Does Renal Dysfunction Predict Mortality After Acute Stroke? A 7-Year Follow-Up Study

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1 Does Real Dysfuctio Predict Mortality After Acute Stroke? A 7-Year Follow-Up Study Roald S. MacWalter, FRCP; Suzae Y.S. Wog, MRCP; Keeth Y.K. Wog, MRCP; Graham Stewart, MRCP; Callum G. Fraser, PhD; Hazel W. Fraser, RGN; Yuksel Ersoy, MD; Simo A. Ogsto, PhD; Roulig Che, PhD Dowloaded from by o Jauary 18, 2019 Backgroud ad Purpose The purpose of this study was to ivestigate real fuctio as a log-term predictor of mortality i patiets hospitalized for acute stroke. Methods This was a cohort study doe i a Scottish tertiary teachig hospital. Participats icluded 2042 (993 male) uselected cosecutive stroke patiets (mea age, 73 years) admitted to hospital withi 48 hours of stroke betwee1988 ad Follow-up was up to 7 years. Mai outcome measure was all-cause mortality. Results The total umber of deaths at the ed of follow-up was Most subjects (1512) had creatiie 124 mol/l. The mea calculated creatiie clearace was 54.8 ml/mi (SD, 23 ml/mi). Real fuctio idexes were aalyzed by quartiles with Cox proportioal-hazards model. Stroke survivors had higher calculated creatiie clearace ad lower serum creatiie, urea, ad ratios of urea to creatiie. Calculated creatiie clearace ml/mi sigificatly predicted better log-term survival i these stroke patiets eve after adjustmet for cofouders (age, eurological score, ischemic heart disease, hypertesio, smokig, ad diuretic use). Similarly, creatiie 119 mol/l [relative risk (RR), 1.59; 95% cofidece iterval (CI), 1.32 to 1.92], urea 6.8 to 8.9 mmol/l (RR, 1.34; 95% CI, 1.09 to 1.65) or 9 mmol/l (RR, 1.74; 95% CI, 1.42 to 2.13), ad ratio of urea to creatiie mmol/ mol (RR, 1.24; 95% CI, 1.03 to 1.50) remaied sigificat predictors of mortality after adjustmet for cofouders. Coclusios After acute stroke, patiets with reduced admissio calculated creatiie clearace, raised serum creatiie ad urea cocetratios (eve withi covetioal referece itervals), ad raised ratio of urea to creatiie had a higher mortality risk. This fidig may be used to stratify risk ad target itervetios, eg, the use of agiotesi-covertig ezyme ihibitors. (Stroke. 2002;33: ) Key Words: cerebrovascular disorders creatiie kidey fuctio tests mortality progosis real disease, ed-stage stroke urea Real dysfuctio, eve to a subtle degree, has bee oted to be a progostic idicator of overall mortality i the presece of comorbidities such as diabetes. 1 Real fuctio has proved to be progostic i may patiets groups. Raised urea cocetratio predicted mortality i patiets with peumoia ad gastroitestial bleedig ad after coroary artery bypass graft. 2 Creatiie cocetratio amog cohorts of post myocardial ifarctio survivors 3 ad hypertesive patiets 4 also predicted mortality. More recetly, calculated creatiie clearace has bee show to be a idepedet predictor of morbidity ad mortality i patiets with left vetricular dysfuctio 5,6 ad amog patiets admitted to a coroary care uit. 7 The latter cohort had a graded icrease i the relative risk of cardiac problems ad earlier mortality i patiets with decreasig real fuctio. 7 A associatio betwee real fuctio ad stroke has previously bee oted i a study desiged to assess the relatioship betwee hypertesio ad fatality rates ad its determiats i black patiets with recet stroke. Survivors of acute stroke had lower plasma urea o admissio tha those who died. 8 Friedma 9 foud that amog stroke survivors (mea age, years) i New Zealad, serum creatiie cocetratio idepedetly predicted mortality eve after adjustmet for cofouders. However, more direct measures of real fuctio were ot doe (eg, creatiie clearace), ad that study was small, ivolvig 492 patiets followed up for a mea of oly 18 moths. Received December 13, 2001; fial revisio received February 4, 2002; accepted February 14, From the Departmet of Medicie (R.S.M., G.S., H.W.F.), Departmet of Cliical Pharmacology ad Therapeutics (S.Y.S.W., K.Y.K.W.), Departmet of Biochemical Medicie (C.G.F.), Departmet of Epidemiology ad Public Health (S.A.O.), ad Cardiovascular Epidemiology Uit (R.C.), Niewells Hospital ad Medical School, Dudee, Scotlad, ad Departmet of Physical Medicie ad Rehabilitatio, Iou Uiversity Faculty of Medicie, Turgut Ozal Medical Cetre, Malatya, Turkey (Y.E.). Correspodece to Dr R.S. MacWalter, Cosultat Physicia, Stroke Studies Cetre, Departmet of Medicie, Niewells Hospital ad Medical School, Dudee, Scotlad DD1 9SY. roald.macwalter@tuht.scot.hs.uk 2002 America Heart Associatio, Ic. Stroke is available at DOI: /01.STR F7 1630

2 MacWalter et al Real Dysfuctio ad Log-Term Mortality i Stroke 1631 TABLE 1. Cohort Baselie Characteristics ad Comorbidities Male Female Total Alive at Dead at Alive at Dead at Alive at Dead at Characteristic Follow-Up Follow-Up Follow-Up Follow-Up Follow-Up Follow-Up Age (SD), y 66.6 (11.3) 74.5 (8.6) 72.6 (10.9) 79.0 (8.8) 70.0 (11.5) 76.9 (9.0) Creatiie clearace (SD), ml/mi 64.3 (22.2) 50.0 (19.1) 55.6 (25.9) 42.6 (16.0) 60.1 (24.4) 46.2 (17.9) Serum creatiie (SD), mol/l (26.1) (67.4) 95.5 (45.5) (46.9) 98.9 (37.3) (58) Serum urea (SD), mmol/l 6.3 (2.3) 8.6 (5.5) 7.3 (4.2) 8.9 (4.3) 6.8 (3.4) 8.8 (4.9) Ratio of urea to creatiie (SD), mmol mol (0.02) (0.02) (0.03) (0.04) 0.07 (0.03) 0.08 (0.03) Neurological score (SD) 67 (27) 48 (32) 67 (26) 39 (29) 70 (27) 43 (31) Presece of IHD, (%) 158 (16) 163 (16) 128 (12) 167 (16) 286 (14) 330 (16) Peripheral vascular disease, (%) 55 (5.5) 53 (5.3) 29 (2.8) 42 (4) 84 (4.1) 95 (4.7) Previous TIA, (%) 55 (5.5) 46 (4.6) 32 (3.1) 49 (4.7) 87 (4.3) 95 (4.7) Previous stroke, (%) 75 (7.6) 115 (12) 92 (8.8) 104 (9.9) 167 (8.2) 219 (11) Treated hypertesio, (%) 142 (14) 124 (12) 169 (16) 134 (12.8) 311 (15) 258 (13) Presece of atrial fibrillatio, (%) 23 (2.3) 26 (2.6) 23 (2.2) 48 (4.6) 46 (2.3) 74 (3.6) Kow diabetes, (%) 40 (4) 46 (4.6) 50 (4.8) 44 (4.2) 90 (4.4) 90 (4.4) Admissio glucose 6 mmol/l, (%) 160 (16) 160 (16) 177 (17) 201 (19) 337 (17) 361 (18) O diuretic o admissio, (%) 89 (9) 155 (16) 157 (15) 227 (22) 246 (12) 382 (19) Ex- or curret smoker, (%) 340 (34) 255 (23) 193 (18) 137 (13) 533 (26) 392 (19) IHD idicates ischemic heart disease; TIA, trasiet ischemic attack. Dowloaded from by o Jauary 18, 2019 I this study, we further ivestigated real fuctio as a log-term predictor of mortality with a large cohort of acute stroke patiets usig several markers of real fuctio obtaied o admissio to hospital. Subjects ad Methods The study was approved by the Tayside Committee o Medical Research Ethics ad was carried out at Niewells Hospital ad Medical School, a major teachig hospital i Scotlad. The study team saw 2042 uselected cosecutive patiets withi 48 hours of acute stroke betwee 1988 ad Iclusio Criteria All patiets had a cliical diagosis of stroke cofirmed i hospital ad were admitted to hospital withi 48 hours of symptom oset. Exclusio Criteria Patiets were excluded if they were already receivig dialysis for chroic real failure. Cliical Variables Details of patiet demography, eurological status ad disabilities, ad curret drug use were recorded. Other relevat cliical data, icludig ECG ad CT sca results, were also collected. Laboratory data, icludig serum urea, creatiie, ad glucose cocetratio o admissio, were collected with the use of a hospital database system. Estimates of real fuctio icluded serum urea ad creatiie cocetratios, calculated creatiie clearace, ad ratio of urea to creatiie. Creatiie clearace (ml/mi) was calculated by use of a recet versio of the Cockcroft-Gault equatio as follows 10 : (140 age) 2.12 weight (kg) k/(plasma creatiie BSA), where k 1 if male or 0.85 if female ad body surface area (BSA) is calculated as follows: BSA height (m) weight (kg) Outcomes The primary outcome was total death from ay cause durig the 7-year follow- up period (miimum, 1 year; maximum, 7 years). The certified cause of death was obtaied by record likage with data from the Registrar Geeral i Scotlad. The accuracy of this data has bee show to be 98%. 11 Statistical Aalysis Urea, creatiie cocetratio, ratio of urea to creatiie, ad creatiie clearace were all aalyzed after categorizatio ito quartile groups. Cox proportioal-hazards models were used to estimate the relative risk of mortality (RR) with adjustmet for age, eurological score, ad comorbidities, icludig ischemic heart disease (icludig previous acute myocardial ifarctio, admissio ischemic ECG, itrates amog their admissio medicatio), hypertesio, ad the use of a diuretic o admissio. RRs are give with 95% cofidece itervals (CIs). For cliical relevace, aalysis was repeated for creatiie as 124, 124 to 199, ad 200 mol/l. 12 Total ad subgroup survival was aalyzed by Kapla-Meier survival aalysis ad log-rak test; a log-rak value of P 0.05 was sigificat. SPSS was used for statistical aalyses. Results Durig the follow-up period, 1026 patiets died. Baselie characteristics of this cohort are described i Table 1. Most patiets i this cohort had ormal real fuctio o admissio accordig to creatiie cocetratio. The calculated creatiie clearace raged from 6 to 235 ml/mi. We foud that 1512 patiets had ormal real fuctio defied by serum creatiie 124 mol/l, 345 had mildly impaired real fuctio with creatiie 124 to 199 mol/l, ad 66 had cliically sigificatly impaired real fuctio with creatiie 200 mol/l. 12 This model showed that age, eurological score, real fuctio parameters o admissio (calculated creatiie clearace, creatiie ad urea cocetratios, ad ratio of urea to creatiie), presece of ischemic heart disease, ad use of diuretics were all sigificatly adversely associated with outcome after acute stroke. More iterestig is the

3 1632 Stroke Jue 2002 TABLE 2. Uadjusted ad Adjusted RR for Mortality Accordig to Real Idexes Dowloaded from by o Jauary 18, 2019 Real Idexes Uadjusted RR 95% CI Adjusted RR* 95% CI Adjusted RR 95% CI Adjusted RR 95% CI Creatiie clearace, ml/mi Creatiie, mol/l Urea, mmol/l Ratio of urea to creatiie, mmol mol *Adjusted for age; adjusted for age ad eurological score; adjusted for age, eurological score, presece of ischemic heart disease or hypertesio, smokig, ad diuretic use. fidig that real idexes remaied sigificat predictors of mortality after takig ito accout sigificat cofouders grouped as omodifiable risk factor (age), major eurological determiat (eurological score), ad modifiable risk factor (ischemic heart disease, treated hypertesio, smokig history, ad diuretic use; Table 2). Preserved creatiie clearace correlated with better survival, ad the secod quartile ( ml/mi) of creatiie clearace sigificatly predicted mortality eve after adjustmet for cofouders (Table 2). The Kapla-Meier curve shows the associatio of quartile groups of calculated creatiie clearace with mortality (the Figure). Similarly, after adjustmet for cofouders, creatiie above quartile 3 ( 119 mol/l) sigificatly predicted icreased mortality. Assessig creatiie groups 124 to 199 ad 200 mol/l ad comparig them with ormal levels ( 124 mol/l) showed that creatiie also remaied a sigificat predictor of log-term mortality after acute stroke (creatiie 124 to 199 mol/l: RR, 1.65; 95% CI, 1.41 to 1.93; creatiie 200 mol/l: RR, 1.63; 95% CI, 1.21 to 2.19). Urea above the media ( 6.8 mmol/l) also sigificatly predicted icreased mortality after acute stroke after adjustmet for all cofouders (Table 2). The highest quartile of the ratio of urea to creatiie ( mmol/ mol) sigificatly predicted death at follow-up (Table 2). Kow diabetes o admissio (RR, 1.03; 95% CI, 0.83 to 1.28) ad sex (RR, 0.91; 95% CI, 0.81 to 1.03) did ot sigificatly ifluece progosis. Real fuctio remaied highly sigificat i predictig mortality amog subgroups: those who died at 30 days compared with those who died at fial follow-up, those who had CT showig ischemic compared with hemorrhagic strokes, those with a first stroke compared with recurret strokes, ad stroke subtypes as classified by the Bamford 13 classificatio. Real fuctio was ot sigificat i predictig outcome i hemorrhagic strokes i which the umber of fatal evets was too small to achieve sigificace (Table 3). Kapla-Meier survival aalysis for calculated creatiie clearace o admissio amog stroke patiets (log-rak test, P ).

4 MacWalter et al Real Dysfuctio ad Log-Term Mortality i Stroke 1633 TABLE 3. Comparative Number of Evets i Each Quartile of Real Fuctio by Specified Subgroups Dowloaded from by o Jauary 18, 2019 Real Idexes Died at 30 d, Dead at Follow-Up, Ischemic Hemorrhagic First Recurret LACS, PACS/TACS, POCS, Creatiie clearace, ml/mi KM log rak NS Creatiie, mol/l KM log rak NS Urea, mmol/l KM log rak Ratio of urea to creatiie, mmol mol 1 L KM log rak NS NS LACS idicates lacuar stroke; PACS, partial aterior circulatio stroke; TACS, total aterior circulatio stroke; POCS, posterior circulatio stroke; ad KM, Kapla-Meier aalysis. Discussio The progostic value of real dysfuctio has bee see i may other patiet groups. 1 7 This prospective, log-term study demostrated that admissio real fuctio as assessed by calculated creatiie clearace, serum cocetratio of creatiie, urea, ad ratio of urea to creatiie all predicted mortality eve whe values were withi covetioal ormal referece itervals. This is cosistet with the previous icidetal fidigs that survivors of acute stroke had a lower urea cocetratio o admissio 8 ad that creatiie cocetratio had progostic value 9 eve withi covetioal populatio-based referece itervals. 14 Stroke outcome i the first 30 days is determied largely by age, level of cosciousess, ad type of stroke. Comorbidities such as diabetes mellitus or hyperglycaemia o admissio, 15 cardiovascular disease, icludig cogestive heart failure, ad hypertesio also predicted a elevated mortality i stroke patiets i loger-term follow-up. 15,16 I this study, we cofirmed that age was a profoud log-term predictor of death after stroke. Patiets 85 years of age were 8 times more likely to die compared with a patiet with a stroke at 59 years of age. This probably suggests frailty ad a higher burde of chroic disorders i those with advacig age ( 80 years of age) i whom the most frequet coditios ted to be heart failure, chroic obstructive pulmoary disease, stroke, ad peumoia. 17 Similarly, the major eurological determiat of outcome, eurological score o admissio, sigificatly predicted log-term mortality. I the Oxford Commuity Stroke Project, log-term stroke survivors of 30 days had a icreased risk of dyig over the ext few years compared with the geeral populatio. The cause of death durig the first 30 days after stroke was stroke-related complicatios (eg, peumoia). Nostroke cardiovascular disease becomes the most commo cause of death after the first year. 16 Real failure was a very rare primary cause of death i our cohort. However, real dysfuctio was a sigificat predictor of icreased mortality i both the short ad log term. The degree of real dysfuctio preset i these stroke patiets may simply be a marker of ed-orga damage from udetected preexistig utreated hypertesio, eg, left vetricular hypertrophy, a potet predictor of mortality. 18 Real dysfuctio may also idicate a higher comorbidity burde, especially atherosclerotic disease. Ideed, a prospective geeral populatio study of British me who were

5 1634 Stroke Jue 2002 Dowloaded from by o Jauary 18, 2019 followed up for 14 years foud that high serum creatiie, eve withi the referece iterval, was a marker for icreased risk of cerebrovascular disease amog both the ormotesive ad hypertesive populatio. 14 Our results are cosistet with aalyses of the Heart Outcomes ad Prevetio Evaluatio (HOPE) 12 ad Hypertesio Optimal Treatmet (HOT) 19 studies i which mild real impairmet idepedetly predicted icreased cardiovascular mortality, total mortality, ad icidece of myocardial ifarctio ad stroke i their cohort of high-cardiovascular-risk ad hypertesive patiets. Coversely, real dysfuctio may correlate with edothelial dysfuctio because patiets with ed-stage real disease have icreased arterial stiffess idepedet of other risk factors for atherosclerosis. Eve amog patiets with mild to moderate real isufficiecy, there was icreased cetral artery stiffess, suggestig that real dysfuctio adversely affected small ad large arteries, 20 which may cotribute to cardiovascular morbidity ad mortality. This study demostrated that real dysfuctio predicted log-term mortality ad therefore ca be used to stratify risk for stroke patiets. A stroke maagemet guidelie has already suggested that urea ad creatiie measuremets are importat i the acute situatio. 21 I stroke patiets, whether the outcome improves with itervetio to lower urea ad creatiie is ot yet kow. I this cohort of patiets, maagemet was routiely itraveous fluid replacemet therapy ad early asogastric feedig. Although a disproportioally high urea to creatiie ratio may reflect dehydratio, that ratio i fact predicted mortality throughout the rage of results. A subgroup aalysis i the HOPE study comparig patiets with mild real impairmet with those with ormal real fuctio showed they were more likely to have cardiovascular evets ad die eve after adjustmet for other cardiovascular risk factors ad treatmets. Ramipril decreased the hazard ratio for these ed poits i both groups. 12 The use of agiotesi-covertig ezyme ihibitors i highcardiovascular-risk patiets (eg, previous stroke) is further supported by the results of the Peridopril Protectio Agaist Recurret Stroke (PROGRESS) study, which showed that blood pressure lowerig was importat i secodary prevetio. 22 Glomerular filtratio rate is the gold stadard for measurig real fuctio. Serum creatiie cocetratio is widely iterpreted as a measure of the glomerular filtratio rate ad is used as a idex of real fuctio i cliical practice, which is far easier tha ad as accurate a guide to glomerular filtratio rate as 24-hour urie collectio i patiets with stable real fuctio. 23 The glomerular filtratio of creatiie, however, is oly oe of the variables that determie its cocetratio i the serum, which could be altered by icreasig age (chage i real hadlig), diabetes, real failure, creatiie metabolism, ad methodological iterferece i its measuremet. More accurate measures of real fuctio are frequetly ecessary. More specific measures of real fuctio other tha glomerular filtratio rate such as serum cystati C 10 could be used i the future to assess more itimately the relatioship betwee real dysfuctio ad morbidity or mortality i patiets who with stroke. A limitatio of our study is that commuity hospital or home-treated stroke patiets were aturally excluded from the study. These patiets are likely to have had less severe strokes, ad it is ot certai whether real dysfuctio i this group will similarly predict mortality. Raised admissio urea ad creatiie cocetratios eve withi covetioal referece itervals, raised ratio of urea to creatiie, ad decreased calculated creatiie clearace i patiets with acute stroke predicted log-term mortality idepedetly of age, eurological score, ischemic heart disease, hypertesio, smokig, ad diuretic use. Real dysfuctio therefore ca help stratify risk i stroke patiets for further itervetios such as cardiovascular ivestigatios or use of agiotesi-covertig ezyme ihibitor i the absece of cotraidicatios. Ackowledgmets Fudig for this study was provided by Tayside Health Board, Tayside Uiversity Hospitals NHS Trust, ad Uiversity of Dudee. S.Y.S.W. is supported by a educatioal grat from Pharmacia; K.Y.K.W., by the British Heart Foudatio. We thak S. 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