Acute arterial fibrinoid deposition and ischaemic parenchymal damage of the kidney. Pathogenic factors in the development of malignant hypertension

Abstract

The development and evolution of hypertensive vascular lesions affecting the arterial supply of (a) the kidney and (b) organs other than the kidney were studied in rats developing either malignant (MHY) or benign (BHY) hypertension 3, 6, 9 and 12 days after aortic ligation between the renal arteries. Vascular disease evolved into two distinct patterns which suggested acute renal damage to be the determinant for the development of either the malignant or benign form of hypertension. Three days after aortic ligation MHY and BHY animals showed widespread fibrinoid deposition in vascular territories above the aortic ligature. However, in MHYs these lesions were much more severe and, in the kidney, they were accompanied by the development of focal parenchymal atrophy, microinfarcts and hyalin droplet degeneration of cells of the Bowman capsule. The degree of renal damage correlated with elevations in blood urea nitrogen (BUN) and plasma creatinine; however, there was no correlation with rises in blood pressure, plasma renin activity (PRA), aldosterone or corticosterone which were similarly elevated in 3-day MHY and 3-day BHY animals. Between 6 and 12 days a marked clearance of fibrinoid took place in all organ beds of BHYs, but in the non-renal vasculature of MHY animals fibrinoid remained prominent and served as the central core for necrotising arterial lesions. In the kidney of MHYs some reduction in the fibrinoid content was observed, but the parenchymal damage perpetuating from the earlier stages had exacerbated leading to collagen deposition and a marked increase in the collagen concentration of the renal cortex. These features were accompanied by further elevations in PRA and corticosteroids and a progressive deterioration of renal function. By contrast, in 12-day BHY animals, despite sustained hypertension, PRA and corticosteroids were falling from their previously higher levels and normal renal function was maintained. These studies warrant inference that extensive parenchymal damage of the kidney due in part to severe arterial fibrinoid deposition is one of the initial events in the development of malignant hypertension.

Malignant hypertension, fibrinoid deposition, and fibrinogen electrophoresis

“…Although degradation products and cross-linked polymers seldom rose to impressive levels (>1% of the fibrinogen), the method of analysis was not designed to detect fibrin complexes that are not cross-linked, because these complexes are fully dissociable by the SDS used for electrophoretically profiling the molecular weights of the protein. As described, 25 we know that fibrinoid deposition occurred at the outset in both BHYs and MHYs, but the extent of deposition was much smaller and the deposits disappeared almost entirely by the ninth day in BHYs. Fibrin monomer without cross-linkages is cleared from the circulation very rapidly.…”

“…Based on pathological assessments of animals killed at either 12 or 24 days postligation, they were characterized as either benign (BHYs) or malignant (MHYs) hypertensives. 25 Immunoprobing of electrophoregrams at the earliest sampling (3 days) regularly showed, as in Figure I A, high concentrations of both polymeric and degraded forms of fibrinogen in the plasma of rats that were subsequently found to be MHYs. 25 By contrast, these derivatives were seldom found (one of 11 animals) at resolvable levels (>1% of the total fibrinogen) in the three-day BHYs and not at all in sham-operated controls.…”

“…25 Immunoprobing of electrophoregrams at the earliest sampling (3 days) regularly showed, as in Figure I A, high concentrations of both polymeric and degraded forms of fibrinogen in the plasma of rats that were subsequently found to be MHYs. 25 By contrast, these derivatives were seldom found (one of 11 animals) at resolvable levels (>1% of the total fibrinogen) in the three-day BHYs and not at all in sham-operated controls. Usually, the levels of both polymers and degradation products dropped substantially over days 6-9.…”

“…The fall in level of the polymers and degradation products coincided with a diminution in the abundance of fibrinoid observed in the parallel matched series of animals. 25 However, the polymers rose again during days 12-24, and this secondary rise appeared to coincide with glomerular fibrinoid deposition. 22 The findings provide evidence that the development of malignant hypertension was either directly or indirectly associated with the appearance of high levels of cross-linked forms of fibrinogen (ranging from 3%-9% of the total fibrinogen) in blood shortly after ligation.…”

“…Although many factors such as elevated glucocorticoids 24,27 could have contributed to the differences in macrophage activity, 25 the cross-linking warrants consideration as a potential factor. Many questions remain to be answered concerning underlying reasons for the fibrinogen alterations seen in MHYs.…”