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)

Aminoglycoside antibiotics maintain a leading role in antibacterial therapy of severe gram-negative infections despite nephrotoxicity complicating 10% to 20% of therapeutic courses. Risk factors for aminoglycoside-induced renal injury have been identified. A variety of maneuvers to protect renal function and minimize toxicity have been suggested, but few have been accepted for clinical use. Aminoglycosides are eliminated by glomerular filtration, but a fraction is reabsorbed in the proximal tubule. Polycationic aminoglycosides bind to anionic, brush-border, phospholipid membranes and are transported intracellularly. Disruption of normal phospholipid trafficking within the cell is evidenced by the presence of myeloid bodies, electron-dense concretions of phospholipid material. Although consistent with aminoglycoside injury, such biochemical and histological changes are observed with other drug exposures in which renal failure does not occur. Therapeutic drug monitoring services have failed to reduce aminoglycoside toxicity over the years, although two pharmacological parameters are imperative. The first is that peak aminoglycoside levels correlate with efficacy, as these agents display concentration-dependent bacterial killing. Second, trough levels reflect nephrotoxicity; the kidney is unable to excrete the dose of aminoglycoside within the dosing interval owing to impaired function. These two points have led to numerous reports evaluating once-daily dosing of aminoglycosides in which the cumulative dose for a 24-hour period would be administered as a single dose. This would take advantage of concentration-dependent "bug" killing as well as the post-antibiotic effect while minimizing repeated exposure and potential nephrotoxicity. Further trials are warranted to establish specific guidelines for once-daily as well as every 36- to 48-hour dosing regimens in patients with established renal impairment for specific organisms and specific types of infection.
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PMID:Aminoglycoside nephrotoxicity. 900 May 47

The consumption of plants containing the diterpenoid atractyloside (ATR) causes selective proximal tubule injury, renal failure and death in humans. We have compared the effects of ATR in freshly isolated renal proximal tubules and glomeruli from rat and also in cell lines: NRK, derived from the proximal tubules, and MDBK and MDCK more closely representing the distal nephron. The effects of ATR (10-500 microM) on proximal tubules and glomeruli were assessed by changes in lipid peroxidation, de novo protein synthesis and the leakage of alkaline phosphatase (ALP), lactate dehydrogenase (LDH), glutamate dehydrogenase (GDH) and N-acetyl-beta-D-glucosaminidase (NAG). The susceptibility of NRK, MDBK and MDCK cell lines to ATR was assessed by the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, measuring mitochondrial reduction. Enzyme leakage was the most sensitive of the markers of cell injury in fresh fragments and ranked LDH > GDH > ALP > NAG in proximal tubules. As little as 20 microM ATR caused significant enzyme leakage from proximal tubules, but there were no increases in enzyme leakage from glomeruli at concentrations < and = 500 microM ATR. De novo protein synthesis was only inhibited 50% at ATR concentration > 5 mM in the proximal tubules, but there were no effects in glomeruli. Malondialdehyde production was significantly elevated at 1 mM ATR for proximal tubules, and 500 microM for glomeruli. NRK cells were sensitive to ATR (IC50, 120 microM), but MDBK or MDCK cells were unaffected by < and = 1 mM of this diterpenoid. Both freshly isolated fragments and continuous cell lines representing the proximal tubules are more sensitive to ATR than either glomeruli or cells representing the distal nephron. These data also show that protein synthesis is a less specific and sensitive measure of ATR cytotoxicity than enzyme leakage in fragments. MTT reduction to formazan was the most sensitive in the NRK cell line. The low levels of lipid peroxidation products in proximal tubular fragments or sensitive renal cell lines at toxic levels of ATR suggest that oxidative injury is not a key mechanism.
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PMID:Selective cytotoxicity associated with in vitro exposure of fresh rat renal fragments and continuous cell lines to atractyloside. 901 May 90

Ischemic renal injury is associated with changes in the expression of a number of genes. Although pH regulation is undoubtedly important during the recovery from ischemia, the expression of acid-base transporters during acute ischemic renal failure has not been studied. In the present study, levels of mRNA encoding the colonic H+-K+-ATPase and four isoforms of the Na+/H+ exchanger (NHE-1, NHE-2, NHE-3 and NHE-4) were measured by quantitative Northern analysis in rat renal cortex and medulla following ischemia-reperfusion injury. Rats were subjected to 30 minutes of renal artery occlusion and then sacrificed either 12 or 24 hours after the occlusion was released. The most striking changes followed 30 minutes of occlusion and 12 hours of reperfusion and involved the mRNA for NHE-3 (involved in HCO3- reabsorption in proximal tubule and thick limb) and colonic H+-K+-ATPase (involved in HCO3- reabsorption in collecting duct). These changes were: (1) a approximately 75% decrease in NHE-3 mRNA in both cortex and medulla; and (2) an approximately 8-fold increase in colonic H+-K+-ATPase mRNA in the cortex. At 12 hours of reperfusion, there was a 66% reduction in the Na+/H+ exchanger (NHE-3) activity as assayed by acid-stimulated 22Na+ influx into brush border membrane vesicles (P < 0.01). After 24 hours of reperfusion, NHE-3 mRNA remained suppressed while cortical colonic H+-K+-ATPase mRNA declined to only twice the control level. Medullary colonic H+-K+-ATPase mRNA did not change significantly. Gastric H+-K+-ATPase mRNA in cortex or medulla remained the same at 0, 12, and 24 hours after reperfusion. Cortical NHE-1 increased mildly at 12 and 24 hours of reperfusion whereas a moderate decrease in NHE-2 and NHE-4 mRNAs was observed in cortex and medulla after both 12 and 24 hours of reperfusion. We suggest that overexpression of colonic H+-K+-ATPase in the early phase of renal reperfusion injury may be responsible for compensatory reabsorption of increased HCO3- load resulting from suppression of NHE-3. This was supported by a fourfold increase in colonic H+-K+-ATPase mRNA in rats treated with acetazolamide, which causes renal HCO3-wasting. Rapid decline in colonic H+-K+-ATPase expression at 24 hours after reperfusion is likely due to reduced HCO3- delivery to distal tubules resulting from decreased GFR. Overexpression of H+-K+-ATPase may be vital to acid-base homeostasis in the early phase of acute ischemic renal failure.
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PMID:Ischemic-reperfusion injury in the kidney: overexpression of colonic H+-K+-ATPase and suppression of NHE-3. 908 76

When kidneys are injured in vivo, the reaction of the renal epithelial is heterogeneous. Some cells, especially those of the proximal tubule, undergo necrosis, other cells undergo apoptosis, and still others survive the injury apparently intact. In addition, injured tubules are relined with new cells actively engaged in DNA synthesis. Nephrotoxic and ischemic renal damage also is accompanied by a typical immediate early gene (IEG) response, which does not always occur in cells that undergo DNA synthesis, suggesting that the role of the IEG response is not necessarily proliferative in this setting. The activation of parts of this pathway is mediated by the stress-activated protein kinases (SAPKs), which may induce cell-cycle arrest and apoptosis. Downregulation of the SAPKs improve renal function and improve long-term outcome during ischemic renal failure. It is thus possible that manipulation of this pathway could ameliorate acute renal failure. Clues to the pertinent pathways and genes to target therapy to alter the course of renal failure will come from continued understanding of the transduction pathways activated by renal cell stress and the identification of factors that promote survival of renal cells.
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PMID:Renal stress response and acute renal failure. 911 39

The kidney is involved in amino acid reabsorption and metabolism; consequently, in renal insufficiency, these important functions are disturbed, as has been reported in animals and patients. In a first experimental series, rats were subjected to degrees of nephrectomy (NX) varying between 10% and 90%. Three weeks later, amino acid levels were measured in plasma to correlate the levels with the degree of NX. The results indicate that in the range of 33% to 74% NX, the plasma concentration of only three to four amino acids was modified, whereas in rats with 84% NX, the concentration of 11 amino acids was disturbed, compared with sham-operated rats. Citrullinemia was enhanced in uremic rats and correlated with the degree of NX. More interestingly, citrullinemia was increased in the range of 10% to 33% NX without any changes in uremia and creatininemia, two well-known markers of uremic states. A second experimental series was designed to study the time course of changes in aminoacidemia to find a marker for the onset of renal failure. Rats were subjected to 36% NX for a period of 1 to 21 days. Uremia and creatininemia peaked 24 to 48 hours after NX, and creatinine clearance (Clcreat) concomitantly diminished. Unfortunately, these three markers of uremic states returned to control values during the next few days before increasing during the last 2 weeks. In contrast, citrullinemia increased twofold 48 hours after NX and plateaued over the next 20 days. We conclude that in rats, citrullinemia could be used (1) to detect acute and chronic renal failure, (2) as a specific marker of normal function of the proximal tubule, and (3) to estimate the degree of renal damage. From this study, renal insufficiency might be easily detected by measuring citrullinemia.
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PMID:Amino acid handling in uremic rats: citrulline, a reliable marker of renal insufficiency and proximal tubular dysfunction. 918 94

Advanced glycation end products (AGEs) generated through the Maillard reaction significantly alter protein characteristics. Their accumulation has been incriminated in tissue injury associated with aging, diabetes, and renal failure. However, little is known about their clearance from the body. The present study delineates the catabolic pathway of a well-defined AGE product, pentosidine. Synthesized pentosidine given intravenously in rats with normal renal function was rapidly eliminated from the circulation through glomerular filtration, but was undetectable in the urine by chemical analysis. Immunohistochemistry with anti-pentosidine antibody disclosed that pentosidine accumulated transiently in the proximal renal tubule one hour after its administration, but had disappeared from the kidney at 24 hours. After an intravenous load of radiolabeled pentosidine, radioactivity peaked in the kidney at one hour and subsequently decreased, whereas it rose progressively in the urine. Over 80% of the radioactivity was recovered in the 72-hour collected urine. However, only 20% of urine radioactivity was associated with intact pentosidine chemically or immunochemically. In gentamicin-treated rats with tubular dysfunction, up to 30% of the pentosidine load was recovered as intact pentosidine in the urine. The present study suggests that free pentosidine (and possibly other AGEs) is filtered by renal glomeruli, reabsorbed in the proximal tubule where it is degraded or modified, and eventually excreted in the urine. Kidney thus plays a key role in pentosidine disposal.
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PMID:Renal catabolism of advanced glycation end products: the fate of pentosidine. 946 Nov 1

Progression to end-stage renal failure is the final common pathway of many forms of glomerular disease, independent of the type of initial insult. Progressive glomerulopathies have in common persistently high levels of urinary protein excretion and tubulointerstitial lesions at biopsy. Among the cellular mechanisms that may determine progression regardless of etiology, the traffic of excess proteins filtered from glomerulus in renal tubule may have functional importance by initiating interstitial inflammation in the early phase of parenchymal injury. This study analyzes the time course and sites of protein accumulation and interstitial cellular infiltration in two different models of proteinuric nephropathies. In remnant kidneys after 5/6 renal mass ablation, albumin and IgG accumulation by proximal tubular cells was visualized in the early stage, preceding interstitial infiltration of MHC-II-positive cells and macrophages. By double-staining, infiltrates developed at or near tubules containing intracellular IgG or luminal casts. This relationship persisted thereafter despite more irregular distribution of infiltrate. Similar patterns were found in an immune model (passive Heymann nephritis), indicating that the interstitial inflammatory reaction develops at the sites of protein overload, regardless of the type of glomerular injury. Osteopontin was detectable in cells of proximal tubules congested with protein in both models at sites of interstitial infiltration, and by virtue of its chemoattractive action this is likely mediator of a proximal tubule-dependent inflammatory pathway in response to protein load. Protein overload of tubules is a key candidate process translating glomerular protein leakage into cellular signals of interstitial inflammation. Mechanisms underlying the proinflammatory response of tubular cells to protein challenge in diseased kidney should be explored, as well as ways of limiting protein reabsorption/deposition to prevent consequent inflammation and progressive disease.
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PMID:In progressive nephropathies, overload of tubular cells with filtered proteins translates glomerular permeability dysfunction into cellular signals of interstitial inflammation. 964 31

The renal functional changes following infusion of dopamine are well documented. The most pronounced effect is the increase in renal blood flow and a marked natriuretic response. Due to its specific renal effects, dopamine has become one of the most frequently used drugs in the treatment of critically ill patients with low cardiac output states and/or acute oliguric renal failure. Pharmacological effects of dopamine are dose dependent. Low doses of dopamine predominantly stimulate dopaminergic receptors, but with increasing doses actions secondary to stimulation of adrenergic beta(1) and alpha receptors also appear. Dopamine receptors are classified into the D1 and the D2 subtype families. Stimulation of D1 receptors increases adenylate cyclase activity and intracellular levels of cAMP, whereas D2 receptor activation decrease or do not change adenylate cyclase activity. In the kidney, dopamine receptors have been localized in the renal vasculature except in glomeruli and in the tubules (the proximal tubule > macula densa > the loop of Henle > the distal tubule > collecting ducts). The postsynaptic D1 receptor mediates vasodilation by a direct mechanism, whereas the presynaptic D2 receptor indirectly may dilate the vessels by inhibition of norepinephrine release. Consistent with previous results in animals, the present haemodynamic studies revealed that dopamine in normal subjects elicits a dose dependent biphasic effect on the mean arterial blood pressure. With 1 and 2 micrograms/kg/min, a depressor effect resulted from a decrease in the diastolic pressure, whereas a pressor effect, seen with doses at and above 7.5 micrograms/kg/min, was mainly caused by elevations of the systolic pressure. The studies indicated that the increase in cardiac output at low doses of dopamine is secondary to a decrease in peripheral vascular resistance, independent of effects of beta(1) receptors on cardiac contractility and heart rate. Dose-response studies demonstrated that the dopamine-induced increase in effective renal plasma flow (ERPF) reaches its maximum at 3 micrograms/kg/min. The increase in ERPF remained unchanged by pretreatment with metoprolol, and a comparison of dopamine and dobutamine in doses producing similar increases in cardiac output demonstrated that only dopamine increased ERPF. These findings indicate that indirect haemodynamic effects secondary to increases in cardiac contractility and cardiac output do not contribute significantly to the increase in renal perfusion caused by dopamine. In normal subjects, acute hypoxaemia attenuated the renal vasodilating effect of dopamine. The well known natriuretic effect of dopamine was significantly expressed in all of our studies, in which doses ranging from 1 to 5 micrograms/kg/min caused about a two-fold increase in sodium excretion. At doses at and above 7.5 micrograms/kg/min which increased mean arterial pressure, dopamine further increased sodium clearance (CNa) while ERPF was decreasing, indicating the contribution of pressure natriuresis at these high doses. Although not affecting the percentage increase in CNa, metoprolol suppressed the absolute, maximal response to non-pressor doses of dopamine, suggesting that a reduced adrenergic beta(1) receptor activity may indirectly affect the natriuretic response, probably by decreasing renal perfusion pressure. Previous studies in animals demonstrated that dopamine natriuresis can occur independent of increases in ERPF and GFR, and, furthermore, that the response can be abolished by specific D1 receptor antagonists. Evidence obtained by in vitro studies indicated that dopamine via D1 receptors may inhibit the Na(+)-H+ antiport at the brush-border membrane of proximal tubular cells and the Na(+)-K(+)-ATPase activity at basolateral membranes of both the proximal tubule and the medullary thick ascending limb of the loop of Henle. (ABSTRACT TRUNCATED)
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PMID:Effects of dopamine on renal haemodynamics tubular function and sodium excretion in normal humans. 967 40

Dent's disease, an inherited disorder characterized by hypercalciuria, nephrolithiasis, nephrocalcinosis, rickets, low-molecular-weight proteinuria, Fanconi's syndrome, and renal failure, is caused by mutations in the renal chloride channel, CLC5. The normal role of CLC5 is unknown. We have investigated the intrarenal and subcellular localization of CLC5 in rat kidney by in situ hybridization and immunohistochemistry. By in situ hybridization, CLC5 mRNA was detected predominantly in cortical medullary ray and outer medullary tubule epithelial cells. Polyclonal antiserum was generated against a CLC5 fusion protein, affinity purified, and immunoadsorbed against CLC3 and CLC4 to yield a CLC5 isoform-specific antiserum. By immunohistochemistry, CLC5 protein was localized to the intracellular domain of tubular epithelial cells in the S3 segment of the proximal tubule and the medullary thick ascending limb. By subcellular membrane fractionation and flow cytometry, CLC5 expression was found in outer medullary endosomes. These findings are consistent with a model in which CLC5 encodes an endosomal chloride channel that facilitates acidification and trafficking of renal epithelial endosomes.
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PMID:Intrarenal and subcellular localization of rat CLC5. 981 33

For the past decade, an attempt has been made by many research groups to define the roles of the growing number of Bcl-2 gene family proteins in the apoptotic process. The Bcl-2 family consists of pro-apoptotic (or cell death) and anti-apoptotic (or cell survival) genes and it is the balance in expression between these gene lineages that may determine the death or survival of a cell. The majority of studies have analysed the role/s of the Bcl-2 genes in cancer development. Equally important is their role in normal tissue development, homeostasis and non-cancer disease states. Bcl-2 is crucial for normal development in the kidney, with a deficiency in Bcl-2 producing such malformation that renal failure and death result. As a corollary, its role in renal disease states in the adult has been sought. Ischaemia is one of the most common causes of both acute and chronic renal failure. The section of the kidney that is most susceptible to ischaemic damage is the outer zone of the outer medulla. Within this zone the proximal tubules are most sensitive and often die by necrosis or desquamate. In the distal nephron, apoptosis is the more common form of cell death. Recent results from our laboratory have indicated that ischaemia-induced acute renal failure is associated with up-regulation of two anti-apoptotic Bcl-2 proteins (Bcl-2 and Bcl-XL) in the damaged distal tubule and occasional up-regulation of Bax in the proximal tubule. The distal tubule is a known reservoir for several growth factors important to renal growth and repair, such as insulin-like growth factor-1 (IGF-1) and epidermal growth factor (EGF). One of the likely possibilities for the anti-cell death action of the Bcl-2 genes is that the protected distal cells may be able to produce growth factors that have a further reparative or protective role via an autocrine mechanism in the distal segment and a paracrine mechanism in the proximal cells. Both EGF and IGF-1 are also up-regulated in the surviving distal tubules and are detected in the surviving proximal tubules, where these growth factors are not usually synthesized. As a result, we have been using in vitro methods to test: (i) the relative sensitivities of renal distal and proximal epithelial cell populations to injury caused by mechanisms known to act in ischaemia-reperfusion; (ii) whether a Bcl-2 anti-apoptotic mechanism acts in these cells; and (iii) whether an autocrine and/or paracrine growth factor mechanism is initiated. The following review discusses the background to these studies as well as some of our preliminary results.
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PMID:Bcl-2 genes and growth factors in the pathology of ischaemic acute renal failure. 1036 Dec 61


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