Serum Potassium Levels and Mortality in Hemodialysis Patients: A Retrospective Cohort Study

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1 Americn Journl of Nephrology Originl Report: Ptient-Oriented, Trnsltionl Reserch Received: April 27, 2016 Accepted: July 10, 2016 Published online: September 3, 2016 Serum Potssium Levels nd Mortlity in Hemodilysis Ptients: A Retrospective Cohort Study Akeem A. Yusuf Yn Hu Bhupinder Singh c José A. Menoyo c Jmes B. Wetmore, b Chronic Disese Reserch Group, Minnepolis Medicl Reserch Foundtion, nd b Division of Nephrology, Hennepin County Medicl Center, Minnepolis, Minn., nd c ZS Phrm Inc., Astr Zenec Group, Sn Mteo, Clif., USA Key Words End-stge renl disese Hemodilysis Hyperklemi Mortlity Potssium Abstrct Bckground: Hyperklemi is common in ptients receiving mintennce hemodilysis. However, few studies hve exmined the ssocition between serum potssium level nd mortlity. Methods: This study used nnul cohorts of hemodilysis ptients during To determine hyperklemi prevlence, monthly hyperklemi ws defined s serum potssium level 5.5 meq/l; prevlence ws clculted s rtio of hyperklemi episodes to follow-up time, reported seprtely by long nd short interdilytic intervl. To determine the impct of hyperklemi on mortlity, ptients in the 2010 cohort were followed from first potssium mesurement until deth or censoring event; hyperklemi ws defined, sequentilly, by potssium levels meq/l t 0.1 meq/l intervls. Time-dependent Cox proportionl hzrds modeling ws used to estimte the ssocition between hyperklemi nd mortlity. Results: The 4 nnul cohorts rnged from 28,774 to 36,888 ptients. Men ge ws pproximtely 63 yers, bout 56% were men, 51% were white nd 44% hd end-stge renl disese cused by dibetes. Hyperklemi prevlence ws consistently estimted t events per 100 ptient-months. Prev- lence on the dy fter the long interdilytic intervl ws times s high s on the dy fter the short intervl. Hyperklemi, when defined s serum potssium 5.7 meq/l, ws ssocited with ll-cuse mortlity (djusted hzrds rtio (AHR) 1.13, 95% CI , p = 0.037, vs. <5.7 meq/l) fter djustment. AHRs incresed progressively s the hyperklemi threshold incresed, reching 1.37 (95% CI , p < ) for 6.0 meq/l. Conclusions: The long interdilytic intervl ws ssocited with incresed likelihood of hyperklemi. Hyperklemi ws ssocited with llcuse mortlity beginning t serum potssium 5.7 meq/l; mortlity risk estimtes incresed ordinlly through 6.0 meq/l, suggesting threshold t which serum potssium becomes substntilly more dngerous. Introduction 2016 S. Krger AG, Bsel Hyperklemi, potentilly life-thretening condition ssocited with ventriculr rrhythmis nd sudden crdic rrest [1 5], is common in ptients with chronic kidney disese, prticulrly those receiving mintennce dilysis. Mintennce hemodilysis ptients, most of whom hve little to no residul renl function, rely lmost exclusively on the intermittent potssium clernce provided by hemodilysis, supplemented in smll mesure by gut E-Mil krger@krger.com S. Krger AG, Bsel /16/ $39.50/0 Akeem A. Yusuf, PhD Chronic Disese Reserch Group Minnepolis Medicl Reserch Foundtion, 914 South 8th Street Suite S2.100, Minnepolis, MN (USA) E-Mil umn.edu

2 potssium excretion [6]. Additionl risks for hyperklemi include non-dherence to dietry restrictions, metbolic cidosis, nemi requiring red blood cell trnsfusions nd ltertions in the intrcellulr/extrcellulr potssium distribution. As result, mny hemodilysis ptients regulrly experience wide vritions in serum potssium levels. Becuse hyperklemi itself nd the rpid shifts in potssium ssocited with hemodilysis sessions pper to confer risk [7 9], tretment of hyperklemi is frught with clinicl chllenges, s well-intentioned ttempts to tret persistently hyperklemic ptients by incresing potssium clernce using low-potssium dilyste my ctully increse risk of deth [10, 11]. Given the high risk of hyperklemi for hemodilysis ptients, severl observtionl studies hve exmined the ssocition between hyperklemi nd dverse events [12 15]. While hyperklemi hs been repetedly ssocited with sudden deth nd other dverse events, there is no universlly ccepted definition of significnt hyperklemi; studies employ vrious thresholds such s 5.0, 5.5 or 6.0 meq/l [16 23]. As such, the precise reltionship between hyperklemi nd deth of ptients on hemodilysis is uncertin. To better understnd the ssocition between hyperklemi nd mortlity in ptients receiving mintennce hemodilysis, we designed lrge retrospective cohort study using ptient level dt on serum potssium levels linked with outcomes scertined from billing clims dt. Our objectives were to (1) scertin the prevlence of hyperklemi, (2) explore how the length of the interdilytic intervl ws ssocited with likelihood of hyperklemi nd (3) determine the reltionship between hyperklemi nd mortlity. By vrying the definition of hyperklemi, we specificlly sought to determine whether there ws threshold t which potssium is ssocited with mrked increse in either ll-cuse or cuse-specific mortlity. Chrcterizing the reltionship between the degree of hyperklemi nd the risk of dverse outcomes my help provide prcticl guidnce to nephrologists nd other helthcre providers working in dilysis settings. Mterils nd Methods Dt Sources Dt for these nlyses were derived from the United Sttes Renl Dt System (USRDS), ntionl system tht collects dt on virtully ll ptients undergoing mintennce dilysis in the US nd lrge dilysis orgniztion (LDO). The LDO is mjor dilysis provider with substntil ntionl presence. We received stndrd ptient records from the USRDS including dt on demogrphics nd comorbid conditions t the time of dilysis commencement, nd on inptient nd outptient medicl clims pid by Medicre. Medicre is federlly funded progrm to which nerly ll dults with end-stge renl disese (ESRD) re entitled [24]. USRDS dt were linked to the LDO dt through n greement with the relevnt project officers of the Ntionl Institute of Dibetes nd Digestive nd Kidney Diseses. Study Cohort nd Design This ws retrospective follow-up study of hemodilysis ptients dilyzing between 2007 nd Two seprte studies were undertken: n nlysis of the frequency of hyperklemi nd n nlysis of the ssocition of hyperklemi with deth. Hyperklemi Prevlence Anlysis We identified yerly cohorts ( ) of prevlent hemodilysis ptients ged 18 yers who were continuously enrolled in Medicre prts A nd B from July 1 of the preceding yer through Jnury 31 of the cohort yer, received t lest 6 hemodilysis tretment sessions in December of the preceding yer, hd t lest 1 recorded serum potssium mesurement in Jnury of the cohort yer nd hd non-missing dilyste potssium concentrtion records for hemodilysis tretments received in December of the preceding yer. The index exposure ws the first serum potssium vlue in Jnury of the cohort yer. Exclusion criteri included fewer thn 6 hemodilysis sessions in December of the preceding yer, chnge in prescribed dilyste potssium concentrtion between December 1 of the preceding yer nd the dte of the index exposure in Jnury of the cohort yer, nd bsence of stble thrice-weekly hemodilysis schedule. On monthly bsis, hyperklemi ws defined s serum potssium concentrtion 5.5 meq/l. Blood smples were drwn during routine hemodilysis sessions t the LDO nd were mesured in centrl lbortory within 24 h. Blood drws for serum potssium mesurements typiclly occur once monthly but cn occur more frequently. If multiple mesurements occurred in ny given month, hyperklemi ws determined using the record with the highest serum potssium concentrtion. Hyperklemi prevlence ws clculted s the cumultive number of monthly episodes divided by cumultive follow-up time in months nd expressed s number of high-potssium events per 100 ptient-months. Hyperklemi prevlence ws lso reported seprtely by long nd short interdilytic intervl. The hemodilysis schedule ws defined s Mondy-Wednesdy-Fridy (MWF) or Tuesdy-Thursdy-Sturdy (TThS). The dy fter the long 3-dy intervl between sessions (long interdilytic intervl) ws defined s Mondy for ptients on MWF schedule nd s Tuesdy for ptients on TThS schedule [8]. Thus, for ptients on MWF schedule, hyperklemi events occurring on Mondy were ttributed to long interdilytic intervl, nd on other dys to the short interdilytic intervl; Tuesdy ws treted nlogously. Mortlity Anlyses These nlyses were limited to ptients included in the 2010 cohort. We defined hyperklemic events s episodes of hyperklemi scertined from mesured serum potssium lbortory vlues; we used severl definitions of hyperklemi, s described below. The key exposure vrible in these nlyses ws determined from monthly serum potssium mesurements; the index dte for ech ptient ws the dte of the first serum potssium mesurement in 180 Yusuf/Hu/Singh/Menoyo/Wetmore

3 Jnury Ptients were followed from the index dte until the erliest of deth, kidney trnsplnt, chnge in dilysis modlity, chnge in dilyste potssium concentrtion, discontinution of Medicre enrollment, loss to follow-up or December 31, 2010 (study end). Becuse ech ptient could (nd lmost lwys did) hve multiple exposure ssessments during the follow-up period, the exposure vrible (hyperklemic event) ws opertionlized s dichotomous, time-vrying (monthly) covrite with 2 levels (high versus norml serum potssium level), defined, sequentilly, by serum potssium levels of meq/l t successive 0.1 meq/l intervls. Covrites Demogrphic nd clinicl vribles were drwn from the Centers for Medicre nd Medicid Services (CMS) Medicl Evidence Report (form CMS-2728) completed upon dilysis initition nd supplemented by Medicre clims. Vribles included ge, sex, rce by ethnicity, body mss index, cuse of ESRD nd comorbid conditions. Initil conditions exmined were dibetes, coronry rtery disese, congestive hert filure, cerebrovsculr disese nd peripherl vsculr disese. Comorbid conditions from Medicre clims were defined during the 6-month bseline period (defined s the 6 months preceding the first index dte). For ech comorbid condition, we required the presence of 1 inptient code or 2 outptient codes [25, 26]. Cumultive number of hospitlized dys ws determined from hospitl inptient clims during the bseline period. Dilyste potssium concentrtion ws identified from records of dilysis tretments received in December Cuse of deth ws defined using the ESRD Deth Notifiction (form CMS-2746). Sttisticl Anlysis Ptient chrcteristics cross cohort yers were exmined using descriptive sttistics for continuous nd ctegoricl vribles. We reported prevlence rtes of hyperklemi overll nd strtified by interdilytic intervl for ech cohort yer. To exmine the ssocition between hyperklemic events nd outcomes of interest (ll-cuse nd crdiovsculr-specific deth, seprtely), we used time-dependent Cox proportionl hzrds regression [27]. We creted multiple records for ech ptient, corresponding to the distinct time intervls between scertinment of consecutive hyperklemic events. Ech such distinct intervl represented time during which ptient ws continuously t risk for the outcome event, nd events could occur only t the end of the intervl. We djusted the regression models for the bove mentioned covrites, nd for hemodilysis ccess type, totl hospitliztion dys during the bseline period, nd dilyste potssium concentrtion. We pplied to nd received pprovl from the Humn Subjects Reserch Committee of the Hennepin County Medicl Center/ Hennepin Helthcre System, Inc. Results Medicre s primry pyer (N (N potssium dilyste bth prescription, nd did not hve thrice (N 2007 = 46,746 N 2009 Study popultion N Fig. 1. Smple size of study cohorts, with itertive ppliction of inclusion nd exclusion criteri. Cohort Chrcteristics For cohort yers 2007 through 2010, we identified 28,774 36,888 hemodilysis ptients, fter ppliction of inclusion nd exclusion criteri ( fig. 1 ). Men ge ws pproximtely 63 yers; slightly more thn hlf of ptients were white nd pproximtely 56% were men ( tble 1 ). Men dilysis durtion ws bout 5 yers. The most common primry cuse of ESRD ws dibetes, t pproximtely 44%. Nerly two-thirds ( %) of ptients were on MWF hemodilysis schedule. The proportions of ptients with potssium bth 3.0 meq/l decresed from 2007 to 2010, from 17.8 to 11.7%. The proportion on low potssium bths (<2.0 meq/l) lso decresed, from 14.8 to 10.7%. A potssium bth concentrtion of 2 <3 meq/l ws the most common in ech yer studied. Hyperklemi Prevlence Overll, hyperklemi prevlence ws consistent t events per 100 ptient-months ( tble 2 ). Prevlence of hyperklemi on the dy fter the long interdilytic intervl ws per 100 ptient-months. In contrst, prevlence on the dy fter the short interdilytic intervl ws per 100 ptient-months. Hyperklemi ws times more likely on the dy fter the long interdilytic intervl thn on the dy fter the short intervl. Becuse few hyperklemi events were recorded on dys without dilysis, hyperklemi prevlence on those dys ws negligible ( per 100 ptientmonths). Serum Potssium nd Mortlity in Hemodilysis 181

4 Tble 1. Chrcteristics of nnul cohorts of hemodilysis ptients Cohort yer Cohort size, n 28,774 34,788 34,571 36,888 Age, yers, men ± SD 62.8± ± ± ±14.6 Age, yers, % Femle, % Rce, % White Blck Other Dilysis durtion, yers, men ± SD 5.0± ± ± ±4.7 Primry cuse of ESRD, % Dibetes Hypertension Glomerulonephritis Other cuse Access type, % Arteriovenous fistul Grft Ctheter Other/unknown Body mss index, kg/m 2, men ± SD 28.3± ± ± ±7.2 < < < Hospitlized b, % Cumultive hospitl dys c, men ± SD 11.7± ± ± ±12.1 Comorbid conditions d, % Atherosclerotic hert disese Congestive hert filure Cerebrovsculr ccident Peripherl vsculr disese Other crdic disese COPD Gstrointestinl disorders Liver disese Dysrhythmi Cncer Dibetes Weekly dilysis schedule d, % TThS MWF Dilyste potssium bth d, meq/l, % < < On index dte. b Accessed during the 180 dys before the index dte. c For hospitlized ptients. d Accessed from clims during the 6 months preceding the index dte. COPD = Chronic obstructive pulmonry disese. 182 Yusuf/Hu/Singh/Menoyo/Wetmore

5 Tble 2. Prevlence of hyperklemi episodes per 100 ptient-months in hemodilysis ptients Hyperklemi episodes interdilytic intervl overll long b short c number of events follow-up time, months rte (95% CI) d number of events follow-up time, months rte (95% CI) d number of events follow-up time, months rte (95% CI) d , , ( ) 11,358 19, ( ) 11,153 38, ( ) , , ( ) 14,610 23, ( ) 12,988 47, ( ) , , ( ) 15,275 24, ( ) 12,749 48, ( ) , , ( ) 14,338 23, ( ) 12,204 46, ( ) Hyperklemi episode ws defined s serum potssium concentrtion 5.5 meq/l, nd ws ccessed on monthly bsis. b Clculted bsed on hyperklemi episodes identified on the dy fter the long interdilytic intervl. c Clculted bsed on hyperklemi episodes identified on the dy fter the short interdilytic intervl. d Rte of hyperklemi ws computed s rtio of totl number of hyperklemi episodes nd cumultive follow-up time; 95% CI for the rtes of hyperklemi were clculted bsed on norml pproximtion. Tble 3. Assocition between elevted serum levels nd ll-cuse nd crdiovsculr-specific mortlity in hemodilysis ptients Serum K thresholds defining hyperklemi, meq/l All-cuse mortlity Crdiovsculr-specific mortlity undjusted djusted undjusted djusted HR (95% CI) b p vlue HR (95% CI) b p vlue HR (95% CI) b p vlue HR (95% CI) b p vlue ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) < ( ) < ( ) ( ) ( ) < ( ) < ( ) ( ) 0.06 Adjusted for ge, sex, rce, dilysis durtion, primry cuse of ESRD, dilysis ccess type, body mss index, bseline cumultive hospitl dys, bseline crdiovsculr hospitliztion, dilyste potssium bth nd comorbid conditions. b Corresponds to the mortlity risk for elevted serum potssium reltive to norml potssium in hemodilysis ptients. For exmple, for serum K threshold of 5.5, comprison groups re those with serum K 5.5 vs. <5.5. Similrly, for serum K threshold of 5.6 meq/l, comprison groups re those with serum K 5.6 vs. <5.6. K = Potssium. Hyperklemi prevlence ppered to decrese with ge; for exmple, in 2010, 18.7 events per 100 ptientmonths occurred mong ptients ged yers nd 12.6 mong those ged 75 yers (online suppl. tble S1; for ll online suppl. mteril, see doi/ / ). Hyperklemi ws more frequent in white thn in blck ptients (18.9 vs per 100 ptient-months) nd in ptients on low potssium dilyste bths (<2 meq/l), nd incresed with dilysis durtion. Mortlity Anlysis During men follow-up of 273 ± 113 dys (equivlent to 0.75 ± 0.31 yers), 10.2% of ptients (n = 3,753) died, 43.1% (4.3% of the totl, n = 1,604) from crdiovsculr cuses. Censoring occurred for 1 ptient who underwent kidney trnsplnt, 2.9% (n = 1,082) who chnged dilysis modlity, 7.7% (n = 2,832) who discontinued Medicre enrollment nd 23.4% (n = 8,633) who chnged dilyste potssium concentrtion; 55.8% (n = 20,587) were censored live t study end. All-cuse mortlity hzrd rtios (HRs) for high reltive to norml potssium when hyperklemi ws defined s serum potssium level of 5.5 meq/l were 1.00 (95% CI ) nd 0.99 (95% CI ) in undjusted nd djusted nlyses, respectively ( tble 3 ). As the serum potssium concentrtion threshold for defining hyperklemi incresed by 0.1 meq/l increments, the undjusted nd djusted HRs (AHRs) for ll-cuse mortlity, which Serum Potssium nd Mortlity in Hemodilysis 183

6 remined generlly similr to ech other throughout, incresed monotoniclly in both undjusted nd djusted models. The AHR for ll-cuse mortlity becme sttisticlly significnt when hyperklemi ws defined s serum potssium 5.7 meq/l (1.13, 95% CI , p = 0.04), incresing to 1.29 (95% CI , p < 0.001) t 5.9 meq/l nd 1.37 (95% CI , p < 0.001) t 6.0 meq/l. As serum potssium concentrtion thresholds for defining hyperklemi incresed by 0.1 meq/l increments, undjusted nd AHRs for crdiovsculr mortlity, which lso remined generlly similr to ech other throughout, incresed monotoniclly in undjusted nd djusted models ( tble 3 ). The undjusted HR for crdiovsculr mortlity becme sttisticlly significnt when hyperklemi ws defined s serum potssium 6.0 meq/l (1.29, 95% CI , p = 0.04). Online supplementry tbles S2 nd S3 show full results of the djusted models. Discussion Despite substntil improvement in the men lifespn of ptients receiving mintennce hemodilysis [28], sudden deth, most of which is thought be rrhythmic in nture, remins mjor thret [29, 30]. Accordingly, previous studies hve ttempted to link hyperklemi to sudden crdic deth directly [13 15] or circumstntilly, but compellingly, vi the interdilytic intervl [8, 31]. To better understnd this phenomenon nd to fill gps in the puttive chin of cuslity, we investigted severl different but relted issues. We sought to determine whether there ws evidence of grded ssocition between serum potssium level nd mortlity, nd to scertin whether potssium levels my be higher fter the long interdilytic intervl. We found tht incresed serum potssium levels were, s expected, ssocited with incresed risk of ll-cuse mortlity with 5.7 meq/l s criticl threshold, nd tht hyperklemi ppered to be substntilly more common fter the long interdilytic intervl. These findings, in conjunction with previous work [8, 13 15, 31], suggest tht hyperklemi my be the mechnism by which the long interdilytic intervl is ssocited with deth. While previous observtionl studies hve demonstrted tht hyperklemi is ssocited with mortlity, vrious definitions of hyperklemi hve been employed. For exmple, Iseki et l. [15] defined hyperklemi s serum potssium concentrtion of 5.5 meq/l nd reported incresed risk of deth reltive to bseline concentrtion of <3.5 meq/l. Kovesdy et l. [14], in lrge observtionl study of contemporry cohort of hemodilysis ptients, showed tht serum potssium concentrtion of 5.6 meq/l ws ssocited with incresed risk of ll-cuse nd crdiovsculr deth. In n investigtion of crdic rrest nd sudden deth in dilysis units, Krnik et l. [11] defined hyperklemi s serum potssium 6.0 meq/l. The present study, which sought to determine the nture of the reltionship between serum potssium level nd risk of deth, enriches this understnding nd therefore could hve both prcticl nd theoreticl relevnce. In our study popultion, we identified grded ssocition between hyperklemi nd mortlity nd found tht the risk becomes sttisticlly significnt t potssium level of pproximtely 5.7 meq/l. This my hve clinicl implictions, s it could be threshold t which clinicins should consider tking ction or t which protocols designed to sfegurd ptients could be employed. The grded ssocition lso estblishes the gin in the clinicl signl, permitting pproximte quntifiction of the incresed risk ssocited with, for exmple, serum potssium level of 6.0 meq/l compred with norml level. This ssocition could lso inform the design of clinicl trils testing interventions on hyperklemi, nd permit initil inferences to be mde on tril effect sizes nd power. The finding tht hyperklemi becomes mrkedly more common fter the long interdilytic intervl, while not intuitively surprising, hs not, to our knowledge, been conclusively demonstrted. This finding lso hs both clinicl nd theoreticl implictions. It suggests tht interventions to prevent hyperklemi nd resultnt sudden crdic deth might most ppropritely be employed if the interdilytic intervl is expected to be longer thn 48 h. It lso provides n estimte of how hyperklemi occurrence could be reduced if ll interdilytic intervls were reduced to 48 h or less. From theoreticl perspective, it helps estblish puttive link between hyperklemi nd the incresed risk of deth ssocited with the long interdilytic intervl [8, 26]. We found no ssocition between hyperklemi nd crdiovsculr mortlity. This ws unexpected becuse hyperklemi cn induce life-thretening crdic electrophysiologic ltertions [32]. Indeed, severl studies hve reported n ssocition between hyperklemi nd incresed risk of lethl crdic rrhythmis in dilysis ptients [13, 14]. However, this phenomenon is not uncommon in observtionl studies [33]. One possible explntion is misclssifiction: crdiovsculr events s cuses of deth re not djudicted by the USRDS, our source of 184 Yusuf/Hu/Singh/Menoyo/Wetmore

7 dt. Importntly, however, the pttern of point estimtes for crdiovsculr mortlity closely mirrored the pttern for ll-cuse mortlity, suggesting tht the reson for lck of sttisticl significnce my hve been power. Our study hs importnt limittions. First, becuse we used retrospective observtionl design, ssocitions cn never be determined to be cusl. Additionlly, s with ll observtionl studies, confounding is likely to be present. While we considered nd djusted for select known confounders (e.g., demogrphic fctors, clinicl fctors such s comorbid conditions nd tretment fctors such s dilyste potssium bth), we were unble to ccount for unknown nd unmesured fctors tht my predispose ptients to dverse clinicl outcomes. However, it is ressuring tht the djustments mde ttenuted the observed effect estimtes only modestly, suggesting the firly robust findings. Additionlly, we did not seek to model fctors ssocited with hyperklemi, which would be n importnt exercise for generting hypotheses bout fctors tht could be trgeted for potentil interventions. In conclusion, we found tht hyperklemi ws ssocited with n incresed risk of ll-cuse mortlity fter djustment for other fctors, but not crdiovsculr-relted mortlity. The threshold nlysis, in which successively greter serum potssium thresholds were used, reveled reltively constnt ordinl increse in risk nd demonstrted sttisticl significnce t potssium level of 5.7 meq/l. Tht the threshold of hyperklemi ssocited with mortlity ws reltively high my be due to dptive mechnisms present in mintennce hemodilysis ptients, mny of whom seem ble to tolerte higher potssium levels thn individuls with intct kidney function. The long interdilytic intervl ws ssocited with substntilly greter likelihood of hyperklemi thn the short intervl, strengthening the cse tht hyperklemi is the mechnism by which the long interdilytic intervl is ssocited with mortlity. These findings rise the possibility tht improved mngement of hyperklemi in ptients receiving hemodilysis my led to reduced mortlity, prticulrly during the long interdilytic intervl. Future work studying how hyperklemi, potssium vribility nd chnges in potssium levels contribute to mortlity, especilly sudden crdic deth, is needed. Acknowledgments The uthors thnk Chronic Disese Reserch Group collegue Nn Booth, MSW, MPH, ELS, for mnuscript editing. The uthors lso thnk Alex Yng, MD, for helpful discussions bout the project. Disclosure Sttement This work ws supported by grnt from ZS Phrm Inc., Sn Mteo, Clif., USA. The interprettion nd reporting of these dt re the responsibility of the uthors, who retin finl uthority over mnuscript content. Dr. A.A. Yusuf, Ms. Y. 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