hypoalbumonemia in ckd

8/13/2019 Hypoalbumonemia in CKD

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J A m Soc N ephro l 9 : 23 68-23 76 , 1998

B io lo g ic a l B a s is o f H y p o a lb u m in e m ia in E S R D

GEORGE A. KAYSEND iv is ion o / N eph ro log v , D epar tm en t o f M ed icine , U n iversity o f C a lifo rn ia D av is; an d the D epar tm en t o fV e te ra n s A ffa irs N orthern C a lifo rn ia H ea lth C a re System , P leasan t H ill, C a lfo rn ia .

A bs trac t . H y poa lb um inem ia is a ssoc ia ted w ith m ortality inp atien ts w ith en d-stag e ren al d isea se (E S R D ) m a in ta ined e ithe ro n pe ritoneab d ia lysis (P D ) or h em od ia lys is (H D ). S erum a l-b um in co ncen tra tion is de term in ed by its ra te o f syn th es is , b yth e catabo lic ra te co nstan t ( the frac tion o f the vascu la r po o lca tabo b ized p e r un it tim e ), by ex te rna l bo sse s, an d b y red istr i-b u tion fro m the v ascu lar to th e ex travascu la r space . H yp oabbu -m inem ia in d ia lysis p atien ts is p r im arily a con sequence o freduced a lbum in syn thesis ra te in bo th H D and P D p atien ts ,an d in the case o f P D pa ten ts , o f tran spe rito neal a lbum in lossesas w ell. C on tinuo us am bula to ry peritonea l d ia ly sis pa tien ts a reab le to in c rea se a lbum in sy n thesis to rep lace losse s. T hus,E S R D do es n o t d irec tly su p p ress a lb u m in sy n th esis . T h e ra te

o f a lbum in syn th esis is in ve rsely p rop ortiona l to the serumcon cen tra tion o f one po ten tia l acu te phase p ro te in (a2 m ac ro -g lob u lin ), an d a lbum in concen tra tio n is inverse ly propo rtio na lto tha t o f e ith er C -reactiv e p ro te in on se rum am yb o id A in bo thH D an d P D p atien ts . T h e cau se o f d ecreased a lb u m in syn th esisis p r im arily a re sp onse to in flam m atio n (th e acu te phase re -sponse), a lth ough it is possib le th a t inadeq ua te nu trition m aya lso con tribu te . T he cause of the in flam m atory response is no tim m edia te ly ev iden t. T here is no ev idence th a t sh ifts o f abbu-m m to the ex travascub ar sp ace o r th a t d ilu tio n of th e p lasm a b yvo lu m e expans io n p lays any ro le in causing hypo albu m in em iain E SR D patien ts .

H yp oa lbu m inem ia is the stro ngest ind ependen t risk facto r fo rdea th in h em od iab ysis pa tien ts (1 ,2 ) on tho se be ing trea ted w ithco n tinu ou s am bu lato ry pen iton ea l d ialy sis (C A P D ) (3 ,4 ) evenw h en h ypo alb um in em ia o ccu rs b e fo re in itia tion o f d ia ly sis (5).T o u n d ers ta nd th e re la t ion sh ip b etw een m o rta lity a n d a lb u m inb ev e ls , it is im p ortan t to und erstand bo th the e ffec ts o f hy -poa lb um in em ia and the p ro cesse s tha t lead to bow a lbum inleve ls .

A ch an ge in th e concen tratio n o f any pro te in in p lasm a is aconseq uence o f a ch ange in its ra te o f syn th es is , in its ra te o fca tab o lism , th e d ev e lo pm ent of on chang e in ra te of ex te rna llosses, o r a chang e in th e d istribu tion v o lum e o f the pro te in . A sw ill be d iscu ssed be low , a lbu m in leve ls are red uced in pa rt bya decrease in the ra te o f a lbum in syn thes is in d ialys is pa tien tsan d in par t b ecause o f ex te rn al lo s se s, e ithe r th rou gh thehem o d ia lyzen as a con sequence o f reuse (6 ) o r th rou gh lossesacross the pen itonea l m em bran e in peritonea l d ia lys is (P D )pa tien ts . D ec rea sed syn th es is m ay be a resu lt o f red uced p ro -te in in take , the in f lam m ato ry respon se , o r a com b ina tion o fthese processes. A ny o f the p rocesses tha t tend to reducea lbum in bev els po ten tia lly can p ro duce b o th m o rb id ity andmortal i ty .Approx imately 50 of p la sm a pro te in is alb um in . B ecauseo f its lo w m olecu la r w e igh t, alb um in con trib u te s g reatly tosup porting p la sm a co bbo id osm otic p re ssu re -onco tic p re ssu re(ir )-and ac ts a s a h igh -cap ac ity b ind ing pro te in fo r free fa tty

R ece iv ed A pr il 3 0 , 1 998 . A ccep ted June 28 , 1 998 .C o rrespo ndence to D r. G eorge A . K aysen , C hief D iv is ion of N eph ro logy ,U n iv ersity of C a lifo rn ia D av is . T B 1 36 , D av is, C A 9561 6 .I046-6673 /090 l2 -2368$03 .0 ( ) /0

Journ al o f the A m erican S oc iety o f N ephro lo gyC o pyrigh t U 1998 b y the A m erican Soc ie ty of N ep hro logy

ac ids and d iva len t ca tions (7 ). A lb um in a lso b inds o ther b io -log ica lly re levan t lipop h ilic m olecu les , su ch as ste ro id ho r-m ones and b ilirub in (7 ) . D esp ite a ll o f the im p ortan t fu nc tionsth a t a lbu m in se rves, he red ita ry anab bum inem ia is com pa tib lew ith life . R a ts w ith hered ita ry anabbu m in em ia reproduce no n-m ably and h ave norm al rena l fun ction and B P (8 ,9 ). H ypo albu -m inem ia m ay affec t b lood v isco sity (10) or end o the lia l ce llfun ctio n as a conseq uence o f inc rea sed con cen tra tion o f freeb ysop hospha tidy bchob ine -ab te r ing ery th rocy te struc tu re (10 ) o rb y in h ib iting n itric ox ide-m edia ted vascu la r re laxa tion ( 1 1 , 12 ) .B ecause a lbum in serv es as a rese rv o ir fo r n itric ox ide , hy -p oabb um in em ia can d irectly lead to redu ced a rter ioba r re lax -a tion th rou gh th is m echan ism as w ell (1 3). A lth ough hypo -a lb um inem ia m ay be po ten tia lly in ju r ious b y the abo ve m ech-an ism s, the observa tion tha t hered ita ry anabb um inem ia im partslittle in the w ay o f decreased v iab ility sup ports a hy po thesisth a t it is th e cause o f red uced a lb um in concen tratio n tha t isrespon sib le fo r m orb id ity and m orta lity in p a tien ts w ith ac-q u ired hyp oa lbum inem ia ra the r than hy poa lbu m inem ia itse lf.

It ha s been prop osed th at the p rim ary cau se o f h ypo alb u -m inem ia is m alnu tritio n (14-1 6), w hich itse lf is p ropo sed to b ea consequence of inadequ ate d ia lys is ( 1 7 ). H ow ev e r, h ypo alb u -m inem ia from pro te in m aln u trition a lone in the absence ofren al fa ilu re is un co m m on in ad u lts . O ra l n u trition a l supp le -m en tatio n has n o t b een s trik in g ly e ffec tive in norm a liz inga lb um in beve ls in hyp oabbu m inem ic d ialy sis pa tien ts , a lthou ghin te rd ia ly tic p aren teral nu tr ition h as b een som ew hat m ore ef-fec tive in som e stud ies ( 1 8). In con trast, k w ash io rkor respond sq u ite easily w hen adequa te pro te in is p rov ided .

R ecen tly , ev idence has accum ula ted in our labo ra to ry (19-2 1 an d e ls ew her e (22 -25 ) su ggesting th at in flam m ation , e ithe ra lon e on in co m bina tion w ith m alnu tritio n , p lays a s ign ifican t,


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J A m So c N ephro l 9 : 2368 -2376 , 1 998 B io lo g ical B asis o f H ypo albu m inem ia in E SR D 236 9

and pe rhap s a co n tro lling , rob e in cau sing h yp oabbu m inem ia inh em odiabys is pa tien ts . T h is e ffec t o f in flam m atio n w ould no tb e expec ted to resp ond to n u tr itiona l sup p lem en ta tion an d m ayh elp to ex p la in bo th the fa ilu re o f h ypo alb um in em ia in d ia ly sisp atien ts to be rev ersed by n u tr itio na l supp lem en tatio n , a s w e llas to exp la in the h ig h m o rta lity ra te assoc ia ted w ith hypo a lb u-m inem ia in th ese p atien ts.

A lb u m in H o m eo sta sisA lb um in is syn th esized exc lus ive ly in the liv e r, at a rate o f

b etw een 1 2 and I S g /d (7 ), and is ca tab ob ized b y the vascu la rend o th eliu m th ro ugh ou t th e bod y w ith a h alf-life o f app ro x i-m a te ly 16 d (2 6-28 ) . T o ta l a lbum in m ass is app rox im a tely 4 .5g /kg bo dy w t. B e tw een 40 an d 50 of the a lbum in p oo l isno rm a lly fo und in the p lasm a com partm en t (2 9 ,30 ) . T he re st isd is trib u ted in in te rstitia l sp aces th ro ugh ou t th e bo dy , m os tly inm u scle an d sk in . P la sm a a lb um in co ncen tratio n m ay be de -c rea sed because o f d ilu tio n o f th e p lasm a p oo l d u ring p la sm avo lum e exp an sion , a s a re su lt o f red istr ibu tio n of the a lbu m inp oo l from pla sm a in to in te rs titia l com partm en ts a s occu rsfo llow ing bu rns o r d u ring sep sis (3 1 , as a con sequence of ad ec rea se in the ra te o f alb um in syn th esis , a s a resu lt o f in -creased a lbum in ca tabo lic ra te o r as a conseq uence o f thed ev elo pm en t o f ex te rn al alb um in bosse s; in to the u rine o r gu t,o r in to d iab ysa te , o r transcu taneou sly in the case o f traum a onb urn s. I w ill rev iew fac to rs tha t regu late th ese p rocesse s andid en tify w hich changes are respo nsib le fo r hy poa lbum inem iain d ia lys is pa tien ts.

A lb u m in S y n th esisT he ra te o f a lbum in syn th es is is regu lated in par t b y ava il-

ability o f am ino ac ids (7 ,32 ). B ecause o f th is re latio nsh ip ,p la sm a a lbu m in con cen tra tion h as been used as a c lin icalm ark er o f n u tritio na l sta tu s. H ow ev er , the ra te o f a lb um insyn th esis re spon ds m ore to acu te changes in d ie tary p ro te in(33 ,34) than to genera l (ch ron ic ) n u trition al sta tus. W hen se-ve re ly m a lno urished an im a ls o r peop le are re -fed , th e rate o fa lbum in syn thesis in creases p rom p tly , even tho ugh to ta l bod ypro te in sto res a re still s ev ere ly d ep le ted (35 ). T h is ve ry sho rt-te rm reg u la tion appea rs to be a t th e p osttran scn ip tio nab step o fin itia tion o f p ro te in syn th es is (36 ) .

In ad d it ion to b e in g m od u la ted b y d ie ta ry p rote in , a lb u m in(37) is a nega tive acu te phase reac tive p ro te in (37 ). T he acu tephase re spo nse is in itia ted by cy tok in es and sign al a cascade ofeven ts w ith in hepa to cy tes (38 ,3 9 ). S yn th esis o f p ositive acu teph ase reac tan t p ro te in s, inc lud in g fib r inog en , C -reac tive p ro -te in (C R P ), a7 -m ac ro gbo bu lin , se rum am y bo id A (S A A ), andlipop ro te in (a ) , is s tim u la ted (4 0 -4 3 ) , and syn thesis o f nega -tive acu te phase reac tiv e p ro tein s-frequ en tly used as nu tr i-tionab m arke rs (alb um in [19 ], p rea lbum in [44 ]) , apo A -I[451)-is sup pressed . D u ring th e acu te phase resp onse, theconcen tratio n o f p ositive acu te phase reactiv e p ro te in s is in -c rea sed in p la sm a, w he rea s th at o f alb um in is redu ced . T h epresen ce o f sev ere p ro te in m a lnu trition m ay preven t the in -c rea se in syn th es is o f acu te p hase p ro te in s even a fte r an ap -p rop ria te stim u lu s (46 ,4 7 ) .

P reabb um in (tran sthy re tin , a lso ca lled thy ro id b ind in g g lob -

u lin ) an d transfem n are also red uced in respon se to p ro te inm a lnu trition and , b ike a lb um in , have a lso been u sed in nu tn i-tion al eva lua tion . B ecause p rea lbu m in leve ls chang e m ore rap -id ly than a lbum in leve ls, it has b een proposed by som e tha tm easurem en t o f th is p ro tein rep lace tha t o f a lbu m in fo r nu tr i-tion ab su rv eillance (4 8 ) . H o w ev er , th e p la sm a con cen tra tion o fno ne o f the se p ro te in s is sim p ly a re flec tion o f nu tr itiona lsta tus , because these , like a lbum in , a re nega tive acu te phasepro te ins an d sub jec t to the sam e lim ita tions . H ep atic tran sfe rringene ex pres sion is also sub ject to iron sto re s (49 ) and toon co tic p re ssu re (5 0 ), add ing a fu rth er leve l o f com p lex ity toin te rp re ting p la sm a leve ls o f th is p ro te in .

A lb u m in C a ta b o lismA lb um in is ca tabob ized th ro ugh a firs t-o rder p rocess a t s ite s

d istr ibu ted th rou gho u t th e vascu la r end o the liu m o r in a com -pa rtm en t in rap id equ ilib rium w ith the p la sm a co m partm en t(26-2 8). W hen plasm a a lbum in concen tra tio n is decreased , th eab so lu te ra te o f a lbu m in catabo lism w ou ld be exp ec ted todec rea se sim p ly becau se the con cen tra tion o f alb um in hav ingaccess to the ca tabo lic site s is decreased . T he frac tiona l ra te o fcatabo lism (F C R ) o f a p la sm a pro te in is the frac tion o f thevascu la r po o l ca tabo lized p er u n it tim e . In th e case of a pro te intha t is ca tab o lized b y a firs t-o rd er p rocess, a chang e in the FC Ris a consequence of a ch ange in the ca tab o lic ra te con stan t andsugg es ts regu la tion of p lasm a pro te in co ncen tra tion by reguba-tion o f p ro te in ca tab o lic ra te . In m ost co nd itio ns in w hichalb um in con cen tra tion is d ec rea sed (m a ln u tritio n , fo r exam p le)(34), the F C R of a lbum in is a lso redu ced . W h en a lb um inco ncen tra tion is in creased , the F C R in crease s, su ggestin g tha tregu latio n o f a lbu m in concen tratio n in p la sm a tak es p lace inpart by regu la tion of a lbum in FC R . T his fo rm of ca tabo licco n tro l dam p ens the e ffec t o f e ithe r in crease s o r dec rea se s inthe ra te o f a lbu m in sy n thesis and pro tects th e a lb um in p oo lw hen the ra te o f a lbum in syn thesis is decreased .

A lb u m in M eta b o lism in E S R DA lb um in leve ls a re no rm a lly g rea ten in m en than w o m en

(F igu re 1 , righ t p an e l) an d d ecrease w ith advanc ing age (le ftpane l). A ltho ugh the m a jo rity o f pa tien ts on d ialy sis havealb um in va lues tha t fall w ith in the norm a l range (F igu re 1 ) ,m any have a lbum in leve ls th at fa ll be low norm al, and bo th thegende r-b ased an d age -b ased va riance tha t n o rm a lly occu rs isef faced (20). W hen pa tien ts w ith o th erw ise norm al ren a l func-tion lose a lbum in in th e u rin e , th ey re spon d by inc rea sing thera te o f a lbum in sy n thesis (F igu re 2 . le ft p an el) (5 1 , al thoughfreq uen tly th is re spo nse is inadeq ua te to no rm a lize se ru malb um in co ncen tra tion . S im ila rly , pa tien ts on P D a lso inc rea sea lbu m in sy n the tic ra te in re sp onse to ex te rna l bo sse s (F igu re 2,le f t pane l) (52 ), b u t a lbum in p oo ls a re p re se rved to a m uchgrea ten ex ten t than in nep hno tic pa tien ts h av ing th e sam e a lbu -m m lo sse s (F igu re 2 , righ t pane l) . T he leve l o f ren al fun ctio nalso does no t im pa ir the ab ility o f p ro te inu ric ra ts fro m alsoinc reas in g a lb um in syn th es is na te (53 ) or inc reas in g h ep aticalb um in m R N A in re spo nse to ex te rn al lo s se s (5 4 ). T h us, rena lfai lu re per se does no t p rod uce a g ross de fec t in th e cap acity o fpa tien ts o r an im als from hav ing a norm al ra te of a lbum in


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A g e y e a rs ) 3 .8F igure 1 . (L eft P an el) R e latio nsh ip b etw een age and se ru m a lbu m in beve ls in hea lthy con tro l sub jects (filled circ les; r = 0 .428 ; P = 0 .0005)and in pa tien ts on hem o d ia lysis (op en do tted circ les ; r = 0 . 124 ; P = 0 .23 3). (R igh t P ane l) S erum album in concen tra tion in hea lth y m ale (and fem ale (L I) con tro l sub jec ts. T h is d iffe rence is no lon ger presen t in hem od ia lys is pa tien ts (d ata n o t sh ow n ). A lbum in w as m easured usingb rom creso l g reen dy e b ind ing . T he figu re sho w s d a ta on hem o diab ysis pa tien ts taken from refe rence 20 . * 0 .005 .

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2370 Journ al o f the A m erican So cie ty of N ephro log y J A m S oc N ep hro l 9 : 2 368-2 376 , 1 998

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E x te rn a l A lb u m in L o ss (gil .7 3 m 2/ day )F igu re 2 . (L e ft P ane l) R ela tion sh ip b etw een the ra te o f alb um in syn th es is and ex te rna l alb um in lo ss in co n tinu ous am bu lato ry pe rito neald ia lys is (C A P D ) pa tien ts (filled c irc les; r = 0 .743 ; P < 0 .01 ; fro m referen ce 52 ) and p a tien ts w ith o therw ise no rm al rena l func tion an d then ep hro tic sy ndrom e (open do tted b oxes; r = 0 .585 ; P < 0 .01 ; f rom referen ce 5 1). (R igh t P ane l) R ela tion sh ip be tw een serum a lbu m inco ncen tra tion in C A P D pa tien ts (r = 0 .744 ; P < 0 .0 01) and nephro tic p atien ts (r = 0 .503 ; P < 0 .05 ) . S ym bols a re the sam e as in the le ft pane l.T h e low er se rum a lbu m in concen tratio n in the nephn o tic pa tien ts is a re su lt o f inc rea sed frac tion al rate o f a lbu m in ca tab o lism in th is g ro up .

syn th esis , o r from resp ond ing to ex te rna l b osse s o f alb um inw ith an approp ria te inc rea se in the ra te o f alb um in sy n thesis(52) . H yp oabbu m inem ia is the refo re caused b y a process o th erthan rena l fa ilu re . T he cau se o f h ypo ab bum inem ia needs to b espec ific a lly e stab lish ed in pa tien ts hav in g th is b iochem icalab norm a lity . R ena l fa ilu re per se is no t respons ib le .

T h e norm a l d eclin e in a lbu m in F C R tha t occu rs d u ringh ypo alb um in em ia is in tact in pa tien ts on C A P D , b u t in then ep hro tic syn drom e a lbu m in F C R inc rea se s a s se rum alb um inco ncen tra tion fa lls , con tribu ting th e low erthan -expec ted S e -rum album in con cen tra tion in neph ro tic pa tien ts (55) . N ever-theb ess, the n orm al m echan ism tha t suppor ts a lbu m in beve ls in


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J A m So c N ephro l 9 : 2368 -2376 , 1 998 B io lo g ical B asis o f H ypo albu m inem ia in E SR D 2371

h ypoabb um inem ic sta tes rem ains in tact in d ia lys is pa tien ts . Ad iso rd er in a lbum in FC R does no t con tribu te to hypo abbum in-em ia in th ese pa tien ts I 9 , 21 ) .

W e fou nd th at the p ro x im a te cau se o f h ypo ab bum inem ia(3. 5 g /d l) in hem odiabys is pa tien ts w as a reduced ra te ofa lbu m in syn thes is co m pared w ith h em odiabys is pa tien ts hav inga n orm al se rum album in concen tra tio n (4 .0 g /d l) (1 9). A lbu-m m F C R w as red uced in the hy poa lbu m inem ic g roup just a s inh ypo a lbum inem ic C A P D p a tien ts (56 ) . D istr ib u tion o f a lbu m inb etw een the v ascu lar and ex travascu la r poo l w ere the sam e inh em odia ly sis (20) an d P D p atien ts (5 2), and in h ealthy sub jec tsreg ard less of serum album in concen tra tion . N eithe r p lasm av o lum e ex pansio n n or red istr ibu tio n of a lbum in o u t o f thep lasm a co m partm en t p lay ed any robe a t a ll in con tribu ting tohy poa lbum inem ia in d ialys is p atien ts. T h erefo re , w e m u st tu rno ur a tten tion to p o ten tia l p ro cesse s causing a d ec rea se in therate o f alb um in syn th esis to e stab lish a m echan ism for hy -p oa lbum inem ia in th is po pu la tion .

M alnu trition causes decreased a lbu m in syn th es is (7 ,32 -34 ,36)and is a p o ten tia l cause of reduced a lbu m in sy n thesis , decreaseda lbum in beve ls, and increased m orb id ity and m orta lity in anychron ica lly ill po pu la tio n , inc lud in g those w ith E SR D . M aln u tri-tion has been c lea rly d ocum en ted in th is pa tien t po pu la tion (1 4 -16 ) , and it h as been genera lly assum ed tha t h yp oa lbum inem ia in

th is popu la tion is pu re ly nu tritiona lly based , p rim arily as a con-sequen ce o f reduced a lb um in syn thes is .

I t is p rop osed th at d ie tary p ro te in in tak e and ca lo r ie in takesh ou ld be be tw een 1 and 1 .2 g lkg an d 3 5 kca l/kg p er d ,resp ec tive ly , in pa tien ts on hem o diab ysis 57 ,58 , a va luegrea te r than the I g /kg pro te in in take recom m ended fo r the re sto f the p opu latio n , and g ene ra lly m ore p ro te in than m ost h e -m odiabys is p atien ts consum e. B ecause insuffic ien t d ia lysis canbead to ano rex ia (59 ) , it ha s b een p ostu la ted th a t inadequ a ted ia lysis b eads to poor nu tritiona l in take fo llo w ed b y the d eve l-op m en t o f h ypo ab bum inem ia . A lbum in leve ls m ay be in creaseda fte r inc rea sed d ialy sis d ose (60 ) . It is sug gested tha t op tim ald ia lysis in c lu de the use of b io com patib be m em branes to de live rKt/V > 1 .4 (u rea red uc tio n ra tio > 65 ) (61 ) .

W ere p ro tein m a lnu tr ition the o n ly cause o f hyp oabbu m ine -m ia in th e d ia lys is pa tien t pop u lation , one w ould exp ec t th atnu trition al supp lem en ta tio n w ou ld be e ffec tiv e in re sto r inga lb um in p oo ls (14 , 16 ). H ow ever, o ra l nu tr itiona l supp lem en-ta tion do es n o t rev erse hy poab bum inem ia in th is pa tien t pop u-latio n (62 -64 ). In trad ia ly tic pa ren terab nu trition is a lso e ithe rineffectual ( 6 5 , 6 6 ) or on ly slo w ly effec tive (67 ) in repa ir o fhyp oabbum inem ia of h em o diabysis p atien ts. T he b ack o f p rom ptsuccess of nu tritiona l in te rven tion , and espec ia lly of en te rabnu tr itiona l in te rven tion in co rrectin g h ypo alb um in em ia , sug -gests tha t n on-nu tritiona l fac to rs m ay con tribu te to or be re -spo nsib le fo r redu ced a lb um in concen tra tion in a frac tion o fhy poa lbu m inem ic d ia lys is .

W e m easu red the ra te o f a lbum in syn th es is in a sm a ll g roupof hyp oabb um in em ic hem o d iabys is pa tien ts , and cou ld find nod iffe ren ce in nu tritiona l fac to rs (19). H ow ever, w e d id fin d th atthe leve ls o f acu te phase p ro te in s w ere inc rea sed , sugg estin gtha t in flam m atio n and n o t m a lnu trition w as the p rim ary cau seof red uced a lbum in syn thes is in th is sm all g roup o f pa tien ts .

F urthe r su pp ortin g a hyp o thesis tha t the in f lam m ato ry re spon sep lays a ro le in es tab lish ing a lbum in leve ls in hem o diab ysispa tien ts , p resum ably by suppressing a lbum in syn the tic ra te ,B ergs t rom e t a l. repo rted in p re lim in ary stu d ie s tha t p la sm aC R P co n cen tra tio n w a s th e m o st p ow er fu l p red ic tor o f seru ma lbum in , and w as a b ette r p red ic to r o f dea th in 1 yr thana lbum in concen tra tion (23). W hen a lbum in lev els w ere s ta tis-ticabb y correc ted fo r C R P, a lbum in los t its va lue in pred ic tingdea th . W e fou nd th at bo th C R P and an o the r acu te ph asep ro te in , S A A , p red ic ted alb um in con cen tra tion in a g roup of 79hem odia lys is p a tien ts by using m ultip le regression ana lysis(20) (F igu re 3 , le ft p an el).

L ym p hok ines, tum o r necrosis facto r-a , and in terbeuk in - I(IL - 1 ) (6 8 ) , a s w e ll a s a grou p o f a cute ph a se reac tive p rote in s(25 ,69) (a1 ac id g lycopro tein , ceru lop lasm in , and C 4 com ple-m ent com pon en t), have b een fo und to be inc rea sed in hem o -d ia lysis p atien ts co m pared to o th er pa tien ts w ith ch ron ic rena lfa ilu re. C y tok in e leve ls w ere a lso recen tly reported to corre la tew ith a lbum in leve ls in h em od ia lys is pa tien ts , as w ell a s w ithw eigh t loss (24) , and cy tok ine leve ls , b ik e a lb um in , p red ic tedsurv iva l (22).

E x tern a l A lb u m in L o sses D u rin g D ia ly sisK ap l an e t a l. rep o rted tha t reuse o f a sp ec if ic ty pe o f d iabyze r

(F resen ius 80 A ) w ith b leach causes in creased pro te in lossesduring d ia lysis and con trib u te s to hy poa lbu m inem ia (6 ). W ea lso fo un d tha t a lbum in losses in c rea sed w ith reuse us ing thesed ia lyzers and th is techn iq ue , to a s m uch as 20 g in a sing led ia ly sis trea tm en t. H o w ever, the m echan ism of h ypoabb um in-em ia-red uced sy n thesis-su ggests tha t the re la tionsh ip be -tw een alb um in los ses and h ypo ab bum inem ia in hem o d iaby sispa tien ts is m ore co m plex than s im ply a lbum in bo ss a lone inh em o dia ly sis pa tien ts . L o ss of a lbu m in across th e PD m em -b rane has a statis tic ab ly s ign if ic an t effec t o n se rum alb um inleve ls in pa tien ts m ain ta ined on th is m oda lity (52 ,70 ,7 1 ) (F ig -u re 2 , righ t pane l) . W e fo un d th a t the resp onse am ong ind iv id -u al C A P D patien ts to th is ex terna l loss w as an increase in thera te o f alb um in syn th esis (5 2 ) , s im ila r to w ha t occu rs in ne -phro tic pa tien ts in response to urina ry loss (51 ,55 ,72 ,73) (F ig -u re 2).

U n like pa tien ts on hem o d ia lysis , transp eriton ea l lo sse s o f a lbu -m m are a co nsequen ce o f a b io lo g ica l ev en t w ith in the d ialy sispa tien t tha t co u ld po ten tially b e a re su lt o f pe r ito neab in f lam m a-t ion an d no t a sepa ra te va riab le . T h is , ho w ev er , is no t the case . W efou nd tha t a ltho ugh transp eritoneab a lbu m in b oss an d th e beve ls o fthe acu te phase p ro te in C R P each s trong ly con tro lled se ru ma lbu m in beve ls in P D pa tien ts (F igu re 3 , righ t p an el) , the tw ov ar iab les w ere s ta tis tica lly ind ep en den t (70). F urthe rm o re , the rew as a lso no re latio nsh ip be tw een se rum b ev e ls o f e ithe r C R P orSA A an d transpe ritonea l alb um in lo sse s, w he th er expre ssed e ithe ras gram s per day o r as peritonea l c lea rance of a lbum in (to acco un tfo r the b ow er serum a lbum in leve ls in pa tien ts w ith h igh boss ra te s)(F igure 4 ). T hese f in d ings are con sisten t w ith the o bserv ation tha talb um in syn thes is inc reases in C A PD patien ts in respo nse totransp eriton ea l alb um in loss (52 ) , a p rocess tha t shou ld be sup -pressed if in flam m ation w ere respons ib le fo r perito neal lo sses ofa lbum in .


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2372 Journa l o f the A m erican S oc ie ty of N eph ro logy I A m S oc N ephro l 9 : 236 8-237 6 , 199 8

H e m o d ia ly s is P e rito n e a l D ia ly s is

..

C R e a c tiv e P ro te in g / m I )F ig ure 3 . R ela tion sh ip be tw een 3-m o average se rum album in concen tra tio n and C -reactive pro te in (C R P ) concen tra tio n in hem od iaby sispa tien ts ( le ft pane l: r = 0 .490 ; P < 0 .001 ; f ro m re ference 20) and be tw een 3-m o ave rag e a lbum in co ncen tra tion and C R P in pen iton ea l d ia ly sispa tien ts (righ t pane l; r = 0 .436 ; P < 0 .01 6 ; from refe rence 70 ).

. . s; 7 {1 49 }

.-.-.-. - ---v #{149} V #{149}V v #{149}

V V {1 4 9 }V {23 1 } II I0 20 40 60 80 100 120 140 160 180 200 220

T ra ns-P e rito nea l A lbum in C lea ra nce(mi /day)

F ig ure 4 . R ela tionsh ip be tw een the leve ls o f se rum am yboid A (openinverted tr iang les ; r = 0 .000 2 , N S) and transperitonea l a lbu m inc lea rance (P eritonea l a lbum in boss X D ay /S erum alb um in concen-tra tion ) and C R P co ncen tra tion (filled c ircle s; r = 0 .0035 , N S ) andtransp eriton ea l albu m in c lea rance in P D p atien ts (from refe rence 70).

H an e t a l. (7 1 ) a lso fou nd th at C A P D p a tien ts w ith a lb um inconcen trat ions 3. 5 g /d b had h ig he r d ia ly sa te a lbu m in bo sse san d h ig he r C R P beve ls (1 7 .5 versus 2 .5 p .g /m b) than those w itha lbumin > 3 . 5 g /d l. W eek ly Kt/V and P C R did no t d iffe r

be tw een the tw o group s, sug gesting th at d ifferences in d ia lysisadequ acy and in p ro te in catabo lic ra te w ere o f les s im po rtanceth an a lbu m in losses and a m easu re o f in f lam m ation in p red ic t-ing a lb um in leve ls in C A PD p atien ts and th at th e tw o pr in cipa lvariab les a re ex te rna l bo sses and the p resen ce o f an in flam m a-to ry response .

R ecen tly , H an e t a l. (71) repo rted the resu lts o f a c ross-sec tiona l stu dy of 106 C A P D pa tien ts and fou nd tha t in th osewith se rum albu m in < 3 .5 g /db , se rum C R P w as s ig n ifican tlyg rea ten . B y stepw ise reg re ssion , they fo und tha t m u ltip le riskfac to rs indep en den tly corre la ted w ith a lb um in con cen tra tion ,in clu d ing C R P , d iab ysa te a lbu m in , and nu tritio na l p aram e te rs( lean b ody m ass, b lood u rea n itrog en , P C R ). T hese da ta a requ ite sim ila r to our ow n c ro ss-sec tion a l stu dy on alb um inleve ls in hem od ia lys is pa tien ts (20), a lthou gh the perito nea llosses of a lbu m in w ere m uch grea te r than the transd iaby zera lbu m in bo sse s tha t w e h av e foun d during hem o d iabys is . T h us,a bo dy o f da ta a re accu m ulating sug gesting tha t the acu te phaseresponse p lays an im por tan t robe in caus ing hypo ab bum inem iain d ialys is pa tien ts . T h is w ould he lp to exp la in the re lativeres istance o f these pa tien ts to nu tritio na l in te rven tion . T hecause of the in flam m atory response , how ever, has no t beeniden tified . T here is ev idence tha t d ia lys is w ith nonb ioco m pat-ibbe m em b ranes m ay be one cause of cyo tok ine ac tiva tio n .

P o ten tia l S o u rce o f I n fla m m a tio nB io incom pa tib le m em bran es , such as cu pro phan e, activ ate

w hite ce lls (74) , com p lem ent (7 5), and can even exert e ffec ts


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J A m So c N ep hro l 9 : 23 68-23 76 , 199 8 B io log ica l B as is o f H ypoa lbum in em ia in E S R D 2 373

on res idua l rena l func tion (76 ). A c tiva tion o f cy to k ines hasa lso been foun d to occur a fte r d ia lys is w ith cu proph an e (77 ) inco n tras t to b io co m pa tibb e m em b ranes (78 ,79 ). R eu se tech n iqu ean d nu m bers o f reu se a lso m ay con tr ibu te to the in te rac tion o fb lo od w ith d iaby ze r (6 ,19 ) , lead in g to chang es in p ro te in los san d poss ib le changes in th e acu te phase re spo nse .

H o n k an en e t a l. a lso found a very rap id and sim ilar inc reasein IL -1 /3 and S A A during 240 m m of d ia lysis w ith cu proph an e,cellu lose ace tate , and po ly m e thyb m e thach ry la te (8 0 ) , the ba ttertw o be in g b iocom pa tib le m em b ranes. P la sm a IL -6 (77 ) andIL - 1 /3 (80 ) leve ls m a y increase d u rin g d ia lysis , an d d ia ly sis ca nalso p rim e b lo od ly m ph ocy te s to re lease IL - 1 , IL -2 (8 1 , an dtum o r n ec rosis fac to r-a (82 ). Ind eed , cy tok in e p ro duc tion oc -cu rs even d uring in v itro d ia lysis o f w hole b lo od (83). D ia lys ism ay ev en alte r b lood m on onuc lea r ce lls in su ch a m anner tom ake th em resp ond m ore v igo rou sly to sub sequen t ex posu re toendo tox in (8 4 ).

W e w ere u n ab le to fin d an y in crease in ex p ress ion fo r gen esencod in g sev era l cy tok ines in circu la ting m ono nuc lea r ce llsco lle cted fro m a sm a ll nu m ber o f h em od iaby sis pa tien ts w ithh igh C R P leve ls, and o th ers a lso have no t b een ab le to iden tifyc ircu la ting m o non uc lea r ce lls a s a po ten tial sou rce fo r stim u-b atin g in fec tion in h em od ia lysis pa tien ts ( 8 5 ) .

It is clear ly p ossib le th at in fla m m atio n m ay b e a con se-qu en ce o f un recogn ized c lin ica l in fec tio n . T h is p ossib ilitym ust be exc lud ed in an y d ia ly sis p atien t w h o deve lop s hy -p o a l b u m i n em i a .

A no the r po ten tial w ay in w hich d ialy sis can ch an ge alb um inlev e ls is b y bo ss o f alb um in ac ross the d ialy sis m em bran e.C lea rly , tran spe rito neab alb um in bo sse s con trib u te to redu cedalb um in leve ls in C A P D pa tien ts (5 2 ,70 ,7 1 ). Sign if ican tam ou n ts o f a lbu m in (up to 20 g pe r treatm en t) can be lostac ross th e hem o d ia lysis d ia ly sis m em brane afte r ex ten sivereu se , e spec ially w h en po ly su lfone d ialy ze rs a re reu sed w ithb leach (6 , 1 9 ) , su ggestin g tha t d iab yze r m em bran e cho ice andbo th reuse n um b er and tech n iqu e m ay b e p a rtly re sp onsib le fo rde ran ged a lbu m in ho m eosta sis in hem o d ia lysis pa tien ts (86 ).

T h e ra te o f a lb um in catab o lism d ecrea ses b o th in h y p oab b u -m inem ic h em od iab ysis pa tien ts a s w e ll as in C A P D p atien ts . Inad d ition , th e F C R of a lbu m in a lso dec rea se s as a lbu m in co n-cen tra tion fa lls in bo th h em od ia lys is and C A P D pa tien ts , rep -resen tin g pre se rva tio n of th e no rm a l rela tion sh ip be tw een F C Rand se ru m a lbum in con cen tra tion . P reserva tion of th is no rm a lrela tion sh ip w ill se rv e to su ppo rt a lbu m in co ncen tra tio n w heno th er fac to rs (dec rea sed sy n thesis and loss ac ro ss th e h em od i-abys is o r p en ton ea l m em brane ) favo r a dec rea sing lev el o fa lbum in in b lood .

R ed is tribu tion of th e alb um in po o l from the vascu la r to theex trav ascu ba r sp ace p lay s n o ro be in the deve lop m en t o f hy -po ab bum inem ia in eith e r the hem od ialy sis o n C A P D pa tien tpo pu la tion . If any th ing , the frac tion o f a lbu m in fo und in theex trav ascu lar p oo l decreases slig h tly in h ypo alb um in em icC A P D p atien ts .

S yn thesis o f acu te p hase reac tiv e p ro te in s, like th at o f abb u-m m , is a lso im peded by pro te in m aln u tr ition (4 6 ,47 ) evenfo llow ing an approp ria te in flam m ato ry stim u lu s. T hu s, th eabsence o f an inc rea se in the p la sm a leve ls o f acu te phase

reac tive p ro tein s do es no t in itse lf p rove th at a lbu m in syn thesisis no t in part inh ib ited as a co m ponen t o f the in flam m atoryresponse . C y to k ine re lease , how ever, is un im peded in pro te inca lo r ie m a lnou rish ed sta tes (87 ) . T hu s, m easu rem en t o f cy to -k ine leve ls m ay prov ide g reate r in sigh t in to an in f lam m ato ryp ro cess than d irec t m easu rem en t o f acu te ph ase reac tan t p ro -te ins a lone .

K ai zu e t a l. (24) foun d th at d ia ly s is m em b rane prop ertie sw ere one fac to r tha t p red ic ted se rum IL -6 b ev el in the ir pa -tien ts . T hey reported th at p red iabysis IL -6 b ev els p red ic ted no to n ly a lbu m in leve ls , b u t a lso nu tr ition al sta tu s m easu red an -th ropom etricab ly . T he ir find in gs sugg es ted tha t in flam m ationm igh t be as soc ia ted w ith m a lnu trition . T h is a ssoc ia tion w o u ldn o t be su rp ris ing , sin ce cy tok in es sup press app etite (88 ,8 9 ) ,cause boss of ad ipo se tissu e d irec tly (90 ) , and a lso m ak e m oresevere the loss o f tissue m ass du ring periods of reduced nu tri-tio nab in take (91 ). T h ese observa tion s w ou ld thu s p rov id e am ore co m plex in te r-rela tion sh ip be tw een in f lam m ation andb o th h ypo ab bum inem ia an d red uced tissue m ass in th is pa tien tp opu la tio n . F irs t, in creased cy tok ine b ev els w o u ld a lter bo thp lasm a co m po sition and b ody m orp hom e try con sisten t w ithw ha t is observed du rin g pure u ncom p lica ted ca lo r ie m a lnu tr i-tio n . S econd , in c rea sed beve ls o f cy to k ines w ou ld d irec tlysuppress appe tite and redu ce ca lo rie in take .

E xp osu re o f b lo od to d ia ly sis m em bran es, ho w eve r , d oes no tex p la in v ar iab ility w ith in th e d ia lysis p op u la tion . T h e m a jo rityo f hem od iab ysis pa tien ts have se rum C R P an d S A A bev elsw ith in th e n orm a l range . F u rthe rm ore , th e acu te phase re sp onsea lso p lay s an im po rtan t ro le in es tab lish ing a lbum in beve ls inC A P D p atien ts (7 0 ,71 ) . In d eed , in ou r o w n p a tien t p o pu la tio nw e foun d tha t C R P and SA A lev els w ere sig n ific an tly g rea te rin P D pa tien ts than in h em od ia lys is pa tien ts (unp ub lishedo bse rva tions) . E x posu re o f th e p eriton eab m em bran e to p la sti-c ize rs fou nd in d ia lysa te m ay b e one source o f in f lam m ation inth is pop u la tion . A no th e r po ten tial so u rce is the transp eritonea laccess . F urthe rm ore , th e d istribu tion of C R P and S A A valu esw ith in the hem od ia lysis pa tien t po pu la tion is h ig h ly sk ew ed ,su ggestin g tha t p atien t-spec ific p ro cesse s, su ch as th e typ e o fv ascu lar access, u n recog n ized in fec tion s, o r va r iab le re sp onsesto the d iaby ze rs used , m ay p lay a ro le a s w e ll.

T hus , hypoa lbum in em ia in the E SR D po pula tion is a con -seq uence p rim arily o f reduced a lbu m in syn th etic rate . T h ere isev idence fo r ac tiva tion o f the acu te phase re spo nse in m anyh ypo abbu m inem ic d ialy sis pa tien ts , su ggestin g tha t on e im p or-tan t m ech an ism resp onsib le fo r decreased alb um in sy n thesis isin flam m atio n , a kno w n cause o f supp re ssio n o f a lbu m in genetransc rip tion . T he cau se o f in flam m atio n is no t c lea rly d efined ,b u t is like ly to b e m ultifa c to r iab . P ro te in m aln u tr itio n m ay alsocon tr ibu te im portan tly to sup pres sion of a lbu m in syn the tic ra tein som e pa tien ts . In add itio n to redu ced alb um in syn th etic ra te ,ex te rna l alb um in b osse s a lso con tr ibu te to h ypo a lbum inem ia .T h is is m o re im portan t in p e riton ea l d ia ly sis pa tien ts than inhem o d iabysis pa tien ts; ho w eve r , w ith ex ten sive d ia lyze r reusew ith b leach , bos ses o f a lbum in ac ross th e h em od ia lys is m em -bran e m ay a lso be sign ific an t. T he re is no ev iden ce tha t e ithe rm a ld istr ibu tio n of th e a lbu m in poo ls o r inc rea sed a lb um in F C R


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23 74 Jo urna l o f the A m erican S oc ie ty of N eph ro logy J A m So c N ephro l 9 : 236 8-237 6 , 1998

is o f sig n ific ance in causin g hyp oabbu m inem ia in E S R D pa-t ien ts .

A c k n o w l e d g m e n t sT his w ork w as supp orted in part b y th e re sea rch se rv ice o f the U .S .

D ep artm en t o f V etera n s A ffa irs, N a tiona l Institu tes o f H ea lth G ran tR O b D K 50 777 , and a gran t fro m D ia lysis C lin ic s , In c.

R e f e r e n c e sI . L ow rie E G , L ew N L : D eath risk in hem od iab ysis p atien ts : T h e

p red ic tive va lue o f co m m o nly m easu red v ariab le s an d an ev a l-ua tion o f dea th rate d iffe rences be tw een fac ilitie s . A m J K idneyDis 15: 458-482 1990

2. L o w ri e E G , L ew N L , H uang W H : R ace an d d iabe tes as d ea thrisk p red ic to rs in h em od ia lys is p atien ts . K idn ey 1w Supp l 38 :S22-S3l 1992

3 . A vram M M , Fein P A , B onom in i L , M ittm an N , L outoby R ,A v ram D K , C h atto padh yay I: P red ic to rs o f su rv iva l in co n tinu -ous am bu la to ry perito neab d ia lys is p atien ts: A five-y ear p rospec-tive stud y. Pent Dial hit l6 [S u pp l 1 ] : 5 190 -5 194 , 1 9964 . K ang S W , K w on K H , N o h H I, Park H C , L ee lH , C ho i K H , Le eH Y , H an D S : S erum a lbum in as a p red icto r o f m orb id ity andm ortality in con tin uou s am bu la to ry pe rito neab d ia lysis pa tien ts:S ing le cen ter expe rien ces in ove r 70 0 p atien ts [A bs trac t]. J AmS oc N ep hr ol 7 : 1 45 0 19 96

5. A v ram M M , G o ldw asser P . E rroa M , F e in P A : P red icto rs o fsu rv iva l in con tinuo us am bula to ry peritonea l d ia ly sis pa tien ts:T he im p ortance o f p reab bum in an d o the r n u tritio na l an d m e ta-b olic m ark ers . Am J Kidney Dis 2 3: 9 1- 98 1 99 4

6 . K ap lan A A , H a lley S E , L ap k in R A , G raebe r C W : D ia lysa tep ro te in losses w ith b leach processed po ly su lph one d iabyzens.Kidney mt 4 7 : 5 7 3- 5 78 1 99 5

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hypoalbumonemia in ckd

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