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      Urinary Excretion of Vascular Endothelial Growth Factor Is Increased in Children with Reflux Nephropathy

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          Background: We determined the urinary levels of vascular endothelial growth factor (VEGF) in patients with reflux nephropathy to elucidate its clinical significance as a predictor of the development of renal damage. Patients and Methods: Seventy-two patients (47 boys and 25 girls) aged 10–18 years with reflux nephropathy were studied. Vesicoureteral reflux was resolved surgically in all cases at least 2 years before enrollment. Urinary VEGF, α<sub>1</sub>-microglobulin and albumin levels were determined using morning spot urine samples. Plasma VEGF, serum creatinine and β<sub>2</sub>-microglobulin levels were measured simultaneously. The severity of renal scarring and right and left kidney function were assessed by <sup>99m</sup>Tc dimercaptosuccinic acid renal scan. Results: No significant correlation was found between the plasma and urinary VEGF levels. Urinary VEGF increased significantly with the increase in severity of renal scarring (p < 0.0001). Urinary VEGF levels correlated significantly with serum β<sub>2</sub>-microglobulin (p < 0.002) and urinary α<sub>1</sub>-microglobulin (p < 0.03). No significant correlation of urinary VEGF levels with serum creatinine and urinary albumin levels was found. Nearly 60% of the patients with elevated urinary VEGF had normal levels of serum β<sub>2</sub>-microglobulin and/or urinary α<sub>1</sub>-miocroglobulin. Conclusions: Urinary VEGF level appears to reflect its production in the kidney. Since urinary VEGF shows a propensity to elevate before the increase in serum β<sub>2</sub>-microglobulin and/or urinary α<sub>1</sub>-microglobulin, urinary VEGF may serve as an early indicator of the development of reflux nephropathy.

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          A role for uric acid in the progression of renal disease.

          Hyperuricemia is associated with renal disease, but it is usually considered a marker of renal dysfunction rather than a risk factor for progression. Recent studies have reported that mild hyperuricemia in normal rats induced by the uricase inhibitor, oxonic acid (OA), results in hypertension, intrarenal vascular disease, and renal injury. This led to the hypothesis that uric acid may contribute to progressive renal disease. To examine the effect of hyperuricemia on renal disease progression, rats were fed 2% OA for 6 wk after 5/6 remnant kidney (RK) surgery with or without the xanthine oxidase inhibitor, allopurinol, or the uricosuric agent, benziodarone. Renal function and histologic studies were performed at 6 wk. Given observations that uric acid induces vascular disease, the effect of uric acid on vascular smooth muscle cells in culture was also examined. RK rats developed transient hyperuricemia (2.7 mg/dl at week 2), but then levels returned to baseline by week 6 (1.4 mg/dl). In contrast, RK+OA rats developed higher and more persistent hyperuricemia (6 wk, 3.2 mg/dl). Hyperuricemic rats demonstrated higher BP, greater proteinuria, and higher serum creatinine than RK rats. Hyperuricemic RK rats had more renal hypertrophy and greater glomerulosclerosis (24.2 +/- 2.5 versus 17.5 +/- 3.4%; P < 0.05) and interstitial fibrosis (1.89 +/- 0.45 versus 1.52 +/- 0.47; P < 0.05). Hyperuricemic rats developed vascular disease consisting of thickening of the preglomerular arteries with smooth muscle cell proliferation; these changes were significantly more severe than a historical RK group with similar BP. Allopurinol significantly reduced uric acid levels and blocked the renal functional and histologic changes. Benziodarone reduced uric acid levels less effectively and only partially improved BP and renal function, with minimal effect on the vascular changes. To better understand the mechanism for the vascular disease, the expression of COX-2 and renin were examined. Hyperuricemic rats showed increased renal renin and COX-2 expression, the latter especially in preglomerular arterial vessels. In in vitro studies, cultured vascular smooth muscle cells incubated with uric acid also generated COX-2 with time-dependent proliferation, which was prevented by either a COX-2 or TXA-2 receptor inhibitor. Hyperuricemia accelerates renal progression in the RK model via a mechanism linked to high systemic BP and COX-2-mediated, thromboxane-induced vascular disease. These studies provide direct evidence that uric acid may be a true mediator of renal disease and progression.
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            Comparing Stroke Incidence Worldwide : What Makes Studies Comparable?

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              Vascular permeability factor mRNA and protein expression in human kidney.

              Vascular permeability factor (VPF), also known as vascular endothelial growth factor (VEGF), is a potent microvascular permeability-enhancing mediator as well as a selective mitogen for vascular endothelium. In this study, in situ hybridization and immunohistochemistry co-localized VPF mRNA and protein to glomerular visceral epithelial cells in human kidneys. Northern analysis confirmed the presence of VPF mRNA of expected size. The finding of VPF in renal glomerular epithelium identifies a potent mediator of permeability and endothelial proliferation whose role in renal physiology and pathology requires investigation.

                Author and article information

                Nephron Clin Pract
                Nephron Clinical Practice
                S. Karger AG
                November 2004
                17 November 2004
                : 98
                : 3
                : c73-c78
                aDepartment of Urology, Iwate Medical University School of Medicine, Morioka, and Departments of bNephrology, Endocrinology and Hypertension, and cUrology, Tohoku University School of Medicine, Sendai, Japan
                80676 Nephron Clin Pract 2004;98:c73–c78
                © 2004 S. Karger AG, Basel

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                Figures: 2, Tables: 2, References: 22, Pages: 1
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