The role of androgens in chronic kidney desease: a missing link in the calcification paradox?

Androgens play an important role in the development and maintenance of the male reproductive system, the so-called classical target. However, they also have pleiotropic effects on other organs like bone and kidney. Although it is well established that androgen action is essential for normal bone mass accrual and maintenance in men, the contribution of specific AR effects either directly or indirectly mediated by the kidney is not fully understood. Moreover, in the setting of CKD, the contribution of androgens to mineral and bone disturbances and vascular calcification (bone-vascular axis) is unknown. In this PhD research project, we focused on the kidney as non-classical androgen target, and aimed to clarify the role of androgens in mineral and bone metabolism in circumstances of normal and decreased kidney function, and in the pathogenesis of the ‘calcification paradox’ in CKD, via prospective clinical studies and preclinical rodent models. We hypothesized that AR signaling is important for bone maintenance in men with normal kidney function, and that hypogonadism worsens the bone- and vascular complications in male CKD patients.

First, we defined short-term effects of ADT (degarelix) with or without ARSI (apalutamide) on mineral and bone metabolism in PCa patients. Bone loss already occurred in these patients after only twelve weeks of treatment. Serum calcium levels increased, resulting in a decrease of PTH and 1,25-(OH)2D3 levels. Bone resorption markers CTx and TRAcP5b markedly increased. We observed an interesting difference between the two treatment arms concerning bone formation marker PINP. This marker only increased in the degarelix + matching placebo group, while it did not change in the degarelix + apalutamide group. This observation potentially reflects specific AR-mediated effects on bone formation. However, the stable calcium isotope ratio, a novel marker of BMB, similarly decreased in serum and urine in both treatment arms. We therefore concluded that ARSI did not lead to more bone loss in the early treatment phase compared to chemical castration alone. Furthermore, these findings emphasize the importance of bone-health-awareness in PCa patients as early as ADT is started.

In a second part, we studied the impact of CKD and kidney transplantation on the gonadal status in male patients, and explored its link with bone-vascular health. Biochemical hypogonadism was prevalent in male patients with CKD, and was hallmarked by high gonadotropin levels. The T/LH ratio, as a proxy of Leydig cell function, was markedly decreased compared to non-CKD controls. Moreover, we demonstrated that the T/LH ratio might be a better CV risk predictor than T alone, though this finding warrants confirmation in larger cohorts. The T/LH ratio increased as soon as three months after kidney transplantation, pointing towards functional Leydig cell dysfunction in CKD. Additionally, we assessed inhibin B as a marker for Sertoli cell function. The inhibin B/FSH ratio was lower in CKD patients compared to age- and BMI-matched controls. However, the inhibin B/FSH ratio did not restore in a similar way as the T/LH ratio after kidney transplantation. We showed that CKD can be regarded as a state of premature testicular ageing. The improvement of Leydig cell function after renal transplantation indicates that it is reasonable to consider a cautious approach towards androgen replacement therapy in male renal transplant recipients.

Third, we studied the role of kidney-specific AR action on mineral and bone metabolism and renal homeostasis in kidney-specific AR knockout (K-ARKO) mouse model developed by our research group. Bone phenotype was not different in adult male K-ARKO compared to control littermates. Serum calcium and phosphate levels were not altered, and the increased renal expression of genes involved in calcium- and phosphate reabsorption and vitamin D metabolism probably reflect a compensatory mechanism to keep serum levels in balance. We concluded that renal AR signaling does not seem to be indispensable for bone mass accrual and maintenance in normal conditions. On the contrary, increase in serum creatinine levels and decrease in uremic toxin clearance was observed, accompanied by reduced renal expression of OAT and OCT. Additionally, we demonstrated that renal AR signaling via the renal tubules is important for determining male kidney size during growth, but this mechanism is different from that involved in compensatory hypertrophy after NX.

In a last part, we investigated the impact of androgen replacement therapy on bone and vascular complications in an established CKD rat model. CKD induced hypogonadism in male rats as shown by a reduction in androgen-sensitive organ weights and decreased in circulating T levels. Androgen replacement therapy successfully restored the male hypogonadism in CKD, but failed to rescue the pronounced bone and vascular phenotype, at least in the presence of a severe hyperparathyroidism characteristic for this experimental CKD model.

In conclusion, we showed that androgen deprivation negatively influences mineral and bone metabolism already very early in men with normal kidney function, and that renal AR signaling seems to be dispensable for bone mass acquisition and maintenance in male mice. Additionally, we contributed to the knowledge on hypogonadism in men with different stages of CKD and after kidney transplantation, and showed that in a rat model with severe CKD-MBD, androgen replacement therapy did not prevent bone and vascular complications.