Possible mechanisms to explain the absence of hyperkalaemia in Addison's disease.
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Addison Disease↗
Biomedical subjects
R F Gagnon
Publications and source records attributed to R F Gagnon.
Acute renal failure in a young woman with endometriosis.
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Abdominal Pain↗
Prospective study of urinalysis abnormalities in HIV-positive individuals treated with indinavir.
Indinavir is a potent protease inhibitor widely used in combination with reverse-transcriptase inhibitors to treat human immunodeficiency virus (HIV) disease. Individuals treated with indinavir are prone to develop urinary complications, including renal colic, renal calculi, lower urinary tract symptoms, and indinavir crystalluria. Although renal stones secondary to indinavir have been described and characterized, little is known about the onset, frequency, and significance of the crystalluria. To document the longitudinal characteristics of indinavir crystalluria and associated urine abnormalities, 54 asymptomatic indinavir-naive HIV-positive individuals had urinalysis testing initially weekly and then monthly during the first year of indinavir treatment. Six hundred eight urinalyses were performed (11 +/- 2 urinalysis/subject), including 579 microscopy examinations performed by a nephrologist (10 +/- 2 examinations/subject). Baseline urinalysis results were essentially normal. After the start of treatment, indinavir crystalluria was frequently observed (67% of subjects). After the first 2 weeks, indinavir crystalluria remained constant at a frequency of approximately 25% of urine sediments examined at each test point. Other urine abnormalities, principally leukocytes (>/=10/high-power field) and casts, were observed in 39% of subjects. These abnormalities were more severe in five subjects, with concomitant increasing serum creatinine levels in three of them. Additional urine findings include the predominance of low pH (</=5. 5 in 72% of urinalyses) and high specific gravity (>/=1.025 in 66% of urinalyses). In conclusion, abnormal urinalysis results were noted frequently during the first year of treatment with indinavir. The main findings were the high proportion of subjects with crystalluria and the relatively high frequency of crystalluria observed consistently throughout. These findings may occasionally be associated with other urine abnormalities, presumably secondary to indinavir crystalluria.
Adult↗
Acquired cystic kidney disease: rapid progression from small to enlarged kidneys simulating adult polycystic kidney disease.
A 57-year-old man on chronic hemodialysis presented marked bilateral renal enlargement due to acquired cystic kidney disease (ACKD). He had been on hemodialysis for less than 3 years only (14 months prior to receiving a functional renal transplant which lasted 8 years, followed by 18 additional months of dialysis), before the diagnosis of ACKD was made following an episode of flank pain with gross hematuria. The marked changes in kidney appearance during this 11-year period were documented by serial ultrasound examination showing the kidneys to be of near-normal size before the start of dialysis (> or =10 cm in 1986), then shrunken and contracted 5 years later while having a functioning renal transplant (<5 cm in 1991), and markedly enlarged reaching the size of adult polycystic kidney disease after returning to dialysis (>13 cm in 1997). Since the risk of ACKD increases with duration of dialysis, we sought additional predisposing factors in this unusual case and found that 2 years after renal transplantation, the patient was diagnosed with breast cancer for which he was treated with surgical excision and tamoxifen. Based on ultrasound evidence that the tamoxifen treatment preceeded the appearance of the renal cystic changes, we wonder whether this drug may have played a role in the rapid development of ACKD.
Antineoplastic Agents, Hormonal↗
Metabolic acidosis during urinary retention in a patient with an enterovesical fistula.
We report a patient known to have an enterovesical fistula who presented severe acute metabolic acidosis during an episode of urinary retention. The enterovesical fistula which had been intermittently symptomatic for 4 years, had developed after several intestinal surgical procedures and related intraperitoneal sepsis following resection of colon cancer 21 years previously. The patient who had a total colectomy and ileostomy, was admitted for hip replacement with the routine placement of a Foley bladder catheter. Three weeks post-operatively, the patient developed acute urinary retention following removal of the urinary catheter. The output from his ileostomy was immediately markedly increased, presumably from bladder urine diverted into the intestines through the enterovesical fistula. Within a few days he presented a normal anion gap metabolic acidosis with raised urea and stable creatinine; his clinical status deteriorated markedly with profound obtundation. These metabolic abnormalities were readily corrected by re-insertion of the Foley catheter with restoration of normal urine flow and immediate corresponding fall in the ileostomy output. Radiographic studies showed the presence of the enterovesical fistula originating from the jejunum. This is the first report of acute metabolic acidosis in association with an enterovesical fistula; the severe metabolic disturbances were triggered by the development of urinary retention resulting in the diversion of urine into the small bowel through the fistula.
Acidosis↗
Erythrocytosis after renal transplantation represents an abnormality of insulin-like growth factor-I and its binding proteins.
BACKGROUND: Secondary erythrocytosis is classically defined by an increase in erythropoietin (EPO) production. Despite increased levels of EPO often seen in secondary erythrocytosis, some of these forms such as that seen after renal transplantation remain undefined. Our group has recently investigated the in vivo function of insulin-like growth factor-I (IGF-I) in erythropoiesis both in humans and in a murine model of chronic renal failure. These data, and the recently recognized role of IGF-I in polycythemia vera, suggested that IGF-I might be involved in secondary erythrocytosis. METHODS: Renal transplant recipients who developed erythrocytosis after transplantation were compared to normal individuals and to renal transplant recipients without erythrocytosis. We measured fasting serum EPO and IGF-I in all three groups. Because binding proteins may modify IGF-I function, IGF-I-binding proteins (IGFBP) 1 and 3, major binding proteins of IGF-I, were also measured. RESULTS: Renal transplant recipients have significantly elevated serum of IGF-I and IGFBP3 compared to normal individuals. When transplant recipients with and without posttransplant erythrocytosis were compared, similar levels of IGF-I were found; however, the group with erythrocytosis had significantly elevated IGFBP1 and IGFBP3. No other significant differences including EPO levels were found between the groups. CONCLUSIONS: Erythrocytosis after renal transplantation represents an anomaly of both IGF-I and its major binding proteins. Further studies are under way to better define this dysregulation and determine whether IGF-I can play a more generalized role in secondary forms of erythropoiesis.
Adult↗
Light microscopy of indinavir urinary crystals.
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Anti-HIV Agents↗
Subtherapeutic erythropoietin and insulin-like growth factor-1 correct the anemia of chronic renal failure in the mouse.
Chronic renal failure (CRF) is associated with a hyporegenerative anemia, which is caused primarily by inadequate production of erythropoietin (EPO) by the diseased kidneys and is responsive to exogenous EPO administration. Little is known about compensatory mechanisms that might supervene in anemia with low levels of EPO. Multiple investigations in vitro suggest an important role for insulin-like growth factor-1 (IGF-1) as well as EPO in erythropoiesis. Recently, both EPO and IGF-1 in vitro have been found to stimulate erythroid colony forming units in the mouse. However, no studies have examined the effect of IGF-1, singly and in combination with EPO, in CRF in vivo. This study examined mice with surgically-induced renal failure of six weeks duration that were treated for three weeks with the combination of subtherapeutic doses of both EPO and IGF-1. The single administration of each cytokine caused no significant change in hemoglobin in all CRF mice. In marked contrast the combined administration of the two cytokines produced a striking rise in hemoglobin, resulting in anemia correction in the majority of animals. The response to the combination therapy was comparable to the maximal response obtained with a single EPO dose (10 U) in a dose-finding study. Although the data are limited to utilizing one dose of each cytokine and one preparation of IGF-1, the large increase in hemoglobin observed with the combination therapy indicates that these two cytokines work in concert to stimulate erythroid precursors in CRF. In addition, untreated CRF mice showed markedly increased serum levels of low molecular weight binding proteins for IGF-1, potentially reducing the bioavailability of IGF-1. These findings taken together suggest that the anemia of CRF may represent both an EPO and a functional IGF-1 deficient state.
Anemia↗
Anemia of chronic renal failure: characterization in the mouse and correction with human recombinant erythropoietin.
Anemia is a cardinal feature of chronic renal failure (CRF) which contributes significantly to the clinical syndrome of chronic uremia. We have conducted a detailed examination of the hematological changes in CRF in the inbred mouse strain C57BL/6J. As in the human situation, CRF mice presented major hematological changes affecting primarily the erythroid cell series. Despite the presence of abundant iron stores in the bone marrow, the CRF mice developed a hypoproliferative anemia of a severity commensurate with the degree of renal impairment. The levels of circulating erythropoietin (EPO) in CRF mice were not significantly different from those in normal control littermates and were therefore inappropriately low for the degree of anemia. In contrast acutely bled control mice with normal renal function showed a significant inverse correlation between the serum EPO level and hemoglobin concentration, indicating an appropriate response to anemia. The chronic administration of recombinant human EPO raised the hemoglobin concentration of CRF mice, a therapeutic effect which was independent of the initial degree of anemia. These observations suggest that this animal model has wide applicability for the study of anemia secondary to CRF.
Anemia↗
Effect of chronic renal failure on the expression of erythropoietin message in a murine model.
The anemia of chronic renal failure (CRF) is largely due to decreased production of erythropoietin (EPO) by the kidney. A small amount of EPO also originates from extra-renal sources, and this would be expected to assume a more important role in maintaining erythropoiesis when renal production is impaired. In this study, we examined the production of EPO mRNA by RT-PCR in kidney, liver, and bone marrow tissues isolated from normal mice, mice rendered acutely anemic by phlebotomy, and from mice with surgically induced CRF. The induction of acute anemia results in an expected increase in the expression of EPO mRNA in renal and hepatic tissue. In contrast, while the expression of EPO mRNA was expectedly reduced in the kidney from CRF mice, it was completely absent in the liver of these same animals. EPO mRNA expression was also absent in the bone marrow in both states of acute anemia and CRF. These results show that CRF can directly or indirectly can suppress the extrarenal production of EPO by the liver and that this effect may further aggravate the anemia of CRF.
Anemia↗
Possible role of mevalonate in the hypercholesterolemia seen in experimental chronic renal failure.
Hypercholesterolemia may contribute to the pathogenesis of atherosclerosis associated with chronic renal failure (CRF). The mechanism underlying CRF-induced hypercholesterolemia, however, is still unknown. Mevalonate is the direct product of the rate-limiting step in cholesterol synthesis which is catalyzed by 3-hydroxy-3-methylglutaryl coenzyme A reductase. We studied the changes in mevalonate metabolism in a mouse model of CRF in which serum total cholesterol levels are directly correlated with the degree of severity of the disease as measured by serum urea levels. The results of these experiments indicated that in CRF mice, the urine mevalonate levels were significantly lower, while serum mevalonate and total cholesterol levels were significantly higher than in normal mice. We believe that by restricting the normal urinary excretion of mevalonate CRF results in more of this precursor being available for direct cholesterol synthesis. In addition, an increase in circulating mevalonate may upregulate the shunt pathway of mevalonate metabolism in the liver and peripheral tissues, thus providing increased levels of the substrates acetoacetate and acetyl coenzyme A for cholesterol synthesis.
Animals↗
The differential activity of aminoglycoside antibiotics with rifampin explored in a kinetic in vitro model of implant-associated infection (Staphylococcus epidermidis).
Implant-associated infections offer resistance to antibiotic treatment and possibly do so because the causative bacteria which reside on the artificial surface are enclosed in a protective matrix (biofilm) shielding the bacteria against the action of host defenses and antibiotic action. We have investigated in vitro the effect of various antimicrobial agents on biofilms of Staphylococcus epidermidis, which is the main organism responsible for implant-associated infections. Rifampin was found to exert superior activity, albeit incomplete, against S. epidermidis biofilms using an assay system which enabled the determination of the kinetics of antibiotic action over five days. In a large screening study looking for agents capable of completing the action of rifampin, gentamicin was unexpectedly found to be antagonistic to rifampin. The present study was undertaken to investigate further the activity of gentamicin and five other aminoglycoside antibiotics using a wider range of concentrations (2.5-20 micrograms/mL). The main findings were a marked synergy with rifampin demonstrated by streptomycin, producing a bactericidal outcome, which contrasted sharply with the indifference or antagonism shown by the other aminoglycosides. We then studied in further detail the effect of separate combinations of streptomycin and gentamicin with rifampin over a wider concentration range of each agent (1.25-40 micrograms/mL). Streptomycin showed strong rapid synergy with rifampin even at the lowest concentration of each antibiotic. Gentamicin demonstrated a concentration-related antagonism towards rifampin which was independent of rifampin concentration. The data support the conclusion that streptomycin, like cell-wall active antibiotics, exerts a potent synergy with rifampin against S. epidermidis biofilms, and that the other aminoglycosides, predominantly gentamicin, strongly antagonize rifampin action.(ABSTRACT TRUNCATED AT 250 WORDS)
Anti-Bacterial Agents↗
Time-kill efficacy of antibiotics in combination with rifampin against Staphylococcus epidermidis biofilms.
Infections associated with implants are frequently resistant to conventional antibiotic therapy. This resistance has been ascribed to the presence of bacteria on the artificial surface within a protective glue-like matrix forming a bacterial biofilm. We have demonstrated that experimental biofilms of Staphylococcus epidermidis, the main pathogen associated with implantation, are exquisitely sensitive to the action of rifampin. This effect of rifampin is incomplete, however, with the emergence of rifampin-resistant survivors that readily repopulate the biofilm. Studies were therefore performed to determine the effect of combinations of 13 different antibiotics with rifampin against standardized S. epidermidis biofilm preparations in an in vitro assay enabling the kinetic measurement of antibiotic action over a five-day period. The antibiotic combinations with rifampin demonstrated unsuspected divergent patterns of antimicrobial activity against the biofilms: 1. rapid synergy with rifampin was observed with cell-wall active antibiotics (cloxacillin, cephalothin, cefazolin, and cefamandole), whereas slower synergy occurred with vancomycin, ciprofloxacin, tetracycline, and amikacin; 2. some antibiotics (tobramycin, erythromycin, clindamycin, fusidic acid) did not influence the outcome; 3. gentamicin unexpectedly showed marked antagonism to rifampin. These results are relevant to the design of optimal therapeutic regimens for the management of resistant implant-associated infections.
Anti-Bacterial Agents↗
Impact of dialysis fluid on the susceptibility of Staphylococcus epidermidis biofilms to rifampin.
Routine laboratory testing of the susceptibility of infecting strains of S. epidermidis to antibiotics is based on the assumptions that the infection is in contact with the stable environment of blood or tissue fluid and that the bacteria are in a susceptible phase of growth. In infections of the continuous ambulatory peritoneal dialysis (CAPD) intraperitoneal catheter, the bacteria are commonly in the resistant biofilm phase of growth, are applied to the surface of the catheter, and are exposed to the nonphysiological impact of peritoneal dialysis solutions. The possible impact of these two variables is not examined in routine testing of antibiotic susceptibility. We describe an assay of antibacterial action on a strain of S. epidermidis in the biofilm phase, exposed to a neutral control environment and to dialysis solutions, both fresh and spent. Rifampin, which has an incomplete action in a neutral control environment, was used as a sensitive indicator of possible synergistic or antagonistic interaction of the biofilm bacteria with the dialysis environments. We demonstrated that peritoneal dialysis solutions (1.5% dextrose), both fresh and spent, were synergistic with rifampin action against S. epidermidis biofilms, converting the incomplete killing action to a total bactericidal outcome, clinically essential for cure. Fresh dialysis solution was more active than spent, but in both instances the synergy was complete, indicating that the crucial complementation of the bactericidal action of rifampin was independent of pH. These findings have implications in the management of catheter-associated infections due to rifampin-susceptible strains of S. epidermidis.
Dialysis Solutions↗
An assay of Staphylococcus epidermidis biofilm responses to therapeutic agents.
Implant-associated infections tend to become persistent, resisting host defences and antibiotic therapy. Routine clinical laboratory testing of bacterial isolates in the fluid phase for antibiotic susceptibility may not be predictive of therapeutic outcomes and therefore a number of antibiotic regimes have been formulated empirically. The resistance of implant-associated infections has been ascribed to the production by bacteria, when adherent to the implant surface, of a shielding matrix of polymerized carbohydrates protecting the enclosed bacteria from immune defences and antibiotics. This complex of surface, bacteria and matrix is termed a biofilm. We describe a technique to evaluate the efficacy of antimicrobial agents directed against biofilm-forming strains of Staphylococcus epidermidis (a major cause of implant infections) utilizing standardized biofilm preparations formed on glass. The impact of the antimicrobial agents was assessed quantally using the end-point of permanent cessation of metabolic activity (cell death) of the entire biofilm determined by the loss of ability to reduce 2,3,5-triphenyltetrazolium chloride to a visible red intracellular precipitate of formazan. The relative rate of action of differing antimicrobial agents could be determined by the minimum period of exposure of the biofilm to the agents that is required to bring about sterilization, the clinically relevant marker. A wide range of antimicrobial substances could be evaluated, including chemical disinfectants, immunoreactive substances, antibiotics; singly and in combination; and the modifying effects of interaction with non-antibacterial therapeutic agents and other environmental factors. The technique is simple, inexpensive, reproducible and readily adaptable to the clinical situation where evaluation of therapeutic regimes for individual cases of prosthetic device-associated infection is required routinely with despatch and ease of interpretation.
Anti-Bacterial Agents↗
A mouse model of implant-associated infection.
Infections of implanted devices are of increasing frequency and importance, representing a significant limitation of many therapeutic modalities. There are puzzling features of implant-associated infection including the changes in microbial flora, the tendency to chronicity and impaired responses to conservative modes of treatment. The concept of the bacterial biofilm as a shielding mechanism generated by bacteria adherent to artificial surfaces has recently been proposed as an explanation for these features. The biofilm is a term applied to a complex comprising the implant surface, adherent bacteria and a specialized matrix enclosing the bacteria. The matrix of the biofilm is an electrostatically charged glue-like extracellular polymer derived by bacterial enzymes acting on tissue carbohydrates, formed by bacteria when adherent to surfaces. This matrix binds the bacteria to the surface providing a sequestration affording selective protection against harmful elements of the environment, especially mechanisms of host defenses and antimicrobial agents. These biological systems are complex to study because of the dynamic interaction of the microbial variables, host defenses, properties of synthetic materials and the biofilm matrix itself. There is a need for a laboratory model in which the variables can be controlled permitting the researcher to examine the outcomes of modifying one variable at a time in a planned and orderly manner. The practical way to attain this end is the conduct of studies in a stable reproducible animal model of localized biofilm-implant infection. Staphylococcus epidermidis is a representative of the class of microorganisms predominant in implant-associated infection. This paper describes the development of a model utilizing an implant-S. epidermidis-biofilm infection localized to the peritoneal cavity of the mouse. The natural history of the infection has been well documented and is stable in all respects for periods exceeding 3 months. This chronicity is especially advantageous in analyzing the impact of long-term therapeutic modalities and necessary periods of recovery and assessment. A representative example of an experimental use of this model to determine the relative efficacy of antibiotic therapeutic regimes is described, demonstrating its scope and efficacy.
Animals↗
Vancomycin therapy of experimental peritoneal catheter-associated infection (Staphylococcus epidermidis) in a mouse model.
Catheter-related sepsis, principally with S. epidermidis, remains a main complication of continuous ambulatory peritoneal dialysis (CAPD). A possible reason for the antibiotic resistance often displayed by these infections is the presence of bacteria growing in a protective biofilm on the catheter surface. We developed a reproducible stable model of experimental peritoneal catheter-associated infection with S. epidermidis in the mouse and used this model to examine the therapeutic efficacy of vancomycin. The response to vancomycin treatment given daily (15 mg/kg body weight) for periods from 1-14 days, relating the proportion of successful outcome (sterilization of implant infection) over time, was typical of an S-shaped biological response curve. These results extend our previous observations in vitro of the activity of vancomycin against S. epidermidis biofilm preparations and serve as a rational basis for the experimental evaluation of synergy and antagonism in the treatment of implant-associated infection.
Animals↗
The effect of peritoneal dialysis solutions on rifampin action against Staphylococcus epidermidis in the fluid and biofilm phases of growth.
Continuous ambulatory peritoneal dialysis (CAPD) catheter-associated infections can be resistant to conservative therapeutic measures despite the apparent susceptibility of the infecting bacterial strains to antibiotics. This chronicity of infection has been ascribed to the development of bacteria on the surfaces of catheter material within a protective polysaccharide shield or matrix. CAPD catheters are unique in being exposed to nonphysiological environments of dialysis fluids of varying physical properties and constitution. We determined that the rate of growth of S. epidermidis in the fluid phase in laboratory media or fresh dialysis solution was significantly influenced by pH. An acid milieu (pH 5) impaired growth compared to a neutral milieu (pH 7). Spent dialysis fluid, however, which had an approximately neutral pH, also impaired bacterial growth, the assumption being that this results from properties of spent fluid unrelated to pH. Using rifampin as the test antibiotic, we noted that its action on S. epidermidis was unaffected by pH or by the differing milieu of fresh and spent fluid. Bacterial growth was arrested regardless of the milieu. We further examined the potential of dialysis fluids to modify the interaction between rifampin and the matrix-enclosed bacteria of standardized S. epidermidis biofilms. We determined that the pH of the dialysis solution was a critical factor influencing the outcome of exposure of the biofilm to rifampin. An acid pH enhanced antibiotic activity, whereas a neutral pH was associated with antibiotic antagonism. These findings have implications in the management of S. epidermidis catheter-associated infections using rifampin.(ABSTRACT TRUNCATED AT 250 WORDS)
Dialysis Solutions↗