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Biomedical subjects

R H Heptinstall

Publications and source records attributed to R H Heptinstall.

At least 19 recordsLinked to original sources
PubMed1988

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)

Angiotensin II↗
PubMed1985

Glomerular hyalinosis and its relation to hyperfiltration.

Reduction in renal mass in rats results in hyperfiltration of the remnant nephrons, accompanied by injury to the glomeruli and their eventual sclerosis. This study was undertaken in a rat model with 5/6 reduction of renal mass to follow the evolution of glomerular damage, over an 11-week period, with particular emphasis on the widely prevalent, although seldom discussed, lesion of hyalinosis. Light, electron, and immunofluorescence microscopic studies were performed and blood pressure, excretion of urinary albumin, and serum creatinine levels determined. Systolic blood pressure, urinary albumin excretion, and serum creatinine levels were all increased by the third week following operation. Blood pressure and serum creatinine continued to increase throughout the period of study. Glomerular damage was focal and segmental, and glomeruli were equally affected in both the juxtamedullary and outer zones of the cortex. Endothelial injury was noted to be the first indicator of glomerular damage, followed closely by alterations in the epithelial cells. The early hyalinosis lesion was characterized by an accumulation of homogeneous electron-dense material beneath damaged endothelial cells with later encroachment on the capillary lumen resulting in the easily recognizable eosinophilic, periodic acid-Schiff-positive lesion by light microscopy. These alterations were accompanied by complex changes within the mesangium, including both mesangiosclerosis and mesangiolysis. Glomerular hyalinosis, glomerular sclerosis, vascular damage, blood pressure, and albuminuria were ranked in order of severity and the rankings subjected to multiple regression analysis. Significant correlations were present between glomerular sclerosis and hyalinosis, arterial damage and blood pressure, and hyalinosis and urinary albumin excretion. The hyalinosis lesion accompanying the progressive glomerular sclerosis in this model resembles that seen in a number of human conditions. In addition, the correlations of hyalinosis with glomerular sclerosis and albuminuria reflect its association with glomerular injury; it is likely that it will prove to be a reliable marker of hyperfiltration injury.

Albuminuria↗
PubMed1979

Clonal characteristics of experimentally induced "atherosclerotic" lesions in the hybrid hare.

The female hybrid hare (Lepus timidus x Lepus europaeus) is heterozygous for electrophoretically separable, X-linked isoenzymes of glucose-6-phosphate dehydrogenase. The isoenzymes of this animal have been used as cellular markers in the study of the clonal origins of experimentally induced atherosclerotic lesions. Aortic lesions produced in the hybrid hare by feeding cholesterol and injuring the aortic wall with a catheter have been shown to have polyclonal characteristics and in this way are fundamentally different from atherosclerotic fibrous plaques in man.

Animals↗
PubMed1979

Monoclonal characteristics of organising arterial thrombi: Significance in the origin and growth of human atherosclerotic plaques.

The clonal characteristics of 26 arterial thrombi at different stages of organisation were determined using the X-linked enzyme, glucose-6-phosphate dehydrogenase (G.-6-P.D.), as a clonal marker in 13 women heterozygous for electrophoretically separable G.-6-P.D. isoenzymes. A gradation of increasing monoclonality was observed with increasing organisation of the thrombi, such that only 21% of poorly organised (red) thrombi displayed monoclonal characteristics similar to those of atherosclerotic plaques, whereas 78% of moderately organised (pink) thrombi and 91% of well-organised (white) thrombi showed such characteristics. These results provide objective evidence for the role of thrombosis in the formation of human atherosclerotic plaques.

Aorta, Thoracic↗
PubMed1979

A morphometric study of arterial intimal thickening in kidneys of dialyzed patients.

Arterial intimal thickening is common in the end-stage kidneys of patients maintained on hemodialysis. We measured the intimal thickening in patients dialyzed for varying periods and in patients with the malignant phase of essential hypertension and with scleroderma-associated renal failure. The ratio of intimal area to medical area in intrarenal arteries was used as a measure of intimal thickening. In the dialysis groups, intimal thickening was relatively constant in arteries of all sizes and correlated with duration of dialysis, particularly in larger arteries. In the malignant hypertension and scleroderma groups, the intimal thickening was greatest in arteries less than 200 mu in diameter and least in those over 500 mu in diameter. There was much less intimal thickening in arteries of all sizes in kidneys of patients with end-stage polycystic disease than in other end-stage kidneys from patients with a similar diastolic blood pressure and similar duration of dialysis. We believe that the intimal thickening in dialyzed patients is probably a disuse type of change and may be related to reduction in the area of the renal microvascular bed.

Adolescent↗
PubMed1978

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.

Child, Preschool↗
PubMed1978

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 isoenzyme 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 leimyomas; 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.

Aorta, Thoracic↗
PubMed1978

Clonal characteristics in layers of human atherosclerotic plaques. A study of the selection hypothesis of monoclonality.

Two hypotheses have been proposed to explain the origin of monoclonal cell populations within human atherosclerotic plaques. The first of these proposes a mutational origin: the second suggests that the single clone of cells with the greatest proliferative advantage is selected following repetitive intimal injury. If the selection hypothesis is true, monoclonality should be observed more frequently in the layer of plaque most recently formed. Glucose-6-phosphate dehydrogenase (G-6-PD) isoenzymes were used as cellular markers in aortas of females heterozygous for the A and B isoenzymes. Ten plaques were divided into 45 portions, each of which was subdivided into upper layer, lower layer, and underlying media. No predominance of monoclonality was observed in the upper or lower layers of plaque, with 53% of samples from each layer being monoclonal. In all, 73% of portions of plaque contained at least one monoclonal layer. The layers tended to resemble each other in their clonal characteristics, with 60% of portions having layers with the same clonal characteristics. A significant correlation between isoenzyme distributions in upper and lower layers of the same portion was observed. No consistent trends in isoenzyme distribution in the three layers of each portion were observed. The results are interpreted as providing no evidence for clonal selection as the mechanism by which human atherosclerotic plaques become monoclonal.

Aorta↗
PubMed1977

The human atherosclerotic plaque.

The fibrous plaque is regarded as the vascular lesion most characteristic of atherosclerosis. The notion that these lesions develop from mural thrombi has received considerable support, and there is also much support for the idea that plaques form as a reaction to mechanical or chemical damage to the endothelium. As an alternative to these two hypotheses, Benditt and Benditt have suggested that plaques represent monoclonal proliferation of altered smooth muscle cells similar to leiomyomas. Evidence in favor of this suggestion has been obtained using tissues from human black females who are heterozygous for the X-linked enzyme glucose-6-phosphate dehydrogenase (G6PD). In such individuals, as a result of random inactivation of the X-chromosome during embryogenesis, all normal tissues contain both the A and B isoenzymes of G6PD, when assayed electrophoretically, whereas plaques and other lesions suspected of being of monoclonal origin contain predominantly one isoenzyme. A certain proportion of fatty streaks also show a single G6PD isoenzyme pattern, suggesting that some fatty streaks act as the foreunners of the fibrous plaque.

Aorta↗
PubMed1977

Beneficial effect of propranolol in a histologically appropriate model of postischemic acute renal failure.

Acute renal failure caused in the rabbit by clamping one renal pedicle for 1 hour and removing the opposite kidney produced a histologic picture very similar to that observed in "hypotensive" acute renal failure in man. Intravenous infusion of propranolol, a drug which prevents renin release, at 1 mg/kg for 70 minutes beginning at time of pedicle clamping resulted in significantly lower serum creatinine in this model (2.8 +/- 0.2 mg% at 48 hours with propranolol versus 5.2 +/- 0.8 mg% without). Renin stimulation by dehydration or feeding a low-salt diet enhanced the difference between treated and untreated groups (2.6 +/- 0.4 mg% with propranolol versus 6.2 +/- 1.8 mg% without, after dehydration; 3.5 +/- 1.0 mg% with propranolol versus 7.6 +/- 1.4 mg% without, after low-salt diet).Suppression of renin production by saline feeding eliminated propranolol's beneficial effect (5.6 +/- 0.9 mg% with propranolol versus 4.0 +/- 0.6 mg% without). In rabbits with a normal food and water intake, renal denervation using phenol also eliminated propranolol's effect (creatinine 8.6 +/- 1.4 mg% with propranolol versus 8.6 +/- 1.8 mg% without). In rabbits with intact kidneys, flow probe recording of renal blood flow showed a significantly higher blood flow immediately after unclamping in the propranolol-treated animals, and renal angiograms showed less vasoconstriction in this group after unclamping. In this model of acute renal failure, renal vasoconstriction plays an important role following the initial ischemic insult. Propranolol lessens the severity of this vasoconstriction and the resulting acute renal failure. Its probable action is interference with neurogenically stimulated renin release.

Acute Kidney Injury↗
PubMed1976

Renomedullary interstitial cell lesions and hypertension.

The notion that renomedullary nodules of the kidney arise as a response to hypertension was tested. Heart weight, ratio of heart weight to body weight, and blood pressure in 160 patients in whom such nodules were found at autopsy were compared with similar measurements in 160 patients without nodules. There were no significant differences between the two groups, and it was concluded that there was no evidence to support the idea that the renomedullary nodule represents a response to hypertension.

Autopsy↗
PubMed1976

Inner medullary plasma flow in the kidney with ureteral obstruction.

To test the thesis that ureteral obstruction causes medullary ischemia, we determined inner medullary plasma flow (IMPF) in rats with bilateral or unilateral ureteral obstruction, and after relief of obstruction, by the intravenous 125I-albumin infusion technique. A progressive decline in IMPF was observed during obstruction of 18 h duration, greater in bilateral obstruction (7% of normal at 5h) than in unilateral obstruction (28% of normal at 5 h). The elevation in ureteral pressure was greater and more sustained in bilateral obstruction. After relief of obstruction, IMPF rose to 69-78% of normal in both groups within 2 h. Histologic studies showed tubular necrosis in portions of the inner and outer medulla immediately beneath the renal pelvic epithelium after bilateral or unilateral obstruction of 18 h duration, and India ink perfusion studies showed very poor filling of vasa recta in these areas. The concentrating defect in the postobstructive kidney may be related, at least in part, to damage inflicted by medullary ischemia during obstruction.

Albumins↗
PubMed1976

Interstitial nephritis. A brief review.

Interstitial nephritis is a common condition, which in spite of a relatively constant pathologic picture has different etiologic agents and pathogenetic mechanisms. Failure to appreciate this, particularly in the chronic group, has led to considerable confusion and has been largely responsible for the overdiagnosis of chronic pyelonephritis. Although we are still largely ignorant of the causes of interstitial nephritis, it is now possible to define many of them. While experimental studies have not made spectacular contributions to our understanding, an attempt is now being made to develop appropriate models, and we hope these will enable us to still further clarify our understanding of other entities.

Adult↗