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K L Heim-Duthoy

Publications and source records attributed to K L Heim-Duthoy.

At least 19 recordsLinked to original sources
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↗
PubMed1998

The pharmacokinetics of a single oral dose of mycophenolate mofetil in patients with varying degrees of renal function.

BACKGROUND: The purpose of this study was to determine the effect of renal function on the elimination and disposition of mycophenolic acid and its glucuronide metabolite (MPAG) after oral administration of the pro-drug mycophenolate mofetil. In addition, this study sought to examine hemodialysis removal of mycophenolic acid and its MPAG. METHODS: Subjects were stratified into five groups on the basis of iohexol clearance. After an overnight fast, all subjects received a single 1 gm dose of mycophenolate mofetil. Plasma concentrations of mycophenolic acid and MPAG were measured from 0 to 96 hours after administration. Mycophenolic acid and MPAG maximum plasma concentration (Cmax) and the time to reach Cmax (tmax) for each group were determined from the mean plasma concentration-time profiles. Area under the plasma concentration-time curve values for mycophenolic acid and MPAG were calculated by the trapezoidal rule. The half-lives of mycophenolic acid and MPAG were calculated from the terminal portions of the concentration-time profiles. RESULTS: Mycophenolic acid clearance was not associated with changes in glomerular filtration rate (GFR). Cmax tended to increase as GFR declined. MPAG clearance correlated well with GFR (r2 = 0.905). Clearance of mycophenolic acid and MPAG were unaffected by hemodialysis. CONCLUSIONS: Clearance of mycophenolic acid after a single 1 gm oral dose of mycophenolate mofetil is unaffected by renal function. Clearance of mycophenolic acid is unaffected by hemodialysis. Diminished renal function should not require preemptive adjustment of 1 gm doses of mycophenolate mofetil; however dosage adjustment may be warranted on the basis of adverse effects or toxicity in individual patients. Mycophenolate mofetil can be administered irrespective of hemodialysis session without effect on mycophenolic acid exposure.

Administration, Oral↗
PubMed1997

A randomized trial comparing cyclosporine induction with sequential therapy in renal transplant recipients.

Calcium antagonists may reduce the nephrotoxicity of cyclosporine (CsA), allowing CsA to be introduced immediately after renal transplantation and thereby obviating the need for sequential induction therapy with a monoclonal or polyclonal antibody. To test this hypothesis, in a pilot feasibility trial 100 cadaveric or one-haplotype-mismatched living-related renal transplant recipients were randomized to either (1) sequential therapy with anti-thymocyte globulin (ATG) (ATGAM; Upjohn, Kalamazoo, MI) 20 mg/kg/d for 7 to 14 days until renal function was established and CsA (Sandimmune; Sandoz, East Hanover, NJ) was started, or (2) CsA 8 mg/kg/d begun immediately before surgery with diltiazem (Cardizem; Marion Merrell Dow, Kansas City, MO) 60 mg sustained release twice daily. Acute rejection episodes during the first 90 days were not different with ATG versus CsA induction (42% v 28%; P = 0.142 by chi-square analysis). Graft failures (10% v 16%; P = 0.372) and the incidence of delayed graft function (28% v 34%; P = 0.516) were also similar with ATG compared with CsA. ATG caused lower platelet counts (138 +/- 59 x 10(3) v 197 +/- 75 x 10(3) at 7 days; P < 0.001) and lower white blood cell counts (9.6 +/- 4.6 x 10(3) v 12.3 +/- 4.9 x 10(3) at 7 days; P = 0.003). Diltiazem reduced the dose of CsA required to maintain target blood levels (479 +/- 189 mg/d v 576 +/- 178 mg/d at 14 days; P = 0.015). There were no statistically significant differences between the groups in serum creatinine levels at days 1, 3, 5, 7, 14, 28, 60, or 90. The results of this pilot feasibility trial suggest that prophylactic treatment with CsA and diltiazem may be equally effective and less toxic than ATG induction after renal transplantation.

Adult↗
PubMed1997

Predictive performance of renal function estimate equations in renal allografts.

AIMS: Various mathematical models have been developed to estimate glomerular filtration rate (GFR) incorporating variables such as age, gender, height, weight, serum creatinine, and body surface area (BSA). Because adjustments in drug dosing are often based on estimated values of renal function, it is important to define which, if any, of the available models, is appropriate for a specific patient population. A study was undertaken to determine the bias and precision of four mathematical models to estimate GFR in renal allograft recipients. METHODS: A retrospective review of 142 stable renal allograft patients, using iohexol clearance as a determinant of GFR, was performed. Renal allograft recipients followed in an outpatient clinic setting underwent iohexol clearance studies as part of clinical monitoring in the post-transplant period. Measured GFR values were compared with four mathematical models used to estimate GFR: the Cockcroft-Gault equation, the Jelliffe equation, the Walser equation, and the Mawer equation. Bias and precision were determined for each model as the mean squared error and the mean squared error, respectively. RESULTS: Patients had a mean age of 44 +/- 13 years, 92 were male, and 50 were female. The serum creatinine concentration was 176.8 +/- 88.4 mumol l-1 (mean +/- s.d.). The mean time post-transplant was 5.1 +/- 5.0 years and 38% of patients had insulin-requiring diabetes mellitus. The bias and precision results for the Jelliffe, Walser, Cockcroft-Gault, and Mawer models were: -3 and 414; -5 and 381; 16 and 688; and 23 and 1084, respectively. CONCLUSIONS: The Jelliffe and Walser equations gave the least biased and most precise estimations of GFR when compared with iohexol-derived measures in patients with renal allografts.

Adult↗
PubMed1995

Clinical impact of replacing Minnesota antilymphocyte globulin with ATGAM.

In August 1992, we replaced Minnesota antilymphocyte globulin (MALG) with lymphocyte immune globulin, antithymocyte globulin (equine) (ATGAM) in our immunosuppression protocols. The clinical impression of increased graft rejection prompted our assessment of the effect of this change on patient and graft outcome. The initial study group consisted of 426 renal transplant recipients transplanted between October 1, 1987, and September 21, 1993. After exclusions, 388 transplant events, with a minimum 8-month follow-up, made up the final study cohort: 323 patients received MALG and 65 received ATGAM. Immunosuppression included intravenous methylprednisolone, oral prednisone, oral AZA, CsA in some cases, and intravenous MALG or ATGAM, 15 mg/kg/day, for 7 to 14 days. Acute rejection was treated with high dose intravenous steroids and steroid-resistant episodes were treated additionally with either MALG or OKT3. Statistical comparisons were stratified for multiple patient characteristics and treatment variations. There was a greater incidence of rejection in general, and a higher incidence of steroid-resistant episodes requiring subsequent antilymphocyte globulin therapy (P = 0.0073) in patients receiving ATGAM versus MALG. No difference was seen in the incidence of CMV infection or blood-borne sepsis. Lymphoma occurred in 3 MALG and 2 ATGAM recipients. MALG recipients were significantly less likely to experience rejection within the first 60 days after transplant (P = 0.0127 using unstratified data; P < 0.0001 when data were stratified for patient characteristics). The relative risk of acute rejection for posttransplant days 5, 7, 10, and 14 was consistently higher for ATGAM-treated patients. We conclude that MALG and ATGAM are not equivalent drugs, and that MALG is a more effective immunosuppressant, and is just as safe as ATGAM in our protocol environment.

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↗
PubMed1993

Cyclosporine-amiodarone interaction.

OBJECTIVE: To report a possible interaction between cyclosporine (CsA) and amiodarone in a kidney transplant recipient. CASE SUMMARY: A 66-year-old kidney transplant recipient with a history significant for hypertension, moderate mitral valve insufficiency, and decreased left ventricular function developed ventricular tachycardia posttransplant and was eventually treated with amiodarone. Maintenance immunosuppression included prednisone, azathioprine, and CsA. CsA concentrations before amiodarone initiation were stable (range 100-150 ng/mL). After amiodarone initiation, the CsA concentration increased more than twofold. Following CsA dosage reduction, concentrations returned to the desired range. The patient did not experience any toxicity with the increased concentration of CsA. DISCUSSION: The possible mechanisms of an interaction between CsA and amiodarone are reviewed. Reports of this interaction in heart transplant recipients are also reviewed. Changes in protein binding, changes in metabolism, or both may explain the interaction. Both CsA and amiodarone are protein bound and metabolized by the cytochrome P-450 enzyme system. CONCLUSIONS: It is likely that there is an interaction between CsA and amiodarone. The exact mechanism of this interaction has not been fully determined. When CsA is administered concurrently with amiodarone, CsA concentrations should be monitored closely and the CsA dosage should be adjusted as necessary.

Aged↗
PubMed1992

Transient reductions in serum cholesterol after renal transplantation.

Declines in serum cholesterol have been reported in patients with altered immune system activity. However, the frequency and clinical significance of transient reductions in serum cholesterol after renal transplantation are unknown. In the present retrospective study, we examined the frequency and clinical setting of reduced serum cholesterol (< or = 4.40 mmol/L [170 mg/dL]) in patients who each had 28 +/- 7 (total, 1,110) cholesterol determinations during the first year posttransplant. Reduced cholesterol was found on at least one occasion in 26 of 40 (65%) patients. Ninety-two percent (119/129) of the reduced cholesterol values occurred in one of three clinical settings: (1) within 10 days after transplantation, (2) within 6 weeks before or after the onset of acute rejection, or (3) within 6 weeks before or after the onset of a cytomegalovirus infection (CMV). Multiple linear regression analysis showed that the relationship between reductions in cholesterol associated with acute rejection was independent of CMV and the type of immunosuppression (one half of the patients were treated with cyclosporine [CSA]). The fact that serum albumin was reduced during CMV, but not during acute rejection, suggested that reduced cholesterol associated with rejection was relatively specific, and was not caused by a generalized leak of plasma proteins or by poor nutrition. Thus, during the first year posttransplant, reductions in serum cholesterol are most often associated with acute rejection episodes and/or CMV.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1992

Patients with a low income have reduced renal allograft survival.

The impact of socioeconomic factors on long-term outcome after renal transplantation is unknown. We examined the effects of family income among 202 patients transplanted between 1976 and 1982 who had an allograft that functioned for at least 1 year. Compared with patients with an adequate income, recipients of medical assistance at the time of transplantation were more likely to return to dialysis after 1 year (16/45 [36%] v 26/157 [17%], P less than 0.01), or after 5 years of graft function (10/38 [26%] v 12/116 [10%], P less than 0.01). Patients who complied with fewer than 85% of visits during the first 2 years were also more likely to return to dialysis after 1 year (17/49 [35%] v 25/153 [16%], P less than 0.01), or after 5 years (8/31 [26%] v 14/123 [11%], P less than 0.05) than were more compliant patients. However, noncompliance was not different in patients with and without a low income (37/157 [24%] v 12/45 [27%], P greater than 0.05). The relative risk for returning to dialysis after 5 years was 2.4 (P less than 0.05) for low income and 3.0 (P less than 0.05) for less than 85% compliance using a Cox proportional hazards model. These effects were independent of prior transplantation, mismatches, pre-formed antibodies, delayed graft function, age, sex, diabetes, alcohol or drug abuse, education, race, distance from the transplant center, and living in an urban environment (relative risk = 2.5, P less than 0.05). Neither income nor compliance could be linked to death.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Effect of concomitant administration of piperacillin on the dispositions of isepamicin and gentamicin in patients with end-stage renal disease.

Piperacillin inactivation of the aminoglycosides isepamicin and gentamicin in 12 chronic hemodialysis patients was assessed. Six subjects each received isepamicin (7.5 mg/kg of body weight) or gentamicin (2 mg/kg) alone and in combination with piperacillin (4 g every 12 h for four doses). Isepamicin and gentamicin concentrations in plasma and urine were monitored over 48 h after each dose and analyzed by high-performance liquid chromatography and fluorescence polarization immunoassay, respectively. The pharmacokinetics of isepamicin were not significantly altered during combination treatment with piperacillin. The total body clearance (3.79 +/- 0.71 versus 3.94 +/- 1.05 ml/min), the steady-state volume of distribution (0.19 +/- 0.04 versus 0.18 +/- 0.03 liter/kg), and the terminal elimination half-life (47.91 +/- 7.20 versus 45.08 +/- 10.34 h) were not significantly altered in the presence of piperacillin. In contrast, the terminal elimination half-life (47.68 +/- 20.58 versus 35.67 +/- 11.18 h) of gentamicin was significantly reduced when gentamicin was given with piperacillin. The total body clearance (4.26 +/- 3.07 versus 4.89 +/- 1.94 ml/min) and the steady-state volume of distribution (0.19 +/- 0.04 versus 0.20 +/- 0.04 liter/kg) of gentamicin were not significantly altered during combination therapy; however, the nonrenal clearance of gentamicin administered in combination with piperacillin (3.56 +/- 0.38 ml/min) increased significantly compared with that of gentamicin (2.03 +/- 0.50 ml/min) given alone. The results of this study suggest that no additional dosage adjustment of isepamicin during concomitant therapy with piperacillin in hemodialysis patients is necessary. However, this does not preclude the need for appropriately ex vivo-handled specimens for monitoring isepamicin concentrations in plasma to ensure therapeutic efficacy and prevent toxicity. Furthermore, additional dosage adjustments may be necessary when gentamicin is used concomitantly with piperacillin, on the basis of the significant in vivo inactivation that takes place in end-stage renal disease patients.

Adult↗
PubMed1991

The adverse impact of cyclosporine on serum lipids in renal transplant recipients.

The extent to which cyclosporine (CsA) directly, or indirectly, influences serum lipid levels in renal transplant patients treated with multiple-drug immunosuppression protocols is unclear. Indeed, patients treated with CsA have reduced corticosteroid requirements, fewer acute rejection episodes, and other differences from patients receiving conventional immunosuppression that may reduce serum lipid levels. We studied patients treated with low-dose CsA, corticosteroids, azathioprine, and Minnesota antilymphocyte globulin ([ALG] n = 205) versus conventional (three-drug) immunosuppression (n = 368) and evaluated the impact of CsA, acute rejection episodes, and other clinical parameters on serum lipids. Fasting serum lipid levels from stable patients transplanted between 1976 to 1989 were studied at 3 (n = 573), 12 (n = 565), 26 (n = 55), and 52 (n = 521) weeks posttransplant using multivariate, linear regression analysis. The incidence of acute rejection episodes was reduced by CsA, but patients with fewer acute rejection episodes in the early posttransplant period had higher serum total cholesterol (increased by .33 +/- .12 mmol/L [13 +/- 5 mg/dL] and .27 +/- .12 mmol/L [10 +/- 5 mg/dL], P less than 0.05, at 3 and 12 weeks, respectively) and low-density lipoprotein (LDL) (increased by .23 +/- .11 mmol/L [9 +/- 4 mg/dL] and .23 +/- .11 mmol/L [9 +/- 4 mg/dL], P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1991

The variable nature of chronic declines in renal allograft function.

Despite having important implications for the design of therapeutic trials, the clinical setting, time of onset, and rate of progression for chronic declines in renal allograft function have not been well characterized. In the present investigation, monthly estimates of glomerular filtration rate (E-GFR) were made using creatinine clearance and interim serum creatinine levels. There were 200 patients transplanted from 1978 to 1982 (precyclosporine) who survived at least 12 months with a functioning allograft. Of these, 25 had irreversible declines in E-GFR (greater than 30%) attributable to acute rejection, 50 had gradual, chronic declines in E-GFR, and 125 maintained stable function. Patients with chronic declines in E-GFR more often returned to dialysis (56%, P less than 0.001) than those with irreversible, acute reductions (24%), or stable function (2%). Chronic declines in allograft function were modeled by one or two least-squares-fitted regression lines. In most cases, the onset was early, but in 26% chronic declines in E-GFR began 2.2 +/- 1.2 (mean +/- SD) years after transplantation. Among those with chronic declines in E-GFR, 20/50 (40%) had spontaneous improvements in the rate of progression after 2.7 +/- 1.1 years and survived 8.4 +/- 2.6 years with functioning grafts, while 30/50 (60%) continued to have progressive declines in E-GFR and survived 6.1 +/- 2.5 years (P less than 0.01). Although chronic declines in E-GFR were evident 3.2 +/- 1.7 years before graft failure, routinely measured clinical and laboratory parameters from the early posttransplant period failed to predict patients who developed chronic declines in E-GFR. Altogether these data suggest that chronic declines in allograft function have an unpredictable onset and variable clinical course.

Creatinine↗
PubMed1990

Lovastatin treatment of hypercholesterolemia in renal transplant recipients.

The treatment of hypercholesterolemia in renal transplant recipients has been problematic. In the present double-blind study, 11 patients were treated with diet for at least 4 weeks. They were then randomized to placebo or the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, lovastatin (20 mg/day) for 6 weeks, followed by crossover to an additional 6 weeks of lovastatin or placebo. All patients had stable allograft function 8.4 +/- 1.2 years (mean +/- SEM) after transplantation, and received low-dose prednisone and azathioprine immunosuppression. Compared with diet alone, lovastatin caused a 21% reduction in total cholesterol from 307 +/- 14 mg/dL to 244 +/- 13 mg/dL (P less than 0.05). Lovastatin reduced LDL cholesterol 28% from 214 +/- 12 mg/dL to 155 +/- 11 mg/dL (P less than 0.05). Trends toward favorable changes in HDL cholesterol, serum triglycerides, and apolipoproteins were not statistically significant. Liver enzymes, creatine phosphokinase, and renal function remained stable. With lovastatin there was a 27% increase in the WBC (from 6220 +/- 530 cells/mm3 to 7780 +/- 510 cells/mm3, P less than 0.05) that was attributable to a 45% increase in neutrophils (P less than 0.05). This effect of lovastatin, possibly the result of reduced azathioprine bone marrow suppression, could have important implications for immunosuppressive therapy in this patient population. Altogether, these results suggest that lovastatin may be a safe and effective treatment for hypercholesterolemia in renal transplant recipients receiving conventional immunosuppression.

Adolescent↗
PubMed1990

Effect of concomitant administration of piperacillin on the dispositions of netilmicin and tobramycin in patients with end-stage renal disease.

The effect of piperacillin administration on the dispositions of netilmicin and tobramycin was assessed in 12 chronic hemodialysis patients. Six subjects each received netilmicin (2 mg/kg) or tobramycin (2 mg/kg) alone and in combination with piperacillin (4 g every 12 h for four doses). Subjects also received a single dose of piperacillin (4 g) on a separate occasion. The serum concentration-versus-time profiles of netilmicin and tobramycin were biexponential. The terminal elimination half-life (t1/2 beta) of tobramycin was markedly reduced (59.62 +/- 25.18 [mean +/- standard deviation] versus 24.71 +/- 5.41 h) and total body clearance (CLP) was significantly increased in the presence of piperacillin (3.45 +/- 1.61 versus 7.16 +/- 1.64 ml/min). In contrast, the t1/2 beta (41.80 +/- 13.24 versus 40.07 +/- 10.37 h) and CLP (5.11 +/- 2.15 versus 5.55 +/- 2.32 ml/min) of netilmicin were not significantly altered when netilmicin was administered in combination with piperacillin. No change in the central or steady-state volume of distribution of netilmicin or tobramycin was observed. The disposition of piperacillin in hemodialysis patients was not altered in the presence of either aminoglycoside antibiotic. Although no adjustment in netilmicin dosing is required, tobramycin should be administered more frequently when given concomitantly with piperacillin to hemodialysis patients to avoid prolonged periods of subtherapeutic concentrations.

Adult↗
PubMed1990

Apparent biliary pseudolithiasis during ceftriaxone therapy.

Biliary pseudolithiasis has been reported in patients who received ceftriaxone therapy. To examine this phenomenon further, serial gallbladder sonograms were evaluated in 44 adult patients who received intravenous ceftriaxone at 2 g or a placebo daily for 14 days in a double-blind controlled study. Ultrasound examinations of gallbladders were performed on days 1 and 14 of therapy and 2 weeks posttherapy if abnormalities were observed on day 14. Eight patients were unevaluable because of abnormal base-line gallbladder sonograms. Thirty-six patients (ceftriaxone, n = 28; placebo, n = 8) demonstrated normal baseline gallbladder sonograms and were evaluated for the development of change. A total of 6 of 28 (21.4%) ceftriaxone-treated patients and 1 of 8 (12.5%) patients who received the placebo demonstrated abnormal gallbladder sonograms on day 14 (P = 0.491). Four of the six ceftriaxone-treated patients demonstrating abnormal sonograms were clinically asymptomatic, while two patients reported vomiting. The abnormal sonograms of gallbladders of patients treated with ceftriaxone returned to normal between 9 and 26 days posttherapy. These data suggest an association between ceftriaxone treatment and the development of gallbladder abnormalities on ultrasound examination which resolve spontaneously on discontinuation of ceftriaxone therapy.

Adult↗