Delayed kidney injury following coronary angiography

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1 530 Delyed kidney injury following coronry ngiogrphy FENG WANG 1*, CHENG PENG 2*, GUANGYUAN ZHANG 3*, QING ZHAO 4, CHANGYOU XUAN 1, MENG WEI 4 nd NIANSONG WANG 1 Deprtments of 1 Nephrology nd Rheumtology, nd 2 Crdiothorcic Surgery, Affilited Sixth People's Hospitl, Shnghi Jio Tong University, Shnghi ; 3 Deprtment of Urology, Shnghi First Hospitl, Shnghi Jio Tong University School of Medicine, Shnghi ; 4 Deprtment of Crdiology, Affilited Sixth People's Hospitl, Shnghi Jio Tong University, Shnghi , P.R. Chin Received Februry 4, 2015; Accepted April 12, 2016 DOI: /etm Abstrct. It is occsionlly observed tht ptients without contrst induced nephropthy (CIN) develop kidney injury within 1 6 months fter coronry ngiogrphy (CAG), termed delyed CIN or delyed kidney injury (DKI) following CAG. The present study imed to investigte the ssocited risk fctors of delyed CIN nd its possible pthogenesis. Subjects with CAG or coronry stenting from Jnury 2008 to December 2009 were studied. A retrospective survey on DKI fter CAG ws conducted nd the risk fctors were nlyzed. There were 436 cses receiving CAG with complete medicl records enrolled in the present cohort, in which the DKI incidence ws 7.1% (31/436). Ptients with DKI fter CAG exhibited lower hemoglobin (121.2±17.3 vs ±18.6 g/l), estimted glomerulr filtrtion rte (egfr; 66.4±30.2 vs. 71.9±28.6 ml/min), higher serum cretinine (110.9±43.2 vs. 91.7±37.6 µmol/l), higher rte of hert filure (22.6 vs. 5.4%) nd 300 mg spirin therpy (29 vs. 5.7%) compred with non DKI ptients (ll P<0.05). However, no differences were observed in morbidities of dibetes, hypertension, hyperlipidemi nd proteinuri, or in the tretments with ngiotensin converting enzyme Correspondence to: Dr Feng Wng or Dr Ninsong Wng, Deprtment of Nephrology nd Rheumtology, Affilited Sixth People's Hospitl, Shnghi Jio Tong University, 600 Yishn Rod, Shnghi , P.R. Chin E mil: zyzwq1030@gmil.com E mil: wngninsong2008@163.com * Contributed eqully Abbrevitions: CIN, contrst induced nephropthy; CAG, coronry ngiogrphy; DKI, delyed kidney injury; egfr, estimted glomerulr filtrtion rte; NSAIDs, non steroid nti inflmmtory drugs; ACEI/ARB, ngiotensin converting enzyme inhibitors/ngiotensin II receptor blockers; CKD, chronic kidney disese Key words: contrst induced nephropthy, cute kidney injury, coronry ngiogrphy, spirin, hert filure (ACE) inhibitors/ngiotensin II receptor 1 blockers (ARBs), diuretics, sttins nd other nti pltelets between the two groups (P>0.05). Logistic regression reveled tht nemi, hert filure nd 300 mg spirin intke were risk fctors of DKI (P<0.05), while the contrst level, isotonic contrst, dibetes, ACE inhibitors/arbs, egfr nd other fctors were not ssocited with DKI (P>0.05). Hert dysfunction nd 300 mg spirin therpy my contribute to DKI fter CAG, nd iodinted contrst medi dministrtion is not risk fctor. Introduction Contrst induced nephropthy (CIN) is n cute kidney injury following dministrtion of iodinted contrst medi, nd is currently the third most common type of hospitl cquired renl filure (1). CIN often ppers in ptients who underwent coronry ngiogrphy (CAG), nd my result in renl function deteriortion nd in certin cses, deth. CIN following CAG often cuses long term decline in renl function (2). CIN is defined s n increse in serum cretinine concentrtion >26.5 µmol/l or >25% of its bseline cretinine level within 3 dys fter contrst medium dministrtion (3). Typiclly fter pek vlue of serum cretinine within the fifth dy, in which grnulr csts nd moderte proteinuri my pper, serum cretinine levels return to the bseline level within 7 10 dys (4). However, it hs lso been observed t Shnghi Jio Tong University Affilited Sixth People's Hospitl (Shnghi, Chin) tht certin ptients tht do not exhibit CIN develop irreversible deteriortion of renl function within 1 6 months following CAG. This is informlly clled ʻdelyed contrst induced nephropthyʼ or ʻdelyed kidney injury (DKI) fter CAGʼ, nd it hs been hypothesized by severl crdiologists t the Shnghi Jio Tong University Affilited Sixth People's Hospitl to be due to iodinted contrst medi dministrtion. However, it is unknown whether delyed CIN relly exists, or whether it is ssocited with CAG or induced by iodinted contrst medi. In the present study, it ws hypothesized tht DKI fter CAG my be cused by numerous fctors, but tht contrst did not contribute. In order to investigte the pthogenesis of DKI, retrospective study ws conducted in ptients receiving CAG nd coronry stenting to investigte whether DKI exists nd to understnd its etiology nd mechnism of ction.

2 WANG et l: DKI AFTER CAG 531 Mterils nd methods Subjects. Ptients receiving CAG nd coronry stenting between Jnury 1, 2008 nd December 31, 2009 t the Shnghi Jio Tong University Affilited Sixth People's Hospitl were enrolled in the present study. The inclusion criteri were s follows: Age, 18 yers old; receiving CAG nd percutneous coronry intervention. The present study ws pproved by the Ethics Committee of Shnghi Jio Tong University Affilited Sixth People's Hospitl nd dhered to the Declrtion of Helsinki (5). Written informed consent ws obtined from ll of the prticipnts. The exclusion criteri were s follows: Dignosis of CIN; electrophysiologicl exmintion nd percutneous trnsluminl septl myocrdil bltion conducted; bseline estimted glomerulr filtrtion rte (egfr) <30 ml/min; occurrence of mlignnt tumors, renl rtery stenosis nd urologicl obstruction illnesses; recurrence of myocrdil infrction during follow up; renl toxic medicine intke (except spirin); prerenl cute kidney injury (AKI); nd AKI secondry to primry kidney diseses. Dignostic criteri nd methods. The CIN dignostic criteri included the following: Cses with serum cretinine increse (fter CAG) 25% within h compred with bseline vlues; or n bsolute increse >44.2 µmol/l (6). The risk scores were tken into ccount in ccordnce with the risk score described by Mehrn (7). The CAG ssocited DKI dignostic criteri were s follows: Any serum cretinine vlue increse 26.5 µmol/l or >50% of the bseline vlue, 1 6 months following CAG. The bseline cretinine ws the serum cretinine level t 1 month fter CAG. The egfr ws clculted in ccordnce with the simplified Cockcroft Gult (CG) formul s follows: CG egfr: Cretinine clernce = (140 ge) x weight x 0.85 (if femle)/(72 x serum cretinine) (8). The hospitl nd follow up medicl records of enrolled ptients were collected nd the different cses were divided into groups, those cses dignosed with DKI (the DKI group) nd those cses without DKI (the non DKI group). The Mehrn scores of the DKI group were clculted nd common clinicl chrcteristics were screened (7). Sttisticl nlysis. SPSS softwre, version 13.0 ws employed for dt nlysis. Student's t test ws used to nlyze the mesurement dt while the χ 2 test ws used for ctegoricl comprison. The risk fctors ssocited with DKI, including ge, gender, body weight, hospitl sty, hert function grde, hemoglobin, bseline serum cretinine, fsting plsm glucose, egfr, contrst dosge, isotonic contrst, urine protein, dibetes, ngiotensin converting enzyme (ACE) inhibitors/ngiotensin II receptor blockers (ARBs), spirin, diuretics nd hydrtion therpy, were nlyzed by logistic regression. P<0.05 ws considered to indicte sttisticlly significnt difference. Results Bsic informtion of DKI nd non DKI subjects. A totl of 769 ptients were receiving CAG in the present study, nd there were 333 cses excluded ccording to the exclusion criteri, including 47 cses with definite CIN nd 29 drop out Tble I. Bsic informtion of ptients with DKI. Non DKI DKI Chrcteristic (n=405) (n=31) Age, yers 65.3± ±12.4 Mle, N (%) 273 (67.4) 22 (80.0) Proteinuri, N (%) Absent 247 (61.0) 16 (51.6) Microlbuminuri 131 (32.3) 12 (38.7) Proteinuri 27 (6.7) 3 (9.7) Comorbities, N (%) Dibetes mellitus 122 (30.1) 14 (45.2) Hypertension 276 (68.1) 21 (67.7) Hyperlipidemi 319 (78.8) 20 (64.5) Hert filure 22 (5.4) 7 (22.6) CVD 34 (8.4) 6 (19.4) PVD 33 (8.1) 5 (16.1) Age dt re presented s the men ± stndrd devition. P<0.05 vs. Non DKI. DKI, delyed kidney injury; CVD, cerebrovsculr disese; PVD, peripherl vsculr disese. Tble II. Biochemicl prmeters in ptients with DKI. Prmeter Non DKI DKI White blood cell, 10 9 /l 6.4± ±1.5 Hemoglobin, g/l 133.8± ±17.3 Hemtocrit, % 38.6± ±5.3 Alnine trnsminse, U/l 35.2± ±12.9 Serum cretinine, µmol/l 91.7± ±43.2 Tc, mmol/l 4.6± ±1.5 Low density lipoprotein, g/l 3.1± ±1.1 egfr, ml/min 71.9± ±30.2 P<0.05 vs. non DKI. egfr, estimted glomerulr filtrtion rte; Tc, totl cholesterol. cses. In totl, there were 436 vlid cses with intct follow up dt enrolled in the present study. In ddition, the egfr levels for ll the subjects prior to CAG were >30 ml/min. The incidence of DKI ws 7.1% (31/436) nd the verge time fter CAG tht DKI occurred ws 16.5±4.0 weeks. The percentge of hert filure nd cerebrovsculr disese were significntly higher in DKI ptients thn tht in the non DKI group (P=0.009 nd 0.041, respectively). However, no differences in proteinuri, dibetes, hypertension or hyperlipidemi were observed between the groups (Tble I). Furthermore, the cses were divided into the non DKI nd DKI group, nd the results presented significnt differences in hemoglobin (Hb), hemtocrit nd serum cretinine levels (P=0.039, nd 0.033, respectively; Tble II), between the two groups but no differences in white blood cell, lnine trnsminse nd low density lipoprotein.

3 532 Tble III. Medicine intke of the DKI ptients during the follow up. A Non DKI (n, %) DKI (n, %) Medicine n=405 n=31 ACEI 181 (44.7) 16 (51.6) ARB 99 (24.4) 5 (16.2) Diuretics 241 (59.5) 20 (64.5) Sttins 258 (63.7) 22 (71.0) Anti pltelet drugs Asp 100 mg 15 (3.7) 1 (3.2) Clop 36 (8.9) 1 (3.2) Wr 10 (24.7) 1 (3.2) Asp 100 mg + clop 243 (60.0) 14 (51.6) Cilostzol + clop 47 (11.6) 3 (9.7) Asp100 mg + clop + wr 31 (7.6) 2 (6.5) Asp 300 mg + clop 23 (5.7) 9 (29) B P<0.01 vs. Non DKI. DKI, delyed kidney injury; ACEI, ngiotensin converting enzyme inhibitor; ARB, ngiotensin receptor blocker; Asp, spirin; clop, clopidogrel; wr, wrfrin. Figure 2. Prognosis of DKI fter coronry ngiogrphy. (A) In totl there were 26 cses with DKI tht survived until the follow up of 6 months, with mortlity rte of 16.1% (5/31). In ddition, there were 402 cses without DKI tht survived, with deth rte of 1.0% (4/405). * P<0.01 vs. mortlity rte in the non DKI group. (B) Cuses of mortlity following DKI included hert nd renl filure. DKI, delyed kidney injury. Figure 1. Chnges of DKI incidence with Mehrn risk scores. The incidence of DKI incresed with Mehrn risk scores. DKI incidence ws 22.5% (9/40) in ptients with scores 16. DKI, delyed kidney injury. DKI incidence incresed with Mehrn risk scores. The results demonstrted tht the incidence rte of DKI incresed with Mehrn risk scores (Fig. 1), with DKI incidence of 22.5% (9/40) in ptients with scores 16. DKI my be ttributed to high dosge spirin intke. As presented in Tble III, totl of 29% (9/31) nd 5.7% (23/405) of ptients in the DKI nd non DKI groups, respectively, were treted with 300 mg spirin + clopidogrel following CAG, presenting significnt difference of P<0.01. However, no difference ws observed in the number of cses treted with ACE inhibitors/arbs, diuretics, sttins nd other nti pltelet drugs (ll P>0.05). Multivrite logistic regression nlysis ws performed to identify the risk fctors for DKI following CAG (Tble IV). The nlyzed fctors included ge, gender, body weight, hospitl sty, hert function grde, hemoglobin, bseline serum cretinine, fsting plsm glucose, egfr, contrst dosge, isotonic contrst, urine protein, dibetes, ACE inhibitors/arbs, spirin, diuretics nd hydrtion therpy. The results demonstrted tht nemi (hemoglobin <110 g/l), hert filure nd 300 mg spirin intke were risk fctors for DKI (P<0.05), wheres the contrst mount, isotonic contrst, dibetes, ACE inhibitors/arbs, egfr nd other fctors were not ssocited with DKI (P>0.05). Poor prognosis for ptients with DKI following CAG compred with non DKI ptients. As presented in Fig. 2A, 26 ptients with DKI, out of totl of 31, survived until the follow up of 6 months; the mortlity rte ws 16.1%. In ddition, there were 402 cses without DKI, out of totl of 405, tht survived, nd the mortlity rte in this group ws 1.0% (P<0.01). Cuses of mortlity following DKI included hert nd renl filure (Fig. 2B). Discussion Ptients with coronry hert disese often present high risk of CIN, therefore studies on the prevention of CIN following CAG is of note (9 13). By contrst, coronry rtery ssocited illnesses such s cute coronry syndrome, myocrdil infrction nd ischemic crdiomyopthy my led to hert filure nd decresed renl blood flow nd kidney injury (14,15). The present study hypothesized tht DKI following CAG my not be result of contrst itself, but other ssocited fctors. In

4 WANG et l: DKI AFTER CAG 533 Tble IV. Results of univrite nd multivrite nlysis for DKI. Univrite nlysis Multivrite nlysis Symptom or mediction OR 95% CI P vlue OR 95% CI P vlue Hert filure < b Hemoglobin (<110 g/l) b Bseline serum cretinine (>106 µmol/l) < egfr (<60 ml/min) Aspirin 300 mg + clopidogrel < <0.001 b Diuretics P<0.05 in the univrite nlysis; b P<0.05 in the multivrite nlysis. DKI, delyed kidney injury; CI, confidence intervl; OR, odds rtio; egfr, estimted glomerulr filtrtion rte. order to exmine this hypothesis, 436 cses tht underwent CAG were enrolled. The results demonstrted tht 7.1% ptients (31/436) developed DKI ccording to the greed dignostic criteri. Thus, DKI existed in ptients fter CAG. DKIs occurring 1 month or lter fter coronry ngiogrphy hd not been previously reported. All of the enrolled cses hd lredy excluded CIN, therefore the renl toxicity of the contrst my not be ble to ccount for the kidney injury within 1 6 months fter CAG. Two questions remin, including whether DKI is ssocited with CAG or coronry hert diseses; nd wht pthogenesis underlies DKI. In the present study, the possible risk fctors were ssessed. The Mehrn score is useful tool for predicting CIN risk, indicting the nti stress cpbility of the kidney (7,14). Therefore, the Mehrn score ws introduced to ssess the risks for DKI in the present study. Through strtifiction by the Mehrn score, it ws reveled tht the incidence of DKI incresed with the Mehrn risk scores. In the present cohort, 22.5% of ptients with Mehrn scores 16 were dignosed with DKI. The univrite nlysis reveled tht the serum levels of cretinine in the DKI group were higher thn those in the non DKI group, while Hb nd egfr levels were lower. Ptients with DKI were chrcterized s older, nd with higher incidence of hert filure nd cerebrovsculr diseses. The nlysis of orl drugs fter CAG during the follow up demonstrted tht spirin ws used more frequently in the DKI group. The multivrite logistic regression nlysis suggested tht nemi, hert filure nd 300 mg spirin intke were risk fctors for DKI, while egfr, dibetes, hypertension, ACE inhibitors/arbs nd sttins were not. Numerous drugs re used in ptients tht hve undergone coronry stenting in order to cure severl combined disorders; these drugs include nti hypertensive drugs, sttins nd nti pltelet drugs. It is estblished tht severl hypotensors, sttins nd nti pltelet drugs cuse renl toxicity, prticulrly in ged ptients with declined renl function. There re severl nti pltelet tretments used to prevent stent thrombosis nd reduce future ischemic events, spirin being one importnt nd common nti pltelet therpy (16). As one of the trditionl non steroid, nti inflmmtory drugs, spirin intke my result in renl filure or ggrvte renl dysfunction (17,18). In ddition, the use of nti pltelets is routine therpy in the tretment of CKD in order to prevent the recurrence of stroke or crdiovsculr complictions, since CKD increses the risk of incident stroke, hert filure nd myocrdil infrction (19). Furthermore, hert filure is importnt in the decline of renl function in CKD ptients, which often leds to deth or other complictions, such s pulmonry infection (20 23). Nowdys, it is considered tht CIN is short term syndrome bsed on the pthophysiology, lbortory reserch nd clinicl studies (24 27). It is currently ccepted tht only cretinine level increse within 7 dys fter CAG should be considered CIN (6). Thus, contrst induced delyed kidney injury is ctully not cused by contrst gents directly. Furthermore, the dt of the present study demonstrted tht 300 mg spirin nd hert filure my ccount for DKI fter CAG in Chinese popultion. Finlly, it is speculted tht DKI will ttrct incresingly more ttention in future studies. As result, it is recommended tht using lrge doses of spirin s long term nti pltelet therpy be voided in Chinese ptients, nd for high risk ptients, the long term renl function follow up results should not be ignored. In conclusion, delyed CIN fter CAG is not logicl term, while delyed kidney injury fter CAG ppers to be more pproprite when used to describe the renl injury occurring 1 month fter CAG. The dt of the present study suggested tht 300 mg spirin nd deteriorted hert function my contribute to the pthogenesis of DKI following CAG, nd tht iodinted contrst medi is not fctor. However, the smll cohort size of the current study is limiting fctor, nd for this reson follow up study with lrger cohort is required in order to investigte delyed renl injury fter CAG, in ddition to subsequent prospective study in order to understnd the etiology of DKI fter CAG. Acknowledgements The current study ws sponsored by the Ntionl Nturl Science Foundtion of Chin (grnt no ), the New 100 Tlent Pln of Shnghi Jio Tong University School of Medicine (grnt no. 2012) nd the Shnghi Tlents Development Fund (grnt no. 2013). We would lso like to thnk Dr Gry C. Mourdin Jr. from the Medicl College of Wisconsin for his English editing of the mnuscript.

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