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)

Cystinosis is an autosomal recessive disorder caused by an impaired transport of cystine out of lysosomes. The most severe infantile form of cystinosis starts with Fanconi syndrome at the age of 3-6 months. Untreated patients develop renal failure before the age of 10. The cystinosis gene (CTNS) maps to chromosome 17p13, spans 23 kb and is composed of 12 exons. CTNS encodes a 367 amino acid protein, cystinosin, which is a H(+)-driven lysosomal cystine transporter. It is enigmatic how lysosomal cystine accumulation induces the clinical symptoms. ATP depletion was demonstrated in an experimental model consisting of loading lysosomes with cystine dimethylester. The amino-thiol cysteamine depletes lysosomal cystine content by a disulfide-exchange reaction with cystine. Therapy with cysteamine should be administered as early as possible and continued after a renal transplantation as the extra renal damage still progresses. Improved life expectancy of cystinotic patients requires the attention of internists with a special interest for this rare disorder.
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PMID:[From gene to disease: cystinosis]. 1504 93

Atractylis gummifera is a poisonous plant widely found in North Africa. The thistle grows commonly in dry areas, and the juice of the rhizome is poisonous. It provokes frequent poisoning, especially of children. Toxic glucosides have been isolated and their identified as atractyloside and carboxyatractyloside. Tissues of high metabolic activity are the main target organs. Atractylis gummifera glucosides cause a severe hepatitis with fatal liver failure common. The plant's poisonous compounds interact with detoxication and/or transformation systems in the liver even at doses not likely to induce cytolysis by blocking ADP-ATP conversion through inhibition of P450 cytochrome. Clinical manifestations are related to an induced hypoglycemia and neurovegetative disorders or subsequent renal failure. Liver transplantation or immunotherapy may improve the often fatal prognosis.
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PMID:A review of acute poisoning from Atractylis gummifera L. 1517 92

Tubular cell apoptosis has been implicated in the development of ischemic renal failure. In in vitro models, ATP depletion-induced apoptosis of tubular cells is mediated by the intrinsic pathway involving Bax translocation, cytochrome c release, and caspase activation. While the apoptotic cascade has been delineated, much less is known about its regulation. The current study has examined the regulation of ATP depletion-induced tubular cell apoptosis by acidic pH, a common feature of tissue ischemia. Cultured renal tubular cells were subjected to 3 h of ATP depletion with azide and then recovered in full culture medium. The treatment led to apoptosis in approximately 40% of cells. Apoptosis was significantly reduced, if the pH of ATP depletion buffer was lowered from 7-7.4 to 6-6.5. This was accompanied by the inhibition of caspase activation. However, acidic pH did not prevent Bax translocation and oligomerization in mitochondria. Cytochrome c release from mitochondria was not blocked either, suggesting that acidic pH inhibited apoptosis at the postmitochondrial level. To determine the postmitochondrial events that were blocked by acidic pH, we conducted in vitro reconstitution experiments. Exogenous cytochrome c, when added into isolated cell cytosol, induced caspase activation. Such activation was abrogated, when pH during the reconstitution was lowered to 6 or 6.5. Nevertheless, acidic pH did not prevent the recruitment and association of caspase-9 by Apaf-1, as shown by coimmunoprecipitation. Together, this study demonstrated the inhibition of tubular cell apoptosis following ATP depletion by acidic pH. A critical step blocked by acidic pH seems to be caspase-9 activation in apoptosome.
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PMID:Acidic pH inhibits ATP depletion-induced tubular cell apoptosis by blocking caspase-9 activation in apoptosome. 1575 25

Thrombospondin 1 (TSP-1) is a matricellular protein that inhibits angiogenesis and causes apoptosis in vivo and in vitro in several cancerous cells and tissues. Here we identify TSP-1 as the molecule with the highest induction level at 3 hours of IR injury in rat and mouse kidneys subjected to ischemia/reperfusion (IR) injury using the DNA microarray approach. Northern hybridizations demonstrated that TSP-1 expression was undetectable at baseline, induced at 3 and 12 hours, and returned to baseline levels at 48 hours of reperfusion. Immunocytochemical staining identified the injured proximal tubules as the predominant sites of expression of TSP-1 in IR injury and showed colocalization of TSP-1 with activated caspase-3. Addition of purified TSP-1 to normal kidney proximal tubule cells or cells subjected to ATP depletion in vitro induced injury as demonstrated by cytochrome c immunocytochemical staining and caspase-3 activity. The deleterious role of TSP-1 in ischemic kidney injury was demonstrated directly in TSP-1 null mice, which showed significant protection against IR injury-induced renal failure and tubular damage. We propose that TSP-1 is a novel regulator of ischemic damage in the kidney and may play an important role in the pathophysiology of ischemic kidney failure.
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PMID:Identification of thrombospondin 1 (TSP-1) as a novel mediator of cell injury in kidney ischemia. 1629 24

Nitric oxide (NO) is produced from amino acid L-arginine via the catalytic action of NO synthases, which use dioxygen and NADH or NADPH as cofactor. This simple molecule acts at nanomolar concentrations and demonstrates a wide spectrum of physiological effects, a primary of which is vasodilatation. The production of NO in endothelium cells is induced by mechanical action (increased blood-vessels wall tension) and chemical agents (catecholamines, acetylcholine, bradykinin, histamine). The endothelium-released NO easily diffuses to the underlying smooth muscles and triggers their relaxation by increasing cyclic guanosine monophosphate level and subsequent opening of endothelial potassium channels (K(ATP), K(Ca)). NO on the endothelium surface inhibits adhesion and aggregation of platelets, regulates the main functions of myocardium, modulates the permeability of endothelium, and weakens the interaction of endothelium cells and leukocytes by reducing the expression of adhesion-stimulating proteins. Direct evidence suggests that free radicals and related reactive oxygen species mostly as O2-, HO-, ONOO-, ROO- are associated with an endothelium dysfunction, which manifests itself as an impairment of endothelium-dependent vasorelaxation. Though reactive oxygen species in a small amount are produced constantly, the decreased metabolic turnover of homocysteine, poor performance of antioxidants or high level of angiotensin II alters the balance between production of free radicals and their neutralization. Such events decrease NO bioavailability and thus condition the development of various diseases like arteriosclerosis, hypertension, diabetes, heart and renal failure. Agents increasing NO bioavailability and depressing the endothelial dysfunction would be the most useful for the treatment above-mentioned pathologies.
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PMID:[The main determinants of endothelial dysfunction]. 1677 63

Acyclic nucleotide phosphonates (adefovir, cidofovir, and tenofovir) are eliminated predominantly into the urine, and renal failure is their dose-limiting toxicity, particularly for adefovir and cidofovir. In this study, we examined the involvement of multidrug resistance-associated protein (MRP)4 (ABCC4) in their luminal efflux in the kidney. ATP-dependent uptake of adefovir and tenofovir but not cidofovir was observed only in the membrane vesicles expressing MRP4. The ATP-dependent uptake of adefovir and tenofovir by MRP4 was not saturated at 1 mM. The ATP-dependent uptake of adefovir by membrane vesicles expressing MRP4 was osmotic-sensitive. No ATP-dependent uptake of either agent was observed in the membrane vesicles expressing human MRP2 or breast cancer resistance protein. These nucleotide analogs were given to mice by constant intravenous infusion, and the plasma, urine, and tissue concentrations were determined. The kidney accumulation of adefovir and tenofovir was significantly greater in Mrp4 knockout mice (130 versus 66 and 191 versus 87 pmol/g tissue, respectively); thus, the renal luminal efflux clearance was estimated to be 37 and 46%, respectively, of the control. There was no difference in the fraction of mono- and diphosphorylated forms of adefovir in the kidney between wild-type and Mrp4 knockout mice. In mice, cidofovir was also eliminated via the urine by tubular secretion as well as glomerular filtration. There was no change in the kinetic parameters of cidofovir in Mrp4 knockout mice. Our results suggest that MRP4 is involved in the luminal efflux of both adefovir and tenofovir, but it makes only a limited contribution to the urinary excretion of cidofovir.
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PMID:Functional involvement of multidrug resistance-associated protein 4 (MRP4/ABCC4) in the renal elimination of the antiviral drugs adefovir and tenofovir. 1711 May 1

Chronic renal failure (CRF) is frequently associated with increased plasma levels of homocysteine (Hcy), an amino acid that can be considered a new uremic toxin according to recent evidence. Studies on Hcy described first homocystinuria, an inherited disease characterized by high plasma Hcy levels and premature cardiovascular disease, resulting in high mortal-ity rates. Hyperhomocysteinemia was then shown to be associated with cardiovascular events both in the general population and in CRF patients. Hcy is a sulfur amino acid derived from dietary methionine, an essential amino acid. Methionine is condensed with ATP to form S-adenosylmethionine (AdoMet), the universal methyl donor in transmethylation reactions. The AdoMet demethylated product is S-adenosylhomocysteine (AdoHcy), which is the direct precursor of Hcy in vivo. Hcy is toxic for the endothelium, it enhances vascular smooth muscle cell proliferation, increases platelet aggregation, and acts on the coagulation cascade and fibrinolysis. Several mechanisms have been discussed to explain Hcy toxicity. Hcy levels increase as renal function declines and progresses to ESRD; the causes of hyperhomocysteinemia are still unclear. Studies in humans show that renal metabolic extraction depends on renal plasma flow; in addition, an alteration of the extrarenal metabolic clearance, depending on uremic toxins, may occur. Among the consequences of hyperhomocysteinemia in renal failure are: impaired protein methylation, with altered protein repair processes; DNA hypomethylation, with an alteration in the allelic expression of genes regulated through methylation; and protein homocysteinylation. Further, this review is dealing with the 'reverse epidemiology' issue, outlining also the main Hcy-lowering strategies.
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PMID:[Hyperhomocysteinemia in chronic renal failure.]. 1712 61

OBJECTIVE: Community health centers (HCs) provide care for millions of medically underserved Americans with disproportionate burdens of hypertension and hyperlipidemia. For both conditions, treatment guidelines recently became more stringent and quality improvement (QI) efforts have intensified. We assessed hypertension and hyperlipidemia management in HCs during this time of guideline revision and increased QI efforts. DESIGN: Cross-sectional chart review. SETTING AND PARTICIPANTS: Eleven Midwestern HCs for 2000 and 9 for 2002 provided audit data from 2,976 randomly chosen patients with hypertension and/or hyperlipidemia. MEASUREMENT: Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC VI/VII) and National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP III) guidelines were used to assess management of these conditions. RESULTS: Hypertension (2000, N=808; 2002, N=692) and hyperlipidemia (2000, N=774; 2002, N=702) outcomes improved for specific clinical subgroups. Hypertensive patients with 1 or more cardiovascular risk factors demonstrated significant improvement (34% vs. 45% controlled at <140/90 mm Hg, p=0.02). Hypertension control for persons with diabetes, renal failure and heart failure increased (16% vs. 28% controlled at <130/85 mm Hg, p=0.006). LDL control increased significantly for patients with 2 or more risk factors (39% vs. 58% controlled at <130 mg/dl, p=0.008). Other clinical subgroups showed trends toward better control, although there was insufficient power to detect significant differences for these groups. CONCLUSION: Hypertension and hyperlipidemia outcomes improved for some risk groups; however, ongoing QI is necessary.
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PMID:Hypertension and hyperlipidemia management in patients treated at community health centers. 1941 46

Classical non-insulin antihyperglycemic drugs currently approved for the treatment of type 2 diabetes mellitus (T2DM) comprise five groups: biguanides, sulfonylureas, meglitinides, glitazones and alpha-glucosidase inhibitors. Novel compounds are represented by the incretin mimetic drugs like glucagon like peptide-1 (GLP-1), the dipeptidyl peptidase 4 (DPP-4) inhibitors, dual peroxisome proliferator-activated receptors (PPAR) agonists (glitazars) and amylin mimetic drugs. We review the cardiovascular effects of these drugs in an attempt to improve knowledge regarding their potential risks when treating T2DM in cardiac patients. Metformin may lead to lethal lactic acidosis, especially in patients with clinical conditions that predispose to this complication, such as recent myocardial infarction, heart or renal failure. Sulfonylureas exert their effect by closing the ATP-dependent potassium channels. This prevents the opening of these channels during myocardial ischemia, impeding the necessary hyperpolarization that protects the cell. The combined sulfonylurea/metformin therapy reveals additive effects on mortality in patients with coronary artery disease (CAD). Meglitinides effects are similar to those of sulfonylureas, due to their almost analogous mechanism of action. Glitazones lower leptin levels, leading to weight gain and are unsafe in NYHA class III or IV. The long-term effects of alpha-glucosidase inhibitors on morbidity and mortality rates is yet unknown. The incretin GLP-1 is associated with reductions in body weight and appears to present positive inotropic effects. DPP-4 inhibitors influences on the cardiovascular system seem to be neutral and patients do not gain weight. The future of glitazars is presently uncertain following concerns about their safety. The amylin mimetic drug paramlintide, while a satisfactory adjuvant medication in insulin-dependent diabetes, is unlikely to play a major role in the management of T2DM. Summarizing the present information it can be stated that 1. Four out the five classical oral antidiabetic drug groups present proven or potential cardiac hazards; 2. These hazards are not mere 'side effects', but biochemical phenomena which are deeply rooted in the drugs' mechanism of action; 3. Current data indicate that the combined glibenclamide/metformin therapy seems to present special risk and should be avoided in the long-term management of T2DM with proven CAD; 4. Glitazones should be avoided in patients with overt heart failure; 5, The novel incretin mimetic drugs and DPP-4 inhibitors--while usually inadequate as monotherapy--appear to be satisfactory adjuvant drugs due to the lack of known undesirable cardiovascular effects; 6. Customized antihyperglycemic pharmacological approaches should be implemented for the achievement of optimal treatment of T2DM patients with heart disease. In this context, it should be carefully taken into consideration whether the leading clinical status is CAD or heart failure.
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PMID:A cardiologic approach to non-insulin antidiabetic pharmacotherapy in patients with heart disease. 1961 27

We examined the activity of sodium transporting systems (STS) in a cellular membrane of erythrocytes in a group of 21 patients under chronic hemodialysis treatment with the dialyzing fluid containing glucose HD-g(+), and 22 patients dialysed with the fluid not containing glucose HD-g(-), 21 patients with chronic kidney failure already not treated with dialysis and 21 control group. We examined the concentration of antioxidative system cofactors, such as zinc, copper and selenium in erythrocytes and plasma. The marker of oxidative stress in erythrocytes and plasma was the concentration of TBARS. Among all STS we examined the activity of Na(+)/K(+) ATP-ase, Na(+)/K(+)/Cl(-); co-transport, Na(+)/Li(+) exchanger, Na(+), K(+)-outflow. Copper zinc and selenium as cofactors of antioxidative enzymes may reflect the antioxidative processes inside the organism undergoing the influence of free radicals.
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PMID:[Oxidative stress and trace elements affect the activity of sodium transporting systems in a cellular membrane of a erythrocyte]. 1983 21


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