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Article

Low Serum Alanine Aminotransferase Blood Activity Is Associated with Shortened Survival of Renal Cell Cancer Patients and Survivors: Retrospective Analysis of 1830 Patients

by
Menachem Laufer
1,2,
Michal Sarfaty
3,
Eyal Jacobi
4,
Edward Itelman
5,6,
Gad Segal
7,* and
Maxim Perelman
8
1
Department of Urology, Chaim Sheba Medical Center, Ramat Gan 5266202, Israel
2
Faculty of Health and Medical Sciences, Tel-Aviv University, Tel-Aviv 6997801, Israel
3
Institute of Oncology, Chaim Sheba Medical Center, Ramat Gan 5266202, Israel
4
Faculty of Medicine, Ben-Gurion University, Beer-Sheva 8410501, Israel
5
Cardiology Division, Rabin Medical Center, Beilenson Campus, Peta-Tiqva 4941492, Israel
6
Department of Internal Medicine E, Rabin Medical Center, Beilenson Campus, Peta-Tiqva 4941492, Israel
7
Education Authority, Chaim Sheba Medical Center, Ramat Gan 5266202, Israel
8
Department of Internal Medicine “I”, Chaim Sheba Medical Center, Ramat Gan 5266202, Israel
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2024, 13(19), 5960; https://doi.org/10.3390/jcm13195960
Submission received: 7 September 2024 / Revised: 27 September 2024 / Accepted: 3 October 2024 / Published: 7 October 2024
(This article belongs to the Section Epidemiology & Public Health)
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Abstract

:
Background: Sarcopenia is characterized by a loss of muscle mass and function and is often associated with frailty, a syndrome linked to physical disability and shortened survival in various patient populations, including cancer patients. Low serum alanine aminotransferase (ALT) values, serving as a biomarker for sarcopenia, were previously associated with frailty and shortened survival in several cancers. In the current study, we aimed to test the association between low ALT and shorter survival in renal cell carcinoma (RCC) patients and survivors. Methods: This was a retrospective analysis of RCC patients and survivors, both in- and outpatients. We defined patients with sarcopenia as those presenting with ALT < 17 IU/L. Results: We identified records of 3012 RCC patients. The cohort included 1830 patients (mean age 65.6 ± 13.3 years, 68% were men) of whom only 179 underwent surgical treatment. Out of the eligible cohort, 811 patients (44.3%) had ALT < 17 IU/L, with a mean ALT value of patients within the low-ALT group of 11.79 IU/L, while the mean value in the higher ALT level group was 24.44 IU/L (p < 0.001). Patients in the low-ALT group were older (67.9 vs. 63.7 years; p < 0.001) and had lower BMIs (26.6 vs. 28; p < 0.001). In addition, patients with low ALT had lower hemoglobin values (12.14 vs. 12.91 g/dL; p < 0.001), higher serum creatinine (1.49 vs. 1.14; p < 0.001) and higher platelet to lymphocyte ratios (178 vs. 156; p < 0.001). In a univariate analysis, low ALT levels were associated with a 72% increase in mortality (95% CI 1.46–2.02, p < 0.001). In a multivariate model controlled for age, gender, hemoglobin, platelets, LDH, neutrophil to lymphocyte ratios and platelet to lymphocyte ratios, low ALT levels were still associated with a 27% increase in mortality (HR = 1.27, 95% CI 1.08–1.51; p = 0.005). Conclusion. Low ALT values, associated with sarcopenia and frailty, are also associated with shortened survival in RCC patients, and survivors and could potentially be applied for optimizing individual treatment decisions.

1. Background

1.1. Sarcopenia and Frailty Assessment amongst Cancer Patients

Assessment of patient’s physiological reserves is critical for treatment decision-making and the estimation of prognoses in cancer patients and survivors. Many cancer patients are surgical candidates, often necessitating major debilitating surgery. Therefore, the Charlson comorbidity index (CCI) and similar indices are commonly used before surgery in cancer patients [1]. Those tools are primarily objective but rather complicated, and other methods for a holistic estimation of patients’ overall capacity are subjective (at times, physicians just “eyeball” their patients) and are therefore difficult to define and standardize. ECOG performance status is a longstanding and universal feature oncologists use prior to medical therapy or radiation. It is short, easily understood and readily estimated. However, it is physician-assessed and, therefore, open to bias, potentially failing to integrate multimorbidity and frailty [2]. Sarcopenia is characterized by a loss of muscle mass and is correlated with frailty, a syndrome that leads to an increased likelihood of falls, disability, recurrent hospitalizations, and mortality [3,4,5]. In cancer patients, assessing sarcopenia and frailty improve the selection of patients eligible for major surgery and chemotherapy [6,7]. Both frailty and sarcopenia have been identified as markers for shortened survival in cancer patients [8].

1.2. Alanine Aminotransferase as a Biomarker for Sarcopenia and Frailty

Alanine aminotransferase (ALT) is a well-known intracellular enzyme, primarily in the liver parenchyma, that is commonly monitored in routine bloodwork. It catalyzes pyruvate to alanine in the skeletal muscle and alanine to pyruvate in the liver [9]. Elevated ALT blood levels are commonly used as a biomarker for hepatocellular injury; however, until recently, little was known regarding the clinical significance of lower-than-normal ALT. Several studies have demonstrated that a below-normal serum ALT activity, representing low muscle mass (sarcopenia, below expected for the same gender and age), is associated with shortened survival in older adults [10] and in patients hospitalized for various causes [11,12]. Furthermore, it was shown in several types of cancers that low ALT values are associated with increased frailty and shortened survival [13,14,15,16]. Based on our experience in previous studies, in diverse patient populations, we defined the value of 17 IU/L as a candidate value for differentiating frail from robust patients. Therefore, in the current study, we also used this value as a cutoff.

1.3. Renal Cell Carcinoma Patients and Survivors

RCC is the sixth most frequently diagnosed cancer in men and the 10th in women. The incidence of RCC has been increasing, and up to 17% of patients suffer from distant metastases at the time of diagnosis. Well-established risk factors include older age, smoking, obesity, hypertension, and chronic kidney disease [17,18]. Treatment options for RCC have changed dramatically over the past two decades. Surgery, specifically a radical nephrectomy or nephron-sparing surgery, is the mainstay of non-metastatic disease. However, active surveillance of small masses and tumor ablation are viable alternatives. The introduction of immune checkpoint inhibitors has significantly improved the overall survival of advanced RCC patients. Immune checkpoint inhibitor doublets or, when administered in combination with a vascular endothelial growth factor, tyrosine kinase inhibitors have (VEGFR-TKI) become the standard primary therapy in metastatic disease. Recently, immune checkpoint inhibitors have been used to offer neoadjuvant and adjuvant treatment settings in patients undergoing surgery [19]. Prognostic models have been developed for localized disease based on tumor stage, grade, subtype, and performance status. However, there is a poor level of evidence regarding their routine use. Traditional risk group assessment for patients with metastatic RCC also use performance statuses and some blood tests: low hemoglobin, high calcium and high LDH blood levels are well-established factors that help determine patients’ risk group classifications. Newly recognized prognostic markers such as platelet counts, white blood cell subtypes and platelet to lymphocyte ratios probably represent inflammatory responses to the cancer. Newer markers in patients receiving targeted treatments are used routinely but have limited accuracy [20]. Despite being a disease frequently found in older and often frail adults, there is only a small amount of available data in regard to guiding treatment decisions in those patients with metastatic RCC. The recent approval of many new agents for this disease poses a clinical challenge: how to best utilize these drugs in a population otherwise under-represented in clinical trials [21,22]. A few studies have investigated more accurate parameters, including sarcopenia and frailty in RCC patients. Unsurprisingly, they found that both syndromes correlated with surgical and oncological outcomes [23,24,25,26]. Both need to be assessed at any stage of RCC to define the most suitable treatment strategy, ranging from surveillance to aggressive treatment [27,28,29].

1.4. Aim of the Current Study

In the current study, we assessed the association between the low serum activity of ALT, suggestive of sarcopenia and frailty, and shorter survival in a large cohort of renal cell carcinoma patients and survivors.

2. Methods

2.1. Study Cohort

In the cohort featured in the current study, we included all men and women diagnosed with RCC who were treated in a large, tertiary medical center as outpatients or inpatients during the years 2013 to 2022. Patients underwent either surgery, immunotherapy, targeted therapy, or active surveillance. The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of the Chaim Sheba Medical Center (IRB approval # SMC-24-1252-D) on 13 May 2024. Following this approval and a waiver of informed consent in light of the retrospective nature of this study, all relevant patient characteristics, demographics, and clinical data were retrieved from the patients’ electronic medical records. We excluded patients with ALT activity levels higher than 40 IU that are generally associated with injured liver cells in various types of hepatitis and, therefore, not a reliable marker for striated muscle mass. The final cohort includes patients with ALT levels that were established at the time of RCC diagnosis. The primary outcome of the current study was all-cause mortality. Survival data were available for all subjects from the National Population Registry.

2.2. Statistical Analysis of Data

The normality of the distribution of continuous variables was determined using the Anderson–Darling and Shapiro–Wilk tests. If normally distributed, continuous variables were expressed as mean ± standard deviation (SD) and, if skewed, by median with the interquartile range (IQR). Categorical variables were presented as numbers and percentages (N; %). Continuous data were compared with the student’s t-test, and categorical data were compared using chi-square or Fisher exact tests. A log-rank test was used to analyze survival, later depicted using a Kaplan–Meier curve. Univariate cox regression modeling was used to determine the unadjusted Hazard Ratio (HR) for the primary outcome, and a multivariate model was constructed to examine the correlation and control for possible confounders. An association was considered statistically significant for a two-sided p value of less than 0.05. All analyses were performed using R software version 4.1.0 (R Foundation for Statistical Computing, Boston, MA.).
The normality of the distribution of continuous variables was determined using the Anderson–Darling and Shapiro–Wilk tests. If normally distributed, continuous variables were expressed as mean ± standard deviation (SD) and, if skewed, by median with the interquartile range (IQR). Categorical variables were presented as numbers and percentages (N; %). Continuous data were compared with the student’s t-test, and categorical data were compared using chi-square or Fisher exact tests. A log-rank test was used to analyze survival, later depicted using a Kaplan–Meier curve. Univariate cox regression modeling was used to determine the unadjusted Hazard Ratio (HR) for the primary outcome, and a multivariate model was constructed to examine the correlation and control for possible confounders. An association was considered statistically significant for a two-sided p value of less than 0.05. All analyses were performed using R software version 4.1.0 (R Foundation for Statistical Computing, Boston, MA.).

3. Results

A total of 3012 renal cell carcinoma patients’ records were identified; after applying our exclusion criteria (available epidemiological data and ALT levels within the normal range), the final study population included 1830 patients. We identified 179 patients who underwent surgical resection (either a radical or partial nephrectomy). Within the whole eligible patients’ cohort, 811 (44.3%) had ALT activity levels that were lower than 17 IU/L and, therefore, compatible with our definition of patients at high risk of suffering from sarcopenia and frailty. Figure 1 details patient consort flow and exclusion diagrams.
The mean age for the entire cohort was 65.3 ± 13.3 years. Relevant patient demographics and clinical characteristics are detailed, according to their ALT levels (lower or ≥ 17 IU/L), in Table 1: patients in the low-ALT group were, as expected, older (67.9 ± 13.5 vs. 63.7 ± 12.9 years, p < 0.001), had lower body mass index (BMI) values (26.6 ± 4.9 vs. 28 ± 5.1, p < 0.001) and had higher percentages of diabetes mellitus (26% vs. 22%, p = 0.036), arterial hypertension (57% vs. 51%, p = 0.017) and atrial fibrillation (9.5% vs. 6.1%, p = 0.008). They also had statistically significant lower values of hemoglobin, higher values of blood creatinine and a higher ratio of platelet to lymphocyte counts. Patients in the lower ALT group had a significantly shorter time in regard to survival and/or loss of follow-up (1822 ± 1487 vs. 2045 ± 1457 days, p = 0.001).

3.1. Univariate Analysis

In a univariate analysis, low ALT levels were associated with a significant 72% increase in mortality (95% CI 1.46–2.02, p < 0.001). Figure 2 shows a Kaplan–Meir curve for the crude survival analysis according to the ALT levels.

3.2. Multivariate Analysis

In a multivariate model (Table 2), low ALT levels were still associated with a 27% increased risk of mortality (HR = 1.27, 95% CI 1.08–1.51, p = 0.005).

4. Discussion

4.1. Personalized vs. Precision Medicine for Cancer Patients

The realms of advanced diagnostics and therapeutics in patients suffering from RCC have significantly advanced during the past several years. Nevertheless, most advancements were in the domains of precision medicine [30,31], addressing diseased tissue itself, rather than in the domain of personalized medicine, that is, addressing the patient rather than the disease. Moreover, some authors describe the movement from precision to personalized medicine in the sense of deepening our understanding of the molecular structure of the cancerous tissue [32], with some authors even bundling both precision and personalized medicine together, namely, PPM [33]. The authors of the current manuscript defy this concept, seeing personalized medicine as taking a “zoom-out” from the diseased tissue to the whole gestalt of a patient. We concentrate on personalized medicine in terms of sarcopenia and frailty assessment.
In former studies, we established the association between low ALT and worse clinical outcomes in other patient populations suffering from different, hematologic and solid malignancies: myelodysplastic syndrome [13], chronic lymphocytic leukemia [16], prostate adenocarcinoma [14] and bladder cancer [15].

4.2. Sarcopenia and Frailty of RCC Patients

As presented at the forefront of this article, sarcopenia, and frailty are a pillar of morbidity in cancer patients as a whole and in RCC patients precisely [25,28]. Massaad et al. evaluated the relative effects of different patients’ characteristics on clinical outcomes among post-operative patients with RCC metastasis. Amongst other variables, sarcopenia and frailty were also assessed [34]. Sarcopenia was assessed by measuring the L3 skeletal muscle index (L3-SMI) on axial CT images at the level of lumbar L3 vertebra, while frailty was assessed using the modified frailty index. Their results found no significant association between these measures and patients’ overall survival. We hypothesize that these findings stem from the fact that all patients were already metastatic as opposed to our cohort of patients with metastatic and localized disease. Moreover, although strongly validated, their methods for sarcopenia and frailty assessment were rather complex.
Low ALT assessment as part of personalized medicine offered for RCC patients: Similarly to our groups’ findings in patients with other urinary system malignancies (urinary, bladder and prostate), we showed that low ALT blood activity, representing a low total-body striated muscle mass, is associated with a poor prognosis. Relying on previous findings that confirmed the association of low ALT with sarcopenia and frailty, we similarly ascertained in RCC patients that low ALT is a reliable biomarker for sarcopenia and frailty.
Our study population was rather diverse, featuring both RCC patients with/without surgical treatment and RCC survivors. This was deliberate, as we strove to give clinicians patient stratification tools that would be effective for as wide a patient population as possible. Low ALT was not significantly associated with clinical outcomes in the whole population, and we would have tested it in RCC sub-populations; however, this was not the case. Future studies may follow, and sub-populations of RCC patients will be investigated.

5. Conclusions

Low ALT blood levels, measured in RCC patients and survivors, are associated with sarcopenia and frailty. This finding should be assimilated into the scheme of personalized medicine for RCC patients as part of their future plans for surgery, medical therapy, and prognostication.

6. Limitations

This was a single-center, retrospective study; therefore, our conclusions necessitate further verification in larger, multi-centered, preferably prospective studies.

Author Contributions

Conceptualization, M.L., M.S., E.J., E.I., G.S. and M.P.; methodology, M.L., M.S., E.J., E.I., G.S. and M.P.; software, E.I.; validation, M.L., M.S., E.J., E.I., G.S. and M.P.; formal analysis, M.L., M.S., E.J., E.I., G.S. and M.P.; investigation, M.L., M.S., E.J., E.I., G.S. and M.P.; resources, M.L., M.S., E.J., E.I., G.S. and M.P.; data curation, M.P. and M.L.; writing—original draft preparation, M.L., M.S., E.J., E.I., G.S. and M.P.; writing—review and editing, M.L., M.S., E.J., E.I., G.S. and M.P.; visualization, M.L., M.S., E.J., E.I., G.S. and M.P.; supervision, M.L., M.S., E.J., E.I., G.S. and M.P.; project administration, G.S.; funding acquisition, G.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of the Chaim Sheba Medical Center (IRB approval # SMC-24-1252-D) on 13 May 2024.

Informed Consent Statement

Informed consent was waived by the IRB due to the retrospective nature of the study.

Data Availability Statement

Research data associated with this research will be available from the corresponding author upon request.

Conflicts of Interest

All authors declare that they have no conflicts of interest regarding this research and manuscript publication.

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Jcm 13 05960 g001
Figure 1. Consort flow diagram of study patients.
Figure 1. Consort flow diagram of study patients.
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Figure 2. Kaplan–Meir Survival Analysis according to ALT levels.
Figure 2. Kaplan–Meir Survival Analysis according to ALT levels.
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Table 1. Patients’ characteristics according to ALT serum activity level.
Table 1. Patients’ characteristics according to ALT serum activity level.
Whole Study Cohort
N = 1830		ALT ≥ 17 IU/L
N = 1019		ALT < 17 IU/L
N = 811		p Value
ALT (Mean IU/L [SD])18.83 (8.01)24.44 (6.07)11.79 (3.04)<0.001
Patients’ Demographics
Age (years, Mean [SD])65.6 (13.3)63.7 (12.9)67.9 (13.5)<0.001
Male Gender (N [%])1238 (68)704 (69)534 (66)0.155
BMI (Mean [SD])27.4 (5)28 (5.1)26.6 (4.9)<0.001
Clinical Background
Diabetes Mellitus (N [%])428 (23)219 (22)209 (26)0.036
Dyslipidemia (N [%])657 (36)379 (37)278 (34)0.214
Arterial Hypertension (N [%])980 (54)520 (51)460 (57)0.017
COPD (N [%])113 (6)53 (5.2)60 (7.4)0.065
CHF (N [%])67 (3.7)30 (2.9)37 (4.6)0.088
Atrial Fib. (N [%])139 (8)62 (6.1)77 (9.5)0.008
S/P Stroke (N [%])95 (5.2)47 (4.6)48 (5.9)0.252
Laboratory Parameters
Albumin (g/dL, Mean [SD])3.9 (1.38)3.93 (0.58)3.86 (1.97)0.32
Hemoglobin (g/dL, Mean [SD])12.57 (2.02)12.91 (1.9)12.14 (2.09)<0.001
Platelets (K/μL, Mean [SD])236 (95)233 (91)239 (100)0.17
Neut./Lymph. (Mean [SD])4.87 (5.85)4.67 (5.06)5.12 (6.71)0.106
Plt./Lymph. (Mean [SD])166 (118)156 (115)178 (121)<0.001
LDH (IU/L, Mean [SD])243 (149)245 (159)240 (135)0.496
Calcium (mg/dL, Mean [SD])7.69 (3.43)7.56 (3.56)7.85 (3.26)0.069
Creatinine (mg/dL, Mean [SD])1.29 (1.08)1.14 (0.69)1.49 (1.4)<0.001
Time to Death/End of Follow-up (Days, Mean [SD])1946 (1474)2045 (1457)1822 (1487)0.001
Table 2. Multivariate Analysis.
Table 2. Multivariate Analysis.
Patient CharacteristicsHR (95% CI)p Value
ALT < 17 IU/L1.27 [1.08–1.51]0.005
Age1.05 [1.05–1.06]<0.001
Male gender1.6 [1.33–1.92]<0.001
Hemoglobin (g/dL)0.84 [0.81–0.87]<0.001
Platelets (K/mcl)1.00 [1.00–1.00]0.003
LHD (IU/L)1.00 [1.00–1.00]<0.001
Platelets/Lymphocytes1.00 [1.00–1.00]0.007
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Laufer, M.; Sarfaty, M.; Jacobi, E.; Itelman, E.; Segal, G.; Perelman, M. Low Serum Alanine Aminotransferase Blood Activity Is Associated with Shortened Survival of Renal Cell Cancer Patients and Survivors: Retrospective Analysis of 1830 Patients. J. Clin. Med. 2024, 13, 5960. https://doi.org/10.3390/jcm13195960

AMA Style

Laufer M, Sarfaty M, Jacobi E, Itelman E, Segal G, Perelman M. Low Serum Alanine Aminotransferase Blood Activity Is Associated with Shortened Survival of Renal Cell Cancer Patients and Survivors: Retrospective Analysis of 1830 Patients. Journal of Clinical Medicine. 2024; 13(19):5960. https://doi.org/10.3390/jcm13195960

Chicago/Turabian Style

Laufer, Menachem, Michal Sarfaty, Eyal Jacobi, Edward Itelman, Gad Segal, and Maxim Perelman. 2024. "Low Serum Alanine Aminotransferase Blood Activity Is Associated with Shortened Survival of Renal Cell Cancer Patients and Survivors: Retrospective Analysis of 1830 Patients" Journal of Clinical Medicine 13, no. 19: 5960. https://doi.org/10.3390/jcm13195960

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