Rev. Nefro. Dial y Traspl. 2023;43(3):138-147

Efectos del neumoperitoneo por dióxido de carbono sobre las funciones renales en la ictericia obstructiva: un estudio experimental en un modelo de rata

Merter Gulen¹, Mustafa Sare², Ramazan Kozan² ORCID: 0000-0002-3835-8759   E-mail: dr.kozan@hotmail.com , Seher Yuksel³, Serpil Müge Deger⁴, Mehmet Senes⁵, Ayse Banu Cayci ⁶

3) Department of Ophthalmology, UT Southwestern Medical Center, Dallas, TX, USA

4) Department of Nephrology, Dokuz Eylül University, Faculty of Medicine, İzmir, Turkey

6) Department of Biochemistry, Gazi University Faculty of Medicine, Ankara, Turkey

Recibido: 18-05-2021
Corregido: 15-06-2022
Aceptado: 21-06-2023

RESUMEN

Introducción: Se sabe que tanto el neumoperitoneo (PNP) como la ictericia obstructiva (IO) conducen potencialmente a una lesión renal aguda (IRA), pero no se ha investigado el efecto combinado. Objetivo: Este estudio tuvo como objetivo investigar los efectos del PNP en las funciones renales en un modelo de rata de IO. Método: Cuarenta y ocho ratas se dividieron en ocho grupos de seis ratas. El grupo 1 fue el grupo de control (operado de forma simulada); A los grupos 2, 3 y 4 se les indujo 5, 10 y 15 mmHg de CO2 PNP respectivamente (Grupos 1-4: “Grupos no OJ”); el grupo 5 fue el grupo IO; y los Grupos 6, 7 y 8 eran grupos IO que fueron inducidos con 5, 10 y 15 mmHg de CO2 PNP respectivamente (Grupos 5-8: “Grupos OJ”). Se ligó el conducto biliar común y se dividió en grupos IO. A las 48 horas se indujo una PNP de 5-10-15 mmHg mediante minilaparotomía con aguja de Veress en los Grupos 6, 7 y 8, mantenida durante 60 minutos. Resultados: No hubo diferencias estadísticamente significativas entre los grupos en cuanto a los niveles de Nitrógeno ureico en sangre y Creatinina (p> 0,05). Los valores de lipocalina asociada a gelatinasa de neutrófilos (NGAL) fueron significativamente más altos en los grupos IO que en los grupos no IO (p < 0,05). Los valores séricos de cistatina-C fueron significativamente más altos en los grupos IO con PNP de 10 y 15 mmHg que en los grupos sin IO (p < 0,05). Conclusión: en la etapa temprana de AKI, los niveles de NGAL y Cystatin-C pueden ser más altos, mientras que las pruebas estándar de función renal fueron normales. Nuestros hallazgos destacan el aparente efecto desfavorable de IO con PNP sobre las funciones renales y el reconocimiento temprano de AKI con la medición de NGAL y Cystatin-C en estas condiciones.

PALABRAS CLAVE: Insuficiencia Renal Aguda (IRA); Cistatina-C; laparoscopia; lipocalina asociada a gelatinasa de neutrófilos (NGAL); ictericia obstructiva (OJ); neumoperitoneo (PNP)

ABSTRACT

Introduction: Both pneumoperitoneum (PNP) and obstructive jaundice (OJ) are known to potentially lead to acute kidney injury (AKI), but the combined effect has not been investigated. Aim: This study aimed to investigate the effects of PNP on renal functions in a rat model of OJ. Method: Forty-eight rats were divided into eight groups of six rats. Group 1 was the control (sham-operated) group; Groups 2, 3 and 4 were induced 5, 10 and 15 mmHg of CO2 PNP respectively (Groups 1-4: “non-OJ Groups”); Group 5 was the OJ group; and Groups 6, 7 and 8 were OJ groups that were induced with 5, 10 and 15 mmHg CO2 PNP was respectively (Groups 5-8: “OJ Groups”). Common bile duct was ligated and divided to OJ Groups. After 48 hours, a 5-10-15 mmHg PNP was induced by minilaparotomy with a Veress needle in Groups 6, 7 and 8, maintained for 60 minutes. Results: There were no statistically significant differences between groups in terms of blood urea Nitrogen and Creatinin levels (p> 0.05). Neutrophil gelatinase-associated lipocalin (NGAL) values were significantly higher in OJ Groups than non-OJ Groups (p< 0.05). Serum Cystatin-C values were significantly higher in OJ Groups with 10 and 15 mmHg PNP than non-OJ Groups (p< 0.05). Conclusion: In the early stage of AKI, NGAL and Cystatin-C levels might be higher while standard renal function tests were normal. Our findings highlight the apparent unfavourable effect of OJ with PNP on renal functions and early recognition of AKI with the measurement of NGAL and Cystatin-C in these conditions.

KEYWORDS: Acute kidney injury (AKI); Cystatin-C; laparoscopy; neutrophil gelatinase associated lipocalin (NGAL); obstructive jaundice (OJ); pneumoperitoneum (PNP)

INTRODUCTION

Laparoscopic approach has been the first choice of techniques in many areas of surgery. The understanding of the increment of intra-abdominal pressure during carbon dioxide (CO2) pneumoperitoneum (PNP) as a part of laparoscopic surgery is important as systemic changes due to CO2 have become important. Despite advantages, laparoscopic surgical procedures and CO2 PNP have effects on many systems and organs such as brain, lungs and liver ^(1,2). Kidney is one of the important organs where such effects may be observed ^(3-5).

When physiological changes associated with PNP are considered, it has been reported that the decrease in blood flow might cause ischemic changes in intra-abdominal organs ⁽⁶⁾. Experimental studies have demonstrated significant and reversible decreases in the glomerular filtration rate (GFR), urinary outflow and renal blood flow ^(3,5-7).Those effects may depend on the pressure applied during PNP, with other several mechanisms such as decrement of cardiac output, renal vein and parenchyma imprinting, and hormonal effects ^(4,6,8-12).

Another condition having an effect on renal functions is obstructive jaundice (OJ) ⁽¹³⁾. The obstruction of the biliary tree and obstruction of bile flow cause the accumulation of many substances with a systemic toxic effect, primarily bile salt and bilirubin ⁽¹⁴⁾. Acute tubular necrosis (ATN) is one of the complications encountered in OJ with the presence rate of 8% ⁽¹⁵⁾. Hence, deterioration in renal function may be due to both OJ along with PNP ⁽¹⁶⁾.

Although there are various human and animal studies in the literature on the effects of PNP and OJ on renal functions, to the best of our knowledge, no study has documented the relation between acute kidney injury (AKI) and PNP along with OJ, especially analysing with NGAL and Cystatin-C assessment ^(3-6,14-16).

Cystatin-C is a basic protein with a low molecular weight (13 kDa) and is a non-glycolysis polypeptide cysteine proteinase inhibitor ^(17,18). It is synthesized at a steady rate in all nuclear cells in the body. Cystatin-C is present in all tissues and biological fluids at measurable amounts. Although, the primary structure, physical, chemical, and immunological characteristics of Cystatin-C have been determined; its biological role is still not well defined ⁽¹⁷⁾. During the structural analysis of the Cystatin-C gene, it has been demonstrated that there is a steady production rate, even in inflammatory conditions which is not affected by any condition ⁽¹⁸⁾. Due to its small molecular weight and basic iso-electric pH, it drains more freely in glomerulus compared to other proteins. Almost all are reabsorbed by proximal tubules and catabolized in tubular cells resulting no return to the blood flow ⁽¹⁹⁾. Hence, it seems like Cystatin-C has some advantages compared to serum Creatinine in measuring renal functions ^(4,20,21). Serum Creatinine levels depend on the muscle mass, age, gender, muscle metabolism and hydration condition. Acute changes in glomerular filtration function, serum Creatinine values do not exactly reflect the kidney functions until the stable condition balance is ensured. A meta-analysis of 46 studies showed that Cystatin-C was superior to serum Creatinine for the determination of AKI ⁽²¹⁾.

Neutrophil gelatinase-associated lipocalin (NGAL), also known as lipocalin-2 or siderocalin is a protein, which creates a covalent bond with neutrophil gelatinase, weighs 25 kDa and consists of 178 amino acids ^(22,23). Various biological functions of NGAL have been identified such as triggering of apoptosis, suppression of bacterial reproduction, regulation of inflammatory response ⁽²²⁾. Neutrophil gelatinase-associated lipocalin is expressed in bone marrow, colon, kidneys, lungs, stomach, uterus, prostate, trachea ^(22,23). Basically, the increase in NGAL expression occurs together with inflammatory and epithelial damage ^(23,24). It has been documented that NGAL levels increase in both blood and urine analyses after toxic or ischemic damage to kidney ^(4,23,25-26).

Based on laparoscopic surgery practices for either benign (choledocholitiasis, benign biliary strictures) or malign (pancreas carcinoma, cholangiocarcinoma, ampulla tumour, choledochal lower end tumour) conditions that might cause OJ, we aimed in this study to determine the effects of PNP applied at different pressures to rats along with the OJ model on renal functions by using new identifiers, NGAL and Cystatin-C.

MATERIALS AND METHODS

A total of 48 male Wistar albino rats weighing between 350-400 grams and having an average age of six months were used in the study. The rats were divided into eight groups of six rats each. Throughout the experiment, the lighting arrangement was in the form of 12 hours of day and 12 hours of night. The rats were placed in cages in groups of six. Room temperature was maintained at 21±2.5 °C. The rats were fed with standard pellets throughout the study and given tap water. Surgical anaesthesia was applied through intramuscular injection of Xylazine hydrochloride (Rompun, Bayer HealthCare) 5 mg/kg dose in addition to 50 mg/kg of ketamine hydrochloride (Ketalar, Parke Davis and Eczacibasi, Istanbul).

Surgical Procedure and Operative Details

After required sterile conditions were ensured following anaesthesia, the front abdominal walls of the rats were shaved and cleaned with 10% povidone-iodine solution. Through a 5-millimeter incision to the abdominal wall, a Veress needle (Ethicon Endo-Surgery, UV120, USA) was fixed to the abdominal cavity with 3/0 silk suture. After the Veress was fixed, an electronic insufflator (Karl Storz GmbH, Tutlingen, Germany) was connected and 5 mmHg, 10 mmHg and 15 mmHg of CO2 constant pressure was insufflated. The insufflator was adjusted so that in case there was absorption of CO2 gas on the peritoneal surface or a leakage, it would automatically insufflate gas in order to ensure that intra-abdominal pressure would be maintained at the desired level.

Minilaparotomy was performed to the rats in Group 1, and after placing a Veress needle into the abdomen without applying PNP and waiting for 60 minutes, intracardiac blood samples were taken and the rats were sacrificed. After 60 minutes of CO2 PNP was applied at pressures of 5, 10, and 15 mmHg respectively as mentioned above to the rats in Groups 2, 3, and 4, intracardiac blood samples were taken and they were sacrificed. After laparotomy was performed to the rats in Group 5, the main bile duct extending to the duodenum from the liver hilum was found and dissected from the surrounding adipose tissues. It was cut after being ligated from its proximal and distal with 4/0 silk sutures. Then, 1 mL normal saline was physiologically injected into the abdomen and the folds were closed as primary and the procedure was finalized. Following the operation, the rats were fed for 48 hours with standard rat feed and for fluid resuscitation purposes tap water was provided. At the end of this period (48 hours), after placing a Veress needle into the abdomen without applying PNP and waiting for 60 minutes, intracardiac blood samples were taken and the rats were sacrificed. For the rats in Groups 6, 7, and 8, OJ was created in the same manner mentioned above. After the operation, fluid resuscitation was applied to the rats in the same manner and they were fed with standard rat feed. In the postoperative 48th hour, after placing a Veress needle in sterile conditions with minilaparotomy on rats in Groups 6, 7, and 8 and after PNP at pressures of 5, 10, and 15 mmHg were applied for 60 minutes with an electronic insufflator (Karl-Storz GmbH, Tutlingen, Germany) controlling the intra-abdominal pressure, intracardiac blood samples were taken and the rats were sacrificed. Therefore, experimental animals were divided as follows: Group 1, Sham rats; Group 2, PNP 5 mmHg; Group 3, PNP 10 mmHg; Group 4, PNP 15 mmHg, Group 5, OJ; Group 6, PNP 5mmHg + OJ; Group 7, PNP 10 mmHg + OJ and Group 8, PNP 15 mmHg + OJ.

Blood Samples

The analyses consisted of Cystatin-C, NGAL, BUN (blood urine Nitrogen), Creatinine, AST (Aspartate aminotransferase), ALT (Alanine aminotransferase), GGT (Gamma-glutamyltransferase), ALP (Alkaline phosphatase), total and direct bilirubin levels. Blood samples taken in tubes with ethylenediaminetetraacetic acid (EDTA) were centrifuged for 10 minutes at 3000 revolutions and serum samples were prepared. Cystatin-C levels were expressed in mg/dL, NGAL levels in as ng/mL; BUN, Creatinine, AST, ALT, GGT, ALP, total and direct bilirubin levels were expressed in mg/dL. 

Statistical Analysis

The data were analysed using SPSS 20.0 software (SPSS Inc., Chicago, IL, USA). The normality of the variables were assessed with Kolmogorov-Smirnov Test. All data were compared with the non-parametric test due to the abnormal distribution. Groups without OJ (Groups 1, 2, 3, 4: “non-OJ Groups”) and groups with OJ (Groups 5, 6, 7, 8: “OJ Groups”) were compared separately with the Kruskal-Wallis Variance Analysis. For the purpose of determining the source of differences in groups where there were significant differences, paired comparisons were conducted with the Mann-Whitney U Test, comparing the pressure in between OJ Groups and non-OJ Groups. Means were provided as mean ± standard deviation or median interquartile range where needed. The significance level for all analyses was taken considered as 0.05.

Ethics Committee Approval

This experimental study was conducted at the Gazi University Faculty of Medicine, Experiment Animal Research Laboratory with the consent nº B.30.2.GUN.0.05.06/78-6487 of the Gazi University Local Ethics Board on Animal Experiments.

RESULTS

No animal loss occurred in any group in the study and all the animals tolerated the surgical procedure. Non-OJ Groups (Groups 1, 2, 3 and 4) were compared in terms of serum AST, ALT, ALP, GGT, total and direct bilirubin levels, and no significant difference was found between the groups (p= 0.57, p= 0.1, p=0.1, p= 0.1, p= 0.2 and p= 0.25, respectively). OJ Groups (Groups 5, 6, 7 and 8) were compared in terms of serum AST, ALT, ALP, GGT, total and direct bilirubin levels, and no significant difference was found (p= 0.38, p= 0.7, p=0.42, p= 0.79, p= 0.22 and p= 0.41, respectively) (Table 1).

Table 1. Comparisons of hepatic enzyme levels, BUN and Creatinine levels in non-OJ Groups and OJ Groups

PNP= pneumoperitoneum, OJ= obstructive jaundice

Non-OJ Groups (Groups 1, 2, 3 and 4) were compared in terms of serum BUN and Creatinine levels, and no significant difference was found between the groups (p= 0.09 and p= 0.39, respectively). OJ Groups (Groups 5, 6, 7 and 8) were compared in terms of serum BUN and Creatinine levels, and no significant difference was found between the groups (p= 0.11 and p= 0.12, respectively) (Table 1).

Hepatic enzyme (total bilirubin, direct bilirubin, AST, ALT, GGT and ALP) levels were higher in OJ Group 5 compared to non-OJ Group 1 (control) (p= 0.002, for all parameters). There was no significant difference between BUN and Creatinine levels between these two groups (p= 0.08 and p= 0.18, respectively). Hepatic enzyme levels were higher in OJ Group 6, which was administered PNP at 5 mmHg pressure, compared to non-OJ Group 2, which was administered PNP at 5 mmHg pressure (p= 0.002, for all parameters). The difference between BUN and Creatinine levels was not significant (p= 0.24 and p= 0.485, respectively). Hepatic enzyme levels were higher in OJ Group 7, which was administered PNP at 10 mmHg pressure, compared to non-OJ Group 3, which was administered PNP at 10 mmHg pressure (p= 0.002, for all parameters). The difference between BUN and Creatinine levels was not significant (p= 0.423 and p= 0.061, respectively). Similarly, hepatic enzyme levels were higher in OJ Group 8, which was administered PNP at 15 mmHg pressure, compared to non-OJ Group 4, which was administered PNP at 15 mmHg pressure (p= 0.002, for all parameters). The difference between urea and Creatinine levels was not significant (p= 0.394 and p= 0.24, respectively) (Table 2).

Table 2. Comparison of hepatic enzyme levels, BUN and Creatinine levels between pneumoperitoneum groups with and without obstructive jaundice

Group 1: Control, Groups 2, 3, 4: Pneumoperitoneum without obstructive jaundice Group 5: Obstructive jaundice, Groups 6, 7, 8: Pneumoperitoneum with obstructive jaundice

Non-OJ Groups (Groups 1, 2, 3 and 4) were compared in terms of serum NGAL and Cystatin-C levels, and no significant difference also was found (p= 0.29 and p= 0.15, respectively). OJ Groups (Groups 5, 6, 7 and 8) were compared in terms of serum NGAL and Cystatin-C levels, and no significant difference was found for Cystatin-C levels (p= 0.42) (Table 3).

However, within comparison analyses for OJ Groups, the highest serum NGAL level was found in OJ Group 8 (p= 0.001) (Table 3, Figure 1).

Table 3. Comparisons of serum NGAL and Cystatin-C levels in non-OJ Groups and OJ Groups

Figure 1. The comparison between all groups for serum NGAL levels

There were no statistically significant differences of serum Cystatin-C level comparison between non-OJ Group 1 and OJ Group 5 (p= 0.13), non-OJ Group 2 and OJ Group 6 (p= 0.09). However, the levels were significantly higher in OJ Groups 7 and 8 compared to non-OJ Groups 3 and 4 (p= 0.009 and p= 0.04, respectively) (Table 4, Figure 2). All OJ Groups showed significantly higher serum NGAL levels compared to non-OJ Groups with PNP (between non-OJ Group 1 and OJ Group 5, non-OJ Group 2 and OJ group 6, non-OJ Group 3 and OJ Group 7, non-OJ Group 4 and OJ Group 8) (p= 0.002, for all comparisons) (Table 4, Figure 2).

Table 4. Comparisons of serum NGAL and Cystatin-C levels between non-OJ Groups and OJ Groups for pneumoperitoneum

Group 1: Control, Groups 2, 3, 4: Pneumoperitoneum without obstructive jaundice, Group 5: Obstructive jaundice, Groups 6, 7, 8: Pneumoperitoneum with obstructive jaundice

Figure 2. The comparison of all groups for serum Cystatin-C levels

DISCUSSION

Laparoscopic interventions are widely used in emergent and elective fields of surgery. Hepatobiliary and pancreatic surgeries either for malign or benign obstructive causes, which are in advanced laparoscopic surgery field, are increasingly being used in recent years ^(27-28).

The CO2 gas used in laparoscopic surgery is revealing the operation area by providing the PNP and CO2 is preferable, due to its superiority over as helium, Nitrogen protoxide, and argon ^(29,30). Adverse effects of CO2 PNP on renal functions have been reported in several studies ^{(3-5,20,31,32)}. The underlying mechanisms were discussed as increase in intra-abdominal pressure, hypercarbia, preoperative position of the patient, and hemodynamic characteristics ^(4,8,10,33). The other factors that might lead to AKI are reduced cardiac output, decrement in renal blood flow and vein compression, increased renal vascular resistance, vasopressin, endothelin, angiotensin-II, and secretion of vasoconstrictor mediators such as catecholamine ^{(3,5,6,7,9-12,14,34-36)}. To the best of our knowledge, there was no study analyzing the effects of PNP with OJ on renal functions.

Here in this experimental study, we first examined the effects of PNP with OJ on liver enzymes. We found no significant effect in PNP with OJ model on liver functions. Our results were similar to the literature ⁽³⁷⁾. In our study, besides the conventional biochemical parameters used for renal functions, we also used new generation indicators such as Cystatin-C and NGAL. Regarding the traditional renal function tests such as Creatinine and BUN, we did not find any difference between group analyses. In terms of to demonstrate the effect of PNP on kidney functions, the comparison analyses between non-OJ Groups 2, 3, 4 with controls showed no significant difference for serum NGAL levels. This result has led us to suggest that PNP may not be a cause of AKI by itself if kidneys have no prior damage. However, OJ Group 5 (control) showed higher NGAL levels compared to non-OJ Groups with PNP (Groups 2, 3, 4). Moreover, OJ Groups with PNP (Groups 6, 7, 8) revealed significantly higher levels of NGAL compared to PNP Groups and even compared with the non-PNP OJ Group (Group 5). No significant differences were observed between OJ Groups 6, 7, and 8 in comparison analyses. According to these results, we can conclude that, the main bile duct obstructions may cause renal damage and this effect may be increased with PNP of from the pressure that is applied during the procedure. It is also emphasized by some authors that renal functions deteriorate in patients with OJ with possible mechanisms including reduced cardiac outflow, reduced peripheral vasoconstriction, hypovolemia, increased renal vasoconstriction, and decrease in glomerular filtration rate ^(38-40). Furthermore, it is also concluded that bile acids and conjugate bilirubin may cause both ischemia and direct tubular necrosis by itself in addition to possible damaging effect of PNP such as increased on kidney structure ^(13,41).

There are several studies indicating the superiority of Cystatin-C over Creatinine for evaluating glomerular filtration rate ^(4,20,21). Here, we also found that serum Cystatin-C levels significantly increased in OJ Groups 7 and 8, suggesting the rising levels of Cystatin-C are more evident in pressures of 10 mmHg and above. Hence, keeping PNP pressure under 10 mmHg or gasless laparoscopic techniques might be considered as a suitable choice for patients who have prior kidney function disorder.

Taken all these results together, in line with the literature in various settings, our findings lead us to conclude that NGAL and Cystatin-C levels are more sensitive in early recognition of renal damage in laparoscopic surgery for the patients with OJ.

In conclusion, AKI is an important complication in the context of laparoscopic surgeries for OJ. It seems like PNP is not an indicator for AKI in these setting unless OJ is present. The matter of fact that early phase of renal damage might not always be determined with conventional biochemical methods. The use of renal novel biomarkers such as Cystatin-C and serum NGAL, is suggested the alternative way to early diagnosis of AKI and improve the post-operative prognosis of the patient.  We believe that this experimental study might shed light on to develop prospective clinical studies including the correlation of novel biomarkers with histopathological changes in this area.

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