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The role of pneumoperitoneum in the glomerular filtration in an experimental model with 2/3 reduction of the renal mass/O papel do pneumoperitonio na funcao renal em um modelo experimental de reducao de 2/3 do parenquima renal.

Introduction

Although the renal transplant frequently allows a better quality of life to chronic renal patients, the donor is still the limiting factor. The number of patients waiting for a transplant is a universal problem. The donor candidate does not always satisfy the ideal criteria of health state for such cases. There is a global tendency to expand the group of renal donors by using the so-called marginal donors: people with diabetes, hypertension, glomerulosclerosis, some types of cancer, and some cardiopathies (Bloom et al., 2005; Merion et al., 2005).

The increase of living donors, due to the facility of video-assisted surgery associated with the use of marginal donors, has supported the importance of the problem of eventual deleterious effects of the pneumoperitoneum in these particular cases (Hazebroek et al., 2002).

Nature and temperature of the gas used (Saad, Minor, Mohri, & Nagelschmidt, 2001; Farias et al., 2011; Berganza & Zhang, 2013), as well as the pressure (Berguer, Gutt, & Stiegmann, 1993), the speed of insufflations and maintenance, hemodynamic repercussions, and the eventual diffusion of microorganisms have been exhaustively studied (Sorbello et al., 2003).

Renal changes depend on the pressure intensity; however, it is transitory and ends after the release of pneumoperitoneum. There is no evidence of either histopathological injuries or tubular lesions. Both renal function and diuresis return to normal state without long-term sequels (Dunn & McDougall, 2000).

Studies on the effects of increased intra-abdominal pressure and volume expansion on renal function with the use of animals, such as rats (Hazebroek et al., 2003; Fagundes, Montero, Novo, & Bandeira, 2001; Lee et al., 1999), pigs (London et al., 2000; Lindberg, Bergqvist, Bjorck, & Rasmussen, 2003; Gudmundsson, Viste, & Myking, 2003), rabbits (Guler, Sade, & Kirkali, 1998; Bentes de Souza, Wang, & Chu, 2003) and humans (Hawasli et al., 2003; Nguyen, Perez, Fleming, Rivers, & Wolfe, 2002; Perez et al., 2002), have brought new knowledge on oliguria, which occurs in laparoscopic procedures and how to reduce such deleterious effects.

The transitory and reversible oliguria without sequel in a kidney of a normal donor would have the same behavior in a previously injured kidney.

From this starting point, this study aimed to analyze the functional changes in experimental animals subjected to both a significant reduction of the renal mass and varying pneumoperitoneum pressures.

Material and methods

Methods

Renal function was evaluated in 50 male rats, aging 2-3 months and weighing 250-300 grams. They were subjected to right nephrectomy and a 2/3 ligature of the renal left vascular branch, as well as to induced C[O.sub.2] pneumoperitoneum.

Rats were randomly distributed in three groups (pressure intensity) and two subgroups (pressure time). Group I (n = 10)--without pneumoperitoneum; Group II (n = 20)--8 mm Hg pneumoperitoneum and Group III (n = 20)--15 mm Hg pneumoperitoneum. Animals of Groups II and III were reassigned to subgroups: IIA (n = 10) and IIIA (n = 10) with two hours of insufflation and one hour of disinsufflation; and IIB (n = 10) and IIIB (n = 10) with three hours of insufflation and one hour of disinsufflation.

The distribution of the animals in different groups is illustrated in the flowchart below (Figure 1).

After intramuscular anesthesia, a xiphopubic incision was performed with the identification of vessels near the emergence of the renal left artery, with inferior arterial branch ligature and nephrectomy to the right, for a 2/3 reduction of the renal mass. After the first week, 1% sodium chloride was added to speed up the level of glomerulosclerosis and proteinuria for about six weeks. Animals were subjected to diuresis control in metabolic cages for 24 hours for collecting the urine for proteinuria determination, and monitoring the chronic renal insufficiency.

After six weeks, animals were subjected to an anesthetic procedure and a preoperative preparation similar to the previous round to install and control the pneumoperitoneum, in addition to the dissection of the carotis communis artery and the left jugular vein, as well as the catheterization with polyethylene catheter (PE 50) in order to measure both the mean arterial pressure (MAP) and the saline solution infusion in pump at two millimeters per hour.

Once the first blood collection for the determination of microhematocrit was completed, a laparotomy with lower midline incision was carried out, with vesicostomy and purse-string suture for catheter fixation and insufflation of pneumoperitoneum according to the groups.

Inulin infusion at mL [h.sup.-1] was performed through the jugular vein by keeping the animal in a thermal box at about 28[degrees]C. Rectal temperature was measured with a digital thermometer.

Forty five minutes after establishing the pneumoperitoneum and beginning the inulin infusion, the urinary bladder was emptied (Figure 2); 60 minutes later, the arterial blood (0.2 mL) was collected for serum inulin dosage. Afterwards, a second blood sample was taken to determine the microhematocrit (hydration control). Sixty minutes after pneumoperitoneum disinsufflation, the urinary bladder was emptied once more, and 75 minutes after that, the arterial blood (0.2) was collected as before, so that the serum inulin was determined. After 90 minutes, a new urinary inulin dosage was performed.

In group I (sham), only the abdominal cavity was opened, with dissection of the carotid, jugular, vesicostomy and introduction of Veress needle (without pneumoperitoneum), as well as collection of blood and urine as previously reported to measure the inulin clearance.

After these procedures, euthanasia, exploratory laparotomy and nephrectomy of the left remaining kidney were performed, the kidney was subjected to a histological study. Qualitative and quantitative evaluations were carried out with the use of a computerized image analyzer to calculate the necrosis area percentage in the remaining left kidney.

Inulin clearance was calculated as follows: urine inulin concentration x urinary volume min.-1 inulin- 1 concentration in plasma.

Wilcoxon's test, Analysis of Variance and Kruskal-Wallis' non-parametric test were used for data analysis.

Results

Once the inulin clearance measurement is difficult, the percentile variation of its values ([DELTA]%) was chosen for statistic calculation. Tables 1 and 2 present the mean and standard deviations by using the tests mentioned above.

Data were subjected to statistical analysis by using the following tests:

Wilcoxon's test evaluated the dependent variables (pneumoperitoneum x disinsufflation). Considering the control group, inulin values were significantly higher in the final exposure time, however, no significant differences were detected between groups IIA and IIB.

Mann Whitney's test (2 hours x 3 hours [DELTA]%) did not evidence any significant difference.

Kruskal Wallis' test evaluated the independent variables (group Sham x Group II x Group III [DELTA]%). The following sequence was registered: group Sham > II B and III A and IIIB.

Wilcoxon's test evaluated the dependent variables (pneumoperitoneum x disinsufflation). No significant values were found.

In Mann Whitney's test (2 hours x 3 hours [DELTA]%) Group II B > II A, however, no significant values were found in Group III.

Kruskal Wallis' test evaluated the undependable variables (group Sham x Group II x Group III [DELTA]%). No significant values were observed.

Microscopic analysis

Non-specific interstitial nephritis, discrete tubular changes with focal dilatation containing proteinaceous material, and focal glomerulosclerosis were observed, which is typical of both renal insufficiency and onset of proteinuria (Figures 3 and 4).

Results and discussion

There still remains the doubt whether transitory and reversible oliguria without sequels in the kidney from a normal donor would have the same behavior as in a previously injured kidney.

The purpose of this study was to produce a rat model with functional and histopathological signs of renal insufficiency. After testing some situations in a pilot study, it was possible to standardize a procedure that allowed the establishment of renal failure that could lead the animal to simulate a chronic renal disease with loss of its glomerular filtration capacity.

Therefore, the population of functioning nephrons was reduced. Both the unilateral nephrectomy and the partial nephrectomy (2/3) of the contralateral kidney, shown in the pilot study, characterized a kidney with renal insufficiency at medium and long-term. However, the observation period necessary for such manifestations was long (over ninety days) and associated with a high morbidity rate, which made it difficult to acquire an adequate sampling.

The inclusion of an overload of sodium chloride to the diet caused a more evident renal insufficiency in a shorter period of time, without loss of animals.

The addition of sodium chloride to the diet has accelerated the glomerulosclerosis and increased the proteinuria rate. In the pilot study, without the addition of salt, the time for obtaining proteinuria was longer. Such addition occurred after the first week of nephrectomy, since if it was promptly performed, the mortality rate would increase during the post-operative period. After the sixth week, the histological evaluation showed evidences of glomerulosclerosis, which is the classical finding that confirms the renal insufficiency and also the onset of proteinuria.

In order to characterize the renal insufficiency, a dosage of inulin, that is, a vegetable starch, was applied. Inulin clearance, according to Tanner (2003), is the virtual volume of plasma which contains inulin eliminated by the kidneys in a certain period of time. The inulin is neither secreted nor reabsorbed by the kidneys, consisting, thus, a freely filtered substance. It is considered the 'gold standard' for measuring the glomerular filtration (Feher, 2012; Takahira et al., 2001; Padrini & Palatini, 2003).

Inulin filtration test has proved to be efficient in several animal models, such as in dogs (Buranakarl, Kijtawornrat, Nampimoon, Chaiyabutr, & Bovee, 2003), cats (Haller et al., 2003; Miyamoto, 2001), pigs (Van Westen et al., 2002; Kriern et al., 2001; Bauer, Walter, & Zwiener, 2000), and rats (Schaeffer, Gratrix, Mucha, & Carbajal, 2002; Fischer, Bogoliuk, Ramirez, Sanchez, & Masnatta, 2000).

The inulin dose used (at the concentration of 16 mg per kilo of weight and with a speed of 2 mL per hour) was attested by similar studies in the literature (Schaeffer et al., 2002; Fischer et al., 2000).

The determination of hematocrit and average arterial pressure had the goal of ensuring that hemodynamic changes would not occur, which could alter the glomerular filtration rate.

Based on Wilcoxon's test, the dependent variables were evaluated considering the differences between the pneumoperitoneum and disinsufflation exposure time. A better glomerular filtration rate was verified in the control group in the final period. Therefore, it can be indirectly stated that during disinsufflation, the renal function is not totally recovered when using a pressure of 8 or 15 mm Hg for a two-three-hour-period of time, in addition to one hour of disinsufflation. These findings are not in accordance with Beduschi, Beduschi, Williams and Wolf (1999), who evaluated the renal function with serum creatinine, however, corroborate Moreira (2002) on hypertensive rats, which showed a potential renal insufficiency. Thus, it can be concluded that the pneumoperitoneum is more injurious to a kidney with renal insufficiency when compared to a normal kidney.

Kruskal Wallis' analysis of variance (Table 1) of independent groups, comparing the two-three -hour-period for the three groups, showed that the glomerular filtration rate is much more efficient in the control group than in group III, but is not significant in group II subjected to a lower pneumoperitoneum pressure. Nevertheless, when these same parameters were analyzed during the three-hour-period of time, these differences appeared in both groups, proving that the pneumoperitoneum is detrimental for kidney in a direct proportion to the time and pneumoperitoneum pressure.

In the literature, there is no study evaluating the glomerular filtration rate in rats with chronic renal insufficiency by using inulin in the presence of different pneumoperitoneum pressures and disinsufflation, thus, a comparative analysis is limited.

The evaluation of the urinary volume (Table 2) based on Wilcoxon's test showed no statistical difference concerning the pneumoperitoneum and disinsufflation exposure times. However, some changes were detected in the renal function when the evaluation was carried out with inulin, which corroborates the fact that diuresis is not a good parameter for the evaluation of renal function (Salas, Giacaman, & Vio, 2003; Schrier, Wang, Poole, & Mitra, 2004; Pickering & Endre, 2014).

The macroscopic evaluation of the fifty kidneys indicated a wide range of small depressions and color changes in the polar site, with reddish brown tint denoting tissue necrosis, represented by areas of collapse with hemorrhage spots and lesser consistency.

Such necrotic changes were confirmed under optical microscopy, in other words, a wide range of ischemic alterations occurred. Among these, representative fields were selected to confirm the established necrosis and the extension of the process with due quantification, which varied from 22 to 28% of the surface of the examined specimens.

Further studies are necessary to clarify the reversibility of the functional behavior of damaged kidneys, as well as those subjected to high pneumoperitoneum pressures, and verify how the procedures for kidney preservation for future transplant can be affected under such situations.

Doi: 10.4025/actascihealthsci.v39i1.27131

Conclusion

Inulin clearance evidenced that renal function is impaired when using the 2/3 reduction model of renal mass, and that it is directly related to both the pressure and the pneumoperitoneum exposure time.

References

Bauer, R., Walter, B., & Zwiener, U. (2000). Comparison between inulin clearance and endogenous creatinine clearence in newborn normal weight and growth restricted newborn piglets. Journal Experimental and Toxicologic Pathology, 52(4), 367-372.

Beduschi, R., Beduschi, M. C., Williams, A. L., & Wolf, J. S. (1999). Pneumoperitoneum does not potentiate the nephrotoxicity of aminoglicosides in rats. Urology, 53(2), 51-54.

Bentes de Souza, A. M., Wang, C. C., & Chu, C. Y. (2003). The effect of intraabdominal pressure on the generation of 8-iso-prostoglandin F2alpha during laparoscopy in rabbits. Human Reproduction, 18(10), 2181-2188.

Berganza, C. J., & Zhang, J. H. (2013). The role of helium gas in medicine. Medical Gas Research, 3(18), 2-7.

Berguer, R., Gutt, C., & Stiegmann, G. V. (1993). Laparoscopic surgery in the rat: description of a new technique. Surgical Endoscopy, 7(1), 345-347.

Bloom, R. D., Sayer, G., Fa, K., Constantinescu, S., Abt, P., & Reddy, K. R. (2005). Outcome of hepatitis C virus-infected kidney transplant candidates who remain on the waiting list. American Journal of Transplantation, 5(1), 139-144.

Buranakarl, C., Kijtawornrat, A., Nampimoon, P., Chaiyabutr, N., & Bovee, K. C. (2003). Comparison of measurements of glomerular filtration rate using single-injection inulin methods and urinary creatinine clearance in dogs with reduced renal blood flow. Thai Journal of Physiological Science, 16(1), 9-16.

Dunn, M. D., & McDougall, E. M. (2000). Renal physiology laparoscopy considerations. Journal of Urologic Clinics of North America, 27(4), 609-614.

Fagundes, M. A. V., Montero, E. F. S., Novo, N. F., & Bandeira, C. O. P. (2001). Efeitos do pneumoperitonio em ratos. Acta Scientiarum. Health Science, 23(3), 703-707.

Farias, I. E. C., Morais, P. H. A., Duraes, L. C., Carneiro, F. P., Oliveira, P. G., & Sousa, J. B. (2011). Effects of carbon dioxide pneumoperitoneum on hepatic and renal morphology of rats after segmental colectomy and colonic anastomosis. Acta Cirurgica Brasileira, 26(4), 279-283.

Feher, J. J. (2012). Quantitative human physiology: an introduction. London, UK: Elsevier.

Fischer, P. A., Bogoliuk, C. B., Ramirez, A. J., Sanchez, R. A., & Masnatta, L. D. A. (2000). New procedure for evaluation of renal function without urine collection in rat. Kidney International, 58(3), 1336-1341.

Gudmundsson, F. F., Viste, A., & Myking, O. L. (2003). Role of angiotensin II under prolonged increased intraabdominal pressure (IAP) in pigs. Surgical Endoscopy, 17(7), 1092-1097.

Guler, C., Sade, M., & Kirkali, Z. (1998). Renal effects of carbon dioxide insufflation in rabbit pneumoperitoneum model. Journal Endourology, 12(4), 367-370.

Haller, M., Rohner, K., Muller, W., Reutter, F., Binder, H., & Estelberger, W. (2003). Single-injection inulin clearence for routine measurement of glomerular filtration rate in cats. Journal of Feline Medicine and Surgery, 5(3), 175-181.

Hawasli, A., Oh, H., Schervish, E., Frontera, R., Gonsherova, I., & Khoury, H. (2003). The effect of pneumoperitoneum on kidney function in laparoscopic donor nephrectomy. American Surgeo, 69(4), 300-303.

Hazebroek, E. J., Bruin, R. W. F., Bouvy, N. D. B., Richard, L. M., Bonthuis, F., & Bajema, I. M. (2003). Long-term impact of pneumoperitoneum used for laparoscopic donor nephrectomy on renal function and histomorphology in donor and recipient rats. Annals of Surgery, 237(3), 351-357.

Hazebroek, E. J., Bruin, R. W., Bouvy, N. D., Van Duikeren, S., Bonthuis, F., & Marquet, R. I. (2002). Short-term impact of carbon dioxide, helium, and gasless laparoscopic donor nephrectomy on renal function and histomorphology in donor and recipient. Surgical Endoscopy, 16(2), 245-251.

Kriern, J. D., Ritman, E. L., Bajzer, Z., Romero, J. C., Lerman, A., & Lerman, L. O. (2001). Noninvasive measurement of concurrent single-kidney perfusion, glomerular filtration, and tubular function. American Journal Physiology-Renal Physiology, 281(4), 630-638.

Lee, B. R., Cadeddu, J. A., Molnar-Nadasdy, G., Enriquez, D., Nadasdy, T., Kavoussi, L. R., .... Ratner, L. E. (1999). Chronic effect of pneumoperitoneum on renal histology.Journal Endourology, 13(4), 279-282.

Lindberg, F., Bergqvist, D., Bjorck, M., & Rasmussen, I. (2003). Renal hemodynamics during carbon dioxide pneumoperitoneum: an experimental study in pigs. Surgical Endoscopy, 17(3), 480-484.

London, E. T., Ho, H. S., Neuhaus, A. M., Wolfe, B. M., Rudich, S. M., & Perez, R. V. (2000). Effect of intravascular volume expansion on renal function during prolonged C[O.sub.2] pneumoperitoneum. Annals of Surgery, 231(2), 195-201.

Merion, R. M., Ashby, V. B., Wolfe, R. A., Distant, D. A., Hulbert-Shearon, T. E., Metzger, R. A., ... Port, F. K. (2005). Deceased-donor characteristics and the survival benefit of kidney transplantation. Journal of the American Medical Association, 294(21), 2726-2733.

Miyamoto, K. (2001). Evaluation of plasma clearence of inulin in clinically normal and partially nephrectomized cats. American Journal of Veterinary Research, 62(8), 1332-1335.

Moreira, M. B. (2002). A funcao renal de ratos espontaneamente hipertensos submetidos ao pneumoperitonio. Acta Cirurgica Brasileira, 17(3), 168-180.

Nguyen, N. T., Perez, R.V., Fleming, N., Rivers, R., & Wolfe, B. M. (2002). Effect of prolonged pneumoperitoneum on intraoperative urine output during laparoscopic gastric bypass. Journal of the American College of Surgeons, 195(4), 476-483.

Padrini, O. F., & Palatini, P. (2003). Determination of inulin clearence by bolus intravenous injection in healthy subjects and ascitic patientes: Equivalence of systemic and renal clearences as glomerular filtration markers. British Journal of Clinical Pharmacology, 46(6), 605-609.

Perez, J., Taura, P., Rueda, J., Balust, J., Anglada, T., Beltran, J., ... Garcia-Valdecasas, J. C. (2002). Role of dopamine in renal dysfunction during laparoscopic surgery. Surgical Endoscopy, 16(9), 1297-1301.

Pickering, J. W., & Endre, Z. H. (2014). The definition and detection of acute kidney injury. Journal of Renal Injury Prevention, 3(1), 21-25.

Saad, S., Minor, I., Mohri, T., & Nagelschmidt, M. (2001). The clinical impact of warmed insuflation carbon dioxide gas for laparoscopic cholecystectomy. Surgical Endoscopy, 15(10), 1244-1255.

Salas, S. P., Giacaman, A., & Vio, C. P. (2003). Pregnant rats with 5/6 nephrectomy have normal volume expansion despite lower renin and kalicrein. Hypertension, 42(4), 744, 748.

Schaeffer, R. C., Gratrix, M. L., Mucha, D. R., & Carbajal, J. M. (2002). The rat glomerular filtration barrier does not show negative charge selectivity. Microcirculation, 9(5), 329-342.

Schrier, R. W., Wang, W., Poole, B., & Mitra, A. (2004). Acute renal failure: definitions, diagnosis, pathogenesis, and therapy. Journal of Clinical Investigation, 114(1), 5-14.

Sorbello, A. A., Damy, S. B., Osaka, J. T., Andretto, R., Franca, L. C. M., Zanotto, A., & Tolosa, E. M. C. (2003). Analise comparativa da evolucao da peritonite induzida por inoculo padronizado de Escherichia Coli em ratos: controles, laparotomia e pneumoperitonio com dioxido de carbono. Revista Brasileira de Videocirurgia, 1(1), 1-8.

Takahira, R., Yonemura, K. O., Iwahara, K., Kanno, T., Fujise, Y., & Hishida, A. (2001). Tryptophan glycoconjugate as a novel marker of renal function. The American Journal of Medicine, 110(3), 192-197.

Tanner, G. A. (2003). Renal physiology and body fluids. In R. A. Rhoades, G. A Tanner (Org.), Medical physiology (p. 377-402). Boston, MA: Lippincott Williams and Wilkins.

Van Westen, D., Almen, T., Chai, C. M., Frennby, B., Mansson, S., & Sterner, G. (2002). Biliary and total extrarenal clearence of inulin and iohexol in pigs: a source of error when determining gfr as body clearence. Nephron, 91(2), 300-307.

Received on March 26, 2015.

Accepted on December 15, 2015.

Marco Aurelio Valadao (1) *, Djalma Jose Fagundes (2), Willian Cesar Cavazana (1) and Gabriel Jorge Fagundes (3)

(1) Departamento de Medicina, Universidade Estadual de Maringa, Av. Colombo, 5790, 87020 -900, Maringa, Parana, Brazil. (2) Departamento de Medicina, Escola Paulista de Medicina, Sao Paulo, Sao Paulo, Brazil. (3) Departamento de Medicina, Faculdade Assis Gurgacz, Cascavel, Parana, Brazil. * Author for correspondence. E-mail: drfagundes@hotmail.com

Caption: Figure 1. Scheme of the animals' distribution in the different groups studied.

Caption: Figure 2. Procedures for establishing the pneumoperitoneum and data collection in the different groups.

Caption: Figure 3. Photomicrography of the kidney of an animal of group I (sham) in the area not subjected to ischemia, showing the endarteritis obliterans (EO) associated with interstitial nephritis (IN). The aspects were similar in all the remaining animals of the three groups (HE - 400 x).

Caption: Figure 4. Photomicrography of the kidney of an animal of group I (sham) in the area not subjected to ischemia, showing focal glomerular change with a slight increase of the mesangial matrix and cellularity (MM), as well as synechia of both the parietal and visceral folium and Bowman's capsule (SB). The aspects were similar in all the remaining animals of the three groups (HE - 400 x).
Table 1. Mean and standard deviation (expressed in mL [min..sup.-1])
of inulin in the initial and final exposure time. [DELTA]% was also
calculated.

                Pneumo            Disinsufflation      [DELTA]%
              (Initial)               (Final)

Groups
Sham     0.1321 [+ or -] 0.3    0.4663 [+ or -] 0.14     277
II A     0.0633 [+ or -] 0.08   0.0712 [+ or -] 0.05     203
II B     0.0983 [+ or -] 0.02   0.1025 [+ or -] 0.02      11
III A    0.0941 [+ or -] 0.05   0.0807 [+ or -] 0.03    -3.57
III B    0.1071 [+ or -] 0.04   0.0962 [+ or -] 0.03    -3.25

Table 1. Mean and standard deviation (expressed in [min..sup.-1])
of inulin in the initial and final exposure time. [DELTA]% was also
calculated.

                Pneumo            Disinsufflation      [DELTA]%
              (Initial)               (Final)

Groups
Sham     1.05 [+ or -] 0.15    1.09 [+ or -] 0.16        4.53
II A     0.7 [+ or -] 0.17     0.64 [+ or -] 0.13       -6.01
II B     0.86 [+ or -] 0.12    0.93 [+ or -] 0.15        8.19
III A    0.93 [+ or -] 0.18    0.90 [+ or -] 0.17       -2.10
III B    0.95 [+ or -] 0.14    0.94 [+ or -] 0.14       -0.11
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Author:Valadao, Marco Aurelio; Fagundes, Djalma Jose; Cavazana, Willian Cesar; Fagundes, Gabriel Jorge
Publication:Acta Scientiarum. Health Sciences (UEM)
Article Type:Ensayo
Date:Jan 1, 2017
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