Serum lactate dehydrogenase concentration after transcatheter renal artery embolization correlates with reduction in renal angiomyolipoma volume

Abstract

Background

The extent of renal angiomyolipoma (AML) volume reduction after renal transcatheter arterial embolization (TAE) varies between patients, with no predictive measure available.

Purpose

To determine whether the serum lactate dehydrogenase (LDH) concentration shortly after TAE correlates with the extent of tumor shrinkage.

Material and Methods

In a cohort of 36 patients undergoing prophylactic renal TAE for unruptured renal AML, we retrospectively acquired data from patient medical records, including serum LDH before and within 7 days after TAE and the tumor volume before and 12–36 months after TAE. The relationship between the serum level of LDH and reduction in tumor volume was evaluated using Spearman correlation analysis.

Results

The median LDH concentration was significantly higher after TAE than before (909.0 U/L vs. 186.5 U/L). This early post-TAE serum LDH level and LDH index (post-TAE LDH / pre-TAE LDH) correlated significantly and positively with the absolute decrease in tumor volume (both P < 0.0001). We observed no significant correlation between the relative tumor volume reduction and serum LDH level or LDH index.

Conclusion

Serum LDH elevation occurs shortly after TAE and correlates with the extent of absolute decrease in AML volume at 12–36 months after TAE. Further large-scale studies are warranted to confirm the predictive role of post-TAE serum LDH level and LDH index in tumor shrinkage in patients with unruptured renal AML.

Keywords

Angiomyolipoma lactate dehydrogenase kidney transcatheter arterial embolization

Introduction

Renal angiomyolipoma (AML) is a rare hypervascular kidney tumor composed of fat, smooth muscle, and blood vessels in varying proportions (1). Renal AML can arise spontaneously or in association with tuberous sclerosis complex (TSC). The overall prevalence of spontaneous AML in the general population is estimated to be 0.44%, with a significantly higher prevalence among women than men (2). Although benign, renal AML can result in hematuria, flank pain, and retroperitoneal bleeding, and rupture can cause severe hemorrhage (3). The standard treatment for renal AML is guided by the size of the lesion. AMLs >2 cm in diameter require active surveillance, and those >4 cm often require further intervention via arterial embolization, ablation therapy, surgery, or the administration of mTOR inhibitors (in patients with TSC-associated AML) (4,5). Patients with renal AML >4 cm, intratumoral aneurysm >5 mm, and/or symptoms of bleeding are at high risk for AML rupture and are recommended to undergo prophylactic selective transcatheter arterial embolization (TAE) to prevent hemorrhage and kidney loss (3).

TAE for renal AML leads to a significant long-term decrease in AML volume while retaining renal function, with a low rate of complications (6,7). The reported extent of tumor shrinkage following TAE is inconsistent between studies and correlates with varying parameters, including the tumor diameter (1,8), tumor fat content (1,9), and TSC status (10). Thus, post-TAE care requires management strategies tailored to each patient. In addition, the effects of TAE on renal AML volume occur over the long term; while the majority of AML shrinkage occurs within the first year after embolization, a plateau is not reached until three years after (11). Thus, an early measure predictive of the extent of AML shrinkage would be useful for planning the treatment trajectory and determining the suitable time interval between visits.

This study investigates whether the serum concentration of lactate dehydrogenase (LDH), a key enzyme in glucose metabolism and marker of cell necrosis, may serve as such a predictive measure. During necrotic cell death, failure in cell membrane permeability results in the releases of cytosolic LDH and the subsequent increase in the serum LDH concentration (12). TAE disrupts the nutrient and oxygen supply to tumor cells, decreasing their viability. If TAE-induced cell death occurs via necrosis, an increase in serum LDH would be expected. To determine whether the serum LDH concentration correlates with the extent of tumor shrinkage, this study investigates the relationship between the maximum serum LDH level within one week after TAE and the AML volume decrease at 12–36 months after TAE. If the tumor shrinkage rate can be predicted from this early serum LDH concentration, the trajectory of post-TAE recovery could be estimated soon after treatment, allowing for follow-up planning.

Material and Methods

Patients

The Institutional Review Board of the Graduate School of Medicine at Juntendo University approved the present study protocol (approval number: 20-103) and waived the requirement of informed consent due to the retrospective nature of this study. The research was conducted in accordance with the 1964 Helsinki Declaration or comparable standards.

Consecutive patients who underwent prophylactic TAE for unruptured AML at our hospital between September 2010 and February 2018 were initially recruited. The inclusion criteria were as follows: (i) only one AML; (ii) no previous therapy; (iii) no acute bleeding or hematoma; and (iv) undergoing radiological follow-up (computed tomography [CT] or magnetic resonance imaging scans) at 12–36 months after TAE. Patients who received additional interventions, such as mTOR therapy, re-embolization, or surgery, within 12 months after TAE were excluded. The final cohort included 36 patients with renal AML.

TAE

Before TAE, every patient underwent a dynamic contrast-enhanced CT scan. On axial 5-mm slice images, the tumor size, presence of intratumoral aneurysm, and vascularity of the tumor were assessed. AML with an aneurysm ≥5 mm in diameter was treated by TAE according to Guidelines for Renal AML with TSC (13). TAE was performed using gelatin sponge particles and/or microcoils for abnormal blood vessels and intratumoral aneurysm. Disappearance of the intratumoral aneurysm and restoration of blood flow in the AML were determined by confirmatory angiography upon the completion of TAE.

Tumor volume calculation

Pre-TAE CT or T2-weighted images were analyzed using Synapse Vincent software, a 3D image analysis system (FUJIFILM, Tokyo, Japan). After delineating tumor margins on images, the original tumor volumes were automatically calculated by the software. Similarly, post-TAE tumor volumes were calculated on images obtained at the last follow-up, 12–36 months after TAE. Subsequently, both absolute tumor reduction (subtracting post-TAE tumor volume from pre-TAE tumor volume) and relative tumor reduction (expressed as the percentage reduction in volume relative to the original volume) were assessed.

Serum LDH concentration

The serum LDH concentration before TAE and within one week after TAE was acquired from each patient's medical records. The LDH index was calculated as the ratio of the post- to pre-TAE LDH concentration.

Statistical analysis

Continuous variables are presented as the median and interquartile range (IQR), and categorical variables are presented as number (percentage). The differences in the serum level of LDH and the tumor volume before and after TAE were examined by Wilcoxon sign rank test. Spearman correlation analysis was performed to evaluate the relationship between the serum level of LDH and reduction in tumor volume. The significance level was set as two-sided P < 0.05. All statistical analyses were performed using SPSS version 22 for Windows (IBM Corp., Armonk, NY, USA).

Results

The flow chart for patient selection is shown in Fig. 1. Between September 2010 and February 2018, 56 consecutive patients with unruptured AML underwent prophylactic TAE. Of them, 16 were excluded due to previous therapy, acute bleeding or hematoma, or multiple AMLs; three were excluded because of a lack of radiological follow-up at 12–36 months after TAE; and one patient undergoing mTOR therapy seven months after TAE was also excluded. Thus, the final cohort included 36 patients (all women; median age = 40.5 years) with a single, unruptured renal AML (Fig. 1). The patient baseline demographic data and clinical characteristics are summarized in Table 1.

Fig. 1.

Flow chart of patient selection.

Table 1.

Baseline demographic and clinical characteristics of study patients.

	Total (n = 36)
Age (years)	40.50 (35.00–55.00)
Sex
Female	36 (100)
Tumor side
Left	26 (72.22)
Right	10 (27.78)

Values are given as n (%) or median (range).

LDH, lactate dehydrogenase.

The median tumor volume statistically decreased from 90.5 mm³ before TAE to 32.0 mm³ after TAE (P < 0.0001) (Table 2). The median absolute reduction in volume was 62.0 mm³, and the median relative reduction in volume was 71%. The median serum LDH level significantly rose from 186.5 U/L before TAE to 909.0 U/L after TAE (P < 0.0001), resulting in an LDH index of 4.15 (Table 2).

Table 2.

Comparison of tumor volumes and serum LDH levels before and after TAE.

	Total (n = 36)
Pre-TAE tumor volume (mm³)	90.50 (54.50, 170.0)
Post-TAE tumor volume* (mm³)	32.00 (13.00–77.75)^†
Absolute reduction in volume (mm³)	62.00 (31.25–121.50)
Relative reduction in volume (%)	71.00 (49.50–78.00)
Pre-TAE serum LDH (U/L)	186.50 (173.00, 210.50)
Post-TAE serum LDH (U/L)	909.00 (551.50–1474.00)^†
LDH index	4.15 (3.10–7.48)

Values are given as median (range).

*Determined at the last radiological follow-up, 12–36 months after TAE.

^†

Significantly different from pre-TAE tumor volume and serum LDH level, respectively, examined by Wilcoxon sign rank test (all P < 0.0001).

LDH, lactate dehydrogenase; TAE, transcatheter arterial embolization.

The relationship between tumor volume reduction and serum LDH was then evaluated (Figs. 2 and 3). The absolute reduction in tumor volume correlated significantly with post-TAE serum LDH concentration (P < 0.0001) (Fig. 2b) and LDH index (P < 0.0001) (Fig. 2c). No significant correlation was observed between relative reduction in tumor volume and serum LDH concentration (Fig. 3).

Fig. 2.

Spearman correlation analysis of the relationship between absolute reduction in tumor volume and LDH concentration. (a) Absolute reduction in tumor volume and pre-TAE LDH concentration. (b) Absolute reduction in tumor volume and post-TAE LDH concentration. (c) Absolute reduction in tumor volume and LDH index. LDH, lactate dehydrogenase; TAE, transcatheter arterial embolization.

Fig. 3.

Spearman correlation analyses between relative tumor volume reduction and LDH concentration. (a) Relative reduction in tumor volume and pre-TAE LDH concentration. (b) Relative reduction in tumor volume and post-LDH concentration. (c) Relative reduction in tumor volume and LDH index. LDH, lactate dehydrogenase; TAE, transcatheter arterial embolization.

Discussion

In this pilot study, we observed a significant increase in the LDH concentration up to one week after TAE compared to the baseline. This early post-TAE serum LDH level and LDH index correlated significantly and positively with the absolute decrease in tumor volume. However, no significant correlation was observed between the relative tumor volume reduction and serum LDH level or LDH index. These findings suggest that the early post-TAE serum LDH concentration or LDH index may be useful for predicting the extent of tumor volume decrease expected during the follow-up of patients undergoing prophylactic TAE for unruptured renal AML.

Serum LDH elevation is indicative of cell necrosis (12). Depending on the severity of tissue injury, LDH can remain elevated in the bloodstream for up to seven days (14). In this pilot study, the observed LDH elevation likely reflects the extent of cell damage caused during the initial response to TAE. We propose that the hypoxia and nutrient loss caused by TAE results in cell necrosis, causing a short-term increase in the serum LDH level that is reflective of the future long-term reduction in AML volume.

Previous studies have shown that the extent of AML shrinkage induced by TAE is affected by several AML characteristics, including tumor composition and initial tumor size. AMLs with a lower fat content are reported to undergo greater decreases in tumor volume after TAE (1,9,15,16), as are smaller AMLs (1,8). Differences in these parameters between AMLs included in this pilot study may underlie the differences in initial LDH elevation and subsequent tumor volume reduction. The lack of correlation between the relative volume decrease and LDH level suggests that the percent change in tumor size is less important than the absolute tumor reduction in volume.

The time of follow-up varies widely between studies, confounding prediction of the time to maximal tumor volume reduction. The most comprehensive data come from a meta-analysis of 30 studies including 653 patients, which reports a mean tumor size reduction of 30.0% after a mean follow-up of 33.3 months and concludes that the observed reduction represents the maximum shrinkage after embolization among these patients (6). Information regarding the rate of tumor reduction would help clinicians to predict the time course of improvement after TAE; however, few studies have addressed the tumor shrinkage rate. In a small cohort of 13 patients, Patatas et al. report an overall reduction of 6.5% at three months, 16.0% at six months, 24.0% at 12 months, 26.5% at two years, 33.0% at three years, and 36.0% at four years, with the greatest reduction occurring during the first 12 months (11).

Despite the lack of immediate clinical usefulness, the results of this retrospective pilot study may have a couple of putative clinical applications. At our institution, follow-up examinations after TAE for AML were performed at one month, six months, and one year after TAE. If no sign of AML enlargement was observed, follow-up would be scheduled once a year thereafter. If the extent of tumor shrinkage after TAE can be predicted as early as possible, the follow-up will be scheduled depending on each individual patient. For patients whose AML continually grows, frequent follow-up may be required and re-treatment may be performed at the appropriate time. On the other hand, the large AML may cause bloating and abdominal pain; TAE can ameliorate abdominal symptoms. Furthermore, for growing AML, tumor angiogenesis also occurs, resulting in intratumoral aneurysms. Therefore, a reduction in tumor size plays a role in preventing tumor hemorrhage.

The present study has some limitations. This single-institution pilot study in Japan has a small sample size. The retrospective nature of the study precludes evaluation of causality. Although unintentional, all study participants were women; this limitation occurred because of the preponderance of women among patients with renal AML (17). Thus, sex differences in the effect of TAE on tumor shrinkage could not be evaluated in this study. Because both post-TAE serum LDH test and follow-up imaging were performed over periods of time, but not at specific time points, sampling variability was inevitable. AMLs were not stratified based on fat content, and no pathological examination was conducted to evaluate the extent of tissue necrosis. Moreover, this pilot study did not examine the predictive role of the extent of AML shrinkage in planning the treatment and determining the suitable time interval between visits yet. Further large-scale multicenter studies and studies conducted in other geographic areas are required to confirm the present results.

In conclusion, our findings show that serum LDH increases shortly after TAE, suggesting that cell necrosis is involved in the mechanism underlying the effects of TAE. This increase in serum LDH correlates with the extent of the long-term decrease in AML volume. Confirmation of these findings in further studies could establish the early change in serum LDH concentration as a predictor of the extent of AML volume reduction after TAE. This clinical measure might be useful for estimating the trajectory of post-TAE recovery, thereby facilitating the development of personalized follow-up care and the follow-up visit interval.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Yoshiki Kuwatsuru

Ryohei Kuwatsuru

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