Adrenocortical suppression increases the risk of relapse in nephrotic syndrome

Objective

Children with nephrotic syndrome (NS) are usually treated with long‐term low dose alternate day prednisolone with or without glucocorticoid sparing therapy, such as levamisole or ciclosporin, to maintain remission. The degree of hypothalamic‐pituitary‐adrenal axis (HPA) suppression with such therapeutic strategies has not been studied systematically. HPA suppression could cause a relapse or adrenal crisis.

Study design

To study the risks of HPA suppression, a modified low dose synacthen test (0.5 μg) was administered to 32 patients (22 male,10 female) with a mean age of 9.7 years (range 3.8–17.6 years) with NS receiving long‐term alternate day prednisolone for over 12 months. Twelve patients received alternate day prednisolone, 11 alternate prednisolone+levamisole and nine alternate prednisolone+ciclosporin. All patients were followed up for 3 years and the relapse rate noted.

Results

20/32 (62.5%) patients had a peak serum cortisol concentration of <500 nmol/l, which suggested suboptimal cortisol secretion and possible HPA suppression. 10/12 children in the prednisolone group and 8/11 in the levamisole group had a suboptimal cortisol response compared with 2/9 in the ciclosporin group. During follow‐up, the 20 children who had a suboptimal cortisol response had significantly more relapses (95 relapses) compared to the 12 children with a normal cortisol response who had 24 relapses (p = 0.01).

Conclusions

Children with NS receiving long‐term alternate day prednisolone therapy are at risk of developing HPA suppression and should be evaluated using the modified synacthen test. Children with evidence of HPA suppression are at a greater risk of relapse.     

Intermittent versus long-term tapering prednisolone for initial therapy in children with idiopathic nephrotic syndrome

Forty-six children with steroid-responsive nephrotic syndrome were randomly allocated to receive two different prednisolone regimens for initial therapy. Twenty-nine children (group 1) received an intermittent regimen (60 mg/m2/day for 4 weeks, followed by 40/mg/m2/day on 3 days a week for 4 weeks); 17 children (group 2) had a long-term regimen (60 mg/m2/day for 4 weeks, followed by the same dose on alternate days for 4 weeks and the doses tapered by 10 mg/m2, given on alternate days every 4 weeks for 5 months). There was no difference between the two groups in the regimen used to treat relapses, steroid responsiveness, number of patients with relapses, and frequency of toxic reactions to steroids. However, the number of patients with a relapse within 6 months after initial therapy and the number of those with frequent relapses or steroid dependence were significantly higher in group 1 than in group 2 (P less than 0.05 for both). The data indicate that the long-term tapering regimen appears to be both safe and preferable to the intermittent regimen for initial therapy in children with idiopathic nephrotic syndrome.     

Long-term, small dose prednisone therapy in frequently relapsing nephrotic syndrome of childhood. Effect on remission, statural growth, obesity, and infection rate

A prospective study was performed to evaluate the effect of long-term small-dose prednisone therapy in frequently relapsing nephrotic syndrome (NS); 37 patients were included, with a relapse rate 4.6/patient/year (range, 3-8) (mean age, 6.7 years; range, 2-15 years). Prednisone was started 2 mg/kg/day once remission was induced. Prednisone was progressively reduced over weeks until 10 mg/day was reached, and then the daily dose was changed to 10 mg on alternate days. On follow-up (mean, 25.4 months; range, 10-58 months), only five had subsequent relapses and their relapse rate decreased significantly to 1.2/patient/year (p less than 0.05). Forty-six episodes of infection were associated with exacerbation of NS; 41 of these excerbations remitted spontaneously without an increase in the dose of prednisone. Serial height and weight measurements revealed evidence of improved height velocity and obesity persisted in only two of 13 initially obese children.     

Prevalence of hypothalamic-pituitary-adrenal axis suppression in children treated for asthma with inhaled corticosteroid

OBJECTIVE:

To determine the prevalence of hypothalamic-pituitary-adrenal (HPA) axis suppression in asthmatic children on inhaled corticosteroids (ICS).

METHODS:

Clinical and demographic variables were recorded on preconstructed, standardized forms. HPA axis suppression was measured by morning serum cortisol levels and confirmed by low-dose adrenocorticotropic hormone stimulation testing.

RESULTS:

In total, 214 children participated. Twenty children (9.3%, 95% CI 5.3% to 13.4%) had HPA axis suppression. Odds of HPA axis suppression increased with ICS dose (OR 1.005, 95% CI 1.003 to 1.009, P<0.001). All children with HPA axis suppression were on a medium or lower dose of ICS for their age (200 μg/day to 500 μg/day). HPA axis suppression was not predicted by drug type, dose duration, concomitant use of long-acting beta-agonist or nasal steroid, or clinical features.

CONCLUSION:

Laboratory evidence of HPA axis suppression exists in children taking ICS for asthma. Children should be regularly screened for the presence of HPA axis suppression when treated with high-dose ICS (>500 μg/day). Consideration should be given to screening children on medium-dose ICS.     

Long-term treatment with corticosteroids/ACTH in asthmatic children. II. Hypothalamic-pituitary-adrenal function

Hypothalamic-pituitary-adrenal (HPA) function was studied in 23 children with severe bronchial asthma during and after long-term treatment with prednisolone and/or ACTH1-24 depot tetracosactrin) by means of ACTH stimulation test and insulin tolerance test. In the 14 children primarily treated with depot tetracosactrin, the cortisol levels in insulin tests were within normal limits both during and after treatment. An enhanced response to ACTH stimulation was found during the treatment period. During treatment with prednisolone a marked impairment of the adrenocortical function was found, with low basal plasma cortisol levels and subnormal response to ACTH stimulation, more marked the lower the age at the start of treatment and the higher the dose per kg body weight. After substitution with depot tetracosactrin the HPA-function was restituted, with plasma cortisol levels within normal limits. Growth hormone levels after insulin induced hypoglycemia were greater than or equal to 7 ng/ml during and after treatment with depot tetracosactrin. As long-term treatment with depot tetracosactrin has little side-effects in terms of suppression of the HPA-axis it is a useful alternative to oral prednisolone in severe asthma in children.     

Pulse Methylprednisolone Therapy in Severe Idiopathic Childhood Nephrotic Syndrome

ABSTRACT. The effect of methyl prednisolone therapy (PM) was studied in 18 children with severe idiopathic nephrotic syndrome (NS). Eight patients were defined as "corticosteroid-resistant" because there was no response to treatment after a minimum of 4 weeks of 2 mg/kg/day of prednisone; 10 patients had a corticosteroid-dependent NS with frequent relapses which occurred under a high threshold dose of prednisone (1 mg/kg/day). Each patient received 4–6 pulses of 1 g/1.73 m² methylprednisolone. Tolerance was generally good. PM therapy permitted a more rapid remission than oral prednisone (average 9±4 days vs. 22±9 days). Remission occurred in 5 of the 8 corticosteroid-resistant patients three of these 5 patients developed corticosteroid-dependent NS. For the children with a corticosteroid-dependent nephrotic syndrome, PM therapy did not affect the threshold dose of prednisone.     

Cyclosporin A plus prednisone treatment of steroid-sensitive frequently relapsing nephrotic syndrome in children

Recently, there have been numerous reports on the use of cyclosporin A (CyA) in children with nephrotic syndrome (NS). In this prospective study, we wanted to evaluate the efficacy of CyA together with prednisone therapy in children with steroid-sensitive frequently relapsing NS. A total of 11 children (7 boys, 4 girls) with steroid-sensitive NS were included in this study. The patients ranged in age from 3.5 to 15 years (average 8.45 +/- 4.26 years). Renal biopsy showed minimal change disease in five, mesangial proliferation in four, focal glomerulosclerosis in one and membranous glomerulonephritis in one. The NS had lasted from 13 to 113 months (average 50.27 +/- 38.60 months). The number of relapses varied from three to 10 episodes with an average of 5.9 +/- 3.3 episodes. Patients received 5 mg/kg CyA daily in two divided doses for five months and prednisone for a total of eight weeks (30 mg/m2 daily for 4 weeks followed by 30 mg/m2 on alternate days for 4 weeks). After the completion of the treatment protocol, no therapy was given unless a relapse was observed. Mean follow-up period was 14.9 +/- 5.99 months with a range from six to 26 months. Before this combined treatment, there was a mean relapse rate of 0.144 +/- 0.05 relapses month with a range from 0.088 to 0.238. After discontinuation of therapy, the relapse rate dropped to a mean of 0.0179 +/- 0.031 with a range of 0 to 0.083. In conclusion, it would appear that a combination of CyA and prednisone is effective, sustaining the remission in steroid-sensitive NS. Corticosteroids in combination with CyA may be a better approach than conventional steroid treatment in such patients.     

Foster children's diurnal production of cortisol: an exploratory study

Young children in foster care have often experienced inadequate early care and separations from caregivers. Preclinical studies suggest that early inadequate care and separations are associated with long-term changes in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. In this study, the daytime pattern of cortisol production was examined among 55 young children who had been placed into foster care and 104 children who had not. Saliva samples were taken at wake-up, in the afternoon, and bedtime for 2 days. Average salivary cortisol values for each time of day were computed. A group (foster vs. comparison) time (morning, afternoon, night) interaction emerged, reflecting less decline in levels across the day for foster than comparison children. Daytime patterns were categorized as typical, low, or high. Children who had been in foster care had higher incidences of atypical patterns of cortisol production than children who had not. These differences suggest that conditions associated with foster care interfere with children's ability to regulate neuroendocrine functioning.     

Eight and 12 week courses of cyclophosphamide in nephrotic syndrome.

Seventy-three children with steroid dependent minimal change nephrotic syndrome were randomly allocated to receive treatment with cyclophosphamide (2 mg/kg/day) for either eight or 12 weeks, in combination with prednisolone. All patients had previously relapsed while the dosage was being reduced or within 14 days of discontinuing prednisolone in the six months before receiving cyclophosphamide treatment (steroid dependent), and had severe steroid toxicity. Thirty two patients were treated with cyclophosphamide for eight weeks, and 41 for 12 weeks. There were no differences between the two groups in age at onset of nephrosis or entry into the study, sex ratio, duration of nephrosis, number of relapses before entry, and follow up period after entry. The relapse free rate of patients treated for eight weeks (25%) was similar to that of those treated for 12 weeks (24%) five years after stopping the treatment, and the mean relapse free interval and the sparing effect of cyclophosphamide (if any) on subsequent treatment with steroids did not differ between the groups. We conclude that cyclophosphamide should be used for no longer than eight weeks at a dose of 2 mg/kg/day in children with steroid dependent minimal change nephrotic syndrome.     

Adrenal function in children with severe asthma treated with high-dose inhaled glucocorticoids: recommended screening tests in outpatient conditions

BACKGROUND: A number of previous studies have suggested that adrenal suppression occurs in asthmatic children treated with high-doses of inhaled glucocorticoids (IGC). This study was designed to determine the frequency of adrenal suppression in children with severe asthma treated with recommended doses of IGC: namely 500-1,000 microg/day of fluticasone propionate or the equivalent of budesonide (1,000-2,000 microg/day) for a period of at least 12 months. METHODS: Early morning cortisol (F) and ACTH serum levels were measured in 27 severe asthmatics aged 6-16 years old. The children underwent a low dose ACTH test (1 microg/1.73 m2) with a parallel glucose measurement. Twenty-four hour urine collection was performed before examination for free F (UfF) and creatinine levels. There were no clinical manifestations of adrenal hypofunction in the analyzed children. RESULTS: Of the 27 patients, 22 had normal basal and post-stimulatory levels of F and normal UfF, and the other five (18.5%) had basal serum F levels of <400 nmol/l. Four of the five also had normal post-stimulatory levels of F and normal UfF. One child had a subnormal peak F value of 484 nmol/l during the ACTH test. None of the patients had a suppressed serum ACTH level, but an elevated ACTH level was found in four children. This study provided biochemical evidence of suboptimal adrenal function in one child in the examined group (3.7%) and a good response to stimulation in all the others, even in those with slightly reduced basal cortisol levels. CONCLUSION: This study showed that the use of fluticasone in doses of up to 1,000 microg/day (or the equivalent of budesonide) as long-term treatment of children with severe asthma did not substantially affect their adrenal function.     

Treatment of Idiopathic Nephrotic Syndrome with Levamisole

Thirty children with frequently relapsing idiopathic nephrotic syndrome (INS) were treated with levamisole (2.5 mg/kg BW) twice a week for a mean period of 9.9 months. A beneficial effect was observed in 16 children in whom corticosteroids could be significantly decreased without relapse. Levamisole was ineffective in 14 patients. There was no difference between the two groups in the duration of INS, the number of relapses and the duration of treatment with levamisole. The mean age at onset of INS was higher in the group of patients where levamisole was effective (5.8 years versus 2.8 years). In 7 patients who responded to levamisole neutrophils decreased below 4×10⁹/l. Transient granulocytopenia was observed in 3. It is concluded that levamisole may be effective in frequently relapsing INS with minimal side effects     

Relapse of minimal change nephrotic syndrome after intravitreal bevacizumab

Reported herein is a case of relapse of nephrotic syndrome (NS) after intravitreal injection of bevacizumab, a monoclonal antibody that binds to vascular endothelial growth factor (VEGF), in a 16‐year‐old girl. She had a diagnosis of steroid‐dependent NS and had been treated with prednisolone, and remained in remission. The patient had had visus brevior 10 years previously, and was diagnosed with severe myopic choroidal neovascularization (mCNV). Intravitreal bevacizumab was given for mCNV. At 9 days after intravitreal injection of bevacizumab, proteinuria was positive. The patient had relapse of NS caused by bevacizumab, and steroid pulse therapy was then given and the proteinuria resolved. It is necessary to take particular care to prevent NS relapses in patients with mCNV treated with intravitreal bevacizumab.     

Single serum cortisol values at 09:00 h can be indices of adrenocortical function in children with Kawasaki disease treated with intravenous immunoglobulin plus prednisolone

Combination treatment with intravenous immunoglobulin (IVIG) plus prednisolone is effective for prevention of cardiovascular complications in children with Kawasaki disease (KD). However, administration of prednisolone for approximately 20 d in this regimen causes adrenocortical suppression in a high proportion of treated children. To establish a simple method to screen for this suppression, we performed a prospective study on 72 children with KD treated with this regimen in our institution from February 2012 to March 2014. By performing ROC analysis of 21 initial patients treated between February and June 2012, a serum cortisol value at 09:00 h of 5 mcg/dL was established as a threshold for intact adrenocortical function, which is equivalent to a peak serum cortisol value of higher than 15 mcg/dL in the CRH stimulation test. Then, we applied this screening test to 51 subsequent patients treated between July 2012 and March 2014. Approximately 90% of the patients with morning serum cortisol values above 5 mcg/dL 2 to 6 mo after the cessation of initial prednisolone treatment had peak serum cortisol values exceeding 15 mcg/dL, suggesting the efficacy of this approach.     

Immunoregulation with levamisole in children with frequently relapsing steroid responsive nephrotic syndrome

The immunological and clinical effects of levamisole were studied in 10 children with frequently relapsing steroid responsive nephrotic syndrome (SRNS). The efficacy of the drug was tested during remission of the disease with all patients on alternate day steroid therapy. The lymphocyte proliferative response to phytohemagglutinin (PHA), concanavalin-A (Con-A) and pokeweed mitogen (PWM) were normal. The Con-A induced suppressor T-lymphocyte activity of 7 patients was low before treatment with levamisole 8 +/- 3.7% and increased to normal values during therapy 34 +/- 6%; p less than 0.001 (control 32 +/- 5%). In these 7 children prednisolone dosage could be decreased significantly or discontinued altogether (44.1 +/- 5.3%). Patients without immunoregulatory abnormalities did not respond to levamisole. In 3 out of 4 children tested the percentage of OKT8+ cells rose during levamisole therapy from 19.7 +/- 2.1 to 37 +/- 2.3 (p less than 0.001), thus correcting the elevated pre-treatment OKT4+/OKT8+ ratio from 3.1 +/- 0.2 to 1.5 +/- 0.2; p less than 0.001 (control 1.47 +/- 0.2). These data support the hypothesis that abnormal immunoregulation may play a role in the pathogenesis of SRNS. Treatment with levamisole can be useful in some patients with the frequently relapsing form of the disease.     

Levamisole in frequently-relapsing and steroid-dependent nephrotic syndrome

Objective

To evaluate the efficacy of levamisole in children with frequently relapsing nephrotic syndrome (FRNS) and steroid dependent nephrotic syndrome (SDNS) when administered on an alternate day (‘initial therapy’ in all cases) or daily basis (‘rescue therapy’ in whom alternate day therapy failed).

Methods

The records of 95 children (age 1–18y) with FRNS (62) and SDNS (33), who were treated at the Pediatric nephrology clinic, and received levamisole therapy (maximum 2 y duration, between 2010–2013) with a follow-up period of minimum 1 y, were included.

Results

Alternate day levamisole therapy was efficacious in 73.7% (n=70). The overall efficacy of levamisole therapy was 88.4% (n=84). Levamisole therapy decreased the mean (SD) number of relapses from 4.22 (0.46)/y to 1.35 (0.36)/y (P<0.01); and cumulative median (IQR) prednisolone dosage from 4200 (3200–4300) mg/m² to 1100 (IQR 500–2900) mg/m² (P<0.001). On a one-year follow up of the cases in whom levamisole therapy was efficacious during therapy (median 24 mo) (n=84), a frequently relapsing or steroid dependent course continued to persist in 48.8% (41), necessitating oral cyclophosphamide (n= 22) or mycophenolate mofetil (n=19).

Conclusions

Daily levamisole therapy was useful in 56% of children who demonstrated failure while on alternate day levamisole therapy, and could be a useful therapeutic option in FRNS and SDNS.

     

Treatment of idiopathic nephrotic syndrome with levamisole

Thirty children with frequently relapsing idiopathic nephrotic syndrome (INS) were treated with levamisole (2.5 mg/kg BW) twice a week for a mean period of 9.9 months. A beneficial effect was observed in 16 children in whom corticosteroids could be significantly decreased without relapse. Levamisole was ineffective in 14 patients. There was no difference between the two groups in the duration of INS, the number of relapses and the duration of treatment with levamisole. The mean age at onset of INS was higher in the group of patients where levamisole was effective (5.8 years versus 2.8 years). In 7 patients who responded to levamisole neutrophils decreased below 4 X 10(9)/l. Transient granulocytopenia was observed in 3. It is concluded that levamisole may be effective in frequently relapsing INS with minimal side effects.     

Decreased cortisol response to insulin induced hypoglycaemia in asthmatics treated with inhaled fluticasone propionate.

AIMS: To assess adrenal function in asthmatic children treated with inhaled fluticasone propionate for up to 16 weeks. METHODS: Children with asthma and bronchial hyperresponsiveness to inhaled methacholine were treated with inhaled fluticasone 250-750 microg/day via Volumatic spacer. The insulin tolerance test (ITT) was performed to assess adrenal function. RESULTS: Eighteen asthmatic patients (10 boys, 8 girls), aged 7-17 years received inhaled fluticasone therapy at a median dose of 477 microg/m2 per day for 5-16 weeks. Adrenal suppression, defined as 60 minute serum cortisol less than 500 nmol/l, was found in 9 of 18 children. Following the ITT, the median basal and 60 minute serum cortisol concentrations of the suppressed group were 135.0 and 350.0 nmol/l, respectively; the corresponding values for the unsuppressed group were 242.2 and 564.7 nmol/l. Repeat ITT in the suppressed group 2-3 months after discontinuation of fluticasone revealed that all patients had a 60 minute serum cortisol greater than 500 nmol/l. CONCLUSION: After therapy for asthma with inhaled fluticasone at approximately 500 microg daily for up to 16 weeks, half the children had evidence of adrenal suppression.     

Immunoregulation with Levamisole in Children with Frequently Relapsing Steroid Responsive Nephrotic Syndrome

ABSTRACT. The immunological and clinical effects of levamisole were studied in 10 children with frequently relapsing steroid responsive nephrotic syndrome (SRNS). The efficacy of the drug was tested during remission of the disease with all patients on alternate day steroid therapy. The lymphocyte proliferative response to phytohemagglutinin (PHA), concanavalin-A (Con-A) and pokeweed mitogen (PWM) were normal. The Con-A induced suppressor T-lymphocyte activity of 7 patients was low before treatment with levamisole 8±3.7% and increased to normal values during therapy 34±6%; p <0.001 (control 32±5%). In these 7 children prednisolone dosage could be decreased significantly or discontinued altogether (44.1±5.3%). Patients without immunoregulatory abnormalities did not respond to levamisole. In 3 out of 4 children tested the percentage of OKT8⁺ cells rose during levamisole therapy from 19.7±2.1 to 37±2.3 ( p <0.001), thus correcting the elevated pre-treatment OKT4⁺/OKT8⁺ ratio from 3.1±0.2 to 1.5±0.2; p <0.001 (control 1.47±0.2). These data support the hypothesis that abnormal immunoregulation may play a role in the pathogenesis of SRNS. Treatment with levamisole can be useful in some patients with the frequently relapsing form of the disease.     

Suppression of adrenal function in children with acute lymphoblastic leukemia following induction therapy with corticosteroid and other cytotoxic agents

OBJECTIVE: To evaluate adrenal function in children with acute lymphoblastic leukemia (ALL) after induction therapy with corticosteroid and other cytotoxic agents.Study design Children with ALL (N=24) were treated with prednisolone (40 mg/m(2) per day) for 28 days during the induction phase followed by 1 week of oral dexamethasone every 4 weeks. A low-dose (1 microg) adrenocorticotropin (ACTH) test was performed 2 weeks after discontinuation of prednisolone; it was repeated 2 weeks later and then every 4 weeks in patients with adrenal suppression until normal response was achieved. RESULTS: Adrenal suppression was found in 46% of patients at 2 weeks after discontinuation of prednisolone; it persisted in 38%, 29%, and 13% of patients through 4 weeks, 8 weeks, and 20 weeks, respectively. Adrenal suppression appeared to last significantly longer in children aged >or=5 years than in children aged <5 years. Four children developed febrile neutropenia; all belonged to the adrenal suppressed group and were unable to mount an adequate adrenal response to the stress. CONCLUSIONS: About 50% of children with ALL developed adrenal suppression 2 weeks after a 4-week induction therapy with prednisolone. The suppression could persist through 20 weeks and may hinder an adequate adrenal response during acute febrile illness.     

Decreased cortisol response to insulin induced hypoglycaemia in asthmatics treated with inhaled fluticasone propionate

Aims: To assess adrenal function in asthmatic children treated with inhaled fluticasone propionate for up to 16 weeks. Methods: Children with asthma and bronchial hyperresponsiveness to inhaled methacholine were treated with inhaled fluticasone 250–750 µg/day via Volumatic spacer. The insulin tolerance test (ITT) was performed to assess adrenal function. Results: Eighteen asthmatic patients (10 boys, 8 girls), aged 7–17 years received inhaled fluticasone therapy at a median dose of 477 µg/m² per day for 5–16 weeks. Adrenal suppression, defined as 60 minute serum cortisol less than 500 nmol/l, was found in 9 of 18 children. Following the ITT, the median basal and 60 minute serum cortisol concentrations of the suppressed group were 135.0 and 350.0 nmol/l, respectively; the corresponding values for the unsuppressed group were 242.2 and 564.7 nmol/l. Repeat ITT in the suppressed group 2–3 months after discontinuation of fluticasone revealed that all patients had a 60 minute serum cortisol greater than 500 nmol/l. Conclusion: After therapy for asthma with inhaled fluticasone at approximately 500 µg daily for up to 16 weeks, half the children had evidence of adrenal suppression.