The glomerular microvasculature is particularly susceptible to injury in thrombotic microangiopathy, but the mechanisms by which this occurs are unclear. We report the cases of six patients who were treated with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), in whom glomerular disease characteristic of thrombotic microangiopathy developed. To show that local reduction of VEGF within the kidney is sufficient to trigger the pathogenesis of thrombotic microangiopathy, we used conditional gene targeting to delete VEGF from renal podocytes in adult mice; this resulted in a profound thrombotic glomerular injury. These observations provide evidence that glomerular injury in patients who are treated with bevacizumab is probably due to direct targeting of VEGF by antiangiogenic therapy.

Abstract-An elevation in circulating serum uric acid is strongly associated with the development of hypertension and renal disease, but whether uric acid has a causal role or whether it simply indicates patients at risk for these complications remains controversial. We tested the hypothesis that uric acid may have a causal role in the development of hypertension and renal disease by examining the effects of mild hyperuricemia in rats. Mild hyperuricemia was induced in rats by providing a uricase inhibitor (oxonic acid) in the diet. Hyperuricemic rats developed elevated blood pressure after 3 weeks, whereas control rats remained normotensive. The development of hypertension was prevented by concurrent treatment with either a xanthine oxidase inhibitor (allopurinol) or a uricosuric agent (benziodarone), both of which lowered uric acid levels. Blood pressure could also be lowered by reducing uric acid levels with either allopurinol or oxonic acid withdrawal. A direct relationship was found between blood pressure and uric acid (rϭ0.75, nϭ69), with a 10 -mm Hg blood pressure increase for each 0.03-mmol/L (0.5-mg/dL) incremental rise in serum uric acid. The kidneys were devoid of urate crystals and were normal by light microscopy. However, immunohistochemical stains documented an ischemic type of injury with collagen deposition, macrophage infiltration, and an increase in tubular expression of osteopontin. Hyperuricemic rats also exhibited an increase in juxtaglomerular renin and a decrease in macula densa neuronal NO synthase. Both the renal injury and hypertension were reduced by treatment with enalapril or L-arginine. In conclusion, mild hyperuricemia causes hypertension and renal injury in the rat via a crystal-independent mechanism, with stimulation of the renin-angiotensin system and inhibition of neuronal NO synthase. Key Words: uric acid Ⅲ hypertension, renal Ⅲ renin-angiotensin system Ⅲ nitric oxide U ric acid is a purine metabolite that in most mammals is degraded by the hepatic enzyme uricase to allantoin. However, mutations in the uricase gene occurred during primate development, with the consequence that humans have relatively higher levels of serum uric acid. 1 An elevation in serum uric acid has been associated with an increased risk for the development of hypertension, 2-4 and 25% to 50% of hypertensive individuals are hyperuricemic. 4 Hyperuricemia also confers increased risk for cardiovascular mortality, especially in women. 5,6 Despite the clinical and epidemiological evidence, many authorities do not consider an elevated uric acid to be a true cardiovascular risk factor, because patients with hyperuricemia often have other wellestablished risk factors for cardiovascular disease, such as hypertension, renal disease, obesity, dyslipidemia, and insulin resistance. 6 Several studies have found that an elevated uric acid level is an independent risk factor for cardiovascular disease after controlling for the contribution of established risk factors by multivariate analyses 2,3,7 ; however, other studies...

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Proteinuria is the hallmark of diabetic kidney disease (DKD) and is an independent risk factor for both renal disease progression, and cardiovascular disease. Although the characteristic pathological changes in DKD include thickening of the glomerular basement membrane and mesangial expansion, these changes per se do not readily explain how patients develop proteinuria. Recent advances in podocyte and glomerular endothelial cell biology have shifted our focus to also include these cells of the glomerular filtration barrier in the development of proteinuria in DKD. This review describes the pathophysiological mechanisms at a cellular level which explain why patients with DKD develop proteinuria.

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