The kidney and IGF-1 axis as a central regulator of linear growth and adult height in pediatric health and disease

Abstract

The kidney plays an important role in normal linear growth throughout childhood by regulating systemic insulin-like growth factor-1 (IGF-1) bioavailability through the filtration and processing of IGF-binding proteins and by serving as a target organ for growth hormone (GH). In pediatric chronic kidney disease (CKD), impaired renal function is associated with reduced availability of bioactive IGF-1 despite normal or modestly elevated total IGF-1 concentrations, reflecting altered binding protein dynamics and functional GH–IGF resistance. These changes are frequently accompanied by impaired growth velocity and reduced height, particularly in advanced CKD stages. This review synthesizes experimental and observational evidence examining the role of the kidney and IGF-1 axis in physiological linear growth and CKD-related growth failure. Observational studies demonstrate consistent associations between renal volume, IGF-1 parameters, and height outcomes. Across CKD stages, progressive reductions in free IGF-1 parallel worsening renal function and growth impairment. Recombinant human GH therapy improves growth velocity and may help children achieve near-adult height closer to their genetic potential when initiated early and appropriately monitored. Collectively, these findings support a renal–endocrine model of pediatric growth regulation in health and disease.

Introduction

Linear growth in children results from the integration of endocrine, nutritional, and organ-specific signals, culminating in adult height, a key health outcome [1]. This process is primarily coordinated by the growth hormone (GH)–insulin-like growth factor-1 (IGF-1) axis, with IGF-1 mediating 60%–80% of the anabolic effects of GH on chondrocytes and somatic tissues [2]. The kidneys contribute uniquely to this axis through abundant expression of IGF-1 receptors, local production of IGF1, and regulation of systemic IGF-1 levels via filtration and degradation of IGF-1–IGF-binding proteins (IGFBPs) complexes [3]. In healthy fetuses, nephrogenesis occurs during weeks 5–36 of gestation, aligning with somatic growth via renal IGF-1 signaling, ensuring proportional kidney-to-body mass development [4]. Postnatally, the kidneys filter low-molecular-weight IGFBPs, thereby increasing the availability of free, bioactive IGF-1 for growth plate activity [5]. However, physiological disruptions such as prematurity and chronic kidney disease (CKD) can disturb this homeostasis, leading to reduced renal mass and impaired linear growth [6].

Pediatric CKD affects approximately 1 in 40,000 children, of which 30%–50% of cases report growth failure, with final height standard deviation scores (SDSs) ranging from −1.5 to −2.5 [7]. Paradoxically, total serum IGF-1 concentrations often remain normal or elevated in these children due to reduced renal clearance. This masks tissue-level GH/IGF-1 resistance driven by uremia, inflammation, and increased IGFBP production [8]. Nevertheless, renal size serves as an important predictor of growth outcomes, with kidney volume SDS below −2.0 strongly associated with height SDS below −2.5 [9].

Apart from CKD, acute kidney injury in neonates can reduce IGF-1 bioavailability and impair postnatal catch-up growth [10]. Additionally, conditions such as diabetic nephropathy and nephrotic syndrome further dysregulate urinary IGF-1 handling, reinforcing the link between renal integrity and pubertal height gain [11]. This kidney–linear growth interaction extends into adolescence, where delayed puberty in children with CKD exacerbates height deficits. IGF-1 also plays a modulatory role in gonadal maturation and pubertal timing [12]. Therapeutically, treatment with recombinant human GH (rhGH) can overcome GH resistance, although careful monitoring of renal function is required, as IGF-1–mediated hyperfiltration may accelerate CKD progression [13].

Genetic syndromes provide important causal insight into this relationship. In Denys–Drash syndrome, WT1 mutations impair podocyte IGF-1 receptor signaling, resulting in renal hypoplasia and severe growth restriction resembling Russell–Silver syndrome [14]. Conversely, states of GH excess, such as acromegaly, induce renal hypertrophy but predispose to glomerular injury [15]. Thus, understanding kidney–IGF-1–growth interactions is essential for precision in pediatric endocrinology. Renal biomarkers, including estimated glomerular filtration rate (eGFR) and cystatin C, can predict IGF-1 responsiveness and guide rhGH initiation before irreversible stature loss occurs [16]. Over the past 25 years, this axis has been elucidated through experimental models, longitudinal cohorts, and randomized trials; however, no comprehensive pediatric-focused integrative synthesis has been available [17]. From a diagnostic perspective, renal IGF-1 profiling improves the evaluation of short stature beyond assessment of pituitary GH secretion alone. Therapeutically, eGFR-stratified rhGH dosing is used to optimize height velocity while minimizing nephrotoxicity. Prognostically, kidney volume at CKD onset predicts adult height below −2.0 SDS in nearly 70% of affected children, enabling earlier growth-preserving interventions and transplantation planning [18].

This review aims to describe the physiological role of the kidney in regulating IGF-1 bioavailability and linear growth in children and adolescents. It examines how CKD alters IGF-1 dynamics and contributes to impaired growth across different disease stages, and summarizes the clinical evidence on the impact of rhGH therapy on growth outcomes in pediatric renal disease.

Literature search strategy

This review was developed a priori and structured in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (2020) framework. Study identification and selection followed predefined screening procedures.

Study selection criteria

A comprehensive literature search was conducted in the PubMed, Scopus, and Embase databases to identify relevant studies published between January 1, 2000, and January 10, 2025. Search terms included combinations of “kidney” OR “renal” OR “chronic kidney disease” OR “IGF-1” OR “insulin-like growth factor” OR “growth hormone” OR “growth” OR “height” OR “stature” AND “child” OR “pediatric” OR “adolescent.” Only human studies published in English were considered for inclusion. Reference lists of selected articles were also screened to identify additional relevant publications. Eligible studies included prospective and retrospective cohort studies, randomized controlled trials, and controlled clinical studies reporting pediatric data (age <20 years) on at least one of the following outcomes: height SDS, growth velocity, total or free IGF-1 concentrations, IGFBP, renal function parameters, or final/near-final height. Case reports, animal-only studies, and studies exclusively involving adults were excluded.

Data extraction and synthesis

Data extraction focused on study design, population characteristics, CKD stage (when applicable), growth outcomes, IGF-1 parameters, and reported response to rhGH therapy. Given the heterogeneity in study design, CKD stage distribution, transplantation status, rhGH dosing, and outcome definitions, findings were synthesized narratively. Due to substantial clinical and methodological heterogeneity, formal pooled effect estimates were not calculated. Reported SDS changes represent descriptive pooled averages derived from comparable cohorts rather than a formal quantitative meta-analysis.

Quality assessment

Risk of bias assessment was performed for selected key interventional and longitudinal studies contributing directly to growth outcome synthesis. Detailed methodological appraisals are tabulated in the Supplementary Tables 1 and 2 (available online).

Results of a narrative synthesis of the included studies

Growth impairment is among the most clinically significant complications of pediatric CKD, reflecting complex interactions between renal dysfunction, endocrine alterations, and impaired growth signaling pathways. A total of 54 primary studies (35 cohort studies and 19 randomized controlled trials) were included in this review. Specifically, Table 1 summarizes studies evaluating renal size/volume and IGF-axis measures in relation to linear growth in non-CKD pediatric populations. Table 2 synthesizes IGF-axis alterations across CKD stage strata. Table 3 summarizes the prevalence and predictors of growth failure in pediatric CKD cohorts. Tables 4 and 5 summarize short-term growth response and longer-term (near-)final height outcomes associated with rhGH therapy, respectively. Because several studies report multiple outcomes or provide results stratified by CKD stage, counts across tables are not additive. Individual studies may therefore contribute to more than one table. The full mapping of all included studies to Tables 1–5 is provided in Supplementary Table 3 (available online). Four additional review articles were screened for reference mining but were not included in the primary synthesis. Across studies, participants were predominantly school-aged children (with an estimated mean age of approximately 9 years) with a substantial proportion representing CKD stages 2–5.

Table 1.

Relationship between renal volume, IGF-1 parameters, and linear growth in children

Author (year)	No.	Age (yr)	Kidney volume SDS	Total IGF-1 (ng/mL)	Free IGF-1 (%)	Height SDS	Height velocity (cm/yr)	r (IGF-1–height)	r (kidney volume–height)	P-value
Zhong et al. (2024) [3]	245	5–12	0.2±0.8	245±65	1.8±0.5	0.1±1.0	6.2±1.1	0.68	0.71	<0.001
Gurevich et al. (2021) [1]	178	8–15	−0.1±0.9	312±72	1.5±0.4	0.3±0.9	5.8±1.2	0.62	0.65	<0.001
Silverstein (2018) [4]	312	3–10	0.4±1.1	198±54	2.1±0.6	−0.2±1.2	6.8±1.4	0.71	0.69	<0.001
Mehls et al. (2008) [6]	156	4–11	0.1±1.0	234±67	1.9±0.4	0.2±0.8	6.4±1.3	0.66	0.70	<0.001
Lippe et al. (1993) [9]	189	7–13	0.2±0.9	278±64	1.6±0.5	0.1±1.0	6.0±1.2	0.69	0.68	<0.001
Pooled [1,3,4,6,9]	1,281	-	0.2±0.9	255±65	1.8±0.5	0.1±1.0	6.3±1.2

Values are presented as range or mean±standard deviation. Consistent associations are observed between kidney volume, circulating bioactive IGF-1, and linear growth across independent cohorts of healthy children.

IGF-1, insulin-like growth factor-1; SDS, standard deviation score.

Table 2.

Dysregulation of IGF-1 across different stages of CKD

CKD stage	No. (studies/patients)	Height SDS	Total IGF-1 (ng/mL)	Free IGF-1 (%)	IGFBP-3 (ng/mL)	eGFR (mL/min/1.73 m²)	r (eGFR–height)	Reference
CKD 2–3	18/1,567	−1.2±0.9	256±68	1.2±0.4	4,500±1,200	45.0±12.0	−0.58	[7,8]
CKD 4	15/1,234	−1.9±1.0	278±75	0.9±0.3	5,400±1,400	22.0±8.0	−0.69	[8,9]
CKD 5	17/1,789	−2.3±1.1	289±82	0.6±0.3	6,200±1,500	12.0±5.0	−0.74	[9,10]
Dialysis	14/1,456	−2.8±1.4	345±95	0.4±0.2	7,800±2,100	8.0±4.0	−0.71	[10,11]
Trend	64/6,046	Decreased significantly (−1.6 SDS)	Increased by 35%	Decreased by 67%	Increased by 73%	Decreased by 82%	More negative (−0.58 to −0.74)	[7–11]

Values are presented as mean±standard deviation. Stage-dependent dissociation between total and free IGF-1 concentrations in pediatric CKD, with declining eGFR associated with reduced bioavailable IGF-1 despite increasing total levels.

IGF-1, insulin-like growth factor-1; CKD, chronic kidney disease; SDS, standard deviation score; IGFBP-3, IGF binding protein-3; eGFR, estimated glomerular filtration rate.

Table 3.

Prevalence and predictors of growth failure across CKD stages

Age group	CKD stage 2–3 growth failure (%)	CKD stage 4–5D growth failure (%)	OR (95% CI) vs. healthy	Key independent predictors (β)	Reference
<5 yr	22.0	48.0	3.20 (2.10–4.80)	eGFR (−0.42), IGFBP-3 (0.31)	[12]
6–12 yr	35.0	62.0	4.50 (3.40–6.10)	Free IGF-1 (−0.38), IL-6 (0.29)	[14]
13–18 yr	28.0	55.0	3.80 (2.70–5.30)	Kidney volume (−0.45), Tanner stage (0.27)	[12,13]
Overall	28.0	55.0	3.80 (3.10–4.70)	eGFR + IGF-1 (R² = 0.62)	[12–14]

Values are presented as mean±standard deviation. Growth failure is most prevalent during the prepubertal period, particularly in advanced CKD. Key predictors include reduced renal function, altered IGF-1 signaling, and inflammatory burden.

CKD, chronic kidney disease; D, dialysis; OR, odds ratio; CI, confidence interval; eGFR, estimated glomerular filtration rate; IGFBP-3, IGF binding protein-3; IGF-1, insulin-like growth factor-1; IL-6, interleukin 6.

Table 4.

Response to recombinant human growth hormone therapy in terms of height, stratified by CKD stage

Duration (CKD stage)	No.	Δ Height SDS (treated)	Δ Height SDS (control)	Net gain (SDS)	IGF-1 response (× baseline)	Reference
1 yr (CKD 3–4)	567	0.6±0.4	−0.1±0.3	0.7	2.1±0.6	[15]
1 yr (CKD 5–dialysis)	456	0.4±0.3	−0.3±0.4	0.7	1.8±0.5	[16]
2 yr (all stages)	1,567	1.1±0.7	−0.3±0.5	1.4	2.4±0.8	[15,17]
>3 yr (pre-transplant)	789	1.5±0.9	−0.6±0.8	2.1	2.6±1.0	[18]
Pooled	3,379	1.0±0.7	−0.3±0.5	1.3	2.3±0.8	[15-18]

Values are presented as mean±standard deviation. Clinically meaningful and sustained height response to rhGH therapy across CKD stages, with greater gains observed with longer treatment duration and preserved renal function.

CKD, chronic kidney disease; SDS, standard deviation score; IGF-1, insulin-like growth factor-1.

Table 5.

Final height outcomes following recombinant human growth hormone therapy in pediatric patients with CKD

Cohort	No.	Age at final height (yr)	Final height SDS (treated)	Final height SDS (untreated)	Δ Final height gain (SDS)	Target final height SDS	Reference
CKD pre-transplant	567	17.8±1.2	−1.4±1.0	−2.4±1.3	1.0	−0.8±0.9	[19]
CKD post-transplant	345	18.1±1.1	−1.1±0.9	−2.0±1.1	0.9	−0.6±0.8	[19]
Dialysis → transplant	456	17.9±1.3	−1.6±1.2	−2.8±1.5	1.2	−0.9±1.0	[20]
Controls	678	18.0±1.0	−0.2±0.8	NA	NA	−0.1±0.7	[20]
Pooled treated	2,046	17.9±1.2	−1.3±1.1	−2.4±1.3	1.0	−0.7±0.9	[19,20]

Values are presented as mean±standard deviation. Improved final height outcomes with rhGH therapy in children with CKD, with benefits observed both before and after transplantation.

CKD, chronic kidney disease; SDS, standard deviation score; NA, not applicable.

Table 1 summarizes the characteristics of the included studies and presents the reported relationships between kidney volume, IGF-1 parameters, and linear growth indices in children, including height SDS, height velocity, correlation coefficients, and statistical significance. Data from the included studies demonstrate consistent associations between kidney volume, circulating bioactive IGF-1, and linear growth parameters in children [1,3-6]. Correlations observed across independent cohorts suggest that renal IGF-1 handling may contribute substantially to variations in childhood height, alongside classical endocrine regulation. Table 2 presents IGF-1 concentrations stratified by CKD stage. The data depict a stage-dependent dissociation between total and free IGF-1 concentrations in pediatric CKD. As eGFR declines, bioavailable IGF-1 decreases progressively despite stable or modestly elevated total IGF-1 concentrations, supporting functional IGF-1 deficiency as a contributing mechanism underlying growth impairment in CKD.

Growth failure is more frequently observed during the prepubertal period, particularly in advanced CKD stages (Table 3). This suggests a period of increased vulnerability during mid-childhood, when the disruptive effects of renal dysfunction on growth regulation are pronounced. In terms of response to rhGH therapy, a clinically meaningful and sustained response to rhGH therapy (in terms of height) was observed across CKD stages (Table 4). Greater gains were generally observed with longer treatment duration, particularly after at least 2 years of therapy, and in children with relatively preserved renal function, usually those with eGFR >15 mL/min/1.73 m² (CKD stages 3–4), whereas responses were less marked in stage 5 CKD or dialysis (eGFR <15 mL/min/1.73 m²). Furthermore, long-term rhGH therapy is associated with improved final height outcomes in children with CKD (Table 5). Treated children achieved higher near-adult height SDS compared with untreated peers, further corroborating its efficacy in achieving partial recovery toward genetic height potential when rhGH therapy is initiated and maintained appropriately.

In terms of the mechanisms underlying growth impairment in pediatric patients with CKD and the impact of therapeutic intervention, the literature supports a central role of the kidney in regulating bioactive IGF-1, with stage-dependent dysregulation of IGF-1 signaling in CKD (Fig. 1). This results in declining renal function, heightened vulnerability to growth failure during early childhood, and the capacity of rhGH therapy to restore growth velocity and improve final height outcomes.

Fig. 1.

Summary of growth regulation and therapeutic outcomes in pediatric chronic kidney disease (CKD). IGF-1, insulin-like growth factor-1; GH, growth hormone; eGFR, estimated glomerular filtration rate; rhGH, recombinant human GH; SDS, standard deviation score.

Supplementary Tables 2 and 3 (available online) showed that the overall methodological quality of the 20 appraised studies was moderate. Among the eight randomized controlled trials, risk of bias was generally low for randomization, outcome measurement, and selection of reported results, although some studies had concerns related to deviations from intended interventions and missing outcome data. In the 12 non-randomized studies, the main limitations were confounding, missing data, and participant selection, while reporting bias was less prominent. Overall, six studies (30.0%) were judged to have low risk of bias, nine (45.0%) had moderate risk or some concerns, and five (25.0%) had high or serious risk. Despite these limitations, the findings across studies were directionally consistent, supporting the robustness of the observed associations between renal function, IGF-1 axis alterations, and growth outcomes in pediatric CKD.

Discussion

This review synthesizes evidence from cohort studies and clinical trials to clarify the role of the kidney–IGF-1 axis in linear growth failure in children with CKD and to evaluate the impact of rhGH therapy on height outcomes in these children. Robust associations have been reported between renal volume, circulating total and free IGF-1 concentrations, and linear growth parameters across multiple pediatric cohorts [1,3-6]. These correlations highlight the significant effect of renal structure and function on interindividual variation in childhood height. Several studies indicate that free IGF-1 levels correlate more closely with height than total IGF-1, supporting the role of renal processing of IGFBPs in determining bioactive IGF-1 availability [3]. However, these findings are based mainly on observational data and should be interpreted as associative rather than causal evidence [1,4,5].

Renal volume has been proposed as a surrogate marker of nephron endowment and long-term growth capacity [4]. Longitudinal studies suggest that children with relatively preserved renal size demonstrate better height growth velocity than those with reduced renal volume. Early postnatal nephron maturation requires sustained IGF-1 signaling, and any impairment during this critical developmental window may result in reduced nephron number and subsequent growth impairment [5,19,20]. These findings reinforce the concept that renal development and growth plate function are biologically interconnected.

Several studies involving pediatric populations with CKD have consistently described progressive disruption of the IGF-1 axis [8,16,21-24]. Declining eGFR is reportedly associated with increasing accumulation of IGFBP complexes, limiting the proportion of bioactive IGF-1 available for growth plate signaling [8,16,22]. Despite stable or mildly elevated total IGF-1 concentrations, reduced levels of circulating free IGF-1 reflect impaired renal clearance of IGFBPs and altered IGF-1 bioavailability [8,16]. In addition, uremia-associated inflammation has been implicated in modifying hepatic IGFBP production and downstream signaling pathways, further contributing to functional IGF-1 deficiency [16,22,23]. Beyond alterations in circulating IGF-1, CKD may induce end-organ resistance to IGF-1 signaling [5,22]. As mentioned above, experimental studies have reported that uremic conditions and inflammatory mediators can impair IGF-1 receptor activation and downstream intracellular pathways within growth plate chondrocytes [22]. Metabolic acidosis, frequently present in advanced CKD, has also been associated with impaired cartilage matrix synthesis and reduced longitudinal bone growth [23]. Collectively, these mechanisms amplify the effects of reduced IGF-1 bioavailability and contribute to progressive growth failure. Growth impairment in CKD appears particularly pronounced during the prepubertal period, particularly in advanced disease stages [17,18]. Apart from experimental studies, observational data also suggest that reduced free IGF-1 concentrations and heightened inflammatory activity are associated with poorer height outcomes during this developmental window [17]. These findings support the concept that mid-childhood represents a period of increased vulnerability during which renal dysfunction and endocrine disruption may influence growth potential [17,18].

Despite intrinsic GH–IGF resistance, rhGH therapy has been associated with clinically meaningful improvements in height velocity and height SDS across multiple cohorts [6,9,10,15,25-29]. Height gains are generally greater with earlier initiation and longer treatment duration, particularly in children with relatively preserved renal function [6,14,18,29]. rhGH therapy increases circulating IGF-1 concentrations, thereby partially overcoming functional resistance at the growth plate [6,14]. However, given the known renal hemodynamic effects of IGF-1, careful monitoring of renal function and albuminuria is recommended during therapy [2,21]. Long-term follow-up studies suggest that rhGH therapy improves near-adult height compared with that in untreated children with CKD [7,9,11,18-20,30]. Although complete normalization of stature is not universally achieved, substantial recovery toward genetic height potential has been reported in many cases [7,9,18]. Future studies using predictive models incorporating baseline renal function, IGF-1 status, and timing of treatment initiation may help identify children most likely to benefit from therapy and further elucidate the importance of early, individualized intervention strategies [7].

Conclusions

Overall, the available evidence supports the kidney–IGF-1 axis as an important contributor to pediatric linear growth regulation. In CKD, disruption of this axis through altered IGFBP dynamics, receptor desensitization, inflammatory signaling, and metabolic disturbances contribute to functional IGF-1 deficiency and impaired growth. Evidence from observational and interventional studies indicates that early, stage-adjusted rhGH therapy improves growth velocity and supports attainment of near-adult height in many children with CKD, particularly when initiated promptly and carefully monitored. Together, these findings support a renal–endocrine framework of growth regulation in which kidney function is a meaningful determinant of childhood height in both healthy children and those with CKD.

Funding Statement

None.

Data availability statement

Data sharing is not applicable as no new data were created or analyzed in this study.

Supplementary Material

Supplementary materials can be found via https://doi.org/10.3339/ckd.26.009.

Supplementary Table 1.

Study-to-table crosswalk (n=54)

Supplementary Table 2.

Risk-of-bias assessment of randomized and non-randomized studies contributing to growth outcome synthesis (n=20)

Supplementary Table 3.

Overall quality summary of the appraised studies (n=20)