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ABSTRACT: The lifespan of children with advanced chronic kidney disease (CKD) remains low compared with the general pediatric population. As in adults with CKD, cardiovascular disease accounts for the majority of deaths in children with CKD, as these patients have a high prevalence of traditional and uremia-related risk factors for cardiovascular disease. The cardiovascular adaptations that precipitate these terminal events begin in predialysis CKD. Initially, these alterations increase left ventricular performance and vascular function to maintain hemodynamic homeostasis. However, these modifications are unable to sustain cardiovascular function in the long term and ultimately lead to left ventricular failure, impaired cardiorespiratory fitness and even sudden death. In this Review, we provide an update on the prevalence of the risk factors associated with cardiovascular disease in pediatric patients with CKD, the cardiac and vascular adaptations that occur in these patients and the management of cardiovascular risk in this population.
Nature Reviews Nephrology 09/2011; 7(11):642-9. · 7.09 Impact Factor
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ABSTRACT: C5a is a proinflammatory mediator that has recently been shown to regulate adaptive immune responses. Here we demonstrate that C5a receptor (C5aR) signaling in DC affects the development of Treg and Th17 cells. Genetic ablation or pharmacological targeting of the C5aR in spleen-derived DC results in increased production of TGF-beta leading to de novo differentiation of Foxp3(+) Treg within 12 h after co-incubation with CD4(+) T cells from DO11.10/RAG2(-/-) mice. Stimulation of C5aR(-/-) DC with OVA and TLR2 ligand Pam(3)CSK(4) increased TGF-beta production and induced high levels of IL-6 and IL-23 but only minor amounts of IL-12 leading to differentiation of Th cells producing IL-17A and IL-21. Th17 differentiation was also found in vivo after adoptive transfer of CD4(+) Th cell into C5aR(-/-) mice immunized with OVA and Pam(3)CSK(4). The altered cytokine production of C5aR(-/-) DC was associated with low steady state MHC class II expression and an impaired ability to upregulate CD86 and CD40 in response to TLR2. Our data suggest critical roles for C5aR in Treg and Th17-cell differentiation through regulation of DC function.
European Journal of Immunology 12/2009; 40(3):710-21. · 5.10 Impact Factor
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Donald J Weaver,
Thomas R Kimball,
Timothy Knilans,
Wayne Mays,
Sandra K Knecht,
Yvette M Gerdes,
Sandy Witt,
Betty J Glascock,
Janis Kartal,
Philip Khoury,
Mark M Mitsnefes
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ABSTRACT: Adult and pediatric patients with ESRD have impaired maximum oxygen consumption (VO(2) max), a reflection of the cardiopulmonary system's ability to meet increased metabolic demands. We sought to determine factors associated with decreased VO(2) max in pediatric patients with different stages of CKD. VO(2) max was measured using a standardized exercise testing protocol in patients with stage 2 to 4 chronic kidney disease (CKD) (n = 46), in renal transplant recipients (n = 22), in patients treated with maintenance hemodialysis (n = 12), and in age-matched healthy controls (n = 33). VO(2) max was similar between children with stage 2 CKD and controls, whereas lower VO(2) max was observed among children with stage 3 to 4 CKD, those treated with hemodialysis, and transplant recipients. In univariate analysis, VO(2) max was significantly associated with body mass index, resting heart rate, C-reactive protein, serum triglycerides, serum creatinine, and measures of diastolic function; no significant associations with left ventricular structure or systolic function were identified. In multivariate regression analysis, patient category versus control and the presence of diastolic dysfunction were independent predictors of lower VO(2) max. These results suggest that aerobic capacity is decreased in the early stages of CKD in children and that lower VO(2) max can be predicted by the presence of diastolic dysfunction, even if systolic function is normal.
Journal of the American Society of Nephrology 04/2008; 19(3):624-30. · 9.66 Impact Factor
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ABSTRACT: We have recently demonstrated that dendritic cells (DC) prepared from nonobese diabetic (NOD) mice, a spontaneous model for insulin-dependent diabetes mellitus, exhibit elevated levels of NF-kappaB activation upon stimulation. In the current study, we investigated the influence of dysregulation of NF-kappaB activation on the APC function of bone marrow-derived DC prepared from NOD vs BALB/c and nonobese diabetes-resistant mice. NOD DC pulsed with either peptide or virus were found to be more efficient than BALB/c DC at stimulating in vitro naive Ag-specific CD8+ T cells. The T cell stimulatory capacity of NOD DC was suppressed by gene transfer of a modified form of IkappaBalpha, indicating a direct role for NF-kappaB in this process. Furthermore, neutralization of IL-12(p70) to block autocrine-mediated activation of DC also significantly reduced the capacity of NOD DC to stimulate T cells. Despite a reduction in low molecular mass polypeptide-2 expression relative to BALB/c DC, no effect on proteasome-dependent events associated with the NF-kappaB signaling pathway or Ag processing was detected in NOD DC. Finally, DC from nonobese diabetes-resistant mice, a strain genotypically similar to NOD yet disease resistant, resembled BALB/c and not NOD DC in terms of the level of NF-kappaB activation, secretion of IL-12(p70) and TNF-alpha, and the capacity to stimulate T cells. Therefore, elevated NF-kappaB activation and enhanced APC function are specific for the NOD genotype and correlate with the progression of insulin-dependent diabetes mellitus. These results also provide further evidence indicating a key role for NF-kappaB in regulating the APC function of DC.
The Journal of Immunology 02/2002; 168(1):188-96. · 5.79 Impact Factor
