Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0035078 (renal failure)
 31,970 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The principal physiologic roles of the kidney are to maintain normal plasma volume and composition, to regulate calcium metabolism by controlling the synthesis of 1,25-dihydroxycholycalciferol (1,25-D3), to regulate hematocrit and to metabolize low molecular weight peptides. Alterations in protein metabolism result principally from losses of these functions. Metabolic acidosis causes increased skeletal muscle protein catabolism through regulated activation of the ATP-ubiquitinproteasome proteolytic pathway. Increased proteolysis is followed by oxidation of branch chain essential amino acids. Alanine and glycine released from muscle and glutamine and glutamate released from liver serve as substrate for renal ammoniagenesis, ultimately correcting acidosis. The cycle is subverted when kidneys are absent. Secretion of a variety of proteins is also perturbed. Hepatic secretion of insulin like growth factor-1 (IGF-I) in response to growth hormone is reduced. This in turn contributes to growth retardation, adding to the effects of acidosis. Muscle is also resistant to insulin in renal failure. Renal production of 1,25-D3 is reduced contributing to hyperparathyroidism, which in turn causes increased intracellular calcium in a variety of tissues contributing to decreased synthesis of immunoglobulins, mitogen-stimulated T-cell proliferation, and decreased glucose-stimulated insulin secretion. Hepatic synthesis of some proteins, such as apolipoprotein A-I and IGF-I are decreased, but synthesis of others, such as albumin, is normal. Low molecular weight peptides such as beta 2-microglobulin, normally filtered and catabolized in the proximal tubule, accumulate in plasma and may have deleterious effects.
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PMID:Derangements of protein metabolism in chronic renal failure. 889 32

X-linked phosphoglycerate kinase (PGK) deficiency is a rare disorder which affects the glycolytic pathway and leads to reduced ATP production. Clinically, PGK deficiency is often associated with nonspherocytic hemolytic anemia and symptoms caused by disturbances of the central nervous system. In addition, myopathy characterized by weakness, cramps, intolerance to exercise, and myoglobinuria has been described in a few cases. We here report on a 23-year-old man who presented with episodes of muscular weakness, cramps, rhabdomyolysis, and renal failure induced by intensive physical exercise. Biochemical analysis of muscle specimens disclosed markedly reduced PGK activity (11.5% compared to normal controls). A moderate increase of glycogen was seen in numerous muscle fibers. Mitochondria in muscle fibers and endothelial cells showed accumulations of glycogen. In muscle fibers unusually large matrix granules were present in several mitochondria. A sural nerve biopsy disclosed scattered large hypomyelinated axons without evidence of demyelination and remyelination. These findings indicate involvement of mitochondria in this case of symptomatic PGK deficiency.
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PMID:Mitochondrial changes in muscle phosphoglycerate kinase deficiency. 899 55

Overproduction of NO by an inducible NO synthase (iNOS) plays a major role in the pathophysiology of septic shock, and selective inhibition of iNOS in this setting could be of great therapeutic value. In the present study, we evaluated the effects of L-canavanine, a selective iNOS inhibitor, in an animal model of septic shock, with a particular focus on tissue oxidative metabolism and organ functions. Anesthetized rats challenged intravenously with lipopolysacharide (LPS) were treated after 1 h by a continuous infusion of either L-canavanine (20 mg/kg/h; n = 11) or an equivalent volume of saline (2 ml/kg/h; n = 17) given for 4 h. A third group (sham rats; n = 9) did not receive LPS and was treated with a continuous infusion of saline (2 ml/kg/h). At the end of experiments, biopsies were taken from the liver, the kidney, and the small intestine for the measurement of tissue ATP. LPS induced a progressive fall in blood pressure, accompanied by biologic signs of liver and kidney failure, concomitant with a marked decrease in tissue ATP stores. L-canavanine largely prevented hypotension and significantly increased tissue ATP while reducing the signs of organ dysfunction. These effects were associated with a significant improvement in survival during the 5 h of study. We conclude that L-canavanine not only reduces hypotension in endotoxin shock but also largely prevents the detrimental consequences of LPS on tissue oxidative metabolism and major organ functions, allowing a decrease in endotoxin lethality.
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PMID:L-canavanine improves organ function and tissue adenosine triphosphate levels in rodent endotoxemia. 915 70

The effect of propionyl L-carnitine on skeletal muscle metabolism in chronic renal failure. Carnitine deficiency, resulting in defective oxidative ATP synthesis, has been implicated in the myopathy of chronic renal failure. Using 31P magnetic resonance spectroscopy we examined calf muscle metabolism in 10 dialysed patients before and after 8 weeks of propionyl L-carnitine (PLC) 2 g.p.o. daily. Resting phosphocreatine/ATP (4.41 +/- 0.20 [SEM]) decreased to normal control levels on PLC (3.98 +/- 0.14; controls 4.00 +/- 0.06). In contrast, there was no effect of PLC on aerobic and anaerobic metabolism of muscle during or following 2-10 min exercise. The maximal calculated oxidative capacity (Qmax) remained below normal (28 +/- 3 mM/min before and 24 +/- 3 mM/min after PLC; controls 49 +/- 3 mM/min). Qmax correlated positively with hemoglobin concentration ([Hb]) after PLC (p < 0.03). Oxidative capacity assessed by phosphocreatine recovery T significantly improved with PLC administration (0.93 +/- 0.1 to 0.74 +/- 0.08 min) in those patients (n = 6) with [Hb] > 10 g/dl. [Hb] was rate limiting to oxidative metabolism in recovery from exercise but only following treatment with PLC. Patients with anemia or those subjects who use relatively more non-oxidatively synthesized ATP during exercise, do not respond to PLC. Oxidative metabolism did not normalize on PLC suggesting that anemia and carnitine deficiency are not the only causes of mitochondrial dysfunction in renal failure.
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PMID:The effect of propionyl L-carnitine on skeletal muscle metabolism in renal failure. 920 67

In view of the hypothesis that suppression of energy demand may prevent ischemic cell damage, it seemed possible that suppression of ATP utilization during ischemia might ameliorate the severity of renal failure following kidney preservation. To test this possibility, a short-term in situ kidney preservation model was prepared in dogs. Euro-Collins solution containing 10(-5) M ouabain (O-EC) was used as the preservation solution. The kidney was preserved with cold O-EC for two hours and reperfused with auto blood. As the control, the kidney was treated with Euro-Collins solution (EC) alone. Three hours after reperfusion, recovery of creatinine clearance was 47.4 +/- 8.0% in the control and 71.6 +/- 14.0% in the O-EC group (p < 0.02). The increase in urinary excretion of N-acetyl-beta-D-glucosaminidase was significantly lower in the O-EC group. It was 21.3 +/- 4.5 nU/gr renal weight for three hours after reperfusion in the control group and 7.2 +/- 1.5 nU/gr renal weight in the O-EC group (p < 0.05). Fractional excretion of sodium three hours after reperfusion was 1.42 +/- 0.44% and 5.51 +/- 0.63% in the control and O-EC groups (p < 0.002), respectively. There were no significant differences in renal blood flow, urine volume and urine osmolality between the two groups. These results suggest that ouabain-containing EC was effective in protecting the kidney, especially renal proximal tubular cell, against ischemic damage.
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PMID:[Ouabain-containing Euro-Collins solution prevents ATN following renal cold storage]. 939 37

Metabolic acidosis increases protein degradation resulting in muscle wasting and a negative nitrogen balance. The branched-chain amino acids serve as useful markers of these changes and their catabolism is increased in acidosis, particularly for the spontaneous acidosis associated with renal failure. As a result, the neutral nitrogen balance is compromised and malnutrition results. Glucocorticoids mediate these changes through the recently discovered ATP-dependent ubiquitin-proteasome pathway. Therapy necessitates correction of the underlying acidosis either through adjustment of the alkalinity of the dialysate for the patient on dialysis or through dietary protein restriction and sodium bicarbonate supplements for the predialysis patient.
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PMID:Metabolic acidosis and protein catabolism: mechanisms and clinical implications. 939 12

The activity of the plasma membrane Ca2+ ATPase of chronic renal failure patients is decreased by circulating inhibitors yet to be characterized. In this study, inhibitors of Ca2+ ATPase were isolated from ultrafiltrate of patients with end-stage renal failure. They were identified as dimethylguanosine, phenylethylamine, and phenylacetic acid by chromatography and mass spectrometry. Ca2+ ATPase activity was measured spectrophotometrically as the difference in hydrolysis of ATP in the presence and absence of Ca2+ with different concentrations of ATP and the isolated substances. All of the identified compounds are sufficiently lipophilic to penetrate the blood-brain barrier and to accumulate in cerebral tissue. The inhibitory effects of these agents were additive. The apparent K(m) values for ATP and Ca2+ were not altered by these substances, suggesting a noncompetitive mechanism of inhibition. In plasma of healthy subjects, the substances were not detectable. The Ca2+ ATPase inhibitors identified may play a role in the pathophysiology of end-stage renal failure and, potentially, in monitoring toxic effects on cellular Ca2+ metabolism in renal failure.
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PMID:Characterization of dimethylguanosine, phenylethylamine, and phenylacetic acid as inhibitors of Ca2+ ATPase in end-stage renal failure. 964 35

Low dose dopamine is widely used to improve diuresis and renal function. This practice is defended by some and fought by others. Acute renal failure in the ICU is often due to tubular necrosis and is a predictor of worse prognosis. Dopamine at low doses is a delta agonist and stimulation of these receptors leads to diuresis and natriuresis. This natriuresis requires additional ATP consumption by the kidney. Low dose dopamine has also systemic hemodynamic effects and these effects can't be dissociated from direct renal effects. Clinical studies of systematic dopamine use in selected high risk patients fail to show a benefit, and side effects of catecholamine administration may lead to additional cardiovascular morbidity. We conclude that low dose dopamine has a demonstrated renal effect but its systematic use to prevent or treat a renal failure cannot be warranted.
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PMID:[Renal-protective dose of dopamine: myth or reality?]. 1021 15

Chronic renal failure is associated with increased cardiovascular morbidity and abnormal arterial tone, but the underlying pathophysiological mechanisms are poorly understood. Therefore, we studied the responses of isolated mesenteric arterial rings from Wistar-Kyoto rats in standard organ chambers 6 wk after subtotal (5/6) nephrectomy or sham operation. Subtotal nephrectomy resulted in a 1.7-fold elevation of plasma urea nitrogen, whereas blood pressure was not significantly affected. Endothelium-mediated relaxations of norepinephrine-precontracted rings to ACh were impaired in renal failure rats. The nitric oxide (NO) synthase inhibitor N(G)-nitro-L-arginine methyl ester inhibited relaxations to ACh more effectively in the renal failure group, whereas the cyclooxygenase inhibitor diclofenac did not significantly affect the response in either group. Inhibition of Ca(2+)-activated K(+) channels by charybdotoxin and apamin attenuated NO synthase- and cyclooxygenase-resistant relaxations to ACh in control but not renal failure rats and abolished the difference between these groups. Endothelium-independent relaxations to isoproterenol and cromakalim, vasodilators acting via beta-adrenoceptors and ATP-sensitive K(+) channels, respectively, were impaired in the renal failure group, whereas relaxations to the NO donor nitroprusside were similar in both groups. In conclusion, endothelium-mediated relaxation in renal failure rats was impaired in the absence and presence of NO synthase and cyclooxygenase inhibition but not with prevented smooth muscle hyperpolarization. Endothelium-independent relaxations to isoproterenol and cromakalim were also attenuated after 5/6 nephrectomy. These results suggest that impaired vasodilatation in experimental renal failure could be attributed to reduced relaxation via arterial K(+) channels.
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PMID:Potassium channel-mediated vasorelaxation is impaired in experimental renal failure. 1051 3

In the kidney, endothelins (ETs) are important regulators of blood flow, glomerular hemodynamics, and sodium and water homeostasis. They have been implicated in the pathophysiology of acute ischemic renal failure, nephrotoxicity by cyclosporine, cisplatin and radiocontrast agents, and vascular rejection of kidney transplants. Here, we used intact killifish renal proximal tubules, fluorescent substrates for Mrp2 (fluorescein-methotrexate, FL-MTX) and P-glycoprotein (a fluorescent CSA derivative, NBD-CSA), and confocal microscopy to reveal a new role for renal ET: regulation of ATP-driven drug transport in proximal tubule. Subnanomolar to nanomolar concentrations of ET-1 rapidly reduced the cell-to-tubular lumen transport of both fluorescent compounds. These effects were prevented by an ET(B) receptor antagonist but not by an ET(A) receptor antagonist. Immunostaining with an antibody to mammalian ET(B) receptors showed specific localization to the basolateral membrane of the fish tubular epithelial cells. ET-1 effects on transport were blocked by protein kinase C-selective inhibitors, implicating protein kinase C in ET-1 signaling. Finally, the nephrotoxic radiocontrast agent iohexol reduced cell-to-lumen FL-MTX and NBD-CSA transport, and these effects were abolished by an ET(B) receptor antagonist. These are the first results linking ET to the control of xenobiotic transport and the first demonstrating control of renal multidrug resistance-associated protein 2 and P-glycoprotein by a hormone.
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PMID:Endothelin B receptor-mediated regulation of ATP-driven drug secretion in renal proximal tubule. 1061 79


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