Robert H. Heptinstall

Nonimmunologic Mechanisms of Glomerular Injury

From the above discussion it is clear that many factors have been invoked in the pathogenesis of progressive glomerular injury. Those which are most important include increased PGC, coagulation, serum lipid abnormalities, and hypertrophy. Although many hemodynamic alterations have been identified, increased PGC was noted most constantly. Furthermore, the loss of autoregulatory capability which was observed in some models with progressive glomerulosclerosis usually resulted in increased PGC. Increased PGC has been associated with augmented dietary protein and is seen in the Munich-Wistar rat made diabetic. Such an increase in PGC could cause direct mechanical injury to endothelial and epithelial cells, as well as be responsible for increased mesangial traffic of macromolecules with the potential for stimulating cellular proliferation and mesangial matrix increase. Additional support for the importance of increased PGC is provided by the protective effect of decreasing PGC with CEI therapy and anemia, and by the enhanced autoregulatory capability in both the Milan and Okamoto hypertensive rats. The significance of coagulation factors is confirmed by the formation of platelet and fibrin thrombi in the development of the glomerular lesions. The sequence of glomerular injury suggests that endothelial damage occurs with subsequent formation of platelet aggregates as a response to this injury. Formation of platelet aggregates may be associated with the production of substances potentially injurious to the endothelial cells. Although blocking the appearance of such thrombi by administration of heparin or thromboxane synthetase inhibitor prevents glomerular injury, the blood pressure lowering effect of these agents complicates the interpretation of the studies. Serum lipid abnormalities are also important factors in the progression of nonimmunologic glomerular injury. Such abnormalities are observed with increased dietary phosphorus or lipid, in the obese Zucker rat, and in rats with diabetes mellitus. Reduction in serum cholesterol by administration of clofibric acid or mevinolin diminishes glomerular injury independent of alterations in glomerular hemodynamics. The possible link between increased serum lipids and augmentation of glomerular injury is at present indirect. The importance of hypertrophy as a contributing factor to the progression of nonimmunologic glomerular injury is suggested by several lines of evidence. Hypertrophy, with increase in glomerular size and caliber of capillary loops, may amplify the effect of increased PGC by further intensifying the tension and mechanical stress on all elements of the capillary wall.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of indomethacin on renal inner medullary plasma flow

Abstract The effects of the prostaglandin system on renal hemodynamics were studied by treating rats with a single intraperitoneal dose of indomethacin, an inhibitor of prostaglandin synthesis. Medullary plasma flow was significantly reduced 30–45 minutes after indomethacin, but was elevated 3–6 hours after indomethacin. These changes in medullary plasma flow correlated well with circulating levels of prostaglandins A and E. Total renal blood flow decreased following indomethacin treatment, but returned to normal levels within an hour. These results indicate that the inhibition of prostaglandin synthesis following a single intraperitoneal dose of indomethacin is short-lived and is followed by a significant elevation in prostaglandin synthesis. It is likely that prostaglandin levels play an important role in the control of renal medullary plasma flow.

Clonal markers in the study of the origin and growth of human atherosclerotic lesions.

The X-linked enzyme, glucose-6-phosphate dehydrogenase (G-6-PD) was used as a cellular marker to study the clonal characteristics of human atherosclerotic lesions from females heterozygous for G-6-PD isoenzymes. Portions of uninvolved aortic wall contained both isoenzyme types (A and B), and their isoehzyme patterns were used to establish criteria for polyclonal lesions. Portions of uterine leiomyomas contained predominantly one isoenzyme type (either all A or all B) and their isoenzyme patterns were used to establish criteria for monoclonal lesions. These techniques were used to address three questions concerning atherogenesis. First, evidence for the monoclonal origin of fibrous-capped plaques was provided by the findings that small plaques had G-6-PD isoenzyme distributions similar to those of leiomyomas; that in large plaques with multiple portions assayed for G-6-PD, a large proportion (25 of 26, 96%) of plaques had monoclonal characteristics; and that multiple monoclonal portions were present in the same plaque. Second, the role of the fatty streak as a precursor of fibrous plaques was supported by the demonstration that a proportion (11 of 66, 16.7%) of fatty streaks contained isoenzyme patterns intermediate between those of polyclonal uninvolved aortic wall and monoclonal leiomyomas. Increased cellularity of fatty streaks correlated with increased deviation of isoenzyme pattern toward monoclonality. Third, the assay of portions of both small and large plaques provided no evidence for clonal selection as plaques increase in size.

Intrarenal Urinary Extravasation With Formation of Venous Polyps Containing Tamm-horsfall Protein

Collections of periodic acid-Schiff-positive material are found in the intrarenal veins and in the renal interstitium in certain cases of hydronephrosis and unexplained unilateral hematuria. Using a fluorescent antibody to Tamm-Horsfall protein, a protein secreted by the ascending limbs and distal convoluted tubules, we have demonstrated that the venous and interstitial masses represent urinary filtrate, which probably enters the kidney parenchyma through forniceal or tubular ruptures.

Atherosclerosis in the hypercholesterolemic hare: Comparison of coronary artery lesions induced by dietary cholesterol in the hare and the rabbit

Atherosclerotic lesions in coronary arteries were compared in 10 hybrid hares and 14 rabbits after induction of hypercholesterolemia, using a cholesterol-enriched diet. All proximal portions of hare coronary arteries contained intimal lesions, often with severe luminal stenosis. These lesions were characterized by the presence of foam cells, smooth muscle cells, and areas of atheronecrosis. Foam cells were also found focally in the media. As part of the intimal changes, iron deposition was present in 65% and calcification was present in 32.5% of proximal segments examined. The proportion of segments with intimal lesions and the intima/media cross-sectional area ratios (I/M ratios) were greatest in proximal segments with stepwise decreases in the mid and distal segments. As area of myocardial infarction was present in one hare. In contrast, 46.5% of proximal segments of rabbit coronary arteries had no intimal lesions and those lesions present had no calcium or iron deposition. No infarction was observed in rabbit hearts. The proportion of segments with lesions and the mean I/M ratios were significantly greater in the hare than the rabbit, with proximal and mid coronary segments showing the most marked differences. The hare appears to develop coronary artery lesions more like those seen in man, with high grade, proximal stenoses occurring uniformly in hypercholesterolemic animals. In contrast, the atherosclerosis developing in rabbit coronary arteries is less uniform and includes involvement of intramyocardial arterioles. The hare offers several advantages as a model of human atherosclerosis.

The Development of Renal Pathology

I N HIS LETTER to the contributors of this special edition, the guest editor suggested that we focus on the years 1950 to 1990-the lifetime of the National Kidney Foundation-and that we draw heavily on our own experiences and reflections. The first is easy but, except to the very brash, the second presents problems because it would be all too easy to turn the article into a brochure of self-aggrandizement. Yet , in spite of these reservations, the suggestions have considerable merit and with due diffidence I shall adopt them.

Relation of hypertension to changes in the arteries

Abstract Hypertension can damage small blood vessels, and this effect is best seen in the arterioles of the kidney, which undergo fibrinoid necrosis. It also has a potentiating effect on arteriosclerosis of the larger vessels such as the coronary, carotid, and vertebral arteries. The relation of hypertension to endarteritis fibrosa of the interlobular arteries of the kidney is not clear; while at one time it was felt that hypertension caused this lesion, recently acquired information raises the possibility that the arterial changes result from intravascular coagulation and may cause or accelerate the hypertension.

Cholesterol-induced atherosclerosis. Clonal characteristics of arterial lesions in the hybrid hare.

Utilizing the observation that a majority of human atherosclerotic fibrous plaques show monoclonal characteristics, we carried out this study to determine the clonal characteristics of cholesterol-induced atherosclerosis in the hybrid hare. If this is a valid model for human atherosclerosis, the lesions produced in the aorta should be monoclonal. Glucose-6-phosphate dehydrogenase (G-6-PD) was used as an X-linked cellular marker in the female hybrid hare (Lepus timidus × Lepus europaeus), which is heterozygous for electrophoretically separable isoenzymes of G-6-PD. Hares were fed cholesterol over either a 6-month ora l 6-month period, and the easily dissectable lesions in the aorta and common iliac arteries were assayed for isoenzyme activity at these times. Of the 93 lesions assayed, all had polyclonal characteristics except a single monoclonal lesion found in an animal fed cholesterol over a 16-month period. Hares fed over the 16-month period showed lesions with isoenzyme patterns having a significantly higher contribution of L. timidus isoenzyme than those found in underlying media. This suggested that a selection of cells with the L. timidus X-chromosome had taken place, but the degree of this selection was not great enough to allow any of the lesions to be defined as monoclonal.

The Anatomy of the Renal Circulation

There is no organ with a blood vascular system more complex than that of the mammalian kidney. To draw an analogy with electrical circuits, the renal vasculature represents an intricate system of constantly varying resistances, arranged in series and parallel, which control the flow of energy required for the many homeostatic roles the kidney must play. Morphologic studies demonstrate the many different routes which blood may take in its passages through the kidney. Such studies cannot capture the dynamic nature of the renal circulation but are important nonetheless in delineating the anatomic substrate upon which functional and disease-related alterations in vessel structure and caliber take place.

The Renal Circulation: Physiology and Hormonal Control

Although much attention has been paid to the immunologic aspects of kidney disease (Germuth and Rodriguez, 1973; McCluskey, 1974; Wilson and Dixon, 1974), it is clear that many of the more common afflictions have a predominantly circulatory rather than an immunologic basis. Vascular abnormalities and altered renal perfusion play a key role in the renal disorders associated with arteriosclerosis, hypertension, shock, liver disease, sepsis, trauma, diabetes, and the toxic effects of certain drugs (Barger, 1966; Siper-stein et al., 1968; Hollenberg, 1973; Hollenberg and Adams, 1974). Disturbed renal hemodynamics are pathogenetically important even in disorders of undisputed immunologic origin, such as renal transplant rejection (Hollenberg et al., 1972).