TAC-treated Patients Research Articles

Diabetes mellitus after kidney transplantation: a French multicentre observational study

New-onset diabetes mellitus (NODM)-a common complication of kidney transplantation-is associated with increases in graft loss, morbidity and mortality. This is a purely observational study of 527 patients taking a calcineurin inhibitor (CNI), based on data collected at a single routine visit 6-24 months after kidney transplantation. Diabetes was defined according to ADA/WHO guidelines. The mean age of the patients was 47.2 years and 61.1% were men; 49.5% were receiving cyclosporine microemulsion (CsA-ME) and 50.5% tacrolimus (Tac). NODM developed in 7.0% after a median interval of 1.6 months. In CsA-ME-treated patients, the unadjusted cumulative risks of NODM were 5.5% and 8.4% at 1- and 2-year post-transplantation, while in Tac-treated patients, the risks were respectively 17.4% and 21%. Four independent risk factors (RFs) were identified by multivariate analysis: maximum lifetime body mass index>25 [odds ratio (OR)=5.1], pre-transplantation impaired fasting glucose (OR=4.7), hepatitis C status (OR=4.7) and Tac vs CsA-ME treatment (OR=3.0). NODM is associated with certain RFs present prior to kidney transplantation, and with treatment with Tac as opposed to CsA-ME.

TGF-β1 mRNA upregulation influences chronic renal allograft dysfunction

Acute rejection (AR) is a dominant risk factor for developing chronic allograft nephropathy (CAN) after kidney transplantation. CAN is characterized by progressive interstitial fibrosis. It has been associated with increased transforming growth factor (TGF)-beta1 expression, however, kinetic studies are absent. We investigated whether intragraft TGF-beta1 expression in various causes of early graft dysfunction may influence late renal allograft dysfunction. A total of 174 human renal biopsies were quantified for TGF-beta1 mRNA expression using real-time reverse transcriptase-polymerase chain reaction. Expression levels were correlated with the Banff histopathological grades, TGF-beta1 immunohistology, and clinical follow-up. TGF-beta1 was most markedly upregulated in AR, CAN, and acute tubular necrosis - delayed graft function compared to non-rejecting controls (P < 0.001). TGF-beta1 expression was heightened in borderline changes (P < 0.01), recurrence of glomerulonephritis, and cyclosporine toxicity (P < 0.05). There was no correlation between intragraft TGF-beta1 expression during AR and short-term outcome of a rejection episode. TGF-beta1 gene overexpression during CAN has been shown to be associated with the increased risk for renal allograft dysfunction 18 months after biopsy (odds ratios 9.9 vs 3.2, respectively). Intragraft TGF-beta1 mRNA expression is significantly upregulated in both AR and CAN. Thus, our results support the hypothesis that TGF-beta1 might play a key role in chronic allograft dysfunction.

Coronary Endothelial Vasomotor Function and Vascular Remodeling in Heart Transplant Recipients Randomized for Tacrolimus or Cyclosporine Immunosuppression

This study aimed to compare changes in coronary endothelial function, systemic endothelin-1 (ET-1) levels, and vascular remodeling in heart transplant recipients randomized to cyclosporin A (CyA) or tacrolimus (Tac) immunosuppression. Functional endothelial abnormalities and intimal thickening are sensitive measures of early cardiac allograft vasculopathy (CAV). The randomized, prospective study was performed in two groups of 22 patients, maintained on Tac or CyA and mycophenolate mofetil immunosuppression, 1 and 12 months after heart transplantation. We investigated epicardial luminal diameter, coronary blood flow velocity, and ET-1 plasma levels at 1 and 12 months after transplantation. Structural coronary alterations were determined using intravascular ultrasound. Epicardial vasomotor function at baseline and during follow-up was comparable between the groups. Deterioration of microvascular endothelial function during follow-up was significantly enhanced in the CyA versus Tac group (p < 0.05). Circulating ET-1 concentration increased in the CyA group but significantly decreased over time in the Tac group (CyA +17% vs. Tac -25%; p < 0.05). The time-dependent increase in mean intimal area was significantly enhanced in the CyA versus Tac group, whereas the vessel area significantly increased during follow-up in the Tac compared with the CyA group. Epicardial endothelial function is comparable between CyA- and Tac-treated patients. Microvascular endothelial function deteriorates more in CyA-treated patients, a finding that correlates with enhanced ET-1 concentration and an increased intimal area during follow-up. The mean vessel area in the Tac group increased over time, indicating positive vascular remodeling. Tac is superior to CyA with respect to microvascular endothelial function, intimal thickening, and vascular remodeling.

Long‐term follow‐up after recurrence of primary biliary cirrhosis after liver transplantation in 100 patients

Orthotopic liver transplantation (OLT) is the only effective curative therapy for end-stage primary biliary cirrhosis (PBC). Survival after OLT is excellent, although recent data have shown a recurrence rate of PBC of up to 32% after transplantation. The aim of this study is to investigate the course after disease recurrence, particularly with regard to liver function and survival in a long-term follow-up. Between April 1989 and April 2003, 1,553 liver transplantations were performed in 1,415 patients at the Charité, Virchow Clinic. Protocol liver biopsies were taken after one, three, five, seven, 10 and 13 yr. One hundred (7%) patients suffered from histologically proven PBC. Primary immunosuppression consisted of cyclosporine (n = 54) or tacrolimus (Tac) (n = 46). Immediately after OLT, all patients received ursodeoxycholic acid. Corticosteroids were withdrawn three to six months after OLT. The median age of the 85 women and 15 men was 55 yr (range 25-66 yr). The median follow-up after liver transplantation was 118 months (range 16-187 months) and after recurrence 30 months (range 4-79 months). Actuarial patient survival after five, 10 and 15 yr was 87, 84 and 82% respectively. Ten patients (10%) died after a median survival time of 32 months. Two of these patients developed organ dysfunction owing to recurrence of PBC. Histological recurrence was found in 14 patients (14%) after a median time of 61 months (range 36-122 months). Patients with Tac immunosuppression developed PBC recurrence more often (p < 0.05) and also earlier (p < 0.05). Fifty-seven patients developed an acute rejection and two patients a chronic rejection episode. Liver function did not alter within the first five yr after histologically proven PBC recurrence. Multivariate analysis of the investigated patients showed that the recipient's age and Tac immunosuppression were significant risk factors for PBC recurrence. Long-term follow-up of up to 15 yr after liver transplantation, owing to PBC, in addition to maintenance of liver function, shows excellent organ and patient survival rates. Although protocol liver biopsies revealed histological recurrence in 14 (14%) patients, only two patients developed graft dysfunction. Tac-treated patients showed more frequently and also earlier histologically proven PBC recurrence; however, in our population we could not observe an impact on graft dysfunction and patient's survival.

Risk factors for new-onset diabetes mellitus following liver transplantation and impact of hepatitis c infection : An observational multicenter study

New-onset diabetes mellitus (NODM) remains a common complication of liver transplantation (LT). We studied incidence and risk factors in 211 French patients who had undergone a primary LT between 6 and 24 months previously. This is a cross-sectional and retrospective multicenter study. Data were collected on consecutive patients at a single routine post-LT consultation. Demographic details, immunosuppressive regimens, familial and personal histories, hepatitis status, and cardiovascular risk were analyzed to compare those who developed NODM (American Diabetes Association/World Health Organization criteria) with the others. The overall incidence of NODM was 22.7%: 24% in tacrolimus (Tac)-treated patients (n = 175; 82.9%) and 16.7% in cyclosporine-treated patients (n = 36; 17.1%). A total of 81% of the cases were diagnosed within 3 months of LT (M3). Among hepatitis C virus (HCV)-infected (HCV(+)) patients, NODM incidence was 41.7% whereas among those patients negative for this virus (HCV(-)), the incidence was only 18.9% (P = 0.008). In Tac-treated patients, the incidence of NODM in the HCV(+) patients was significantly higher than in the HCV(-) patients (46.7% and 19.3%, respectively, P = 0.0014). Only 1 of 6 (16.7%) of the HCV(+) patients developed NODM on cyclosporine. Other independent pretransplantation risk factors for NODM included impaired fasting glucose (IFG) and a maximum lifetime body-mass index (BMI) over 25 kg/m2. In conclusion, emergence of NODM after LT is related to risk factors that can be detected prior to the graft, like maximum lifetime BMI, IFG, and HCV status. Tac induced a significantly higher incidence of NODM in the HCV(+) compared to the HCV(-) patients. The treatment should therefore be tailored to the patient's risk especially in case of HCV infection.

The effect of different immunosuppressive regimens on TGF-beta1 expression in kidney transplant patients

Transforming growth factor (TGF)-beta1 is a key profibrogenic cytokine associated with the pathogenesis of chronic allograft nephropathy (CAN). The primary aim of this study was to evaluate TGF-beta1 expression in protocol kidney graft biopsy in patients treated with different immunosuppressive regimens. Protocol kidney graft biopsies were carried out in 77 patients with stable graft function at 1 year after kidney transplantation, treated with a triple-drug regimen based on cyclosporin A (CyA; n = 49) or tacrolimus (TAC; n = 28). Morphological findings were assessed using the Banff 97 classification. TGF-beta1 expression was analysed using immunochemistry, and semiquantitatively scored in different renal structures (total score 0-18). Clinical data were analysed at the time of biopsy, and 12 months thereafter. No significant relation was found between the used immunosuppressive regimen and the histomorphological picture in the graft. TGF-beta1 expression within graft tissue was significantly higher in patients treated with CyA when compared with TAC (9.94 +/- 4.2 vs. 5.0 +/- 3.2; P < 0.001). Serum creatinine and glomerular filtration rate (GFR; Cockroft-Gault calculation) were comparable in both groups but, in the course of the next 12 months, GFR significantly decreased only in the CyA-treated group (from 1.03 +/- 0.33 to 0.96 +/- 0.37 ml/s) while not changing in the TAC-treated group. Patients treated with TAC had significantly lower diastolic blood pressure and serum cholesterol. The significantly lower TGF-beta1 expression in 1-year protocol kidney graft biopsy in TAC-treated patients with stable renal function, and the different development of graft function in both groups suggest a possible benefit of TAC for long-term graft acceptance.

Blood pressure profile and treatment quality in liver allograft recipients—benefit of tacrolimus versus cyclosporine

Organ transplant recipients display a high cardiovascular mortality rate. The type of immunosuppression has a major impact on cardiovascular risk factors (e.g., hypertension [HTN]). We assessed 24-hour blood pressure (BP) and metabolic profiles in a cohort of 106 long-term liver allograft recipients treated with either tacrolimus (Tac) or cyclosporine (CyA). The median age of patients was 50.8 years (range, 11 to 77) and the median time of follow-up was 65.4 months (ranges 12 to 168). Immunosuppression included low-dose steroids and either Tac ( n = 46) or CyA ( n = 60). Twenty-four-hour BP measurements revealed a significant difference in systolic BP (127.1 mmHg [94 to 163] Tac versus 132.7 mmHg [103 to 177] CyA; P < .03), and in mean arterial and diastolic blood pressures. In addition, the relative number of normotensive patients was significantly higher among Tac-treated patients (69.6% versus 34.8%). It is of note that the true incidence of HTN was higher after the number of patients with a pathological 24-h BP measurement was added to the initial number of patients already known to have HTN. No less than 76.4% of all long-term liver transplanted patients showed HTN. The results were unrelated to cumulative steroid dosage, frequency of antirejection therapy or underlying primary liver disease. In summary, immunosuppression-induced HTN is more common in CyA-treated than Tac-based regimens. Moreover, we found a substantial lack of detection of HTN in long-term liver transplant patients who received an insufficient quality of antihypertensive treatment. These findings have implications for the early diagnosis and treatment of HTN in liver transplant recipients.

Electron paramagnetic resonance study of erythrocyte membrane fluidity in renal transplant recipients

Renal transplantation (KTx) patients receiving calcineurin inhibitors—cyclosporine (CsA) or tacrolimus (TAC)—are known to be at risk for the development of posttransplant hemolytic uremic syndrome. The syndrome has been reported to occur more often with CsA than TAC treatment. It has also been noted that CsA affects erythrocyte membrane fluidity. The aim of this study was to investigate whether the impairment of erythrocyte membrane fluidity is similar among patients under treatment with different calcineurin inhibitors (CsA or TAC). Venous blood was collected from 29 KTx patients and from nine healthy volunteers. To investigate the fluidity of intact erythrocyte membranes spin label electron paramagnetic resonance spectroscopy was applied. Comparison of values for controls versus CsA-treated patients demonstrated a significant decrease in membrane viscosity in the hydrophobic region of the lipid bilayer among CsA-treated patients, whereas there was no significant difference between control and patients treated with TAC. There was no significant difference in the molecular order close to the polar heads of lipid molecules among all groups. The observed changes in erythrocyte membrane fluidity among CsA-treated patients and the lack of this phenomenon in the TAC group may correlate with more frequent prevalence of hemolytic anemia among CsA than TAC-treated patients.

A low incidence of New-Onset Insulin-Dependent diabetes mellitus using tacrolimus in kidney recipients in Europe

Employing tacrolimus (Tac) for routine immunosuppression in renal transplantation (RT), produced an incidence of new-onset, insulin-treated, diabetes mellitus (newDM) as high as 20%. More recently, several large multicenter kidney studies using Tac as the primary immunosuppressant have been reported in Europe. Between 1997 and 2001, we performed 155 RTs using Tac (0.2 mg/k/per day, targeting whole blood trough levels <15 ng/mL) with a rapid steroid taper. The acute rejection rate was 13%, and 89% of grafts are still functioning. Only 5 Tac-treated patients not previously requiring insulin needed insulin therapy for ≥30 days (3.2%). Eight separate studies employing Tac in at least one arm (N = 2728) have been reported between 1997 and 2002. Tac was combined with azathioprine or MMF, and/or steroids. The incidence of new DM at study end ranged from 2.3% to 8.3%. The only trial with >6% incidence was the first one, using an initial dose of 0.3 mg/kg per day. The most recent studies utilized an initial dose of 0.2 mg/kg per day, targeting whole blood trough levels of <15 ng/mL and a steroid taper, with newDM at <6%. On the basis of these data, we confirm in that the use of Tac as a first-line immunosuppressant in renal transplant patients affords protection against acute rejection with a low level of newDM. The tendency to employ lower oral doses of Tac, lower blood target levels, and a reduced steroid dose appear to minimize glucose disturbances in RT.

Tacrolimus vs. cyclosporine A as primary immunosuppression in pediatric renal transplantation: a NAPRTCS study.

Using the North American Renal Transplant Cooperative Study (NAPRTCS) database, we performed a retrospective cohort study of 986 pediatric renal transplant recipients (index transplant 1997-2000) who were treated either with Cyclosporine A (CSA), Mycophenolate Mofetil (MMF) and steroids (n = 766) or tacrolimus (TAC), MMF and steroids (n = 220) to examine potential difference in clinical outcomes between these two groups. In the first year post-transplant, time to first rejection (29.1% vs. 29%, p = 0.840), risk for rejection [Adjusted Relative Risk (aRR) 1.01, 95% Confidence Interval (CI) 0.77, 1.323], graft survival (96.8% vs. 97.9%, p = 0.607) and risk for graft failure (aRR 0.988, 95% CI 0.64, 1.928) were not significantly different in TAC and CSA-treated patients. At 2 yr post-transplant, there was also no difference in risk for rejection (aRR 0.918, 95% CI 0.669, 1.259), graft survival (91.4% vs. 95.1%, p = 0.152) and risk for graft failure (aRR 0.702, 95% CI 0.461, 1.762) in the subset of 391 CSA-treated patients and 77 TAC-treated patients on whom 2 yr follow data were available in the database. TAC-treated patients were significantly less likely to require antihypertensive medication at 1 yr [aRR 0.74 (95% CI 0.454, 0.637)] and 2 yr post-transplant [aRR 0.67 (95% CI 0.56, 0.793)]. At 1 yr post-transplant, TAC-treated patients enjoyed a higher mean GFR as estimated by the Schwartz formula [89.1 mL/min/1.73 m(2) (SE 2.64) vs. 78.6 mL/min/1.73 m(2) (SE 1.07), p = 0.0003]. In addition, in the subset of patients with 2 yr of follow-up, TAC patients had a higher mean GFR at both 1 yr [98.6 mL/min/1.73 m(2) (SE 3.83) vs. 78.0 mL/min/1.73 m(2) (SE 1.44), p = 0.0003] and 2 yr post-transplant [96.7 mL/min/1.73 m(2) (SE 3.33) vs. 73.2 mL/min/1.73 m(2) (SE 1.48), p < 0.0001]. In summary, TAC and CSA, in combination with MMF and steroids, produce similar rejection rates and graft survival in pediatric renal transplant recipients. However, TAC is associated with improved graft function at 1 and 2 yr post-transplant. Further analysis as more patient data are obtained will be necessary to determine if this difference in graft function persists and translates into improved graft survival.

Tacrolimus is superior to cyclosporine in liver transplantation

WITH the addition of cyclosporine (CyA) to azathioprine and corticosteroids in the early 1980s, rejection rates were decreased and graft survival and patient survival rates were dramatically increased in liver allograft recipients. While CyA-based regimens became the standard for orthotopic liver transplant (OLT) recipients, issues such as the frequency and severity of acute and chronic rejection, steroid-induced adverse effects, and outcomes in pediatric liver transplants remained problematic. Tacrolimus (TAC) was approved by the Food and Drug Administration (FDA) in 1994 for primary immunosuppressive therapy in adult and pediatric OLT recipients. In animal models, TAC inhibited both T-cell-mediated immune, and to a lesser extent, humoral immune responses (B-cell proliferation). When compared to CyA, TAC appears to be 10 to 100 times more potent in its ability to inhibit interleukin-2 (IL-2). On the molecular level, TAC, once bound to its intracellular binding protein (FKBP), is believed to form a drug-isomerase complex with calcineurin and reduce its phosphatase activity. As a result, translocation of the nuclear factor of activated T cells (NF-AT) is prevented which ultimately results in a reduction of the transcription of IL-2. By limiting IL-2 transcription, TAC inhibits the proliferation of helper, cytotoxic T lymphocytes, and natural killer cells, which ultimately can be responsible for graft loss. The premise of the present position is that TAC is superior to CyA in liver transplantation. To validate this hypothesis, the following points will be demonstrated based on an analysis of the results of randomized controlled trials involving over 1000 patients in whom TAC was compared to CyA as the primary immunosuppressive therapy in liver transplantation and of several open-labeled trials enrolling up to 1500 patients. Data from these studies confirm the following advantages of TAC over CyA in liver transplant recipients: (1) TAC usage decreases acute rejection rates versus CyA (from 65% in CyA-treated patients to 56% in TAC-treated patients; P 5 .0001) and improves outcome; (2) use of TAC spares corticosteroid dose (cumulative prednisone dosages were significantly lower [P 5 .003] over 3 years in TAC-treated patients vs CyA-treated patients, with CyA patients receiving a mean of 25 mg/kg more steroid than TAC-treated patients) and reduces OKT3 usage (19% vs 36% in adults; 21% vs 32% in pediatric patients); (3) TAC is superior in preventing and treating chronic rejection (1.5% in TAC-treated patients vs 5.3% in CyA-treated patients; P 5 .032); (4) TAC use results in an improved 5-year patient and graft survival compared to CyA in patients transplanted with hepatitis C (78.9% and 73.7% vs 60.5% and 58.7%, respectively); (5) TAC is well tolerated over the long term; (6) TAC-based regimens improve cardiovascular risk profile; (7) TAC-based regimens improve long-term patient (80% vs 73%, respectively; P 5 .02) and graft survival (76% vs 68%, respectively; P 5 .04); (8) TAC demonstrates superior patient and graft half-lives compared to CyA-based regimens (25.1 6 5.1 and 20.6 6 4.0 vs 15.2 6 2.5 and 15.7 6 2.7 years, respectively); and of significant importance (10) TAC use results in improved outcomes in pediatric OLT recipients. Thus, the current data provide compelling evidence that TAC is the drug of choice in OLT recipients. TAC is superior to CyA in reducing acute rejection rates and improving outcome, as demonstrated by the US and European multicenter trials. In these trials involving over 1000 OLT recipients, A Kaplan-Meier estimate of the incidence of acute rejection at 1 year shows a marked reduction from 65% in CyA-treated patients to 56% in TAC-treated patients (P 5 .0001). The importance of achieving freedom from acute rejection cannot be underestimated. In fact, freedom from acute rejection is strongly associated with long-term patient and graft survival. As shown in Fig 1, TAC-treated patients who were free from early rejection had significantly better survival at 3 years compared to CyA-treated patients (80% vs 68%; P 5 .004). A similar advantage in graft survival was observed in the TAC group with a 3-year graft survival rate of 73% versus 61% for CyA (P 5 .007). In addition to decreasing acute rejection and improving outcome, another advantage of TAC is that it is steroid sparing and decreases the need for OKT3. For instance, in the European multicenter liver study, cumulative pred-