Douglass F. Adams

Renal failure in the patient with cirrhosis: The role of active vasoconstriction

Renal hemodynamics were studied with the 133 Xe washout technic and renal arteriography in fifteen patients with cirrhosis and varying degrees of renal functional impairment. In cirrhotic patients with renal failure extreme hemodynamic instability was encountered, characterized by variability and irregularity of xenon washout, in contrast to patients with renal failure of other etiology. Marked instability was more frequent in cirrhotic patients with azotemia, and was so severe in three instances that the curves were unanalyzable. The remaining curves revealed a decrease in both mean renal blood flow and the percentage of flow in the rapid flow component in approximate proportion to the decrease in creatinine clearance, suggesting a reduction in cortical perfusion. The arteriographic findings, including the absence of a cortical nephrogram and unrecognizable renal cortical vasculature in the patients with the most severe degree of renal failure, support the concept of a reduction in renal cortical perfusion. The finding of marked hemodynamic instability strongly suggests that the renal ischemia is secondary to active vasoconstriction. Consistent reversal of all the vascular abnormalities in the kidneys of five cirrhotic patients at postmortem angiography provides further evidence for the functional basis of the renal failure, operating through active renal vasoconstriction. Phentolamine infusion into the renal artery in four patients did not significantly alter renal hemodynamics indicating that increased sympathetic nervous system activity was not responsible for the active vasoconstriction and cortical ischemia.

Senescence and the Renal Vasculature in Normal Man

The xenon washout technique and the renal blood flow response to vasoactive agents or alterations in sodium intake were used to characterize the effect of aging on the renal vasculature in 207 normal human subjects ranging in age from 17 to 76 years. A highly significant, progressive reduction in the mean blood flow, the rapid-component flow rate, and the percent of flow into the rapid-flow (cortical) compartment accompanied advancing age. Because 133Xe measures flow per unit tissue mass, the results indicated a larger reduction in flow than in mass—the anticipated finding if flow reduction is primary in the genesis of atrophy. Age also reduced the vasodilation consequent to administration of acetylcholine or a sodium load; this finding is consistent with a fixed lesion of the vessels. Responses to angiotensin were not modified by age. Thus, offsetting factors of increased ratio of wall to lumen thickness and smooth muscle atrophy are precisely matched. The findings in this study agree with earlier hypotheses based on morphology that suggest a primary vascular process in the development of age-related renal changes.

Reciprocal Influence of Salt Intake on Adrenal Glomerulosa and Renal Vascular Responses to Angiotensin II in Normal Man

The adrenal glomerulosa cell and the renal vasculature respond to similar arterial angiotensin II (A II) levels. We have assessed the effect of decreased sodium intake on their responses to A II in man. Studies were performed in 42 normal subjects in balance on a daily intake of 100 meq potassium and either 200 or 10 meq sodium/day. Renal blood flow was measured with (133)Xe and arterial A II, renin and aldosterone concentrations by radioimmunoassay. A II was infused intravenously (1, 3, or 10 ng/kg/min) for 40-60 min; 14 subjects received graded doses. The A II level increased linearly with dose and plateaued within 3 min; blood pressure and renal vascular resistance showed a similar time-course. Aldosterone rose within 10 and plateaued within 20 min. Dose-response relationships were established between the rate of A II infusion and the adrenal, the renal vascular, and pressor responses. Sodium restriction reduced the pressor (P < 0.01) and the renal vascular response (P < 0.01), but potentiated the adrenal response to A II (P < 0.01). An excellent correlation was found between the plasma A II and aldosterone levels, but the slope of their regression relationship on a high (y = 0.13x + 6) and low salt intake (y = 0.32x + 14) differed significantly (P < 0.0005). Thus, sodium intake reciprocally influences vascular and adrenal responses to A II: salt restriction blunts the vascular response and potentiates the adrenals, a physiologically important influence in view of aldosterones role in sodium conservation.

The Complications of Coronary Arteriography

A nationwide survey was undertaken to determine the rate of complications due to coronary arteriography during 1970-71. The responses from 173 hospitals-including a total of 46,904 coronary arteriograms-were analyzed in relationship to the technique employed and to the number of examinations performed at each hospital during the two-year period. The overall mortality rate was 0.45% (brachial 0.13%, femoral 0.78%). The mortality rate in institutions performing fewer than 200 examinations per two years was eight times higher than in institutions performing more than 800 examinations per two years. Similarly, the incidence of myocardial infarction and cerebral embolism was significantly higher when a smaller number of examinations was performed. The incidence of major complications-including death, myocardial infarction, and cerebral embolism-was higher in examinations using the femoral approach than the brachial approach. The incidence of arterial thrombosis and contrast agent reactions was higher for the brachial approach. Factors which may help to explain these differences are considered and discussed.

Essential hypertension: abnormal renal vascular and endocrine responses to a mild psychological stimulus.

SUMMARY We have assessed the influence of a mild emotional stimulus on arterial blood pressure, heart rate, renal blood flow, plasma resin activity (PRA), and plasma aldosterone concentration in 24 normal subjects, eight of whom had a parent with hypertension, and in IS patients with essential hypertension. A nonverbal IQ test, Ravens Progressive Matrices, was employed as the stimulus. In 11 of the 15 hypertensives, arterial blood pressure rose transiently by 7 mm Hg or more, but in only three of 16 normal subjects (x 2 = 7.23, p < 0.01). Transient moderate increases in heart rate were also more common in the hypertensives (p < 0.01). Renal blood flow rose in 11 of 16 normal subjects and fell in each of the 15 patients with essential hypertension (x* − 15.1;/> < 0.005). As opposed to the transient changes in arterial pressure and heart rate, the fall in renal perfusion was sustained. The PRA fell in 10 of the 16 normal subjects with a negative family history and rose In 14 of 15 patients with essential hypertension (p < 0.005). Changes in plasma angiotensin II concentration and in plasma aldosterone were in accord with the changes in PRA, but plasma cortisol did not change. Both the renal vascular response and the change in PRA were intermediate in normal subjects in whom family history was positive for hypertension. For the entire group of 39 subjects there was statistically significant agreement between the direction of the renal vascular response and the directional change in PRA: renal blood flow rose when PRA fell and fell when PRA rose (p < 0.005). We conclude that there is an abnormality in the control of both the renal circulation and of renin release in patients with essential hypertension in response to psychological provocation, and that a similar process is present in some normotensive subjects whose parents have hypertension.

Magnetic resonance imaging of skeletal muscle. Prolongation of T1 and T2 subsequent to denervation.

The changes seen in the T1 and T2 relaxation times, water content and size of the extracellular fluid spaces of rat muscle samples following 15 days of denervation were studied by in vitro proton NMR spectrometry (10 MHz). Two different skeletal muscle groups (gastrocnemius and soleus) were studied. Denervation led to longer T1 values: 548 ± 61 msec vs. 486 ± 16 msec (P<.05) for the gastrocnemius and 581 ± 27 msec vs. 521 ± 25 msec (P < .05) for the soleus. Similar increases in T2 were measured. The sizes of the extracellular fluid spaces of denervated muscle were significantly larger despite a minor increase in total water content. Overall, the relaxation times of skeletal muscle correlated better with the size of the extracellular fluid space than with the total water content.

Blockade and stimulation of renal, adrenal, and vascular angiotensin II receptors with 1-Sar, 8-Ala angiotensin II in normal man.

We have assessed the capacity of an analogue of angiotensin II (A II), 1-Sar, 8-Ala A II (P113) in normal man to stimulate and block responses to A II in four systems: blood pressure was monitored directly from an arterial catheter, and renal blood flow was measured with 133Xe and arterial renin and aldosterone concentrations by radioimmunoassay. The 31 normal subjects were in balance on a daily intake of 200 meg sodium and 100 meq potassium to suppress endogenous renin. P113 administered intravenously induced a dose-related renal blood flow reduction, with a threshold dose of 0.1 mug/kg/min. This dose also induced a small but significant increase in arterial blood pressure and plasma aldosterone as well as a reduction in plasma renin activity. In contrast to its effect on the renal vasculature, no tendency to a progressive response in the latter three parameters was noted as the P113 dose was increased 30-fold, to 3.0 mug/kg/min. P113 also reduced the clearance of para-aminohippurate, creatinine, sodium, and potassium, a pattern similar to that induced by A II. P113 at 0.1 mug/kg/min reduced significantly the blood pressure and renal vascular and aldosterone responses to graded doses of A II. Higher P113 doses totally obliterated all three responses to A II infused at 10 ng/kg/min, a dose that provides arterial A II concentrations in the range found in angiotensin-mediated hypertension. When A II was infused first, to induce a pressor, renal vascular, and aldosterone response, P113 induced a dose-related reversal of the response in each system. In conclusion, P113 is a partial agonist in normal man, inducing an angiotensin-like response in settings in which endogenous A II is not playing a tonic role, and displaying dominant antagonist activity in settings in which A II is active. Moreover, the studies suggest that the receptors mediating the responses to A II are different in the renal vasculature and other systemic vascular beds. The adrenal receptor must also differ. This agent should be useful in dissecting the role of A II in diseases characterized by hypertension or abnormalities of renal and adrenal function.

Renal vascular tone in essential and secondary hypertension: hemodynamic and angiographic responses to vasodilators.

The renal vascular response to graded doses of acetylcholine, dopamine and phentolamine, assessed by xenon washout and selective arteriography was used to define the relative contribution of fixed and reversible vascular abnormalities to increased renal vascular resistance in patients with essential or secondary hypertension. The increase in blood flow induced by acetylcholine and dopamine was blunted strikingly in patients with advanced nephrosclerosis, chronic pyelonephritis and polycystic kidney disease and was normal in the kidney contralateral to a significant renal artery stenosis. Conversely, the response to both was potentiated in 9 of 13 (69%) patients with mild essential hypertension. Equivalent potentiation of the response to acetylcholine was induced in normal subjects by increasing renal vascular tone pharmacologically with angiotensin. Phentolamine infused into the renal artery also increased renal blood flow significantly in 6 of 9 (67%) patients with mild essential hypertension, but in none of 15 normal subjects, over a dose reange that paralleled that for alpha-adrenergic blockade. Changes in the selective renal arteriogram were in excellent accord: potentiated response to acetylcholine, phentolamine or dopamine was associated with reversal of the small vessel abnormalities visualized in the arteriogram. The reduced blood flow response in advanced nephrosclerosis or parenchymal disease was associated with a reduced angiographic change during dilator infusion. The results suggest a quantitatively important, functional renal vascular abnormality--perhaps mediated by the sympathetic nervous system--in many patients with mild essential hypertension. Conversely the renal vascular abnormality associated with advanced nephrosclerosis or renal parenchymal disease is largely fixed and is probably due to organic changes.

The renal circulation in hypertensive disease.

The pivotal role of the kidney in sustaining hypertension from any source or etiology is becoming increasingly clear. The possibility that the renal vasculature participates not only in the pathogenesis of renal vascular hypertension, but also in that of essential hypertension, has been the subject of continuing interest for 40 years. Evidence that a functional abnormality resulting in increased renal vascular tone is present in about two-thirds of patients with uncomplicated essential hypertension is reviewed, along with more circumstantial evidence that sympathetic nervous system activity operating on the renal vasculature is responsible. Two additional groups of patients in whom a characteristic abnormality of the renal vasculature is present have also been identified. In one group there is severe hypertension which is resistant to most forms of antihypertensive therapy but which is especially responsive to propranolol. In these patients renal blood flow and glomerular filtration rate are reduced, renin secretion rate is increased and the renal vessels are resistant to vasodilators, suggesting the presence of advanced organic arteriolonephrosclerosis, as a complication of long-standing, severe hypertension. The renal lesion, in turn, contributes to the increasing severity of the process. In a second group of patients, generally young and with uncomplicated hypertension, renal blood flow is inappropriately increased. In these patients a number of observations on their renal vasculature, renin and aldosterone responses to a volume challenge suggest an abnormality in the perception of extracellular fluid volume. A perfectly normal renal arterial tree, free of organic abnormality or an increase in tone due to active vasoconstriction, is distinctly unusual in essential hypertension.

Acute Renal Failure Due to Nephrotoxins

Abstract Seven patients with nephrotoxin-induced acute renal failure had characteristic renal hemodynamic and angiographic abnormalities identical to those found in patients with acute renal failure due to shock and hemolysis. The abnormalities include the absence of recognizable cortical arterial vessels and the cortical nephrogram, delayed transit of contrast medium through the kidney and disappearance of the rapid — or cortical — flow component of xenon washout from the kidney. These observations suggest a persistent homogeneous reduction in renal cortical perfusion sufficient to induce the cessation of glomerular filtration and thus account for the failure of renal function. The similarity of the hemodynamic pattern in patients with acute renal failure of widely different etiology suggests a pathogenetic final common pathway involving undefined mediators that induce severe, sustained preglomerular vasoconstriction.