Gastric emptying time in renal transplant recipients treated with cyclosporine

Gastric emptying time (GET) appears to be a rate-limiting factor in the absorption of cyclosporine-A (CsA) and may be responsible for intra- and interpatient variability of CsA bioavailability. Few studies have assessed gastric motility after renal transplantation. The purpose of this study was to evaluate gastric emptying of semi-solid material in stable renal transplant patients with reference to blood CsA levels. The GET of semi-solids (GET t(1/2), half emptying time) was measured in 16 transplant recipients who were taking CsA (Neoral), prednisolone and azathioprine (or mycophenolate mofetil). The GET (t(1/2)) measured by radionuclide methods, was analyzed with reference to the daily CsA doses, levels of CsA (C(0)), and serum creatinine concentrations. The mean GET (t(1/2)) was 89.1 +/- 26.4 minutes. Twelve patients exhibited delayed gastric emptying with a mean CsA level of 171.8 +/- 56 ng/mL and a mean dose of 4.1 +/- 1.1 mg/kg/d. The GET (t(1/2)) was not significantly correlated with the serum creatinine levels, the time since transplantation, or the CsA concentration. In addition, the correlation between the mean daily CsA dose and the GET (t(1/2)) was only weakly positive, (r =.33, P =.2) and therefore, statistically insignificant. In conclusion, it could not be ascertained whether a higher dose of CsA delays gastric emptying or whether patients with delayed emptying require higher doses of CsA. However, it is believed that determining the GET after transplantation helps in the adjustment of immunosuppressant doses.     

Comparison of FK-506 and cyclosporine regimens in pediatric renal transplantation

Clinical aspects of FK-506 or cyclosporine immunosuppression regimens were evaluated in 48 consecutive pediatric renal transplant recipients. Tapering and discontinuation of prednisone was employed only in children receiving FK-506 who experienced minor or no rejection episodes during the 1st posttransplant month. At 1 year follow-up, 17 of 22 (77%) of all children with functioning allografts were receiving no prednisone (n=13) or a mean dosage of 0.07 mg/kg per day (n=4). During the 1st month, acute cellular rejection was more common in the FK-506 group (0.58 vs. 0.21 rejections per patient,P<0.05) but allograft survival (92%) and renal function at 1 year posttransplant were identical in both groups. Compared with the cyclosporine regimen, FK-506 immunosuppression may be associated with a higher incidence of cytomegalovirus or reversible Epstein-Barr virus-induced lymphoproliferative disease. However, the FK-506 group had less hirsutism and gingival hypertrophy and required fewer antihypertensive medications independent of steroid use. Height standard deviation scores and weight-for-height index improved only in preadolescents receiving FK-506 but no prednisone (P<0.02 andP<0.05, respectively), but did not differ between children on FK-506 plus prednisone and those in the cyclosporine group. We conclude that the major advantages of FK-506 over cyclosporine immunosuppression are a reduced severity of hypertension and an improved cosmetic appearance which may improve long-term medical compliance. When used as monotherapy, FK-506 also shows promise in relieving the growth retardation associated with cyclosporine regimens that include prednisone.     

Compliance with cyclosporine in adolescent renal transplant recipients

  Inadequate compliance with prescribed medication regimens in children is complex and poorly understood. We measured the extent and pattern of noncompliance with cyclosporine in our adolescent renal transplant population and attempted to determine factors associated with poor compliance. After informed consent, each patient was provided cyclosporine capsules in a medication bottle equipped with an electronic monitoring device (MEMS-4) in the lid. Of the 24 patients eligible, 19 patients (8 female, 11 male) completed the study. Four (21%) patients took less than 80% of the prescribed cyclosporine doses. Five (26%) patients took drug holidays involving ≥3 consecutive doses. There was a trend towards improved compliance with the evening dose (88.5% vs. 93.4%, P = 0.09) and a downward trend in compliance over the course of the study (P = 0.17). None of the variables tested were found to be associated with noncompliance. Experienced physicians and nurses were able to identify 2 of the 4 individuals who were identified by MEMS as noncompliant. Additionally, 2 of the 4 noncompliant patients demonstrated low cyclosporine trough levels (<50 ng/ml). Noncompliance with cyclosporine regimens occurs commonly in adolescent renal transplant recipients. Unexpectedly low cyclosporine levels are strongly suggestive of noncompliance, whereas other variables, including prediction by physicians and nurses intimately involved in the care, were not reflective of noncompliance. Received October 19, 1996; received in revised form February 18, 1997; accepted March 18, 1997     

Hyperlipidemia in pediatric kidney transplant recipients treated with cyclosporine

Hyperlipidemia is a risk factor for cardiovascular disease in adult kidney transplant (Tx) recipients. We sought to determine the prevalence of, and the risk factors associated with, hyperlipidemia in pediatric kidney Tx recipients on cyclosporine (CsA). We identified 59 patients (mean age 8.2+/-5.7 years) transplanted between 1 January 1991 and 31 December 1993. Pre Tx, 34% had elevated total cholesterol [TC >200 mg/dl (5.17 mmol/l)]; 54% had elevated triglycerides [TG >200 mg/dl (2.26 mmol/L)]. Mean TG was higher pre Tx in dialysis (versus nondialysis) patients: 306 mg/dl (3.46 mmol/l) versus 228 mg/dl (2.58 mmol/l) ( P=0.04). Mean TC was higher in peritoneal dialysis than hemodialysis patients: 222 mg/dl (5.74 mmol/l) versus 169 mg/dl (4.37 mmol/l) ( P=0.03). Pre Tx and 3-year values correlated (TC, r=0.49, P=0.0008; TG, r=0.41, P=0.001); 3- and 5-year TC values correlated ( r=0.57, P=0.003). At 5 years post Tx, 41% of the recipients had elevated TC; 14% had elevated TG. Recipients with elevated TC had higher mean CsA concentrations at 1 year post Tx ( P=0.03). Recipients with elevated TG tended to receive more prednisone ( P=0.06). At 5 years post Tx, recipients had a high prevalence of hyperlipidemia. The identification and treatment of hyperlipidemia should be included in pediatric kidney Tx protocols.     

Protocol biopsies in pediatric renal transplant recipients on cyclosporine versus tacrolimus-based immunosuppression

Background

Protocol biopsies can detect subclinical rejection and early signs of calcineurin inhibitor-induced nephrotoxicity.

Methods

In a prospective study, protocol biopsies 3 and 12 months after transplant in transplanted children from two centers were studied. One center used cyclosporine (CsA)-based immunosuppression and the other center used tacrolimus. Patients were on CsA (n?=?26, group 1) or on tacrolimus (n?=?10, group 2). Patients received basiliximab induction, mycophenolate mofetil, and prednisone.

Results

In patients on CsA, 26 kidney biopsies were performed during the 6 months after transplantation. Eighteen protocol biopsies were performed at 3 months post transplant; 13 were normal and five showed rejection (two borderline and three Banff II rejections). Eight biopsies were motivated by an increase of serum creatinine; four were normal and four revealed signs of acute rejection (two borderline and two Banff II). Twelve protocol biopsies were performed after 12 months; all were normal. For patients on tacrolimus (n?=?10), ten protocol transplant biopsies were performed at 3 months post-transplant; none showed signs of rejection. No biopsy was performed for an increase of serum creatinine. There were no differences in patient age, number of human leukocyteantigen (HLA) incompatibilities, or other patient characteristics.

Conclusions

Patients on tacrolimus had less acute rejection episodes detected on protocol biopsies 3 months after transplant. Protocol biopsies seem to play an important role in the detection of subclinical rejection in patients on CsA.     

Vascular endothelial function in cyclosporine and tacrolimus treated renal transplant recipients.

BACKGROUND: Endothelial dysfunction is an early key event in the development of arteriosclerotic cardiovascular disease (ASCVD), thus an early marker of subclinical ASCVD. Endothelial function is impaired in renal transplant recipients (RTR) treated with cyclosporine (CyA). Tacrolimus is associated with less hyperlipidemia and hypertension than CyA, however, there are no data on endothelial function in tacrolimus-treated RTR. METHODS: High-resolution brachial ultrasonography was used to assess endothelium-dependent dilatation (EDD), and endothelium-independent dilatation (EID) in 20 stable RTR and a control group of 10 healthy subjects without clinical evidence of ASCVD. The RTR group included patients receiving CyA (n=10) and tacrolimus (n=10). EDD and EID were measured as percent increase in brachial artery diameter in response to reactive hyperemia and nitroglycerin, respectively. RESULTS AND CONCLUSIONS: EDD was significantly lower in RTR versus controls (1.7+/-0.7 vs. 7.3+/-0.7%, P<0.0001), whereas EID was similar in the two groups. No significant differences were found in EDD or in EID between CyA- and tacrolimus-treated RTR. Glomerular filtration rate, plasma homocysteine, blood pressure, and lipid profiles were similar in CyA- and tacrolimus-treated RTR.     

Long term efficacy of simvastatin in renal transplant recipients treated with cyclosporine or tacrolimus

BACKGROUND: Hyperlipidemia is frequently developed following renal transplantation and results in worsening of the patient's prognosis. METHODS: In this study, 14 patients who had hypercholesterolemia [total cholesterol (TC) >200 mg/dL] and hypertriglyceridemia [triglyceride (TG) >150 mg/dL] 1 month after renal transplantation (post-transplantation), seven patients each under the treatment with immunosuppressant, either cyclosporine or tacrolimus started simvastatin treatment of 5-10 mg/d and continued the treatment for 4 yr. The effect of simvastatin treatment was assessed by comparison in serum lipid levels (TC, TG, cholesterol in lipoprotein fractions, and apolipoproteins) and the lipid metabolism related enzyme activities for post-transplantation, after 6-month and 4-yr simvastatin treatment. RESULTS: Simvastatin treatment of 4 yr significantly decreased the elevated levels of serum TC from 234.5 +/- 30.8 to 186.3 +/- 20.5 mg/dL (p < 0.001), low density lipoprotein cholesterol (LDL-C) from 116.7 +/- 22.5 to 82.7 +/- 16.6 mg/dL (p < 0.05) and TG from 200.3 +/- 109.2 to 97.0 +/- 45.2 mg/dL (p < 0.001). In addition, there were significant decreases in elevated serum very-low-density lipoprotein cholesterol (VLDL-C) from 47.8 +/- 18.4 to 28.6 +/- 9.5 mg/dL (p < 0.001) and LDL2 cholesterol (LDL2-C) from 20.8 +/- 8.2 to 5.7 +/- 1.8 mg/dL (p < 0.001). CONCLUSION: The results indicate that 4-yr treatment of simvastatin improves profiles of the atherogenic lipids in renal transplant patients with immunosuppressant caused hypercholesterolemia and hypertriglyceridemia treated either cyclosporine or tacrolimus in similar manner.     

他克莫司替代环孢素A在肾移植术后肝功能损害患者中的应用

目的 :评价对肾移植术后肝功能损害患者用他克莫司 (FK5 0 6 )替代环孢素A(CsA)治疗的有效性及安全性。方法 :2 3例肾移植术后肝功能损害患者由CsA加霉酚酸酯 (MMF)加泼尼松 (Pred)方案改为FK5 0 6加MMF加Pred方案。FK5 0 6按 0 .1mg/kg·d-1剂量口服 ,随后根据血药浓度调整用量。结果 :2 3例患者除 1例因肺部感染死亡外 ,其余均在替代用药后 6 0d内肝功能恢复正常。有 6例患者出现血糖升高 ,1例血脂升高。 6例血糖升高者有 4例既往有糖尿病史 ,1例并发丙型肝炎。结论 :FK5 0 6替代CsA治疗肾移植术后肝损害患者效果好 ,无排斥反应发生、安全     

Posttransplantation diabetes mellitus in FK-506-treated renal transplant recipients: analysis of incidence and risk factors.

BACKGROUND: The development of posttransplantation diabetes mellitus has a major impact on the quality of life and long-term outcome. METHODS: One hundred thirty-nine patients without known glucose metabolism abnormalities and treated with FK-506, methylprednisolone, and mycophenolate mofetil/azathioprine were analyzed for incidence of and risk factors for developing impaired fasting glycemia (IFG) and diabetes mellitus (DM). RESULTS: Using the American Diabetes Association criteria, 15% developed IFG and 32% developed DM in the first year after transplantation. High trough levels of FK-506 during the first month after transplantation (especially >15 ng/ml) and high body mass index (BMI) were significant risk factors for IFG or DM. Patients with (steroid-treated) acute rejections in addition to high trough levels of FK-506 were most prone to develop DM, whereas high BMI conferred risk of developing IFG. Patients with posttransplantation glycemic abnormalities also had higher levels of serum triglycerides at the time of transplantation, but they needed a lower dose of FK-506 to obtain higher trough levels of FK-506, suggesting metabolic differences already present before transplantation. The only risk factor retained for persistent IFG or DM beyond the first year was a higher number of trough levels of FK-506 >15 ng/ml during the first month after transplantation. CONCLUSIONS: Induction with an FK-506 based immunosuppressive regimen resulted in a high incidence of glucose metabolism disorders in renal transplantation recipients. Higher trough levels of FK-506 during the first month, acute rejections, and higher BMI were the most obvious risk factors.     

Subclinical inflammation in renal transplant recipients: impact of cyclosporine microemulsion versus tacrolimus

BACKGROUND: Renal insufficiency and renal transplant (RT) provoke a microinflammatory state that leads to increased atherosclerosis. It is not fully known whether calcineurin inhibitors (CNIs) play a role in the inflammation observed in these patients or whether any differences exist between CNIs. OBJECTIVES: The study aimed to establish differences in the inflammatory state of two groups treated with cyclosporine microemulsion (CyA) or tacrolimus (TC). PATIENTS AND METHODS: This prospective study included 81 RT patients divided into two groups according to the CNI: CyA group, n = 35 versus TC group, n = 46. The markers of inflammation (MIF) were determined preRT and at 3 and 12 months' postRT: C-reactive protein (CRP), serum amyloid protein A (SAA), interleukin-6 (IL-6), soluble interleukin-2 receptor (sIL-2R), tumor necrosis factor-alpha (TNF-alpha), and pregnancy-associated plasma protein A (PAPP-A). Samples were collected in stable patients in the absence of rejection, active infection, or inflammatory processes. RESULTS: No significant differences existed between the markers of inflammation in the two treatment groups prior to transplantation. At 3 months' posttransplant, patients treated with CyA showed significantly higher levels of IL-6 (P = .05), SAA (P = .03), and sIL-2R (P = .008) compared with patients treated with TC. These differences were maintained for IL-6 (P = .03) and sIL-2R (P = .027) at 12 months' posttransplant. A multivariate analysis at 3 months showed that only age [OR 10.1; CI (95% 2.6-38.4); P = .001], SAA [OR 4.8; IC (95% 1.4-16.5); P = .015], and sIL-2R [OR 4.9; IC (95% 1.5-16.2); P = .009] were independent predictors of the CNI used. At 12 months, age [OR 3.7; IC (95% 0.9-14.2] and sIL-2R [OR 6.04; IC (95% 1.5-23); P = .006] continued to be independent predictors. CONCLUSIONS: Patients treated with CyA displayed significantly higher levels of inflammatory markers (IL-6, SAA, sIL-2R) at 3 and 12 months' posttransplantation, independent of age, gender, time on dialysis, diabetes mellitus (preRT and de novo postRT), and renal function measured by serum creatinine.     

Risk factors for allograft failure in United kingdom renal transplant recipients treated with cyclosporine A

BACKGROUND: After the introduction of cyclosporine A (CsA), 2-year graft survival of transplanted kidneys improved from less than 60% to more than 80%, but long-term graft survival and graft half-life have shown less change. This study investigates the impact of a range of demographic and treatment factors on long-term graft survival in renal recipients treated with CsA from all renal transplant centers in the United Kingdom. METHODS: Data were obtained from the Long-Term Efficacy and Safety Surveillance study of renal transplant recipients receiving CsA (Neoral; Novartis, Basel, Switzerland). A total of 1,757 de novo patients with a functioning graft at 1 year were evaluated. The endpoints considered were the need for regular dialysis or death. A stepwise stratified Cox model was used to identify the factors associated with outcome. RESULTS: Seven independent risk factors for allograft failure were identified: older recipient (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.2-2.6), male recipient (HR 1.8, 95% CI 1.2-2.7), younger donor (HR 1.7, 95% CI 1.2-2.5), above average creatinine (HR 1.9, 95% CI 1.3-2.8), chronic allograft nephropathy (HR 7.0, 95% CI 4.7-10.4), diabetic recipient (HR 2.2, 95% CI 1.2-4.1), and neoplasm after transplant (HR 1.7, 95% CI 1.2-2.6). CONCLUSION: Seven independent risk factors were found to influence graft survival. Only two of these can be modified by clinical intervention, elevated serum creatinine at 1 year and the occurrence of chronic allograft nephropathy. To influence these two factors, the optimization of immunosuppressive therapy is essential.     

Post-transplant acute renal failure in cadaver renal recipients treated with cyclosporine

The outcome of patients with acute renal failure following cadaveric renal transplant has been evaluated in a prospective, controlled trial, comparing treatment with cyclosporine (CSA) to prednisone, azathioprine, and antilymphocyte globulin (AZA). There was a high incidence of acute post-transplant renal failure in both groups: 37 of 51 CSA and 31 of 45 AZA patients, due to the long exposure of kidneys to warm and cold ischemia. Onset of adequate renal function was delayed for three or more weeks in 27 (53%) CSA and only nine (20%) AZA patients, and the only predisposing factor found was donor hypotension. All nine AZA and 18 of the 27 CSA patients with prolonged oliguria subsequently had a spontaneous diuresis. Nine of the CSA patients were changed to azathioprine and prednisone because of suspected CSA toxicity, and eight of these kidneys began functioning within days, even though they had been oliguric for 21 to 83 days. Of these nine patients, five had adequate long-term function on AZA, three developed CMV infections that were fatal to two individuals, and two rejected their grafts. Plasma CSA levels fluctuated widely in all patients, but were not higher in any group, including those with prolonged oliguria. During the oliguric period, biopsy specimens proved rejection was more common in the nine patients who had their CSA stopped than in the other CSA patients, and seven of these nine developed a diffuse interstitial fibrosis that was thought to be a manifestation of CSA toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)