Classification of hydration in clinical conditions: indirect and direct approaches using bioimpedance

nu ien s Re iew Classi ica ion o Hyd a ion in Clinical Condi ions: Indi ec and Di ec App oaches Using Bioimpedance Hen y C. Lukaski 1, Nicano Vega Diaz 2, An onio Tallu i 3and Lexa Nescola de 4,* 1Depa men o Kinesiology and Public Heal h Educa ion, Uni e si y o No h Dako a, G and Fo ks, ND 58202-7166, USA; hen y[email p o ec ed] 2Neph ology Se ice, Uni e si y Hospi al o G and Cana y and Facul y o Science, Uni e si y Los Palmas, 35019 Los Palmas, G and Cana y, Spain; [email p o ec ed] 3An onio Tallu i, Fa by e, Inc., 50012 Bagno a Ripoli, Flo ence, I aly; [email p o ec ed] 4Depa men o Elec onic Enginee ing, Uni e si a Poli ècnica de Ca alunya, 08034 Ba celona, Spain *Co espondence: [email p o ec ed]; Tel.: +34-93-4137286 Recei ed: 5 Ma ch 2019; Accep ed: 8 Ap il 2019; Published: 10 Ap il 2019   Abs ac : Al hough he need o assess hyd a ion is well ecognized, labo a o y es s and clinical imp essions a e imp ac ical and lack sensi i i y, espec i ely, o be clinically meaning ul. Di e en app oaches use bioelec ical impedance measu emen s o o e come some o hese limi a ions and aid in he classi ica ion o hyd a ion s a us. One indi ec app oach u ilizes single o mul iple equency bioimpedance in eg ession equa ions and heo e ical models, espec i ely, wi h an h opome ic measu emen s o p edic luid olumes (bioelec ical impedance spec oscopy—BIS) and es ima e luid o e load based on he de ia ion o calcula ed o e e ence ex acellula luid olume. Al e na i ely, bioimpedance ec o analysis (BIVA) uses di ec phase-sensi i e measu emen s o esis ance and eac ance, measu ed a 50 kHz, no malized o s anding heigh , hen plo ed on a bi a ia e g aph, esul ing in a ec o wi h leng h ela ed o luid con en , and di ec ion wi h phase angle ha indexes hyd a ion s a us. Compa ison wi h heal hy popula ion no ms enables BIVA o classi y (no mal, unde -, and o e -) and ank (change ela i e o p e- ea men ) hyd a ion independen o body weigh . Each app oach has wide- anging uses in e alua ion and managemen o clinical g oups wi h o e -hyd a ion wi h an e ol ing emphasis on p ognosis. This e iew discusses he ad an ages and limi a ions o BIS and BIVA o hyd a ion assessmen wi h commen s on u u e applica ions. Keywo ds: luid o e load; esis ance; eac ance; bioelec ical impedance ec o analysis; bioelec ical impedance spec oscopy; malnu i ion 1. In oduc ion Rou ine assessmen o hyd a ion s a us o suppo pa ien ca e pe sis s as a challenge. The p eponde ance o me hods su e s om imp ac icali y and insensi i i y [ 1 , 2 ]. His o ically, hyd a ion assessmen was synonymous wi h he use o ace dilu ion me hods o es ima e o al body wa e (TBW), ex acellula wa e (ECW), and plasma olume (PV) wi h he calcula ion o in acellula wa e (ICW, ICW = TBW − ECW). This app oach is in asi e, ime-consuming, cos ly, and p one o ambiguous in e p e a ions o hyd a ion s a us because o eliance on he assump ion o cons an TBW o body weigh (% TBW), which is p ejudiced by in e -indi idual di e ences in body composi ion (adipose, muscle mass, o cachexia) , o TBW o a - ee mass (FFM) (% TBW/FFM) ha equi es an independen de e mina ion o FFM [ 3 – 6 ]. Thus, he measu emen o luid olumes o assess human hyd a ion s a us has limi ed alue. Labo a o y es s o plasma o se um cons i uen s (osmolali y, sodium, na iu e ic pep ide, and o he p omising p o eins), u ine cha ac e is ics (osmolali y, speci ic g a i y, conduc i i y, and 24-h Nu ien s 2019,11, 809; doi:10.3390/nu11040809 www.mdpi.com/jou nal/nu ien s Nu ien s 2019,11, 809 2 o 22 ou pu ), and sali a and ea composi ion (osmolali y) ha e inadequa e easibili y and lack sensi i i y in a clinical se ing [ 2 ]. Imaging echniques ( adiog aphy and ul asound) and in asi e p ocedu es (ca he iza ion) a e cos ly and ail o iden i y ea ly dis u bances in hyd a ion. Simple assessmen s such as sel - epo ed hi s , pa ien his o y, and physical examina ion a e subjec i e and lack sensi i i y [ 2 , 7 ]. Thus, he need pe sis s o a me hod ha is non-in asi e, alid (accu a e and sensi i e), p ac ical, cos -e ec i e, and p o ides eal- ime disc imina ion wi hin he spec um o he hyd a ion s a us. Classi ica ion o hyd a ion as no mal, less, o g ea e han no mal is a p ac ical and alid app oach ha can o e come hese limi a ions. Bu geoning e idence suppo s bioelec ical impedance as a unique and p omising me hod o classi y he hyd a ion s a us o an indi idual. Bioimpedance (BI) is he gene al e m desc ibing he sa e, non-in asi e measu emen o he passi e elec ical cha ac e is ics o an o ganism a e in oduc ion o a painless, low-le el al e na ing cu en in o he body [ 8 – 10 ]. Bioimpedance analysis (BIA), howe e , augmen s BI measu emen s wi h heo e ical biophysical models and s a is ical ( eg ession) equa ions con ibu ing o “black box” p edic ions o luid olumes ha can be un eliable and imp ecise. Bioimpedance pe se o e s di ec , uncomplica ed measu emen s ha acili a e a p ac ical and alid app oach o moni o hyd a ion. This e iew emphasizes he use o BI o classi y hyd a ion. I desc ibes he biophysical basis o he BI me hod, summa izes di e en echnical app oaches and hei limi a ions o es ima e luid olumes, discusses ad an ages o BI measu emen s compa ed o calcula ed luid olumes, highligh s clinical applica ions o BI emphasizing i s eme ging ole in p ognosis, and p o ides ecommenda ions o imp o e and expand he use o BI in clinical applica ions. 2. Bioelec ical Impedance 2.1. Bioimpedance Basics The physical basis o he BI me hod is he awa eness ha he human body is a ne wo k o esis o s and capaci o s [ 8 ]. Physiological luids beha e as esis o s and cell memb anes ac as capaci o s (Figu e 1). Thus, he body may be ep esen ed as a pa allel esis o -capaci o (RC) equi alen ci cui (Figu e 2) in which he in oduced al e na ing cu en di ides in o esis i e ( luid and elec oly es) and capaci i e (cell memb anes and issue in e aces) pa hways. The lowe speci ic esis i i y o body luids and issues con aining wa e and elec oly es compa ed o in ac lipid-laden cell memb anes [ 11 ] enables equency-dependen impedance measu emen s [ 12 ]. A low-le el al e na ing cu en con inuously passes p edominan ly h ough he esis i e componen bu concu en ly delayed ( empo a ily s o ed) by capaci i e elemen s in issues and issue in e aces. Impo an ly, a a iable amoun o e y low- equency cu en , ega dless a which equency he cu en is in oduced, can pene a e he memb anes o muscle cells, pa icula ly when he cu en is pa allel o he muscle ibe [ 13 ]. Cell memb anes a e capaci i e elemen s su ounding he in acellula luid (ICF) in a se ies ci cui ha exis s in pa allel wi h he wa e -con aining in e s i ial gel o ex acellula luid (ECF). Any al e na ing cu en will pene a e he capaci i e componen ( eac ance, Xc) o he cell memb ane in p opo ion o he equency o he applied cu en . Reac ance is in e sely ela ed o equency ( ) and capaci ance (C, Fa ads): Xc (ohm, Ω ) = 1/[(2 π• • C)]. Capaci ance is he abili y o a sys em o ci cui o s o e an elec ical cha ge. Nu ien s 2019,11, 809 3 o 22 Nu ien s 2019, 11, x FOR PEER REVIEW 3 o 21 Figu e 1. Illus a ion o he body as a ne wo k o esis o s and capaci o s in a pa allel con igu a ion. The al e na ing cu en usually exceeds 1 kHz and ypically is 50 kHz. C M is memb ane capaci ance and R e and R i is ex acellula and in acellula esis ance, espec i ely. Figu e 2. Rep esen a ion o he body as a pa allel esis o -capaci o (RC) equi alen ci cui . Delay o he cu en pene a ion a he cell memb ane causes an ou -phasing o cu en . A low equencies (e.g., 1–5 kHz), al e na ing cu en lows la gely in he ECF bu no in a di ec o ixed p opo ion ela i e o he ICF. Simila ly, a 50 kHz al e na ing cu en does no dis ibu e in p opo ion o luid dis ibu ion (ex a- o in a-cellula luid olume) bu ela i e o capaci i e elemen s. Thus, he phase angle (PhA) is equency-dependen , p incipally due o he amoun o Xc, and is an index o he amoun o applied cu en ha pene a es he capaci i e elemen o cell memb anes. Cu en ha is es ic ed o delayed a (in ac ) cell memb anes becomes ou -phased om he ol age d op ha occu s a he cell. Impedance (Z) is he b oad e m desc ibing he opposi ion o he low o al e na ing cu en by any biological conduc o , and is de ined by he ype o elec ical cu en in oduced o a ci cui . When di ec cu en is applied, he o al conduc o is e med esis ance (R) whe eas when al e na ing cu en is in oduced, i is called Z. Di ec cu en passes only h ough esis i e elemen s bu al e na ing cu en lows h ough esis i e and capaci i e elemen s. The esis i e (R) componen o Z is independen o equency so i has he same measu emen alue (Ω) when ei he di ec o al e na ing cu en is used. The capaci o in a biological ci cui se es as an insula o and may be en isioned as an imagina y componen o Z when di ec cu en is in oduced. Howe e , when al e na ing cu en is p esen , he imagina y componen ac s as a poo conduc o wi h capaci i e Figu e 1. Illus a ion o he body as a ne wo k o esis o s and capaci o s in a pa allel con igu a ion. The al e na ing cu en usually exceeds 1 kHz and ypically is 50 kHz. C M is memb ane capaci ance and Reand Riis ex acellula and in acellula esis ance, espec i ely. Nu ien s 2019, 11, x FOR PEER REVIEW 3 o 21 Figu e 1. Illus a ion o he body as a ne wo k o esis o s and capaci o s in a pa allel con igu a ion. The al e na ing cu en usually exceeds 1 kHz and ypically is 50 kHz. C M is memb ane capaci ance and R e and R i is ex acellula and in acellula esis ance, espec i ely. Figu e 2. Rep esen a ion o he body as a pa allel esis o -capaci o (RC) equi alen ci cui . Delay o he cu en pene a ion a he cell memb ane causes an ou -phasing o cu en . A low equencies (e.g., 1–5 kHz), al e na ing cu en lows la gely in he ECF bu no in a di ec o ixed p opo ion ela i e o he ICF. Simila ly, a 50 kHz al e na ing cu en does no dis ibu e in p opo ion o luid dis ibu ion (ex a- o in a-cellula luid olume) bu ela i e o capaci i e elemen s. Thus, he phase angle (PhA) is equency-dependen , p incipally due o he amoun o Xc, and is an index o he amoun o applied cu en ha pene a es he capaci i e elemen o cell memb anes. Cu en ha is es ic ed o delayed a (in ac ) cell memb anes becomes ou -phased om he ol age d op ha occu s a he cell. Impedance (Z) is he b oad e m desc ibing he opposi ion o he low o al e na ing cu en by any biological conduc o , and is de ined by he ype o elec ical cu en in oduced o a ci cui . When di ec cu en is applied, he o al conduc o is e med esis ance (R) whe eas when al e na ing cu en is in oduced, i is called Z. Di ec cu en passes only h ough esis i e elemen s bu al e na ing cu en lows h ough esis i e and capaci i e elemen s. The esis i e (R) componen o Z is independen o equency so i has he same measu emen alue (Ω) when ei he di ec o al e na ing cu en is used. The capaci o in a biological ci cui se es as an insula o and may be en isioned as an imagina y componen o Z when di ec cu en is in oduced. Howe e , when al e na ing cu en is p esen , he imagina y componen ac s as a poo conduc o wi h capaci i e Figu e 2. Rep esen a ion o he body as a pa allel esis o -capaci o (RC) equi alen ci cui . Delay o he cu en pene a ion a he cell memb ane causes an ou -phasing o cu en . A low equencies (e.g., 1–5 kHz), al e na ing cu en lows la gely in he ECF bu no in a di ec o ixed p opo ion ela i e o he ICF. Simila ly, a 50 kHz al e na ing cu en does no dis ibu e in p opo ion o luid dis ibu ion (ex a- o in a-cellula luid olume) bu ela i e o capaci i e elemen s. Thus, he phase angle (PhA) is equency-dependen , p incipally due o he amoun o Xc, and is an index o he amoun o applied cu en ha pene a es he capaci i e elemen o cell memb anes. Cu en ha is es ic ed o delayed a (in ac ) cell memb anes becomes ou -phased om he ol age d op ha occu s a he cell. Impedance (Z) is he b oad e m desc ibing he opposi ion o he low o al e na ing cu en by any biological conduc o , and is de ined by he ype o elec ical cu en in oduced o a ci cui . When di ec cu en is applied, he o al conduc o is e med esis ance (R) whe eas when al e na ing cu en is in oduced, i is called Z. Di ec cu en passes only h ough esis i e elemen s bu al e na ing cu en lows h ough esis i e and capaci i e elemen s. The esis i e (R) componen o Z is independen o equency so i has he same measu emen alue ( Ω ) when ei he di ec o al e na ing cu en is used. The capaci o in a biological ci cui se es as an insula o and may be en isioned as an imagina y componen o Z when di ec cu en is in oduced. Howe e , when al e na ing cu en is p esen , he imagina y componen ac s as a poo conduc o wi h capaci i e esis ance and is e med eac ance Nu ien s 2019,11, 809 4 o 22 (Xc), which is equency-dependen . Thus, Z is a complex numbe , Z 2 = R 2 + Xc 2 , and cha ac e izes he speci ic luid and cellula componen s o an o ganism. Impedance is a ec o wi h leng h and posi ion on he bi a ia e RXc plo (Figu e 3). The PhA desc ibes he posi ion o Z and is he angula ans o ma ion o Xc o R [a c angen (Xc/R) •(180◦/π)] exp essed in adian deg ees. Nu ien s 2019, 11, x FOR PEER REVIEW 4 o 21 esis ance and is e med eac ance (Xc), which is equency-dependen . Thus, Z is a complex numbe , Z 2 = R 2 + Xc 2 , and cha ac e izes he speci ic luid and cellula componen s o an o ganism. Impedance is a ec o wi h leng h and posi ion on he bi a ia e RXc plo (Figu e 3). The PhA desc ibes he posi ion o Z and is he angula ans o ma ion o Xc o R [a c angen (Xc/R) • (180°/𝜋)] exp essed in adian deg ees. Figu e 3. Geome ic ela ionships among he esis ance, eac ance (capaci ance, C M ), impedance, and phase angle. 2.2. Measu emen o Bioelec ical Impedance Assessmen o whole-body hyd a ion uses su ace, gel (sil e -sil e chlo ide) o mode n hyd ogel elec odes, and e apola elec ode placemen s. Whole-body BI measu emen s employ adi ional limb placemen s wi h pai ed cu en -in oducing (sou ce) and ol age-d op-sensing (de ec o ) elec odes placed on he dis al w is and ankle [8,10]. 3. Volume Quan i ica ion in Hyd a ion Assessmen : Limi a ions and Imp ecision A p ima y ac o o eliable hyd a ion assessmen is he echnical alidi y o he BI measu emen . I includes he accu acy o he ins umen , which is de e mined wi h a p ecision (<1%) ci cui o a esis o and a capaci o in a pa allel ci cui , and p ecision o ep oducibili y ha equi es epea ed measu emen s o a alida ion ci cui and epe i i e in i o measu emen s. The echnical alidi y should be <2% o all BI measu emen s [9]. Simila ly, he alidi y o he e e ence ace dilu ion me hods mus be assessed wi h echnical accu acy and p ecision de e mined o be <2%. In e -indi idual biological sou ces o e o o he ace dilu ion me hods, including hyd ogen exchange and anion (b omine-chlo ine) shi s ha a e >4% [14,15], di ec ly a ec he a iabili y o luid olume es ima es. 3.1. Single-F equency Bioimpedance Clinical in es iga o s applied di e en BI app oaches o es ima e luid olumes as indica o s o hyd a ion. They mos ly used phase-sensi i e single- equency (50 kHz) BI because o he high signal- o-noise a io [9,16] o mul iple- equency (5 kHz o 1 MHz) measu emen s coupled wi h ei he mul iple eg ession equa ions o heo e ical biophysical models o p edic luid olumes [10,17–19]. Each o hese app oaches has no able conce ns ha limi hei gene al applica ion in he es ima ion o luid olumes. The elec ical olume model adap ed om Ohm’s Law is he physical basis o es ima ion o luid olumes wi h single- and mul iple- equency BI measu emen s [10]. The olume (V) o a conduc o ( luid plus elec oly es) depends on he leng h (L) and c oss-sec ional a ea (A) o a cylind ical conduc o wi h cons an geome y and composi ion (speci ic esis i i y o ρ), so ha V = ρ(L 2 /R). S anding heigh (H ) is a biological su oga e o L, so V = ρ(H 2 /R). The assump ions o his model, which include he body is a uni o m cylinde o cons an chemical composi ion (e.g., wa e Figu e 3. Geome ic ela ionships among he esis ance, eac ance (capaci ance, CM), impedance, and phase angle. 2.2. Measu emen o Bioelec ical Impedance Assessmen o whole-body hyd a ion uses su ace, gel (sil e -sil e chlo ide) o mode n hyd ogel elec odes, and e apola elec ode placemen s. Whole-body BI measu emen s employ adi ional limb placemen s wi h pai ed cu en -in oducing (sou ce) and ol age-d op-sensing (de ec o ) elec odes placed on he dis al w is and ankle [8,10]. 3. Volume Quan i ica ion in Hyd a ion Assessmen : Limi a ions and Imp ecision A p ima y ac o o eliable hyd a ion assessmen is he echnical alidi y o he BI measu emen . I includes he accu acy o he ins umen , which is de e mined wi h a p ecision (<1%) ci cui o a esis o and a capaci o in a pa allel ci cui , and p ecision o ep oducibili y ha equi es epea ed measu emen s o a alida ion ci cui and epe i i e in i o measu emen s. The echnical alidi y should be <2% o all BI measu emen s [ 9 ]. Simila ly, he alidi y o he e e ence ace dilu ion me hods mus be assessed wi h echnical accu acy and p ecision de e mined o be <2%. In e -indi idual biological sou ces o e o o he ace dilu ion me hods, including hyd ogen exchange and anion (b omine-chlo ine) shi s ha a e >4% [ 14 , 15 ], di ec ly a ec he a iabili y o luid olume es ima es. 3.1. Single-F equency Bioimpedance Clinical in es iga o s applied di e en BI app oaches o es ima e luid olumes as indica o s o hyd a ion. They mos ly used phase-sensi i e single- equency (50 kHz) BI because o he high signal- o-noise a io [ 9 , 16 ] o mul iple- equency (5 kHz o 1 MHz) measu emen s coupled wi h ei he mul iple eg ession equa ions o heo e ical biophysical models o p edic luid olumes [ 10 , 17 – 19 ]. Each o hese app oaches has no able conce ns ha limi hei gene al applica ion in he es ima ion o luid olumes. The elec ical olume model adap ed om Ohm’s Law is he physical basis o es ima ion o luid olumes wi h single- and mul iple- equency BI measu emen s [ 10 ]. The olume (V) o a conduc o ( luid plus elec oly es) depends on he leng h (L) and c oss-sec ional a ea (A) o a cylind ical conduc o wi h cons an geome y and composi ion (speci ic esis i i y o ρ ), so ha V = ρ(L2/R) . S anding heigh (H ) is a biological su oga e o L, so V = ρ (H 2 /R). The assump ions o his model, which include he body is a uni o m cylinde o cons an chemical composi ion (e.g., wa e con en ) o he conduc o , a e open o c i icism [ 18 ]. Speci ically, he body consis s o i e cylinde s Nu ien s 2019,11, 809 5 o 22 ( wo a ms, wo legs, and he ho ax) wi h di e en geome y ( a ying leng h and diame e ) and di e en chemical composi ion (speci ic esis i i ies o di e en issues) including a dispu ed cons an hyd a ion o he a - ee body (73%). Resea che s exploi ed his bioelec ical olume model, oge he wi h a ious an h opome ic in o ma ion (H , weigh (W ), age, and gende ), o de elop and alida e mul iple eg ession p edic ion equa ions using single- and mul iple- equency measu emen s o TBW es ima es in heal hy and ill adul s [18]. A echnical issue exis s wi h any applica ion o hese eg ession models. The independen a iable is R and no Z. Thus, only phase-sensi i e BI ins umen s should be used in he applica ion o speci ic single- equency p edic ion models using R as an independen a iable. Al hough Z and R a e highly co ela ed (R 2 > 0.9), he magni ude o Z is g ea e han R (1% o 2%) because Z includes he alue o Xc, which is no negligible (~10% o R) and includes biologically impo an in o ma ion o hyd a ion classi ica ion [ 9 , 10 ]. Simila ly, p edic ions based on mul i- equency BI measu emen s should ensu e ha app op ia e de ices a e used o ob ain he equi ed Z o R measu emen s. C i ical e alua ion o a popula ion-based model o p edic TBW highligh s a p ac ical limi a ion o he use o BIA o es ima e he luid olume. Sun e al. [ 20 ] de i ed and alida ed TBW p edic ion equa ions in a la ge sample o heal hy adul s o di e se e hnici y: Males: TBW (L) = 0.87 + 0.43 (H 2/R) + 0.20 W Females: TBW (L) = 3.27 + 0.45 (H 2/R) + 0.12 W C oss- alida ion o hese equa ions e ealed a la ge p edic i e e o (s anda d e o o es ima e (SEE)) o 3.8 L and 2.6 L, o he males and emales, espec i ely. The magni ude o hese p edic ion e o s is oo la ge (e.g., imp ecise) o es ima e TBW o o iden i y change in TBW o an indi idual and, he e o e, limi s hese equa ions o obse a ional o epidemiological s udies. 3.2. Bioelec ical Impedance Spec oscopy (BIS) Some BI ins umen s measu e Z o e a wide ange o equencies (e.g., 5 kHz up o 1 MHz), epo a ious measu emen s and hen use p og ammed so wa e o es ima e luid olumes [ 17 ]. Ce ain non-phase-sensi i e de ices only measu e Z and p o ide he a io o Z a low and high equencies (Z low /Z high ) ha is equi alen o PhA a 50 kHz. Simila ly, hey also use he Z low /Z high o compu e he phase and canno pe o m alid calcula ions o o m he impedance modulus o he Cole plo . The BIS me hod elies on he assump ion ha low- equency cu en lows h ough he ECF and high- equency cu en pene a es ECF and ICF. These assump ions a e open o c i icism la gely because hey we e de i ed om in i o s udies o cells suspended in luid and igno e he cell-cell in e aces ha occu in issues [ 10 ]. Addi ionally, in es iga o s ag ee ha a he lowes equencies some cu en pene a es cell memb anes (e.g., ex acellula and in acellula pa hs) and ha a he highes equencies cu en does c oss all cells (e.g., ex acellula and in acellula pa hs) [11,21–23]. The BIS me hod uses non-linea leas -squa e (polynomial) modeling o limi ed phase-sensi i e mul i- equency measu emen s o Z and Xc, calcula ed om PhA, hen ex apola es hese alues o gene a e a Cole plo (Figu e 4). This ma hema ical model [ 24 ] calcula es heo e ical esis i i y alues ha a e used o app oxima e luid olumes. The ex apola ed (modeled) a iables a e R 0 , also e med as Re ( he esis ance o he ex acellula luid o in e s i ial esis i i y), and R ∞ ( esis ance associa ed wi h he sum o ex acellula and in acellula luids), c i ical equency ( C ) o he equency a which Xc is maximal, and memb ane capaci ance (Cm). The alue o calcula ed Cm depends on ano he i ed a iable, ime delay (Td), which ep esen s he e ec o cell memb ane and o ien a ion on he cu en ansmission in he body. These esis ance pa ame e s a e used o calcula e in acellula esis ance (Ri) as 1/Ri = 1/R∞−1/Re. Mix u e heo y uses hese calcula ed esis ance pa ame e s wi h an h opome ic measu emen s and some wide- anging assump ions o es ima e luid olumes [ 17 , 25 , 26 ]. I elies on a heo e ical model ha es ima es appa en conduc i i y in a he e ogeneous en i y composed o conduc i e (wa e and ions) and non-conduc i e (anhyd ous ma e ials such as bone, a , and cell memb anes) componen s such as he body. Fluid olumes, ECW, and ICW a e p edic ed sepa a ely and summed o ob ain Nu ien s 2019,11, 809 6 o 22 he TBW. Calcula ion o he ECW and ICW depends on he es ima ed Cole esis ance pa ame e s, body scala ac o s calcula ed om he H and W o an indi idual, an assumed body densi y alue de i ed om body mass index (BMI), empi ically de i ed gende -speci ic esis i i y alues, and o he assump ions. Ex acellula luid olume (V ECF ) is calcula ed as V ECF = k ECF • (H 2• W 0.5 /Re) 2/3 wi h k ECF = 10 -3 • (K B2•ρECF2 /D b ) 1/3 , whe e K B is a body geome y ac o ha ela es ela i e olume o he legs, a ms, and unk, ρECF is he esis i i y o he ex acellula luid, and D b is o al body densi y. In acellula luid olume (V ICF ) also is calcula ed om he de i ed Cole esis ance a iables and gende -dependen esis i i ies o he ECW and ICW. These calcula ions a e pe o med wi h so wa e p o ided by he manu ac u e s o he di e en BIS ins umen s, and a e subjec o change. Nu ien s 2019, 11, x FOR PEER REVIEW 6 o 21 o ob ain he TBW. Calcula ion o he ECW and ICW depends on he es ima ed Cole esis ance pa ame e s, body scala ac o s calcula ed om he H and W o an indi idual, an assumed body densi y alue de i ed om body mass index (BMI), empi ically de i ed gende -speci ic esis i i y alues, and o he assump ions. Ex acellula luid olume (V ECF ) is calcula ed as V ECF = k ECF • (H 2 • W 0.5 /Re) 2/3 wi h k ECF = 10 -3 • (K B2 • ρ ECF2 /D b ) 1/3 , whe e K B is a body geome y ac o ha ela es ela i e olume o he legs, a ms, and unk, ρ ECF is he esis i i y o he ex acellula luid, and D b is o al body densi y. In acellula luid olume (V ICF ) also is calcula ed om he de i ed Cole esis ance a iables and gende -dependen esis i i ies o he ECW and ICW. These calcula ions a e pe o med wi h so wa e p o ided by he manu ac u e s o he di e en BIS ins umen s, and a e subjec o change. Figu e 4. Plo o eac ance and esis ance o a heal hy male ob ained wi h a Xi on 4200 and de i ed using non-linea cu e- i ing so wa e based on he Cole model. No e ha he majo i y o alues (dashed lines) we e es ima ed. R 0 and R ∞ we e calcula ed and hey app oxima e esis ance a 0 and he highes equency, espec i ely. Unce ain basic assump ions and cons an s o he o iginal BIS app oach [26–29] esul ed in e o s in he p edic ions o luid olumes. Speci ically, signi ican e o s in he es ima ion o TBW (2 L) and ECW (~1 L) in indi iduals wi h inc easing adiposi y, cha ac e ized using BMI, we e explained as he e ec o inc easing adipose issue on he assumed esis i i y o he ECW [30–32]. A p oposed emedy o his limi a ion was he use o BMI as a p oxy o adiposi y [33]. A mul i-cen e alida ion ial [33] o his e ised BIS app oach included heal hy adul s and dialysis pa ien s and ound ha his change imp o ed he sensi i i y o he e ised ECW p edic ions by dec easing he a iabili y o he ECW es ima e by 24% (0.6 L) in heal hy and dialysis pa ien s and educing he a iabili y o he TBW p edic ion in adul s wi h BMI alues o less han 20 and g ea e han 30 kg/m 2 . Al hough no signi ican di e ences be ween ace dilu ion e e ence measu emen s and BIS p edic ions o he TBW, ECW, and ICW we e ound, he e we e wide limi s o ag eemen (95% con idence in e als—95% CI). Speci ically, he mean di e ences we e small wi h wide limi s o ag eemen o p edic ion o he TBW (−0.2 L (95% CI: 4.6 L)), ECW (−0.4 L; 95% CI: 2.9 L)), and ICW (0.2 L (95% CI: 4.1 L)). A limi a ion o he use o BMI as a su oga e o body a ness is he insensi i i y o BMI o eliably di e en ia e he body composi ion (body a and muscle mass) o an indi idual, heal hy o ill [34]. These wide limi s o ag eemen con ibu e o poo sensi i i y o he ECW and TBW es ima es es ima ed wi h BIS o indi iduals. 3.3. Compa ison o Fluid Volumes Es ima ed wi h Single-F equency Bioimpedance and Bioelec ical Impedance Spec oscopy Al hough a common opinion is ha BIS, compa ed o a single- equency BIA, p o ides mo e accu a e es ima es o luid olume [23], expe imen al da a ail o con i m his supposi ion. Impedance p edic ions o he TBW and ICW we e equally accu a e in compa ison o iso ope dilu ion es ima es Figu e 4. Plo o eac ance and esis ance o a heal hy male ob ained wi h a Xi on 4200 and de i ed using non-linea cu e- i ing so wa e based on he Cole model. No e ha he majo i y o alues (dashed lines) we e es ima ed. R 0 and R ∞ we e calcula ed and hey app oxima e esis ance a 0 and he highes equency, espec i ely. Unce ain basic assump ions and cons an s o he o iginal BIS app oach [ 26 – 29 ] esul ed in e o s in he p edic ions o luid olumes. Speci ically, signi ican e o s in he es ima ion o TBW (2 L) and ECW (~1 L) in indi iduals wi h inc easing adiposi y, cha ac e ized using BMI, we e explained as he e ec o inc easing adipose issue on he assumed esis i i y o he ECW [ 30 – 32 ]. A p oposed emedy o his limi a ion was he use o BMI as a p oxy o adiposi y [33]. A mul i-cen e alida ion ial [ 33 ] o his e ised BIS app oach included heal hy adul s and dialysis pa ien s and ound ha his change imp o ed he sensi i i y o he e ised ECW p edic ions by dec easing he a iabili y o he ECW es ima e by 24% (0.6 L) in heal hy and dialysis pa ien s and educing he a iabili y o he TBW p edic ion in adul s wi h BMI alues o less han 20 and g ea e han 30 kg/m 2 . Al hough no signi ican di e ences be ween ace dilu ion e e ence measu emen s and BIS p edic ions o he TBW, ECW, and ICW we e ound, he e we e wide limi s o ag eemen (95% con idence in e als—95% CI). Speci ically, he mean di e ences we e small wi h wide limi s o ag eemen o p edic ion o he TBW ( − 0.2 L (95% CI: 4.6 L)), ECW ( − 0.4 L; 95% CI: 2.9 L)), and ICW (0.2 L (95% CI: 4.1 L)). A limi a ion o he use o BMI as a su oga e o body a ness is he insensi i i y o BMI o eliably di e en ia e he body composi ion (body a and muscle mass) o an indi idual, heal hy o ill [ 34 ]. These wide limi s o ag eemen con ibu e o poo sensi i i y o he ECW and TBW es ima es es ima ed wi h BIS o indi iduals. 3.3. Compa ison o Fluid Volumes Es ima ed wi h Single-F equency Bioimpedance and Bioelec ical Impedance Spec oscopy Al hough a common opinion is ha BIS, compa ed o a single- equency BIA, p o ides mo e accu a e es ima es o luid olume [ 23 ], expe imen al da a ail o con i m his supposi ion. Impedance p edic ions o he TBW and ICW we e equally accu a e in compa ison o iso ope dilu ion es ima es bu Nu ien s 2019,11, 809 7 o 22 included a signi ican bias (e o ) in single- equency and BIS p edic ion o he ECW in s eady-s a e hemodialysis pa ien s [ 35 ]. Bo h impedance me hods had a p opo ional e o in es ima ion o he ICW la gely due o assump ions o he BIS model and he single equency equa ion used o p edic he ICW wi h calcula ions om o al body po assium, a speci ic ma ke o body cell mass. Simila indings came om ano he s udy o hemodialysis pa ien s [ 36 ]. A consis en obse a ion is he wide limi s o ag eemen be ween he impedance and e e ence me hods ha cau ions agains he use o hese me hods o indi idual assessmen o luid olumes [37]. O he esea ch suppo s hese indings. In adul s ecei ing g ow h ho mone eplacemen he apy, he TBW was de e mined using iso ope dilu ion and p edic ed om BI measu emen s, collec ed wi h he same mul i- equency ins umen , using 50 kHz alues and ou published equa ions and he Hanai mix u e [ 25 ] model wi h and wi hou adjus men o BMI [ 38 ]. Measu ed and p edic ed TBW alues we e signi ican ly and simila ly co ela ed o linea i y and conco dance ( > 0.9). Compa isons o measu ed and p edic ed TBW alues e ealed limi s o ag eemen wi h sligh ly g ea e a iabili y (0.9 L o 2.7 L o 4% o 7%) o he 50 kHz p edic ions compa ed o a iabili y es ima es (0.6 L o 0.9 L o 1% o 2%) om he BIS p edic ions. Thus, bo h he single equency p edic ion equa ions and BIS models pe o med equally well in p edic ing he TBW a he popula ion le el. Follow up analyses de e mined he compa abili y o hese di e en app oaches o es ima e he TBW a he le el o an indi idual [ 38 ]. The mean absolu e e o o BIS was sligh ly imp o ed compa ed o mul iple eg ession equa ions using 50 kHz alues (5% s. 7% o 2 L s. 3 L). These indings indica e ha he p ecision o hese BIA app oaches may be app op ia e o g oup compa isons bu is oo la ge o moni o ing changes in he TBW in clinical condi ions. Any compa ison o BIA-p edic ed luid olumes wi h ace dilu ion e e ence measu emen s su e s om echnical and biological limi a ions. Sou ces o e o include he alidi y (accu acy and p ecision) o he impedance measu emen , e o o p edic ion om he eg ession equa ion, in insic e o o he e e ence me hod ( echnical accu acy and ep oducibili y, biological e o s in assump ions o he dilu ion me hod), elec ical- olume e o s (aniso opy and body geome y), and biological a iabili y (in e -indi idual di e ences in he diame e o body segmen s, limb leng hs, and a ia ion in body a ness) [ 37 ]. Use o he Cole model depends on he eliabili y o he i ing o he impedance da a. Re iew o ecen BIS publica ions e eals ha indi idual subjec s a e emo ed om analyses because o ailu e o achie e accep able ole ances (>99% ep oducibili y) o he epea ed ime delay es ima es de i ed om cu e i ing [ 35 , 36 ]. This obse a ion indica es signi ican imp ecision in he calcula ion o he cu en delay a memb anes. Finally, use o di e en single- equency ma hema ical p edic ion equa ions complica es compa isons. As sugges ed by Seone e al. [ 38 , 39 ], olume p edic ion models ha include mo e independen a iables han H 2 /R and weigh end o p oduce g ea e e o s in es ima ed TBW ha indica es a speci ici y o ha eg ession equa ion and, hus, excludes i s applica ion in any sample o indi idual di e ing in cha ac e is ics om he o iginal sample in which he eg ession model was de eloped. These ac o s as well as he imp ecision o he p edic ion models, single- equency and BIS, impedes hei use in poin -o -ca e indi idual assessmen s o hyd a ion. 4. Classi ica ion o Hyd a ion wi h Bioelec ical Impedance Vec o Analysis (BIVA) In con as o he use o ma hema ical modeling o limi ed BI measu emen s, heo e ical and eg ession p edic ion models, classi ica ion o hyd a ion only equi es p ecise BI measu emen s and e e ence alues [ 40 ]. A 50 kHz phase-sensi i e BI ins umen di ec ly measu es R and Xc, which a e no malized o s anding heigh o achie e a s anda d esis i i y and plo ed on he RXc g aph (Figu e 5). The ec o (Z) has a leng h ha is in e sely ela ed o TBW and i s posi ion, desc ibed as he PhA, and p o ides in o ma ion on issue hyd a ion. Nu ien s 2019,11, 809 8 o 22 Nu ien s 2019, 11, x FOR PEER REVIEW 8 o 21 Figu e 5. Resis ance- eac ance (RXc) plo wi h ole ance ellipses om heal hy Caucasian males. Bioelec ical impedance ec o analysis (BIVA) enables classi ica ion (unde -, no mal, and o e - hyd a ion) and anking o change in hyd a ion (mo e o less han be o e ea men ), as well as classi ica ion (mo e o less) o so issue mass by compa ing ec o posi ion o an indi idual o a g oup o a heal hy e hnici y-, age-, and gende -ma ched popula ion [40]. Implemen a ion o BIVA ollows he wo k o Moo e and Boyden [3] in which hyd a ion is a unc ion o luid dis ibu ion in he ex acellula and in acellula spaces, no ably BCM. Clinically, o e -hyd a ion is exp essed as an expansion o he ex acellula luid (in e s i ial luid plus plasma), also e med luid o e load, ela i e o he BCM (in acellula luid); pa ien s wi h enal disease and hea ailu e a e cha ac e ized as o e -hyd a ed. Malnu i ion, including cachexia, also is associa ed wi h an inc ease in ECW and a dec ease in BCM. Hypo-hyd a ion is seen wi h a dec ease in ECW and li le o no change in BCM. I can be acu e as wi h excess luid emo al he apy o sho - e m wi h diseases causing excessi e luid loss (dia hea o emesis). Compa ed o single- equency BIA and BIS p edic ions o luid olumes, BIVA only has minimal e o associa ed wi h BI measu emen and ep oducibili y (1–2%) whe eas luid olume p edic ions include addi ional sou ces o e o including eg ession e o o he p edic ion equa ion (~10%), echnical e o in he e e ence me hod (~4%), limi a ions o he bioelec ical olume model (i.e., aniso opy o issues and geome y), and biological a iabili y (i.e., in e -indi idual body composi ion di e ences) ha p opaga e. The e o e, o an indi idual, classi ica ion and anking o hyd a ion is mo e p ecise and accu a e han is he quan i ica ion o luid olume because BIVA is independen o eg ession equa ions and heo e ical models ha a e acqui ed wi h limi ed and speci ic samples and, hus, a e no obus in he assessmen o hyd a ion ou side o he g oup in which hey we e de eloped, and a e ad e sely a ec ed by illness. The RXc g aph (Figu e 5) is a p obabili y dis ibu ion ha classi ies a ec o acco ding o i s dis ance om he mean heal hy ec o . The a iabili y o he impedance ec o is ep esen ed in he bi a ia e no mal dis ibu ion wi h ellip ical p obabili y a eas (50%, 75%, and 95%) in he ole ance o e e ence ellipses. Vec o s displacemen s pa allel o he majo axis indica e changes in hyd a ion (mo e o less luids). Vec o s wi hin he 50% ole ance ellipse a e conside ed o be a no mal hyd a ion whe eas leng hening o ec o s om he 51% o 75% and >76% pe cen ile o he uppe ange o pe cen iles indica e mode a e and se e e dehyd a ion, espec i ely. Con e sely, sho ening o ec o s om he 51% o 75% and >76% pe cen ile e e ence ellipses in he lowe ange indica e inc easing luid o e load. Vec o s posi ioned o he le o he majo axis e lec inc easing cell mass and ec o s o he igh indica e dec easing cell mass, espec i ely. Thus, BIVA uses pa e ns o Figu e 5. Resis ance- eac ance (RXc) plo wi h ole ance ellipses om heal hy Caucasian males. Bioelec ical impedance ec o analysis (BIVA) enables classi ica ion (unde -, no mal, and o e -hyd a ion) and anking o change in hyd a ion (mo e o less han be o e ea men ), as well as classi ica ion (mo e o less) o so issue mass by compa ing ec o posi ion o an indi idual o a g oup o a heal hy e hnici y-, age-, and gende -ma ched popula ion [ 40 ]. Implemen a ion o BIVA ollows he wo k o Moo e and Boyden [ 3 ] in which hyd a ion is a unc ion o luid dis ibu ion in he ex acellula and in acellula spaces, no ably BCM. Clinically, o e -hyd a ion is exp essed as an expansion o he ex acellula luid (in e s i ial luid plus plasma), also e med luid o e load, ela i e o he BCM (in acellula luid); pa ien s wi h enal disease and hea ailu e a e cha ac e ized as o e -hyd a ed. Malnu i ion, including cachexia, also is associa ed wi h an inc ease in ECW and a dec ease in BCM. Hypo-hyd a ion is seen wi h a dec ease in ECW and li le o no change in BCM. I can be acu e as wi h excess luid emo al he apy o sho - e m wi h diseases causing excessi e luid loss (dia hea o emesis). Compa ed o single- equency BIA and BIS p edic ions o luid olumes, BIVA only has minimal e o associa ed wi h BI measu emen and ep oducibili y (1–2%) whe eas luid olume p edic ions include addi ional sou ces o e o including eg ession e o o he p edic ion equa ion (~10%), echnical e o in he e e ence me hod (~4%), limi a ions o he bioelec ical olume model (i.e., aniso opy o issues and geome y), and biological a iabili y (i.e., in e -indi idual body composi ion di e ences) ha p opaga e. The e o e, o an indi idual, classi ica ion and anking o hyd a ion is mo e p ecise and accu a e han is he quan i ica ion o luid olume because BIVA is independen o eg ession equa ions and heo e ical models ha a e acqui ed wi h limi ed and speci ic samples and, hus, a e no obus in he assessmen o hyd a ion ou side o he g oup in which hey we e de eloped, and a e ad e sely a ec ed by illness. The RXc g aph (Figu e 5) is a p obabili y dis ibu ion ha classi ies a ec o acco ding o i s dis ance om he mean heal hy ec o . The a iabili y o he impedance ec o is ep esen ed in he bi a ia e no mal dis ibu ion wi h ellip ical p obabili y a eas (50%, 75%, and 95%) in he ole ance o e e ence ellipses. Vec o s displacemen s pa allel o he majo axis indica e changes in hyd a ion (mo e o less luids). Vec o s wi hin he 50% ole ance ellipse a e conside ed o be a no mal hyd a ion whe eas leng hening o ec o s om he 51% o 75% and >76% pe cen ile o he uppe ange o pe cen iles indica e mode a e and se e e dehyd a ion, espec i ely. Con e sely, sho ening o ec o s om he 51% o 75% and >76% pe cen ile e e ence ellipses in he lowe ange indica e inc easing luid o e load. Vec o s posi ioned o he le o he majo axis e lec inc easing cell mass and ec o s o he igh indica e dec easing cell mass, espec i ely. Thus, BIVA uses pa e ns o impedance ec o dis ibu ion wi hou he need o p edic ion equa ions, body weigh o eliance on he assump ion Nu ien s 2019,11, 809 9 o 22 o s able composi ion (wa e con en ) o he FFM. BIVA enables de ec ion and anking o changes in issue hyd a ion s a us o <500 mL in eal- ime [40]. App op ia e de i a ion and implemen a ion o he RXc g aph o classi y hyd a ion equi es some impo an echnical conside a ions. All measu emen s should be acqui ed wi h a phase-sensi i e (e.g., phase angle di ec ly measu ed) BI ins umen . Failu e o use a phase-sensi i e de ice esul s in signi ican e o s in R (10 Ω ) and Xc (10–12 Ω ) measu emen s [ 41 ] con ibu ing o 8–10% eposi ioning o e e ence and pa ien ec o s. Addi ionally, use o high-impedance elec odes can lead o misclassi ica ion o hyd a ion [42]. 4.1. Clinical Applica ions o BIVA A ocal applica ion o BIVA is he assessmen o he hyd a ion s a us in pa ien s wi h luid o e load and e alua ion o e ec s o he apeu ic p ocedu es designed o achie e homeos asis wi hou undesi able side e ec s. Kidney disease and hemodynamic impai men s a e he p incipal condi ions in which BIVA is used o classi y hyd a ion and o moni o changes in esponse o ea men s. T adi ional app oaches o assess hyd a ion in hese pa ien s a e un eliable because hey ely on body weigh o designa e excess luid and a e insensi i e o luid o e load in he p esence o edema [43]. 4.1.1. Hyd a ion Assessmen in Hemodialysis (HD) Dialysis, pa icula ly hemodialysis (HD), is amenable o BIVA because o he need o luid emo al and pos -dialy ic luid e en ion. Rou ine e alua ion o hyd a ion includes moni o ing o body weigh and blood p essu e changes ha a e no eliably de e mined by luid olume. Edema is no usually de ec able un il in e s i ial luid olume inc eases 30% o e no mal le els (4–5 kg gain in body weigh ) and se e e dehyd a ion can occu be o e appea ance o clinical signs. Thus, adi ional indica o s o o e - and unde -hyd a ion in pa ien s wi h enal disease a e insensi i e and inadequa e [40]. 4.1.2. Hyd a ion Changes and Vec o Pa e ns Du ing he HD Cycle The objec i e o HD is o emo e excess luid wi hou complica ions o he pa ien . Es ima ion o he olume o luid o emo al is subjec i e and gene ally ela ed o p e ious pos -dialy ic body weigh , which may be un eliable [ 43 ]. Fluid emo al occu s du ing HD. I can be symp oma ic o uncompensa ed wi h episodes o hypo ension, malaise, and c amps o asymp oma ic (compensa ed). Fluid o e load can occu du ing he in e -dialy ic pe iod and is symp oma ic wi h edema, exace ba ed hype ension, and pulmona y conges ion. D y weigh is a gene al e m associa ed wi h he pos -dialy ic body weigh a which mos o he excess luid has been emo ed. The op imal “d y weigh ” is de e mined clinically and ope a ionally as he weigh a which a pa ien can ole a e HD wi hou ad e se in a-dialy ic symp oms, no ably hypo ension. Body luid olumes, howe e , change con inuously du ing he in e -dialy ic pe iod so ha euhyd a ion occu s only o a b ie pe iod. Se ial BI measu emen s and examina ion o ec o s be o e and a e HD e eal a classic pa e n o luid emo al and eple ion du ing a s anda d 3-d HD cycle. Fluid emo al ia ul a il a ion (UF) accompanies ec o leng hening pa allel o he mean ec o o heal hy adul s [ 44 ]. Wi hin he i s 2 pos HD, ec o s a e ela i ely s able nea he pos HD ec o . Du ing he nex 24, 48, and 72 h howe e , ec o s p og essi ely sho en wi hin he 50% o 75% ole ance ellipse and e lec luid eple ion o 1.4, 2.6, and 3.4 L. Thus, BIVA is speci ic and sensi i e o moni o luid du ing he we and d y cycle o HD. 4.1.3. Vec o T ajec o ies: Adequacy o Ul a il a ion (UF) Measu emen o he elec ical p ope ies o issues enables he classi ica ion o ec o s as abno mal and iden i ica ion o HD pa ien s a isk o in a-dialy ic p oblems. Obse a ional indings indica e ha BIVA can iden i y po en ial symp oma ic HD pa ien s. Be o e dialysis, HD pa ien s, compa ed o heal hy con ols, exhibi e idence o luid o e load wi h sho e ec o s and lesse phase angles [ 44 , 45 ]. P e-HD ec o posi ion disc imina ed uns able (symp oma ic), compa ed o s able (asymp oma ic), Nu ien s 2019,11, 809 16 o 22 signi ican ly a ec ed ec o posi ion on he RXc g aph esul ing in signi ican di e ences in hyd a ion classi ica ion o heal hy adul s. S anda diza ion o BI measu emen s emains a challenge o clinical use s o BI o hyd a ion classi ica ion. The lack o in e na ional manu ac u ing s anda ds, coo dina ion o echnology, and c oss-calib a ion o elec ical accu acy hinde s g ow h in clinical applica ions o BI. Concu ence on app op ia e measu emen s condi ions in hyd a ion assessmen is imminen bu clinical in es iga o s need o be awa e o ele a ed co e and pe iphe al empe a u es as well as high impac BI measu emen s. Use o a i ac - ee con ac elec odes is ecommended o eliable classi ica ion o hyd a ion. Small di e ences in BI measu emen s incu ed by measu emen in luences can al e hyd a ion classi ica ion in clinical condi ions. 8. Summa y and Conclusions Bioimpedance measu emen s a e gaining in e es o assess and moni o hyd a ion s a us in dialy ic and c i ically ill pa ien s because hey o e come many o he limi a ions o adi ional me hods o hyd a ion assessmen . Whe eas wo app oaches use o BI measu emen s each has speci ic ad an ages and ce ain limi a ions. Use o di ec 50 kHz, phase-sensi i e BI measu emen s in he BIVA model o hyd a ion assessmen is p og essing in a a ie y o clinical condi ions. BIVA illus a es a ec o whose posi ion is e alua ed ela i e o heal hy e e ence anges and is in e p e ed as no mal o abno mal hyd a ion based on dis ance om he mean heal hy ec o . Mig a ion o he ec o (sho ening o leng hening) in esponse o p og ession o a physiological p ocess, pa hology, o an in e en ion indica es changes in hyd a ion (gain o loss o luids). Classi ica ion o hyd a ion s a us (no mal o abno mal) a oids insensi i i ies (>10% a iabili y and imp ecision o indi idual es ima ions) associa ed wi h eg ession equa ions and unp o en biophysical models, and does no ely on body weigh o assess hyd a ion. Use o BIVA imp o es he p esc ip ion o UF in dialysis by moni o ing he backwa d- o wa d displacemen o ec o s in ela ion o he we -d y cycle o HD. I u he enhances decision-making in dialysis by acili a ing he in e p e a ion o al e a ions in blood p essu e ela i e o he hyd a ion s a us and, hus, adjus ing UF. Among c i ically ill pa ien s, BIVA is signi ican ly and in e sely co ela ed wi h CVP. On he RXc g aph, impedance ec o s o pa ien s wi h low, no mal, and high CVP mo e downwa d and ou side o he 75% ole ance le el wi h inc easing CVP, which indica es excess luid accumula ion. Iden i ica ion o hypohyd a ion in s able CAD pa ien s be o e angiog aphic p ocedu es enabled ehyd a ion wi h app op ia e olumes o saline o a enua e isk o CI-AKI. Use o BIVA in assessmen o malnu i ion, no ably in illnesses wi h muscle loss when hyd a ion is al e ed, is inc easing. Phase-sensi i e mul i- equency BIS measu emen s coupled wi h biophysical models indi ec ly es ima e ECW ha is compa ed wi h p ojec ions o no mal ECW o calcula e excess ECW desc ibed as FO. The es ima es o ECW, adjus ed o BMI, a e de i ed om eg ession equa ions using gende , heigh , and body weigh as independen a iables wi h wide limi s o ag eemen and, hence imp ecision o an indi idual ECW es ima e. Es ima es o FO >2.5 L o >15% p edic ed ECW a e associa ed wi h inc eased mo bidi y in dialysis pa ien s bu he p ognos ic alue o mo ali y is lacking. 9. Fu u e Di ec ions Ad ancemen o he use o BI measu emen s o aid in luid managemen o dialysis pa ien s equi es p ospec i e con olled s udies wi h mo e ocus on ou comes [ 79 , 90 – 92 ]. Ea ly e o s we e desc ip i e emphasizing p oo -o -p inciple esea ch. Adequa e con i ma ion o posi i e indings ela ed o alidi y BIVA and BIS is a ailable. New esea ch should c i ically e alua e he bene i o hese BI app oaches in pa ien ca e. Impo an ly, he e is a need o mo e consis ency and sc u iny in esea ch design wi h app op ia e sample sizes o es hypo heses and compa abili y in epo ing o esul s. Some opics include he abili y o p edic in a- and in e -dialy ic complica ions and mo ali y Nu ien s 2019,11, 809 17 o 22 o HD pa ien s, measu e he e ec s o he apeu ic in e en ions on changes in hyd a ion and luid s a us on p ese a ion o enal unc ion, e alua e he speci ici y and sensi i i y o a ailable and pu a i e clinical ma ke s o hyd a ion, de e mina ion o changes in body composi ion as well as nu i ional s a us/in ake ela i e o longe i y o dialysis, and he e ec o in e en ions o p ese e muscle mass on su i al. The goal is o p o ide indings ha can be applied p ac ically o imp o e pa ien ou comes. 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