The Role of Renal Regulatory Mechanisms in the Evolution and Treatment of Pediatric Diabetic Ketoacidosis

Diabetic ketoacidosis (DKA) is a life threatening complication of diabetes mellitus in pediatric patients with new onset insulin dependent diabetes. Despite advances in therapy mortality from DKA, especially in children less than two years, remains high. This review highlights the role of obligatory renal defense mechanisms in the evolution of DKA and its implication for therapy: to accomplish this goal the review starts with a cursory description of the pathogenesis and pathophysiology of metabolic derangements in DKA as a basis for understanding the renal compensatory mechanisms geared towards restoration of acid-base balance;then, the next section of the review describes how alterations in fluid and electrolyte balance at the onset of DKA and the extent of renal regulatory defense mechanisms geared towards its restoration can predispose to cerebral edema at the beginning of therapy. We conclude by suggesting that restoration of fluid and electrolyte balance should be based on the severity of metabolic acidosis as determined by the extent of renal impairment at the onset and during the course of DKA rather than strictly by protocols.

Dynamics of circulating microparticles in chronic kidney disease and transplantation:Is it really reliable marker?

The deterioration of endothelial structure plays a very important role in the development of vascular diseases. It is believed that endothelial dysfunction starts in the early stage of kidney disease and is a risk factor of an unfavorable cardiovascular prognosis. Because a direct assessment of biological states in endothelial cells is not applicable, the measurement of endothelial microparticles(EMPs) detached from endothelium during activation or apoptosis is thought to be a marker of early vascular disease and endothelial dysfunction in children with chronic kidney disease(CKD). Few studies have shown increased circulating EMPs and its relationship with cardiovascular risk factors in patients with CKD.MPs contain membrane proteins and cytosolic material derived from the cell from which they originate. EMPs having CD144, CD 146, CD31+/CD41-, CD51 and CD105 may be used to evaluate the vascular endothelial cell damage and determine asymptomatic patients who might be at higher risk of developing cardiovascular disease in CKD and renal transplant.

Pediatric lupus nephritis: Management update

Childhood-onset systemic lupus erythematosus(c SLE) is a severe multisystem autoimmune disease. Renal involvement occurs in the majority of c SLE patients and is often fatal. Renal biopsy is an important investigation in the management of lupus nephritis. Treatment of renal lupus consists of an induction phase and maintenance phase. Treatment of childhood lupus nephritis using steroids is associated with poor outcome and excess side-effects. The addition of cyclophosphamide to the treatment schedule has improved disease control. In view of treatment failure using these drugs and a tendency for non-adherence, many newer agents such as immune-modulators and monoclonal antibodies are being tried in patients with c SLE. Trials of these novel agents in the pediatric population are still lacking making a consensus in the management protocol of pediatric lupus nephritis difficult.

Age-adjusted NT-proBNP could help in the early identification and follow-up of children at risk for severe multisystem inflammatory syndrome associated with COVID-19(MIS-C)

BACKGROUND Multisystem inflammatory syndrome in children(MIS-C) has emerged as a new disease associated with COVID-19 that presents in acute critically ill children with acute cardiovascular dysfunction.AIM To determine whether the age-adjusted N-terminal pro-brain natriuretic peptide(NT-proBNP) value(Z-log-NT-proBNP) is associated with severe MIS-C and myocardial dysfunction.METHODS A retrospective study was conducted which included children with MIS-C managed at our institution between April 1,2020,and February 28,2022.We divided the population into groups depending on severity based on pediatric intensive care unit(PICU) admission.We compared Z-log-NT-proBNP values across these groups and analyzed Z-log-NT-proBNP dynamics during the onemonth follow-up.RESULTS We included 17 participants [median age 3(2-9) years] and seven(41%) required PICU admission.All(100%) of these cases presented very high(Z-log > 4) levels of NT-proBNP at the time of admission compared to only 5(50%) patients with non-severe MIS-C(P = 0.025).NT-proBNP was significantly correlated with highsensitive Troponin I levels(P = 0.045),Ross modified score(P = 0.003) and left ventricle ejection fraction(P = 0.021).CONCLUSION Raised NT-proBNP,specifically very high values(Z-log-NT-proBNP > 4) could help in the early identification of MIS-C patients with myocardial dysfunction requiring inotropic support and PICU admission.

Endothelin-1 Antagonist in the Management of Refractory Systemic Hypertension in Children with End Stage Kidney Disease: A Case Series

Uncontrolled hypertension is a significant problem in children with end stage kidney disease. We studied 10 children on chronic hemodialysis who received the endothelin-1 receptor antagonist, bosentan as adjunctive therapy in refractory systemic hypertension. Data were retrospectively analyzed on systolic (SBP) and diastolic blood pressure (DBP), antihypertensive medications and hospitalization days per patient per year, at baseline and 3 months after initiation of bosentan. The standard deviation (Z) score of BP for age, height and gender was calculated. Mean age and weight of these children were 11.4 ± 4.8 years (range 1 - 17.5 years) and 32.9 ± 14.4 kg (range 7.4 - 57 kg) respectively and 90% were African American. Seven were on hemodialysis ≥4 times weekly. The average inter-dialytic weight gain was 4.7% ± 1.8%. The pre-dialysis SBP and DBP Z scores were 4.9 ± 1.8 and 4.0 ± 1.0 at baseline and decreased to 1.3 ± 0.4 and 1.3 ± 0.8, 3 months after initiation of bosentan (p < 0.0001). Similarly, anti-hypertensive medications were decreased from 5 ± 1.5 to 2.1 ± 2.6 (p < 0.01). Hospitalization days decreased from 35.6 ± 52.4 days to 1.5 ± 3.3 days (p < 0.0001). This preliminary report indicates bosentan may be beneficial in the management of children with severe refractory hypertension.

Hepcidin-25 negatively predicts left ventricular mass index in chronic kidney disease patients

AIM: To assess the correlation between the serum hepcidin-25 level and left ventricular mass index.METHODS: This study was a cross-sectional study conducted between March 2009 and April 2010. Demo-graphic and biochemical data, including the serum hepcidin-25 level, were collected for chronic kidney disease(CKD) patients. Two-dimensional echocardiography was performed to determine the left ventricle mass(LVM), left ventricular mass index(LVMI), interventricular septum thickness(IVSd), left ventricle posterior wall thickness(LVPW), right ventricular dimension(RVD), left atrium(LA) and ejection fraction(EF).RESULTS: A total of 146 patients with stage 1 to 5 CKD were enrolled. Serum hepcidin-25 levels were 16.51 ± 5.2, 17.59 ± 5.32, 17.38 ± 6.47, 19.98 ± 4.98 and 22.03 ± 4.8 ng/mL for stage 1 to 5 CKD patients, respectively. Hepcidin-25 level was independently predicted by the serum ferritin level(β = 0.6, P = 0.002) and the estimated glomerular filtration rate(β =-0.48, P = 0.04). There were negative correlations between the serum hepcidin level and the LVM and LVMI(P = 0.04 and P = 0.005, respectively). Systolic blood pressure(BP) was positively correlated with the LVMI(P = 0.005). In the multivariate analysis, a decreased serum hepcidin-25 level was independently associated with a higher LVMI(β =-0.28, 95%CI:-0.48--0.02, P = 0.006) after adjusting for body mass index, age and systolic BP. CONCLUSION: A lower serum hepcidin level is associated with a higher LVMI in CKD patients. Low hepcidin levels may be independently correlated with unfavorable cardiovascular outcomes in this population.

Hypertension in children with obesity

The prevalence of obesity related hypertension has dramatically increased in children with the parallel increase in pediatric obesity.This pediatric health problem may adversely affect cardiovascular health in adult life.The pathogenesis of hypertension in obese children is not widely understood.We therefore undertake this review to raise public awareness.Early childhood parameters like birth weight and postnatal weight gain may play important roles in risk for obesity and obesity related hypertension later in childhood and adult life.Further information is required to confirm this origin of hypertension so that appropriate measures are taken in the peri-natal period.The role of sympathetic nervous system has now been well established as one of the principle mechanisms involved in obesity related hypertension.The Renin-Angiotensin system,insulin resistance due to obesity and as a part of metabolic syndrome along with imbalance in adipokines such as leptin and adiponectin,cause activation of the sympathetic system,vasoconstriction,endothelial dysfunction and sodium reabsorption among other perturbations.Multi-step interventions targeting these various mech-anisms are required to break the cycle of obesity and metabolic syndrome.Vitamin D deficiency,sleep apnea due to airway obstruction and hyperuricemia may also play a significant role and should not be ignored in its early stages.Obesity is a risk factor for other comorbid conditions like chronic kidney disease and fatty liver which further accentuate the risk of hypertension.Increased awareness is required to prevent,diagnose and treat obesity related hypertension among the pediatric population.

Renal Amyloidosis Following Chronic Osteomyelitis in a Patient with Congenital Insensitivity to Pain and Anhidrosis

Congenital insensitivity to pain and anhidrosis (CIPA) is a rare form of hereditary sensory and autonomic neuropathy. It is characterized by impaired perception of pain and temperature, anhidrosis and intellectual disability. Self mutilating behaviors lead to accidental injuries. The limb lesions are often infected and frequently progress to chronic osteomyelitis. In pediatrics, amyloidosis usually occurs secondary to chronic inflammatory diseases. The coexistence of amyloidosis and CIPA has not previously been reported in literature. A CIPA case complicated with nephrotic syndrome and renal amyloidosis following chronic osteomyelitis is presented here. This report emphasizes the importance of close follow-up of patients by urine analysis for the risk of developing amyloidosis particularly in the presence of chronic infections.

Bacteroides ovatus-mediated CD27^(−)MAIT cell activation is associated with obesity-related T2D progression

Type 2 diabetes(T2D)is highly associated with obesity.However,the factors that drive the transition from excessive weight gain to glucose metabolism disruption are still uncertain and seem to revolve around systemic immune disorder.Mucosal-associated invariant T(MAIT)cells,which are innate-like T cells that recognize bacterial metabolites,have been reported to be altered in obese people and to lead to metabolic dysfunction during obesity.By studying the immunophenotypes of blood MAIT cells from a cross-sectional cohort of obese participants with/without T2D,we found an elevation in CD27^(-)negative(CD27−)MAIT cells producing a high level of IL-17 under T2D obese conditions,which could be positively correlated with impaired glucose metabolism in obese people.We further explored microbial translocation caused by gut barrier dysfunction in obese people as a triggering factor of MAIT cell abnormalities.Specifically,accumulation of the bacterial strain Bacteroides ovatus in the peripheral blood drove IL-17^(-)producing CD27−MAIT cell expansion and could be associated with T2D risk in obese individuals.Overall,these results suggest that an aberrant gut microbiota–immune axis in obese people may drive or exacerbate T2D.Importantly,CD27−MAIT cell subsets and Bacteroides ovatus could represent targets for novel interventional strategies.Our findings extend current knowledge regarding the clinical relevance of body mass index(BMI)-associated variation in circulating MAIT cells to reveal the role of these cells in obesity-related T2D progression and the underlying cellular mechanisms.