Effects of High-Dose Radioactive Iodine Treatment On Renal Function In Patients With Differentiated Thyroid Carcinoma: A Retrospective Study

Aim: This study aimed to investigate the effects of high-dose radioactive iodine ( 131 I) treatment on the clinical metrics of renal function in patients with differentiated thyroid carcinoma (DTC). Patients and methods: The clinical metrics of renal function were analysed in 850 patients with DTC who received 131 I therapy between January 2012 and December 2019. According to the baseline renal function metrics, the patients were divided into normal renal function group (group A) and abnormal renal function group (group B). Each group was further divided into three subgroups (subgroups 1, 2, and 3) based on the cumulative dose of 131 I. The clinical metrics of renal function including serum creatinine (SCr) levels, blood urea nitrogen (BUN) levels and estimated glomerular ltration rate (eGFR) were measured within 1 month before the initiation of 131 I therapy, 1 year after the last therapy, and 5 years after the initial therapy. The changes in renal function metrics before and after 131 I therapy were compared in each group. Result: In group A (588 patients), no signicant difference in the mean levels of SCr and BUN and eGFR was observed in the three subgroups (P >0.05), regardless of gender, before the initial 131 I therapy and 1 year after the last therapy. A total of 8, 3, and 2 patients presented with abnormal renal function after 131 I treatment in subgroups 1, 2, and 3, respectively. No statistically signicant difference was observed in the incidence of renal dysfunction among the three subgroups (P = 0.287). The mean age of patients with renal dysfunction was signicantly greater than that of patients without renal dysfunction after 131 I treatment. In group B, of the 262 patients with abnormal renal function, SCr and BUN levels were elevated in 168 and 155 patients, respectively, and eGFR <60 mL/min/1.73 m 2 was found in 87 patients before the initial 131 I therapy. No signicant difference was observed in the parameters among the three subgroups. However, SCr and BUN levels were found to be increased in all subgroups 5 years after the initial 131 I therapy, and they were positively correlated with the cumulative dose of 131 I. The difference was statistically signicant (P <0.05). Furthermore, eGFR was found to be decreased in all subgroups after 131 I therapy, and it was negatively correlated with the cumulative dose of 131 I. The difference was statistically signicant (P <0.05). A gender bias was not observed in the changing trends of SCr and BUN levels and eGFR. Conclusion: Our ndings suggest that the nephrotoxicity of high-dose 131 I therapy, regardless of gender, is very low in patients with DTC with normal renal function; however, high-dose 131 I therapy may exacerbate the loss of renal function in those with renal dysfunction. exhibit a long life expectancy; hence, the use of 131 I therapy has raised concern regarding its potential for developing renal dysfunction. It is critical to comprehensively dene the risk of renal impairment caused by 131 I in such patients. To our knowledge, the current literature lacks published data regarding the nephrotoxicity of radioiodine owing to high-dose 131 I treatment. However, with regard to the quality of life, it is important to explore whether relevant nephrotoxicity is caused by 131 I therapy. The aim of this study is to examine whether high-dose 131 I used for the treatment of DTC can result in any change in the metrics of renal function during a relatively long period. was the impairment of renal function. A gender bias observed in the changing trends of SCr and BUN levels and increase in nephrotoxicity a radiation dose 19 Gy in the follow-up period of the study used 177 Lu-PSMA (prostate-specic antigen) castrate-resistant prostate cancer. a very low doses of 137 Cs with activities of 4000 or 8000 Bq/kg of internal IR (ionizing radiation) only induced early renal histological injury and acute oxidative but also DNA damage from such each radiopharmaceutical different potential toxicity and side owing to its special biodistribution patterns, dosage, nuclide type, and radiation energy. water-soluble 131 I-labelled are preferentially excreted through the renal with a high renal uptake Approximately 90% 131 is excreted 48 of In the 131 I experimental trials, Nihat cell proliferation the seventh day and during the week on the immunohistochemical of the kidneys. Kolbert


Introduction
The incidence of thyroid cancer is increasing worldwide, and the most common histological subtype of thyroid cancer is papillary carcinoma followed by follicular carcinoma. The carcinomas are collectively referred to as well-differentiated thyroid carcinoma (DTC). The de nitive therapy for DTC includes surgical thyroidectomy, with or without adjuvant 131 I therapy depending on histological information and the presence of residual, unresectable, and metastatic disease [1][2][3]. 131 I therapy has been successfully applied for more than 60 years for the management of DTC. Various studies have proven that ablative 131 I therapy signi cantly reduces the frequency of recurrences and tumour spread in patients with thyroid cancer. In patients with distant metastases, approximately 50% complete responses may be achieved with 131 I treatment.
The well-known possible side effects of high-dose 131 I therapy include radiation thyroiditis, nausea, vomiting, sialadenitis, xerostomia, dental caries, long-term dysphagia, nasolacrimal duct obstruction, increased risk of leukaemia, secondary cancers, and pulmonary brosis in advanced stages [3][4][5]. Considering that 131 I is eliminated from the body mainly by the kidneys, the pathway potentially exposes the associated organs to radiation [6]. Moreover, the sodium/iodide symporter (NIS) protein that accumulates 131 I has been found in the kidneys, primarily in the distal tubular system; it is present at a low concentration in the proximal tubules and is absent in the glomeruli [7]. However, most patients with DTC exhibit a long life expectancy; hence, the use of 131 I therapy has raised concern regarding its potential for developing renal dysfunction. It is critical to comprehensively de ne the risk of renal impairment caused by 131 I in such patients. To our knowledge, the current literature lacks published data regarding the nephrotoxicity of radioiodine owing to high-dose 131 I treatment. However, with regard to the quality of life, it is important to explore whether relevant nephrotoxicity is caused by 131 I therapy. The aim of this study is to examine whether high-dose 131 I used for the treatment of DTC can result in any change in the metrics of renal function during a relatively long period.

Patients
We have examined all records of the patients admitted for the treatment of DTC after thyroid hormone withdrawal at the Department of Nuclear Medicine, Tianjin Medical University General Hospital from January 2012 to December 2019. Patients with incomplete data were excluded. A total of 850 patients were enrolled in the study; 326 patients were men and 524 patients were women, both aged between 18 and 72 years (mean age, 47.8 ± 23.4 years). Of the 850 patients, 716 patients presented with papillary carcinoma and 134 patients presented with follicular carcinoma.
All patients had undergone total or near-total thyroidectomy and received 131 I treatment for the rst time. After surgery, 633 patients were treated for the ablation of the thyroid remnant and 217 patients were treated for tumour recurrence and/or metastatic disease. 131 I was administered at a dose of 2.59-7.40 GBq at each time to all patients. If required, subsequent 131 I doses were administered every 6-12 months. The applied accumulated doses ranged from 2.59 to 55.50 GBq with a mean of 13.69 GBq per patient, and the mean number of therapy cycles was 3.65 ± 2.84 (range, 1-7). After the administration of 131 I, the patients were asked to drink more water and urinate more frequently.
Grouping and follow-up The 131 I treatment of all patients ended within 4 years, and all patients were followed up for 1-5 years or for at least 1 year after the last treatment. The follow-up (FU) was continued based on clinical examination; neck ultrasonography; hepatorenal function; and blood tests for thyroid hormones, including thyroid-stimulating hormone (TSH) and thyroglobulin (Tg), anti-Tg, and anti-thyroperoxidase antibodies. All renal function parameters were evaluated using an automated analyser (Siemens Viva-ProE). The metrics of renal function, including blood urea nitrogen (BUN; normal range, 3.1-8.0 mmol/L) and serum creatinine (SCr; normal range, 57-97 µmol/L) levels and estimated glomerular ltration rate (eGFR), were evaluated using the Modi cation of Diet in Renal Disease (MDRD) equation [8].The data were systematically recorded in clinical records, and they were collected at least once per year.
SCr and BUN levels and eGFR evaluated within 1 month before the initial 131 I treatment were used as baseline values. The post-therapy SCr and BUN levels and eGFR evaluated 1 year after the last treatment and 5 years after the initial treatment were used as the '1-year FU' and '5-year FU' values, respectively. The development of renal function insu ciency was de ned as SCr levels > 97 µmol/L and/or BUN levels > 8.0 mmol/L (based on the reference standard of the clinical laboratory of Tianjin Medical University General Hospital) and/or eGFR < 60 mL/min/1.73 m 2 (based on the chronic kidney disease criteria) [9].
Based on the baseline values, the patients were divided into two groups, namely, normal renal function group (group A) and abnormal renal function group (group B). Group A was de ned as patients with baseline SCr levels ≤ 97 µmol/L, BUN levels ≤ 8.0 mmol/L, and eGFR ≥ 60 mL/min/1.73 m 2 , and none of the patients in group A presented with acute or chronic nephropathy or any disease or received any medications that can possibly affect renal function. Whereas those who presented with any disease or received such medications and any of the abnormalities in SCr, BUN and eGFR were included in group B. None of the patients received external irradiation to the abdomen in both the groups.
Based on different cumulative doses of 131 I, the two groups were further divided into three subgroups, namely, subgroup 1, if the cumulative dose was less than 11.1 GBq; subgroup 2, if the cumulative dose was between 11.1 GBq and 18.5 GBq; and subgroup 3, if the cumulative dose was more than 18.5 GBq.

Statistical analysis
The statistical analysis was performed on SPSS 22.0. The distribution of all parameters was found to be normal. The results were reported as mean ± standard deviation (SD). The changes in parameters among the three subgroups were evaluated using repeated measures analysis of variance (ANOVA). The comparison between baseline and follow-up levels of SCr and BUN and eGFR or the comparison of values among the subgroups was analysed using the Student's t-test. The chi-squared test was used for comparing the incidence of renal insu ciency among the subgroups after 131 I therapy. Two-tailed P values < 0.05 were considered to indicate statistically signi cant relationships.

Results
The patients in groups A were subdivided into three groups based on the cumulative dose of 131 I. In group A (588 patients, with 224 male patients and 364 female patients with mean age 44.6 ± 28.2 years), no signi cant difference was observed in the mean levels of SCr and BUN and eGFR in subgroups 1, 2, and 3, regardless of gender, before the initial 131 I therapy and 1 year after the last therapy. The clinical metrics of renal function are summarised in Table 1. A total of 13 (2.2%) patients developed renal function impairment, which was de ned as SCr levels > 97 µmol/L, BUN levels > 8.0 mmol/L, or eGFR < 60 mL/min/1.73 m 2 . A total of 8, 3, and 2 patients presented with abnormal renal function after 1 year of initial 131 I treatment in subgroups 1, 2, and 3, respectively. No statistically signi cant difference was observed in the incidence of renal dysfunction among the three subgroups (Table 2). In subgroup 3, 4 patients received a cumulative dose of more than 3.7 GBq and none of them presented with abnormal renal function after 131 I therapy. The patients who developed renal impairment were older than those who did not (age, 55.3 ± 13.6 years versus 47.6 ± 18.9 years, respectively; P = 0.023), and the difference was statistically signi cant. In all patients, the absolute increase in SCr and BUN levels was 1.79 µmol/L and 0.10 mmol/L, respectively, and the absolute decrease in eGFR was 2.11 mL/min/1.73 m 2 .  In group B, of the 262 patients (102 male patients and 160 female patients; mean age, 55.0 ± 21.3 years) who presented with abnormal renal function before 131 I treatment, SCr and BUN levels were elevated in 168 and 155 patients, respectively, and eGFR < 60 mL/min/1.73 m 2 was found in 87 patients. Before the initial 131 I therapy, there was no signi cant difference in the three parameters among the three subgroups.
The patients in group B were also subdivided into three subgroups (subgroups 1, 2, and 3) based on the cumulative dose of 131 I. SCr and BUN levels were found to be increased in all subgroups 5 years after the initial 131 I therapy compared with the levels before treatment. The higher the cumulative dose was, the more increase in SCr and BUN levels was observed. The difference was statistically signi cant. Furthermore, eGFR was found to be decreased in all groups after 131 I treatment, and the greater the cumulative dose was, the more decrease in eGFR was observed.
The difference was statistically signi cant. However, a gender bias was not observed in the changing trends of SCr and BUN levels and eGFR. The results of biochemical parameters are summarised in Table 3-5.

Discussion
We compared the renal function parameters between 131 I pre-therapy and post-therapy patients. It should be emphasized that this is a retrospective study that used a database not speci cally designed for this protocol because it is virtually impossible to design a prospective study on the nephrotoxicity of 131 I therapy owing to the long timespan involved. In this retrospective study, we investigated 850 patients treated with 131 I. In 588 patients with normal renal function, our ndings revealed a non-statistically signi cant change in the mean values of renal function parameters (SCr, BUN, and eGFR) after 131 I treatment compared with baseline values, regardless of gender. We did not nd an association between radiation exposure and the incidence of renal dysfunction despite the administration of a higher dose of 131 I. However, high-dose 131 I therapy aggravated renal impairment in 262 patients with abnormal renal function. The higher the 131 I cumulative dose was, the greater was the impairment of renal function. A gender bias was not observed in the changing trends of SCr and BUN levels and eGFR.
The kidney is probably most radiosensitive among the abdominal organs [10]. Although the renal tissue is capable of tolerating some radiation depending on the dosage and nuclide types, radiation nephropathy owing to renal irradiation has been recognized as an important complication of external beam radiation therapy (EBRT) or internal radiation therapy such as peptide receptor radionuclide therapy (PRRT). Based on the data derived from patients who have undergone EBRT, it is generally accepted that a dose of 23 Gy to the kidneys, in fractions of approximately 2 Gy, leads to a 5% risk of renal failure in patients within 5 years and that a dose of 28 Gy leads to a 50% risk of renal failure within the same period [11]. In addition, other studies have demonstrated that it is di cult to tolerate ionising radiation of more than 25-30 Gy because the outcome can be hazardous [12,13]. These data cannot be simply translated to internal irradiation therapy with radionuclides. Unlike external radiation, the dose rate in internal isotope therapy is much lower and of a longer duration than that in EBRT. Radionuclides used in vivo generally deliver a radiation dose over an extended period depending on their physical and biological half-lives [14]. Data from various cancer studies, including studies on neuro-endocrine tumours (NETs) and castrate-resistant prostate cancer, provide some insight into renal damage caused by radio pharmaceuticals. In the largest study group about 90 Y-labelled peptides that included 1106 patients, renal toxicity was found to be 9.2% with a maximum follow-up period of 23 months and 8% with a longer follow-up for approximately 157 months, based on plasma creatinine levels and eGFR evaluated with MDRD formula [15,16]. In the largest study group of 504 patients about 177 Lu-labelled peptides with a median follow-up of 19 months, serious nephrotoxicity was found to be 0.4% [17]. Anna Yordanova et al [18] suggest that no relevant increase in nephrotoxicity was detected in patients who received a kidney radiation dose > 19 Gy in the follow-up period of the study that used 177 Lu-PSMA (prostate-speci c membrane antigen) therapy for patients with castrate-resistant prostate cancer. The results of a study demonstrated that very low doses of 137 Cs with activities of 4000 or 8000 Bq/kg of internal IR (ionizing radiation) not only induced early renal histological injury and acute oxidative stress but also caused DNA damage [19]. As evident from such studies, each radiopharmaceutical exhibit different potential toxicity and side effects owing to its special biodistribution patterns, dosage, nuclide type, and radiation energy. Adequately water-soluble 131 I-labelled radiopharmaceuticals are preferentially excreted through the renal route, with a high renal uptake [20]. Approximately 90% 131 I is excreted in the urine within 48 h of administration [21]. In the 131 I experimental trials, Nihat Yumusak et al [22] demonstrated that cell proliferation and apoptosis began on the seventh day and peaked during the tenth week based on the immunohistochemical analyses of the kidneys. Kolbert et al [23] provided dose-volume histograms and mean absorbed doses for 14 normal organs; the calculations were performed using a 3D voxelbased method. The mean 131 I dose was approximately 0.10 Gy/GBq in the kidneys. In our study, the patients were usually advised to drink plenty of water to reduce the risk of nephrotoxicity after 131 I therapy. No obvious renal toxicity was observed in patients with normal renal function. A possible explanation is the limited follow-up time in relation to the longer latency period from the time of initial treatment to the development of renal dysfunction. The mean age of 13 patients with renal dysfunction was older greater than that of patients with normal renal function, which in turn raises a speculation regarding radiation damage being more severe in older patients, as is commonly believed for radiation damage [24]. However, a signi cant radiation dose to the kidneys was observed in patients with pre-therapy for renal insu ciency, despite renoprotection. In patients with abnormal renal function before 131 I therapy, renal function declined after 5 years mainly because of factors such as age, diabetes, high blood pressure, and poor baseline renal function. However, the higher the cumulative dose, the more severe the renal damage, which indicates that high-dose 131 I treatment also leads to the aggravation of renal damage. The excretion of 131 I by the kidneys may be reduced in patients with renal insu ciency [25], which may aggravate further damage of renal function. Vogel K et al [26] stipulated that the biological half-life of 131 I was signi cantly in uenced by eGFR; a decrease in GFR may signi cantly prolong the half-life of 131 I. Similarly, in some studies, the prescribed activity of 131 I in patients with renal insu ciency is reduced by approximately 30% or 50% to compensate for the prolonged clearance of radioiodine [27][28][29].
SCr, an amino acid with a molecular mass of 113 D and that is freely ltered by the glomerulus, is the most commonly used metabolite for the assessment of renal function despite several drawbacks. SCr levels are affected by several factors, such as body weight, exercise, diet, tumour burden, sex, and muscle mass, which need to be corrected for the accuracy of assessing renal function [30]. The diagnostic sensitivity of SCr evaluation is considered insu cient for analysing moderate GFR reduction. Therefore, the use of SCr levels as a means to assess the renal function levels alone is not recommended. In some studies, post-therapy SCr levels did not increase proportionately with cumulative radioactivity and renal absorbed doses of the kidneys [31]. To date, GFR has been proposed as the standard that should be used for evaluating radiation-induced renal damage [32]. However, the measured GFR was not a feasible marker in the present study because its measurement requires continuous intravenous (i.v.) infusion of an ideal ltration marker such as inulin and multiple blood or urine collections, which is not practical for clinical routine use [33]. Radiopharmaceuticals for renal function measurements such as 51 Cr-ethylenediaminetetraacetic acid Epidemiology Collaboration (CKD-EPI) equations. MDRD seems to be more reliable [34]; hence, we used it to estimate GFR. However, the accuracy of evaluating eGFR using SCr levels remained questionable. During the initial decrease in GFR, the tubular secretion of creatinine enhances, which can alleviate the increase in SCr levels. Until the tubular secretory capacity is saturated, SCr levels may remain normal and eGFR may be overestimated [35,36].

Study Limitations
The major limitation of this quality study was the unavailability of control data of patients with thyroid cancer who did not receive 131 I treatment. Another limitation was a relatively short follow-up period for patients with normal renal function before 131 I therapy. Furthermore, the identi cation of renal dysfunction based on SCr and BUN levels and eGFR instead of measured GFR was another limitation. GFR gradually decreased with age, and age strati cation was not performed in this study. In addition, the evidence derived from a retrospective cohort study is typically lower in statistical quality because of various sources of inherent bias such as surveillance bias, which may result in a classi cation bias.

Conclusions
In the present study, we found that nephrotoxicity was low in patients with DTC with normal renal function treated with 131 I. Although the cumulative dose was approximately 37 GMq, 131 I did not cause signi cant nephrotoxicity in the patients. After we subdivided the patients into three subgroups based on the cumulative doses, we failed to demonstrate a statistical difference, and the incidence of renal dysfunction did not achieve a statistically signi cant level, which was not associated with the cumulative doses. However, our ndings revealed an increasing trend in BUN and SCr levels and a decreasing trend in eGFR in patients with renal dysfunction who received 131 I treatment. Moreover, the damage to renal function becomes more severe with an increase in cumulative doses. The present study indicates that close attention should be paid to patients with abnormal renal function before treatment in order to maintain an appropriate balance between therapeutic e cacy and the reduction of nephrotoxicity.

Declarations
Funding: The present study did not receive any funding.