European Journal of Internal Medicine

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1 Europen Journl of Internl Medicine 22 (2011) Contents lists vilble t ScienceDirect Europen Journl of Internl Medicine journl homepge: Originl rticle Incidence of cute kidney injury in cncer ptients: A Dnish popultion-bsed cohort study Christin Fynbo Christinsen,, Mrtin Berg Johnsen, Wendy J. Lngeberg b, Jon P. Fryzek b, Henrik Toft Sørensen Deprtment of Clinicl Epidemiology, the Clinicl Institute, Arhus University Hospitl, Olof Plmes Alle 43-45, 8200 Arhus N, Denmrk b Center for Observtionl Reserch, Amgen, One Amgen Center Drive, Thousnd Oks, CA , USA rticle info bstrct Article history: Received 4 Februry 2011 Received in revised form 8 My 2011 Accepted 11 My 2011 Avilble online 8 June 2011 Keywords: Cncer Acute kidney injury Epidemiology Risk Incidence Comorbidity Bckground: Cncer ptients my be t incresed risk of cute kidney injury, but evidence is limited. Methods: We ssembled cohort of incident cncer ptients dignosed within popultion-bsed hospitl setting in Northern Denmrk (popultion:~1.2 million) between 1999 nd Ptients were followed up to five yers for cute kidney injury, identified using cretinine mesurements recorded in lbortory dtbse covering the study re. Acute kidney injury ws defined ccording to recent consensus criteri s 50% increse in cretinine level. We computed incidence rte, 1-yer, nd 5-yer risks of cute kidney injury, ccounting for competing risk from deth. Acute kidney injury incidence ws compred between cncers using Cox regression model djusted for importnt confounders. Results: Among 37,267 incident cncer ptients with cretinine mesurement, 9613 (25.8%) developed cute kidney injury during 77,376 person-yers. The incidence ws 258 (95%CI: ) per 1000 personyers the first yer fter cncer dignosis decresing to 43 (95%CI: 41 44) therefter. The 1-yer risk ws 17.5% (95%CI: %), nd the 5-yer risk ws 27.0% (95%CI: %). We observed the highest 1-yer risk in ptients with kidney cncer [44.0% (95%CI: )], liver cncer [33.0% (95%CI: %)], or multiple myelom [31.8% (95%CI: %)]. Similr results were observed fter djustment for confounders. Both overll nd for most specific cncer sites, risks were higher mong ptients with distnt metstses t cncer dignosis. Conclusion: Acute kidney injury is common compliction in cncer ptients, prticulrly in ptients with kidney cncer, liver cncer, or multiple myelom Europen Federtion of Internl Medicine. Published by Elsevier B.V. All rights reserved. 1. Introduction Cncer ptients my be t incresed risk of cute kidney injury (AKI) due to mlignnt infiltrtion, tumor lysis syndrome, urinry trct obstruction, sepsis, rdiotherpy, or use of nephrotoxic drugs [1 3]. In ddition, common comorbidities to cncer such s chronic kidney disese, congestive hert filure, hypertension, dibetes, nd liver disese my increse risk. Use of nonsteroidl nti-inflmmtory drugs (NSAIDs) is lso risk fctor [4 6]. The few previous studies describing AKI mong newly dignosed cncer ptients were restricted to ptients with multiple myelom [7 9], leukemi [10 13], lymphom [11], nd renl metstses from solid tumors [14,15]. Limittions of these studies include smll study size (n=1 to 775), lck of covrite informtion, dt collection t single referrl center [9,11], combintion of selected cohorts from rndomized studies [7], restriction to ptients with prevlent AKI t Corresponding uthor. Tel.: ; fx: E-mil ddress: cc@dce.u.dk (C.F. Christinsen). cncer dignosis [7,8], nd restriction to decesed ptients [10]. Only one of the studies used the recent consensus definition of AKI [13]. It hs been reported tht AKI confers 3-month mortlity of more thn 30% [1] nd 6-month mortlity s high s 73% in criticlly ill cncer ptients [16]. Furthermore, dignosis of AKI nd ssocited poor renl functioning my reduce the likelihood tht cncer ptients receive optiml therpeutic mngement nd supportive cre [1]. For these resons, reserch is needed to understnd nd potentilly prevent cute kidney injury in cncer ptients. This study exmined the incidence of AKI in lrge cohort of ptients with incident cncer within popultion-bsed hospitl setting, nd ddressed the impct of cncer site nd stge. Welldefined consensus criteri, the RIFLE criteri [17], were used to mesure renl function. 2. Ptients nd methods We conducted this cohort study in Northern Denmrk, with popultion of 1.2 million people (pproximtely 21% of the Dnish Popultion) [18] /$ see front mtter 2011 Europen Federtion of Internl Medicine. Published by Elsevier B.V. All rights reserved. doi: /j.ejim

2 400 C.F. Christinsen et l. / Europen Journl of Internl Medicine 22 (2011) Cncer ptients The study cohort included ll ptients with n incident cncer dignosis between Jnury 1, 1999 nd December 31, 2006, who hd resided for t lest two yers in Northern Denmrk. Lbortory dtbses in the study region hd complete dt for the Jnury 1, 1997 December 31, 2007 period, i.e., for two yers before nd one yer fter the study period. Cncer ptients were identified from the Dnish Cncer Registry (DCR), which contins dt on ll incident cncer cses dignosed in Denmrk since The DCR hs been described previously [19,20]; briefly, it collects dt from registrtion forms completed by hospitls, pthology institutes, nd prcticing physicins. Since 2004, electronic dt from the Dnish Ntionl Ptient Registry (DNPR) nd the Ntionl Pthology Registry hve been included in the DCR. The DNPR covers ll Dnish hospitl contcts, including non-psychitric hospitliztions since 1977 nd emergency room nd outptient clinic visits since 1995 [21,22]. The DNPR contins informtion on ptients' civil registrtion number, tretment codes, nd up to 20 dischrge dignoses coded by physicins. Cncers re clssified ccording to the Dnish version of the Interntionl Clssifiction of Diseses, 10th revision (ICD-10) nd TNM-stging. Dt in the DCR hs been vlidted nd found to hve high level of completeness [19,20]. Ptients with precncerous lesions nd non-melnom skin cncer were excluded from the present study (ICD-10 codes: C44, D05, N87, D06, O01, D39.2, D45.9, D46, D47.1, D47.3) Acute kidney injury Incident AKI fter cncer dignosis ws ssessed using cretinine mesurements recorded in lbortory dtbses. These dtbses include the time nd result of ll nlyses performed in hospitl lbortories in the study region, including virtully ll plsm cretinine mesurements requested by generl prctices, outptient clinics, emergency rooms, nd hospitl deprtments. We used RIFLE consensus criteri to clssify AKI into the five severity ctegories: risk, injury, filure, loss, ndend-stge renl disese[23]. Cncer ptients with 50% increse in cretinine compred with their bseline levelwereconsideredtohveakiintherisk or higher ctegory. The ctegory injury corresponds to 2-fold incresed cretinine, nd filure to 3-fold incresed cretinine or cretinine 350 μmol/l with n cute rise 44 μmol/l [23]. The bseline level ws defined s the cretinine level mesured t dy of cncer dignosis or the most recent mesurement within one yer prior to the cncer dignosis. Ptients without bseline cretinine mesurement were nlyzed seprtely. In these ptients, renl function ws ssumed to be norml (Glomerulr Filtrtion Rte (GFR)=75 ml/min/1.73 m 2 ) nd the cretinine level ws estimted bsed on ge nd gender using the modifiction of the diet in renl disese (MDRD) formul [24,25]. We obtined dt on dilysis tretment from the DNPR nd defined loss s ny dilysis tretment between 30 nd 90 dys fter the criterion for AKI ws fulfilled. We defined end-stge renl disese s dilysis between 90 nd 365 dys fter AKI onset. Dt on deth before development of AKI were obtined from the Dnish Civil Registrtion System (CRS), which includes records of ll chnges in vitl sttus nd migrtion for the entire Dnish popultion, updted dily since 1968 [18] Previous cute kidney injury nd chronic kidney disese AKI within the yer before cncer dignosis ws ssessed ccording to the RIFLE criteri described bove. Dt on ny dignosis of chronic kidney disese in the five yers prior to cncer dignosis ws obtined from the DNPR Other predictors of AKI Chronic diseses, frilty, lifestyle fctors, nd drug use my increse the risk of AKI mong cncer ptients, nd thus ct s confounders [5]. We used the DNPR nd prescription dtbses in the study re to identify presence of chronic diseses nd ssocited drug use prior to cncer dignosis, including both estblished risk fctors for AKI nd diseses ssocited with lifestyle fctors such s smoking. All phrmcies in the region re equipped with electronic ccounting systems, estblished to ensure prtil reimbursement of prescription expenses from the Ntionl Helth Service [26]. The prescription dtbses contin informtion on customers' civil registrtion number, type nd mount of drugs prescribed (ccording to the Antomic Therpeutic Chemicl (ATC) clssifiction system), nd the prescription fill dtes. We used dt on prescriptions filled within five yers before cncer dignosis. We combined dignoses from the DNPR nd dt from the prescription dtbses to identify prevlent dibetes mellitus, hypertension, osteoporosis, nd dyslipidemi. We lso used the DNPR to obtin dt on ny dignosis, within five yers prior to cncer dignosis, of myocrdil infrction, congestive hert filure, peripherl vsculr disese, cerebrovsculr disese, hemiplegi, dementi, chronic pulmonry disese (COPD), connective tissue disese, peptic ulcer disese, nd mild nd moderte/severe liver disese. We lso obtined dt on ll prescriptions filled during the yer prior to cncer dignosis for potentilly nephrotoxic drugs including NSAIDs [27,28], cyclooxygense 2 receptor ntgonists (COX-2-I) [28], bisphosphontes [29], nd methotrexte [30] Follow-up Ptients were followed for up to five yers from the dte of their cncer dignosis through the development of AKI, emigrtion, deth or December 31, 2007, whichever cme first Sttistics Incidence rtes were estimted by dividing the number of incident AKI events by the person-yers (PY) t risk. PY t risk were defined s yers from the dte of cncer dignosis to the first occurrence of AKI, deth, or emigrtion. Incidence rtes (IRs) within the first yer nd in the second to fifth yers were clculted for ech cncer site nd cncer stge. We plotted the cumultive incidence curve for the AKI stges of risk, injury, nd filure for the 5-yer follow-up period. We computed the risk (cumultive incidence) of AKI 1 nd 5 yers fter cncer dignosis ccounting for competing risk from deth before AKI [31]. Confidence intervls for these risk estimtes were computed using non-prmetric estimtion [32]. To estimte the risk of AKI in the generl popultion, we smpled popultion comprison cohort by serching for 10 ge- nd sex-mtched persons for ech cncer ptient. We used Cox regression model to compute the hzrd rtio s mesure of the incidence rte rtio (IRR) of AKI for ech cncer site. We chose colon cncer to serve s the reference becuse this is common cncer site. In the djusted nlyses we introduced potentil confounders, including ge, sex, nd the comorbidities listed in Tble 1. Dichotomous vribles were included for filled prescriptions for NSAIDs or COX-2 inhibitors, orl bisphosphontes, or methotrexte during the yer before cncer dignosis. The ssumption of proportionl hzrds ws checked grphiclly nd found pproprite for ll vribles except previous AKI nd chronic kidney disese, which therefore were included with time-vrying effects.

3 C.F. Christinsen et l. / Europen Journl of Internl Medicine 22 (2011) Tble 1 Chrcteristics of cncer ptients with nd without bseline cretinine mesurements, Northern Denmrk, Jnury 1, 1999 December 31, Cncer ptients without cretinine mesurement within the yer prior to dignosis Cncer ptients with cretinine mesurement t or within the yer prior to dignosis All cncer ptients N % N % N % Overll , , Age 0 49 yrs yrs yrs , yrs , , yrs Sex Femle , , Mle , , Comorbidity prior to dignosis Acute kidney injury the yer before cncer dignosis Chronic kidney disese Dibetes Hypertension , , Osteoporosis Dyslipidemi Myocrdil infrction Congestive hert filure Peripherl vsculr disese Cerebrovsculr disese Hemiplegi Dementi Chronic obstructive pulmonry disese Connective tissue disese Peptic ulcer disese Mild liver disese Moderte/severe liver disese Drug use prior to dignosis Non-steroidl nti-inflmmtory drugs , , or cyclooxygense-2-inhibitors Bisphosphontes Methotrexte Tble 2 Incidence nd risk of cute kidney injury (AKI) in cncer ptients with bseline cretinine mesurement. Cncer site N cncer N AKI Totl risk time (yrs) Incidence rte per 1000 person-yrs 0 1yer Incidence rte per 1000 person-yrs 1 5yers 1-yer risk b of AKI% 5-yer risk b of AKI% Overll 37, , ( ) 43 (41 44) 17.5 ( ) 27.0 ( ) Prostte (C61) ( ) 53 (49 58) 12.1 ( ) 29.0 ( ) Urinry bldder (C67, D090, D303, D414) ( ) 53 (47 59) 21.8 ( ) 36.3 ( ) Kidney (C64) ( ) 76 (58 99) 44.0 ( ) 51.8 ( ) Ovry (C56, C570 C574) ( ) 70 (58 83) 20.9 ( ) 36.2 ( ) Corpus uteri (C54 C55) ( ) 41 (33 50) 12.7 ( ) 26.7 ( ) Cervix uteri (C53) ( ) 38 (27 53) 17.4 ( ) 28.6 ( ) Testis (C62) (27 75) 7 (3 13) 4.3 ( ) 7.3 ( ) Lymphom (C81 C85) c ( ) 42 (36 50) 18.8 ( ) 30.8 ( ) Leukemi (C91 C95) ( ) 56 (47 67) 27.5 ( ) 40.0 ( ) Multiple myelom (C900) ( ) 125 (99 156) 31.8 ( ) 52.7 ( ) Colon (C18 C19) ( ) 46 (41 51) 22.5 ( ) 33.0 ( ) Rectum (C20) ( ) 48 (41 56) 25.1 ( ) 36.6 ( ) Stomch (C16) ( ) 51 (37 71) 19.9 ( ) 24.7 ( ) Esophgus (C15) ( ) 24 (11 53) 19.8 ( ) 21.4 ( ) Liver (C22) ( ) 133 (85 208) 33.0 ( ) 38.6 ( ) Gll bldder/billiry trct (C23 C24) ( ) 131 (83 208) 33.6 ( ) 42.6 ( ) Pncres (C25) ( ) 131 (93 184) 29.7 ( ) 32.6 ( ) Brest (C50) , (41 56) 25 (22 28) 4.5 ( ) 14.5 ( ) Lung, bronchus, trche (C33 C34) ( ) 56 (48 64) 18.6 ( ) 22.4 ( ) Brin/centrl nervous system (85 134) 19 (14 27) 7.2 ( ) 11.0 ( ) (C71, D33, D352 D354, D43, D443 D445) Mlignnt melnom (C43) (34 66) 25 (20 32) 4.5 ( ) 14.3 ( ) Other sites , ( ) 39 (35 43) 15.1 ( ) 23.2 ( ) b c Cncers were clssified ccording to the Interntionl Clssifiction of Diseses, 10th revision (ICD-10). Risk ws clculted s the cumultive incidence proportion, ccounting for competing risk from deth. Lymphom lso ws identified through morphology codes.

4 402 C.F. Christinsen et l. / Europen Journl of Internl Medicine 22 (2011) Tble 2b Incidence nd risk of cute kidney injury (AKI) in cncer ptients without bseline cretinine mesurement. Cncer site N Cncer N AKI Totl risk time (yrs) Incidence rte per 1000 person-yrs 0 1 yer Incidence rte per 1000 person-yrs 1 5 yers 1-yer risk b of AKI% 5-yer risk b of AKI% Overll , (81 96) 21 (19 23) 7.4 ( ) 14.7 ( ) Prostte (C61) ( ) 46 (34 63) 12.4 ( ) 26.9 ( ) Urinry bldder (C67, D090, ( ) 42 (29 61) 13.5 ( ) 27.0 ( ) D303, D414) Kidney (C64) ( ) 48 (20 116) 20.3 ( ) 28.5 ( ) Ovry (C56, C570 C574) (60 207) 30 (16 56) 9.7 ( ) 20.6 ( ) Corpus uteri (C54 C55) (23 84) 17 (10 29) 4.1 ( ) 11.5 ( ) Cervix uteri (C53) (25 83) 9 (5 17) 4.3 ( ) 8.1 ( ) Testis (C62) (7 106) 0 ( ) 2.6 ( ) 2.6 ( ) Lymphom (C81 C85) c (45 165) 20 (10 41) 7.5 ( ) 14.7 ( ) Leukemi (C91 C95) ( ) 36 (17 76) 20.0 ( ) 30.5 ( ) Multiple myelom (C900) ( ) 229 (74 710) 37.3 ( ) 59.2 ( ) Colon (C18 C19) ( ) 51 (35 74) 15.2 ( ) 28.6 ( ) Rectum (C20) ( ) 44 (30 65) 19.5 ( ) 31.3 ( ) Stomch (C16) ( ) 32 (8 128) 17.6 ( ) 20.7 ( ) Esophgus (C15) (49 281) 83 (37 184) 7.8 ( ) 18.5 ( ) Liver (C22) ( ) 140 (20 997) 20.8 ( ) 25.0 ( ) Gll bldder/billiry trct (C23 C24) (57 911) 207 (67 643) 10.5 ( ) 26.3 ( ) Pncres (C25) ( ) 123 (31 492) 20.5 ( ) 25.0 ( ) Brest (C50) (27 46) 17 (14 21) 3.4 ( ) 10.6 ( ) Lung, bronchus, trche (C33 C34) ( ) 61 (37 99) 12.7 ( ) 16.8 ( ) Brin/centrl nervous system (C71, D33, (2 36) 13 (7 23) 0.8 ( ) 6.2 ( ) D352 D354, D43, D443 D445) Mlignnt melnom (C43) (10 26) 9 (7 12) 1.6 ( ) 5.8 ( ) Other sites (98 140) 21 (16 26) 9.2 ( ) 15.6 ( ) b c Cncers were clssified ccording to the Interntionl Clssifiction of Diseses, 10th revision (ICD-10). Risk ws clculted s the cumultive incidence proportion, ccounting for competing risk from deth. Lymphom lso ws identified through morphology codes. We conducted nlyses restricted to ptients with loco-regionl disese, distnt metstsis, nd unknown stge t the time of cncer dignosis. All nlyses were strtified on ptients with nd without bseline cretinine mesurement, to ddress the effect of estimting cretinine levels. Sttisticl nlyses were performed with SAS softwre (version 9.2, SAS Institute, Cry, NC). The study ws pproved by the Dnish Dt Protection Agency (record No ). 3. Results 3.1. Ptient chrcteristics The study cohort included 37,267 cncer ptients with bseline cretinine mesurement nd 6849 cncer ptients without bseline cretinine. Among ptients with bseline cretinine, 9613 (25.8%) developed AKI during 77,376 PY of follow-up (medin time=2.13 yers, Tble 3 Incidence rte rtios (IRRs) of cute kidney injury (AKI) in specific cncer sites compred with colon cncer in ptients with bseline cretinine mesurement. Tble 3b Incidence rte rtios (IRRs) of cute kidney injury (AKI) in specific cncer sites compred with colon cncer in ptients without bseline cretinine mesurement. Cncer site N AKI, n Crude IRR Adjusted IRR Cncer site N AKI, n Crude IRR Adjusted IRR Colon Prostte ( ) 0.58 ( ) Urinry bldder ( ) 0.93 ( ) Kidney ( ) 2.31 ( ) Ovry ( ) 1.26 ( ) Corpus uteri ( ) 0.67 ( ) Cervix uteri ( ) 1.01 ( ) Testis ( ) 0.25 ( ) Lymphom ( ) 0.92 ( ) Leukemi ( ) 1.32 ( ) Multiple myelom ( ) 1.57 ( ) Rectum ( ) 1.08 ( ) Stomch ( ) 0.95 ( ) Esophgus ( ) 0.96 ( ) Liver ( ) 1.85 ( ) Gll bldder/billiry trct ( ) 1.99 ( ) Pncres ( ) 2.04 ( ) Brest ( ) 0.34 ( ) Lung, bronchus, trche ( ) 1.00 ( ) Brin/centrl nervous system ( ) 0.42 ( ) Mlignnt melnom ( ) 0.32 ( ) Other sites ( ) 0.77 ( ) Adjusted for ge, sex, previous cute kidney injury, chronic kidney disese, dibetes, hypertension, osteoporosis, dyslipidemi, myocrdil infrction, congestive hert filure, peripherl vsculr disese, hemiplegi, dementi, COPD, connective tissue disese, peptic ulcer disese, liver disese, nd ny previous prescription for NSAIDs, COX-2 inhibitors, orl bisphosphontes, or methotrexte. Colon Prostte ( ) 0.61 ( ) Urinry bldder ( ) 0.75 ( ) Kidney ( ) 1.42 ( ) Ovry ( ) 1.25 ( ) Corpus uteri ( ) 0.47 ( ) Cervix uteri ( ) 0.80 ( ) Testis ( ) 0.38 ( ) Lymphom ( ) 0.52 ( ) Leukemi ( ) 1.10 ( ) Multiple myelom ( ) 1.85 ( ) Rectum ( ) 0.96 ( ) Stomch ( ) 0.96 ( ) Esophgus ( ) 1.00 ( ) Liver ( ) 2.44 ( ) Gll bldder/billiry trct ( ) 1.25 ( ) Pncres ( ) 1.79 ( ) Brest ( ) 0.45 ( ) Lung, bronchus, trche ( ) 0.83 ( ) Brin/centrl nervous system ( ) 0.34 ( ) Mlignnt melnom ( ) 0.29 ( ) Other sites ( ) 0.53 ( ) Adjusted for ge, sex, previous cute kidney injury, chronic kidney disese, dibetes, hypertension, osteoporosis, dyslipidemi, myocrdil infrction, congestive hert filure, peripherl vsculr disese, hemiplegi, dementi, COPD, connective tissue disese, peptic ulcer disese, liver disese, nd ny previous prescription for NSAIDs, COX-2 inhibitors, orl bisphosphontes, or methotrexte.

5 C.F. Christinsen et l. / Europen Journl of Internl Medicine 22 (2011) interqurtile rnge yers). Among cncer ptients with bseline cretinine, 18,415 (49.4%) were women nd 18,852 (50.6%) were men, lmost 75% were ged 60 yers or older, 3115 (8.4%) hd previous history of dibetes, 692 (1.9%) hd chronic kidney disese, nd 19,242 (51.6%) hd hypertension (Tble 1). Ptients without bseline cretinine mesurement were younger nd hd less comorbidity compred to ptients with bseline mesurement (Tble 1). Of those ptients with bseline cretinine mesurement, 95.8% hd cretinine mesurement within 5 yers fter cncer dignosis while only 85.5% of ptients without bseline cretinine hd cretinine mesurement within 5 yers fter cncer dignosis Risks nd incidence rtes of cute kidney injury The 1-yer risk of AKI in cncer ptients with bseline cretinine ws 17.5% (95%CI: %), with the lowest risk in ptients with testiculr cncer nd the highest risk in ptients with kidney cncer (Tble 2). The overll 5-yer risk of AKI ws 27.0% (95%CI: %). The overll IR of AKI during the first yer fter cncer dignosis ws 258 (95%CI: ) per 1000 PY, decresing to 43 (95%CI: 41 44) per 1000 PY in the period from 1 to 5 yers fter cncer dignosis. The highest 0 1 yer incidence rtes were in ptients with cncer loclized to the liver, pncres, kidney, or gll bldder/biliry trct, nd in ptients with multiple myelom. The 1 5 yer incidence rtes were lso highest for these cncers. The lowest rtes occurred mong ptients with brest, brin, or testis cncer, nd mong those with mlignnt melnom (Tble 2). For ptients without bseline cretinine, the 1-yer risk of AKI ws 7.4% (95%CI: ) nd 5-yer risk ws 14.7% (95%CI: ) (Tble 2b). The IRR ws computed compring ech cncer site with colon cncer s the reference nd djusted for other risk fctors for AKI (Tbles 3 nd 3b). Cncers ssocited with mrkedly incresed risk of AKI compred with colon cncer included cncer of the liver, kidney, gll bldder/biliry trct nd pncres, nd multiple myelom. Dt on stge t cncer dignosis were vilble for 27,957 (74.3%) ptients (Tble 4). Among these ptients, those with distnt metstses t dignosis, compred with loco-regionl cncer, were t highest risk of AKI (Tble 4). We found the sme pttern for most of the specific cncer sites, with prticulrly high rte of AKI in ptients presenting with metsttic cncer of the urinry bldder or ovry (Tble 4). The popultion comprison cohort comprised 172,197 persons with bseline cretinine mesurement nd 210,867 without. In persons with bseline cretinine, the 1-yer risk of AKI ws substntilly lower thn in cncer ptients, 6.7% (95%CI: ), but lso the 5-yer risk of AKI ws lower, 18.6% (95%CI: ). The 1- nd 5-yer risks were even lower in persons without cretinine mesurement [1-yer risk: 3.4% (95%CI: ), 5-yer risk: 10.4% (95%CI: )]. Tble 4 Incidence nd risk of cute kidney injury (AKI) strtified by cncer stge t dignosis for mjor cncers in ptients with bseline cretinine. Cncer site N cncer N AKI Totl risk time (yrs) Incidence rte per 1000 person-yrs 0 1 yer fter dignosis Incidence rte per 1000 person-yrs 1 5 yers fter dignosis 1-yer risk of AKI % 5-yer risk of AKI % All cncer sites Loco-regionl 19, , ( ) 37 (35 38) 15.4 ( ) 26.1 ( ) Distnt metstses ( ) 83 (75 91) 22.4 ( ) 28.0 ( ) Unknown , ( ) 46 (43 50) 17.0 ( ) 27.7 ( ) Prostte Loco-regionl (91 129) 44 (38 51) 9.9 ( ) 26.9 ( ) Distnt metstses ( ) 86 (72 103) 16.6 ( ) 31.6 ( ) Unknown ( ) 51 (45 59) 11.2 ( ) 28.9 ( ) Urinry bldder Loco-regionl ( ) 54 (46 62) 23.4 ( ) 38.4 ( ) Distnt metstses ( ) 259 ( ) 41.1 ( ) 50.0 ( ) Unknown ( ) 48 (39 57) 17.0 ( ) 31.3 ( ) Kidney Loco-regionl ( ) 59 (41 85) 53.9 ( ) 62.8 ( ) Distnt metstses ( ) 163 ( ) 33.3 ( ) 40.3 ( ) Unknown ( ) 66 (29 146) 35.6 ( ) 41.7 ( ) Ovry Loco-regionl ( ) 55 (43 69) 18.0 ( ) 33.2 ( ) Distnt metstses ( ) 124 (89 173) 27.0 ( ) 42.1 ( ) Unknown ( ) 157 (79 314) 22.0 ( ) 40.5 ( ) Colon Loco-regionl ( ) 43 (38 49) 21.8 ( ) 34.1 ( ) Distnt metstses ( ) 88 (66 118) 23.5 ( ) 29.7 ( ) Unknown ( ) 36 (24 56) 25.3 ( ) 33.3 ( ) Rectum Loco-regionl ( ) 44 (37 53) 25.2 ( ) 38.2 ( ) Distnt metstses ( ) 102 (69 151) 27.3 ( ) 36.3 ( ) Unknown ( ) 37 (21 63) 21.6 ( ) 28.1 ( ) Brest Loco-regionl , (29 42) 22 (19 24) 3.4 ( ) 12.7 ( ) Distnt metstses ( ) 79 (54 114) 15.7 ( ) 27.2 ( ) Unknown (50 108) 45 (34 60) 6.3 ( ) 21.3 ( ) Lung, bronchus, trche Loco-regionl ( ) 54 (46 63) 19.6 ( ) 26.0 ( ) Distnt metstses ( ) 59 (42 83) 18.3 ( ) 19.8 ( ) Unknown ( ) 70 (39 127) 15.6 ( ) 17.4 ( ) Mlignnt melnom Loco-regionl (25 57) 24 (19 32) 3.7 ( ) 13.7 ( ) Distnt metstses ( ) 94 (23 374) 19.5 ( ) 24.4 ( ) Unknown (15 74) 21 (12 36) 3.2 ( ) 11.9 ( ) Risk ws clculted s the cumultive incidence proportion, ccounting for competing risk from deth.

6 404 C.F. Christinsen et l. / Europen Journl of Internl Medicine 22 (2011) Progression of cute kidney injury nd need for dilysis We included ptients with ny level of AKI severity (RIFLE ctegory risk or worse). Some ptients hd progression of AKI to more severe stging, i.e. RIFLE ctegory injury or filure. The cumultive incidences of these severities re illustrted in Fig. 1. While the 1- nd 5-yer risks for ny severity of AKI in ptients with bseline cretinine were 17.5% (95%CI: %) nd 27.0% (95%CI: %), respectively, the risks for AKI ctegories of injury or worse were 8.8% (95%CI: %) nd 14.6% (95%CI: %), respectively, nd for AKI ctegory of filure the risks were 4.5% (95%CI: %) nd 7.6% (95%CI: %), respectively (dt not shown). In ptients without bseline cretinine, the 1- nd 5-yer risks of AKI injury were 3.5% (95%CI: ) nd 7.6% (95%CI: ). The 1- nd 5-yer risks of AKI filure were 1.6% (95%CI: ) nd 3.5% (95%CI: ). Among the 9613 ptients with AKI nd bseline cretinine mesurement, 492 were treted with dilysis within yer from dte of AKI onset. The RIFLE ctegory loss (dilysis between 30 nd 90 dys fter AKI) ws reched by 146 cncer ptients nd 75 progressed to end-stge renl disese (dilysis between 90 dys nd 365 dys fter AKI). Among the 948 AKI ptients without bseline cretinine mesurement, 20 were treted with dilysis within yer; 13 within the first 30 dys, 5 between 30 nd 90 dys (RIFLE loss), nd 2 between 90 dys nd 365 dys (RIFLE end-stge renl disese). 4. Discussion This is the first popultion-bsed study to ssess the risk of AKI in cncer ptients. The risk of AKI within the yer fter cncer dignosis ws more thn 17% in cncer ptients who hve cretinine mesurement the yer before dignosis, but only 7% in the younger nd helthier ptients without such bseline cretinine mesurement. The five-yer risks were 27% nd 15% in these two groups. The highest risks of AKI were observed mong ptients with kidney cncer, liver cncer, multiple myelom, nd metsttic cncer. The study's mjor strength is its popultion-bsed hospitl setting within free tx-supported helthcre system. This design limits referrl nd informtion bis [21]. In ddition, registrtion completeness in the Dnish Cncer Registry, which is known to be high [20], Fig. 1. Cumultive incidence (risk) of cute kidney injury (AKI) during the first 5 yers fter cncer dignosis, clssified by severity ccording to the RIFLE criteri nd ccounting for competing risk from deth (dshed line). The gry re represents ny stge of AKI; risk (light gry), injury (middle gry) nd filure (drk gry).

7 C.F. Christinsen et l. / Europen Journl of Internl Medicine 22 (2011) is n importnt strength. Furthermore, bis is unlikely becuse ny missing cncer registrtion is unlikely to be ssocited with AKI. While registrtion of cncer site nd stge could be misclssified, this is unlikely to be mjor problem in the current study of mjor cncer groups nd stges. As well, clssifiction of AKI depends on the qulity nd completeness of lbortory dtbses, which re considered to be high in Denmrk [33]. A potentil wekness is use of cretinine mesurements to ssess AKI in the bsence of dt on urine output. However, our estimtes re likely to be conservtive becuse 50% increse in cretinine, the lowest ctegory we mesured, is ssocited with mrkedly decresed glomerulr filtrtion rte. Further, use of cretinine criteri lone leds to identifiction of more severely ill AKI ptients. Finlly, results bsed on cretinine criteri re less ffected by use of diuretics thn results bsed on urine output criteri [34]. Our study ws dependent on the vilbility of bseline cretinine mesurements. Cretinine is often mesured for minor indictions, nd most ptients hd cretinine mesurement during the yer before their cncer dignosis.we find it resonble to ssume norml renl function in the remining ptients without cretinine mesurement in the yer prior to cncer dignosis becuse these ptients tended to be young nd hd virtully no comorbidity. We strtified the nlyses to ddress the impct of mesured nd estimted bseline cretinine. It is noteworthy, tht ptients without bseline cretinine mesurement hve mrkedly lower incidence of AKI. This my be explined by their low prevlence of other risk fctors for AKI, such s dibetes, hypertension, congestive hert filure, nd chronic kidney disese. The study results re dependent on the definition of bseline cretinine level [34,35]. Despite its importnce for the ssessment of AKI, bseline cretinine level is not well-defined in the literture [25]. We therefore conducted sensitivity nlysis without using predignosis bseline cretinine level, nd relying insted on n increse in cretinine level within seven-dy time window. As expected, this chnge decresed the estimted risk of AKI. Our study definition of bseline cretinine (lowest cretinine mesurement within one yer prior to the cncer dignosis) is likely very sensitive in identifying AKI, but t the expense of specificity. Both cute nd chronic kidney disese nd even minor renl impirment were cptured, s severl months or yers my hve elpsed between the bseline cretinine mesurement nd the mesurement showing n incresed cretinine level. Regrdless of the method for determining the bseline cretinine vlue, however, rtes of AKI were still high for specific cncers (kidney, lung, multiple myelom) nd for cncers with distnt metstses t dignosis. Our dt extends former reserch. A recent study by Lhoti nd collegues included 537 ptients with cute myelogenous leukemi or high-risk myelodysplstic syndrome nd found tht 36% developed AKI fter induction chemotherpy [13]. Ryner nd collegues followed 141 ptients with multiple myelom for up to two yers nd found tht renl impirment (defined s cretinine vlue bove 120 μmol/l) developed in 56% of ptients [9]. We found 31.8% risk of AKI within the first yer of multiple myelom in ptients with bseline cretinine. This lower risk my be explined by n incresed bseline cretinine level t the time of dignosis. A cohort study by Knudsen et l., including two cohorts with totl of 775 multiple myelom ptients, found tht 29% hd renl impirment (cretinine bove 130 μmol/l) t time of dignosis [7]. We found substntilly higher risk of AKI in leukemi nd lymphom ptients, compred with previous reports. In review of medicl records of 700 ptients with non- Hodgkin's lymphom nd chronic lymphocytic leukemi, D's nd collegues found evidence of renl filure in 83 ptients (11.9%) [11]. Similrly, study of 88 decesed leukemi ptients identified renl filure in 10 (11.4%) ptients [10]. Neither study provided definition of cute renl filure, nd my hve included only the most severe cses. Severl mechnisms my underlie the high rte of AKI in cncer ptients [1]. Urinry trct obstruction my explin the high risk of AKI in ptients with kidney cncer nd with disseminted cncer of the urinry bldder nd prostte [2]. Differences in lifestyle fctors such s smoking my be ssocited both with risk of AKI nd with n up to 9-fold incresed risk of cncer [36]. Such fctors my ccount for the higher incidence rtes of AKI in pncres, lung, liver, kidney, nd urinry bldder cncer. We djusted the IRRs for mjor lifestyle-ssocited diseses, but residul nd unmesured confounding my hve ffected our results. Use of nephrotoxic chemotherpy my explin the high AKI rte in kidney cncer, ovrin cncer nd disseminted urinry bldder cncer [37 39]. Our study indictes tht renl impirment is common in cncer ptients. While some cncers re ssocited with very high risk of AKI within the first yer fter dignosis, others re ssocited with mrkedly incresed long-term risk. In conclusion, AKI ws found to be common compliction in cncer ptients. The highest risks occurred mong ptients with liver cncer, kidney cncer, or multiple myelom, nd in ptients presenting with distnt metstses t time of cncer dignosis. This could hve clinicl implictions for choice of tretment nd supportive cre in cncer ptients to void progression to cute renl filure. 5. Lerning points Acute kidney injury is common compliction in cncer ptients. The risk of cute kidney injury ws 18% during the first yer fter cncer dignosis, nd 27% during the first five yers in ptients with cretinine mesurement before cncer dignosis. 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