (mmHg) 126 72–182
Change in body weigh du ing hospi al s ay (kg) 2 0–11
Plasma c ea inine max (μmol/L) 186 51–1499
Hema oc i max 0.44 0.33–0.60
Pla ele s min (x10
9
/L) 52 5–150
Plasma sodium min (mmol/L) 130 109–139
Plasma po assium max (mmol/L) 4.2 3.3–5.3
Plasma albumin min (g/L) 25 18–34
Leukocy es max (x10
9
/L) 10.8 4.2–45.0
IL-6 max (ρg/mL) 11.8 1.6–66.6
CRP max (ρg/mL) 57 8–199
Min, minimum alue du ing hospi al s ay; max, maximum alue du ing hospi al s ay; IL-6, In e leukin-6; CRP, C-
eac i e p o ein
h ps://doi.o g/10.1371/jou nal.pone.0208017. 001
Resis in in Puumala han a i us induced acu e kidney inju y
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le els (Fig 1B) signi ican ly lowe in he acu e phase, compa ed o hose measu ed in he eco -
e y phase o one yea a e he acu e illness. The e was also a sligh bu s a is ically signi ican
dec ease in adiponec in le el in he acu e phase compa ed o he eco e y phase o one yea
a e he acu e illness (Fig 1C).
The co ela ions o maximum plasma esis in concen a ion, minimum plasma adiponec in
and minimum plasma lep in wi h clinical and labo a o y a iables in he acu e phase o PUUV
in ec ion a e shown in Table 3. The high esis in le el co ela ed wi h highe maximum plasma
c ea inine concen a ion. The median o maximum esis in was signi ican ly highe in pa ien s
wi h c ea inine le el >100 μmol/L compa ed o hose wi h maximum c ea inine �100 μmol/
L ( esis in 32 ρg/mL, ange 11–107 s. 21 ρg/mL, ange 11–42, p<0.001). The maximum esis-
in alues also co ela ed wi h many o he a iables e lec ing disease se e i y (Table 3). In e -
es ingly, he highes measu ed esis in alue o his coho (107 pg/mL) was de ec ed in one o
he wo pa ien s wi h a clinical shock. The changes in he o he wo adipokines, minimum adi-
ponec in and minimum lep in didn’ ha e any clea co ela ions wi h he clinical disease se e -
i y ma ke s in PUUV in ec ion (Table 3).
The maximum plasma c ea inine le el measu ed du ing he hospi al s ay, didn’ ha e any
co ela ion wi h BMI ( = 0.145;p = 0.223). The minimum plasma lep in concen a ion had a
weak co ela ion wi h BMI ( = 0.350; p = 0.003) bu no wi h maximum c ea inine alues
(Table 3).
P o einu ia on hospi al admission (de ined as u ine albumin dips ick es �2+) was
de ec ed in 54 (68%) pa ien s. Hema u ia (�2+ in u ine dips ick es ) was de ec ed in 34 (43%)
o he pa ien s. When analyzing he amoun o p o einu ia ca ego ized by dips ick albuminu ia
0/1+, 2+ o 3+ a he acu e phase, he maximum esis in le el was signi ican ly highe in
pa ien s wi h albuminu ia 3+ han in pa ien s wi h 0/1+ o 2+ albuminu ia (Table 4). The
o he adipokines s udied we e no associa ed wi h dips ick-albuminu ia. When combining
albuminu ia and hema u ia indings in he u ine dips ick es (0–2+, 3–4+ o 5–6+), he highe
he combined posi i e esul , he highe was he maximum plasma esis in concen a ion
(Table 4).
We gene a ed ecei e ope a ing cu es (ROC) o he maximum plasma esis in, IL-6 and
CRP le els, as well as o he maximum leukocy e coun , in he acu e phase o disc imina e
upcoming se e e AKI (c ea inine �353.6 μmol/L) om non-se e e AKI (Fig 2). Resis in was a
s onge disc imina o wi h a ea unde ROC cu e (AUROC) o 0.82 (95%CI 0.70–0.91,
p<0.001) when compa ed wi h leukocy e coun (AUROC 0.74, 95% CI 0.62–0.87; p = 0.001).
IL-6 o CRP did no disc imina e se e e AKI om non-se e e AKI (AUROC 0.55, 95% CI
0.40–0.70; p = 0.493 and AUROC 0.39, 95% CI 0.26–0.51; p = 0.105, espec i ely).
Table 2. The le els o plasma adipokines ( esis in, lep in, adiponec in), and o he ma ke s o in lamma ion (leukocy es, plasma IL-6, CRP) in he acu e phase o
Puumala han a i us in ec ion compa ed o he eco e y phase and one yea a e he in ec ion.
Acu e phase�(n = 79) Reco e y phase (n = 74) A e 1 yea (n = 67) p- alue
median ange median ange median ange
Resis in (ρg/mL) 28 11–107 17 7–36 14 7–31 <0.001
Lep in (ρg/mL) 5.3 1.2–48.4 12.2 1.6–68.7 12.1 1.8–84.0 <0.001
Adiponec in (ρg/mL) 3.76 0.23–10.66 4.07 0.62–10.25 4.36 0.80–13.49 <0.001
Leukocy es (x10
9
/L) 10.8 4.2–44.4 7.6 3.7–14.5 6.7 3.7–11.4 <0.001
IL-6 (ρg/mL) 11.8 1.7–66.6 1.2 0.4–12.5 0.9 0.4–15.9 <0.001
CRP (ρg/mL) 57.3 8.4–198.5 1.7 0.2–36.0 1.3 0.1–13.2 <0.001
IL-6, in e leukin-6; CRP, C- eac i e p o ein. P- alue s ands o he di e ences be ween he h ee phases.
�Acu e phase alues a e maximum ( esis in, leukocy es, IL-6, CRP) o minimum (lep in, adiponec in)
h ps://doi.o g/10.1371/jou nal.pone.0208017. 002
Resis in in Puumala han a i us induced acu e kidney inju y
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Resis in in Puumala han a i us induced acu e kidney inju y
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We pe o med a logis ic eg ession analysis o e alua e he associa ions o age, gende ,
BMI, dips ick albuminu ia and plasma esis in le el wi h se e e AKI (Table 5). In a uni a ia e
model, male gende , dips ick albuminu ia o 3+, and maximum esis in le el we e all associ-
a ed wi h se e e AKI. In he mul i a iable analysis only male gende and maximum plasma
esis in le el we e ound o be independen isk ac o s o se e e AKI.
Discussion
The p esen s udy shows ha plasma esis in concen a ions a e ele a ed in he acu e phase o
PUUV han a i us in ec ion. High esis in le els co ela ed wi h he se e i y o AKI, as well as
wi h se e al o he ma ke s e lec ing he se e i y o he disease. High plasma esis in le els
du ing he acu e in ec ion also associa ed wi h p onounced albuminu ia and hema u ia
de ec ed wi h u ine dips ick es a hospi al admission. Plasma esis in showed an independen
in luence on se e e AKI.
Resis in was i s desc ibed in 2001 when i was ound o be p oduced by adipose issue and
p omo e insulin esis ance in mice [27]. Fu he s udies showed ha in humans, esis in is
mainly p oduced by leukocy es, especially mac ophages, and i s con ibu ion o he de elop-
men o insulin esis ance emains unclea [28,29]. The ole o esis in as an in lamma o y ac-
o s a ed o be un a eled by he ea ly inding ha injec ion o bac e ial lipopolysaccha ide
(LPS) in o heal hy olun ee s caused a ise in ci cula ing esis in le els [30]. Speci ic ecep o s
o esis in ha e no been iden i ied, bu i belongs o he endogenous ligands o he in lamma-
ion igge ing oll-like ecep o 4 (TLR-4) [31]. Acco dingly, esis in is associa ed wi h an
a ay o in lamma o y diseases including sepsis, in lamma o y bowel disease, a h i is and
as ma [32,33]. We ha e p e iously ound esis in as a con ibu ing ac o and bioma ke
in ol ed in os eoa h i is [34], heuma oid a h i is [35], in lamma o y lung diseases [36,37]
and ischemia- epe usion synd ome associa ed wi h ca diac su ge y [38]. In e es ingly, esis in
seems also o be p oduced by umo s / umo associa ed mac ophages. Fo ins ance, esis in
was ecen ly epo ed as a p edic i e ac o o he ecu ence and long- e m p ognosis in
enal cell cance [39]. Fu he mo e, plasma esis in le els ha e been ound o be signi ican ly
highe in pa ien s wi h sep ic shock and AKI, when compa ed wi h pa ien s wi h sep ic shock
wi hou AKI, and i was ound o modula e he in lamma o y esponse in hose pa ien s [23].
Fig 1. Plasma esis in (A), lep in (B), and adiponec in (C) le els du ing acu e Puumala han a i us (PUUV)
in ec ion, in he eco e y phase, and one yea a e he hospi aliza ion. Median ( hick line inside box), 25 h-75 h
pe cen iles (box), ange (whiske s), and ou lie s (�).
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Table 3. Co ela ions o plasma esis in concen a ion wi h clinical and labo a o y ma ke s o disease se e i y in acu e Puumala han a i us in ec ion.
Resis in maximum, p- alue Adiponec in minimum, p- alue Lep in minimum, p- alue
Du a ion o hospi al s ay 0.507 <0.001 0.004 0.970 0.142 0.213
Sys olic blood p essu e on admission -0.257 0.022 -0.240 0.033 -0.103 0.368
Change in body weigh du ing hospi al s ay 0.433 <0.001 -0.017 0.888 0.002 0.988
C ea inine max 0.633 <0.001 0.029 0.802 -0.044 0.700
Pla ele s min -0.254 0.024 -0.085 0.456 0.106 0.352
Sodium min -0.368 0.001 -0.015 0.895 0.241 0.032
Po assium max 0.369 0.001 -0.004 0.971 0.038 0.742
Leukocy es max 0.520 <0.001 0.060 0.600 -0.078 0.495
IL-6 max 0.329 0.003 -0.270 0.016 -0.160 0.160
CRP max -0.071 0.536 -0.457 <0.001 -0.034 0.763
max, maximum; min, minimum; CRP,C- eac i e p o ein; IL-6, in e leukin-6
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The e a e a ew s udies in es iga ing he signi icance o esis in in o he acu e i us in ec-
ions. Plasma esis in was ele a ed in he ea ly phase o acu e Dengue e e , bu associa ions
wi h kidney unc ion o o he disease se e i y ma ke s we e no epo ed [22]. In pa ien s wi h
C imean-Congo hemo hagic e e , caused by ick-bo ne i us, plasma esis in was ele a ed
and highe concen a ions associa ed wi h se e e disease, de ined by he mani es a ions o
bleeding. Resis in had a nega i e co ela ion wi h pla ele coun , bu i did no ha e a co ela-
ion wi h plasma c ea inine. The kidney unc ion o hese pa ien s was epo ed o be almos
no mal and AKI was no add essed [40].
Table 4. Plasma esis in le els in di e en ca ego ies o u ine dips ick albuminu ia and hema u ia in 79 pa ien s
wi h Puumala han a i us in ec ion.
U ine dips ick albumin Resis in max
median (pg/mL)
ange
0–1+ (n = 25) 24.7 11.6–90.7
2+ (n = 24) 25.4 11.9–80.4 p = 0.002
3+ (n = 30) 39.6 11.1–107.3
U ine dips ick albumin+e y h ocy es
0–2+ (n = 26) 22.2 11.6–90.7
3–4+ (n = 35) 27.1 11.1–80.4 p<0.001
5–6+ (n = 18) 42.7 16.8–107.3
p- alue s ands o he di e ences be ween he h ee g oups
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Fig 2. Recei e ope a ing cha ac e is ic (ROC) cu es o plasma esis in and di e en plasma in lamma o y
ma ke s (maximum C- eac i e p o ein, maximum in e leukin-6, and maximum leukocy e coun ) in p edic ing
se e e acu e kidney inju y (plasma c ea inine �353.6 μmol/L) du ing acu e Puumala han a i us in ec ion.
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The plasma esis in ele a ion in PUUV in ec ion could be a sign o in lamma ion as p e i-
ously shown in sepsis [21]. Plasma esis in is ele a ed in pa ien s wi h sep ic shock [41,42]. In
he p esen s udy, only wo pa ien s su e ed om clinical shock, one o hem ha ing he high-
es plasma esis in concen a ion o his coho . Fu he mo e, high esis in le el co ela ed
wi h low sys olic blood p essu e a admission. The clinical shock synd ome in PUUV in ec ion
is ela ed o an inc eased ascula pe meabili y, which p obably has a ole also in he pa hogen-
esis o he neph o ic- ange p o einu ia [7].
In adul in ensi e ca e uni (ICU) pa ien s, esis in was supe io o CRP in dis inguishing
sepsis om sys emic in lamma o y esponse (SIRS) due o auma wi hou in ec ion, and he
le el o esis in was signi ican ly highe in sepsis compa ed o auma ela ed SIRS [43]. In ICU
pa ien s, high esis in was shown o associa e wi h wo se long- ime-su i al in non-sep ic
pa ien s, maybe as a sign o conside able ha m o excessi e in lamma o y esponse [44]. We
ha e p e iously epo ed ha plasma CRP poo ly co ela es wi h disease se e i y in PUUV in ec-
ion compa ed o plasma IL-6 [12]. This inding was consolida ed by he p esen s udy, whe e
he ise in CRP did no associa e wi h se e e AKI and he ROC cu es didn’ show any diagnos-
ic abili y o CRP o ind se e e AKI. In he ROC cu es maximum plasma esis in le el had he
bes diagnos ic accu ancy o indica e se e e AKI compa ed o leukocy es, IL-6 and CRP.
Many ma ke s o in lamma ion a e al e ed du ing acu e PUUV in ec ion, bu no much is
known abou hei ela ionship wi h p o einu ia, which in u n seems o ha e a clea associa-
ion wi h disease se e i y [18]. Inc eased capilla y leakage seems o con ibu e o he amoun
o p o einu ia du ing acu e PUUV in ec ion [18,45], and some in lamma ion ma ke s may
ha e a mo e p onounced e ec on his han o he s. Resis in has been p e iously ela ed o as-
cula pe meabili y and endo helial ac i a ion. In eme gency depa men pa ien s wi h sepsis,
esis in and NGAL co ela ed wi h he exp ession o he endo helial cell adhesion molecules
(VCAM-1, ICAM-1) [42] and we e associa ed wi h sep ic shock, bu no wi h mo ali y [41].
Any possible associa ion wi h AKI was no discussed.
Plasma le els o adiponec in did no show any associa ion wi h maximum c ea inine alues
o albuminu ia in hospi al- ea ed pa ien s in he p esen s udy. Low plasma adiponec in had,
howe e , nega i e co ela ion o in lamma o y ma ke s CRP and IL-6. Adiponec in is a
Table 5. Mul i a ia e logis ic eg ession analysis o isk ac o s o se e e AKI (plasma c ea inine �353.6 μmol/L) among 79 hospi alized pa ien s wi h acu e Puu-
mala han a i us in ec ion.
Uni a ia e Mul i a iable
No se e e AKI
n = 54
Se e e AKI
n = 25
OR 95% CI OR 95% CI
Median ( ange) Median ( ange)
Age (yea s) 42 (22−67) 39 (21−74) 0.99 0.96−1.03 1.00 0.95−1.06
Sex (n)
Female 28 3 1 1
Male 26 22 7.90 2.11−29.54 6.73 1.16−38.90
BMI (kg/m
2
) n = 72 25.8 (18.5−37.0) 26.2 (22.6−32.3) 1.04 0.91−1.18 1.00 0.81−1.23
Albumin dips ick (n)
0–1+ 22 3 1 1
2+ 20 4 1.47 0.29−7.37 0.81 0.10−6.70
3+ 12 18 11.00 2.69−45.06 4.61 0.76−28.08
Resis in max (ρg/mL) 25.0 (11.6−52.6) 45.0 (11.0−107.3) 1.10 1.05−1.154 1.08 1.02−1.14
Max = maximum, min = minimum, IL-6 = in e leukin-6, CRP = C- eac i e p o ein.
Mul i a iable analysis Hosme —Lemeshow es p = 0.591
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