CT-based renal artery caliber change as a potential imaging marker of treatment response in renal cell carcinoma; an exploratory imaging study

Abstract

Background

To evaluate whether treatment-induced changes in tumor-bearing renal artery caliber on contrast-enhanced CT are associated with pathological response and pathological downstaging after systemic therapy in locally advanced or metastatic renal cell carcinoma (RCC), and to explore the clinical relevance of this vascular parameter.

Methods

We retrospectively analyzed 43 patients with locally advanced or metastatic RCC who underwent systemic therapy followed by nephrectomy. Renal artery inner diameter was measured on arterial-phase CT before and after treatment using curved planar reformation. Interobserver reproducibility of the measurement was excellent (intraclass correlation coefficient [ICC] = 0.992). A subset of 33 patients had adequate bilateral imaging for tumor-bearing versus contralateral comparison. Tumor size was measured as the longest axial diameter on contrast-enhanced CT, and tumor shrinkage was expressed as percentage change from baseline according to RECIST 1.1 measurement principles. Choi criteria incorporated tumor size and attenuation changes. Pathological response was defined as the proportion of treatment-induced necrosis and fibrosis. Associations between arterial caliber change, pathological response, and pathological downstaging were assessed. Multivariable regression analysis identified independent predictors of pathological response. Discriminative ability for downstaging was evaluated using receiver operating characteristic analysis.

Results

At baseline, the tumor-bearing renal artery had a larger inner diameter than the contralateral artery. After systemic therapy, its diameter significantly decreased (6.35 to 5.65 mm, p < 0.001). In the paired subset (n = 33), significant reduction occurred only in tumor-bearing arteries. Percentage diameter reduction correlated with pathological response (r = 0.314, p = 0.040). Patients with pathological downstaging showed greater diameter reduction than those without downstaging (16.3% vs 6.83%, p = 0.021). Tumor size change based on RECIST principles and Choi criteria were not significantly associated with downstaging. Multivariable analysis confirmed renal artery diameter change rate as an independent predictor of pathological response. ROC analysis showed moderate discrimination for downstaging (AUC 0.71, 95% CI: 0.55–0.87).

Conclusion

Reduction in tumor-bearing renal artery caliber was independently associated with pathological response and downstaging. This vascular parameter may complement conventional tumor-centered imaging criteria in selected patients.

Clinical trial number

Not applicable

Supplementary Information

The online version contains supplementary material available at 10.1186/s40644-026-01023-x.

Background

Renal cell carcinoma (RCC) with locally advanced or metastatic disease is increasingly managed using multimodal treatment strategies that combine systemic therapy including vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitors (TKIs), and immunotherapy (IO) [1–3]. Surgical interventions after systemic therapy administered have attracted interest as a potential approach to improve clinical outcomes in locally advanced or metastatic RCC [4–8]. Consequently, accurately evaluating treatment effects before surgery is essential for multiple aspects of clinical decision-making.

Conventional radiographic response criteria, such as Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [9], Choi criteria [10], or Dual-Energy CT [11] are used to assess treatment response. However, in RCC, these tumor-centered metrics do not always reflect pathological tumor regression or downstaging, particularly in the era of immune-based or combination therapies [12]. As a result, clinicians may face uncertainty not only regarding the appropriateness or timing of surgery, but also regarding whether continuation, modification, or escalation of systemic therapy should be considered. Pathological response and downstaging represent objective indicators of tumor response to systemic therapy and have direct implications for subsequent management and prognosis [13, 14]. Identifying treatment-related changes that correlate with pathological response and downstaging could provide clinically meaningful information to support clinical decisions, including surgical planning and evaluation of therapeutic efficacy.

Beyond changes in tumor size or attenuation, systemic therapy can induce hemodynamic and structural alterations in tumor-associated vasculature [15]. In hepatic tumors, treatment-induced changes in tumor-feeding arteries have been reported to reflect therapeutic response [16]. Given the hypervascular nature of RCC and its strong dependence on angiogenic signaling, we hypothesized that similar vascular remodeling of tumor-bearing renal arteries might occur following systemic therapy and could capture treatment effects not adequately represented by conventional imaging criteria. Such vascular changes may reflect the dynamic interplay between tumor perfusion demand and therapy-induced vascular modulation.

Therefore, the aim of this study was to explore whether changes in the caliber of the tumor-bearing renal artery after systemic therapy are associated with pathological response rate and downstaging, and whether this vascular parameter could serve as an adjunctive imaging feature to support clinical decision-making in patients with advanced RCC.

Materials and Methods

Subjects

We retrospectively reviewed 62 patients with metastatic or locally advanced RCC who received systemic therapy followed by radical or partial nephrectomy between 2012 and 2025 at Hirosaki University Hospital. Among these, 43 patients with contrast-enhanced CT scans of sufficient quality for precise renal artery measurement before and after treatment were included (Fig. 1).

Fig. 1.

Patient selection flow diagram. Patients with locally advanced or metastatic renal cell carcinoma (RCC) who underwent nephrectomy after systemic therapy between 2012 and 2025 were initially screened (n = 62). Nineteen patients were excluded due to CT imaging-related limitations, including insufficient slice thickness (n = 9) and absence of arterial-phase CT imaging (n = 5). A total of 43 patients were included in the radiological, pathological, and prognostic analyses. For bilateral comparative analysis, additional exclusions were applied because of multiple renal arteries (n = 6) and significant image artifacts (n = 4), resulting in 33 patients eligible for paired analysis

For locally advanced RCC (clinical T2b or higher), TKIs (axitinib, cabozantinib, or sunitinib) were administered prior to surgery as preoperative systemic therapy. Patients with mRCC received TKIs, IO-based therapy, or combination regimens. This study was approved by the ethics review board of Hirosaki University School of Medicine (approval no. 2019–099-3) and conducted in accordance with the Declaration of Helsinki.

Patient selection, treatment protocol, and patient follow-up

These patients underwent renal biopsy for histopathological confirmation of RCC. Following biopsy, TKI therapy was administered for 3–6 months. Surgical intervention was performed in patients demonstrating radiologic response rendering resection technically feasible. Since the immunotherapy era, metastatic patients received either IO-IO or IO-TKI combinations per current standards [2, 3]. Patient treatment regimens (TKI monotherapy, IO-TKI, or IO-IO combinations) were determined at conferences based on disease stage, performance status, and contemporary clinical guidelines. All patients in this cohort underwent nephrectomy with curative intent after systemic therapy. Patients who underwent nephrectomy were allowed to receive TKIs or adjuvant immunotherapy according to pathological findings (Figure S1). Baseline cardiovascular and metabolic comorbidities were assessed prior to initiation of systemic therapy. Hypertension was defined as a documented diagnosis of hypertension or the use of antihypertensive medications. Diabetes mellitus was defined as a physician diagnosis of diabetes or the use of antidiabetic medications. History of cardiovascular disease (CVD) was defined as a documented history of stroke, ischemic heart disease, arrhythmia, or other clinically diagnosed cardiac conditions. Baseline renal function was evaluated using estimated glomerular filtration rate (eGFR) calculated at the time of treatment initiation.

Measurement of tumor size and Choi score assessment

Tumor size was assessed by measuring the longest diameter on contrast-enhanced CT at baseline and after treatment. Specifically, cT at baseline refers to the clinical stage at diagnosis before initiation of systemic therapy. Radiologic response was evaluated according to RECIST 1.1 criteria [9]. Tumor attenuation was measured in Hounsfield units (HU) on portal venous phase CT images, and Choi score was calculated as previously described [10, 17]. The percentage change in Choi score was calculated to reflect treatment-induced changes in tumor vascularity.

Renal artery diameter measurement

Vascular curved planar reformation (CPR), a technique validated for accurate vessel diameter measurement in cardiovascular imaging, was used to quantify inner and outer arterial diameters [18, 19]. Given the retrospective design spanning multiple years, CT acquisition parameters were not fully standardized across all patients. To ensure measurement reliability, only arterial-phase contrast-enhanced CT scans with thin-slice reconstruction (≤1.0 mm) were included. All measurements were performed using a standardized CPR-based protocol on original DICOM data. Detailed acquisition parameters, including contrast administration and reconstruction settings, are provided in the Supplementary Methods. Original DICOM datasets were imported without additional filtering into SYNAPSE VINCENT version 7.0 (FUJIFILM, Tokyo, Japan), a commercially available software platform routinely used in our clinical practice to generate three-dimensional renal models prior to radical or partial nephrectomy. This commercially available software platform CPR-based measurements are considered relatively robust to minor variations in CT acquisition parameters when high-resolution arterial-phase imaging is available, as the method enables centerline-based orthogonal cross-sectional assessment and reduces geometric distortion. Cross-sectional measurements were obtained perpendicular to the centerline. Measurements were initiated at the renal artery origin in cases without calcification; in cases with calcification at the ostium, measurements were started approximately 5 mm distal to the origin to avoid calcified segments. The measurement segment extended from the starting point to the first major branching point. The same protocol was applied for both pre- and post-treatment CT scans. Along this segment, inner and outer diameters were automatically sampled at 1-mm intervals, and the mean values across the entire segment were calculated as representative diameters (Fig. 2). The measurement time was approximately 3–5 minutes per case. Inner diameter (luminal diameter) was predefined as the primary imaging variable reflecting arterial inflow, whereas outer diameter and wall thickness were analyzed as secondary parameters. Patients with diffuse circumferential calcification involving the entire renal artery were predefined to be excluded due to unreliable boundary delineation. In cases with focal calcification at the renal artery ostium, measurements were obtained at a slightly more distal, non-calcified segment to ensure accurate boundary identification. All measurements were performed blinded to pathological outcomes. To evaluate the reproducibility and reliability of the measurements, a second observer who was blinded to radiologic and pathological responses independently and randomly measured 20 renal arteries. Interobserver agreement was assessed using the intraclass correlation coefficient (ICC). The mean diameter across the entire vessel length was used as the representative value. Percent change was calculated as: Change rate (%) = (pre-treatment diameter - post-treatment diameter)/pre-treatment diameter × 100. Vessel wall thickness was calculated as (outer diameter − inner diameter)/2. In patients with multiple renal arteries (all cases had two arteries, n = 6), we quantified inner diameter for each measurable artery and used the sum of inner diameters as the representative parameter for that kidney, considering inner diameter as a physiologically relevant surrogate of arterial inflow. In contrast, analyses of outer diameter and wall thickness were restricted to patients with a single renal artery per kidney.　For cases with multiple renal arteries (≥2 branches, n = 6), the sum of average diameters from each artery was used as the representative value for that kidney. Contralateral arteries provided internal controls. We compared the arterial diameter of the tumor-bearing side with that of the contralateral side before and after treatment. Six patients with multiple renal arteries and 4 patients with inadequate contralateral imaging were excluded from this comparison. Importantly, these patients were not excluded from the primary analyses evaluating pathological response and PFS.

Fig. 2.

Measurement of renal artery diameter using curved planar reformation (CPR). (A) arterial-phase contrast-enhanced CT images were reconstructed using CPR along the centerline of the main renal artery from the ostium to the proximal branching point. (B) inner and outer arterial diameters were measured continuously along the reconstructed vessel, and the mean diameter across the entire segment was calculated as the representative value for each artery. This method allowed standardized and reproducible assessment of renal artery caliber before and after systemic therapy

Pathological assessment

Nephrectomy specimens were bivalved along the long axis and serially sectioned at approximately 10 mm intervals. The cut surfaces were grossly examined to identify areas of viable tumor, necrosis, fibrosis, sarcomatoid change, and suspected vascular invasion. Sections were systematically submitted from the largest tumor cross-section and from all grossly suspicious areas, including regions of necrosis, fibrosis, sarcomatoid morphology, and vascular invasion.　All specimens were independently reviewed by two board-certified genitourinary pathologists using hematoxylin and eosin (H&E)-stained slides, and discrepancies were resolved by consensus. Pathological response was defined as the estimated proportion of treatment-induced necrosis and fibrosis relative to the total tumor area. Estimation was based on integrated gross and microscopic assessment across representative whole-tumor sections rather than limited focal sampling, in order to minimize sampling bias. Downstaging was defined as pathological T stage lower than clinical T stage. Pathological complete response (pCR) was defined as the absence of viable tumor cells [20].

Although formal interobserver agreement was not assessed due to the retrospective nature of the study, pathological evaluation was performed by experienced genitourinary pathologists as part of routine clinical practice, with diagnoses established through multi-pathologist review, which likely enhances diagnostic reliability.

Statistical Methods

The statistical analysis was conducted using GraphPad Prism 5.03 (GraphPad Software, San Diego, CA, USA) and EzR: R commander (version 1.6–3). For normally distributed continuous variables, the data were presented as means (standard deviation [SD]), while non-normally distributed variables were expressed as medians (interquartile ranges [IQR]). Side-to-side comparisons within the same patients (tumor-bearing artery vs. contralateral renal artery diameters at baseline and post-treatment) employed the Wilcoxon signed-rank test. Pre/post-treatment changes within the same kidney also used the Wilcoxon signed-rank test. Between independent patient groups and correlation analyses employed the Mann-Whitney U and Spearman’s rank correlation coefficient, respectively. Multiple linear regression identified predictors of pathological response (standardized β). Receiver operating characteristic (ROC) curve analysis was performed to evaluate the ability of treatment-induced changes in the caliber of the tumor-bearing renal artery to discriminate pathological downstaging. The area under the ROC curve (AUC) was calculated to assess discriminative performance. The exploratory cutoff value was determined using the Youden index, defined as the maximum value of (sensitivity + specificity − 1). To assess the independent association between renal artery diameter reduction and pathological downstaging while accounting for potential confounding by treatment duration, we performed a logistic regression analysis with two predictors: percentage reduction in renal artery inner diameter and duration of systemic therapy prior to surgery

Results

Patient Background

A total of 43 patients were included in the analysis. Clear cell carcinoma was the predominant histological subtype according to biopsy pathology (Table 1). Systemic therapy before surgery consisted of TKI monotherapy, IO–IO therapy, or combination regimens. Approximately 80% of patients received TKIs (30 received axitinib, 3 received sunitinib or cabozantinib). Immune-based regimens included nivolumab–ipilimumab (n = 2), nivolumab–cabozantinib (n = 1), pembrolizumab–axitinib (n = 1), and pembrolizumab–lenvatinib (n = 4).

Table 1.

Baseline characteristics of the patients

Number of patients	43
Age (years)	67 (59–73)
Duration of medication before surgery (months)	6.0 (3.5–8.5)
Male gender (%)	31 (72%)
Metastatic RCC at diagnosis (%)	16 (37%)
Biopsy pathology; clear cell carcinoma (%)	40 (93%)
estimated Glomerular Filtration Rate (mL/min)	63.3 (51.7–75.4)
Hypertension	22 (51%)
Diabetes mellitus	8 (19%)
History of Cardiovascular disease	6 (14%)
cT stage
cT1b (%)	1 (2.0%)
cT2a-b (%)	5 (12%)
cT3a-c (%)	26 (60%)
cT4(%)	11 (26%)
Treatment
TKI (%)	35 (81%)
IO-TKI (%)	6 (14%)
IO-IO (%)	2 (5%)
Tumor size (mm)	91 (72–100)
Choi score (HU)	104 (86–130)
Outer diameter of the renal artery (mm)	7.53 (6.50–8.45)
Inner diameter of the renal artery (mm)	6.35 (5.70–7.31)
Adjuvant or maintenance therapy after surgery (%)	19 (44%)
Follow up period after surgery (months)	35 (17–61)

RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor; IO, immune oncology therapy, HU; Household unit

Baseline comparison between tumor-bearing and contralateral renal arteries

At baseline, paired analysis was performed in 33 patients. The tumor-bearing renal artery demonstrated a significantly larger inner diameter compared with the contralateral side (Fig. 3A). Although the outer diameter also tended to be larger on the tumor-bearing side, the wall thickness of the tumor-bearing artery was significantly thinner than that of the contralateral side (Figs. 3B, C). In the present cohort, no patients were excluded because of severe tumor-bearing renal arterial calcification. Interobserver agreement for renal artery measurements was excellent, with an ICC of 0.992 (95% CI: 0.977–0.997, p < 0.001, Figure S2).

Fig. 3.

Baseline comparison of tumor-bearing and contralateral renal arteries. Paired analysis of renal artery morphology before systemic therapy in patients with evaluable bilateral renal arteries (n = 33). (A) inner diameter of the main renal artery was significantly larger on the tumor-bearing side compared with the contralateral side. (B) outer diameter tended to be larger on the tumor-bearing side, although the difference did not reach statistical significance. (C) wall thickness of the tumor-bearing artery was significantly thinner than that the contralateral artery

Treatment characteristics and radiologic response

The median duration of systemic therapy prior to surgery was 6.0 months (IQR, 3.5–8.5). The median radiological response rate was 23.1% (IQR, 6.65–39.2).　The median Choi score decreased from 104.0 to 63.8 HU (IQR; 50.5–79.6) after treatment (p < 0.001).　The median change rate of Choi score was 32.9% (IQR, 6.80–62.1). Radical nephrectomy was performed in the majority of patients, while one patient with solitary kidney who achieved marked tumor shrinkage underwent partial nephrectomy. Thirty-two patients had pure clear cell carcinoma; 5 had mixed clear cell carcinoma with sarcomatoid or papillary components; 3 had chromophobe carcinoma; and 3 achieved pCR.

Changes in the tumor-bearing renal artery diameter after systemic therapy

The median inner diameter significantly decreased after treatment (p < 0.001, n = 43, Fig. 4A). Similarly, the median outer diameter significantly decreased (p < 0.001, n = 37, Fig. 4B). The wall thickness significantly increased (p = 0.049, n = 37, Fig. 4C). The median percent change in tumor-bearing inner diameter was 10.7% (IQR, 3.59–21.5). A representative case demonstrating marked reduction in the tumor-bearing renal artery diameter after systemic therapy is shown in Fig. 5.

Fig. 4.

Changes in renal artery diameter on the tumor-bearing side after systemic therapy. Comparison of renal artery measurements before and after systemic therapy in 43 patients. Excluded from outer diameter and wall thickness analyses due to multiple renal arteries (n = 6). (A) renal arterial inner diameter decreased from a median of 6.35 mm (IQR 5.31–7.31) to 5.65 mm (IQR 4.84–6.64), corresponding to a median absolute reduction of 0.70 mm and a relative reduction of 10.7% (IQR, 3.59–21.5). (B) outer diameter also showed a significant reduction following therapy.(C) wall thickness significantly increased after treatment, indicating vascular changes

Fig. 5.

Representative case demonstrating marked renal artery diameter reduction after systemic therapy. A representative case of metastatic renal cell carcinoma treated with lenvatinib plus pembrolizumab, including thyroid metastasis, who achieved pathological complete response (pCR) after 9 months of systemic therapy. (A) pre-treatment axial contrast-enhanced CT image demonstrating the primary renal tumor at baseline. (B) post-treatment axial contrast-enhanced CT image after 9 months of systemic therapy, showing tumor shrinkage (23% reduction in maximal diameter). (C) pre-treatment curved planar reformation (CPR) image of the tumor-bearing renal artery, illustrating the arterial centerline and measurement of the inner diameter at baseline (5.50 mm). (D) post-treatment CPR image of the same renal artery after systemic therapy, demonstrating marked reduction of the inner diameter to 3.82 mm, corresponding to a 30.4% decrease

Arterial diameter change and radiologic response

A significant positive correlation was observed between the percentage reduction in tumor-bearing renal artery inner diameter and radiologic tumor response rate (Spearman’s correlation coefficient r = 0.527, p < 0.001, Fig. 6A). In contrast, no significant correlation was found between the percentage change rate of Choi score and arterial diameter reduction (r = 0.215, p = 0.167).

Fig. 6.

Correlation between renal artery diameter reduction and radiologic tumor response and pathological response. (A) percentage reduction in inner diameter of the tumor-bearing renal artery showed a significant positive correlation with radiologic tumor shrinkage assessed by RECIST 1.1. (B) percentage reduction in inner diameter of the tumor-bearing renal artery correlated positively with pathological response rate. (C) percentage change in Choi score was positively associated with pathological response rate. (D) post-treatment Choi score demonstrated a significant negative correlation with pathological response rate

Correlation with pathological response

Pathological evaluation revealed variable degrees of treatment-induced tumor necrosis. The percentage reduction in tumor-bearing renal artery inner diameter showed a significant positive correlation with pathological response rate (r = 0.310, p = 0.040, Fig. 6B). We also observed a significant positive correlation between the change of Choi score and pathological response rate (r = 0.351, p = 0.021, Fig. 6C), and negative correlation between the post-treatment Choi score and pathological response rate (r = −0.561, p < 0.001, Fig. 6D). In contrast, no significant correlation was found between the radiological response rate and pathological response rate (r = 0.272, p = 0.078). Multiple regression analysis confirmed post-treatment Choi score and inner diameter change rate as independent predictors of pathological response rate after accounting for the presence of hypertension and the duration of treatment before surgery (Table 2). Patients who achieved pathological downstaging demonstrated significantly greater arterial diameter reduction compared with those without downstaging (16.3% vs. 6.83%, p = 0.021, Fig. 7A). ROC analysis demonstrated a moderate ability of renal artery caliber reduction to discriminate pathological downstaging, with an AUC of 0.71 (95% confidence interval, 0.54–0.87, Fig. 7B). The exploratory cutoff value for percentage reduction in renal artery caliber was 10.0%, as determined by the Youden index. The sensitivity and specificity for pathological downstaging were 70.8% and 68.4%, respectively. In a sensitivity analysis including time to nephrectomy, renal artery caliber reduction of ≥10% remained significantly associated with pathological downstaging (odds ratio, 6.96; 95% confidence interval, 1.78–27.3; p = 0.005), whereas duration of systemic therapy prior to surgery was not.

Table 2.

Multiple regression analysis for the pathological response

Variable	Standardized β	P value
Choi score after treatment	−0.56	<0.001
Duration of medication before surgery	0.16	0.210
Hypertension	0.08	0.570
Change rate of inner diameter	0.31	0.025

Fig. 7.

Association between renal artery diameter reduction and pathological downstaging. (A) patients who achieved pathological downstaging (pT < cT) showed significantly greater renal artery diameter reduction compared with those without downstaging. (B) ROC analysis demonstrated a moderate ability of renal artery caliber reduction to discriminate pathological downstaging

Discussion

In this exploratory study, we found that tumor-bearing renal arteries exhibited distinct baseline characteristics compared with contralateral arteries, and that systemic therapy for locally advanced or mRCC induced measurable changes in tumor-bearing renal arteries, assessed using reliable, clinically available software. Reduction in tumor-bearing renal arterial diameter correlated significantly with radiologic tumor shrinkage, pathological response.

We observed a significant difference in the inner arterial diameter and the wall thickness between the tumor-bearing side and the contralateral side at baseline. RCC is characterized by dysregulated angiogenesis driven primarily by VEGF signaling pathways [21]. This angiogenic phenotype leads to increased intratumoral blood flow and altered vascular dynamics [22]. In the present study, the tumor-bearing renal artery exhibited a larger luminal diameter and thinner vessel wall at baseline compared with the contralateral side. This likely reflects adaptive arterial dilation in response to increased downstream blood flow demand from RCC [23].

Two potential mechanisms may explain the observed post-treatment arterial narrowing on the tumor-bearing side. First, effective systemic therapy may induce tumor necrosis, fibrosis, and reduction in viable tumor mass, leading to decreased downstream perfusion and metabolic demand. Pathological studies have demonstrated marked reductions in intratumoral microvessel density following VEGF-targeted therapy [15]. From a physiological standpoint, sustained reductions in blood flow demand may induce structural remodeling of upstream feeding arteries [24]. Alternatively, a direct pharmacologic effect on the arterial wall cannot be excluded. TKIs and IO-based therapies are associated with systemic vascular effects, including changes in vascular tone [25]. A preclinical study demonstrated that sunitinib induced vascular remodeling with collagen deposition and wall thickening in rat aortas, accompanied by endothelial dysfunction and oxidative stress [26]. Our two representative cases may illustrate heterogeneous vascular responses to systemic therapy. In the first case, a marked reduction in the diameter of the tumor-bearing renal artery was accompanied by prominent structural remodeling of the intrarenal arterial wall, despite the absence of hypertension or other systemic vascular complications (Figure S3A). In contrast, the second case showed only a modest reduction in renal arterial diameter with limited arterial wall remodeling, although treatment-related hypertension and nephrotic syndrome developed during therapy (Figure S3B). These contrasting patterns suggest that arterial caliber reduction in tumor-bearing kidneys might reflect localized vascular remodeling because of systemic therapy. These findings may support the hypothesis that treatment-induced renal arterial changes represent vascular remodeling rather than transient functional vasoconstriction. In the contralateral artery, a significant increased wall thickness without consistent caliber reduction was observed (Table S1).　The pattern of the changes in the contralateral artery is consistent with vascular remodeling characterized by significant arterial wall thickening without an increase in intraluminal diameter, as previously reported in healthy rats treated with sunitinib [26]. However, these interpretations remain speculative, as no histological assessment of the main renal artery was performed, and further validation in prospective studies incorporating standardized imaging and, where feasible, histopathological correlation is warranted.

Our findings may suggest that treatment-induced changes in the diameter of the tumor-bearing renal artery may have potential clinical implications. Notably, percentage reduction in renal artery diameter showed a strong correlation with radiological tumor response and significantly differed according to pathological downstaging status (p = 0.021, Fig. 7A). In contrast, conventional radiological metrics, including RECIST response (p = 0.845), Choi percentage change (p = 0.951), and post-treatment Choi score (p = 0.633) did not have significant difference between downstaged and non-downstaged tumors (Figure S4). Importantly, arterial diameter reduction remained independently associated with pathological response even after adjustment for post-treatment Choi score, suggesting that changes in the tumor-bearing renal artery diameter might provide complementary information beyond attenuation–based metrics. Although the number of patients achieving pCR was limited, all pCR cases demonstrated marked arterial diameter reduction exceeding 30% (Table S2), corresponding to approximately 3 times the median reduction observed in the overall cohort. Notably, pCR was observed in patients treated with IO–IO, IO–TKI, and TKI monotherapy, and all such cases demonstrated > 30% reduction in arterial diameter. Marked arterial narrowing may reflect profound treatment response irrespective of therapeutic class. Similar treatment-induced arterial caliber changes have been reported in hepatocellular carcinoma, where shrinkage of tumor-feeding hepatic arteries reflected treatment responses after anti-angiogenic and locoregional therapies [16]. These findings support the concept that vascular remodeling of feeding arteries may represent a shared response in hypervascular tumors. In this context, our observation suggests that such imaging-based vascular changes may not be specific to renal cell carcinoma, but could potentially be applied to the evaluation of treatment response in other hypervascular malignancies. Clinically, treatment-induced changes in the caliber of the tumor-bearing renal artery may provide complementary information for decision-making after systemic therapy. Marked arterial diameter reduction may support continuation of the current regimen and consideration of surgical intervention, whereas limited vascular change may prompt reassessment of treatment efficacy or surgical timing, particularly when conventional imaging criteria are inconclusive.

We also investigated disease progression analysis after surgery on 40 patients with ≥6 months postoperative follow-up (median follow-up duration: 35 months) in additional analyses. Despite its association with radiologic and pathological response, attenuation–based metrics and renal artery diameter change were not predictors of PFS (Table S3) and overall survival (data not shown) in this study. While a study has suggested utility of combined Choi and RECIST criteria for predicting PFS and overall survival, results have been limited by small sample sizes and marginal statistical significance [17]. Actual pathological parameters such as pT stage and microvascular invasion may be more reliable prognostic predictors than radiological imaging biomarkers [27]. Preoperative imaging biomarkers may provide complementary short-term response assessment rather than long-term survival prediction. Also, the lack of a significant link between arterial caliber change and prognosis in our analysis may derive from this selection bias. Therefore, our future studies should focus on investigating all patients with RCC receiving systemic therapy are warranted to explore whether these vascular changes may have prognostic relevance.

A strength of this study is the high reproducibility and practical feasibility of renal artery caliber measurement using CPR. Interobserver agreement was excellent, with minimal variability observed regardless of clinical experience level. The measurement process is technically straightforward and can be completed within a few minutes using a standardized workstation. These findings indicate that renal artery caliber assessment is simple, rapid, and highly reproducible, and may be readily incorporated into routine preoperative imaging workflows.

Several limitations of this study should be acknowledged. First, the cohort consisted exclusively of patients who proceeded to nephrectomy after systemic therapy, which likely enriched the population for a specific subset of responders. Therefore, selection bias is inherent, and the findings may not be generalizable to non-surgical advanced RCC populations. Second, because of the retrospective design, CT parameters were not fully standardized. In addition, formal sensitivity analyses were not performed due to the limited sample size and heterogeneity in CT acquisition protocols over time, which would have rendered such analyses underpowered and potentially unreliable.　Future studies should be prospectively designed with predefined imaging schedules, standardized arterial-phase thin-slice CT acquisition, and independent external validation in separate datasets to confirm reproducibility and clinical utility. Third, heterogeneity in systemic therapy regimens and treatment duration, may have influenced vascular responses. Given the small number of IO-based cases in this cohort, treatment-stratified sensitivity analyses were not feasible, and this observation should therefore be interpreted cautiously. In addition, the cutoff value for percentage reduction in renal artery caliber should be interpreted as exploratory, given the limited sample size and single-center design. Fourth, the timing and interval of CT imaging before and after systemic therapy were not uniform across patients. Differences in treatment duration and imaging intervals may have affected the magnitude of observed arterial diameter changes. Fifth, patients with multiple renal arteries were included in the primary analyses but were excluded from the contralateral comparative analysis due to the inability to standardize bilateral assessment. In addition, capturing dynamic changes across multiple arterial branches may be technically challenging and could introduce variability in representative diameter estimation. Therefore, findings in patients with multiple renal arteries should be interpreted with caution. Sixth, although the presence of sarcomatoid differentiation is associated with more aggressive tumor biology, the number of cases with sarcomatoid features was limited [28, 29], precluding meaningful subgroup analysis. Therefore, the potential impact of histological variants on arterial caliber change could not be evaluated. In addition, distinguishing treatment-induced necrosis and fibrosis from pre-existing tumor necrosis is inherently challenging, particularly in hypervascular tumors. Therefore, although tumor necrosis and fibrosis were evaluated as treatment-related changes in line with prior studies [13, 30], these findings may not be exclusively attributable to systemic therapy. Finally, our findings and previous studies imply adaptive vascular remodeling rather than transient vasoconstriction. However, histopathological confirmation of the main renal artery is needed to definitively distinguish structural from functional changes.

Conclusions

Tumor-bearing renal arteries exhibited distinct baseline characteristics compared with contralateral arteries in patients with locally advanced or metastatic RCC. Renal artery diameter change after systemic therapy was associated with radiologic and pathological response. The observed pattern is consistent with treatment-related vascular adaptation; however, mechanistic interpretation should remain cautious. These findings should not be generalized beyond RCC or the CT conditions used in this study. This exploratory study is hypothesis-generating and suggests that vascular change assessment may serve as a complementary imaging marker in selected patients receiving systemic therapy.

Electronic supplementary material

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Abbreviation

CI

Confidence Interval

CPR

Curved Planar Reformation

CT

Computed Tomography

CVD

Cardiovascular disease

HU

Hounsfield Units

ICC

Intraclass Correlation Coefficient

IO

Immunotherapy

IQR

Interquartile Range

mRCC

Metastatic Renal Cell Carcinoma

pCR

Pathological Complete Response

PFS

Progression-Free Survival

RCC

Renal Cell Carcinoma

RECIST

Response Evaluation Criteria in Solid Tumors

SD

Standard Deviation

TKI

Tyrosine Kinase Inhibitor

VEGF

Vascular Endothelial Growth Factor

Authors’ contributions

Conceptualization: Teppei Okamoto; Data curation: Teppei Okamoto, Himawari Asauma, Takuya Oishi, Tadashi Yoshizawa, Tohru Yoneyama; Formal analysis and investigation: Teppei Okamoto, Tadashi Yoshizawa; Writing - original draft preparation: Teppei Okamoto, Himawari Asanuma; Editing, Tomoko Hamaya, Hirotake Kodama, Takuma Narita, Jotaro Mikami, Naoki Fujita, Hayato Yamamoto, Atsushi Imai, Tadashi Yoshizawa, Tohru Yoneyama; Supervision: Shingo Hatakeyama and Chikara Ohyama.

Funding

None.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

We followed an opt-out consent approach in accordance with ethical guidelines. Patient data were collected and analyzed to investigate the long-term prognosis. All data used in this study were anonymized and stripped of any personally identifiable information to ensure strict patient confidentiality in accordance with applicable regulations. This study was approved by the ethics review board of Hirosaki University School of Medicine (approval no. 2019–099-3)

Declaration of generative AI and AI-assisted technologies in the writing process

During the preparation of this work the authors used ChatGPT (OpenAI) in order to revise and edit English grammar. After using this tool, the author reviewed and edited the content as needed and take full responsibility for the content of the publication.

Consent for publication

We obtained consents from two individuals to use their histopathological pictures.

Competing interests

The authors declare no competing interests.