Thomas H. Hostetter

Molecular basis of proteinuria of glomerular origin.

THE process of urine formation begins at the walls of the glomerular capillaries with the separation of as much as a third of the plasma entering the glomeruli of each kidney into a solution having...

Role of angiotensin II in the altered renal function of congestive heart failure.

Glomerular and tubule functions were assessed by micropuncture in rats with extensive myocardial infarction produced by ligation of the left coronary artery 4 weeks prior to study. When compared to sham-operated control rats, rats with myocardial infarction involving 40 ± 4% of the left ventricular circumference had lower mean arterial pressure (96 ± 5 vs. 122 ± 4 mm Hg, P < 0.005), and higher left ventricular end-diastolic pressure (24 ± 3 vs. 5 ± 0 mm Hg, P < 0.001). Renal cortical microcirculatory dynamics of rats with myocardial infarction were characterized by reduced glomerular plasma flow rate (75 ± 8 vs. 165 ± 17 nl/min, P < 0.005), but a proportionately lesser decline in single nephron glomerular filtration rate (28.0 ± 2.8 vs. 41.7 ± 3.1 nl/min, P < 0.025), accounting for the observed rise in single nephron filtration fraction (0.38 ± 0.02 vs. 0.25 ± 0.02, P < 0.005). These renal hemodynamic alterations in myocardial-infarcted rats were accompanied by a striking elevation in efferent arteriolar resistance (3.03 ± 0.31 vs. 0.95 ± 0.16 × 1010 dyn · sec · cm−5, P < 0.001). In addition, fractional proximal fluid reabsorption, assessed by end-proximal tubule fluid-to-plasma inulin concentration ratio, was elevated (2.21 ± 0.12 vs. 1.64 ± 0.09, P < 0.025). The intravenous infusion of teprotide, an angiotensin I-converting enzyme inhibitor, led to the return of glomerular plasma flow rate, single nephron filtration fraction, single nephron glomerular filtration rate, efferent arteriolar resistance, and fractional proximal fluid reabsorption in myocardial-infarcted rats to, or toward, the levels found in control rats. In contrast, teprotide exerted little or no effect in control rats. Thus, the renal cortical microcirculatory and proximal tubule functions of rats with congestive heart failure are profoundly influenced by the vasoconstrictor properties of angiotensin II.

Compensatory Renal Hemodynamic Injury: A Final Common Pathway of Residual Nephron Destruction

F OLLOWING LOSS of functional renal mass, the residual renal tissue undergoes progressive hypertrophy and hyperplasia. Single nephron glomerular filtration rate (SNGFR) increases dramatically and this enhancement of SNGFR in remnant units has generally been considered a beneficial response in that the animals total fall in GFR is thereby mitigated. However, evidence has been developed which suggests that single nephron hyperfiltration may have maladaptive and eventually injurious consequences. For nearly 50 yr it has been recognized that removal of approximately 3,4 or more of the renal mass in the rat, either by surgical resection, infarction, or a combination of these maneuvers, results in a syndrome of progressive azotemia, proteinuria and arterial hypertension. 1.2 Furthermore, striking structural alterations appear in these initially normal residual glomeruli during the course of this process of adaptation, eventuating ultimately in glomerulosclerosis. Shimamura and Morrison 3 carefully documented the progression of glomerular damage in adult rats subjected to surgical resection of approximately 5/6 of their total renal mass. They described an increase in glomerular size within the first 3 mo of nephrectomy. This hypertrophy was accompanied by ultrastructural alterations, including vacuolization of glomerular epithelial cells, deposition of osmophilic droplets within these cells, and fusion of foot processes. By about 6 mo, expansion of mesangial matrix became evident along with denudation of cells from areas of glomerular basement membrane. These ultrastructural alterations heralded progressive hyalinization and ultimately sclerosis of these remnant glomeruli. Studies employing unilateral nephrectomy and 3/5 infarction of the remaining kidney

Mechanisms of Glomerular Permselectivity

The hydraulic pressure gradient acting across the glomerular capillary wall serves as the principal driving force for the separation of plasma into a nearly ideal ultrafiltrate. In spite of its remarkably low resistance to water flow, however, this capillary network retains within it the plasma proteins, so that only a small fraction of these circulating macromolecules appear in the glomerular urine. The basis for this retention of proteins within the glomerular capillary has been investigated primarily by clearance techniques and by ultrastructural analyses, using various types of tracer macromolecules. These studies have demonstrated that the filtration of macromolecules is influenced both by the intrinsic permeability properties of the glomerular capillary and by the presures and flows determining the filtration rate of water. The intrinsic permeability properties of the various membrane and cell layers of the glomerulus derive from their ability to discriminate on the basis of molecular size and net molecular charge. In this review, the operation of these mechanisms in health and in disease will be explored.

Hyperfiltration as a Major Causative Factor in Initiation and Progression of Glomerulosclerosis

The augmentation of single-nephron glomerular filtration rate (SNGFR) that follows loss of functioning renal mass is generally regarded as a beneficial adaptation in the sense that total filtration by the remnant kidney falls less than would be the case had this augmentation not occurred. However, several lines of evidence have been developed that, when taken together, suggest that single-nephron hyperfiltration may have maladaptive and eventually injurious consequences. For nearly 50 years it has been recognized that removal of approximately three fourths or more of the renal mass in the rat, either by surgical resection, infarction, or a combination of these maneuvers, results in a syndrome of progressive azotemia, proteinuria, and eventual glomerular sclerosis.l–3

The Role of Hemodynamic Alterations in the Pathogenesis of Diabetic Glomerulopathy

Although nephrotic-range proteinuria and progressive azotemia are unequivocal indications of disordered glomerular function in patients with long-standing insulin-dependent diabetes mellitus, it is apparent that alterations in glomerular function also occur at an early stage of this disease in humans and experimental animals. Stalder and Schmid1 reported more than 20 years ago that the glomerular filtration rate (GFR) is elevated above normal in diabetic children and young adults, a finding confirmed by Ditzel and Schwartz2 and extensively investigated in recent years by Mogensen.3,4 Mogensen described a 40% increment in GFR in 11 newly diagnosed juvenile diabetic patients when compared with values in 31 normal subjects of similar age.3 This remarkable hyperfiltration was shown to be related to the patient’s metabolic status since reduction of blood sugar levels over several days to weeks by standard insulin therapy tended to return GFR to normal or near-normal levels. Indeed, recent studies by Christiansen et al.5 have demonstrated that with reduction in blood glucose levels to normal in diabetics by continuous insulin infusion, GFR also declines from elevated to near-normal values in a matter of hours.