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Biomedical subjects

B L Kasiske

Publications and source records attributed to B L Kasiske.

At least 91 records · Page 5Linked to original sources
PubMed1994

The evaluation of candidates for renal transplantation. The current practice of U.S. transplant centers.

The criteria for acceptance of candidates for renal transplantation varies throughout the United States. The Patient Care and Education Committee of the American Society of Transplant Physicians conducted a survey of all U.S. centers that participate in the United Network for Organ Sharing (UNOS) concerning their evaluation of adult candidates for kidney transplantation. The response to each question was examined according to the specialty of the individual who filled out the questionnaire, as well as the type of transplant center (university or private) and the size of the center. The response rate to the survey was 81% (147/182). We found the following: (1) university-based and larger centers accepted more medically complicated patients; (2) 83% noted that attendance to dialysis was an important indicator of compliance after transplantation; (3) 79% did not require preoperative blood transfusions for cadaver kidney recipients; (4) 66% set no specific upper age limit for transplantation; (5) 56% excluded patients with chronic active hepatitis in the setting of hepatitis B antigenemia; (6) 50% had no specific policy for evaluating hepatitis C antibody-positive patients, while 54% excluded the use of hepatitis C antibody-positive donors, and (7) 15% obtained coronary angiography on all diabetic patients. U.S. transplant centers have a heterogeneous approach to the evaluation of patients for renal transplantation, particularly in the areas of viral hepatitis, cardiovascular disease, and noncompliance. University-based centers and centers that perform a larger number of transplants accept more medically complicated patients.

Adult↗
PubMed1994

Elective cyclosporine withdrawal 1 year after renal transplantation.

Whether the risks of acute rejection after elective cyclosporine (CsA) withdrawal in renal transplantation outweigh the potential benefits is unclear. We examined results for 236 patients who underwent transplantation between January 1986 and June 1991. Patients were treated with prophylactic CsA, prednisone, and azathioprine, and had grafts that functioned at least 1 year. We elected to withdraw CsA after 1 year in 192 patients who were rejection free for 12 months. Thirty-four patients elected to continue CsA. In 1988 a protocol that tapered CsA over 6 weeks was abandoned when eight (29.6%) of the first 27 patients developed acute rejection within 6 months. We then adopted a 12-week CsA taper preceded by 1 month of increased azathioprine (2.5 mg/d as tolerated) and followed by increased prednisone (30 mg/d for 1 week, 20 mg/d for 1 week, 15 mg/day for 6 months, then 15 mg/d on alternate days). With this protocol the incidence of postwithdrawal acute rejection within 6 months was reduced to 9.1% among 165 patients (P < 0.01 v 6-week taper). Actuarial 5-year graft survival (patients living with a functioning graft) was 81.7% for patients left on CsA, 88.9% for patients tapered over 6 weeks, and 81.5% for patients tapered over 12 weeks (P > 0.05). We also examined risk factors for acute rejection after CsA withdrawal using a Cox proportional hazards model and found that the relative risk of acute rejection within 6 months of taper was approximately two times greater for each DR mismatch (P < 0.001). We conclude that CsA withdrawal has not affected renal allograft survival at our center.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1994

Cholesterol synthesis inhibitors inhibit more than cholesterol synthesis.

The beneficial effects of HMG-CoA reductase inhibition in models of progressive glomerular injury may not all be due to reductions in circulating lipoproteins and decreases in glomerular lipoprotein deposition. Indeed, HMG-CoA reductase inhibitors may have direct effects on glomerular mesangial cells that could explain the amelioration of renal injury. Specifically, HMG-CoA reductase inhibitors block the synthesis of isoprenoids that are necessary for mesangial cell proliferation and other important cell functions. Thus, protein isoprenylation may play a critical role in the pathogenesis and treatment of lipid-induced glomerular injury.

Animals↗
PubMed1993

Elective cyclosporine withdrawal after renal transplantation. A meta-analysis.

OBJECTIVE: To determine whether it is safe to electively discontinue cyclosporine therapy after renal transplantation. DATA SOURCES: MEDLINE and bibliographies from recent publications. STUDY SELECTION: Controlled trials assessing the rate of acute rejection, graft loss, and mortality after elective cyclosporine withdrawal. DATA EXTRACTION: We compared outcomes in patients who underwent withdrawal from cyclosporine treatment with patients who were not withdrawn (part 1), and in a separate analysis (part 2), with patients who never received cyclosporine. DATA SYNTHESIS: In part 1 of the meta-analysis, consisting of 10 randomized and seven nonrandomized trials, there was a greater combined rate of acute rejection among patients in whom cyclosporine was withdrawn compared with control patients who continued to receive cyclosporine (weighted difference in episodes per patient, 126; 95% confidence interval [CI], 0.085 to 0.167; P < .001). However, there were no differences in graft loss (weighted difference in grafts lost per patient per year, -0.009; 95% CI, -0.022 to 0.004; P = 0.19) or mortality (weighted difference in deaths per patient per year, -0.005; 95% CI, -0.016 to 0.006; P = .40) attributable to cyclosporine withdrawal. In part 2 of the meta-analysis, consisting of three randomized and three nonrandomized trials, the combined rate of graft loss for patients who were withdrawn from cyclosporine was not significantly different vs control patients who never received cyclosporine (weighted difference in grafts lost per patient per year, -0.020; 95% CI, -0.043 to 0.003; P = .08). However, when the three randomized trials were analyzed separately, graft survival was better in patients who were withdrawn from cyclosporine (weighted difference in grafts lost per patient per year, 0.0382; 95% CI, 0.0002 to 0.0762; P = .049). None of the outcomes was affected by the timing or manner of the cyclosporine withdrawal. CONCLUSIONS: The increased incidence of acute rejection following elective cyclosporine withdrawal does not affect short-term graft or patient survival after renal transplantation. Whether long-term consequences will outweigh the benefits of elective withdrawal remains to be determined.

Cyclosporine↗
PubMed1993

Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis.

OBJECTIVE: To assess the relative effect of different antihypertensive agents on proteinuria and renal function in patients with diabetes. DATA SOURCES: We used MEDLINE and bibliographies in recent articles to identify studies of the effects of antihypertensive agents on renal function in patients with diabetes. STUDY SELECTION: We selected 100 controlled and uncontrolled studies that provided data on renal function, proteinuria, or both, before and after treatment with an antihypertensive agent. DATA EXTRACTION: Data on blood pressure, renal function, proteinuria, patient characteristics (for example, age, sex, and type of diabetes), and study design (for example, random allocation and the use of a placebo) were extracted from selected studies. DATA SYNTHESIS: Multiple linear regression analysis indicated that angiotensin-converting enzyme (ACE) inhibitors decreased proteinuria independent of changes in blood pressure, treatment duration, and the type of diabetes or stage of nephropathy, as well as study design (P < 0.0001). Reductions in proteinuria from other antihypertensive agents could be entirely explained by changes in blood pressure. Blood pressure reduction in itself was associated with a relative increase in glomerular filtration rate (regression coefficient [+/- SE], 3.70 +/- .92 mL/min for each reduction of 10 mm Hg in mean arterial pressure; P = 0.0002); however, compared with other agents, ACE inhibitors had an additional favorable effect on glomerular filtration rate that was independent of blood pressure changes (3.41 +/- 1.71 mL/min; P = 0.05). CONCLUSION: Angiotensin-converting enzyme inhibitors can decrease proteinuria and preserve glomerular filtration rate in patients with diabetes. These effects occur independent of changes in systemic blood pressure.

Adolescent↗
PubMed1993

Value of liver biopsy in the evaluation and management of chronic liver disease in renal transplant recipients.

PURPOSE: Liver disease is a frequent complication in renal transplant recipients. To understand the nature and progression of hepatic disease in these patients, we performed percutaneous biopsies in 77 subjects who had chronic liver dysfunction in the posttransplant period. The purpose of the present investigation is to delineate the morphologic spectrum of chronic liver disease in the renal allograft recipients and to characterize the clinical and histologic progression of each of the different morphologic forms. PATIENTS AND METHODS: Between 1971 and 1990, 915 patients received renal transplants at the Hennepin County Medical Center, Minneapolis, Minnesota. One hundred nineteen (13%) of them had abnormal liver function that persisted for longer than 6 months. Percutaneous liver biopsies were performed in 77 of these patients, but adequate tissue for histologic evaluation was available in only 72. After the biopsy, the clinical and histologic course of each subject was monitored in relation to the baseline hepatic morphology. To assess the predictive value of serum enzymes in diagnosing the histologic lesions, the level of serum enzymes at the time of the biopsy was correlated with the morphologic diagnosis. In addition, several clinical, biochemical, etiologic, and histologic variables were screened for their association with histologic progression to liver cirrhosis. RESULTS: The morphologic diagnosis in the 72 specimens evaluated at baseline was as follows: fat metamorphosis in 8 (11%), chronic persistent hepatitis in 20 (28%), early chronic active hepatitis in 20 (28%), advanced chronic active hepatitis in 15 (21%), and hemosiderosis in 9 (12%). There was no statistical correlation between the serum enzyme levels and the histologic diagnosis. During a mean follow-up of 5.7 +/- 3.9 years, clinical progression to hepatic failure and death occurred in 35% of patients with early chronic active hepatitis, 55% with hemosiderosis, and 60% with advanced chronic active hepatitis. None of the patients with the morphologic diagnosis of fat metamorphosis or chronic persistent hepatitis died as a consequence of hepatic failure. Follow-up liver specimens were obtained in 34 (47%) of the original 72 subjects after a mean interval of 4.5 +/- 4.3 years. Of the 15 patients with the initial diagnosis of early chronic active hepatitis, 9 (60%) showed morphologic transition to advanced chronic active hepatitis, and in 1 of the 5 patients with hemosiderosis (20%), the lesion had resolved after successive phlebotomies. During the follow-up, 60% with early chronic active hepatitis (9 of 14), 66% with hemosiderosis (2 of 3), and 100% with advanced chronic active hepatitis (4 of 4) showed histologic progression to liver cirrhosis. On the contrary, no morphologic alterations were observed in the follow-up specimens of patients with fat metamorphosis or chronic persistent hepatitis. Of the different variables screened for their association with histologic progression, older age at transplant, female sex, and morphologic diagnosis of advanced chronic active hepatitis were found to be significant. CONCLUSION: Histologic diagnosis can be a useful marker in predicting the course of chronic liver disease after renal transplantation. Liver biopsy should be incorporated into the evaluation and management of chronic liver disease in renal transplant recipients.

Adult↗
PubMed1993

Hypertension, hyperlipidemia, and renal damage.

Experimental studies have demonstrated that a number of factors participate in the progression of renal disease. Systemic and glomerular hypertension have been shown to be critical factors in renal injury. Hyperlipidemia that frequently coexists with renal disease also has been suggested as an important participatory factor in nephron damage. Interestingly, both hypertension and hyperlipidemia seem to evoke glomerular growth, a factor that has also been postulated to be involved in glomerular and tubular destruction. Recently, experimental and clinical data suggest that an important interaction occurs between hyperlipidemia and hypertension. Not only do they frequently coexist, but hypertension dramatically exaggerates hyperlipidemic injury, and hyperlipidemia alters systemic and glomerular vascular production of vasoactive substances which maintain basal vascular tone. Thus, these recent observations underscore the interactive potential of the various risk factors that participate in progression of renal disease. They also suggest that multiple interventional strategies may be needed to optimally prevent progressive nephron loss.

Animals↗
PubMed1993

Lovastatin retards the progression of established glomerular disease in obese Zucker rats.

Considerable experimental evidence indicates that hyperlipidemia can induce glomerular injury. The importance of lipids in the progression of established glomerular disease has not been established and is of clinical relevance because of the frequent association of lipid abnormalities with human renal disease. In the present study, 26-week-old hyperlipidemic obese Zucker rats (OZRs) with established nephropathy were treated for a period of 18 weeks with daily injections of the cholesterol synthesis inhibitor lovastatin (4 mg/kg). Compared with control OZRs treated with vehicle, lovastatin-treated OZRs had significantly (P < 0.05) lower serum cholesterol and triglyceride levels throughout the treatment period. Blood pressure and urine albumin excretion in lovastatin-treated OZRs were reduced over the first 12 weeks of therapy, but increased toward the levels in the control OZRs at the end of the protocol. After 18 weeks of therapy, the incidence of glomerulosclerosis in lovastatin-treated OZRs (23.2% +/- 5.8%) was approximately half of that in vehicle-treated OZRs (44.6% +/- 7.7%) (P < 0.05). The reduction in glomerular injury in lovastatin-treated OZRs was not associated with changes in either glomerular area or glomerular macrophage content. In separate experiments, mesangial cells were cultured from glomeruli isolated from 26-week-old proteinuric OZRs. Lovastatin (5 to 40 mumol/L) caused a significant dose-dependent inhibition of serum-stimulated mesangial cell DNA synthesis. The inhibitory effects of lovastatin were completely prevented in the presence of exogenous mevalonate (100 mumol/L). Thus, lovastatin retarded the progression of established glomerular disease in OZRs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Treatment of hyperlipidemia in chronic progressive renal disease.

Experiments in animal models suggest that correcting abnormalities in lipid metabolism could help slow the rate of functional decline in patients with chronic progressive renal disease. Circumstantial evidence in humans also suggests that lipids may play a role in the pathogenesis of glomerulosclerosis. Nevertheless, large controlled clinical trials examining the effect of lipid-lowering strategies on renal disease progression have not been carried out. However, the recent development of antilipemic agents that appear to be safe and effective in patients with renal disease should make it possible to determine whether treating hyperlipidemia will reduce the rate of renal disease progression.

Animals↗
PubMed1993

Lovastatin inhibits proliferation of rat mesangial cells.

Products of intracellular mevalonate metabolism are essential for cell growth and proliferation. Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, blocks the formation of mevalonate and its metabolites, and has been shown to inhibit proliferation of several cell types. In vivo, lovastatin has reduced mesangial cellularity and glomerular injury in experimental renal disease. In this study, we investigated the effects of lovastatin on DNA replication and proliferation in rat glomerular mesangial cells. Growth-arrested mesangial cells were exposed to medium containing 10% fetal bovine serum to stimulate mitogenesis. Lovastatin (1-20 microM) caused a significant (P < 0.05) dose-dependent reduction in DNA synthesis ([3H]thymidine incorporation) which was completely prevented in the presence of exogenous mevalonate (100 microM). Lovastatin (1 microM) inhibited cell proliferation by 90% over a 5-d period, and this was largely overcome by added mevalonate. Exogenous low density lipoprotein (100 micrograms/ml) did not prevent lovastatin inhibition of DNA synthesis. The isoprenoid end product isopentenyl adenine (5 or 50 microM) had little effect on DNA synthesis and cell proliferation in lovastatin-blocked cells. By contrast, the isoprenoid farnesol (5 microM) largely prevented lovastatin inhibition of DNA synthesis. We conclude that mevalonate metabolism is essential for mesangial cell proliferation, possibly through the production of the isoprenoid farnesol. Moreover, the action of lovastatin to reduce experimental glomerular injury may involve a direct effect on mesangial cells.

Adenine↗
PubMed1993

Alterations in glomerular proteoglycan metabolism in experimental non-insulin dependent diabetes mellitus.

Glomerular proteoglycans (PG) are important in modulating extracellular matrix assembly and glomerular permselectivity. In the obese Zucker rat, an experimental model of non-insulin dependent diabetes mellitus, expansion of the mesangial matrix, and microalbuminuria occur before the development of overt renal disease. The in vivo incorporation of (35S)sulfate into glomerular PG in 12-wk-old obese Zucker rats at the onset of microalbuminuria was compared with that of 12-wk-old lean Zucker rats. Specific (35S)sulfate incorporation into glomerular PG over 8 h was increased by 57% in obese rats compared with lean rats, suggesting increased PG synthesis. However, at variance with the observation in experimental models of insulin-dependent diabetes mellitus, the proportion of total glomerular (35S)PG released by heparin treatment was unchanged. Heparan sulfate (HS)-PG constituted over 60% of radiolabeled de novo synthesized glomerular PG. Similar proportions of HS-PG were extracted from the glomeruli of obese and lean rats. Isolated glomeruli spontaneously released two HS-PG, which constituted approximately 30% of total glomerular (35S)PG. On the basis of their chromatographic and electrophoretic patterns, these PG were similar in obese and lean rats. Heparin treatment of isolated glomeruli released an additional HS-PG, which appeared to be derived primarily from the glomerular extracellular matrix compartment and not from the detergent soluble cell fraction. Heparin-releasable HS-PG from both the lean and obese Zucker rats eluted at a KAV of 0.31 from Sepharose CL-6B chromatographic columns, indicating a hydrodynamic size similar to that reported for glomerular basement membrane HS-PG. However, gel electrophoresis demonstrated faster migration of the HS-PG released by heparin from the glomeruli of obese Zucker rats, suggesting increased electronegativity. Thus, early in the course of nephropathy in the obese Zucker rat, there is increased glomerular PG synthesis with no change in the proportions of the constitutively releasable and heparin-releasable HS-PG. Whether electrophoretic abnormalities of the heparin-releasable HS-PG observed in the obese rats contribute to the development of albuminuria and/or mesangial matrix expansion remains to be established.

Animals↗
PubMed1993

Oxidative modification of low-density lipoproteins by mesangial cells.

Because hypercholesterolemia and mesangial cell proliferation may be important in the pathogenesis of glomerulosclerosis, the effects of low-density lipoprotein (LDL) on human mesangial cell proliferation were evaluated. Native LDL (20 to 200 micrograms/mL) caused a dose-dependent increase in (3H)thymidine incorporation and increased mesangial cell numbers over 96 h. The mitogenic effect of LDL was partially blocked by the inhibition of cytochrome P-450, but not by the inhibition of cyclooxygenase or lipoxygenase pathways. Higher LDL concentrations (1,000 to 2,000 micrograms/mL) inhibited (3H)thymidine incorporation and reduced cell numbers, possibly as a result of the oxidative modification of LDL, indicated by an increase in thiobarbituric reactive substances. This peroxidation of LDL involved superoxide, because superoxide dismutase and butylated hydroxytoluene prevented it, whereas hydroxyl radical scavengers were without effect. Native LDL subjected to chemical oxidation by copper sulfate also inhibited mesangial cell proliferation. These results suggest that low concentrations of LDL may stimulate human mesangial cell proliferation, which may, in turn, cause the production of reactive oxygen molecules. Moreover, the oxidative modification of LDL may mediate the toxic effects of high LDL concentrations on human mesangial cells.

Antioxidants↗
PubMed1993

The renin-angiotensin system in the type II diabetic obese Zucker rat.

Recently, the obese Zucker rat (OZR), an animal model of non-insulin-dependent (type II) diabetes, was shown to respond to converting enzyme inhibition with decreased albuminuria and a marked attenuation of glomerular injury. It was hypothesized that the OZR would possess low plasma renin values and an increased vascular responsiveness to angiotensin II, and therefore, the renin-angiotensin system (PRA, active renin, inactive renin, renal renin content, and plasma angiotensinogen) and vascular reactivity in OZR at 10 and 24 wk of age were investigated. PRA and renin concentration, inactive plasma renin, and renal renin content were all significantly (P < 0.05) reduced in OZR when compared with age-matched lean controls. The ratio of inactive to total renin was significantly increased in the OZR. OZR aortic ring vascular reactivity to KCl, norepinephrine, and angiotensin II was assessed. Despite essentially equal or increased contractile responses to KCl and norepinephrine at both 10 and 24 wk of age, the OZR was not more sensitive to angiotensin II and displayed a significantly reduced contractile response to angiotensin II at 24 wk of age, when compared with lean age-matched controls. It was concluded that the renal protective effect of converting enzyme inhibition in OZR, despite significantly reduced PRA and concentration, inactive plasma renin, and renal renin content, may not be due to a diabetes-induced increased vascular reactivity to angiotensin II.

Angiotensin I↗
PubMed1993

The mevalonate pathway: importance in mesangial cell biology and glomerular disease.

Products of intracellular mevalonate metabolism are critical for the growth and proliferation of eukaryotic cells. These products include cholesterol and several nonsterol isoprenoids. The isoprenoid farnesyl is a particularly important intermediate in the mevalonate pathway. Farnesyl can be used to synthesize cholesterol and can also bind covalently to several low molecular mass GTP-binding proteins such as p21 ras. Farnesylated p21 ras may be critical for mitogenic signalling stimulated by growth factors such as platelet-derived growth factor. Inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, such as lovastatin and compactin, block the production of mevalonate and its metabolites. These agents have been shown to inhibit proliferation of many cell types. Recently we demonstrated that lovastatin inhibited proliferation of cultured glomerular mesangial cells. Lovastatin inhibition was overcome by the simultaneous addition of either mevalonate or farnesol, but not by exogenous low density lipoprotein cholesterol. These results suggested that farnesyl is critical for mesangial cell proliferation. In several experimental models of renal disease, chronic lovastatin administration reduced the extent of glomerular injury. The beneficial effects of lovastatin have been attributed to lowering of circulating lipid and lipoprotein levels. In view of recent data, however, it is possible that lovastatin may act to reduce glomerular injury, at least in part, through a direct action on mesangial cell proliferation.

Animals↗
PubMed1993

Risk factors for cardiovascular disease after renal transplantation.

The incidence of cardiovascular disease is high after renal transplantation. Risk factors include pretransplant cardiovascular disease, diabetes, male sex, serum cholesterol, hypertension, cigarette smoking, and allograft dysfunction. Prevention of cardiovascular disease can probably best be approached by modifying multiple risk factors. Thus, efforts should be made to identify and treat patients with severe coronary artery disease before transplantation. After transplantation, hypertension and hyperlipidemia should be treated, and efforts should be made to help patients abstain from smoking. Chronic immunosuppression protocols should attempt to balance the need to prevent allograft rejection with the known adverse effects of immunosuppressive agents on cardiovascular disease. Altogether, an aggressive, coordinated program to modify multiple risk factors is probably the best approach to the prevention of cardiovascular disease after renal transplantation.

Cardiovascular Diseases↗