Adrenocortical suppression in children with nephrotic syndrome treated with corticosteroids

doi:10.21203/rs.3.rs-3250716/v1

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Adrenocortical suppression in children with nephrotic syndrome treated with corticosteroids

https://doi.org/10.21203/rs.3.rs-3250716/v1

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published 23 Jan, 2024

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Background: While single morning cortisol values are used for screening, an ACTH stimulation test is more definitive to identify adrenocortical suppression in children with nephrotic syndrome.

Methods: This cross-sectional study enrolled children (2-18 years) with both SSNS (n=27) and SRNS (n=25); those on daily prednsiolone or having serious bacterial infections or hospitalized were excluded. The primary objective was to determine prevalence of adrenocortical suppression in those on low dose alternate day steroids for more than 8 weeks or having received >2mg/kg/d for more than 2 weeks in past 1 year and currently in remission. A baseline morning fasting sample of serum cortisol was taken and 25 IU of ACTH (Acton Prolongatum*) injected intramuscularly and repeat serum cortisol sample was taken after 1 hour. All patients with 1 hr post ACTH cortisol <18.0 µgm/dl were diagnosed with adrenal insufficiency. Receiver operating characteristic curve was drawn to predict the prednisolone dose for adrenal insufficiency.

Results: 52 (33 males) children were enrolled (meanage 9.4years);proportion of adrenal insufficiency was 50% and 64% using baseline and poststimulationcutoffs. The total cumulative annual dose of prednisolone 0.22 mg/kg/day predicted adrenocortical suppression with AUC 0.76 (95% CI as 0.63-0.89), with a sensitivity of 63.9% and specificity of 81.3%.

Conclusions: A significant proportion of children with nephrotic syndrome were detected with adrenal insufficiency on ACTH stimulation test. A cumulative steroid intake of > 0.22 mg/kg/day emerged as a risk factor for predicting adrenocortical suppression.

ACTH stimulation

cortisol

adrenocortical suppression

nephrotic syndrome

Cushingoid

prednisolone

Nephrotic syndrome is a chronic disorder in children characterized by selective proteinuria (primarily albumin) of > 40 mg/m²/h or a spot urine protein to creatinine ratio of > 2 mg/mg and manifested by edema, proteinuria, hypoalbuminemia, hyperlipidemia. More than 90% children respond to treatment with oral steroids, and about 60% patients have a frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS) that requires a prolonged period of steroid therapy or treatment with other immunosuppressant(s) like alkylating agents, levamisole and mycophenolate mofetil and rituximab. Children with steroid resistant disease are treated with drugs like calcineurin inhibitors (CNI) cyclosporine and tacrolimus along with low dose alternate day prednisolone for prolonged duration [1].

Adrenal suppression refers to decreased or inadequate cortisol production that results from the exposure of hypothalamic-pituitary-axis (HPA) from exogenous corticosteroids. Adrenal suppression has been demonstrated after exposure to even 5 days of high dose glucocorticoid therapy [2]. In practice, children with nephrotic syndrome are exposed to frequent and prolonged courses of corticosteroids, and are more likely to have an iatrogenic cause of adrenocortical suppression. The signs and symptoms of adrenal suppression are very non-specific and may be easily missed or misdiagnosed. If adrenal suppression is left unrecognized and the body is subjected to physiological stress, such as injury, surgery, severe infection, pronounced physical activity, and psychological stress, the condition can lead to an adrenal crisis [3].

Adrenocortical suppression in documented in children treated with steroids for non-renal systemic conditions like asthma, leukemia, Duchenne muscular dystrophy [4–6]. A previous study from our centre on adrenocortical suppression in children with nephrotic syndrome receiving alternate day low dose steroids identified 40% suppression using single morning cortisol values [7]. While single low morning cortisol can be used for screening of adrenocortical suppression, the confirmation by adrenocorticotropic hormone (ACTH) stimulation is discriminatory with the need of further endocrinology referral. A few studies in children with nephrotic syndrome have ascertained the proportion of adrenal insufficiency as 35-62.5% in first few months after steroids [8–10]. It is evident that adrenal suppression is associated with increased mortality and morbidity in children with nephrotic syndrome and other conditions but there is no clear protocol on the assessment of adrenal suppression in children with nephrotic syndrome.

The insulin tolerance test is one of the dynamic function test that estimates the body’s response to hypoglycaemia by measuring cortisol and growth hormone levels. However, the test requires strict monitoring for induced hypoglycaemia and is no longer preferred in children. The standard synacthen test with 250 ug of ACTH is the most widely used test to diagnose adrenal insufficiency. The availability of synacthen is limited in India making this test nonfeasible for testing adrenal function. The modified form of ACTH available as ACTH prolongatum has been validated for testing adrenal insufficiency in earlier studies [11]. This form of ACTH is widely used in management of West syndrome in children.

The present study was done to measure the proportion of children and adolescents with nephrotic syndrome having adrenocortical suppression as assessed by ACTH (Acton prolongatum) stimulation test who were on alternate day prednisolone (< 1mg/kg/d) for atleast 8 weeks or those having received > 2mg/kg/d for more than 2 weeks in past 1 year and presently in remission.We also aimed to study of association of cortisol levels with disease type, duration and doses of prednisolone therapy.

This cross sectional study enrolled children and adolescents with nephrotic syndrome (steroid sensitive or steroid resistant) in age group of 2-18 years attending outpatient or Pediatric Nephrology Clinic of a tertiary care teaching hospital. The study was approved by the Ethics Committee of the institute and written informed consent/assent was taken from the caregivers/patients enrolled.

Parents of children with nephrotic syndrome fulfilling the inclusion criteria were approached for enrolment. Children and adolescents with steroid sensitive (SSNS) or steroid resistant nephrotic syndrome (SRNS) in the age group of 1-18 years, presently in remission (partial or complete) and who received daily prednisolone in any dosage for ≥ 2 weeks in the last 1 year and had completed steroid therapy, or were presently receiving low dose alternate day prednisolone therapy (<1 mg/kg/day) for atleast 8 weeks. Children were excluded if they had received daily corticosteroid therapy in any dosages in the last 8 weeks, were having serious bacterial infections like pneumonia, cellulitis, sepsis, meningitis etc or were hospitalized for any reason.

The primary outcome was to estimate the proportion of patients having adrenocortical insufficiency defined as serum cortisol <18 ug/dL by ACTH (Acton prolongatum) stimulation test [12]. The secondary outcomes were to associate the disease type, duration, cumulative steroid doses with serum cortisol values. A pre-structured data collection form consisting of clinical details and history regarding age of onset, type of disorder (steroid sensitive or resistant), cumulative dose of steroids in the last one year, and current treatment regimen was filled. The anthropometry including weight and height, body mass index (BMI) and blood pressures of the subject were recorded. Weight, height and blood pressure of the patients was interpreted as per age and gender-specific charts [13,14].

Clinical features of corticosteroid toxicity were assessed through a detailed history and clinical examination for moon facies, nuchal hump, dermatologic changes like purple striae, stretch marks, cataracts. Any signs and symptoms of adrenocortical suppression like nausea, vomiting, myalgia, arthralgia, diarrhoea, fatigue, morning headache and psychiatric symptoms were assessed. Clinical remission was ascertained by absence of edema and proteinuria on dipsticks. The remission was further confirmed by biochemical tests.

A five mL of venous blood sample was collected from each patient under all aseptic precautions on a pre decided day on which no steroid dose was scheduled (at 8 am after overnight fasting). One of the serum aliquots was processed for lipid profile including serum cholesterol, high-dose lipoproteins (HDL), low-dose lipoproteins (LDL) and triglyceride, urea, creatinine, electrolytes (sodium, potassium, and calcium), fasting blood sugar and serum protein and albumin levels, and was tested by fully automated clinical chemistry analysers. Second serum aliquot was separated for baseline serum cortisol levels and the third aliquot collected in EDTA vial was processed for glycated hemoglobin (HbA_1C) and tested by D-10^TM Dual HbA_1c program 220-0201.

Twenty-five international units of ACTH (Acton Prolongatum)was injected intramuscularly and one mL blood sample was collected after 60 minutes for estimation of serum cortisol. Injection Acton Prolongatum® Ferring pharmaceuticals (Saint Prex, Switzerland) (available as a 5-mL vial with a concentration of 60 units per mL, 40 IU = 1 mg) was used [12]. A baseline cortisol of ≤5 mcg/dL was considered as low; any subject with one hour post ACTH cortisol <18.0 microg/dl was diagnosed as having adrenal insufficiency [11,12]. Aliquots for baseline and stimulated cortisol were transported from study site and stored at -20⁰ C until tested for estimation of cortisol levels. Cortisol levels were quantitatively estimated by Chemilluminescence immunoassay.

SAMPLE SIZE: By estimating the proportion of children with nephrotic syndrome with adrenocortical suppression and with likely population prevalence of 40% based on a previous study[7], confidence level of 95%, precision of 10%, the sample size calculated was 92. However, due to the ongoing COVID pandemic during the study period, we could enroll a total of 52 patients; with this sample size we achieved a precision of 13.3% with 95% confidence level.

STATISTICAL ANALYSIS

The collected data were transformed into variables, coded and entered in Microsoft Excel. Data were analyzed and statistically evaluated using SPSS-PC-25 version. Normal distribution of different parameters was tested by the Shapiro-Wilkis normality test. Quantitative data was expressed in mean (standard deviation) or median with interquartile range as dependent on the normality. The difference between mean of two groups were compared by student t-test or Mann Whiney U test. Categorical data were expressed in frequency and percentage and statistical differences between the proportions were tested by chi square test or Fisher’s exact test while McNemar Test was used for pre-post comparison. Receiver operating characteristic (ROC) Curve was prepared for total cumulative prednisolone dose for prediction of adrenocortical suppression. The cut off was calculated using Youden index and sensitivity and specificity were calculated. A p value less than 0.05 was considered statistically significant.

A total of 52 (33 males) children (27 SSNS and 25 SRNS) with nephrotic syndrome were enrolled with a mean (SD) age of 9.8 (4.4) years and age of onset 4 (2.8) years. A total of 27(51.9%) children had SSNS and 25(48.1%) had SRNS (21/25 with late resistance). Among 27 with SSNS, 12 (44.4%) had a steroid dependent disease, 9 (33.3%) had a frequently relapsing disease (FRNS) while 6 (22.2%) had infrequently relapsing disease (IFRNS). The majority (68%) of the SRNS children had minimal change disease, 7 (28%) had focal segmental glomerulosclerosis and 1(4%) had C3 nephropathy on biopsy.

The baseline parameters of the study population are provided in Table 1. Out of 52 children enrolled, 8(15.4%) had short stature of (-2 to -3 SD) and 4 (7.7%) had severe stunting (<-3 SD). Children with SRNS had a higher risk of hypertension odds ratio (95% CI) 6.81 (1.64, 28.23); p = 0.008.

Table 1

Comparison of baseline features between SSNS and SRNS
Parameter	SSNS (n = 27)	SRNS (n = 25)	P value
Height SDS	-0.45 (1.73)	-1.28 (1.33)	0.06
Weight SDS	-0.12 (1.15)	-0.80 (1.14)	0.037
BMI SDS	0.25 (1.41)	-0.23 (1.01)	0.167
Weakness/Fatigue/ malaise^a	12 (44.4%)	11 (44%)	0.97
Poor weight gain/growth^a	7 (25.9%)	11 (44%)	0.17
Cushingoid features^a	17 (63%)	13 (52%)	0.42
Hypertension^a	14 (51.9%)	22 (88%)	0.005
Urea(mg/dL)	17.30 (6.20)	24.28 (13.26)	0.017
Creatinine(mg/dL)	0.31 (0.10)	0.41 (0.23)	0.10
Calcium(mg/dL)	9.09 (0.72)	8.92 (0.80)	0.44
Phosphate(mg/dL)	5.08 (1.10)	4.57 (0.96)	0.08
ALP(IU/L)	242.52 (166.78)	242 (166.87)	0.99
S. Albumin(g/dL)	4.1 (0.62)	3.9 (0.68)	0.30
Cholesterol(mg/dL)	164.93 (75.71)	184.72 (70.89)	0.05
Fasting blood sugar (mg/dL)	102.15 (18.28)	100.4 (11.66)	0.68
HbA1C(gm%)	5.27 (0.30)	5.36 (0.62)	0.54
Data shown as mean (SD) or ^an (%); Student t-test for comparison

Five (18.5%) children received only prednisolone therapy; 16 (30.8%) children received calcineurin inhibitors along with prednisolone, 15 (28.5%) received alkylating agents, 22(42.3%) received other agents like mycofenolate mofetil (MMF) or levamisole and 6(11.5%) received Rituximab. Forty six (88.5%) were receiving low dose alternate day steroids for 8 weeks or more at the time of enrollment while 6 with IFRNS disease were off steroids. The cumulative dosage of steroids received over the last 12 months in all patients was 0.23 (0.10) mg/kg/day; maximum of 0.29 mg/kg/day in FRNS, 0.25 mg/kg/day in SDNS and 0.22 mg/kg/day in SRNS disease ( p > 0.05).

The mean (SD) baseline serum cortisol levels were 6.16 (4.71) mcg/dL. Twenty-six patients (50%) had morning baseline serum cortisol levels below 5 mcg/dL which included 12 SRNS, 6 FRNS, 6 SDNS and 2 with IFRNS disease. The mean (SD) stimulated cortisol levels were 15.31(7.24) mcg/dL and 36 (69.2%) children had levels below 18 mcg/dL; this included 16 SRNS, 9 SDNS, 7 FRNS and 4 with IFRNS disease and was significantly higher than baseline detection rate (p = 0.045).

The baseline and stimulated cortisol levels in different types of nephrotic syndrome are given in Table 2. The ACTH stimulation test was able to detect adrenal insufficiency in 20 (74.1%) children with SSNS that was more than 14 (51.9%) on basal cortisol levels; p = 0.042. The proportion of adrenal insufficiency in SRNS on baseline and ACTH stimulation was 12 (48%) and 16 (64%), respectively; p = 0.132. A comparison of baseline characteristics and biochemical parameters of children with adrenocortical insufficiency and those without is provided in Table 3.

Table 2

Serum Cortisol levels in children with nephrotic syndrome
Type of Nephrotic Syndrome	Baseline Cortisol	1 hour Cortisol post-ACTH stimulation
All patients	5.07 (2.91–8.23)	15.36 (11.34–18.69)
FRNS	3 (0.78–8.08)	14 (4.92–18.05)
IFRNS	7.37 (3.54–12.87)	16.07 (10.3-22.93)
SDNS	5.26 (2.97–7.44)	14.24 (11.62–18.73)
SSNS	4.84 (2.59–8.44)	14.68 (10.83–19.53)
SRNS	5.36 (2.97–7.93)	15.95 (11.68–18.58)
Data expressed as median (IQR); Mann Whitney test for comparison; p value > 0.05 for within group comparisons

Table 3

Comparison of baseline parameters between children with or without adrenal insufficiency
Parameters	Adrenocortical Insufficiency (n = 36)	No insufficiency (n = 16)	p value
Height SDS	-0.77 (1.40)	-1.04 (2.0)	0.43
BMI SDS	-0.09 (1.19)	0.26 (1.37)	0.45
Cumulative annual prednisolone dose (mg/kg/d)	0.26 (0.10)	0.17 (0.06)	0.002*
Hypertension^a	24 (66.7%)	12 (75%)	0.74
Cataract^a	4 (25%)	0	0.53
Creatinine(mg/dL)	0.36 (0.19)	0.38 (0.153)	0.50
Calcium (mg/dL)	8.96 (0.77)	9.14 (0.75)	0.44
Phosphate (mg/dL)	4.94 (1.06)	4.6 (1.04)	0.27
Serum ALP(IU/L)	249.61 (190.91)	225.75 (85.44)	0.48
S. Albumin(g/dL)	4 (0.73)	4.08 (0.47)	0.59
Fasting blood sugar (mg/dL)	101.5(16.23)	100.9 (13.6)	0.89
HbA1C (gm%)	5.28 (0.41)	5.41 (0.61)	0.35
Baseline Cortisol (mcg/dL)	4.39 (2.76)	10.15 (5.77)	< 0.001*
Stimulated Cortisol (mcg/dL)	11.86 (4.40)	23.09 (6.34)	< 0.001*
Data expressed as mean (SD), ^an(%); Adrenal insufficiency defined as cortisol below 18 mcg/dL on ACTH stimulation test; Student t-test for comparison; p value < 0.05 significant*

The ROC curve between cumulative dose of prednisolone intake in last 1 year and post-ACTH stimulated serum cortisol levels showed that a prednisolone dose of 0.22 mg/kg/d predicted risk of adrenocortical insufficiency with AUC 0.76 (95% CI as 0.63–0.89), with a sensitivity of 63.9% and specificity of 81.3% (Fig. 1).

The present study was aimed at identifying adrenal insufficiency in children with nephrotic syndrome based on stimulation test using long-acting Porcine Sequence ACTH (Acton Prolongatum). Corticosteroids form the mainstay of therapy in most forms of nephrotic syndrome including SRNS and prednisolone is used in low doses on alternate days in both disease forms with or without other immunosuppressants. Majority of the patients in the present study 22(42.3%) were being treated with mycophenolate mofetil or levamisole along with alternate day steroids. This was primarily because most patients in SSNS group were steroid dependant or FRNS and needed alternative steroid sparing agents. About 16 (30.8%) received calcineurin inhibitors either tacrolimus or cyclosporine which are the first line therapies for steroid resistant disease [15].

Early morning fasting serum cortisol levels have been documented to be low in 40-52.5% of children with nephrotic syndrome in previous studies [7, 8]. Single cortisol levels are subject to preanalytical and analytical errors and need to be confirmed if they are low on a stimulation test. A stimulation test is often recommended for confirmation; insulin stimulation test maybe associated with hypoglycemic seizures while glucagon stimulation test generates a high false-positive rate, therefore it is safer to use cosyntropin (ACTH) stimulation test as an alternative for adrenal status assessment [16, 17]. Acton prolongatum, an ACTH analogue is the most easily available form in India and is used in stimulation tests for detection of adrenocortical insufficiency. It has been shown that both high dose or low dose cosyntropin or ACTH stimulation tests yield almost similar results for detecting secondary adrenocortical suppression [11, 12, 18].

Early morning fasting serum cortisol levels were used to determine the proportion of patients with baseline serum cortisol suppression and 26 (50%) had levels below the cutoff of 5 mcg/dL (indicating adrenocortical suppression). Children with FRNS disease had the lowest mean level of 5.28mcg/dL while patients with IFRNS course had the highest mean levels of 8.37 mcg/dL. A study done by N Hansen et al, on children with idiopathic SSNS treated with corticosteroids, revealed that 22 out of the 42 (52.5%) children had adrenocortical suppression [9]. An earlier study from our hospital identified adrenocortical suppression in 40% children with nephrotic syndrome on low doses of alternate day steroids using single morning cortisol values [7].

After stimulation 36 (69.2%) of our patients were detected to have adrenocortical suppression; 44% had SRNS,25% children had SDNS, 11.1% had IFRNS and 19.4% had FRNS course. The mean post stimulation serum cortisol levels were 15.3 mcg/dL. The patients with FRNS disease had the lowest mean levels (12.2mcg/dL) while patients with IFRNS disease had the highest mean levels (17.4 mcg/dL). The proportion of patients detected with adrenal insufficiency was 62.5% on stimulation testing in an earlier report [8], similar to our study. In another study, 13/ 37(35%) SSNS patients who had discontinued steroid for 4–6 weeks and had normal baseline cortisol levels had adrenal insufficiency on low dose synacthan stimulation test [10].

Cumulative steroid dosages over previous 12 months were calculated individually for patients and were 0.23 mg/kg/day for all children. As expected, lowest cumulative steroid doses were received by children with IFRNS as they remained in remission for longer periods, unlike those with FRNS who received maximum annual steroid doses. The mean annual cumulative low steroid dosage was sufficient to cause adrenocortical suppression in 69.2% of children indicating the need for early screening for suppression. A steroid dose of 0.22 mg/kg/day best predicted adrenal suppression in this study. However, patients with FRNS had the highest annual steroid doses that indicated this group to be most predisposed to adrenal insufficiency. Recent data suggest the use of shorter regimes with lower doses for treatment of first episode and subsequent relapses [19–21].

A significant proportion of children in this study had evidence of steroid toxicity (cataract and Cushingoid facies) that indicates their risk for iatrogenic adrenal insufficiency. A higher proportion of hypertension in this cohort (88% in SRNS vs 51.9% in SSNS group) could probably be due to poorly monitored therapy in the preceding year during the COVID pandemic.

The present study was conducted as a cross-sectional design that limited data collection on outcome of children with adrenal insufficiency. The sample size was lower than that proposed due to the preceding COVID pandemic when the regular services in our hospital were disrupted. The treatment protocol were as per the national guidelines that ensured a uniform protocolized management for all children [15, 22].

The identification of adrenocortical suppression is vital because it predisposes the child to the development of life-threatening adrenal crisis, especially in periods of stress like infections and surgery, which leads to significant morbidity and mortality. This should be considered as a long term complication of immunosuppression [23]. The present study highlights the need to educate parents for stress dosing and supplement the children with oral or intravenous steroids during sick-days [24]. This is routinely followed in our clinic and the present study substantiates the practice.

Based on the results of our study we conclude that children with both SSNS and SRNS are at a high risk of adrenocortical suppression even when treated with low doses of prednisolone on alternate days. In periods of stress like surgery or infections, steroids in stress dosages must be considered for them if the cumulative dose is more than 0.22 mg/kg/day with likely adrenocortical suppression. Stress dose steroids in these patients would help in preventing the life-threatening adrenal crisis.

Legends: Fig. 1: ROC curve to predict adrenal insufficiency with cumulative annual prednisolone dose

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Adrenocortical suppression in children with nephrotic syndrome treated with corticosteroids

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INTRODUCTION

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