Adrenal Insufficiency in Children With Nephrotic Syndrome Treated With High Doses of Glucocorticoids

Nephrotic syndrome is a condition in which the glomeruli of the kidney leak protein from the blood into the urine. It results in hypoproteinaemia and generalised oedema. The disease has a 70% risk of relapse [1]. Idiopathic nephrotic syndrome is a rare disease and has the incidence of 2 of 100 000 children corresponding to 20–25 new cases in Denmark. Mean age of debut is 5 years of age. The standard treatment of nephrotic syndrome consists of prednisolone 60 mg/m2/day for 4 weeks, followed by 4 weeks with 40 mg/m2/day and another 4 weeks with weekly tapering until termination of the treatment. The treatment with high doses of prednisolone may cause suppression of the hypothalamic–pituitary–adrenal axis (HPA) [2]. Patients with unrecognised adrenal suppression who are subjected to physiological stress such as injury, surgery, severe infection can develop symptoms of adrenal insufficiency and potentially develop an adrenal crisis. The signs and symptoms of adrenal suppression are non-specific and may easily be missed or misdiagnosed. Non the less the standard treatment of nephrotic syndrome does not routinely lead to testing for adrenal suppression at the end of the treatment period. The standard treatment of nephrotic syndrome does not routinely include testing for adrenal suppression at the end of the treatment period. We prospectively included 14 children with nephrotic syndrome from 1 October 2019 until 31 December 2023 from the paediatric departments at two university hospitals in Copenhagen. A non-fasting adrenocorticotropic hormone (ACTH) stimulation test with 250 μg ACTH (Synacthen, tetracosactide 0.25 mg/mL, New Neopharm BV, Netherlands) as a bolus was performed after tapering to the lowest dose of glucocorticoids (Gc). Gc was not taken on the test. Serum ACTH was measured at 0 min (reference range 1.2–16.7 pmol/L). At 0 min, serum sodium, potassium, albumin and creatinine were measured. Serum cortisol was analysed by using high performance liquid chromatography at 0, 30 and 60 min. A response above 440 nmol/L at any time was considered normal; 400–440 nmol/L was classified as borderline. Patients with adrenal insufficiency were treated with hydrocortisone three times daily (8–10 mg/m2), with a borderline response only on sick days until a normal response. The stimulation test was repeated every 3 months until normal. The data analysis was performed using Microsoft Excel and IBM SPSS. For all statistical tests, a P-value less than 0.05 (p < 0.05) was used as statistical significance. Non-parametric Spearman's tests were used to assess the correlation between the mean serum cortisol at 60 min and the accumulated dose of Gc in the whole treatment period and 7 days before the synachten test. The study was conducted in accordance with the Helsinki II declaration after written informed consent from all parents or guardians. The study was approved by the ethical committees of the Capital Region of Denmark (H-19028533). Fourteen patients were included. A detailed description of the patients, their treatment, the accumulated dose of Gc 7 days before the ACTH test and test results is shown in Table 1. Four patients (28%) had an insufficient ACTH response; two patients (14%) had a borderline response. None of the patients had clinical symptoms. All patients had normal sodium, potassium, albumin and creatinine levels. There was no correlation between the mean serum cortisol at 60 min and the accumulated dose of Gc in the whole treatment period and 7 days before the synachten test. One patient with a pathologic synachten test had eight tests within 2 years before normalisation. ACTH was suppressed at the first test, but within the normal range hereafter (1.9–6.3 pmol/L). The two patients with borderline synachten test and three patients with pathologic test results showed normal response at re-testing 3 months later. We found that 28% of the patients with nephrotic syndrome treated with high doses of Gc showed transient and mild, asymptomatic adrenal insufficiency without any adrenal crisis. Our findings were in accordance with a recent study showing 35.1% of patients with adrenal suppression after treatment with high doses of Gc [3]. We could not find a correlation between adrenal insufficiency and the cumulated Gc dose. Our data suggest that the risk of adrenal insufficiency may be highly individual and thus difficult to predict. We found that, except for one case, children with borderline or pathologic adrenal suppression quickly recover. Recently, an Indian study found a significant proportion of children with nephrotic syndrome and reported that a cumulative steroid intake of > 0.22 mg/kg/day on an alternate day basis emerged as a risk factor for adrenal suppression [4]. Our study could not corroborate this. We had difficulties recruiting patients, resulting in a long recruitment period. We speculate that this may be related to the lack of symptoms in their patients or a general lack of awareness of the risk related to Gc treatment. It has previously been described that children with HPA suppression may have a greater risk for relapse of nephrotic syndrome [5]. We could not reproduce these results, likely due to the relatively small number of patients included in our study. It is important to draw attention to the risk of adrenal insufficiency when treating patients with high doses of Gc and to consider treatment with steroid-sparing agents. We suggest performing a synachten test in case of infection in children with nephrotic syndrome, if they were not tested at the end of their treatment. We recommend a prospective multicenter study to find the incidence of adrenal insufficiency and to further study the impact of having HPA suppression on the risk of relapse. Furthermore, the ideal timing of performing a synachten test should be studied for the early identification of patients with HPA axis suppression. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.