Main findings
The frequency of pubertal alterations in male patients was 45.7% (6 patients at the beginning of the study had delayed puberty and 26 had puberty arrest during follow-up). Of the hormonal alterations that the patients presented, hyperprolactinemia and high levels of the leptin receptor were related to PD development. However, the diagnosis of CKD at an early age was more frequent in PD patients.
The presence of hypogonadism is a common finding in end-stage CKD patients and those with kidney transplantation (26, 27). The etiology is multifactorial and the term “uremic hypogonadism” has been coined to describe the hormonal status associated with kidney disease. Patients with stage V CKD have protein loss (loss of muscle mass) and low concentrations of serum albumin, transferrin, and pre-albumin; all this is secondary to various factors, such as anorexia, nausea, and vomiting associated with uremia, administration of medications, hormonal disorders, acidosis and increased energy expenditure that reduces the muscle mass, and consequently malnutrition (28, 29). Pubertal initiation and development require a greater amount of energy from the body; therefore, the initiation and progression of puberty is compromised in malnourished subjects; this results in functional hypogonadotrophic hypogonadism (30, 31).
Although no difference was identified in the nutritional status of patients with and without PD; the percentage of fat and free leptin was lower in wPD patients. There is considerable metabolic heterogeneity between the different adipose stores. Therefore, proteins secreted by the adipose tissue are actively involved in energy homeostasis and regulation of autonomic neuroendocrine function; the endocrine role of adipose tissue is better characterized by leptin (32). Leptin transmits information to the brain about the stored energy available, acts through its receptor to stimulate the secretion of kisspeptin, a hypothalamic hormone that promotes GnRH secretion (33), although it is not clear if it is a direct action on kisspeptin-neurokinin B-dynorphin neurons or if leptin acts through an intermediate cell (34). Thus, the importance of leptin in puberty has been indicated and it has been implicated as a factor that contributes to puberty abnormalities in CKD patients (35, 36). Although we found no difference in the serum levels of total leptin, if we observe the low levels of free leptin in wPD patients and a correlation between growth and sexual maturation parameters has been demonstrated in men, with free leptin, without identifying a direct correlation with body fat (18). In contrast, in populations with a negative energy balance due to insufficient caloric consumption with respect to energy expenditure, the serum leptin receptor levels are increased; this may represent a protective mechanism that decreases free leptin bioavailability that would further conserve energy (37).
Thus, it is necessary to monitor the nutritional status regularly in all children and especially in those with a chronic disease that compromises their health, such as CKD, because it is known that malnutrition is a serious problem and a common complication in these patients that is associated with increased morbidity and mortality (30, 38, 39).
Hyperprolactinemia was also a risk factor for PD development in male adolescents with CKD. Hyperprolactinemia causes disturbances in the concentration of dopamine, inhibiting the secretion of GnRH and consequently the pulsatile secretion of LH and FSH (40, 41). A direct action of hyperprolactinemia at the level of Leydig cells is suggested, suppressing testosterone secretion (6, 42). Finally, this produces functional hypogonadotropic hypogonadism in CKD patients (7). Hyperprolactinemia is a multifactorial condition in this population, and probably the management that could be offered is an increase in dialyxzacy to increase prolactin clearance or drugs that decrease prolactin levels, which in both cases should be evaluated. the risk-benefit balance (21).
Although, when renal functionality was compared in patients with and without pubertal impairment, no relevance was documented in the uremic status, bone mineral metabolism, or anemic status, it is important to note that puberty depends on several conditions (2, 43), and we probably did not show a difference owing to the sample size and the differences in these parameters are probably less evident than in hormonal alterations.
Delayed puberty, especially in boys, can have significant psychosocial repercussions (25, 44). In a time of extreme sensitivity and psychological liability, where body image is very important for the self-esteem of the subject, the lack of pubertal development and short stature, which frequently accompanies pubertal delay, can cause low self-esteem, depressive behaviors, and reaching poor adherence to renal replacement therapy (1, 45). While managing these patients, the use of testosterone is not recommended, as in adults (45) because the premature closure of the growth plates may occur, resulting in short stature, greater than that already present in these patients (46). The ideal approach would be early kidney transplantation early; however, in developing countries this is complicated; thus, the multidisciplinary management of these patients becomes a challenge.
Based on these results, we recommend that all patients aged > 10 y with stage 4 and 5 CKD should undergo extensive physical examination, including testicular examination and correlate biochemically with the hormonal profile for early identification of factors that alter pubertal development and in addition to assessing, improve nutritional conditions, and in case of presenting hyperprolactinemia, perform interventions to lower serum prolactin levels.
The fact that only body fat was determined and not the entire body composition including muscle mass, which in the present cohort would be vital, was a study limitation. The relatively small sample size however, according to the group studied and the inclusion criteria, the population is restricted.