1 INTRODUCTION

Kidney transplantation is the most effective treatment of end-stage kidney failure in children,¹ but in many cases prevention and treatment of rejection still rely on corticosteroid therapy.^2-5 Prolonged corticosteroid exposure in other chronic disease settings has been associated with the development of secondary adrenal insufficiency (AI),^6-9 especially as corticosteroids are weaned or withdrawn.^{7, 10-12} Important clinical findings of AI include fatigue, hypotension, vomiting, lethargy, hypoglycemia, nausea, weight loss, and anorexia. Symptoms of AI are generally nonspecific, making it difficult to diagnose.^{6, 12} Furthermore, pediatric kidney transplant (PKT) recipients with AI may be at risk for adrenal crisis, resulting from inadequate cortisol stress response during acute stress events such as infection, surgery, and physical trauma, and can present with hemodynamic instability or shock. Precipitation of adrenal crisis is prevented by administering glucocorticoid stress doses during stressful events.^{9, 13, 14} The incidence of adrenal crisis in children with AI has been estimated to be 5–10 episodes/100 patient-years.¹⁵ AI is a potentially underrecognized issue in pediatric transplant centers, with few routinely screening for AI or no transplant-specific clinical guidelines that recommend it. This may leave undiagnosed patients at risk for adrenal crisis.

There are few studies that comprehensively characterize the prevalence and risk factors associated with AI specifically in PKT recipients.^16-18 In two separate reports of pediatric transplant recipients on maintenance corticosteroids, the prevalence of AI varied between 31% (10/32)¹⁶ and 85% (11/13),¹⁷ with the cohort of kidney and liver transplant recipients having a lower prevalence (31%) of AI compared to the kidney-only transplant cohort (85%). In both cohorts, the risk of AI was associated with the duration of corticosteroid treatment prior to diagnosis.^{16, 17} A similar association was found in a third cohort of pediatric kidney and liver transplant recipients (n = 26), which found an inverse correlation between methylprednisolone exposure over time and morning cortisol levels.¹⁸ However, the relatively small size of these cohorts leaves them underpowered to effectively estimate the prevalence, additional risk factors and adverse outcomes associated with AI.

The potential need for routine AI surveillance has been recommended by Valentin et al., after identifying an AI prevalence of 43% in an adult kidney transplant cohort.⁹ Since cortisol secretion follows a diurnal pattern with a morning peak at approximately 8 a.m., the morning cortisol (MC) test is commonly used for this purpose.¹⁹ Selecting an accurate threshold value for diagnosing AI in children is challenging, considering variability related to sex and pubertal status.²⁰ One review suggests that for children, an MC level of <83 nmol/L is indicative of AI, whereas ≥500 nmol/L rules it out.²¹ For this reason, confirmation of AI typically requires definitive testing using an adrenocorticotropic hormone (ACTH) stimulation test.^22-24

In this study, we hypothesize that AI is relatively common in PKT recipients and is associated with important clinical adverse events. We report on the prevalence of AI in a single-center PKT cohort and explore potential risk factors and adverse effects associated with AI. We also evaluate the utility of an MC threshold of 240 nmol/L, which was implemented to identify risk of AI and indicate the need for confirmatory low-dose ACTH stimulation testing.

2 METHODS

We conducted a retrospective, cross-sectional, single-center cohort study of PKT recipients from a tertiary pediatric transplant center between January 2015 and July 2021. Ethics approval was obtained from the University of British Columbia Research Ethics Board at the BC Children's Hospital (BCCH; REB #H21-00546). The requirement for additional informed consent for the current study was waived.

2.1 Study population

Children and adolescents younger than 21 years at the time of kidney transplantation who completed at least one valid MC test or a low-dose ACTH stimulation test during the study period were eligible for inclusion (Figure 1). Patients with a prior diagnosis of AI were excluded, as were patients who declined to participate or withdrew consent.

Standard immunosuppression for transplant recipients included IV basiliximab and methylprednisolone induction (300 mg/m² for 2 doses), and initial maintenance immunosuppression with prednisone, tacrolimus, and mycophenolate mofetil. Prednisone was tapered from an initial daily dose of 60 mg/m² over 4–6 months to a final dose of 3 mg/m² on alternating days (Monday, Wednesday, and Friday). Patients on alternating day prednisone were not given hydrocortisone supplementation. Rejection episodes were treated at the discretion of the treating nephrologist with high dose IV methylprednisolone (300 mg/m²/dose) for three doses, followed by an oral prednisone taper over 2 weeks to a final daily dose of 3–5 mg/m². The higher final dose of prednisone within this range was sometimes used for treatment of chronic inflammation.

3 RESULTS

3.4 Associations of potential risk factors with MC level

Univariate linear mixed effects modeling of risk factors potentially associated with MC level is summarized in Table 3. Each model was adjusted for repeated measures. A total of 83 valid MC samples (mean 1.6 ± 0.9 samples per patient) were evaluated at a median age of 11.8 (IQR 7.3, 15.7) years and 2.5 (IQR 1.1, 5.1) years post-transplant. The mean MC level for all samples was 246.1 ± 121.3 nmol/L. There were no significant associations found with MC level for baseline transplant or contemporaneous risk characteristics, other than measures of corticosteroid exposure.

TABLE 3. Potential risk factors associated with morning cortisol level at the time of testing adjusted for repeated measures.

	Total (n = 83)	β	95% CI	R2 marginal	p-value
Baseline transplant characteristics
Age at transplant	7.2 (3.3, 11.9)	4.1	[−2.3, 10.6]	0.024	.20
Male sex	51 (61.4%)	13.5	[−47.7, 74.6]	0.003	.66
Race
White	38 (45.8%)	6.9	[−53.2, 66.9]	<0.001	.82
Asiana	19 (22.9%)	9.0	[−61.8, 79.9]	<0.001	.80
Otherb	26 (31.3%)	−15.7	[−80.2, 48.7]	0.004	.63
Glomerular diagnosis	30 (36.1%)	8.6	[−53.0, 70.2]	0.001	.78
Preemptive transplant	19 (22.9%)	−28.0	[−98.6, 42.5]	0.009	.43
Years on dialysis (n = 64 non-preemptive)c	1.7 (1.0, 2.2)	0.06	[−0.02, 0.13]	0.04	.14
Previous transplant	2 (2.4%)	62.0	[−112, 236]	0.006	.48
Contemporaneous characteristics
Age at event (years)	11.8 (7.3, 15.7)	1.1	[−5.5, 7.6]	0.001	.75
Years since transplant	2.5 (1.1, 5.1)	−6.2	[−15.1, 2.7]	0.03	.17
Height (cm) Z-score	−0.60 (1.87, 0.20)	9.3	[−11.3, 29.8]	0.01	.37
BMI Z-score	0.76 (−0.59, 1.33)	−3.0	[−24.8, 18.8]	0.001	.78
Corticosteroid exposure
Current prednisone dosage (mg/m2)	2.6 (1.3, 4.1)	−16.8	[−25.5, −8.1]	0.15	<.001
Prior 6-month prednisone dosage (mg/m2)	2.4 (1.5, 4.3)	−22.6	[−35.7, −9.5]	0.14	.001
Daily (vs. not dailyd) prednisone administration	45 (54.2%)	−75.0	[−127.8, −22.3]	0.09	.006
Rejections since transplant	1 (0, 1)	−54.7	[−82.9, −26.6]	0.18	.003
Months since last rejection	15.1 (6.9, 38.1)	0.3	[−0.45, 1.07]	0.009	.42

• Note: All variables were measured at time of MC testing or during 6 months prior unless otherwise stated. Values reported as median (interquartile range) for non-normally distributed variables, mean ± standard deviation for normally distributed variables, or count (%). Significant results were bolded. Abbreviations: BMI, Body mass index; MC, Morning cortisol.
• ^a Including southeast and far east Asia, India, and the Philippines.
• ^b Race groups with <5 counts have been grouped as “Other.” Includes black/African American, Middle Eastern/Arabian, American Indian, Alaskan native, Latin American, multiracial, or other.
• ^c 64 samples were taken from patients who were transplanted non-preemptively.
• ^d Samples on “not daily” administration schedule were taken from patients who had three times a week (MWF) administration, except for one sample taken from a patient who was not on prednisone at the time of MC testing. Linear mixed effects modeling adjusted for repeated measures was conducted to report results.

3.4.1 Increased corticosteroid exposure is associated with low MC level

Increased corticosteroid exposure was associated with lower MC levels across several measures (Table 3, Figure 2): 1) current prednisone dosage (β = −16.8; CI = −25.5, −8.1; p < .001); 2) mean prednisone dosage in the 6 months prior (β = −22.6; CI = −35.7, −9.5; p = .001); 3) daily (vs. not daily) prednisone administration (β = −75.0; CI = −127.8, −22.3; p = .006); and 4) number of rejection episodes since transplant (β = −54.7; CI = −82.9, −26.6; p = .003). These measures were highly intercorrelated (all p ≤ .001; Table S1). Time since the last rejection episode was not significantly associated with a low MC level (p = .42).

3.4.2 Excess corticosteroid exposure is associated with high risk for AI

MC samples were categorized as “high-risk” (<240 nmol/L) and “not high-risk” (≥240 nmol/L) for evaluation according to the clinical decision-making framework used. A similar number of samples fell into the high-risk (n = 39; 47%) and not high-risk (n = 44; 53%) categories. The primary comparison was made between the high- and not high-risk groups for the four corticosteroid exposure measures identified (Table 4). Greater corticosteroid exposure was identified in the high-risk group for 3 of the 4 measures: (1) current prednisone dosage (β = 0.44; CI = 0.12, 0.76; p = .008); (2) mean prednisone dosage in the 6 months prior (β = 0.36; CI = 0.065, 0.66; p = .017); (3) number of rejection episodes since transplant (β = 0.71; CI = 0.70, 0.72; p < .001).

TABLE 4. Potential risk factors associated with the high-risk grouping at the time of testing adjusted for repeated measures.

Corticosteroid exposure	Not high-risk (n = 44)	High-risk (n = 39)	β	95% CI	R2 marginal	p-value
Current prednisone dosage (mg/m2)	1.8 (1.3, 3.2)	3.7 (1.9, 4.1)	0.44	[0.12, 0.76]	0.28	.008
Prior 6-month prednisone dosage (mg/m2)	1.8 (1.3, 3.3)	3.7 (1.9, 4.6)	0.36	[0.065, 0.66]	0.12	.017
Daily (vs. not dailya) prednisone administration	21 (47.7%)	24 (61.5%)	0.69	[−0.36, 1.73]	0.030	.20
Rejections since transplant	0 (0, 1)	1 (0, 2)	0.71	[0.70, 0.72]	0.10	<.001

• Note: All variables were measured at time of MC or during 6 months prior unless otherwise stated. Values reported as median (interquartile range) for non-normally distributed variables or count (%). Significant results were bolded. Abbreviation: MC, Morning cortisol.
• ^a Samples on “not daily” administration schedule were taken from patients who had three times a week (MWF) administration, except for one sample taken from a patient who was not on prednisone at the time of MC testing. Logistic mixed effects modeling adjusted for repeated measures was conducted to report results. MC samples with <240 nmol/L were defined as high-risk, ≥240 nmol/L as not high-risk. Only variables that demonstrated a trend towards significance (p < .1) in the univariate modeling with MC level were included.

3.6 Associations of potential adverse effects with MC level

Adverse clinical events that may be associated with AI were tested for associations with MC level using linear mixed effects modeling adjusted for repeated measures (Table 6).

TABLE 6. Potential adverse effects associated with morning cortisol level at the time of testing adjusted for repeated measures.

	Total (n = 83)	β	95% CI	R2 marginal	p-value
Medical complexity
Number of medications	7 (6, 9)	−16.3	[−25.6, −7.0]	0.14	<.001
Prior 6-month hospitalizations	0 (0, 1)	−15.5	[−36.5, 5.5]	0.03	.15
Prior 6-month hospitalization days	0 (0, 3.5)	−3.3	[−5.9, −0.7]	0.08	.013
Prior 6-month PICU hospitalizationsa	0 (0, 0)	−121.8	[−255.9, 12.4]	0.04	.075
Hemodynamic
Systolic BP percentile	0.68 (0.44, 0.89)	22.3	[−72.1, 116.7]	0.003	.64
Diastolic BP percentile	0.74 (0.55, 0.90)	−5.2	[−117.6, 107.3]	<0.001	.93
Metabolic
Serum glucose (mmol/L)	5.0 (4.7, 5.5)	6.3	[−19.4, 32.1]	0.003	.63
On Insulin	3 (3.6%)	−83.0	[−231.0, 65.0]	0.02	.27
Serum sodium (mmol/L)	138.9 ± 2.6	0.95	[−9.5, 11.4]	<0.001	.86
Kidney function lability
eGFR (mL/min/1.73 m2)b	67.1 ± 26.8	0.91	[−0.1, 1.9]	0.04	.080
Prior 6-month CV of creatinine	9.9 (6.7, 14.4)	−2.4	[−4.4, −0.3]	0.06	.025
Prior 6-month AKI50%c	28 (33.7%)	−70.6	[−123.9, −17.2]	0.08	.010
Prior 6-month AKI hospitalizations	0 (0, 1)	−16.2	[−41.2, 8.8]	0.02	.20

• Note: All variables were measured at time of MC or during 6 months prior unless otherwise stated. Values reported as median (interquartile range) for non-normally distributed variables, mean ± standard deviation for normally distributed variables, or count (%). Significant results were bolded. Abbreviations: AKI, Acute kidney injury; BP, Blood pressure; CV, Coefficient of variation; eGFR, Estimated glomerular filtration rate; MC, Morning cortisol; PICU, Pediatric Intensive Care Unit.
• ^a Hospitalizations with admission to pediatric intensive care unit (PICU).
• ^b eGFR calculated using the bedside Schwartz equation.
• ^c Experienced an AKI50% during 6 months prior to MC, which was defined as having a 50% increase in creatinine from baseline level. Linear mixed effects modeling adjusted for repeated measures was conducted to report results.

3.6.1 Medical complexity is associated with AI risk

The number of medications (β = −16.3; CI = −25.6, −7.0; p < .001) and the number of prior 6-month hospitalization days (β = −3.3; CI = −5.9, −0.7; p = .013) were associated with lower MC level (Table 6 and Figure 3). Number of medications was correlated with hospitalization days (rho = 0.34, p = .002), but not with PICU hospitalizations (Table S2). A significant association was also identified between the high-risk group (Table 7) and greater number of medications (β = 0.28; CI = 0.062, 0.50; p = .012).

TABLE 7. Potential adverse effects associated with the high-risk group at the time of testing adjusted for repeated measures.

	Not high-risk (n = 44)	High-risk (n = 39)	β	95% CI	R2 marginal	p-value
Medical complexity
Number of medications	6 (5, 8)	8 (6, 10.5)	0.28	[0.062, 0.50]	0.14	.012
Prior 6-month hospitalization days	0 (0, 1)	1 (0, 5.5)	0.045	[−0.010, 0.10]	0.055	.11
Prior 6-month PICU hospitalizationsa	0 (0, 0)	0 (0, 0)	0.84	[−1.80, 3.48]	0.007	.53
Kidney function lability
eGFR (mL/min/1.73 m2)b	71.1 ± 24.7	62.6 ± 28.7	−0.013	[−0.032, 0.006]	0.033	.17
Prior 6-month CV of creatinine	9.3 (6.7, 11.2)	11.6 (7.3, 16.0)	0.015	[−0.022, 0.053]	0.011	.42
Prior 6-month AKI50%c	10 (22.7%)	18 (46.2%)	1.08	[0.075, 2.09]	0.069	.035

• Note: All variables were measured at time of MC or during 6 months prior unless otherwise stated. Values reported as median (interquartile range) for non-normally distributed variables or count (%). Significant results were bolded. Abbreviations: AKI, Acute kidney injury; CV, Coefficient of variation; eGFR, Estimated glomerular filtration rate; MC, Morning cortisol; PICU, Pediatric Intensive Care Unit.
• ^a Hospitalizations with admission to pediatric intensive care unit (PICU).
• ^b eGFR calculated using the bedside Schwartz equation.
• ^c Experienced an AKI50% during 6 months prior to MC, which was defined as having 50% increase in creatinine from baseline level. Logistic mixed effects modeling adjusted for repeated measures was conducted to report results. MC samples with <240 nmol/L were defined as high-risk, ≥240 nmol/L as not high-risk. Only variables that demonstrated a trend towards significance (p < .1) in the univariate modeling with MC levels was included.

3.6.2 Greater kidney function lability is associated with AI risk

Serum creatinine levels (median 11 (7.5, 15) creatinine samples per MC sample) were used to calculate the coefficient of variation (CV) in the 6 months prior to each event. The 6-month serum creatinine CV (β = −2.4; CI = −4.4, −0.3; p = .025) and occurrence (vs. not) of an AKI50% episode (β = −70.6; CI = −123.9, −17.2; p = .01) were significantly associated with lower MC level (Table 6 and Figure 3). A significant association was also identified between the high-risk group (Table 7) and occurrence of AKI50% (β = 1.08; CI = 0.075, 2.09; p = .035). Prior 6-month serum creatinine CV and AKI50% were highly correlated (p < .001) (Table S3), but neither was correlated with eGFR.

Prior 6-month AKI50% exhibited correlation (p ≤ .01) with both measures of medical complexity (number of medications: r = 0.29, prior 6-month hospitalization days: r = 0.52). We conducted post-hoc bivariate regressions to explore their independence relative to MC level. The model including 6-month AKI and medication number was indeterminate (Table S4), with neither exhibiting independent association; however, the model with 6-month AKI (β = −82.9; CI = −144.9, −20.9; p = .009) and 6-month hospitalization days (β = −30.9; CI = −49.6, −12.2; p = .001) confirmed that each was independently associated with MC level (Table S5).

4 DISCUSSION

This is the largest study to date that reports on the prevalence, risk factors, and adverse effects of secondary AI in a PKT cohort. We found a high prevalence of AI (25.5%), which was greater (46.4%) when only definitively tested patients were considered. We identified that excess corticosteroid exposure was the primary risk factor for AI and medical complexity (i.e., medication burden and hospitalization days) and greater kidney function lability (i.e., serum creatinine lability and occurrence of AKI50%) were significantly associated with AI in this population.

The prevalence rate in this report is similar to the 31% prevalence reported by Bilavsky et al. but lower than the 85% reported by Revermann et al.^{16, 17} Bilavsky et al. included both pediatric liver and kidney transplant recipients, whereas Revermann et al. included only PKT recipients, similar to our study. Bilavsky et al. evaluated AI risk with a standard 250 ug ACTH stimulation test and used a higher stimulated cortisol threshold (<550 nmol/L) to diagnose AI, which would be expected to overestimate AI risk, compared with this cohort. The timing of AI testing post-transplant was not readily discernible in these two studies,^{16, 17} and the lower prevalence in our study may be due to screening for AI a relatively longer time post-transplant, leading to lesser ongoing steroid exposure in this cohort.

Similar to these two studies,^{16, 17} we identified corticosteroid exposure as the only significant risk factor for AI, as current prednisone dosage, prior 6-month average daily dosage of prednisone, daily administration of prednisone, and number of rejection episodes since transplant were all associated with AI. Bilavsky et al. only confirmed an association with prior 6-month dosage despite exploring multiple corticosteroid exposure-related variables and did not evaluate the effect of the current prednisone dose. Additionally, while our analysis found that most AI-confirmed patients had daily prednisone administration (12/13), Bilavsky et al. found that only 3/10 patients diagnosed with AI were on daily treatment; however, these contrasts may be due to their study lacking sufficient power to show weaker associations with other corticosteroid exposure-related measures they tested.¹⁶ In concordance with our findings, Tomkins et al. concluded that adult kidney transplant recipients with AI had a significantly greater daily prednisone dose and cumulative glucocorticoid exposure (including pretransplant, perioperative, and post-transplant exposure) compared to those without AI.⁴² Furthermore, multiple adult population studies have also reported corticosteroid exposure as the only risk factor for AI.^{9, 43, 44}

This study also identified an association between corticosteroid exposure and MC level, which was not identified by Revermann et al.¹⁷ This stands in contrast to Sarna et al., where an association was identified between low MC level and corticosteroid exposure over time (area under serum methylprednisone time vs. concentration curve).¹⁸ They did not, however, identify an association with current methylprednisone dosage, whereas our analysis identified several measures of corticosteroid exposure associated with a lower MC level including current prednisone dosage, prior 6-month prednisone dosage, daily administration of prednisone, and number of rejection episodes, all of which were highly correlated with each other. It is possible that our larger sample size allowed us to detect significant associations, but the common finding is that a prolonged recent corticosteroid exposure (i.e., over 6 months) appears to be the consistent risk factor associated with risk of AI among multiple studies,^{16, 18, 42} and may be a preferred metric for risk evaluation and future research.

While our study did not focus on adrenal function recovery after corticosteroid exposure, the time since last rejection was not associated with AI nor low MC levels. This could indicate that recovery of adrenal function was not associated with how much time has passed after a steroid pulse; however, our results may be limited by the range of available follow-up data and by the fact that after treatment of rejection, most patients remained on daily prednisone. Nonetheless, this is concordant with Laulhé et al.'s findings, that delay between arrest of steroid treatment and time of ACTH stimulation testing did not predict adrenal function recovery.⁴⁵

As proxies for medical complexity, number of medications^30-34 and rates of hospitalization^35-37 were both associated with a greater AI risk as reflected by lower MC level. Although causality cannot be inferred, the most likely explanation is that impaired cortisol responsiveness to stress contributes to a risk for more severe illness and sequelae.^46-48 Although this has not been previously reported in PKT recipients, Worth et al. reported that 30% of their cohort (children with AI, n = 127) had a recorded emergency department visit due to acute illness,⁴⁹ and Eyal et al. reported recurrent hospital admissions were significantly associated with adrenal crisis among children with AI.⁵⁰ Increased rates of ICU admission, longer length of hospital stays, and higher rates of readmission have also been reported in adults with AI.⁵¹

AKI episodes are common after PKT and their frequency is associated with progressive allograft dysfunction and loss.⁵² This study identified an increased risk of AKI with risk for AI, which is likely related to hemodynamic instability and impaired renal perfusion with episodes of acute illness and adrenal crisis.⁵³ Functional renal impairment is a typical laboratory feature of adrenal crisis.⁵³ There have been multiple case reports demonstrating a diagnosis of AI or adrenal crisis presenting in AKI.^54-57 Aside from the AKI, concurrent symptoms experienced by patients reported in these cases included lethargy, general weakness, nausea, poor oral intake, weight loss, light-headedness, and hypotension.^54-57 This report is the first to identify association between AI risk and rates of AKI in PKT recipients. Perhaps unsurprisingly, AKI rates in this population are also associated with measures of medical complexity; however, we were able to confirm that the AKI risk as it relates to association with MC levels is independent of hospitalization days that may have occurred in the same period. The increased risk for AKI way be explained by exacerbated allograft hypoperfusion with adrenal insufficiency during otherwise typical intercurrent illnesses. Timely corticosteroid stress dosing in these scenarios, as is typically recommended for AI management, could also potentially mitigate the risk for AKI.

For surveillance of AI risk, the MC level was associated with corticosteroid exposure on a continuum and the lack of a definitive threshold for diagnosing AI is similarly reflected in other reports.^{25, 27, 58} We evaluated the threshold set for our clinical program at the BCCH (<240 nmol/L) to indicate when confirmatory ACTH stimulation testing would be needed and observed that the majority (54.2%, 13/24) of those with an at-risk MC (<240 nmol/L) were diagnosed with AI, and the highest MC level reported among the AI diagnosed patients was 226 nmol/L, which is close to the 240 nmol/L, suggesting that this threshold is practically useful for AI screening in the transplant clinic. The utility of MC testing as an AI screening tool has been supported by studies in other populations. Tomkins et al. found that MC cutoff values of <130 nmol/L and > 288 nmol/L were optimal to rule in and rule out AI and could reduce the need for ACTH stimulation testing by 44%.⁴² Manosroi et al. concluded that ≤90 nmol/L and ≥ 380 nmol/L were optimal cutoff values for MC testing in adults and could reduce the need for ACTH stimulation testing by 10% and 30% (true positive and true negative rate, respectively).⁵⁹ Despite this, the absence of consensus on threshold values and the lack of studies on MC testing utility in PKT recipients indicates need for further research.

Although this is the largest pediatric transplant cohort reported to date, the sample size limited the number of covariates we could reliably include and thereby the complexity of multivariable models for more refined analysis. The MC threshold for confirmatory ACTH stimulation testing was set by clinical consensus in our transplant program after close discussion with the division of endocrinology at BCCH, since there was insufficient prior data available. As a result, we could not fully model thresholds between 240 and 400 nmol/L, since for pragmatic reasons we could not justify clinical testing within this range.

Another potential limitation was that our study included MC samples taken up to 9 a.m. Cortisol secretion reaches morning peak at approximately 8 a.m., and therefore MC testing is usually conducted at this time.^{19, 20, 26} Due to some individuals having been screened with MC past this 8 a.m. peak, it is possible that our study overtested individuals who had an MC <240 nmol/L with a confirmatory ACTH stimulation test.

5 CONCLUSION

We identified that AI is relatively common in children who continue to receive maintenance corticosteroid dosing after kidney transplant, and the risk is associated with the magnitude of recent corticosteroid exposure. AI is consequential in this population, associated with increased medication complexity, hospitalization risk, and allograft AKI. Although this analysis did not evaluate the utility of stress dosing of corticosteroids during acute illness, it is recommended for the management of AI. These findings highlight the potential need for regular clinical surveillance in PKT recipients who have been treated with corticosteroids.

AUTHOR CONTRIBUTIONS

Hyunwoong Harry Chae, Shazhan Amed, Trisha Patel, and Tom D. Blydt-Hansen: conceptualized the study; Hyunwoong Harry Chae and Tom D. Blydt-Hansen: involved in data collection; Hyunwoong Harry Chae, Azim Ahmed, Jeffrey N. Bone, and Tom D. Blydt-Hansen: formally analyzed the study; Hyunwoong Harry Chae and Tom D. Blydt-Hansen: involved in methodology; Hyunwoong Harry Chae and Tom D. Blydt-Hansen: administered the project; Hyunwoong Harry Chae: wrote and led the manuscript preparation; Hyunwoong Harry Chae, Fatema S. Abdulhussein, Shazhan Amed, Trisha Patel, Tom D. Blydt-Hansen: reviewed and edited the manuscript.

CONFLICT OF INTEREST STATEMENT

There are no conflicts of interest from all authors involved.