Impact of Repeated Hilar Clamping on Renal Function During Laparoscopic and Robot-Assisted Partial Nephrectomy

Abstract

Background and Purpose:

Conventional wisdom and small animal studies suggest repeated hilar clamping during partial nephrectomy is deleterious to renal function. We describe the impact of repeated renal hilar clamping during laparoscopic partial nephrectomy (LPN) and robot-assisted partial nephrectomy (RPN) on the overall function of the operated kidney.

Patients and Methods:

A retrospective analysis of all patients undergoing RPN or LPN with repeated hilar clamping was performed. Patient and tumor characteristics were recorded. All patients had preoperative and postoperative mercaptoacetyltriglycine (MAG)3 renal scans, and the change in function was calculated. Change in glomerular filtration rate (GFR) was calculated with the modified Modification of Diet in Renal Disease equation as well.

Results:

Seven patients were studied with an average age of 60 and a body mass index of 32. Tumors averaged 3.6 cm, and there were four and three right- and left-sided tumors, respectively. The reasons for repeated clamping were bleeding in three patients and either gross or microscopic positive margins in four patients, all of whom had repeated resection. The average initial clamp time was 20 minutes, and the average reclamp time was 12 minutes. The average operative time was 185 minutes. and average blood loss was 171 mL. All renal units were functioning postoperatively. The average change in absolute renal function on the operated kidney was −4.9%, and the relative loss of function was −10%, both measured on MAG3 scan. The average GFR before surgery was 61.4 (mL/min/1.73m²); after surgery, the average GFR was 57.1 (mL/min/1.73m²), for an average loss of −7%. The range of change in GFR was from 0% to −23%.

Conclusions:

Although not optimal, repeated clamping of the renal hilum during partial nephrectomy to control bleeding or to obtain a clear surgical margin is associated with minimal loss of renal function.

Introduction

W ith the widespread use of cross-sectional imaging, more asymptomatic solid renal masses are being detected. As a result, the incidence of smaller and earlier stage renal-cell carcinoma (RCC) is rising.¹ Concurrently, the minimally invasive treatment of patients with RCC has also been growing,^2,3 although the use of nephron-sparing surgery (NSS) has not been as thoroughly adopted as would be preferred.^1,4,5 In recent years, it has become clear that radical nephrectomy for RCC adversely affects renal function compared with NSS.^6,7 This decrement in renal function has also been shown to be a risk for subsequent mortality, especially from cardiac disease.^8,9 Therefore, when feasible, NSS is currently the treatment of choice for the incidentally detected, small renal mass. Given the equivalent oncologic outcomes for small renal masses compared with radical nephrectomy, the role of laparoscopic partial nephrectomy (LPN) and robot-assisted partial nephrectomy (RPN) will continue to grow in the management of RCC.^10,11

One of the main differences between LPN/RPN and open partial nephrectomy is the method in which renal ischemia is achieved.¹² Compared with open surgery, where cold ischemia is readily induced, LPN and RPN are usually performed with warm ischemia. Although definitive human trials have not been conducted, there is evidence from sources as varied as animal trials,¹³ deceased human organ donor data,¹⁴ and retrospective analyses of partial nephrectomy series¹⁵ suggesting that periods of warm ischemia of 20 to 30 minutes are tolerated by the kidney. The kidney may tolerate longer periods of ischemia, but an extensive ischemic time is clearly a risk factor for irreversible postoperative renal dysfunction.^16

–19

An area that is poorly understood is the impact of repetitive renal ischemia on renal function. Some animal data suggest that this may be renoprotective, while other data suggest that it may be harmful.^13,20
–22 Conventional wisdom holds that repeated hilar clamping will lead to ischemia and reperfusion and will potentiate the ischemic insult to the kidney.¹² In large series of LPN and RPN, there is passing mention of needing to reclamp the renal hilum in individual cases for either bleeding or a positive margin, but with no mention of the impact on ultimate renal function.^23,24 Because such data on repeated hilar clamping, for cause, during LPN and RPN are lacking, we sought to determine the impact of repeated hilar clamping on renal function by evaluating the experience of two advanced minimally invasive surgeons in performing minimally invasive partial nephrectomy.

Patients and Methods

A retrospective analysis of databases approved by the Institutional Review Board of two surgeons (RM, RG) with patient deidentifiers was performed of cases of LPN and RPN that necessitated repeated hilar clamping. In patients for whom reclamping was needed, LPN and/or RPN was performed in a standard fashion. After complete renal mobilization and isolation of the artery and vein, hilar control was achieved with laparoscopic bulldog clamps. Intravenous mannitol was administered 8 to 10 minutes before hilar clamping and immediately after hilar unclamping. Excellent hydration was maintained throughout the cases. Both renal artery and vein were occluded in all patients. The tumor resection and reconstruction were performed under warm ischemia. The collecting system was entered and repaired in all cases. In cases where a suspicion of positive margins existed, frozen section analysis of the tumor bed was performed. Renal reclamping was performed for significant hemorrhage or positive margins—either grossly or microscopically. The hilum was reclamped in all cases by occluding the renal artery and vein with bulldog clamps.

Patient and tumor characteristics; initial clamp time; reason for repeated clamping; repeated clamp time; and creatinine level before surgery, immediately after surgery, and at most recent follow-up were recorded. Estimated glomerular filtration rate (GFR) was calculated with the four factor Modification of Diet in Renal Disease (MDRD) equation, as other authors have reported previously.^19,25 GFR calculations were based on the preoperative creatinine level and the creatinine level at the most recent follow-up, which was a median of 12 months from surgery. All patients in this series had preoperative and postoperative diuretic mercaptoacetyltriglycine (MAG)3 furosemide renal scans, delineating differential renal function before and after surgery. Renal scans were performed before the procedure and after the procedure, usually at 2 or 3 months. Pathologic findings and length of follow-up were also recorded.

Results

There were 289 patients in the combined databases. In seven patients who underwent hilar reclamping, five procedures were performed via the laparoscopic approach and two were performed robotically. The average age was 60, and the average body mass index was 32. There were four right-sided tumors and three left-sided tumors. The average tumor size was 3.6 cm. In this series, hilar control involved clamping of the artery and vein both initially and during the reclamp phase (Table 1). Initial clamp time ranged from 5 to 30 minutes and averaged 20 minutes. The reclamp time ranged from 4 to 42 minutes, with a mean of 12 minutes (Table 2). Repeated hilar clamping was performed for bleeding in three patients and suspected positive margins in four patients. In all patients with significant bleeding after initial clamp removal, vascular control was achieved after reclamping of the renal hilum. In patients with a positive margin on frozen section analysis, the initial reconstruction was undone, the parenchymal defect was reexcised, and the collecting system along with the renal parenchyma was reconstructed de novo (Figs. 1 –3). The average operative time was 185 minutes, and the average blood loss was 171 mL. No residual tumors were identified in the reresected tumor craters in cases of positive margins, and there have been no recurrences after an average follow-up of 21 months.

FIG. 1.

Index case (patient 6): 4 cm interpolar tumor with irregular endophytic component.

FIG. 2.

(A) Robotic resection and (B) reconstruction. (C) Microscopic focal positive margin on frozen section after primary repair and robot undocking.

FIG. 3.

(A) Reresection of the tumor crater after takedown of the repair and reclamping with pure laparoscopic technique. (B) Index case computed tomography at 1 year postoperatively.

Table 1.

Tumor Characteristics of Patients Needing Repeated Hilar Clamping

Patient	Tumor size (cm)	Side	Location	Percent exophytic	Pathology
Patient 1	2	Right	Lateral, interpolar	20%	RCC
Patient 2	3.8	Left	Posterior, upper pole	50%	RCC
Patient 3	2.2	Left	Anterior, lower pole	50%	RCC
Patient 4	3.5	Right	Endophytic, lower pole	10%	RCC
Patient 5	4.8	Right	Anterior, upper pole	40%	RCC
Patient 6	4	Left	Lateral, interpolar	50%	RCC
Patient 7	5	Right	Medial, lower pole	40%	Oncocytoma

RCC=renal-cell carcinoma.

Table 2.

Reasons for Repeated Clamping and Ischemic Times of Patients Needing Repeated Hilar Clamping

Patient	Surgical approach	Reason for reclamp	Initial ischemic time (min)	Repeated ischemic time (min)
Patient 1	Laparoscopic	Bleeding	25	4
Patient 2	Laparoscopic	Margin status	21	7
Patient 3	Laparoscopic	Margin Status	18	5
Patient 4	Robotic	Bleeding	5	42
Patient 5	Robotic	Margin Status	22	6
Patient 6	Laparoscopic	Margin Status	22	14
Patient 7	Laparoscopic	Bleeding	30	5

Six of seven patients had no postoperative complications. There was one Clavien classification IIIb complication: Patient 1 had a urine leak that necessitated ureteral stent placement, and the leak resolved. All other patients had an uneventful postoperative course and standard postoperative care.

All renal units were functioning postoperatively. The average change in absolute renal function on the operated kidney, as measured by MAG3 scan, was −4.9%. This correlates to a relative loss of −10% of function, as measured by the MAG3 scan. The average GFR before surgery was 61.4 (mL/min/1.73m²); after surgery, the average GFR was 57.1 (mL/min/1.73m²), for an average loss of −7%. The range of change in GFR was from 0% to −23%. Table 1 describes the characteristics of each patient's tumor. Table 2 shows the data on ischemic time and reasons for repeated clamping. Table 3 illustrates renal function and GFR, broken down by individual patient.

Table 3.

Impact of Repeated Hilar Clamping on Glomerular Filtration Rate and Renal Function (Mercaptoacetyltriglycine-3 Scan)

Patient	Preop GFR (mL/min/1.73m ² )	Postop GFR (mL/min/1.73 m ² )	Change in GFR (%)	Change in renal function (%)
Patient 1	37	36	−2.7	5.8
Patient 2	49	49	0	−8.0
Patient 3	63	63	0	−9.6
Patient 4	59	53	−10	7.1
Patient 5	71	65	−8.4	−8.3
Patient 6	78	78	0	−22
Patient 7	73	56	−23.2	−36

Preop = preoperative; GFR = glomerular filtration rate; postop = postoperative.

Discussion

Conventional wisdom holds that a repeated period of hilar ischemia results in ischemia/reperfusion injury, which is a complex cascade of vascular and tubular events that leads to global kidney dysfunction.¹² This series of events begins with endothelial damage, leads to parenchymal hypoxia, and ultimately to tubular epithelial injury.¹² The net effect is a decrease in GFR.¹² Although our data represent a small series of only seven patients, the results of our analysis suggest that repeated hilar clamping, for cause, during LPN and RPN does not affect renal function as drastically as previously thought.

Several factors are associated with decreased GFR after partial nephrectomy. These include patient factors (older age, male sex, lower preoperative GFR, solitary kidney), tumor size and surgical factors (ischemic time, percent of parenchyma resected, and postoperative complications).²⁶ The duration of renal ischemia is the most salient modifiable surgical risk factor for impaired renal function after partial nephrectomy.²⁶ Because cold renal ischemia cannot be achieved reliably during LPN and RPN, these procedures are usually performed under warm ischemia. The kidney cannot tolerate warm ischemia for the same amount of time as cold ischemia, and there is little doubt that the longer the warm ischemic time, the higher the chance of irreversible renal injury. Generally, a warm ischemic period of roughly 30 minutes is accepted as the target upper length of time for clamping the renal hilum during LPN and RPN.^12,15

–18 For periods of ischemia less than 30 minutes, the benefit of cold over warm ischemia is not as well supported.²⁷ Furthermore, the benefit of clamping the renal artery only, versus the artery and vein, is unclear.¹² It is our practice to clamp the artery alone in cases where the tumor can be resected expeditiously; however, if the tumor abuts the hilum or if a major parenchymal resection and reconstruction is needed, such as with a predominantly endophytic lesion, we occlude both the artery and vein—all cases in this series were of this more complex type, and thus all hilar vessels were occluded.

Although there are descriptions of needing to reclamp the hilum among case series of LPN and RPN,^23,24 our work is the first that we are aware of that specifically assesses the impact on renal function of repeated clamping of the hilum during LPN and RPN. We used both renal function obtained from preoperative and postoperative MAG3 scans and the MDRD equation to determine changes in renal function after repeated hilar clamping. In our cohort of seven patients, all renal units functioned after surgery; there was a loss of 10% function on MAG3 scan, three patients had no change in GFR, and the total average GFR change was merely −7%, clearly in line with large scale series showing a comparable loss of GFR during routine partial nephrectomy.^16,18,26 These outcomes were better than anticipated. Furthermore, the loss of GFR is substantially less than from radical nephrectomy, even with reclamping of the renal hilum during RPN and LPN.⁶

This study was not equipped to determine why repeated hilar clamping had a small impact on renal function; however, there are some data to suggest that repeated ischemia may be protective. There is an entity known as ischemic preconditioning where transient ischemia is induced either at or remote from the operative site. This is thought to change the milieu under which the subsequent procedure is performed, mitigating the deleterious impact of ischemia and reperfusion injury.^28
–30 Although the jury is still out on the effect on the kidney, in procedures such as aortic surgery or cardiac bypass, there is some evidence that it may prove to be organ-protective. Such a mechanism may have been at play in our series and could be worthy of further investigation in animal models. We must stress, however, that no controlled human trials on ischemic preconditioning on the kidney have been performed and, as such, repeated hilar clamping is not indicated for this purpose.

A further limitation of our study is the small number of patients who underwent hilar reclamping. Our patients were a heterogeneous group who needed reclamping for different reasons, some of whom had preexisting renal dysfunction. Nonetheless, because hilar reclamping is certainly not recommended, addressing this issue is extremely difficult in a prospective or controlled fashion, and such observational data are the best surrogate, given this limitation.

It is important to stress that we do not advocate repeated hilar clamping unless absolutely indicated, and we cannot impeach the well-established phenomenon of ischemic reperfusion injury; however, as more complex LPN and RPN are performed, a scenario in which the surgeon may need to reclamp the hilum is sure to arise. In our series, both senior authors are experienced minimally invasive surgeons who decided to reclamp the hilum for uncontrolled bleeding and questionable surgical margins and were expeditiously able to resolve these problems. In fact, in all but one case, repeated ischemic time was under 14 minutes. In our series, in cases where reclamping was performed for microscopic positive margins on frozen section analysis, no residual renal tumor was encountered in the subsequently resected renal crater. Clearly in this setting, a radical nephrectomy would have removed a renal remnant with no viable tumor. Arguably, repeated renal clamping, even if more harmful to renal function than a single period of ischemia, may be preferred to the certain loss of renal function from a radical nephrectomy.

On the other hand, both novice and expert laparoscopic and robotic surgeons should be cautioned against performing repeated renal clamping. In the setting of a complex renal mass, life-threatening hemorrhage, gross positive margins, or obvious tumor spillage, open conversion or a radical nephrectomy should be considered as a first-line option. When faced with substantial bleeding after hilar unclamping, or an incomplete tumor resection, the alternative to reclamping is a radical nephrectomy or attempting nephron sparing in a bloody operative field, where visualization may be obscured and adequate nephron sparing may be compromised. The reasonable outcomes in this small series must not supersede sound surgical judgment.

Conclusions

We have demonstrated that there is a small loss of renal function in the kidney that is subjected to partial nephrectomy under conditions of repeated hilar clamping; however, this loss in renal function is not as pronounced as after a total nephrectomy. When presented with the decision to remove the entire kidney compared with clamping the hilum again, it appears that in the event of substantial bleeding or issues with cancer control and margins, in the hands of an experienced surgeon, repeated hilar clamping can be performed with a reasonable impact on ultimate renal function.

Footnotes

Disclosure Statement

No competing financial interests exist.

Abbreviations Used

References

Miller

, Ruterbusch

, Colt

et al. Contemporary clinical epidemiology of renal cell carcinoma: Insight from a population based case-control study. J Urol, 2010; 184:2254–2258.

Gill

, Desai

, Kaouk

et al. Laparoscopic partial nephrectomy for renal tumor: Duplicating open surgical techniques. J Urol, 2002; 167:469–476.

Winfield

, Donovan

, Godet

, Clayman

. Laparoscopic partial nephrectomy: Initial case report for benign disease. J Endourol, 1993; 7:521–526.

Hollenbeck

, Taub

, Miller

et al.

National utilization trends of partial nephrectomy for renal cell carcinoma: A case of underutilization?

Urology, 2006; 67:254–259.

Dulabon

, Lowrance

, Russo

, Huang

. Trends in renal tumor surgery delivery within the United States. Cancer, 2010; 116:2316–2321.

Huang

, Levey

, Serio

et al. Chronic kidney disease after nephrectomy in patients with renal cortical tumours: A retrospective cohort study. Lancet Oncol, 2006; 7:735–740.

Russo

. Functional preservation in patients with renal cortical tumors: The rationale for partial nephrectomy. Curr Urol Rep, 2008; 9:15–21.

, Chertow

, Fan

et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med, 2004; 351:1296–1305.

Mathew

, Devereaux

, O'Hare

et al. Chronic kidney disease and postoperative mortality: A systematic review and meta-analysis. Kidney Int, 2008; 73:1069–1081.

10.

Simmons

, Weight

, Gill

. Laparoscopic radical versus partial nephrectomy for tumors >4 cm: Intermediate-term oncologic and functional outcomes. Urology, 2009; 73:1077–1082.

11.

Crépel

, Jeldres

, Sun

et al. A population-based comparison of cancer-control rates between radical and partial nephrectomy for T1A renal cell carcinoma. Urology, 2010; 76:883–888.

12.

Simmons

, Schreiber

, Gill

. Surgical renal ischemia: A contemporary overview. J Urol, 2008; 180:19–30.

13.

Lyrdal

, Olin

. Renal blood flow and function in the rabbit after surgical trauma. III. Effects of temporary occlusion of renal artery. Scand J Urol Nephrol, 1975; 9:151–160.

14.

Nishikido

, Noguchi

, Koga

et al. Kidney transplantation from non–heart-beating donors: Analysis of organ procurement and outcome. Transplant Proc, 2004; 36:1888–1890.

15.

Thompson

, Frank

, Lohse

et al. The impact of ischemia time during open nephron sparing surgery on solitary kidneys: A multi-institutional study. J Urol, 2007; 177:471–476.

16.

Desai

, Gill

, Ramani

et al. The impact of warm ischaemia on renal function after laparoscopic partial nephrectomy. BJU Int, 2005; 95:377–383.

17.

Secin

. Importance and limits of ischemia in renal partial surgery: Experimental and clinical research. Adv Urol, 2008; 102461.

18.

Becker

, Van Poppel

, Hakenberg

et al. Assessing the impact of ischaemia time during partial nephrectomy. Eur Urol, 2009; 56:625–634.

19.

Shikanov

, Lifshitz

, Chan

et al. Impact of ischemia on renal function after laparoscopic partial nephrectomy: A multicenter study. J Urol, 2010; 183:1714–1718.

20.

Frank

, Frank

, Zelenock

, D“Alecy

. Ischemia with intermittent reperfusion reduces functional and morphologic damage following renal ischemia in the rat. Ann Vasc Surg, 1993; 7:150–155.

21.

Truss

. Advantages and disadvantages of intermittent pedicle clamping in renal preserving surgery. Br J Urol, 1971; 43:35–38.

22.

Willgoss

, Zhang

, Gobé

et al. Repetitive brief ischemia: Intermittent reperfusion during ischemia ameliorates the extent of injury in the perfused kidney. Ren Fail, 2003; 25:379–395.

23.

Bollens

, Rosenblatt

, Espinoza

et al. Laparoscopic partial nephrectomy with “on-demand” clamping reduces warm ischemia time. Eur Urol, 2007; 52:804–809.

24.

Steinberg

, Kilciler

, Abreu

et al. Laparoscopic nephron-sparing surgery for two or more ipsilateral renal tumors. Urology, 2004; 64:255–258.

25.

Kim

, Shah

, Tan

et al. Estimation and prediction of renal function in patients with renal tumor. J Urol, 2009; 181:2451–2461.

26.

Lae

, Babineau

, Poggio

et al. Factors predicting renal functional outcome after partial nephrectomy. J Urol, 2008; 180:2363–2369.

27.

Thompson

, Frank

, Lohse

et al. The impact of ischemia time during open nephron sparing surgery on solitary kidneys: A multi-institutional study. J Urol, 2007; 177:471.

28.

Ali

, Callaghan

, Lim

et al. Remote ischemic preconditioning reduces myocardial and renal injury after elective abdominal aortic aneurysm repair: A randomized controlled trial. Circulation, 2007; 116:I98–105.

29.

Glanemann

, Vollmar

, Nussler

et al. Ischemic preconditioning protects from hepatic ischemia/reperfusion-injury by preservation of microcirculation and mitochondrial redox-state. J Hepatol, 2003; 38:59–66.

30.

Barakat

, Hussein

, Abdel-Maboud

et al. Ischaemia-reperfusion injury in renal transplantation: The role of nitric oxide in an experimental rat model. BJU Int, 2010; 106:1230–1236.