Assessment of subclinical acute kidney injury after abdominal aortic aneurysm surgery using novel markers: L-FABP and H-FABP
Evaluación de fracaso renal agudo subclínico tras cirugía de aneurisma aórtico abdominal utilizando nuevos marcadores: L-FABP y H-FABP
Michał Kokota, Grzegorz Biolikb, Damian Ziajab, Tadeusz Fojta, Leszek Kędzierskia, Katarzyna Antoniaka, Mirosława Janowskaa, Krzysztof Pawlickic, Krzysztof Ziajab, Jan Duławaa
a Department of Internal Medicine and Metabolic Diseases, Medical University of Silesia, Katowice, Poland,
b Department of General and Vascular Surgery, Medical University of Silesia, Katowice, Poland, Katowice, Poland,
c Department of Biophysics Medical University of Silesia, Katowice, Poland, Katowice, Poland,
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] "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">INTRODUCTION</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">In the past years, due to the application of new imaging techniques, the number of newly recognized aortic aneurysms has increased considerably. However, the results of surgical treatment are negatively affected by complications among which acute kidney injury (AKI) is regarded as one of the most significant.<span class="elsevierStyleSup">1,2</span> Clinical observations have revealed that even minor rises in serum creatinine could have an unfavourable impact on mortality. AKI could result in the necessity of renal replacement therapy, the development of chronic kidney disease or increased mortality.<span class="elsevierStyleSup">3,4</span> Up to now, a lot of attention has been directed to meticulous investigation of AKI in critically ill patients, after cardiac surgery or following the use of iodinated contrast mediums.<span class="elsevierStyleSup">5,6</span> Despite the fact that the AKI is a well known complication of AAA operations<span class="elsevierStyleSup">1</span> less attention was paid to detailed analysis of pathophysiology of this phenomenon. The problem of AKI after AAA surgery is of significant importance because it concerns older people with other comorbidities and very often with already compromised renal function. Moreover, appropriate markers enabling researchers to scrutinize early phases and further dynamics of AKI, which, additionally, outperform serum creatinine, were found only recently.<span class="elsevierStyleSup">7,8</span> Among these markers are Liver and Heart Type of Fatty Acid Binding Proteins (L-FABP and H-FABP respectively).<span class="elsevierStyleSup">9</span></p><p class="elsevierStylePara">The family of fatty acid binding proteins (FABPs) comprises nine members. They play an important role in intracellular long-chain fatty acid transport and could have protective effect against cell injury. FABPs are expressed in different tissues with various intensity. Only two FABPs occur in the kidney, ie., H-FABP and L-FABP. Of particular interest is that L-FABP is expressed specifically in proximal tubular cells and H-FABP in distal ones. Therefore, the application of these two cognate markers allows the assessment and simultaneous comparison of the injury to proximal and distal segments of the renal tubule.<span class="elsevierStyleSup">9-11</span> While L-FABP has already been used as an efficient AKI marker, H-FABP, up to our current knowledge, has been scarcely used in this context. Nevertheless, a combination of two closely akin markers of the two nephron segments has already been efficiently employed in the assessment of progression of idiopathic membranous nephropathy.<span class="elsevierStyleSup">12</span></p><p class="elsevierStylePara">The aim of this study was to assess the dynamics and severity of kidney injury after AAA surgery using these novel, promising indicators. Furthermore, the selective differential assessment of injury of proximal and distal segment of renal tubules was of our particular interest. We decided to scrutinize early signs of kidney injury during AAA surgery sequentially at different time points with regard to aorta cross-clamping. We would like to analyze the overall dynamics of kidney damage after AAA surgery as indicated by these new markers in typical clinical settings.</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">MATERIAL AND METHODS</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Study population<span class="elsevierStyleItalic"> </span></span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The study comprised 22 consecutive patients (Table 1) admitted to the Department of Vascular Surgery for elective AAA surgery, who signed informed consent and did not meet the exclusion criteria including: (1) the use of aminoglycoside antibiotics within one month before surgery, (2) treatment with cyclosporine A, (3) neoplastic disease, (4) another surgical procedure during one month prior to enrollment, (5) stroke during the preceding two months, (6) myocardial infarction during the preceding three months, (7) essential psychiatric, metabolic, neurological, blood or major internal organs disorders, (8) incident of acute renal failure (ARF) or renal replacement therapy during the preceding six months, (9) an ongoing acute inflammatory response, (10) urinary tract obstruction. The research was approved by the Bioethics Committee of the Medical University of Silesia. Patients characteristics, comorbidities and basic laboratory data are shown in Table 1. Before the enrollment, 7 patients were treated with statins, 11 with ACE-I, one with AT1-bloker, 4 with nonsteroid anti-inflammatory drugs, 12 with β-blockers, 3 with Ca-channel blockers, 4 with nitrates, 2 with diuretics, but none with spironolactone and pentoxyphylline. No patients received nephrotoxic drugs two weeks before and within the study period.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">AAA surgery</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Between days 2 and 108 before surgery the subjects underwent <span class="elsevierStyleItalic">contrast</span>-enhanced <span class="elsevierStyleItalic">computed tomographic angiography</span>. After infra-renal cross-clamping, the aortic aneurysm was excised and the aorta was reconstructed using a PTFE graft. Surgery was performed under general anaesthesia; the details are given in Table 2.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Design</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The study protocol was as follows. All admitted patients underwent AAA and kidney ultrasound as well as <span class="elsevierStyleItalic">renal artery Doppler exam</span><span class="elsevierStyleItalic">ination</span>. Blood samples were obtained from an upper extremity vein <span class="elsevierStyleItalic">(B-before)</span> on the day before surgery (day - 1). The successive blood samples were drawn from an upper extremity vein: <span class="elsevierStyleItalic">(B4h)</span> 4 hours (day 0), <span class="elsevierStyleItalic">(B24h)</span> 24 hours (day 1), <span class="elsevierStyleItalic">(B48h)</span> 48 hours (day 2), <span class="elsevierStyleItalic">(B72h)</span> 72 hours (day 3), <span class="elsevierStyleItalic">(B96h)</span> 96 hours (day 4) and <span class="elsevierStyleItalic">(B120h)</span><span class="elsevierStyleBold"> </span>120 hours (day 5) following the moment of aortic clamp removal. Urine samples were taken <span class="elsevierStyleItalic">(U-before)</span> before operation (day - 1), and then from the urinary catheter <span class="elsevierStyleItalic">(U-surgery)</span> just before removal of aortic clamp, <span class="elsevierStyleItalic">(U2h)</span><span class="elsevierStyleBold"> </span>2 hours, <span class="elsevierStyleItalic">(U4h)</span> 4 hours, <span class="elsevierStyleItalic">(U12h)</span><span class="elsevierStyleBold"> </span>12 hours (<span class="elsevierStyleItalic">U-surgery – U12h</span>: day 0), <span class="elsevierStyleItalic">(U24h)</span> 24 hours (day 1), <span class="elsevierStyleItalic">(U48h)</span> 48 hours (day 2), and <span class="elsevierStyleItalic">(U72h)</span> 72 hours (day 3) after the removal of aortic clamp. The duration of surgery and aortic clamping, total volume of intravenous infusions and blood loss during surgery were all considered. Complete blood count (samples <span class="elsevierStyleItalic">B-before</span> and <span class="elsevierStyleItalic">B4h</span>) and C-reactive protein CRP (samples <span class="elsevierStyleItalic">B-before</span> and <span class="elsevierStyleItalic">B72h</span>) were assessed. Creatinine concentrations were determined in <span class="elsevierStyleItalic">B-before, B24h, B48h, B72h, B96h,</span> and <span class="elsevierStyleItalic">B120h</span> samples. L-FABP, H-FABP and creatinine concentrations were determined in all urine samples (i.e. <span class="elsevierStyleItalic">U-before</span><span class="elsevierStyleBold"> – </span><span class="elsevierStyleItalic">U72h</span>). Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease Study equation (MDRD) or, alternatively, by CKD-EPI Study formula.<span class="elsevierStyleSup">13</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Laboratory methods</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">Immediately after clotting blood samples were centrifuged for 15min at 3000g (rotation 4000min<span class="elsevierStyleSup">-1</span>); frozen serum and urine were stored at -80˚C. Serum and urine creatinine concentrations were determined by the Jaffe colorimetric method. Urine L-FABP and H-FABP were assessed using commercially available enzyme-linked immunosorbent assays (Human L-FABP ELISA Kit and Human H-FABP ELISA Kit Hycult-Biotech, The Netherlands) according to the manufacturer’s instructions. Other laboratory parameters were determined using routine tests.</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Statistical analyses</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The data were analyzed using Statistica 8.0. computer software. All variables were tested for normality of distribution by means of the Kolmogorov-Smirnov test. Statistical analysis was carried out using non parametric the Kruskal-Wallis/Mann-Whitney U for independent and Wilcoxon for paired samples. Anova test were used for parametric analyses. The correlation rate was calculated using Spearman’s test. The Spearman rank correlation coefficient (rs) was determined. The multiple stepwise forward regression analyses were done. All results were expressed as mean ± standard deviation (mean±SD) or median with lower and upper quartiles. Statistical significance was set at p<0.05.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">RESULTS</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The blood count parameters after surgery were moderately, and yet significantly lower then before surgery (Table 1). These results indicate that blood loss and supplementation were not fully balanced during and after the operation, and, consequently, the lowered blood supply to the kidneys might have influenced kidney function, at least to a certain extent. After surgery, serum creatinine concentrations did not increase significantly. However, on the first day after surgery the “p” value of creatinine rise approximated 0.05 (Table 3). GFRs, estimated before surgery according to MDRD and CKD-EPI Study equations were 72.24±23.18 and 86.63±26.23mL/min/1.73m<span class="elsevierStyleSup">2</span>, respectively.</p><p class="elsevierStylePara">Urine L-FABP expressed as concentrations or urinary excretions normalized to urinary creatinine (L-FABP/Cr) increased significantly at almost all successive time points compared to day (-1). A significant increase in urine H-FABP concentrations was delayed until after 24 hours. However, when expressed as urinary excretions normalized to urinary creatinine (H-FABP/Cr), the significant increases in H-FABP were observed at all successive time points compared to day (-1) (Table 4).</p><p class="elsevierStylePara">Using the multiple stepwise forward regression methods we analysed the influence of independent values such as: age, smoking, diabetes, coronary artery disease (CAD), hypertension, peripheral vascular disease, taking of ACE-I or nonsteroid anti-inflammatory drugs (NAID), aneurysm diameter, time since last radiocontrast administration, operative time, aorta cross-clamping time, blood loss during surgery, Mehran score<span class="elsevierStyleSup">14</span> on the dependent values: L-FABP/Cr and H-FABP/Cr determined in the last time-point of observation (<span class="elsevierStyleItalic">U72h</span>). We found that: <span class="elsevierStyleBold">a.</span> CAD (β=0.61; p<0.01), age (β=- 0.55; p<0.01), time since last radiocontrast administration (β=-0.39; p=0.04) and blood loss during surgery (β=-0.54; p=0.04) explained 52.38% of the variation in L-FABP/Cr as measured by the coefficient of determination R<span class="elsevierStyleSup">2 </span>(F(7,12)=3.98; p=0.02), <span class="elsevierStyleBold">b.</span> NLPZ (β=0.60; p<0.01), peripheral vascular disease (β=-0.57; p<0.01) and CAD (β=0.51; p=0.02) explained 41.05% of the variation in H-FABP/Cr as measured by the coefficient of determination R<span class="elsevierStyleSup">2 </span>(F(5,15)=3.79; p=0,02).</p><p class="elsevierStylePara">Serum creatinine concentrations were correlated with urine L-FABP and H-FABP concentrations and also with L-FABP/Cr and H-FABP/Cr determined at the same successive time-points. Significant correlations were found on day (-1) and, randomly, 24 and 48 hours after surgery (Table 5).</p><p class="elsevierStylePara">L-FABP concentrations and L-FABP/Cr excretions were also correlated with H-FABP concentrations and H-FABP/Cr excretions at the same time-points, respectively. Except for correlation between L-FABP/Cr and H-FABP/Cr determined 12 hours after clamp release, all the other “rs” values were significant as presented in the Table 5.</p><p class="elsevierStylePara">No significant correlations were found between the time of aorta clamping (aorta clamping should be regarded as the major event of AAA surgery that may lead to kidney injury) and serum creatinine, urine L-FABP and H-FABP concentrations, L-FABP/Cr and H-FABP/Cr at any time-point.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">DISCUSSION</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">FABPs play a crucial role in the metabolism of long chain and very long chain free fatty acids (FFAs). In the kidneys, the albumin-bound FFAs are filtered through glomeruli and subsequently reabsorbed by proximal tubules. During massive proteinuria, FFAs, filtered in excess, overload the tubular epithelium. Furthermore, other damaging factors such as diabetes, ischemia, toxins or overexertion could result in accumulation of FFAs and their oxidation products in the cytoplasm of tubular cells.<span class="elsevierStyleSup">11,15</span> After peroxidation, FFAs induce an inflammatory response resulting in tubulointerstitial injury. FABP is an intracellular FFAs-carrier facilitating their physiological β-oxidation in the mitochondria or peroxisomes.<span class="elsevierStyleSup">16</span> Therefore vigorous FFAs metabolism stimulated by FABPs prevents their undesirable peroxidation. L-FABP also has affinity to FFA oxidation products thus acting as intracellular antioxidant.<span class="elsevierStyleSup">17</span> L-FABP is a regulator of genes controlling lipid metabolism.<span class="elsevierStyleSup">18</span></p><p class="elsevierStylePara">Urinary L-FABP (u-L-FABP) is a reliable indicator of AKI (the area under the receiver operating characteristic curve could reach 0.93).<span class="elsevierStyleSup">19</span> It has been used successfully for surveillance of AKI after cardiac surgery,<span class="elsevierStyleSup">20</span> in contrast medium-induced nephropathy,<span class="elsevierStyleSup">21,22</span> acute ischemic injury<span class="elsevierStyleSup">23</span> or in AKI of varying etiology.<span class="elsevierStyleSup">19</span> H-FABP also is a reliable indicator of tissue damage. It is an early and sensitive marker of heart injury in acute coronary syndromes, exceeding in this respect, myoglobin, creatine kinase-MB fraction (CK-MB) or troponine I.<span class="elsevierStyleSup">24,25</span> H-FABP has been confirmed as a sensitive indicator of toxic distal tubular injury, particularly after gentamicin administration.<span class="elsevierStyleSup">11</span> However, up till now and compared to L-FABP, H-FABP has been used very rarely for the assessment of kidney injury.</p><p class="elsevierStylePara">These two FABPs are biochemically and functionally very similar, yet specifically expressed in different segments of the nephron,<span class="elsevierStyleSup">11,26</span> thus providing a unique possibility to simultaneously investigate damage to proximal and distal tubules using akin “biochemical tools”. Hofstra has already used L-FABP and H-FABP for this purpose in patients with idiopathic membranous nephropathy.<span class="elsevierStyleSup">12</span></p><p class="elsevierStylePara">Our study revealed very early and impressive FABPs increases (already during surgery - just before aortic clamp removal: time-point [<span class="elsevierStyleItalic">U-surgery</span>]; Table 4), which persisted with different intensity throughout the study period.</p><p class="elsevierStylePara">Portilla et al. studied AKI in the population of children after cardiac surgery. In this study u-L-FABP already increased 4 hours after cardiopulmonary bypass and remained elevated until 12 hours afterwards. In the subgroup with AKI defined as a 50% increase in the serum creatinine, u-L-FABP rose about 95 times after 4 hours and about 45 times after 12 hours. In the non-AKI subgroup, the increases were 10-fold and about 6-fold respectively.<span class="elsevierStyleSup">20</span> Different results were obtained in a study of contrast medium-induced nephropathy.<span class="elsevierStyleSup">21</span> u-L-FABP levels were determined in adults before and 1, 2 and 14 days after coronary angiography and showed a 1.7-2.5 -fold increase in the contrast-induced nephropathy subgroup (criterion of nephropathy: relative creatinine increase of 25% or more from baseline) during the observation period, but remained stable in the non-nephropathy subgroup. The results suggest that there is a strong discrepancy concerning the intensity of u-L-FABP excretion between these two studies. After cardiac surgery, u-L-FABP was considerably elevated even in the non-AKI group. In contrast-induced nephropathy, despite creatinine elevation, u-L-FABP excretion rose only moderately, and not in the creatinine-stable subgroup. Strangely enough, in the study on AKI of varying etiology there were no statistical differences in u-L-FABP among diagnostic categories, including contrast nephropathy.<span class="elsevierStyleSup">19</span> In our study population the creatinine level did not increase significantly after surgery (however, on day 1 after surgery, the p value corresponding to moderate serum creatinine elevation reached 0.095). One of the possible reasons of the lack of creatinine rise, particularly on the first day after surgery, could be the blood dilution. The blood dilution after the surgery is testified by the significant fall of hematocrite (summary effect of blood loss and crystalloids transfusion) (Table 1). u-L-FABP factored for creatinine excretion already increased during AAA surgery (<span class="elsevierStyleItalic">U-surgery</span>, Table 4), grew abruptly at 2 hours after aortic clamp release, formed more or less a plateau between 4 and 48 hours, but continued to increase at 72 hours of observation. The plateau reaction was observed in the contrast medium-induced nephropathy, but was very stable until the 14th day after angiography.<span class="elsevierStyleSup">21</span> On the contrary, after cardiac surgery, the peak excretion was already observed at 4 hours of intervention, followed by a distinct decline. Thus, our results seem to confirm the observations made in contrast nephropathy study and prove long-term stable reaction of u-L-FABP after kidney injury. From the other side, the very early first peak value of FABPs observed in our study in the 2<span class="elsevierStyleSup">nd</span> hour after the aorta clamp release (<span class="elsevierStyleItalic">U2h</span>) is consistent with the very early peak excretion noted after cardiac surgery.<span class="elsevierStyleSup">20</span> The reason for this bi-phasic reaction of u-FABPs in our study (early peak in 2<span class="elsevierStyleSup">nd</span> hour after intervention, then plateau on lower level with steady tendency to increase, Table 4) is not easy to explain. It is possible that the early peak in 2<span class="elsevierStyleSup">nd</span> hour is caused by the process of sudden secretion of constitutively stored supplies of FABPs in tubular cells. As for the further plateau and steady increase of excretion, it might originate from the constantly intensifying process of “de novo” synthesis of FABPs.</p><p class="elsevierStylePara">The intensity of u-L-FABP response in our population was rather moderate compared to the two studies mentioned above.</p><p class="elsevierStylePara">As remarked earlier, L-FABP and H-FABP are variants of the same substance performing, supposedly, similar physiological and pathophysiological role.<span class="elsevierStyleSup">9,11,16,27</span> Thus, both FABPs create a relatively homogenous tool for the investigation of two different segments of the nephron. These two FABPs were determined simultaneously in idiopathic membranous nephropathy.<span class="elsevierStyleSup">12</span> u-L-FABP correlated strongly with urinary H-FABP (u-H-FABP), r=0.88. We also found relatively strong correlations between FABPs, ranging from rs=0.486 to rs=0.781, at different time-points. This fact confirms that the putative damage to both segments of the nephron would occur simultaneously (Table 5). Despite the positive correlation between both FABPs at all time-points, their dynamics were rather different, as shown in Table 4. Nevertheless, each marker had a plateau in the middle phase of observation (between hour 4 and 48 for u-L-FABP and between hour 2 and 24 for u-H-FABP), and showed a strong tendency to increase in the final phase of observation. This might indicate a tendency to rise beyond the time of observation (Table 4). The magnitude of u-FABPs increases might correspond to the severity of tubular injury. Hence the need for a more detailed comparison of their dynamics. The direct juxtaposition is impossible, because the baseline values of L-FABP/Cr and H-FABP/Cr (determined before surgery: time-point-<span class="elsevierStyleItalic">U-before</span>) differ in factor 70.5 (9.94 vs. 0.141ng/mg) (Table 4). Therefore, we present also the increases as percentages of baseline values (Figure 1). The authors of the study on idiopathic membranous nephropathy suggest that the proximal tubule is injured earlier and stronger than the distal one, so an involvement of the distal tubule should be considered a sign of a more advanced pathology.<span class="elsevierStyleSup">12</span> This seems consistent with Eisei Noiri’s opinion that in the renal ischemia/reperfusion model the proximal tubules are much more sensitive to the hypoxic stress than the distal ones.<span class="elsevierStyleSup">28</span> Our analysis of percentage increases of both u-FABSs makes us draw an opposite conclusion, ie., that, following AAA surgery, the distal segment of the nephron could be more susceptible to injury than the proximal one.</p><p class="elsevierStylePara">In order to compare u-FABP dynamics with other urinary AKI markers, we adapted the data from our previous publication<span class="elsevierStyleSup">29</span> in which the urinary excretions of neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL-18) were described. The NGAL and IL-18 were determined strictly according to the same protocol during AAA surgery, however in the smaller population comprising 14 subjects. As can be seen from Figure 2, in which analogically to the Figure 1 the percentage changes of NGAL and IL-18 baseline values (U-before) during successive time-points are shown, the dynamics was somewhat different. The rises of NGAL and IL-18 in comparison to both FABPs are less impressive and the absolute peak values appeared between 2<span class="elsevierStyleSup">nd</span> and 12<span class="elsevierStyleSup">th</span> hour after declamping of aorta. Strangely enough, the peak value of IL-18 excretion coincided exactly with the first peak value of FABPs observed in the 2<span class="elsevierStyleSup">nd</span> hour after the aorta clamp release (<span class="elsevierStyleItalic">U2h</span>). The values of NGAL and IL-18 noted in further time-point were erratic and distinctly lower as compared to their early peak values. In contrast to them, the second u-H-FABP impressive rise in the later time-points (<span class="elsevierStyleItalic">U24</span>-<span class="elsevierStyleItalic">U72</span>) was observed. Therefore this juxtaposition of FABPs with NGAL and IL-18 determined in the same conditions suggest that FABPs reacts to tubular injury equally early but distinctly stronger (percentage increases) and more persistently.</p><p class="elsevierStylePara">We found positive, moderate correlations between FABPs and serum creatinine levels at baseline, which were not so apparent following AAA surgery (Table 5). These results suggest that under physiological conditions there is a link between GFR and u-FABPs levels. This link is partially lost after AAA surgery, maybe as an expression of ensuing kidney damage (disparate changes in tubular function and glomerular filtration).</p><p class="elsevierStylePara">As mentioned above, the serum creatinine level was non-significantly elevated in our study population. In historical perspective, the first notion describing sudden and mostly transitory kidney damage was “acute renal failure” and/or “acute tubular necrosis”. Later on a wider term “acute renal injury” was formed based on the RIFLE or AKIN criteria.<span class="elsevierStyleSup">30,31</span> This evolution was associated with the recognition of the fact that even small rises in serum creatinine level in different clinical settings could have unfavourable clinical and also economic consequences.<span class="elsevierStyleSup">3,4,32</span> But the usefulness of serum creatinine as a biomarker for diagnosis of AKI has been widely criticized. It has many disadvantages, as discussed elsewhere, and is therefore a suboptimal biomarker of kidney tissue injury. In fact, serum creatinine is a marker of kidney function loss (glomerular filtration), but not a direct indicator of kidney tissue injury.<span class="elsevierStyleSup">19,33</span> Moreover, chronic progressive renal failure correlates better with the intensity of tubulointerstitial damage than with glomerular injury.<span class="elsevierStyleSup">34,35</span> This situation, as a matter of fact, gave rise to a search for new, more sensitive biomarkers of AKI which led to the discovery of novel AKI indicators like L-FABP, H-FABP, Kidney Injury Molecule 1, NGAL, IL-18 or others. In our study, despite of no changes in serum creatinine levels, we found very early, strong and persistent rise of u-FABPs. Similar results were also found by other authors, ie., significant changes in kidney injury markers without changes in serum creatinine levels.<span class="elsevierStyleSup">22,36</span> We hypothesize that our results relate to the very early phase of AKI or, to use the RIFLE-AKIN criteria, the “pre-AKI” stage. Therefore a question arises concerning clinical sequelae of this “pre-AKI” condition for the general health status of these patients - a subject for further investigations. There is also an urgent need to redefine the term “acute kidney injury”. Currently, new direct indicators of renal tissue injury are available, performing without doubt much better than serum creatinine. But up till now, there is no “gold standard” of kidney injury. Histology result might be referred to;<span class="elsevierStyleSup">37</span> however this approach seems to be quite impractical from the clinical point of view. This important methodological problem should remain a subject of further discussion.</p><p class="elsevierStylePara">We conclude that very early, significant and persistent rise of both u-L-FABP and u-H-FABP after elective AAA surgery could indicate the damage of renal proximal and distal tubule in our study population. The obtained results also suggest that after AAA surgery the distal tubules could be more affected than the proximal ones. The u-FABPs could serve as very sensitive and early biomarkers of kidney injury and may allow to detect the very early and subtle phases of AKI (or “pre-AKI”), yet not reflected by increases of serum creatinine levels.</p><p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflict of interest</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The authors declare they have no potential conflicts of interest related to the contents of this article.<span class="elsevierStyleItalic"> </span>The study was funded by the Medical University of Silesia – grant No KNW-1-147/P/1/0.</p><p class="elsevierStylePara"><a href="grande/11953_19904_58972_en_11953_t1.jpg" class="elsevierStyleCrossRefs"><img src="11953_19904_58972_en_11953_t1.jpg" alt="Patients characteristics"></img></a></p><p class="elsevierStylePara">Table 1. Patients characteristics</p><p class="elsevierStylePara"><a href="grande/11953_19904_58975_en_11953_t2.jpg" class="elsevierStyleCrossRefs"><img src="11953_19904_58975_en_11953_t2.jpg" alt="Surgery details"></img></a></p><p class="elsevierStylePara">Table 2. Surgery details</p><p class="elsevierStylePara"><a href="grande/11953_19904_58976_en_11953_t3.jpg" class="elsevierStyleCrossRefs"><img src="11953_19904_58976_en_11953_t3.jpg" alt="Serum creatinine levels on successive days"></img></a></p><p class="elsevierStylePara">Table 3. Serum creatinine levels on successive days</p><p class="elsevierStylePara"><a href="grande/11953_19904_58982_en_11953_t4.jpg" class="elsevierStyleCrossRefs"><img src="11953_19904_58982_en_11953_t4.jpg" alt="Urine concentrations and urinary excretion normalized to urinary creatinine of L-FABP and H-FABP at successive time points"></img></a></p><p class="elsevierStylePara">Table 4. Urine concentrations and urinary excretion normalized to urinary creatinine of L-FABP and H-FABP at successive time points</p><p class="elsevierStylePara"><a href="grande/11953_19904_58983_en_11953_t5.jpg" class="elsevierStyleCrossRefs"><img src="11953_19904_58983_en_11953_t5.jpg" alt="Correlations"></img></a></p><p class="elsevierStylePara">Table 5. Correlations</p><p class="elsevierStylePara"><a href="grande/11953_19904_58984_en_11953_f1.jpg" class="elsevierStyleCrossRefs"><img src="11953_19904_58984_en_11953_f1.jpg" alt="Urinary FABPs in successive time-points expressed as the percentage changes of baseline value: (U-before)=100%"></img></a></p><p class="elsevierStylePara">Figure 1. Urinary FABPs in successive time-points expressed as the percentage changes of baseline value: (U-before)=100%</p><p class="elsevierStylePara"><a href="grande/11953_19904_58985_en_11953_f2_copy1.jpg" class="elsevierStyleCrossRefs"><img src="11953_19904_58985_en_11953_f2_copy1.jpg" alt="Urinary NGAL and IL-18 in successive time-points expressed as the percentage changes of baseline value: (U-before)=100%"></img></a></p><p class="elsevierStylePara">Figure 2. Urinary NGAL and IL-18 in successive time-points expressed as the percentage changes of baseline value: (U-before)=100%</p>" "pdfFichero" => "P1-E574-S4691-A11953-EN.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:4 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec437495" "palabras" => array:1 [ 0 => "Proteína hepática transportadora de ácidos grasos" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec437497" "palabras" => array:1 [ 0 => "Proteína cardíaca transportadora de ácidos grasos" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec437499" "palabras" => array:1 [ 0 => "Fracaso renal agudo" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec437501" "palabras" => array:1 [ 0 => "Cirugía de aneurisma aórtico abdominal" ] ] ] "en" => array:4 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec437496" "palabras" => array:1 [ 0 => "Liver-type fatty acid-binding protein" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec437498" "palabras" => array:1 [ 0 => "Heart-type fatty acid-binding protein" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec437500" "palabras" => array:1 [ 0 => "Acute kidney injury" ] ] 3 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec437502" "palabras" => array:1 [ 0 => "Abdominal aortic aneurysm surgery" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "es" => array:1 [ "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Antecedentes:</span> Una de las complicaciones más graves de la cirugía reparatoria de aneurisma aórtico abdominal (AAA) es el fracaso renal agudo (FRA). Incluso un pequeño ascenso de creatinina sérica se asocia a un aumento de la mortalidad. El objetivo de este estudio ha sido valorar la dinámica del FRA después de cirugía electiva de AAA utilizando nuevos marcadores. <span class="elsevierStyleBold">Métodos:</span> En el estudio se incluyeron 22 pacientes con AAA. Medimos la proteína hepática transportadora de ácidos grasos (u-L-FABP) y la proteína cardíaca transportadora de ácidos grasos (u-h-FABP) en orina, antes, durante y dentro de los tres días siguientes a la cirugía. <span class="elsevierStyleBold">Resultados:</span> Se observó una brusca y significativa elevación de ambas FABP en orina, normalizada a creatinina en orina; el nivel de u-L-FABP alcanzó su pico dos horas después de quitar la abrazadera aórtica {137,79 (38,57-451,79) frente a 9,99 (6,82-12,42) ng/mg del valor basal p < 0,05; los valores son medianos (cuartil inferior-superior)}. El pico de la u-H-FABP se notó 72 horas después de quitar la abrazadera aórtica {16,462 (4,182-37,595) frente a 0,141 (0,014-0,927) ng/mg del valor basal}. El nivel de creatinina sérica no cambió de manera significativa durante el período de estudio. <span class="elsevierStyleBold">Conclusiones:</span> El aumento significativo de ambas u-L-FABP y u-H-FABP después de cirugía de AAA indica la lesión tubular renal distal y proximal en la población estudiada. Nuestros resultados sugieren que después de una cirugía de AAA el túbulo distal puede ser más afectado que el proximal. Las u-FABP podrían servir como biomarcadores sensitivos de la lesión tubular renal y permitir detectar la fase más precoz de FRA.</p>" ] "en" => array:1 [ "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">Background:</span> One of the most severe complications of repair surgery for abdominal aortic aneurysms (AAA) is acute kidney injury (AKI). Even small rises in serum creatinine are associated with increased mortality. The aim of this study was to assess the dynamics of AKI after elective AAA surgery using novel markers. <span class="elsevierStyleBold">Methods:</span> The study group consisted of 22 patients with AAA. We measured urinary liver- (u-L-FABP) and heart-type fatty acid-binding proteins (u-H-FABP) before, during and within 3 days after surgery. <span class="elsevierStyleBold">Results:</span> We found an abrupt and significant elevation of both urine FABPs normalized to urinary creatinine; u-L-FABP reached its peak value 2 hours after aortic clamp release {137.79 (38.57-451.79) vs. 9.94 (6.82-12.42) ng/mg baseline value, p<0.05; values are medians (lower-upper quartile)}. The peak value of u-H-FABP was reported 72 hours after aortic clamp release {16.462 (4.182-37.595) vs. 0.141 (0.014-0.927) ng/mg baseline value, p<0.05}. The serum creatinine level did not changed significantly during the investigation period. <span class="elsevierStyleBold">Conclusions:</span> The significant rise of both u-L-FABP and u-H-FABP after AAA surgery indicates renal proximal and distal tubule injury in this population. Our results suggest that, after AAA surgery, the distal tubules could be more affected than the proximal ones. u-FABPs could serve as sensitive biomarkers of kidney tubular injury and may allow to detect the very early phases of AKI.</p>" ] ] "multimedia" => array:7 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11953_19904_58972_en_11953_t1.jpg" "Alto" => 781 "Ancho" => 343 "Tamanyo" => 410922 ] ] "descripcion" => array:1 [ "en" => "Patients characteristics" ] ] 1 => array:8 [ "identificador" => "fig2" "etiqueta" => "Tab. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11953_19904_58975_en_11953_t2.jpg" "Alto" => 316 "Ancho" => 421 "Tamanyo" => 158722 ] ] "descripcion" => array:1 [ "en" => "Surgery details" ] ] 2 => array:8 [ "identificador" => "fig3" "etiqueta" => "Tab. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11953_19904_58976_en_11953_t3.jpg" "Alto" => 79 "Ancho" => 773 "Tamanyo" => 78194 ] ] "descripcion" => array:1 [ "en" => "Serum creatinine levels on successive days" ] ] 3 => array:8 [ "identificador" => "fig4" "etiqueta" => "Tab. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11953_19904_58982_en_11953_t4.jpg" "Alto" => 193 "Ancho" => 703 "Tamanyo" => 211867 ] ] "descripcion" => array:1 [ "en" => "Urine concentrations and urinary excretion normalized to urinary creatinine of L-FABP and H-FABP at successive time points" ] ] 4 => array:8 [ "identificador" => "fig5" "etiqueta" => "Tab. 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11953_19904_58983_en_11953_t5.jpg" "Alto" => 140 "Ancho" => 701 "Tamanyo" => 113811 ] ] "descripcion" => array:1 [ "en" => "Correlations" ] ] 5 => array:8 [ "identificador" => "fig6" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11953_19904_58984_en_11953_f1.jpg" "Alto" => 509 "Ancho" => 699 "Tamanyo" => 149226 ] ] "descripcion" => array:1 [ "en" => "Urinary FABPs in successive time-points expressed as the percentage changes of baseline value: (U-before)=100%" ] ] 6 => array:8 [ "identificador" => "fig7" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "11953_19904_58985_en_11953_f2_copy1.jpg" "Alto" => 498 "Ancho" => 700 "Tamanyo" => 147485 ] ] "descripcion" => array:1 [ "en" => "Urinary NGAL and IL-18 in successive time-points expressed as the percentage changes of baseline value: (U-before)=100%" ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:37 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Hagivara S, Saima S, Negishi K, Takeda R, Miyauchi N, Akiyama Y, et al. 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| 2023 July | 50 | 27 | 77 |
| 2023 June | 39 | 26 | 65 |
| 2023 May | 58 | 35 | 93 |
| 2023 April | 47 | 18 | 65 |
| 2023 March | 70 | 22 | 92 |
| 2023 February | 60 | 27 | 87 |
| 2023 January | 57 | 29 | 86 |
| 2022 December | 46 | 21 | 67 |
| 2022 November | 58 | 42 | 100 |
| 2022 October | 48 | 29 | 77 |
| 2022 September | 47 | 24 | 71 |
| 2022 August | 49 | 43 | 92 |
| 2022 July | 43 | 40 | 83 |
| 2022 June | 39 | 34 | 73 |
| 2022 May | 44 | 35 | 79 |
| 2022 April | 52 | 40 | 92 |
| 2022 March | 47 | 36 | 83 |
| 2022 February | 46 | 38 | 84 |
| 2022 January | 36 | 20 | 56 |
| 2021 December | 32 | 37 | 69 |
| 2021 November | 42 | 37 | 79 |
| 2021 October | 37 | 34 | 71 |
| 2021 September | 30 | 37 | 67 |
| 2021 August | 28 | 38 | 66 |
| 2021 July | 31 | 35 | 66 |
| 2021 June | 22 | 17 | 39 |
| 2021 May | 52 | 39 | 91 |
| 2021 April | 120 | 54 | 174 |
| 2021 March | 53 | 32 | 85 |
| 2021 February | 33 | 31 | 64 |
| 2021 January | 24 | 13 | 37 |
| 2020 December | 26 | 19 | 45 |
| 2020 November | 25 | 14 | 39 |
| 2020 October | 27 | 17 | 44 |
| 2020 September | 30 | 19 | 49 |
| 2020 August | 40 | 13 | 53 |
| 2020 July | 37 | 11 | 48 |
| 2020 June | 24 | 13 | 37 |
| 2020 May | 41 | 5 | 46 |
| 2020 April | 35 | 19 | 54 |
| 2020 March | 27 | 9 | 36 |
| 2020 February | 35 | 18 | 53 |
| 2020 January | 38 | 15 | 53 |
| 2019 December | 47 | 25 | 72 |
| 2019 November | 41 | 20 | 61 |
| 2019 October | 26 | 12 | 38 |
| 2019 September | 34 | 15 | 49 |
| 2019 August | 25 | 10 | 35 |
| 2019 July | 40 | 23 | 63 |
| 2019 June | 32 | 18 | 50 |
| 2019 May | 97 | 22 | 119 |
| 2019 April | 87 | 26 | 113 |
| 2019 March | 56 | 23 | 79 |
| 2019 February | 33 | 20 | 53 |
| 2019 January | 46 | 24 | 70 |
| 2018 December | 110 | 39 | 149 |
| 2018 November | 94 | 21 | 115 |
| 2018 October | 115 | 14 | 129 |
| 2018 September | 84 | 18 | 102 |
| 2018 August | 66 | 15 | 81 |
| 2018 July | 56 | 11 | 67 |
| 2018 June | 61 | 13 | 74 |
| 2018 May | 52 | 8 | 60 |
| 2018 April | 70 | 10 | 80 |
| 2018 March | 48 | 12 | 60 |
| 2018 February | 63 | 12 | 75 |
| 2018 January | 55 | 11 | 66 |
| 2017 December | 59 | 8 | 67 |
| 2017 November | 84 | 12 | 96 |
| 2017 October | 49 | 5 | 54 |
| 2017 September | 77 | 9 | 86 |
| 2017 August | 87 | 16 | 103 |
| 2017 July | 96 | 9 | 105 |
| 2017 June | 106 | 8 | 114 |
| 2017 May | 112 | 8 | 120 |
| 2017 April | 85 | 16 | 101 |
| 2017 March | 74 | 6 | 80 |
| 2017 February | 73 | 21 | 94 |
| 2017 January | 46 | 14 | 60 |
| 2016 December | 77 | 10 | 87 |
| 2016 November | 103 | 16 | 119 |
| 2016 October | 164 | 12 | 176 |
| 2016 September | 262 | 5 | 267 |
| 2016 August | 241 | 10 | 251 |
| 2016 July | 230 | 14 | 244 |
| 2016 June | 157 | 0 | 157 |
| 2016 May | 170 | 0 | 170 |
| 2016 April | 157 | 0 | 157 |
| 2016 March | 117 | 0 | 117 |
| 2016 February | 145 | 0 | 145 |
| 2016 January | 132 | 0 | 132 |
| 2015 December | 146 | 0 | 146 |
| 2015 November | 114 | 0 | 114 |
| 2015 October | 119 | 0 | 119 |
| 2015 September | 103 | 0 | 103 |
| 2015 August | 98 | 0 | 98 |
| 2015 July | 131 | 0 | 131 |
| 2015 June | 59 | 0 | 59 |
| 2015 May | 93 | 0 | 93 |
| 2015 April | 9 | 0 | 9 |
Show all
