Role of altered capillary hemodynamics in the initiation and progression of diabetic microangiopathy

Reprint requests to be sent to: Barry M. Brenner, MD, Renal Division, Brighamand Women’s Hospital, 75 Francis Street, Boston, MA 02115. Microangiopathy remains a major cause of disability in diabetic patients, a prominent clinical example being diabeticglomerulopathy. Despite the frequency with which Type I and Type II diabetes results in end-stage renal disease, these patients may exhibit striking elevations in glomerular filtration rate (GFR) at the time diabetes is diagnosed.’ That this hemodynamic abnormality may in fact contribute to the pathogenesis of diabetic glomerulopathy is suggested by the observation that those patients with the highest GFR values early in the course of diabetes are more likely to progress to persistent proteinuria or overt renal disease than are those patients with more normal values for GFR.* That renal hyperperfusion and hyperfiltration might contribute to the develo‘pment of diabetic glomerulopathy has been further suggested by observations in diabetic patients with unilateral renal artery stenosis, in whom morphologic evidence of diabetic glomerulopathy was confined to the non-stenosed kidney.3e4 Since abnormal metabolic conditions would be expected to affect both kidneys equally, it seems likely that the stenosis protected the ipsilateral kidney from hemodynamic influences such as hyperperfusion and hyperfiltration. Recent experimental studies have yielded considerable insight into the importance of hemodynamic factors in the initiation and pathogenesis of diabetic microangiopathy. VA useful model is provided by induction of diabetes in the rat by streptozotocin, and maintenance of moderate hyperglycemia with insulin therapy. In this model, Hostetter and coworkers7 found increases of approximately 40% in whole kidney and single nephron glomerular filtration rates, as compared to normal rats. Reductions in intrarenal vascular resistances resulted in elevation of the glomerular capillary plasma flow rate. Because the decrease in afferent arteriolar resistance was proportionately greater than that in efferent resistance, glomerular capillary hydraulic pressure was also elevated. Thus, both glomerular capillary hyperperfusion and hypertension contributed to the observed single nephron hyperfiltration in this model. Of note, these hemodynamic changes are similar to those observed in a non-metabolic model, surgical reduction of renal mass, suggesting that hemodynamic abnormalities may be a common pathogenetic pathway in many renal diseases. In long-term studies, diabetic rats develop morphologic changes similar to those observed clinically, including renal hypertrophy,*sg enlargement of glomerular size,‘O glomerular basement membrane thickening,‘O and hyaline deposition and glomerular sclerosis.*sg To further explore the hemodynamic basis of diabetic glomerulopathy, Zatz and co-workers* used dietary protein restriction, which limits glomerular capillary pressures and flows in many other models of hyperfiltration associated with progressive renal disease. Moderately hyperglycemic diabetic rats were fed diets containing 6, 12, or 50% protein; standard rat chow contains 24 percent protein. Both the 6 and 12% protein diets limited single nephron hyperfiltration in the diabetic rats by reducing the supranormal glomerular capillary pressures and flows. After 14 months of diabetes, protein-restricted rats exhibited virtually no albuminuria or glomerular morphologic injury. In contrast, diabetic rats fed the50% protein diet exhibited overtglomerularcapillary hyperfiltration, hyperperfusion and hypertension, and sharp increases in