Visual Abstract
Keywords: idiopathic nephrotic syndrome, nephrotic syndrome
Abstract
Background
Early morning single-dose prednisolone has a hypothetical advantage of less hypothalamic-pituitary-adrenal (HPA) axis suppression, but lack of robust evidence has resulted in variation in practice, with divided-dose prednisolone still commonly used. We conducted this open-label randomized control trial to compare HPA axis suppression between single-dose or divided-dose prednisolone among children with first episode of nephrotic syndrome.
Methods
Sixty children with first episode of nephrotic syndrome were randomized (1:1) to receive prednisolone (2 mg/kg per day), either as single or two divided doses for 6 weeks, followed by single alternative daily dose of 1.5 mg/kg for 6 weeks. The Short Synacthen Test was conducted at 6 weeks, with HPA suppression defined as postadrenocorticotropic hormone cortisol <18 µmg/dl.
Results
Four children (single=1 and divided dose=3) did not attend the Short Synacthen Test and were hence excluded from analysis. Remission was induced in all, and no relapse postremission was noted during the 6+6 weeks of steroid therapy. After 6 weeks of daily steroids, HPA suppression was greater in divided (100%) versus single dose (83%) (P = 0.02). Time to remission and final relapse rates were similar, but for those children who relapsed within 6 months of follow-up period, time to first relapse was shorter for divided dose (median 28 versus 131 days) P = 0.002.
Conclusions
Among children with first episode of nephrotic syndrome, single-dose and/or divided-dose prednisolone were equally effective in inducing remission with similar relapse rates, but single dose had less HPA suppression and longer time to first relapse.
Clinical Trial registry name and registration number:
CTRI/2021/11/037940
Podcast
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Introduction
Prednisolone remains the standard therapy for first episode of nephrotic syndrome.1,2 Studies have confirmed the physiological diurnal variation of endogenous steroid secretion as well as the lesser risk of hypothalamic-pituitary-adrenal (HPA) axis suppression if exogenous steroid doses are synchronized with the early morning diurnal peak.3–5 The risk of HPA axis suppression secondary to the use of steroid is well recognized,6–8 and it has also been associated with higher relapse rate among childhood nephrotic syndrome.9,10 Hence, apart from the advantage of better adherence, early morning single-dose administration of prednisolone in comparison with divided-dose prednisolone should make physiological sense. Despite this physiological plausibility, lack of robust clinical evidence has prevented guidelines in coming out strongly in favor of early morning single-dose prednisolone for nephrotic syndrome.1,2 In our experience from a low-resource setting tertiary center, we continue to be referred for many children treated by nonspecialists using divided-dose prednisolone.
We therefore undertook an open-labeled randomized control trial (RCT) with the hypothesis that early morning single-dose steroid among children with first episode of nephrotic syndrome would result in fewer children with HPA axis suppression (post-Synacthen cortisol <18 μg/dl) in comparison with those treated with divided-dose steroid.
Methods
This was an open-labeled RCT with 1:1 allocation set in a tertiary care children hospital in Eastern India. All children aged 1–17 years with first episode of nephrotic syndrome were eligible. Excluded were secondary nephrotic syndromes or children with evidence of any infection at the time of recruitment. In addition, anyone already started on steroid or administered systemic steroid within the past 6 months or for >2 weeks between 6 months to 1 year before first episode of nephrotic syndrome were excluded (Figure 1). Participants were recruited from December 2021 to September 2022, and the last follow-up was completed by January 2023.
Figure 1.
Trial profile. HPA, hypothalamus-pituitary-adrenal; SST, Short Synacthen Test.
Intervention
Management was as per Indian Society of Pediatric Nephrology guideline1 wherein children with first episode of nephrotic syndrome were treated with 6 weeks of daily prednisolone at 2 mg/kg, and in steroid-responsive nephrotic syndrome, this was followed by 1.5 mg/kg alternate day for another 6 weeks. Relapse was defined as urine dip 3+ for consecutive 3 days and remission as urine dip −ve/trace for 3 consecutive days. Frequently relapsing nephrotic syndrome was defined as two or more relapses in the first 6 months after stopping initial therapy or ≥3 relapses in any 6 months or ≥4 relapses in 1 year. Steroid-dependent nephrotic syndrome was defined as two consecutive relapses when on alternate day steroids or within 14 days of its discontinuation. Steroid resistance was defined as lack of complete remission despite therapy with daily prednisolone at a dose of 2 mg/kg daily for 6 weeks.
Children were randomized to receive the first 6 weeks of daily prednisolone therapy either as early morning (between 6 am and 9 am) single dose or in two divided doses with first dose given before 9 am and the next after 8 pm. Subsequent alternate day prednisolone was given as early morning single dose in both groups.
Measurement
Early morning cortisol was measured before commencement of prednisolone. At completion of 6 weeks daily steroid, early morning cortisol was repeated, and in addition, the Short Synacthen Test (SST) was undertaken (details in Supplemental Document). HPA axis suppression was defined as a post-SST peak cortisol <18 μg/dl.10
Follow-Up
In addition to regular clinic visits as per treating clinician's discretion, families were contacted by phone every 2 weeks and asked about adherence with medication regimen, daily urine dipstick results, and evidence of any adverse symptoms. Fortnightly telephone follow-up was continued after completion of 6+6 weeks prednisolone until first relapse or 6 months, whichever was earlier. Postremission families were asked to inform if urine dipstick showed 3+ for 3 days. A history of relapse, including time to first relapse, and any significant adverse events (gastrointestinal events, significant infection requiring antibiotics/hospital admission) were noted during the clinic/telephonic contacts.
Primary Outcome Measure
The primary outcome was the prevalence of HPA axis suppression assessed by SST on completion of 6 weeks of daily prednisolone at 2 mg/kg. As per Endocrine Society clinical practice guidelines, SST was performed using the standard dose 250 μg intramuscular of tetracosactrin corticotrophin, with peak cortisol levels below 18 μg/dl (500 nmol/L) within 60 minutes indicating adrenal insufficiency.11
Secondary Outcome Measures
Secondary outcomes included comparing between single-dose and divided-dose prednisolone early morning cortisol at before and end of 6 weeks of steroid, remission rate, time to remission, and time to first relapse. Baseline morning unstimulated serum cortisol levels <3 μg/dl were defined as suggestive of suppression. However, the Endocrine Society has advised against using unstimulated morning cortisol to diagnose HPA axis suppression because even low levels may overlap with normal ranges.11 All cortisol levels were measured using electro chemiluminescence immunoassay Roche-Hitachi Cobas e411 analyzer.
Ethical Approval
The study was conducted in adherence to the Declaration of Helsinki. Institute of Child Health Review Board granted ethical approval. Written prior informed consent for participating in this study was obtained from parents/guardians. The trial was registered at Clinical Trial Registry of India (CTRI/2021/11/037940).
Randomization
Enrollment was undertaken by the investigators in either outpatient or inpatient, and after enrollment, the participants were allocated to either the single-dose or divided-dose prednisolone group. Group allocation was undertaken by randomization, which was performed through computer-generated random number by our departmental administrative coordinator. Children were allocated in 1:1 ratio into either the single-dose or divided-dose group. Group allocation was kept in a sealed opaque envelope with our departmental administrative coordinator who was not involved with recruitment, data collection, or data analysis. The envelopes were opened in sequence once a child was enrolled. As it was an open-label study, neither the investigator nor the participant were blinded to the intervention, but the medical staff involved with conducting the SST was not part of the investigating team.
Sample Size Calculation
Precise data to guide power calculation were unavailable for this study. As shown in Supplemental Table 1, previous studies8–10,12–14 were limited by their heterogeneity, with HPA axis being assessed by different methods among children with nephrotic syndrome receiving either low-dose long-term steroids or while on high-dose or recently discontinued steroids. None of the studies exclusively focused on our study population (first episode of nephrotic syndrome) or had similar primary outcome (HPA axis suppression at end of 6 weeks among single-dose versus divided-dose steroid recipients). The results of HPA axis suppression varied from 35% to 93%.8,9,12–15 From these studies, estimating a pragmatic baseline of 75% HPA axis suppression to show 50% relative risk reduction with 80% power and a two-tailed test performed at a 0.05 significance level, 26 patients were required in each group. Allowing for dropout, 30 participants were recruited to each arm.
Statistical Method
Descriptive statistics were expressed as median and interquartile range (IQR) or mean and SD. Categorical variables were expressed as number of patients and percentage of patients and compared across the groups using Pearson's χ2 test for independence of attributes. We used the log-rank test to compare the distribution of time to relapse and plotted Kaplan–Meier survival curve. Continuous variables were expressed as median (IQR) and compared using the Mann–Whitney U test.
Results
Sixty children with first episode of nephrotic syndrome were randomized to receive their daily steroid dose as either single dose or in divided dose (Figure 1). At the end of 6 weeks of daily steroid, four children (one single and three divided dose) did not attend hospital for SST and were lost to follow-up and were excluded from subsequent analysis. The details of baseline demographic characters and outcome parameters are given in Tables 1 and 2, respectively. Demographic characters and presteroid early morning cortisol levels were similar in both groups.
Table 1.
Baseline parameters between single-dose and divided-dose prednisolone
| Baseline Variables | Single-Dose Prednisolone (n=30) | Divided-Dose Prednisolone (n=30) |
|---|---|---|
| Age in mo (IQR) | 42 (29–60) | 41 (25–54) |
| Sex, male (%) | 18/29 (62) | 17/27 (63) |
| Weight in kg at presentation (IQR) | 14.5 (13–16.8) | 14.8 (12.1–16.4) |
| Serum creatinine in mg/dl (IQR) | 0.34 (0.32–0.40) | 0.35 (0.33–0.45) |
| Spot urine protein/urine creatinine ratio in mg/mg (IQR) | 6.4 (4.8–7.6) | 5.75 (3.8–7.5) |
| Baseline early morning serum cortisol in μg/dl (IQR) | 5.09 (4.23–8.23) | 5.25 (3.59–6.5) |
Continuous variables expressed as medians and IQR. IQR, interquartile range.
Table 2.
Comparison of outcome parameters between single-dose and divided-dose prednisolone continuous variables expressed as median and interquartile range
| Variables after 6 wk of Daily Prednisolone | Single-Dose Prednisolone (n=29) | Divided-Dose Prednisolone (n=27) | P Value |
|---|---|---|---|
| Primary outcome | |||
| Prevalence of HPA axis suppression defined as cortisol <18 μg/dl post-SST (%) | 24/29 (83) | 27/27 (100) | 0.02 |
| Secondary outcomes | |||
| Days from steroid initiation when HPA axis suppression was assessed (IQR) | 44 (44–45) | 44 (44–45) | 0.43 |
| Pre-Synacthen early morning cortisol in μg/dl (IQR) | 0.37 (0.16–5.16) | 0.4 (0.06–2.11) | 0.34 |
| Prevalence of early morning cortisol <3 μg/dl (%) | 17/29 (58) | 22/27 (81) | 0.06 |
| Post-SST cortisol level in μg/dl (IQR) | 4.4 (1.6–13.1) | 4 (2.1–7.4) | 0.18 |
| Remission and relapse outcomes | |||
| Time (d) to initial remission (IQR) | 9 (8–13.5) | 10 (7–12) | 0.40 |
| Incidence of relapse after completion of 6+6 wk of steroid (%) | 9/29 (31) | 10/27 (37) | 0.64 |
| Time in days to first relapse (IQR) | 131 (85–145) | 28 (18–40) | 0.002 |
HPA, hypothalamic-pituitary-adrenal; SST, Short Synacthen Test; IQR, interquartile range.
Primary Outcome Measures
After 6 weeks of daily high-dose steroids at 2 mg/kg, HPA axis was assessed at a median of 44 (IQR, 44–45) days from the start of steroid by SST. HPA axis suppression was more prevalent in divided dose (100%) than in single dose (83%), P = 0.02 (Table 2).
Secondary Outcome Measures
Secondary outcomes are also detailed in Table 2. After 6 weeks of daily steroid, early morning cortisol levels were reduced in both single-dose (5.09 [IQR, 4.23–8.23] to 0.37 [IQR, 0.16–5.16] μg/dl, P < 0.001) and divided-dose groups (5.25 [IQR, 3.59–6.51] to 0.4 [IQR, 0.06–2.11] μg/dl, P < 0.001). Early morning cortisol level <3 μg/dl suggesting HPA axis suppression showed a trend of being more prevalent in the divided-dose group (81%) versus the single-dose group (58%) but did not reach statistical significance (Table 2).
As per protocol, all children were followed up through telephonic interviews every 2 weeks apart from clinical review as per the requirement of the treating team. All participants (single dose and divided dose) were steroid sensitive, and no difference in time to remission was noted between single dose in comparison with divided dose (Table 2). Once in remission, none relapsed during 6+6 weeks of steroid therapy. Once steroid course was completed, similar rates of relapses were noted in the follow-up period between divided dose (10 of 27, 37%) and single dose (nine of 29, 31%). Among those who relapsed, relapse occurred earlier in divided-dose participants (median 28 days) than among single-dose participants (131 days, P = 0.002) (Table 2). Kaplan–Meier survival curve is displayed in Figure 2; log-rank test did not show significant difference (P = 0.35) between the two groups because the relapse rate at 180 days was similar.
Figure 2.
Kaplan–Meier curve of time to first relapse among children on single-dose versus divided-dose steroid. Figure 2 can be viewed in color in online at www.cjasn.org.
In the telephone and clinic follow-up, parents did not report issues with medication adherence, and no significant adverse events were noted in either group during the follow-up period.
Discussion
In this open-labeled RCT, majority of children with first episode of nephrotic syndrome had biochemical HPA axis suppression after 6 weeks of daily prednisolone. Single-dose steroid in comparison with divided-dose steroid was associated with a marginal but statistically significant lower prevalence of biochemical HPA axis suppression and longer time to first relapse.
To the best of our knowledge, this is the first RCT focusing on HPA axis suppression among those receiving single-dose versus divided-dose steroid. The only previous RCT comparing single versus divided dose in childhood nephrotic syndrome was reported by Ekka et al., but their cohort also included children with relapsed steroid-sensitive nephrotic syndrome, and assessment of HPA axis was not undertaken.15 They reported similar outcomes between single dose versus divided dose at a follow-up of 9 months in induction of remission, frequency of relapse, duration of remission, cumulative dose of steroid, and significant adverse event.
HPA axis suppression has been linked to various complications, especially adrenal crisis.6,7,16 A limited number of studies exist on HPA axis status among childhood nephrotic syndrome8,9,12–15 (Supplemental Table 1), and similar to our study, they too showed significant HPA axis suppression. Defining clinical HPA axis suppression is not easy. Despite significant biochemical HPA axis suppression, children are usually asymptomatic, and this does create management uncertainties in any stress exposure, such as infections.7,14 To help with these questions, a UK-wide surveillance study is underway to ascertain prevalence and outcome of symptomatic glucocorticoid-induced adrenal suppression.17 HPA axis suppression has also been shown to be associated with nephrotic syndrome relapse.9,10 As per Abeyagunawardena et al., in children with nephrotic syndrome on long-term low-dose alternate day steroid with or without other steroid-sparing drugs, relapses were more prevalent among those with suppressed HPA axis.9 Similarly, Leisti et al. reported longer period of remission among children with normal HPA axis.10
Hence, it is generally agreed that HPA axis suppression should be minimized. Among children with frequently relapsing/steroid-dependent nephrotic syndrome, judicious use of potent steroid-sparing agent is one such option for minimizing HPA axis suppressions, but routine prescription of steroids as early morning single dose may be a less expensive and simple intervention that has not gained limelight. Apart from the advantage of lesser HPA axis suppression, early morning single-dose steroid might have the added advantage of better adherence. Although we did not find any difference in adherence, our study asked about adherence only using parental report, which is not a robust method to detect adherence.
Cutoff values to screen for biochemical HPA axis suppression is challenging to define. Current diagnostic criteria for glucocorticoid-induced adrenal suppression are transposed from those for primary adrenal insufficiency and not on patient outcome. Because of lack of evidence and varying interpretation of the scanty evidence available, international guidelines are low grade for thresholds for screening versus diagnosis for symptomatic patients, utility of baseline morning unstimulated serum cortisol, dosage for SST, and even timing of blood sampling11 (Supplemental Document).
It is unclear why less HPA axis suppression is associated with prolonged time to relapse. Nephrotic relapses are often associated with intercurrent infections, and there are hypotheses that less HPA axis suppression might allow children to mount better defense against interleukins released during these infections, thus minimizing the relapse rates.8,9 Supporting this hypothesis are RCTs from South Asia wherein increasing steroid during episode of upper respiratory tract infection has been shown to reduce relapse.18,19 This has been recently refuted by the PREDNOS 2 trial done in the United Kingdom,20 but some reviewers have attributed the difference in outcome to a different environmental and genetic makeup of PREDNOS 2 cohort in comparison with previous South Asian studies.21
We acknowledge the limitation of our study. Financial and logistic limitations meant that we were not able to conduct a multicenter double-blind placebo-controlled RCT. Our primary objective was to assess the HPA axis suppression between single-dose and divided-dose steroid and hence we felt it to be appropriate to assess the HPA axis at 6 weeks of daily steroid as subsequent 6 weeks of alternate day steroid are usually given as single morning dose. Unfortunately, we did not have the resources to repeat the SST at completion of 6+6 weeks of steroid therapy, which, along with a longer follow-up, would have made the information gained on outcomes, including subsequent relapses, clinically more relevant. It also has to be acknowledged that in our study, both groups showed very high levels of HPA axis suppression, and realistically improving HPA suppression may be feasible only with reducing cumulative dose of steroid without decreasing efficacy, and our trial was not designed to answer this point. New technologies such as using salivary cortisol could also increase the acceptability of this study for children and parents.
In conclusion, early morning single-dose corticosteroid when prescribed for first episode of nephrotic syndrome resulted in lesser biochemical HPA axis suppression with longer time to first relapse compared with divided dose. As the primary objective of the trial was to assess biochemical HPA axis suppression, we do need larger studies with longer follow-up to determine whether the marginal but significant reduced HPA axis suppression seen with single-dose steroid confers real clinical benefit.
Disclosures
S. Akhtar, S. Basu, T. Khan, and R. Sinha report employment with Institute of Child Health, Kolkata. All remaining authors have nothing to disclose.
Supplementary Material
Acknowledgments
We would like to acknowledge the help of Prof. Apurba Ghosh (Director of Institute of Child Health) for the Institute's support to this project. We would also like to acknowledge Dr. Agnisekhar Saha (Consultant Pediatrician, Apollo Multi Specialty Hospital, Kolkata) in helping us in designing this study.
Funding
None.
Author Contributions
Conceptualization: Shakil Akhtar, Rajiv Sinha.
Data curation: Shakil Akhtar, Surupa Basu, Tania Khan, Rajiv Sinha.
Formal analysis: Tania Khan, Rajiv Sinha, Yincent Tse.
Funding acquisition: Rajiv Sinha.
Investigation: Tania Khan, Rajiv Sinha.
Methodology: Shakil Akhtar, Devdeep Mukherjee, Rajiv Sinha.
Project administration: Rajiv Sinha.
Resources: Devdeep Mukherjee, Rajiv Sinha.
Software: Rajiv Sinha, Yincent Tse.
Supervision: Rajiv Sinha.
Writing – original draft: Rajiv Sinha, Yincent Tse.
Writing – review & editing: Shakil Akhtar, Surupa Basu, Devdeep Mukherjee, Rajiv Sinha, Yincent Tse.
Supplemental Material
This article contains the following supplemental material online at http://links.lww.com/CJN/B783.
Supplemental Table 1. Published studies assessing hypothalamus-pituitary-adrenal (HPA) axis suppression among children with nephrotic syndrome.
Supplemental Document. Assessment of hypothalamus pituitary axis (HPA).
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