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Biomedical subjects

W M Bennett

Publications and source records attributed to W M Bennett.

At least 37 records · Page 2Linked to original sources
PubMed1999

Renal transplantation across the ABO barrier using A2 kidneys.

BACKGROUND: The waiting list for cadaveric kidney transplantation has continued to grow, and with the relative scarcity of cadaver donors, the median waiting time for patients in the United States increased to 824 days in 1994. The median waiting times for patients with blood groups B or O were 1329 and 1007 days, respectively. Allocation of blood group A2 kidneys (20% of group A) to blood group O and B patients expands their potential donor pool and shortens their waiting time for a kidney transplantation. METHODS: Between May 1991 and June 1998, we transplanted 15 A2 kidneys into 6 blood group O and 9 blood group B patients. Anti-A isoagglutinins were measured before transplantation, and patients with anti-A1 titers > or = 1:8 underwent plasmapheresis (PP). RESULTS: One patient with high titer anti-A antibodies, who did not receive PP, lost her allograft because of hyperacute rejection. Allograft function was excellent in the remaining 14 patients, with a mean serum creatinine level of 1.7 (+/-0.89) mg/dl at 1 month and 1.3 (+/-0.34) mg/dl at 1 year. The actuarial 1-year graft survival rate was 93.3+/-6.4% and the patient survival rate was 100%. CONCLUSION: We conclude that the allocation of blood group A2 kidneys for blood group O and B recipients is a practical way to expand the donor pool for these transplant candidates. PP may be important for reducing the levels of anti-A1 and anti-A2 antibodies and for reducing the risk of hyperacute rejection. Splenectomy seems to be unnecessary.

ABO Blood-Group System↗
PubMed1999

Focal segmental glomerulosclerosis: a need for caution in live-related renal transplantation.

Focal segmental glomerulosclerosis (FSGS) has increasingly been recognized to occur in a familial pattern. We have observed the development of biopsy-confirmed FSGS and subsequent end-stage renal disease (ESRD) in one live related kidney donor and ESRD without biopsy in another. Both donors had family members with ESRD secondary to FSGS. Both donors were apparently healthy by routine physical examination, urinalysis, and serum creatinine at the time of evaluation as live related donors. We believe these cases emphasize the need for great caution when evaluating siblings as potential live related donors.

Adult↗
PubMed1999

Drug-related renal dysfunction in the elderly.

Because of its high blood flow and function to excrete and metabolize xenobiotics, the kidney is especially prone to injury by drugs and chemicals. In elderly patients, renal function is also often reduced by age itself or comorbid diseases leading to a high incidence of adverse drug reactions both to the kidney itself and to other organs because of drug accumulation. This paper reviews this issue with specific emphasis on drugs that are often used in elderly subjects such as nonsteroidal antiinflammatory agents, angiotension converting enzyme inhibitors, antibiotics, and immunosuppressive drugs.

Aging↗
PubMed1999

HLA-identical sibling renal transplantation--a 21-yr single-center experience.

Human lymphocyte antigen (HLA)-identical sibling organs offer the best long-term outcomes for recipients of a renal transplant apart from an identical twin. Unlike cadaveric transplants, however, factors that affect long-term survival of these immunologically privileged grafts are not well described. We reviewed 108 HLA-identical transplants performed at our institution between January 1977 and February 1993. Variables chosen for graft survival analysis were: gender, age and ABO blood type of donors and recipients, panel reactivity antibodies (PRA), blood transfusions prior to transplant, pregnancies, and the underlying renal disease. Additionally, incidence of acute rejection (AR), timing of AR, serum creatinine levels at 1 wk and at 1 yr, and presence of hypertension were included in the analysis. Mean follow-up was 130.9 +/- 58.2 months (range 38-250 months). Actual 5-yr patient and graft survivals were 92 and 88%, respectively. Thirty-eight grafts were lost, and 22 recipients died during the observation period. Death was the main cause of graft failure. Cardiac events accounted for the majority of deaths. AR occurred in 46% and repeated rejections in 11% of recipients. Actuarial graft survival at 10 yr was poorer for patients with any AR (69%), and significantly worse with repeated AR (33%), compared to patients without AR (86%), p = 0.001). Sixty percent of all rejections and 88% of the first rejections occurred in the first 60 d post-transplantation. The first AR that occurred after 60 d was associated with poor graft survival (49 vs. 70%, p = 0.04). Recipients with renal diseases with potential to recur (membranous glomerulonephritis (MGN), membrano-proliferative glomerulonephritis (MPGN), focal and segmental glomerulonephritis (FSGN), polyarteritis nodosa (PAN), rapid progressive glomerulonephritis (RPGN), Henoch-Schoenlein purpura (HSP), diabetes mellitus (DM), interstitial nephritis, systemic lupus erythematosus (SLE) and chronic glomerulonephritis (CGN)) faired worse as a group than recipients with hypertensive nephrosclerosis (HTN), autosomal dominant polycystic kidney disease (ADPKD), Alport's, reflux or congenital dysplasia (68 vs. 96% at 10 yr, p = 0.0009). Poor patient survival was seen in diabetics (71 vs. 88% at 10 yr, p = 0.01). There was a trend to poorer graft survival in diabetic recipients when compared to non-diabetics (65 vs. 81% at 10 yr, p = 0.054). Elevated creatinine at 1 yr was associated with worse graft survival. Likewise, the magnitude of creatinine increase during the first year directly correlated with the risk of graft loss. Hypertensive patients were more likely to lose their grafts than normotensive recipients (72 vs. 86%, p = 0.04). Pre-transplant blood transfusion, pregnancy, and PRA level were not associated with increased graft failure or AR. Graft survival was not affected by gender, age, or ABO blood type of donors or recipients. In conclusion, better prevention and treatment of AR, hypertension, and cardiac disease should improve graft and patient survival. Close attention to recurrence of disease and subtle changes in the creatinine level during the first year might dictate early diagnostic and, hopefully, therapeutic interventions.

ABO Blood-Group System↗
PubMed1999

Effects of FK506 in rat and human resistance arteries.

BACKGROUND: FK506 is widely used in organ transplantation and causes hypertension. However, little is known about the impact of the drug on the cardiovascular system. METHODS: We therefore investigated the effect of FK506 on resistance artery and blood pressure responsiveness to vasoconstrictors and vasodilators. Studies were conducted in vitro using human and murine resistance artery, ex vivo in resistance artery isolated from rats treated with FK506 (6 mg/kg/day), and in vivo in conscious, treated animals. RESULTS: In vitro exposure (24 hr) of human and rat resistance artery to FK506 (1000 ng/ml) increased the sensitivity to norepinephrine (NE) and impaired the response to acetylcholine (Ach) and sodium nitroprusside (SNp). In contrast, arteries isolated from rats given FK506 for eight days showed a reduced sensitivity to NE (P < 0.05) and a normal endothelium-dependent relaxation. Their incubation with L-arginine caused a significant reduction in Ach sensitivity in the FK506 group (P < 0.05) but not in controls, suggesting enhancement of nitric oxide production by the drug. The sensitivity to SNp was reduced, as in the in vitro experiments (P < 0.05). Rats given FK506 for eight days presented blood pressure similar to that in controls but also presented signs of a compensatory response to excess vasodilation: tachycardia (P < 0.01), reduced blood pressure sensitivity to NE and Ach, blunted heart rate response to both agonists, and exaggerated hypotension at high doses of Ach. After 21 days of treatment, blood pressure remained similar to that in controls, but resistance artery showed further functional deterioration, with significant impairment of the maximum responses to Ach and to SNp. CONCLUSION: FK506 presents significant vascular toxicity affecting mainly smooth muscle relaxation and alters vascular hemodynamics. The data suggest that similar cardiovascular changes may occur in transplant patients and represent the forerunner of hypertension often seen with more prolonged use of the drug.

Adult↗
PubMed1999

Expression of apoptosis regulatory genes in chronic cyclosporine nephrotoxicity favors apoptosis.

UNLABELLED: Expression of apoptosis regulatory genes in chronic cyclosporine nephrotoxicity favors apoptosis. BACKGROUND: Chronic cyclosporine (CsA) nephrotoxicity is characterized by interstitial fibrosis, tubular dropout, and loss of cellularity in areas of fibrosis. Apoptosis was found to play a role in CsA-induced fibrosis. We evaluated the role of the death genes p53, Bax, and Fas-L (ligand), survival gene Bcl-2, interleukin-converting enzyme (ICE), and caspase-3. METHODS: Salt-depleted rats were administered CsA 15 mg/kg/day or vehicle (VH) and were sacrificed at 7 or 28 days. Apoptosis was detected by TdT-mediated dUTP-biotin nick end labeling assay. p53 and Bax expressions were evaluated by Northern and Western blot analysis. Fas-L and Bcl-2 expressions were evaluated by immunofluorescence. In addition to ICE mRNA, caspase-3 enzymatic activity was assayed. RESULTS: Although no differences were seen at one week, apoptosis-positive cells increased with CsA at four weeks (P < 0.05) and correlated with tubular atrophy and interstitial fibrosis (r = 0.8, P < 0.05). CsA induced the expression of p53 (P < 0.05) and Bax (P < 0.01) and decreased that of Bcl-2 (P < 0.05). CsA up-regulated Fas-L expression (P < 0.001). ICE mRNA and caspase-3 activity were also increased (P < 0.01). The changes occurred as early as one week and remained statistically significant at four weeks. CONCLUSIONS: Specific apoptotic genes are increased in chronic CsA nephrotoxicity. The balance favors the induction of apoptosis. Increased apoptosis could explain the tubular dropout and loss of cellularity with fibrosis. This then may impair the ability of the tubulointerstitium to remodel. Apoptosis could also contribute to some of CsA immunosuppressive effects on activated lymphocytes.

Animals↗
PubMed1999

Factors in cardiac risk stratification of candidates for renal transplant.

BACKGROUND: Renal transplant candidates are at high risk of fatal and nonfatal cardiac events. METHODS: This study evaluated five clinical risk factors--age at least 50 years, insulin-requiring diabetes mellitus, angina, congestive heart failure and an abnormal electrocardiogram (ECG) (excluding left ventricular hypertrophy)--that had been used in the first tier of a two-tiered prospectively applied risk stratification algorithm. RESULTS: Using multiple logistic regression analysis, age at least 50 years, abnormal ECG, and diabetes mellitus were independently predictive of cardiac death. Of the two remaining clinical risk factors, the presence of angina had independent predictive value for nonfatal cardiac events (myocardial infarction, coronary angioplasty, bypass surgery, and unstable angina). The independent predictive value of congestive heart failure approached statistical significance. CONCLUSION: Clinical risk-factor analysis is helpful in identifying renal transplant candidates at high risk for fatal or nonfatal cardiac events.

Algorithms↗
PubMed1999

Immunosuppressant-induced nephropathy: pathophysiology, incidence and management.

Immunosuppressant-induced nephrotoxicity, in particular chronic progressive tubulointerstitial fibrosis/arteriopathy induced by the calcineurin inhibitors cyclosporin and tacrolimus, has become the 'Achilles heel' of immunosuppressive agents. The use of calcineurin inhibitors as primary immunosuppressants in hepatic and cardiac transplantation has led to end-stage renal disease and dialysis. Calcineurin inhibitor-induced acute renal failure may occur as early as a few weeks or months after initiation of cyclosporin therapy. The clinical manifestations of acute renal dysfunction are caused by vasoconstriction of renal arterioles, and include reduction in glomerular filtration rate, hypertension, hyperkalaemia, tubular acidosis, increased reabsorption of sodium and oliguria. The acute adverse effects of calcineurin inhibitors on renal haemodynamics are thought to be directly related to the cyclosporin or tacrolimus dosage and blood concentration. However, new clinical data indicate that calcineurin inhibitor-induced chronic nephropathy can occur independently of acute renal dysfunction, cyclosporin dosage or blood concentration. Several strategies have been evaluated to attenuate cyclosporin-induced nephropathy, but their efficacy remains unknown. Cytokine release syndrome associated with the use of muronomab-CD3 (OKT-3) can also contribute to the pathogenesis of transient acute tubular necrosis and renal dysfunction following renal transplantation. Continued research and clinical experience should provide information regarding the aetiology of cyclosporin-induced chronic progressive tubulointerstitial fibrosis/arteriopathy and its potential treatment.

Animals↗
PubMed1999

A practical guide to the management of hypertension in renal transplant recipients.

Hypertension as well as hypotension can be harmful to a newly transplanted renal allograft. Elevated blood pressure is also a major risk factor for cardiovascular death, which is a frequent occurrence despite successful renal transplantation. Renal artery stenosis, immunosuppressive drugs, chronic rejection, retained native kidneys, and excessive extracellular fluid volume may all contribute to post-transplant hypertension. Antihypertensive agents are widely used in the management of post-transplant hypertension. Careful clinical judgement and knowledge of the pharmacology, pharmacodynamics, pharmacokinetics, adverse drug reaction profiles, potential contraindications, and drug-drug interactions of antihypertensive agents are important when therapy with antihypertensive drugs is initiated in renal transplant recipients. Since blood pressure elevation in any individual is determined by a large number of hormonal and neuronal systems, the effect of antihypertensive agents on the allograft should be considered a critical factor in the management of hypertension in renal transplant recipients. Most renal transplant recipients have other risk factors for premature cardiovascular death such as diabetes mellitus, hypercholesterolemia, insulin resistance, obesity, left ventricular hypertrophy and ischaemic heart disease. Initial antihypertensive therapy should be tailored individually according to the patient's risk factors. A realistic therapeutic goal for blood pressure management in the initial post-operative state is a systolic blood pressure <160 mm Hg and a diastolic blood pressure <90 mm Hg with lower pressure targets becoming applicable late post-transplantation.

Animals↗
PubMed1998

Efficacy and safety of low molecular weight heparin in renal transplantation.

BACKGROUND: Deep venous thrombosis (DVT) is a common problem with potentially devastating results in patients undergoing major surgical procedures. Certain renal transplant recipients are particularly at risk for allograft loss as a consequence of renal vein and artery thrombosis. Over the past few years, low molecular weight heparin has been well established as an accepted modality of treatment and prophylaxis of DVT. The efficacy and safety of low molecular weight heparin in the prophylaxis of DVT following renal transplantation in adults has not previously been reported. METHODS: Dalteparin was administered to 120 adult renal transplant recipients postoperatively at the Oregon Health Sciences University. RESULTS: No patient developed allograft arterial or venous thrombosis. One patient developed subclavian vein thrombosis. No bleeding complications were encountered, and side effects were very minimal. CONCLUSION: Prophylaxis with dalteparin is an effective and safe modality for the prevention of thrombosis in adult patients undergoing renal transplantation.

Adolescent↗
PubMed1998

Cyclosporine suppresses rat hepatic cytochrome P450 in a time-dependent manner.

BACKGROUND: Cyclosporine is a potent immunosuppressant know to selectively suppress specific cytochrome P450 (P450) isoforms following chronic therapy in the rat. Cyclosporine undergoes significant hepatic metabolism in the rat, primarily due to P450 3A isoforms. Hence, alterations in hepatic metabolism of cyclosporine may lead to changes in drug pharmacokinetics or pharmacodynamics. The purpose of this study was to examine the temporal effect of chronic cyclosporine dosing on P450 protein expression and metabolic activity in a rat model of chronic cyclosporine nephropathy. METHODS: Adult male rats were administered cyclosporine 15 mg/kg/day or vehicle 1 ml/kg/day by subcutaneous injection for up to 28 days. To examine whether or not metabolic activity recovered following drug removal, additional rats were administered cyclosporine for 28 days followed by vehicle for up to an additional 15 days. Hepatic P450 protein expression and microsomal metabolic activity were measured by Western blot analysis and in vitro steroid hydroxylation, respectively. RESULTS: Cyclosporine trough levels progressively increased over the 28 days period and were still measurable for up to 15 days after discontinuation. Immunoblot analysis indicated that chronic cyclosporine treatment suppressed P450 3A2 expression and in vitro steroid hydroxylation in a time-dependent manner. Fifteen days following discontinuation of cyclosporine dosing, hepatic metabolic activity and microsomal P450 3A2 levels returned to near pre-dosing levels. CONCLUSIONS: We conclude that the time-dependent P450 suppression by cyclosporine may at least partially explain the variability in cyclosporine pharmacokinetics. These studies support the hypothesis that hepatic isoforms other than P450 3A2 may be responsible for cyclosporine metabolism during chronic treatment in the rat.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1998

Cyclosporine arteriolopathy: effects of drug withdrawal.

Renal arteriolopathy in chronic cyclosporine-induced nephrotoxicity is characterized by an eosinophilic granular transformation of vascular smooth muscle cells of afferent glomerular arterioles that is thought to eventually progress to necrosis of individual muscle cells and hyalinization of the vessel wall. Although the lesion is highly specific for cyclosporine-induced injury in humans, it has been difficult to reproduce in normotensive animals. To study the natural history of the cyclosporine arteriolopathy, we conducted sequential studies in salt-depleted Sprague-Dawley rats using cyclosporin A (15 mg/kg subcutaneously) treatment for 35 days, 49 days, 35 days plus 14 or 56 days of drug washout, or placebo (olive oil). Cyclosporin A produced a progressive decrease in renal function that significantly improved after discontinuation of the drug. The arteriolopathy, scored semiquantitatively, was present by day 35 and did not improve with cyclosporine withdrawal within 2 weeks but did dramatically regress after 56 days. However, tubulointerstitial changes did not regress with drug discontinuation and were present despite improvement in renal function. We conclude that cyclosporine-induced arteriolopathy may be reversible and associated with improving renal function. Thus, the morphological evidence of arteriolopathy is dissociable from the progressive tubulointerstitial scarring.

Animals↗
PubMed1998

Chronic cyclosporine nephrotoxicity.

Cyclosporine has improved patient and graft survival rates in solid organ transplantation, and has been increasingly applied with considerable clinical benefit in the treatment of autoimmune diseases. However, the therapeutic benefits of immunosuppressive therapy for transplant and autoimmune indications have frequently been limited by the occurrence of chronic nephrotoxicity. Cyclosporine nephrotoxicity therefore remains an important clinical challenge. The clinical aspects and pathophysiology of chronic cyclosporine nephrotoxicity, which is characterized by a decrease in glomerular filtration rate, afferent arteriolopathy, and striped tubulointerstitial fibrosis, are reviewed. Insights gained from experimental models of chronic nephrotoxicity associated with tubulointerstitial fibrosis are presented to elucidate the pathophysiology.

Autoimmune Diseases↗
PubMed1998

Accelerated apoptosis characterizes cyclosporine-associated interstitial fibrosis.

Recently we developed a model of cyclosporine nephropathy in rats characterized by tubulointerstitial (TI) injury, macrophage infiltration, and progressive interstitial fibrosis [1, 2]. To determine if the TI injury accompanying cyclosporine A (CsA) nephropathy was associated with accelerated apoptosis and ischemia, we treated rats for five weeks with CsA with or without losartan (to block angiotensin II type 1 receptor), or hydralazine/furosemide (H/F) (protocol #1). In protocol #2, rats received CsA with or without L-NAME (to block nitric oxide) or L-arginine (to provide a precursor to nitric oxide formation). Cyclosporine A treated rats had increased apoptosis of tubular and interstitial cells documented by PAS, propidium iodide staining, TUNEL assay, and electron microscopy compared to vehicle treated controls. Macrophages containing apoptotic cells could be confirmed by TUNEL/ED-1 doublestaining and colocalized in areas of TI injury. Animals treated with CsA + losartan had a statistically significant decrease in apoptosis (TUNEL + cells/mm2) when compared to CsA treated animals (6.0 vs. 19.9, P < or = 0.0001). The decrease in apoptosis in the CsA + H/F group was not statistically significant. Animals treated with CsA + L-NAME had a statistically significant increase in apoptosis compared to the CsA treated animals (12.3 vs. 6.4, P = 0.001). L-arginine administration with CsA resulted in a decrease in tubulointerstitial apoptosis versus CsA treated animals, however, this did not reach statistical significance. The addition of L-arginine did result in a significant reduction in interstitial fibrosis (P < 0.0001). Regression analysis revealed a significant correlation between apoptosis and interstitial fibrosis in both protocols. (CsA vs. CsA + losartan r = 0.63, P < 0.0001; CsA vs. CsA + L-NAME r = 0.83, P < 0.0001). We conclude that CsA nephropathy is associated with a marked increase in apoptosis of tubular and interstitial cells. Cyclosporine A induced apoptosis is partially mediated by angiotensin II and nitric oxide inhibition, suggesting a role for renal ischemia in this process, and CsA induced apoptosis correlates with interstitial fibrosis.

Angiotensin II↗
PubMed1998

Pharmacology of immunosuppressive drugs.

Immunosuppressive therapy of solid organ transplantation has become more potent, effective and selective since the results of earlier use of prednisone and azathioprine post renal transplantation. Calcineurin inhibitors and mycophenolate mofetil have been important additions to the effective antirejection armamentarium. Today, cyclosporin, tacrolimus, azathioprine, mycophenolate and prednisone are all effective immunosuppressive agents and are the cornerstone of immunosuppressive protocols used posttransplant. However, the use of these agents is hindered by a 20% rate of rejection, lack of selectivity and a high rate of major adverse drug reactions which ultimately lead to a decrease in patient and graft survival. A number of clinical trials are underway to compare efficacy, safety and tolerability of different combination protocols to improve patient and allograft survival and decrease adverse drug reactions. Clinical knowledge of the pharmacology, pharmacokinetics, pharmacodynamics, adverse drug reactions and therapeutic drug monitoring of antirejection agents is essential for designing an effective immunosuppressive protocol for individual solid organ transplant recipients. The clinical application of pharmacotherapeutic principles into the clinical practice will improve both long-term patient and allograft survival while minimizing systemic toxicity of immunosuppressive drugs.

Journal Article↗
PubMed1998

The nephrotoxicity of new and old immunosuppressive drugs.

The above snapshot of the relevant literature on chronic Cyclosporine and Tacrolimus nephropathy indicate fertile areas for further study. The reader is referred to recent reviews for a more in-depth analysis of this problem (2).

Acute Disease↗