uticaj antihipertenzivne terapije, unosa … filezlatni standard za skrining pa, odreÿivanje odnosa...

Tijana Lali

UTICAJ ANTIHIPERTENZIVNE TERAPIJE, UNOSA NATRIJUMA I KONCENTRACIJE KALIJUMA U PLAZMI NA KONCENTRACIJU ALDOSTERONA I PLAZMA RENINSKU AKTIVNOST

APSTRAKT: Uvod: Primarni aldosteronizam (PA) predstavlja grupu poreme aja koja se odlikuje neadekvatnom i nesupresibilnom produk-cijom aldosterona. Prevalenca PA je rastu a u hipertenzivnoj populaciji. Zlatni standard za skrining PA, odre ivanje odnosa (ARR) aldosterona i plazma reninske aktivnosti (PRA) posturalno, pod uticajem je brojnih endogenih i egzogenih faktora. Testiranje u optimalnim uslovima nije uvek mogu e.

Cilj rada: Utvrditi kakav je uticaj antihipertenzivnih lekova i koncentra-cije kalijuma i natrijuma u krvi i urinu na vrednosti aldosterona i plazma reninsku aktivnost.

Metod rada: U retrospektivnoj studiji analizirana je medicinska dokumentacija pacijenata primljenih na Odeljenje za bolesti štitaste žlezde u periodu 2009–2011. godine sa pove anim rizikom za primarni aldosteronizam. Kod svih pacijenata analizirani su telesna masa i visi-na, koncentracije natrijuma i kalijuma u serumu i urinu, koncentracije aldosterona u plazmi i PRA, podaci o lekovima u terapiji i pridruženim bolestima. Od statisti kih metoda koriš eni su metodi deskriptivne sta-tistike, Studentov T test i jednostruka linearna povezanost.

Rezultati: Od 137 pacijenata bilo je više pacijenata sa rezistentnom hipertenzijom (53,28%) nego sa tumorima nadbubrega (46,72%). Najviše pacijenata bilo je na terapiji kalcijumskim antagonistima. Terapija alfa adrenergi kim i kalcijumskim antagonistima ne uti e na ARR. Blokatori beta adrenergi kih receptora i ACE inhibitori mogu da uti u, a diuretici i vazodilatatori sigurno uti u. Dijabetes melitus može da nosi ve i rizik od lažno negativnih rezultata. Natriureza je zna ajno povezana sa plazma aldosteronom i kalijumom u serumu. Plazma aldosteron i PRA zna ajno su povezani sa koncentracijama elektrolita u urinu.

45UTICAJ ANTIHIPERTENZIVNE TERAPIJE, UNOSA NATRIJUMA I KONCENTRACIJE KALIJUMA...

Zaklju ak: Pove ana prevalenca primarnog aldosteronizma name e potrebu za preciznijom i boljom dijagnostikom.

Klju ne re i: aldosteron, PRA, lekovi, natrijum, kalijum

UVOD

Primarni aldosteronizam (PA) predstavlja grupu poreme aja u kojima je produkcija aldosterona neodgovaraju e velika, relativno autonomna i nesupre-sibilna nakon optere enja natrijumom (2). Najvažniji poreme aji su aldosteron produkuju i adenom (APA), unilateralna ili bilateralna hiperplazija nadbubrega (UAH ili BAH, IHA), glukokortikoidima korektibilan aldosteronizam (GKA) i aldosteron produkuju i adrenalni karcinom (1, 2). Od kada je Kon (Conn) 1954. godine prvi opisao klini ki sindrom hipertenzije, hipokalemije i metaboli ke al-kaloze kao rezultat autonomne produkcije aldosterona iz adenoma nadbubrega, brojna istraživanja pokušavaju da utvrde prevalencu ovog poreme aja (2). Primarni aldosteronizam je ranije smatran retkim i dijagnoza prakti no nije bila mogu a bez hipokalemije. Danas više od polovine pacijenata sa PA ima normalan kalijum (1). Novija istraživanja ukazuju na sve ve u prevalencu – više od 10% hipertenzivnih pacijenata, a od 5 do 20% u slu aju tip 2 dijabetesa i rezistentne hipertenzije (3). Primarni aldosteronizam je u osnovi 36,4% slu ajeva hipertenzije sa adrenalnim incidentalomima i ak 52% adrenalnih incidentaloma, otkrivenih ispitivanjem zbog hipertenzije (4). Procenjuje se da APA ini 30% a BAH oko 60% slu ajeva primarnog aldosteronizma.

Klini ke karakteristike aldosteronizma su nespeci ne i varijabilne. Zavise od veli ine ekscesa aldosterona i komorbiditeta. Na hiperaldosteronizam naj eš e upu uju hipertenzija, hipokalemija, hipervolemija bez edema i metaboli ka alkalo-za. Hipertenzija, eš e dijastolna, može da bude teška i refraktorna na standardnu antihipertenzivnu terapiju. U BAH pacijenti mogu da imaju neznatno pove an krvni pritisak, zbog ega hipertenzija nije sine qua non dijagnoze hiperaldosteronizma. Hipokalemija, ukoliko je prisutna, može da uzrokuje miši ne slabosti, gr eve i pare-stezije. Hipernatremija je retka. Posledica je retencije natrijuma, poliurije i resetovanja osmosata. Pove anu retenciju natrijuma prati po etna pove ana natriureza, fenomen poznat kao izmicanje od aktivnosti aldosterona (escape of aldosterone action). Rezul-tat je aktiviranja atrijalnog natriureti kog peptida. Metaboli ka alkaloza i pove anje serumskih bikarbonata, obi no je blaga, bez zna ajnih posledica i može da pro e neopaženo. Pove ane koncentracije aldosterona imaju direktne toksi ne efekte na kardiovaskularni sistem i bubrege, nezavisno od hipertenzije. U PA eš e postoje hipertro ja leve komore, ošte enje dijastolne i endotelne funkcije, zadebljane intime karotidnih arterija, pove ana albuminurija i snižena intrarenalna rezistenca nego u esencijalnoj hipertenziji sa istim nivoom pove anja krvnog pritiska. Hiperaldostero-

46 MEDICINSKI GLASNIK / str. 44-57

nizam je udružen sa ve om u estaloš u infarkta miokarda i moždanog udara. Postoje dokazi o povezanosti aldosteronizma i metaboli kog sindroma, odnosno hiperglikemije i insulinske rezistencije.

Odre ivanje odnosa aldosterona i plazma reninske aktivnosti posturalno (ARR) predstavlja skrining za primarni aldosteronizam u grupama sa pove anim rizikom. U Klini kom vodi u Endokrinološkog društva za otkrivanje, dijagnostiku i tretman primarnog aldosteronizma de nisane su grupe sa pove anim rizikom: 1) umerena do teška hipertenzija (160–179/100–109mmHg – umerena, >180mmHg/>110mmHg – teška), 2) rezistentna hipertenzija (krvni pritisak >140/90mmHg na terapiji sa tri i/ili više antihipertenzivnih lekova), 3) hipertenzivni pacijenti sa spontanom ili diureticima indukovanom hipokalemijom, 4) hipertenzija i slu ajno otkriven adrenalni adenom (incidentalom), 5) hipertenzija i porodi na anamneza za rani nastanak hipertenzije i ce-rebrovaskularnih doga aja pre 40. godine života, zbog pove ane sumnje na GKA.

Brojni faktori odre uju sekreciju aldosterona i/ili renina i mogu da uti u na vrednosti ARR u smislu lažno pozitivnih i lažno negativnih rezultata. Na vrednosti ARR uti u: životna dob, položaj, doba dana, dijeta, lekovi, pridružena stanja i bolesti. Stariji od 65 godina imaju mnogo niže vrednosti renina u odnosu na aldosteron, što vodi ve em broju lažno pozitivnih ARR. Uzimanje uzoraka u okviru testiranja za PA treba sprovoditi u bolni kim uslovima, ujutru, nakon osam sati ležanja u krevetu, dva sata sedenja, stajanja ili hodanja i 5–15 minuta sedenja. Važan je podatak o unosu soli jer restrikcija dovodi do zna ajnog osloba anja renina i aldosterona, odnosno smanjenja ARR i lažno negativnih rezultata, dok prekomeran unos ima suprotan efekat. Hipokalemija može da dovede do ve eg broja lažno negativnih vrednosti ARR, uglavnom uticajem na smanjenje aldosterona, dok prekomeran unos kalijuma daje mogu nost za lažno pozitivne rezultate. Potrebno je da se zna na kojoj terapiji su pacijenti i da li je testiranje sprovedeno u suboptimalnim uslovima. Od posebnog zna aja su antihipertenzivni lekovi, naro ito mineralokortikoidni antagonisti (MRA), kao i antidepresivi, nesteroidni antiin amatorni lekovi i preparati estrogena (oralni kontraceptivi, hormonska supstituciona terapija). Beta adrenergi ki blokatori i cen-tralni alfa agonisti (klonidin, metil-dopa) pove anjem vrednosti ARR pove avaju mogu nost lažno pozitivnih rezultata. Inhibitori angiotenzin konvertuju eg enzima, diuretici koji troše kalijum (amilorid i triamteren), blokatori angiotenzinskih recep-tora i dihidropiridinski blokatori kalcijumskih kanala svojim efektima na ARR daju mogu nost lažno negativnih rezultata. Da bi se umanjio uticaj lekova, savetuje se njihovo obustavljanje (washout period) tokom dve do etiri nedelje, odnosno etiri do šest nedelja u slu aju spironalaktona, eplerenona i diuretika koji štede kalijum. Ukidanje antihipertenzivnih lekova mogu e je u blagoj hipertenziji, ali može biti opa-sno u slu aju teške hipertenzije. Lekovi koji imaju minimalni efekat na ARR i mogu da se koriste za kontrolu krvnog pritiska tokom skrininga i testova potvr ivanja PA jesu: nondihidropiridinski antagonisti kalcijumskih kanala, alfa adrenergi ki blokatori


(prazosin, doksazosin, terazosin) i hidralazin. U drugim istraživanjima se nalazi da je testiranje mogu e kada se kontrola krvnog pritiska postiže primenom fosinoprila. Nesteroidni antireumatici pove avaju vrednost ARR i broj lažno pozitivnih slu ajeva PA. U slu aju inhibitora renina i oralnih kontraceptiva važno je da li se odre uje di-rektna koncentracija renina (DRC) u plazmi ili PRA. Obe grupe uti u na pove anje vrednosti DRC i lažno pozitivnih slu ajeva PA. Osim toga, uo eno je da komponente sistema renin-angiotenzin imaju najve e nivoe kada su koncentracije estrogena najviše, tokom lutealne faze menstrualnog ciklusa. Selektivni inhibitori preuzimanja serotonina kod normotenzivnih muškaraca mogu zna ajno da snize ARR, bilo da se odre uje PRA ili DCR. Na aldosteron i renin uti u bubrežna insu cijencija, renovaskularna hipertenzija, dijabetes i trudno a.

Zbog nedostatka uniformnosti dijagnosti kih protokola i eseja za merenje aldo-sterona i PRA postoji varijabilnost referentnih vrednosti za ARR. Neki autori predlažu da to budu vrednosti izme u 20 i 100, dok je za druge prihvatljiv opseg od 20 do 40. Jedni smatraju da je neophodno da su pove ane vrednosti aldosterona, > 15ng/dl, pored uve anog ARR, dok su drugi protiv grani nih vrednosti za aldosteron. Odnos ve i od 20 ukazuje na mogu i PA. ARR ve i od 30, u uslovima kada je aldosteron >15ng/dl, ima senzitivnost 90% i speci nost 91% za dijagnozu PA, a odnos ve i od 50 potvr uje dijagnozu. U opsegu 25–35 nalazi se ’siva zona’, u kojoj je ve a u estalost lažno po-zitivnih i negativnih rezultata. Tri ponovljena povišena rezultata ARR zahtevaju dalju potvrdu ili isklju ivanje autonomne sekrecije aldosterona primenom jednog od etiri testa: oralno optere enje natrijumom, akutna intravaskularna ekspanzija volumena izotoni nim slanim rastvorom, kaptoprilski i udrokortizonski test.

Kada je biohemijska dijagnoza PA potvr ena, neophodno je dalje ispitivanje u cilju otkrivanja etiologije ovog poreme aja. U utvr ivanju etiologije zna ajno mesto imaju radiološka ispitivanja i vizuelizacione metode. Serijski preseci na 3mm spi-ralnim CT-om predstavljaju najbolju radiološku metodu za vizuelizaciju nadbubrega i omogu avaju prepoznavanje tumora veli ine 5mm. Preporuka je da svi pacijenti sa PA budu podvrgnuti CT pregledu nadbubrega da bi se, izme u ostalog, isklju ilo postajanje adrenokortikalnog karcinoma. Magnetna rezonanca nadbubrega nema dodatnih prednosti u dijagnostici. Adrenokortikalna scintigra ja sa NP-59 (131J-6-b-jodometil-19-norholesterol) diferencira APA od IHA. Uzorkovanje adrenalnih vena je zlatni standard za lateralizaciju hipersekrecije aldosterona i diferentovanje unilateralne od bilateralne varijante PA. To je najsenzitivniji na in za dijagnostikovanje IHA i APA. Primenjuje se kada biohemijska i radiološka ispitivanja nisu dala konkluzivne rezultate. Kriterijumi za odre ivanje lateralizacije hipersekrecije aldosterona zavise od toga da li je uzorkovanje sprovedeno za vreme ACTH stimulacije. Odnos kortizol korigovanog aldosterona, izme u dve strane, za vreme kontinuirane ACTH stimulacije, koji je ve i od 4:1 ukazuje na unilateralni eksces aldosterona, dok odnos manji od 3:1 odgovara bilateralnoj hiperplaziji. Sa ovim referentnim vrednostima adrenalno vensko


uzorkovanje ima senzitivnost 95% i speci nost 100% u dijagnostici unilateralnog ekscesa aldosterona. Vrednosti izme u navedenih mogu da ukazuju na unilateralnu ili bilateralnu adrenalnu zahva enost. Bez ACTH stimulacije odnos lateralizacije 2:1 je dijagnosti ki za unilateralni eksces. U diferencijalnoj dijagnostici PA naj eš e se izvodi test posturalni odgovor aldosterona i PRA. Poželjno je da se test ponovi dva ili tri puta. Kod ranog nastanka, pre 20. godine života, potvr enog PA ili sa porodi nom istorijom za PA i/ili moždane udare u ranim godinama života, preporu uje se genetsko testiranje na GKA.

Unilateralna laparoskopska adrenalektomija je metod izbora za le enje pacijenata sa potvr enim PA, bilo APA ili UAH. Medikamentna terapija mineralokortikoidnim antagonistima savetuje se za pacijente koji ne mogu ili odbijaju da budu operisani. Ona je terapija izbora u slu ajevima IHA, bilateralnih APA i GKA. Mogu a je i pri-mena standardnih antihipertenzivnih lekova.

Kod pacijenata sa sumnjom na PA nije uvek mogu e prekinuti primenu antihi-pertenziva u odgovaraju em periodu i nije poznato na kakvoj su dijeti pacijenti.

Pacijenti sa PA imaju ve u incidencu kardiovaskularnih, cerebrovaskularnih i renalnih komplikacija. PA predstavlja naj eš i speci no le en i potencijalno izle iv uzrok sekundarne hipertenzije. Utvr ivanje uticaja pojedinih faktora na vrednosti aldosterona i PRA ima dijagnosti ki zna aj. Identi kovanjem pacijenata kod kojih su faktori doveli do promene aldosterona i plazma reninske aktivnosti poboljšava se dijagnostikovanje aldosteronizma.

CILJ RADA

Cilj rada je bio da se utvrdi kakav je uticaj antihipertenzivnih lekova i koncen-tracije kalijuma i natrijuma u krvi i urinu na vrednosti aldosterona i plazma reninsku aktivnost.

MATERIJAL I METODE

U retrospektivnoj studiji analizirana je medicinska dokumentacija pacijenata primljenih na Odeljenje za bolesti štitaste žlezde Klinike za endokrinologiju, dijabetes i bolesti metabolizma Klini kog centra Srbije u periodu od 2009. do 2011. godine. U istraživanje su uklju eni pacijenti sa hipertenzijom i hipokalemijom, tumorima nadbubrega, otkrivenim slu ajno (incidentalomi) ili ispitivanjem zbog hipertenzije, hiperplazijom nadbubrega, rezistentnom hipertenzijom. Kod svih pacijenata od zna aja za istraživanje bili su telesna masa i visina, indeks telesne mase, koncentracije natriju-ma i kalijuma u serumu i urinu, koncentracija aldosterona u plazmi i plazma reninska aktivnost, anamnesti ki podaci o lekovima u terapiji i pridruženim bolestima.


Uzorci krvi uzimani su ujutru do 9 h. Koncentracije elektrolita u serumu odre ivane su pomo u ISE jedinice za elektrolite OLYMPUS aparata. Dvadeset etvoro asovni urin sakupljan je u plasti nu posudu bez kiseline, odbacivanjem prve jutarnje mokra e na dan kada po inje sakupljanje, zaklju no sa prvim urinom slede eg jutra. Pacijentima je uzimana krv, za odre ivanje koncentracije aldosterona i plazma reninsku aktiv-nost, ujutru oko 9h, posle 8 sati ležanja i dva sata hodanja ili stajanja. Za odre ivanje aldosterona u serumu, plazmi i urinu koriš en je radioimunoesej ALDO-RIACT kit (referentne vrednosti za normalnu populaciju sa normalnim unosom soli su: 5. percentil 97, srednja vrednost 201, 95. percentil 626). Koriš en je REN-CT2 radioimunoesej kit za kvantitativno odre ivanje angiotenzina I u humanoj plazmi. Ovim esejem indirektno je merena plazma reninska aktivnost koja se izražava u ng angiotenzina I koji nastane u ml za jedan sat. Referentne vrednosti za ovaj esej pri unosu soli 100–150mmol/24h su: period mirovanja 0,2–2,8, napor 1,5–5,7.

Anamnezom su dobijani podaci o antihipertenzivnoj i drugoj terapiji, dijabetesu, bubrežnoj insu cijenciji i drugim bolestima. Dihotomno je ozna avana upotreba beta adrenergi kih antagonista, ACE inhibitora, kalcijumskih antagonista, vazodilatatora, alfa adrenergi kih antagonista, diuretika, kalijuma.

Podaci su analizirani primenom metoda deskriptivne i analiti ke statistike (Stu-dentov T test i jednostruka linearna povezanost). Za obradu je koriš en softverski paket SPSS 12.0.

REZULTATI

Ukupan broj pacijenata iji su podaci analizirani je 137.

Tabela 1. Zastupljenost pacijenata prema polu i druge antropometrijske karakteristike

Ž M Ukupno pacijenata

Pol 92 (67.15%) 45 (32.85%) 137

TV 81.36 ± 22.00 107

TM 167.24 ± 10.32 111

ITM 28.92 ± 7.47 107

Apsolutna u estalost pacijenata u odnosu na terapiju prikazana je na gra konu 1.

Gra kon 1 Distribucija pacijenata u odnosu na terapiju

Najve u srednju vrednost plazma aldosterona imalo je 13 pacijenata na terapiji alfa adrenergi kim antagonistima 221,8 (±122,4). Deset pacijenata sa dijabetesom na terapiji oralnim hipoglikemicima ili insulinom imalo je najmanje srednje vrednosti


aldosterona 110,4 (±75,53). Pacijenti koji nisu bili na terapiji imali su sli ne srednje vrednosti plazma aldosterona, sa izuzetkom nešto nižih srednjih vrednosti u grupama alfa adrenergi kih antagonista i druge terapije. Najve e srednje vrednosti PRA bile su u grupama na terapiji vazodilatatorima 4,64 (±5,45) i supstituciji kalijumom 4,66 (±5,45). Pacijenti na terapiji antagonistima alfa adrenergi kih receptora imali su naj-manju srednju vrednost PRA 2,659 (±2,83). Devedeset tri pacijenta koja nisu bila na terapiji antagonistima beta adrenergi kih receptora imali su najviše srednje vrednosti PRA 3,76 (±3,91). Najniže srednje vrednosti PRA me u pacijentima koji nisu bili na terapiji bile su u grupi Druga terapija 3,21 (±3,69). Srednje vrednosti plazma aldo-sterona bile su niže u grupi Tumori nadbubrega 167,74 (±109,8) u odnosu na druge dijagnoze 208,59 (±122,66), dok je srednja vrednost PRA bila niža u pacijenata sa hipertenzijom i/ili hipokalemijom 3,88 (±3,73) u pore enju sa tumorima nadbubrega 3,20 (±3,52).

Primenom t testa za procenu zna ajnosti razlike dva nezavisna uzorka dobijeni su rezultati prikazani u tabeli 2.

Tabela 2. Zna ajnost razlike srednjih vrednosti aldosterona, PRA i ARR kod pacijenata koji su bili na odre enoj terapiji i pacijenata iz grupe Tumori nadbubrega

Aldosteron PRA ARR

DA NE p DA NE p DA NE

blokatori 158,4 198,1 0,054 2,8 3,7 0,120 169,5 232,3

ACE inhibitori 151,4 200,9 0,032 3 3,7 0,300 122,1 259,3

Ca antagonisti 174,9 193,2 0,007 3,4 3,5 0,844 253,8 189,5

Diuretici 145,1 192,7 0,067 2,8 3,6 0,373 94,5 231,7

blokatori 221,8 182,9 0,292 2,7 3,6 0,29 237,9 212

Vazodilatatori 113,3 192,3 0,017 4,6 3,4 0,522 65,1 225,9

Dijabetes 196,2 180,6 0,464 2,9 3,5 0,503 122 222,5

KCL 161,6 188 0,635 4,6 3,4 0,579 99,9 220,3

Druga terapija 196,2 180,6 0,465 3,9 3,2 0,281 289,4 165,1

Tu nadbubrega 187,5 189,2 0,943 4,5 3,2 0,105 85,7 246,6

Primenom jednostruke linearne regresije u analizi povezanosti i zna ajnosti povezanosti dobijeni su rezultati koji su detaljno prikazani u tabeli 3.

Tabela 3. Koe cijent korelacije, veli ina uzorka i zna ajnost povezanosti razli itih varijabli

Postoji srednje jaka, pozitivna povezanost plazma aldosterona i koncentracija kalijuma i natrijuma u urinu. Povezanost plazma aldosterona i natriureze je statisti ki


zna ajna (p<0,05). Plazma reninska aktivnost pokazuje jaku pozitivnu povezanost sa koncentracijom kalijuma u urinu i srednje jaku statisti ki zna ajnu povezanost sa koncentracijom natrijuma u urinu (p<0,05). Koncentracija kalijuma u urinu pokazuje jaku mada ne i statisti ki zna ajnu korelaciju sa PRA. Povezanost sa koncentracijom aldosterona je srednje jaka, a sa koncentracijom natrijuma u urinu srednje jaka i sta-tisti ki zna ajna (p<0,05).

U ovom istraživanju utvr ena je zna ajna povezanost izme u koli ine natriju-ma u dvadeset etvoro asovnom urinu i plazma aldosterona (p<0,05) i koncentracije kalijuma u serumu (p<0,05). Koncentracija natrijuma u urinu pokazuje srednje jaku povezanost grani ne zna ajnosti sa plazma aldosteronom (p=0,05) i srednje jaku sta-tisti ki zna ajnu povezanost sa PRA (p<0,05). Statisti ki zna ajna povezanost postoji i sa kaliurezom (p<0,05) i koncentracijom kalijuma u urinu (p<0,05).

DISKUSIJA

U ovom istraživanju analizirani podaci dobijeni su od dva puta više osoba žen-skog pola. To je zna ajno jer postoje razlike u odnosu na pol u ziološkom reagova-nju sistema renin-angiotenzin na stimulatorne i inhibitorne uticaje, što je pokazano u istraživanjima (22,27). Drugi autori (16) isti u uticaj faze menstrualnog ciklusa, odnosno da komponente sistema renin-angiotenzin dostižu najviše vrednosti za vreme lutealne faze menstrualnog ciklusa (fenomen poznat kao ’aktivacija’ sistema renin-angiotenzin). Time se, u uslovima odre ivanja direktne koncentracije renina, objašnjava ve a incidenca lažno pozitivnih ARR kod hipertenzivnih žena u odnosu na muškarce. Aldosteronomi pokazuju ve u u estalost kod žena (1,2). Srednje vred-nosti indeksa telesne mase, dobijene u ovom istraživanju, odgovaraju prekomernoj uhranjenosti – blagoj gojaznosti. Rossi i saradnici (27) su pokazali da, i pored toga što postoji pozitivna povezanost BMI i plazma aldosterona u esencijalnoj hipertenziji, naro ito prekomerno uhranjenih–gojaznih osoba, nije bilo efekta na plazma aldosteron i ARR u PA. Analiza povezanosti u ovom radu pokazala je da BMI nije povezan ni sa jednom od varijabli zna ajnih za istraživanje, što se delimi no slaže sa rezultatima ovih autora. U ovom istraživanju bilo je više pacijenata sa rezistentnom i malignom hipertenzijom, hipertenzijom i hipokalemijom nego pacijenata sa hiperplazijom ili adenomom nadbubrega. U radu D. A. Calhouan i saradnika (20) navodi se da je rezistentna hipertenzija prisutna kod 10–30% osoba sa esencijalnom hipertenzijom. Primarni aldosteronizam je est uzrok rezistentne hipertenzije.

Najve a zastupljenost kalcijumskih antagonista u terapiji pacijenata iz ovog istraživanja je odraz injenice da su oni, prema vodi ima svetskog i evropskog udru-ženja za hipertenziju, me u naj eš e prepisivanim lekovima za le enje hipertenzije. To se posebno odnosi na dihidropiridne. Osim toga, injenica da se nedihidropiridinski kalcijumski antagonisti mogu koristiti za kontrolu krvnog pritiska tokom testiranja


primarnog aldosteronizma podržava tu u estalost (2,3). Inhibitori angiotenzin konver-tuju eg enzima veoma esto predstavljaju prvi terapijski izbor u le enju hipertenzije, ime se može objasniti njihova ve a zastupljenost. Sli no je i sa antagonistima beta

adrenergi kih receptora, naro ito u onim indikacijama u kojima imaju prednost. Ne-o ekivano je mali broj pacijenata sa dijabetes melitusom i pored direktne povezanosti dijabetesa i hipertenzije, posebno rezistentne hipertenzije (8, 10, 11, 13, 14). Mogu e objašnjenje za manji broj osoba sa dijabetesom je to što su podaci dobijeni od pacijenata primljenih na Odeljenje za bolesti štitaste žlezde. Time se može objasniti i ve i broj pacijenata na drugoj terapiji. Terapija blokatorima beta adrenergi kih receptora uticala je na promenu plazma koncentracije aldosterona, u smislu nižih srednjih vrednosti u pacijenata koji su bili na terapiji. Nije bilo promene PRA i ARR. I pored grani ne zna ajnosti navedene promene, terapija beta adrenergi kim antagonistima mogla bi da uti e na rezultate skrininga PA. U studiji Mulateroa i saradnika (3) terapija beta adrenergi kim antagonistima dovodi do statisti ki zna ajnog snižavanja PRA i plaz-ma aldosterona i na taj na in do ve eg ARR. U jednoj davnašnjoj studiji utvr eno je da propranol dovodi do redukcije metaboli kog klirensa aldosterona i, kako se ini, pove ava produkciju druga ijim mehanizmima od poznatih stimulusa. Istovremeno, na terapiji propranololom dolazi do snižavanja PRA za 25% (37). Propranolol je bio est u terapiji naših pacijenata. Pacijenti koji su bili na terapiji ACE inhibitorima

imaju statisti ki zna ajno niže srednje vrednosti plazma aldosterona. ACE inhibitori nisu uticali na PRA i ARR. Takvi rezultati se delimi no slažu sa rezultatima drugih istraživanja, prema kojima primena ACE inhibitora zna ajno uti e na ARR u smislu statisti ki zna ajno viših vrednosti PRA. Neki autori to povezuju sa ve im rizikom od lažno negativnih dijagnoza PA, dok, prema drugima, terapija fosinoprilom ne uti e na dijagnozu PA. Blokatori kalcijumskih kanala nisu uticali na promenu koncentracije aldosterona, PRA i ARR. To ne isklju uje mogu nost lažno negativnih dijagnoza zbog redukovanog ARR što je dobro poznat efekat naj eš e primenjivanih dihidropiridinskih blokatora kalcijumskih kanala (2,3). Diuretici nisu uticali pojedina no i nezavisno na koncentraciju aldosterona i PRA, ali su ipak uticali na ARR. Kod pacijenata koji su uzimali diuretike zna ajno su niže srednje vrednosti ARR i ve a je mogu nost lažno negativnih rezultata testiranja. U drugim istraživanjima (35) isti e se da dugotrajna primena tiazidnih diuretika akutno pove ava PRA sa dostizanjem maksimalnih vred-nosti unutar dve nedelje od po etka terapije. Prema rezultatima ovog rada, terapija alfa adrenergi kim antagonistima nije uticala na promenu plazma koncentracije aldosterona, PRA i ARR, što je u saglasnosti sa rezultatima drugih istraživanja i klini kim vodi em za dijagnostiku PA (2). Terapija vazodilatatorima uticala je na promenu plazma aldosterona i ARR. Pacijenti koji su uzimali vazodilatatore imali su zna ajno niže srednje vrednosti aldosterona i ARR bez promene PRA, u odnosu na pacijente koji nisu bili na ovoj terapiji. Primena vazodilatatora bi, dakle, mogla da pove a rizik od lažno negativnih slu ajeva PA tokom testiranja. U literaturi nema


mnogo podataka o uticaju organskih nitrita na aldosteron, PRA i ARR. U radovima drugih autora uglavnom se pominje hidralazin kao lek koji se može koristiti u toku skrininga, što zna i da je bez uticaja na komponente sistema renin-angiotenzin. Sup-stitucija kalijumom nije uticala na promenu koncentracije aldosterona, PRA i ARR. Time je potvr en zna aj korekcije hipokalemije koja bi uticala na ve i rizik od lažno negativnih slu ajeva PA (2,3). Pacijenti sa dijabetes melitusom imaju zna ajno niže srednje vrednosti koncentracije aldosterona u odnosu na nedijabeti are. Terapija za dijabetes nije uticala na promene PRA i ARR. N.K. Hollenberg i saradnici u svom radu iznose da pacijenti sa dijabetes melitusom pokazuju porast PRA, koncentracije angiotenzina II i plazma koncentracije aldosterona (41). Prema mišljenju drugih autora, ve ina pacijenata sa tipom 2 dijabetesa ima normalne cirkulišu e nivoe plazma aldo-sterona. Me utim, kod pacijenata sa dugotrajnim dijabetesom i disautonomijom može da bude narušena konverzija prekursora renina u dijabetesom ošte enom bubregu. Rezultat ovakvog stanja je sindrom hiporeninemijskog hipoaldosteronizma, u kome nagomilan prorenin uti e na stvaranje nestimulativnog renina i smanjenje aldosterona i nosi rizik za nastanak hiperkalemije. Kod pacijenata sa nekomplikovanim tipom 1 dijabetesa plazma aldosteron je relativno niži u odnosu na PRA, nezavisno od unosa soli (42). Primarni aldosteronizam je est u dijabeti ara sa rezistentnom hipertenzijom sa prevalencom od 14%.

Nije bilo promene plazma koncentracije aldosterona, PRA i ARR zavisno od klini ke dijagnoze. Prema tome, pre po etka skrininga za primarni aldosteronizam, na osnovu klini ke dijagnoze ne može se predvideti ishod testiranja. Podaci iz literature, me utim, pokazuju porast u estalosti PA u rezistentnoj hipertenziji. U izveštaju Clarck D. i koautora istaknuto je da se prevalenca PA u rezistentnoj hipertenziji kre e od 14 do 21% (45). Kao anatomski supstrat PA u rezistentnoj hipertenziji eš i je adrenalni adenom, dok je hiperplazija prisutna u drugim hipertenzivnim oblicima. Procenjuje se da je incidenca adrenalnih incidentaloma 8,4% u populaciji bez hipertenzije, a od 18,9 do 24,4% u hipertenzivnoj populaciji (57).

Rezultati ovog istraživanja pokazali su da postoji zna ajna povezanost natriu-reze, kao mere unosa soli, i koncentracija plazma aldosterona i kalijuma u serumu. Plazma koncentracije aldosterona i PRA su zna ajno povezane sa koncentracijama natrijuma i kalijuma u urinu. Osim toga, kaliureza i koncentracija kalijuma u urinu u korelaciji su sa koncentracijom natrijuma u urinu, i obrnuto. W.G. Walker i sarad-nici su u svom radu izneli da postoji visoko zna ajna i jaka povezanost aldosterona i urinarnog kalijuma, bilo da se on izražava preko koncentracije kalijuma u urinu ili odnosa kalijuma i kreatinina u urinu (kao mere izlu ivanja kalijuma) (46). Tako e su pokazali snažnu povezanost izme u koncentracije kalijuma u urinu i krvnog pritiska i slabu povezanost PRA i natrijuma. Oni su istakli zna aj kalijuma za aktivnost si-stema renin-angiotenzin, umesto natrijuma, koji je do tada smatran najodgovornijim (46). Jedna druga studija pokazala je da je pove ano urinarno izlu ivanje natrijuma


bilo snažno povezano sa niskim nivoima plazma aldosterona, pri emu je izlu ivanje natrijuma izraženo kao indeks natrijum/kreatinin (47, 48, 49, 52, 54).

ZAKLJU AK

Testiranju eš e mogu da budu podvrgnute pacijentkinje sa rezistentnom hiper-tenzijom. Najmanje uticaja na rezultate testiranja ima primena alfa adrenergi kih i kalcijumskih antagonista; blokatori beta adrenergi kih receptora i ACE inhibitori mogu da imaju uticaj. De nitivan uticaj na ARR imaju diuretici i vazodilatatori. Dijabetes melitus može da uti e, u smislu ve eg broja lažno negativnih rezultata. Utvr ivanje dijagnoze primarnog aldosteronizma mogu e je odre ivanjem koncentracije elektrolita u urinu umesto ukupne koli ine.

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Tijana Lali

INFLUENCE OF ANTIHYPERTENSIVE THERAPY, SODIUM INTAKE AND THE CONCENTRATION OF POTASSIUM IN PLASMA ON CONCENTRATION OF ALDOSTERONE AND PLASMA RENIN ACTIVITY

ABSTRACT: Introduction: Primary aldosteronism (PA) is a group of disorders which are characterized by inadequate and non-suppressi-ble production of aldosterone. The prevalence of PA is increasing in hypertensive population. The golden standard of screening for primary aldosteronism, determination of aldosterone/plasma renin activity (ARR), is in uenced by numerous exogenous and endogenous factors. Testing cannot always be conducted under optimal conditions.

Objective: To determine in uence of antihypertensive drugs and con-centrations of potassium and sodium in blood and urine on values of aldosterone and plasma renin activity.

Methods: In this retrospective study, we analyzed medical reports of patients admitted to Department of thyroid gland disease in the period from 2009 to 2011, with increased risk for primary aldosteronism. Body weight and height, sodium and potassium in serum and urine, plasma aldosterone concentrations and plasma renin activity, data on medicines and comorbidity were analyzed in all patients. In processing data, stati-stical methods descriptive analysis, Student T test and univariate linear regression were applied.

Result: Of 137 patients, there were more patients with resistant hyper-tension (53,28%) than with adrenal tumors (46,72%). Most patients used calcium channel blockers. Treatment with alpha blockers and calcium channel blockers does not in uence ARR. Beta blockers and ACE inhi-bitors can in uence ARR and diuretics and vasodilatators have de nite in uence. Diabetes mellitus can have higher risk of false negative results. Urine sodium excretion is signi cantly correlated with plasma aldoste-ron and serum potassium. Plasma aldosteron and PRA are signi cantly correlated with concentrations of electrolites in urine.

59INFLUENCE OF ANTIHYPERTENSIVE THERAPY, SODIUM INTAKE AND...

Conclusion: Increased prevalence of primary aldosteronism necessitates need for accurate and better diagnostics.

Key words: primary aldosteronism drugs sodium potassium correla-tions

INTRODUCTION

Primary aldosteronism (PA) is a group of disorders in which aldosterone produc-tion is inappropriately high, relatively autonomous and non-suppressible by sodium loading (2). The most important disorders are aldosterone producing adenoma (APA), unilateral or bilateral adrenal hyperplasia (UAH and BAH, IHA), glucocorticoid-remediable aldosteronism (GRA) and aldosterone producing adrenal carcinoma (1, 2). Since the Conn rst described, in 1954, the clinical syndrome of hypertension, hypokalemia and metabolic alkalosis as a result of the autonomous production of aldosterone from the adrenal adenoma, numerous studies are trying to determine the prevalence of this disorder (2). Primary aldosteronism was previously considered rare and the diagnosis was not practically possible without hypokalemia. Today, more than half of patients with PA have normal potassium (1). Recent studies point to the increasing prevalence - more than 10% of hypertensive patients, and from 5 to 20% in the case of type 2 diabetes and resistant hypertension (3). Primary aldosteronism is basically 36.4% of cases of hypertension with adrenal incidentaloma and 52% of adrenal incidentalomas, detected by examining the hypertension (4). It is estimated that APA makes 30% and BAH about 60% of cases of primary aldosteronism.

Clinical characteristics of aldosteronism are nonspeci c and variable. They depend on the size of excess aldosterone and comorbidity. Hyperaldosteronism is usually indicated by hypertension, hypokalemia, edema, and hypervolaemia without metabolic alkalosis. Hypertension, frequently diastolic, can be severe and refractory to standard antihypertensive therapy. In BAH, patients may have a slight increase in blood pressure due to hypertension is not a sine qua non hyperaldosteronism diagno-sis. Hypokalemia, if present, may cause muscle weakness, cramps, and paresthesias. Hypernatremia is rare. It is the consequence of sodium retention, polyuria and osmosat reset. Increased sodium retention follows starting increased natriuresis, a phenome-non known as a escape of aldosterone activity (escape of aldosterone action). The result is activation of atrial natriuretic peptide. Metabolic alkalosis and increased serum bicarbonate, is usually mild, with no signi cant consequences and may pass unnoticed. Increased concentrations of aldosterone have direct toxic effects on the cardiovascular system and kidneys, independent of hypertension. Patients with PA may have left ventricular hypertrophy, impaired diastolic and endothelial function, carotid artery intima thickened, increased albuminuria and reduced intrarenal resistance, compared to the same level of increase in blood pressure in essential hypertension.


Hyperaldosteronism is associated with an increased risk of myocardial infarction and stroke. There is evidence of links between aldosteronism and metabolic syndrome, or insulin resistance and hyperglycemia.

Determination of aldosterone plasma renin activity ratio (ARR or postural al-dosterone/PRA ratio) is a screening for primary aldosteronism in high risk groups. Clinical guide of endocrine society for the detection, diagnosis and treatment of primary aldosteronism de nes high risk groups: 1) patients with moderate to severe hypertension (160-179/100-109mmHg - moderate,> 180mmHg /> 110mmHg - seve-re), 2) resistant hypertension (blood pressure > 140/90mmHg on therapy with three and / or more antihypertensive drugs), 3) hypertensive patients with spontaneous or diuretic-induced hypokalemia, 4) hypertension and accidentally discovered adrenal adenoma (incidentaloma), 5) hypertension and family history of early development of hypertension and cerebrovascular events before the age of 40, due to increased suspicion of GKA.

Many factors determine the secretion of aldosterone and/or renin and may affect the value of the ARR in terms of false positive and false negative results. ARR value is in uenced by: age, posture, time of day, diet, medications, associated conditions and diseases. Older than 65 years have much lower values of renin compared to al-dosterone which leads to a greater number of false-positive ARR. Sampling in tests of PA should be given in hospital, the morning after eight hours of lying in bed, two hours of sitting, standing and walking and sitting 5-15 minutes. A noteworthy fact about salt intake, because of restrictions, leads to a signi cant release of renin and aldosterone, or reduction in ARR and false negative results, while excessive intake has the opposite effect. Hypokalemia can lead to more false-negative ARR values , mainly in uenced by the decrease in aldosterone, while excessive intake of pota-ssium gives a possibility for false-positive results. It is necessary to know on which therapy patients and whether the test was conducted under less than ideal conditions. Of particular importance are the antihypertensive drugs, especially mineralocorticoid antagonists (MRA), and antidepressants, nonsteroidal anti-in ammatory drugs and preparations of estrogen (oral contraceptives, hormone replacement therapy). Beta-adrenergic blockers and central alpha agonists (clonidine, methyl-dopa) increase the possibility of false positive results by increasing the value of the ARR. Angiotensin converting enzyme inhibitors, diuretics sparing potassium (amiloride and triamtere-ne), angiotensin receptor blockers and dihydropyridine calcium channel blockers, in their effects on the ARR, give the possibility of false negative results. In order to reduce the in uence of drugs, their discontinuance is advised (washout period), for two weeks, or four to six weeks in the case spironalakton, eplerenone and diuretics. Reversal of antihypertensive drugs can be in mild hypertension, but can be dangerous in the event of severe hypertension. Drugs that have a minimal effect on the ARR and that can be used to control blood pressure during the screening and con rmation


tests of PA are: nondihydropyridine calcium channel antagonists, alpha adrenergic blockers (prazosin, doxazosin, terazosin) and hydralazine. Some other studies show that testing is possible when the blood pressure control is achieved through the use of fosinopril. Nonsteroid antyreumatics increase the value of the ARR and the number of false-positive cases of PA. In the case of renin inhibitors and oral contraceptives it is important whether to determine the direct renin concentration (DRC) in plasma or PRA. Both groups in uence on increase of the values of DRC and false positive cases of PA. In addition, it was observed that the components of the renin-angioten-sin system have the highest levels when estrogen concentrations are highest during the luteal phase of the menstrual cycle. Selective serotonin reuptake inhibitors with normotensive men can signi cantly lower the ARR, either the PRA or DCR is deter-mined. Aldosterone and renin is in uenced by renal failure, renovascular hypertension, diabetes and pregnancy.

Because of the lack of uniformity of diagnostic protocols and assay for measure-ment of aldosterone and PRA, there is variability of normal values for the ARR. Some authors suggest that those values should be between 20 and 100, while for others, acceptable range is 20 to 40. Some believe that it is essential that higher levels of aldosterone, > 15ng/dl, in addition to increased ARR, while others are against limit values of aldosterone. Ratio greater than 20 indicates a possible PA. ARR greater than 30, in conditions where aldosterone > 15ng/dl, has sensitivity of 90% and speci city of 91% for the diagnosis of PA, but ratio greater than 50 con rms the diagnosis. In the range between 25-35 there is a gray zone in which there is a higher incidence of false positive and negative results. Three repeated elevated ARR results require fur-ther con rmation or exclusion of autonomous aldosterone secretion by applying one of four tests: oral sodium load, acute intravascular volume expansion with isotonic saline solution, udrocortisone and captopril test.

Once the biochemical diagnosis of PA is con rmed, further research is necessary to uncover the etiology of this disorder. In determining the etiology, the important role have radiological surveys and visualization methods. Serial sections at 3mm spiral CT are the best method for radiological visualization of the adrenal tumor and allow identi cation of the size of 5mm tumor. It is recommended that all patients with PA undergo CT of the adrenal gland that would, among other things, exclude presence of adrenocortical carcinoma. Magnetic resonance imaging of renal glands has no additional bene ts in diagnosis. Adrenocortical scintigraphy with NP-59 (131I-6-B-19-jodomethyl norcholesterol) differentiate APA from IHA. Adrenal venous sampling is the gold standard for lateralization of aldosterone hypersecretion and differentiation of unilateral from bilateral PA variants. That was the most sensitive method for dia-gnosing IHA and APA. It is used when biochemical and radiological tests have not yielded conclusive results. The criteria for determining the lateralization of aldosterone hypersecretion depend whether sampling was conducted during the ACTH stimula-


tion. Cortisol corrected aldosterone ratio between the two sides continued during the ACTH stimulation, which is higher than 4:1 indicates on unilateral aldosterone excess, while the ratio lower than 3:1 match bilateral hyperplasia. With these reference values, adrenal vein sampling has a 95% sensitivity and 100% speci city in the diagnosis of unilateral aldosterone excess. Values between mentioned may indicate on unilateral or bilateral adrenal involvement. Without ACTH stimulation, lateralization ratio 2:1 is diagnostic for unilateral excess. In the differential diagnosis of PA, the most com-monly performed test is postural response to aldosterone and PRA. It is desirable that the test is repeated two or three times. In the early beginning, before 20 years of age, a certi ed PA, or with a family history of PA and/or stroke at an early age, genetic testing is recommended at GKA.

Unilateral laparoscopic adrenalectomy is the method of choice for the tre-atment of patients with confirmed PA, either APA or UAH. Pharmacological treatment of mineralocorticoid receptor antagonists is advised for patients who cannot be, or refuse to be operated on. It is the treatment of choice in cases of IHA, bilateral APA and GKA. It is possible to use standard antihypertensive drugs.Patients with suspected PA it is not always possible to discontinue the use of antihyperten-sive drugs in the corresponding period and it is not known on what kind of diet they are.Patients with PA have a higher incidence of cardiovascular, cerebrovascular and renal complications. PA is the most common speci cally treated and potentially curable cause of secondary hypertension. Determining the impact of various factors on the values of aldosterone and PRA has diagnostic signi cance. Identifying patients with whom the factors led to the changes of plasma aldosterone and PRA activities, the diagnosis of aldosteronism is improved.

OBJECTIVE

The aim of this study was to determine the impact of antihypertensive drugs and the concentration of potassium and sodium in the blood and urine on the values of aldosterone and plasma renin activity.

MATERIALS AND METHODS

In a retrospective study medical records of the patients admitted to the Depar-tment of thyroid disease Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Center of Serbia in the period since 2009. to 2011 were analyzed. The study included patients with hypertension and hypokalemia, adrenal tumors, detected inci-dentally (incidentalomas) or tested because of hypertension, adrenal hyperplasia and resistant hypertension. With all patients, of the importance for the research were body


weight, height, body mass index, concentrations of sodium and potassium in serum and urine concentrations in plasma aldosterone and plasma renin activity and history data on drugs in therapy and associated diseases.

Blood samples were taken in until 9am. Electrolyte concentrations in serum were determined by ISE unit of OLYMPUS apparatus for electrolytes. Twenty-four hours urine was collected in a plastic container without acid, discarding the rst morning urine on the day of collection, ending with the rst urine the next morning. Patients’ blood samples were taken for determination of plasma concentrations of aldosterone and renin activity, at around 9am, after 8 hours of lying down and two hours of walking or standing. For the determination of aldosterone in serum, plasma and urine radioimmunoassay kit ALDO-RIACT was used (reference values for the normal population with a normal salt intake are: 5th percentile 97, 201 median, 95th percentile 626). For the quantitative determination of angiotensin REN-CT2 radioi-mmunoassay kit was used in human plasma. Plasma PRA activities were indirectly measured with this assay which is expressed in ng angiotensin I, which occurs in ml per hour. Reference values for this essay under salt intake of 100-150mmol/24h are: idle period from 0.2 to 2.8, 1.5 to 5.7 effort.

Medical history data were obtained on the second and antihypertensi-ve therapy, diabetes, kidney failure and other diseases. Dichotomously, use of beta-adrenergic antagonists, ACE inhibitors, calcium antagonists, vaso-dilators, alpha adrenergic antagonists, diuretics, potassium was denoted.Data were analyzed using the methods of descriptive and analytical statistics (Student’s T test and a single linear relationship). For processing, the software package SPSS 12.0.

RESULTS

Total number of patients whose data were analyzed is 137.

Table 1 Representation of patients by gender and other anthropometric characteristics

Ž M Ukupno pacijenata

Pol 92 (67.15%) 45 (32.85%) 137

ì TV 81.36 ± 22.00 107

ì TM 167.24 ± 10.32 111

ITM 28.92 ± 7.47 107

The absolute frequency of patients in relation to treatment is shown in Chart 1.


Figure 1 Distribution of patients in relation to treatment

The highest mean value of plasma aldosterone were found in 13 patients treated with alpha adrenergic antagonists 221.8 (± 122.4). Ten patients with diabetes treated with insulin or oral hypoglycemic agents had at least mean aldosterone 110.4 (± 75.53). Patients who were not on therapy had similar mean values of plasma aldosterone, with the exception of slightly lower average value of alpha adrenergic antagonist groups and other therapies. The highest average PRA were in groups treated with vasodilators 4.64 (± 5.45) and the substitution of potassium 4.66 (± 5.45). Patients treated with alpha adrenergic receptor antagonists had the lowest mean PRA 2.659 (± 2.83). Ninety-three patients who were not treated with beta adrenergic receptor antagonists had the highest mean values of PRA 3.76 (± 3.91). The lowest mean PRA among patients who were not on therapy were in the second therapy group 3.21 (± 3.69). Mean values of plasma aldosterone were lower in the group of tumors of the adrenal 167.74 (± 109.8) compared to other diagnoses 208.59 (± 122.66), while the mean value of the PRA was lower in patients with hypertension and/or hypokalemia 3.88 (± 3.73) compared with the tumor that was 3.20 (± 3.52).

Results presented in Table 2 were obtained by the use of T test to assess the signi cance of difference of two independent samples.

Table 2 The signi cance of differences in the mean values of aldosterone, PRA and ARR in patients who were on therapy and some patients in the tumor group

Aldosteron PRA ARR

DA NE p DA NE p DA NE p

â blokatori 158,4 198,1 0,054 2,8 3,7 0,120 169,5 232,3 0,471

ACE inhibitori 151,4 200,9 0,032 3 3,7 0,300 122,1 259,3 0,052

Ca antagonisti 174,9 193,2 0,007 3,4 3,5 0,844 253,8 189,5 0,513


Diuretici 145,1 192,7 0,067 2,8 3,6 0,373 94,5 231,7 0,014

á blokatori 221,8 182,9 0,292 2,7 3,6 0,29 237,9 212 0,797

Vazodilatatori 113,3 192,3 0,017 4,6 3,4 0,522 65,1 225,9 0,005

Dijabetes 196,2 180,6 0,464 2,9 3,5 0,503 122 222,5 0,226

KCL 161,6 188 0,635 4,6 3,4 0,579 99,9 220,3 0,155

Druga terapija 196,2 180,6 0,465 3,9 3,2 0,281 289,4 165,1 0,237

Tu nadbubrega 187,5 189,2 0,943 4,5 3,2 0,105 85,7 246,6 0,005

By using single linear regression analysis of the correlation and signi cance of correlation obtained results are detailed in Table 3.

Table 3 The correlation coef cient, sample size and signi cance of the association between different variables


There is a medium strong, positive correlation between plasma aldosterone concentration of potassium and sodium in the urine. Correlation between plasma aldosterone and natriuresis was statistically signi cant (p <0.05).

Plasma renin activity shows a strong positive correlation with the concentration of potassium in the urine and medium strong statistically signi cant correlation with the concentration of sodium in the urine (p <0.05). The concentration of potassium in the urine shows a strong but not statistically signi cant correlation with PRA. Correlation with the concentration of aldosterone is medium strong, and with the concentration of sodium in the urine is also medium strong and statistically signi cant (p <0.05).

The study found a signi cant relationship between the amount of sodium in the twenty-four hour urine, and plasma aldosterone (p <0.05) and serum potassium concentrations (p <0.05). The concentration of sodium in the urine indicates a strong connection of high marginal signi cance with plasma aldosterone (p = 0.05) and me-dium strong statistically signi cant association with the PRA (p <0.05). Statistically signi cant correlation exists with kaliuresis (p <0.05) and with the concentration of potassium in the urine (p <0.05).

DISCUSSION

This study evaluated data from two times more females. This is important because there are differences based on gender in the physiological response of the renin-angiotensin system on the stimulatory and inhibitory effects, as demonstrated in research (22,27). Other authors (16) assert the effects of menstrual cycle phase, and that the components of the renin-angiotensin system reach highest values during the luteal phase of the menstrual cycle (a phenomenon known as “activation” of the renin-angiotensin system). Thus, in terms of determining the direct renin concentra-tion, a higher incidence of false-positive ARR in hypertensive women is explained compared to men. Aldosteronoma show a higher prevalence in women (1,2). The mean body weight obtained in this study correspond to excessive nutritional status - mild obesity. Rossi et al (27) have shown that, besides a positive association of BMI and plasma aldosterone in essential hypertension, especially over-fed-obese subjects, there was no effect on plasma aldosterone and ARR in PA. Correlation analysis in this study showed that BMI is not associated with any of the variables relevant to the study, what partially agrees with the results of these authors. In this study, there were more patients with resistant and malignant hypertension, hypokalemia and hypertension than patients with adrenal hyperplasia or adrenal adenoma. In paper of D. A. Calhoun and associates (20) it is stated that resistant hypertension is present in 10-30% of persons with essential hypertension. Primary aldosteronism is a common cause of resistant hypertension.


The highest incidence of calcium antagonists in the treatment of patients in this study is a re ection of the fact that they are, according to the guides of World and the European Society of Hypertension, among the most widely prescribed drugs for the tre-atment of hypertension. This is especially referred to dihydropyridines. In addition, the fact that non dihydropyridine calcium antagonists can be used to control blood pressure during the test for primary aldosteronism, supports this frequency (2,3). Angiotensin converting enzyme inhibitors are often the rst therapeutic choice in the treatment of hypertension, which may explain their higher prevalence. It is similar to the beta adrenergic receptor antagonists, especially in those indications in which they have an advantage. Unexpectedly, there is a small number of patients with diabetes mellitus in spite of the direct connection between diabetes and hypertension, especially resistant hypertension (8,10,11,13,14). A possible explanation for the small number of people with diabetes is that the data were obtained from patients admitted to the Department of thyroid disease. This can be explained by the greater number of patients in other therapies. Treatment of beta adrenergic receptor blockers resulted in a change in plasma aldosterone, in terms of lower mean values in the patients who were in therapy. There was no change in PRA and ARR. Despite the marginal signi cance of these changes, the beta adrenergic antagonist therapy could affect the results of the screening of PA. In the study of Mulateroa and associates (3), beta adrenergic antagonist therapy leads to a statistically signi cant decrease in PRA and plasma aldosterone and thus to increased ARR. In one study, it was found that propranolol reduces the aldosterone metabolic clearance and, it seems, increases the production of different mechanisms of the known stimuli. At the same time, the treatment with propranolol leads to reduc-tion of PRA by 25% (37). Propranolol was common in the treatment of our patients. Patients who were treated with ACE inhibitors had a signi cantly lower mean plasma aldosterone. ACE inhibitors had no effect on PRA and ARR. These results partially agree with the results of other studies, where the use of ACE inhibitors signi cantly affect the ARR in terms of signi cantly higher PRA values. Some authors relate that to a higher risk of false-negative diagnoses of PA, while for others fosinopril therapy does not affect the diagnosis of PA. Calcium channel blockers had no effect on the concentrations of aldosterone, PRA and ARR. This does not exclude the possibility of false-negative diagnoses due to reduced ARR, which is a well-known effect of most used dihydropyridine calcium channel blockers (2,3). Diuretics had not in uenced the individual and independent concentration of aldosterone and PRA, but they in uenced the ARR. In patients which were taking diuretics, there is a signi cantly lower mean of ARR and the greater the possibility of false negative test results. In other studies, it is pointed out that the long-term use of thiazide diuretics acutely increases PRA, and that the time to reach maximum values is within two weeks since the beginning of the therapy. The results of this study, alpha adrenergic antagonist therapy did not affect the change in plasma concentration of aldosterone, PRA and ARR, which is


in agreement with results of other research and clinical guidelines for the diagnosis of PA (2). Vasodilators therapy resulted in a change in plasma aldosterone and ARR. Patients taking vasodilators had signi cantly lower mean values of aldosterone and ARR, without PRA changes, compared to patients who were not on this therapy. The use of vasodilators could, therefore, increase the risk of false-negative cases of PA during testing. In the literature, there is little data on the impact of organic nitrites on aldosterone, PRA and ARR. In the works of other authors, it is generally referred that a drug called hydralazine can be used during the screening, which means that it is without the in uence on the components of the renin-angiotensin system. Sub-stitution of potassium had no effect on the concentrations of aldosterone, PRA and ARR. This con rmed the importance of the correction of hypokalemia, which would affect a greater risk of false-negative cases of PA (2,3). Patients with diabetes mellitus have a signi cantly lower mean concentration of aldosterone than non-diabetics. The therapy for diabetes did not affect the change in PRA and ARR. N. K. Hollenberg and colleagues, in their work indicate that patients with diabetes mellitus show an increase in PRA, angiotensin II concentration and plasma aldosterone concentration (41). In the opinion of other authors, most patients with type 2 diabetes have normal circulating levels of plasma aldosterone. However, in patients with long-term diabetes and dysautonomia, conversion of precursors of renin may be disrupted in diabetes damaged kidney. The result of this situation is hyporeninemic hypoaldosteronism syndrome, in which the accumulated prorenin affects the formation of non- stimulated renin and aldosterone reduction and carries the risk of hyperkalemia. In patients with uncomplicated type 1 diabetes, plasma aldosterone is relatively lower compared to the PRA, independent of salt intake (42). Primary aldosteronism is common in diabetic patients with resistant hypertension with a prevalence of 14%.

There was no change in plasma concentrations of aldosterone, PRA and ARR depending on the clinical diagnosis. Therefore, before the screening of primary aldo-steronism, based on clinical diagnosis, the outcome of the test cannot be predicted. Data from the literature, however, show an increase of the PA frequency in resistant hypertension. In the report of D. Clark and co-authors, it is noted that the PA prevalence in resistant hypertension ranges from 14 to 21% (45). As anatomical PA substrate in resistant hypertension, adrenal adenoma is more common, and hyperplasia is present in other hypertensive forms. It is estimated that the incidence of adrenal incidental is 8.4% of the population without hypertension, and from 18.9-24.4% in the hyper-tensive population(57). The results of this study showed that there was a signi cant correlation between natriuresis, as a measure of salt intake, and plasma concentrations of aldosterone and potassium levels. Plasma concentrations of aldosterone and PRA were signi cantly correlated with the concentrations of sodium and potassium in urine. In addition, kaliuresis and potassium concentrations in urine are correlated with the concentration of sodium in urine, and vice versa. W.G. Walker and colleagues in their


work demonstrated that there is a highly signi cant and strong association between aldosterone and urinary potassium, whether it is expressed through the concentration of potassium in urine or the relationship of potassium and creatinine in urine (as a me-asure of excretion of potassium) (46). They also showed a strong correlation between the concentration of potassium in urine and blood pressure, and weak associations between PRA and sodium. They stressed the importance of potassium for activity of the renin-angiotensin system, instead of sodium, which until then was considered the most responsible (46). Another study showed that the increased urinary excretion of sodium was strongly associated with low levels of plasma aldosterone, with the excre-tion of sodium expressed as an index of sodium/creatinine (47, 48, 49, 52, 54).

CONCLUSION

Patients with resistant hypertension may be more often subjected to testing. The least impact on the results of the test had administered alpha blockers and calcium antagonists. Beta-adrenergic receptor blockers and ACE inhibitors may have an im-pact. Diuretics and vasodilators have de nite impact on ARR. Diabetes mellitus can affect, with a greater number of false negative results. Establishing the diagnosis of primary aldosteronism is possible by determining the concentration of electrolytes in urine instead of the total amount.

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