Biomedical subjects
Publications and source records attributed to W M Bennett.
Explore the source record for details and available documents.
As understanding of the molecular basis for the immune response has expanded rapidly, so have the possibilities for designing therapeutic interventions that are more effective, more specific, and safer than current treatment options. The promise of therapeutic advances in the future is based on the rapidly expanding insights into the pathogenesis of abnormal immunologic reactions. Nowhere is the understanding of molecular mechanisms, pathophysiology, and targeted therapy more relevant than in the field of renal transplantation, which makes up much of the clinical database for the use of immunosuppressive therapy for renal disease. Despite the recent advances in basic immunology, clinical validation of new agents and approaches is lacking for most drugs at present. This review will focus in the pharmacology of agents used in the therapy of immunologic renal disease and in renal transplantation. It should be recognized that clinical pharmacology and experience with newer agents is limited, and potential utility is based largely on experimental data.
The renal effects of nonsteroidal anti-inflammatory drugs are reviewed with special emphasis on the clinical, pathophysiologic, and risk factors for acute renal failure. Renal papillary necrosis and chronic renal insufficiency can occur with the prolonged use of these drugs, although the prevalence of this manifestation of nonsteroidal anti-inflammatory drug nephrotoxicity is unknown. Current recommendations based on a critical literature survey are provided, along with a list of suggested areas in which more research is needed.
The pathogenesis of fibrosis in chronic cyclosporine (CsA) nephropathy remains unknown. Since TGF-beta 1 plays a key role in the fibrogenesis of a number of renal diseases, we studied a salt-depleted rat model of chronic CsA nephropathy which shows similarity to the structural and functional lesions described in patients. Pair fed rats were treated with either CsA (15 mg/kg/day s.c.) or an equivalent dose of olive oil and sacrificed at 7 and 28 days. Characteristic histologic changes of proximal tubular injury, tubulointerstitial fibrosis and arteriolopathy developed in CsA-treated rats at day 28. They were accompanied by physiologic changes of increased serum creatinine, decreased creatinine clearance, increased enzymuria and decreased concentrating ability. CsA-treated rats showed a progressive increase in mRNA expression of TGF-beta 1 and matrix proteins at days 7 and 28. Most of the changes were in the tubulointerstitial and vascular compartments by immunofluorescence with a predominant involvement of the medulla as compared to cortex. The mRNA expression of plasminogen activator inhibitor, a protease inhibitor stimulated by TGF-beta 1, followed TGF-beta 1 and matrix proteins, suggesting that the fibrosis of chronic CsA nephropathy likely involves the dual action of TGF-beta on matrix deposition and degradation.
Explore the source record for details and available documents.
Acute cyclosporine (CsA) nephrotoxicity is characterized by a reduction of glomerular filtration rate (GFR), hypomagnesemia and tubular injury. The mechanisms of CsA's immunosuppressive action and presumably its nephrotoxicity are mediated through inhibition of the renal phosphatase, calcineurin. FK506 (FK), which has a different chemical structure and binding immunophilin, also inhibits calcineurin. We compared the renal effects of these drugs to those of rapamycin (RAPA), which although similar in structure and intracellular binding to FK, does not work by changing calcineurin activity. Rats were given CsA (15 mg/kg/s.c.), FK (6 mg/kg/p.o.), RAPA (3 mg/kg/p.o.) or vehicle (V) for two weeks on a low salt diet. CsA and FK strikingly decreased urinary excretion of nitric oxide, renal blood flow and GFR, whereas RAPA did not. In contrast, all these three drugs caused significant hypomagnesemia associated with inappropriately high fractional excretion of magnesium, suggesting renal magnesium wasting. In addition, with all three drugs there were lesions in the rat kidneys consisting of tubular collapse, vacuolization and nephrocalcinosis. We thus showed that only the calcineurin inhibitors produced glomerular dysfunction in an acute experimental model of nephrotoxicity. The mechanism of hypomagnesemia and tubular injury induced by all three immunosuppressive drugs is unclear but may be independent of calcineurin. The mechanism of renal vasoconstriction on the other hand may be related to inhibition of calcineurin.
Tubulointerstitial inflammation and fibrosis are critical determinants for renal function and prognosis in a variety of human nephropathies. Yet, the pathophysiology of the injury remains obscure. We investigated the expression of SPARC (secreted protein acidic and rich in cysteine) by immunohistochemistry and in situ hybridization in experimental models characterized by tubulointerstitial fibrosis and matrix expansion in rats. SPARC is a secreted glycoprotein that has been demonstrated to affect cellular interaction with matrix proteins, modulate cell proliferation, bind to and/or inhibit growth factors such as PDGF and bFGF, and regulate angiogenesis. Interstitial expression of SPARC was most prominent in passive Heyman nephritis (PHN), chronic cyclosporine A (CsA) nephropathy, and the remnant kidney model and, to a lesser extent, in angiotensin II (Ang II)-infused animals. SPARC protein and mRNA were substantially increased at sites of tubulointerstitial fibrosis/matrix expansion. In the PHN model, SPARC protein was expressed by interstitial fibroblasts that also produced alpha-smooth muscle actin ("myofibroblasts") and correlated both temporally (r = 0.97) and spatially with sites of type I collagen deposition. Interstitial cell proliferation preceded the development of interstitial fibrosis, and maximal SPARC expression (d15) coincided with the initial decline in interstitial proliferation. In the Ang II-infusion model, which is characterized by arteriolopathy and tubulointerstitial injury, an increase in SPARC protein and mRNA was also seen in injured blood vessels. SPARC was shown to be expressed by vascular smooth muscle cells and also by cells in the adventitia of hypertrophied arteries. In summary, SPARC was transiently expressed by interstitial fibroblasts at sites of tubulointerstitial injury and fibrosis, and by smooth muscle cells and cells in the adventitia of injured arteries in the Ang II-model. In addition to its proposed role in extracellular matrix deposition. the antiproliferative properties of SPARC might contribute to the resolution of interstitial fibroblast proliferation in the PHN model.
Explore the source record for details and available documents.
Cyclosporine and related compounds have dramatically improved the short-term success of solid organ transplantation. This paper outlines the pathophysiologic mechanisms of the nephrotoxicity of these compounds, highlighting relevant clinical and experimental work. It is hoped that as further understanding of these mechanisms evolves, rational therapeutic strategies will be available.
Cyclosporine is an immunosuppressant that undergoes extensive hepatic biotransformation to hydroxylated and demethylated metabolites. At present, the CYP3A gene family is thought to be the primary enzyme system responsible for cyclosporine metabolism. The effect of chronic cyclosporine therapy on the suppression of drug metabolism was studied in male and female rats maintained on a low-salt diet. After 28 days of subcutaneous cyclosporine dosing 15 mg/kg, cyclosporine-treated rats had significant renal dysfunction as compared with gender-matched control rats. Creatinine clearance in male cyclosporine-treated rats was reduced by 47% (P < .01) as compared with male controls. Female rats demonstrated a 38% (P < .01) decrease in creatinine clearance as a result of chronic cyclosporine therapy. Despite similar nephrotoxicity, female rats had whole blood cyclosporine levels 48% (P < .01) less than male rats. Immunoblot analysis of hepatic microsomal proteins indicated that chronic cyclosporine treatment decreased the protein levels of P450 3A2 in male rats. This loss was paralleled by reduced production of 6 beta-hydroxytestosterone, the primary product of P450 3A activity, by hepatic microsomes from cyclosporine-treated male rats by 76% (P < .001). In addition, cyclosporine treatment of male rats also reduced the formation of 2 alpha-hydroxytestosterone and 16 alpha-hydroxytestosterone by 81% (P < .01) and 84% (P < .001), respectively. At the end of the study period, steroid 5 alpha-reductase activity in control male rats was only 4% (P < .001) of female counter-parts; however, cyclosporine treatment increased steroid 5 alpha-reductase activity in male rats to 79% (P < .001) of female values. These alterations in testosterone metabolism are consistent with the suppression of the predominately male-associated P450 3A2, P450 2C11 and P450 2C13 isoforms. Levels of 6 alpha-hydroxytestosterone and 7 alpha-hydroxytestosterone were not statistically different between rat groups. Taken together, the steady-state blood levels and metabolism studies suggest that, after chronic cyclosporine treatment, isoforms other than those from the CYP3A family or unidentified members of the CYP3A family are likely responsible for cyclosporine metabolism.
BACKGROUND: Jet injection eliminates the risk of contaminated needlestick injuries when giving intramuscular or subcutaneous medications. Clinical efficacy of the Biojector System was equivalent to that of needle and syringe injection in unpublished trials with vaccines, but had not been studied using other drugs. OBJECTIVE: To compare the effectiveness of the Biojector with conventional needle and syringe injection in administering intramuscular morphine and subcutaneous heparin to healthy adults, as measured by plasma drug concentration. METHODS: Intramuscular injections of morphine 8 mg (5 mg if weight < or = 65 kg) were given 24 hours apart with the jet injector and with a needle and syringe to 30 subjects at the deltoid site and 10 subjects at the dorsogluteal site. Blood samples for plasma concentrations of free morphine were drawn at 15, 30, 45, 60, 120, and 240 minutes and were analyzed using radioimmunoassay. Abdominal subcutaneous injections of heparin 3500 U were given every 8 hours for 5 days with both injection methods to 29 subjects, with 48 hours between the two series. Daily blood samples for plasma heparin were analyzed by colorimetric assay for antifactor Xa activity. RESULTS: Mean free morphine concentration, peak value, and area under the curve did not differ significantly between the deltoid and dorsogluteal sites or between the jet injector and needle and syringe. Values of mean daily heparin concentrations and area under the curve were low and did not differ between the two injection methods. CONCLUSION: Plasma drug concentrations provided by the Biojector were equivalent to those provided by conventional needle and syringe when administering intramuscular morphine and low-dose subcutaneous heparin.
Explore the source record for details and available documents.
In the following report, a case of severe hyperphosphatemia and tetanic hypocalcemia resulting from the inadvertent oral ingestion of a phosphate enema is described. The physiology of serum phosphate regulation and the mechanism by which the elevation of serum phosphate is thought to induce hypocalcemia is discussed, and the treatment of hyperphosphatemia is reviewed. Finally, the potential consequences of the administration of calcium to treat tetany in a patient with severe hyperphosphatemia are considered.
Cyclosporine has proven to be an invaluable immunosuppressive agent in solid organ transplantation. However, its major side effect is dose-related acute and chronic nephrotoxicity. The acute effects of cyclosporine are predominantly hemodynamic and mediated by a variety of vasoactive compounds, including endothelin, thromboxane A2, and/or inhibition of nitric oxide synthase. The chronic lesion of cyclosporine nephropathy which consists of afferent arteriolopathy combined with striped tubulointerstitial fibrosis and glomerulosclerosis has been much more difficult to understand. An experimental model using the salt-depleted rat has been developed which reproduces the structural and functional changes of chronic cyclosporine nephropathy. Furthermore, it has been shown in this animal model that the renin angiotensin system within the kidney is activated and is important in the pathogenesis of this lesion. Inhibition of the renin angiotensin system with angiotensin II receptor blockade or ACE inhibition markedly reduces the tubulointerstitial fibrosis and arteriolopathy while leaving the glomerular and hemodynamic effects of the drug unchanged. Thus, in the chronic animal model, the vascular and tubulointerstitial effect of cyclosporine can be dissociated. Recent studies have shown the involvement of TGF-beta 2 and osteopontin in the scarring process. Interestingly, the TGF-beta 2 and osteopontin response can also be markedly abrogated by inhibition of the renin angiotensin system. This is of great interest since recent information has suggested that the immunosuppressive effect of cyclosporine is at least partially mediated through TGF-beta 2. The therapeutic and clinical implications of further work in this area are obvious and may lead to better management strategies for the patient who must necessarily be on long-term cyclosporine therapy.
Explore the source record for details and available documents.
What we accomplish today as a matter of routine was only imagined by a few 4 decades ago. The journey from that first successful kidney transplant in the 1950s to the multidisciplinary, multiorgan transplant program of today has been a fascinating one. Although we attribute our current results to careful recipient selection and preparation, improvements in organ procurement and preservation, refinement of surgical techniques, improvement in histocompatibility techniques and organ sharing, improvements in immunosuppression and infection control, and careful monitoring of recipients, we and our patients have benefited from significant contributions from our colleagues in government and the law. The 4 that come to mind are the provision of near-universal insurance coverage for end stage renal disease patients in 1972 under the Medicare program, the passage of brain death laws in the mid 1970s, the passage of the National Transplant Act in 1984, and the passage of the Oregon required request law in 1985.
An earlier reported trial suggests that omega-3 fatty acids in fish oil supplements at 6 g/day with administration commencing at the time of engraftment may reduce acute CsA renal dysfunction. When started at the time of renal transplant, there are improvements in renal hemodynamics and blood pressure, and a decrease in rejection episodes. To examine the effect of later introduction of omega-3 fatty acids, 133 cadaver renal transplant recipients received CsA, prednisone, and AZA for 16 weeks (period 1). If patients were stable without rejection or infection activity, they were randomized to 9 g of eicosapentanoic acid (EPA), 18 g of EPA, 9 g of corn oil, or 18 g of corn oil in 1-g capsules as supplements. Glomerular filtration rate, renal blood flow, number of rejection episodes, blood pressure, and episodes of CsA nephrotoxicity were followed for 26 weeks in a double-blind manner (period 2). Ninety patients were evaluable and completed the protocol. There were 50 corn oil placebo patients, 22 low dose EPA patients, and 18 high dose EPA patients. In period 1, there were 27 rejection episodes in 21 patients without differences among subsequent treatment groups. In period 2, there were 13 rejection episodes in 4 patients. No patient with an EPA level in plasma statistically higher than placebo had a rejection episode. All allografts functioned for the entire 6 months with none lost to rejection. All 5 episodes of acute CsA nephrotoxicity occurred in placebo-treated patients without differences in whole blood CsA among toxic patients, other placebo patients, and EPA-treated recipients. At the end of the study, there were no differences in glomerular filtration rate, renal blood flow, or creatinine clearance among groups. Diastolic blood pressure fell by 9 mmHg during period 2 in high dose fish oil recipients and by 10 mmHg in low dose fish oil recipients (P < 0.05), while it rose by 2 mmHg in placebo patients. No serious adverse effects of EPA supplements were noted, although compliance based on plasma EPA was erratic. Based on our experience and that in the literature, administration of omega-3 fatty acids for purposes of kidney protection would seem to be most useful when started early after surgery. Late administration in our study was associated with minor clinical benefits.
Explore the source record for details and available documents.