Biomedical subjects
F C Luft
Publications and source records attributed to F C Luft.
The effect of angiotensin II on glomerular function and morphology in the rat.
We have observed alterations of glomerular and afferent arteriolar structure in nephrotoxic and ischemic models of acute renal failure. These alterations may have been caused by angiotensin II. To test this notion, we infused the peptide directly into the left renal artery of anesthetized rats. At sub-pressor doses of 1.9 and 6.5 ng/100g body weight/min, the peptide caused dose-related decreases in glomerular filtration rate similar to those that occur in models of acute renal failure. In some animals, methacrylate casts of the infused and contralateral kidneys were made for later examination by scanning electron microscopy. In other animals, the kidneys were fixed with glutaraldehyde for examination of the glomerular epithelium and endothelium by scanning electron microscopy. Cast analysis showed no detectable alteration of afferent arteriolar diameter, and only moderate bilateral changes in the tapering of the arterioles. In contrast, the diameter of the casted glomerular tuft was significantly reduced by the highest dose of angiotensin II. No alterations of the glomerular epithelium or endothelial fenestrae were observed. We conclude that angiotensin II probably did not mediate the changes in glomerular structure in our earlier studies of acute renal failure, even though similar reductions of glomerular filtration rate occurred. Reduced diameter of the glomerular tuft is consistent with a possible role for angiotensin II as a modulator of intrinsic contractile elements in glomeruli.
Electrolyte intake and blood pressure: a study in contradictions and controversy.
The widely accepted recommendation that hypertensive subjects benefit from a reduction of sodium intake has lately been challenged by a number of publications. From one analysis of the First National Health and Nutrition Examination Survey (NHANES) in the USA, the conclusion was reached that hypertension was associated more frequently with low nutritional sodium intake and low calcium intake. Other authors analysing the same data but using different criteria and statistical methods did not confirm such conclusions. The criticisms of epidemiological data concerning the relationship between salt intake and hypertension include frequently inconsistent definition of hypertension, failure to consider methodological uncertainties in the measurement of salt intake and excretion and inadequate control of confounding variables such as age, race, sex, body mass index and lifestyle. The claimed link between nutritional calcium and blood pressure is completely unclear and needs careful investigation. A reduction of sodium intake from the present day excessive amounts to moderate intakes of 3-6 g per day is still recommended in order to prevent the establishment of high blood pressure, to reduce hypertensive blood pressure levels or to reduce the doses of antihypertensive drugs. With mild hypertension being the main problem of high blood pressure management, further research is necessary to place dietary intervention in the non-pharmacological treatment of hypertension on a firmer, more rational footing.
[Salt or no salt? Contradictory theses on the role of cooking salt in the origin and prolongation of hypertension].
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The efficacy of quantitative and qualitative chloride titrators in the estimation of human salt intake.
We evaluated the utility of chloride titrator sticks for facilitating the assessment of dietary salt intake, in a systematic series of clinical trials. These inexpensive devices were applied daily to 24-h or nocturnal urine specimens, thereby avoiding the inter- and intra-subject variability in salt excretion which confounds the use of occasional 24-h urine collections. Chloride and sodium concentrations in urine were highly correlated (r greater than 0.92) in either nocturnal, diurnal, or 24-h collections. The quantitative chloride titrator estimates and measured chloride concentrations were highly correlated as well (r greater than 0.99). The qualitative chloride titrator was graded on a simple scale, and was successfully employed by outpatients attempting to limit their salt intake. Commonly used antihypertensive medications did not interfere with the determinations. Additional chloride intake, such as supplemental potassium chloride, interfered with estimates of salt ingestion, but if the daily amount of potassium chloride supplement was constant, adjustments in interpretation could be made. Renal insufficiency introduced a systematic over-estimation of salt intake by the qualitative chloride tirator, but only at high salt intakes. Relative estimates of salt intake in subjects with renal failure were still possible. We conclude that chloride titrators can facilitate the management of patients who require a prescribed salt intake.
Effect of protein intake on renal function and structure in partially nephrectomized rats.
To examine the effect of high protein intake on renal function and structure in rats with 5/6 nephrectomy chronic renal failure, we pairfed rats with chronic renal failure and sham-operated control rats diets of 14 or 37% protein content for up to 6 months. High protein intake accelerated mortality in rats with chronic renal failure and resulted in a more rapid rate of decrease in renal function as established by plotting the reciprocal of plasma creatinine versus time. High protein intake also increased urine protein excretion in experimental and control rats. High protein intake was associated with increased tubular dilatation and interstitial inflammation, both of which were striking features in rats with chronic renal failure. Glomerular sclerosis was prominent in rats with chronic renal failure. These rats had smaller glomerular tuft dimensions than control rats irrespective of their protein intake. We conclude that high protein intake accelerates the course of chronic renal failure in rats. The pathologic process involves glomerular sclerosis; however, interstitial inflammation and renal tubular changes leading to cyst formation also appear to influence the process adversely.
The effect of chloride-containing potassium supplements on chloride titrator estimates of dietary sodium intake.
To examine the effect of chloride-containing potassium supplements on chloride titrator estimates of dietary sodium intake, we gave normal subjects diet containing 10, 100, or 200 mEq/d sodium in random order either as such, or supplemented with one of two potassium supplements. One regimen consisted of potassium 45 mEq/d with 12 mEq/d chloride and 33 mEq/d of citrate and gluconate; the other contained 48 mEq/d potassium and 48mEq/d chloride. Increased potassium intake with either supplemented regimen resulted in increased 24-hour potassium excretion, which was manifested in only the diurnal collections. Increased chloride intake resulted in increased urinary chloride excretion both during the day and at night. At all chloride intakes, urinary sodium and chloride excretion were highly correlated. The 48 mEq/d chloride intake generated a relationship with the same slope but with a different intercept from the other two regimens. The highest chloride intake resulted in a greater chloride titrator reading; however, the relationship was sufficiently predictable that adjustments in interpretation could be easily made. We conclude that if daily potassium chloride intake is known, chloride titrators continue to be reliable tools for estimating dietary sodium intake.
Time course of glomerular endothelial injury related to pulsatile perfusion preservation.
To elucidate the time course of glomerular and arterial endothelial injury resulting from pulsatile perfusion preservation of human kidneys, we examined two kidneys, one at 16 and the other at 42 hr, for which no suitable recipient could be found. The scanning electron microscope revealed subtle changes at 16 hr in the filtration barrier. These included mild endothelial swelling with an increase in the appearance of bulbous processes, and elongated fenestrae. The visceral epithelial surface was normal as was the arterial endothelial surface. By 42 hr the glomerular endothelial surface displayed very prominent cytoplasmic ridges and clearly distorted fenestrae. The arterial endothelium exhibited a tendency to separate from the vessel wall. The proximal tubular epithelium revealed scattered loss of microvilli. These changes are similar in kind to, albeit less severe than, those described after 60 hr of perfusion. They may represent cell swelling following ischemia, or be the result of altered cell permeability engendered by low temperature. The possibility remains that such changes could be minimized by modifying the perfusate. Scanning electron microscopy provides a versatile tool in the study of vascular and other surfaces of tissues stored with perfusion preservation.
Relationship between rat renal accumulation of gentamicin, tobramycin, and netilmicin and their nephrotoxicities.
Gentamicin, tobramycin, and netilmicin were given to rats in daily doses of either 5 or 20 mg/kg for 30 days to determine the renal accumulation kinetics of the compounds and to correlate steady-state renal parenchymal concentrations with nephrotoxicity. Four rats from each group were sacrificed daily and renal parenchymal tissue concentrations were determined microbiologically. Nephrotoxicity was assessed by changes in creatinine values in serum, renal creatinine clearances, and pathological scores. There was no indication of aminoglycoside-induced nephrotoxicity in any tests performed. The following steady-state levels resulted: 36, 148, and 176 micrograms/g after 5 mg/kg per day and 148, 260, and 510 micrograms/g after 20 mg/kg per day for tobramycin, gentamicin, and netilmicin, respectively. We conclude that aminoglycoside parenchymal accumulation in rats follows this order: tobramycin less than gentamicin less than netilmicin. Therefore, differences in the relative toxicities of gentamicin, tobramycin, and netilmicin do not correlate with the renal parenchymal accumulation of these agents and may be more dependent on intrinsic toxicity to the renal proximal tubule than to the concentration of the aminoglycoside in the kidney.
Cardiopulmonary effects of volume expansion in man: radiographic manifestations.
Cardiovascular and humoral responses to extremes of sodium intake (10-1500 mEq/day) were studied. Chest radiographs of eight normal men were obtained to measure changes in heart volume and central vascular structures. Echocardiographic measurements of cardiac chamber dimensions were also obtained. Sodium loading resulted in a 16-mm-Hg increase in mean arterial pressure and increases in cardiac output, stroke volume, left ventricular end-diastolic volume, and all radiographically determined cardiac dimensions. There was direct correlation between the radiographic cardiac dimensions and left ventricular end-diastolic volume. There was no echocardiographic evidence of pericardial fluid. After sodium loading, there was enlargement of the superior vena cava, innominate veins, azygos vein, pulmonary vessels, and the aortic knob. Small pleural effusions were commonly seen. Volume expansion may cause radiographic changes that may mimic those associated with congestive heart failure. This may particularly be the case in patients with renal failure, those receiving dialysis treatment, or patients receiving large volumes of intravenous fluids.
Acute renal failure: contemporary management.
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Dietary sodium restriction in the treatment of mild hypertension.
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The effect of alloxan, and alloxan-induced diabetes on the kidney.
Alloxan is known to induce diabetic renal changes as well as causing nephrotoxic alterations. However, no ultrastructural study has been performed to differentiate diabetic verses toxic affects of alloxan to the tubule and/or glomerulus. Therefore the present study used the "protected" kidney model to prevent one kidney from being exposed to the alloxan while allowing the other to receive the drug immediately. In all experimental animals the right renal hilum was gently occluded for 5 minutes and then released. This was performed prior to the injection of alloxan. Subsequently, the left renal hilum was occluded at the time of, and for 5 minutes after, alloxan administration (40 mg/kg i.v.). The experimental rats were divided into three groups: untreated diabetics, diabetics treated with protamine-zinc-insulin, and alloxan-treated rats that failed to become diabetic. Three groups of controls were included: one group received an equal volume of saline diluent as the experimental rats but no clamping of either renal hilum; another group received the saline and had the left renal hilum occluded for 5 minutes; and a third group had both the right and left renal hila occluded. All animals were followed and sacrificed after 9 weeks. Endogenous creatinine clearance did not change among groups. Alloxan-treated nondiabetic rats displayed marked interstitial nephritis in unprotected kidneys, while protected kidneys were normal. The diabetic state resulted in mesangial proliferation and focal glomerular basement membrane thickening as well as glomerular capillary endothelial abnormalities and visceral epithelial foot-process fusion. The endothelial changes consisted of focal areas showing a reduction in the size of endothelial fenestrae. All glomerular changes were ameliorated by insulin treatment. We conclude: 1) alloxan per se is distinctly nephrotoxic; and 2) the glomerular endothelium and epithelium are involved early in the course of experimental diabetes.
Clinical significance of renal changes engendered by aminoglycosides in man.
Aminoglycoside antibiotics are associated with decreasing renal function of sufficient magnitude to influence adversely the management of approximately 10% of cases. Onset usually occurs after one week's treatment, but may be delayed until after the drugs are discontinued. Renal insufficiency is generally transient, mild, non-oliguric, and is characterized by recovery. There is currently no clear evidence that aminoglycosides cause permanent or subsequent progressive renal damage. Although age, pre-existing renal dysfunction, volume depletion, prior exposure to other nephrotoxic drugs and total drug dose have been suggested as host variables on the basis of animal studies, human studies have not shown predictive factors of toxicity. Peak and valley serum concentrations are more likely to reflect renal function than to predict toxicity. Studies in man are dogged by confounding variables characteristic of the critically ill. Comparative trials of toxicity have required the enrolment of large numbers of patients to show statistical differences which may have little clinical significance. Thus the choice of aminoglycoside should not be governed by nephrological criteria.
Genetic, familial and racial influences on blood pressure control systems in man.
This paper reviews investigations by the Indiana University Medical Centre Hypertension Research Centre into genetic influences on blood pressure control systems in man. Our studies have used the families of adult identical twins to partition the relationships of age, sex and body size to the genetic contribution to blood pressure variability. These studies provide little evidence for environmental influence on the familial aggregation of blood pressure and suggest that at least 63% of the variability is due to genetic factors. Studies on the renin-angiotensin-aldosterone system and on the kidney's ability to excrete sodium were also undertaken in identical and fraternal twins, as well as in black and white subjects, and provided unequivocal evidence of genetic control. Studies in first degree relatives of patients with essential hypertension have demonstrated higher plasma renin levels and a decreased ability to excrete a sodium load when compared to first degree relatives of normotensive subjects. Blacks in the U.S.A. have a decreased ability to excrete a sodium load and a greater rise in blood pressure with sodium loading than do whites. We suggest that the heritability of blood pressure is directly related to a genetic influence on the level of renin and that this increase in renin level results in subtle increases in angiotensin II. These chronic elevations of angiotensin II directly increase blood pressure and decrease the kidney's ability to excrete sodium by either a direct renal effect or indirectly by stimulating aldosterone-dependent sodium retention.
Ceftazidime nephrotoxicity in rats.
The nephrotoxicity of ceftazidime compared with that of cefazolin or cephaloridine and the capacity of ceftazidime to enhance the nephrotoxicity of tobramycin were evaluated in rats. Only cephaloridine and tobramycin given alone altered creatinine clearance or caused significant histological injury. Our data suggest that ceftazidime is no more nephrotoxic than cefazolin and does not enhance the nephrotoxicity of tobramycin.
Renal afferent and efferent arterioles of the rabbit.
The present study employed our microdissection-digestion technique to determine the three dimensional organization of the walls of the afferent and efferent arterioles of the adult rabbit kidney. Each smooth muscle cell of an afferent arteriole is characterized by a somal enlargement and two lateral processes. The cells of the distal segment of the afferent arterioles are modified into myoepithelioid cells, which are closely apposed to one another. The cells of the proximal efferent arteriole are irregularly shaped and regions of adjacent cells may be separated from one another so that gaps exist and areas of the underlying endothelium are not covered by smooth muscle cells. The cells of the distal segments of efferent arterioles are multipolar pericytes, of which the processes branch. Thus the afferent arteriole possesses a complete muscular wall while only the proximal efferent possesses smooth muscle cells with a sphincteric orientation. The distal efferent arteriole possesses pericytes that appear to have a limited capability to modulate renal hemodynamics.
The effect of streptozotocin and streptozotocin-induced diabetes on the kidney.
The study of diabetic nephropathy in experimental animals generally relies on the chemical induction of the diabetic state. Streptozotocin is commonly employed to that end; however, streptozotocin has an inherent nephrotoxic potential. We studied the effects of both streptozotocin, and diabetes on the kidneys of rats given streptozotocin 60 mg/kg, which was sufficient to induce severe diabetes. Our studies, which utilized both transmission and scanning electron microscopy, considered the pharmacokinetics of streptozotocin in renal tissue, as well as the effect of insulin treatment. Renal tissue kinetics were altered by occluding the renal hilum of one kidney during, and for 5 min after, the administration of streptozotocin. We found that, in contrast to alloxan, streptozotocin caused no detectable renal injury at the dose employed. Previously described renal epithelial papillomas were identified, and were not influenced by altering the renal tissue kinetics of the drug. We conclude that no 'protection' procedure is necessary for the kidney when the streptozotocin model of diabetes is employed. In this regard streptozotocin may have greater utility than alloxan.