vit d dan ckd

8/11/2019 vit d dan ckd

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VITAMIND ANDCHRONICKIDNEYDISEASE

Chronic kidney disease (CKD) is an emerin

!"#$ic hea$%h !ro#$em and one o& %he mos%

!o'er&"$ !redic%ors o& !rema%"re cardioasc"

Sandra *i$$iams+ MD, Kar$a Ma$a%es%a+ -S, Kei%h Norris+ MD

$ar disease. Emerin eidence s"es%s %ha% %he

!roression o& CKD and many o& %he

cardioasc"$ar com!$ica%ions may #e $inked %o

hy!oi%aminosis D. /a%ien%s 'i%h CKD hae an

e0ce!%iona$$y hih ra%e o& seere i%amin D

de&iciency %ha% is &"r%her e0acer#a%ed #y %he

red"ced a#i$i%y %o coner% 12(OH)i%amin D

in%o %he ac%ie &orm+ 3+12 dihydro0yi%amin D.

As ne' eidence has im!roed o"r

"nders%andin o& c$assica$+ as 'e$$ as %he non

c$assica$+ &"nc%ions &or i%amin D+ i% has #ecome

a!!aren% %ha% %he a"%ocrine ro$e o& i%amin D is

an im!or%an% mod"$a%or o& seera$ sys%ems

inc$"din %he imm"ne+ rena$ and cardioasc"$ar

sys%ems. In addi%ion %o %he %radi%iona$

s"!!$emen%a%ion o& 3+12i%amin D %o CKD

!a%ien%s+ #y assessin and re!$e%in 12

(OH)i%amin D de&iciency+ !hysicians 'i$$ade4"a%e$y &"e$ #o%h %he rena$ and e0%rarena$

!a%h'ays o& ca$ci%rio$ syn%hesis main%ainin %he

c$assica$+ as 'e$$ as %he nonc$assica$+ &"nc%ions

o& i%amin D %ha% "$%ima%e$y in&$"ence c$inica$

o"%comes in %his hihrisk ro"! o& !a%ien%s.

-eca"se o& %he hih ra%es o& hy!oi%aminosis D

and !roression o& CKD %o ends%ae rena$

disease in minori%y !o!"$a%ions+ %hese &indins

are hih$y re$ean% %o %he na%iona$ e&&or%s %o

red"ce hea$%h dis!ari%ies. Hea$%hcare !roiders

are ca$$ed %o 5oin %he in%ensi&ied e&&or%s o& !"#$ic

hea$%h o&&icia$s %o dissemina%e and im!$emen%

"!da%ed "ide$ines and recommenda%ions %o

ha$% %he ro'in e!idemic o& i%amin D

de&iciency+ !ar%ic"$ar$y in hihrisk !o!"$a%ions.(E%hn Dis.1667, 37 8S"!!$29:s2;


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Nonc$assica$ Ro$e o& Vi%amin D

Eidence no' sho's %ha%+ in addi%ion

%o %he c$assica$ !a%h'ay &or ac%ia%ion o&

12(OH)i%amin D %o 3+12(OH)1i%amin

D+ a !eri!hera$ a"%ocrine !a%h'ay e0is%s

and res"$%s in ca$ci%rio$ syn%hesis in a

arie%y o& !eri!hera$ (nonrena$) %is

s"es.3+1

In &ac%+ i% a!!ears %ha% %he #"$k o&

dai$y me%a#o$ic "%i$ia%ion o& 12(OH)

i%amin D is ia %he !eri!hera$ a"%ocrine

!a%h'ay+ a$%ho"h i%s con%ri#"%ion %o

circ"$a%in 3+12(OH)1i%amin D is

minima$ d"e %o immedia%e $oca$ dera

da%ion.1 Ca$ci%rio$ syn%hesied in %his

manner in %he ce$$s and %iss"es %ha% !ossess

%hese !a%h'ays seres as a cri%ica$

com!onen% in %he sina$in cascades %ha%

#ride e0%erna$ s%im"$i %o ene %ranscri!

%ion.3+1 -y #indin 'i%h i%s in%race$$"$ar

i%amin D rece!%or (VDR) in %hese %iss"es+

ca$ci%rio$ can re"$a%e ce$$"$ar !ro$i&era%ion

and di&&eren%ia%ion+ in&$amma%ion+ %he

imm"ne sys%em and %he endocrine sys%em+

inc$"din RAS+ ins"$in resis%ance and $i!id

me%a#o$ism.3+36

The discoery o& %his nonc$assica$!a%h'ay ('hich is a$so !resen% in rena$

VITAMIND ANDCHRONICKIDNEYDISEASE *i$$iams e% a$

=i 3. Conce!%"a$ mode$ o& ma5or !a%h'ays %hro"h 'hich i%amin D de&iciency in !a%ien%s

'i%h chronic kidney disease (CKD) may $ead %o CKD !roression and com!$ica%ions s"ch

as !rema%"re cardioasc"$ar disease (CVD). VSM < asc"$ar smoo%h m"sc$e. Ada!%ed &rom

re& 3F.

%iss"e) has #ro"h% ne' sini&icance %o

%he im!or%ance o& addressin n"%ri%iona$

i%amin D de&iciency ien %he !o%en%ia$

ro$e %ha% hy!oi%aminosis D may !$ay inm"$%i!$e chronic diseases s"ch as dia#e

%es+ chronic in&ec%io"s !rocesses+ hy!er

%ension+ cardioasc"$ar disease and

CKD.3+2

Vi%amin D de&iciency is o&

hih !rea$ence in %he enera$ !o!"$a

%ion1+2+F

and !a%ien%s 'i%h CKD are

a&&ec%ed %o an een rea%er deree.3+2+

Nonc$assica$ Ro$e o& Vi%aminD in CKD

The kidney a!!ears %o #e a ma5or

%are% oran &or #o%h %he c$assica$ and

nonc$assica$ ac%ions o& i%amin D+ 'i%h

%he i%amin D rece!%or #ein a!!ro!ri

a%e$y hih$y e0!ressed in %his si%e.The

nonc$assica$ e&&ec%s o& i%amin D may

!$ay a re$ean% ro$e in %he mor%a$i%y and

mor#idi%y o& !a%ien%s 'i%h CKD+ s!e

ci&ica$$y a&&ec%in %he !ossi#$e !rores

sion o& %heir rena$ disease and co

e0is%in cardioasc"$ar disease+ 'hich is

%he ma5or ca"se o& dea%h in %his

!o!"$a%ion.2(=i"re 3)

One s!eci&ic !a%h'ay %ha% a!!ears %o

#e re"$a%ed #y %he a"%ocrine &"nc%ion o&

i%amin D in %he CKD !a%ien% is %he

reninanio%ensin sys%em (RAS). This

cascade &ea%"res a se4"en%ia$ ac%ia%ion

o& anio%ensin II+ 'hich+ in !a%ien%s 'i%h

CKD+ is $ike$y %o hae de$e%erio"s

e&&ec%s on #$ood !ress"re and %he

asc"$a%"re+ and may con%ri#"%e %o rena$

!arenchyma$ damae.VDR (i%amin D

rece!%or)n"$$ mice hae an increased

e0!ression o& renin and anio%ensin II

!rod"c%ion+ 'hich $eads %o hy!er%en

sion+ cardiac hy!er%ro!hy and increased

'a%er in%ake.33

Ho'eer+ 'i%h in%ac%VDR ac%ii%y+ eidence s"es%s %ha%

%hese de$e%erio"s e&&ec%s may #e reersed

%hro"h mod"$a%ion o& %he RAS sys%em

and ins%ead a #ene&icia$ e&&ec% on #$ood

!ress"re+ as 'e$$ as on dysre"$a%ed

asc"$ar and cardiac &"nc%ion+ may #e

&o"nd.33

="r%her+ 'hen ac%ia%ed i%a

min D ana$os are adminis%ered in

anima$ mode$s %ha% mimic ario"s s%aes

o& CKD+ a s"!!ressed ac%ia%ion o& %he

RAS sys%em 'as demons%ra%ed a$on

'i%h conc"rren% a%%en"a%ion o& $omer

"$ar and %"#"$oin%ers%i%ia$ des%r"c%ion

and im!roemen% in #$ood !ress"re+"nderscorin %he sini&icance o& %his

cascade in rena$ damae.+33

Ano%her im!or%an% ro$e o& %he RAS

a!!ears %o #e in dia#e%ic ne!hro!a%hy+

'hich remains one o& %he $eadin ca"ses

o& CKD. -o%h hy!er$ycemia and

i%amin D de&iciency a!!ear %o #e s%ron

ac%ia%ors o& %he in%rarena$ com!onen%s

o& %he RAS. Indeed+ research has sho'n

%ha% in dia#e%es+ %he in%rarena$ in%ers%i%ia$

anio%ensin II $ee$s can reach as m"ch

as 3666 %imes hiher %han norma$.31

Ine0!erimen%a$ dia#e%ic mode$s+ "se o&

i%amin D ana$o"es %o !reen% RAS

ac%ia%ion a!!ears %o hae %hera!e"%ic

#ene&i% #y a"men%in %he %radi%iona$

inhi#i%ors o& RAS c"rren%$y in "se.3

One o& %he ha$$marks o& ne!hro!a%hy

is a$#"min"ria. Eidence &rom c$inica$

s%"dies3

and associa%ion da%a &rom %he

Third Na%iona$ Hea$%h and N"%ri%ion

E%hnici%y Disease+ Vo$"me 37+ A"%"mn 1667 S27


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E0amina%ion S"rey (NHANES III)

demons%ra%ed an inerse re$a%ionshi!

#e%'een %he $ee$ o& i%amin D and

deree o& a$#"min"ria.32

These &indins

s"es% %ha% i%amin D may hae an%i

!ro%ein"ric e&&ec%s+ $ike$y ia a RAS

anio%ensin IImedia%ed mechanism.

In addi%ion %o i%s ro$e in !roression o&

rena$ disease and !ro%ein"ria+ %he $oca$$y

syn%hesied in%rarena$ (a"%ocrine)

anio%ensin II has an e&&ec% on %he

cardioasc"$ar sys%em #y i%s e&&ec% on

#$ood !ress"re+ asc"$ar smoo%h m"sc$e

ce$$s and cardiac myocy%es.3

-eca"se

cardioasc"$ar disease is %he ma5or ca"se

o& dea%h in CKD !a%ien%s+ %he !o%en%ia$

ro$e o& i%amin D re!$e%ion %o !osi%ie$y

re"$a%e %his sys%em may #e 4"i%e

sini&ican% in a&&ec%in !rema%"re mor

%a$i%y associa%ed 'i%h CKD.2

Ano%her !a%h'ay sini&ican% inCKD+ 'hich may #e re"$a%ed #y %he

nonc$assica$ a"%ocrine ac%ions o& i%a

min D is %he N=k- !a%h'ay.+3F

N=k- re&ers %o a ro"! o& %ranscri!%ion

&ac%ors %ha% mod"$a%e enes ino$ed in

%he imm"ne res!onse as 'e$$ as in %he

!rocess o& in&$amma%ion and &i#rosis+

'hich "nder$ie %he !a%hoenesis o&

CKD. In CKD !a%ien%s+ i% a!!ears %ha%

N=k- may !$ay a ro$e in #o%h %he!roression o& rena$ disease and in

dia#e%ic ne!hro!a%hy.Ac%ia%ion o& %he

N=k# !a%h'ay %riers a cascade o&

een%s yie$din cy%okines+ chemokines

and o%her in&$amma%ory &ac%ors+ 'hich

e0acer#a%e %iss"e in5"ry in %he rena$

disease !rocess. In dia#e%ic ne

!hro!a%hy+ anio%ensin II a!!ears %o

ac%ia%e N=k-+ 'hich in %"rn ac%ia%es

anio%ensinoen e0!ression in rena$

ce$$s 'hen hy!er$ycemia is !resen%.3F

This cyc$e is $ike$y !ar%$y res!onsi#$e&or %he $oca$ acc"m"$a%ion o&

anio%ensin II in dia#e%ic

ne!hro!a%hy.+3F

Vi%amin D has #een

sho'n in n"mero"s s%"dies %o inhi#i% %he

ac%ia%ion o& N=k- and &"r%her s%"dies

hae sho'n an inerse re$a%ionshi!

#e%'een ser"m i%amin D $ee$s and %he

deree o& %iss"e in&$amma%ion !resen%

in ario"s %y!es o& kidney disease.+3F

Trea%men%?ien i%s ne' e0!anded ro$e+ %he

%rea%men% !aradim &or i%amin D

s"!!$emen%a%ion in CKD has no'

shi&%ed %o ass"re %ha% #o%h %he c$assica$

and nonc$assica$ re4"iremen%s are me%.

As CKD !roresses and rena$ mass

decreases+ %he a#i$i%y %o !rod"ce rena$

hydro0y$a%ed 3+12 i%amin D diminish

es and 3+12 i%amin D de&iciency

ens"es.3+

I% is %here&ore necessary %o

re!$e%e 3+12 i%amin D "sin ca$ci%rio$ or

i%s ana$o"es %o com!ensa%e &or %he

com!romised !rod"c%ion o& 3+12 i%a

min D+ 'hich occ"rs in %he $a%er s%aes

o& CKD (#eyond S%ae ) so %ha% %he

c$assica$ &"nc%ions o& hormona$ 3+12

i%amin D may #e addressed.3+

In con%ras% %o i%s c$assica$ endocrine&"nc%ion+ i% a!!ears %ha% in CKD %he

a"%ocrine &"nc%ion o& i%amin D remains

in%ac% as $on as 12(OH)i%amin D+ %he

necessary s"#s%ra%e+ is aai$a#$e.3No da%a

e0is% demons%ra%in %he $oss o& e0%rarena$

3a$!hahydro0y$ase ac%ii%y in any s%ae

o& CKD+3and+ in &ac%+ i% a!!ears %ha% %his

enyme ac%ii%y is main%ained een in

ane!hric !a%ien%s.3 A$%ho"h %he

mechanisms o& %hese a"%ocrine e0%rarena$

!a%h'ays remain "na&&ec%ed #y rena$

dys&"nc%ion+ !a%ien%s 'i%h CKD are

dis!ro!or%iona%e$y de&icien% in %he neces

sary s"#s%ra%e+ 12(OH)i%amin D+ #e

innin in %he ery ear$y s%aes o& %heir

disease.3++2

The reason &or %his marked

12(OH)i%amin D de&iciency een in ear$y

CKD is $ike$y m"$%i&ac%oria$ and d"e in

!ar% %o n"%ri%iona$ de&iciency1 as 'e$$ as

s"!erim!osed increased rena$ $oss o&

i%amin D #indin !ro%ein+ 'hich occ"rs as

a res"$% o& !ro%ein"ria+ a common

occ"rrence in CKD !a%ien%s.3+

?ien %he

!o%en%ia$ im!or%ance o& %hese a"%ocrine&"nc%ions and %heir e&&ec%s on %he

comor#idi%ies+ s"ch as cardioasc"$ar

disease &o"nd in associa%ion 'i%h CKD+2i%

is im!era%ie %ha% ade4"a%e amo"n%s o&

i%amin D or 12(OH)i%amin D #e

!roided %o s"!!or% %he !rod"c%ion o&

a"%ocrinederied ca$ci%rio$.3

In a$$ !a%ien%s+ ser"m $ee$s o& 12(OH)i%amin D are %he !rime indica%or

o& %he ade4"acy o& s"#s%ra%e !resen% %o&"e$ %he a"%ocrine !a%h'ays+ and %hese

$ee$s may a$so !redic% risk o& CVD and

mor%a$i%y in CKD.2+3

A$$ !a%ien%s+

inc$"din CKD !a%ien%s+ are considered

%o hae s"#o!%ima$ $ee$s o& i%amin D

'hen ser"m a$"es &a$$ #e$o' 6


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ade4"a%e re!$e%ion+ one common es%ima

%ion is %ha% &or each 366 I> o& i%amin D

adminis%ered+ %he ser"m $ee$ o& 12

(OH)i%amin D 'i$$ rise #y 3 nm@+

a$%ho"h %here is 'ide indiid"a$ aria

%ion in %he res!onse %o i%amin D dosin.1

To0ici%y does no% a!!ear %o #e a

sini&ican% !ro#$em 'i%h i%amin D

adminis%ra%ion #eca"se o& a 'ide marin

o& sa&e%y #e%'een doses recommended &or

re!$e%ion and doses considered "nsa&e.1+F

CONC@>SION

Vi%amin D has emered as a i%a$

com!o"nd in CKD 'i%h ne'$y ascri#ed

a"%ocrine &"nc%ions as%$y di&&eren% &rom

i%s c$assica$ &"nc%ion in minera$ homeos%asis. To inore %he sini&icance o& %his

i%amin and i%s !o%en%ia$ im!ac% on

mor#idi%y and mor%a$i%y in %he CKD

!a%ien% is no $oner a!!ro!ria%e.3+2+3

In

addi%ion %o %he %radi%iona$ s"!!$emen

%a%ion o& 3+12i%amin D %o CKD

!a%ien%s+ #y assessin and re!$e%in

12(OH) i%amin D de&iciency+ !hysi

cians 'i$$ ade4"a%e$y &"e$ #o%h %he rena$

and e0%rarena$ !a%h'ays o& ca$ci%rio$

syn%hesis+ main%ainin %he c$assica$ and

nonc$assica$ &"nc%ions o& i%amin D %ha%"$%ima%e$y in&$"ence c$inica$ o"%comes

in %his hihrisk ro"! o& !a%ien%s.

-eca"se o& %he hih ra%es o&

hy!oi%aminosis D and !roression o&

CKD %o ends%ae rena$ disease in

minori%y !o!"$a%ions+ %his a!!roach is

hih$y re$ean% %o na%iona$ e&&or%s %o

red"ce hea$%h dis!ari%ies. /rimary care

!hysicians are ca$$ed %o 5oin %he in%en

si&ied e&&or%s o& ne!hro$ois%s+ endocri

no$ois%s+ n"%ri%ionis%s+ o%her s!ecia$is%s

and !"#$ic hea$%h aencies %o dissemi

na%e and im!$emen% "!da%ed "ide$ines

and recommenda%ions %o ha$% %he ro'

in e!idemic o& i%amin D de&iciency+

!ar%ic"$ar$y in %he hih$y s"sce!%i#$e

CKD !o!"$a%ion. The res"$%s o& emer

in s%"dies may hera$d noe$ aen%s+'hich may &"r%her mod"$a%e %hese

i%amin Dre$a%ed ce$$ sina$in !a%h

'ays and con%ri#"%e %o many o& %he co

mor#idi%ies enco"n%ered in %he CKD

!a%ien% de&icien% in i%amin D.

DISC@AIMER

Kei%h Norris has receied honoraria

&rom A##o%%+ Amen+ Merck+ /&ier and

Monarch !harmace"%ica$s 'i%hin %he $as%3; mon%hs.

ACKNO*@ED?MENTS

Kei%h Norris is s"!!or%ed #y NIH ran%sRR33+ RR3332+ RR6371 andMD663;1.

RE=ERENCES3. Bones ?. E0!andin ro$e o& i%amin D in

chronic kidney disease: im!or%ance o& #$ood

12OHD $ee$s and e0%rarena$ 3ahydro0y

$ase in %he c$assica$ and nonc$assica$ ac%ionso& 3a+12dihydro0yi%amin D. Seminars inDia$ysis. 166F,16():3

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vit d dan ckd