In a cross‐sectional study, we assessed effects of calcineurin inhibitor (CNI) or rapamycin on T‐regulatory (Treg) cells from children with stable liver (n = 53) or kidney (n = 9) allografts several ...years posttransplant. We analyzed Treg number, phenotype, suppressive function, and methylation at the Treg‐specific demethylation region (TSDR) using Tregs and peripheral blood mononuclear cells. Forty‐eight patients received CNI (39 as monotherapy) and 12 patients received rapamycin (9 as monotherapy). Treg numbers diminished over time on either regimen, but reached significance only with CNI (r =−0.424, p = 0.017). CNI levels inversely correlated with Treg number (r =−0.371, p = 0.026), and positively correlated with CD127+ expression by Tregs (r = 0.437, p = 0.023). Patients with CNI levels >3.6 ng/mL had weaker Treg function than those with levels <3.6 ng/mL, whereas rapamycin therapy positively correlated with Treg numbers (r = 0.628, p = 0.029) and their expression of CTLA4 (r = 0.726, p = 0.041). Overall, CTLA4 expression, TSDR demethylation and an absence of CD127 were important for Treg suppressive function. We conclude that rapamycin has beneficial effects on Treg biology, whereas long‐term and high dose CNI use may impair Treg number, function and phenotype, potentially acting as a barrier to attaining host hyporesponsiveness to an allograft.
In a cross‐sectional clinical study of pediatric liver and kidney transplant recipients, analysis of FOXP3+ Treg cells shows that rapamycin has beneficial effects on Treg parameters, whereas long‐term and high‐dose calcineurin inhibitor use may impair Treg number, function and phenotype, potentially acting as a barrier to attaining host hyporesponsiveness to an allograft.
Hypertension and blood pressure variability (BPV; SD and average real variability) in primary proteinuric glomerulopathies are not well described. Data were from 433 participants in the NEPTUNE ...(Nephrotic Syndrome Study Network). Hypertensive BP status was defined as previous history of hypertension or BP ≥140/90 mm Hg for adults/≥95th percentile for children at baseline. BPV was measured in participants with ≥3 visits in the first year. Two-hundred ninety-six adults (43 years interquartile range, 32-57.8 years, 61.5% male) and 147 children (11 years interquartile range, 5-14 years, 57.8% male) were evaluated. At baseline, 64.8% of adults and 46.9% of children were hypertensive. Histological diagnosis was associated with hypertensive status in adults (
=0.036). In adults, hypertensive status was associated with lower hazard of complete remission (hazard ratio, 0.36; 95% confidence interval, 0.19-0.68) and greater hazard of achieving the composite end point (end-stage renal disease or estimated glomerular filtration rate decline >40%; hazard ratio, 4.1; 95% confidence interval, 1.4-12). Greater systolic and diastolic SD and average real variability were also associated with greater hazard of reaching the composite end point in adults (all
<0.01). In children, greater BPV was an independent predictor of composite end point (determined by systolic SD and average real variability) and complete remission (determined by systolic and diastolic average real variability; all
<0.05). Hypertensive status was common among adults and children enrolled in NEPTUNE. Differences in hypertensive status prevalence, BPV, and treatment were found by age and histological diagnosis. In addition, hypertensive status and greater BPV were associated with poorer clinical outcomes.
Pediatric solid-organ transplantation is an increasingly successful treatment for solid-organ failure. With dramatic improvements in patient survival rates over the last several decades, there has ...been a corresponding emergence of complications attributable to pretransplant factors, transplantation itself, and the management of transplantation with effective immunosuppression. The predominant solid-organ transplantation sequelae are medical and psychosocial. These sequelae have a substantial effect on transition to adult care; as such, hurdles to successful transition of care arise from the patients, their families, and pediatric and adult health care providers. Crucial to successful transitioning is the ongoing development of a sense of autonomy and responsibility for one's own care. In this article we address the barriers to transitioning that occur with long-term survival in pediatric solid-organ transplantation. Although a particular transitioning model is not promoted, practical tools and strategies that contribute to successful transitioning of pediatric patients who have received a transplant are suggested.
The Nephrotic Syndrome Study Network (NEPTUNE) is a North American multicenter collaborative consortium established to develop a translational research infrastructure for nephrotic syndrome. This ...includes a longitudinal observational cohort study, a pilot and ancillary study program, a training program, and a patient contact registry. NEPTUNE will enroll 450 adults and children with minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy for detailed clinical, histopathological, and molecular phenotyping at the time of clinically indicated renal biopsy. Initial visits will include an extensive clinical history, physical examination, collection of urine, blood and renal tissue samples, and assessments of quality of life and patient-reported outcomes. Follow-up history, physical measures, urine and blood samples, and questionnaires will be obtained every 4 months in the first year and biannually, thereafter. Molecular profiles and gene expression data will be linked to phenotypic, genetic, and digitalized histological data for comprehensive analyses using systems biology approaches. Analytical strategies were designed to transform descriptive information to mechanistic disease classification for nephrotic syndrome and to identify clinical, histological, and genomic disease predictors. Thus, understanding the complexity of the disease pathogenesis will guide further investigation for targeted therapeutic strategies.
Dense deposit disease (DDD, formerly known as membranoproliferative glomerulonephritis (MPGN) type II) is a subtype of C3 glomerulopathy (C3G). Electron-dense deposits in the glomerular basement ...membrane characterize this glomerulonephritis. DDD typically presents with a nephritic syndrome that progresses to end-stage renal failure in 50 % of patients despite treatment. The pathogenic basis of DDD is uncontrolled activation of the alternative complement cascade although the potential triggering events that precipitate the development of complement dysregulation are typically unknown. There are isolated reports of an apparent association between streptococcal infection and DDD, as well as with MPGN types I and III. However, this association has not been deemed compelling, perhaps because so few cases have been reported or because of a current lack of evidence for a plausible hypothesis to connect a streptococcal infection with subsequent disease. In this report, we describe two patients with DDD who definitely had an antecedent streptococcal infection with the phenotype of acute post-streptococcal glomerulonephritis and whose initial kidney biopsy findings on light microscopy were indistinguishable from acute post-streptococcal glomerulonephritis. These patients had additional points of interest: recurrence of gross hematuria with recurrent streptococcal infections, slowly progressive course, persistently low serum C3 concentration, positive C3 nephritic factor, and positive risk alleles in the complement factor H (CFH) gene.
Conclusion
: We suggest that streptococcal infection may trigger DDD in individuals genetically predisposed by virtue of a disorder in complement regulation.
The endothelin (ET) system seems to play a pivotal role in hypertension and in proteinuric kidney disease, including the micro- and macro-vascular complications of diabetes. Endothelin-1 (ET-1) is a ...multifunctional peptide that primarily acts as a potent vasoconstrictor with direct effects on systemic vasculature and the kidney. ET-1 and ET receptors are expressed in the vascular smooth muscle cells, endothelial cells, fibroblasts and macrophages in systemic vasculature and arterioles of the kidney, and are associated with collagen accumulation, inflammation, extracellular matrix remodeling, and renal fibrosis. Experimental evidence and recent clinical studies suggest that endothelin receptor blockade, in particular selective ET
A
R blockade, holds promise in the treatment of hypertension, proteinuria, and diabetes. Concomitant blockade of the ET
B
receptor is not usually beneficial and may lead to vasoconstriction and salt and water retention. The side-effect profile of ET receptor antagonists and relatively poor antagonist selectivity for ET
A
receptor are limitations that need to be addressed. This review will discuss what is currently known about the endothelin system, the role of ET-1 in the pathogenesis of hypertension and kidney disease, and summarize literature on the therapeutic potential of endothelin system antagonism.
Children and adolescents with renal disease experience daily social, emotional, and medical challenges. Renal transplantation can help to improve quality of life but requires a lifelong regimen of ...immunosuppressant medication to maintain health. Adherence to a daily complex regimen can be difficult, particularly for adolescents who are beginning to develop autonomy from caregivers and are faced with a unique set of socio‐emotional challenges. This study examines two factors that have shown to influence adherence in other pediatric populations, namely family functioning and parent health locus of control, from mothers’ perspectives, in predicting medication non‐adherence for adolescents (ages 12‐19 years) 1 year post‐transplant. Non‐adherence was defined as the percentage of missed doses and late doses of the weekly immunosuppressant doses prescribed. Regression results demonstrated that mothers’ perceptions of poorer overall family functioning predicted missed medication doses (ΔR2 = 0.383, F(7, 21) = 2.570, P = 0.044) with significant contributions in the domains of problem‐solving (β = −0.795, t(21) = −2.927, P = 0.008) and affective involvement (β = 0.872, t(21) = 3.370, P = 0.003). Moreover, mothers who perceived that their adolescent had control over his/her health also predicted more missed medication doses (ΔR2 = 0.133, F(1, 27) = 5.155, P = 0.031). Important implications for these findings include implementation of family‐based interventions that promote developmentally appropriate skills for adolescents and cultivate emotional involvement within the family.
Idiopathic mid-aortic syndrome in children Sethna, Christine B.; Kaplan, Bernard S.; Cahill, Anne Marie ...
Pediatric nephrology (Berlin, West),
07/2008, Volume:
23, Issue:
7
Journal Article
Peer reviewed
Mid-aortic syndrome (MAS) is an uncommon condition characterized by narrowing of the abdominal aorta and stenosis of its major branches. Our goal was to illustrate the presentation, diagnosis and ...management of six new cases of idiopathic MAS together with 96 cases of idiopathic MAS from the literature. The mean age of the 102 cases was 14.3 years (19 days to 49 years). Our patient who presented at 19 days of age is the youngest reported to date. Clinical presentations included hypertension (94%), claudication (17%), renal failure (4%) and intestinal ischemia (1%). Angiography was the diagnostic imaging study of choice. Renal arteries were involved in 91% of patients, while the superior mesenteric artery and celiac artery were involved in 35%. Thirteen percent of cases were managed medically, and the remainder was treated surgically. Our experience shows that initial conservative blood pressure management of idiopathic MAS is feasible unless medical control of hypertension is unsatisfactory, renal function is at risk or there are symptoms of claudication or intestinal ischemia. Careful timing and planning of a surgical intervention is possible for most cases and may, in select cases, be considered after completion of puberty to allow growth to be completed.
Carotid-femoral pulse wave velocity (cfPWV) is a measure of arterial stiffness associated with cardiovascular events in the general population and in adults with chronic kidney disease. However, few ...data exist regarding cfPWV in children with chronic kidney disease. We compared observed cfPWV assessed via applanation tonometry in children enrolled in the CKiD cohort study (Chronic Kidney Disease in Children) to normative data in healthy children and examined risk factors associated with elevated cfPWV. cfPWV Z score for height/gender and age/gender was calculated from and compared with published pediatric norms. Multivariable linear regression was used to assess the relationship between cfPWV and age, gender, race, body mass index, diagnosis, urine protein-creatinine ratio, mean arterial pressure, heart rate, number of antihypertensive medications, uric acid, and serum low-density lipoprotein. Of the 95 participants with measured cfPWV, 60% were male, 19% were black, 46% had glomerular cause of chronic kidney disease, 22% had urine protein-creatinine ratio 0.5 to 2.0 mg/mg and 9% had >2.0 mg/mg, mean age was 15.1 years, average mean arterial pressure was 80 mm Hg, and median glomerular filtration rate was 63 mL/min per 1.73 m
Mean cfPWV was 5.0 m/s (SD, 0.8 m/s); mean cfPWV Z score by height/gender norms was -0.1 (SD, 1.1). cfPWV increased significantly with age, mean arterial pressure, and black race in multivariable analysis; no other variables, including glomerular filtration rate, were independently associated with cfPWV. In this pediatric cohort with mild kidney dysfunction, arterial stiffness was comparable to that of normal children. Future research is needed to examine the impact of chronic kidney disease progression on arterial stiffness and associated cardiovascular parameters in children.
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