Introduction

Preserving renal function while achieving oncological clearance is a unique surgical challenge in renal cell carcinoma. Partial nephrectomy has become the standard of care for small renal masses amenable to nephron-sparing strategies [1]. The surgical complexity of these procedures varies, particularly with renal hilar and completely endophytic tumors. These are considered among the most challenging because of their anatomical positions, as categorized by the R.E.N.A.L. [2] or PADUA [3] scoring systems. The debate within the surgical community primarily centers on achieving a balance between oncological efficacy and patient safety. Oncological efficacy is typically gaged by the completeness of tumor resection, as evidenced by surgical margins. Additionally, patient safety has a dual focus: minimizing perioperative adverse events and preserving long-term renal function. The latter is of particular importance in partial nephrectomy, where nephron conservation is a critical goal. Warm ischemia time (WIT) as well as remnant healthy renal parenchyma are reported to be surgery-related factors related to long-term postoperative renal function [4, 5].

The advantage of robot-assisted partial nephrectomy (RAPN) over conventional laparoscopic partial nephrectomy (cLPN) has been reported [6,7,8]. Moreover, the advent of RAPN has introduced potential advantages for the management of complex renal tumors, such as hilar tumors [9, 10] or completely endophytic tumors. The key benefit of RAPN lies in the multijoint movement of its robotic arms, which offers enhanced precision, superior maneuverability, and improved access to difficult-to-reach tumors.

Our study was a single-arm trial, where outcomes from RAPN were compared with historical cLPN data while focusing on oncological and renal functional outcomes. We particularly emphasized the importance of the WIT as a surrogate marker of postoperative renal function. Our research aimed to provide a deeper understanding of the oncological and functional outcomes in the context of modern renal cancer surgery. We also investigated the key factors affecting renal function at POD 180, providing insight into the medium-term impacts of RAPN.

Patients and methods

Overview and settings

Our study was conducted as a prospective, multicenter, single-arm, open-label clinical trial over a 17-month recruitment period (trial registration number: jRCT1052200016). We compared our findings with those of previous studies on cLPN. This investigation included 17 distinguished academic hospitals across Japan equipped with da Vinci surgical systems (Intuitive Surgical, Inc. (Sunnyvale, CA, USA)). This study was approved by a central review board (approval number C190037), and all participants gave their written informed consent for participation. Although this study is planned for a 5-year follow-up period to evaluate long-term outcomes, this report includes findings up to POD180 to present short and midterm results.

Exclusions

Eligible patients were those scheduled for partial nephrectomy because of completely endophytic renal tumors classified as cT1, cN0c, M0. A completely endophytic renal tumor is defined as one that does not protrude from the renal cortex. Patients with a history of synchronous cancer and kidney transplant recipients were excluded.

Procedure

The surgical technique adhered to the methodology detailed in prior research [10]. The approach for renal artery clamping was individualized by each participating institution and was not standardized for this study.

Primary outcomes

The primary endpoints of this study were WIT and the proportion of positive surgical margins (PSM), emphasizing the importance of preserving renal function in urological surgery and achieving oncological efficacy through complete resection.

Secondary outcomes

Secondary outcomes are as follows.

  1. 1.

    Achieving both negative tumor margins and WIT of ≤ 25 min.

  2. 2.

    Changes in the estimated glomerular filtration rate (eGFR).

  3. 3.

    Trifecta achievement, defined as follows: (a) negative surgical margins. b. Maintenance of ≥ 90% of the preoperative eGFR at POD 180. c. No pseudoaneurysms, postoperative bleeding, or urinary fistula (Clavien–Dindo ≥ 3) within POD 180.

  4. 4.

    Pre- and post-operative operated renal function variation, measured by split eGFR adjusted for renal scintigraphy-derived uptake ratios [11].

  5. 5.

    Time-free from the progression of chronic kidney disease (CKD). CKD progression was defined as worsening by one or more stages occurring after POD 30.

Secondary outcomes (2), (4), and (5) were geared toward evaluating renal function, while (1) and (3) were oriented toward both renal function and oncological outcomes.

Sample size

To select historical data for comparison, we conducted a systematic search via PubMed in November 2019 using the search terms ["Laparoscopic Partial Nephrectomy" AND "complete endophytic renal tumors"] and ["Laparoscopic Partial Nephrectomy" AND "central tumor"]. We included original articles that reported on two or more patients. Four articles [12,13,14,15] met our inclusion critertia. Based on these four studies, the historical control for WIT was established at 25.2 min. For RAPN, the expected WIT was set at 22.2 min with a 7.9 standard deviation according to our internal data including previous report [10].

For sample size estimation, we adopted a mean WIT of 22 ± 7.9 min to test for superiority against the historical control. The study was designed with a stringent one-sided significance level of 0.5% (α = 0.005) and a power of 90% to account for multiple endpoint testing and reduce the risk of type I and II errors. These calculations determined a sample size of 95 subjects, which was increased to 100 to allow for any potential discontinuations or dropouts.

In the binomial test for PSM, utilizing the sample size calculated for WIT evaluation, with a 13% threshold (following previous studies [10]) and an anticipated PSM rate of 2%, at a one-sided significance level of 0.5%, the detection power exceeds 98%. The threshold was set at 13% following previous study. This suggests that the study is well-powered to assess this oncological endpoint.

Statistical methods

Statistical analyses were performed to determine the efficacy and safety of the RAPN. For both primary endpoints, 95% and 99% confidence intervals (CIs) were estimated. A one-sample t-test was used to assess the significance of WIT reduction, with the alpha level set at 0.5% for one-sided tests. The PSM rate was analyzed using the binomial test against a threshold of 13%.

The mean estimates and their 95% CIs were computed for the remaining secondary endpoints. In analyzing factors contributing to the decline in renal function after surgery, the dependent variable was the percentage of post- and pre-operative split eGFR of the operated kidney. Independent factors included in the analysis were age, sex, baseline renal function, surgical complexity, surgical time, WIT, and weight of the resected kidney tissue.

Multivariate regression analyses were performed to identify predictors of split renal function, with each factor above entered into the model. If a factor has two or more variables, one of them is chosen in each model. Model selection was guided by the Akaike Information Criterion (AIC), with preference given to the model with the lowest AIC value. Exploratory analyses were performed using SAS 9.4 (SAS Institute, Cary, NC, USA).

Results

Patients

Of the 100 patients initially enrolled in the study, one withdrew consent before surgery. During surgery, one patient discontinued due to bleeding requiring conversion to radical nephrectomy. Consequently, 98 participants completed the intervention and were follow-up to POD 180 (Fig. 1). The detailed demographics and clinical characteristics of 98 patients are presented in Table 1. Regarding renal tumor complexity (which is assessed by the PADUA and R.E.N.A.L. scoring systems) nearly half of the patients were in the high complexity category. For a comparative overview of our findings with historical data, please refer to Supplementary Table S1.

Fig. 1
figure 1

Trial flow chart

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Table 1 Characteristics of patients
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Primary outcomes

The mean WIT achieved in RAPN was 20.3 min, which was significantly less than the historical control value of 25.2 min (99% CI 18.3–22.3, p < 0.001, one-sided) (Fig. 2). Furthermore, the incidence of PSM was 0% in the cohort, markedly lower than the null hypothesis value of 13% (99% CI 0–5.3, p < 0.0001, one-sided). These findings collectively indicate that RAPN provided superior outcomes compared with cLPN data for these critical parameters.

Fig. 2
figure 2

Mean WIT with the 95%CI of four historical studies and the present study. The dotted error bar is the 99%CI of the present study. A reference line at 25.2 min is included, representing the average WIT across the four historical studies. This line serves as a benchmark against which the WITs of the individual studies and our current trial data are compared

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Secondary outcomes

Early outcomes

In the immediate postoperative period, we focused on the preservation of renal function and the oncological efficacy. Eighty (81.6%) of the patients achieved a WIT of 25 min alongside securing a negative surgical margin. Detailed results of each of these outcomes are presented in Table 2.

Table 2 Surgical outcome of robot-assisted surgery
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Midterm outcomes

The midterm outcomes focused on renal function stability and the achievement of trifecta. The “trifecta” was achieved by 47 patients (48.0%, 95% CI 38.3–57.7) at POD 180. Details of the trifecta are shown in Table 2. Urinary leakage was observed in two patients, one of whom underwent nephrectomy.

Our analysis revealed a mean ratio of split eGFR at POD180 for the baseline was 0.707 (95% CI 0.66–0.751) Fig. 3A) showed the relation between pre- and post-operative split eGFR. The Kaplan–Meier curve highlighted a significant drop in renal function immediately after surgery, which plateaued after that. By POD 180, 63.5% of patients (95% CI 55.0–73.8) showed no CKD progression (Fig. 3B).

Fig. 3
figure 3

A The distribution of preoperative and postoperative (POD180) split eGFR (mL/min 1.73 m2) of operated kidneys. B Kaplan–Meier curve of CKD progression-free survival in RAPN. CKD progression is defined as the advancement of CKD by at least one stage in the CKD classification. The gray-shaded area represents the 95% CI

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Safety assessment

Overall, 12 adverse events were identified during the perioperative period, which is within POD30. Among these, five events were related to surgery: grade < 3 included one case of hypothermia and one case of pneumonia, while grade ≥ 3 included two cases of urinary fistula and one case of intraoperative bleeding. From POD30 to POD180, three neoplastic lesions occurred, including one case each of recurrent lung cancer, bladder cancer, and colon carcinoid, which were considered unrelated to the current study.

Factors influencing postoperative renal function

According to a multivariate analysis, the selected model (Table 3) identified several perioperative factors associated with the renal function of the operated kidney (percentage of postoperative eGFR against preoperative eGFR).

Table 3 Factors affecting postoperative renal function (percentage postoperative split eGFR against preoperative split eGFR)
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The surgical time, weight of the resected renal mass, and WIT were all predictors of postoperative renal function. Specifically, for every additional 10 min of surgical time, renal function declined by 0.85% (95% CI  − 1.58 to − 0.11), for each gram of resected renal weight, it decreased by 0.52% (95% CI  − 0.84 to − 0.32), and for WIT exceeding 25 min, the reduction was 11.23% (95% CI  − 22.34 to − 0.12). Among patients with a WIT exceeding 25 min., only one exhibited a postoperative split renal function above 80% against preoperative function (Supporting Figure S1).

Discussion

Our study of RAPN for completely endophytic renal tumors has yielded significant results, especially in terms of the two primary endpoints (WIT and PSM rate). The observed WIT of 20.3 min (99% CI 18.3–22.3) not only significantly surpassed the historical values associated with cLPN but also remained well below the critical 25-min benchmark crucial for preserved postoperative renal function. The achievement of a 0% in PSM (99% CI 0–5.3%) reflects the oncological efficacy of RAPN, particularly in managing the complexities of completely endophytic tumors. Successfully meeting both primary endpoints clearly demonstrated functional and oncological efficacy of RAPN.

Numerous studies have compared RAPN with cLPN [6,7,8, 16,17,18], and although there is general agreement that RAPN offers superior outcomes, the specific variables where RAPN outperforms cLPN vary between studies. Even among these reports, few are focusing on complex tumors. Overall, the findings contribute to the consensus that RAPN is becoming the standard approach, including complex tumors such as completely endophytic tumors.

There has been a recent trend toward individualized evaluations for surgically challenging tumors. Recent reports have highlighted the shorter WIT in RAPN compared with cLPN for renal hilar tumors, as comparably challenging as completely endophytic tumors [9, 10]. However, studies focusing on completely endophytic tumors, which present even greater surgical challenges, are less common. Observational studies [19,20,21] indicate a WIT of 17–27 min in RAPN for these tumors, which is consistent with our findings. As noted in these study, RAPN, which can be operated in 3D, may be superior to cLPN in highly difficult surgical procedures. This lack of direct comparisons between cLPN and RAPN for completely endophytic tumors underscores the unique contribution and importance of our study. Furthermore, our results highlight the critical role of RAPN in renal function preservation, with WIT averages consistently below the crucial 25-min threshold.

The concept of “trifecta” in partial nephrectomy, initially introduced by Hung et al. [22], encompasses three key outcomes: negative cancer margins, minimal renal functional decrease, and absence of urological complications. It is noteworthy that various papers have modified the latter two criteria. Our study tailored these criteria to evaluate midterm outcomes, specifically defining them as maintaining an eGFR of 90% or above the preoperative level at POD 180 and the absence of significant complications within POD 180.

The trifecta achievement rate of 47.96% (95% CI 38.33–57.74) in our study is notable despite being lower than previously reported rates (61.7–84.1%) [22,23,24]. Considering our 81.6% achievement rate of WIT ≤ 25 min, the difference in trifecta achievement rate between present and previous studies is likely due to differing criteria for renal function. While they set WIT, we based on renal function at POD 180. In studies that expanded the trifecta criteria to include eGFR evaluations several months postsurgery, the reported attainment rates ranged from 54.6 to 67%, slightly higher than that in the present study [24, 25]. This discrepancy suggests that factors beyond early functional success may influence the preservation of midterm renal function. A direct evaluation is difficult to perform because the viewpoints of renal function differ for each paper; however, it seems that 3.2%–50% of patients may have decreased renal function after RAPN [18, 24,25,26].

Our study contributes to understanding the factors influencing postoperative renal function in RAPN. Post-PN renal function had been evaluated by several outcomes such as acute kidney injury [27], split renal functions [28], trifecta or pentafecta [23, 25], or progress of CKD grade [4]. In this study, we evaluated renal function using split renal function, following the previous report [10]. Although preoperative comorbidities such as age, body mass index, and comorbidities are known to impact renal outcomes [29], our analysis focused on surgical factors. We found that the resection weight, WIT, and overall surgical time significantly influenced the postoperative split renal function of operated kidney, Reported surgical factors include the R.E.N.A.L. score, pentafacta, WIT, and bleeding [4, 21, 30]. WIT is often considered to be around 25 min; however, there are also reports that it can have an impact in min [4, 5]. Our findings indicate that although patients with WIT under 25 min exhibit a mix of preserved and decreased renal function, those with WIT over 25 min consistently show decreased renal function, with a few exceptions, suggesting that 25 min is a reasonable threshold, as cases preserving renal function beyond this duration were rare. Several reports have indicated that the R.E.N.A.L. score impact renal function after PN, and in present study, inclusion criteria specifically limited the “R” and “E” factors of the R.E.N.A.L. score. Consequently, these did not exhibit the same impact on renal function as reported previously. In this cohort, the category labeled as “Low risk” within “E” factor was not represented. This absence of the “low risk” group in “E” factor might account for this result. There have been reports suggesting an association with tumor diameter. Resection weight, often dictated by tumor size, was also correlated with achieving negative surgical margins. It is critical to balance the extent of resection with the need to preserve renal function while avoiding excessive healthy renal parenchymal removal. These factors may indicate that enhancing surgical skills and techniques can improve patient outcomes.

Looking forward, while this report has focused on midterm renal function and surgical efficacy, our ongoing research will extend the follow-up period to five years. This long-term follow-up will provide a more comprehensive picture of RAPN outcomes, including sustained renal function and recurrence rates. The forthcoming data will be crucial in further establishing the long-term benefits and potential limitations of RAPN, thereby contributing to the continuous evolution of surgical strategies in renal cancer treatment.

A major limitation of our study is the comparison with historical cLPN data, which may affect the comparative validity. Nevertheless, the use of 99% CIs helps mitigate some uncertainties in our analysis. In addition, renal function after PN has been evaluated using various definitions, and influencing factors may also differ depending on the definition employed. The constant evaluation of renal function will become necessary in the future.

Conclusion

In conclusion, RAPN shows clear superiority over cLPN (especially in terms of WIT) and proves effective in performing complex surgical procedures such as those performed for completely endophytic tumors, as evidenced by favorable surgical margin rates. The key predictors of midterm renal function in our study were the total surgical time, WIT, and resection weight.