De Ritis Ratio (Aspartate Transaminase/Alanine Transaminase) as a Significant Prognostic Factor With Upper Urinary Tract Carcinoma Who Underwent Radical Nephroureterectomy and Adjuvant Chemotherapy

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J Urol Oncol. 2022;20(1):34-42

Publication date (electronic) : 2022 February 24

doi : https://doi.org/10.22465/kjuo.2022.20.1.34

Jee Hwan Yoon¹, Chang Wook Jeong¹, Cheol Kwak¹, Hyeon Hoe Kim¹, Ja Hyeon Ku¹, Ji Hyeong Yu^2,, Hyeong Dong Yuk^1,

¹Department of Urology, Seoul National University Hospital, Seoul, Korea

²Department of Urology, Inje University Sanggye Paik Hospital, Seoul, Korea

Corresponding author: Ji Hyeong Yu Email: uroone@paik.ac.kr

Co-corresponding author: Hyeong Dong Yuk Email: armenia8@snu.ac.kr

Received 2021 October 11; Revised 2021 October 28; Accepted 2021 November 09.

Abstract

INTRODUCTION

Upper urinary tract carcinoma (UTUC) is a malig- nant tumor of the urothelium of the urinary tract from calyx to distal ureter.¹ UTUC is relatively uncommon, and represents only 5%–7% of the tumors that develop in the kidneys.¹ UTUC accounts for approximately 5%–10% of all genitourinary malignancies.¹ The disease has a multifocal nature and is diagnosed twice as often in the renal pelvis, as in the ureters.² The standard treatment for localized UTUC is a radical nephroureterectomy (RNU), with bladder cuff excision.³ RNU series studies performed in the last years have shown that the proportion of locally advanced UTUC is about 60%, the proportion of high-grade tumors is about 70%, and that the proportion of aggressive disease is increasing.⁴ The 5-year survival rate of UTUC is 20%, and the prognosis is relatively poor.⁵ For these advanced UTUCs, adjuvant chemo- therapy (ACH) is recommended to improve long- term prognosis.⁶ However, some advanced UTUC patients progress or the disease recurs to a distant metastasis site.⁷ About 7% of patients experience metastatic disease.⁸ It is important to accurately predict oncologic outcomes and to properly classify patients at risk for progression or recurrence, to perform additional salvage treatments. For this reason, prognostic factors of survival before treatment are clinically important. We have focused on alanine aminotransferase (ALT) and aspartate aminotransferase (AST), among the many pretreatment predictive factors. ALT and AST are liver enzymes commonly used in different clinical fields, and have been reported in several studies as important biomarkers in various malignant tumors, such as kidney cancer, lung cancer, pan- creatic cancer, and colorectal cancer, as well in as chronic liver disease.^9–12 Recent studies have also shown that UTUC was useful as a preoperative predictor.^13–15 However, no studies have been reported on the role of AST and ALT as prognostic factors in patients with end-stage UTUC, who received ACH. Therefore, we aimed to identify the prognostic significance of AST and ALT before ACH, in patients with UTUC who underwent RNU and ACH.

MATERIALS AND METHODS

RESULTS

The clinicopathologic characteristics of all patients are shown in Table 1. Patients were divided into 2 groups based on an AST/ALT ratio of 1.2. Mean age was 61.4 years and mean AST/ALT ratio was 1.2. Overall mortality was 47.7%, cancer-specific mortality was 44.3%, and mean survival time was 50.5 months. Twenty-eight percent of patients experienced recurrence within the bladder during follow-up. In the high AST/ALT group, the mean age was 64.1 years (p=0.015), the mean mortality rate was 65.9% and the cancer-specific mortality rate was 61.0% (p=0.003 and p=0.006), higher than the low AST/ALT group. The mean survival time of the high AST/ALT group was 40.4 months (p=0.020), which was shorter than the low AST/ALT group. Overall survival (OS) was poor in the high AST/ALT group compared to the low AST/ALT group (p=0.007), and the cancer-specific survival was also poor in the high AST/ALT group, compared to the low AST/ALT group (p=0.011) (Fig. 1).

Table 1.

Clinicopathological characteristics of patients before and after propensity score matching

Fig. 1.

Overall and cancer-specific survival analyses. Kaplan-Meier survival curves comparing overall and cancer-specific survivals according to the aspartate aminotransferase/alanine aminotransferase (AST/ALT).

In multivariate analysis, age (hazard ratio [HR], 1.041; 95% confidence interval [CI], 1.003–1.074; p=0.039), pT3 or higher (HR, 1.464; 95% CI, 1.156–1.857; p=0.002), LVI (HR, 1.445; 95% CI, 1.153–1.854; p=0.005), pN1-N2 (HR, 1.342; 95% CI, 1.011–1.773), pN3 (HR, 3.893; 95% CI, 2.284–6.648; p<0.001), high AST/ALT ratio (HR, 5.428; 95% CI, 1.803–16.334; p=0.002), were significant predictors of poor OS. And pT3 or higher (HR, 1.475; 95% CI, 1.172–1.904; p=0.002), pN3 (HR, 3.815; 95% CI, 2.235–6.493; p<0.001), high AST/ALT ratio (HR, 4.417; 95% CI, 1.545–12.632; p=0.005) were significant predictors of poor cancer-specific sur- vival (CSS) (Table 2).

Table 2.

Multivariate Cox proportional hazards analyses of the AST/ALT ratio on overall survival and cancer-specific survival

After propensity score matching, the overall mortality rate was significantly higher (65.9% vs. 34.1%) in the high AST/ALT group (p=0.008) and the cancer-specific mortality rate were also significantly higher (61.0% vs. 31.7%) in the high AST/ALT group (p=0.015) than in the low AST/ALT group (Table 1). The multivariate Cox analysis showed that a high prechemotherapy AST/ALT ratio was a significant independent predictor of poor prognosis such as OS (HR, 2.095; 95% CI, 1.090–4.024; p=0.026), CSS (HR, 2.074; 95% CI, 1.053–4.086; p=0.035) (Table 3). In addition, pathologic T stage, N stage, positive surgical margin are also associated with poor prognosis (Table 3).

Table 3.

Multivariate Cox proportional hazards analyses of the AST/ALT ratio on overall survival and cancer-specific survival after propensity score matching

DISCUSSION

In this study, we evaluated patients with increa- sed AST/ALT. We observed poor survival outcomes after ACH for advanced UTUC. The AST/ALT ratio was a predictor of OS (HR, 5.428; 95% CI, 1.803–16.334; p=0.002) and CSS (HR, 4.417; 95% CI, 1.545–12.632; p=0.005). Previous studies on UTUC have also reported that the AST/ALT ratio is a predictor of oncological prognosis.^13–15 Lee et al.¹⁴ reported that preoperative high AST/ALT ratio was significantly associated with a poor prognosis of progression-free survival (PFS), CSS, and OS (all p<0.001) in 263 UTUC patient who underwent RNU. They also reported that a high preoperative AST/ALT ratio greater than 1.5 was an independent predictor of PFS (HR, 2.335; 95% CI, 1.633–3.340; p=0.001), CSS (HR, 2.550; 1.689–3.851; p=0.001), and OS (HR, 2.069; 95% CI, 1.409–3.038; p<0.001) through Cox multivariate analysis.¹⁴ Cho et al.¹³ reported that a high preoperative AST/ALT ratio was significantly associated with a poor prognosis of CSS and OS (all p=0.001), in a multicenter study of 1,049 patients who underwent RNU. They also reported that a preoperative AST/ALT ratio higher than 1.6 was an independent predictor of CSS (HR, 2.49; 95% CI, 1.70–3.64; p=0.001) and OS (HR, 1.84; 95% CI, 1.34–2.52; p=0.001) through Cox multivariate analysis.¹³ In Nishikawa's study of 109 patients with localized UTUC who underwent RNU, a high AST/ALT was significantly independent of extravesical recurrence-free survival (HR, 4.21; 95% CI, 1.95–9.08; p<0.001). In a study of 153 patients with urothelial bladder cancer who underwent radical cystectomy, Gorgel et al.¹⁶ reported that the preoperative AST/ALT ratio was significantly associated with a poor prognosis of disease- specific survival (DSS) and OS (all p<0.001). They also reported that preoperative AST/ALT ratios higher than 1.3 were independent predictors of DSS (HR, 5.79; 95% CI, 2.25–15.13; p<0.001) and OS (HR, 2.61; 95% CI, 1.49–4.56; p<0.001) through Cox multivariate analysis.¹⁶

The exact mechanism of the relationship between elevated AST/ALT and poor prognosis of cancer patients, including those with UTUC is not yet known. But there are several hypotheses that explain the relationship between AST/ALT ratio and cancer. The most prominent of them is the Warburg effect.¹⁷ In normal cells, energy is produced by mitochondrial oxidative phosphorylation. However, cancer cells produce energy through lactic acid fermentation glycolysis, rather than oxidative phosphorylation, even under oxygen- rich conditions. This aerobic glycolysis is a less efficient pathway than oxidative phosphorylation, and increases the production of metabolites that can contribute to cancer cell proliferation. These metabolites provides anabolic support essential for cancer cell proliferation and growth.¹⁷ Increased lactate has been suggested to play an important role in maintaining glycolysis, affecting lactate dehydrogenase, the Nicotinamide adenine dinucleotide (NADH)/Nicotinamide adenine dinucleotide (NAD)+ratio, and affecting glucose transport materials. AST plays an important role in the process by relocating NADH to the mitochondria.^18,19 In addition, increases in glucose metabolites due to increased lactate, affects the microenvironment of the tumor and promotes local invasion, progression, and metastasis of cancer cells.^18,19

This study has some limitations. First, since this was a retrospective study of a relatively small number of patients, there may be a recall bias. However, the study population was limited to UTUC patients who underwent RNU and ACH, and that limited the number of patients. Second, we didn't know whether the patient was taking unchecked drugs that would affect AST/ALT.

Despite the limitations, this is the first study to identify the AST/ALT ratio as an important prognostic biomarker of ACH in advanced UTUC. There are many cancer biomarkers, but the AST/ALT ratio has the merit of cost effectiveness, com- pared with other methods, and the advantage that it is a quick method that may predict prognosis before cancer treatment.

CONCLUSIONS

An increased AST/ALT ratio is a significant inde- pendent predictor of CSS and OS in advanced UTUC patients receiving systemic ACH after RNU. We suggest that the AST/ALT ratio is a useful and valuable biomarker for predicting oncological outcomes after systemic ACH, as well as RNU in UTUC. The results presented here provide an important insight into the clinical significance of aminotransferase-based markers in postoperative UTUC patients with progressive stage disease, receiving ACH.

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