31.05.

2013

Association between Plasma Neutrophil Gelatinase Associated Lipocalin Level and Obstructive Sleep Apnea or Nocturnal Intermittent Hypoxia

Association between Plasma Neutrophil Gelatinase Associated Lipocalin Level and Obstructive Sleep Apnea or Nocturnal Intermittent Hypoxia
Kimihiko Murase, Kiyoshi Mori, [...], and Kazuo Chin

Abstract
Background
Bot h obst r u ct iv e sleep a pn ea (OSA ) a n d a n ov el lipoca lin , n eu t r oph il g ela t in a se a ssocia t ed lipoca lin (Ng a l), h a v e been r epor t ed t o be closely lin k ed w it h ca r diov a scu la r disea se a n d loss of k idn ey fu n ct ion t h r ou g h ch r on ic in fla m m a t ion . How ev er , t h e r ela t ion sh ip bet w een OSA a n d Ng a l h a s n ev er been in v est ig a t ed.

Objectives
T o ev a lu a t e t h e r ela t ion sh ip bet w een Ng a l a n d OSA in clin ica l pr a ct ice.

Methods
In 1 0 2 pa t ien t s, poly som n og r a ph y w a s per for m ed t o dia g n ose OSA a n d pla sm a Ng a l lev els w er e m ea su r ed. T h e cor r ela t ion s bet w een Ng a l lev els a n d OSA sev er it y a n d ot h er clin ica l v a r ia bles w er e ev a lu a t ed. Of t h e 4 6 pa t ien t s w h o beg a n t r ea t m en t w it h con t in u ou s posit iv e a ir w a y pr essu r e (CPA P), Ng a l lev els w er e r eev a lu a t ed a ft er t h r ee m on t h s of t r ea t m en t in 2 5 pa t ien t s.

Results
T h e Ng a l lev el cor r ela t ed sig n ifica n t ly w it h OSA sev er it y a s det er m in ed by t h e a pn ea h y popn ea in dex (r = 0 .2 4 , p = 0 .0 1 ) a n d 4 % ox y g en desa t u r a t ion in dex (ODI) (r = 0 .2 6 , p = 0 .0 1 ). Mu lt iple r eg r ession a n a ly sis sh ow ed t h a t t h e Ng a l lev el w a s a ssocia t ed w it h 4 %ODI in depen den t ly of ot h er clin ica l v a r ia bles. Com plia n ce w a s g ood in 1 3 of t h e 2 5 pa t ien t s w h o u sed CPA P. A lt h ou g h t h e OSA (4 %ODI: 3 3 .1 1 6 .7 t o 1 .1 1 .9 /h , p<0 .0 1 ) h a d sig n ifica n t ly im pr ov ed in t h ose w it h g ood com plia n ce, t h e Ng a l lev els w er e n ot sig n ifica n t ly ch a n g ed (6 0 .5 1 8 .1 befor e CPA P v s 6 4 .2 1 3 .9 n g /m l a ft er CPA P, p = 0 .2 7 ).

Conclusions
Pla sm a Ng a l lev els w er e posit iv ely a ssocia t ed w it h t h e sev er it y of OSA . How ev er , t h e con t r ibu t ion r a t e of OSA t o sy st em ic Ng a l secr et ion w a s sm a ll a n d ch a n g es in Ng a l lev els a ppea r ed t o be in flu en ced la r g ely by ot h er con fou n din g fa ct or s. T h er efor e, it does n ot seem r ea son a ble t o u se t h e Ng a l lev el a s a specific biom a r k er of OSA in clin ica l pr a ct ice.

Introduction
Neu t r oph il g ela t in a se a ssocia t ed lipoca lin (Ng a l), a lso k n ow n a s lipoca lin 2 , is a 2 5 -k Da secr et or y g ly copr ot ein t h a t w a s or ig in a lly iden t ified in h u m a n n eu t r oph ils. T h is pr ot ein w a s or ig in a lly k n ow n a s a n in n a t e im m u n it y a n t iba ct er ia l fa ct or r elea sed by a ct iv a t ed n eu t r oph ils. [1 ], [2 ] It h a s a lso becom e k n ow n t o be pr odu ced by r en a l t u bu la r cells in r espon se t o differ en t t y pes of in ju r y . [3 ] Ba sed on ex per im en t a l a n d clin ica l fin din g s, Ng a l is w idely con sider ed a s a n ex cellen t in dica t or of a cu t e a n d ch r on ic k idn ey in ju r y .[3 ][7 ] Mor eov er , beca u se t h is pr ot ein is a lso r elea sed by en dot h elia l cells a n d fa ilin g m y oca r diu m , a close r ela t ion sh ip bet w een blood Ng a l lev els a n d h ea r t fa ilu r e or ca r diov a scu la r disea ses h a s been su g g est ed.[8 ][1 0 ]. Obst r u ct iv e sleep a pn ea (OSA ) is a h ig h ly pr ev a len t disor der , a ffect in g a bou t 4 2 0 % of a du lt s a n d is
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Association between Plasma Neutrophil Gelatinase Associated Lipocalin Level and Obstructive Sleep Apnea or Nocturnal Intermittent Hypoxia

ch a r a ct er ized by r epet it iv e episodes of pa r t ia l or com plet e obst r u ct ion of t h e u pper a ir w a y du r in g sleep a ssocia t ed w it h t r a n sien t ox y g en desa t u r a t ion .[1 1 ][1 3 ] A ccu m u la t in g clin ica l ev iden ce su g g est s t h a t OSA is a n in depen den t r isk fa ct or for ca r diov a scu la r disea se a n d loss of k idn ey fu n ct ion t h r ou g h n oct u r n a l h y pox ia a n d ch r on ic in fla m m a t ion .[1 4 ][1 7 ] Fr om a n in v it r o m odel of OSA , it w a s su g g est ed t h a t t h e pr o-in fla m m a t or y t r a n scr ipt ion fa ct or , n u clea r fa ct or -k a ppa B (NF- B), pla y s a n im por t a n t r ole in t h e in fla m m a t or y pr ocess of a cells r ea ct ion t o in t er m it t en t h y pox ia /r eox y g en a t ion . [1 8 ] Mea n w h ile, it h a s been r epor t ed t h a t sev er a l in fla m m a t or y st im u li, su ch a s in t er leu k in 1 , st im u la t e sy st em ic Ng a l ex pr ession a n d secr et ion . NF- B a lso h a s been sh ow n t o t r a n sa ct iv a t e Ng a l ex pr ession , su g g est in g t h a t Ng a l m ig h t be in v olv ed in in fla m m a t or y r espon ses. [1 9 ], [2 0 ]. T h er efor e, a posit iv e cor r ela t ion bet w een OSA sev er it y a n d sy st em ic Ng a l secr et ion t h r ou g h ch r on ic in fla m m a t ion seem s possible. How ev er , t h is r ela t ion sh ip h a s n ev er been in v est ig a t ed. T h u s, w e h y pot h esized t h a t blood Ng a l lev els a r e elev a t ed in pa t ien t s w it h OSA a n d t h a t it s lev els a r e m odified by t h e t r ea t m en t of OSA w it h con t in u ou s posit iv e a ir w a y pr essu r e (CPA P). In t h e pr esen t st u dy , w e m ea su r ed pla sm a Ng a l lev els in pa t ien t s w it h OSA a n d ev a lu a t ed it s u t ilit y in clin ica l pr a ct ice.

Methods
Subjects
St u dy pa t ien t s w er e con secu t iv ely r ecr u it ed fr om t h e Sleep Un it of Ky ot o Un iv er sit y Hospit a l bet w een Ja n u a r y 2 0 0 9 a n d Ma y 2 0 1 2 . A ll h a d been r efer r ed t o ou r sleep u n it u n der su spicion of OSA w it h sy m pt om s su ch a s h a bit u a l sn or in g or da y t im e sleepin ess. Non e h a d been pr ev iou sly dia g n osed w it h or t r ea t ed for OSA . Pa t ien t s w it h ov er t r en a l fa ilu r e (ser u m cr ea t in in e >1 .3 m g /dl) or w it h a n y h ist or y of ca r diov a scu la r disea ses, h ea r t fa ilu r e or a r r h y t h m ia w er e ex clu ded beca u se sev er e r en a l a n d/or h ea r t fa ilu r e ca n dir ect ly a ffect pla sm a Ng a l lev els. A lso ex clu ded w er e pa t ien t s w it h pu lm on a r y disea ses, ch r on ic in fect ion , h ist or y of ca n cer or colla g en disea se. Sin ce a con sen su s a bou t t h e r ela t ion sh ip bet w een Ng a l lev els a n d m et a bolic sy n dr om e h a s n ot y et been for m ed, w e a im ed t o ev a lu a t e t h e cor r ela t ion s bet w een r isk fa ct or s for m et a bolic sy n dr om e a n d pla sm a Ng a l lev els in a ct u a l clin ica l pr a ct ice. W e did n ot ex clu de pa t ien t s w it h com pon en t s of m et a bolic sy n dr om e su ch a s h y per t en sion , dia bet es a n d dy slipidem ia ev en if t h ey w er e u n der t r ea t m en t for t h ese com or bidit ies.[2 1 ][2 3 ] T h is st u dy w a s a ppr ov ed by Ky ot o Un iv er sit y Gr a du a t e Sch ool a n d Fa cu lt y of Medicin e Et h ics Com m it t ee, a n d w r it t en in for m ed con sen t w a s obt a in ed fr om a ll pa t ien t s.

Polysomnography and CPAP Implementation

T h e dia g n osis of OSA w a s con fir m ed by poly som n og r a ph y (Som n oSt a r pr o, Ca r din a l Hea lt h , Du blin , OH, USA or A lice 4 , Ph ilips Respir on ics, In c., Mu r r y sv ille, PA , USA ), w h ich w a s st a r t ed a t 2 2 :0 0 a n d en ded a t 6 :0 0 t h e follow in g m or n in g . Su r fa ce elect r odes w er e a t t a ch ed u sin g st a n da r d t ech n iqu es t o obt a in a n elect r oocu log r a m , elect r om y og r a m of t h e ch in a n d 1 2 -lea d elect r oen ceph a log r a ph . Sleep st a g es w er e defin ed a ccor din g t o t h e cr it er ia of Rech t ch a ffen a n d Ka les. [2 4 ] V en t ila t ion w a s m on it or ed by in du ct iv e plet h y sm og r a ph y (Respit r a ce QDC, V ia sy s Hea lt h ca r e, Pa lm Spr in g s, CA , USA ). A ir flow w a s m on it or ed by a n a sa l pr essu r e t r a n sdu cer a n d su pplem en t ed by a n or on a sa l t h er m a l sen sor . A r t er ia l ox y g en sa t u r a t ion (SpO 2) w a s m on it or ed con t in u ou sly w it h a pu lse ox im et er . A pn ea w a s defin ed a s t h e con t in u ou s cessa t ion of a ir flow for m or e t h a n 1 0 secon ds a n d h y popn ea w a s defin ed a s a r edu ct ion in a ir flow of 3 0 % or m or e la st in g for 1 0 secon ds or m or e a ccom pa n ied by a decr ea se in SpO 2 of a t lea st 4 %. [2 5 ] A pn ea -h y popn ea in dex (A HI) v a lu es w er e ca lcu la t ed a s t h e n u m ber of episodes of a pn ea a n d h y popn ea per h ou r ov er t h e t ot a l sleep t im e. 4 % ox y g en desa t u r a t ion in dex (ODI) v a lu es w er e defin ed a s t h e n u m ber of desa t u r a t ion s 4 % per h ou r of sleep.
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Association between Plasma Neutrophil Gelatinase Associated Lipocalin Level and Obstructive Sleep Apnea or Nocturnal Intermittent Hypoxia

T h e len g t h of t im e SpO 2<9 0 % du r in g sleep w a s ca lcu la t ed in ea ch pa t ien t . Pa t ien t s w it h cen t r a l sleep a pn ea w er e ex clu ded. OSA sev er it y w a s defin ed by t h e A HI a s follow s: n on OSA (A HI<5 ), m ild OSA (5 A HI<1 5 ), m oder a t e OSA (1 5 A HI<3 0 ) a n d sev er e OSA (3 0 A HI). Pa t ien t s w it h a n A HI 1 5 w er e ca n dida t es for n a sa l CPA P. T h ose w h o a g r eed w it h CPA P im plem en t a t ion u n der w en t a secon d poly som n og r a ph y w it h CPA P t it r a t ion . W e im plem en t ed CPA P w it h t h e a u t o a dju st in g posit iv e a ir w a y pr essu r e (PA P) fu n ct ion for a ll pa t ien t s. Ba sed on t h e secon d sleep st u dy , m in im u m a n d m a x im u m PA P w er e det er m in ed t o a bolish a ll r espir a t or y ev en t s, a r ou sa l a n d desa t u r a t ion ev en t s.

Follow-Up
A t t h e t h r ee-m on t h follow -u p, w e u r g ed t h e pa t ien t s t o u n der g o a t h ir d sleep st u dy t o con fir m w h et h er a n a dju st m en t of t h e CPA P set t in g w a s n ecessa r y . T o in v est ig a t e t h e effect of CPA P t r ea t m en t on pla sm a Ng a l lev els, a t t h e t h ir d sleep st u dy blood sa m ples w er e collect ed in t h e sa m e w a y a s a t t h e fir st sleep st u dy . W e a lso ch eck ed u se t im e of t h e CPA P m a ch in e by r ea din g t h e t im e cou n t er on t h e CPA P m a ch in es. Sim ila r t o pr ior st u dies, w e defin ed g ood com plia n ce a s t h e u se of CPA P for >4 h per n ig h t on >7 0 % of n ig h t s a n d ca t eg or ized t h e pa t ien t s in t o t w o g r ou ps, t h ose w it h g ood com plia n ce or poor com plia n ce. [2 6 ] W e a n a ly zed t h e da t a sepa r a t ely for ea ch g r ou p a n d com pa r ed clin ica l v a r ia bles befor e a n d a ft er CPA P t r ea t m en t .

Blood Sampling and Measurement of Plasma Ngal Level

Blood sa m ples w er e dr a w n a t 7 :0 0 in t h e m or n in g a ft er t h e su bject s h a d fa st ed beg in n in g a t 2 0 :0 0 t h e pr ev iou s n ig h t . Blood sa m ples w er e cen t r ifu g ed im m edia t ely a t 3 ,0 0 0 r pm a t 4 C for 1 0 m in . T h e sepa r a t ed sa m ples w er e st or ed 8 0 C u n t il a ssa y . Pla sm a Ng a l con cen t r a t ion s w er e det er m in ed by a n ELISA k it pr ov ided by Biopor t o Dia g n ost ics, Gen t oft e, Den m a r k . In t r a - a n d in t er -a ssa y coefficien t s of v a r ia t ion for Ng a l w er e 1 .2 4 .0 % a n d 2 .2 1 1 .2 %, r espect iv ely .

Definition of Metabolic Syndrome

In cla ssify in g pa t ien t s ba sed on t h e com pon en t s of m et a bolic sy n dr om e, w e u t ilized Ja pa n ese cr it er ia . [2 7 ] W a ist cir cu m fer en ce (W C) w a s m ea su r ed a t t h e lev el of t h e n a v el w it h t h e pa t ien t st a n din g , a n d v iscer a l fa t a ccu m u la t ion w a s det er m in ed t o be posit iv e a t W C 8 5 cm for m en a n d 9 0 cm for w om en . A dia g n osis of m et a bolic sy n dr om e r equ ir ed t h e su bject t o h a v e v iscer a l fa t a ccu m u la t ion a n d 2 or 3 of t h e follow in g : (a ) dy slipidem ia (t r ig ly cer ides 1 5 0 m g /dL a n d/or h ig h den sit y lipopr ot ein ch olest er ol lev el <4 0 m g /dL, or specific t r ea t m en t for t h ese lipid a bn or m a lit ies); (b) h y per t en sion (sy st olic blood pr essu r e 1 3 0 m m Hg a n d/or dia st olic blood pr essu r e 8 5 m m Hg , or t r ea t m en t of pr ev iou sly dia g n osed h y per t en sion ); a n d (c) h y per g ly cem ia (fa st in g pla sm a g lu cose 1 1 0 m g /dL or specific t r ea t m en t for dia bet es m ellit u s). A n t h r opom et r ic pa r a m et er s a n d blood pr essu r e w er e m ea su r ed im m edia t ely a ft er poly som n og r a ph y r ecor din g en ded.

Statistical Analysis
In t h e a n a ly sis of da t a , w e cla ssified t h e pa t ien t s depen din g on t h e sev er it y of OSA a n d com pa r ed t h eir clin ica l ba ck g r ou n ds. W e a lso com pa r ed pla sm a Ng a l lev els bet w een pa t ien t s w it h a n d w it h ou t ea ch com pon en t of m et a bolic sy n dr om e t o in v est ig a t e t h e r ela t ion sh ips bet w een pla sm a Ng a l lev els a n d m et a bolic sy n dr om e. Da t a w er e ex pr essed a s m ea n s st a n da r d dev ia t ion . T h e sig n ifica n ce of in t er g r ou p differ en ces ba sed on t h e sev er it y of OSA w a s det er m in ed by a n a n a ly sis of v a r ia n ce. W h en a sig n ifica n t differ en ce w a s fou n d, w e u sed t h e T u k ey s h on est ly sig n ifica n t differ en ce pr ocedu r e t o iden t ify w h er e t h e differ en ce w a s sig n ifica n t . A ch i-squ a r e t est a n d t h e Ma n n -W h it n ey U t est w er e u sed t o com pa r e ca t eg or ica l a n d con t in u ou s v a r ia bles, r espect iv ely . W e u sed Pea r son s coefficien t t est s t o ev a lu a t e t h e r ela t ion sh ip bet w een t h e pla sm a Ng a l lev el a n d ot h er con t in u ou s v a r ia bles. Ba sed on t h e r esu lt s of t h is a n a ly sis, m u lt iple r eg r ession a n a ly ses w er e
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Association between Plasma Neutrophil Gelatinase Associated Lipocalin Level and Obstructive Sleep Apnea or Nocturnal Intermittent Hypoxia

per for m ed t o cla r ify t h e con t r ibu t ion r a t e of OSA a n d ot h er com or bidit ies t o sy st em ic Ng a l secr et ion . W ilcox on sig n ed r a n k t est w a s u sed t o com pa r e clin ica l v a r ia bles befor e a n d a ft er CPA P t r ea t m en t . T w o-t a iled p-v a lu es <0 .0 5 w er e con sider ed st a t ist ica lly sig n ifica n t . A ll st a t ist ica l a n a ly ses w er e per for m ed u sin g JMP 7 .0 .2 st a t ist ica l soft w a r e (SA S In st it u t e In c., Ca r y , NC, USA ).

Results
Baseline Characteristics of Study Patients
A t ot a l of 1 0 2 pa t ien t s w er e st u died, a n d t h eir ba selin e ch a r a ct er ist ics a r e sh ow n in t a ble 1 .T h ose w it h sev er e OSA w er e ch a r a ct er ized by a sig n ifica n t ly h ig h er body m a ss in dex (BMI) t h a n in t h e ot h er t h r ee g r ou ps. T h e per cen t a g es of pa t ien t s w h o fu lfilled t h e cr it er ion for v iscer a l fa t a ccu m u la t ion in cr ea sed a s t h e sev er it y of OSA in cr ea sed. Ot h er a n t h r opom et r ic pa r a m et er s w it h sig n ifica n t differ en ces a m on g t h e g r ou ps a r e a lso sh ow n in t a ble 1 . W it h t h e ex cept ion of t h e pa r a m et er s for OSA , t h er e w er e n o sig n ifica n t differ en ces a m on g t h e fou r g r ou ps in ot h er clin ica l ba ck g r ou n d fa ct or s. (T a bles 1 a n d 2 ).
Tab l e 1
Baseline characteristics and data on metabolic syndrome and its components in study patients.

Tab l e 2
OSA parameters and laboratory profiles.

Plasma Ngal Levels in Patients at Diagnosis and follow up

T a ble 2 sh ow s ba selin e pla sm a Ng a l lev els in t h e fou r g r ou ps, w it h n o st a t ist ica lly sig n ifica n t differ en ces fou n d a m on g t h em . How ev er , sim ple lin ea r r eg r ession a n a ly sis sh ow ed sig n ifica n t cor r ela t ion s of t h e pla sm a Ng a l lev el w it h t h e follow in g pa r a m et er s of OSA : A HI (r = 0 .2 4 , p = 0 .0 1 ), 4 %ODI (r = 0 .2 6 , p = 0 .0 1 ) a n d t im e of SpO 2<9 0 % (r = 0 .2 3 , p = 0 .0 2 ). (Fig u r e 1 ) T h e pla sm a Ng a l lev el w a s a lso cor r ela t ed w it h v a lu es for ser u m low den sit y lipopr ot ein (LDL) ch olest er ol (r = 0 .3 1 , p<0 .0 1 ), t r ig ly cer ides (r = 0 .2 4 , p = 0 .0 1 ) a n d cr ea t in in e (r = 0 .3 4 , p<0 .0 1 ). On t h e ot h er h a n d, n on e of a n t h r opom et r ic pa r a m et er s a n d pa r a m et er s a ssocia t ed w it h dia bet es su ch a s fa st in g pla sm a g lu cose a n d HbA 1 c lev els sh ow ed sig n ifica n t cor r ela t ion s w it h Ng a l lev els.(T a ble 3 ) Fu r t h er m or e, in t h e pr esen t coh or t , sig n ifica n t differ en ces w er e n ot fou n d in pla sm a Ng a l lev els bet w een pa t ien t s w it h a n d w it h ou t ea ch of t h e com pon en t s of m et a bolic sy n dr om e. (T a ble 4 ).

Fi gur e 1
Simple correlations between plasma neutrophil gelatinase associated lipocalin (Ngal) levels and parameters of obstructive sleep apnea.

Tab l e 3
Simple correlations between plasma neutrophil gelatinase associated (Ngal) levels and clinical variables.

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Association between Plasma Neutrophil Gelatinase Associated Lipocalin Level and Obstructive Sleep Apnea or Nocturnal Intermittent Hypoxia

Tab l e 4
Plasma Ngal levels in patients with and without each component of metabolic syndrome.

For t h e m u lt iple r eg r ession a n a ly sis, w e ch ose 4 %ODI a s t h e r epr esen t a t iv e v a r ia ble for OSA sev er it y a s it h a d t h e best cor r ela t ion w it h t h e Ng a l lev el a m on g OSA pa r a m et er s in t h e sim ple cor r ela t ion a n a ly sis. T h e a n a ly sis dem on st r a t ed t h a t 4 %ODI w a s a ssocia t ed w it h t h e Ng a l lev el in depen den t ly of cr ea t in in e a n d LDL-ch olest er ol lev els. T h e con t r ibu t ion r a t e of 4 % ODI t o t h e Ng a l lev el w a s 6 .2 % (T a ble 5 ).
Tab l e 5
Multiple regression analyses using plasma neutrophil gelatinase associated lipocalin (Ngal) level as a dependent variable.

CPA P w a s im plem en t ed for 4 6 of t h e 5 0 pa t ien t s w it h m oder a t e or sev er e OSA . Of t h e 4 6 pa t ien t s, 2 7 a g r eed t o a follow -u p sleep st u dy . Ju st befor e t h e r eev a lu a t ion , ca r dia c m edicin e w a s pr escr ibed for on e pa t ien t a n d a n u pper a ir w a y in fect ion w a s fou n d in a n ot h er pa t ien t . T h ese t w o pa t ien t s w er e ex clu ded fr om t h e a n a ly sis, a n d t h e r em a in in g 2 5 pa t ien t s w er e r eev a lu a t ed. T h ir t een w er e ca t eg or ized in t o t h e g ood com plia n ce g r ou p a n d t h e ot h er 1 2 pa t ien t s in t o t h e poor com plia n ce g r ou p. T h ose in t h e g ood com plia n ce g r ou p w er e sig n ifica n t ly older t h a n pa t ien t s in t h e poor com plia n ce g r ou p. T h e det er m in ed m a x im u m a n d m in im u m PA P did n ot differ bet w een t h e t w o g r ou ps. A ft er CPA P im plem en t a t ion , OSA w a s sig n ifica n t ly im pr ov ed in bot h g r ou ps. In t h e g ood com plia n ce g r ou p, despit e im pr ov em en t s in OSA , n o sig n ifica n t ch a n g e w a s n ot ed in pla sm a Ng a l lev els fr om v a lu es befor e CPA P u se. Fu r t h er m or e, in t h e poor com plia n ce g r ou p, Ng a l lev els w er e sig n ifica n t ly elev a t ed a ft er CPA P im plem en t a t ion . T h er e w er e n ot sig n ifica n t differ en ces in t h e ot h er con fou n din g fa ct or s befor e a n d a ft er CPA P t r ea t m en t (T a ble 6 ).

Tab l e 6
Changes in clinical variables from baseline to after CPAP implementation.

Discussion
In t h is cr oss sect ion a l ev a lu a t ion , a lt h ou g h sig n ifica n t differ en ces in pla sm a Ng a l lev els w er e n ot fou n d a m on g g r ou ps cla ssified a ccor din g t o t h e sev er it y of OSA , pa r a m et er s of OSA , su ch a s 4 %ODI a n d A HI per se, cor r ela t ed w it h pla sm a Ng a l lev els in r eg r ession a n a ly sis. T h is su g g est s t h a t OSA con t r ibu t es, a lt h ou g h w ea k ly , t o elev a t ed pla sm a Ng a l lev els t h r ou g h n oct u r n a l h y pox ia . Beca u se it h a s been r epor t ed t h a t h y pox ia in du ces a n elev a t ion in pla sm a Ng a l lev els in a n ex per im en t a l a n im a l m odel, it is possible t h a t OSA in du ces Ng a l elev a t ion t h r ou g h n oct u r n a l in t er m it t en t h y pox ia . [2 8 ] T o t h e best of ou r k n ow ledg e, t h is is t h e fir st r epor t t o ev a lu a t e t h e r ela t ion sh ip bet w een t h e Ng a l pr ot ein lev el a n d OSA sev er it y in clin ica l pr a ct ice. T h e r ela t ion sh ip bet w een a n ot h er pr ot ein in t h e lipoca lin fa m ily a n d OSA h a s been in v est ig a t ed. Ma k in o et a l a n d Nen a et a l, r espect iv ely , in v est ig a t ed t h e r ela t ion sh ip bet w een t h e pla sm a lev el of r et in ol bin din g pr ot ein 4 (RBP-4 ), w h ich a lso belon g s t o t h e lipoca lin pr ot ein fa m ily , a n d OSA . [2 9 ],
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[3 0 ] How ev er , n eit h er st u dy fou n d a cor r ela t ion bet w een RBP-4 lev els a n d a pn ea -r ela t ed in dices. A lt h ou g h bot h Ng a l a n d RBP-4 belon g t o t h e lipoca lin fa m ily a n d sh a r e a com m on t er t ia r y st r u ct u r e, t h ese t w o pr ot ein s a ppea r t o h a v e differ en t pa t t er n s of r eg u la t ion in r espon se t o in fla m m a t or y m edia t or s. [2 1 ], [2 3 ]. Ou r r esu lt s a lso dem on st r a t ed a sig n ifica n t in v er se cor r ela t ion bet w een Ng a l a n d LDL ch olest er ol lev els. W a llen iu s et a l a lso r epor t ed su ch a n in v er se cor r ela t ion in t h eir epidem iolog ica l st u dy . [2 1 ] How ev er , in ot h er st u dies, cor r ela t ion s bet w een t h ese t w o v a r ia bles w er e n ot fou n d. [2 3 ], [3 1 ], [3 2 ] A lt h ou g h t h is in v er se cor r ela t ion is possible, t h e r esu lt s seem t o v a r y depen din g on t h e clin ica l ch a r a ct er ist ics of t h e ex a m in ed coh or t s. Fu r t h er m or e, t h e m ech a n ism s of t h is cor r ela t ion r em a in u t t er ly u n k n ow n . T h e r ela t ion sh ip bet w een Ng a l a n d m et a bolic sy n dr om e is qu it e con t r ov er sia l. W h er ea s W a n g et a l a n d Y a n et a l r epor t ed a close a ssocia t ion bet w een Ng a l a n d obesit y or in su lin r esist a n ce, W a llen iu s et a l fou n d n o cor r ela t ion bet w een t h ese r isk fa ct or s. [2 1 ], [2 2 ], [3 1 ] Ou r r esu lt s did n ot sh ow a n y sig n ifica n t cor r ela t ion bet w een Ng a l lev els a n d obesit y or dia bet ic in dices. A lso, in t h e pr esen t coh or t t h er e w er e n o sig n ifica n t differ en ces in Ng a l lev els bet w een pa t ien t s w it h a n d w it h ou t m et a bolic sy n dr om e. T h ese r esu lt s a lso seem t o depen d on t h e clin ica l ch a r a ct er ist ics of t h e coh or t s. Specifica lly , w e did n ot ex clu de pa t ien t s u n der t r ea t m en t for m et a bolic sy n dr om e t o in v est ig a t e t h e u t ilit y of t h e pla sm a Ng a l lev el in a ct u a l clin ica l pr a ct ice. Beca u se it w a s r epor t ed t h a t t h e ph a r m a ceu t ica l t r ea t m en t of dia bet es a n d dy slipidem ia ca n ch a n g e pla sm a Ng a l lev els, t r ea t m en t of m et a bolic sy n dr om e in ou r coh or t possibly a ffect ed t h e r esu lt s. [3 1 ], [3 3 ] Fu r t h er m or e, in m ost of t h ese st u dies, r en a l fu n ct ion w a s n ot t a k en in t o a ccou n t a s a n ex pla n a t or y v a r ia ble of t h e Ng a l lev el. Risk fa ct or s for m et a bolic sy n dr om e in du ce la t en t r en a l fu n ct ion im pa ir m en t a n d ev en a su bt le ch a n g e in r en a l fu n ct ion is k n ow n t o a ffect blood a n d u r in a r y Ng a l lev els. [3 4 ] Gia g in is et a l r epor t ed t h a t pla sm a Ng a l lev els w er e h ig h er in pa t ien t s w it h t h a n w it h ou t h y per t en sion a n d t h ey specu la t ed t h a t t h e a ssocia t ion bet w een elev a t ed Ng a l lev els a n d h y per t en sion is secon da r y t o t h e con fou n din g effect of r en a l im pa ir m en t . [3 5 ] In ou r st u dy , ev en t h ou g h w e did n ot in clu de pa t ien t s w it h ov er t r en a l fa ilu r e, t h e pla sm a Ng a l lev els cor r ela t ed sig n ifica n t ly w it h ser u m cr ea t in in e lev els. T h er efor e, in ev a lu a t in g t h e dir ect lin k bet w een m et a bolic sy n dr om e a n d Ng a l lev els, st a t ist ica l cor r ect ion for r en a l fu n ct ion seem t o be n ecessa r y . In fa ct , Liu et a l r epor t ed t h a t t h e sig n ifica n t cor r ela t ion bet w een Ng a l a n d in su lin r esist a n ce det ect ed in t h eir st u dy coh or t disa ppea r ed a ft er a dju st m en t for ser u m cr ea t in in e v a lu es. [3 2 ]. Con t r a r y t o ou r ex pect a t ion , pla sm a Ng a l lev els did n ot ch a n g e ev en w it h t h e a ppr opr ia t e u se of CPA P t h a t effect ed a n im pr ov em en t in OSA . W e cou ld n ot con fir m a dir ect ca u sa lit y bet w een Ng a l lev els a n d OSA . A lt h ou g h w e ba sed t h e t h r ee-m on t h t r ea t m en t obser v a t ion per iod on ex per ien ces in pr ev iou s st u dies, w e m ig h t n eed a n ex t en ded per iod t o fin d m or e r em a r k a ble ch a n g es in Ng a l lev els in t h e pr esen t coh or t . [2 3 ], [3 1 ]. Ng a l lev els w er e elev a t ed a ft er CPA P im plem en t a t ion in pa t ien t s w it h poor com plia n ce w it h CPA P. Beca u se w e did n ot in clu de a n a ct u a l con t r ol g r ou p t h a t did n ot u se CPA P, w e cou ld n ot ju dg e w h et h er t h e ch a n g e in Ng a l lev els w a s ca u sed by in com plet e CPA P u se or ot h er r ea son s. A lt h ou g h w e t ook ev er y con ceiv a ble con fou n din g fa ct or in t o a ccou n t , ot h er det er m in a n t s t h a t w e w er e n ot a w a r e of m ig h t h a v e in flu en ced t h e r esu lt s. In t h e cr oss sect ion a l st u dies, t h e con t r ibu t ion r a t e of 4 %ODI t o Ng a l lev els w a s n ot la r g e (6 .2 %). T h er efor e, it seem s qu it e possible t h a t ot h er det er m in a n t s n eg a t ed t h e in flu en ce of t h e im pr ov em en t in OSA . T h e pr esen ce of cer t a in com pon en t s of m et a bolic sy n dr om e a n d t h eir t r ea t m en t in t h e pr esen t coh or t m ig h t be a m on g t h ese det er m in a n t s. W e r ecog n ize sev er a l lim it a t ion s in t h e pr esen t st u dy . Fir st , t h e sa m ple size w a s sm a ll, so it is n ot r ea son a ble t o ex t r a pola t e ou r da t a t o t h e g en er a l popu la t ion . In a ddit ion , t h e r esu lt s of t h is st u dy m ig h t h a v e been in flu en ced by t h e sm a ll sa m ple size. Secon d, a s w e pr ev iou sly n ot ed, w e did n ot ex clu de pa t ien t s w it h com or bidit ies su ch a s h y per t en sion a n d dia bet es ev en if t h ey w er e u n der
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t r ea t m en t . It is possible t h a t t h ese com or bidit ies a n d t h eir t r ea t m en t a ffect ed t h e r esu lt s. T h ir d, a s m en t ion ed a bov e, w e did n ot h a v e a pla n n ed con t r ol g r ou p w it h ou t CPA P u se. T h er efor e, w e cou ld n ot ju dg e pr ecisely w h et h er ch a n g es in Ng a l lev els a ft er CPA P im plem en t a t ion w er e ca u sed by CPA P u se or ot h er r ea son s. La st ly , w e did n ot m ea su r e C r ea ct iv e pr ot ein (CRP) lev els. Beca u se in fla m m a t ion h a s a n in flu en ce on Ng a l, r esu lt s of m ea su r em en t of h ig h sen sit iv e CRP w ou ld h a v e been a g ood r eflect ion of t h e in fla m m a t ion st a t u s of pa t ien t s a n d w ou ld h a v e been h elpfu l t o a ch iev e a m or e com pr eh en siv e u n der st a n din g of t h e r ela t ion sh ip bet w een OSA a n d Ng a l. In su m m a r y , t h e pr esen t st u dy pr ov ides t h e fir st clin ica l ev iden ce dem on st r a t in g t h a t pla sm a Ng a l lev els w er e posit iv ely bu t w ea k ly a ssocia t ed w it h t h e sev er it y of OSA . Pla sm a Ng a l lev els did n ot ch a n g e a ft er im pr ov em en t in OSA , so w e cou ld n ot t est ify t o t h e ca u sa lit y bet w een Ng a l lev els a n d OSA sev er it y . Beca u se Ng a l lev els w er e ju st w ea k ly cor r ela t ed w it h t h e sev er it y of OSA , ch a n g es in t h ose lev els a ppea r t o be in flu en ced la r g ely by ot h er con fou n din g fa ct or s. T h u s, it w ou ld be difficu lt t o u se t h e Ng a l lev el a s a specific biom a r k er r epr esen t in g n oct u r n a l h y pox ia in OSA . T h e lin k s bet w een Ng a l lev els a n d m et a bolic sy n dr om e r em a in con t r ov er sia l, a n d u n r ecog n ized det er m in a n t s of pla sm a Ng a l lev els a r e lik ely t o be pr esen t . Fu r t h er st u dies a r e w a r r a n t ed t o m or e com pr eh en siv ely u n der st a n d t h e r eg u la t ion of Ng a l in r ela t ion t o OSA a n d m et a bolic sy n dr om e.

Funding Statement
T h is w or k w a s pa r t ly su ppor t ed by g r a n t s fr om t h e Ja pa n ese Min ist r y of Edu ca t ion , Cu lt u r e, Spor t s, Scien ce a n d T ech n olog y , Respir a t or y Fa ilu r e Resea r ch Gr ou p fr om t h e Min ist r y of Hea lt h , La bor a n d W elfa r e of Ja pa n . T h e fu n der s h a d n o r ole in st u dy desig n , da t a collect ion a n d a n a ly sis, decision t o pu blish , or pr epa r a t ion of t h e m a n u scr ipt .

Article information
PLoS One. 2013; 8(1): e54184. Published online 2013 January 14. doi: 10.1371/journal.pone.0054184 PMCID: PMC3544801 Kimihiko Murase,1 Kiyoshi Mori,2 Chikara Yoshimura,3 Kensaku Aihara,1 Yuichi Chihara,4 Masanori Azuma,1 Yuka Harada,1 Yoshiro Toyama,1 Kiminobu Tanizawa,1 Tomohiro Handa,1 Takefumi Hitomi,3 Toru Oga,3 Michiaki Mishima,1 and Kazuo Chin 3,* Philippe Rouet, Editor
1 Department of Respiratory Medicine, Graduate 2 Department of Medicine

School of Medicine, Kyoto University, Kyoto, Japan

and Clinical Science, Graduate School of Medicine, Kyoto University, Kyoto, Japan and Sleep Control Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan Cross Otsu Hospital, Shiga, Japan

3 Department of Respiratory Care

4 Department of Respiratory Medicine, Red

I2MC INSERM UMR U1048, France * E-mail: chink/at/kuhp.kyoto-u.ac.jp Competing Interests: The authors have declared that no competing interests exist. Conceived and designed the experiments: K. Murase K. Mori KC. Performed the experiments: K. Murase CY KA YC MA YH. Analyzed the data: K. Murase K. Mori. Contributed reagents/materials/analysis tools: YT KT T. Handa T. Hitomi TO MM. Wrote the paper: K. Murase K. Mori KC. Received September 8, 2012; Accepted December 7, 2012. Copyright notice This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Articles from PLoS ONE are provided here courtesy of Public Library of Science

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