Copper metabolism in uremia: effect of dialysis and zinc supplementation.
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Adult↗
Biomedical subjects
F D McDonald
Publications and source records attributed to F D McDonald.
Effect of renal transplantation on zinc metabolism and taste acuity in uremia. A prospective study.
The effect of successful renal transplantation on zinc metabolism and taste acuity was determined prospectively in 15 adult uremic patients. Before transplantation all patients had subnormal concentrations of zinc in plasma and hair, as well as abnormal taste detection and recognition thresholds for sodium (salty), sucrose (sweet), hydrochloric acid (sour), and urea (bitter). Following renal transplantation, abnormalities of taste acuity and zinc metabolism persisted and were accompanied by increased urinary zinc excretion in all patients. Normalization of zinc concentration in plasma and hair as well as taste acuity did not occur until one year after transplantation and was associated with a concomitant decrease in urinary zinc excretion. The plasma zinc levels and daily urinary zinc excretion were inversely related (r = 0.62, P less than .001) in all patients with normal allograft function. None of the zinc parameters was significantly related to azathioprine or corticosteroid dosage. The results of this study suggest that zinc deficiency and taste abnormalities of uremia persist up to one year posttransplant and may be related to increased urinary zinc losses. The mechanisms underlying post-transplant hyperzincuria as well as clinical significance of zinc deficiency following transplantation remain to be determined.
Adult↗
Mechanism of effect of dibutyryl cyclic adenosine 3',5'-monophosphate on canine renal renin release.
We evaluated the effect of intrarenal arterial infusion of dibutyryl cyclic AMP on renal renin release. Dibutyryl cyclic AMP (300 micrograms/kg X min) produced significant and reversible increases in renin secretion rate, renal blood flow and urinary Na+ excretion. In the non-filtering kidneys, dibutyryl cyclic AMP increased renin secretion rate and renal blood flow. In indomethacin-treated dogs, dibutyryl cyclic AMP also produced significant and reversible increases in renin secretion rate and renal blood flow but had no effect on Na+ excretion. During infusion of dibutyryl cyclic AMP, infusion of the Ca ionophore A23187 failed to inhibit renin release. These findings suggest that the effect of dibutyryl cyclic AMP on renin release is not mediated by prostaglandins or intracellular Ca and does not involve the macula densa. We conclude that dibutyryl cyclic AMP has a direct effect on the juxtaglomerular cells.
Animals↗
Mechanism of effect of diphenylhydantoin on renal renin release.
This study was undertaken to delineate the mechanism of the effect of diphenylhydantoin (DPH) on renal renin release. DPH at a dose of 0.18 mg X kg-1 X min-1 was infused for 30 min into the renal artery of anesthetized dogs with acute unilateral renal denervation. In the innervated kidney, DPH infusion increased renin secretion rate (RSR) from 189 +/- 54 to 939 +/- 279 ng ANG I X h-1 X min-1. In the contralateral denervated kidneys, RSR did not change. An identical study was done in a second group of dogs in which unilateral renal denervation was done 24 h prior to DPH infusion. In this group, DPH infusion increased RSR from 63 +/- 57 to 643 +/- 180 ng ANG I X h-1 X min-1 in the innervated kidneys. In the contralateral denervated kidneys, RSR did not change. In a separate group of indomethacin-treated nondenervated dogs, intrarenal infusion of DPH increased RSR from 131 +/- 32 to 452 +/- 88 ng ANG I X h-1 X min-1. The percent increase in RSR in the indomethacin-treated dogs was not significantly different from the non-indomethacin-treated dogs. These data suggest that the stimulatory effect of DPH on renin release is mediated by or requires the presence of renal nerves. The step(s) after the renal nerves is (are) not mediated by prostaglandins.
Animals↗
Hypoxemia during hemodialysis using acetate versus bicarbonate dialysate.
To evaluate the extent and cause(s) of dialysis-related hypoxemia, we studied 10 patients, 7 days apart using acetate (AC) and bicarbonate dialysate (HCO3). We measured arterial blood gases, WBC, minute ventilation (VE) and inspired and expired gas concentrations and calculated the respiratory quotient (R) and the alveolar-arterial oxygen difference (A-a)DO2 before and during hemodialysis. 8 patients developed hypoxemia. Arterial PO2 (PaO2) dropped similarly at 30 min from 93 +/- 5 to 78 +/- 6 (p less than 0.05) and 89 +/- 4 to 79 +/- 5 mm Hg (p less than 0.05) with AC and HCO3, respectively. R and VE decreased during AC (p less than 0.05). (A-a)DO2 increased at 30 min and correlated with the drop in PaO2 during both AC (r = 0.68, p less than 0.025) and HCO3 (r = 0.76, p less than 0.025). The fall in PaO2 also correlated with the fall in WBC count for both AC and HCO3 (r = 0.63, p less than 0.005). The increase in arterial pH during HCO3 (up to 7.45 +/- 0.01) was significantly greater than that during AC (up to 7.42 +/- 0.01) (p less than 0.025), and coincided with a relative decrease in VE. We conclude that (1) HCO3 does not prevent hypoxemia, and (2) hypoventilation V/Q abnormalities and increase in arterial pH, contribute variably to dialysis related hypoxemia depending on the type of dialysate and the time during dialysis.
Acetates↗
Sexual dysfunction in uremic male: improvement following oral zinc supplementation.
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Dose-Response Relationship, Drug↗
Action and mechanism of action of veratrine on renin secretion from rat kidney slices.
It is well known that norepinephrine released from the renal nerves stimulates the secretion of renin by a beta adrenergic mechanism. In the present experiments, we investigated the effects of renin secretion of veratrine, which depolarizes nerve terminals and thereby causes transmitter release. The rat renal cortical slice preparation was used. Veratrine (10-200 microM) stimulated renin secretion in a concentration-dependent manner. Veratrine-stimulated secretion was antagonized by timolol (0.9 and 9.0 microM) and by tetrodotoxin (0.5 and 5.0 microM), a sodium channel blocker. Neither drug abolished completely the stimulatory effect of veratrine. Moreover, veratrine stimulated renin secretion in slices prepared from previously denervated kidneys; this response was not antagonized by timolol. These results are consistent with the hypothesis that veratrine stimulates renin secretion by at least two mechanisms. One component probably consists of veratrine-induced depolarization of renal nerve terminals, release of norepinephrine and activation of juxtaglomerular cell beta adrenergic receptors; the other component appears to be independent of nerve terminals in the preparation. We conclude that the tetrodotoxin-sensitive component of veratrine-stimulated renin secretion in this preparation is an in vitro model of renal nerve-stimulated renin secretion; it should be useful in investigating substances which affect renin secretion by presynaptic modulation of transmitter release.
Animals↗
Comparison of the effects of rubidium and potassium on renin secretion from rat kidney slices.
It has been shown previously that both low (less than 2 mM) and high (greater than 45 mM) concentrations of extracellular K inhibit the renin secretory rate of rat kidney slices, and that nonidentical Ca-dependent mechanisms appear to be involved. As Rb can substitute for K in many biological systems, the present experiments were designed to compare the effects of K and Rb on renin secretion of rat kidney slices. Adding either KCl or RbCl to a nominally K-free incubation medium stimulated renin secretory rate in concentration-dependent manners; secretory rate was half-maximally stimulated at approximately 1.5 mM and maximally stimulated at approximately 2-3 mM concentrations of either KCl or RbCl. Ouabain completely abolished the basal secretory rate, in either KCl- or RbCl-containing media. These results suggest that the effects of increasing KCl or RbCl in the range of 0.5-4 mM are attributable to stimulatory effects of Rb and K on Na-K-ATPase activity. Renin secretory rate was greatly inhibited by incubating kidney slices in media containing 60 mM concentrations of either KCl or RbCl. A concentration of methoxy-verapamil which completely blocked the inhibitory effects of 60 mM KCl or of 60 mM RbCl failed to antagonize the inhibitory effects of a nominally K-free medium or of media containing ouabain and either 4 mM KCl or 4 mM RbCl. Taken together with previous results, these observations suggest that Rb can substitute for K in the renin secretory process. Furthermore, they support the hypothesis that inhibitors of Na-K-ATPase, and depolarization inhibit renin secretion by Ca-dependent mechanisms which are not identical.
Animals↗
Evidence that beta 1-adrenoceptor activation mediates isoproterenol-stimulated renin secretion in the rat.
The goal of these experiments was to determine if isoproterenol-stimulated renin secretion in the rat is mediated by activation of beta 1- and/or beta 2-adrenoceptors. The rat renal cortical slice preparation was used. The renin secretory rate was a sigmoid function of the logarithm of the isoproterenol concentration; half-maximal and maximal stimulation occurred at approximately 0.01 and 0.1 microM isoproterenol, respectively. Neither timolol (a nonselective beta-antagonist) nor atenolol (a beta 1-selective antagonist) had a significant effect on basal secretory rate, but both shifted the isoproterenol dose-response curve to the right without changing its slope, suggesting competitive antagonism. Timolol was the more potent, but the response to a maximally effective concentration of isoproterenol could be blocked by timolol (0.9 microM), atenolol (110 microM), or a combination of the two (0.45 microM timolol plus 55 microM atenolol). This latter finding is consistent with action of the two antagonists at one and the same site. If it is assumed that timolol antagonizes both beta 1- and beta 2-adrenoceptors and that atenolol antagonizes only beta 1-adrenoceptors, it follows that isoproterenol-stimulated renin secretion in this preparation is mediated by activation of beta 1-adrenoceptors.
Animals↗
Zinc metabolism and taste acuity in renal transplant recipients.
To determine the effect of renal transplantation on taste acuity and zinc metabolism, we tested 43 patients with functioning allografts for 2.5 to 96 months. They were tested for taste by the 3-drop stimulus technique. In 30 of them, we determined zinc levels in plasma, hair, and urine. Subnormal plasma and hair zinc, as well as hyperzincuria, was present in all of the 15 patients less than 12 months posttransplant. In contrast, 10 patients who were more than 12 months posttransplant had plasma zinc levels, hair zinc, and urinary zinc excretions in the normal range. Zinc concentrations in plasma and hair of 5 patients who were more than 12 months posttransplant with renal failure, were subnormal and were similar to those in hemodialysis patients. Similarly, taste detection and recognition thresholds for sodium chloride, sucrose, urea, and hydrochloric acid were normal only in patients more than 12 months posttransplant with normal renal function. Plasma zinc, hair zinc, and urinary zinc were not related to prednisone or azathioprine dosage. These results suggest that abnormalities of zinc and taste persist up to 12 months posttransplant and may be related to increased urinary zinc losses.
Adult↗
Leukocyte metabolism and function in uremia.
Leukocyte metabolism was studied in 13 non-diabetic hemodialysis patients, 8 clinically stable, nondiabetic transplant recipients, and 13 control subjects. Metabolic parameters included rates of oxygen consumption (nmoles/min/10(6) cells), glucose uptake, lactate production (nmoles/hr/10(6) cells), and 14C-l-glucose oxidation to 14CO2 (nmoles/hr/10(6) cells). Granulocyte metabolism was stimulated by phagocytosis of opsonized zymosan (Z) and by the membrane perturbing agent phorbol myristate acetate (PMA). Granulocyte motility in response to zymosan-activated plasma (ZAP) was also studied. Granulocytes from hemodialysis patients showed significantly impaired stimulated oxygen consumption (Z = 2.41 +/- 0.30 vs. 3.73 +/- 0.39; PMA = 2.63 +/- 0.33 vs. 3.67 +/- 0.19), resting glucose uptake (17.7 +/- 2.9 vs. 36.5 +/- 3.5), stimulated glucose uptake (Z = 44.2 +/- 7.1 vs. 71.8 +/- 5.3; PMA = 63.7 +/- 5.5 vs. 92.8 +/- 5.6), stimulated lactate production (Z = 68.4 +/- 5.1 vs. 97.5 +/- 9.3; PMA = 70.7 +/- 4.9 vs. 92.7 +/- 5.4), and ZAP-stimulated granulocyte motility (16 +/- 3 vs. 30 +/- 4 mu). Metabolic responses of granulocytes from transplant recipients were frequently intermediate between those of hemodialysis patients and controls, but not significantly different from controls. Abnormalities of glucose and oxygen metabolism in granulocytes from uremic patients may cause or contribute to granulocyte dysfunction and vulnerability to infection in such patients.
Adult↗
Glucose tolerance, insulin release, and insulin binding to monocytes in kidney transplant recipients.
In order to evaluate glucose tolerance following renal transplantation, intravenous glucose tolerance tests (IVGTT), with evaluation of hormonal responses to the intravenous glucose load and percent specific 125I-insulin binding to peripheral blood monocytes, were studied in eight clinically stable kidney transplant recipients. For comparison purposes, identical studies were done in eight control subjects and seven clinically stable hemodialysis patients. One transplant recipient was glucose intolerant, with fasting hyperglycemia, elevated HbA1C, and abnormal glucose decay constant. Impaired pancreatic insulin release appeared to be the major factor accounting for his glucose intolerance. The seven glucose-tolerant transplant recipients had significantly increased insulin release during IVGTT compared to control subjects, and significant correlations were found among insulin release, glucose decay constant, and fasting blood sugar in those patients. Insulin binding to monocytes was significantly greater in transplant recipients than control subjects due to an increase in insulin binding capacity per cell. A significant correlation was found between percent specific 125I-insulin binding and steroid dose, expressed as mg/kg body weight/day, in those patients. Thus, chronic steroid administration does not cause glucose intolerance in transplant recipients who manifest steroid-associated increases in pancreatic insulin release and cellular insulin binding capacity.
Adolescent↗
Lymphocyte and granulocyte function in zinc-treated and zinc-deficient hemodialysis patients.
Lymphocyte blast transformation and granulocyte motility were studied in 20 clinically stable hemodialysis patients, 10 of whom were receiving 50 mg of zinc (as zinc acetate) per day and 10 of whom were not. Plasma zinc concentration was significantly higher in zinc-treated than in untreated patients (108 +/- 5 vs. 82 +/- 2 micrograms/dl). Mononuclear cell subpopulation analysis showed equivalent proportions of T lymphocytes and monocytes in both groups, but B lymphocytes were reduced in untreated patients (10 +/- 0.7 vs 14 +/- 0.5%). Lymphocyte blast transformations in response to nonspecific mitogens, soluble antigen and mixed lymphocyte culture were not significantly different in the two groups, nor was lymphocyte zinc concentration. Zinc-treated patients showed significantly greater granulocyte responsiveness to zymosan-activated serum (21 +/- 1 vs. 14 +/- 2 mean), greater chemokinetic activity (50 +/- 4 vs. 27 +/- 3 mean) and higher granulocyte zinc concentration (114 +/- 6 vs. 47 +/- 2 micrograms/10(6) cells) than untreated patients. Granulocyte zinc correlated significantly with plasma zinc (r = 0.81, P less than 0.001) and with granulocyte motility (r = 0.63, P = 0.001). Moderate zinc deficiency in hemodialysis patients does not result in abnormal lymphocyte blast transformation in vitro, but it does result in granulocyte zinc depletion and impaired granulocyte motility.
Acetates↗
Zinc deficiency: a reversible complication of uremia.
Subnormal plasma zinc levels and decreased zinc concentration in hair and leucocytes as well as increased plasma ammonia and ribonuclease activity in dialyzed and nondialyzed uremic patients indicate that zinc metabolism is abnormal in uremia and is not corrected by dialysis. The effect of oral supplementation with zinc acetate (12 patients) or placebo (12 patients) on the above biochemical parameters in hemodialysis patients was determined as a part of a double-blind study. The zinc-supplemented, but not the placebo, group demonstrated significant increases in mean (+/- SD), plasma zinc (80 +/- 9 to 110 +/- 14, micrograms/dl), leucocyte zinc (56 +/- 13 to 1098 +/- 18, micrograms/10(10) cells), hair zinc (140 +/- 12 to 190 +/- 16 micrograms/g), and decreases in plasma ammonia (76 +/- 10 to 40 +/- 6 micrograms/dl) and plasma ribonuclease activity (1.49 +/- 0.08 to 0.78 +/- 0.10, OD/min/ml). Abnormalities of taste and sexual function improved significantly in patients receiving zinc but not in those on placebo therapy. These improvements in biochemical as well as clinical parameters confirm and extend our earlier observations of improvement in taste and sexual function after zinc supplementation. Together, they suggest that zinc deficiency is a complicating feature of uremia and can be corrected by oral zinc supplementation.
Acetates↗
Effect of imidazole on the recovery from bilateral ureteral obstruction in dogs.
The effects of indomethacin (INDO) and imidazole (IMID) on postobstructed kidney functions were evaluated in dogs after 24 h of bilateral ureteral obstruction (BUO). In vehicle-treated dogs 1 h after release of BUO, clearances of inulin and PAH (Cin and Cpah) were 37 and 26%, respectively, of the preobstruction values. Fractional sodium excretion (FEna) increased from 0.5 +/- 0.1 to 2.9 +/- 0.6. Urine osmolality (Uosmol) increased by 55 +/- 9 mosmol/kg H2O in response to 50 mU of aqueous vasopressin. In INDO-treated dogs, Cin and Cpah were 39 and 21%, respectively, of the preobstruction values. FEna increased from 0.7 +/- 0.2 to 4.0 +/- 0.9. Uosmol increased by 91 +/- 19 mosmol/kg H2O in response to vasopressin. This lack of beneficial effects of INDO may reflect its cancelling effect on prostaglandins' and thromboxanes' (TX) effects on the renal hemodynamics of the postobstructed kidney. To further assess the roles of TX in the postobstructed kidney, IMID, and inhibitor of TX synthesis, was given before the release of obstruction. In this group of dogs, the Cin of the postobstructed kidney did not differ from the preobstruction value. CC pah was 45% of the preobstruction value, a level significantly higher than in either vehicle- or INDO-treated dogs. FEna wa 1.5 +/- 0.2 before and 3.5 +/- 2.3 after obstruction. Uosmol increased by 187 +/- 51 mosmol/kg H2O after vasopressin, a level significantly higher than in vehicle-treated dogs. The present study suggests that IMID improves Cin, Cpah, FEna, and concentrating ability of the postobstructed kidney. TX may be responsible for the persistent reductions of Cin and Cpah in the postobstructed kidney.
Animals↗
Effect of oral zinc therapy on gonadal function in hemodialysis patients. A double-blind study.
Zinc deficiency may account for the persistence of gonadal dysfunction in a majority of uremic men despite adequate dialysis. Twenty stable patients having hemodialysis three times a week completed a double-blind trial using either 50 mg of elemental zinc as zinc acetate (10 patients) or placebo (10 patients), orally. At the end of the 6-month study period, a significant increase in the mean (+/- SE) plasma zinc (75 +/- 2 micrograms/dL to 100 +/- 2 micrograms/dL, p less than 0.001), serum testosterone (2.8 +/- 0.3 ng/dL to 5.2 +/- 0.5 ng/mL, p less than 0.001), and sperm count (30 +/- 3 million/mL to 63 +/- 5 million/mL, p less than 0.001) occurred in the zinc-treated group, but not in those receiving the placebo. The zinc-treated group also had a significant fall in serum luteinizing hormone (92 +2- 10 mIU/mL to 49 +/- 26 mIU/mL, p less than 0.005) and follicle stimulating hormone (45 +/- 9 mIU/mL to 25 +/- 7 mIU/mL, p less than 0.05), not seen in the placebo group. Patients receiving zinc had an improvement in potency, libido, and frequency of intercourse not found in the placebo group. These results suggest that zinc deficiency is a reversible cause of gonadal dysfunction in patients having regular hemodialysis.
Adult↗
Effect of diltiazem, a calcium antagonist, on renin secretion from rat kidney slices.
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Angiotensin II↗
Lymphatic complications in renal allografts--a new look.
The pathophysiology of lymphatic complications was evaluated in 10 patients as to the possible source of lymphatic fluid. Both the recipient's peripheral lymphatics and the allograft's lymphatics were found to contribute to lymphatic complications. The prevention of lymphoceles and lymphatic fistulas may be accomplished by careful ligation of both the recipient's and the allograft's lymphatics.
Fistula↗