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Biomedical subjects

B M Tune

Publications and source records attributed to B M Tune.

At least 19 recordsLinked to original sources
PubMed1998

Plasma glutathione peroxidase and its relationship to renal proximal tubule function.

Selenium-dependent extracellular glutathione peroxidase (E-GPx) is found in plasma and other extracellular fluids. Previous studies have indicated that patients with chronic renal failure on dialysis have low plasma GPx activity. In this study, dialysis patients had approximately 40% of control plasma GPx activity, while anephric individuals had lowest plasma GPx activities ranging from 2 to 22% of control. The residual plasma GPx activity in anephric individuals could be completely precipitated by anti-E-GPx antibodies, indicating that all plasma GPx activity can be attributed to E-GPx in both normal and anephric individuals. Plasma GPx activity rises rapidly following kidney transplantation, often reaching normal values within 10 days. The plasma GPx activity in some transplanted patients rises to levels higher than the normal range, followed by a return to the normal range. Since E-GPx in the kidney is primarily synthesized in the proximal tubules, we investigated whether nephrotoxic agents known to disrupt proximal tubule function also affected plasma GPx activity. The beta-lactam antibiotic cephaloglycin rapidly caused a decrease in plasma GPx activity in rabbits. In addition, the chemotherapeutic agent ifosfamide caused a decrease in plasma GPx activity in pediatric osteosarcoma patients. Fanconi syndrome associated with either ifosfamide therapy or valproic acid therapy also caused a decrease in plasma GPx activity. Thus plasma GPx activity is related to kidney function and is decreased in certain situations where nephrotoxic drugs are administered. Monitoring plasma GPx activity may have predictive value in evaluating the function of transplanted kidneys or in predicting those patients particularly at risk of nephrotoxic injury associated with certain medications.

Adult↗
PubMed1997

Nephrotoxicity of beta-lactam antibiotics: mechanisms and strategies for prevention.

The nephrotoxic beta-lactam antibiotics cause acute proximal tubular necrosis. Significant renal toxicity, which has been rare with the penicillins and uncommon with the cephalosporins, is a greater risk with the penems. Mechanisms of injury include: (1) transport into the tubular cell, mainly through the antiluminal organic anion secretory carrier; (2) acylation of target proteins, causing respiratory toxicity by inactivation of mitochondrial anionic substrate carriers; and (3) lipid peroxidation. The most nephrotoxic beta-lactams available for study are cephaloridine, cephaloglycin, and imipenem; panipenem, which is comparably nephrotoxic, is currently available only in Japan. Cephaloridine has several unique properties, probably all caused by its pyridinium side-group: (1) its secretory transport into the tubular cell is followed by minimal cell to luminal fluid movement, resulting in extreme intracellular sequestration; (2) it is the only beta-lactam shown to cause significant oxidative injury; (3) it has a limited ability to attack the mitochondrial carriers for pyruvate and the short-chain fatty anions. Cephaloglycin and imipenem undergo less intracellular trapping than cephaloridine, but have sufficient tubular cell uptake, reactivity, and generalized toxicity to mitochondrial substrate carriers to be severely nephrotoxic. Cephaloridine and cephaloglycin are no longer used clinically. Imipenem and panipenem are marketed in combination with nephroprotective renal transport inhibitors. Strategies for avoiding renal toxicity with new cephalosporins and penems are discussed.

Animals↗
PubMed1997

Treatment of the idiopathic nephrotic syndrome: regimens and outcomes in children and adults.

This review compares the biopsy patterns, complications, responses to therapy, and long-term outcomes of idiopathic NS in children and adults. On first examination, distinctions between the pediatric and adult diseases seem more quantitative than absolute. However, underlying determinants of outcome, including immunocompetence, growth, maturity, and senescence, can present very different challenges for pediatricians and internists. The major biopsy patterns in pediatric NS include MCD, FSGS, and DMP. MCD is overwhelmingly the most frequent and most steroid-responsive of the three but commonly presents problems of massive edema, serious bacterial infections, and multiple relapses. Because of the prompt response of pediatric MCD to corticosteroids, steroid resistance in children has generally been defined as persistence of proteinuria after 1 month of daily followed by 1 month of intermittent prednisone administration. By this criterion, nephrotic FSGS is usually steroid-resistant and, if not controlled by more aggressive therapy, typically progresses to ESRD. DMP is commonly steroid-resistant but may slowly resolve. It is not clear to what extent remissions of DMP represent a delayed response to steroids or would have occurred without treatment. Biopsies showing a few globally obsolescent glomeruli or mild mesangial hypercellularity may be associated with greater difficulty in management but have been included in the broad category of MCD. Moreover, evolution of patterns in serial biopsies, variable steroid-responsiveness of FSGS and DMP, and progression of some cases of MCD to ESRD suggest common features in the three major categories. Among adults with idiopathic NS, FSGS is the most frequent biopsy pattern, followed by MN (which is rare in children) and then by MCD. In contrast to its pediatric counterpart, MCD in adults is less regularly and more slowly responsive to corticosteroids and in the elderly is more commonly associated with hypertension and renal failure. MCD in adults is less likely to relapse once remission is achieved. Adults with FSGS present less commonly with severe edema than do children with this lesion. Although children and adults with FSGS present similar challenges of resistance to therapy and loss of renal function, the more aggressive oral steroid regimens used by internists preclude strict comparisons between pediatric and adult series. There is insufficient information to support a systematic analysis of DMP in adults. Cytotoxic agents and cyclosporine have been used with varying success in children and adults with difficult cases of NS. In MCD, an alkylating agent can increase the likelihood and duration of remission. Cyclosporine can also improve control in MCD, but continued treatment is often needed to maintain remission. Significant control of steroid-resistant FSGS has not been achieved with limited courses of an alkylating agent or cyclosporine. Longer courses of either of these immunosuppressants, especially when combined with intermittent steroid administration, can produce more complete and/or more sustained remissions. However, cyclosporine nephrotoxicity is more severe in FSGS than in MCD and in steroid-resistant than in steroid-dependent NS, regardless of biopsy pattern. A protocol combining iv M-P pulses, alternate-day prednisone, and an alkylating agent in steroid-resistant pediatric FSGS has produced the highest percentage of sustained remissions with normal renal function, of all reported regimens. Controlled trials of this and other combined drug protocols are needed in children and adults.

Adult↗
PubMed1996

Cephalosporin and carbacephem nephrotoxicity. Roles of tubular cell uptake and acylating potential.

Three beta-lactams, desacetylcephaloglycin, ampicillin, and loracarbef, were studied to test a hypothesis derived from retrospective analysis of previously studied cephalosporins: that beta-lactam nephrotoxicity develops in approximate proportion to tubular cell antibiotic concentrations and lactam ring reactivities. Concentrations of each beta-lactam (and insulin) in rabbit renal cortex and serum were measured at the end of 0.5-hr infusions of 100 mg antibiotic/kg body weight and 0.5 to 0.67 hr later. Total cortical AUCs (total areas under the curve of concentration and time in renal cortex) and transported cortical AUCs (total minus insulin-space beta lactam) were calculated from these measurements. Reactivities, determined by the rate constants of lactam-ring opening at pH 10, were taken from the literature. Nephrotoxicity was quantified by grades of proximal tubular cell necrosis and by serum creatinine concentrations 2 days after infusion of 100-1500 mg/kg of the antibiotics. Desacetylcephaloglycin was slightly less nephrotoxic than cephaloglycin; the AUCs reactivities, and toxicities of these two cephalosporins fit the proposed model, particularly when allowance is made for hepatic and renal deacetylation of cephaloglycin. The very low AUCs, limited reactivity, and absence of nephrotoxicity of ampicillin also fit the model. Loracarbef had a transported AUC less than three times, and reactivity one-thirtieth, those of cefaclor, respectively. Although only at 1500 mg/kg, loracarbef was significantly more nephrotic than cefaclor. If the relativity of loracarbef with its targeted bacterial proteins, which is essentially the same as that of cefaclor, is considered instead of the base hydrolysis rate constant, than loracarbef also fits the model. By the same analysis, the comparatively high in vitro stability of other carbacephems, although pharmaceutically convenient, may not limit their nephrotoxicity.

Acylation↗
PubMed1996

Steroid-resistant nephrotic focal segmental glomerulosclerosis: a treatable disease.

If not aggressively treated, oral steroid-resistant (SRst) nephrotic focal segmental glomerulosclerosis (FSGS) is likely to progress to end-stage renal failure. Three observations challenge the conclusion of the International Study of Kidney Diseases in Children (ISKDC) that SRst FSGS is unresponsive to further immunosuppression: (1) The ISKDC definitions of response and relapse, which fit the patterns in minimal change disease, precluded appropriate recognition of partial or gradual responses. (2) In two ISKDC studies, a small number of children with FSGS in one case, and the use of a year of alternate-day prednisone as a control in the other, may have obscured the effects of cyclophosphamide. (3) Recent studies of more aggressive therapies have provided strong evidence of benefit. High-dose methylprednisolone infusion therapy, with alternate-day prednisone alone or with alternate-day prednisone plus an alkylating agent (the M-P/ triple therapy protocol) has achieved sustained, complete remissions with stable renal function in 66% of children with SRst FSGS, and near-complete resolution of proteinuria in another 9%. Cyclosporine (CsA) plus alternate-day prednisone has produced complete or near-complete remissions in 35% of similar cases. Whether or not controlled studies will confirm the apparently greater efficacy of the M-P/triple therapy protocol, the favorable outcomes with both the M-P and the CsA regimens support the conclusion that a conservative approach to SRst FSGS is no longer appropriate.

Child↗
PubMed1995

Effects of L-carnitine on the renal tubular transport of cephaloridine.

It has been demonstrated recently that cephaloridine (Cld) inhibits the tubular reabsorption of filtered carnitine (Carn) in the rabbit kidney. This interaction has suggested that the limited net cell-to-luminal fluid movement of Cld following its secretory transport across the antiluminal membrane might result from a balance of active Cld reabsorption by a Carn carrier at the brush border approximately equal to its secretion into the tubular fluid, rather than the previously proposed luminal membrane block. Studies were done to determine the effects of L-Carn, 750 mg/kg, i.v. on the tubular secretion and cortical concentrations of Cld, infused i.v. at a dose of 28 mg/kg (Carn:Cld molar ratio = 70:1). The fractional excretions of Cld during three consecutive periods of 10 min each, one before and two following the bolus infusion of Carn, were (means +/- SEM): 1.18 +/- 0.14, 1.20 +/- 0.14, and 1.16 +/- 0.11, respectively (N = 6 each; differences NS). Cortex-to-serum concentration ratios of Cld in control and Carn-treated rabbits were 10.43 +/- 0.32 and 10.16 +/- 0.86, respectively (NS). The data provide evidence against the reabsorptive transport of Cld by a Carn carrier, and do not support a model of balanced secretion and reabsorption as the cause of limited clearance despite significant secretory transport of Cld into the tubular cell.

Animals↗
PubMed1995

Toxicity of cephalosporins to fatty acid metabolism in rabbit renal cortical mitochondria.

UNLABELLED: Cephaloglycin (Cgl) and cephaloridine (Cld) are acutely toxic to the proximal renal tubule, in part because of their cellular uptake by a contraluminal anionic secretory carrier and in part through their intracellular attack on the mitochondrial transport and oxidation of tricarboxylic acid (TCA) cycle anionic substrates. Preliminary studies with Cgl have provided evidence of a role of fatty acid (FA) metabolism in its nephrotoxicity, and work with Cld has shown it to be a potent inhibitor of renal tubular cell and mitochondrial carnitine (Carn) transport. Studies were therefore done to examine the effects of Cgl and Cld on the mitochondrial metabolism of butyrate, the anion of a short-chain FA that does not require the Carn shuttle to enter the inner matrix, and the effects of Cgl on the metabolism of palmitoylcarnitine (PCarn), the Carn conjugate of a long-chain FA that does enter the mitochondrion by the Carn shuttle. The following was found: (1) Cgl reduced the oxidation and uptake of butyrate after in vitro (2000 micrograms/mL, immediate effect) and after in vivo (300 mg/kg body weight, 1 hr before killing) exposure; (2) Cld caused milder in vitro toxicity, and no significant in vivo toxicity, to mitochondrial butyrate metabolism; (3) like Cld, Cgl reduced PCarn-mediated respiration after in vivo exposure, but, unlike Cld, it did not inhibit respiration with PCarn in vitro; (4) the Carn carrier was stimulated slightly by in vitro Cgl but was unaffected by in vivo Cgl; (5) in vivo Cgl had no effect on mitochondrial free Carn or long-chain acylCarn concentrations in the in situ kidney; (6) Cgl increased the excretion of Carn minimally compared with the effect of Cld; and (7) cephalexin, a nontoxic cephalosporin, caused mild reductions of respiration with butyrate and PCarn during in vitro exposure, but stimulated respiration with both substrates after in vivo exposure. CONCLUSIONS: Cgl has essentially the same patterns of in vitro and in vivo toxicity against mitochondrial butyrate uptake and oxidation that both Cgl and Cld have against TCA-cycle substrates. Cld has little or no in vivo toxicity to mitochondrial butyrate metabolism, whereas in vivo Cgl is as toxic as Cld to respiration with PCarn. The greater overall in vivo toxicity of Cgl to mitochondrial FA metabolism, with lower cortical concentrations and AUCs than those of Cld, supports earlier evidence that Cld is less toxic than Cgl at the molecular level.

Animals↗
PubMed1995

Management of the difficult nephrotic patient.

Most children with nephrotic syndrome do well, usually with multiple relapses and remissions. Some children require high doses of oral steroids to sustain a remission and develop significant steroid toxicity. These patients frequently can be managed with oral alkylating agents or with cyclosporine. A few nephrotic children to not respond to oral prednisone. The most common biopsy finding in steroid-resistant patients is focal segmental glomerulosclerosis. Many patients with this condition progress to chronic renal failure. Evidence suggests that the outcome is improved with either cyclosporine or with a protocol using pulse intravenous methylprednisolone and oral alkylating agents.

Child↗
PubMed1995

Effects of nephrotoxic beta-lactam antibiotics on the mitochondrial metabolism of monocarboxylic substrates.

UNLABELLED: The nephrotoxic beta-lactam antibiotics (beta-lactams) cephaloridine, cephaloglycin and imipenem are toxic to the mitochondrial transport and (secondarily) oxidation of succinate and other dicarboxylic substrates. However, compared to cephaloglycin, cephaloridine is minimally toxic to the mitochondrial uptake and uncoupled oxidation of the short-chain fatty anion butyrate. Further studies were therefore done to compare the early effects of nephrotoxic doses (300 mg/kg body weight) of imipenem, cephaloridine and cephaloglycin on the mitochondrial metabolism of three important monocarboxylic substrates, butyrate, valerate and pyruvate, in rabbit renal cortex. The following was found: 1) imipenen reduces the oxidation of all three monocarboxylates, within 0.5 to 1 hr after administration. 2) The respiratory toxicity of cephaloglycin is essentially the same as that of imipenem with all three substrates. 3) cephaloridine causes little or no toxicity to pyruvate or butyrate oxidation and is significantly less toxic than imipenem or cephaloglycin to valerate oxidation. 4) The effects of the three beta-lactams on butyrate and pyruvate uptake parallel their effects on butyrate and pyruvate oxidation. CONCLUSIONS: Imipenem and cephaloglycin have essentially the same patterns of toxicity to the mitochondrial metabolism of all metabolic substrates that have been tested. Although cephaloridine has similar effects on dicarboxylic substrates, it is significantly less toxic to the mitochondrial metabolism of pyruvate and the short-chain fatty anions. It is proposed that cephaloridine's zwitterionic charge may restrict its ability to acylate monocarboxylic and other anionic carriers, resulting in less nephrotoxicity than might otherwise result from its uniquely high intracellular concentrations and singular ability among the toxic beta-lactams to produce oxidative injury.

Animals↗
PubMed1995

Intravenous methylprednisolone and oral alkylating agent therapy of prednisone-resistant pediatric focal segmental glomerulosclerosis: a long-term follow-up.

UNLABELLED: Prednisone-resistant nephrotic syndrome (NS) due to focal segmental glomerulosclerosis (FSGS), the most common acquired disease requiring chronic dialysis and transplantation in children, has a low likelihood of response to alkylating agent therapy. This report summarizes the results of a 0.75-12.5 (average 6.33) year follow-up of 32 pediatric cases of prednisone-resistant FSGS treated with a regimen of high-dose intravenous methylprednisolone (M-P) and alternate-day prednisone, plus an alkylating agent in 25/32. On last followup: 21/32 were in remission [urine protein-to-creatinine ratios (Pru/Cru) < or = 0.2]; 3/32 had mild proteinuria (Pru/Cru > 0.2-0.5); 2/32 had moderate proteinuria (Pru/Cru > 0.5-1.9); and 6/32 remained nephrotic (Pru/Cru > or = 2.0). Of the incomplete or nonresponders; 3/11 progressed to end-stage renal failure; 5/11 had decreased creatinine clearances (CrCl): and 3/11 had persistent proteinuria with normal CrCl. All of the persistently nephrotic children, but none of the complete responders, developed decreased CrCl. All of the complete responders were able to stop treatment; four relapsed but responded well to retreatment. CONCLUSIONS: This regimen of methylprednisolone and alternate-day prednisone, with or without an alkylating agent, is effective in achieving sustained remissions and preserving normal renal function in the great majority of children with FSGS and prednisone-resistant NS.

Child, Preschool↗
PubMed1994

Renal tubular transport and nephrotoxicity of beta lactam antibiotics: structure-activity relationships.

Several of the cephalosporin and carbapenem antibiotics produce acute renal failure when given in large single doses. Antibiotic concentrations in the tubular cell, determined by the net effects of contraluminal secretory transport and subsequent movement across the luminal membrane, make the proximal tubule the sole target of injury, and are important determinants of the nephrotoxic potentials of different beta-lactams in different animal species. At least three molecular mechanisms of injury have been shown with cephaloridine, the most widely studied nephrotoxic beta-lactam: (1) lipid peroxidation, (2) competitive inhibition of mitochondrial carnitine (zwitterionic) transport and fatty acid oxidation, and (3) acylation and inactivation of tubular cell proteins, most thoroughly evaluated with mitochondrial anionic substrate transporters. The first two of these injuries are dependent upon one or both of cephaloridine's side group substituents, which are not present on the other nephrotoxic cephalosporins or carbapenems. It is not surprising, therefore, that only toxicity to mitochondrial anionic substrate carriers has been found in studies of the other beta-lactams. However, the several effects of cephaloridine on the tubular cell indicate a potential for different mechanisms of attack on different molecular targets. Continuing studies of the effects of existing and newly developed beta-lactams are likely to identify further nephrotoxic mechanisms of this complex and rapidly growing group of antimicrobials.

Acute Kidney Injury↗
PubMed1994

Toxicity of cephaloridine to carnitine transport and fatty acid metabolism in rabbit renal cortical mitochondria: structure-activity relationships.

Cephaloridine (Cld), the most widely studied nephrotoxic cephalosporin, has significant structural homology with carnitine, which facilitates the transport of long-chain fatty acids into the mitochondrial inner matrix. Because of this homology, and evidence of a role of lipids in cephaloglycin (Cgl) nephrotoxicity, protocols were designed to compare the effects of Cld and Cgl on renal cortical mitochondrial carnitine transport, on long-chain fatty acylcarnitine-mediated respiration and on the in situ mitochondrial pools and urinary excretion of carnitine and acylcarnitines. The following was found: 1) both cephalosporins reduced carnitine-facilitated pyruvate oxidation (CFPO) and palmitoylcarnitine-mediated respiration (PCMR) by 40 to 50% in mitochondria exposed in vivo (300 mg/kg b.wt., 1 hr). CFPO could be decreased by reduction of carnitine uptake, pyruvate oxidation or carnitine acetyltransferase activity; 2) neither cephalosporin reduced mitochondrial carnitine acetyltransferase or carnitine palmitoyltransferase; 3) with in vitro exposure (2000 micrograms/ml, immediate effect) Cgl had no significant toxicity to mitochondrial CFPO. Cld inhibited CFPO in a dose-dependent manner, up to 100% at 2000 micrograms/ml; this effect was reduced by increasing carnitine concentrations; 4) in vitro Cld prevented the potentiation of PCMR by preloading with carnitine, reduced mitochondrial acetylcarnitine/carnitine exchange by 70% and reduced PCMR by 30%; 5) in vivo Cld increased mitochondrial-free carnitine in the in situ kidney by 100%; and 6) in vivo Cld increased the fractional renal excretion of carnitine from 0 +/- 0 to 0.29 +/- 0.03 and the fractional excretion of long-chain acylcarnitines from 0.06 +/- 0.01 to 0.79 +/- 0.17.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Treatment of childhood nephrotic syndrome.

This review examines selected aspects of the treatment of the nephrotic syndrome in children. Particular attention has been paid to two groups of nephrotic children. First, children with steroid-responsive nephrotic syndrome are discussed. Recently, a series of controlled studies have provided important information regarding the optimal duration of steroid therapy. Initial episodes of the nephrotic syndrome are best treated with "long" courses of prednisone therapy (6 wk of high-dose daily prednisone followed by 6 wk of alternate-day prednisone). In contrast, relapses do as well with "short" courses (about 2 wk of daily prednisone and 2 wk of alternate-day therapy). Some children who are steroid responsive require high doses of prednisone to remain in remission. These patients may require alkylating agent therapy. The most common cause of steroid-resistant nephrotic syndrome is focal segmental glomerulosclerosis. Over the past 10 yr, these patients have been treated with an intensive protocol involving multiple infusions of high-dose methylprednisolone and, in many cases, oral alkylating agent therapy. Current experience with this treatment is presented. The protocol appears to improve the outcome in children with focal segmental glomerulosclerosis, although it is believed that it is essential that these observations be confirmed by a controlled trial. There is also interest in the use of angiotensin-converting enzyme inhibitors and cyclosporine in the treatment of childhood nephrotic syndrome. The experience with these agents is briefly reviewed, but the current data are inadequate to indicate their role(s) in this condition.

Administration, Oral↗
PubMed1991

A study of nephrotoxin-induced acute tubular necrosis with 31P magnetic resonance spectroscopy.

Phosphorus magnetic resonance spectroscopy (31P MRS) was used to obtain in vivo spectra from rat kidneys undergoing acute tubular necrosis induced by a nephrotoxic dose of cephaloridine (CLD). Spectra were obtained 0, 24, and 48 h after injection of CLD (experimental group, n = 6) or saline vehicle (control group, n = 6). The nephrotoxicity of CLD was demonstrated by severely increased serum creatinine levels and the development of extensive proximal tubular necrosis in the CLD-injected rats, and the lack of such changes in the controls. 31P MRS showed an increase in the inorganic phosphate region signal (Pi, p = 0.004) and a decrease in the phosphodiester region signal (PDE, p = 0.01) in the experimental group by 48 h, whereas these parameters did not vary significantly in the control group during the experiment. Significant correlations were found between serum creatinine and the same two 31P MRS parameters. In summary, rat kidneys which have developed severe CLD-induced proximal tubular necrosis exhibit changes in the 31P spectrum 48 h after administration of the drug. The causes of these changes were not determined.

Animals↗
PubMed1990

Continuous venovenous hemofiltration.

Continuous venovenous hemofiltration (CVVH) is a technique characterized by a venovenous circuit and a pump to perfuse the hemofilter. CVVH is suited to individualization of ultrafiltration and solute clearance in patients with acute renal failure and volume overload, specifically when there is impaired cardiovascular function or where arterial access is problematic. Examples, indications and relative advantages of this and other dialytic modalities are discussed.

Acute Kidney Injury↗
PubMed1990

Treatment of steroid-resistant focal segmental glomerulosclerosis with pulse methylprednisolone and alkylating agents.

In children, steroid-resistant nephrotic syndrome due to focal segmental glomerulosclerosis (FSGS) is frequently a progressive condition resulting in end-stage renal disease. There have been no reports of effective treatment for this condition. For the past several years, the Pediatric Nephrology services at the University of California, San Diego and Stanford University Schools of Medicine have treated these patients with a protocol involving infusions of high doses of methylprednisolone, often in combination with oral alkylating agents. Twenty-three children have been treated in this manner with a follow-up of 46 +/- 5 months. Twelve of these children are in complete remission. Six have minimal to moderate proteinuria. Four children remain nephrotic. Each of these children has a normal glomerular filtration rate. One child developed chronic renal failure and subsequently died while on dialysis. These results appear significantly better than previous series of children with FSGS. A controlled, multi-center trial of this protocol has been proposed.

Adolescent↗