Research Article 
Corresponding author: Olga A. Zhdanova ( olga.vr9@yandex.ru ) Academic editor: Tatyana Pokrovskaya
© 2018 Galina A. Batishcheva, Olga A. Zhdanova, Tatiana L. Nastausheva, Natalia Y. Goncharova, Yuri N. Chernov.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation:
Batishcheva GA, Zhdanova OA, Nastausheva TL, Goncharova NY, Chernov YN (2018) New methods to detect early manifestations of adverse side effects of glucocorticosteroids in children. Research Results in Pharmacology 4(1): 2732. https://doi.org/10.3897/rrpharmacology.4.25252

Introduction: The article focuses on the early manifestations of adverse side effects in children with nephrotic syndrome receiving glucocorticosteroids. The search for criteria of early side effect manifestations is a real challenge nowadays. The authors developed new diagnostic criteria for early detection of pharmacotherapeutical side effects in children with nephrotic syndrome.
Objective: The aim of the study was to develop integral quantitative diagnostic criteria for early detection of side effects of glucocorticosteroids when treating nephrotic syndrome in children.
Materials and Methods: The study included 58 inpatients, aged 118. All the children had been thoroughly examined and their parameters had been investigated: height and body mass by calculating Zscores (WHO ANTHRO Plus) and body mass index (BMI), a biochemical blood test, a full blood count by studying the total number of leukocytes, the percentage of neutrophils and monocytes in peripheral blood, systolic and diastolic blood pressure.
Results and Discussion: The parameters that changed in the patients with nephrotic syndrome taking corticosteroids are referred to as diagnostic criteria. They included leukocytes, neutrophils and monocytes parameters in the full blood count, blood glucose and amylase level, patients’ body mass, BMI, systolic and diastolic arterial pressure. The authors defined the change range of the parameters under study in the children with nephrotic syndrome based on the obtained findings.
Conclusion: The authors conclude that application of the developed indices will make it possible to diagnose early metabolic, cardiovascular and immunologic changes in patients with nephrotic syndrome taking glucocorticoids and perform their individual pharmacological correction in a timely manner.
adverse drug reaction, nephrotic syndrome, glucocorticoids, children
The pharmacotherapy applied in treating most diseases is characterised not only by the efficiency of arresting diverse pathologies, but also by developing various adverse side effects (
High doses of glucocorticosteroids which make remission possible in most patients are used in treating nephrotic syndrome in children (
Objective: This study was aimed at developing integral quantitative diagnostic criteria for early detection of side effects of glucocorticosteroids administered in the therapy of nephrotic syndrome in children.
In 20122014, 58 inpatients were examined with nephrotic syndrome, aged 118, receiving treatment at Voronezh Regional Clinical Paediatric Hospital № 1. The height and body mass with calculation of the body mass index (BMI) according to the formula had been measured in all the children. Zscores (WHO ANTHRO Plus) and BMI reference ranges were calculated in the children from birth to 5 years and from 5 to 19 years (
The children with nephrotic syndrome received a prolonged therapy with high doses of corticosteroids (
The priority of the suggested methods was recognised by the patents granted by the Russian Federation (
All stages of the study were consistent with legislation of the Russian Federation, international ethical standards and approved by the Ethics Committee of Voronezh State Medical Academy named after N.N. Burdenko.w
As a result of the studies conducted, methods were proposed for early detection of side effects of corticosteroids to various types of metabolism and leukocytes of peripheral blood in children with nephrotic syndrome, so that timely pharmacological correction of adverse side effects of corticosteroids could be performed.
To develop diagnostic criteria, the parameters that changed in patients with nephrotic syndrome during corticosteroid therapy were selected. They included leukocytes, neutrophils and monocytes parameters in the full blood count, blood glucose and amylase level, patients’ body mass, systolic and diastolic arterial pressure findings. The measurement of the changeable parameters in the patients was carried out repeatedly at various stage of the disease: at the onset or relapse stage, prior to corticosteroid administration, weekly during their administration, during remission and after drug withdrawal. The change range of the parameters under study in the children with nephrotic syndrome was determined based on the obtained findings. The comparison group included 120 healthy children and adolescents, whose parameters under study were also measured. Table
Change Range of Parameters Under Study in Healthy Children and in Patients with Nephrotic Syndrome
Parameters  Healthy children  Patients with nephrotic syndrome  Values of the parameters under study  

No adverse drug side effects to corticosteroids  Adverse drug effect to corticosteroids  
Min*  Max*  Min*  Max*  Min*  Max*  Amin**  Amax**  
Leukocytes, ∙10^{9}/l  4.0  10.3  3.5  10.5  11.0  31.5  3.5  31.5 
Neutrophils, %  21  63  19  62  44  84  19  84 
Monocytes, %  2  8  3  7  7  17  2  17 
A modification coefficient was calculated for each of the defined parameters according to formula (1):
$\mathrm{\ufeff}\mathrm{\ufeff}\u041c\mathrm{\ufeff}\mathrm{\ufeff}=30\mathrm{}\mathrm{\times}\mathrm{}{\scriptscriptstyle \frac{\mathrm{A}\mathrm{i}\mathrm{A}\mathrm{m}\mathrm{i}\mathrm{n}}{\mathrm{A}\mathrm{m}\mathrm{a}\mathrm{x}\mathrm{A}\mathrm{m}\mathrm{i}\mathrm{n}}}$ (1),
where M – a modification coefficient of each parameter,
Аi – a value of one of the parameters to study,
Amax and Amin –change limits of the parameters in healthy people and in patients with nephrotic syndrome (Table
With the help of formula (1), the parameters under study are brought to the unified scale from 1 to 30, which makes it possible to differentially assess and compare the deviation scope of the studied values.
The values of segmented neutrophils (Segs), systolic arterial pressure (SAP), diastolic arterial pressure (DAP) and heart rate (HR) obtained in the patients were expressed in deviation percent of the mean value of the age norm using formula (2):
$\mathrm{A}\mathrm{i}\mathrm{}\left(\mathrm{\%}\right)=\frac{\mathrm{A}\mathrm{p}\mathrm{a}\mathrm{t}\mathrm{*}50}{\mathrm{A}\mathrm{m}\mathrm{e}\mathrm{a}\mathrm{n}}$ (2),
where Аi – a value of one of the investigated parameters,
Apat – a value of the investigated parameter in a patient,
Amean – a mean value for a child of a given age and gender.
Diagnostic indices – index of metabolic reactions (IMR) by formula (3), index of immunological reactions (IIR) by formula (4), index of cardiovascular reactions (ICR) by formula (5) – were calculated by applying the modification coefficient.
$\mathrm{I}\mathrm{M}\mathrm{R}\mathrm{}={\scriptscriptstyle \frac{\mathrm{M}\mathrm{b}\mathrm{m}\mathrm{i}+\mathrm{M}\mathrm{g}\mathrm{l}+\mathrm{M}\mathrm{a}\mathrm{m}}{3}}$ (3),
where IMR – index of metabolic reactions,
Mbmi – a modification coefficient of BMI,
Mgl – a modification coefficient of glucose,
Mam – a modification coefficient of amylase.
$\mathrm{I}\mathrm{I}\mathrm{R}=\frac{\mathrm{M}\mathrm{l}\mathrm{e}\mathrm{u}+\mathrm{M}\mathrm{s}\mathrm{t}\mathrm{a}\mathrm{b}+\mathrm{M}\mathrm{s}\mathrm{e}\mathrm{g}\mathrm{m}+\mathrm{M}\mathrm{m}\mathrm{o}\mathrm{n}}{4}$ (4),
where IIR – index of immunological reaction,
Mleu – a modification coefficient of leukocytes,
Mstab – a modification coefficient of stab neutrophils,
Msegm – a modification coefficient of segmented neutrophils,
Mmon – a modification coefficient of monocytes.
$\mathrm{I}\mathrm{C}\mathrm{R}=\frac{\mathrm{M}\mathrm{s}\mathrm{y}\mathrm{s}\mathrm{t}+\mathrm{M}\mathrm{d}\mathrm{i}\mathrm{a}\mathrm{s}\mathrm{t}+\mathrm{M}\mathrm{h}\mathrm{r}}{3}$ (5),
where ICR – index of cardiovascular reactions,
Msyst – a modification coefficient of systolic blood pressure,
Mdiast – a modification coefficient of diastolic blood pressure,
Mhr – a modification coefficient of the heart rate.
Reference index values – IIR <12 units, IMR ≤ 14.5, ICR < 14 units  were developed on the basis of the performed studies of the test parameters in the healthy children. If the patient’s indices are within these ranges, no pharmacological correction for the adverse side effects of glucocorticosteroids is necessary.
A boy X, aged 6, was examined during a regular checkup prior to school admission. His diagnosis was: healthy. The results of this examination are shown in Table
Examination Results of Boy X
Group of findings  Parameters*  Modification coefficients of the parameters**  Integral indices*** 
Metabolic findings  Height – 120 cm, Body mass – 22 kg, BMI – 15.3zscore BMI = 0.15  Мbmi = 13.2  IMR = 8.0 
Glucose = 4.2 mmol/L  Мgluc = 5.7  
Amylase = 42 mg%  Мam = 5.1  
Full blood test findings  leukocytes = 4.7∙10^{9}/л  Мleuk = 2.9  IIR = 5.6 
Stab neutroph. = 1 %  Мstab = 2.0  
Segm. neutroph. – 44% Segm. neutroph. = 47.3% of the norm  Мsegm = 13.8  
Monocytes = 5%  Мmon = 3.9  
Cardiovascular system  Syst. BP – 95 mm Hg Syst. BP = 46.6% of the norm  Мsyst. = 8.6  ICR = 9.0 
Diast. BP – 65 mm Hg Diast. = 49.2% of the norm  Мdias. = 9.7  
HR – 90 beat per min HR = 46.4% of the norm  Мhh = 8.6 
The calculated integral indices (Table
A boy Z, aged 7, was diagnosed with nephrotic syndrome, steroidsensitive variant. He had been ill for two months, now in a remission period. He had a safe kidney function. He had received a glucocorticoid (prednisolone) therapy, dose 60 mg/m^{2} of his body surface, for 6 weeks. The boy was examined before transfer to the alternating treatment period.
The results of this examination are given in Table
Examination Results of Boy Z
Group of findings  Parameters*  Modification coefficients of the parameters **  Integral indices*** 
Metabolic findings  Height  129 cm, Body mass – 35 kg, BMI – 21.0 zscore BMI = 2.48  Мbmi = 20.4  IMR = 16.1 
Glucose = 5.2 mmol/L  Мgluc = 9.3  
Amylase = 128 mg%  Мam = 18,6  
Full blood test findings  Leukocytes = 22∙10^{9}/l  Мleuk = 21.4  IIR = 14.8 
Stab neutroph. = 2 %  Мstab = 4.6  
Segm. neutroph. – 62% Segm. neutroph. = 63.5% of the norm  Мsegm = 20.1  
Monocytes = 12%  Мmon = 13.0  
Cardiovascular system  Syst. BP – 100 mm Hg Syst. BP = 48% of the norm  Мsyst = 9.1  ICR = 9.5 
Diast. BP – 60 mm Hg Diast. BP = 45% of the norm  Мdiast = 7.8  
HR – 100 beats per min HR = 54% of the norm  Мhh = 11.5 
The calculated integral indices (Table
Assessment of the influence of various schemes of corticosteroid therapy on the development of nephrotic syndrome relapses in children and frequency of detection of adverse side effects is highlighted in the Cochrane review (
There are some recommendations known nowadays on monitoring children with nephrotic syndrome receiving corticosteroid therapy (
Sporadic metabolic side effects of corticosteroids in children with nephrotic syndrome are described in literature, for example, pancreatoxicity, obesity (
When taking glucocorticoids for a long period of time, some changes may occur in the full blood test parameters which are well known, i.e. a decrease in the number of lymphocytes, eosinophils, basophils with simultaneous development of neutrophil leukocytosis, persisting for 14 weeks (
Application of the developed indices will make it possible to diagnose early metabolic, cardiovascular and immunologic changes in patients with nephrotic syndrome in the context of glucocorticoid therapy and perform their individual pharmacological correction in a timely manner.
The authors have no conflict of interest to declare.
Galina A. Batishcheva, Doctor of Medical Sciences, Full Professor, Head of Department of Clinical Pharmacology, Voronezh State Medical University named after N.N. Burdenko, Voronezh, Russia, email: bat13@mail.ru, ORCID ID 0000000347717466. The author provided the idea of research, analysed the results and made conclusions.
Olga A. Zhdanova, Candidate of Medical Sciences PhD in Medicine, Associated Professor of the Department of Clinical Pharmacology, Voronezh State Medical University named after N.N. Burdenko, Voronezh, Russia, email: olga.vr9@yandex.ru, ORCID ID 0000000239170395. The author defined the idea of research, analysed the clinical material, results and conclusions.
Tatiana L. Nastausheva, Doctor of Medical Sciences, Full Professor, Head of Department of Hospital and Polyclinic Pediatrics, Voronezh State Medical University named after N.N. Burdenko, Voronezh, Russia, email: nastat53@mail.ru, ORCID ID 0000000160961784. The author consulted on the research idea, the analysis of the clinical material and conclusions.
Natalia Y. Goncharova, Candidate of Medical Sciences PhD in Medicine, Associated Professor of the Department of Clinical Pharmacology, Voronezh State Medical University named after N.N. Burdenko, Voronezh, Russia, email: _sumerki_@mail.ru. The author was engaged in the design of the article and statistical processing of the material.
Yuri N. Chernov, Doctor of Medical Sciences, Full Professor, Department of Clinical Pharmacology, Voronezh State Medical University named after N.N. Burdenko, Voronezh, Russia. The author took part in the analysis of the clinical material, results and conclusions.