Segmental versus main renal artery clamping in nephron sparing surgery: an updated Meta-analysis

Ischemia-reperfusion injury is very harmful in partial nephrectomy (PN) in renal cell carcinoma (RCC). It is important to choose an appropriate surgical method to reduce ischemia-reperfusion injury. To compare the impact of segmental artery clamping (SAC) and main artery clamping (MAC) on some clinical data of the patients underwent PN. Methods Studies from January 2008 to November 2019 were identified by electronical search of the English databases including PubMed, EMBASE, the Cochrane Library and Chinese database including Wanfang, VIP and CNKI without language restriction. Two reviewers were involved in the trial. The impact on operation time(OT), Warm ischemia time (WIT), length of stay in hospital (LOS), blood transfusion rate, postoperative complication rate, Clavien classification ≥3 and positive surgery margin (PSM) were evaluated using Stata software, and standardized mean difference (SMD)%(for the continuous data) and the pooled odds ratios (ORs) (used for counting data) with 95% confidence interval (CI) were used as effect indicators.


Introduction
Renal cell carcinoma (RCC) is the most lethal malignancy of urinary system tumors ranking the second in the incidence with a higher incidence than prostate cancer and a slightly lower incidence than bladder cancer in North America and Europe [1]. It was reported that there was a significant increase of asymptomatic small renal cell carcinoma (SRMs) and micro renal cell carcinoma with increasing use of imaging for other medical indications by incidental detection [2].
Surgical resection was once the preferred treatment for renal tumors. Radical nephrectomy (RN) and partial nephrectomy (PN) which was firstly performed by Winfield in 1992 are the main two important treatment options [3]. PN is appropriate in carefully selected patients with RCC with the advantages of reducing CKD risk, decreasing the overall and tumor-specific mortality, and improving long-term renal function compared with RN [4][5][6]. The limitation is that renal artery occlusion is often required and the accompanying thermal ischemic injury is an important cause of postoperative acute renal failure or long-term chronic kidney disease [7]. It is worth noting that main renal artery occlusion adopts the extensive renal blood flow occlusion, which blocks the blood supply of tumor and healthy nephrons at the same time, and the postoperative recovery of blood flow is bound to lead to the ischemia/reperfusion injury of healthy nephrons [8]. It was reported that blocking renal artery branch supplying tumor blood as far as possible in operation with high selective blockade technology and even not blocking the renal artery 4 trunk was safe and feasible in PN because it can maintain normal blood supply of residual kidney tissues, and no significant difference in total kidney [9]. Trehan reported that Offclamp PN was associated with a significantly lower reduction in eGFR than on-clamp PN [10]. RPN with sequential SRA clamping, represents a good alternative for selected patients with Multiple ipsilateral renal tumors (MIRTs). The precise segmental artery clamping technique with the guidance of dual-source computed tomography (DSCT) can maximize renal function preservation [11]. Some studies in China have reported that SRAC is associated with decreasing warm ischemia appears promising in terms of reserving postoperative function [12,13]. SAC was preferred by many surgical doctors. Li and Zhang [12] showed that SAC was safer and had a better renal function preservation compared with MAC in PN by reviewing the previous literatures [13]. However, Taweemonkongsap showed that clamping techniques does not impact on renal functions and complication rate was low even in small-volume center [14]. Therefore, So far, there is a lack of some systematic elaborations on the advantages and disadvantages of the SAC and MAC. The indicators for MAC and SAC are not clear. Therefore, it is necessary to constantly track and analyze the newest researches in the world for more powerful and more systematic evidence.
In this study, we conducted a retrieval and systematic analysis of the latest literature using case-control studies associated with comparing the features of SAC and MAC. In this way, it can provide more convincing evidence-based medicine basis for doctors and supply better services for clinical diagnosis and treatment.

Inclusion and exclusion criteria
The patients diagnosed as patients with renal tumors including benign and malignant tumors. And the above patients were subjected to SAC and MAC. The review literature and the studies which were not control-case studies were not included in this study.
Documents without necessary and incomplete basic information are excluded. Low-quality studies were excluded.
Two researchers (Xu and Zhang) reviewed the related articles separately and extracted the data using a uniform standardized table including made with EXCEL 2010. They preliminary screened the article titles and abstracts independently. Then the studies that meet the criteria were included in this meta analysis. When disagreements arise, another researcher (SX Xu) will enroll in a discussion until agreement was reached. Interested outcome measures are as follows: operating time(OT), estimated blood loss(EBL), warm 6 ischemia time (WIT), bleeding requiring transfusion, length of hospital stay(LOS), postoperative complication rate, post-operative estimated glomerular filtration rate (eGFR) change value and percentage decrease in eGFR. In the process of data extraction, the continuous variables expressed using median and quartile spacing were conversed to approximate mean and standard deviation according to the methods proposed by Luo and Wan, respectively.

Quality evaluation
The quality of each eligible article was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS).The papers scores above 8 points are considered as being of high quality. The papers scoring 6 to 8 points were considered methodologically sound. The studies scoring under 5 points are considered as being of low quality and were excluded from the final meta-analysis.

Statistical analyses
Statistical analysis was performed with Stata software version 12.0 (2011) (Stata Corp, Colledge Station, TX, USA). The heterogeneity was assessed using the Cochrane's Q-test and the inconsistency index value (I 2 ). I 2 was more than 50%, which indicated that there was obvious heterogeneity. A random-effects model was used. A fixed-effects model was used when I 2 was less than 50%. Otherwise, Descriptive evaluation was adopted for outcome indicators that cannot be quantitatively evaluated. Egger's linear regression test was used to judged publication bias when the number of studies was more than 10.

Baseline characteristics of the eligible studies
A total of 429 studies were identified from a search of the aforementioned databases. Blood transfusion rate:Total 12 articles [12-14, 24, 26, 29, 30, 33, 35, 37, 43, 44]were included. Heterogeneity showed that there is no heterogeneity among the studies (I 2 =0, P=0.922). Therefore, a fixed-effect model was used. The result showed there was no significant difference in blood transfusion rate between SAC group and MAC group  articles [19,27,29,30,33,42] were included. Heterogeneity showed that there was severe heterogeneity among the studies (I 2 =72.0%, P=0.003). Subgroup analysis was performed according to the operation methods LPN and RPN. And I 2 value was changed to some extent in the subgroups. Therefore, operation method was the heterogeneity resource in LPN group but not in the RPN group. Therefore, random-effect model was used.

Discussion
In the current study, we systemically evaluated the impact of SAC and MAC on OT, EBL, WIT, LOS, postoperative complication rate, postoperative percentage decrease in eGFR.
During the reports, the doctors conducted a case-control study by dividing the patients into two groups including SAC and MAC. However, some patients included into SAC had to be subjected to main arterial clamping when excessive bleeding from the defect and no enough time for modulating the clamped branches or no satisfactory ischemic area obtained by clamping multiple branches. That is that the two operation ways can be transferred when it is necessary. Shao et al. first reported the nephrectomy technique of selectively blocking renal artery, and learned that SAC not only retains the affected nephrons, but also reduces the disadvantages of renal ischemic injury [13]. RPN with segmental SRA clamping with the guidance of double source computerized tomography(DSCT), and skilled robotic experience, can be feasible and maximize renal function preservation [46]. However, Large-scale multicenter clinical studies are still needed to further prove these results.
Our result showed that OT in LPN with SAC is a little longer in SAC group than that in LPN with MAC group, which wasn't observed in the RPN group. Compared with traditional PN with MAC, PN with SAC requires the separation of renal artery, anterior and posterior branches and segmental renal arteries. When necessary, the kidney should be slightly cut open to separate the 3rd and 4th grade renal artery branches, which requires more steps of vessel separation. The above mentioned procedures can result in prolonged surgery.
The length of time it takes to separate blood vessels during surgery is related to the doctor's skill and familiarity with the anatomical location of blood vessels. In addition to the duration of surgery, WIT's length was emphasized because WIT is a key factor affecting renal function.
About Ischemia reperfusion injury(IRI), it is a major cause of acute ischemic renal injury.
In PN, in order to control intra-operative hemorrhage and maintain clear vision, it is often necessary to temporarily block renal pedicle vessels, which can cause renal ischemia and 13 reperfusion injury [47]. LPN is widely used in the surgical treatment of renal tumors because of its safe and effective minimally invasive features . LPN with MAC has a good operative field, but the heat ischemia for a long time will cause damage to renal function [48,49]. Benway showed that branch occlusion significantly reduced the thermal ischemia reperfusion injury using pig kidney model [50]. In recent years, selective renal artery branch blocking technology is gradually used in PN, the technology only block renal artery branch of supply of the tumor blood supply, can effectively avoid or reduce the normal renal unit thermal ischemia injury. It was reported the WIT over 30 min will produce irreversible damage to kidney function, some position is deeper, especially those with intra-operative need to suture the drainage system, warm ischemia time difficult to control. This Meta analysis showed that OT is longer in SAC group than in MAC group in LPN, but there was no significant difference in OT between SAC and MAC in RPN Group.
Meanwhile, it was proved that no significant difference in WIT was observed between SAC and MAC group. The length of hospital stay is mainly related to the patient's condition.
Our study showed no obvious difference between PN with SAC and PN with MAC which indicating that the PN with SAC did not affect the length of hospital stay.
About EBL the result showed that EBL is more in SAC group than in MAC group (P=0.000).
However, our result also showed no significant difference was observed in blood transfusion rate between SAC and MAC group. Although the combined effect indicator showed that there was difference between the two groups, however 17 articles of 30 articles showed that no difference was observed between the two groups. The number of articles in which no difference existed between the two groups is more than the number of the articles in which difference was observed between the two groups. Therefore, the conclusion that EBL in SAC group was more than MAC group cannot be drawn. The amount of bleeding may have a lot to do with a doctor's experience and skill. Which kind of operation should be adopted depends on the ability of the doctor and the patient's condition.
About PSM%, 17 articles of 23 articles showed that none of the patients had positive surgery margin. 6 articles of the left 6 articles showed that no difference in PSM % between SAC and MAC group. And the combined effect indicator also proved that no difference was observed between SAC and MAC groups (P=0.8). The result showed there was no significant difference in post-operative complications (hemorrage, hematuria, urine leak) and Clavien≥3 between SAC group and MAC group. Heterogeneity analysis showed that there was no heterogeneity among the studies.
Eight articles related to 1 week postoperative change percentage of eGFR were eligible for this Meta-analysis, which indicated SAC group had a less change than MAC group in LPN group and RPN group. Total 6 articles related to postoperative 1 month-percentage change of eGFR were included, which indicated that SAC group had a less change than MAC group. Total 6 articles related to 3 months postoperative change percentage of eGFR of the total kidney were included, which indicated that no significant difference in 3 months postoperative change percentage of eGFR between SAC group and MAC group. Total 3 articles with severe heterogeneity related to postoperative 3 months change percentage of eGFR of the affected kidney were included, which indicated that SAC group had a less change than MAC group in 3 months postoperative change percentage of eGFR of the affected kidney between SAC group and MAC group. Total 4 articles with severe heterogeneity related to 6 months postoperative change percentage of eGFR of the total kidney were included, which indicated that no significant difference in 6 months postoperative change percentage of eGFR between the two groups was observed.
The number of articles investigating eGFR change was 3 to 10. Our study showed that SAC reduces the percentage change of eGFR within 3 months but had no obvious effect on eGFR in 6 months. The analysis on 6 months and above eGFR change wasn't carried out because of lacking in relative literatures. No kidney loss by 18 months' median followup was observed in T Taweemonkongsap's study. This study suggests SAC has certain advantage in the short term recovery of renal function, which also needs more random clinical experimental to further demonstrate the results. Our study results provide a basis for surgeons to actively screen and adapt patients to perform branch occlusion.       Figure 1 Flow chart of the included literature.

Deficiencies
28 Forest plot and meta-analysis of estimated blood loss (EBL) between SAC and MAC group.

Figure 5
Forest plot and meta-analysis of blood transfusion rate in SAC and MAC group.
32 Figure 6 Forest plot and meta-analysis of LOS between SAC and MAC group.

Figure 7
Forest plot and meta-analysis of postoperative complication rate between SAC and MAC group.
34 Figure 8 Forest plot and meta-analysis of Clavien classification≥3 between SAC and MAC group.
35 Figure 9 Forest plot and meta-analysis of PSM between SAC and MAC group.     Forest plot and meta-analysis of 6 months postoperative change percentage of eGFR between SAC and MAC group.