Hyperuricemia and gout among heart transplant recipients receiving cyclosporine.

PURPOSE: To determine the frequency and characteristics of hyperuricemia and gouty arthritis among cyclosporine-treated heart transplant recipients. PATIENTS AND METHODS: One hundred ninety-six surviving adult heart or heart/lung transplant recipients were evaluated. Medical records were reviewed to determine peak serum uric acid levels after transplantation, and to evaluate potential risk factors for hyperuricemia. Patients were surveyed by postal questionnaire for a history of gouty arthritis, with positive responses evaluated by telephone interview and/or examination of the patient. RESULTS: Hyperuricemia occurred in 72% of male and 81% of female patients and was not correlated with cyclosporine level, presence of hypertension, or degree of renal insufficiency. Eleven (6%) patients had gout prior to transplantation; 14 (8%) had onset of definite gout and seven (4%) had probable gout a mean of 17 months after transplantation. Polyarticular arthritis and/or tophi developed in six (43%) of the posttransplant-onset definite gout group within a mean of 31 months. CONCLUSION: Both hyperuricemia and gouty arthritis occur with increased frequency among cyclosporine-treated heart or heart/lung transplant recipients. The clinical course of gout in these patients is often accelerated, with management complicated by the patients' renal insufficiency and interaction with transplant-related medications.     

Changes in lipid metabolism and effect of simvastatin in renal transplant recipients induced by cyclosporine or tacrolimus

Hyperlipidemia is frequently developed following renal transplantation and results in worsening of the patient's prognosis. In study 1, the effects of immunosuppressants, cyclosporine (CsA) and tacrolimus on serum lipids were compared in-patients undergoing renal transplantation. The study included 32 cases of renal transplantation recipients who randomized to the CsA treatment group (15 patients) and the tacrolimus group (17 patients). Before and 1 month after the transplantation, we assessed the serum lipid levels, apolipoprotein levels, the concentrations of cholesterol in the respective lipoprotein fractions and the enzyme activities related to lipid-metabolism. The serum lipid levels in both groups were significantly increased at 1 month after renal transplantation. In the CsA group, there were significant increases in cholesterol contents in very-low-density lipoprotein (VLDL), LDL2 and HDL2 fractions, whereas, in the tacrolimus group, cholesterol content was increased in VLDL and HDL2 fractions. In study 2, 1 month after renal transplantation, 19 patients with hypercholesterolemia (total cholesterol (TC) >200 mg/dl) and hypertriglyceridemia (triglyceride (TG) >150 mg/dl) were treated with simvastatin 5-10 mg/day for 6 months. Simvastatin treatment significantly decreased serum TC (240+/-29-200+/-22 mg/dl, P<0.001), low-density lipoprotein cholesterol (LDL-C; 114+/-20-99+/-17 mg/dl, P<0.05) and TG levels (217+/-103-130+/-38 mg/dl, P<0.01). In addition, there were significant decreases in very-low-density lipoprotein cholesterol (VLDL-C; 53+/-20-34+/-15 mg/dl, P<0.001). The Cmax and AUC of simvastatin were increased about eight-fold, when simvastatin was given in combination with CsA. In contrast, no significant changes in simvastatin levels were observed when combination with tacrolimus. Although simvastatin levels were increased with CsA, there were no abnormal changes in renal and liver functions, creatinine phosphokinase (CPK) levels or in incidence of adverse effects.     

肾移植术后“爬行肌酐”患者使用他克莫司替换环孢素A疗效观察

目的观察他克莫司（FK506）替换环孢素A（CsA）逆转肾移植术后“爬行肌酐”的可行性。方法24例肾移植患者术后均采用以CsA为主的三联免疫抑制方案，出现“爬行肌酐”后用FK506替换CsA。观察替换前后的移植肾功能变化，同时监测血压、抗高血压药物分值（AHS值）、血糖和血脂的变化，随访12个月。结果“爬行肌酐”患者采用FK506替换CsA后，移植肾功能较替换前明显好转，血肌酐下降明显（P〈0．05）；同时降低了血脂水平，并减少降脂药物及抗高血压药物的使用。结论肾移植术后“爬行肌酐”患者采用FK506替换CsA的治疗方案可以有效地改善或者稳定移植肾的功能。     

Infectious complications in heart transplant recipients receiving cyclosporine and corticosteroids

The rate of infectious complications differed significantly in two groups of heart transplant recipients who received different immunosuppressive regimens. Compared with patients who received conventional immunosuppression, patients treated with cyclosporine had a lower rate of infectious complications, and the contribution of infection to observed mortality was lower. Herpes simplex virus caused less morbidity and there were fewer active cytomegalovirus infections in seropositive recipients treated with cyclosporine. The incidence of bacterial pulmonary infections and associated bacteremia also decreased impressively. A decrease in nocardial infections was offset by a rise in those due to Legionella species. The frequency of aspergillosis was decreased by 54% in the cyclosporine-treated group, but half of these infections disseminated beyond the lung and such dissemination was always fatal. Infections with Pneumocystis carinii were significantly less common with cyclosporine-based immunosuppression. Screening serologic tests for toxoplasma should be done routinely and consideration given to prophylaxis in heart transplant recipients at high risk.     

Pharmacokinetic study and limited sampling strategy of cyclosporine in Japanese heart transplant recipients.

BACKGROUND: The purpose of this study was to characterize the pharmacokinetics of cyclosporine (CsA) in Japanese heart transplant patients, and to optimise the monitoring strategy based on measurements of the area under the curve of plasma concentration absorption phase or 2 h post-dose concentrations (C(2)). METHODS AND RESULTS: At defined time periods during the first year after transplantation, the area under the curve for the CsA serum concentration from 0 to 4 h (AUC(0-4 h)) was evaluated. Pharmacokinetic parameters and renal function at 1 month and 12 months after transplantation were compared in 7 Japanese patients. The highest coefficient of determination between CsA AUC(0-4 h) and a single concentration was observed using C2 (r2 =0.838). For CsA pharmacokinetics, the mean measurement of whole blood trough levels value at 12 months was significantly lower than at 1 month after transplantation (p=0.026). The mean serum creatinine level at 12 months was significantly higher than at 1 month (1.00 mg/dl vs 0.73 p=0.0194). CONCLUSION: A single-time-point model that includes C2 is useful for predicting CsA AUC(0-4 h) in Japanese heart transplant patients. Mean C2 values >1,000 ng/ml were obtained in patients with no rejection at 1 month and 12 months after transplantation; however, renal impairment may occur.     

Limited sampling strategy for mycophenolic acid in Japanese heart transplant recipients: comparison of cyclosporin and tacrolimus treatment.

BACKGROUND: The purpose of the study was to characterize the pharmacokinetics of mycophenolic acid (MPA) in Japanese heart transplant recipients and to find the time point that has the best correlation with the MPA area under the plasma concentration curve (AUC). METHODS AND RESULTS: Twenty-two Japanese recipients treated with mycophenolate mofetil were evaluated in the study. Approximately 9 months after transplantation, the area under the MPA serum concentration-time curve from 0 to 12 h (AUC(0-12 h)) was evaluated. The MPA AUC(0-12 h) h values in the cyclosporine (CsA) and tacrolimus (FK) groups ranged from 13.11 to 50.98 mug . h/ml and from 39.19 to 93.18 mug . h/ml, respectively. Fourteen models were developed and analyzed for their ability to estimate the MPA AUC(0-12 h) based on a limited number of samples in the CsA group. Sixteen models were developed in the FK group. The best model for predicting the full MPA AUC(0-12 h) in the CsA group was a 3-time-point model that included C(0 h), C(1 h) and C(2 h) (r(2), 0.96; mean prediction error, 0.15+/-7.85%); a 2-time-point model that included C(0 h), and C(2 h) (r(2), 0.94; mean prediction error, 0.495+/-10.35%) was also reliable. In the FK group, a 3-time-point model that included C(1 h), C(2 h) and C(4h) (r(2), 0.73; mean prediction error, 2.73+/-17.09%) was the best model for predicting the full MPA AUC(0-12 h), but it was not reliable in clinical practice. CONCLUSION: A 3-(C(0 h), C(1 h) and C(2 h)) and a 2-time-point model (C(0 h) and C(2 h)) are useful for predicting the full MPA AUC(0-12 h) in Japanese heart transplant recipients treated with CsA but not with FK.     

以西罗莫司为基础环孢素A早期减量和撤除方案对比的临床观察

目的:评价以西罗莫司(SRL)为基础,环孢素(CsA)早期减量和撤除的免疫抑制方案在肾移植患者中的疗效和安全性.方法:2004年7月～2005年9月间17例肾移植患者使用SRL CsA 激素的免疫抑制方案.术后第3个月,使SRL浓度在4～12μg/L,同时逐渐减少CsA用量;至术后第6～9个月,使CsA浓度降至50～100 ng/ml或停用CsA,SRL浓度维持在6～12μg/L(减量者)或8～15μg/L(停CsA者).术后定期监测血肌酐(SCr)水平,观察不良反应及人、肾存活情况.结果:13例于术后第6～9个月完成CsA减量(mCsA,10例)或撤除(eCsA,3例)方案,10例mCsA患者的CsA用量由(4.6±0.71)mg/(kg·d)减至(2.9±1.10)mg/(kg·d)(P＜0.05).术后2年,患者和移植肾全部存活,各有3例、5例分别维持eCsA和mCsA方案,CsA用量减至(1.1±0.26)mg/(kg·d).完成并维持eCsA和mCsA方案的患者,术后第12、24个月的SCr分别为(101±32.7)μmol/L(n=10)、(101±25.8)μmol／L(n=8).1例在CsA减量前发生急性排斥(AR),1例CsA减量后因自行停用SRL发生AR.主要不良反应有高脂血症(n=11)、肝功能损害(n=7)和感染(n=7)等.结论:以西罗莫司为基础用药而减少或停用CsA,可有效防治AR,同时可减少CsA的肾毒性等不良反应.高脂血症和肝功能异常等是主要不良反应,西罗莫司的不良反应及对停用CsA的疑虑会影响该方案的实施.     

Coronary artery intimal thickening and ventricular dynamics in pediatric heart transplant recipients

Objective: Pediatric heart transplant recipients are at risk of posttransplant coronary artery disease known as cardiac allograft vasculopathy (CAV), and also may develop diastolic dysfunction. As CAV begins with a process of progressive intimal thickening, these occult diffuse changes may be detected using optical coherence tomography (OCT). We hypothesized that the development of CAV, as identified via OCT, may be a mechanism of declining ventricular function. Accordingly, the purpose of this study was to assess coronary artery intimal thickening and LV strain in children who have undergone heart transplantation.
Methods: In 17 children, we analyzed OCT images for coronary intima and media thickness, and cross‐sectional area (CSA). We also performed speckle tracking imag‐ ing (STI) of the LV to determine longitudinal strain and strain rate, in addition to standard echocardiographic measures.
Results: Longitudinal diastolic strain rate was associated with maximum intima thick‐ ness (r = −.497, P = .042), intima CSA, (r = −.489, P = .047), maximum media thickness (r = −.503, P = .039), and media CSA (r = −.614, P = .009). The intima maximum thick‐ ness, intima/media, and intima/lumen ratios were associated with stroke volume index (Std. β = −0.487, P = .023 and Std. β = −0.488, P = .022, respectively).
Conclusions: These findings suggest coronary artery intimal thickening may be mechanistically linked to changes in ventricular function following cardiac transplantation.     

Diffusion capacity in heart transplant recipients.

Preoperative diffusion capacity per liter alveolar volume (Kco) in cardiac transplant recipients with an intrinsic normal lung is within the normal range. In the first postoperative year, Kco showed a significant mean decrease of 12 percent (p less than 0.004). Lung function (TLC, VC, FEV1) tended to normalize after heart transplantation. Ventilation distribution remained stable before and after heart transplantation. Preoperatively, weak correlations were found between Kco and diastolic pulmonary arterial pressure (dPAP) and mean pulmonary capillary wedge pressure (PCWP). Postoperatively, correlation between Kco and PCWP was weak, and between Kco and dPAP it was not significant at all. These pressures determine the capillary blood volume before and after transplantation. Probably these weak correlations indicate that intrapulmonary factors, not cardiac factors, are of primary importance in the regulation of blood distribution. The percentage of decrease in Kco in the first postoperative year correlated with the change in dPAP and PCWP, but also with the cyclosporine level in the first posttransplant year. No correlation was found between cyclosporine level and pulmonary vascular resistance. It is suggested that higher levels of cyclosporine influence the alveolar capillary membrane, so that Kco decreases. The percentage of decrease in Kco was significantly more outspoken in patients who had rales on auscultation preoperatively. Using multiple regression analysis, we found that the factors most strongly related to the percentage of change in Kco in the first posttransplant year were the preoperative Kco, the cyclosporine level in the first postoperative year, and the change in dPAP in that year.     

Effect of pravastatin on plasma markers of inflammation and peripheral endothelial function in male heart transplant recipients

Statins appear to have several biologic effects beyond those of lipid metabolism, and we hypothesized that immunomodulating effects of statins are important for the beneficial effects of these medications after heart transplantation. Our findings suggest that pravastatin treatment reduces plasma markers of inflammation and improves peripheral endothelial function in heart transplant recipients, possibly contributing to the observed clinical benefits of statin treatment in these patients.     

Sirolimus-based immunosuppression for treatment of cutaneous warts in kidney transplant recipients

Dermatological complications, especially skin infections, are very common following organ transplantation, and result in a lot of distress in the recipient. Herpes zoster, herpes simplex, and human papillomavirus infections are common infections in kidney transplant recipients, and therapeutic management is usually disappointing in immunosuppression state. We report here 2 cases of kidney transplant recipients who developed diffuse human papillomavirus-induced cutaneous warts with no response to conventional treatments. According to similar reports in organ transplant recipients, we modified the immunosuppressive regimen by converting to sirolimus, which led to a rapid relief from cutaneous warts in both patients. This evidence along with other case reports suggest that conversion to sirolimus may be considered as an effective strategy in cases of giant or multiple viral warts in kidney and perhaps other transplant recipients.     

Blood pressure, endothelial function and circulating endothelin concentrations in liver transplant recipients

OBJECTIVES: To study candidates for liver transplant before and 6 weeks after transplant, and to elucidate the role of endothelial dysfunction and plasma endothelin concentrations in the development of hypertension. DESIGN PROSPECTIVE: follow-up study. SETTING: Institutional, outpatient. PATIENTS: and controls Fifteen patients (11 men, four women, mean age 46.7+/-13.2 years) with end-stage liver disease (ESLD) and healthy volunteers of comparable age and sex. METHODS: We performed office blood pressure readings and 24 h ambulatory blood pressure monitoring (ABPM), measurements of endothelial-dependent vasodilatation using high-resolution ultrasound in the brachial artery at rest and during reactive hyperemia, and plasma endothelin-1 assays 3 months before and 6 weeks after the transplant. RESULTS: Office systolic and diastolic blood pressures increased significantly 6 weeks after liver transplantation (from 116.6+/-14.1 to 139.9+/-19.5 mmHg and from 68.6+/-9.5 to 84.1+/-9.8 mmHg, respectively; both P < 0.001). Hypertension based on office blood pressure readings increased from 6.7 to 40% (P < 0.05). Mean 24 h systolic blood pressure increased from 118.7+/-10.3 to 140.0+/-19.0 mmHg (P < 0.001), mean 24 h diastolic blood pressure increased from 86.0+/-7.7 to 104.8+/-13.9 mmHg (P < 0.001) and heart rate increased from 74.8+/-10.2 to 80.2+/-8.2 beats/min (P < 0.05). Brachial artery flow-mediated dilatation did not change throughout the study (before transplant: 4.2+/-4.0%; after transplant: 6.3+/-5.4%; NS) and did not differ from that in controls (5.2+/-3.8%). Plasma endothelin-1 was increased in patients with ESLD (15.3+/-2.6 pg/ml) compared with controls (5.6+/-0.4 pg/ ml; P < 0.001) and remained unchanged 6 weeks after liver transplantation (14.1+/-3.7 pg/ml). CONCLUSION: Our results show increased blood pressure with suppressed circadian blood pressure variability in liver graft recipients 6 weeks after transplant and no change in endothelial function and plasma endothelin concentrations. Therefore, the blood pressure increase documented in our study cannot be explained by endothelial dysfunction. Twenty-four hour ABPM should be performed routinely in patients who have undergone liver transplant.