Abstract
Objectives
Controversies regarding renal function impairment after open and endovascular aortic aneurysm repair still exist. The purpose of this study was to evaluate the renal function following open repair and endovascular aneurysm repair using Cystatin C.
Methods
This prospective, observational case–control study was conducted in tertiary referral centre over 3 years, starting from 2012. In total, 60 patients operated due to infrarenal AAA either by means of open repair (30 patients) or endovascular aneurysm repair (30 patients) were included in the study. Biochemical markers of renal function (sCr, urea, potassium) were recorded pre-operatively and at these specific time points, immediately after the operation and at discharge, home (third postoperative day, endovascular aneurysm repair group) or from intensive care unit (third postoperative day, open repair group). Multivariate and propensity score adjustments were used to control for the baseline differences between the groups.
Results
Creatinine levels in serum remained unchanged during the hospital stay in both groups without significant differences at any time point. Cystatin C levels in endovascular aneurysm repair patients significantly increased postoperatively and restored to values comparable to baseline at the discharge (0.865 ± 0.319 vs. *0.962 ± 0.353 vs. 0.921 ± 0.322, *p < 0.001). Cystatin C levels in patients treated with the open surgery was decreasing over time but not statistically significant comparing to Cystatin C values at the admission. However, decrease in Cystatin C serum levels in patients treated with conventional surgery resulted in statistically significant lower values compared to endovascular aneurysm repair patients both postoperatively and at the time of discharge (0.760 ± 0.225 vs. 0.962 ± 0.353, p < 0.05; 0.750 vs. 0.156, p < 0.05). Both multivariate linear regression models and propensity score adjustment confirm that, even after correction for previously observed intergroup differences, type of surgery, i.e. endovascular aneurysm repair is independently associated with the higher levels of Cystatin C both postoperatively and at the discharge.
Conclusions
Dynamics of Cystatin C levels have been proven as a more vulnerable marker of renal dysfunction. Endovascular aneurysm repair is associated with higher levels of kidney injury markers.
Introduction
Controversies regarding the renal function impairment after open and endovascular aortic aneurysm repair still exist. The cause of renal dysfunction after AAA repair has been attributed to atheroembolism (mural thrombus or atheromatous debris), renal ischemia, intraoperative hypotension and technical issues related to the renal arteries. Despite the lack of aortic cross clamping, renal injury is also identified during endovascular aneurysm repair (EVAR). 1 The need for contrast administration, extensive wire manoeuvring as well as graft deployment in close proximity to renal arteries may be responsible for EVAR related kidney injury. Serum creatinine (sCr) and estimated glomerular filtration rate (eGFR) are the most widely used kidney damage markers both after open repair (OR) and after EVAR. Recently, the low molecular weight protein serum Cystatin C (sCC) has been validated as a superior marker of renal injury to sCr that can be used to discern even a sub-clinical renal impairment.2,3 Additionally, sCC levels are successfully used as a marker of tubular dysfunction following EVAR.4,5 The purpose of this study was to evaluate the renal function following OR and EVAR using sCC.
Material and methods
This prospective, observational case–control study was conducted in tertiary referral centre over a period of 3 years, starting from 2012. In total, 60 patients operated due to infrarenal AAA either by means of OR (30 patients) or EVAR (30 patients) were included in the study. Preoperative contrast-enhanced computed tomography (CT) scans were obtained in all patients using multidetector scanners. There were no signs of thrombus formation in both groups in the neck zone. Exclusion criteria were pre-operative renal failure requiring renal replacement therapy (i.e. haemo- or peritoneal dialysis), symptomatic patients and inflammatory AAA. At study enrolment, recorded patient factors were sex, age, weight, smoking habit and sac sizes (calibrated on CT scan) and medical co-morbidity. Biochemical markers of renal function (sCr, sUrea) were recorded pre-operatively, immediately after the operation and at discharge, home (EVAR group) or from intensive care unit (third postoperative day, OR group). At the same timepoints, a separate clotted blood sample was collected for sCC analysis. The study was approved by our institutional Ethics Committee. Informed consent was obtained from each subject enrolled in the study.
Data analysis
The continuous variables are expressed as a mean ± standard deviation (SD), while categorical variables are presented in percentages (%). Data were analysed using the SPSS statistics 20.0. Independent variables were tested with the Student t test for unpaired measurements, while the paired variables are tested with repeated measures ANOVA with Bonferroni post hoc analysis or paired Student t test. Chi square test and Fisher exact test were used for analysis of categorical variables. Multivariate linear regression models were used to assess effect of procedure type on investigated renal function markers corrected for the marker’s baseline values, clinically relevant parameters and significantly different parameters between the groups.
To additionally reduce the effect of treatment selection bias and to adjust for possible confounding factors on the values of sCr, sUrea and sCC, the propensity-adjusted multivariable logistic regressions and propensity score-matching were performed. Propensity scores (conditional probability for receiving a certain treatment) for each patients were calculated using a binary logistic regression based on following covariates: age, hypertension, diabetes mellitus, angina pectoris, previous myocardial infarction, preoperative renal failure, smoking and AAA size. Results were considered significant if the p value was less than 0.05.
Results
Patient data
Patients treated by EVAR had emphasized cardiac comorbidities and were significantly older. Other investigated parameters were comparable. After the adjustment for calculated propensity scores, differences between the groups were neutralized. Only parameter that differed after propensity score adjustment was total operative time that was significantly shorter for EVAR procedure. Demographic characteristics, comorbid conditions as well as AAA size are presented in Table 1.
Demographic, clinical and intraoperative parameters.
Bold values represent statistical significance.
Peri-operative factors
Two different types of endovascular stent grafts with suprarenal fixation were used in the study group. Twenty-four (80%) patients received the Medtronic (Endurant, Santa Rosa, USA) with the other 6 (20%) cases undergoing EVAR using the Zenith device (Cook Lp). Median radiological contrast load (300 mg iodine/ml) during endovascular repair was 148 ml (range 100–300 ml). All patients were operated the day after contrast admission. Stent-graft implantation was technically successful in all cases. No renal complications were identified in both groups. There was no need for suprarenal clamping in OR group. The average bleeding in OR group was 750 ml while in endovascular group was 250 ml.
Markers of renal function
Values of all investigated markers of renal function were comparable between the groups at the time of admission (Figure 1). Creatinine levels in serum remained unchanged during the hospital stay in both groups without significant differences at any time point (Figure 1(a)). Serum potassium levels statistically decreased after surgery and at the discharge time in both groups, while the intergroup difference was not observed (Figure 1(d)).
Biochemical renal injury markers: (a) Creatinine, (b) urea, (c) Cystatin C and (d) K+.
On the contrary, levels of sUrea in group of patients who underwent open surgical repair had decreasing trend after surgery and reached statistical significance at the time of release compared to admission (6.06 ± 2.12 vs. 5.73 ± 2.06 vs. 5.15 ± 1.41*, p < 0.05; Figure 1(b)). Additionally, this trend was not observed in the EVAR group, which resulted in statistically higher values of serum urea compared to open surgery patients in both time points, immediately after operation and at the time of discharge (6.94 ± 2.54 vs. 5.73 ± 2.06, p < 0.05; 7.09 ± 3.21 vs. 5.15 ± 1.41, p < 0.01, respectively; Figure 1(b)).
Cystatin C (CC) levels in EVAR patients significantly increased postoperatively and restored to values comparable to baseline at the discharge (0.865 ± 0.319 vs. *0.962 ± 0.353 vs. 0.921 ± 0.322, *p < 0.001). CC levels in patients treated with the open surgery was decreasing over time but not statistically significant comparing to CC values at the admission. However, decrease in CC serum levels in patients treated with conventional surgery resulted in statistically significant lower values compared to EVAR patients both postoperatively and at the time of discharge (0.760 ± 0.225 vs. 0.962 ± 0.353, p < 0.05; 0.750 vs. 0.156, p < 0.05; Figure 1(c).
Multivariate linear regression models confirmed that, even after correction for previously observed intergroup differences, type of surgery, i.e. EVAR is independently associated with the higher levels of CC both postoperatively and at the discharge (b = 0.141, SE = 0.041, p = 0.001; b = 0.170, SE = 0.051, p = 0.002; respectively; Table 2). In addition to that, corrected for the same parameters, EVAR patients had higher values of serum urea at discharge (b = 2.121, SE = 0.635, p = 0.002), but not postoperatively compared to their counterparts treated conventionally (Table 3). Based on the multivariate linear regression, creatine levels changes were not associated with the type of surgery (Table 4), while higher values of potassium at discharge were independently associated with the EVAR procedure (b = 0.249, SE = 0.122, p = 0.046; Table 5).
Multivariate linear regression model for serum Cystatin C postoperative levels and levels at discharge.
Model statistics: F = 48.163, p-value < .001, R2 = .866, adjusted R2 = .848.
Model statistics: F = 19.004, p-value < .001, R2 = .719, adjusted R2 = .681.Bold values represent statistical significance.
Multivariate linear regression model for serum urea postoperative levels and levels at discharge.
Model statistics: F = 11.162, p-value < .001, R2 = .600, adjusted R2 = .547.
Model statistics: F = 8.913, p-value < .001, R2 = .545, adjusted R2 = .484.Bold values represent statistical significance.
Multivariate linear regression model for serum Creatinine postoperative levels and levels at discharge.
Model statistics: F = 19.531, p-value < .001, R2 = .724, adjusted R2 = .687.
Model statistics: F = 16.460, p-value < .001, R2 = .689, adjusted R2 = .647.Bold values represent statistical significance.
Multivariate linear regression model for serum K+ postoperative levels and levels at discharge.
Model statistics: F = 2.235, p-value = 0.038, R2 = .238, adjusted R2 = .136.
Model statistics: F = 3.313, p-value < .005, R2 = .308, adjusted R2 = .215.Bold values represent statistical significance.
Propensity scores denoting conditional probability of each patient to receive one of the two treatment modalities were calculated to attenuate the effect of the possible selection bias. The propensity scores were included in multivariate regression as an independent variable together with baseline levels of investigated kidney injury markers. After the correction with the propensity scores, EVAR procedure was independently associated with higher sCC levels both postoperatively and at the discharge. Additionally, EVAR procedure was independently associated with higher sUrea levels at discharge, while type of surgery does not influence either sCreatinine levels or sK+ levels (Table 6).
Propensity-adjusted and baseline value adjusted multivariate linear regression.
Model statistics: F = 112.735, p-value < .001, R2 = .858, adjusted R2 = .850.
Model statistics: F = 44.617, p-value < .001, R2 = .705, adjusted R2 = .689.
Model statistics: F = 26.519, p-value < .001, R2 = .587, adjusted R2 = .565.
Model statistics: F = 17.217, p-value < .001, R2 = .480, adjusted R2 = .452.
Model statistics: F = 40.576, p-value < .001, R2 = .685, adjusted R2 = .668.
Model statistics: F = 39.254, p-value < .001, R2 = .678, adjusted R2 = .660.
Model statistics: F = 4.836, p-value = .005, R2 = .206, adjusted R2 = .163.
Model statistics: F = 5.256, p-value = .003, R2 = .220, adjusted R2 = .178.Bold values represent statistical significance.
Propensity score matching procedure in a 1:1 (OR:EVAR) ratio, yielded 11 pairs of patients who were included in the paired analysis. Due to low number of observations in this subset of patients, only parameter that is significantly different between the groups was sUrea at discharge, which was higher in the EVAR patients (5.68 ± 1.73 vs. 7.29 ± 0.95, p < 0.031; Figure 2). However, the change of sCC values after the operation and at the discharge normalized to values at admission were significantly higher in the EVAR patients (−0.067 ± 0.200 vs. 0.078 ± 0.030, p = 0.03; −0.136 ± 0.300 vs. 0.092 ± 0.183, p = 0.029, respectively; Figure 3). CC values show strong positive correlation with creatinine serum levels both in OR and EVAR patients at all three investigated time points (Figure 4). This finding further strengthens the claim that observed increase in CC levels in our group of patients is indeed associated with renal injury and that CC may be regarded as a more sensitive indicator of kidney damage.
Biochemical renal injury markers after propensity score matching (11 pairs, 22 patients): (a) Creatinine, (b) urea, (c) Cystatin C and (d) K+.
Change of biomedical renal injury markers after propensity score matching (11 pairs, 22 patients): (a) Creatinine, (b) urea, (c) Cystatin C and (d) K+.
Correlation between serum levels of Cystatin C and creatinine for patients treated with open surgery at admission (a), postoperative (b) and at discharge (c); and with EVAR at admission (d), postoperative (e) and at discharge (f).
Discussion
Recent study reported a worrying substantial incidence of acute kidney injury (AKI) of 18.8% after elective procedures in a cohort study as per the ‘Acute Kidney Injury Network’ (AKIN) and ‘Kidney Disease Improving Global Outcomes’ (KDIGO) criteria. Development of AKI after surgery increases mortality, cardio-vascular morbidity, hospital stay and potentially long-term survival. 6 A lot studies were performed with the purpose of estimating the effect of different procedures (EVAR vs. OR) on kidney function. So far the results are opposite but different methods were applied as well. In 2002, Kramer et al. 7 published the first report of fixation-specific renal outcome following EVAR, but the study was not concerned with the renal function. The study didn’t find any association between renal function and type of procedure. After that, the majority of studies were based on detection of sCr values in serum. Cayne et al. reported comparative renal outcome in 130 EVAR patients with a mean follow-up of 17 months. There was a significant increase in sCr from pre-operative values in both groups, but without difference between fixation-type was observed. 8 Recently, a meta analysis on EVAR, conducted by Karthikesalingam et al., showed that deterioration in renal function of up to 18% at 1 year was associated with significant SCr increase and creatinine clearance decrease, making renal dysfunction after EVAR a real point of interest. 9 On the other hand, there are a few limitations of using sCR as a biochemical kidney function parameter which should be mentioned. One of the major problem is that sCr is formed by the non-enzymatic conversion of muscle creatine and phosphocreatine and hence its production rate is unstable, under direct influence from many non-renal factors (e.g. dietary preference, sex, muscle mass and surgical intervention). 10 Furthermore, sCr and eGFR only show significant change at 24 h and therefore may underestimate long-term renal damage after EVAR. 11
sCC is generally accepted as a better marker of excretory renal function. 12 The low molecular weight protein is produced by all nucleated cells, is unaffected by sex or muscle mass and is freely filtered and metabolised in the kidney.3,13 Furthermore, CC appears more sensitive in signifying earlier reductions in GFR (25–30%) 3 and therefore renal injury at a level that may be currently undetected in those EVAR patients with supra-renal stent systems. Pirgakis et al. 5 used urinary CC as a superior marker to sCr in the early diagnosis of acute renal dysfunction following open and endovascular AAA repair. In spite of that, recent study showed that biomarkers in plasma showed markedly better discriminative performance for preoperative risk stratification and early postoperative (within 24 h after surgery) detection of AKI than urine biomarkers. 14
The major finding of our study is that patients with AAA treated by EVAR most likely have more pronounced subtle renal injury presented with the rise of renal injury biochemical markers. We have observed that CC, one of the most sensitive markers of renal damage, rises immediately after procedure and that this rise is exclusively related to procedure type, i.e. endovascular approach. This observation is strengthened by the fact that higher serum urea levels at discharge are as well independently associated with EVAR both after multivariate and propensity adjusted analysis. It is important to note that the dynamics of sCC values may be of greater importance for monitoring kidney function after AAA repair. Therefore, having the preoperative values of sCC can improve renal injury detection. One of the explanations for such renal damage during endovascular procedure is based on usage of contrast during endovascular procedure. The major contributor to contrast nephropathy is increase of intra-renal vasoconstriction and decrease of medullar blood supply while renal microembolizations are often the major factors that lead to renal malperfusion. The amount of contrast used in our patients is high, but it didn’t differ significantly in comparison with other studies. 6 In fact, the amount of contrast in some cases was a little bit higher than it should be but it didn’t affect results significantly in that particular cases. Usage of fusion image techniques nowadays are improving performance of EVAR by reducing radiation exposure and iodine contrast consumption. 15 Also, a new contrast agents like CO2 may further decrease renal damage. Another explanation is that during placement, self-expanding grafts are often partially deployed in the suprarenal position and pulled down the aorta into the final position. This manoeuvre may potentially dislodge aortic debris, resulting in atheroemboli into the renal vessels, as evidenced by renal infarction rates as high as 19% during EVAR. 16 Finally, many devices use balloon fixation of the proximal graft, which may temporarily occlude the renal vessels potentially resulting in thrombosis, embolus or dissection. An interesting thing is that the majority of studies report significant worsening of the renal function during follow-up in patients who were treated with suprarenal fixation. 17 Alsac et al. published their data after EVAR in 277 patients and demonstrated an approximate 10% decrease in calculated creatinine clearance within the first year after EVAR. 18 Unfortunately, we haven’t followed these patients in terms of renal function, but certainly we have to keep in mind that initial worsening of the renal function should alert us on more frequent check of renal function especially during the first year after the treatment.
Despite all the efforts to achieve a good match between patients, EVAR patients were significantly older than those in open group. Older patients are more susceptible to renal insults in comparison with younger patients and somehow these results may impact the data. In addition, our groups included significantly fewer women. This is consistent with previous data that demonstrated that more than half of female patients fail to be candidates for EVAR, whereas approximately 70% of male patients qualify. 19
On the other hand, a renal dysfunction during open surgery is associated with a couple of different mechanisms. The location of the aortic clamp during the repair may have an effect on postoperative short-term and midterm renal function, although a consensus in the literature does not exist. Some investigators report no association between clamp site and postoperative renal dysfunction, 20 whereas others have noted a positive correlation. 21 Clamping of infra-renal aorta is associated with ascertain risk of distal embolization of the pelvic system via hypo-gastric arteries. Percentage of embolization in hypo-gastric system is not known, but the incidence of embolization, for example, in the visceral system, is high, 77%, which was confirmed in one autopsy study. 22 In order to avoid distal embolization, it is proposed that iliac artery are clamped first and then infra-renal aorta. However, Lipsitz et al. in a study which compared proximal and distal clamping in dogs have shown that in primary clamping of iliac arteries more than 90% of the embolic particles went in to the renal arteries and visceral system, probably by mechanism of reflective waves and turbulent flow. 23
Study limitations
Despite the efforts made to accomplish appropriate patient matching between the groups, a couple of different parameters were observed. This in homogeneity between groups was somehow anticipated due to rigid selection criteria for EVAR procedures in our clinic. Eventually, influence of patients’ comorbid condition to our results was excluded by multivariate analysis and propensity adjustments. In a view of the relatively small number of patients included in the study, its power must be taken into context. Furthermore, the unavoidable use of two specific differing endograft designs within the study group may act as a source of bias.
Conclusion
According to our results, EVAR is followed with a higher degree of renal function deterioration in comparison with open OR based on investigated markers of renal injury. CC has been proven as a more vulnerable marker of renal dysfunction in comparison with sCr.
Footnotes
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The presented study is a part of a scientific research project (No 175008) supported by the Ministry of Education and Science of the Republic of Serbia.