Huggins and Hodges reported for the first time that androgen deprivation was beneficial and effective in patients with metastatic prostate cancer (mPCa) (1). Since then, both medical and surgical androgen deprivation therapy (ADT) have been widely used to treat patients with clinically localized or mPCa (2,3).

ADT is the main treatment for progressive prostate cancer. Although ADT has been shown to improve oncological outcomes (2), it is associated with a non-negligible risk of important side-effects (2,4,5). There are numerous well recognized adverse events of ADT, which include hot flushes, loss of libido, fatigue, gynecomastia, anemia, and osteoporosis. In addition, obesity, insulin resistance, and dyslipidemia were recently suggested to be potential metabolic complications of ADT (6). The long-term use of ADT also has deleterious effects on cardiovascular health (7).

Recently, it was reported that the use of ADT is significantly associated with increased risk of acute kidney injury (AKI) in patients with newly diagnosed non-mPCa (8). AKI was also found to be one of the adverse events of ADT. Gandaglia et al. (9) showed that the 10-yearAKI rate was 30.7% among patients treated with ADT and that administration of gonadotropin-releasing hormone agonists, but not bilateral orchiectomy, increased the risk of AKI in patients with prostate cancer. These studies were conducted in Europe or the United States, and to the best of our knowledge no such studies have been carried out in Asia, including Japan. Furthermore, previous studies examined the occurrence of AKI during long-term ADT treatment, but not the incidence of AKI in the early period of ADT treatment.

In the present study, we investigated the incidence of early renal dysfunction in Japanese prostate cancer patients receiving ADT.

Study subjects. This was a retrospective study that used data extracted from electronic records. One hundred and thirty-five patients with prostate-specific antigen (PSA) levels of >4.0 ng/ml, or PSA levels of <4.0 ng/ml and positive digital rectal examination findings, who underwent prostate biopsy examinations (PBx) at the Department of Urology, Teikyo University Chiba Medical Center (Ichihara, Japan) between January 2009 and July 2013 were included in the study. The PBx were performed transrectally under ultrasound sonography and local anesthesia. They were conducted routinely using the 14-region template in all patients. The biopsy specimens were examined by a dedicated histopathologist at our hospital. All the patients who participated in this study had been pathologically diagnosed with prostate cancer and had undergone ADT for >6 months.

Clinical and laboratory assessments. The rate of change in the estimated glomerular filtration rate (ΔeGFR) was used to evaluate renal dysfunction in each period. The ΔeGFR was calculated using the following formula: (eGFR at 1/3/6 months-pretreatment eGFR)/pretreatment eGFR×100.

With regard to risk factors for renal dysfunction after 6 months ADT, we investigated the following factors: age; the levels of PSA, testosterone, and hemoglobin; the rates of change in the eGFR seen after 1 and 3 months of ADT, the presence/absence of pretreatment renal dysfunction, clinical stage, the treatment method, body mass index, the Gleason score, the presence/absence of hypertension, the presence/absence of diabetes mellitus, and the presence/absence of dyslipidemia. To assess the presence/absence of renal dysfunction after 6 months of ADT, the mean rate of decline in the eGFR seen over 6 months in healthy Japanese aged ≥40 years was calculated based on data from a previous study (14). Next, that value was compared with the mean eGFR value seen after 6 months ADT. If the mean ΔeGFR value for the healthy individuals was lower than the mean ΔeGFR value seen after 6 months ADT, we considered the patient to have renal dysfunction.

Statistical analysis. The results are shown as the mean±SE. The Mann-Whitney U test and Chi-squared test were used for statistical analyses. All analyses were performed with JMP version 10 (SAS Institute Inc., Cary, NC, USA). Probability values of <0.05 were considered statistically significant.

Ethical approval. The institutional review board of the Teikyo University approved this study (TUIC-COI 19-1407).

Of the 135 eligible patients, 110 were evaluated in this study. Combined androgen blockade (CAB) was employed in 101 of the 110 cases (Table I). After 6 months CAB treatment, renal dysfunction was observed in 69 of the 110 patients (63%). The patients that exhibited renal dysfunction after 6 months ADT (the renal dysfunction group) demonstrated significantly lower mean ΔeGFR values after 1 month ADT (–2.7±1.3) than those that had normal renal function (the normal renal function group) after 6 months ADT (1.4±2.2; p=0.0016). The renal dysfunction group also exhibited a significantly lower mean ΔeGFR value after 3 months ADT (–6.3±1.2) than the normal renal function group (2.4±1.4; p<0.001). The presence/absence of renal dysfunction before treatment did not affect the incidence of renal dysfunction after 6 months ADT (p=0.6008) (Table II). The mean ΔeGFR values after 1, 3, and 6 months of ADT were –0.6%, –3.1%, and –1.7%, respectively (p<0.001) (Figure 1). Univariate analyses showed that the incidence of renal dysfunction after 6 months ADT was significantly associated with the ΔeGFR after 1 month ADT, the ΔeGFR after 3 months ADT, the presence/absence of hypertension, and the presence/absence of dyslipidemia (Table III). Multivariate analysis showed that the ΔeGFR after 3 months ADT [odds ratio (OR)=0.95, 95% confidence interval (CI)=0.905-0.986, p=0.007] and hypertension (OR=3.17, 95%CI=1.303-8.080, p=0.0107) were independent risk factors for renal dysfunction after 6 months ADT (Table III).

In the present study, it was revealed that renal dysfunction due to ADT for prostate cancer occurred early in the course of treatment. Moreover, it was confirmed that renal dysfunction was worst after 3 months ADT, and 63% of the patients treated with ADT had reduced renal function after 6 months ADT.

Although ADT has been shown to have beneficial effects against prostate cancer progression, serious adverse events can occur during such treatment (10). Specifically, ADT reduces testosterone levels, leading to a hypogonadal condition marked by metabolic changes, such as dyslipidemia (11), hyperglycemia (12), and an increase in fat mass (13).

Recently, it was reported that ADT has harmful effects on renal dysfunction. Specifically, it was found that ADT for newly diagnosed non-mPCa significantly increased the risk of AKI (8). Also, the latter study showed that when the ADT treatment period was split into tertiles, the highest risk of AKI occurred within the first third of the ADT treatment period (<386 days) (8). However, no previous studies have investigated the early renal dysfunction induced by ADT.

In the present study, we evaluated the presence/absence of renal dysfunction using the ΔeGFR in newly diagnosed prostate cancer patients with local or metastatic lesions that were treated with ADT. We confirmed that renal dysfunction due to ADT was first seen after 1 month of ADT, peaked after 3 months of ADT, and was still seen after 6 months of ADT. Furthermore, surprisingly the incidence of renal dysfunction after 6 months of ADT was 63% (69 cases). There was no significant association between the presence/absence of pretreatment renal dysfunction and the presence/absence of renal dysfunction after 6 months of ADT. Thus, it seems that pretreatment renal dysfunction did not affect the incidence of early renal dysfunction due to ADT. Consequently, it is suggested that ADT induces renal dysfunction.

It has been reported that the mean rate of decline in the eGFR in healthy Japanese aged ≥40 years was 0.36 ml/min/1.73 m²/year (14). In the present study, the mean reduction in the eGFR was 0.5 ml/min/1.73 m² after 1 month ADT, 2.3 ml/min/1.73 m² after 3 months ADT, and 1.3 ml/min/1.73 m² after 6 months ADT. Therefore, the rate of decline in renal function seen in the patients treated with ADT exceeded that of healthy Japanese, indicating that ADT induced early renal dysfunction.

Also, it was reported that up to 36.67% of people who take bicalutamide (Bic) for 1-6 months experience kidney failure (15), which supports our results. Although only one case report of Bic-related AKI has been published to date (16), ADT and its hypogonadal effects have well-known consequences that are consistent with our findings. We speculate on how ADT affects renal function below.

In the renal system, hyperglycemia and dyslipidemia may disrupt glomerular function by expanding and thickening the interstitial tubular membrane (17). Furthermore, by lowering testosterone levels to similar levels to those seen after castration, ADT may antagonize the vasodilatory effects of testosterone on renal blood vessels (18), while also creating an estrogen deficiency, which can negatively affect renal tubular function (19). Thus, ADT may increase the risk of AKI through these mechanisms. As for Bic therapy, Bic may provoke renal mesangial damage, and ultimately fibrosis, via multiple mechanisms, including ADT (16).

In our study, hypertension was identified as a predictor of renal dysfunction after 6 months ADT. It was demonstrated that receiving ADT increased the risk of renal dysfunction by about 3-fold. The INTERSALT study found that there was an association between mean salt intake and mean blood pressure (20). Also, a few studies have reported that salt reduction has anti-hypertensive effects (21,22). Singer et al. (23) reported that it was necessary for patients taking antihypertensive drugs to reduce their salt intake. Estimated salt intake can be calculated from urinalysis, and it is important to use estimated salt intake for blood pressure control. We suggest that patients receiving ADT should undergo periodic urinalysis. During ADT in hypertensive patients, early renal dysfunction may be avoided if the patient’s blood pressure is adequately controlled. Therefore, it is suggested that patient guidance, such as regarding salt restriction and weight reduction, is important for patients receiving ADT.

We would like to emphasize several limitations of our study. Firstly, it was a retrospective cohort study, which involved the extraction of electronically stored clinical data, and it had a small sample size. Thus, it will be necessary to validate the findings of this retrospective analysis in prospective studies, including a randomized study, with larger populations in the future. Secondly, the evaluation period was as short as 6 months. However, this is the first study to evaluate renal function during the early period of ADT. We are also interested in assessing renal function in the medium term in future studies. Thirdly, the ΔeGFR was used to evaluate renal function in the present study. We considered that it was necessary to evaluate renal function after 6 months ADT. The reason why we used the ΔeGFR as a parameter of renal function was that we considered that it could also be used to evaluate patients with renal dysfunction. Hence, the ΔeGFR was used instead of the eGFR itself to assess renal function. In this study, we demonstrated that the ΔeGFR that we adopted seems to be a useful tool for monitoring changes in renal function over time, and it is expected to become more widespread in the future. Finally, in this study, only the presence/absence of hypertension was assessed. We should have assessed the severity of hypertension and the types of anti-hypertensive medication used as well. As the number of cases increases, it is expected that the association between hypertension and early renal dysfunction will become clearer.

The findings of this study suggest that ADT for prostate cancer induces early renal dysfunction, and that the renal dysfunction persists for at least 6 months. Furthermore, it was demonstrated that hypertensive prostate cancer patients that are receiving ADT are at high risk of developing renal dysfunction and that such cases should be treated very carefully. Therefore, it is suggested that periodic PSA, renal function, and urinary salt intake examinations are necessary after the initiation of ADT. Further investigation of the changes in renal function that occur during ADT are required.

The Authors declare that they have no conflicts of interest related to this study.

HM designed the study and acquired the data. HM prepared and edited the manuscript. MS, KH, KA, SK, and YN were involved in the patient care and reviewed the electronic records. All the Authors have read and approved the manuscript.