Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nephrotoxicities of gentamicin and three other experimental aminoglycosides were compared at a single 60 mg. per kilogram per day dose in rats. Renal function, lysosomal enzymuria, and antibiotic concentrations in plasma, urine, and renal tissue were measured at regular intervals throughout the course of treatment. Kidney tissue was examined by light and electron microscopy in animals killed at intervals throughout the period of antibiotic administration. Proteinuria and enzymuria were early indicators of nephron dysfunction, whereas endogenous creatinine clearance declined later in the course of treatment. All animals were killed 24 hours after a previous antibiotic injection and displayed sustained renal tissue antibiotic concentrations which were 5 to 10 times higher than those in serum or urine. When assayed separately, renal cortical tissue had a fivefold greater antibiotic concentration than renal medulla. Light microscopy displayed necrosis of the pars convoluta of the proximal tubule. Electron microscopy revealed appearance of cytosegrosomes with myeloid bodies. It is possible that impaired cytoplasmic degradation of sequestered organelle membranes, resulting from aminoglycoside accumulation, is responsible for the myeloid body formation and subsequent tubular necrosis.
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PMID:Experimental aminoglycoside nephrotoxicity. 16 76

A single intraperitoneal injection of hexochloro-1 : 3-butadiene (HCBD) at 100 mg/kg or above produced renal tubular necrosis in the rat by 24 h. Histological examination of the kidneys indicated damage to the straight portion of the proximal tubules. Urinary analysis showed diuresis, increased proteinuria and an increase in the excretion of N-acetyl-beta-D-glucosaminidase, and alkaline phosphatase at doses above 100 mg/kg. At doses below 100 mg/kg only a mild increase in protein excretion was observed. Twenty-four hours after 200 mg/kg HCBD, i.p., there was a marked decrease in the glomerular filtration rate (inulin clearance) and in the clearance of the organic anion (p-aminohippuric acid, PAH) and the organic cation (tetraethylammonium bromide, TEA) by the kidney. HCBD did not affect the accumulation of PAH or TEA by renal cortical slices when added in vitro at a concentration up to 0.1 mM. However, a decrease in PAH, but not TEA accumulation, was seen in renal cortical slices from rats treated with HCBD 24 h previously. Mercuric chloride (HgCl2), a known nephrotoxin, was used as a positive control for these studies. HCBD appears to specifically damage the straight portion of the proximal renal tubule and thereby selectively damage the organic anion transport system.
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PMID:The acute toxic effects of hexachloro-1 : 3-butadiene on the rat kidney. 53 62

Administration of D-serine to rats induced acute necrosis of the proximal straight tubules, proteinuria, glucosuria, and aminoaciduria. Proteinuria and glucosuria developed at the onset of tubular necrosis and disappeared when the tubules were completely relined by new epithelium. Our findings suggest (1) that abnormal loss of protein and glucose in urine is due to diffusion of these substances from interstitium to tubular fluid across the denuded permeable basement membranes of the necrotic tubules, and (2) that tubular cells normally are a barrier to diffusion of certain solutes betweeen interstitial and tubular fluids. Amino-aciduria preceded the onset of tubular necrosis and increased excretion of some amino acids persisted after tubular repair. Thus, D-serine-induced aminoaciduria may be due to impaired reabsorption of amino acids by the injured proximal straight tubules, as well as by backward diffusion of amino acids from the interstitium.
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PMID:D-serine nephrotoxicity. The nature of proteinuria, glucosuria, and aminoaciduria in acute tubular necrosis. 120 37

We investigated the influence of the type rather than the degree of renal insufficiency on the renal clearance of drugs. Different models of site specific experimental renal failure (ERF) have been developed in the rat; proximal tubular necrosis, induced by cisplatin; papillary necrosis, induced by 2-bromoethylamine, and glomerulonephritis, induced by sodium aurothiomalate or by antiglomerular basement membrane antibody. Several parameters of kidney function were assessed: the clearance of inulin, PAH, and endogenous N-1-methylnicotinamide (NMN). Plasma BUN and creatinine concentrations, and the presence of proteinuria and glucosuria were also measured. Our results showed a nonparallel decrease in glomerular filtration rate (GFR) and tubular secretion as measured by the secretory clearance of endogenous NMN or by the secretory clearance of p-aminohippuric acid (PAH), that is incompatible with the "intact nephron hypothesis." As a result, the renal clearance of cimetidine, a drug eliminated mainly by renal secretion, correlated better with the renal clearance of endogenous NMN than with the GFR. We conclude that (i) our models of ERF demonstrated the existence of glomerulo-tubular imbalance that is contrary to expectations based on the intact nephron hypothesis; (ii) the type of the renal disease has a direct influence on the renal clearance of cimetidine; (iii) the clearance of endogenous NMN may be a valuable noninvasive test for assessing renal tubular secretion which could be useful in predicting the clearance of drugs eliminated predominantly by tubular secretion.
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PMID:Prediction of the renal clearance of cimetidine using endogenous N-1-methylnicotinamide. 182 32

There are currently no reliable early markers of renal tubular damage. Since aminoaciduria is an accompanying feature of this condition, the usefulness of increased urinary amino acid excretion as a marker was investigated by inducing renal tubular necrosis in male Wistar rats by the administration of gentamicin (40 mg/kg/d) for 14 d. Plasma amino acids, urea, creatinine, protein and electrolytes, and urine amino acids, protein and N-acetylglucosaminidase (a lysosomal enzyme) were measured over a 20 d period. Amino acid excretion increased dramatically within 24 h of the initial dose for 14 of the 16 amino acids measured. The conventional renal disease markers listed above did not increase until after day 7. Glomerular damage caused by puromycin aminonucleoside did not induce aminoaciduria until marked proteinuria occurred (day 9), and even then amino acid excretion was much less than that caused by gentamicin. To distinguish whether the gentamicin-induced aminoaciduria was a consequence of tubular damage or inhibition of amino acid transport, isolated rat kidneys were perfused with a Krebs-Henseleit albumin buffer with and without gentamicin for 20 min, during which time urinary amino acids were quantitated. Gentamicin did not inhibit amino acid reabsorption. Thus, it appears that in the rat-gentamicin model of acute renal failure, urinary amino acids are early markers of renal tubular damage.
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PMID:Aminoaciduria is an earlier index of renal tubular damage than conventional renal disease markers in the gentamicin-rat model of acute renal failure. 206 Jan 88

The experimental agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) has been shown to be a nephrotoxicant in Fischer 344 rats. Results of a previous study conducted in our laboratory suggested that glutathione might be an important modulator of NDPS-induced nephrotoxicity. The purpose of this study was to examine the effect of DL-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of glutathione synthesis, on NDPS-induced renal effects. Male Fischer 344 rats received an intraperitoneal (i.p.) injection of BSO (890 mg/kg) in 0.9% saline (10 ml/kg) followed 2 h later by an i.p. injection of NDPS (0.4 or 1.0 mmol/kg) or sesame oil (2.5 ml/kg), and renal function monitored at 24 and 48 h. BSO pretreatment attenuated the diuresis, proteinuria, elevation in blood urea nitrogen (BUN) concentration and kidney weight, and decreases in organic ion accumulation by renal cortical slices induced by NDPS (0.4 or 1.0 mmol/kg) administration. Proximal tubular necrosis induced by NDPS administration also was attenuated by BSO pretreatment. These results indicate that BSO pretreatment attenuates NDPS-induced renal effects and that glutathione is important for modulating acute NDPS-induced nephropathy.
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PMID:Effect of buthionine sulfoximine on acute N-(3,5-dichlorophenyl)succinimide-induced nephrotoxicity in Fischer 344 rats. 235 74

Phensuximide (PSX) is a 2-arylsuccinimide useful in the treatment of absence seizures. PSX is a mild urotoxicant and is structurally related to N-phenylsuccinimide (NPS) and its antifungal derivatives. Since substitution of the phenyl ring of NPS with chloro or tert-butyl groups can produce compounds with enhanced nephrotoxic potential, it was felt that similar substitutions on the phenyl ring of PSX also might produce derivatives with enhanced nephrotoxic potential. Three derivatives of PSX were prepared and tested: 2-(3-chlorophenyl)-N-methylsuccinimide (CPMS); 2-(4-tert-butylphenyl)-N-methylsuccinimide (BPMS) and 2-(3,5-dichlorophenyl)-N-methylsuccinimide (DPMS). In one set of experiments, male Fischer 344 rats were administered a single intraperitoneal (i.p.) injection of a succinimide (0.4 or 1.0 mmol kg-1) or vehicle (sesame oil, 2.5 ml kg-1) and renal function monitored at 24 and 48 h. Only minor changes in renal function were noted with the PSX derivatives. BPMS and DPMS (1.0 mmol kg-1) treatment induced mild renal tubular necrosis and thickening of the glomerular membranes. However, no significant morphological changes were noted in ureters, bladder or liver in any treatment group. In a second set of experiments, rats were pretreated with phenobarbital (75 mg kg-1 day-1, i.p., 3 days) followed by a single i.p. injection of DPMS (0.4 or 1.0 mmol kg-1) or DPMS vehicle. Renal function was monitored as before. Phenobarbital pretreatment did not markedly enhance the functional nephrotoxicity induced by DPMS (0.4 mmol), but tubular necrosis was greater than observed in non-phenobarbital-pretreated rats receiving DPMS (1.0 mmol kg-1). In addition, hepatotoxicity was observed as the appearance of numerous non-staining vacuoles in hypertrophied hepatocytes. In the phenobarbital plus DPMS (1.0 mmol kg-1) treatment group, all rats died by 48 h. Prior to death, rats exhibited increased proteinuria (+3), hematuria (+3) and blood urea nitrogen concentration. At 24 h, kidneys from rats treated with phenobarbital plus DPMS (1.0 mmol kg-1) exhibited extensive proximal tubular necrosis and numerous glomeruli with thickened membranes. Hepatotoxicity was more pronounced than with phenobarbital plus DPMS (0.4 mmol kg-1) at 48 h and urinary bladders had focal areas of erythrocytes pooling below the epithelial lining. These results demonstrate that although NPS and PSX are structural analogs, chemical substitutions that enhance the nephrotoxic potential of NPS do not have a similar effect on PSX. In addition, DPMS can induce urotoxicity in a manner similar to that observed for PSX and probably induces toxicity via one or more metabolites.
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PMID:Acute toxicity induced by 2-aryl-N-methylsuccinimides. 236 80

Chlorinated anilines are widely used as chemical intermediates in the manufacture of numerous dyes, pesticides, drugs and industrial compounds. The purpose of this study was to examine the nephrotoxic potential of the six dichloroaniline (DCA) isomers in vivo and in vitro. In the in vivo studies, male Fischer 344 rats (4-8 rats/group) were administered a single, intraperitoneal injection of a DCA isomer (0.4, 0.8 or 1.0 mmol/kg) as the hydrochloride salt or given vehicle (0.9% saline, 2.5 ml/kg), and renal function monitored at 24 and 48 h. Renal effects induced by DCA were characterized by decreased urine volume, increased proteinuria, hematuria, modest elevations in blood urea nitrogen (BUN) concentrations, decreased accumulation of p-aminohippurate (PAH) by renal cortical slices, and no change or a slight decrease in kidney weight. Renal morphological changes were observed as proximal tubular necrosis with lesser effects on distal tubular cells and collecting ducts. Based on the overall effects on renal function and morphology, the decreasing order of nephrotoxic potential was found to be 3,5-DCA greater than 2,5-DCA greater than 2,4-, 2,6- and 3,4-DCA greater than 2,3-DCA. The ability for the DCA to induce nephrotoxicity correlated well with the lipophilic properties of the DCA isomers and Hammett constants (sigma) for the various chloro substitutions. In the in vitro studies, renal cortical slices from naive male Fischer 344 rats were co-incubated with a DCA isomer (0-10(-3) M) and PAH or tetraethylammonium (TEA). All DCA isomers decreased PAH and TEA accumulation at 10(-3) M DCA concentration in the media with 3,5-DCA inducing the largest decrease at this concentration. These results indicate that DCA are capable of altering renal function in vivo and in vitro and that 3,5-DCA possesses the greatest nephrotoxic potential in vivo and in vitro.
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PMID:Acute nephrotoxicity induced by isomeric dichloroanilines in Fischer 344 rats. 239 36

In the present investigation, administration of a single i.p. dose of the anticancer drug merbarone [5-(N-phenylcarboxamido)-2-thiobarbituric acid] produced an acute and reversible decrease in renal function in female but not male Fischer 344 rats. The renal lesion in female rats was biochemically characterized as a decrease in p-aminohippuric acid accumulation by renal slices along with polyuria, glucosuria, proteinuria, and enzymuria. These functional changes were accompanied by histopathologic changes of focal tubular necrosis that was confined to the deep cortex and outer stripe of the outer medulla. The changes in these parameters were dose-dependent and were observed at doses as low as 0.2 x MELD(10) (12 mg/kg). This low merbarone dose increased urinary glucose and protein excretion by 26- and 9-fold, respectively, in the initial 16-h urine collection in female rats. This increase was accompanied by a 2- to 15-fold increase in the excretion of N-acetyl-beta-D-glucosaminidase (NAG), gamma-glutamyl transpeptidase (gamma-GTP), and lactate dehydrogenase (LDH) activities. No significant changes in renal function were observed in male rats apart from mild enzymuria after a high dose of merbarone (36 mg/kg). The drug did not increase urea nitrogen levels in male or female rats, reflecting the focal nature of this tubular lesion. Merbarone produced small elevations in serum transaminase activities [i.e., glutamic-oxalacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT)] at doses that produced marked alterations in renal function in female rats, suggesting only mild hepatotoxicity. The present study establishes the kidney as a possible dose-limiting target organ for merbarone toxicity.
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PMID:Nephrotoxicity of 5-(N-phenylcarboxamido)-2-thiobarbituric acid in the Fischer 344 rat. 259 97

HIV-associated nephropathy (HIVAN) is a renal disease characterized clinically by heavy proteinuria and renal failure and morphologically by severe and rapidly evolving focal and segmental glomerulosclerosis, tubular necrosis, interstitial edema, and ultrastructural cellular inclusions. In an attempt to elucidate its pathogenesis, we evaluated the role of direct viral (HIV) infection of renal epithelium with the use of a cDNA probe for viral nucleic acid and an immunoperoxidase-labeled antibody to p24 core protein. In 10 of 11 kidneys with HIVAN, nucleic acid was localized to glomerular and tubular epithelium, while only 2 of 4 kidneys from HIV-infected patients with immune complex glomerulonephritis were similarly affected, but with considerably less cellular involvement. Kidneys from patients with acquired immune deficiency syndrome but without renal disease had only rare cellular positivity. In all instances, the cDNA probe was more sensitive than anti-p24 immunoperoxidase. These data suggest a role for direct HIV infection of renal epithelial cells in the initiation and/or progression of HIV-associated nephropathy.
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PMID:Demonstration of human immunodeficiency virus in renal epithelium in HIV-associated nephropathy. 265 19


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