Search PubMed⌕ Search

Biomedical subjects

W M Bennett

Publications and source records attributed to W M Bennett.

At least 55 records · Page 3Linked to original sources
PubMed1997

Mechanism of fibrosis in experimental tacrolimus nephrotoxicity.

The clinical use of tacrolimus (FK506) is limited by nephrotoxicity. The pathogenesis of fibrosis in chronic FK506 nephrotoxicity remains unknown. Because transforming growth factor (TGF)-beta plays a key role in the fibrogenesis of many diseases, including cyclosporine nephrotoxicity, we studied a salt-depleted rat model of chronic FK506 nephropathy in which clinically relevant FK506 blood levels are obtained and which shows similarities to the lesions described in patients receiving FK506. Pair-fed rats were treated with either FK506 (1 mg/kg/day s.c.) or an equivalent dose of vehicle and were killed at 7 or 28 days. Characteristic histologic changes of tubular injury, interstitial fibrosis, and arteriolopathy developed in FK506-treated rats at 28 days and were accompanied by worsening kidney function, decreased concentrating ability, and enzymuria. FK506-treated kidneys had a progressive increase in the expression of TGF-beta1 and matrix proteins (biglycan, tenascin, fibronectin, and type I collagen). This effect seems to be specific because the expression of type IV collagen, a basement membrane collagen, was not affected. Matrix deposition was present mostly in the tubulointerstitium and vessels in accordance with the FK506 chronic lesion. The expression of plasminogen activator inhibitor-1, a protease inhibitor influenced by TGF-beta, followed TGF-beta1 and matrix proteins, suggesting that the fibrosis of chronic FK506 nephropathy likely involves the dual action of TGF-beta1 on matrix deposition and degradation. Since both peripheral and tissue renin expression were elevated with FK506, the renin-angiotensin system may play a role in the pathogenesis of this condition.

Animals↗
PubMed1997

Protective effects of dietary L-arginine supplementation on chronic cyclosporine nephrotoxicity.

BACKGROUND: L-Arginine (L-Arg), the substrate for nitric oxide (NO) synthase producing NO, and the NO synthase inhibitor, N-nitro-L-arginine-methyl ester (L-NAME), have both been shown to modify acute cyclosporine (CsA)-induced intrarenal vasoconstriction. However, the mechanism of chronic CsA nephrotoxicity characterized by progressive tubulointerstitial fibrosis (TIF) remains unclear. Thus, we examined the pathogenetic role of NO in a rat model of chronic CsA nephropathy. METHODS: Rats were given vehicle, CsA (7.5 mg/kg), CsA + L-Arg (1.7 g/kg), CsA + D-arginine (1.7 g/kg), and CsA + L-NAME (3.5 mg/kg) for 28 days on a low-salt diet. NO production, glomerular filtration rate (GFR), blood and urine chemistry, and histology were assessed. RESULTS: L-Arg treatment significantly enhanced NO biosynthesis and protected animals from impaired GFR and development of TIF induced by CsA, whereas D-arginine did not. In contrast, L-NAME strikingly reduced urinary NO and worsened both GFR and TIF compared to the CsA alone group, whereas L-NAME did not change renal function and histology in the vehicle group. CONCLUSIONS: Chronic CsA nephrotoxicity can be aggravated by NO blockade and ameliorated by NO enhancement, suggesting that NO has an important role in the mechanism of chronic CsA nephropathy.

Animals↗
PubMed1997

Cardiac risk stratification in renal transplantation using a form of artificial intelligence.

The purpose of this study was to determine if an expert network, a form of artificial intelligence, could effectively stratify cardiac risk in candidates for renal transplant. Input into the expert network consisted of clinical risk factors and thallium-201 stress test data. Clinical risk factor screening alone identified 95 of 189 patients as high risk. These 95 patients underwent thallium-201 stress testing, and 53 had either reversible or fixed defects. The other 42 patients were classified as low risk. This algorithm made up the "expert system," and during the 4-year follow-up period had a sensitivity of 82%, specificity of 77%, and accuracy of 78%. An artificial neural network was added to the expert system, creating an expert network. Input into the neural network consisted of both clinical variables and thallium-201 stress test data. There were 5 hidden nodes and the output (end point) was cardiac death. The expert network increased the specificity of the expert system alone from 77% to 90% (p < 0.001), the accuracy from 78% to 89% (p < 0.005), and maintained the overall sensitivity at 88%. An expert network based on clinical risk factor screening and thallium-201 stress testing had an accuracy of 89% in predicting the 4-year cardiac mortality among 189 renal transplant candidates.

Adult↗
PubMed1997

Sodium depletion enhances fibrosis and the expression of TGF-beta1 and matrix proteins in experimental chronic cyclosporine nephropathy.

The major limitation to the clinical use of cyclosporine (CsA) is renal toxicity. In the past, the lack of an animal model of chronic CsA nephropathy has hampered the study of its pathogenesis. Rats given CsA and placed on a low sodium diet (LSD) develop a histology similar to human lesions of chronic CsA nephropathy, a phenomenon not observed in animals on a normal sodium diet (NSD). We have previously shown that transforming growth factor-beta1 (TGF-beta1) is involved in the CsA-induced renal fibrosis in rats on a LSD. We hypothesized that sodium depletion is critical to the increase in TGF-beta1 expression, which, in turn, results in excessive matrix accumulation. Pair-fed rats were placed on a NSD or LSD, treated with CsA or vehicle, and killed at 7 or 28 days (N = 4 to 6 in each group). All rats achieved similar blood pressure control, and all CsA-treated rats achieved similar CsA blood levels. However, while CsA did not affect creatinine clearance in rats on a NSD, it lowered creatinine clearance in rats on a LSD (P < 0.01). Cyclosporine-induced tubulointerstitial fibrosis and arteriolopathy was observed at 28 days only in the rats on a LSD (P < 0.05). In addition, peripheral renin activity was increased only in the rats on a LSD (P < 0.01), while it remained normal in the rats on a NSD. In addition, CsA-treated rats on a LSD developed a progressive increase in the mRNA expression of TGF-beta1 and the matrix proteins biglycan and type I collagen at 7 and 28 days. Most of the changes were seen at 28 days (P < 0.001 for TGF-beta1, P < 0.01 for biglycan and type I collagen). On the other hand, CsA treatment in rats on a NSD did not affect the mRNA expression of TGF-beta1 and matrix proteins. Most of the changes in the immunofluorescence deposition of the glycoproteins tenascin and fibronectin EDA+ were in the tubulointerstitium and vessels of the kidneys of rats on a LSD and were mostly significant at 28 days, in accordance with the characteristic histology of chronic CsA nephropathy. The mRNA expression of plasminogen activator inhibitor-1, a protease inhibitor involved in matrix degradation and stimulated by TGF-beta1, was observed only in kidneys of rats on a LSD (P < 0.01). Since sodium depletion elevates peripheral renin activity, our experiments suggest a role for the renin-angiotensin system in the expression of TGF-beta1 and matrix proteins in CsA-induced renal fibrosis of rats on a LSD.

Animals↗
PubMed1997

Interleukin-12 p40 m-RNA expression in human kidney allograft biopsies.

Interleukin-12 (IL-12) is a heterodimeric cytokine implicated in the early differentiation of naive T-lymphocytes into the Th1 subset. IL-12 is important for induction of the cellular immune response against viruses, intracellular parasites and neoplasms. Its role in alloresponsiveness has not been fully elucidated. Preliminary data in the literature point toward the prevalence of Th1 lymphocytes in processes of allograft rejection. In attempt to further investigate the expression of this cytokine during episodes of cellular rejection of renal allografts, we searched for IL-12 message in human kidney allograft biopsies using the reverse transcriptase-polymerase chain reaction technique. Twenty-three allograft core biopsies from 19 patients were obtained percutaneously for clinical indications in 18 cases, and as part of an investigational protocol in five cases. A portion of the tissue was used for RNA extraction using the guanidium-thiocyanide phenol-chloroform method. Histology was performed on the remaining core material. Ten mg of total RNA were used for reverse transcription. PCR of the c-DNAs was done for 40 cycles using primers for the p40 subunit of IL-12 and GAPDH which was used as a control. PCR products were photographed after electrophoresis, transferred to a nylon membrane and hybridized with a radiolabelled cloned human IL-12 p40 1 kb c-DNA fragment. Autoradiographies were developed after 20-min exposure. All samples were run in triplicate. IL-12 p40 m-RNA was expressed in all 17 biopsies showing acute cellular rejection as well as in all three biopsies showing focal interstitial fibrosis. No message was found in the presence of normal allograft histology. This is the first in vivo report of IL-12 p40 subunit m-RNA expression during renal allograft rejection in humans. The role of this Th1 cytokine in the alloresponse deserves further investigation.

Adult↗
PubMed1997

Angiotensin II blockade decreases TGF-beta1 and matrix proteins in cyclosporine nephropathy.

Angiotensin II (Ang II) is implicated in fibrosis but the precise mechanism of this effect remains unclear. In a model of chronic cyclosporine (CsA) nephropathy, we previously showed that TGF-beta1 plays a role in CsA-induced tubulointerstitial fibrosis and arteriolopathy by stimulating extracellular matrix (ECM) protein synthesis and inhibiting ECM degradation through increasing the synthesis of plasminogen activator inhibitor (PAI)-1. We hypothesized that Ang II contributes to fibrosis by inducing TGF-beta1. Salt-depleted rats were given placebo, CsA alone, CsA + nilvadipine, CsA + hydralazine/hydrochlorthiazide, CsA + losartan (AT1 receptor antagonist) or CsA + enalapril (Ang converting enzyme inhibitor) and were sacrificed at 7 and 28 days. All treated groups achieved similar blood pressures and glomerular filtration rates. The lesion of chronic CsA nephropathy was ameliorated by concomitant therapy with losartan or enalapril at 28 days, a phenomenon not observed in the other treatment groups. Similarly, Ang II blockade resulted in decreased expression of TGF-beta1 and PAI-1 by Northern and ELISA. Similarly, the expression of ECM proteins directly influenced by TGF-beta decreased with Ang II blockade. These results suggest that CsA-induced fibrosis in this model is independent of renal hemodynamics and is mediated, at least partly, through Ang II induction of TGF-beta1 expression.

Angiotensin II↗
PubMed1997

Drug interactions and consequences of sodium restriction.

Dietary sodium restriction has several clinical benefits, particularly that of enhancing the antihypertensive action of diuretics and other blood pressure-lowering drugs. In individuals who form hypercalciuric stones, sodium restriction along with thiazide diuretics helps to reduce urinary calcium. However, there are adverse consequences of sodium restriction, particularly in elderly patients with impaired sodium conservation mechanisms. Ischemic and nephrotoxic injuries are induced more readily in sodium-depleted animals and patients because of impaired renal hemodynamics and activation of the renin-angiotensin system. Acute renal failure can be precipitated by sodium restriction and concomitant angiotensin-converting enzyme inhibitors, nonsteroidal antiinflammatory drugs, and immunosuppressive drugs. Dietary sodium restriction in animals enhances the chronic nephrotoxicity of cyclosporine and tacrolimus, whereas similar doses of these drugs do not produce structural damage in salt-replete animals. Maneuvers that block angiotensin II protect against renal scarring and drug-induced arteriolopathy in this model. Sodium restriction can enhance the renal tubular reabsorption of drugs such as lithium, leading to toxic blood concentrations. Calcium antagonists may have better efficacy when prescribed to salt-replete hypertensive persons. Finally, there is evidence that activation of the renin-angiotensin system by sodium depletion will enhance the growth of cysts in animal models of cystic renal disease. In individual patients, the effects of sodium restriction by diet should balance anticipated benefits against any possible adverse consequences.

Acute Kidney Injury↗
PubMed1997

Switching between cyclosporin formulations. What are the risks?

The introduction of cyclosporin, refinement in surgical techniques and improvement in allograft preservation have all led to an improvement in graft and ultimately patient survival. Cyclosporin is a lipophilic cyclic polypeptide produced by Trichoderma, a fungus isolated from Norwegian soil. Cyclosporin is a potent, selective and powerful immunosuppressive agent possessing a narrow therapeutic window. Substitution among different formulations of cyclosporin for economic reasons, without close monitoring of pharmacokinetics and pharmacodynamics, can induce undesirable toxic effects. A number of recent reports, largely anecdotal, of adverse drug reactions and acute cellular rejection after conversion from the standard formulation to the microemulsion formulation of cyclosporin have created uncertainty over the therapeutic equivalency of these agents. This leading article reviews the pharmacology, pharmacokinetics and adverse drug reactions of cyclosporin as well as the potential risks associated with switching between cyclosporin formulations in stable renal transplant recipients. Caution should be employed when switching between cyclosporin formulations. Since data are limited, long-term prospective studies are necessary to delineate the role of high peak concentrations obtained from the microemulsion formulation in relation to cyclosporin-induced chronic nephropathy. The significance of the reduction in pharmacokinetic variability with use of the microemulsion formulation in terms of graft and patient survival remains unclear.

Adolescent↗
PubMed1997

Drug nephrotoxicity: an overview.

Drug-induced nephrotoxicity is common in clinical practice and should be sought out by clinicians seeking to understand the causes of renal disease and renal syndromes in particular patients. Insights into the pathophysiology of drug-induced disorders should provide clues to disease mechanisms which ultimately might lead to better treatments and more rational prevention of all renal diseases.

Acute Kidney Injury↗
PubMed1997

Posttransplant acute renal failure.

Acute renal failure posttransplant is a multifactorial syndrome in the early phases of transplantation. Delayed graft function is common and confers an adverse prognosis for both short- and long-term survival of the renal allograft. Later out from transplantation, the differential diagnosis of acute renal failure is usually between acute renal failure secondary to rejection or cyclosporine nephrotoxicity. Transplant biopsies are often needed to distinguish these possibilities.

Acute Kidney Injury↗
PubMed1997

Heparin decreases blood pressure and response to exogenous endothelin but does not protect against chronic experimental cyclosporine nephropathy.

Cyclosporine nephrotoxicity is caused by renal arteriolar vasoconstriction and tubulointerstitial fibrosis. Endothelin has been proposed as a major mediator of these phenomena. Heparin inhibits vascular smooth muscle cell proliferation and lowers blood pressure by regulating endogenous endothelin 1 production. In a model of chronic cyclosporine nephrotoxicity in the rat, animals were treated with cyclosporine alone, cyclosporine plus heparin, and heparin alone for 28 days. Independent experiments determined that these doses of heparin resulted in a marked decrease in responsivity to exogenous endothelin. Despite this, there were no beneficial effects on renal structure or function in this animal model of chronic cyclosporine nephrotoxicity. Thus, the role of endothelin in the pathogenesis of the chronic tubulointerstitial changes and arteriolopathy in this model is probably minor.

Animals↗
PubMed1997

Nephrotoxicity of immunosuppressive drugs: experimental and clinical observations.

Cyclosporine has improved patient and graft survival rates in solid organ transplantation since its introduction in 1976, and has been increasingly applied with considerable clinical benefit in the treatment of autoimmune diseases. However, the therapeutic benefits of immunosuppressive therapy for transplantation and autoimmune indications have been frequently limited by the occurrence of acute and chronic nephrotoxicity, which is the most obvious common side effect. Cyclosporine nephrotoxicity therefore remains an important clinical challenge. The clinical aspects and pathophysiology of nephrotoxicity induced by current and future immunosuppressive drugs are reviewed in this article, with an emphasis on the studies of chronic cyclosporine nephropathy, which is characterized by a decrease in glomerular filtration rate, afferent arteriolopathy, and striped tubulointerstitial fibrosis. Insights gained from experimental models of chronic nephrotoxicity associated with tubulointerstitial fibrosis and arteriolopathy are presented to elucidate the pathophysiology. Thus, experimental and clinical data regarding tacrolimus (FK506) and sirolimus (rapamycin) are presented.

Animals↗
PubMed1996

Synergistic effects of cyclosporine and rapamycin in a chronic nephrotoxicity model.

Rapamycin (RAPA) acts synergistically with cyclosporine (CsA) to achieve powerful immunosuppression in several animal models of organ transplantation and autoimmune disease. If these drugs are to be used together, they should not enhance toxicity. Thus, we examined the effects of combining CsA and RAPA on renal structure and function in a rat model of chronic CSA nephropathy. Rats were given placebo, CSA (2, 4, and 8 mg/kg), RAPA (0.01 and 0.1 mg/kg), or CsA+RAPA for 28 days while on a low-salt diet. RAPA at a subtherapeutic dose of 0.1 mg/kg worsened glucose metabolism and potentiated chronic nephrotoxicity induced by CsA at 8 mg/kg in terms of both renal function and structural injury. Since hyperglycemia is known to accelerate fibrotic processes, the impairment of glucose metabolism may play a role in tubulointerstitial fibrosis (plasma glucose vs. tubulointerstitial fibrosis, r=0.72, n=18, P<0.001). RAPA had to be given at a dose 10-fold lower (0.01 mg/kg) and CsA at a dose 4-fold lower (2 mg/kg) than the dose required for complete immunosuppression to minimize nephrotoxicity. Although the CsA+RAPA combination acts synergistically on immunosuppression, the combination at the subtherapeutic dose of each drug may be synergistically nephrotoxic, perhaps due to hyperglycemia. Clinical combinations of CsA and RAPA must be tested carefully for chronic nephrotoxicity.

Animals↗
PubMed1996

Clinically relevant doses and blood levels produce experimental cyclosporine nephrotoxicity when combined with nitric oxide inhibition.

Cyclosporine (CsA) administration and nitric oxide (NO) blockade promote similar chronic renal hemodynamic alterations in rats. We evaluated various clinical CsA doses under conditions of NO blockade using L-NAME (N-nitro L-arginine methyl ester). Groups of Sprague-Dawley rats kept on a normal salt (+NaCl) or low-salt (-NaCl) diet were given CsA 7.5 mg/kg, 2.5 mg/kg, or vehicle (VH) for 21 days. CsA or VH treatment was preceded by one week of L-NAME and continued for three weeks. Inulin clearance, CsA blood level, and weekly blood pressure change were assessed at 28 days. Marked CsA dose dependent reductions in GFR in -NaCl animals (P < 0.01 versus VH + L-NAME) and +NaCl animals (P < 0.05 versus VH + L-NAME, +NaCl) as well as blood pressure elevations (P < 0.01 versus VH + L-NAME at 28 days) occurred in groups concurrently treated with CsA and L-NAME. In addition, Impaired renal function and morphologic lesions in rats (CsA 2.5 mg/kg) receiving L-NAME or CsA alone demonstrated CsA blood levels within the therapeutic range of human renal transplant patients. VH groups treated with L-NAME alone produced blood pressure elevations but were spared of renal functional or morphological alterations. Primary renal morphologic lesions in CsA treated animals included proximal tubule collapse and vacuolization and, less frequently, interstitial edema and vacuolization of interstitial cells. Unique to rats treated simultaneously with CsA and L-NAME were vascular abnormalities consisting of endothelial and arteriolar medial hyperplasia and occasional acute medial necrosis. In conclusion, acute CsA nephrotoxicity can be enhanced by simultaneous NO blockade, suggesting NO has a protective effect in CsA-induced nephropathy. These results can be achieved with a drug exposure profile that correlates with clinical therapy.

Animals↗
PubMed1996

Cadaver kidney transplantation in patients more than 65 years old.

Elderly patients with end-stage renal disease often remain on dialytic therapy because they are at increased risk for mortality and morbidity. We placed 24 cadaver kidney transplants into 24 patients aged 65-74 years between September 1, 1985, and August 31, 1995. Rates of patient and graft survival were compared with those of 404 concurrent first cadaver-kidney transplant recipients between the ages of 20 and 44 years. The 5-year rates of patient and graft survival were not significantly different (86% versus 92% and 77% versus 63%, respectively; study group presented first). Primary cadaver kidney transplantation can be successfully performed in patients older than 65 years when a selection algorithm is applied to exclude active infection, active malignancy, unsuitable anatomy for technical success, high probability of operative mortality, and noncompliance. Pelvic arteriosclerosis and lower urinary tract abnormalities can cause intraoperative technical problems.

Adult↗