Cardiovascular risk factors in renal transplant patients: cyclosporin A versus tacrolimus

The hypertensive and hyperlipidemic effects of cyclosporin A (CsA) may contribute to the high cardiovascular morbidity in renal transplant patients and to the development of chronic transplant nephropathy. Tacrolimus is reported to have less effect on BP and lipids, but steroids, other drugs, and renal function may confound this. This study assessed 24-h BP and lipid profile in stable renal transplant recipients (n = 17) while they were receiving CsA, after 4 wk of receiving tacrolimus, and again after 4 wk of receiving CsA. Antihypertensives were stopped at least 3 wk before. A few patients used low-dose steroids and lipid-lowering drugs, which were not changed during the study. Mean daytime BP decreased from 149 +/- 12 and 95 +/- 8 mmHg to 138 +/- 13 and 87 +/- 9 mmHg (P: < 0.001) after patients were switched to tacrolimus. Mean nighttime BP also decreased, from 140 +/- 12/86 +/- 7 mmHg to 132 +/- 17/79 +/- 10 mmHg (P: < 0.05). Total and low-density lipoprotein cholesterol decreased from 6.1 +/- 0.7 and 3.84 +/- 0.79 mmol/L to 5.1 +/- 0.8 and 2.98 +/- 0.75 mmol/L (P: < 0.001). Return to CsA caused an increase in BP and cholesterol to values similar as during the first CsA period. The conclusion is that tacrolimus has fewer unfavorable effects on BP and lipids than does CsA. Elective conversion from CsA to tacrolimus in stable renal transplant recipients may lead to attenuation of cardiovascular morbidity and chronic transplant nephropathy in the long term.     

Cardiovascular risk profile after conversion from cyclosporine A to tacrolimus in stable renal transplant recipients

BACKGROUND: Cardiovascular disease is a major cause of morbidity and mortality in renal recipients. In addition to steroids, cyclosporine A (CsA) has been implicated in contributing to increased cardiovascular risk. Conversion from CsA to tacrolimus (TAC) has been shown to improve hyperlipidemia and hypertension, but little is known about the differential effects of CsA versus TAC on other cardiovascular risk factors. We investigated overall cardiovascular risk profile after conversion from CsA to TAC. METHODS: This was an open-label, single-arm prospective study; 22 adult renal recipients who were receiving CsA-based immunosuppression with serum total cholesterol greater than 200 mg/dL more than 1 year after transplantation were enrolled. CsA was replaced by TAC. Blood pressure, fasting lipid profile, homocysteine, fibrinogen, C-reactive protein, hemoglobin A1c, and creatinine were measured at baseline and at 3 and 6 months after conversion. RESULTS: There was a significant improvement in fibrinogen (366 +/- 81 - 316 +/- 65 mg/dL, P <0.001), total cholesterol (250 +/- 50 - 207 +/- 29 mg/dL, P <0.001), and low-density lipoprotein cholesterol (155 +/- 43 - 121 +/- 24 mg/dL, P <0.001) after conversion. No new onset or worsening of diabetes mellitus was observed after conversion. There were no significant differences in HDL cholesterol, triglycerides, homocysteine, C-reactive protein, hemoglobin A1c levels, serum creatinine, mean blood pressure, and mean number of antihypertensive medications required before and after conversion. CONCLUSIONS: Our results indicate that conversion to low-dose TAC may be preferable over CsA for chronic maintenance immunosuppression because it improves the overall cardiovascular risk profile without any apparent adverse effects.     

Improved cardiovascular risk profile and renal function in renal transplant patients after randomized conversion from cyclosporine to tacrolimus

Cyclosporine is considered to contribute to the high cardiovascular morbidity and mortality in patients after renal transplantation. Tacrolimus may be more favorable in this respect, but controlled data are scarce. In this prospective randomized study in 124 stable renal transplant patients, the effects of conversion from cyclosporine to tacrolimus on cardiovascular risk factors and renal function were investigated. Follow-up was 6 mo. Statistical analysis was performed by ANOVA for repeated measurements. The serum creatinine level decreased from 137 +/- 30 micromol/L to 131 +/- 29 micromol/L (P < 0.01). Three months after conversion from cyclosporine to tacrolimus, mean BP significantly decreased from 104 +/- 13 to 99 +/- 12 mmHg (P < 0.001). Serum LDL cholesterol decreased from 3.48 +/- 0.80 to 3.11 +/- 0.74 mmol/L (P < 0.001,) and serum apolipoprotein B decreased from 1018 +/- 189 to 935 +/- 174 mg/L (P < 0.001). Serum triglycerides decreased from 2.11 +/- 1.12 to 1.72 +/- 0.94 mmol/L (P < 0.001). In addition, both rate and extent of LDL oxidation were reduced. The fibrinogen level decreased from 3638 +/- 857 to 3417 +/- 751 mg/L (P < 0.05). Plasma homocysteine concentration did not change. Three months after conversion, plasma fasting glucose level temporarily increased from 5.4 +/- 1.3 mmol/L to 5.8 +/- 1.9 mmol/L (P < 0.05). Conversion to tacrolimus resulted in a significant reduction of the Framingham risk score. In conclusion, conversion from cyclosporine to tacrolimus in stable renal transplant patients has a beneficial effect on renal function, BP, serum concentration and atherogenic properties of serum lipids, and fibrinogen.     

Cardiovascular risk factors in renal transplant patients after switch from standard tacrolimus to prolonged-release tacrolimus

Cardiovascular (CV) diseases are the leading cause of death after renal transplantation. Renal transplant patients present CV risk factors that correlate with renal function and the use of immunosuppressive drugs. Noncompliance with immunosuppressive therapy after organ transplantation increases the incidence of rejection, graft loss, and patient death. A simple posology regimen is the best way to promote compliance with prescribed therapy. To meet this need, a new formulation of tacrolimus that is suitable for once-daily administration, is now available on the market: prolonged-release tacrolimus (Fkpr). We analyzed changes in CV risk factors observed in renal transplant patients after transition from standard tacrolimus (Fk) to Fkpr and the rate of patients with the investigated parameters within the normal ranges before and after conversion. The study enrolled 40 Caucasian renal transplant patients (26 men and 14 women) who were being followed at our posttransplantation day hospital clinics. After a varying time interval after transplantation, patients on treatment with tacrolimus, mycophenolate + mofetil (MMF), and steroid entered a 12-month observation period. Thereafter, they were switched to Fkpr, also in association with MMF and steroid, and were observed for a further 12-month period. The following parameters were tested in all patients: creatinine, creatinine clearance, insulin resistance, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, uric acid, homocysteine, and urine magnesium. The switch from Fk to Fkpr showed an improvement of the parameters investigated. Moreover, the proportion of patients with normal laboratory values after the transition from Fk to Fkpr was noted either to increase or to remain stable at the improved levels observed during therapy with Fk. Immunosuppressive treatment with Fkpr represents an even better option than Fk for renal transplant patients, because by reducing CV risk factors it favorably affects the long-term outcomes for graft and patient.     

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.     

Comparison of the temporal profile of calcineurin inhibition by cyclosporine and tacrolimus in renal transplant patients

Calcineurin phosphatase (CaN) activity has been the focus of several recent studies on renal transplant patients as the calcineurin inhibitors tacrolimus (FK) and cyclosporine (CsA) are still the cornerstone in the immunosuppressive treatment. The aim of this study was to compare the temporal inhibition profiles of CaN using CsA or FK in two groups of renal transplant patients. Nineteen tacrolimus-treated and 10 cyclosporine-treated renal transplant patients had blood samples drawn before and at 1, 2, 3, 4, and 6 hours after ingestion of drug. CaN activity was measured as the release of 32P from a previously phosphorylated peptide and radioactivity quantitated by liquid scintillation counting. Results were expressed as units CaN. Blood concentrations of tacrolimus were determined with an IMx method and of CsA with an EMIT assay. FK-treated patients showed maximal inhibition of CaN activity at 1 to 3 hours, returning to the predose level 4 hours after drug intake. CsA-treated patients showed a gradual decrease in CaN activity with a nadir after 3 hours, failing to return to predose levels during the observation period. Both groups showed a significant rise in drug blood concentrations. To conclude, we have demonstrated that two widely used immunosuppressants, CsA and FK, show different CaN inhibitory profiles in renal transplant patients.     

Assessing the relative risk of cardiovascular disease among renal transplant patients receiving tacrolimus or cyclosporine

Calcineurin inhibitors potentially contribute to risk of cardiovascular events through the development of new-onset diabetes mellitus, hypertension and hyperlipidemia. The exact extent to which calcineurin inhibitors affect these risk factors is difficult to establish since pre-existing renal disease and concomitant immunosuppressive agents (such as steroids or TOR inhibitors) also exert an effect. Clinical trials have consistently shown a higher incidence of new-onset diabetes mellitus with tacrolimus, which has been borne out in large-scale registry analyses. However, the risk of hypertension is approximately 5% higher with cyclosporine than tacrolimus, as is the risk of hyperlipidemia. Statin therapy is effective in treating dyslipidemia and has significant benefits in renal transplant patients. An individualized approach to choice of calcineurin inhibitor, by which cyclosporine or tacrolimus are selected based on the patient's particular risk profile, may thus help to reduce the toll of cardiovascular mortality among renal transplant recipients in the future.     

Randomized trial of tacrolimus versus cyclosporine in steroid withdrawal in living donor renal transplant recipients

The introduction of new immunosuppressants has prompted trials of steroid withdrawal. However, several groups have reported a higher incidence of rejection. We conducted a randomized two-arm, parallel-group, open-label, prospective study to compare steroid withdrawal (at 6 months posttransplant) from the regimens of tacrolimus + mycophenolate mofetil (MMF) (FK group) versus cyclosporine + MMF (CSA group). The entry criteria were recipients of first living donor transplants with no diabetes mellitus (DM), congestive heart failure, chronic liver disease, or acute rejection within 6 months posttransplant. The primary endpoint was a biopsy-proven acute rejection episode or treatment failure within 1 year posttransplant. While 87 recipients were assigned to FK (n = 43) and CSA groups (n = 44) before transplantation, 76 recipients (FK 39, CSA 37) could be tapered off steroids at 6 months posttransplant, since 11 were excluded due to acute rejection within 6 months posttransplant (FK two, CSA three) or protocol violations (FK two, CSA four). After steroid withdrawal, the incidence of acute rejection episodes was 0% in the FK group and 13.5% in the CSA group (P < .05). Other results at 12 months posttransplantation were comparable: the incidences of DM 7.8% versus 0% (FK group vs CSA group), hypercholesterolemia 41.0% versus 59.5%, hypertensives 48.7% versus 59.6% as well as the levels of plasma creatinine 1.21 +/- 0.24 versus 1.31 +/- 0.50 mg/dL (P > .05 in every variable). These data suggest that steroid withdrawal is successful in first living donor renal transplant recipients. Tacrolimus may be significantly more effective than cyclosporine to prevent acute rejection after steroid withdrawal.     

Oral cyclosporine but not tacrolimus reduces renal transplant blood flow

BACKGROUND: Calcineurin inhibitors are important immunosuppressive agents, but cause nephrotoxicity. METHODS: Instantaneous intra-renal transplant hemodynamics were assessed in 22 patients using quantitative cineloop color Doppler imaging after dosing with microemulsion cyclosporine (CSA) or tacrolimus (TAC). RESULTS: CSA dosing resulted in renal hypoperfusion, with a mean relative reduction of 43%+/-20% (range 22-76%) in maximal fractional area (MFA) of color pixels to nadir, compared to baseline. The mean effect occurred 1.1+/-0.9 hr (median 1 hr) after CSA dosing and was abrogated by calcium channel blockers (P <0.05). The main renal artery velocities, resistive index and small vessel perfusion were unchanged, suggestive of medium-sized arteries mediated vasoconstriction. In contrast, TAC did not alter renal vascularity (2.3+/-4.0% absolute reduction of MFA color pixels vs. 10.7+/-6.5% with CSA, P <0.01). CONCLUSION: CSA, but not TAC, induces phasic hypoperfusion of variable severity within small to medium sized intra-renal arteries soon after dosing, mitigated by calcium channel blockade.     

Cardiovascular morbidity and risk factors in renal transplant patients.

BACKGROUND: Cardiovascular disease is now the major cause of death in renal transplant patients. This study aimed to assess the prevalence of cardiovascular disease in stable renal transplant patients as compared with the general background population, and to assess risk factors for cardiovascular disease in this patient group. METHODS: A cross-sectional multicentre study comprising 406 stable renal transplant patients (age 47+/-16 years, 60% males, 71% taking cyclosporin A) were assessed clinically and biochemically 48 months (median) after transplantation and compared with the general population. Multivariate analysis was used to assess the relation between cardiovascular disease and risk factors. RESULTS: Hypertension was present in 55% of males and 34% of females (P<0.001), in 51% with cyclosporin A and in 33% without (P<0.001). Ischaemic heart disease (i.e. angina pectoris and/or previous myocardial infarction) was present in 14% (males: 18%, females: 10%, P<0.05) and in 24% of diabetics vs 12% of non-diabetics (P<0.01). Cerebro- and peripheral vascular disease was found in 3% and 4%, respectively. Odds ratio for angina pectoris (patients vs general population) was: in age group 40-49 years (males/females), 12/16; 50-59 years, 6/4; 60-69 years, 3/4. Ischaemic heart disease was, besides age and gender, independently associated with total cholesterol (P<0.01), and peripheral vascular disease to systolic blood pressure (P<0.01). CONCLUSIONS: Cardiovascular disease is highly prevalent in renal transplant patients, and is independently associated with age, gender, total cholesterol and systolic blood pressure.     

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.     

A randomized, prospective, pharmacoeconomic trial of tacrolimus versus cyclosporine in combination with thymoglobulin in renal transplant recipients

BACKGROUND: To date, the clinical trials of tacrolimus (TAC) versus cyclosporine modified (CsA), have not defined which agent is more cost-effective for immunosuppression in renal transplant recipients especially in a quadruple immunosuppressive regimen. METHODS: The objective of this randomized, prospective study was to compare the clinical and economic outcomes of TAC versus CsA, in a regimen that consisted of Thymoglobulin induction, an antimetabolite, and prednisone. Between December 2000 and October 2002, 200 patients were enrolled and randomized in a 2:1 fashion (TAC n=134, CsA n=66). RESULTS: At 1 year, acute rejection (4% TAC vs. 6% CsA), patient survival (TAC 99% vs. CsA 100%), and graft survival (95% TAC versus 100% CsA, P=0.059) were similar. Serum creatinine levels were lower in the TAC group compared with the CsA group (1.3+/-0.3 vs. 1.6+/-0.7 mg/dL, P=0.03). The incidence of CMV infection was similar between the groups and two patients, both in the TAC arm, developed malignancy. Anti-hypertensive requirement (32% TAC vs. 32% CsA) and the incidence of posttransplant diabetes mellitus (4% TAC vs. 2% CsA) were similar. Pretransplant, fewer TAC patients received dyslipidemia treatment (40% TAC vs. 67% CsA, P=0.0005), while more CsA patients were able to discontinue these medications posttransplant (absolute change 25% TAC vs. 47% CsA). Total 12-month medication costs were similar (17,723 +/- 11,647 dollars TAC vs. 16,515 +/- 10,189 dollars CsA). CONCLUSIONS: When combined with Thymoglobulin induction, an antimetabolite, and corticosteroids, TAC and CsA are comparable in safety, efficacy, and cost in renal transplantation.     

Single-center experience with tacrolimus versus cyclosporine-Neoral in renal transplant recipients

Tacrolimus has proven to be superior to cyclosporine-Sandimmune with regard to the prevention of acute rejections, but data comparing tacrolimus with Neoral are scarce. A total of 128 consecutive renal transplant recipients was studied. The patients were treated with Neoral-based (n = 74) or tacrolimus-based (n = 54) immunosuppressive regimens. Survival analyses (Cox regression analysis) were performed on an intention-to-treat basis. Renal function and cardiovascular risk profile were analyzed by means of a repeated-measures analysis of variance (ANOVA) up to 12 months after transplantation. Immunological features were less favorable in the tacrolimus group. Two-year patient and graft survival were comparable. Acute-rejection-free survival was 82 % in the tacrolimus group versus 40 % in the Neoral group (P < 0.0001). The severity of the rejections (1997 Banff classification) was comparable (P = 0.43). Immunological graft loss (3.7 % vs. 12.2 %, P = 0.02) and conversion because of rejection (0 % vs. 28.4 %, P < 0.001) were less in the tacrolimus group. A higher proportion (68.5 % vs. 14.9 %, P < 0.001) was successfully put on monotherapy. Creatinine clearance, proteinuria, and fractional uric acid clearance were similar. In the tacrolimus group mean blood pressure was comparable, but patients needed less anti-hypertensive drugs (P < 0.001) and, even with fewer patients on lipid-lowering drugs, total cholesterol was lower (5.2 vs. 6.0 mmol/l, P = 0.003). Treatment for post-transplant diabetes mellitus was 18.5 % versus 10.8 % (P = 0.22). In both groups, antidiabetic medication could be withdrawn for most patients. This study indicates that tacrolimus is superior to cyclosporine-Neoral in preventing acute rejection with comparable patient and graft survival rates. Because of a lower need for treatment of hypertension and hypercholesterolemia, the cardiovascular risk profile is more favorable. A considerable proportion of patients can be successfully weaned off co-medication and treated with tacrolimus monotherapy.     

Cardiovascular risk profile in patients treated with sirolimus after renal transplantation

Renal transplant patients are inherently predisposed to cardiovascular disease (CVD) as a result of prolonged exposure to multiple cardiovascular risk factors. Approximately one half of all late graft losses are due to death with a functioning graft, and CVD is the most frequent cause of death with a functioning graft among these patients. Immunosuppressive therapies associated with a reduced burden of risk for CVD would therefore greatly decrease post-transplantation morbidity and mortality. The nephrotoxic effects observed with the use of calcineurin inhibitors (CNIs), such as cyclosporine (CsA), run counter to the goal of renal transplant therapy. Sirolimus, a more recent immunosuppressive agent with a unique mechanism of action, offers an alternative to CsA. Recent data from a 4-year study investigating early CsA withdrawal from a sirolimus-CsA-steroid (SRL-CsA-ST) combination demonstrated significantly better renal function, lower blood pressure, and improved graft survival after CsA withdrawal. During that trial, the increase in serum lipids induced by sirolimus was generally manageable with lipid-lowering therapy. Further investigation is warranted to evaluate the value of CNI-free therapy compared with CNI-based regimens in reducing cardiovascular risk factors and improving patient and graft survival.