Europen Journl of Internl Medicine 22 (2011) 399 406 Contents lists vilble t ScienceDirect Europen Journl of Internl Medicine journl homepge: www.elsevier.com/locte/ejim 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 91320-1799, 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 2006. 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: 252 264) 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: 17.1 17.9%), nd the 5-yer risk ws 27.0% (95%CI: 26.5 27.5%). We observed the highest 1-yer risk in ptients with kidney cncer [44.0% (95%CI: 40.5 47.5)], liver cncer [33.0% (95%CI: 28.2 37.8%)], or multiple myelom [31.8% (95%CI: 27.3 36.3%)]. 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. 2011 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.: +45 89424800; fx: +45 89424801. 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]. 0953-6205/$ see front mtter 2011 Europen Federtion of Internl Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2011.05.005
400 C.F. Christinsen et l. / Europen Journl of Internl Medicine 22 (2011) 399 406 2.1. 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 1943. 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). 2.2. 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]. 2.3. 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. 2.4. 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]. 2.5. 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. 2.6. 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.
C.F. Christinsen et l. / Europen Journl of Internl Medicine 22 (2011) 399 406 401 Tble 1 Chrcteristics of cncer ptients with nd without bseline cretinine mesurements, Northern Denmrk, Jnury 1, 1999 December 31, 2006. 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 6849 100.0 37,267 100.0 44,116 100.0 Age 0 49 yrs 1876 27.4 3803 10.2 5679 12.9 50 59 yrs 1541 22.5 6057 16.3 7598 17.2 60 69 yrs 1371 20.0 9277 24.9 10,648 24.1 70 79 yrs 1184 17.3 11,027 29.6 12,211 27.7 80+yrs 877 12.8 7103 19.1 7980 18.1 Sex Femle 4314 63.0 18,415 49.4 22,729 51.5 Mle 2535 37.0 18,852 50.6 21,387 48.5 Comorbidity prior to dignosis Acute kidney injury the yer before 0 0.0 1516 4.1 1516 3.4 cncer dignosis Chronic kidney disese 17 0.2 692 1.9 709 1.6 Dibetes 198 2.9 3115 8.4 3313 7.5 Hypertension 1878 27.4 19,242 51.6 21,120 47.9 Osteoporosis 108 1.6 1473 4.0 1581 3.6 Dyslipidemi 37 0.5 766 2.1 803 1.8 Myocrdil infrction 39 0.6 1121 3.0 1160 2.6 Congestive hert filure 90 1.3 1869 5.0 1959 4.4 Peripherl vsculr disese 107 1.6 1636 4.4 1743 4.0 Cerebrovsculr disese 173 2.5 2584 6.9 2757 6.2 Hemiplegi 6 0.1 73 0.2 79 0.2 Dementi 24 0.4 401 1.1 425 1.0 Chronic obstructive pulmonry disese 231 3.4 3467 9.3 3698 8.4 Connective tissue disese 48 0.7 835 2.2 883 2.0 Peptic ulcer disese 93 1.4 1352 3.6 1445 3.3 Mild liver disese 20 0.3 376 1.0 396 0.9 Moderte/severe liver disese 3 0.0 143 0.4 146 0.3 Drug use prior to dignosis Non-steroidl nti-inflmmtory drugs 1 406 20.5 10,735 28.8 12,141 27.5 or cyclooxygense-2-inhibitors Bisphosphontes 59 0.9 857 2.3 916 2.1 Methotrexte 7 0.1 276 0.7 283 0.6 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 37,267 9613 77,376 258 (252 264) 43 (41 44) 17.5 (17.1 17.9) 27.0 (26.5 27.5) Prostte (C61) 3513 915 9481 140 (127 154) 53 (49 58) 12.1 (11.1 13.2) 29.0 (27.4 30.6) Urinry bldder (C67, D090, D303, D414) 2267 791 5845 284 (261 311) 53 (47 59) 21.8 (20.2 23.6) 36.3 (34.3 38.4) Kidney (C64) 761 388 811 1012 (909 1126) 76 (58 99) 44.0 (40.5 47.5) 51.8 (48.1 55.4) Ovry (C56, C570 C574) 849 293 1767 288 (249 334) 70 (58 83) 20.9 (18.2 23.7) 36.2 (32.8 39.6) Corpus uteri (C54 C55) 779 195 2398 148 (121 180) 41 (33 50) 12.7 (10.5 15.2) 26.7 (23.5 30.0) Cervix uteri (C53) 358 98 983 222 (173 284) 38 (27 53) 17.4 (13.6 21.5) 28.6 (23.9 33.5) Testis (C62) 354 24 1367 45 (27 75) 7 (3 13) 4.3 (2.5 6.8) 7.3 (4.8 10.6) Lymphom (C81 C85) c 1262 371 3288 246 (217 280) 42 (36 50) 18.8 (16.7 21.0) 30.8 (28.1 33.4) Leukemi (C91 C95) 1108 426 2290 419 (374 468) 56 (47 67) 27.5 (24.9 30.2) 40.0 (37.0 43.0) Multiple myelom (C900) 406 203 643 508 (427 603) 125 (99 156) 31.8 (27.3 36.3) 52.7 (47.5 57.7) Colon (C18 C19) 3488 1104 7290 336 (314 361) 46 (41 51) 22.5 (21.2 23.9) 33.0 (31.3 34.6) Rectum (C20) 1618 567 3559 352 (319 388) 48 (41 56) 25.1 (23.0 27.2) 36.6 (34.2 39.0) Stomch (C16) 795 194 863 373 (319 436) 51 (37 71) 19.9 (17.2 22.7) 24.7 (21.8 27.8) Esophgus (C15) 419 89 358 421 (339 522) 24 (11 53) 19.8 (16.1 23.8) 21.4 (17.6 25.4) Liver (C22) 370 141 208 1016 (851 1213) 133 (85 208) 33.0 (28.2 37.8) 38.6 (33.6 43.6) Gll bldder/billiry trct (C23 C24) 215 90 178 768 (610 968) 131 (83 208) 33.6 (27.3 39.9) 42.6 (35.8 49.2) Pncres (C25) 1216 394 504 948 (855 1051) 131 (93 184) 29.7 (27.2 32.3) 32.6 (30.0 35.3) Brest (C50) 3938 518 13,909 48 (41 56) 25 (22 28) 4.5 (3.9 5.2) 14.5 (13.3 15.7) Lung, bronchus, trche (C33 C34) 5523 1225 4798 392 (369 417) 56 (48 64) 18.6 (17.6 19.7) 22.4 (21.3 23.6) Brin/centrl nervous system 1024 108 1958 107 (85 134) 19 (14 27) 7.2 (5.8 8.9) 11.0 (9.1 13.1) (C71, D33, D352 D354, D43, D443 D445) Mlignnt melnom (C43) 812 104 2772 47 (34 66) 25 (20 32) 4.5 (3.2 6.0) 14.3 (11.8 17.0) Other sites 6192 1375 12,106 242 (226 258) 39 (35 43) 15.1 (14.2 16.0) 23.2 (22.2 24.3) 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.
402 C.F. Christinsen et l. / Europen Journl of Internl Medicine 22 (2011) 399 406 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 6849 948 21,799 88 (81 96) 21 (19 23) 7.4 (6.8 8.1) 14.7 (13.8 15.5) Prostte (C61) 324 79 871 149 (109 203) 46 (34 63) 12.4 (9.1 16.2) 26.9 (21.8 32.3) Urinry bldder (C67, D090, 216 57 687 159 (111 229) 42 (29 61) 13.5 (9.3 18.4) 27.0 (21.2 33.1) D303, D414) Kidney (C64) 65 18 114 334 (194 576) 48 (20 116) 20.3 (11.5 30.8) 28.5 (18.0 39.9) Ovry (C56, C570 C574) 103 20 339 112 (60 207) 30 (16 56) 9.7 (5.0 16.4) 20.6 (13.2 29.1) Corpus uteri (C54 C55) 219 23 837 44 (23 84) 17 (10 29) 4.1 (2.0 7.3) 11.5 (7.5 16.4) Cervix uteri (C53) 257 20 1011 46 (25 83) 9 (5 17) 4.3 (2.3 7.3) 8.1 (5.1 12.0) Testis (C62) 79 2 320 27 (7 106) 0 ( ) 2.6 (0.5 8.1) 2.6 (0.5 8.1) Lymphom (C81 C85) c 120 17 400 86 (45 165) 20 (10 41) 7.5 (3.7 13.1) 14.7 (8.9 21.8) Leukemi (C91 C95) 75 22 200 268 (162 445) 36 (17 76) 20.0 (11.9 29.7) 30.5 (20.2 41.3) Multiple myelom (C900) 17 9 16 754 (339 1677) 229 (74 710) 37.3 (15.3 59.5) 59.2 (30.7 79.3) Colon (C18 C19) 238 64 569 207 (150 287) 51 (35 74) 15.2 (10.9 20.0) 28.6 (22.7 34.7) Rectum (C20) 241 73 608 257 (193 342) 44 (30 65) 19.5 (14.8 24.7) 31.3 (25.4 37.4) Stomch (C16) 69 14 80 309 (175 543) 32 (8 128) 17.6 (9.7 27.5) 20.7 (12.0 31.0) Esophgus (C15) 65 11 89 117 (49 281) 83 (37 184) 7.8 (2.9 16.0) 18.5 (9.8 29.4) Liver (C22) 24 6 10 975 (406 2342) 140 (20 997) 20.8 (7.6 38.5) 25.0 (10.2 43.1) Gll bldder/billiry trct (C23 C24) 19 5 18 228 (57 911) 207 (67 643) 10.5 (1.8 28.4) 26.3 (9.6 46.8) Pncres (C25) 44 11 24 669 (348 1285) 123 (31 492) 20.5 (10.1 33.3) 25.0 (13.5 38.4) Brest (C50) 1665 162 6286 36 (27 46) 17 (14 21) 3.4 (2.6 4.3) 10.6 (9.1 12.2) Lung, bronchus, trche (C33 C34) 405 67 358 255 (194 335) 61 (37 99) 12.7 (9.6 16.1) 16.8 (13.3 20.6) Brin/centrl nervous system (C71, D33, 238 14 922 9 (2 36) 13 (7 23) 0.8 (0.2 2.8) 6.2 (3.6 9.9) D352 D354, D43, D443 D445) Mlignnt melnom (C43) 1025 53 4128 16 (10 26) 9 (7 12) 1.6 (0.9 2.5) 5.8 (4.4 7.5) Other sites 1341 201 3910 117 (98 140) 21 (16 26) 9.2 (7.7 10.8) 15.6 (13.7 17.6) 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 2005-41-5281). 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 3488 1104 1.00 1.00 Prostte 3513 915 0.66 (0.60 0.72) 0.58 (0.52 0.64) Urinry bldder 2267 791 0.98 (0.89 1.07) 0.93 (0.85 1.02) Kidney 761 388 2.45 (2.18 2.75) 2.31 (2.05 2.60) Ovry 849 293 1.04 (0.91 1.18) 1.26 (1.11 1.44) Corpus uteri 779 195 0.62 (0.53 0.72) 0.67 (0.58 0.79) Cervix uteri 358 98 0.75 (0.61 0.92) 1.01 (0.81 1.24) Testis 354 24 0.15 (0.10 0.22) 0.25 (0.16 0.37) Lymphom 1262 371 0.82 (0.73 0.92) 0.92 (0.81 1.05) Leukemi 1108 426 1.25 (1.11 1.39) 1.32 (1.17 1.50) Multiple myelom 406 203 1.78 (1.53 2.07) 1.57 (1.34 1.84) Rectum 1618 567 1.05 (0.95 1.16) 1.08 (0.96 1.21) Stomch 795 194 0.97 (0.83 1.13) 0.95 (0.82 1.11) Esophgus 419 89 0.96 (0.77 1.19) 0.96 (0.77 1.19) Liver 370 141 2.38 (2.00 2.84) 1.85 (1.53 2.25) Gll bldder/billiry trct 215 90 2.04 (1.64 2.52) 1.99 (1.60 2.47) Pncres 1216 394 2.04 (1.82 2.29) 2.04 (1.81 2.31) Brest 3938 518 0.30 (0.27 0.33) 0.34 (0.31 0.38) Lung, bronchus, trche 5523 1225 0.99 (0.92 1.08) 1.00 (0.92 1.10) Brin/centrl nervous system 1024 108 0.33 (0.27 0.40) 0.42 (0.35 0.52) Mlignnt melnom 812 104 0.29 (0.24 0.36) 0.32 (0.26 0.39) Other sites 6192 1375 0.74 (0.69 0.81) 0.77 (0.70 0.85) 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 238 64 1.00 1.00 Prostte 324 79 0.80 (0.57 1.11) 0.61 (0.43 0.87) Urinry bldder 216 57 0.85 (0.60 1.22) 0.75 (0.52 1.08) Kidney 65 18 1.30 (0.77 2.19) 1.42 (0.83 2.41) Ovry 103 20 0.61 (0.37 1.00) 1.25 (0.75 2.08) Corpus uteri 219 23 0.29 (0.18 0.47) 0.47 (0.29 0.76) Cervix uteri 257 20 0.22 (0.13 0.36) 0.80 (0.47 1.35) Testis 79 2 0.07 (0.02 0.28) 0.38 (0.09 1.59) Lymphom 120 17 0.43 (0.25 0.74) 0.52 (0.30 0.91) Leukemi 75 22 1.07 (0.66 1.73) 1.10 (0.66 1.83) Multiple myelom 17 9 3.43 (1.71 6.90) 1.85 (0.91 3.80) Rectum 241 73 1.08 (0.77 1.51) 0.96 (0.66 1.38) Stomch 69 14 1.07 (0.60 1.91) 0.96 (0.53 1.72) Esophgus 65 11 0.78 (0.41 1.49) 1.00 (0.52 1.89) Liver 24 6 2.88 (1.25 6.67) 2.44 (1.04 5.76) Gll bldder/billiry trct 19 5 1.76 (0.71 4.37) 1.25 (0.50 3.14) Pncres 44 11 2.22 (1.17 4.22) 1.79 (0.93 3.46) Brest 1665 162 0.27 (0.20 0.36) 0.45 (0.33 0.61) Lung, bronchus, trche 405 67 0.98 (0.70 1.39) 0.83 (0.57 1.20) Brin/centrl nervous system 238 14 0.16 (0.09 0.29) 0.34 (0.19 0.62) Mlignnt melnom 1025 53 0.14 (0.10 0.20) 0.29 (0.20 0.42) Other sites 1341 201 0.51 (0.39 0.68) 0.53 (0.39 0.74) 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.
C.F. Christinsen et l. / Europen Journl of Internl Medicine 22 (2011) 399 406 403 interqurtile rnge 0.38 4.58 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. 3.2. 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: 17.1 17.9%), 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: 26.5 27.5%). The overll IR of AKI during the first yer fter cncer dignosis ws 258 (95%CI: 252 264) 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: 6.8 8.1) nd 5-yer risk ws 14.7% (95%CI: 13.8 15.5) (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: 6.6 6.9), but lso the 5-yer risk of AKI ws lower, 18.6% (95%CI: 18.4 18.8). The 1- nd 5-yer risks were even lower in persons without cretinine mesurement [1-yer risk: 3.4% (95%CI: 3.4 3.5), 5-yer risk: 10.4% (95%CI: 10.2 10.5)]. 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 19,751 4918 52,869 196 (189 203) 37 (35 38) 15.4 (14.9 16.0) 26.1 (25.5 26.7) Distnt metstses 8206 2263 6840 496 (473 519) 83 (75 91) 22.4 (21.5 23.3) 28.0 (27.0 29.0) Unknown 9668 2465 18,702 260 (248 273) 46 (43 50) 17.0 (16.3 17.8) 27.7 (26.7 28.7) Prostte Loco-regionl 1268 302 4089 108 (91 129) 44 (38 51) 9.9 (8.3 11.6) 26.9 (24.3 29.6) Distnt metstses 825 251 1453 215 (181 254) 86 (72 103) 16.6 (14.2 19.3) 31.6 (28.4 34.9) Unknown 1472 368 4084 127 (109 148) 51 (45 59) 11.2 (9.6 12.8) 28.9 (26.3 31.6) Urinry bldder Loco-regionl 1231 466 3432 299 (266 336) 54 (46 62) 23.4 (21.1 25.8) 38.4 (35.7 41.2) Distnt metstses 124 60 62 1122 (852 1476) 259 (135 498) 41.1 (32.4 49.6) 50.0 ( ) Unknown 923 266 2376 212 (181 248) 48 (39 57) 17.0 (14.7 19.5) 31.3 (28.1 34.6) Kidney Loco-regionl 384 237 536 1214 (1059 1391) 59 (41 85) 53.9 (48.8 58.7) 62.8 (57.6 67.5) Distnt metstses 274 108 169 794 (647 975) 163 (101 262) 33.3 (27.8 38.9) 40.3 (34.4 46.1) Unknown 104 43 106 806 (584 1113) 66 (29 146) 35.6 (26.5 44.7) 41.7 (32.1 51.0) Ovry Loco-regionl 541 170 1390 221 (181 270) 55 (43 69) 18.0 (14.8 21.3) 33.2 (29.1 37.4) Distnt metstses 259 105 322 461 (365 583) 124 (89 173) 27.0 (21.8 32.5) 42.1 (35.9 48.2) Unknown 50 19 56 458 (254 827) 157 (79 314) 22.0 (11.8 34.2) 40.5 (26.3 54.3) Colon Loco-regionl 2314 756 6016 292 (268 319) 43 (38 49) 21.8 (20.1 23.5) 34.1 (32.1 36.1) Distnt metstses 781 228 666 470 (407 543) 88 (66 118) 23.5 (20.5 26.5) 29.7 (26.4 32.9) Unknown 400 122 620 442 (364 537) 36 (24 56) 25.3 (21.1 29.6) 33.3 (27.9 38.8) Rectum Loco-regionl 1104 402 2893 328 (292 369) 44 (37 53) 25.2 (22.7 27.8) 38.2 (35.2 41.1) Distnt metstses 305 108 309 473 (382 587) 102 (69 151) 27.3 (22.4 32.4) 36.3 (30.8 41.9) Unknown 218 60 378 347 (260 461) 37 (21 63) 21.6 (16.4 27.3) 28.1 (22.2 34.3) Brest Loco-regionl 3320 381 12,558 35 (29 42) 22 (19 24) 3.4 (2.8 4.0) 12.7 (11.5 14.0) Distnt metstses 261 69 397 242 (179 329) 79 (54 114) 15.7 (11.6 20.4) 27.2 (21.8 32.8) Unknown 411 75 1118 74 (50 108) 45 (34 60) 6.3 (4.3 9.0) 21.3 (16.9 26.1) Lung, bronchus, trche Loco-regionl 2551 652 3375 323 (296 353) 54 (46 63) 19.6 (18.1 21.2) 26.0 (24.3 27.8) Distnt metstses 2357 465 1163 481 (438 529) 59 (42 83) 18.3 (16.8 19.9) 19.8 (18.2 21.5) Unknown 620 108 265 530 (435 647) 70 (39 127) 15.6 (12.9 18.6) 17.4 (14.6 20.5) Mlignnt melnom Loco-regionl 631 78 2282 38 (25 57) 24 (19 32) 3.7 (2.4 5.3) 13.7 (11.0 16.7) Distnt metstses 41 10 32 372 (186 744) 94 (23 374) 19.5 (9.2 32.7) 24.4 (12.7 38.2) Unknown 191 19 633 33 (15 74) 21 (12 36) 3.2 (1.3 6.4) 11.9 (7.3 17.6) Risk ws clculted s the cumultive incidence proportion, ccounting for competing risk from deth.
404 C.F. Christinsen et l. / Europen Journl of Internl Medicine 22 (2011) 399 406 3.3. 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: 17.1 17.9%) nd 27.0% (95%CI: 26.5 27.5%), respectively, the risks for AKI ctegories of injury or worse were 8.8% (95%CI: 8.5 9.1%) nd 14.6% (95%CI: 14.2 15.0%), respectively, nd for AKI ctegory of filure the risks were 4.5% (95%CI: 4.3 4.7%) nd 7.6% (95%CI: 7.3 7.8%), respectively (dt not shown). In ptients without bseline cretinine, the 1- nd 5-yer risks of AKI injury were 3.5% (95%CI: 3.1 4.0) nd 7.6% (95%CI: 6.9 8.2). The 1- nd 5-yer risks of AKI filure were 1.6% (95%CI: 1.3 1.9) nd 3.5% (95%CI: 3.1 4.0). 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).
C.F. Christinsen et l. / Europen Journl of Internl Medicine 22 (2011) 399 406 405 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. The incidence ws prticulrly high in ptients with kidney cncer, liver cncer, or multiple myelom. Grnt support Funding ws provided by reserch grnts to Arhus University from Amgen Inc. nd from the Kren Elise Jensen Foundtion. Conflicts of interest sttement None of the uthors hve ny conflict of interest with regrd to the present study. W.J.L. nd J.P.F. hd n employment nd own stock in Amgen. None of the other uthors hve ny personl finncil disclosures to report. References [1] Lmeire NH, Flombum CD, Moreu D, Ronco C. Acute renl filure in cncer ptients. Ann Med 2005;37:13 25. [2] Givens ML, Wethern J. Renl complictions in oncologic ptients. Emerg Med Clin North Am 2009;27:283 91. [3] Cohen EP. Cncer nd the kidney. Oxford: Oxford University Press; 2005. [4] Lmeire N, Vn BW, Vnholder R. Acute renl filure. Lncet 2005;365:417 30. [5] Leblnc M, Kellum JA, Gibney RT, Lieberthl W, Tumlin J, Meht R. Risk fctors for cute renl filure: inherent nd modifible risks. Curr Opin Crit Cre 2005;11: 533 6. 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