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Biomedical subjects

B L Kasiske

Publications and source records attributed to B L Kasiske.

At least 19 recordsLinked to original sources
PubMed2001

Cytomegalovirus disease is not a major risk factor for ischemic heart disease after renal transplantation.

BACKGROUND: It has been suggested that cytomegalovirus infection increases the risk of ischemic heart disease. Both cytomegalovirus and ischemic heart disease are common after renal transplantation, suggesting a possible causal association in this population. METHODS AND PATIENTS: We studied 1004 consecutive renal transplants with no prior history of ischemic heart disease and grafts that functioned at least 12 months. We performed univariate and multivariate analyses to examine the effect of cytomegalovirus disease and other risk factors (measured during the first posttransplant year) on the development of primary ischemic heart disease events after the first posttransplant year. RESULTS: More than 1 year after transplantation, 116 patients (11.6%) experienced their first ischemic event (75 myocardial infarction, 12 percutaneous angioplasty, 18 bypass grafting, and 11 deaths). Patients with ischemic heart disease were more likely to have known risk factors (age, diabetes, smoking, hypercholesterolemia, systolic blood pressure, low serum albumin, and acute rejections). However, the incidence of cytomegalovirus disease was not different for those with or without ischemic heart disease (36.2% vs. 31.1%). Moreover, a similar proportion of those with and without ischemic heart disease (19.8% vs. 15.5%) had a rise in cytomegalovirus antibodies during follow-up. By multivariate analysis, risk factors for ischemic heart disease (P<0.05) were age, diabetes, smoking, low serum albumin, and two or more acute rejections during the first year. Cytomegalovirus disease was not associated with ischemic heart disease events: unadjusted relative risk=1.14 (95% confidence interval 0.78-1.67, P=0.485). After adjusting for multiple risk factors, the relative risk was 0.91 (0.60-1.37, P=0.657). CONCLUSION: These data suggest that cytomegalovirus disease is not a significant risk factor for the development of primary ischemic heart disease after renal transplantation.

Adult↗
PubMed2001

Epidemiology of cardiovascular disease after renal transplantation.

A large proportion of late renal allograft failures are attributable to patient death with a functioning graft, with almost half of the deaths related to cardiovascular events. Using data from the Framingham Heart Study and our own renal transplant population, risk factors for cardiovascular disease in the general population, such as hypertension, hyperlipidemia, and cigarette smoking, were found to be predictive in renal transplant recipients. However, diabetes mellitus dramatically elevated the risk in renal transplantation. Also, two or more acute rejection episodes in the first year after transplantation were associated with a greater risk, whereas pretransplantation nephrectomy and higher serum albumin levels reduced the risk for ischemic heart events. Pretransplantation screening assists identification of patients who are at risk of, or who have preexisting, cardiovascular disease. Management interventions such as antihypertensives, lipid-lowering agents, antidiabetic therapy, aspirin prophylaxis, and smoking cessation have a positive impact on known risk factors for cardiovascular disease, and their use may decrease cardiovascular morbidity and mortality in renal transplant recipients.

Adult↗
PubMed2001

The effects of lipid-lowering agents on acute renal allograft rejection.

BACKGROUND: Preliminary results from clinical trials suggest that 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitors may help prevent acute renal allograft rejection. However, the mechanism for this putative effect of 3-hydroxy-3-methylglutaryl co-enzyme A reductase inhibitors, and whether it is independent of lipid-lowering per SE are unknown. METHODS: Immediately after renal transplantation we randomly allocated (proportioned 2:1:2) patients to: 1) simvastatin (10 mg/day, n=53), 2) simvastatin placebo plus gemfibrozil (dose adjusted for renal function, n=36), and 3) simvastatin placebo (n=52). RESULTS: Simvastatin, but not gemfibrozil, reduced total and low density lipoprotein cholesterol during the first 90 days posttransplant. There were no major adverse effects of therapy. However, there were no effects of treatment on acute rejection. Indeed, survival free of acute rejection at 90 days was 72% in the simvastatin group, 72% in the gemfibrozil group, and 77% in the placebo control group (P=0.771). A post hoc power analysis suggested that there was only a 7.5% chance that a true effect of simvastatin on acute rejection (versus placebo) was not detected, and a 2.5% chance that an effect of gemfibrozil on acute rejection (versus placebo) was not detected in this study. CONCLUSION: Lipid-lowering agents may not reduce the incidence of acute renal allograft rejection. However, additional studies are needed to confirm this observation. In the mean time, many if not most renal transplant recipients should be treated with HMG-CoA reductase inhibitors starting early posttransplant to prevent cardiovascular disease complications. The results of this study suggest that starting lipid-lowering therapy immediately after renal transplantation is both safe and effective in lowering total and low density lipoprotein cholesterol.

Adult↗
PubMed2001

Small molecule selectin ligand inhibition improves outcome in ischemic acute renal failure.

BACKGROUND: The pathophysiologic and potential therapeutic role of selectins in renal ischemia-reperfusion injury (IRI) is not fully understood, due in part to redundancy in the roles of individual selectins. We hypothesized that blockade of ligands for all three selectins using a novel small molecule (TBC-1269) would improve the course of renal IRI by overcoming redundancy issues. This was investigated in a rat model of renal IRI. METHODS: Rats were treated with TBC-1269 either during or post-IRI. The effects of TBC-1269 were investigated in two models of renal IRI: moderate IRI (30 minutes bilateral renal artery clamping) and severe IRI (45 minutes clamping). The combination of anti-E- and anti-P-selectin antibodies also was investigated in rats subjected to moderate IRI. Renal function, histological injury and mortality were assessed. RESULTS: Rats treated with TBC-1269 during moderate IRI showed significantly reduced serum creatinine (SCr) and tubular necrosis post-ischemia compared to control animals. By contrast, delayed treatment (post-IRI) did not show a reduction in SCr. In rats with severe IRI, TBC-1269 treatment during IRI significantly reduced mortality at 48 hours post-ischemia. Rats with moderate IRI and treated with the combination of anti-E- and anti-P-selectin antibodies showed significantly reduced SCr compared to control rats at 24 hours post-ischemia. CONCLUSIONS: Small molecule selectin ligand inhibition provides a novel and effective approach to attenuate ischemic acute renal failure. Timing of treatment is crucial to success.

Acute Kidney Injury↗
PubMed2001

Effect of lipid reduction on the progression of renal disease: a meta-analysis.

BACKGROUND: It has been proposed that hyperlipidemia contributes to the progression of renal disease. A large trial has not been performed; however, a number of small, controlled trials have been reported. We examined the effects of antilipemic agents on glomerular filtration rate and proteinuria or albuminuria in patients with renal disease. METHODS: We used Medline, abstracts from scientific meetings, and bibliographies from recent reviews and scientific reports to locate pertinent studies. Thirteen prospective controlled trials examining the effects of antilipemic agents on renal function, proteinuria, or albuminuria were included. Studies were published as full reports or abstracts and were at least three months in duration. For five of the studies, individual patient data were obtained. Other summary data were independently extracted from the published reports by two investigators and included study quality, subject characteristics, cause of renal disease, change in serum cholesterol, blood pressure, glomerular filtration rate, proteinuria, and albuminuria. RESULTS: There was a lower rate of decline in glomerular filtration rate with treatment compared with controls (treated controls, 0.156 mL/min/month; 95% CI, 0.026 to 0. 285 mL/min/month, P = 0.008). The study results were statistically homogeneous, and in a regression analysis, the effect of treatment on glomerular filtration rate did not correlate with study quality, the percentage change in cholesterol, the type of lipid-lowering agent, or the cause of renal disease. However, longer follow-up correlated with the amount of improvement in glomerular filtration rate from treatment (P = 0.007). There was a tendency for a favorable effect of treatment on protein or albumin excretion [Ln (treatment) - Ln (control) = -0.248, 95% CI, -0.562 to 0.064, P = 0. 077]. However, these results were statistically heterogeneous between studies (P < 0.001). No obvious explanation for this heterogeneity was apparent in a regression analysis examining potential reasons for differences in study results. CONCLUSIONS: Lipid reduction may preserve glomerular filtration rate and may decrease proteinuria in patients with renal disease.

Controlled Clinical Trials as Topic↗
PubMed2001

Comparing methods for monitoring serum creatinine to predict late renal allograft failure.

Few studies have systematically investigated what changes in chronic renal allograft function best predict subsequent graft failure, when these changes occur, and whether they occur soon enough to allow possible intervention. We collected serum creatinine values (mean, 183 +/- 75 values/patient) measured over a maximum follow-up of 22 years in 101 consecutive renal transplant recipients (excluding creatinine levels from periods of acute rejection). We determined the dates of first decline in inverse creatinine (Delta1/Cr; < -20%, -30%, -40%, -50%, and -70%), declines in estimated creatinine clearance (CCr; <55, 45, 35, 25, and 15 mL/min), and declines in measured slope of 1/Cr over time. We used time-dependent covariates in Cox proportional hazards analyses to determine the relative effect of each renal function parameter on outcomes while adjusting for other risk factors. The best predictor of subsequent graft failure was Delta1/Cr. Delta1/Cr less than -40% first occurred at a median of 1.28 years after transplantation in 73 patients, and 67 patients went on to have graft failure a median of 3.28 years after Delta1/Cr less than -40%. The independent relative risk for graft failure attributable to Delta1/Cr less than -40% was 5.91 (95% confidence interval, 3.25 to 10.8; P < 0.0001). A decline in CCr, eg, less than 45 mL/min, also was a strong predictor of subsequent graft failure. Conversely, declines in allograft function estimated from slopes of 1/Cr were poor predictors of graft failure. In analysis limited to patients followed up for 2.5 years or less, Delta1/Cr continued to predict graft failure, suggesting that Delta1/Cr will be a useful predictor in populations with shorter follow-up. If confirmed in other populations, eg, patients treated with calcineurin inhibitors, this simple marker of chronic allograft dysfunction may prove to be a practical tool for defining patients at high risk for late graft failure.

Adolescent↗
PubMed2000

Payment for immunosuppression after organ transplantation. American Society of Transplantation.

Dramatic improvements in organ transplantation have meant that a growing number of patients must take expensive immunosuppressive medications for the rest of their lives. Currently, Medicare covers most transplantation procedures in the United States, but ends coverage for outpatient immunosuppressive medications after 36 months. Evidence suggests that at least some patients have reduced immunosuppression and their transplants fail because they cannot afford these medication costs. In the years since the advent of effective immunosuppressive therapy, the US Congress has struggled with this issue, and in 1999 temporarily extended medication coverage for eligible patients (based on age and disability) by 8 months. However, a more permanent solution is needed. We advocate that Medicare should cover the cost of all immunosuppressive therapy for all solid organ transplant recipients who cannot afford to pay. A number of potentially cost-effective approaches could be taken, but, in any case, something must be done to ensure that transplants do not fail because recipients cannot pay for immunosuppression.

Federal Government↗
PubMed2000

Low-density lipoprotein-induced expression of interleukin-6, a marker of human mesangial cell inflammation: effects of oxidation and modulation by lovastatin.

Low-density lipoprotein (LDL) may contribute to the pathogenesis of glomerulosclerosis by stimulating a mesangial cell inflammatory response. Interleukin-6 (IL-6) is a marker of active inflammation and ongoing glomerular injury. Therefore, we investigated the effects of native and oxidized LDL on human mesangial cell production of IL-6 and a possible modulation of this inflammatory response by lovastatin, which has been shown to ameliorate experimental glomerulosclerosis. Human mesangial cells were exposed for 6 or 24 h to culture medium containing either native LDL alone or a LDL mixture containing 5 or 20% oxidized LDL. We found that native LDL stimulated 6 h mRNA expression and secretion of IL-6. This effect was further enhanced, in a dose-related manner, when mesangial cells were exposed to increasing concentrations of oxidized LDL. Lovastatin markedly inhibited mesangial cell expression of IL-6 mRNA and reduced IL-6 secretion. The inhibitory effects of lovastatin were overridden at least partially by exogenous mevalonate. We conclude that LDL, and particularly oxidized LDL, might contribute to the pathogenesis of glomerular disease by modulating the inflammatory response of human mesangial cells, as assessed by the stimulation of IL-6 expression. Moreover, this inflammatory response can be prevented by lovastatin, providing a potential direct anti-inflammatory mechanism by which HMG-CoA reductase inhibitors may attenuate lipid-induced glomerular injury.

Base Sequence↗
PubMed2000

Cardiovascular disease after renal transplantation.

Cardiovascular disease (CVD) is common after renal transplantation. In the absence of controlled intervention trials, the strength of evidence that modifying a risk factor will reduce the incidence of CVD in renal transplant recipients must rest on: (1) evidence from studies in the general population, (2) observational studies linking the risk factor to CVD in renal transplant recipients, and (3) studies showing that the risk factor can be safely and effectively treated in transplant patients. Accordingly, the evidence is strong that hyperlipidemia should be treated after renal transplantation. Evidence is very suggestive that pretransplant screening for CVD, treatment of hypertension, the use of low-dose aspirin, and smoking cessation will also help to reduce the incidence of posttransplant CVD. Less compelling are data suggesting that intensive glucose control in diabetics will safely decrease the incidence of CVD. Although there is little evidence that treatment of erythrocytosis will reduce CVD, hematocrits above 55% to 60% should probably be treated to prevent venous thrombosis. Vitamins for reducing homocysteine, antioxidant vitamins, and prophylaxis for potentially atherogenic infections are therapies that warrant additional study. In summary, the best current approach to reducing the high incidence of posttransplant CVD is to aggressively identify, and then systematically treat modifiable risk factors.

Antihypertensive Agents↗
PubMed2000

Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation.

Many complications after renal transplantation can be prevented if they are detected early. Guidelines have been developed for the prevention of diseases in the general population, but there are no comprehensive guidelines for the prevention of diseases and complications after renal transplantation. Therefore, the Clinical Practice Guidelines Committee of the American Society of Transplantation developed these guidelines to help physicians and other health care workers provide optimal care for renal transplant recipients. The guidelines are also intended to indirectly help patients receive the access to care that they need to ensure long-term allograft survival, by attempting to systematically define what that care encompasses. The guidelines are applicable to all adult and pediatric renal transplant recipients, and they cover the outpatient screening for and prevention of diseases and complications that commonly occur after renal transplantation. They do not cover the diagnosis and treatment of diseases and complications after they become manifest, and they do not cover the pretransplant evaluation of renal transplant candidates. The guidelines are comprehensive, but they do not pretend to cover every aspect of care. As much as possible, the guidelines are evidence-based, and each recommendation has been given a subjective grade to indicate the strength of evidence that supports the recommendation. It is hoped that these guidelines will provide a framework for additional discussion and research that will improve the care of renal transplant recipients.

Ambulatory Care↗
PubMed2000

The impact of transplantation on survival with kidney failure.

Although the growth in the incidence and prevalence of ESKD has slowed, there will nevertheless be a substantial increase in the number of patients over the next decade. Indeed, between 1998 and 2010 there will be a doubling in the number of patients in the United States treated with renal replacement therapy. There has also been an increase in the number of new transplants carried out every year. Much of the growth in the number of new transplants has been from the growth in living-unrelated donor transplants. Unfortunately, the rate of increase in the number of new transplants has not been enough to keep pace with the growing number of ESKD patients. As a result, the number of patients on the transplant waiting list continues to increase. The inability to offer more ESKD patients transplantation is unfortunate, since transplantation is associated with improved survival. Indeed, analyses of comparable patients who are placed on the transplant waiting list suggest that transplantation reduces the risk of death by roughly 50%. Thus, it is likely that the overall survival of patients with ESKD will improve if a greater proportion of patients receive transplants in a timely manner. Reducing allograft rejection and the need for repeat transplants may help reduce the demand for donor kidneys. However, this is unlikely to have a major effect on the organ shortage, since the number of repeat transplants has been relatively small (and constant) over the past decade. Thus, only if more cadaveric and living-donor kidneys are made available will more ESKD patients enjoy the improved survival of kidney transplantation.

Adolescent↗
PubMed1999

Risk factors for cancer in renal transplant recipients.

BACKGROUND: Cancer continues to be an important cause of morbidity and mortality after renal transplantation. Unfortunately, risk factors for cancer have not been well defined. METHODS: We examined risk factors for invasive, life-threatening malignancies among 1500 renal transplant recipients. Both univariate and multivariate Cox proportional hazards analyses were used. RESULTS: There were 87 tumors in 88 patients. Actuarial survival free of cancer was 95.9% at 5 years, 92.3% at 10 years, 86.6% at 15 years, and 82.6% at 20 years. Among multiple possible risk factors, the adjusted, relative risk attributable to age at transplantation (compared to age <45 years) was 2.00 (95% confidence interval: 1.21-3.30, P = 0.007) for age > or =45 and <60 years (29.1% of total were in this age range), and 3.81 (95% confidence interval: 2.05-7.06, P<0.001) for age > or =60 years (11.6%). The relative risk attributable to pretransplant splenectomy (47.8%, now large abandoned) was 1.87 (95% confidence interval: 1.12-3.12, P = 0.016). Patients with renal disease from type 1 diabetes had a lower risk of cancer, 0.19 (95% confidence interval: 0.05-0.08, P = 0.015). A history of invasive cancer pretransplant (2.5%) increased the risk of posttransplant cancer to 2.38 (95% confidence interval: 1.18-4.83, P = 0.015). Cigarette smoking was also associated with an increased risk, with each 10 pack-years smoked at transplant increasing the risk of cancer by 1.12 (1.02-1.21, P = 0.016). The era when transplantation occurred, the type of prophylactic immunosuppression used, the occurrence of acute rejection, or its treatment did not alter the risk of cancer. CONCLUSIONS: The risk of cancer continues to increase 15-20 years after transplantation. The identification of splenectomy as a new risk factor, even several years after this immunosuppression strategy has been abandoned, demonstrates that the risk of immunosuppression may take years to become manifest. Efforts to reduce immunosuppression, particularly for patients > or =45 years of age at transplant, along with a greater effort to discourage cigarette smoking, may help reduce the risk of cancer after renal transplantation. cer in a cohort of patients with long-term follow-up. Although this is a retrospective study, the ongoing, continuous follow-up of these patients has made it possible to accurately assess the incidence of invasive malignancy.

Adult↗
PubMed1999

Role of circulating lipid abnormalities in chronic renal allograft rejection.

The evidence that circulating lipid abnormalities may play a role in the pathogenesis of chronic renal allograft rejection is tantalizing but circumstantial. In animal models of cardiac and aorta allograft rejection, lipogenic diets accelerate vascular injury, and treatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors reduce vascular injury. Histological studies have demonstrated foam cells and apolipoprotein deposits in the intima of arteries from chronically rejecting human kidneys. Observational studies have found correlations between plasma lipid levels and both acute and chronic rejection. The association between lipid levels and acute rejection in cyclosporine A (CsA)-treated renal transplant recipients suggests the possibility that plasma lipids may influence the immunosuppressive effects of CsA by modulating the lipoprotein-free levels of CsA. If true, such an effect could also explain the result of recent controlled trials showing that HMG-CoA reductase inhibitors reduced graft coronary artery disease and that they prolonged survival in heart transplant recipients. In any case, the hypothesis that circulating lipid abnormalities contribute to chronic renal allograft rejection deserves further testing in well-designed, clinical trials.

Chronic Disease↗
PubMed1999

The central role of nuclear factor-kappa B in mesangial cell activation.

BACKGROUND: Nuclear factor-kappa B (NF-kappa B) is a family of transcription factors that is recognized by the kappa B enhancer element. Numerous proinflammatory genes have binding sites for NF-kappa B, and the products of these genes are an integral part of cellular activation and inflammatory response systems. Because there is a close relationship between NF-kappa B and mediators of cell activation, it is possible that a disruption of NF-kappa B-activating pathways may effectively influence mesangial cell activation. METHODS: We reviewed available studies related to both NF-kappa B and mesangial cells in order to provide evidence for the role of NF-kappa B in mesangial cell activation. RESULTS: Studies reported by this laboratory and others showed that various experimental maneuvers that modulate NF-kappa B activation result in a parallel modulation of proinflammatory molecule production in cultured mesangial cells. Likewise, the ability of the inhibitors of NF-kappa B activation to down-regulate the inflammatory response in animal models of renal disease has been recently demonstrated. CONCLUSIONS: These data suggest a pivotal role of NF-kappa B in mesangial cell activation and designate it as an obvious target for the modulation of this activation. Studies are necessary to characterize the role of NF-kappa B in human renal injury.

Animals↗
PubMed1999

Effects of lovastatin on expression of cell cycle regulatory proteins in vascular smooth muscle cells.

BACKGROUND: The sequential appearance of cyclins D and E is thought to initiate subsequent DNA synthesis in proliferating cells. Previous studies have reported that DNA synthesis in cultured rat vascular smooth muscle cells (VSMCs) was suppressed by the HMG-CoA reductase inhibitor lovastatin. The effects of lovastatin on cell cycle regulatory proteins in proliferating VSMCs, however, are largely unknown. Thus, we investigated the sequential expression of cyclin D1, cyclin E, cyclin-dependent kinase (CDK) 4, CDK2, and p27Kip1 in cultured rat VSMCs stimulated by platelet-derived growth factor (PDGF)-BB in the presence or absence of lovastatin. METHODS: Quiescent VSMCs, with and without lovastatin (20 microM) pretreatment for nine hours, were stimulated by PDGF-BB (25 ng/ml). The incorporation of tritiated thymidine was done to assess DNA synthesis. VSMC lysates were obtained every 6 hours for up to 36 hours after stimulation and were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot analysis using relevant polyclonal antibodies. Autoradiograms were analyzed using a densitometer. RESULTS: The peak expression of cyclins D1 and E occurred at 18 and 30 hours of PDGF stimulation, respectively. Concomitant expression of CDK4 and CDK2 was also observed. The expression of p27Kip1, by contrast, was reduced in association with DNA synthesis. Lovastatin suppressed DNA synthesis and reduced the expression of cyclin D1 and cyclin E, whereas p27Kip1 expression was strongly induced by lovastatin pretreatment. CDK4 and CDK2 expression was unaffected by lovastatin treatment. CONCLUSIONS: PDGF-BB induces cyclins D1 and E prior to the onset of DNA synthesis in VSMCs. Lovastatin may suppress DNA synthesis in VSMCs by inducing p27Kip1 and reducing expression of cyclins D1 and E.

Animals↗