Adenosine A1 receptor antagonist improves intradialytic hypotension

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1 & 26 Interntionl Society of Nephrology originl rticle see commentry on pge 789 Adenosine A1 receptor ntgonist improves intrdilytic hypotension E Imi 1, M Fujii 2, Y Kohno 3, H Kgeym 3, K Nkhr 3, M Hori 4 nd Y Tsukihr 1 Deprtment of Nephrology, Osk University Grdute School of Medicine, Suit, Osk, Jpn; 2 Deprtment of Internl Medicine, Osk Koseinenkin Hospitl, Fukushim-ku, Osk, Jpn; 3 Fujisw Phrmceuticls Co. Ltd, Osk, Jpn; 4 Deprtment of Crdiology, Osk University Grdute School of Medicine, Suit, Osk, Jpn nd Deprtment of Nephrology, Osk Generl Medicl Center, Osk, Jpn Intrdilytic hypotension is most frequent compliction of hemodilysis nd my contriute to crdiovsculr events nd high mortlity. There is hypothesis tht n increse in denosine genertion during hemodilysis my cuse vsodiltion nd decrese in crdic output, which results in systemic hypotension. We studied whether this cn e locked y n denosine A1 receptor ntgonist. We investigted the effects of n A1 ntgonist,, injection in 3 chronic hemodilysis ptients with frequent intrdilytic hypotension y prospective, multicenter, doule-lind plceo-controlled study for 4 weeks fter 4 weeks of the oservtion. Intrdilytic hypotension ws defined s systolic lood pressure (SBP) less thn 1 mmhg, with SBP drop of more thn 3 mmhg from the predilysis level. The efficcy of ws primrily ssessed y the reduction rte of dilysis hypotension etween the nd plceo groups. Incidence of emergency tretments cused y hypotension ws evluted. ( mg, intrvenous) or n equivlent plceo ws injected into the dilysis circuit 1 h fter strting dilysis. Blood pressure nd hert rte were monitored every 3 min during dilysis. significntly improved intrdilytic hypotension (P ¼.46), in tht the reduction rtes of intrdilytic hypotension in the nd plceo groups were 12.8% (Q1 (first quntile), Q3 (third quntile): 27., 1.7), nd þ 8.3% (Q1, Q3: 16.6, þ 16.7), respectively. The frequency of discontinution of dilysis ws significntly reduced y. No pprent side effects were oserved from tretment with. In conclusion, the A1 ntgonist my offer novel therpeutic option for chronic dilysis ptients ssocited with intrdilytic hypotension. Kidney Interntionl (26) 69, doi:.38/sj.ki.88; pulished online 4 Jnury 26 KEYWORDS: denosine; A1 ntgonist; intrdilytic hypotension Correspondence: E Imi, Deprtment of Nephrology, Osk University Grdute School of Medicine, Suit 6-871, Osk, Jpn. E-mil: imi@medone.med.osk-u.c.jp Received 1 Decemer 24; revised 17 June 2; ccepted 14 July 2; pulished online 4 Jnury 26 End-stge renl disese (ESRD) ptients re continuously incresing nd the totl numer of hemodilysis ptients is estimted to e over 1 6 in the world. 1 In Jpn, the numer of ESRD ptients in 24 exceeded 24, nd the ptients receiving long-term hemodilysis hs considerly incresed. More thn 1 hemodilysis ptients hve een undergoing hemodilysis therpy for more thn 2 yers. Long-term dilysis therpy cuses vrious complictions including intrdilytic hypotension. There re two types of dilysis hypotension: intrdilytic hypotension nd chronic persistent hypotension. Up to 33% of hemodilysis ptients re suffering from intrdilytic hypotension, which requires n ction to resume lood pressure during hemodilysis, 2,3 nd the incidence of intrdilytic hypotension is expected to increse in ccordnce with the increse of the elderly, dietic ptients, nd ptients with crdiovsculr diseses. 4 Intrdilytic hypotension often engenders hemodilysis interruption nd my e responsile for reluctnce in ptients to extend their dilysis tretment time, eventully leding to incresed moridity nd mortlity y rin ischemi nd crdiovsculr diseses.,6 Severl fctors contriute to intrdilytic hypotension. These include rpid fluid removl, rpid reduction in plsm osmollity, utonomic dysfunction, limited crdic reserve, nd incresed synthesis of endogenous vsodiltors. 7,8 The grdul lood pressure reduction results from n intrvsculr hypovolemic condition due to hemodilysis. In contrst, sudden nd profound hypotension from diminished crdic output nd vsodiltion hs een theorized. Krepel et l. 9, reported tht the level of reltive lood volume ws not correlted with lood pressure nd the level of reltive lood volume reduction t which hypotension occurred ws highly vrile. The ccumultion of the loclly relesed denosine my ply centrl role in sudden intrdilytic hypotension. The proposed hypothesis is tht vicious cycle my occur in ptients with sudden hypotension: hypotension induces ischemi, which, in turn, increses locl denosine relese, which then cuses inhiition of norepinephrine relese nd eventully cuses vsodiltion, thus resulting in deepening hypotension. 11,12 In fct, concentrtions of denosine nd its metolite, inosine, nd hypoxnthine, re reported to increse fter hemodilysis. 11,12 Kidney Interntionl (26) 69,

2 o r i g i n l r t i c l e E Imi et l.: Adenosine A1 ntgonist comts intrdilytic hypotension Adenosine exerts its physiologicl ctions to stimulte denosine receptors (A1, A2, A2, nd A3) on the cell memrne. 13 Functions of A1 nd A2 receptors hve een well studied. Adenosine A1 receptor stimultion results in suppression of crdic contrctility, hert rte reduction, suppression of ctecholmine relese from sympthetic nerve endings, nd renin relese., n denosine receptor A1 ntgonist, exhiits high ffinity nd high selectivity for the humn denosine A1 receptor. Although the centrl nervous system ounds in denosine A1 receptors, 14 hs little effect on the centrl nervous system. One of the resons is thought to e tht the chrcter of hydrophilicity of does not llow it to e distriuted into the centrl nervous system (dt not shown). To prove the hypothesis tht dilysis hypotension is cused y ischemi-induced denosine genertion, we investigted the effects of infusion on dilysis hypotension y multicenter, rndomized, doule-lind, plceo-controlled, intergroup comprtive study. RESULTS Effects of tretment on the incidence of intrdilytic hypotension significntly improved intrdilytic hypotension (P ¼.46), in tht the reduction rtes of dilysis hypotension in the nd plceo groups were 12.8% (Q1 (first quntile), Q3 (third quntile): 27., 1.7), nd þ 8.3% (Q1, Q3: 16.6, þ 16.7), respectively (Figure 1). Intrdilytic hypotension ws significntly suppressed in the group (P ¼.), wheres it ws not chnged in the plceo group (P ¼.637) (Figure 1). As the two vriles of frequency of intrdilytic hypotension nd durtion of hemodilysis exhiited imlnce (Po.1), the incidence of intrdilytic hypotension during the oservtion ws djusted. After djustment, significntly suppressed intrdilytic hypotension lso (P ¼.3). To further nlyze the efficcy of on intrdilytic hypotension, we compred the nd plceo groups fter omitting the dilysis sessions in which ody fluid ws removed t the excessive ultrfiltrtion rte of more thn.3 ml/kg/min. Three ptients in the group were omitted ecuse they were frequently treted with the excessive ultrfiltrtion rte. On the other hnd, no ptient in the plceo group ws removed from the dt for nlysis. The reduction rtes of dilysis hypotension in the nd plceo groups were 12.8% (Q1, Q3: 3., 8.3) nd þ 8.3% (Q1, Q3: 16.6, þ 16.7), respectively (Figure 2), suggesting tht significntly improved intrdilytic hypotension (P ¼.49). As shown in Figures 3 nd 4, the intrdilytic hypotension of the hemodilysis ptients ws significntly suppressed y nd the efficcy ws more prominent in proportion to the degree of drop in lood pressure. With the intrdilytic hypotension defined t systolic lood pressure (SBP) less thn mmhg, the reduction rtes of dilysis hypotension in the nd plceo groups were 16.7% (Q1, Q3: 34., þ.8) nd þ 8.3% (Q1, Q3: 16.7, þ 2.), respectively (Figure 3), suggesting tht significntly improved intrdilytic hypotension (P ¼.18). With intrdilytic hypotension defined s SBP less thn 9 mmhg, the P =.49 Figure 2 Effects of dministrtion of or plceo on intrdilytic hypotension (SBP drop elow 1 mmhg) fter omitting the cses with excess ultrfiltrtion. () Chnge in the incidence of intrdilytic hypotension in ech ptient., n ¼ 13; plceo, n ¼ 14. Dt show medin nd Q1 Q3. () Reduction rte of intrdilytic hypotension. Dt re expressed s medin nd Q1 Q3. 2 P = Figure 1 Effects of dministrtion of or plceo on intrdilytic hypotension. () Chnge in the incidence of intrdilytic hypotension in ech ptient., n ¼ 16; plceo, n ¼ 14. Dt show medin nd Q1 Q3. () Reduction rte of intrdilytic hypotension. Dt re expressed s medin nd Q1 Q P = Figure 3 Effects of dministrtion of or plceo on intrdilytic hypotension (SBP drop elow mmhg) fter omitting the cses with excess ultrfiltrtion. () Chnge in the incidence of intrdilytic hypotension in ech ptient., n ¼ 13; plceo, n ¼ 14. Dt show medin nd Q1 Q3. () Reduction rte of intrdilytic hypotension. Dt re expressed s medin nd Q1 Q Kidney Interntionl (26) 69,

3 E Imi et l.: Adenosine A1 ntgonist comts intrdilytic hypotension o r i g i n l r t i c l e reduction rtes of dilysis hypotension in the nd plceo groups were 12.% (Q1, Q3: 16.7,.) nd þ 2.8% (Q1, Q3:., þ 27.3), respectively (Figure 4), suggesting tht significntly improved intrdilytic hypotension (P ¼.32). prominently improved intrdilytic hypotension, prticulrly in severer cses. Effect of on events with emergent tretment during hemodilysis The incidence of dilysis sessions with emergency tretments is shown in Tle 1. The incidence of infusion ws not different etween the nd plceo groups during the oservtion (Tle 1). However, discontinution of dilysis ws significntly suppressed y tretment (Tle 1 nd Figure ). The mjor prolem of intrdilytic hypotension is discontinued dilysis, which often cuses overhydrtion nd underdilysis of the ptients. In the plceo group, only one of eight showed n improved chnge, wheres ll the sujects in the group (Figure ) hd reductions in the frequency of discontinution or suspension of fluid removl. Phrmcokinetics of in dilysis ptients Plsm concentrtion of in hemodilysis ptients ws initilly t mg/ml nd grdully decresed to 1 mg/ml, 2 h P =.32 Figure 4 Effects of dministrtion of or plceo on intrdilytic hypotension (SBP drop elow 9 mmhg) fter omitting the cses with excess ultrfiltrtion. () Chnge in the incidence of intrdilytic hypotension in ech ptient., n ¼ 13; plceo, n ¼ 14. Dt show medin nd Q1 Q3. () Reduction rte of intrdilytic hypotension. Dt re expressed s medin nd Q1 Q3. fter the injection (Figure 6). The plsm concentrtions of of hemodilysis ptients were similr to those of helthy volunteers. No pprent side effects were oserved with use of for dilysis hypotension. DISCUSSION It is criticlly importnt to keep n dequte dilysis dose nd sufficient dilysis time for improving the prognosis of dilysis ptients. Intrdilytic hypotension is mjor prolem in mintining dequte dilysis ecuse it compels limit to dilysis time nd dilysis condition. In the present study, improved intrdilytic hypotension significntly in chronic hemodilysis ptients, who were intrdilytic hypotension prone. Although the incidence of sline infusion for intrdilytic hypotension ws not significntly different with dministrtion, the incidence of discontinution of hemodilysis ws significntly decresed, indicting tht improves intrdilytic hypotension, prticulrly in severer cses. Intrdilytic hypotension occurs s result of intrvsculr hypovolemi nd impired crdiovsculr rectivity to the decrese of intrvsculr volume. When the dry weight P =.3 Figure Effects of dministrtion of or plceo on discontinution of dilysis for intrdilytic hypotension. () Chnge in the incidence of discontinution of dilysis in ech ptient., n ¼ 16; plceo, n ¼ 14. Dt show medin nd Q1 Q3. () Reduction rte of discontinution of dilysis. Dt re expressed s medin nd Q1 Q3. Tle 1 Event with the emergent tretments for lood pressure reduction incidence of dilysis sessions with event group (n=16) group (n=14) Tretments Dosing Dosing group vs plceo group Infusion 28.7% ( ) 27.% ( ) 2.% ( ) 26.7% ( ) P=.226 P=.197 P=.91 Discontinution of hemodilysis.% (. 4.2).% (..).% (. 8.3) 4.2% (..) P=.3 P=.12 p=.63 Reduction or suspension of ultrfiltrtion.% (. 8.3).% (. 8.3).% (. 8.3).% (. 9.1) P=.436 P=.46 P=.211 Others c.% (. 16.7).% (. 8.3).% (. 8.3).% (. 8.3) P=.69 p=.922 p=.344 Dt re expressed s medin (Q1 Q3). Mnn Whitney U-test for the group comprison of difference etween dosing nd oservtion. Wilcoxon signed rnk test for the intrgroup comprison of difference etween dosing nd oservtion. c Body positionl chnges, reduction of lood flow rte, lowering dilyste temperture, O 2 inhltion, nd so on. Kidney Interntionl (26) 69,

4 o r i g i n l r t i c l e E Imi et l.: Adenosine A1 ntgonist comts intrdilytic hypotension Plsm conc. (μg/ml) 1.1 Dilyzed ptients Helthy sujects 1 2 Time fter dose (h) Figure 6 Phrmcokinetics of. Plsm concentrtion in helthy sujects ( ) nd dilyzed ptients (----). is optiml, the ultrfiltrtion rte is the min determinnt of intrvsculr volume. The excess removl of extrcellulr volume, when the ultrfiltrtion rte is eyond.3 ml/kg/ min, frequently results in intrdilytic hypotension. If the dilysis sessions with excess ultrfiltrtion eyond.3 ml/kg/ min re removed, the impct of on intrdilytic hypotension ecomes more prominent, s shown in Figures 2 4. Most cses of intrdilytic hypotension seem to hppen y impired crdiovsculr rectivity. The mechnism for the impired rectivity of the crdiovsculr system is lrgely oscure lthough severl hypotheses hve een proposed: utonomic dysfunction, genertion of denosine nd so on. It hs een proven tht the increse in denosine, which is generted from ischemic tissue y ATP degrdtion, reduces vessel tone nd lowers lood pressure. A high concentrtion of denosine nd its metolites hs een reported fter ischemic events. Woolliscroft nd Fox 1 demonstrted tht the increse in urine oxypurine/cretinine rtio ws oserved fter hypotensive events of 19 ptients who were ssocited with chronic hert filure, liver diseses nd so on. In hemodilysis ptients under cette dilysis, dilysis hypotension ws often seen nd plsm inosine, hypoxnthine, xnthine, nd uric cid were incresed fter dilysis. 16 According to their dt, the increse in ATP metolites ws prominent in cette dilysis within 1 h fter dilysis, which ws often ssocited with dilysis hypotension, wheres icronte dilysis ws not often ssocited with significnt increse in ATP metolites, lthough mild pek ws seen t 2 h fter dilysis. The most relevnt report ws pulished y Shinzto et l. 11 They mesured inosine, hypoxnthine nd xnthine t the time of sudden hypotension nd showed significnt increse in these denosine metolites t the time of hypotension. Guieu et l. 12 lso mesured serum denosine nd inosine concentrtions in dilysis ptients nd showed tht the serum denosine concentrtions were incresed more thn twice s much s the controls efore nd fter dilysis. A1 receptor inhiition ws ttempted y dministrtion of cffeine in ptients with hemodilytic hypotension. Shinzto et l. 11 showed tht dministrtion of cffeine ttenuted dilysis hypotension significntly. These results suggest tht denosine my ply mjor role in dilysis hypotension. However, cffeine is not selective A1 ntgonist nd increses lood pressure nd hert rtes in most cses. In contrst, is selective A1 ntgonist nd does not ffect crdiovsculr function nd locomotor ctivity in the rin. Wht is the mechnism for prevention of dilysis hypotension y? The A1 receptors, which re reported to e distriuted in the ends of sympthetic nerves, suppress the relese of ctecholmines from the ends of the nerves. 17 Adenosine selectively inhiits contrctions of the rit portl vein evoked y drenergic nerve stimultion vi ctivtion of n A1 receptor. 18 This mens tht denosine could inhiit constriction of peripherl vessels vi the A1 receptors in the ends of the nerves. my restore the denosine-induced decline in constriction. It is known tht denosine decreses crdic function nd expnds coronry rteries to protect the orgn from ischemi-induced dmge. The crdic ction of denosine is depression of sinorteril nd rterioventriculr node ctivity, leding to reduced hert rte. However, hert rte ws not chnged significntly in the present study. We might hve missed the reduction in hert rte ecuse we did not continuously monitor hert rte nd lood pressure. In dilysis ptients, the increse in denosine concentrtion in peripherl tissue presumly precedes the increse in denosine in systemic circultion, s peripherl tissue ischemi occurs in dvnce of systemic hypotension. Alterntively, the A1 ntgonist my directly ffect utonomic regultion. This possiility needs to e studied. The A1 receptor does not involve diltion of coronry rteries. These rteries express denosine A2 receptors, which medite vsodiltion. 19 Therefore, does not inhiit these protective ctions of denosine. This hs een reported s eneficil role of ntgonism of the crdiodepressnt effects of denosine. 19,2 The crdiodepressnt ctions of denosine my protect our odies ginst hemorrhge or ngin. However, it is plusile tht the depressnt effect of denosine induces sudden hypotension, which in turn cuses serious injuries to the rin nd hert. does inhiit the excessive suppressive ction of denosine on crdic function. In our study, the frequency of dilysis hypotension ws ttenuted y, ut not totlly eliminted. This result my imply tht the dministrtion of might hve een insufficient to prevent the intrdilytic hypotension in some cses. The dequte tretment dose of nd injection time to completely prevent dilysis hypotension need to e determined y further studies. Alterntively, the cuse of hemodilytic hypotension is vrile nd A1 inhiition is not enough to prevent dilysis hypotension. In this study, intrdilytic hypotension tended to hppen more frequently in control sujects during the dosing compred to the oservtion. The reson is oscure, ut we speculted tht the ptients were stressed out oeying the protocol ecuse the dilysis condition ws not to e chnged for 8 weeks. Such tense condition might 88 Kidney Interntionl (26) 69,

5 E Imi et l.: Adenosine A1 ntgonist comts intrdilytic hypotension o r i g i n l r t i c l e reduce the frequency of intrdilytic hypotension during the first 4 weeks of the oservtion. The dilysis conditions, in prticulr dry weight, re usully mde through fine djustment to retin the ptients physicl condition ppropritely. There ws possiility tht the rel dry weight might e chnged in the lst 4 weeks, lthough the crdiothorcic rtio nd the size of inferior ven cv were not chnged. Nevertheless, the incidence of intrdilytic hypotension ws significntly reduced with, suggesting tht my e effective even under dverse conditions nd we my e underestimting the ction. In conclusion, ws cliniclly useful for improvement of intrdilytic hypotension in this smll clinicl tril, prticulrly in severe cses, which my improve the prognosis of hemodilysis ptients. The outcome of this study suggests tht intrdilytic hypotension is, t lest in prt, cused y genertion of denosine during hemodilysis in peripherl tissue. In ddition, significntly reduces the frequency of emergency tretment during dilysis therpy, which my decrese the prcticl lor of the dilysis stff. The fvorle impct of needs to e confirmed in lrge-scle clinicl tril y enrolling severer cses. MATERIALS AND METHODS Study sujects Chronic hemodilytic ptients who were suffering from frequent intrdilytic hypotension lsting 6 months were recruited from hospitls nd outptient clinics in the Osk re etween Jnury of 22 nd Jnury of 23. The inclusion criteri were outptients on chronic hemodilysis three times week in supine position, whose predilytic SBP is 12 mmhg or more, nd who hve four or more dilysis sessions with intrdilytic hypotensive episode(s) out of 12 hemodilysis sessions in 4 weeks. Ages rnge from over 2 to less thn 7 yers of ge. The exclusion criteri were s follows: ptients with serious hemodilysis-induced hypotension, y which it mens tht hemodilysis could not e completed without pressure gent. Ptients with ny of the following complictions were excluded: serious hypertension (SBP 2 mmhg or more nd distolic lood pressure 1 mmhg or more), serious hemorrhge disese (cererl hemorrhge nd ulcer ccompnied y hemorrhge), serious crdiovsculr diseses (myocrdil infrction tht occurred in the pst 6 months, severe hert filure), nd liver diseses, dietic retinopthy in pre-prolifertive stge or prolifertive stge (lthough cses with stilized leeding y photocogultion were enrolled), severe nemi requiring lood trnsfusion nd hving just strted erythropoietin therpy. Informed consent ws otined from 3 ptients. Twenty ptients were withdrwn from the clinicl tril for the following resons: seven ptients did not meet the criteri of dilysis hypotension; five ptients voluntrily withdrew; five ptients needed to hve their dry weight chnged; one ws dmitted to hospitl; one hd troule with shunt; one could not hve his/her dilysis condition djusted. Three ptients were omitted from the dt for nlysis ecuse the numer of dilysis tretments for sttisticl nlysis on these ptients ws insufficient. The Investigtionl Product Alloction Director independently decided the eligiility of sujects under inclusion criteri nd exclusion criteri nd llocted them to nd plceo groups t 1:1 rtio. An oservtion of 4 weeks ws estlished efore the initil dministrtion of the investigtionl product, nd the Investigtionl Product Alloction Director judged when to progress to the dosing. Fourteen sujects ( men, four women) were ssigned to the plceo group nd 16 sujects (11 men, five women) were ssigned to the group. Ptient profiles t the entry of this study re shown in Tle 2. The sujects provided written, informed consent for the study nd pprovl ws otined from oth the Osk Prefecture Medicl Assocition reserch ethics committee nd the individul hospitl review ords. The study ws crried out in ccordnce with the Declrtion of Helsinki. ((E,R)-[1-[3-(2-phenylpyrzolo[1,-]pyridin-3-yl)cryloyl]- piperidin-2-yl] cetic cid), which is n denosine receptor A1 ntgonist developed y Fujisw Phrmceuticl Co., Ltd, exhiits high ffinity nd high selectivity for humn denosine receptor A1. Study protocol The study ws performed in rndomized, doule-lind, plceocontrolled nd comprtive mnner. All sujects were djusted to hemodilysis condition for 2 weeks followed y the oservtion for 4 weeks, nd finlly the sujects were treted with or plceo dministrtion for 4 weeks. During the dosing, mg of or plceo ws dministrted 1 h fter hemodilysis, s the elimintion hlf-life of is 3 h. The hemodilysis djusted condition ws set to ensure constnt hemodilysis conditions during the oservtion (4 weeks) nd the mediction (4 weeks), totling 8 weeks. During this, ll hemodilytic conditions hd to e set, including dry weight, 4 h of hemodilysis, dys of the week with hemodilysis, scheduled hemodilysis hours of the dy, lood flow volume, dilysis solution type (icronte dilysis solution), dilysis solution flow volume, dilysis solution temperture, nticogulnt type, dilyzer type, (memrne type), mel timing, nd timing of ody positionl chnges (e.g. lifting legs nd so on). Periodic ody position chnges were permitted only s routine ction to prevent dilysis hypotension prophylcticlly. Fesiility of hemodilysis under the ove conditions during the oservtion nd the dosing for totl of 8 weeks ws confirmed. Hemodilysis ws performed with icronte dilyste. The dilyste sodium concentrtion ws meq/l, dilyste potssium 2 meq/l nd dilyste clcium 2. or 3. meq/l. The durtion of dilysis sessions ws set to e 4 h except when infusion therpy ws performed. Ultrfiltrtion rte ws set to e constnt over the course of dilysis session. The postdilytic ody weight hs een governed to chieve dry weight not in every dilysis session, ut t lest once week. Blood pressure ws mesured every 3 min. To tret the symptoms ssocited with intrdilytic fll of lood pressure or to prevent the further reduction of lood pressure, sline infusion ws performed t first. As rule, when SBP is less thn 14 mmhg, with 2 mmhg or more reduction compred to SBP 1 h efore, ml (one unit) sline infusion or injection of 2 ml (one unit) of % NCl is permitted. Emergency ctions other thn infusion therpy were sed on specific criteri. If the infusion therpy ws unsuccessful, positionl chnge (lifting the legs), reduction of ultrfiltrtion rte, oxygen inhltion, discontinution of hemodilysis, nd shortening of dilysis were conducted. Kidney Interntionl (26) 69,

6 o r i g i n l r t i c l e E Imi et l.: Adenosine A1 ntgonist comts intrdilytic hypotension Tle 2 Ptients profile Sttistics Totl numer Sex Mle 11 (68.8) (71.4) P=1. Femle (31.3) 4 (28.6) Age (yers) (18.8) 1 (7.1) 9 6 (37.) 6 (42.9) 6 69 (31.3) 4 (28.6) (12.) 3 (21.4) Men7s.d P=.88 Medin Q1 Q Min mx Primry kidney disese Chronic (31.3) 6 (42.9) glomerulonephiritis Chronic pyelonephiritis Polycystic kidney 1 (6.3) Nephrosclerosis 1 (7.1) Dietic nephropthy 4 (2.) 6 (42.9) Renl hypoplsi 1 (6.3) Chronic nephritis 1 (6.3) Tuerculous nephritis 1 (6.3) Acute nephritis 1 (6.3) Horseshoe kidney/ 1 (6.3) nephrolith Unidentified 1 (6.3) Dilysis-experienced yers o2 2 (12.) 3 (21.4) 2p o (3.7) p o 8 (.) 4 (28.6) p o2 6 (37.) 2 (14.3) 2p Men7s.d P=.36 Medin Q1 Q Min mx Decrese rte of ody weight during dilysis session p% 7 (43.8) 8 (7.1) %o 9 (6.3) 6 (42.9) Men7s.d P=.6 Medin.1. Q1 Q Min mx Men systolic lood pressure efore dilysis o14 6 (37.) 3 (21.4) 14p o1 2 (12.) 7 (.) 1p o16 4 (2.) 1 (7.1) 16p 4 (2.) 3 (21.4) Men7s.d P=.828 Medin Q1 Q Min mx Men distolic lood pressure efore dilysis o7 2 (12.) 3 (21.4) 7p o8 6 (37.) 6 (42.9) 8p o9 (31.3) 4 (28.6) 9p 3 (18.8) 1 (7.1) Men7s.d P=.43 Medin Q1 Q Min mx The dt shown in this tle were otined t the entry of this study. Percentge of the relevnt item in the totl numer of sujects in plceo/ group is given in prentheses. Fisher s exct test. t-test. Evlution of the efficcy of on dilysis hypotension The primry ssessment of efficcy ws the reduction rte in the incidence of intrdilytic hypotension etween the plceo nd the groups. Intrdilytic hypotension is defined s SBP decresing to less thn 1 mmhg, with 3 mmhg or more reduction of lood pressure from the predilysis level. An event is defined s emergency tretments ginst lood pressure reduction: infusion of sline or % NCl, reduction of ultrfiltrtion, oxygen inhltion nd discontinution of hemodilysis or shortening of dilysis time. Incidence of hemodilysis sessions with intrdilytic hypotension(s) nd event(s) ws evluted. In cses of excessive ody weight increse due to too much food nd fluid intke, however, the dilysis sessions inevitly set t n ultrfiltrtion rte of more thn.3 ml/kg/min often hve prolems. The dt were excluded from sttisticl nlysis when ptients underwent n excessive ultrfiltrtion rte of.3 ml/kg/min or more. After the exclusion of dilysis sessions with excess ultrfiltrtion, three ptients who hd less thn six dilysis sessions for the dt nlysis were excluded. To further nlyze the efficcy of on severe intrdilytic hypotension, intrdilytic hypotension ws defined s SBP decresing to less thn 1,, nd 9 mmhg. Phrmcokinetic mesurement of Whole lood concentrtion of ws nlyzed efore dministrtion nd t 3,, nd 3 min nd 1 nd 2 h fter dministrtion of during hemodilysis. concentrtion ws mesured y liquid chromtogrphy nd mss spectrometry. Estimted plsm concentrtion of (C) ws clculted from the concentrtions t 3 nd min fter dministrtion. Phrmcokinetics of norml sujects ws mesured in helthy volunteers fter informed consent ws otined from them. Sttisticl nlysis For demogrphic nd other seline vriles, Fisher s exct test, t-test or Mnn Whitney U-test were used to ssess comprility etween the nd plceo groups. Vriles tht exhiited imlnce (Po.1) etween tretment groups were to e included s covrite in secondry nlysis (rnk nlysis of covrince) to ssess the effect of the imlnce. Mnn Whitney U-test ws used for group comprison (comprison etween the plceo nd groups) nd Wilcoxon signed rnk test ws used for intrgroup comprison (comprison etween the oservtion nd mediction s). Sttisticl significnce level ws defined s Po.. REFERENCES 1. USRDS. Bckground on the US ESRD progrm. Am J Kid Dis 23; 41: S1 S Dugirds J. Preventing nd mnging hypotension. Semi Dil 1994; 7: Perzell M. Approch to ptients with intrdilytic hypotension: focus on therpeutic options. Semi Dil 1999; 12: vn der Snde F, Koomn J, Leunissen K. Strtegies for improving homodynmic stility in crdic-compromised dilysis ptients. Am J Kid Dis 2; 3: E19.. Koch M, Thoms B, Tschope W, Ritz E. Survivl nd predictors of deth in dilysed dietic ptients. Dietologi 1993; 36: Shoji T, Tsukihr Y, Fujii M, Imi E. Hemodilysis-ssocited hypotension s n independent risk fctor for two-yer mortlity in hemodilysis ptients. Kidney Int 24; 66: Dugirds J. Dilysis hypotension: hemodynmic nlysis. Kidney Int 1991; 39: Kidney Interntionl (26) 69,

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