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

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.

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.