Blood pressure levels and mortality risk among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study

Transcription

1 originl rticle & 202 Interntionl Society of Nephrology Blood pressure levels nd mortlity risk mong hemodilysis ptients in the Dilysis Outcomes nd Prctice Ptterns Study Bruce M. Roinson,2, Lin Tong, Jinyo Zhng, Roert A. Wolfe, Dvid A. Goodkin, Roger N. Greenwood 3, Peter G. Kerr 4, Hl Morgenstern,5, Yun Li,6, Ronld L. Pisoni, Rjiv Srn 7, Frncesc Tentori, Tdo Akizw 8, Shunichi Fukuhr 9 nd Friedrich K. Port Aror Reserch Collortive for Helth, Ann Aror, Michign, USA; 2 Deprtment of Internl Medicine, Nephrology, University of Michign, Ann Aror, Michign, USA; 3 Renl Services, Lister Hospitl, Stevenge, UK; 4 Deprtment of Nephorology, Monsh Medicl Centre nd Monsh University, Clyton, Victori, Austrli; 5 Deprtment of Epidemiology nd Environmentl Helth Sciences, University of Michign School of Pulic Helth, Ann Aror, Michign, USA; 6 University of Michign School of Pulic Helth, Biosttistics nd Kidney Epidemiology nd Cost Center, Ann Aror, Michign, USA; 7 Deprtment of Internl Medicine nd Kidney Epidemiology nd Cost Center, University of Michign, Ann Aror, Michign, USA; 8 Division of Nephrology, Deprtment of Medicine, Show University School of Medicine, Tokyo, Jpn nd 9 Epidemiology nd Helthcre Reserch, Kyoto University School of Medicine, Kyoto, Jpn KDOQI prctice guidelines recommend predilysis lood pressure o40/90 mm Hg; however, most prior studies hd found elevted mortlity with low, not high, systolic lood pressure. This is possily due to unmesured confounders ffecting systolic lood pressure nd mortlity. To lessen this is, we nlyzed 24,525 ptients y Cox regression models djusted for ptient nd fcility chrcteristics. Compred with predilysis systolic lood pressure of mm Hg, mortlity ws 3% higher in fcilities with 20% more ptients t systolic lood pressure of 0 29 mm Hg nd 6% higher in fcilities with 20% more ptients t systolic lood pressure of X60 mm Hg. For ptient-level systolic lood pressure, mortlity ws elevted t low (o30 mm Hg), not high (X80 mm Hg), systolic lood pressure. For predilysis distolic lood pressure, mortlity ws lowest t mm Hg, wide rnge implying less chnce to improve outcomes. Higher mortlity t systolic lood pressure of o30 mm Hg is consistent with prior studies nd my e due to excessive lood pressure lowering during dilysis. The lowest risk fcility systolic lood pressure of mm Hg indictes this rnge my e optiml, ut my hve een influenced y unmesured fcility prctices. While dditionl study is needed, our findings contrst with KDOQI lood pressure trgets, nd provide guidnce on optiml lood pressure rnge in the sence of definitive clinicl tril dt. Correspondence: Bruce M. Roinson, Aror Reserch Collortive for Helth, 340 Est Huron Street, Suite 300, Ann Aror, Michign 4804, USA. E-mil: ruce.roinson@rorreserch.org This study ws presented in prt t the nnul meeting of the Americn Society of Nephrologists, 4 9 Novemer 2008, Phildelphi, PA; nd hs ppered in strct form (J Am Soc Nephrol 9: 28A, 2008). Received 28 June 202; revised Jnury 202; ccepted 7 Ferury 202; pulished online 20 June 202 Kidney Interntionl (202) 82, ; doi:0.038/ki ; pulished online 20 June 202 KEYWORDS: lood pressure; crdiovsculr; hemodilysis; hypertension; mortlity Hypertension (HTN) is leding cuse of mortlity worldwide.,2 Bsed on lrge clinicl outcomes trils, clinicl prctice guidelines recommend tretment to lood pressure (BP) o40/90 mm Hg in most ptients with HTN nd o30/ 80 mm Hg in ptients with dietes or chronic kidney disese. 3 Ptients with end-stge renl disese (ESRD) treted y dilysis hve n incresed risk of mortlity, with nerly 50% of deths due to crdiovsculr (CV) cuses. 4,5 The urden of ESRD is rising interntionlly, with prevlence of ESRD treted y dilysis exceeding 350,000 in the United Sttes. 4,6 Becuse the prevlence of HTN mong mintennce dilysis ptients is 60 90%, 5,7 its tretment is considered n importnt mens to improve outcomes. The 2005 Ntionl Kidney Foundtion Kidney Disese Outcomes Qulity Inititive (KDOQI) clinicl prctice guideline recommends pre- nd postdilysis BP gols of o40/90 nd 30/ 80 mm Hg, sed in prt on dt in the nondilysis popultion. A direct reltion etween tretment of elevted BP levels nd improved outcomes mong dilysis ptients hs not een demonstrted, nd definitive clinicl trils investigting optiml trget BP hve yet to e crried out. Oservtionl studies consistently hve found elevted mortlity in ptients with low, ut not high, BP levels. 5,8 3 Some hve speculted tht the explntion for the oserved reltion etween lower BP nd elevted mortlity is tht hemodilysis (HD) ptients hve serious coexisting illnesses (for exmple, poor ventriculr function) tht lower BP nd increse mortlity risk (tht is, ssocition of lower BP with elevted mortlity is confounded y poor helth 570 Kidney Interntionl (202) 82,

2 BM Roinson et l.: Blood pressure nd survivl in HD originl rticle % Of ptients Within-fcility % of ptients with SBP in ech ctegory Europe/ANZ North Americ Jpn <00 < Percentile 35 95th 75th 30 50th 25 25th 5th Predilysis SBP (mm Hg) Predilysis SBP (mm Hg) Figure Predilysis systolic lood pressure (SBP) distriution. () Distriution of ptient-level predilysis SBP (y region). () Distriution of fcility-level predilysis SBP (overll). A totl of 25,907 hemodilysis ptients from 922 fcilities in Dilysis Outcomes nd Prctice Ptterns Study (DOPPS) I III with endstge renl disese durtion of 480 dys. Europe/Austrli/New Zelnd (Europe/ANZ) includes Frnce, Germny, Itly, Spin, United Kingdom, Belgium, Sweden, Austrli, nd New Zelnd. North Americ includes United Sttes nd Cnd. The men (s.d.) of predilysis SBP in Europe/ANZ, North Americ, nd Jpn ws 4 (24), 5 (24), nd 5 (22) mm Hg, respectively. sttus). 5 Becuse oservtionl nlyses of BP nd clinicl outcomes re suject to is due to unmesured ptient chrcteristics ffecting BP nd helth sttus (tht is, unmesured confounders), n ojective of the study ws to lessen this is using nlysis of BP mngement prctices t the dilysis fcility level, relting ptient-level survivl to the frction of ptients in ech BP ctegory t ech dilysis fcility. Anlyses of ptient-level BP re lso presented. A gol of the study ws to identify the optiml rnge of chieved BP for most of the ptients in n HD unit, directly informing tretment decisions in routine clinicl prctice. RESULTS Among 24,525 ptients, totl ptient yers of follow-up were 42,74, numer of deths ws 5849, nd mortlity rte ws 0.4 per yer. Distriutions of predilysis BP nd ptient chrcteristics y predilysis SBP Figures nd 2 show distriution of predilysis systolic lood pressure (SBP) nd distolic lood pressure (DBP) y % Of ptients Within-fcility % of ptients with DBP in ech ctegory Europe/ANZ North Americ Jpn < Predilysis DBP (mm Hg) 70 Percentile 60 95th 75th 50 50th 25th 40 5th < Predilysis DBP (mm Hg) Figure 2 Predilysis distolic lood pressure (DBP) distriution. () Distriution of ptient-level predilysis DBP (y region). () Distriution of fcility-level predilysis DBP (overll). A totl of 25,836 hemodilysis ptients from 92 fcilities in Dilysis Outcomes nd Prctice Ptterns Study (DOPPS) I III with endstge renl disese durtion of 480 dys. For revitions, see footnote of Figure. The men (s.d.) of predilysis DBP in Europe/ ANZ, North Americ, nd Jpn ws 76 (4), 79 (5), nd 79 (3) mm Hg, respectively. region. Among ll study prticipnts, men SBP ws 47±24 mm Hg; men DBP ws 77±4 mm Hg. By region, Europe nd Austrli/New Zelnd hd lower verge BP levels. Figures nd 2 show fcility-level predilysis SBP nd DBP distriution, demonstrting sustntil vrition etween fcilities. Tle shows distriutions of selected seline ptient chrcteristics y ptient-level SBP, demonstrting generlly unlnced distriutions of mesured vriles cross SBP ctegories. Lrge vritions in ptient chrcteristics cross ptient-level SBP ctegories were lso found within ech region. When ptients were ctegorized ccording to fcility-level SBP (y qurtiles, sed on percent of fcility hving ptients with SBP X60 mm Hg) within ech region, the mjority of ptient chrcteristics were lnced (Supplementry Tle A online). All-cuse mortlity y predilysis SBP ctegories (ptient level nd fcility level) Figure 3 nd shows results of fully djusted multivrile models. Compred with the reference ctegory of mm Hg, ll-cuse mortlity ws elevted for ptients with SBP 0 9 mm Hg (hzrd rtio (HR) ¼.4, 95% confidence intervl (CI) ¼.0.28, P ¼ 0.03) nd mm Hg (HR ¼., 95% CI ¼.23, P ¼ 0.04), nd lower for ptients with SBP mm Hg (HR ¼ 0.90, 25 Kidney Interntionl (202) 82,

3 originl rticle BM Roinson et l.: Blood pressure nd survivl in HD Tle Bseline ptient chrcteristics (mens or proportions) y ctegory of ptient SBP t seline Ptient SBP ctegories o0 mm Hg 0 29 mm Hg mm Hg X60 mm Hg Chrcteristic (men or %) (n=370) (n=4209) (n=2,39) (n=888) P-vlue* SBP (mm Hg) Demogrphics Age (yers) Body mss index Blck rce (overll) 9% 9% 2% 6% o0.000 Blck rce (USA only) 8% 8 % 5% o0.000 Mle 54% 55% 58% 58% 0.0 Yers with ESRD o0.000 Eduction (ove high school) 47% 48% 5% 5% o0.000 Income (ove $20,000 or equivlent) 32% 33% 33% 30% 0.02 Coexisting conditions Coronry hert disese 50% 47% 44% 45% 0.5 Cncer 4% 3% % 9% Other crdiovsculr disese 50% 4% 36% 33% o0.000 Cererovsculr disese 7% 6% 6% 8% o0.000 Congestive hert filure 4% 35% 3% 34% Dietes mellitus 24% 27% 33% 44% o0.000 Gstrointestinl leed in pst 2 months 7% 6% 6% 6% 0.68 HIV/AIDS 0.5% 0.5% 0.9% 0.9% 0.7 Lung disese 5% 3% % 0% 0.0 Neurologicl disorders 4% % 0% 0% 0.89 Psychitric disorder 20% 8% 7% 6% 0.8 Peripherl vsculr disese 29% 25% 25% 26% o0.000 Recurrent cellulitis/gngrene % 8% 8% 8% 0.07 Ls nd dilysis vriles Hemogloin (g/dl) Serum PTH (pg/ml) Serum phosphorus (mg/dl) o0.000 Serum lumin (g/dl) o0.000 Serum ferritin (ng/ml) Serum cretinine (mg/dl) Use of ctheter (%) 2% 7% 3% 3% Single-pool Kt/V o0.000 Numer of ntihypertensive medictions o0.000 Arevitions: ESRD, end-stge renl disese; PTH, prthyroid hormone; SBP, systolic lood pressure. A totl of 25,907 HD ptients from 922 fcilities in Dilysis Outcomes nd Prctice Ptterns Study (DOPPS) I III (ll countries) with ESRD durtion of 480 dys. *P-vlues were otined from seprte liner mixed or logistic models with ech ptient chrcteristic s outcome nd ctegoricl vrile of lood pressure ctegory s predictor, djusting for geogrphic region nd study phse nd ccounting for fcility-clustering effects, to test for difference in ech ptient chrcteristic (men or percent) cross three SBP ctegories (excluding SBP o0 mm Hg (shded; see text for detils)). 95% CI ¼ , P ¼ 0.03). For ptients with SBP X60 mm Hg, there ws no consistent difference in mortlity from the reference ctegory. Anlyses of fcility-level SBP ctegories (6 continuous vriles, representing the proportion of fcility ptients in ech SBP ctegory except mm Hg) showed elevted mortlity consistently cross low nd high SBP ctegories. Comining ctegories sed on results in Figure 3, for fcilities with 20% more ptients in ctegories other thn mm Hg, higher mortlity ws oserved for 0 29 mm Hg (HR ¼.3, 95% CI ¼.05.2, P ¼ 0.00) nd X60 mm Hg (HR ¼.6, 95% CI ¼.0.23, Po0.00). As corroortive dt, Supplementry Tle B online shows generlly lower crude mortlity rtes mong fcilities with more ptients in the SBP mm Hg rnge. The result of instrumentl vrile nlysis lso indicted U-shpe ssocition etween SBP nd mortlity, with elevted hzrds t o30 nd X50 mm Hg (Supplementry Tle C online). As sensitivity nlysis, we exmined the ssocition of SBP with ll-cuse mortlity mong ll ptients, including those with SBP o0 mm Hg (n ¼ 25,907). As expected, in ptient-sed nlysis, the HR for SBP o0 mm Hg ws elevted (HR ¼.55, 95% CI ¼.39.7, po0.00), compred with mm Hg. Fcility-level nlyses were corroortive: ptients in fcilities with 20% more ptients with SBP o0 mm Hg versus the reference group (30 59 mm Hg) hd 27% higher mortlity rte (HR ¼.27, 95% CI ¼.3.4, Po0.00). An dditionl nlysis sed on most recent SBP level, rther thn medin of three vlues, yielded similr findings. Comprle results were otined when missing dt were clculted y multiple imputtion, with point estimtes vrying o2% nd P-vlues not pprecily ltered. Predilysis DBP Mortlity risk ws lowest t mm Hg in fully djusted ptient- nd fcility-level models (Figure 4 nd ). Fewer ptients hd DBP outside the rnge of mm Hg (4%) thn outside the lowest risk SBP rnge of mm Hg (53%; Figures nd 2). 572 Kidney Interntionl (202) 82,

4 BM Roinson et l.: Blood pressure nd survivl in HD originl rticle.37***.4*.* * Predilysis SBP (mm Hg) Predilysis DBP (mm Hg) HR t fcilities with 20% more ptients in nonreference SBP ctegory nd correspondingly fewer ptients in the reference ctegory HR t fcilities with 20% more ptients in nonreference SBP ctegory nd correspondingly fewer ptients in the reference ctegory.5*.8** **.7*.24***.2*** * Predilysis SBP (mm Hg) Figure 3 Predilysis systolic lood pressure (SBP) nd mortlity (fully djusted model). () Mortlity y ptient-level predilysis SBP ctegories (fully djusted). () Mortlity y fcilitylevel predilysis SBP ctegories (fully djusted). A totl of 24,525 hemodilysis ptients from 920 fcilities in Dilysis Outcomes nd Prctice Ptterns Study (DOPPS) I III with end-stge renl disese durtion of 480 dys, excluding ptients with predilysis SBP o0 mm Hg. Cox models were strtified y geogrphic region nd study phse, ccounting for fcility-clustering effects, nd djusted for ll demogrphics, comorid conditions, nd ls listed in Tle. Fcility-level nlyses were djusted dditionlly for five fcility prctices. For this nd susequent figures, verticl lines represent 95% confidence intervls (CIs). HR, hzrd rtio. *0.0pPo0.05; **0.00pPo0.0; ***Po0.00. Influence of covrite djustment Figures 5 nd nd 6 nd show the influence of progressively more comprehensive djustment on the ssocitions of predilysis BP with survivl. For ptient-level SBP, the ssocitions were modestly ttenuted (rought towrd null) t higher BP, with djustment for demogrphics, comoridities, nd lortory vlues. Estimtes for DBP were sustntilly ttenuted y djustment for demogrphics (minly ge), nd were ltered to smller extent y djustment for comoridities nd l vlues. At high DBP, progressive djustment reversed direction of the ssocition, from lower-to-higher mortlity. As dditionl sensitivity nlyses, djustment for eduction level, household income, nd ntihypertensive gents hd very little influence on the estimtes presented herein. Antihypertensive gents were nlyzed in three different wys: () ny use (yes/no), (2) numer of ntihypertensive gents, nd (3) seprte dummy Predilysis DBP (mm Hg) Figure 4 Predilysis distolic lood pressure (DBP) nd mortlity (fully djusted model). () Mortlityyptient-level predilysis DBP ctegories (fully djusted). () Mortlity y fcilitylevel predilysis DBP ctegories (fully djusted). A totl of 25,424 hemodilysis ptients from 99 fcilities in Dilysis Outcomes nd Prctice Ptterns Study (DOPPS) I III with end-stge renl disese durtion of 480 dys, excluding ptients with predilysis DBP o50 mm Hg. Cox models re s descried for Figure 3. *0.0pPo0.05; ***Po0.00. CI, confidence intervl; HR, hzrd rtio. vriles for seven clsses of ntihypertensive medictions (yes/no for: ngiotensin receptor lockers, ngiotensinconverting enzyme inhiitors, -lockers, clcium chnnel lockers, -lockers, centrl gonists, nd vsodiltors). Postdilysis BP Postdilysis SBP. Ptterns of ssocitions with survivl were comprle to those for predilysis SBP, ut the lowest risk levels were (s expected) shifted lower thn for predilysis SBP (Figure 7 nd ). For ptient-level SBP, mortlity risk ws elevted for ptients with low (o0 or 20 mm Hg) ut not high SBP levels. For fcility-level SBP, mortlity risk ws lowest t mm Hg. Postdilysis DBP. Mortlity risk ws lowest t mm Hg (ptient level) nd or mm Hg (fcility level; Figure 8 nd ). Sugroup nlyses Sugroups studied were: with or without hert filure, dietes, nd CV disese; serum lumin o or X3.8 g/dl; ESRD durtion o or X80 dys; or use of ny ntihypertensive mediction (yes/no). Findings were consistent cross sugroups for nlyses of ptient-level nd fcility-level SBP. Kidney Interntionl (202) 82,

5 originl rticle BM Roinson et l.: Blood pressure nd survivl in HD Model : undjusted Model 2: +demogrphics Model 3: demogrphics+comoridities+ls Hzrd rtios: Model.7** *** * 0.98 Model 2 Model 3.5*.4*.08.* *** 0.90* Predilysis SBP (mm Hg) HR t fcilities with 20% more ptients in nonreference SBP ctegory nd correspondingly fewer ptients in the reference ctegory Model : undjusted Model 2: +demogrphics Model 3: +demogrphics+comoridities+ls Hzrd rtios: Model Model *.2.9** Model 3.7*.9** **.8** *** Predilysis SBP (mm Hg) Figure 5 Predilysis systolic lood pressure (SBP) nd mortlity (stepwise djustment). () Mortlity y ptient-level predilysis SBP ctegories (stepwise djustment). () Mortlity y fcility-level predilysis SBP ctegories (stepwise djustment). A totl of 24,525 ptients, s descried for Figure 3. Adjusted for demogrphics in Tle ; djusted for demogrphics, comorid conditions, nd ls in Tle. For the fcility-level SBP model, djustment dditionlly for fcility prctices ltered the hzrd rtio (HR) slightly (not shown). *0.0pPo0.05; **0.00pPo0.0; ***Po0.00. CI, confidence intervl. Chnge in BP from efore to fter dilysis The distriution of chnge in SBP from efore to fter dilysis (pre minus post) ws: 25th percentile ¼ 0 mm Hg, 50th percentile ¼ mm Hg, nd 75th percentile ¼ 25 mm Hg. Associtions of SBP with mortlity were similr for ptients with chnge in SBP ove versus elow medin vlue (2 mm Hg) in oth ptient- nd fcility-level models. No interction effect ws found etween predilysis SBP nd chnge in SBP (pre- to post-hd) in ptient- or fcility-level model (P40.05). DISCUSSION The finding (Figure 3) of elevted mortlity for HD ptients with predilysis SBP o30 mm Hg, ut not for ptients with uncontrolled HTN, is consistent with most prior oservtionl findings of elevted mortlity rtes t low, not high, BP. Interprettion of results from oservtionl studies hs een complicted ecuse BP level mong HD ptients tends to e correlted with confounders (Tle ). This imlnce in helth sttus my potentilly is the ssocition etween BP nd deth rtes. 5 The Dilysis Outcomes nd Prctice Ptterns Study (DOPPS) collects n extensive list of comoridities, lortory vlues, medictions, nd clinicl events, nd our multivrile nlyses djust for numerous potentil confounders. Nonetheless, s this nlysis relies exclusively on mesured ptient-level dt, it remins suject to is due to unmesured ptient chrcteristics ffecting BP nd helth sttus (tht is, unmesured confounders). Some exmples of informtion typiclly not cptured completely in the medicl records (nd therefore not in our nlyses) include informtion out the severity, chronicity, disility, functionl sttus, nd psychosocil impct of dignosed comoridities, nd the ptient s ility to cope with ESRD nd other conditions. In generl, predicting the direction of is from hypotheticl confounders such s these is difficult Kidney Interntionl (202) 82,

6 BM Roinson et l.: Blood pressure nd survivl in HD originl rticle Hzrd rtios: Model 2.3*** Model 2 Model Model : undjusted Model 2: +demogrphics Model 3: +demogrphics+comoridities+ls.59.59***.37*** ***.23*** 0.84*** 0.74***.4***.09* Predilysis DBP (mm Hg) Model : undjusted Model 2: +demogrphics Model 3: +demogrphics+comoridities+ls HR t fcilites with 20% more ptients in nonreference SBP ctegory nd correspondingly fewer ptients in the reference ctegory Hzrd rtios: Model.32***.6** Model 2.23*** * Model 3.20** * Predilysis DBP (mm Hg) Figure 6 Predilysis distolic lood pressure (DBP) nd mortlity (stepwise djustment). () Mortlity y ptient-level predilysis DBP ctegories (stepwise djustment). () Mortlity y fcility-level predilysis DBP ctegories (stepwise djustment). A totl of 25,424 ptients, s descried for Figure 4. Adjusted for demogrphics in Tle ; djusted for demogrphics, comorid conditions, nd ls in Tle. For the fcility-level DBP model, djustment dditionlly for fcility prctices ltered the hzrd rtio (HR) slightly (not shown). *0.0pPo0.05; **0.00pPo0.0; ***Po0.00. CI, confidence intervl. To potentilly lessen is due to unmesured ptient chrcteristics, we chose nlysis of prctice ptterns t the dilysis fcility level, relting ptient-level mortlity to the frction of ptients in ech BP ctegory t ech dilysis fcility, rther thn oserved BP level for ech ptient. This pproch is strightforwrd extension of the single grouped-tretment method. 5 In their results, Johnston et l. 5 noted tht the is resulting from grouped tretment ppers to e much smller thn tht resulting from stndrd nlyses using individul tretment vriles. Our nlysis voids ecologic is 6,7 ecuse it incorportes ptient-level outcome nd covrite dt. The method lso hs similrities to instrumentl vrile (IV) nlysis (nd we performed supplementry IV nlysis tht corroorted the fcility-level BP findings) Recent pplictions of IV nlysis in clinicl medicine hve een pulished Our nlytic pproch tkes dvntge of the qusirndom ssignment of ptients to different tretment strtegies t different fcilities, sed on the resonle ssumption tht differences in oserved BP levels etween fcilities re due in prt to differences in provider BP tretment protocols or preferences. In support of the vlidity of this ssumption, we oserved lrge vrition etween fcilities in the percentge of ptients t high nd low SBP levels (Figure ). We lso found tht fcility trget SBP is ssocited with ptient-level SBP (in suset of DOPPS III fcilities with these dt ville, P ¼ 0.003); tht is, provider preference influences chieved BP levels. Additionlly, we Kidney Interntionl (202) 82,

7 originl rticle BM Roinson et l.: Blood pressure nd survivl in HD.4* ***.08* *** 0 9.4* oserved tht ptient helth sttus is more nerly, lthough imperfectly, lnced when we ctegorize ptients ccording to fcility-level mesure of chieved BP levels (for exmple, frction of ptients t SBP X60 mm Hg) versus ccording to ech ptient s individully chieved BP (Supplementry Tle A online). We found tht, on verge, ptients treted t fcilities with higher proportion of ptients t predilysis SBP mm Hg hve longer survivl. A cusl interprettion of this ssocition (sed on motivtion for the nlysis of fcility prctice) is tht tretment to predilysis SBP mm Hg leds to longer survivl. However, s in ny clinicl study, the potentil for lterntive explntions merits considertion. In prticulr, the oserved differences in survivl ccording to fcility-level BP my e ecuse of other differences etween fcilities (for exmple, good/d fcility effect). Our nlysis controls for fcility chievement of widely ccepted (KDOQI) clinicl prctice guidelines (Figure 3), Postdilysis SBP (mm Hg) HR t fcilities with 20% more ptients in nonreference SBP ctegory nd correspondingly fewer ptients in the reference ctegory ** Postdilysis SBP (mm Hg) ** Figure 7 Postdilysis systolic lood pressure (SBP) nd mortlity (fully djusted model). () Mortlity y ptient-level postdilysis SBP ctegories (fully djusted). () Mortlity y fcility-level postdilysis SBP ctegories (fully djusted). A totl of 24,303 hemodilysis ptients from 95 fcilities in Dilysis Outcomes nd Prctice Ptterns Study (DOPPS) I III with endstge renl disese durtion of 480 dys, excluding ptients with postdilysis SBP o00 mm Hg. Cox models re s descried for Figure 3. *0.0pPo0.05; **0.00pPo0.0; ***Pp0.00. CI, confidence intervl; HR, hzrd rtio..9** Postdilysis DBP (mm Hg) HR t fcilities with 20% more ptients in nonreference SBP ctegory nd correspondingly fewer ptients in the reference ctegory.*.0* Postdilysis DBP (mm Hg) Figure 8 Postdilysis distolic lood pressure (DBP) nd mortlity (fully djusted model). () Mortlity y ptient-level postdilysis DBP ctegories (fully djusted). () Mortlity y fcility-level postdilysis DBP ctegories (fully djusted). A totl of 24,805 hemodilysis ptients from 9 fcilities in Dilysis Outcomes nd Prctice Ptterns Study (DOPPS) I III with endstge renl disese durtion of 480 dys, excluding ptients with postdilysis DBP o50 mm Hg. Cox models re s descried for Figure 3. *0.0pPo0.05; ***Po0.00. CI, confidence intervl; HR, hzrd rtio..5 nd hence the oserved ssocition is not explined y chievement of these metrics of good prctice. Nonetheless, we cnnot rule out fcility-level confounding (tht is, unmesured or incompletely specified fcility-level vriles tht cn influence oth BP levels nd mortlity) s n lterntive explntion for our findings. Stted in clinicl terms, etter survivl in fcilities with more ptients t predilysis SBP mm Hg my not e ecuse of BP control, ut due to other prctices more common in these fcilities tht we did not ccount for nlyticlly. Exmples include specific BP tretments, chievement of other stndrd of cre clinicl prctices, or generlly higher qulity cre tht my occur in fcilities with more ptients in the SBP mm Hg rnge. Future studies to confirm or refute this possiility re indicted. In the sence of definitive clinicl tril dt, our findings help clrify understnding of optiml BP on dilysis. At high BP, fcilities with more ptients t predilysis SBP X60 mm Hg hve elevted mortlity. This finding (ssuming cusl interprettion) contrsts with other oservtionl studies in HD reporting no incresed mortlity t elevted predilysis SBP in this rnge or higher. 5,8 3 It is 576 Kidney Interntionl (202) 82,

8 BM Roinson et l.: Blood pressure nd survivl in HD originl rticle consistent with well-estlished ssocitions etween HTN nd mortlity in the generl popultion, 3 nd with recent studies chllenging the notion tht there is no ssocition etween HTN nd dverse outcomes mong HD ptients Two met-nlyses of smll clinicl trils found tht tretment with ntihypertensive medictions ws ssocited with longer survivl nd fewer CV events. 3,34 In contrst to our study, these met-nlyses investigted ntihypertensive mediction use, not BP levels, lthough one study reported tht the ssocition etween mediction use nd etter outcomes ws stronger mong ptients with HTN. At low BP, this nlysis found higher mortlity mong ptients with SBP o30 mm Hg, nd t fcilities with more ptients t SBP o30 mm Hg. The finding of elevted risk t low BP is consistent with prior oservtionl nlyses of HD ptient, nd severl possile explntions merit discussion. First, could excess mortlity t low BP e ecuse of ptient helth sttus lone? It is unlikely, s djustment for comoridities (such s coronry hert disese nd hert filure) hd little effect on ssocitions etween SBP nd mortlity t the low SBP end (Figure 5 nd ). An nlysis of fcility BP prctice further reduces the likelihood tht excess mortlity t low BP levels is due to unmesured ptient chrcteristics (such s illness severity). Insted, our findings generlly support the possiility tht low predilysis SBP my cuse mortlity. Mngement of hemodynmic sttus in dilysis ptients hs unique considertions, nd tretment of some HD ptients to the generl popultion s optiml BP rnge my e dngerous. One likely reson is hemodynmic instility during HD sessions. Recent pulictions demonstrted crdic regionl wll motion normlities nd impired myocrdil lood flow during dilysis y crdic positron emission tomogrphy scn. 35,36 These findings dd to historicl oservtions of ST segment normlities on electrocrdiogrm monitoring nd elevtions of troponin during HD. Repeted intrdilytic ischemi, often suclinicl, leds to myocrdil stunning nd hierntion, which cn cuse remodeling, scrring, hert filure, nd rrhythmis, incresingly recognized s importnt cuses of deth in HD ptients. 37,38 In this study, the ssocition of low predilysis SBP with elevted mortlity ws not modified y chnge in SBP from efore to fter dilysis, ut this vrile my e insensitive to intrdilytic hypotension or hemodynmic compromise during dilysis. Although our study did not collect dt on intrdilytic BP levels, nother study of 244 ptients showed tht intrdilytic hypotension ssocited strongly with elevted mortlity risk over 2 yers. 39 The optiml predilysis SBP rnge (30 to 59 mm Hg) my e higher thn expected ecuse it represents the pek of the 48- to 72-h dilysis cycle nd overestimtes the verge BP. This is supported y our nlyses identifying lowest risk postdilysis SBP (Figure 7 nd ) 0 20 mm Hg lower thn for predilysis SBP (Figure 3 nd ). A recent study found n verge interdilytic increse in SBP of 3 mm Hg y multory BP monitoring nd 8 mm Hg y stndrd home BP monitoring. 40 Additionlly, clinicins often instruct HD ptients to withhold predilysis doses of ntihypertensive medictions. This prctice would excerte overestimtion of optiml BP cused y relying on predilysis mesurement. The finding of lower-limit optiml SBP vlue is consistent with recent dt in nondilysis popultions. The ACCORD study, clinicl tril of ptients with type 2 dietes t high CV risk, found tht trgeting SBP o20 mm Hg versus o40 mm Hg (chieved SBP 9 vs. 34 mm Hg) did not reduce composite ftl nd nonftl mjor CV events. 4 In 2009, the Europen Society of Hypertension rised concerns tht excessive BP lowering my increse the rte of coronry events in ptients t high CV risk, possily ecuse of impirment of utoregultory mechnisms tht ensure orgn perfusion. 42 They recommended trget SBP mm Hg rther thn single cut-point vlue for higher-risk ptients receiving ntihypertensive therpy. Our findings indicte tht mngement of DBP my e less importnt thn SBP. The risk for DBP in the djusted model (Figure 4) ws lowest t mm Hg, tht is, cross the rnge of commonly oserved DBP levels. Only 4% of ptients hd predilysis DBP outside the rnge; 53% of ptients hd predilysis SBP outside the lowest-risk rnge of mm Hg. Thus, the opportunity for improving outcomes y modifying current prctice is greter for SBP. Adjustment for demogrphics (especilly ge) nd comoridities hd greter effect on the ssocition with outcomes for ptient-level DBP thn SBP (Figures 5 nd 6). Ventriculr stiffness in older ptients nd in hypertrophic crdiomyopthy (common mong dilysis ptients) 43 my explin much of the ssocition of lower DBP with elevted mortlity. Additionlly, the following points my e noted regrding our study. () Becuse the DOPPS ptient smple is rndom cross-section of ptients t prticipting HD units, this study s findings cn e generlized to the vriety of ptients seen nd BP mngement decisions encountered on rounds in the dilysis unit; (2) The study informs mortlity risks over the entire BP rnge in dilysis ptients, unlike rndomized controlled tril. (3) Our findings sed on oserved fcilitylevel BP vlues inform understnding of the ssocition etween trget BP nd outcomes to the extent tht vritions in fcility-ggregted oserved BP reflect differences etween fcility BP trgets. (4) Our study is not intended to compre specific tretments (for exmple, volume mngement nd/or phrmcotherpy) for BP mngement. 3,32,34,44 (5) Lst, we studied BP levels mesured in the dilysis center to inform current prctice for most HD ptients. Interdilytic BP monitoring such s home BP monitoring hs promise s future tretment trget, ut its prctice is uncommon nd my not e fesile in mny ptients Conclusion Survivl is significntly etter mong ptients with predilysis SBP X30 mm Hg, nd t fcilities with more ptients t predilysis SBP 30 to o60 mm Hg. Opportunities for improving outcomes my e greter for tretment of SBP thn DBP. The finding of elevted mortlity Kidney Interntionl (202) 82,

9 originl rticle BM Roinson et l.: Blood pressure nd survivl in HD mong fcilities with more ptients t high SBP, if indictive of cusl link etween HTN nd poor outcomes, clrifies pprently contrdictory results from prior oservtionl studies in HD ptients versus clinicl trils in the generl popultion. Elevted mortlity t low SBP, in oth our ptient nd fcility BP models, is consistent with prior studies of dilysis ptients nd emerging concerns out excessive BP lowering in nondilysis ptients t high CV risk. It corroortes ccumulting evidence from clinicl studies in dilysis tht myocrdil stunning, ssocited with intrdilytic hypotension, my e common nd is likely hrmful. Although dditionl investigtion is indicted, these findings contrst with opinion-sed KDOQI BP trgets, providing guidnce on optiml BP rnge in the sence of definitive clinicl tril dt in the ner future. MATERIALS AND METHODS Dt source nd study ptients The DOPPS is prospective cohort study of HD prctices nd ptient outcomes. Study smpling pln nd methods hve een descried. 49,50 Dt were from DOPPS I ( ), II ( ), nd III ( ). There were 38,5 dult (X8 yers of ge) HD ptients with predilysis SBP mesurement reported t study entry, rndomly selected from 928 dilysis fcilities: 308 fcilities in DOPPS I (n ¼ 5,473 ptients from Frnce, Germny, Itly, Jpn, Spin, United Kingdom, nd United Sttes), 32 fcilities in DOPPS II (n ¼ 2,3 ptients from DOPPS I countries, plus Austrli, Belgium, Cnd, New Zelnd, nd Sweden), nd 299 fcilities in DOPPS III (n ¼ 0,727 ptients from the sme 2 countries). Detiled cse-mix nd comorid dt were collected for ech ptient t study entry. Longitudinl lortory vlues, mediction dt, nd cuse-specific mortlity events were collected during study followup. Informed ptient consent ws otined s indicted in ccordnce with locl requirements. For primry nlyses, ptients with predilysis SBP o0 mm Hg were excluded on the rtionle tht SBP o0 is generlly ecuse of sustntil comorid illness, tht is, SBP is not treted to this level nd is not reflective of provider prctice. A sensitivity nlysis including ptients with SBP o0 mm Hg is presented. Ptients from six fcilities with less thn seven ptients with recorded BP levels were excluded. For primry nlyses of prevlent HD ptients, 25,907 ptients from 922 fcilities hd ESRD 480 dys t DOPPS enrollment. Of these, 24,525 ptients from 920 dilysis fcilities hd predilysis SBP X0 mm Hg t study entry (used for primry nlyses). The 0th, 50th, nd 90th percentiles for the numer of ptients per fcility were 7, 26, nd 37, respectively. Outcomes nd exposures The primry outcome ws mortlity. In Cox regression models, time t-risk ws from study entry until deth; study deprture ecuse of kidney trnsplnt, chnge in dilysis modlity, or trnsfer to nother fcility; or the end-of-study follow-up. In DOPPS I nd II, the three most recent BP mesurements over week on or efore study enrollment were reported; the medin vlue ws used. In DOPPS III, only the most recent mesurement ws reported. The primry exposure ws predilysis (tht is, mesured in the HD unit efore the strt of dilysis session) SBP level t DOPPS enrollment ( seline ). For nlyses of ptient-level SBP, ptients were clssified into 7 0 mm Hg SBP groups, from 0 9 to mm Hg, nd X80 mm Hg (with ech ptient in one of seven SBP ctegories). For nlyses of fcility-level SBP, we creted seven continuous vriles representing the proportion of ptients in ech fcility tht were in ech of the seven SBP ctegories. The seven fcility-level vriles were ssigned to ll ptients in tht fcility. Bsed on results with seven ctegories, we performed dditionl nlyses with predilysis SBP levels divided into three ctegories: 0 29, 30 59, nd X60 mm Hg. Associtions of predilysis DBP, postdilysis SBP, nd postdilysis DBP with mortlity re lso presented. Sttisticl nlysis Distriutions of ptient-level nd fcility-level predilysis SBP nd DBP were depicted grphiclly. To exmine cross-sectionl ssocitions of seline ptient chrcteristics with ptient-level nd fcility-level SBP, seprte liner mixed nd logistic models with ptient seline chrcteristic s outcome nd n ordinl vrile of BP ctegory s predictor were used. Cox regression ws used to ssess the ssocition etween llcuse mortlity (ptient level) nd exposure vriles: () ptientlevel SBP t seline (ech ptient in one of seven SBP ctegories) nd (2) fcility-level SBP (the proportion of fcility ptients in ech SBP ctegory for ll ptients in the fcility). The fcility-level pproch is n extension of the single grouped-tretment method. 5 Only 6 of 7 fcility-level SBP ctegories (excluding mm Hg) were included to void liner dependence (tht is, 6 proportions do not dd up to ). Fcility-level results were reported s HRs t fcilities with 20% more ptients in nonreference SBP ctegory, nd correspondingly fewer ptients in the reference ctegory. We divide oth coefficient nd stndrd error of the Cox regression in the fcility-level nlysis y fctor of 5 to otin the mgnitude of the ssocition corresponding to every 20% of fcility ptients, ut the significnce level nd qulittive interprettion of the results sty unchnged whether reported for 20% or, for exmple, 0% or 00% of fcility ptients. Cox models were strtified y geogrphic region nd study phse, ccounted for fcility-clustering effects, nd djusted sequentilly for potentilly confounding vriles (Tle ). Fcility-level nlyses were further djusted for five fcility prctices, including percent of ptients in guidelines for hemogloin, serum lumin, serum phosphorous, single pool Kt/V, nd percent of ptients using ctheter for dilysis. Roust vrince estimtes (sndwich estimtor) were used to ccount for fcility-level clustering. 46 Proportionlity of hzrds ws confirmed grphiclly nd y n interction term etween ech covrite nd logtrnsformed follow-up time. For missing dt, missing indictors were used. In confirmtory nlyses, multiple imputtion of missing dt ws performed using IVEwre (Ann Aror, MI), nd mortlity nlyses were repeted using the imputed dt. In support of nlyses of fcility-level BP, supplementl nlyses used instrumentl vrile nlysis with fcility indictors s the instrument. 8,9,5,52 A liner-cox IV pproch ws used, with similrities to the trditionl two-stge lest-squre IV method, using liner pproximtion in the first stge nd Cox regression in the second stge. 24,25,53 Anlyses used SAS 9.2 (SAS Institute, Cry, NC). The uthors followed STROBE Sttement guidelines for reporting oservtionl studies. 54 DISCLOSURE The DOPPS is dministered y Aror Reserch Collortive for Helth nd is supported y scientific reserch grnts from Amgen 578 Kidney Interntionl (202) 82,

10 BM Roinson et l.: Blood pressure nd survivl in HD originl rticle (since 996), Kyow Hkko Kirin (since 999, in Jpn), Snofi Renl (since 2009), Aott (since 2009), Bxter (since 20), nd Vifor Fresenius Renl Phrm (since 20) without restrictions on pulictions. DAG hs consulted for Alnylm, Bxter, ChemoCentryx, FiroGen, nd Xenon. He holds stock options from Xenon Phrmceuticls. TA receives consulting fees from Chugi, Kirin, nd Aott; grnts/funds from Chugi nd Kirin. PGK is on clinicl dvisory ords for Amgen, Fresenius, nd Bxter. All the other uthors declred no competing interests. ACKNOWLEDGMENTS We grtefully cknowledge Hether Vn Doren, MFA, of Aror Reserch Collortive for Helth, for ssistnce with editing nd mnuscript preprtion. SUPPLEMENTARY MATERIAL Tle A. Descriptive sttistics y ptient-level nd fcility-level SBP ctegory, presented y region. Tle B. Crude mortlity rtes y fcility SBP qurtiles nd region. Tle C. IV pproch results. Supplementry mteril is linked to the online version of the pper t REFERENCES. Ezzti M, Lopez AD, Rodgers A et l. Selected mjor risk fctors nd glol nd regionl urden of disese. Lncet 2002; 360: Kerney PM, Whelton M, Reynolds K et l. Glol urden of hypertension: nlysis of worldwide dt. Lncet 2005; 365: Chonin AV, Bkris GL, Blck HR et l. The Seventh Report of the Joint Ntionl Committee on Prevention, Detection, Evlution, nd Tretment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289: US Renl Dt System: USRDS Annul Dt Report: Atls of Chronic Kidney Disese nd End-Stge Renl Disese in the United Sttes. In Ntionl Institutes of Helth, Ntionl Institute of Dietes nd Digestive Disese nd Kidney Diseses: Bethesd, MD, Ansell D, Feehlly J, Feest TG et l. K/DOQI clinicl prctice guidelines for crdiovsculr disese in dilysis ptients. Am J Kidney Dis 2005; 45: S S UK Renl Registry Report In: UK Renl Registry of the Renl Assocition Agrwl R, Nissenson AR, Btlle D et l. Prevlence, tretment, nd control of hypertension in chronic hemodilysis ptients in the United Sttes. Am J Med 2003; 5: Port FK, Hulert-Sheron TE, Wolfe RA et l. Predilysis lood pressure nd mortlity risk in ntionl smple of mintennce hemodilysis ptients. Am J Kidney Dis 999; 33: Klntr-Zdeh K, Kilptrick RD, McAllister CJ et l. Reverse epidemiology of hypertension nd crdiovsculr deth in the hemodilysis popultion: the 58th nnul fll conference nd scientific sessions. Hypertension 2005; 45: Li Z, Lcson Jr E, Lowrie EG et l. The epidemiology of systolic lood pressure nd deth risk in hemodilysis ptients. Am J Kidney Dis 2006; 48: Zger PG, Nikolic J, Brown RH et l. U curve ssocition of lood pressure nd mortlity in hemodilysis ptients. Medicl Directors of Dilysis Clinic, Inc. Kidney Int 998; 54: Lowrie E, Hung WH, Lew NL et l. The reltive contriution of mesured vriles to deth risk mong hemodilysis ptients. In: Friedmn EA (ed). Deth on Hemodilysis. Kluwer Acdemic: Boston, 994 pp Besr A, Bolton WK, Browne JK et l. The effects of norml s compred with low hemtocrit vlues in ptients with crdic disese who re receiving hemodilysis nd epoetin. N Engl J Med 998; 339: Greenlnd S, Lsh TL. In: Rothmn KJ, Greenlnd S, Lsh TL (eds). Anlysis of uncontrolled confounding. Modern Epidemiology. vol. 3rd edn Lippincott, Willims & Wilkins: Phildelphi, 2008, pp Johnston SC, Hennemn T, McCulloch CE et l. Modeling tretment effects on inry outcomes with grouped-tretment vriles nd individul covrites. Am J Epidemiol 2002; 56: Johnston SC. Comining ecologicl nd individul vriles to reduce confounding y indiction: cse study surchnoid hemorrhge tretment. J Clin Epidemiol 2000; 53: Morgenstern H. Ecologic studies. In: Rothmn KJ, Greenlnd S, Lsh TL (eds). Modern Epidemiology. 3rd edn. Lippincott, Willims & Wilkins: Phildelphi, 2008 pp Angrist JD, Imens GW, Ruin DB. Identifiction of cusl effects using instrumentl vriles. J Am Stt Assoc 996; 9: Newhouse JP, McClelln M. Econometrics in outcomes reserch: the use of instrumentl vriles. Annu Rev Pulic Helth 998; 9: Johnston J, DiNrdo J. Econometric Methods. 4th edn McGrw-Hill: New York, 997 xviii, 53 p.pp. 2. Brookhrt MA, Rssen JA, Wng PS et l. Evluting the vlidity of n instrumentl vrile study of neuroleptics: cn etween-physicin differences in prescriing ptterns e used to estimte tretment effects? Med Cre 2007; 45: S6 S Mrtens EP, Pestmn WR, de Boer A et l. Instrumentl vriles: ppliction nd limittions. Epidemiology 2006; 7: Judge GG, Hill RC, Griffiths WE et l. Introduction to the Theory nd Prctice of Econometrics. 2nd edn John Wiley & Sons, New York, Tentori F, Alert JM, Young EW et l. The survivl dvntge for hemodilysis ptients tking vitmin D is questioned: findings from the Dilysis Outcomes nd Prctice Ptterns Study. Nephrol Dil Trnsplnt 2009; 24: Rmirez SP, Alert JM, Blyney MJ et l. Rosiglitzone is ssocited with mortlity in chronic hemodilysis ptients. J Am Soc Nephrol 2009; 20: Brookhrt MA, Wng PS, Solomon DH et l. Evluting short-term drug effects using physicin-specific prescriing preference s n instrumentl vrile. Epidemiology 2006; 7: Stukel TA, Fisher ES, Wennerg DE et l. Anlysis of oservtionl studies in the presence of tretment selection is: effects of invsive crdic mngement on AMI survivl using propensity score nd instrumentl vrile methods. JAMA 2007; 297: Brdury BD, Do TP, Winkelmyer WC et l. Greter Epoetin lf (EPO) doses nd short-term mortlity risk mong hemodilysis ptients with hemogloin levels less thn g/dl. Phrmcoepidemiol Drug Sf 2009; 8: Brookhrt MA, Schneeweiss S, Avorn J et l. Comprtive mortlity risk of nemi mngement prctices in incident hemodilysis ptients. JAMA 200; 303: Stidley CA, Hunt WC, Tentori F et l. Chnging reltionship of lood pressure with mortlity over time mong hemodilysis ptients. J Am Soc Nephrol 2006; 7: Agrwl R, Sinh AD. Crdiovsculr protection with ntihypertensive drugs in dilysis ptients: systemtic review nd met-nlysis. Hypertension 2009; 53: Wizemnn V, Wel P, Chmney P et l. The mortlity risk of overhydrtion in hemodilysis ptients. Nephrol Dil Trnsplnt 2009; 24: Foley RN, Prfrey PS, Hrnett JD et l. Impct of hypertension on crdiomyopthy, moridity nd mortlity in end-stge renl disese. Kidney Int 996; 49: Heerspink HJ, Ninomiy T, Zoungs S et l. Effect of lowering lood pressure on crdiovsculr events nd mortlity in ptients on dilysis: systemtic review nd met-nlysis of rndomised controlled trils. Lncet 2009; 373: McIntyre CW, Burton JO, Sely NM et l. Hemodilysis-induced crdic dysfunction is ssocited with n cute reduction in glol nd segmentl myocrdil lood flow. Clin J Am Soc Nephrol 2008; 3: Dsselr JJ, Slrt RH, Knip M et l. Hemodilysis is ssocited with pronounced fll in myocrdil perfusion. Nephrol Dil Trnsplnt 2009; 24: McIntyre CW. Effects of hemodilysis on crdic function. Kidney Int 2009; 76: Burton JO, Jefferies HJ, Sely NM et l. Hemodilysis-induced crdic injury: determinnts nd ssocited outcomes. Clin J Am Soc Nephrol 2009; 4: Shoji T, Tsukihr Y, Fujii M et l. Hemodilysis-ssocited hypotension s n independent risk fctor for two-yer mortlity in hemodilysis ptients. Kidney Int 2004; 66: Agrwl R, Light RP. Chronoiology of rteril hypertension in hemodilysis ptients: implictions for home lood pressure monitoring. Am J Kidney Dis 2009; 54: Cushmn WC, Evns GW, Byington RP et l. Effects of intensive loodpressure control in type 2 dietes mellitus. N Engl J Med 200; 362: Kidney Interntionl (202) 82,

11 originl rticle BM Roinson et l.: Blood pressure nd survivl in HD 42. Mnci G, Lurent S, Agiti-Rosei E et l. Repprisl of Europen guidelines on hypertension mngement: Europen Society of Hypertension Tsk Force document. J Hypertens 2009; 27: Glssock RJ, Pecoits-Filho R, Brerto SH. Left ventriculr mss in chronic kidney disese nd ESRD. Clin J Am Soc Nephrol 2009; 4(Suppl ): S79 S Agrwl R, Alorzi P, Styn S et l. Dry-weight reduction in hypertensive hemodilysis ptients (DRIP): rndomized, controlled tril. Hypertension 2009; 53: Agrwl R, Peixoto AJ, Sntos SF et l. Pre- nd postdilysis lood pressures re imprecise estimtes of interdilytic multory lood pressure. Clin J Am Soc Nephrol 2006; : Mzzuchi N, Cronell E, Fernndez-Cen J. Importnce of lood pressure control in hemodilysis ptient survivl. Kidney Int 2000; 58: Alorzi P, Ptel N, Agrwl R. Home lood pressures re of greter prognostic vlue thn hemodilysis unit recordings. Clin J Am Soc Nephrol 2007; 2: Levin NW, Kotnko P, Eckrdt KU et l. Blood pressure in chronic kidney disese stge 5D-report from Kidney Disese: Improving Glol Outcomes controversies conference. Kidney Int 200; 77: Young E, Goodkin D, Mpes D et l. The Dilysis Outcomes nd Prctice Ptterns Study (DOPPS): n interntionl hemodilysis study. Kidney Int 2000; 57: S74 S Pisoni RL, Gillespie BW, Dickinson DM et l. The dilysis outcomes nd prctice ptterns study (DOPPS): design, dt elements, nd methodology. Am J Kidney Dis 2004; 44: Wooldridge JM. Introductory Econometrics, Chpter 5. 4th edn Greenlnd S. An introduction to instrumentl vriles for epidemiologists. Int J Epidemiol 2000; 29: Pisoni RL, Arrington CJ, Alert JM et l. Fcility hemodilysis vsculr ccess use nd mortlity in countries prticipting in DOPPS: n instrumentl vrile nlysis. Am J Kidney Dis 2009; 53: von Elm E, Altmn DG, Egger M et l. The Strengthening the Reporting of Oservtionl Studies in Epidemiology (STROBE) sttement: guidelines for reporting oservtionl studies. Ann Intern Med 2007; 47: Kidney Interntionl (202) 82,