The osmolal gap in renal failure.
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Acute Kidney Injury↗
Biomedical subjects
S L Linas
Publications and source records attributed to S L Linas.
Mechanism of the decreased renal blood flow in the potassium-depleted conscious rat.
Although chronic potassium deficiency is a common clinical problem, the hemodynamic consequences of chronic sustained potassium depletion have not been clearly delineated. In this study, the hemodynamic consequences of chronic potassium depletion were evaluated in the conscious rat. Potassium-depleted rats had a decrease in mean arterial pressure which was caused by a decrease in systemic vascular resistance. In association with these changes in systemic hemodynamics, renal blood flow (RBF) was also decreased. The decreased renal blood flow was caused by an increased renal vascular resistance (RVR). Because plasma renin activity was increased the role of angiotensin II as a renal vasoconstrictor was evaluated by utilizing two angiotensin antagonists. Although the administration of saralasin to potassium-depleted rats did not alter systemic hemodynamics, RVR was decreased and RBF was increased. Similar results were obtained with the converting enzyme inhibitor teprotide. Because products of endoperoxide metabolism may cause renal vasoconstriction, the role of prostaglandins and thromboxanes as renal vasoconstrictors were evaluated by utilizing cyclo-oxygenase and thromboxane synthetase inhibitors. None of these agents altered systemic hemodynamics. Following the administration of indomethacin, RVR was decreased and RBF was increased in potassium-depleted rats. Similar results were obtained with another cyclo-oxygenase inhibitor, meclofenamate, and with imidazole, an inhibitor of thromboxane synthetase. Because neither angiotensin II nor products of endoperoxide metabolism could alone account for the increased renal vascular resistance of potassium depletion, studies were performed in potassium-depleted rats treated with indomethacin plus either saralasin or teprotide. In these potassium-depleted animals, renal blood flow was restored to normal. In conclusion, the decrease in renal blood flow and the increase in renal vascular resistance in potassium depletion is mediated by angiotensin II and a product of prostaglandin endoperoxide metabolism, most likely, thromboxane.
Angiotensin II↗
Role of vasopressin in impaired water excretion in conscious rats with experimental cirrhosis.
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Animals↗
Mechanism of hyperreninemia in the potassium-depleted rat.
Although dietary potassium deficiency (KD) results in an increase in plasma renin activity (PRA), the mechanism of this effect has not been elucidated. In the present study, isolated kidneys from normal rats or from rats made KD by diet were perfused at constant pressure (120 mm Hg) with a Krebs-Ringer-Bicarbonate medium containing albumin. KD led to an increase in PRA (3.6 vs. 1.1 ng angiotensin I ml per h, P less than 0.01), which was associated with a decrease in macula densa (MD) fluid delivery as estimated by urine flow (70 vs. 166 microliters/min per g, P less than 0.005), and an increase in renal vascular resistance (RVR) as perfusion flow rate was decreased from 34 to 24 ml/min per g, P less than 0.005. The increase in PRA was independent of the MD because PRA could not be suppressed when macula densa delivery was increased by perfusing KD kidneys with hypooncotic albumin. Moreover, when kidneys were made nonfiltering by perfusing with hyperconcotic albumin, PRA remained increased in KD kidneys (8.1 vs. 3.5 ng angiotensin I ml per h, P less than 0.01) despite the absence of MD delivery. Because the increase in PRA in both filtering and nonfiltering KD kidneys was associated with an increase in RVR, filtering and nonfiltering kidneys were perfused with the vasodilator papaverine. Despite lower tissue K levels in KD kidneys (278 vs. 357 mu eq/g, P less than 0.01), RVR and PRA were normalized in both filtering and nonfiltering KD kidneys perfused with papaverine. In conclusion, PRA is increased in the KD isolated perfused kidney. This increase occurs independently of both the MD and of tissue K levels and is mediated by the renal vascular receptor.
Animals↗
Minoxidil.
Minoxidil is an orally active vasodilator for treatment of severe hypertension. In combination with diuretics and beta-adrenergic blocking agents, it is effective treatment for more than 80% of patients whose blood pressure has been inadequately controlled with combinations of other been inadequately controlled with combinations of other antihypertensive drugs. Major adverse reactions include reflex activation of the adrenergic nervous system, renal sodium retention, and hypertrichosis. Despite the possibility of adverse reactions, minoxidil is indicated in patients whose blood pressure cannot be controlled with conventional therapy, in persons with major adverse reactions to other drugs, and in patients who are candidates for bilateral nephrectomy for control of hypertension.
Adrenergic beta-Antagonists↗
Plasma demeclocycline levels and nephrotoxicity. Correlation in hyponatremic cirrhotic patients.
In five hyponatremic, cirrhotic patients, demeclocycline hydrochloride was used to inhibit the hydroosmotic effect of vasopressin. In four, renal impairment developed during the 7 to 20 days of demeclocycline hydrochloride (900 to 1,200 mg/day) administration. In these four patients, creatinine clearance fell (72 to 20 mL/min, P less than .01) as BUN (12 to 47 mg/dl, P less than .02) and serum creatinine (0.9 to 4.2 mg/dl, P less than .01) levels rose. The azotemic effect of the drug could not be accounted for consistently by volume depletion secondary to its natriuretic effect. However, a close correlation between plasma demeclocycline levels and its azotemic effect was observed. We conclude that a nephrotoxic effect of demeclocycline severly limits its usefulness in treating hyponatremia in the cirrhotic patient.
Adult↗
The effect of anesthesia on hemodynamics and renal function in the rat.
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Animals↗
Role of vasopressin in the impaired water excretion of glucocorticoid deficiency.
The mechanism whereby glucocorticoid deficiency impairs renal water excretion was studied in the conscious mineralocorticoid-replaced, adrenalectomized rat. Control animals received physiologic replacement with prednisolone, and experimental animals were deprived of glucocorticoid hormone for either 1 or 14 days. The control animals excreted 95 +/- 1.9% of an acute water load (30 ml/kg) in 3 hours, a value significantly higher than the volume excreted by animals deprived fo glucocorticoid hormone for 1 day (70.0 +/- 3.6%, P less than 0.01) and 14 days (40.0 +/- 3.9%, P less than 0.01). Following the acute water load, plasma vasopressin levels, as measured by radioimmunoassay, was 1.08 pg/ml in the control rats, a value significantly lower than values obtained after the water load in rats deprived of glucocorticoid hormone for 1 day (2.5 +/- 0.2 pg/ml, P less than 0.01) and 14 days (2.4 +/- 0.3 pg/ml, P less than 0.01). To further examine the effect of plasma vasopressin in the impaired water excretion of glucocorticoid deficiency, we performed studied in Brattleboro rats with central diabetes insipidus. In these animals with absence of vasopressin, a defect in water excretion was observed after 14 days, but no 1 day, of glucocorticoid deficiency. In Sprague-Dawley rats, the impaired water excretion after 14 days of glucocorticoid deficiency was associated with a significantly lower cardiac index (209 +/- 14 vs. 291 +/- 11 ml/min/kg, P less than 0.01) and renal blood flow (3.8 +/- 0.3 vs. 5.7 +/- 0.2 ml/min/g, P less than 0.01) than that observed after 1 day of glucocorticoid deficiency. In diabetes insipidus rats, after 14 days of glucocorticoid deficiency, the percentage of an acute water load excreted (121 +/- 7% vs. 158.7 +/- 7.0%, P less than 0.01) was lower than that observed after 1 day of glucocorticoid deficiency. In summary, the present results indicate that glucocorticoid deficiency impairs renal water excretion by both vasopressin-dependent and vasopressin-independent mechanisms. The vasopressin-dependent renal mechanism is associated with a marked decrease in both systemic and renal hemodynamics.
Adrenalectomy↗
Role of antidiuretic hormone in impaired urinary dilution associated with chronic bile-duct ligation.
1. The effect of chronic bile-duct ligation on systemic and renal haemodynamics and on the capacity to dilute the urine was studied in conscious rats. Sham-operated rats served as controls. 2. In the rats with bile-duct ligation, the maximal urinary diluting capacity was impaired, despite an expanded plasma volume, a normal mean arterial pressure and cardiac output, and normal intrarenal determinants of water excretion including distal delivery of fluid and function of the diluting segment. 3. In contrast, maximal urinary dilution capacity was intact in rats with congenital central diabetes insipidus and chronic bile-duct ligation. 4. It is concluded that the defect in urinary dilution in rats with chronic bile-duct ligation is dependent on antidiuretic hormone.
Animals↗
Renal concentrating defect in the hypokalemic rat is prostaglandin independent.
The renal concentrating defect in the hypokalemic rat is prostaglandin independent. The present study was undertaken to test whether the renal concentrating defect in potassium-depleted rats is at least in part mediated by prostaglandins. Rats on a K-deficient (n = 12) and K-supplemented (n = 12) diet underwent a urinary concentrating test before and after prostaglandin inhibition with indomethacin. The drug did not alter maximal urinary osmolality in normokalemic rats. Likewise, the abnormal maximal urinary osmolality of K-depleted rats was not improved by prostaglandin inhibition (1,533 +/- 124 before and 1,475 +/- 88 mosmol/kg H2O after indomethacin). Control animals receiving a blank diluent instead of indomethacin showed no change in maximal concentrating ability between equally timed dehydration tests. Indomethacin caused no significant alterations in blood urea nitrogen or creatinine. Direct measurements of renal medullary prostaglandings revealed no difference between K-depleted (22.9 +/- 4.4 pg/mg) and normokalemic (23.6 +/- 2.3 pg/mg) rats. Indomethacin significantly and comparably lowered prostaglandin content in both K-depleted and normokalemic rats. These studies, therefore, reveal no enhancement of prostaglandin synthesis with K depletion and demonstrate that the renal concentrating defect of K depletion in the rats is prostaglandin independent.
Animals↗
Mechanism of renal potassium conservation in the rat.
The mechanisms responsible for renal potassium (K) conservation during dietary potassium deficiency are poorly understood. This study was undertaken to investigate the time course of potassium conservation as well as the roles of distal sodium (Na) delivery, the distal delivery or sodium plus a nonpermeable anion, mineralocorticoid hormone, renal tissue potassium content, and Na-K-ATPase activity in renal potassium conservation. After 72 hours of a low-potassium diet, basal potassium excretion was negligible. After 24 hours, and even more so after 72 hours of potassium restriction, the kaliuretic response to increasing distal delivery of sodium or sodium plus a nonpermeable anion was impaired. After 24 hours of a low-potassium diet, plasma aldosterone levels fell from 180 +/- 25 to 32 +/- 9 pg/ml (P less than 0.001). Mineralocorticoid hormone given in the first 24 hours of a low-potassium diet resulted in a greater potassium loss (1564 +/- 125 muEq) than it did in controls on the same diet not receiving mineralocorticoid hormone (1032 +/- 83 muEq, P less than 0.005). In contrast, after 72 hours of diet, large doses of mineralocorticoid hormone failed to cause a kaliuresis in either anesthetized or conscious rats. After both 24 and 72 hours, outer medullary Na-K-ATPase was increased. At 72 hours, cortical, medullary, and papillary tissue potassium concentrations were significantly depressed. Acute administration of potassium repleted tissue potassium levels and restored basal and saline-stimulated potassium excretion to normal. Although potassium excretion was markedly depressed after 24 hours of the low-potassium diet, 42K microinjection studies of the distal nephron did not suggest any increase in potassium reabsorption. Following 72 hours of diet, potassium reabsorption increased significantly from 26 +/- 2% to 41 +/- 2% (P less than 0.001). We conclude that renal potassium conservation is at first primarily related to a decrease in potassium secretion, which is most likely mediated by falling levels of mineralocorticoid hormone. After 72 hours of the potassium-deficient diet, however, potassium conservation becomes independent of mineralocorticoid hormone, distal delivery of sodium, and Na-K-ATPase. The decreased tissue potassium content appears to be the primary mediator of both the increase in potassium reabsorption by the distal nephron and of renal potassium conservation at this time.
Aldosterone↗
Catecholamines and sodium transport in the kidney.
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Animals↗
Role of the renin-angiotensin system in post-transplantation hypertension in patients with multiple kidneys.
To define the role of the renin-angiotensin system in post-transplantation hypertension we studied 12 hypertensive recipients of renal transplants. The patients received saralasin acetate, an angiotensin II antagonist, while on a normal sodium diet and again after seven days of sodium restriction. In six patients with only one kidney, saralasin did not lower blood pressure on either diet; salt depletion did not lower systolic or diastolic blood pressures. In six patients with more than one kidney, salt depletion also did not lower blood pressure; however, salt depletion plus saralasin lowered their systolic pressures from a mean (+/- S.E.M.) of 146 +/- 9 to 128 +/- 8 mm Hg, and mean diastolic pressures fell from 103 +/- 5 to 89 +/- 5 (P less than 0.001). In four of five patients renal-vein renin activity was greater in one or more host kidneys than in the transplant kidney (or kidneys). Although pre-transplant blood pressure was the same in both groups, post-transplantation hypertension is more likely to be angiotensin II-dependent in patients with more than one kidney.
Adolescent↗
Urinary diagnostic indices in acute renal failure: a prospective study.
A prospective analysis of the value of urinary diagnostic indices in ascertaining the cause of acute renal failure was undertaken. Our results show that in the setting of acute oliguria a diagnosis of potentially reversible prerenal azotemia is likely with urine osmolality greater than 500 mosm/kg H2O, urine sodium concentration less than 20 meq/litre, urine/plasma urea nitrogen ratio greater than 8, and urine/plasma creatinine ratio greater than 40. Conversely, a urine osmolality less than 350 mosm/kg, urine sodium concentration greater than 40 meq/liter, urine/plasma urea nitrogen ratio less than 3, and urine/plasma creatinine ratio less than 20 suggest acute tubular necrosis. A significant number of oliguric patients will not have urinary indices that fall within these guidelines. In this setting, urine sodium concentration divided by the urine-to-plasma creatinine ratio (the renal failure index) and the fractional excretion of filtered sodium provide a reliable means of differentiating reversible prerenal azotemia from acute tubular necrosis.
Acute Kidney Injury↗
Nonoliguric acute renal failure.
To delineate the clinical spectrum of nonliguric renal failure, we studied prospectively 90 patients with acute renal failure 54 of whom were nonoliguric throughout their periods of azotemia. Although the causes of nonoliguric renal failure varied, nephrotoxic failure occurred more frequently in nonoliguric than in oliguric subjects (P is less than 0.01). As com pared to oliguric patients, those without oliguria had significantly lower urinary sodium concentrations (P is less than 0.05) and fractional excretions of sodium (P is less than 0.02), had shorter hospital stay (P is less than 0.01), had fewer septic episodes, neurologic abnormalities, gastrointestinal bleeding and acidemia, required dialysis less frequently (P is less than 0.001) and had lower mortality rate (26 per cent in nonoliguric vs. 50 per cent in oliguric patients -- P is less than 0.05). Nonoliguric renal failure occurs more often than is generally recognized and causes less morbidity and mortality than oliguric acute renal failure.
Acute Kidney Injury↗
On the mechanism of polyuria in potassium depletion. The role of polydipsia.
The association of potassium (K) depletion with polyuria and a concentrating defect is established, but the extent to which these defects could be secondary to an effect of low K on water intake has not been systematically investigated. To determine whether hypokalemia has a primary effect to increase thirst and whether any resultant polyuria and polydipsia contribute to the concentrating defect, we studied three groups of rats kept in metabolic cages for 15 days. The groups were set up as follows: group 1, normal diets and ad lib. fluids (n = 12); group 2, K-deficient diet on ad lib. fluids (n = 12); and group 3, K-deficient diet and fluid intake matched to group 1 (n = 14). Daily urine flow and urinary osmolality of groups 1 and 3 were not significantly different throughout the study. In contrast, as of day 6, group 2 rats consistently had a higher fluid intake (P < 0.0025), higher urine flow (P < 0.001), and lower urinary osmolality (P < 0.001) than the other two groups. These alterations in fluid intake and urine flow preceded a defect in maximal concentrating ability. On day 7, maximal urinary osmolality was 2,599+/-138 msmol/kg in rats on K-deficient intake and 2,567+/-142 msmol/kg in controls. To determine whether this primary polydipsia is itself responsible for the development of the concentrating defect, the three groups of rats were dehydrated on day 15. Despite different levels of fluid intake, maximal urinary osmolality was impaired equally in groups 2 and 3 (1,703 and 1,511 msmol/kg, respectively), as compared to rats in group 1 (2,414 msmol/kg), P < 0.001. We therefore conclude that K depletion stimulates thirst, and the resultant increase in water intake is largely responsible for the observed polyuria. After 15 days of a K-deficient diet, the impaired maximal urinary concentration in hypokalemia, however, was not related to increased water intake, since fluid restriction did not abolish the renal concentrating defect.
Animals↗
Hemodynamic effects of alterations in potassium.
Potassium is the major intracellular cation. Despite this fact, the systemic and renal hemodynamic effects of alterations in either serum K or in total body K are only partially understood. In isolated preparations acute K excess causes vasodilation while acute K deficiency results in vasoconstriction. Although chronic K excess may decrease arterial pressure in experimental models of hypertension, no definitive conclusions can be stated on the effect of K excess in hypertensive patients. In normotensive animals, chronic K depletion is associated with decreased systemic vascular resistance and increased renal vascular resistance. Although a number of studies have shown that K depletion ameliorates experimental hypertension, no definitive conclusions can be stated on the effect of K depletion in hypertensive patients. The vasodilatory effect of K depletion appears to be a direct effect on vascular smooth muscle since it is associated with an increase in total body Na as well as an increase in cardiac output and in renin ane arginine vasopressin levels. Although renin levels are increased in K deficient rats to a value comparable to na-depleted rats, angiotensin antagonism results in a substantially smaller decrease in arterial pressure than in Na-depleted rats (11 +/- 1.6 vs 24 +/- 3.4 mm Hg, p less than 0.01). This relative resistance to the pressor effect of angiotensin also results in a blunted pressor sensitivity to exogenous angiotensin II. Since changes in K balance appear to have a major effect on the control of hemodynamics, further studies are warranted to determine whether alterations in K balance would be useful in the treatment of hypertension.
Animals↗