Abstract
Androgen deprivation therapy (ADT) is the major treatment for advanced prostate cancer (PCa). Although ADT has been shown to improve oncological outcomes against PCa, it can also induce various adverse events, such as loss of libido, gynecomastia, fatigue, hot flashes, anemia, obesity, insulin resistance, dyslipidemia, cardiovascular events, and acute kidney injury (AKI). ADT reduces testosterone levels; consequently, ADT may antagonize the vasodilatory effects of testosterone on renal blood vessels, which could negatively affect renal tubular function. However, the renal impairment due to ADT is transient; i.e., it improves after the discontinuation of ADT. The recovery of serum testosterone levels may contribute to the amelioration of renal impairment induced by ADT. Serum testosterone levels are probably implicated in these changes, but the mechanism has not been studied in detail. With regard to the preservation of renal function and the anti-cancer effect of PCa, intermittent ADT may be a useful treatment for PCa. This is a review of the recent reports on the mechanism, current status, and prevention of renal impairment induced by ADT; future prospects in this field are also discussed.
- Renal impairment
- androgen deprivation therapy
- prostate cancer
- estimated glomerular filtration rate
- review
Huggins and Hodges demonstrated that prostate cancer (PCa) was an androgen-dependent disease and androgen deprivation therapy (ADT) was the effective treatment in patients with advanced PCa (1). Since their study, both medical and surgical ADT have been performed to treat patients with clinically localized or metastatic prostate cancer (mPCa) (2, 3). In randomized trials, ADT has been shown to improve overall survival in cases of locally advanced (4, 5) and lymph node-positive PCa (6), and after surgery for lymph node-positive PCa (7).
Although ADT has been shown to be effective and useful treatment against PCa progression, numerous recognized adverse events of ADT, which include loss of libido, gynecomastia, fatigue, hot flashes (HF), osteoporosis, insulin resistance, dyslipidemia, cardiovascular events, and acute kidney injury (AKI), occur during such treatment (8, 9). Recently, it was reported that in newly diagnosed non-mPCa patients, ADT usage is significantly associated with an increased risk of AKI (10). Glomerular function may be disrupted in the renal system by hyperglycemia and dyslipidemia, which dilate and thicken the interstitial tubular membranes (11). Moreover, it is suggested that ADT may antagonize the vasodilatory effects of testosterone on renal blood vessels (12), simultaneously, it may create estrogen deficiency and negatively affect renal tubular function (13). Through these mechanisms, ADT may increase the risk of AKI. Serum testosterone levels are probably implicated in these changes, but the mechanism has not been studied in detail. Although there have been several meta-analyses of randomized studies of ADT and its cardiovascular outcomes (14-17), there have not been any such analyses of randomized studies of the link between ADT and AKI. Therefore, retrospective studies are critical for assessing renal impairment associated with ADT in PCa patients.
Shere et al. reported that the incidence of AKI at two years after diagnosis was 10.5% in the radiotherapy (RT) + ADT group and 7.9% in the RT group (p<0.01) (18). Multivariate analysis confirmed that ADT usage was significantly associated with an increased risk of any AKI. ADT was also found to be significantly associated with an increased risk of mild AKI and moderate AKI, but not severe AKI (p=0.11). Thus, they suggested that the use of ADT is associated with an increased risk of AKI in patients receiving definitive RT for PCa. AKI may also cause chronic kidney disease (CKD), which may eventually require hemodialysis. Hence, it is necessary to consider AKI as a complication that impacts the patients’ quality of life (QOL).
This is a review of the literature on the mechanisms, current status, and prevention of renal impairment elicited by ADT. strategies to prevent adverse events are also discussed.
ADT for PCa and AKI
Criteria for AKI. In 2012, the Kidney Disease Improving Global Outcomes (KDIGO) criteria were suggested, which integrated the Risk, Injury, Failure, Loss, and End-stage renal disease (RIEFLE) and Acute Kidney Injury Network (AKIN) criteria. The KDIGO criteria for AKI include any one of the following: #1) an increasing level in the serum creatinine (sCr) by ≥0.3 mg/dl within 48 hours, #2) an increasing level in the sCr to ≥1.5 times compared to the baseline within the preceding 7 days, and #3) a urine volume of <0.5 ml/kg/h for 6 h. The severity of AKI is categorized from stage 1 to 3 according to the patient’s sCr level or urine output volume by the KDIGO criteria (19). Since few studies in the literature fulfill the aforementioned definition, in this review the term “renal impairment” was used instead of “AKI”. Moreover, it has been reported that ADT-induced renal impairment is transient, as it tends to improve after the discontinuation of ADT (20). Therefore, in this review, the term “renal impairment” was used rather than “renal dysfunction”.
Parameters Used to Investigate Renal Function
Utility of the rate of change in the estimated glomerular filtration rate (ΔeGFR). With regard to the evaluation of renal function, there have been several reports using the rate of change in the eGFR (ΔeGFR) rather than the level of eGFR itself. In addition, 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 (21). The value of the decline in eGFR is determined. Hence, individual eGFR values may be compared. It may be useful to compare previously reported data with the data gained from these new studies. Recently, the concept of CKD became widespread in Japan. The eGFR has been used to classify CKD. We should use the eGFR more frequently in the evaluation of renal function. The ΔeGFR seems to be a useful tool for monitoring changes in renal function over time, and its use is expected to become more widespread.
Impact of decreased testosterone levels on renal function. In the renal system, metabolic changes associated with ADT, such as dyslipidemia and hyperglycemia, may disrupt glomerular function by expanding and thickening of the interstitial tubular membrane (11). In addition, ADT may antagonize the vasodilatory effects of testosterone on renal blood vessels (12). Through these mechanisms, ADT may induce AKI. It was reported that serum testosterone levels increased after the discontinuation of ADT (22), and the recovery of serum testosterone levels may be associated with improvements in renal function. Serum testosterone levels may be a critical factor on renal function during ADT. There have been reported that the renal impairment seen in Japanese patients during ADT for PCa is temporary; i.e., renal function tends to recover after the discontinuation of ADT (20). Lapi et al. investigated the United Kingdom Clinical Practice Research Datalink and identified 10,250 males that had been newly diagnosed with non-mPCa in 2013. The crucial finding was that the use of ADT within the previous 90 days was associated with a significantly increased risk of AKI compared with that seen in males that had never been exposed to ADT [odds ratio (OR)=2.48; 95%CI=1.61-3.82]. All treatments of prostate cancer, including the use of luteinizing hormone-releasing hormone agonists, estrogen, combined androgen blockade, and other combination therapies significantly increased the risk of AKI. In addition, oral antiandrogens and bilateral orchiectomy were also shown to be associated with an increased risk of AKI, though this was not significant (10). Gandaglia et al. have reported that the 10-yr AKI rates were 24.9% versus 30.7% for ADT-naive patients versus those treated with ADT, respectively (p<0.001). Multivariate analyses revealed that the administration of gonadotropin-releasing hormone agonists [hazard ratio (HR)=1.24; 95% confidence interval (CI)=1.18-1.31; p<0.001], but not bilateral orchiectomy (HR=1.11; 95%CI=0.96-1.29; p=0.1), was associated with an increased risk of experiencing AKI. In addition, Gandaglia et al. demonstrated that the highest risk of AKI occurred within the first third of the ADT treatment period (<386 days) (23). Also, it was indicated that about one third of people who took bicalutamide (Bic) for 1-6 months experienced renal failure (24). Moreover, Peng et al. have reported the renal damage elicited by bicalutamide therapy as evidenced in a cell model (25).
Risk factors for renal impairment. Recently, it was reported that hypertension is an independent risk factor for renal impairment after 6 months of ADT. Therefore, PCa patients that are treated with ADT should periodically perform not only prostate specific antigen (PSA) but also renal function and urinary salt intake examinations (26). Although it was not considered to be a risk factor of AKI, it was reported that the presence/absence of HF after ADT influenced renal function in Japanese PCa patients treated with RT (27). This report is very interesting. In the future, it is expected that the association between the occurrence of HF and renal impairment will be elucidated. Moreover, it has been reported that renal function improves after the discontinuation of ADT, and decreased serum testosterone levels may be a risk factor for renal impairment. It may be worth paying attention to changes in serum testosterone levels.
Period of renal impairment. In a retrospective study, it was reported that renal impairment induced by ADT for PCa occurs from 1 month of ADT (26). Moreover, it was confirmed that renal impairment was worst after 3 months of ADT. Masuda et al. have shown that renal impairment persisted for 24 months during the ADT with radiation therapy (RT) in Japanese patients with high-risk prostate cancer, but renal function tended to improve after the discontinuation of ADT (27). In addition, they concluded that the renal impairment caused by 24 months of ADT was transient.
Permanence of renal impairment. Whether the renal impairment induced by ADT is transient or permanent is extremely important because if the renal impairment continues to progress, it will advance to end-stage renal disease (ESRD), and hemodialysis will be required in the future. ESRD negatively impacts the QOL of patients by adversely affecting their social, financial, and psychological status. In addition to patients physical, functional, metabolic, social, and mental status, the general QOL of patients may also be impaired (28, 29). It was reported that the health-related quality of life (HRQOL) of dialysis patients is usually worse than that of the age-matched subjects from the general population because of the typically high burden of comorbidities and complications of associated with ESRD (30). Hence, although the treatment of PCa with ADT could be curative, a subsequent requirement for hemodialysis, which is harmful to QOL, should be avoided. A previous study suggested that renal function may improve after the discontinuation of ADT in Japanese high-risk PCa patients (20). Therefore, the recovery of testosterone levels may be related to improvements in renal function after the discontinuation of ADT. However, the reason for this is unclear.
Future Perspectives
Renal impairment due to ADT is an important adverse event. Therefore, it is suggested that periodic PSA levels, renal function, and urinary salt intake examinations are necessary during ADT. The discontinuation of ADT may be expected to result in the recovery of testosterone levels and improvements in renal function. In this regard, bipolar androgen therapy (BAT) is assumed to be an effective treatment that both preserves renal function and achieves cancer control. BAT has been demonstrated to be effective against castration-resistant PCa (CRPC) (31). In CRPC patients, BAT may contribute to the preservation and improvement of renal function. There has also been a report about BAT for androgen ablation-naïve PCa (32). Approximately 60% of patients who received BAT maintained a PSA of <4.0 ng/ml, and the objective response rate was about 80%. In addition, BAT may improve the QOL of males treated with ADT. Furthermore, the recovery of serum testosterone levels observed after the discontinuation of ADT for PCa may be associated with improvements in renal function. Intermittent ADT (IAD) may be considered as one of endocrine treatments for PCa in order to preserve renal function, because it may recover serum testosterone levels. However, there have not been any reports concerning the link between AKI and IAD. Although prospective studies are essential for clarifying the relationship between ADT and AKI, until now there have not been any such studies. Therefore, when examining the association between ADT and renal impairment, we have to rely on retrospective studies, which provide low levels of evidence. Murphy et al. have reported that AKI after esophageal cancer is associated with dyslipidemia and dyslipidemia was one of the independent preoperative factors predicting AKI (p=0.002) (33). Dyslipidemia may be a risk factor for exacerbating renal function. Considering the abnormal lipid metabolism induced by ADT, treatment for dyslipidemia may prevent ADT-induced renal impairment. Moreover, Wu et al. have reported that the use of statin is independently associated with reduced risks of 1-year in patients with dialysis requiring AKI (34). To verify the protective effect of statin on renal function, it will be necessary to investigate the assessment of renal function for patients administered statins in PCa patients treated with ADT. In the investigation of renal impairment, the ΔeGFR seems to be a useful and effective tool. Consequently, its use is expected to become more widespread in the future.
Conclusion
Although ADT is associated with an increased risk of renal impairment, such changes may be considered to be transient, since the discontinuation of ADT leads to the recovery of renal impairment. Testosterone is probably implicated in these changes, but the mechanism has not been studied in detail. During ADT, BAT or IAD should be considered as ways of protecting renal function. With regard to renal dysfunction due to ADT, the term “renal impairment” should be used instead of “AKI”.
Footnotes
Conflicts of Interest
The Author declares no conflicts of interest in relation to this study.
- Received October 16, 2022.
- Revision received November 1, 2022.
- Accepted November 2, 2022.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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