Among patients with nonmetastatic renal cell carcinoma (RCC), up to 20 to 30% suffer recurrence after curative surgery [
Recently, researchers have been focusing on the prognostic value of a preoperative aspartate aminotransaminase (AST)/alanine aminotransaminase (ALT) (De Ritis) ratio in patients with nonmetastatic RCC who underwent radical nephrectomy [
Both previous studies, however, focused on preoperative AST/ALT ratio alone, and the prognostic value of postoperative and pre-to-postoperative dynamics of the AST/ALT ratio remains unexplored. We hypothesized that dynamic features of the pre- and postoperative AST/ALT ratio can have a prognostic value, given the prognostic effect of the preoperative AST/ALT ratio. Here, we evaluated the potential prognostic significance of pre-to-postoperative dynamics of the AST/ALT ratio on survival in patients with RCC who underwent radical nephrectomy.
We collected and reviewed the clinicopathological data of 785 patients with RCC who underwent radical nephrectomy between October 1996 and December 2012 at Samsung Medical Center. Among these, 115 patients were excluded from our analysis for the following reasons: synchronous metastasis (
Clinical data on age at surgery, sex, height, weight, and body mass index (BMI) were recorded at admission for operation. An abdomen and pelvis computed tomography (CT) scan and a chest CT scan were performed before surgery in all patients to assess the status of regional lymph nodes and the presence of distant metastases. Aminotransaminase (AST/ALT) levels were measured within 1 month prior to surgery and 6 months after surgery. The median preoperative AST/ALT ratio was 1.00 and the postoperative AST/ALT ratio was 1.12, respectively. The cutoff points for preoperative and postoperative AST/ALT ratios were assigned based on the median values of each. To evaluate the prognostic impact of the dynamics of the pre-to-postoperative AST/ALT ratio on survival outcomes, we classified patients into four different groups according to the dynamics of AST/ALT ratios between preoperative and postoperative status as follows: group 1 (lower (≤1.0) to lower (≤1.12) level), group 2 (lower (≤1.0) to higher (>1.12)), group 3 (higher (>1.0) to lower (≤1.12)), and group 4 (higher (>1.0) to higher (>1.12)).
Tumor size was defined as the longest dimension of the tumor in preoperative CT images. The assessment of pathology was performed by experienced pathologists at our center. Tumor stage was classified by the American Joint Committee on Cancer/Union for International Cancer Control TNM system [
The primary endpoint was overall survival following radical nephrectomy. The secondary endpoint was cancer-specific survival after surgery. All patients were routinely followed up according to the standard protocol in our institution. We assessed medical history, physical examinations, laboratory tests, and imaging screening, such as an abdomen and pelvis CT scan and/or a chest CT scan, at intervals of 3 to 6 months during the first 2 years, and yearly thereafter. Death information for all patients was collected based on the vital record data of our institution, which incorporated data from the Korean National Statistical Office.
Descriptive analysis of demographic and clinicopathological variables was performed. Data are shown as median values with interquartile range (IQR) or by the frequency of relevant events. For group comparisons according to dynamics of the AST/ALT ratio, we used a chi-square test for categorical variables and the Mann-Whitney
We estimated and compared survival outcomes between groups using Kaplan-Meier survival analysis with a log-rank test. Multivariate Cox proportional hazards regression analysis was performed to identify the predictors of survival outcomes after adjusting for potential confounding factors.
The results are described as hazard ratios (HR) with 95% confidence intervals (CI).
Table
Baseline demographics of patients with renal cell carcinoma following radical nephrectomy.
Clinicopathological variables | |
---|---|
No. of patients | 670 |
Age at surgery | |
Median (yr) | 55 (48–64) |
<60 years | 411 (61.3) |
≥60 years | 259 (38.7) |
Sex | |
Male | 473 (70.6) |
Female | 197 (29.4) |
BMI (kg/m2) | |
Median | 24.5 (22.4–28.6) |
<25 | 370 (55.2) |
≥25 | 300 (44.8) |
Preoperative AST/ALT ratio | |
Median | 1.00 (0.79–1.27) |
≤1.00 (lower) | 317 (47.3) |
>1.00 (higher) | 353 (52.7) |
Postoperative AST/ALT ratio | |
Median | 1.12 (0.86–1.36) |
≤1.12 (lower) | 341 (50.9) |
>1.12 (higher) | 329 (49.1) |
AST/ALT dynamics (pre-to-postoperative) | |
Lower → lower | 228 (34.0) |
Lower → higher | 89 (13.3) |
Higher → lower | 114 (17.0) |
Higher → higher | 239 (35.7) |
Laterality | |
Left | 322 (48.1) |
Right | 348 (51.9) |
Tumor size (cm) | |
Median | 5.0 (3.9–6.5) |
<7.0 | 546 (81.5) |
≥7.0 | 124 (18.5) |
Histology | |
Clear cell | 573 (85.5) |
Nonclear cell | 93 (13.9) |
|
|
pT stage | |
pT1–2 | 520 (77.6) |
pT3–4 | 150 (22.4) |
Fuhrman grade | |
Low (grade 1–2) | 198 (29.6) |
High (grade 3–4) | 461 (68.8) |
|
|
Survival outcomes | |
All-cause death | 108 (16.1) |
Cancer-specific death | 78 (11.6) |
Median F/U duration (mon) | 59 (41–81) |
Based on pre-to-postoperative dynamics of the AST/ALT ratio, the number of patients in group 1 (lower (≤1.0) ⟶ lower (≤1.12)), group 2 (lower (≤1.0) ⟶ higher (>1.12)), group 3 (higher (>1.0) ⟶ lower (≤1.12)), and group 4 (higher (>1.0) ⟶ higher (>1.12)) was 228 (34.0%), 89 (13.3%), 114 (17.0%), and 239 (35.7%), respectively. Table
Figures
Kaplan-Meier analysis for estimating CSS according to various types of the De Ritis ratio.
Kaplan-Meier analysis for estimating OS according to various types of the De Ritis ratio.
More importantly, multivariate analysis revealed that the postoperative AST/ALT ratio (hazard ratio, HR: 1.88, 95% CI: 1.18–2.99) and pre-to-postoperative dynamics of the AST/ALT ratio (HR: 3.45, 95% CI: 1.73–6.88) remained as significant prognostic factors for CSS, in addition to tumor size (HR: 4.23, 95% CI: 2.66–6.72) and pT stage (HR: 2.45, 95% CI: 1.53–3.94) (Table
Multivariate Cox regression analyses to identify predictors for cancer-specific survival in patients with renal cell carcinoma following radical nephrectomy.
Variables | Univariate | Multivariate | ||||
---|---|---|---|---|---|---|
Hazard ratio | 95% CI |
|
Hazard ratio | 95% CI |
| |
Age at surgery | ||||||
<60 years | Reference | |||||
≥60 years | 1.22 | 0.77–1.92 | 0.382 | |||
Sex | ||||||
Male | Reference | |||||
Female | 0.65 | 0.38–1.12 | 0.128 | |||
BMI (kg/m2) | ||||||
<25 | Reference | Reference | ||||
≥25 | 0.53 | 0.32–0.85 | 0.009 | 0.64 | 0.39–1.06 | 0.082 |
Preoperative AST/ALT ratio | ||||||
≤1.00 (lower) | Reference | |||||
>1.00 (higher) | 1.21 | 0.77–1.88 | 0.411 | |||
Postoperative AST/ALT ratio | ||||||
≤1.12 (lower) | Reference | Reference | ||||
>1.12 (higher) | 1.64 | 1.04–2.59 | 0.031 | 1.88 | 1.18–2.99 | 0.008 |
AST/ALT dynamics | ||||||
Lower → lower | Reference | Reference | ||||
Lower → higher | 3.37 | 1.71–6.64 | <0.001 | 3.45 | 1.73–6.88 | <0.001 |
Higher → lower | 2.34 | 1.17–4.69 | 0.016 | 1.70 | 0.83–3.46 | 0.145 |
Higher → higher | 1.81 | 0.96–3.41 | 0.064 | 1.75 | 0.92–3.31 | 0.087 |
Tumor size | ||||||
<7 cm | Reference | Reference | ||||
≥7 cm | 4.78 | 3.06–7.48 | <0.001 | 4.23 | 2.66–6.72 | <0.001 |
Histology | ||||||
Clear cell | Reference | |||||
Nonclear cell | 0.97 | 0.49–1.88 | 0.927 | |||
pT stage | ||||||
pT1–2 | Reference | Reference | ||||
pT3–4 | 3.50 | 2.24–5.46 | <0.001 | 2.45 | 1.53–3.94 | <0.001 |
Fuhrman grade | ||||||
Low | Reference | Reference | ||||
High | 2.43 | 1.31–4.50 | 0.005 | 1.72 | 0.91–3.29 | 0.096 |
Multivariate Cox regression analyses to identify predictors for overall survival in patients with renal cell carcinoma following radical nephrectomy.
Variables | Univariate | Multivariate | ||||
---|---|---|---|---|---|---|
Hazard ratio | 95% CI |
|
Hazard ratio | 95% CI |
| |
Age at surgery | ||||||
<60 years | Reference | Reference | ||||
≥60 years | 2.16 | 1.48–3.16 | <0.001 | 2.03 | 1.36–3.02 | 0.008 |
Sex | ||||||
Male | Reference | |||||
Female | 0.63 | 0.39–1.01 | 0.052 | |||
BMI (kg/m2) | ||||||
<25 | Reference | Reference | ||||
≥25 | 0.61 | 0.41–0.91 | 0.014 | 0.68 | 0.45–1.03 | 0.068 |
Preoperative AST/ALT ratio | ||||||
≤1.00 (lower) | Reference | |||||
>1.00 (higher) | 1.17 | 0.80–1.71 | 0.414 | |||
Postoperative AST/ALT ratio | ||||||
≤1.12 (lower) | Reference | Reference | ||||
>1.12 (higher) | 1.51 | 1.03–2.21 | 0.034 | 1.43 | 0.96–2.13 | 0.074 |
AST/ALT dynamics | ||||||
Lower → lower | Reference | Reference | ||||
Lower → higher | 2.41 | 1.36–4.25 | 0.002 | 2.18 | 1.23–3.89 | 0.008 |
Higher → lower | 1.74 | 0.97–3.10 | 0.062 | 1.19 | 0.65–2.17 | 0.571 |
Higher → higher | 1.57 | 0.95–2.60 | 0.077 | 1.24 | 0.74–2.08 | 0.417 |
Tumor size (cm) | ||||||
<7 | Reference | Reference | ||||
≥7 | 3.12 | 2.09–4.62 | <0.001 | 2.91 | 1.93–4.40 | <0.001 |
Histology | ||||||
Clear cell | Reference | |||||
Nonclear cell | 1.09 | 0.63–1.88 | 0.759 | |||
pT stage | ||||||
pT1–2 | Reference | Reference | ||||
pT3–4 | 3.11 | 2.12–4.56 | <0.001 | 2.20 | 1.47–3.28 | <0.001 |
Fuhrman grade | ||||||
Low | Reference | Reference | ||||
High | 1.17 | 1.10–2.83 | 0.018 | 1.29 | 0.79–2.12 | 0.303 |
A number of studies have been conducted on the prognostic factors that predict high-risk RCC patients. Leibovich et al. developed a prognosis score that stratifies the risk of progression to metastasis after radical nephrectomy [
AST is widely synthesized in different types of tissues, whereas synthesis of ALT is thought to be more liver specific [
Recently published articles have addressed the prognostic significance of the preoperative AST/ALT (De Ritis) ratio on prognosis in nonmetastatic RCC after surgery [
However, underlying liver disease or other malignancies could be confounding factors that influence the metabolism of both AST and ALT [
To the best of our knowledge, this study is the first to suggest the prognostic value of the dynamics of the pre-to-postoperative AST/ALT ratio in localized RCC patients following radical nephrectomy. With regard to the preoperative AST/ALT ratio, Bezan et al. suggested that the elevated aerobic glycolysis and pyruvate production in tumor cells, which is the Warburg effect, was the key biological mechanism of the poor survival outcomes in patients with elevated De Ritis ratio [
In our results, patients in group 2 (lower (≤1.0) ⟶ higher (>1.12)) showed significantly worse oncological outcomes compared to the other groups. Considering there were no significant differences in tumor size, pT stage, and Fuhrman grade between the four groups, these results indicate that the pre-to-postoperative dynamics of the AST/ALT ratio can be a valuable prognostic marker in patients with RCC who were treated by surgery. Interestingly, patients with an increased AST/ALT ratio (lower ⟶ higher) had poorer prognosis than those with a persistently elevated AST/ALT ratio (higher ⟶ higher). Based on these findings, we assume that an increasing tendency of the AST/ALT ratio from the preoperative basement, rather than the AST/ALT ratio itself, is more closely related to worse survival outcomes, even in those with a higher postoperative AST/ALT ratio.
We acknowledged that our study has several limitations. First, our findings should be interpreted in the context of the retrospective design, which might possess an inherent structural bias. However, we performed consecutive patient sampling to reduce selection bias and tried to obtain patients’ information as completely as possible. Second, our study only included patients that underwent radical nephrectomy, and therefore, a distinction to those who are treated by nephron-sparing surgery should be examined in a further study. Third, we did not adjust the analyses for potentially confounding factors such as liver diseases or other metabolic conditions that may significantly impact on the levels of aminotransferase and therefore on the AST/ALT ratio. Fourth, we did not conduct a subanalysis based on histological types of RCC. Fifth, patients with disease progression underwent different kinds of salvage therapies according to their treating clinicians and timing, which may have influenced survival outcomes. Additionally, our dataset lacks additional information known to be associated with poor prognosis at presentation such as performance status, the comorbidity status, and other clinical variables such as calcium, hemoglobin, platelet, and neutrophil counts. Finally, our study was based on only Korean patients and should be validated before the results can be applied to other racial groups.
In conclusion, our data revealed that the postoperative AST/ALT ratio was identified as a better prognostic factor for survival than the preoperative AST/ALT ratio in patients who were surgically treated for nonmetastatic RCC. Furthermore, the pre-to-postoperative dynamics of the AST/ALT ratio have prognostic significance for postoperative survival in these patients, particularly in those with lower preoperative to higher postoperative AST/ALT ratio. Our findings suggest the potential use of this simple serum marker, particularly dynamics of pre-to-postoperative status, as a valuable prognostic factor of survival outcomes after radical nephrectomy in patients with nonmetastatic RCC.
Renal cell carcinoma
Aspartate aminotransaminase
Alanine aminotransaminase
Cancer-specific survival
Overall survival
Body mass index
Computed tomography
Interquartile range
Hazard ratios
Confidence intervals.
Data are available on request.
This retrospective study was approved by the Samsung Medical Center institutional review board (approval number: SMC 2018-09-001).
All of the details can be published, and consent for publication was not required for the present study. The IRB at our institution waived the requirement for written informed consents from patients due to the retrospective nature of the current study.
The authors have no conflicts of interest in this study to report.
MK, SJS, and SIS designed the study. MK and SJS wrote the manuscript. MK, SJS, and SIS performed the statistical analyses. All authors interpreted and collected the data, contributed to the interpretation of analyses, and approved the manuscript. Minyong Kang and Seung Jea Shin contributed equally as first authors of this article (co-first authors).
This study was supported by a research grant from the National Research Foundation (NRF) of Korea, funded by the Ministry of Science and ICT (2018M3A9H1078336). This study was also funded by Samsung Medical Center (SMC) Research and Development Grant (#OTC1190501).
Table S1: Comparison of clinicopathological characteristics of patients with renal cell carcinoma following radical nephrectomy according to pre-to-postoperative AST/ALT dynamics.