Association of Mortality Risk with Various Definitions of Intradialytic Hypotension

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1 Assocition of Mortlity Risk with Vrious Definitions of Intrdilytic Hypotension Jennifer E. Flythe,* Hui Xue, Ktherine E. Lynch,* Gry C. Curhn,* nd Steven M. Brunelli* *Renl Division nd Chnning Division of Network Medicine, Deprtment of Medicine, Brighm nd Women shospitl, Boston, Msschusetts; Hrvrd Medicl School, Boston, Msschusetts; University of North Crolin Kidney Center, Chpel Hill, North Crolin; Divisions of Hospitl Medicine nd Nephrology nd Hypertension, Deprtment of Medicine, University of Cliforni, Sn Diego, Cliforni; nd DVit Clinicl Reserch, Minnepolis, Minnesot ABSTRACT Intrdilytic hypotension is serious nd frequent compliction of hemodilysis; however, there is no evidence-bsed consensus definition of intrdilytic hypotension. As result, coherent evlution of the effects of intrdilytic hypotension is difficult. We nlyzed dt from 1409 ptients in the HEMO Study nd 10,392 ptients from single lrge dilysis orgniztion to investigte the ssocitions of commonly used intrdilytic hypotension definitions nd mortlity. Intrdilytic hypotension definitions were selected priori on the bsis of literture review. For ech definition, ptients were chrcterized s hving intrdilytic hypotension if they met the corresponding definition in t lest 30% of bseline exposure period tretments or chrcterized s control otherwise. Overll nd within subgroups of ptients with predilysis systolic BP,120 or mmhg, n bsolute ndir systolic BP,90 mmhg ws most potently ssocited with mortlity. Within the subgroup of ptients with predilysis BP$160 mmhg, ndir BP,100 mmhg ws most potently ssocited with mortlity. Intrdilytic hypotension definitions tht considered symptoms, interventions, nd decreses in BP during dilysis were not ssocited with outcome, nd when dded to ndir BP, symptom nd intervention criteri did not ccentute ssocitions with mortlity. Our results suggest tht ndir-bsed definitions best cpture the ssocition between intrdilytic hypotension nd mortlity. J Am Soc Nephrol 26: , doi: /ASN Intrdilytic hypotension (IDH) is serious compliction of hemodilysis(hd). IDH hs been ssocited with subsequent vsculr ccess thrombosis, 1 indequte dilysis dose, 2 nd mortlity. 3,4 Additionlly, IDH-precipitted fluid dministrtion nd erly HD termintion cn leve ptients volume-expnded nd t risk for ssocited crdiovsculr morbidity. 5 IDH prevlence reports rnge from 15% to 50% of mbultory HD sessions. 6 This wide rnge is explined, in prt, by differing criteri used to define IDH. There is no consensus definition. The Ntionl Kidney Foundtion s Kidney Disese Outcomes Qulity Inititive (KDOQI) guidelines define IDH s decrese in either systolic BP (SBP)$20 mmhg or men rteril pressure$10 mmhg s well s ssocited symptoms. 7 Others define IDH on the bsis of requisite SBP fll during tretment ccompnied by interventions, such s sline bolus dministrtion, ultrfiltrtion (UF) reduction, or blood flow reduction. 8 Becuse symptom nd intervention dt re often unvilble in lrge dtbses, some IDH definitions re bsed exclusively on SBP mesurements, such s SBP reduction by some requisite mount during tretment (20, 30, nd 40 mmhg) or ndir intrdilytic SBP below threshold vlue (90, 95, nd 100 mmhg) Received Februry 28, Accepted My 19, Published online hed of print. Publiction dte vilble t Correspondence: Dr. Jennifer E. Flythe, University of North Crolin Kidney Center, 7024 Burnett-Womck CB #7155, Chpel Hill, NC Emil: jflythe@med.unc.edu Copyright 2015 by the Americn Society of Nephrology 724 ISSN : / J Am Soc Nephrol 26: , 2015

2 CLINICAL EPIDEMIOLOGY Compound definitions re lso common; exmples include $30-mmHg SBP fll+ndir SBP,110 mmhg nd $20-mmHg SBP fll+fluid bolus6symptoms. 14,15 Discrepncies in IDH definitions limit synthesis of the existing dt regrding puttive IDH sequele nd potentil strtegies for IDH prophylxis nd tretment. Despite the lrge body of dt surrounding IDH, there is surprisingly little evidence linking IDH to mortlity. Shoji et l. 3 showed tht $40-mmHg SBP fll nd ndir SBP (seprtely) predict 2-yer mortlity. Contrstingly, Tisler et l. 4 reported no ssocition between mortlity nd frequent IDH (defined s $10 tretments during 10-month run-in period in which ndir SBP,90 mmhg or 30-mmHg SBP fll+ssocited symptoms nd intervention). To ssemble coherent evidence bse tht cn guide clinicl decisions, it is impertive tht we develop consistent, evidence-bsed IDH definition. We undertook this study to exmine the ssocition of commonlyusedidhdefinitions ndmortlity. IDH definitions(tble 1) were selected priori by literture review. We conducted secondry nlysis of the Hemodilysis (HEMO) Study to test mortlity ssocitions cross rnge of IDH definitions, tking dvntge of HEMO-reported intrdilytic SBP, symptom, nd intervention dt. We then performed repliction study to confirm results nd explore IDH mortlity ssocitions cross ctegories of pre-hd SBP using dt from ntionlly representtive cohort of ptients on prevlent, three times per week, incenter HD from single lrge dilysis orgniztion (LDO). RESULTS Bseline Chrcteristics of Cohorts Chrcteristics of the HEMO nd LDO cohorts re presented in Tble 2. Compred with ptients without Ndir90-defined Tble 1. Term Ndir90 Ndir100 Fll20 Fll30 Fll20Ndir90 Fll30Ndir90 KDOQI HEMO A priori IDH definitions Definition Minimum intrdilytic SBP,90 mmhg Minimum intrdilytic SBP,100 mmhg (Pre-HD SBP2minimum intrdilytic SBP) $20 mmhg (Pre-HD SBP2minimum intrdilytic SBP) $30 mmhg (Pre-HD SBP2minimum intrdilytic SBP) $20 mmhg nd minimum intrdilytic SBP,90 mmhg (Pre-HD SBP2minimum intrdilytic SBP) $30 mmhg nd minimum intrdilytic SBP,90 mmhg (Pre-HD SBP2minimum intrdilytic SBP) $20 mmhg nd symptoms of crmping, hedche, lighthededness, vomiting, or chest pin during HD Fll in SBP resulting in intervention of UF reduction, blood flow reduction, or sline dministrtion IDH, ptients with Ndir90-defined IDH in both cohorts were more likely to be women, be of longer dilytic vintge, be dilyzed by ctheter, nd hve lower pre-hd SBP nd lbumin; they were less likely to be prescribed clcium chnnel blockers, -blockers, nd other ntihypertensive gents. Primry Anlyses In 1409 ptients in the HEMO cohort, ptients underwent 12,561 tretments during the bseline exposure period of pproximtely 6 months (men= sessions/ptient) (Supplementl Figure 1A displys the study timeline). Figure 1 displys the IDH frequency by definition: 19.1% of sessions hd HEMO-defined IDH, nd 11.3% of sessions hd Ndir90- defined IDH. Overll, 25.0% of ptients experienced HEMOdefined IDH in t lest 30% of the bseline tretments, nd 11.9% of ptients experienced Ndir90-defined IDH in t lest 30% of the bseline tretments. During the subsequent 2-yer t-risk period, 432 (30.7%) ptients died. In undjusted nlyses, meeting the Ndir90, Fll20Ndir90, Fll30Ndir90, nd HEMO IDH definitions in t lest 30% of bseline sessions (versus not) ws ech ssocited with higher 2-yer mortlity. After djustment for potentil confounders, only Ndir90 (versus not) remined ssocited with higher 2- yer mortlity: djusted odds rtio (OR), 1.56; 95% confidence intervl (95% CI), 1.05 to 2.31 (Figure 2, Tble 3). In 10,392 ptients in the LDO cohort, ptients underwent 136,754 tretments during the bseline period of 30 dys (men= sessions/ptient) (Supplementl Figure 1B displys the study timeline). The frequencies of IDH by different definitions were similr to those in the HEMO cohort (Figure 1): 9.7% of sessions hd Ndir90-defined IDH. Overll, 10.1% of ptients experienced Ndir90-defined IDH in t lest 30% of the bseline tretments. During the subsequent 1- yer t-risk period, 1253 (12.1%) ptients died. In undjusted nlyses, IDH (by ech definition) in t lest 30% of sessions (versus not) ws ssocited with 1-yer mortlity; Ndir90 hd the most potent ssocition with higher mortlity: undjusted OR, 2.10; 95% CI, 1.78 to After multivrible djustment, only Ndir90 (versus not) remined ssocited with higher 1-yer mortlity: djusted OR, 1.30; 95% CI, 1.07 to 1.57 (Figure 2, Tbles 3). Secondry Anlyses Corrobortive time-to-deth nlyses with Ndir90 were conducted in the full HEMO cohort (n=1753). There were 809 deths, nd the medin t-risk time ws 2.3 yers. Ndir90 in t lest 30% of sessions (versus not) ws ssocited with higher mortlity risk: djusted hzrd rtio (HR), 1.38; 95% CI, 1.11 to Associtions between other IDH definitions nd mortlity did not rech sttisticl significnce. Anlogous nlyses were performed in the LDO cohort. Both Ndir90 nd Fll20- Ndir90 in t lest 30% of sessions (versus not) were ssocited with higher mortlity risk, nd the mgnitude of ssocition ws greter for Ndir90: djusted HR, 1.22; 95% CI, 1.10 to J Am Soc Nephrol 26: , 2015 Intrdilytic Hypotension Definition 725

3 Tble 2. Bseline chrcteristics of the HEMO (n=1409) nd LDO (n=10,392) cohorts cross binry Ndir90-defined IDH Chrcteristic HEMO Cohort LDO Cohort (+) Ndir90 (n=167) (2) Ndir90 (n=1242) (+) Ndir90 (n=1055) (2) Ndir90 (n=9337) Age (per 10 yr) Women 108 (64.7%) 676 (54.4%) 548 (51.9%) 4220 (45.2%) Blck 97 (58.1%) 808 (65.1%) 330 (31.3%) 3860 (41.3%) ICED #1 30 (18.0%) 448 (36.1%) 2 54 (32.3%) 404 (32.5%) 3 83 (49.7%) 390 (31.4%) Dibetes 88 (52.7%) 543 (43.7%) 644 (61.0%) 5593 (59.9%) Hert filure 71 (42.5%) 505 (40.7%) 479 (45.4%) 4167 (44.6%) Peripherl vsculr disese 62 (37.1%) 313 (25.2%) 424 (40.2%) 4325 (46.3%) Cerebrovsculr disese 36 (21.6%) 248 (20.0%) 40 (3.8%) 283 (3.0%) Coronry rtery disese 79 (47.3%) 484 (39.0%) 163 (15.5%) 1278 (13.7%) Vintge (yr) # (22.2%) 326 (26.2%) 233 (22.1%) 2667 (28.6%) (19.8%) 248 (20.0%) 137 (13.0%) 1467 (15.7%) (17.9%) 291 (23.4%) 243 (23.0%) 2326 (24.9%) $ (40.1%) 377 (30.4%) 440 (41.7%) 2860 (30.6%) Missing (0.2%) 17 (0.2%) Access Grft 101 (60.5%) 752 (60.6%) 328 (31.3%) 2876 (31.0%) Fistul 46 (27.5%) 410 (33.0%) 338 (32.3% 3486 (37.6%) Ctheter 20 (12.0%) 90 (6.4%) 382 (36.4%) 2909 (31.4%) Post-HD weight (kg) b Qurtile 1 40 (24.0%) 313 (25.2%) 292 (27.7%) 2309 (24.7%) Qurtile 2 39 (23.4%) 313 (25.2%) 267 (25.3%) 2330 (25.0%) Qurtile 3 36 (21.5%) 316 (25.4%) 248 (23.5%) 2348 (15.1%) Qurtile 4 52 (31.1%) 300 (24.2%) 248 (23.5%) 2350 (25.2%) Tretment time delivered (min) UF volume (L) Pre-HD SBP (mmhg) # (40.1%) 114 (9.2%) 488 (46.2%) 911 (9.8%) (43.7%) 665 (53.5%) 429 (40.7%) 4940 (52.9%) $ (16.2%) 463 (37.3%) 138 (13.1%) 3486 (37.3%) Nonoliguric (.200 ml/d) 10 (6.0%) 140 (11.3%) Albumin (g/dl) #2.9 7 (4.2%) 45 (3.6%) 97 (9.2%) 425 (4.6%) (89.8%) 1026 (82.6%) 595 (56.4%) 5048 (54.1%) $4 10 (6.0%) 171 (13.8%) 359 (34.0%) 3795 (40.6%) Missing (0.4%) 69 (0.7%) Hemtocrit (%) Hemoglobin (g/dl) Hospitlized during exposure 61 (36.5%) 376 (30.3%) 332 (31.5%) 2811 (30.1%) period c b-blocker use 30 (18.0%) 362 (29.2%) 89 (8.5%) 839 (9.0%) Clcium chnnel blocker 49 (29.3%) 643 (51.8%) 84 (8.0%) 964 (10.3%) Renin-ngiotensin system blocker 27 (16.2%) 314 (25.3%) 98 (9.3%) 910 (9.8%) use Nitrte use 33 (19.8%) 221 (17.8%) 33 (3.1%) 275 (3.0%) -Blocker use 3 (1.8%) 76 (6.1%) 1 (0.1%) 120 (1.3%) Other ntihypertensive use 14 (8.4%) 306 (24.6%) 80 (7.6%) 940 (10.1%) High Kt/V group 86 (51.5%) 623 (50.2%) 726 Journl of the Americn Society of Nephrology J Am Soc Nephrol 26: , 2015

4 CLINICAL EPIDEMIOLOGY Tble 2. Continued Chrcteristic HEMO Cohort LDO Cohort (+) Ndir90 (n=167) (2) Ndir90 (n=1242) (+) Ndir90 (n=1055) (2) Ndir90 (n=9337) equilibrted Kt/V, (19.8%) 2152 (23.0%) $ (77.0%) 6850 (73.4%) Missing 34 (3.2%) 335 (3.6%) High-flux group 91 (54.5%) 613 (49.4%) Positive (+) IDH defined s meeting the Ndir90 definedidhdefinition (minimum intrdilytic SBP,90 mmhg) in $30% of exposure period dilysis sessions. Vlues re presented s men (SD) or n (%). Not vilble in both cohorts. b HEMO cohort (quntile 1: #62.7, quntile 2: , quntile 3: , quntile 4: $89.2 kg); LDO cohort (quntile 1: #58.7, quntile 2: , quntile 3: , quntile 4: $78.2). c Missed HD sessions used s surrogte for hospitliztions in LDO cohort. Figure 1. Frequency of IDH ws similr cross both cohorts. Frequency of IDH ws defined by the number of dilysis sessions with events meeting the specified IDH definition divided by the totl number of dilysis tretments in the bseline period. Fll20, (pre-hd SBP2minimum intrdilytic SBP) $20 mmhg; Fll20Ndir90: (pre-hd SBP2 minimum intrdilytic SBP) $20 mmhg nd minimum intrdilytic SBP,90 mmhg; Fll30, (pre-hd SBP2minimum intrdilytic SBP) $30 mmhg; Fll30Ndir90, (pre-hd SBP2minimum intrdilytic SBP) $30 mmhg nd minimum intrdilytic SBP,90 mmhg; HEMO, fll in SBP resulting in intervention of UF reduction, blood flow reduction, or sline dministrtion; KDOQI, (pre-hd SBP 2 minimum intrdilytic SBP) $20 mmhg nd symptoms of crmping, hedche, lighthededness, vomiting, or chest pin during HD; Ndir90, minimum intrdilytic SBP,90 mmhg; Ndir100, minimum intrdilytic SBP,100 mmhg. HEMO nd KDOQI definitions of IDH could not be ssessed in the LDO cohort becuse of the lck of symptom nd intervention dt in this cohort. Additionlly, we investigted whether dding criteri for intrdilytic symptoms (crmping, hedche, lighthededness, vomiting, or chest pin) or intervention (fluid bolus dministrtion, UF reduction, or bloodflow reduction) to Ndir90 ltered the ssocition with mortlity. No ssocitions between Ndir90+symptoms or Ndir90+intervention nd outcome were observed in djusted nlyses (Tble 3). Finlly, we exmined IDH definition mortlity ssocitions cross pre-hd SBP strtof #129, , nd $160mmHg in the LDO cohort. Restriction subgroup nlyses showed differences in Ndir90 mortlity ssocitions cross strt (P interction=0.02). In strtified nlyses, Ndir90 in t lest 30% of sessions (versus not) ws most potently ssocited with 1- yer mortlity in the #129- nd mmhg SBP strt. In the $160-mmHg pre-hd SBP strt, Ndir100 (versus not) ws most potently ssocited with mortlity (Tble 4). To investigte the ssocition of greter SBP flls during dilysis, we exmined the ssocition of 1-yer mortlity nd 10-mmHg incrementl increses in SBP fll cross pre-hd SBP strt; no ssocitions between greter SBP flls nd outcome were observed (Tble 4) for Ndir90 nd HR, 1.14; 95% CI, 1.02 to 1.27 for Fll20- Ndir90. To exmine dose response, we ctegorized ptients s hving,5%, 6% 29%, 30% 49%, nd $50% of bseline tretments with Ndir90-defined IDH. Compred with,5% tretments, higher frequency of Ndir90-defined IDH ws incrementlly ssocited with greter 2-yer mortlity (P trend=0.02) (Figure 3). DISCUSSION There is no consensus evidence-bsed definition of IDH. As result, the existing evidence bse is frught with mny definitions, rendering dt synthesis impossible. Our nlysis shows tht n bsolute intrdilytic ndir SBP,90 mmhg is most potently ssocited with mortlity; this ssocition ws consistent cross pre-hd SBP strt of #129 nd J Am Soc Nephrol 26: , 2015 Intrdilytic Hypotension Definition 727

5 Figure 2. Adjusted ssocitions between IDH definitions nd mortlity in (A) the HEMO cohort nd (B) the LDO cohort. Outcome for the HEMO cohort is 2-yer mortlity, nd outcome for the LDO cohort is 1-yer mortlity. IDH ws defined s $30% of the exposure period HD sessions meeting the specified definition. Multivrite logistic models for the HEMO cohort were djusted for ge (per 10 yers), sex, rce (blck or nonblck), ICED (#1, 2, or 3), smoking sttus (current smoker or nonsmoker), dibetes, hert filure, ischemic hert disese, cerebrovsculr disese, peripherl vsculr disese, vintge (#0.9, 1 1.9, 2 3.9, or $4 yers or missing), ccess (grft, fistul, or ctheter), postdilysis weight (qurtiles; kilogrms), delivered tretment time (minutes), lbumin (#2.9, 3 3.9, or $4 g/dl or missing), hemtocrit (percentge), UFvolume(liters),predilysisSBP(#129, , or $160 mmhg), residul renl function (#200 or.200 ml/d), hospitliztion during exposure period(yesorno),kt/vgroup(highorlow),flux group (high or low), center, nd use of -drenergic blocker, renin-ngiotensin system blocker, b-blocker, clcium chnnel blocker, nitrtes, or other ntihypertensives. Multivrite logistic models for the LDO cohort were djusted for ge (per 10 yers), sex, rce (blck, nonblck, or missing), dibetes, hert filure, ischemic hert disese, cerebrovsculr disese, peripherl vsculr disese, vintge (#0.9, 1 1.9, 2 3.9, or $4 yers or missing), ccess (grft, fistul, or ctheter), postdilysis weight (qurtiles; kilogrms), delivered tretment time (minutes), lbumin (#2.9, 3 3.9, or $4 g/dl or missing), hemoglobin (grms per deciliter), UF volume (liters), predilysis SBP (#129, , or $160 mmhg), equilibrted Kt/V (,1.2, $1.2, or missing), missed sessions during exposure period (0,1,2,or$3), nd use of -drenergic blocker, renin-ngiotensin system blocker, b-blocker, clcium chnnel blocker, nitrtes, or other ntihypertensives. mmhg. Intrdilytic ndir SBP,100 mmhg ws most strongly ssocited with mortlity in the pre-hd SBP strt of $160 mmhg. The dt suggest dose response reltionship between Ndir90 nd mortlity: greter frequency of Ndir90- defined IDH is ssocited with incrementlly greter mortlity risk. In our nlysis, IDH definitions on the bsis of intrdilytic SBP fll, symptoms, nd interventions without considertion of the bsolute ndir SBP were not significntly ssocited with outcome. Finlly, dding symptom nd intervention criteri to ndir SBP definitions did not ugment their strengths of ssocition with mortlity. Prior observtionl studies hve shown inconsistent ssocitions between IDH nd mortlity. Shoji et l. 3 exmined the effect of IDH on mortlity in 1206 Jpnese ptients nd showed tht SBP fll$40 mmhg ws ssocited with 2-yer mortlity; the ssocition persisted cross pre-hd SBP strt. Additionlly, Shoji et l. 3 showed tht lower intrdilytic ndir SBP ws ssocited with higher mortlity. Notble limittions to this nlysis include low deth rte (6.2% per yer) nd considertion of single tretment session s the exposure. Tisler et l. 4 studied 263 Hungrin ptients on HD using time-to-event djusted nlyses nd found tht ptients with frequent IDH (defined s $10 episodes per 40-week run-in period of Ndir90 or Fll30+ssocited symptoms nd intervention) hd no greter mortlity risk thn those without IDH. In the study by Tisler et l., 4 ptients with s few s one episode of IDH per month met the criteri for frequent IDH, potentilly leving too little seprtion between the exposure nd control groups to detect cliniclly importnt difference. In contrst, our study definition required tht ptients meet the specified IDH definition in t lest 30% of bseline sessions to qulify s (+) IDH; for exmple, ptients with 13 tretments in the LDO cohort s 4-week t-risk period hd to hve four IDH episodes to qulify, nerly four times the number required in the study by Tisler et l. 4 Despite the plethor of IDH-relted studies ( Pubmed serch for IDH cptured 318 rticles 16 ) nd common llusions to IDH being crdiovsculr risk fctor, 17,18 strikingly little dt exist to inform prognosticlly relevnt IDH definition. In publishing its IDH dignostic criteri, the Europen guidelines group cknowledged tht no evidence-bsed recommendtion regrding the definition of IDH cn be given Journl of the Americn Society of Nephrology J Am Soc Nephrol 26: , 2015

6 CLINICAL EPIDEMIOLOGY Tble 3. Undjusted nd djusted ssocitions between IDH definitions nd mortlity on the bsis of logistic regression models HEMO Cohort (n=1409) LDO Cohort (n=10,392) Definition (+) IDH b (2) IDH Undjusted OR (95% CI) (+) IDH versus (2) IDH Adjusted OR c (95% CI) (+) IDH versus (2) IDH (+) IDH b (2) IDH Undjusted OR (95% CI) (+) IDH versus (2) IDH Adjusted OR d (95% CI) (+) IDH versus (2) IDH Ndir90 n=167 n= e 1.56 f n=1054 n= e 1.30 f Died: 79 (47.3%) Died: 353 (28.4%) (1.63 to 3.14) (1.05 to 2.31) Died: 218 (20.7%) Died: 1035 (11.1%) (1.78 to 2.47) (1.07 to 1.57) Ndir100 n=390 n= e 1.22 n=2841 n= e 1.13 Died: 162 (41.5%) Died: 270 (26.5%) (1.54 to 2.52) (0.90 to 2.31) Died: 475 (16.7%) Died: 778 (10.3%) (1.54 to 1.98) (0.97 to 1.31) Fll20 n=1288 n= n=9271 n= e 0.84 Died: 394 (30.6%) Died: 38 (31.4%) (0.64 to 1.44) (0.47 to 1.24) Died: 1066 (11.5%) Died: 187 (16.7%) (0.55 to 0.77) (0.69 to 1.02) Fll30 n=1049 n= n=7428 n= e 0.99 Died: 325 (31.0%) Died: 107 (29.7%) (0.82 to 1.38) (0.68 to 1.31) Died: 837 (11.3%) Died: 416 (14.0%) (0.69 to 0.88) (0.86 to 1.15) Fll20Ndir90 n=151 n= e 1.32 n=898 n= e 1.20 Died: 67 (44.4%) Died: 365 (29.0%) (1.38 to 2.75) (0.88 to 1.97) Died: 171 (19.0%) Died: 1082 (11.4%) (1.53 to 2.19) (0.98 to 1.47) Fll30Ndir90 n=131 n= f 1.27 n=740 n= e 1.15 Died: 57 (43.5%) Died: 375 (29.3%) (1.29 to 2.67) (0.83 to 1.95) Died: 124 (16.8%) Died: 1129 (11.7%) (1.24 to 1.86) (0.92 to 1.43) KDOQI n=118 n= Died: 35 (29.7%) Died: 397 (30.8%) (0.63 to 1.43) (0.65 to 1.66) HEMO n=353 n= f 1.01 Died: 130 (36.8%) Died: 302 (28.6%) (1.13 to 1.88) (0.75 to 1.37) Ndir90+Sx g n=6 n= Died: 2 (33.3%) Died: 430 (30.7%) (0.21 to 6.20) (0.06 to 2.04) Ndir90+Int g n=100 n= f 1.39 Died: 45 (45.0%) Died: 387 (29.6%) (1.29 to 2.94) (0.86 to 2.23) Outcome for the HEMO cohort is 2-yer mortlity, nd outcome for the LDO cohort is 1-yer mortlity. b IDH defined s $30% of exposure period HD sessions meeting the specified definition. c Multivrite logistic models were djusted for ge (per 10 yers), sex, rce (blck or nonblck), ICED (#1, 2, or 3), smoking sttus (current smoker or nonsmoker), dibetes, hert filure, ischemic hert disese, cerebrovsculr disese, peripherl vsculr disese, vintge (#0.9, 1 1.9, 2 3.9, or $4 yers or missing), ccess (grft, fistul, or ctheter), postdilysis weight (qurtiles; kilogrms), delivered tretment time (minutes), lbumin (#2.9, 3 3.9,or $4 g/dl or missing), hemtocrit (percentge), UF volume (liters), predilysis SBP (#129, ,or $160 mmhg), residul renl function (#200 or.200 ml/d), hospitliztion during exposure period (yes or no),kt/v group (high or low),flux group (high or low), center, nd use of -drenergic blocker, renin-ngiotensin system blocker, b-blocker, clcium chnnel blocker, nitrtes,or other ntihypertensives. d Multivrite logistic models were djusted for ge (per 10 yers), sex, rce (blck, nonblck, or missing), dibetes, hert filure, ischemic hert disese, cerebrovsculr disese, peripherl vsculr disese, vintge (#0.9, 1 1.9, 2 3.9, or $4 yers or missing), ccess (grft,fistul, or ctheter), postdilysis weight (qurtiles; kilogrms), delivered tretment time (minutes), lbumin (#2.9, 3 3.9, or $4 g/dl or missing), hemoglobin (grms per deciliter), UF volume (liters), predilysis SBP (millimeters Hg), equilibrted Kt/V (,1.2,$1.2, or missing), missed sessions during exposure period (0,1, 2,or $3), nd use of -drenergic blocker, reninngiotensin system blocker, b-blocker, clcium chnnel blocker, nitrtes, nd other ntihypertensives. e P vlue, f P vlue,0.05. g Given the smll n meeting the IDH definition in $30% of HD sessions, definition tertiles were exmined; point estimtes were similr (dt not shown). J Am Soc Nephrol 26: , 2015 Intrdilytic Hypotension Definition 729

7 Figure 3. In the HEMO cohort, ptients with more frequent episodes of IDH hd incrementlly greter mortlity in both undjusted nd djusted nlyses. Anlyses were djusted for ge (per 10 yers), sex, rce (blck or nonblck), ICED (#1, 2, or 3), smoking sttus (current smoker or nonsmoker), dibetes, hert filure, ischemic hert disese, cerebrovsculr disese, peripherl vsculr disese, vintge (#0.9, 1 1.9, 2 3.9, or $4 yers or missing), ccess (grft, fistul, or ctheter), postdilysis weight (qurtiles; kilogrms), delivered tretment time (minutes), lbumin (#2.9, 3 3.9, or $4 g/dl or missing), hemtocrit (percentge), UF volume (liters), predilysis SBP (#129, , or $160 mmhg), residul renl function (#200 or.200 ml/d), hospitliztion during exposure period (yes or no), Kt/V group (high or low), flux group (high or low), center, nd use of -drenergic blocker, renin-ngiotensin system blocker, b-blocker, clcium chnnel blocker, nitrtes, or other ntihypertensives. Error brs indicte 95% CI. Lck of n evidence-bsed IDH definition hs led to vrition in IDH definitions cross studies; we identified 15 different IDH definitions by literture review. Such wide vrition renders synthesis of dt cross studies impossible nd prevents the development of meningful prctice recommendtions. In our nlysis, we show tht ndir SBP-bsed definitions hve greter ssocitions with mortlity thn non-ndir bsed or compound definitions. These findings chllenge the oftcited IDH dignostic criteri tht include the presence of symptoms nd/or interventions. 7,19 Our findings in this regrd my reflect provider-to-provider vribility in intervention thresholds nd/or ptient-to-ptient vribility in symptom reporting. The impetus for intervention nd the choice of intervention vry from fcility to fcility nd even provider to provider. These prctice vritions introduce substntil inconsistency into IDH definitions dependent on delivered intervention. Similrly, ptient-reported symptoms vry widely. In one survey, Weisbord et l. 20 found tht 39.0% of ptients reported crmping, 23.0% of ptients reported dizziness, nd 21.0% of ptients reported hedche with HD. In contrst, HD-relted symptom frequency ws much higher in nother survey, with 74.3% of ptients reporting crmping, 63.0% of ptients reporting dizziness, nd 53.6% of ptients reporting hedche. 21 Such differences my result from reporting bis but my lso reflect differences in physiology, becuse ptients experience symptoms t vrying thresholds of BP chnge nd ndir. Ptient symptoms my be importnt fctors t the individul level, becuse they plusibly reflect ischemi, but their use in popultion-level definitions my be questionble becuse of wide ptient-to-ptient vrition. Additionlly, we were surprised to find tht incrementlly lrger SBP flls, independent of ndir, were not significntly ssocited with outcome. Although it is widely held tht HD ptients suffer from impired utoregultory responses to SBP chnges, our results my suggest tht their compenstory mechnisms re sufficiently ctive until certin SBP thresholds:,90 mmhg for pre-hd SBP,160 nd,100 for pre-hd SBP $160 mmhg. Reduction in blood volume to criticl ndir my be necessry to induce enough microcircultory nd microcrdic ischemi to yield reduced crdic output nd ssocited mortlity. Lrger SBP flls tht do not result in ndirs,90 mmhg my hve clinicl relevnce beyond mortlity, nd this possibility should be explored in dditionl nlyses exmining ssocitions of IDH nd morbidities other thn deth. Our results suggest the need for development of n evidence-bsed IDH definition tht more ccurtely cptures IDH morbidity nd mortlity ssocitions. Strengths of this study include the use of two cohorts: (1)the HEMO Study cohort (notble for its rigorous dt collection protocols nd detiled informtion on intrdilytic hemodynmics, interventions, nd ptient symptoms) nd (2) the LDO cohort (notble for its ntionl representtion nd robust number of HD sessions with intrdilytic SBP dt. Stbility in frequency of IDH definitions nd IDH definition mortlity ssocitions cross both cohorts lends credence to our reported findings. Our study does hve importnt limittions. First, uncontrolled confounding is n inherent risk of observtionl reserch. To minimize this risk, we djusted our nlyses for vribles plusibly ssocited with IDH nd mortlity; however, we cnnot exclude the possibility of residul confounding from these vribles or unconsidered vribles. Notbly, pre- HD SBP is strongly ssocited with outcome. 22 We ttempted 730 Journl of the Americn Society of Nephrology J Am Soc Nephrol 26: , 2015

8 CLINICAL EPIDEMIOLOGY Tble 4. Adjusted ssocitions between IDH nd 1-yer mortlity cross predilysis SBP strt in the LDO cohort Definition Ptients Meeting IDH Definition n (%) Adjusted OR b (95% CI) for Ptients Meeting Versus Not Meeting IDH Definition Pre-HD SBP#129 mmhg (6448 ptients) Ndir (21.6%) 1.32 (1.10 to 1.57) c Ndir (48.0%) 1.23 (1.05 to 1.44) c Fll (46.8%) 1.08 (0.93 to 1.26) Fll (20.7%) 1.02 (0.85 to 1.23) Fll (6.8%) 1.30 (0.98 to 1.73) Fll (1.7%) 1.34 (0.80 to 2.23) Fll60 35 (0.5%) 1.51 (0.61 to 3.73) Fll30Ndir (13.1%) 1.06 (0.85 to 1.32) Fll20Ndir (17.6%) 1.18 (0.98 to 1.42) Pre-HD SBP= mmhg (9759 ptients) Ndir (10.7%) 1.28 (1.05 to 1.55) c Ndir (27.7%) 1.14 (0.98 to 1.31) Fll (82.6%) 1.03 (0.86 to 1.24) Fll (63.3%) 1.06 (0.92 to 1.22) Fll (40.6%) 1.11 (0.97 to 1.28) Fll (20.3%) 1.04 (0.88 to 1.22) Fll (7.9%) 1.16 (0.92 to 1.46) Fll30Ndir (10.7%) 1.27 (1.05 to 1.54) c Fll20Ndir (10.7%) 1.27 (1.05 to 1.54) c Pre-HD SBP$160 mmhg (8307 ptients) Ndir (7.0%) 1.08 (0.83 to 1.41) Ndir (17.0%) 1.29 (1.07 to 1.56) c Fll (96.0%) 0.78 (0.55 to 1.11) Fll (88.9%) 1.13 (0.88 to 1.46) Fll (76.4%) 1.06 (0.88 to 1.28) Fll (60.7%) 1.13 (0.96 to 1.33) Fll (44.1%) 1.13 (0.96 to 1.32) Fll30Ndir (7.0%) 1.13 (0.86 to 1.48) Fll20Ndir (7.0%) 1.13 (0.86 to 1.48) Positive (+) IDH defined s ndir SBP,90 mmhg in $30% of exposure period dilysis sessions (versus not). b Multivrite logistic models were djusted for ge (per 10 yers), sex, rce (blck, nonblck, or missing), dibetes, hert filure, ischemic hert disese, cerebrovsculr disese, peripherl vsculr disese, vintge (#0.9, 1 1.9, 2 3.9, or $4 yers or missing), ccess (grft, fistul, or ctheter), postdilysis weight (qurtiles; kilogrms), delivered tretment time (minutes), lbumin (#2.9, 3 3.9, or $4 g/dl or missing), hemoglobin (grms per deciliter), UF volume (liters), predilysis SBP (millimeters Hg), equilibrted Kt/V (,1.2, $1.2, or missing), missed sessions during exposure period (0, 1, 2, or $3), nd use of -drenergic blocker, renin-ngiotensin system blocker, b-blocker, clcium chnnel blocker, nitrtes, nd other ntihypertensives. c P vlue,0.05. to limit confounding of the IDH outcome ssocition on the bsis of pre-hd BP by strtifiction on pre-hd BP nd inclusion of pre-hd SBP in our strtified multivrible models. We cnnot fully exclude the possibility of residul confounding by pre-hd SBP. Second, intrdilytic SBPs, intervention, nd symptom dt were only vilble from monitored HEMO Study sessions, which were conducted monthly. To ensure tht our IDH exposure ws representtive of ptients broder HD hemodynmic experiences nd reduce misclssifiction error, we ggregted tretment dt over 6-month exposure period. This exposure period durtion my hve imposed survivor bis; however, only 93 ptients (5.0%) were excluded for filing to survive this period, mking meningful bis unlikely. Also, in this regrd, it is ressuring tht similr findings were observed in the LDO cohort, where only 30-dy bseline survivl ws necessry. Third, HD hemodynmic dt were only vilble for one tretment per month in the HEMO Study, introducing possible misclssifiction bis. The consistency of IDH frequencies cross the HEMO cohort nd LDO cohort (where session-to-session hemodynmic dt were vilble) provides ressurnce tht misclssifiction in the HEMO cohort ws miniml. Fourth, reporting bis my hve influenced IDH definitions relying on ptient-reported symptoms; however, in s much s individul ptients hve differing reporting thresholds; this finding represents n inherent limittion of symptoms-bsed IDH definitions. Fifth, becuse of dt limittions in the LDO cohort, we were unble to consider residul renl function s confounder, but we did include dilytic vintge s prtil surrogte for this vrible. Also, we included residul renl function in our HEMO cohort nlyses, nd outcomes were similr cross cohorts. Sixth, no dt were vilble on ntihypertensive mediction dherence or timing in either cohort, nd therefore, we were unble to ssess the influence of these fctors on IDH. Finlly, there ws no systemtic ttempt to clibrte individul BP devices. However, ny resulting bis should hve ttenuted ndir-bsed definitions towrd the null. In conclusion, this study shows tht, mong the definitions considered, n bsolute ndir intrdilytic SBP,90 mmhg ws most potently ssocited with mortlity overll, nd for subgroups of ptients with pre-hd SBP, it is,160 mmhg. For ptients with pre-hd SBP$160 mmhg, Ndir100 my hve more robust mortlity ssocition. IDH defined by SBP fll nd IDH symptoms or interventions ws not significntly ssocited with mortlity, even when considered cross differing pre-hd SBP strt. Additionl studies re needed to confirm findings, nd prospective studies using consistent IDH definitions re needed to effectively evlute IDH tretment nd preventive strtegies. CONCISE METHODS Study Popultion nd Dt Collection This study ws pproved by the Prtners Helth Cre Institutionl Review Bord. Study dt were derived from the HEMO Study nd obtined from the Ntionl Institute of Dibetes nd Digestive nd Kidney Diseses dt repository nd cohort of prevlent dult ptients receiving three times per week in-center HD t one LDO. The HEMO Study design nd methods hve been reported. 8,23 Briefly, the HEMO Study ws 232 fctoril, 15-center, rndomized tril to evlute the outcome effects of HD dose nd membrne flux. HEMO prticipnts were enrolled between 1995 nd 2000 nd ges J Am Soc Nephrol 26: , 2015 Intrdilytic Hypotension Definition 731

9 yers. Ptients were followed until deth or December of 2001 nd censored t the time of kidney trnsplnt. Notble HEMO exclusion criteri included severe hert filure, unstble ngin pectoris, nd lbumin#2.6 g/d. Supplementl Figure 1A displys our study timeline. For this nlysis, we excluded ptients who did not survive the bseline exposure period of prerndomiztion time+4 months (n=93) nd ptients who were trnsplnted or trnsferred fcilities nd thus, hd,2 yers of potentil follow-up time brring deth (n=344), resulting in 1409 ptients. Corrobortive time-to-event nlysis ws conducted in the full cohort of ptients who survived the bseline exposure period (n=1753). The LDO cohort ws derived from 12,417 ptients on prevlent three times per week in-center HD dilyzing t one LDO between 2005 nd Ptients were followed until deth or Februry of Ptients were dilyzed t 1 of 1263 United Sttes mbultory dilysis fcilities locted in diverse geogrphic regions. Supplementl Figure 1B displys our study timeline. We excluded ptients who did not survive the 30-dy exposure period (n=24) nd ptients who remined live but hd,1 yer of follow-up time kidney becuse of trnsplnt, cre trnsfer, or dilysis modlity chnge (n=2021), resulting in 10,392 ptients. For the HEMO cohort, ll dtwere obtined by ptient interviews, medicl chrt reviews, nd self-reported questionnires per HEMO protocols; HEMO dt collection methods hve been previously reported. 8,24 For the LDO cohort, ll dt were obtined from the electronic medicl record of the LDO nd collected ccording to stndrd protocols s previously reported Designtion of Exposures nd Outcome The exposures of interest were differing IDH definitions selected priorion the bsis of prominent definitions identified by literture review (Tble 1). In the HEMO cohort, IDH ws considered for bseline period, including tretments incurred during the prerndomiztion period nd the 4 months fter rndomiztion. More frequent HD session dt were vilble in the LDO cohort, nd therefore, 30-dy exposure period ws selected to minimize survivor bis. To ccount for differences in follow-up time cross ptients in both cohorts, we divided the number of HD sessions meeting the specified IDH definition by the totl number of HD sessions during the exposure period in which IDH defining criteri (intrdilytic SBPs, interventions, nd symptoms) were considered. For the HEMO IDH definition, n episode of IDH ws defined by n ffirmtive response to the following question from the monitored HD sessions: Ws there hypotension requiring sline infusion, lowering of the UF rte, or reduced blood flow? Becuse the percentge of HD sessions with HEMO-defined IDH ws symmetriclly distributed, we divided the HEMO IDH definition exposure into qurtiles nd identified the 75th percentile ($30% of exposure HD sessions meeting the definition); ptients were then dichotomized on the bsis of whether they hd met the HEMO-defined IDH t lest this number of times. For the KDOQI IDH definition, n episode of IDH ws defined s pre-hd SBP 2 minimum intrdilytic SBP$20 mmhg +intrdilytic symptoms of crmping, hedche, lighthededness, vomiting, or chest pin s recorded on the symptom ssessment form. 7 Additionl priori IDH definitionsreshownintble1. To foster interpretbility nd consistency, 30% cutpoint of totl exposure period HD sessions with events meeting the specified IDH definition ws pplied to ll IDH definitions. This dichotomiztion threshold ws supported by literture precedent 1,27 nd felt to be cliniclly meningful. Ptients with $30% exposure period HD sessions meeting the individully specified IDH definition were clssified s (+) IDH, nd ptients not meeting the specified IDH definition in $30% of sessions were clssified s (2) IDH (the referent group). Lck of symptom nd intervention dt precluded the exmintion of HEMO nd KDOQI IDH definitions in the LDO cohort. SBP were recorded pre- nd post-hd in seted position using utomted devices per routine prctice. Intrdilytic SBPs were mchine-mesured in the seted position nd typiclly occurred every 30 minutes during ll tretment sessions. The outcome of interest ws 2-yer ll-cuse mortlity in the HEMO cohort nd 1-yer mortlity in the LDO cohort. A shorter risk period in the LDO cohort ws selected becuse of limited vilble follow-up dt nd desire to mximize the cohort size. Sttisticl Anlyses Anlyses were performed with STATA 12.0MP (College Sttion, TX). Bseline subject chrcteristics were described s counts nd proportions for ctegoricl vribles nd mens nd SDs for continuous vribles. Bivrible comprisons cross IDH ctegories were mde using chi-squred nd t tests. In the primry nlyses, ORs for 2-yer mortlity (in the HEMO cohort) nd 1-yer mortlity (in the LDO cohort) cross binry IDH definitions were estimted by fitting logistic regression models. Model covrites were selected s those vribles hypothesized to be ssocited with IDH nd/or mortlity. In the HEMO cohort, multivrible models were djusted for ge (per 10 yers); sex; rce (blck versus nonblck); comorbidities (dibetes, hert filure, peripherl vsculr disese, cerebrovsculr disese, coronry rtery disese, Index of Coexistent Disese [ICED], nd smoking sttus); HD fctors, including vsculr ccess type (grft, fistul, or ctheter), post- HD weight (qurtiles; kilogrms), tretment time (minutes), nd UF volume (liters); lbortory vlues (lbumin [#1.9, 3 3.9, or $4 g/dl] nd hemtocrit [percentge]); residul urine output (#200 versus.200 ml/d); hospitliztion during the exposure period; ntihypertensive mediction use (b-blocker, clcium chnnel blocker, renin-ngiotensin system blocker, nitrte, -blocker, or other ntihypertensives); intervention group (high- or stndrd-dose HD nd high- or low-flux membrne); nd clinicl center. Postweight, tretment time, UF volume, pre-hd SBP, nd lbortory vlues were considered s men vlues during the exposure period. Missing vlues (smoking [n=2], hemtocrit [n=3], nd residul urine output [n=16]) were multiply imputed in five replictes using the outcome s predictor for imputtion. In the LDO cohort, nlogous vribles were used with the exception of residul urine output, ICED, nd smoking, which were not vilble. Equilibrted Kt/V (,1.2 versus $1.2; missing) ws used in plce of dose rndomiztion group; flux rndomiztion group ws nonpplicble. Center ws not included becuse of the lrge number of centers (n=1263) in the cohort. Missed sessions (0, 1, 2, nd $3) were used s surrogte for hospitliztion. In both cohorts, the 732 Journl of the Americn Society of Nephrology J Am Soc Nephrol 26: , 2015

10 CLINICAL EPIDEMIOLOGY specifiction of continuous covrites (liner versus ctegoricl) ws guided by ech covrite s ssocition with outcome. Individul logistic model fit ws exmined by Hosmer Lemeshow testing. Twotiled P vlues,0.05 were considered significnt. The Ndir90 mortlity ssocition ws further explored by nlysis of time to deth with Cox proportionl hzrds model. The proportionlity ssumption ws confirmed by Schoenfeld residul testing. Given the durtion of follow-up, the need for time-updted nlyses ws evluted by exmining IDH frequency over increments of follow-up time. IDH frequencies remined stble over time, nd therefore, time-updted nlyses were not performed. To exmine for dose response reltionship between IDH nd outcome, Ndir90-defined IDH ws considered s ctegoricl exposure (,5%, 6% 29%, 30% 49%, nd $50% of sessions with IDH); ctegory thresholds were selected to mximize clinicl ppliction. The incrementl mortlity effects of dding the presence of IDH symptoms nd the presence of intervention to the IDH definition Ndir90 were explored (seprtely) through logistic models with expnded IDH definition criteri. Given the smll number of ptients who met the Ndir90+symptoms-defined IDH nd Ndir90+interventiondefined IDH in $30% of sessions, we exmined the ssocitions considering the top tertile of ech exposure nd 2-yer mortlity. No sttisticlly significnt ssocitions were observed (dt not shown). Effect modifiction of the IDH mortlity ssocition on the bsis of pre-hd SBP ws evluted using likelihood rtio testing of nested models tht did nd did not include two-wy crossproduct terms. IDH definition mortlity ssocitions were then considered cross strt of pre-hd SBP in the LDO cohort. Smll numbers within pre- HD SBP strt precluded prllel nlysis in the HEMO cohort. Multivrite logistic models strtified by pre-hd SBP were nlogous to those in the primry nlyses nd further djusted for men exposure period pre-hd SBP to ccount for residul confounding introduced by strt width. ACKNOWLEDGMENTS The uthors thnk the Hemodilysis (HEMO) Study investigtors nd the Ntionl Institute of Dibetes nd Digestive nd Kidney Diseses (NIDDK) dt repository nd DVit Clinicl Reserch for the study dt. The HEMO Study ws performed by the HEMO Study investigtors nd supported by the NIDDK. This work ws conducted with the support of KL2 Medicl Reserch Investigtor Trining Awrd (n ppointed KL2 wrd) from Hrvrd Ctlyst, The Hrvrd Clinicl nd Trnsltionl Science Center (Ntionl Center for Reserch Resources nd the Ntionl Center for Advncing Trnsltionl Sciences) nd Ntionl Institutes of Helth Awrd 1KL2-TR (to J.E.F.). This work ws lso supported by NIDDK Grnt DK91417 (to G.C.C.). This mnuscript ws not prepred in collbortion with the investigtors of the HEMO Study nd does not necessrily reflect the opinions or views of the HEMO Study or the NIDDK. The content is solely the responsibility of the uthors nd does not necessrily represent the officil views of Hrvrd Ctlyst, Hrvrd University, nd its ffilited cdemic helth cre centers or the Ntionl Institutes of Helth. DISCLOSURES J.E.F. hs received speking honorri from Dilysis Clinic Incorported. G.C.C. hs served s consultnt to Allen Phrmceuticls, AstrZenec, nd Exponent; is n uthor nd section editor for UpToDte; nd is the Editor-in- Chief of CJASN. When the study begn, S.M.B. ws employed by Brighm nd Women s Hospitl. As of September of 2012, the employment of S.M.B. shifted to DVit Clinicl Reserch, the compny tht provided the dt for this reserch. The continution of S.M.B. on the study is s DVit Clinicl Reserch employee. Additionlly, S.M.B. hs received speking honorri from Fresenius Medicl Cre North Americ nd served on dvisory bords for Amgen, C.B. Fleet, Keryx, nd Otsuk, nd his spouse is employed by AstrZenec. REFERENCES 1. Chng TI, Pik J, Greene T, Desi M, Bech F, Cheung AK, Chertow GM: Intrdilytic hypotension nd vsculr ccess thrombosis. JAmSoc Nephrol 22: , Ronco C, Brendoln A, Miln M, Rodeghiero MP, Znell M, L Grec G: Impct of biofeedbck-induced crdiovsculr stbility on hemodilysis tolernce nd efficiency. Kidney Int 58: , Shoji T, Tsubkihr Y, Fujii M, Imi E: Hemodilysis-ssocited hypotension s n independent risk fctor for two-yer mortlity in hemodilysis ptients. Kidney Int 66: , Tisler A, Akócsi K, Borbás B, Fzks L, Ferenczi S, Görögh S, Kulcsár I, Ngy L, Sámik J, Szegedi J, Tóth E, Wágner G, Kiss I: The effect of frequent or occsionl dilysis-ssocited hypotension on survivl of ptients on mintennce hemodilysis. 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11 15. Munoz Mendoz J, Byes LY, Sun S, Doss S, Schiller B: Effect of lowering dilyste sodium concentrtion on interdilytic weight gin nd blood pressure in ptients undergoing thrice-weekly in-center nocturnl hemodilysis: A qulity improvement study. Am J Kidney Dis 58: , PubMed: PubMed serch. Avilble t: pubmed. Accessed Jnury 23, Plmer BF, Henrich WL: Recent dvnces in the prevention nd mngement of intrdilytic hypotension. J Am Soc Nephrol 19: 8 11, Sulowicz W, Rdziszewski A: Pthogenesis nd tretment of dilysis hypotension. Kidney Int 70: S36 S39, Koomn J, Bsci A, Pizzrelli F, Cnud B, Hge P, Fouque D, Konner K, Mrtin-Mlo A, Pedrini L, Tttersll J, Tordoir J, Vennegoor M, Wnner C, ter Wee P, Vnholder R: EBPG guideline on hemodynmic instbility. Nephrol Dil Trnsplnt 22[Suppl 2]: ii22 ii44, Weisbord SD, Fried LF, Mor MK, Resnick AL, Unruh ML, Plevsky PM, Levenson DJ, Cooksey SH, Fine MJ, Kimmel PL, Arnold RM: Renl provider recognition of symptoms in ptients on mintennce hemodilysis. Clin J Am Soc Nephrol 2: , Cplin B, Kumr S, Dvenport A: Ptients perspective of hemodilysisssocited symptoms. Nephrol Dil Trnsplnt 26: , Zger PG, Nikolic J, Brown RH, Cmpbell MA, Hunt WC, Peterson D, Vn Stone J, Levey A, Meyer KB, Klg MJ, Johnson HK, Clrk E, Sdler JH, Teredesi P: U curve ssocition of blood pressure nd mortlity in hemodilysis ptients. Medicl Directors of Dilysis Clinic, Inc. Kidney Int 54: , Greene T, Beck GJ, Gssmn JJ, Gotch FA, Kusek JW, Levey AS, Levin NW, Schulmn G, Eknoyn G: Design nd sttisticl issues of the hemodilysis (HEMO) study. Control Clin Trils 21: , Flythe JE, Curhn GC, Brunelli SM: Shorter length dilysis sessions re ssocited with incresed mortlity, independent of body weight. Kidney Int 83: , Flythe JE, Inrig JK, Shfi T, Chng TI, Cpe K, Dinesh K, Kunprju S, Brunelli SM: Assocition of intrdilytic blood pressure vribility with incresed ll-cuse nd crdiovsculr mortlity in ptients treted with long-term hemodilysis. Am J Kidney Dis 61: , Flythe JE, Curhn GC, Brunelli SM: Disentngling the ultrfiltrtion rte-mortlity ssocition: The respective roles of session length nd weight gin. Clin J Am Soc Nephrol 8: , Chesterton LJ, Selby NM, Burton JO, McIntyre CW: Cool dilyste reduces symptomtic intrdilytic hypotension nd increses broreflex vribility. Hemodil Int 13: , 2009 See relted editoril, Mesuring Intrdilytic Hypotension to Improve Qulity of Cre, on pges This rticle contins supplementl mteril online t org/lookup/suppl/doi: /asn /-/dcsupplementl. 734 Journl of the Americn Society of Nephrology J Am Soc Nephrol 26: , 2015