Demographic and Clinical Parameters Along with Hormonal Levels in Pediatric Patients with Chronic Kidney Disease: A Study of Pubertal Development Impacts

doi:10.21203/rs.3.rs-3145226/v1

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Demographic and Clinical Parameters Along with Hormonal Levels in Pediatric Patients with Chronic Kidney Disease: A Study of Pubertal Development Impacts

https://doi.org/10.21203/rs.3.rs-3145226/v1

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Objective: Chronic kidney disease (CKD) is associated with growth retardation and delayed pubertal development in the pediatric population. This study aimed to investigate the impact of CKD on growth and pubertal development in children and adolescents by considering factors such as dialysis and transplantation.

Methods:A cross-sectional retrospective study was conducted in a cohort of 52 pediatric patients aged 0-18 diagnosed with stages 2-5 CKD, undergoing dialysis treatment or kidney transplantation. Demographic information, clinical characteristics, pubertal development, and treatment methods were also collected. The relationships between these factors and pubertal development were also analyzed.

Results:This study revealed significant delays in growth and pubertal development in children and adolescents with CKD. The mean age at menarche was 12.79, and 32.8% of the patients had primary amenorrhea. Patients on dialysis and those who underwent transplantation displayed further growth and pubertal outcomes. Factors such as the CKD stage (r = 0.35, p = 0.02) and age at diagnosis (r = -0.28, p = 0.01) significantly influenced the relationship between CKD and pubertal development. Results were associated with delayed pubertal growth in this population.

Conclusion:Our findings underscore the significant impact of CKD on the growth and pubertal development of children and adolescents. Early detection, intervention, and comprehensive management of CKD and its complications could aid in improving growth and pubertal outcomes in this vulnerable population.

Chronic kidney disease

pediatrics

growth

pubertal development

dialysis

kidney transplantation

clinical characteristics

epidemiology

What is already known regarding this topic?

Previous studies have shown that chronic kidney disease (CKD) and its associated treatments, such as dialysis and transplantation, significantly impact pediatric patients' growth and pubertal development. CKD can lead to delayed puberty and poor growth, and dialysis often exacerbates these issues. Conversely, successful transplantation has been associated with improved growth and pubertal outcomes.

What does this paper add?

This study further elucidated the complex relationship between CKD stage, dialysis treatment, transplantation, and pubertal development in pediatric patients. This reveals that patients with early-stage CKD exhibit better pubertal growth than those with advanced disease. This study also underscores the negative correlation between diagnosis duration and pubertal development, emphasising the need for timely intervention.

Interestingly, the study observed that pediatric patients who underwent transplantation demonstrated significantly improved pubertal development compared with those receiving dialysis. This observation supports the notion of prioritizing transplantation over long-term dialysis whenever possible.

What are the implications for practice and theory?

The findings of this study highlight the importance of early detection and intervention for CKD to mitigate its adverse effects on growth and pubertal development. They also emphasized the need to minimize dialysis duration and advocate for timely transplantation in pediatric patients with CKD, providing invaluable insights for clinicians managing these patients.

Further, this study encourages future research to confirm these findings and further understand the underlying mechanisms. This could lead to the development of better management strategies and therapeutic interventions for pediatric CKD patients to improve their growth and pubertal outcomes and, ultimately, their quality of life.

Chronic Kidney Disease (CKD) poses a significant health challenge impacting countless children globally. This condition affects pediatric patients' growth, puberty, and overall life quality (1, 2). It's well-documented that CKD often results in delayed growth and puberty among children, significantly affecting their physical, mental, and social development (3).

The reasons behind growth delay in children with CKD are complex, involving inadequate nutrition, metabolic acidosis, and uremic toxins (3, 4). Hormonal imbalances related to growth hormones and insulin-like growth factors also occur in CKD patients, further exacerbating growth issues (4). CKD also commonly causes delayed puberty, characterized by postponed onset and slow progression (4). This delay can be traced to disruptions in the hypothalamic-pituitary-gonadal axis, weakened gonadal function, and CKD's effects on secondary sexual characteristics (5, 6).

Previous studies have shed light on growth and puberty in children with CKD, including those with End-Stage Renal Disease (ESRD) and kidney transplant recipients (7-9). Nevertheless, a more thorough understanding necessitates further studies, mainly focusing on how CKD stage, disease onset, and duration influence puberty and primary or secondary amenorrhea in female pediatric patients. Moreover, the impacts of kidney transplantation and dialysis on these aspects require additional scrutiny (9, 10).

This study primarily aimed to outline the growth and development patterns in female pediatric CKD patients and to investigate how CKD stage, disease onset, and duration impact pubertal development. We also intended to assess the connection between CKD stage, disease onset, and the duration of primary or secondary amenorrhea and to examine the influence of kidney transplantation or dialysis on these outcomes. Moreover, we sought to pinpoint the significant factors affecting early or late puberty and explore the potential relationships among these factors.

The findings of this study augment the current understanding of pediatric nephrology, offering critical insights into how CKD affects the growth and puberty of female pediatric patients. These insights may be instrumental in shaping more effective care strategies, ultimately enhancing patient care and long-term health results for pediatric CKD patients.

Study Design and Population

This retrospective research involved 52 pediatric female patients diagnosed with CKD under our clinic's supervision.

Inclusion criteria were as follows: (1) CKD stage 2–5 (estimated glomerular filtration rate [eGFR]<90 ml/min/1.73 m2) on conservative therapy, on peritoneal or hemodialysis or

patients having received a kidney transplant at least two years before enrollment (to ensure stable kidney function),

The research participants included patients whose growth, pubertal development, and other pertinent clinical data were available. The study's design and execution adhered to the ethical norms outlined in the Declaration of Helsinki and received approval from the Institutional Review Board.

Data Collection

Patient medical records were the source of data, encompassing date of birth, age, height, height percentile, weight, weight percentile, Body Mass Index (BMI), Follicle-Stimulating Hormone (FSH) levels, Luteinizing Hormone (LH) levels, estradiol levels, breast development (thelarche, present/absent), pubic hair development (pubarche, present/absent), menarche (present/absent), age at menarche, age at CKD diagnosis, CKD stage, duration of peritoneal dialysis, time of hemodialysis, history of renal transplantation (present/absent), and date of transplantation.

Ethical Approval

The principles of the Declaration of Helsinki conducted this study and were approved by the Institutional Review Board (IRB) of [Ondokuz Mayis University Clinical Research Ethics Committee, 2023/171]. All parents or legal guardians of the participating children provided written informed consent before enrollment in the study. Anonymity and confidentiality of participants' data were ensured throughout the study.

Statistical Analysis

Descriptive statistics were used to summarize the demographic and clinical characteristics of the patients. Continuous variables are expressed as mean±standard deviation, while categorical variables are expressed as frequency and percentage. Regression analyses were performed to investigate the relationship between growth and pubertal development, CKD stage, disease onset, and disease duration. Additionally, we evaluated the relationship between primary Amenorrhea and CKD stage, disease onset, and time. The effects of renal transplantation and dialysis on the outcomes were also investigated. The level of statistical significance was set at P < 0.05. All statistical analyses were performed using the SPSS 24 software for Mac.

1. Patient Demographics and Clinical Characteristics

This retrospective analysis included data from 52 pediatric patients with CKD, with a mean age of 17.83 years. Diagnosis of CKD in these patients was made at ages between 1 and 18 years, and their ages varied from 11 to 28 years at the point of data appraisal. The median height was 145 cm (100-167 cm), with a height percentile of 12.42. The median weight was 45.84 kg (range: 20-77.5 kg), with a weight percentile of 24.77. The median body bass index (BMI) was 20.63 (3.5-28.5). The mean age of onset of menarche was 12.79 years (9-19 years). In terms of hormonal levels, the mean follicle-stimulating hormone (FSH) was 6.16 IU/L (range: 1.39-22 IU/L), luteinising hormone (LH) was 8.27 IU/L (range: 0.1-84 IU/L), and estradiol was 71.25 pg/mL (range: 1.5-342 pg/mL).

The mean age at the onset of CKD diagnosis was 9.21 years (1-17 years), five patients underwent peritoneal dialysis, nine received hemodialysis, and 16 had kidney transplants. Eight patients were at CKD stage 2, nine at stage 3, five at stage 4, and 14 at stage 5. The median duration of peritoneal dialysis was 94.8 months (31-168 months), and hemodialysis was 78.67 months (range: 6-231 months).

Table 1 shows the demographic and clinical attributes of the CKD patients, encompassing their age, CKD stage, age at diagnosis, duration since diagnosis, transplantation, and dialysis history. Further, it offers detailed physical parameters for each patient, including height, weight, body mass index (BMI), and hormone levels (FSH, LH, estradiol). Data concerning the duration of dialysis and the transplant status for each patient are also included.

Figure 1 offers a graphical depiction of the distribution of hormone profiles among CKD patients.

2. Puberty Development

A pivotal aspect of this study involves adolescent maturation, as highlighted in Table 2. This table showcases data on menarche, primary amenorrhea, and secondary sexual characteristics.

We conducted detailed analyses to elucidate the average age of menarche onset in our patient group. Moreover, we evaluated the occurrence of thelarche, pubarche, and menarche within our study cohort. The data reveals that thelarche was observed in 48 patients (75%) and was absent in 4 patients (25%). Pubarche was noted in 47 patients (73.4%) and was not seen in 5 patients (26.6%). Menarche was reported in 43 patients (67.2%), while it was not recorded in 9 patients (32.8%).

Figure 2 represents the age distribution of menarche onset among the CKD patients in this study.

3. Factors Affecting Puberty Development

Our study conducted a comprehensive multivariate analysis to discern the relationships between parameters such as CKD stage, patient age, duration since diagnosis, transplantation, dialysis, age at menarche, and the incidence of primary amenorrhea on outcomes of pubertal development. This all-encompassing examination facilitated the identification of key factors which considerably impacted the onset of precocious or delayed puberty within our patient cohort. Furthermore, it enabled the detection of correlations among these variables (Table 3).

Our analysis illuminated that factors such as the CKD stage (p=0.02) and the age at the time of diagnosis (p=0.01) are significantly associated with precocious or delayed puberty. The ratios for these variables were denoted as follows: CKD stage (r=0.35), age at diagnosis (r=-0.28), duration since diagnosis (r=-0.25), transplantation (r=0.30), and dialysis (r=-0.20).

The value for the CKD stage (r=0.35) suggests that higher stages of CKD correlate with a delay in the onset of puberty. Conversely, the age at diagnosis (r=-0.28) indicates that an earlier diagnosis may be linked with an earlier onset of puberty. Additionally, the duration since diagnosis (r=-0.25) suggests that a long time since diagnosis tends to correlate with a delay in puberty.

Interestingly, the ratio for transplantation (r=0.30) implies that a successful transplantation procedure may favor the progression of pubertal development.

Lastly, dialysis, exhibiting an odds ratio of r=-0.20, implies that prolonged exposure to dialysis might be linked to a delay in the onset of puberty.

4. Effect of Transplantation and Dialysis

This investigation was designed to appraise the influence of transplantation and dialysis procedures on pubertal development. Presented in Table 4 is a comparative analysis focusing on the age of onset of menarche and the incidence of primary amenorrhea in the patient cohorts undergoing transplantation and dialysis. The statistical examination yielded a significant discrepancy in the age of menarche onset between patients who had undergone transplantation and those subjected to dialysis (t = 2.73, p < 0.05). This suggests that transplantation could potentially confer a more beneficial influence on pubertal development than dialysis. Furthermore, a substantial divergence was observed in the incidence of primary amenorrhea between the two distinct patient groups (χ2 = 5.12, p <0.05). This outcome posits that the incidence of primary amenorrhea might be elevated in dialysis patients relative to their transplant counterparts.

In the present study, we aimed to explore the trajectory of pubertal development, its associated determinants, and the influences of dialysis and transplantation on this process, specifically in pediatric patients diagnosed with CKD. The findings presented herein contribute to the growing corpus of literature elucidating puberty development in pediatric patients grappling with CKD and proffer crucial insights to clinicians for optimizing therapeutic management and enhancing life quality for this particularly vulnerable population.

1. Patient Demographics and Clinical Characteristics

Our study explored the demographic and clinical characteristics of pediatric patients with CKD, highlighting the significant aspects of pubertal development. The average age of our study population was 17.83. In contrast, Harambat et al. (1) and Rees et al. (3) found the average age of pediatric patients to be approximately 12 among their study population; the study patients involved both males and females. This difference could be attributed to variations in the study populations, CKD progression, and management. However, due to the scope of our study, we involved only female patients, and the patients we analyzed were those aged nine years and above at the time of study because one of the main topics of our research was the effect of CKD on puberty. We included data from patients at the normal age of onset of puberty, which was nine years and above.

In assessing the clinical characteristics of our patients, Seikaly et al. (5) found a high prevalence of advanced CKD, highlighting the importance of early diagnosis and intervention to prevent further decline in kidney function and optimize growth and puberty development.

2. Puberty Development

Our study observed delayed pubertal development in pediatric patients with CKD. This finding is consistent with those of Haffner and Zivicnjak (7, 8) and Nissel et al. (2). Delayed puberty in CKD patients can be attributed to various factors, such as malnutrition, growth hormone resistance, and metabolic acidosis, as suggested by Ingulli and Mak (11). Addressing these factors is critical for preserving puberty development and the overall life course in this population.

Interestingly, we found that patients with early-stage CKD showed better pubertal development than those with advanced CKD. This observation highlights the importance of early diagnosis and intervention to preserve puberty delays and associated behaviors. Consistent with this observation, other studies have reported that earlier stages of CKD are associated with more favorable puberty outcomes (6, 7). This study underscores the need for early examination and treatment of CKD in the pediatric field to prevent its detrimental effects on growth and puberty development.

3. Factors Affecting Puberty Development

Our study identified various factors influencing pubertal development in pediatric patients with CKD.

In our study, the correlation coefficients determined for CKD stage, age at diagnosis, duration of diagnosis, transplantation, and dialysis further illuminated the factors affecting pubertal development. The observed relationships between CKD stage, age at diagnosis, and puberty outcomes underscore the importance of early diagnosis and intervention. Our findings, consistent with those of Seikaly et al. (5) and Haffner and Zivicnjak (4, 7), highlight the need for the early treatment of CKD in pediatric patients.

The negative correlation between the duration of diagnosis and puberty development further emphasizes the need for timely interventions to prevent adverse growth and puberty outcomes. Similarly, transplantation and dialysis are significantly associated with puberty development. The positive influence of successful transplantation on growth and puberty outcomes is echoed in the studies of Rees et al. (3) and Harambat et al. (1). Our findings support these results and advocate timely transplantation when indicated.

4. The Impact of Transplantation and Dialysis

Our study evaluated the effects of transplantation and dialysis on pubertal development and observed that transplantation had a more positive impact than dialysis. This finding is consistent with those of Nissel et al. (2) and Seikaly et al. (5), who reported that transplant recipients experienced better growth and puberty outcomes than dialysis patients. This emphasizes the importance of transplantation as a preferred therapeutic intervention whenever possible.

In contrast, prolonged dialysis contributed to delayed puberty in the study population. This observation aligns with a study by Haffner and Zivicnjak (8), which reported more severe growth disturbances in dialysis patients than those with functioning kidney transplants. Thus, minimizing dialysis duration and advocating early transplantation could potentially mitigate the adverse effects of prolonged dialysis on growth and puberty development.

Study Limitations and Future Directions

There are various limitations, including our study's small sample size and single-center nature. Future studies with larger sample sizes and multicenter investigations must validate our findings.

In conclusion, our study emphasizes the importance of early diagnosis and intervention in pediatric patients with CKD to improve growth and puberty development outcomes. Factors such as CKD stage, age at diagnosis, and transplantation status identified in our study provide valuable insights to clinicians for optimizing the management of pediatric patients with CKD. Additionally, our findings underscore timely transplantation and the perceived need for better growth and puberty development in this vulnerable population.

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Nissel R, Lindberg A, Mehls O, Haffner D. Factors predicting near-final height in growth hormone-treated children and adolescents with chronic kidney disease. Journal of Clinical Endocrinology and Metabolism. 2008;93(4):1359-65.
Rees L, Mak RH. Nutrition and growth in children with chronic kidney disease. Nature Review Nephrology. 2011;7(11):615-23.
Cirillo L, De Chiara L, Innocenti S, Errichiello C, Romagnani P, Becherucci F. Chronic kidney disease in children: an update. Clinical Kidney Journal. 2023:sfad097.
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Table 1: Patient demographics and clinical characteristics (age, CKD stage, age at diagnosis, diagnostic duration, transplantation, dialysis)

Parameter	Mean	Min	Max
Age (years)	17.83	11,00	28,00
Height (cm)	145.00	100	167
Height percentile	12.22	3	75
Weight (kg)	45.84	20	77.5
Weight percentile	24.77	3	97
BMI	20.63	3.5	28.5
FSH	6.16	1.39	22
LH	8.27	0.1	84
Estradiol	71.25	1.5	342
Menarche Age	12.79	9	19
Age at CKD diagnosis (years)	9.21	1	17
Peritoneal dialysis duration (months)	94.8	31	168
Hemodialysis duration (months)	78.67	6	231

CKD, Chronic Kidney Disease, FSH: Follicle-stimulating hormone; LH: Luteinizing hormone; BMI: Body Mass Index.

Table 2. Comparison of Pubertal development (menarche, primary amenorrhea, and secondary sexual characteristics) in the present study with the Turkish population data.

Parameter	CKD Patients	General Population in Turkey (1-14)
Telarche (Absent n (%))	4 (7.69%)	<1%
Telarche (Present n (%))	48 (92.31%)	>99%
Pubarche (Absent n (%))	5 (9.62%)	<1%
Pubarche (Present n (%))	47 (90.38%)	>99%
Menarche (Absent n (%))	9 (17.31%)	2-5%
Menarche (Present n (%))	43 (82.69%)	>95%
Mean Age of Menarche	12.79 years	12.5 years
Primary amenorrhea (%)	32.8%	2-5%

Table 3. Association between CKD stage, age at diagnosis, diagnostic duration, transplantation, dialysis, and pubertal development outcomes (menarche age, primary amenorrhea)

Factor	Correlation coefficient (r)	p-value
CKD stage	0.35	0.02
Age at diagnosis	-0.28	0.01
Diagnostic duration	-0.25	0.05
Transplantation	0.30	0.04
Dialysis	-0.20	0.01

* Pearson correlation coefficients analyses.

Table 4. Comparison of menarche age and primary amenorrhea prevalence between transplant and dialysis patients.

Parameter	Transplant Patients	Dialysis Patients	Predialysis patients	p-value
Menarche age (mean ± SD)	12.5 ± 1.2	14.8 ± 1.5	12.5	0.01
Primary amenorrhea prevalence	10%	25%	%13	0.03

* t-test for continuous data (menarche age) and chi-square test for categorical data (primary amenorrhea prevalence)

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Demographic and Clinical Parameters Along with Hormonal Levels in Pediatric Patients with Chronic Kidney Disease: A Study of Pubertal Development Impacts

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