Donald J Weaver

Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States

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Publications (8)37.73 Total impact

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    ABSTRACT: Hyperuricemia is associated with essential hypertension in children. No previous studies have evaluated the effect of hyperuricemia on progression of chronic kidney disease (CKD) in children. Prospective observational cohort study. Children and adolescents (n=678 cross-sectional; n=627 longitudinal) with a median age of 12.3 (IQR, 8.6-15.6) years enrolled at 52 North American sites of the CKiD (CKD in Children) Study. Serum uric acid level (<5.5, 5.5-7.5, and >7.5mg/dL). Composite end point of either >30% decline in glomerular filtration rate (GFR) or initiation of renal replacement therapy. Age, sex, race, blood pressure status, GFR, CKD cause, urine protein-creatinine ratio (<0.5, 0.5-<2.0, and ≥2.0mg/mg), age- and sex-specific body mass index > 95th percentile, use of diuretics, and serum uric acid level. Older age, male sex, lower GFR, and body mass index > 95th percentile were associated with higher uric acid levels. 162, 294, and 171 participants had initial uric acid levels < 5.5, 5.5 to 7.5, or >7.5 mg/dL, respectively. We observed 225 instances of the composite end point over 5 years. In a multivariable parametric time-to-event analysis, compared with participants with initial uric acid levels < 5.5mg/dL, those with uric acid levels of 5.5 to 7.5 or >7.5mg/dL had 17% shorter (relative time, 0.83; 95% CI, 0.62-1.11) or 38% shorter (relative time, 0.62; 95% CI, 0.45-0.85) times to event, respectively. Hypertension, lower GFR, glomerular CKD cause, and elevated urine protein-creatinine ratio were also associated with faster times to the composite end point. The study lacked sufficient data to examine how use of specific medications might influence serum uric acid levels and CKD progression. Hyperuricemia is a previously undescribed independent risk factor for faster progression of CKD in children and adolescents. It is possible that treatment of children and adolescents with CKD with urate-lowering therapy could slow disease progression. Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
    American Journal of Kidney Diseases 07/2015; DOI:10.1053/j.ajkd.2015.06.015 · 5.76 Impact Factor
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    Rukshana Shroff, Donald J Weaver, Mark M Mitsnefes
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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. DOI:10.1038/nrneph.2011.116 · 8.37 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 03/2010; 40(3):710-21. DOI:10.1002/eji.200939333 · 4.52 Impact Factor
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    ABSTRACT: A significant number of children with chronic kidney disease (CKD) have eccentric left ventricular hypertrophy (LVH), suggesting the role of preload overload. Therefore, we hypothesized that increased cardiac output (CO) might be a contributing factor for increased left ventricular mass index (LVMI) in these children. Patients aged 6-20 years with CKD stages 2-4 were enrolled. Echocardiograms were performed to assess LV function and geometry at rest and during exercise. Heart rate, stroke volume, and CO were also assessed at rest and during exercise. Twenty-four-hour ambulatory blood pressure (AMBP) monitoring was performed. Of the patients enrolled in this study, 17% had LVH. Increased stroke volume and CO were observed in patients with LVH compared to patients without LVH. Univariate analysis revealed significant positive associations between LVMI and CO, stroke volume, body mass index, pulse pressure from mean 24-h AMBP, and mean 24-h systolic BP load. No association with heart rate, age, parathyroid hormone, glomerular filtration rate, or anemia was observed. Only CO (beta = 1.98, p = 0.0005) was independently associated with increased LVMI in multivariate modeling (model R (2) = 0.25). The results of this study suggest that increased CO might predispose to increased LVMI in pediatric patients with CKD. Adaptations may be required to meet increased metabolic demand in these patients.
    Pediatric Nephrology 03/2009; 24(3):565-70. DOI:10.1007/s00467-008-1052-2 · 2.88 Impact Factor
  • Molecular Immunology 10/2008; 45(16):4108-4108. DOI:10.1016/j.molimm.2008.08.039 · 3.00 Impact Factor
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    ABSTRACT: Midwall shortening (mwSF) is thought to be a more accurate measure of myocardial performance in the presence of left ventricular hypertrophy (LVH). We examined mwSF in pediatric patients with varying degrees of chronic kidney disease (CKD). Fifty-seven children with CKD stages 2 to 4, 25 who were undergoing hemodialysis and 49 who were transplant recipients, were compared with 35 healthy control subjects. Left ventricular (LV) geometry and indices of LV function were assessed echocardiographically. There were no significant differences in LV contractility or endocardial shortening fraction between patients and control subjects. Yet, patients undergoing hemodialysis had significantly lower mwSF compared with control subjects (P < .01) and patients with stage 2 to 4 CKD (P < .01). Renal transplant patients had lower mwSF compared with control subjects (P < .01). The prevalence of abnormal mwSF (ie, <16) was significantly higher in patients undergoing hemodialysis (40%) compared with patients who were renal transplant recipeints (12%) and patients with CKD stages 2 to 4 (9%; P = .03). With stepwise regression, mwSF was demonstrated to be predicted by using relative wall thickness (P < .0001), dialysis group (P = .005), and endocardial shortening fraction (P = .001; model R(2) = 0.86). Children undergoing maintenance hemodialysis and children with concentric LVH have subclinical systolic dysfunction, which might be an indicator for the development of more severe cardiac disease.
    The Journal of pediatrics 06/2008; 153(4):565-9. DOI:10.1016/j.jpeds.2008.04.026 · 3.74 Impact Factor
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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. DOI:10.1681/ASN.2007070773 · 9.47 Impact Factor
  • Donald J. Weaver, Mark M. Mitsnefes
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    ABSTRACT: Hypertension is a significant public health challenge because of its high prevalence as well as its associated complications including cerebrovascular disease, renal failure, and heart failure (1). In fact, hypertension is the second leading cause of end-stage renal disease (ESRD) among adults in the USA (2). Moreover, hypertension is the leading risk factor for cardiovascular mortality and ranked third as a cause of disability-adjusted life years in adults (1,3). A recent study examining the economic burden of chronic cardiovascular disease suggested that medical expenditures attributable to hypertension account for 8% of annual US healthcare costs at more than 20 billion dollars (3). There is also increasing evidence that the pathogenesis of hypertension begins in childhood, and hypertension in children is a risk factor for development of adult cardiovascular disease (4,5). However, hypertension in children is often underdiagnosed, and the alterations in end-organ structure and function noted in adult hypertensive patients begin in childhood (6,7). Since treatment of hypertension has been shown to improve cardiovascular outcomes and to reduce the risk for development of these complications in the adult population, prompt recognition of these alterations in children and adolescents may prevent future morbidity and mortality in these patients (8).