Apoptosis-Controlling, Clinical, Laboratory, Anamnestic Factors in Prediction of the Early Stage of Diabetic Nephropathy in Children.

Background. The most prevalent microvascular consequence of type 1 diabetes (T1D) is diabetic nephropathy (DN). Aim of the Study. To find the clinical, anamnestic, and genetic markers that characterize and forecast early diabetic nephropathy in T1D children. Methods. One hundred four children with T1D and DN between the ages of 2 and 17 were surveyed. Stepwise logistic regression models and linear regression models were used. Results. BMI, systolic blood pressure, concurrent kidney pathology, anamnesis viral infections, ESR level, serum cholesterol, blood urea, number of DKA episodes/year, and GFR were determined to be predictors of early DN in children with T1D. Bcl-xL, caspase-3, and HIF-1alfa were discovered to predict DN among all previously identified variables influencing apoptosis. Conclusion. BMI, systolic blood pressure, concurrent kidney disease, anamnesis viral infections, ESR level, serum cholesterol, blood urea, number of DKA episodes/year, GFR, apoptotic and hypoxia markers were discovered as variables predicting early DN.

DIABETIC NEPHROPATHY: NOVELTY ABOUT THE DIABETIC NEPHROPATHY TREATMENT IN CHILDREN.

OBJECTIVE: The aim: To analyze and discuss the main aspects of the DN treatment in children. PATIENTS AND METHODS: Materials and methods: Basic and modern data about the new aspects of the DN treatment analyzed in current review paper. Conclusions: DN is a major healthcare challenge and is a major cause of irreversible kidney damage. The DN course and progression leads to severe cardiovascular complications and early death. Treatment of DN is complicated clinical issue and requires individual and complex approach, including renoprotection, antihypertensive treatment. Nowadays, we are able to provide additional medications that can enhance the benefits of the renin-angiotensin-aldosterone (RAAS) blocking, Further search of neproprotective medicines for early DN correction in pediatric patients is still of high importance.

To the Question of Vitamin D Network in Type 1 Diabetes and Diabetic Nephropathy in Children Nursed in Ukrainian Endocrinology Unit.

Background: Vitamin D deficiency is a great problem worldwide. Vitamin D plays an essential role in calcium and bone metabolism. Diabetic nephropathy (DN) is a dangerous kidney-related complication of type 1 diabetes (T1D). Aim of the study: To evaluate levels of Vitamin D3 in pediatric patients with T1D and DN; to study the dependence between the Vitamin D level and main clinical and laboratory parameters of the disease, that is, duration, complications episodes, albuminuria levels, glomerular filtration rate (GFR). Material and methods: A survey of 72 children with T1D and DN aged 3-17 years was done. Complex examination including conventional methods (physical examination, blood pressure measurement, blood tests, study of urinary sediment, renal ultrasound, etc.) was done for all patients. Data was processed using GraphPad Prism 9.0 Software for Windows (USA, San Diego, CA). p-values <.05 were considered statistically significant. Results: Majority of patients from T1D group have normal value of Vitamin D, only 27.7% of children have Vitamin D insufficiency. In contrast, in children from DN group only 16.7% of children have Vitamin D insufficiency and 83.3% have Vitamin D deficiency. Vitamin D serum level negatively correlates with disease duration and albuminuria level in the group with DN. Serum levels of Vitamin D positively correlate with GFR in patients with T1D. Patients with DN who had a duration of T1D for 10 years and more have a higher progression rate to Vitamin D deficiency as compared to those who have a T1D duration of less than 10 years. Conclusions: The authors conclude that Vitamin D has a direct relationship with functional disorders with DN, that is, albuminuria, GFR, kidney function. Further investigations of Vitamin D supplementation on different stages of the ND development and progression are needed.

Analysis of Apoptotic, Clinical, and Laboratory Parameters in Type 1 Diabetes and Early Diabetic Nephropathy: Clustering and Potential Groups Evaluation for Additional Therapeutic Interventions

Objective: Type 1 diabetes (T1D) is one of the most prevalent chronic illnesses diagnosed in childhood. Diabetic nephropathy (DN) is one of the commonest complication of T1D. Therefore the development of specific treatment that arrests progression of DN based on an individual approach would be beneficial. Analysis of criteria of apoptosis, and clinical, and laboratory characteristics in T1D and early DN in the framework of clustering may be helpful in the identification of potential groups for additional therapeutic interventions. Methods: A survey of 104 children (62 males, 42 females) with T1D and DN aged 2 to 17 years in the Endocrinology unit of Clinical Pediatric Hospital No 6 (Kyiv, Ukraine) was performed. Clinical data (age, gender, disease duration, blood pressure), conventional laboratory markers including complete blood count, serum cholesterol, hemoglobin A1c (Hb1Ac), glomerular filtration rate (GFR), and microalbuminurea (MAU), and markers of apoptosis (BcL-xL, caspase-3) and transcriptional factor HIF-1alfa were analyzed. Results: A cluster group in T1D children was characterized by somewhat higher number of platelets (PLT) - 344.9±7.88·109/L, increased GFR up to hyperfiltration level 124.5±8.86 mL/min/1.73 m2 and decreased anti-apoptotic defense - BcL-xL 144.9±2.35 a.u. was identified. Children with DN may be divided into three groups based on age, body mass index, systolic blood pressure, PLT count, erthyrocyte sedimentation rate, albumin/globulin ratio, serum cholesterol, Hb1Ac, number of diabetic ketoacidosis (DKA) episodes, GFR, MAU, HIF-1alfa, Bcl-xL, caspase-3 levels. Among children with early DN a cluster characterized by the following parameters was found: PLT count - 311.±12.05·109/L, frequency of DKA episodes - 4.82±0.26 episodes/year, MAU - 112.0±10.12 mm/24 h, HIF - 200.5±3.49 a.u., BcL-xL - 128.8±3.1 a.u., and caspase-3 - 159.6±5.5 a.u. Conclusion: Thus, we hypothesize that T1D pediatric patients with increased PLT count, hyperfiltration and reduced anti-apoptotic defense may represent a group for additional therapeutic interventions, such as antioxidants along with stndard therapies to achieve optimal glycemic control. Within the DN group there was a sub-group with somewhat increased PLT count, high frequency of DKA episodes/year, high MAU, prominent increase in HIF level, prominent disturbances in apoptosis controlling factors BcL-xL and caspase-3 tht may require additional therapeutic interventions, again including antioxidants, but may additionally benefit from anti-apoptotic effectors along with optimal glycemic control, and management of hypertension and albuminuria.

Clinical and Apoptotic Factors Defining and Predicting Steroid Resistance in Nephrotic Syndrome in Children.

Introduction. Nephrotic syndrome (NS) is a kidney disease characterized by albuminuria, hyperlipidemia, edema, and hypoalbuminemia. Above 20 % of nephrotic children do not show response to steroid treatment. Molecular markers controlling apoptosis have not been studied as a predictors of steroid resistant NS (SRNS) and steroid sensitive NS (SSNS) in children. Aim of the Study. To identify clinical and molecular markers which define and predict the steroid-resistance phenomenon in children with NS. Methods. Fifty-six clinical cases of children hospitalized in Pediatric Hospital No. 7 (Kyiv, Ukraine) with NS (26 SSNS and 30 SRNS) studied. Stepwise logistic regression models used to analyze data. Data processed using GraphPad Prism 9.0 Software for Windows (USA, San Diego, CA). Results. Arterial hypertension, WBC and RBC count, serum creatinine, serum urea, serum cholesterol found to be factors defining and predicting SRNS. Apoptosis regulating BcL-xL, Bax but not caspase-8 found to be those defining SRNS. Among transcriptional factors HIF-1alfa selected as a factor predicting steroid resistance phenomenon. For SSNS group significant negative correlation observed between BcL-xL and Bax, BcL-xL and caspase-3, significant positive correlation observed between marker of cellular hypoxia HIF-1alfa and proapoptotic factor caspase-3. For SRNS group significant negative correlation observed between BcL-xL and Bax, BcL-xL and caspase-3 level, significant positive correlation observed between HIF-1alfa and proapoptotic factor caspase-3. Conclusions. Arterial hypertension, serum creatinine level, serum urea level, serum cholesterol level, WBC and RBC count, BcL-xL, Bax, caspase-3, and HIF-1alfa identified as candidate biomarkers to predict and define SRNS in pediatric NS.

Early functional and metabolic disorders in children with type I diabetes mellitus and diabetic nephropathy.

Type 1 diabetes (T1D) is mainly a disease of children and young adults. The onset of disease is associated with 3 classical symptoms: polydipsia, polyphagia, and polyuria. Hyperglycaemia is the main and primary metabolic disorder in T1D. One of the complications developing as a result of microangiopathy is diabetic nephropathy (DN). Additionally, diabetes remains the most common reason for progressing to end-stage renal disease (ESRD). The aim of the study was to evaluate the most initial metabolic and functional disorders in diabetic children and children with DN. The study involved 76 children with T1D and diabetic nephropathy (aged 3 to 17 years). The levels of ET-1 measured using ELISA assay and ratio of lipid oxidation measured spectrophotometrically. Main clinical parameters (blood pressure, glycaemia, albuminuria, creatininaemia, HbA1C, cholesterol levels) were measured using conventional methods available in Clinical Paediatric Hospital No. 6 (Kyiv, Ukraine). The glomerular filtration rate (GFR) was calculated using the Schwartz formula. Patterns of the BP changes, kidney function impairment, ET-level, and metabolic and functional disorders in children with T1D and DN were found.

Clinical, Laboratory, Instrumental, Anamnestic Characteristics in Children With Type I Diabetes Mellitus and Early Stage of Diabetic Nephropathy.

Type 1 diabetes (T1D) is mainly a disease of children and young adults. Diabetic nephropathy (DN) is a common finding in diabetic patients. Microalbuminuria is the earliest clinical evidence of DN. Aim of the study was analysis of clinical, laboratory, instrumental, anamnestic examinations data in pediatric patients with T1D and early stage of DN in order to evaluate possible factors associated with early stage of DN and predictors of DN development and progression. A survey of 105 children (62 males, 43 females) with T1D and DN aged 5 to 17 years in Endocrinology unit on Clinical Pediatric Hospital №6 (Kyiv, Ukraine) done. Following clinical and biochemical characteristics found associated with an early DN: inflammatory phenotype (increased ESR, decreased albumin/globulin ratio), functional cardiovascular disorders (increased systolic blood pressure, "minor" ECG changes), signs of secondary metabolic disorders (high HbA1c, increased serum cholesterol level, increase ALAT and ASAT levels). Kidney function impairment at early stage of DN shows: higher MAU grade, GFR decline, rise in serum creatinine level as compared to T1D group. Presence of concomitant kidney and endocrine disease; positive family history found in a bigger number of patients with DN. DKA episodes number found as a factor associated with higher levels of MAU in children with DN. Patients who had microalbuminuria and more than 5 episodes of DKA/year (poorly controlled T1D) have higher progression rate to macroalbuminuria as compared to those who have less than 5 episodes of DKA/year after a 6-year follow-up study.

Usage and Attitudes Towards Natural Remedies and Homeopathy in General Pediatrics: A Cross-Country Overview.

In order to better understand the global approach and country differences in physicians' usage, knowledge, and attitudes towards natural remedies and homeopathy in pediatric practice, an online survey involving 582 general pediatricians and general practitioners treating pediatric diseases was conducted in 6 countries. Overall, 17% of the pediatric prescriptions refer to phytotherapy and 15% refer to homeopathic preparations. Natural remedies and homeopathic preparations are more frequently used in upper respiratory tract infections, infant colic, sleep disturbances, and recurrent infections. In the majority of cases, they are used together with chemical drugs. Both treatment options are typically used if parents are concerned about side effects of conventional drugs or prefer natural remedies for themselves. Physicians express high interest in natural remedies and homeopathy; however, their knowledge is variable. Lack of proven efficacy, knowledge on mechanism of action, and information on indications are main factors that limit their usage.

Prevention of apoptosis averts glomerular tubular disconnection and podocyte loss in proteinuric kidney disease.

There is a great need for treatment that arrests progression of chronic kidney disease. Increased albumin in urine leads to apoptosis and fibrosis of podocytes and tubular cells and is a major cause of functional deterioration. There have been many attempts to target fibrosis, but because of the lack of appropriate agents, few have targeted apoptosis. Our group has described an ouabain-activated Na,K-ATPase/IP3R signalosome, which protects from apoptosis. Here we show that albumin uptake in primary rat renal epithelial cells is accompanied by a time- and dose-dependent mitochondrial accumulation of the apoptotic factor Bax, down-regulation of the antiapoptotic factor Bcl-xL and mitochondrial membrane depolarization. Ouabain opposes these effects and protects from apoptosis in albumin-exposed proximal tubule cells and podocytes. The efficacy of ouabain as an antiapoptotic and kidney-protective therapeutic tool was then tested in rats with passive Heymann nephritis, a model of proteinuric chronic kidney disease. Chronic ouabain treatment preserved renal function, protected from renal cortical apoptosis, up-regulated Bax, down-regulated Bcl-xL, and rescued from glomerular tubular disconnection and podocyte loss. Thus we have identified a novel clinically feasible therapeutic tool, which has the potential to protect from apoptosis and rescue from loss of functional tissue in chronic proteinuric kidney disease.

Calcium oscillations triggered by cardiotonic steroids.

Na(+), K(+)-ATPase (NKA) is well known for its function as an ion pump. Studies during the last decade have revealed an additional role for NKA as a signal transducer. In this brief review, we describe how cardiotonic steroids, which are highly specific NKA ligands, trigger slow Ca(2+) oscillations by promoting the interaction between NKA and the inositol trisphosphate receptor, and how this Ca(2+) signal activates the NF-κB subunit p65 and increases the expression of the antiapoptotic factor Bcl-xL. The potential tissue-protective effects of this signal are discussed.

Ouabain protects against Shiga toxin-triggered apoptosis by reversing the imbalance between Bax and Bcl-xL.

Hemolytic uremic syndrome, a life-threatening disease often accompanied by acute renal failure, usually occurs after gastrointestinal infection with Shiga toxin 2 (Stx2)-producing Escherichia coli. Stx2 binds to the glycosphingolipid globotriaosylceramide receptor, expressed by renal epithelial cells, and triggers apoptosis by activating the apoptotic factor Bax. Signaling via the ouabain/Na,K-ATPase/IP3R/NF-κB pathway increases expression of Bcl-xL, an inhibitor of Bax, suggesting that ouabain might protect renal cells from Stx2-triggered apoptosis. Here, exposing rat proximal tubular cells to Stx2 in vitro resulted in massive apoptosis, upregulation of the apoptotic factor Bax, increased cleaved caspase-3, and downregulation of the survival factor Bcl-xL; co-incubation with ouabain prevented all of these effects. Ouabain activated the NF-κB antiapoptotic subunit p65, and the inhibition of p65 DNA binding abolished the antiapoptotic effect of ouabain in Stx2-exposed tubular cells. Furthermore, in vivo, administration of ouabain reversed the imbalance between Bax and Bcl-xL in Stx2-treated mice. Taken together, these results suggest that ouabain can protect the kidney from the apoptotic effects of Stx2.