Impact of glucocorticoid therapy on hypothalamic-pituitary-adrenal axis function in pediatric nephrotic syndrome: A narrative review

Abstract

Glucocorticoids (GCs) such as prednisolone are widely used in conditions like nephrotic syndrome, asthma, and autoimmune diseases. However, prolonged or high-dose use may suppress the hypothalamic-pituitary-adrenal (HPA) axis, leading to secondary adrenal insufficiency (AI). This condition occurs when the adrenal glands fail to produce adequate cortisol, which is essential for regulating metabolism, immune response, and stress adaptation. Corticotropin-releasing hormone (CRH) from the hypothalamus stimulates the pituitary to release adrenocorticotropic hormone (ACTH), which then triggers cortisol production in the adrenal glands. Prolonged GC use disrupts this system by inhibiting CRH and ACTH secretion, leading to adrenal atrophy and reduced cortisol production. HPA axis suppression is primarily diagnosed through dynamic tests. Early morning cortisol levels above > 18 ng/mL typically indicate normal function, while levels < 3 ng/mL suggest AI. Intermediate values require additional testing, such as the insulin tolerance test, ACTH stimulation test, and metyrapone test. Prednisolone in nephrotic syndrome suppresses the HPA axis, heightening AI risk, influenced by dose, duration, and timing of administration. Careful GC management is essential to balance disease control with risks of HPA axis suppression. Early recognition and timely intervention can prevent adrenal crises and improve outcomes in pediatric patients.

Key Words: Glucocorticoids; Hypothalamic-pituitary-adrenal axis; Adrenal insufficiency; Nephrotic syndrome; Prednisolone; Cortisol; Hypothalamic-pituitary-adrenal axis suppression; Steroid therapy; Low-dose Synacthen test

Core Tip: Children with nephrotic syndrome often require repeated glucocorticoid therapy, which can lead to hypothalamic-pituitary-adrenal axis suppression and secondary adrenal insufficiency. This impaired stress response may contribute to relapse during infections. This review summarizes the mechanisms, diagnostic methods, clinical implications, and preventive strategies, underscoring the need for early identification and tailored steroid management to reduce long-term risks.

INTRODUCTION

Glucocorticoids such as prednisolone are commonly used in treating nephrotic syndrome, and repeated courses with often-prolonged use are common. Exposure to exogenous glucocorticoids, even at low doses and for brief periods, can result in detectable suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Secondary adrenal insufficiency is found in 150 per million in the general population[1]. It is rare in children and is usually caused by exposure to prolonged high-dose steroids[2]. Patients with acute adrenal insufficiency present with severe symptoms like hypoglycemia, hypovolemia, and altered mental status, while those with chronic adrenal insufficiency are usually asymptomatic or present with nonspecific symptoms such as anorexia, weight loss, fatigue, myalgias, abdominal pain and psychiatric symptoms. Hence, a high index of clinical suspicion and appropriate biochemical evaluation are needed to diagnose chronic adrenal insufficiency. As corticosteroids remain the mainstay in the treating childhood nephrotic syndrome, they are more prone to develop HPA axis suppression. During any stressful condition like an upper respiratory infection (URTI), children with a suppressed HPA axis may be prone to relapse due to the inability to mount an appropriate response to infection. These might explain the hypothesis of steroid supplementation during URTI for preventing/reducing relapse risk[3].

However, the extent of HPA axis suppression in children with nephrotic syndrome remains unclear. Moreover, the current literature does not establish any direct link between HPA axis suppression and disease relapse and other potential consequences, such as immune dysfunction and increased susceptibility to infections. The objective of this review is to explore the current understanding of glucocorticoid-induced HPA axis suppression in children with nephrotic syndrome, with a focus on its potential role in disease relapse and other clinical consequences. The expected outcome is synthesizing available evidence, identifying knowledge gaps, and providing insights that may improve clinical monitoring. An electronic search was conducted across the following databases: PubMed, EMBASE, Scopus, and CENTRAL (Cochrane). In addition, reference lists of relevant articles were manually screened to identify any further eligible studies. The complete search strategy is presented in Supplementary Table 1.

HPA AXIS PHYSIOLOGY

The HPA axis is a complex system of neuroendocrine pathways wherein feedback loops among the hypothalamus, pituitary, and adrenal glands regulate and sustain physiological homeostasis. In response to stress, corticotropin-releasing hormone (CRH) is secreted by the paraventricular nucleus of the hypothalamus, which stimulates the release of adrenocorticotropic hormone (ACTH) from the pituitary gland into circulation. ACTH prompts the adrenal glands to synthesize and release corticosteroids, primarily cortisol and corticosterone.

Synthesis and secretion of glucocorticoids from adrenal glands follow a circadian pattern, which is regulated by the central circadian oscillator in the suprachiasmatic nucleus of the hypothalamus[4]. In healthy individuals, cortisol peaks in the early morning (6:00 am to 9:00 am) and gradually declines to minimal levels by late evening (11:00 pm to 1:00 am)[5]. Corticosteroids are crucial to a wide range of physiological functions influenced by the HPA axis, such as stress response, immune response and regulation of inflammation, carbohydrate and protein metabolism, and regulation of blood electrolyte levels. Corticosteroids can also initiate a negative feedback loop within the HPA axis via glucocorticoid receptor activation in the brain to shut down its production (Figure 1). Thus, a deregulated HPA axis can cause several pathologies.

Figure 1 Hypothalamic-pituitary-adrenal axis. CRH: Corticotropin-releasing hormone; ACTH: Adrenocorticotropic hormone.

METHOD TO DETECT HPA AXIS SUPPRESSION

The normal cortisol output from the adrenal glands most accurately reflects HPA axis integrity. There is a fluctuation in serum cortisol levels because of pulsatile and diurnal patterns in cortisol secretion, even among healthy individuals. To overcome this issue, dynamic tests such as adrenal or corticotropin stimulation or hypoglycemia are needed to assess corticotropin function (Table 1).

Table 1 Tests to detect hypothalamic-pituitary-adrenal axis integrity.

Test name	Methods	Expected result
Serum cortisol level	Measurement of early morning between 7:00 am to 9:00 am	Normal: Serum cortisol level ≥ 18 μg/dL. Insufficient: < 3 μg/dL. Indeterminate: 3-18 μg/dL
Insulin tolerance testing	Insulin (0.05 0.15 U/kg IV). Serum measurements of cortisol at 0, 30, 60 minutes	Normal: Peak cortisol ≥ 18 μg/dL. Insufficient: Serum cortisol level < 18 μg/dL
Metyrapone test	Metyrapone 30 mg/kg administered at midnight and measurement of serum cortisol and 11-deoxycortisol at 8:00 the next morning	Serum cortisol < 7 μg/dL confirms enzymatic blockade. Normal: Serum 11-deoxycortisol > 7 μg/dL. Insufficient: Serum 11-deoxycortisol, 7 μg/dL
ACTH stimulation test	Synthetic ACTH (250 μg IV or IM or 1 μg IV). Serum measurements of cortisol at 0, 30, 60 minutes	Normal: Serum cortisol level ≥ 18 μg/dL. Insufficient: Serum cortisol < 18 μg/dL

ACTH: Adrenocorticotropic hormone.

Early morning serum cortisol level

An early morning (7:00 am to 9:00 am) serum cortisol level greater than 18 ng/mL is often used as a threshold to indicate an adequate adrenal response in dynamic testing. While levels < 3 ng/mL strongly suggests adrenal insufficiency, intermediate values typically require dynamic testing for confirmation[6].

Insulin tolerance testing

Insulin tolerance testing is widely regarded as the gold standard for diagnosing adrenal insufficiency, particularly for detecting secondary adrenal insufficiency. Inducing symptomatic hypoglycemia (blood glucose < 40 mg/dL) with intravenous insulin (0.1 units/kg), followed by a cortisol level > 18 ng/mL at 0, 30, and 60 minutes, indicates a normal response[7]. The procedure is generally performed in a specialized facility, with measures in place to minimize the risk of hypoglycemia and adrenal crisis. Because of its potential complication, it is not standard in clinical practice, particularly among children.

Metyrapone test

Metyrapone inhibits 11β-hydroxylase, reducing cortisol synthesis and thereby diminishing negative feedback on the HPA axis. The test is performed by administering 30 mg/kg metyrapone at approximately midnight, and measuring serum cortisol and 11-deoxycortisol levels the next morning (8:00 am). A serum cortisol concentration < 7 μg/dL indicates effective enzyme inhibition, consistent with adrenal insufficiency[8]. This test can be performed without hospital admission. If baseline morning cortisol levels are < 7 μg/dL, the test should be postponed to prevent adrenal crisis risk.

ACTH stimulation testing

This is the standard test most often used to assess adrenal gland function. The standard ACTH stimulation test involves administering 250 μg/m² (or a fixed dose of 250 μg) of synthetic ACTH via intravenous or intramuscular injection. Serum cortisol levels are obtained at baseline, 30 and 60 minutes. Peak serum cortisol levels > 18 ng/dL indicate normal adrenal reserve[8]. Some modifications of this test include: (1) ACTH injection replaced by an 8-hour infusion test; and (2) Low-dose ACTH stimulation test (LDST) to improve sensitivity.

In LDST, 1 μg synthetic ACTH has been used for this purpose. Synthetic ACTH is not commercially available in 1 μg doses; a dilution can be prepared by mixing 250 μg of ACTH with 249 mL normal saline, resulting in a 1 μg/mL concentration. Studies have demonstrated similar or even better sensitivity for secondary adrenal insufficiency with LSDT. Further modification of LDST has been performed with 0.5 μg/m² (or 0.5 μg) ACTH. Abu Bakar et al[9] demonstrated that 35% of children with nephrotic syndrome exhibited HPA axis suppression on LDST, including those with normal early morning cortisol levels[9]. Mild forms of adrenal insufficiency, sometimes missed by standard ACTH stimulation tests, can be detected by LDST[10]. The definite cut-off cortisol level for diagnosing HPA axis suppression varies according to the method and dose of ACTH used. In an adult study involving primary adrenal insufficiency, Mongioì et al[11] reported that a serum cortisol threshold of 500 nmol/L achieved perfect sensitivity (100%) and notable specificity (67.3%). Increasing the cortisol threshold to 550 nmol/L in LDST resulted in 100% sensitivity and 89% specificity[9].

CRH stimulation test

The test is performed by administering 100 μg CRH (bovine or human) intravenously, and blood levels are measured at 0, 15, 30, 45, 60, 90, and 120 minutes. The intact HPA axis is indicated by a two- to fourfold increase in ACTH from baseline.

ROLE OF CORTICOSTEROIDS IN NEPHROTIC SYNDROME

Glucocorticoid performs potent anti-inflammatory and immunosuppressant action by both genomic and non-genomic mechanisms[12-14]. Due to its lipophilic nature, it easily diffuses across the cell membrane, binds to cytoplasmic glucocorticoid receptors and exerts its genomic function by activating or repressing specific genes encoding anti- and pro-inflammatory proteins. Compared with genomic mechanisms, non-genomic mechanisms do not alter gene expression; their effects occur rapidly and are short-lived. Prednisolone is the first-line drug of choice for nephrotic syndrome, both at initial presentation and during relapse. However, the exact action mechanism is still unclear and can be variable, ranging from direct action on podocytes to immune regulation[15].

HPA SUPPRESSION IN NEPHROTIC SYNDROME

A supraphysiologic dose of exogenous glucocorticoids suppresses the HPA axis by reducing both the production and release of CRH and inhibiting CRH’s stimulatory effects on the anterior pituitary to release ACTH. This leads to reduced ACTH synthesis and subsequent atrophy of corticotroph cells in the anterior pituitary. Consequently, the adrenal cortex cannot produce sufficient cortisol. If this inhibition continues after withdrawal of exogenous glucocorticoids, it is defined as suppression of the adrenal or HPA axis. HPA axis suppression can continue for 6-12 months after treatment cessation[16]. HPA axis suppression depends on several factors, including: (1) Timing of steroid administration - morning doses are less likely to cause suppression[17]; (2) Formulation - long-acting preparations cause greater suppression; (3) Duration of therapy - prolonged exposure leads to sustained suppression; and (4) Route of administration - suppression can occur with oral, topical, or inhaled steroids, but is more pronounced with parenteral administration[18]. Studies also showed that treatment with fluconazole can extend the adrenal insufficiency period[19,20]. HPA axis suppression seems to be a significant contributor to nephrotic syndrome relapse. Still, no age-specific cut-offs for corticosteroid duration or dose that result in HPA axis suppression are uniformly established. However, suppression is more likely when corticosteroids are administered for more than 2–3 weeks, particularly at doses ≥ 2 mg/kg/day or 20–30 mg/day, which exceed physiologic levels[21]. Prolonged use of supraphysiologic steroid doses (> 7.5 mg/day prednisolone) further suppresses ACTH secretion and leads to adrenal cortical atrophy[22-24]. This is particularly relevant in children, where developmental variations in HPA function must also be considered[25]. Children with nephrotic syndrome are usually exposed to supra-physiologic doses of steroids to achieve disease control, which inhibits cortisol production. Even a short 14-day course of oral steroids can produce biochemical evidence of HPA axis suppression lasting up to 24 months, depending on the dose and duration of exposure[26-28].

In nephrotic syndrome, most of the available data on HPA axis suppression are centered on prednisolone, which remains the primary treatment in both initial and relapsing cases (IPNA, KDIGO). Other corticosteroids used include methylprednisolone pulses, particularly in steroid-dependent/frequently relapsing or steroid-resistant cases. Deflazacort has also been employed in some centers historically, though its use has become less common. Although comparative data are limited, it is well established that all glucocorticoids can cause HPA axis suppression, with the degree of risk varying according to their potency, half-life, and systemic bioavailability[29,30]. The impact of glucocorticoids on the HPA axis should be considered as a class effect rather than attributed solely to prednisolone, as each steroid has a distinct risk profile determined by its bioavailability, receptor affinity, and duration of action[30]. Future prospective studies are needed to define steroid-specific thresholds for HPA suppression and to identify regimens that balance disease control with minimal risk of adrenal insufficiency. Such research would be instrumental in individualizing therapy and improving long-term outcomes in children with nephrotic syndrome.

CLINICAL IMPLICATIONS OF HPA AXIS SUPPRESSION IN NEPHROTIC SYNDROME

A suppressed HPA axis impairs the ability to respond to stressors such as infection difficult and may precipitate acute adrenal insufficiency with circulatory collapse. Therefore, standard guidelines recommend administering stress-dose steroids during incurrent illness or surgery[3,31]. This may partially explain why children with frequently relapsing nephrotic syndrome often experience fewer relapses when treated with low-dose daily or alternate-day steroids, even during stressful events such as URTI[3,31,32]. Leisti et al[33] were the first to note that children with marked HPA axis suppression had a higher relapse risk and that administering low glucocorticoid doses helped reduce relapse frequency. The observation was explained by inadequate stress-induced glucocorticoid production in nephrotic syndrome cases with HPA axis suppression. Subsequently, several reports suggested that supplementation of at least 0.5 mg/kg daily for 5-7 days might reduce relapse during URTI[33-38]. Thus, the 2021 KDIGO guidelines advised short-term daily glucocorticoid therapy (0.5 mg/kg for 5–7 days) during infections like URTIs to minimize relapse rates in children with FRNS or SDNS[32]. More recently, Christian et al[39] examined the above hypothesis in the PREDNOS2 randomized control trial and found no benefit. Despite these findings, it it is important to note that previous randomized controlled trials were conducted in tropical climates, whereas the PREDNOS2 trial was performed in a temperate climate[39]. In addition, the role of ethnicity could not be fully addressed. Although not statistically significant, South Asian children who switched to daily steroids at the onset of URTI had a lower relapse rate in the PRREDNOS2 trial, which was not sufficiently powered for this sub-analysis. Asian children are recognized to have higher steroid dependence, and in the sub-continent, more intensive and prolonged steroid regimens are often required. Consequently, they are more likely to develop HPA axis suppression, which may help explain the differing outcomes between PREDNOS2 and other studies. The latest IPNA guidelines recommend transitioning to daily steroid therapy for children on low-dose alternate-day prednisolone who have a pattern of frequent infection-triggered relapses[3].

Studies reporting the prevalence of HPA axis suppression in nephrotic syndrome following corticosteroids are summarized in Table 2[9,17,33,40-43]. Abeyagunawardena et al[40] observed a high prevalence (62.5%, n = 32) of HPA axis suppression in steroid-dependent nephrotic syndrome, even while on alternate-day prednisolone. Mantan et al[41] reported that up to 40% of children receiving low-dose steroids exhibited HPA axis suppression. In a systematic review, Aljebab et al[16] analyzed the effect of short-course oral and inhaled corticosteroids (≤ 14 days) in children with asthma and found that the HPA axis was suppressed in 43 out of 53 (81%) patients. M et al[42] reported that among 80 children with nephrotic syndrome, 32.5% developed HPA suppression after discontinuing prednisolone. Recovery improved from 39% at 1 month to 23% at 6 months. A basal cortisol concentration > 138 nmol/L (OR 25.0; P = 0.03) and a prolonged steroid-free duration (OR 10.07; P = 0.019) were significantly associated with recovery. In a study of 52 children (mean age 9.4 years) with steroid-sensitive (n = 27) and steroid-resistant nephrotic syndrome (n = 25), Krishna et al[43] found that 64% had adrenal insufficiency, defined by an ACTH-stimulated cortisol level < 18 μg/dL. A cumulative prednisolone dose exceeding 0.22 mg/kg/day predicted suppression with an AUC of 0.76, sensitivity of 63.9%, and specificity of 81.3%. Theoretically, early morning corticosteroids, coinciding with endogenous cortisol surge, are likely to cause less HPA axis suppression[44]. Our group recently confirmed this in a randomized controlled trial involving children with nephrotic syndrome, where a single early morning prednisolone dose prevented HPA axis suppression and resulted in longer time to first relapse compared to a divided dose regimen[17].

Table 2 Studies evaluating hypothalamic-pituitary-adrenal axis suppression in children with nephrotic syndrome.

Ref.	Patient characteristics	Sample size	Method of evaluation	HPA suppression (%)	Conclusion of the study
Leisti et al[33], 1983	SSNS	47	Two-hour ACTH test	51	HPA axis suppression increased relapse risk. Cortisol substitution may prevent relapse in severe suppression, but not in moderate cases
Abeyagunawardena et al[40], 2007	SSNS with LTAD	32	LDST, Synacthen 0.5 mg	62.5	SSNS on LTAD risk HPA suppression. Assess HPA suppression via modified LDST. HPA suppression in SSNS on LTAD increases relapse risk
Mantan et al[41], 2018	SSNS on LTAD	70	Morning serum cortisol levels	40	NS on prolonged LTAD should screened for HPA suppression using single morning cortisol, confirmed by LDST
Abu Bakar et al[9], 2020	SSNS, off steroid for 4–6 weeks	37	LDST, Synacthen 0.5 μg/m2	35	HPA suppression can be missed without proper screening. Normal early morning cortisol alone can’t rule out HPA suppression. LDST is useful, especially in children under 5 years
Khan et al[17], 2023	First episode NS, on steroid	60	Synacthen test	100 in divided dose. 83 in single dose	Single and divided-dose prednisolone equally effective for remission. Single-dose causes less HPA axis suppression. Single-dose delays time to first relapse
M et al[42], 2025	First episode. SSNS, off steroid 4 weeks	80	Early morning baseline and ACTH stimulation	32.5	Around 66% of children with mild NS showed HPA recovery within 1–6 months post-steroids. Duration since cessation and basal cortisol independently predicted recovery
Krishna et al[43], 2024	SSNS (52%), SRNS (48%), off steroid (11.5%) and/or LTAD (88.5%)	52	Baseline and ACTH stimulation	Baseline: 50%. Post ACTH stimulation: 60%	Adrenal insufficiency was common in children with nephrotic syndrome. Steroid dose > 0.22 mg/kg/day (alternate days) predicted adrenocortical suppression

SRNS: Steroid-resistant nephrotic syndrome; NS: Nephrotic syndrome; HPA: Hypothalamic-pituitary-adrenal; SSNS: Steroid sensitive nephrotic syndrome; LTAD: Long-term low dose alternate day; LDST: Low-dose adrenocorticotropic hormone stimulation test; ACTH: Adrenocorticotropic hormone.

The underlying mechanism of nephrotic syndrome relapse in children with HPA axis suppression is complex and multifactorial. The current hypotheses on its pathogenesis have evolved from ‘immune dysregulation’ and ‘increased glomerular permeability’ to ‘podocytopathy’[45]. The hallmark of nephrotic syndrome is proteinuria, strongly related to cytokines, namely interleukin 2, 4 and 13. In URTI, nephrotic syndrome relapse is primarily triggered by viral infection, possibly resulting in cytokine release and causing immune dysregulation. Most immune suppressive medicines influence cytokine production, a mechanism used to achieve nephrotic syndrome remission. Therefore, patients with HPA axis suppression have heightened cytokine responses to infection, leading to relapse. Thus, adrenal insufficiency is not a direct cause of relapse but may contribute to clinical deterioration in specific scenarios, such as abrupt steroid withdrawal, intercurrent infections, or inadequate stress-dose corticosteroid coverage, potentially exacerbating or mimicking the features of nephrotic relapse[28,29,46]. Such groups of patients will benefit in the short term by adding steroids at the onset of stress. In the long term, they may benefit by using glucocorticoid-sparing agents, which allow the HPA axis to recover.

STRATEGIES TO MINIMIZE HPA SUPPRESSION

Use of standardized protocols

Adhering to evidence-based steroid regimens (e.g., KDIGO or IPNA guidelines) ensures appropriate dosing and duration, reducing unnecessary exposure.

Avoid over-treatment

Extending the course of steroids beyond recommended durations does not reduce relapse rates but increases the risk of HPA suppression.

Gradual tapering

Taper steroids slowly after prolonged use (> 4 weeks) to allow recovery of endogenous adrenal function and reduce the risk of adrenal insufficiency.

Consider alternate-day therapy

In patients with frequent relapses or steroid dependence, alternate-day dosing may reduce cumulative HPA axis suppression while maintaining remission.

Monitor for suppression

Clinical signs (e.g., fatigue, hypotension, hypoglycemia) and biochemical tests (e.g., morning cortisol, ACTH stimulation test) should be used in at-risk patients, especially before stopping steroids or during intercurrent illness.

Educate caregivers

Parents should be counseled on the risk of adrenal insufficiency and the need for stress-dose steroids during illness, surgery, or trauma.

Steroid-sparing strategies

In patients with frequent relapses, early introduction of steroid-sparing agents (e.g., levamisole, mycophenolate mofetil, or cyclophosphamide) can reduce cumulative steroid exposure.

CONCLUSION

The frequency of glucocorticoid-related HPA axis suppression is high. Still, the onset and duration of adrenal insufficiency vary in different studies, probably due to the heterogeneous methods of HPA axis evaluation and the heterogeneous study population. Various techniques are available to assess the integrity of the HPA axis. The Synacthen stimulation test is frequently used in clinical practice. Still, LDST can be a more appropriate test in routine clinical practice to identify children with HPA axis suppression after a course of steroids. These children might benefit from steroid supplementation in the presence of any stress, including viral URTI. Future studies on the use of steroids during URTI to prevent relapse should incorporate HPA axis assessment for better clinical correlation.