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Is Renal Warm Ischemia over 30 Minutes during Laparoscopic Partial Nephrectomy Possible? One-Year Results of a Prospective Study
european urology 52 (2007) 1170–1178
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Kidney Cancer
Is Renal Warm Ischemia over 30 Minutes during Laparoscopic Partial Nephrectomy Possible? One-Year Results of a Prospective Study Francesco Porpiglia a,*, Julien Renard a, Michele Billia a, Francesca Musso a, Alessandro Volpe a, Rodolfo Burruni a, Carlo Terrone a, Loredana Colla b, Giorgina Piccoli b, Valerio Podio c, Roberto Mario Scarpa a a
Department of Urology, University of Turin, San Luigi Hospital, Orbassano Torino, Italy Department of Nephrology, University of Turin, San Giovanni Battista Hospital, Torino, Italy c Department of Radiology and Nuclear Medicin, University of Turin, San Luigi Hospital, Orbassano, Torino, Italy b
Article info
Abstract
Article history: Accepted April 5, 2007 Published online ahead of print on April 11, 2007
Objective: To evaluate renal damage and impairment of renal function 1 yr after laparoscopic partial nephrectomy (LPN) with warm ischemia >30 min. Methods: From July 2004 to June 2005, 18 patients underwent LPN with warm ischemia time >30 min. Kidney damage markers (daily proteinuria and tubular enzymes) and renal function (serum creatinine, cystatin C, and creatinine clearances) were assessed on postoperative days 1 and 5 and at 12 mo. Glomerular filtration rate (GFR) was evaluated before surgery and at 3 mo. Renal scintigraphy was performed before the procedure, at 5 d and at 3 and 12 mo postoperatively. Statistical analysis was performed using the Student t test and logistic regression analysis. Results: In terms of kidney damage and renal function markers, the statistical analysis demonstrated that at 1 yr there was complete return to the normal range and no statistical difference between the values at the various time points. The GFR was not significantly different before and 3 mo after surgery. In terms of scintigraphy of the operated kidney, the values were 48.35 3.82% (40–50%) before the procedure, 36.88 8.42 (16–50%) on postoperative day 5 ( p = 0.0001), 40.56 8.96 (20–50%) at 3 mo ( p = 0.003), and 42.8 7.2% (20–50%) 1 yr after surgery ( p = 0.001). Conclusion: Our results demonstrate that kidney damage occurs during LPN when warm ischemia is >30 min. This damage is only partially reversible and efforts should be made to keep warm ischemia within 30 min.
Keywords: Laparoscopy Partial nephrectomy Renal function Warm ischemia
# 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, San Luigi Hospital, Regione Gonzole 10, 10043, Orbassano, Torino, Italy. Tel. +39 011 9026558; Fax: +39 011 9026244. E-mail address: [email protected] (F. Porpiglia). 0302-2838/$ – see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2007.04.024
european urology 52 (2007) 1170–1178
1.
Introduction
The evolution of minimally invasive surgery led laparoscopic partial nephrectomy (LPN) to be accepted as a surgical option. Although this technique is still considered challenging, this approach has become the first choice for the treatment of selected renal tumors in centers with high laparoscopic expertise [1–4]. To perform a correct surgery it is essential to operate in a bloodless field [5]. This can be obtained by temporary occlusion of the renal artery or of the entire renal pedicle. The subsequent renal ischemia can cause impairment of renal function. It is already known that renal ischemia time of <30 min is safe [6–9], whereas longer ischemia can cause kidney damage. In some cases of LPN, for example, in the presence of technical difficulties ischemia >30 min can be necessary. When this is expected, kidney cooling can guarantee a safe ischemia time up to 3 h [10]. When warm ischemia is chosen and the duration of ischemia is >30 min, the entity of the potential kidney damage has not been yet clearly defined. For this reason, the issue of warm ischemic renal damage needs to be better investigated. The objective of this prospective study was to evaluate renal damage in patients 1 yr after LPN performed with a warm ischemia time >30 min. 2.
Materials and methods
From July 2004 to June 2005, 18 patients who underwent LPN with a warm ischemia time >30 min were enrolled in this prospective study. All patients underwent the same protocol.
tubular enzymes can be used as markers of kidney damage [12]. The tubular enzymes are alanine aminopeptidase (AAP, normal range: 0–12 U/l), lysozyme (normal range: 0–3 mg/l), and g-glutamyl transpeptidase (GGT, normal range: 0–50 U/l). Evaluation of these markers was performed before the procedure, on postoperative days 1 and 5, and 12 mo after the procedure. To evaluate the impact of warm ischemia time on renal function, serum creatinine (normal range: 0.6–1.2 mg/dl), cystatin C [13] (normal range: 0.50–1.00 mg/dl) and creatinine clearances calculated with the Cockroft-Gault equations (normal range: 90–150 ml/min) were assessed before the procedure, on postoperative days 1 and 5, and 12 mo after the procedure. To have a more precise evaluation of the kidney function [12], the glomerular filtration rate (GFR) was evaluated also by nuclear medicine using 51Cr-ethylenediaminetetraacetic acid (EDTA) before surgery and 3 mo after surgery (normal range: 45–93 ml/min/1.73 m2). Moreover, to evaluate the effects of the procedure on the operated kidney, all patients underwent radionuclide renal scintigraphy with 99mTc-mercaptoacetyltriglycine (99mTc-MAG3) before the procedure and 5 d, 3 mo, and 12 mo after the procedure. The onset of new morbidity during follow-up was also recorded.
2.4.
Pathology assessment
Pathology assessment included histology of the lesion and measurement of lesion diameter and minimum and maximum thickness of resected healthy parenchyma.
2.3.
Statistical evaluation
Patients
In all patients LPN was indicated for a benign or malignant disease. For each case, we recorded age, gender, comorbidities, lesion size, cause of the procedure, type of surgical approach, operating time, warm ischemia time, estimated blood loss, and complications.
2.2.
Kidney damage prevention
The renal artery was accurately isolated. In all cases only the artery and not the entire hilum was clamped. To prevent ischemic damage, all patients received proper hydration and mannitol infusion (0.25 g/kg) 10 min before clamping [10]. Moreover, before clamping, lidocaine 20 ml (2%) was injected over the renal artery to prevent vascular spasm. In all cases, clamping was achieved using a bulldog clamp. After declamping, furosemide 20 mg was injected intravenously. Warm ischemia time was evaluated using the operating room chronometer.
2.5. 2.1.
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Statistical analysis was carried out using the Student t test (Software Statistics 6.0) to evaluate the renal damage and the functional impairment at the various time points. A p value superior to 0.05 was considered not significant (ns). A linear regression model was used to determine if total daily proteinuria on postoperative days 1 and 5 was influenced by the length of warm ischemia time. At 1 yr, a logistic regression model was used to evaluate the influence of patient age, comorbidity, lesion diameter, maximum thickness of resected healthy parenchyma, and warm ischemia time on the renal function of the operated kidney. All data were adjusted to the baseline values of the radionuclide scintigraphy.
Evaluation of kidney damage
Kidney damage is defined as the presence of structural or functional abnormalities of the kidney [11]. The peripheral region of the renal medulla, which includes both glomeruli and proximal tubuli, is the most sensitive zone to ischemia. Its damage causes loss of protein and specific enzymes. Therefore, total daily proteinuria (normal range: 0–150 mg/d) and
3.
Results
3.1.
Patients
Eighteen patients underwent LPN and reached a 1-yr follow-up. Mean age was 59.6 16.9 yr (range:
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Table 1 – Perioperative parameters Patient
Age, yr
Gender
Motive of procedure
Comorbidities
Side
Approach
Operative time, min
Warm ischemia time, min
Blood loss, ml
Complications
69 71 33 67 67 64 62 58 12 34 71 57 63 78 61 77 69 60
Male Female Female Female Female Male Female Female Female Female Male Male Male Female Female Male Female Male
Tumor Tumor Tumor Tumor Tumor Tumor Tumor Tumor Stone Stone Tumor Tumor Tumor Tumor Tumor Tumor Tumor Tumor
HP, Diab — — HP, Diab, LLC HP HP — HP — — — — Past chemotherapy HP HP, IMA HP, IMA — —
R L L L L R L L L R L L R R L L R R
Retroperitoneal Retroperitoneal Transperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal
90 130 135 150 210 120 180 120 210 225 120 120 165 130 120 150 120 150
33 33 32 44 32 39 40 52 47 60 46 34 32 38 40 31 31 39
300 50 350 100 100 200 50 250 200 750 200 50 100 100 250 200 350 200
— — — — — — Fistula, reintervention — — Bleeding — — — — Bleeding — — —
Mean
59.6 16.9
7 male/11 female
16 tumors 2 stones
—
7 R 11 L
17 retroperitoneal 1 transperitoneal
146.9 37.4
39.0 8.1
211.1 165.8
3 patients
HP = hypertension; Diab = diabetes, IMA = cardiac infarction; LLC = leukemia; R = right; L = left.
european urology 52 (2007) 1170–1178
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
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12–78 yr). Seven patients were males and 11 were females. Eight patients were affected by cardiovascular diseases, two had diabetes, one had chronic lymphoid leukemia, and one underwent chemotherapy. Sixteen patients underwent the procedure for a tumor and two patients underwent LPN for benign disease (hydrocalyx and upper calyx stone). In 17 cases we used a retroperitoneal approach and in one a transperitoneal approach. Mean operating time and mean estimated blood loss are reported in Table 1. Mean warm ischemia time was 39 8.1 min (range: 31–60 min). Postoperative complication rate was 16% (two postoperative transfusions, one reintervention, one fistula; Table 1). 3.2.
Pathology assessment
Eight lesions were benign and 10 were malignant. Mean lesion diameter was 3.4 1.8 mm (range: 1– 8 mm). The mean maximum margin of resected healthy parenchyma was 8.25 4.1 mm (range: 2– 35 mm), and the mean minimum margin of resected healthy parenchyma was 3.0 1.9 mm (range: 1–7). Results are reported in Table 2. 3.3.
Evaluation of kidney damage
As far as the proximal tubular enzymes are concerned, mean AAP, GGT, and lysozyme values did not significantly change over time after surgery (Table 3). Mean total daily proteinuria was level 106.26 161.78 mg/d (range: 30–700 mg/d) preoperatively,
Fig. 1 – Total daily proteinuria at the various time points. It is evident that the value of proteinuria returns to normal range 1 yr after surgery.
818.6 968.9 mg/d (range: 156–4380 mg/d) on postoperative day 1 ( p = 0.009), 632.4 1063.6 mg/d (range: 60–4620 mg/d) on postoperative day 5 ( p = 0.007), and 72.6 35.4 mg/d (range: 15–148 mg/d) 1 yr after surgery ( p = ns). The statistical analysis demonstrates that total daily proteinuria increases significantly in the immediate postoperative period, but returns to the normal range 1 yr after surgery (Table 3 and Fig. 1). However, according to the linear regression model it is important to point out that the variation of total daily proteinuria on postoperative days 1 and 5 is not dependent on the warm ischemia time ( p = 0.47). The values of serum creatinine, serum cystatin C, and creatinine clearance are reported in Table 4. No statistical difference was observed among the values at the various time points. Minor variability of the values is observed for serum cystatin C and
Table 2 – Pathologic results Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Lesion size, cm
Maximum thickness of healthy parenchyma, mm
Minimum thickness of healthy parenchyma, mm
1 2 8 1.5 2 2 8 5 — — 5 4.5 2.9 5 2 3.5 2 3.5 3.4 1.8
12 5 10 9 18 10 8 15 35 — 6 8 9 4 2 5 5 6 9.82 7.6
7 2 5 2 6 2 4.5 3 — — 1 1 4 2 1 3 1 1.5 3.0 1.9
Pathology Clear cell carcinoma Oncocytoma Angiomiolipoma Angiomiolipoma Hematic cyst Angiomiolipoma Angiomiolipoma Clear-cell carcinoma Pyelonephritis (stone) Calyx ectasis Papillary carcinoma Papillary carcinoma Collective ducts carcinoma Clear-cell carcinoma Papillary carcinoma Papillary carcinoma Clear-cell carcinoma Clear-cell carcinoma
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Table 3 – Assessment of renal damage by daily proteinuria and enzymes Preoperative (range) u-Lysozyme mg/l (range: 0–3) u-n AAP, U/l (range: 0–12) u-GGT, U/l (range: 0–50) Proteinuria, mg/d
0.99 0.88 (0.2–3) 7.89 4.91 (2–23) 44.06 22.05 (12–103) 106.26 161.78 (30–700)
POD 1 0.91 0.64 9.50 5.08 47.5 30.63 818.6 968.9
p value, preop vs. POD 1
POD 5
p value, preop vs. POD 5
ns ns ns 0.009
1.07 0.71 (0.20–2.40) 12.71 8.501 (3–36) 41.47 19.88 (13–84) 632.4 1063.6
ns ns ns 0.007
(0.10–2.70) (4–25) (15–157) (156–4380)
1 yr 0.9 0.39 4.4 1.69 34.7 17.8 72.6 35.4
(0.5–2) (2–8) (25–51) (15–148)
p value, preop vs. 1 yr ns 0.017 ns ns
The total daily proteinuria, which showed an significant increase, returned to normal at 1 yr from surgery; POD = postoperative day; ns = not significant; AAP = alanine aminopeptidase; GGT = g-glutamyl transpeptidase.
p-Cystatin C mg/l (range: 0.5–1.00) p-Creatinine mg/dl (range: 0.6–1.2) Creatinine clearance ml/min (range: 90–150)
Preoperative
POD 1
p value, preop vs. POD 1
POD 5
p value, preop vs. POD 5
At 1 yr
1.03 0.19 (0.76–1.45) 0.91 0.17 (0.6–1.2) 67.88 26.38 (28–127)
0.99 0.16 (0.66–1.26) 1.06 0.21 (0.7–1.5) 65.94 46.42 (13–204)
ns ns ns
1.02 0.18 (0.77–1.36) 0.95 0.2 (0.6–1.4) 88.17 33.78 (29–133)
ns ns ns
1.03 0.17 (0.65–1.2) 1.02 0.24 (0.8–1.5) 90.3 29.31 (49–135)
p value, preop vs. 1 yr ns ns ns
POD = postoperative day; ns = not significant.
Table 5 – GFR evaluated by nuclear medicine and contribution of the operated kidney to the overall renal function
GFR (nuclear medicine), mean ml/min Contribution of operated kidney to overall renal function (scintigraphy)
Preoperative
At POD 5
p value preop vs. POD 5–7
At 3 mo
p value, preop vs. 3 mo
At 1 yr
91.60 22.68 (56.40–144.8) 48.3 3.82% (40–53%)
— 36.8 8.4% (16–50%)
— 0.0001
79.12 13.69 (59.70–100.2) 40.56 8.9% (20–50%)
ns 0.003
— 42.8 7.2% (20–50%)
GFR = glomerular filtration rate; POD, postoperative day; ns = not significant.
p value, preop vs. 1 yr — 0.001
european urology 52 (2007) 1170–1178
Table 4 – Renal function evaluated by serum creatinine, serum cystatin C, and creatinine clearance
european urology 52 (2007) 1170–1178
serum creatinine, whereas creatinine clearance showed a paradoxical increase. The GFR (evaluated by nuclear medicine using 51 Cr-EDTA) was not significantly different before and 3 mo after the procedure: mean GFR was 91.60 22.68 ml/min/1.73 m2 preoperatively and 79.12 13.69 ml/min/1.73 m2 3 mo after surgery ( p = ns) (Table 5). As far as the contribution of the operated kidney to the overall renal function (evaluated by renal scintigraphy with 99mTc-MAG3) is concerned, the preoperative value was 48.35 3.82% (range: 40– 50%), 36.88 8.42% (range: 16–50%) on postoperative day 5 ( p = 0.0001), 40.56 8.96% (range: 20–50%) at 3 mo ( p = 0.003), and 42.8 7.2% (range: 20–50%) 1 yr after surgery ( p = 0.001) (Table 5). One year after surgery, there is still a significant difference compared to the preoperative values, although it is evident that after an initial drop there is a trend toward a progressive recovery (Fig. 2). However, it is important to point out that the number of patients included in this study could affect the statistical power. At the 1-yr follow-up, no patient had developed new morbidities. As far as the logistic regression model is concerned, the statistical analysis demonstrated that the loss of function in the operated kidney (evaluated by radionuclide scintigraphy) is not influenced by lesion size at pathology, patient age, and presence of comorbidities, but it is influenced significantly ( p < 0.05) by the maximum thickness of resected healthy parenchyma and duration of warm ischemia. The loss of renal function is maximal between 32 and 42 min of warm ischemia time, as shown by the drop of the curve in Fig. 3. Between 42 and 60 min, the curve flattens out, demonstrating a minor further loss of function when the warm ischemia time is in this range.
Fig. 2 – Contribution of operated kidney to the overall renal function at the various time points (radionuclide renal scintigraphy with 99mTc-mercaptoacetyltriglycine). POD = postoperative day.
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Fig. 3 – Logistic regression model. Full orange curve = evolution of kidney damage over time; it is evident that between 32 and 42 min there is a major drop, corresponding to the phase in which parenchymal damage is maximum. The ‘‘starting point’’ of the ‘‘critical phase’’ of warm ischemia is at the 32-min time mark. The interrupted curves correspond to the confidence intervals.
4.
Discussion
Although considered a challenging technique, LPN is gaining wide acceptance worldwide, especially in urologic departments where advanced laparoscopy is carried out [26]. To perform an accurate surgery, it is essential to resect the lesion and to obtain hemostasis in a short warm ischemia time to avoid kidney damage [3,27]. According to Rocca Rossetti [10], warm ischemia in open surgery can be classified as follows: (1) <10 min—harmless; (2) up to 30 min—generally reversible lesions; (3) >30 min—risk of irreversible parenchymal lesions increasing rapidly with the ischemic time; and (4) >60 min—irreversible lesions. Regarding the site of kidney damage, the same author states that nephrons react differently to ischemia; glomeruli tolerate the ischemia better than tubular epithelia, whereas proximal convoluted tubules are more sensitive to ischemic damage [10]. More recently, other authors suggested that warm ischemia determines a reduction in medullary blood flow causing hypoxic injury to the tubular structures in this region [9]. Furthermore, it seems that the degree of damage is proportional to the warm ischemia time. The higher sensitivity of the proximal tubuli to ischemia is due to a low capacity of the cells to generate adenosine triphosphate (ATP), whereas the remaining tubular cells are protected by the persistence of ATP. When warm ischemia is prolonged, the cells from the distal
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tubuli produce cytokines responsible for their apoptosis [6]. The same cytokines exacerbate the inflammatory response and enhance vascular tone, stimulating further injury [9]. To reduce these possible injuries to the kidney, protective procedures are used, such as mannitol infusion or kidney cooling. According to Marberger, when longer ischemia time (>30 min) is expected, kidney cooling in situ is essential (at 10–25 8C, temporary ischemia up to 3 h is tolerated without permanent impairment) [25]. During laparoscopy, the increase of intra-abdominal pressure due to the pneumoperitoneum generally causes oliguria [14]. This situation can create an ischemic preconditioning that reduces tissue injury [15,16]. For this reason, it is theoretically possible to increase warm ischemia time during LPN, compared to open surgery, even if there is much controversy on this issue. For instance, in an experimental porcine model, Laven et al demonstrated that there is no difference between LPN and open surgery in terms of kidney damage after prolonged ischemia [17]. Therefore, it is essential to reproduce in laparoscopy the same protective measures used in open surgery when renal ischemia is produced. As far as kidney cooling is concerned, methods such as laparoscopic ice slush cooling, intraureteral cooling, and intravascular hypothermic perfusion have been described to obtain kidney hypothermia [18–21]. Unfortunately, these techniques, although efficient and reliable for some authors, are complicated to manage [22]. Considering that use of LPN is expanding in urologic centers to the treatment of increasingly complex lesions without using tedious cooling procedures, it is today essential to assess the effects of warm ischemia between 30 to 60 min during LPN [1–4,22]. Using only serum creatinine levels, Bhayani et al demonstrated that a warm ischemia time up to 55 min does not influence long-term renal function after LPN [8]. In a series of LPNs with a mean warm ischemia of 43 min (range: 25–65 min) and a fairly short follow-up (mean: 130 d), Kane et al showed that temporary arterial occlusion does not appear to affect short-term renal function [23]. Using GFR evaluation, Shekarriz demonstrated that LPN can be performed safely and efficiently using temporary hilar clamping. However, in this study in only two cases was warm ischemia time >30 min (33 and 45 min) [24]. All these studies were performed on patients with a normal contralateral kidney. In patients with a solitary kidney, Thompson et al [28] emphasize that warm ischemia during open nephron-sparing surgery is associated with a high incidence of renal complications (increase in the risk
of permanent dialysis) if warm ischemia is >20 min. However, the weakness of this study is that it was done in situations where surgery was an imperative indication and, therefore, did not consider the amount of residual healthy parenchyma. Our study assessed kidney damage in patients 1 yr after LPN with a warm ischemia time between 30 and 60 min. We evaluated total daily proteinuria and tubular enzymes (AAP, GGT, lysozyme). AAP expresses the damage to the entire nephron, whereas GGT and lysozyme are more specific for the proximal tubuli. Our results demonstrate that tubular enzyme levels do not change significantly in the immediate postoperative period, whereas total daily proteinuria shows a significant increase on the first postoperative day before returning to the normal range 1 yr after surgery. This means that the damage to the proximal tubuli does not determine an alteration of enzyme values, therefore indicating that these enzymes cannot be proposed as suitable markers of kidney damage. Total daily proteinuria, which is a more sensitive measure to evaluate overall nephron damage, presented a significant increase on the first postoperative day (expressing ischemic damage), before starting to return to normal range, as demonstrated by the values observed on the fifth postoperative day and 1 yr after the procedure (Fig. 1). However, to assess the exact location of the damage, a more precise discrimination of proteins should have been performed. Furthermore, we observed that the variations of total daily proteinuria were not influenced by the length of warm ischemia. Therefore, the total daily proteinuria assessment can indicate the presence of kidney damage, but it cannot be used to quantify the entity of the damage. In terms of renal function, we demonstrate that in the immediate postoperative period and at 3 mo and 1 yr from surgery, mean serum creatinine, mean serum cystatin C, creatinine clearance, and GFR have not significantly changed compared to the preoperative data. It is therefore possible to use any one of these parameters to evaluate renal function. These parameters did not change significantly because the resection of parenchyma was performed on patients with a normal contralateral kidney, which is responsible for the compensation of parenchymal loss. However, it is obvious that the GFR values (evaluated by nuclear medicine using 51 Cr-EDTA) are more precise than creatinine clearance, because the nuclear medicine method is less influenced by extrarenal factors. Therefore, to evaluate whether the renal function is not completely taken by the normal, contralateral
european urology 52 (2007) 1170–1178
kidney, and because no patient had a solitary kidney, it was essential to use another study procedure. We evaluated the contribution of the operated kidney to the overall renal function by radionuclide scintigraphy with 99mTc-MAG3. We observed that there is an initial significant drop of 11.4% 7.3% in the operated kidney’s contribution to overall function, followed by a constant and progressive recovery that never reaches the preoperative value (42.8% at 1 yr vs. 48.3% before surgery), with a loss of contribution of 5.5% 6.4% and a recovery at 1 yr of 4%. This damage is probably due to the amount of resected healthy renal parenchyma and to the warm ischemia time. It could also be influenced by the patient’s age and comorbidities and by parenchymal suture. To clarify this issue, we applied a logistic regression model that demonstrated that the loss of function of the operated kidney depends mostly on the warm ischemia time ( p < 0.05) and less importantly on the maximum thickness of resected healthy parenchyma. As far as the warm ischemia time is concerned, we observed that the maximum loss of renal function occurs between 32 and 42 min, defining the 32-min time mark as the ‘‘starting point’’ of the ‘‘critical phase’’ of warm ischemia. It seems that, although there is a correspondence between damage and ischemia time, the relationship between these two parameters is not linear. We can hypothesize that in the time period between 32 and 42 min the damage involves the largest number of nephrons. Moreover, in this time period there may be a liberation of cytokines that convey damage to the medulla causing an inflammatory infiltration [6]. However, it is important to point out that, even though there is a documented loss of renal function, this is limited in time and is incomplete, as demonstrated by the progressive recovery, suggesting that the lesions to some nephrons are reversible. Nevertheless, longer follow-up is needed to discover whether the kidney is able to achieve a full recovery over time.
5.
Conclusions
When renal warm ischemia time during LPN lasts from 30 to 60 min, partial damage to the operated kidney is likely produced. The impairment in renal function depends on the length of the warm ischemia time and on the thickness of the removed healthy parenchyma. Results at 1 yr demonstrate that this damage is partially reversible.
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Conflicts of interest The authors have nothing to disclose.
Acknowledgements Prof. Dario Gregori, Deptartment of Statistics, University of Turin, is acknowledged for his contribution to the statistical evaluations. References [1] Gill IS, Desai MM, Kaouk JH, et al. Laparoscopic partial nephrectomy for renal tumor: duplicating open surgical techniques. J Urol 2002;167:469–76. [2] Reisiger K, Venkatesh R, Figenshau RS, Bae K, Landaman J. Complex laparoscopic partial nephrectomy for renal hilar tumors. Urology 2005;65:888–91. [3] Haber G-P, Gill IS. Laparoscopic partial nephrectomy: contemporary technique and outcomes. Eur Urol 2006; 49:660–5. [4] Ha¨cker A, Albadour A, Jauker W, et al. Nephron sparing surgery for renal tumours: acceleration and facilitation of the laparoscopic technique. Eur Urol 2007;51:358–65. [5] Colombel M, Timsit M, Badet L. Chirurgie conservatrice et hypothermie re´nale: bases physiologiques et technique ope´ratoire. Annales d’Urologie 2007;41:2–22. [6] Uzzo RG, Novick AC. Nephron sparing surgery for renal tumours: indications, techniques and outcomes. J Urol 2001;166:1264–6. [7] Novick AC. Nephron sparing surgery for renal cell carcinoma. Annu Rev Med 2003;53:393–407. [8] Bhayani SB, Rha KH, Pinto PA, et al. Laparoscopic partial nephrectomy: effect of warm ischemia on serum creatinine. J Urol 2004;172:1264–6. [9] Derweesh IH, Novick AC. Mechanisms of renal ischaemic injury and their clinical impact. BJU Int 2005;95:948–50. [10] Rocca Rosetti S. Impact of acute ischemia on human kidney. In: Margerger M, Dreikorn K, editors. Renal preservation. Baltimore: Williams & Wilkins; 1983. p. 21–37. [11] National Kidney Foundation Clinical Practice Guidelines for Chronic Kidney Disease. Evaluation, Classification and Stratification. Part 4. Definition and classification of chronic kidney disease, 2006. [12] National Kidney Foundation Clinical Practice Guidelines for Chronic Kidney Disease. Evaluation, Classification and Stratification. Part 5. Evaluation of laboratory measurements for clinical assessment of kidney disease, 2006. [13] Lance D, Dworkin J. Serum cystatin C a marker of glomerular filtration rate. Curr Opin Nephrol Hypertens 2001;10:551–3. [14] Peters CA, Kavoussi LR. Laparoscopic surgery in the children and the adult. In: Campbell’s urology, ed. 7. Saunders; 1998. [15] Toosy N, McMorris EL, Grace PA, Mathie RT. Ischaemic preconditioning protects the rat kidney from reperfusion injury. BJU Int 1999;84:489.
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european urology 52 (2007) 1170–1178
[16] Yilmaz S, Koken T, Tokyol C, et al. Can preconditioning reduce laparoscopy-induced tissue injury? Surg Endosc 2003;17:819. [17] Laven BA, Orvieto MA, Chuang MS, et al. Renal tolerance to prolonged warm ischemia time in a laparoscopic versus open surgery porcine model. J Urol 2004;172: 2471. [18] Yossepowitch O, Eggener SE, Serio A, et al. Temporary renal ischemia during nephron sparing surgery is associated with short term but not long term impairment in renal function. J Urol 2006;176:1339–43. [19] Gill IS, Abreu SC, Desei MM, et al. Laparoscopic ice slush renal hypothermia for partial nephrectomy: the initial experience. J Urol 2003;170:52–6. [20] Landamn J, Rehman J, Sundaram CP, et al. Renal hypothermia achieved by retrograde intracavitary saline perfusion. J Endourol 2002;16:445–9. [21] Janetschek G, Abdelmaksoud A, Bagheri F, et al. Laparoscopic partial nephrectomy in cold ischemia: renal artery perfusion. J Urol 2004;171:68–71. [22] Janetschek G. Laparoscopic nephron sparing surgery: ischemic renal damage. Curr Opin Urol 2006;16:45–6.
[23] Kane CJ, Mitchell JA, Meng MV, Anats J, Carroll PR, Stoller ML. Laparoscopic partial nephrectomy with temporary arterial occlusion: description of technique and renal function outcomes. Urology 2004;63:241–6. [24] Shekarriz B, Shah G, Upadhyay J. Impact of temporary hilar clamping during laparoscopic partial nephrectomy on postoperative renal function: a prospective study. J Urol 2004;172:54–7. [25] Marberger M. In situ cooling of the kidney. In: Marberger M, Dreikorn K, editors. Renal preservation. Baltimore: Williams & Wilkins; 1983. p. 38–63. [26] Wille AH, Tu¨llmann M, Roigas J, Loening SA, Deger S. Laparoscopic partial nephrectomy in renal cell cancer— results and reproducibility by different surgeons in a high volume laparoscopic center. Eur Urol 2006;49:337–43. [27] Aron M, Gill IS. Minimally invasive nephron sparing surgery (MINSS) for renal tumours. Part I: laparoscopic partial nephrectomy. Eur Urol 2007;51:337–47. [28] Houston Thompson R, Frank I, Lohse CM, et al. The impact of ischemia during open nephron sparing surgery on solitary kidneys: a multi-institutional study. J Urol 2007; 177:471–6.
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Kidney Cancer
Is Renal Warm Ischemia over 30 Minutes during Laparoscopic Partial Nephrectomy Possible? One-Year Results of a Prospective Study Francesco Porpiglia a,*, Julien Renard a, Michele Billia a, Francesca Musso a, Alessandro Volpe a, Rodolfo Burruni a, Carlo Terrone a, Loredana Colla b, Giorgina Piccoli b, Valerio Podio c, Roberto Mario Scarpa a a
Department of Urology, University of Turin, San Luigi Hospital, Orbassano Torino, Italy Department of Nephrology, University of Turin, San Giovanni Battista Hospital, Torino, Italy c Department of Radiology and Nuclear Medicin, University of Turin, San Luigi Hospital, Orbassano, Torino, Italy b
Article info
Abstract
Article history: Accepted April 5, 2007 Published online ahead of print on April 11, 2007
Objective: To evaluate renal damage and impairment of renal function 1 yr after laparoscopic partial nephrectomy (LPN) with warm ischemia >30 min. Methods: From July 2004 to June 2005, 18 patients underwent LPN with warm ischemia time >30 min. Kidney damage markers (daily proteinuria and tubular enzymes) and renal function (serum creatinine, cystatin C, and creatinine clearances) were assessed on postoperative days 1 and 5 and at 12 mo. Glomerular filtration rate (GFR) was evaluated before surgery and at 3 mo. Renal scintigraphy was performed before the procedure, at 5 d and at 3 and 12 mo postoperatively. Statistical analysis was performed using the Student t test and logistic regression analysis. Results: In terms of kidney damage and renal function markers, the statistical analysis demonstrated that at 1 yr there was complete return to the normal range and no statistical difference between the values at the various time points. The GFR was not significantly different before and 3 mo after surgery. In terms of scintigraphy of the operated kidney, the values were 48.35 3.82% (40–50%) before the procedure, 36.88 8.42 (16–50%) on postoperative day 5 ( p = 0.0001), 40.56 8.96 (20–50%) at 3 mo ( p = 0.003), and 42.8 7.2% (20–50%) 1 yr after surgery ( p = 0.001). Conclusion: Our results demonstrate that kidney damage occurs during LPN when warm ischemia is >30 min. This damage is only partially reversible and efforts should be made to keep warm ischemia within 30 min.
Keywords: Laparoscopy Partial nephrectomy Renal function Warm ischemia
# 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Department of Urology, San Luigi Hospital, Regione Gonzole 10, 10043, Orbassano, Torino, Italy. Tel. +39 011 9026558; Fax: +39 011 9026244. E-mail address: [email protected] (F. Porpiglia). 0302-2838/$ – see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2007.04.024
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1.
Introduction
The evolution of minimally invasive surgery led laparoscopic partial nephrectomy (LPN) to be accepted as a surgical option. Although this technique is still considered challenging, this approach has become the first choice for the treatment of selected renal tumors in centers with high laparoscopic expertise [1–4]. To perform a correct surgery it is essential to operate in a bloodless field [5]. This can be obtained by temporary occlusion of the renal artery or of the entire renal pedicle. The subsequent renal ischemia can cause impairment of renal function. It is already known that renal ischemia time of <30 min is safe [6–9], whereas longer ischemia can cause kidney damage. In some cases of LPN, for example, in the presence of technical difficulties ischemia >30 min can be necessary. When this is expected, kidney cooling can guarantee a safe ischemia time up to 3 h [10]. When warm ischemia is chosen and the duration of ischemia is >30 min, the entity of the potential kidney damage has not been yet clearly defined. For this reason, the issue of warm ischemic renal damage needs to be better investigated. The objective of this prospective study was to evaluate renal damage in patients 1 yr after LPN performed with a warm ischemia time >30 min. 2.
Materials and methods
From July 2004 to June 2005, 18 patients who underwent LPN with a warm ischemia time >30 min were enrolled in this prospective study. All patients underwent the same protocol.
tubular enzymes can be used as markers of kidney damage [12]. The tubular enzymes are alanine aminopeptidase (AAP, normal range: 0–12 U/l), lysozyme (normal range: 0–3 mg/l), and g-glutamyl transpeptidase (GGT, normal range: 0–50 U/l). Evaluation of these markers was performed before the procedure, on postoperative days 1 and 5, and 12 mo after the procedure. To evaluate the impact of warm ischemia time on renal function, serum creatinine (normal range: 0.6–1.2 mg/dl), cystatin C [13] (normal range: 0.50–1.00 mg/dl) and creatinine clearances calculated with the Cockroft-Gault equations (normal range: 90–150 ml/min) were assessed before the procedure, on postoperative days 1 and 5, and 12 mo after the procedure. To have a more precise evaluation of the kidney function [12], the glomerular filtration rate (GFR) was evaluated also by nuclear medicine using 51Cr-ethylenediaminetetraacetic acid (EDTA) before surgery and 3 mo after surgery (normal range: 45–93 ml/min/1.73 m2). Moreover, to evaluate the effects of the procedure on the operated kidney, all patients underwent radionuclide renal scintigraphy with 99mTc-mercaptoacetyltriglycine (99mTc-MAG3) before the procedure and 5 d, 3 mo, and 12 mo after the procedure. The onset of new morbidity during follow-up was also recorded.
2.4.
Pathology assessment
Pathology assessment included histology of the lesion and measurement of lesion diameter and minimum and maximum thickness of resected healthy parenchyma.
2.3.
Statistical evaluation
Patients
In all patients LPN was indicated for a benign or malignant disease. For each case, we recorded age, gender, comorbidities, lesion size, cause of the procedure, type of surgical approach, operating time, warm ischemia time, estimated blood loss, and complications.
2.2.
Kidney damage prevention
The renal artery was accurately isolated. In all cases only the artery and not the entire hilum was clamped. To prevent ischemic damage, all patients received proper hydration and mannitol infusion (0.25 g/kg) 10 min before clamping [10]. Moreover, before clamping, lidocaine 20 ml (2%) was injected over the renal artery to prevent vascular spasm. In all cases, clamping was achieved using a bulldog clamp. After declamping, furosemide 20 mg was injected intravenously. Warm ischemia time was evaluated using the operating room chronometer.
2.5. 2.1.
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Statistical analysis was carried out using the Student t test (Software Statistics 6.0) to evaluate the renal damage and the functional impairment at the various time points. A p value superior to 0.05 was considered not significant (ns). A linear regression model was used to determine if total daily proteinuria on postoperative days 1 and 5 was influenced by the length of warm ischemia time. At 1 yr, a logistic regression model was used to evaluate the influence of patient age, comorbidity, lesion diameter, maximum thickness of resected healthy parenchyma, and warm ischemia time on the renal function of the operated kidney. All data were adjusted to the baseline values of the radionuclide scintigraphy.
Evaluation of kidney damage
Kidney damage is defined as the presence of structural or functional abnormalities of the kidney [11]. The peripheral region of the renal medulla, which includes both glomeruli and proximal tubuli, is the most sensitive zone to ischemia. Its damage causes loss of protein and specific enzymes. Therefore, total daily proteinuria (normal range: 0–150 mg/d) and
3.
Results
3.1.
Patients
Eighteen patients underwent LPN and reached a 1-yr follow-up. Mean age was 59.6 16.9 yr (range:
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Table 1 – Perioperative parameters Patient
Age, yr
Gender
Motive of procedure
Comorbidities
Side
Approach
Operative time, min
Warm ischemia time, min
Blood loss, ml
Complications
69 71 33 67 67 64 62 58 12 34 71 57 63 78 61 77 69 60
Male Female Female Female Female Male Female Female Female Female Male Male Male Female Female Male Female Male
Tumor Tumor Tumor Tumor Tumor Tumor Tumor Tumor Stone Stone Tumor Tumor Tumor Tumor Tumor Tumor Tumor Tumor
HP, Diab — — HP, Diab, LLC HP HP — HP — — — — Past chemotherapy HP HP, IMA HP, IMA — —
R L L L L R L L L R L L R R L L R R
Retroperitoneal Retroperitoneal Transperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal Retroperitoneal
90 130 135 150 210 120 180 120 210 225 120 120 165 130 120 150 120 150
33 33 32 44 32 39 40 52 47 60 46 34 32 38 40 31 31 39
300 50 350 100 100 200 50 250 200 750 200 50 100 100 250 200 350 200
— — — — — — Fistula, reintervention — — Bleeding — — — — Bleeding — — —
Mean
59.6 16.9
7 male/11 female
16 tumors 2 stones
—
7 R 11 L
17 retroperitoneal 1 transperitoneal
146.9 37.4
39.0 8.1
211.1 165.8
3 patients
HP = hypertension; Diab = diabetes, IMA = cardiac infarction; LLC = leukemia; R = right; L = left.
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
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12–78 yr). Seven patients were males and 11 were females. Eight patients were affected by cardiovascular diseases, two had diabetes, one had chronic lymphoid leukemia, and one underwent chemotherapy. Sixteen patients underwent the procedure for a tumor and two patients underwent LPN for benign disease (hydrocalyx and upper calyx stone). In 17 cases we used a retroperitoneal approach and in one a transperitoneal approach. Mean operating time and mean estimated blood loss are reported in Table 1. Mean warm ischemia time was 39 8.1 min (range: 31–60 min). Postoperative complication rate was 16% (two postoperative transfusions, one reintervention, one fistula; Table 1). 3.2.
Pathology assessment
Eight lesions were benign and 10 were malignant. Mean lesion diameter was 3.4 1.8 mm (range: 1– 8 mm). The mean maximum margin of resected healthy parenchyma was 8.25 4.1 mm (range: 2– 35 mm), and the mean minimum margin of resected healthy parenchyma was 3.0 1.9 mm (range: 1–7). Results are reported in Table 2. 3.3.
Evaluation of kidney damage
As far as the proximal tubular enzymes are concerned, mean AAP, GGT, and lysozyme values did not significantly change over time after surgery (Table 3). Mean total daily proteinuria was level 106.26 161.78 mg/d (range: 30–700 mg/d) preoperatively,
Fig. 1 – Total daily proteinuria at the various time points. It is evident that the value of proteinuria returns to normal range 1 yr after surgery.
818.6 968.9 mg/d (range: 156–4380 mg/d) on postoperative day 1 ( p = 0.009), 632.4 1063.6 mg/d (range: 60–4620 mg/d) on postoperative day 5 ( p = 0.007), and 72.6 35.4 mg/d (range: 15–148 mg/d) 1 yr after surgery ( p = ns). The statistical analysis demonstrates that total daily proteinuria increases significantly in the immediate postoperative period, but returns to the normal range 1 yr after surgery (Table 3 and Fig. 1). However, according to the linear regression model it is important to point out that the variation of total daily proteinuria on postoperative days 1 and 5 is not dependent on the warm ischemia time ( p = 0.47). The values of serum creatinine, serum cystatin C, and creatinine clearance are reported in Table 4. No statistical difference was observed among the values at the various time points. Minor variability of the values is observed for serum cystatin C and
Table 2 – Pathologic results Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Lesion size, cm
Maximum thickness of healthy parenchyma, mm
Minimum thickness of healthy parenchyma, mm
1 2 8 1.5 2 2 8 5 — — 5 4.5 2.9 5 2 3.5 2 3.5 3.4 1.8
12 5 10 9 18 10 8 15 35 — 6 8 9 4 2 5 5 6 9.82 7.6
7 2 5 2 6 2 4.5 3 — — 1 1 4 2 1 3 1 1.5 3.0 1.9
Pathology Clear cell carcinoma Oncocytoma Angiomiolipoma Angiomiolipoma Hematic cyst Angiomiolipoma Angiomiolipoma Clear-cell carcinoma Pyelonephritis (stone) Calyx ectasis Papillary carcinoma Papillary carcinoma Collective ducts carcinoma Clear-cell carcinoma Papillary carcinoma Papillary carcinoma Clear-cell carcinoma Clear-cell carcinoma
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Table 3 – Assessment of renal damage by daily proteinuria and enzymes Preoperative (range) u-Lysozyme mg/l (range: 0–3) u-n AAP, U/l (range: 0–12) u-GGT, U/l (range: 0–50) Proteinuria, mg/d
0.99 0.88 (0.2–3) 7.89 4.91 (2–23) 44.06 22.05 (12–103) 106.26 161.78 (30–700)
POD 1 0.91 0.64 9.50 5.08 47.5 30.63 818.6 968.9
p value, preop vs. POD 1
POD 5
p value, preop vs. POD 5
ns ns ns 0.009
1.07 0.71 (0.20–2.40) 12.71 8.501 (3–36) 41.47 19.88 (13–84) 632.4 1063.6
ns ns ns 0.007
(0.10–2.70) (4–25) (15–157) (156–4380)
1 yr 0.9 0.39 4.4 1.69 34.7 17.8 72.6 35.4
(0.5–2) (2–8) (25–51) (15–148)
p value, preop vs. 1 yr ns 0.017 ns ns
The total daily proteinuria, which showed an significant increase, returned to normal at 1 yr from surgery; POD = postoperative day; ns = not significant; AAP = alanine aminopeptidase; GGT = g-glutamyl transpeptidase.
p-Cystatin C mg/l (range: 0.5–1.00) p-Creatinine mg/dl (range: 0.6–1.2) Creatinine clearance ml/min (range: 90–150)
Preoperative
POD 1
p value, preop vs. POD 1
POD 5
p value, preop vs. POD 5
At 1 yr
1.03 0.19 (0.76–1.45) 0.91 0.17 (0.6–1.2) 67.88 26.38 (28–127)
0.99 0.16 (0.66–1.26) 1.06 0.21 (0.7–1.5) 65.94 46.42 (13–204)
ns ns ns
1.02 0.18 (0.77–1.36) 0.95 0.2 (0.6–1.4) 88.17 33.78 (29–133)
ns ns ns
1.03 0.17 (0.65–1.2) 1.02 0.24 (0.8–1.5) 90.3 29.31 (49–135)
p value, preop vs. 1 yr ns ns ns
POD = postoperative day; ns = not significant.
Table 5 – GFR evaluated by nuclear medicine and contribution of the operated kidney to the overall renal function
GFR (nuclear medicine), mean ml/min Contribution of operated kidney to overall renal function (scintigraphy)
Preoperative
At POD 5
p value preop vs. POD 5–7
At 3 mo
p value, preop vs. 3 mo
At 1 yr
91.60 22.68 (56.40–144.8) 48.3 3.82% (40–53%)
— 36.8 8.4% (16–50%)
— 0.0001
79.12 13.69 (59.70–100.2) 40.56 8.9% (20–50%)
ns 0.003
— 42.8 7.2% (20–50%)
GFR = glomerular filtration rate; POD, postoperative day; ns = not significant.
p value, preop vs. 1 yr — 0.001
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Table 4 – Renal function evaluated by serum creatinine, serum cystatin C, and creatinine clearance
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serum creatinine, whereas creatinine clearance showed a paradoxical increase. The GFR (evaluated by nuclear medicine using 51 Cr-EDTA) was not significantly different before and 3 mo after the procedure: mean GFR was 91.60 22.68 ml/min/1.73 m2 preoperatively and 79.12 13.69 ml/min/1.73 m2 3 mo after surgery ( p = ns) (Table 5). As far as the contribution of the operated kidney to the overall renal function (evaluated by renal scintigraphy with 99mTc-MAG3) is concerned, the preoperative value was 48.35 3.82% (range: 40– 50%), 36.88 8.42% (range: 16–50%) on postoperative day 5 ( p = 0.0001), 40.56 8.96% (range: 20–50%) at 3 mo ( p = 0.003), and 42.8 7.2% (range: 20–50%) 1 yr after surgery ( p = 0.001) (Table 5). One year after surgery, there is still a significant difference compared to the preoperative values, although it is evident that after an initial drop there is a trend toward a progressive recovery (Fig. 2). However, it is important to point out that the number of patients included in this study could affect the statistical power. At the 1-yr follow-up, no patient had developed new morbidities. As far as the logistic regression model is concerned, the statistical analysis demonstrated that the loss of function in the operated kidney (evaluated by radionuclide scintigraphy) is not influenced by lesion size at pathology, patient age, and presence of comorbidities, but it is influenced significantly ( p < 0.05) by the maximum thickness of resected healthy parenchyma and duration of warm ischemia. The loss of renal function is maximal between 32 and 42 min of warm ischemia time, as shown by the drop of the curve in Fig. 3. Between 42 and 60 min, the curve flattens out, demonstrating a minor further loss of function when the warm ischemia time is in this range.
Fig. 2 – Contribution of operated kidney to the overall renal function at the various time points (radionuclide renal scintigraphy with 99mTc-mercaptoacetyltriglycine). POD = postoperative day.
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Fig. 3 – Logistic regression model. Full orange curve = evolution of kidney damage over time; it is evident that between 32 and 42 min there is a major drop, corresponding to the phase in which parenchymal damage is maximum. The ‘‘starting point’’ of the ‘‘critical phase’’ of warm ischemia is at the 32-min time mark. The interrupted curves correspond to the confidence intervals.
4.
Discussion
Although considered a challenging technique, LPN is gaining wide acceptance worldwide, especially in urologic departments where advanced laparoscopy is carried out [26]. To perform an accurate surgery, it is essential to resect the lesion and to obtain hemostasis in a short warm ischemia time to avoid kidney damage [3,27]. According to Rocca Rossetti [10], warm ischemia in open surgery can be classified as follows: (1) <10 min—harmless; (2) up to 30 min—generally reversible lesions; (3) >30 min—risk of irreversible parenchymal lesions increasing rapidly with the ischemic time; and (4) >60 min—irreversible lesions. Regarding the site of kidney damage, the same author states that nephrons react differently to ischemia; glomeruli tolerate the ischemia better than tubular epithelia, whereas proximal convoluted tubules are more sensitive to ischemic damage [10]. More recently, other authors suggested that warm ischemia determines a reduction in medullary blood flow causing hypoxic injury to the tubular structures in this region [9]. Furthermore, it seems that the degree of damage is proportional to the warm ischemia time. The higher sensitivity of the proximal tubuli to ischemia is due to a low capacity of the cells to generate adenosine triphosphate (ATP), whereas the remaining tubular cells are protected by the persistence of ATP. When warm ischemia is prolonged, the cells from the distal
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tubuli produce cytokines responsible for their apoptosis [6]. The same cytokines exacerbate the inflammatory response and enhance vascular tone, stimulating further injury [9]. To reduce these possible injuries to the kidney, protective procedures are used, such as mannitol infusion or kidney cooling. According to Marberger, when longer ischemia time (>30 min) is expected, kidney cooling in situ is essential (at 10–25 8C, temporary ischemia up to 3 h is tolerated without permanent impairment) [25]. During laparoscopy, the increase of intra-abdominal pressure due to the pneumoperitoneum generally causes oliguria [14]. This situation can create an ischemic preconditioning that reduces tissue injury [15,16]. For this reason, it is theoretically possible to increase warm ischemia time during LPN, compared to open surgery, even if there is much controversy on this issue. For instance, in an experimental porcine model, Laven et al demonstrated that there is no difference between LPN and open surgery in terms of kidney damage after prolonged ischemia [17]. Therefore, it is essential to reproduce in laparoscopy the same protective measures used in open surgery when renal ischemia is produced. As far as kidney cooling is concerned, methods such as laparoscopic ice slush cooling, intraureteral cooling, and intravascular hypothermic perfusion have been described to obtain kidney hypothermia [18–21]. Unfortunately, these techniques, although efficient and reliable for some authors, are complicated to manage [22]. Considering that use of LPN is expanding in urologic centers to the treatment of increasingly complex lesions without using tedious cooling procedures, it is today essential to assess the effects of warm ischemia between 30 to 60 min during LPN [1–4,22]. Using only serum creatinine levels, Bhayani et al demonstrated that a warm ischemia time up to 55 min does not influence long-term renal function after LPN [8]. In a series of LPNs with a mean warm ischemia of 43 min (range: 25–65 min) and a fairly short follow-up (mean: 130 d), Kane et al showed that temporary arterial occlusion does not appear to affect short-term renal function [23]. Using GFR evaluation, Shekarriz demonstrated that LPN can be performed safely and efficiently using temporary hilar clamping. However, in this study in only two cases was warm ischemia time >30 min (33 and 45 min) [24]. All these studies were performed on patients with a normal contralateral kidney. In patients with a solitary kidney, Thompson et al [28] emphasize that warm ischemia during open nephron-sparing surgery is associated with a high incidence of renal complications (increase in the risk
of permanent dialysis) if warm ischemia is >20 min. However, the weakness of this study is that it was done in situations where surgery was an imperative indication and, therefore, did not consider the amount of residual healthy parenchyma. Our study assessed kidney damage in patients 1 yr after LPN with a warm ischemia time between 30 and 60 min. We evaluated total daily proteinuria and tubular enzymes (AAP, GGT, lysozyme). AAP expresses the damage to the entire nephron, whereas GGT and lysozyme are more specific for the proximal tubuli. Our results demonstrate that tubular enzyme levels do not change significantly in the immediate postoperative period, whereas total daily proteinuria shows a significant increase on the first postoperative day before returning to the normal range 1 yr after surgery. This means that the damage to the proximal tubuli does not determine an alteration of enzyme values, therefore indicating that these enzymes cannot be proposed as suitable markers of kidney damage. Total daily proteinuria, which is a more sensitive measure to evaluate overall nephron damage, presented a significant increase on the first postoperative day (expressing ischemic damage), before starting to return to normal range, as demonstrated by the values observed on the fifth postoperative day and 1 yr after the procedure (Fig. 1). However, to assess the exact location of the damage, a more precise discrimination of proteins should have been performed. Furthermore, we observed that the variations of total daily proteinuria were not influenced by the length of warm ischemia. Therefore, the total daily proteinuria assessment can indicate the presence of kidney damage, but it cannot be used to quantify the entity of the damage. In terms of renal function, we demonstrate that in the immediate postoperative period and at 3 mo and 1 yr from surgery, mean serum creatinine, mean serum cystatin C, creatinine clearance, and GFR have not significantly changed compared to the preoperative data. It is therefore possible to use any one of these parameters to evaluate renal function. These parameters did not change significantly because the resection of parenchyma was performed on patients with a normal contralateral kidney, which is responsible for the compensation of parenchymal loss. However, it is obvious that the GFR values (evaluated by nuclear medicine using 51 Cr-EDTA) are more precise than creatinine clearance, because the nuclear medicine method is less influenced by extrarenal factors. Therefore, to evaluate whether the renal function is not completely taken by the normal, contralateral
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kidney, and because no patient had a solitary kidney, it was essential to use another study procedure. We evaluated the contribution of the operated kidney to the overall renal function by radionuclide scintigraphy with 99mTc-MAG3. We observed that there is an initial significant drop of 11.4% 7.3% in the operated kidney’s contribution to overall function, followed by a constant and progressive recovery that never reaches the preoperative value (42.8% at 1 yr vs. 48.3% before surgery), with a loss of contribution of 5.5% 6.4% and a recovery at 1 yr of 4%. This damage is probably due to the amount of resected healthy renal parenchyma and to the warm ischemia time. It could also be influenced by the patient’s age and comorbidities and by parenchymal suture. To clarify this issue, we applied a logistic regression model that demonstrated that the loss of function of the operated kidney depends mostly on the warm ischemia time ( p < 0.05) and less importantly on the maximum thickness of resected healthy parenchyma. As far as the warm ischemia time is concerned, we observed that the maximum loss of renal function occurs between 32 and 42 min, defining the 32-min time mark as the ‘‘starting point’’ of the ‘‘critical phase’’ of warm ischemia. It seems that, although there is a correspondence between damage and ischemia time, the relationship between these two parameters is not linear. We can hypothesize that in the time period between 32 and 42 min the damage involves the largest number of nephrons. Moreover, in this time period there may be a liberation of cytokines that convey damage to the medulla causing an inflammatory infiltration [6]. However, it is important to point out that, even though there is a documented loss of renal function, this is limited in time and is incomplete, as demonstrated by the progressive recovery, suggesting that the lesions to some nephrons are reversible. Nevertheless, longer follow-up is needed to discover whether the kidney is able to achieve a full recovery over time.
5.
Conclusions
When renal warm ischemia time during LPN lasts from 30 to 60 min, partial damage to the operated kidney is likely produced. The impairment in renal function depends on the length of the warm ischemia time and on the thickness of the removed healthy parenchyma. Results at 1 yr demonstrate that this damage is partially reversible.
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Conflicts of interest The authors have nothing to disclose.
Acknowledgements Prof. Dario Gregori, Deptartment of Statistics, University of Turin, is acknowledged for his contribution to the statistical evaluations. References [1] Gill IS, Desai MM, Kaouk JH, et al. Laparoscopic partial nephrectomy for renal tumor: duplicating open surgical techniques. J Urol 2002;167:469–76. [2] Reisiger K, Venkatesh R, Figenshau RS, Bae K, Landaman J. Complex laparoscopic partial nephrectomy for renal hilar tumors. Urology 2005;65:888–91. [3] Haber G-P, Gill IS. Laparoscopic partial nephrectomy: contemporary technique and outcomes. Eur Urol 2006; 49:660–5. [4] Ha¨cker A, Albadour A, Jauker W, et al. Nephron sparing surgery for renal tumours: acceleration and facilitation of the laparoscopic technique. Eur Urol 2007;51:358–65. [5] Colombel M, Timsit M, Badet L. Chirurgie conservatrice et hypothermie re´nale: bases physiologiques et technique ope´ratoire. Annales d’Urologie 2007;41:2–22. [6] Uzzo RG, Novick AC. Nephron sparing surgery for renal tumours: indications, techniques and outcomes. J Urol 2001;166:1264–6. [7] Novick AC. Nephron sparing surgery for renal cell carcinoma. Annu Rev Med 2003;53:393–407. [8] Bhayani SB, Rha KH, Pinto PA, et al. Laparoscopic partial nephrectomy: effect of warm ischemia on serum creatinine. J Urol 2004;172:1264–6. [9] Derweesh IH, Novick AC. Mechanisms of renal ischaemic injury and their clinical impact. BJU Int 2005;95:948–50. [10] Rocca Rosetti S. Impact of acute ischemia on human kidney. In: Margerger M, Dreikorn K, editors. Renal preservation. Baltimore: Williams & Wilkins; 1983. p. 21–37. [11] National Kidney Foundation Clinical Practice Guidelines for Chronic Kidney Disease. Evaluation, Classification and Stratification. Part 4. Definition and classification of chronic kidney disease, 2006. [12] National Kidney Foundation Clinical Practice Guidelines for Chronic Kidney Disease. Evaluation, Classification and Stratification. Part 5. Evaluation of laboratory measurements for clinical assessment of kidney disease, 2006. [13] Lance D, Dworkin J. Serum cystatin C a marker of glomerular filtration rate. Curr Opin Nephrol Hypertens 2001;10:551–3. [14] Peters CA, Kavoussi LR. Laparoscopic surgery in the children and the adult. In: Campbell’s urology, ed. 7. Saunders; 1998. [15] Toosy N, McMorris EL, Grace PA, Mathie RT. Ischaemic preconditioning protects the rat kidney from reperfusion injury. BJU Int 1999;84:489.
1178
european urology 52 (2007) 1170–1178
[16] Yilmaz S, Koken T, Tokyol C, et al. Can preconditioning reduce laparoscopy-induced tissue injury? Surg Endosc 2003;17:819. [17] Laven BA, Orvieto MA, Chuang MS, et al. Renal tolerance to prolonged warm ischemia time in a laparoscopic versus open surgery porcine model. J Urol 2004;172: 2471. [18] Yossepowitch O, Eggener SE, Serio A, et al. Temporary renal ischemia during nephron sparing surgery is associated with short term but not long term impairment in renal function. J Urol 2006;176:1339–43. [19] Gill IS, Abreu SC, Desei MM, et al. Laparoscopic ice slush renal hypothermia for partial nephrectomy: the initial experience. J Urol 2003;170:52–6. [20] Landamn J, Rehman J, Sundaram CP, et al. Renal hypothermia achieved by retrograde intracavitary saline perfusion. J Endourol 2002;16:445–9. [21] Janetschek G, Abdelmaksoud A, Bagheri F, et al. Laparoscopic partial nephrectomy in cold ischemia: renal artery perfusion. J Urol 2004;171:68–71. [22] Janetschek G. Laparoscopic nephron sparing surgery: ischemic renal damage. Curr Opin Urol 2006;16:45–6.
[23] Kane CJ, Mitchell JA, Meng MV, Anats J, Carroll PR, Stoller ML. Laparoscopic partial nephrectomy with temporary arterial occlusion: description of technique and renal function outcomes. Urology 2004;63:241–6. [24] Shekarriz B, Shah G, Upadhyay J. Impact of temporary hilar clamping during laparoscopic partial nephrectomy on postoperative renal function: a prospective study. J Urol 2004;172:54–7. [25] Marberger M. In situ cooling of the kidney. In: Marberger M, Dreikorn K, editors. Renal preservation. Baltimore: Williams & Wilkins; 1983. p. 38–63. [26] Wille AH, Tu¨llmann M, Roigas J, Loening SA, Deger S. Laparoscopic partial nephrectomy in renal cell cancer— results and reproducibility by different surgeons in a high volume laparoscopic center. Eur Urol 2006;49:337–43. [27] Aron M, Gill IS. Minimally invasive nephron sparing surgery (MINSS) for renal tumours. Part I: laparoscopic partial nephrectomy. Eur Urol 2007;51:337–47. [28] Houston Thompson R, Frank I, Lohse CM, et al. The impact of ischemia during open nephron sparing surgery on solitary kidneys: a multi-institutional study. J Urol 2007; 177:471–6.