Bieke F. Schrijvers

Pathophysiological role of vascular endothelial growth factor in the remnant kidney.

Background: Subtotal renal ablation is characterized by initial glomerular hypertrophy, followed by progressive development of glomerulosclerosis and interstitial fibrosis. Vascular endothelial growth factor (VEGF) is involved in glomerular hypertrophy and dysfunction in several pathophysiological conditions. On the other hand, progressive glomerulosclerosis and tubulo-interstitial fibrosis in the remnant kidney have been associated with loss of VEGF expression. Methods: To explore the pathophysiological role of VEGF in the development of glomerular hypertrophy and renal damage in the remnant kidney model, we examined the effect of a neutralizing VEGF antibody on glomerular volume and kidney function in rats after subtotal nephrectomy or sham operation. Erythropoietin was administered to exclude a confounding effect of anaemia. Results: Six weeks after subtotal nephrectomy, plasma urea and creatinine concentrations, urinary albumin excretion, and mean glomerular volume were elevated in the placebo-treated uraemic rats as compared with the sham-operated rats. Inhibition of VEGF partially prevented the glomerular hypertrophy and largely prevented the rise in urinary albumin excretion, but did not affect creatinine clearance in uraemic rats. Conclusions: VEGF is a mediator of glomerular hypertrophy after subtotal renal ablation. In view of glomerular hypertrophy as the initial deleterious event ultimately leading to progressive glomerulosclerosis, agents that block this glomerular growth could be useful in preventing scarring in progressive renal disease.

NOVEL INSIGHTS IN THE TREATMENT OF DIABETIC NEPHROPATHY

Abstract Diabetes is currently one of the leading causes of end-stage renal failure requiring renal replacement therapy in the Western World. About 15% to 20% of type 1 diabetic patients and 30% to 40% of type 2 diabetic patients will eventually develop end-stage renal failure. To prevent the development or progression of diabetic kidney disease, good glycaemic control remains the cornerstone in the management of diabetic patients. Beyond glycaemic control, other metabolic factors have been shown to be involved in the development of diabetic kidney disease, i.e. advanced glycation endproducts (AGEs) and the aldose reductase pathway. Furthermore, an adequate control of high blood pressure and treatment of microalbuminuria are major therapeutic targets. To achieve adequate blood pressure control, a combination therapy with different classes of antihypertensive agents is often necessary, especially including angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Other vasoactive factors involved in diabetic nephropathy such as endothelin and nitric oxide will be covered briefly. Besides hyperglycaemia and high blood pressure, other risk factors have been identified in the development or progression of diabetic kidney disease: smoking, hyperlipidaemia, obesity and high protein intake. Their impact on renal function will be highlighted. Finally, recent research has also identified intracellular pathways such as the diacylglycerol-protein kinase C pathway and several growth factors, such as growth hormone, insulin-like growth factor, transforming growth factor-ß, vascular endothelial growth factor, and platelet derived growth factor as players in diabetic kidney disease.

Kidney growth in normal and diabetic mice is not affected by human insulin-like growth factor binding protein-1 administration

Insulin-like growth factor I (IGF-I) accumulates in the kidney following the onset of diabetes, initiating diabetic renal hypertrophy. Increased renal IGF-I protein content, which is not reflected in messenger RNA (mRNA) levels, suggests that renal IGF-I accumulation is due to sequestration of circulating IGF-I rather than to local synthesis. It has been suggested that IGF-I is trapped in the kidney by IGF binding protein 1 (IGFBP-1). We administered purified human IGFBP-1 (hIGFBP-1) to nondiabetic and diabetic mice as three daily sc injections for 14 days, starting 6 days after induction of streptozotocin diabetes when the animals were overtly diabetic. Markers of early diabetic renal changes (i.e., increased kidney weight, glomerular volume, and albuminuria) coincided with accumulation of renal cortical IGF-I despite decreased mRNA levels in 20-day diabetic mice. Human IGFBP-1 administration had no effect on increased kidney weight or albuminuria in early diabetes, although it abolished renal cortical IGF-I accumulation and glomerular hypertrophy in diabetic mice. Increased IGF-I levels in kidneys of normal mice receiving hIGFBP-1 were not reflected on kidney parameters. IGFBP-1 administration in diabetic mice had only minor effects on diabetic renal changes. Accordingly, these results did not support the hypothesis that IGFBP-1 plays a major role in early renal changes in diabetes.