The Prevention of Renal Dysfunction in High-risk CKD Patients Undergoing Carotid Artery Stenting

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1 Journal of Neuroendovascular Therapy 2016; 10: Online September 9, 2016 DOI: /jnet.oa The Prevention of Renal Dysfunction in High-risk CKD Patients Undergoing Carotid Artery Stenting Naoki Hatsuda, 1 Masayuki Nakajima, 1 Tadahiro Tanimoto, 1 and Yayoi Yoshimura 2 Objective: Contrast-induced acute kidney injury is more likely to result in various morbidities than to develop into renal dysfunction. To prevent acute kidney injury from occurring, we performed hydration therapy and administered reduced contrast medium concentrations for patients with preexisting high-risk chronic kidney disease (CKD; stage 3 or 4). The objective of this study was to evaluate the effectiveness of these procedures. Methods: Fifty-one sites underwent carotid artery stenting. We divided the patients into two groups by CKD stage (group A: stage 1 2, group B: stage 3 4) and reduced the dose of contrast medium during the intervention for the patients in group B. Furthermore, intravenous hydration peri-intervention was performed in patients with CKD stage 3b or 4. The differences in the estimated glomerular filtration rate (egfr) between before and after therapy, were retrospectively assessed. Results: There was a significant difference in the two groups in terms of the dose of contrast medium administered (group A: 58.3 ml ± 18.5 ml, group B: 32.8 ml ± 21.5 ml, p <0.01). Moreover, there was a significant difference between the two groups in terms of the difference in egfr before and after the intervention (group A: 4.87 ml ± 8.23 ml, group B: 1.03 ml ± 6.07 ml, p <0.05). Conclusion: Our findings indicate the effectiveness of a reduction in the dose contrast medium and hydration for the prevention of renal dysfunction in high-risk CKD patients undergoing carotid artery stenting. Keywords carotid artery stenting, chronic kidney disease, low dose of contrast medium, hydration, contrast-induced acute kidney injury Introduction Contrast-induced acute kidney injury (CI-AKI) occurs in 1% 3% of the general population and 10% 20% of patients with advanced chronic kidney disease (CKD) in treatments or examinations using a contrast medium. 1) CI-AKI is known to be more likely to occur when CKD is observed as an underlying disease and to be associated with the need for dialysis or exacerbation of the subsequent life prognosis. 2,3) 1 Division of Neurosurgery, Omihachiman Community Medical Center, Omihachiman, Shiga, Japan 2 Department of Neurosurgery, Shiga University of Medical Science, Otsu, Shiga, Japan Received: March 3, 2016; Accepted: June 15, 2016 Corresponding author: Naoki Hatsuda. Division of Neurosurgery, Omihachiman Community Medical Center, Tsuchida-cho 1379, Omihachiman, Shiga , Japan nhtsd2381@yahoo.co.jp 2016 The Editorial Committee of Journal of Neuroendovascular Therapy. All rights reserved. With the propagation of endovascular treatment, the necessity of evaluation of the kidney function has increased, and it has become an important factor in treatment restriction and selection. Carotid artery stenting (CAS) is a typical endovascular treatment in which the dose of the contrast medium can be restricted. It is usually performed electively, the procedure is relatively simple, and imaging using a contrast medium is limited to the determination of the stenting site and post-procedural checking for acute in-stent occlusion and distal embolization. Therefore, it is possible to minimize the dose of the contrast medium or even to perform the entire procedure under fluoroscopy and carotid artery ultrasonography. At our hospital, we considered pre-procedural contrastenhanced imaging as essential for the determination of the stenting site and examination of the state of stenosis and performed it immediately before stenting. Otherwise, the use of contrast media was minimized, and pre-procedural hydration was performed, according to the CKD stage (Table 1), and the results of these measures were evaluated. 183

2 Hatsuda N, et al. Table 1 egfr and CKD stage CKD stage egfr (ml/min/1.73 m 2 ) < a < b < < <15 CKD: chronic kidney disease; egfr: estimated glomerular filtration rate Material and Methods The subjects were 44 patients with 51 lesions (35 males and nine females, mean age: 71.9 years) who underwent carotid artery stenting between October 2011 and November The estimated glomerular filtration rate (egfr) was calculated from the results of pre-procedural blood tests and age, and CKD staging was performed. According to the 2002 guidelines, 4) the egfr values were categorized into five levels using cut-off values of 90, 60, 30, and 15, but stage 3 was divided into 3a and 3b by the 2011 classification. 5) By this 6-grade staging, the age-adjusted hospitalization period, frequency of cardiovascular disorders, and overall mortality have been reported to rise with the stage. 2) Since we minimized the dose of the contrast medium in patients with stage 3 or more advanced CKD, who are considered a high-risk group, the patients were divided into groups A (stages 1 and 2) and B (stages 3 and 4) for comparisons. No pre-procedural hydration was performed in stage 3a patients, but iv infusion of at least 500 ml of lactated Ringer s solution was made with post-procedural continuous drip infusion over 24 h or longer in stage 3b and four patients. In CKD stage five patients, who were all undergoing maintenance dialysis, dialysis was scheduled on the day after the treatment, and the dose of the contrast medium was not restricted. As stage five patients were receiving dialysis, they were not included in group A or B. In group A, angiography of the neck and head was performed both before and after stenting. In group B, angiography was performed to determine the stenting site in the neck, but contrast-enhanced imaging for other purposes was performed only when it was necessary. The post-procedural condition of the stent lumen was evaluated using IVUS, and contrast-enhanced imaging was performed when necessary. Basically, the dose of the contrast medium (g) was regulated in a range not exceeding the egfr (ml/min/1.73 m 2 ). In both groups, the contrast medium used was Oypalomin 300 injection (612.4 mg/ml iopamidol) or Iopaque 300 injection (647.1 mg/ml iohexol). CAS was performed by the transfemoral approach in 49 and transcubital approach in 2. By the transfemoral approach, after proximal occlusion by placing a Cello 9Fr. (Fuji Systems, Tokyo) or Optimo 9Fr. (Tokai Medical Products, Aichi) in the common carotid artery, an embolic protection device (Carotid Guardwire PS (Medtronics, Minneapolis, MN, USA) in all patients) was guided superiorly into the internal carotid artery to prevent distal embolization. In the two patients treated by the transcubital approach, Emvoy 6Fr. (Cordis Neurovascular, Miami FL, USA) was used. After pre-dilation using a balloon with an inflated diameter of 60% 70% of the original vascular diameter, the stent was deployed. Carotid Wall stent (Boston Scientific, Natic, MA, USA) was used when soft plaque was suggested by the black blood imaging, but Precise or Protage RX (Cordis, Johnson & Johnson, Fremont, CA, USA) was used otherwise. Post-dilation was not performed, in principle, but was performed when dilation was judged to be insufficient by IVUS. A representative therapeutic course is shown in Fig. 1. For the calculation, the dose of the contrast medium used for imaging was assumed to be 5 ml/time. It was assumed to be 20 ml/time when rotational DSA was performed. The egfr was compared between before and after CAS as an index of kidney dysfunction. It was measured within 72 h after the procedure, in principle. The patients age, sex, and the presence or absence of hypertension, diabetes, hyperlipidemia, symptoms, smoking, drinking, treatment-associated hypotension, and cerebral infarction were also evaluated. EZR ( statmed.html) was used for statistical analysis. Fisher s exact test was performed for comparison of the sex, presence or absence of hypertension, diabetes, hyperlipidemia, smoking, drinking, symptoms, treatment-associated hypotension (the lowest systolic blood pressure after the post-procedural return to the ward being 20 mmhg or more lower than the preprocedural systolic blood pressure), and infarction (positive on post-procedural diffusion-weighted imaging of MRI) according to the CKD stage separately in Groups A and B. Student s t-test was performed for comparison of the age, pre-procedural egfr, difference in the egfr between before and after the procedure (post-procedural egfr pre-procedural egfr), difference in the systolic pressure (lowest value after the postprocedural return to the ward pre-procedural value), dose of the contrast medium, and ratio between the pre-procedural egfr and the dose of the contrast medium. 184

3 The Prevention of Renal Dysfunction in High-risk CKD Patients Undergoing Carotid Ar tery Stenting Admission Drip infusion of 1500 ml/day CAS Discharge Blood tests MRI Carotid artery ultrasonography Pre-procedural check of stenting site Pre-dilation Stent placement IVUS Examination of the vascular system by MRA at MRI plaque imaging Check of post-procedural condition Fig. 1 Treatment of a patient with CKD stage 3b or 4. MRA from the puncture site to the treatment site is performed before the procedure. After admission, IV drip infusion is started at least from the day before CAS. In the treatment, the optimal imaging angle is predicted from the MRA images obtained in advance, and angiography is performed for the determination of the stenting site by injecting the contrast medium via the guiding catheter. Then, after pre-dilation and stent placement, the stent is evaluated by IVUS. Angiography is performed again if necessary. CAS: carotid artery stenting; CKD: chronic kidney disease; IVUS: intravascular ultrasound Results Table 2 shows the data of the 51 lesions in 44 patients (35 males and nine females, mean age: 71.9 years) according to the CKD stage and group. Stenting was successful in all patients. Four patients (1 stage 1 and 3 stage five patients) fulfilled the definition of CI-AKI: An increase in the creatinine level by 0.5 mg/dl or more or 25% or more within 72 h after the use of the contrast medium. The condition of the stage 1 patient advanced to stage 2, but no subsequent development of kidney disorder was observed. Since the egfr is dependent on age, it decreases in older patients if the creatinine level is the same. In our patients, also, the mean age tended to rise with advances in the CKD stage. The difference in the egfr between before and after the procedure was unrelated to the age, sex, or history of smoking, drinking, hypertension, diabetes, or hyperlipidemia. It was also unrelated to post-procedural hypotension, use of a vasopressor, procedure-related cerebral infarction, or the presence or absence of symptoms. Next, the patients were divided according to the preprocedural CKD stage into groups A (stage 1 2) and B (stage 3 4) and compared. Figure 2 shows changes in the egfr between before and after CAS in the two groups. The dose of the contrast medium was 58.3 ± 18.5 and 32.8 ml ± 21.5 ml in groups A and B, respectively (p <0.01). The change in the 185

4 Hatsuda N, et al. Table 2 Dose of the contrast medium and egfr by the CKD stage CKD stage Number of lesions Mean age (years) Mean dose of contrast medium (ml) Mean egfr (ml/min/1.73 m 2 ) Post-procedural increase in egfr (ml/min/1.73 m 2 ) ± ± ± ± ± ± ± ± a ± ± ± ± b ± ± ± ± ± ± ± ± ± ± ± ± 1.16 Group A ± ± ± ± 8.23 Group B ± ± ± ± 6.07 Group A: stage 1, 2, Group B: stage 3a, 3b, 4. CKD: chronic kidney disease; egfr: estimated glomerular filtration rate egfr (ml/min/1.73 m 2 ) Group A Group B Dose of contrast medium (ml) Group A Group B before Fig. 2 Changes in egfr between before and after CAS. Changes in the egfr between before and after the procedure in individual patients in groups A and B. CAS: carotid artery stenting; egfr: estimated glomerular filtration rate egfr after the procedure was 4.87 ± 8.23 and 1.03 ± 6.07, respectively (p <0.05). Figure 3 shows the relationship between the dose of the contrast medium and change in the egfr between before and after the procedure. Significant differences were also observed in the age and history of hypertension between the two groups (p <0.05) (Tables 3 and 4). However, no significant difference was observed in the change in the systolic blood pressure, presence or absence of infarction, or the history of smoking, drinking, diabetes, or hyperlipidemia between the two groups (Tables 3 and 4). Discussion after In 2002, the Kidney Disease Outcomes Quality Initiative (KDOQI) issued guidelines, 4) and treatments corresponding Change in egfr(ml/min/1.73 m 2 ) Fig. 3 Ratio between the dose of the contrast medium and change in the egfr in groups A and B. Scattergrams of the change in the egfr between before and after CAS and the dose of the contrast medium in individual patients in groups A and B. CAS: carotid artery stenting; egfr: estimated glomerular filtration rate to the severity of kidney dysfunction became necessary. Kidney dysfunction began to be predicted according to the CKD stage based on the egfr, which is calculated in Japan by the following equation from the serum creatinine level and age: 6) egfr (ml/min/1.73 m 2 ) = 194 Cr Age (female: 0.739) It has been shown that the mortality due to all diseases, incidence of cardiovascular disorders, and hospitalization period all increase as the CKD stage advances. 1,2,7) Particularly, CI-AKI is more likely to occur in patients with stage 3 or more advanced CKD, and measures such as hydration and the use of a kidney-protecting solution are commonly employed for contrast studies in such patients as a CKD highrisk group. 8) At our hospital, the egfr of each patient who undergoes blood tests began to be automatically calculated 186

5 The Prevention of Renal Dysfunction in High-risk CKD Patients Undergoing Carotid Ar tery Stenting Table 3 Comparison of evaluation items between groups A and B (binary variables) Evaluation item Group A absent/present Group B absent/present Fisher s exact test p-value Sex F: 3/M: 27 F: 4/M: Hypertension 15/15 1/ ** Diabetes 17/13 6/ Hyperlipidemia 20/10 9/ Smoking 15/15 11/ Drinking 21/9 13/ Symptoms 20/10 10/ Post-procedural hypotension 17/13 7/ Post-procedural cerebral infarction 20/10 7/ ** : p value <0.01 Table 4 Comparison of evaluation items between groups A and B (continuous variables) Evaluation item Group A Group B Student t-test p-value Age (years) 68.9 ± ± * Pre-procedural egfr (ml/min/1.73 m 2 ) 78.9 ± ± 11.8 <0.001 ** Post-procedural change in egfr (ml/min/1.73 m 2 ) ± ± * Difference in systolic blood pressure (mmhg) 32.8 ± ± Dose of contrast medium (ml) 58.3 ± ± 21.5 <0.001 ** Ratio between pre-procedural egfr and dose of contrast medium 2.29 ± ± egfr: estimated glomerular filtration rate; * : p value <0.05; ** : p value <0.01 and indicated on the electronic chart since 2011 facilitating the detection of CKD, and all members of the medical staff became involved in risk management for kidney dysfunction. Factors that exacerbate the kidney function are known to include (1) aging, (2) diseases such as hypertension, diabetes, myocardial ischemia and heart failure that reduce the renal blood flow, vascular disorders such as renal artery stenosis, and anemia, (3) smoking and drinking habits and lifestyledependent factors such as a high BMI, and (4) iatrogenic factors such as the use of antihypertensive agents and contrast media. 7 9) Patients in whom the egfr continues to be less than 60 for 3 months or longer due to causes related to these factors (CKD stage 3) are defined as a CKD high-risk group. In this group, multiple factors shown above are present, and the condition progressively deteriorates. The lifetime morbidity of CKD is reported to be 50% or higher, which is higher than those of diabetes (33% 39%), heart disease (32% 49%), and cancer (38% 45%), though not as high as that of hypertension (83% 90%). 10) The CKD high-risk group is reported to be likely to develop CI-AKI. 11) Frequent occurrence of CI-AKI after IVR for coronary artery disease, in which the dose of the contrast medium exceeds 100 ml, has been reported. 12) CI-AKI is defined as an elevation of the creatinine level of 0.5 mg/dl or more or 25% or more, but the fulfillment of this definition does not immediately lead to severe kidney failure. From this viewpoint, Maioli et al. compared a group in which exacerbation of the kidney function was transient and a group in which it persisted in patients who exhibited temporary CI-AKI. 13) According to their report, age, diabetes, progressive heart failure, use of diuretics, unstable angina, ejection fraction, proteinuria, serum creatinine level, and contrast nephropathy risk score were related to whether or not the patient developed CI-AKI, and hypertension, progressive heart failure, use of diuretics, ejection fraction, creatinine level, a 1.5-fold or greater increase in the creatinine level within 5 days after treatment, and an increase in the contrast nephropathy risk score were factors related to the persistence of kidney dysfunction after CI-AKI. Also, Mehran 13) et al. scored risk factors of CI-AKI in endovascular treatment of the coronary artery and reported increases in the mortality after 1 year with the score. They scored hypertension, the use of intra-aortic balloon pumping, heart failure, age ( 75 years), anemia, diabetes, contrast medium dose (1 for every 100 ml), and egfr (three levels based on the value) and showed elevations in the risk of CI-AKI and dialysis initiation rate with increases in the score. 14,15) The cytotoxicity of contrast media has been reported from before, but the cause of CI-AKI remains unclear. Patients who have developed CI-AKI exhibit symptoms of osmotic nephropathy, which include edema and vacuolation of cells of the proximal renal tubules. When a contrast medium is 187

6 Hatsuda N, et al. administered at a large dose, vacuolation begins to appear in cells of the distal renal tubules, collecting ducts, and glomerular surface, and intussusception of cells appears in the proximal renal tubules. 16,17) In addition, contrast media have been suggested to induce vasospasm of renal vessels and cause renal ischemia by increasing endothelin and intracellular Ca and reducing nitric oxide. 18) In a study that compared nonionic isotonic and non-ionic hypotonic contrast media, 19) no significant difference was observed between the two groups, so the problem is not considered to be ascribed to the osmotic pressure alone. For the prevention of CI-AKI, homedialysis 20) and the administration of N-acetylcysteine, which is an antidote for acetaminophen, 21,22) sodium bicarbonate used for the correction of acidosis derived from the proximal renal tubules, 23,24) a high dose of statin, 25) and physiologic saline 26) have been shown to be effective. Except for hemodialysis, the administration from before the procedure is necessary, but as CI-AKI is caused by exposure to contrast media, minimization of their dose is the first priority. Creatinine is examined for the early detection of CI-AKI. However, as the creatinine level reaches a peak 3 5 days after the occurrence of renal dysfunction, cystatin C was measured for the early prediction of its occurrence in one report. 27) In the subjects of this study, CI-AKI occurred in only 1 patient in group A, with its incidence being 3.3% in group A and 0% in group B. In this patient, the dose of the contrast medium was 60 ml, but post-procedural bradycardia and hypotension (decrease in the systolic blood pressure: 45 mmhg) are considered to have promoted its occurrence. Regarding the dose of the contrast medium, Nash et al. 28,29) reported that the incidence of CI-AKI was 5% when the fraction of the contrast medium dose (g) to the pre-procedural egfr (ml/min/1.72 m 2 ) did not exceed 1 but 25% when it exceeded 1. Although we also applied this ratio to our data, it did not serve as a predictive index perhaps because of the smallness of the dose. A disadvantage of restricting the dose of the contrast medium is the difficulty in pre-procedural assessment of the condition of the stenosis site and intracranial vessels. In our patients, hyperintensity was more often positive in group B on post-procedural diffusion-weighted MRI, although the difference was not significant. In this study, impairment of the kidney function could be prevented by minimization of the dose of the contrast medium in Group B, which was a high-risk group for CKD, and by the addition of hydration in patients with stage 3b or more advanced CKD, without a decrease in the egfr. Also, hypotension after CAS did not lead to a decrease in the egfr. Since prolonged hypotension that occurs after CAS exacerbates renal dysfunction, 30) it is desirable to reduce the amount of the contrast medium that passes the renal tubules and avoid its retention, and minimization of the dose of the contrast medium is considered to be an important preventive factor. Disclosure Statement The first author and the co-authors have no conflicts of interest. References 1) Sterner G, Nyman U: Contrast medium-induced nephropathy. Aspects on incidence, consequences, risk factors and prevention, Libyan J Med 2007; 2: ) Go AS, Chertow GM, Fan D, et al: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 2004; 351: ) Schiffrin EL, Lipman ML, Mann JF: Chronic kidney disease: effects on the cardiovascular system. Circulation 2007; 116: ) National Kidney Foundation: K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002; 39: S1 S266. 5) Levey AS, de Jong PE, Coresh J, et al: The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int 2011; 80: ) Matsuo S, Imai E, Horio M, et al: Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 2009; 53: ) Gansevoort RT, Correa-Rotter R, Hemmelgarn BR, et al: Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet 2013; 382: ) Bellomo R, Kellum JA, Ronco C: Acute kidney injury. Lancet 2012; 380: ) Fraser SD, Roderick PJ, May CR, et al: The burden of comorbidity in people with chronic kidney disease stage 3: a cohort study. BMC Nephrol 2015; 16: ) Grams ME, Chow EK, Segev DL, et al: Lifetime incidence of CKD stages 3 5 in the United States. Am J Kidney Dis 2013; 62: ) McCullough PA, Sandberg KR: Epidemiology of contrastinduced nephropathy. Rev Cardiovasc Med 2003; 4: S3 S9. 12) Silver SA, Shah PM, Chertow GM, et al: Risk prediction models for contrast induced nephropathy: systematic review. BMJ 2015; 351: h ) Maioli M, Toso A, Leoncini M, et al: Persistent renal damage after contrast-induced acute kidney injury: incidence, 188

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