Effectiveness and safety of the conversion to MeltDose® extended-release tacrolimus from other formulations of tacrolimus in stable kidney transplant patients: A retrospective study.

Tacrolimus is the cornerstone of immunosuppressive therapy after kidney transplantation. Its narrow therapeutic window mandates serum level strict monitoring and dose adjustments to ensure the optimal risk-benefit balance. This observational retrospective study analyzed the effectiveness and safety of conversion from twice-daily immediate-release tacrolimus (IR-Tac) or once-daily prolonged-release tacrolimus (PR-Tac) to the recent formulation once-daily MeltDose® extended-release tacrolimus (LCP-Tac) in 365 stable kidney transplant recipients. We compared kidney function three months before and three months after the conversion. Three months after conversion, the total daily dose was reduced ~35% (P < .0001), and improved bioavailability and stable serum LCP-Tac concentrations were observed. There was no increase in the number of patients requiring tacrolimus dose adjustments after conversion. Renal function was unaltered, and no cases of BPAR were reported. Reports of tremors, as collected in the clinical histories for each patient, decreased from pre-conversion (20.8%) to post-conversion (11.8%, P < .0001). LCP-Tac generated a cost reduction of 63% compared with PR-Tac. In conclusion, the conversion strategy to LCP-Tac from other tacrolimus formulations in stable kidney transplant patients showed safety and effectiveness in a real-world setting, confirming the data from RCTs. The specific pharmacokinetic properties of LCP-Tac could be potentially advantageous in patients with tacrolimus-related adverse events.

Renin-angiotensin system blockade and kidney transplantation: a longitudinal cohort study.

BACKGROUND: The beneficial effect of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) in kidney transplant recipients on modern immunosuppression is not yet well established. Our objective was to investigate the impact of the use of ACEI/ARB on patient and graft survival in a cohort of kidney transplant recipients. METHODS: A total of 990 patients, who received a single deceased donor kidney at our institution between 1996 and 2005, were included in this longitudinal cohort study. All-cause mortality and death-censored graft loss were the primary outcomes. We used traditional time-dependent Cox model (unweighted) and inverse-probability-of-treatment weighting of marginal structural models (weighted Cox model), controlling for time-dependent confounding by indication. RESULTS: A total of 414 patients (42%) received ACEI/ARB through the study period (median duration 14 months, interquartile range 6-40 months). ACEI/ARB use was associated with reduction of risk for mortality in the crude [hazard ratio (HR) 0.627, 95% confidence interval (CI) 0.412-0.953] and adjusted Cox analysis (HR 0.626, 95% CI 0.407-0.963). Similar results were observed after adjusting for confounding by indication (HR 0.629, 95% CI 0.407-0.973). By contrast, ACEI/ARB use was not associated with significant improvement of graft survival after kidney transplantation. CONCLUSION: ACEI/ARB prescription may be suggested as beneficial among multiple medications for reducing mortality in kidney transplant recipients, but its use was not associated with longer graft survival.

Randomized controlled study comparing reduced calcineurin inhibitors exposure versus standard cyclosporine-based immunosuppression.

BACKGROUND: Immunosuppressive regimens based on low doses of cyclosporine A (CsA) or tacrolimus (TAC) may improve short-term outcome after kidney transplantation (KT), but the optimal immunosuppressive protocol is currently unknown. METHODS: This study compared the 24-month efficacy and safety of two immunosuppressive regimens using reduced calcineurin inhibitors (CNIs) exposure with standard dosage of CsA in 240 patients who were randomized into three groups: group A (n=80): Thymoglobulin, CsA (4 mg/kg twice daily) plus azathioprine (1.5 mg/kg once daily); group B (n=80): basiliximab, CsA (2 mg/kg/ twice daily) plus mycophenolate mofetil (MMF; 1 g twice daily); and group C (n=80): basiliximab, TAC (0.05 mg/kg/ twice daily) plus MMF (1 g twice daily). Steroid administration was identical for all groups. RESULTS: A significantly better creatinine clearance at 12 months, estimated by Cockcroft-Gault (57+/-12, 65.2+/-20, 73.5+/-27 ml/min, P=0.044), the Jelliffe-2 (51.5+/-16, 56+/-19, 59.4+/-19 ml/min/1.73 m2, P=0.041) and the Modification of Diet in Renal Disease equations (53+/-17, 58.5+/-20, 61.6+/-22 ml/min/1.73 m2, P=0.035), was observed in group C compared with group A. No significant differences were observed between groups B and C. The incidence of biopsy-proven acute rejection was similar between groups (15%, 13.8%, and 16.3%). In addition, patient and graft survival at 24 months were not different between groups. Adverse effects were similar among groups, but cytomegalovirus infections was significantly higher in group A (41% vs. 20% vs. 25%; P=0.008). CONCLUSIONS: Immunosuppressive regimens with reduced CNI exposure provide similar preservation of renal function compared with standard dose of CsA after KT and do not lead to underimmunosuppression.

Carotid atheromatosis in nondiabetic renal transplant recipients: the role of prediabetic glucose homeostasis alterations.

BACKGROUND: Prediabetic glucose homeostasis alterations are important cardiovascular risk factors but their role in renal transplant recipients (RTR) has not been established. METHODS: In 172 RTRs without pretransplant or de novo diabetes, we measured carotid intima media thickness (c-IMT) and performed an oral glucose tolerance test (OGTT). RESULTS: In multivariate analysis, age, hypertension and male sex were independently associated with a c-IMT in the third tertile. A significant interaction between gender and glucose homeostasis parameters was observed. Among male RTR, those with a c-IMT in the third tertile showed significantly higher plasma glucose and HbA1c levels (5+/-0.5% vs. 5.1+/-0.5% vs. 5.5+/-0.4%; P<0.01 tertile 3 vs. 2 or 1) than those in other tertiles. Insulin action parameters were not significantly different. The odds ratio of being in the higher c-IMT tertile was 2.9 (95% CI: 1.05-8.1) per each 1% increase of HbA1c. By contrast, glucose and HbA1c levels were not significantly different between c-IMT tertiles in female RTR. However, age-adjusted insulin levels after OGTT were higher (86+/-10 vs. 51.7+/-9.4; P=0.02) and the insulin sensitivity index lower (0.8+/-0.3 vs. 0.048+/-0.03; P=0.04) among females in the third tertile as compared to the first one. CONCLUSION: Prediabetic glucose homeostasis alterations in RTRs are related to carotid atherosclerosis, although there may be gender differences in the underlying alteration.

Artery Wall Assessment Helps Predict Kidney Transplant Outcome.

BACKGROUND: Kidney transplant recipients have high cardiovascular risk, and vascular inflammation may play an important role. We explored whether the inflammatory state in the vessel wall was related to carotid intima-media thickness (c-IMT) and patient survival following kidney transplantation. METHODS: In this prospective observational cohort study we measured c-IMT and expression of proinflammatory cytokines and adhesion molecules in the inferior epigastric artery in 115 kidney transplant candidates. Another c-IMT measurement was done 1-year post-transplantation in 107. By stepwise multiple regression analysis we explored factors associated with baseline c-IMT and their changes over time. Multivariate Cox regression analysis was constructed to identify risk factors for mortality. RESULTS: A worse cardiovascular profile (older age, smoker, diabetic, carotid plaque, systolic blood pressure and vascular calcification) and higher VCAM-1 levels were found in patients in the highest baseline c-IMT tertile, who also had a worse survival. Factors independently related to baseline c-IMT were age (ß=0.369, P<0.0001), fasting glucose (ß=0.168, P=0.045), smoking (ß=0.228, P=0.003) and VCAM-1 levels (ß=0.244, P=0.002). Independent factors associated with c-IMT measurement 1-year post-transplantation were baseline c-IMT (ß=-0.677, P<0.0001), post-transplant diabetes (ß=0.225, P=0.003) and triglycerides (ß=0.302, P=0.023). Vascular VCAM-1 levels were associated with increased risk of mortality in bivariate and multivariate Cox regression. Notably, nearly 50% of patients showed an increase or maintenance of high c-IMT 1 year post-transplantation and these patients experienced a higher mortality (13 versus 3.5%; P=0.021). CONCLUSION: A worse cardiovascular profile and a higher vascular VCAM-1 protein levels at time of KT are related to subclinical atheromatosis. This could lead to a higher post-transplant mortality. Pre-transplant c IMT, post-transplant diabetes and triglycerides at 1-year post-transplantation may condition a high c-IMT measurement post-transplantation, which may decrease patient survival.

Type 1 diabetes increases the expression of proinflammatory cytokines and adhesion molecules in the artery wall of candidate patients for kidney transplantation.

OBJECTIVE: Diabetes may accelerate atheromatosis in uremic patients. Our aim was to assess the influence of type 1 diabetes on the atheromatosis-related inflammation in patients with chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS: We analyzed the expression of proinflammatory cytokines and adhesion molecules in the inferior epigastric artery walls of type 1 diabetic patients with CKD (n = 22) and compared it with nondiabetic uremic patients (n = 92) at the time of kidney transplantation. We evaluated the expression of interleukin (IL)-6, monocyte chemotractant protein (MCP)-1, vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule-1, and the activation of nuclear factor-κß p65 (NFkB-p65). Common carotid intima-media thickness (c-IMT) was determined by conventional echography. RESULTS: IL-6, MCP-1, and VCAM-1 proteins were elevated in type 1 diabetic patients compared with nondiabetic subjects (P < 0.05). The nuclear localization of NFkB-p65 was higher in type 1 diabetic patients (P < 0.01) and correlated with the levels of MCP-1 in this group (r = 0.726, P < 0.001). Arterial fibrosis correlated with IL-6 and MCP-1 levels (r = 0.411, P < 0.001 and r = 0.378, P = 0.001). A significant correlation was observed between VCAM-1 levels and both the degree of arterial narrowing and c-IMT. CONCLUSIONS: Type 1 diabetes produces a proinflammatory state in the arteries of end-stage CKD patients, with increased levels of IL-6, MCP-1, and VCAM-1, as well as a greater degree of p65 activation, which are associated with more severe vascular lesions and higher c-IMT. Although causality is not demonstrated, these findings support the major role of inflammation in type 1 diabetic patients with CKD.

Early association of low-grade albuminuria and allograft dysfunction predicts renal transplant outcomes.

BACKGROUND: Data on the combined associations of albuminuria and estimated glomerular filtration rate (eGFR) with renal transplant outcomes are limited. Our objective was to explore how renal transplant outcomes could be predicted by a combined variable of early low-grade albuminuria and allograft dysfunction. METHODS: We studied a cohort of adult deceased-donor kidney transplant recipients who were subdivided into four groups according to median albuminuria (100 mg/day, interquartile range, 0-470 mg/day) and median eGFR (60 mL/min/1.73 m(2); interquartile range, 30-73 mL/min/1.73 m(2)) at third month posttransplantation as follows: group I (albuminuria <100 and eGFR >60, n=238); group II (albuminuria ≥100 and eGFR >60, n=151); group III (albuminuria <100 and eGFR ≤60; n=167); and group IV (albuminuria ≥100 and eGFR ≤60, n=228). RESULTS: Death-censored graft survival was significantly lower in group IV compared with the rest (P<0.0001). Multivariate Cox regression analysis using fixed and time-dependent covariates showed that the combination of low-grade albuminuria and lower eGFR was associated with graft failure (hazard ratio, 2.2, 95% confidence interval, 1.3-3.7; P=0.003). Likewise, but to a lesser extent, the risk of mortality was increased for group IV (hazard ratio, 1.7, 95% confidence interval, 1.01-2.8; P=0.042). CONCLUSIONS: Early association of low-grade albuminuria and allograft dysfunction represents an important risk factor of graft failure and mortality. This additive effect should be considered to identify individuals at risk for adverse kidney transplantation outcomes.

Pre-transplant weight but not weight gain is associated with new-onset diabetes after transplantation: a multi-centre cohort Spanish study.

Background. New-onset diabetes after transplantation (NODAT) is associated with poorer outcomes in kidney transplantation (KT). Thus, identification of modifiable risk factors may be crucial for ameliorating the impact of this entity on transplant outcomes. We assessed the relationships between the weight, body mass index (BMI) and weight gain with NODAT.Methods. We retrospectively analysed 2168 KT performed in Spain during 1990, 1994, 1998 and 2002, with a functioning graft after the first year. At 1 year after KT, three groups were considered: (i) NODAT group (n = 215); (ii) impaired fasting glucose (IFG) group (n = 389); (iii) control group (n = 1564).Results. The incidence of NODAT was 10.8%, 9.9% and 10.0% at 3, 12 and 24 months post-transplantation, respectively. Older recipient age (P < 0.0001) and greater use of tacrolimus (P < 0.0001) were observed in NODAT group. Obesity was more frequent in NODAT group (P < 0.0001), but patients with NODAT had a lower weight gain during the first year after KT (P = 0.038). On multivariate analysis, independent risk factors associated with the development of NODAT were: recipient age [odds ratio (OR): 1.060, P = 0.0001], tacrolimus (OR: 1.611, P = 0.005), triglycerides (OR: 1.511, P = 0.018), positive hepatitis C virus (HCV) status (OR: 1.969, P = 0.001) and pre-transplant body mass index (BMI) (OR: 1.135, P = 0.0001), but not the weight gain.Conclusions. BMI, but not the weight gain at 1 year after transplant, is an independent risk factor for NODAT. Tailoring clinical strategies may minimize the impact of this complication.

A novel risk score for mortality in renal transplant recipients beyond the first posttransplant year.

BACKGROUND: All-cause mortality is high after kidney transplantation (KT), but no prognostic index has focused on predicting mortality in KT using baseline and emergent comorbidity after KT. METHODS: A total of 4928 KT recipients were used to derive a risk score predicting mortality. Patients were randomly assigned to two groups: a modeling population (n=2452), used to create a new index, and a testing population (n=2476), used to test this index. Multivariate Cox regression model coefficients of baseline (age, weight, time on dialysis, diabetes, hepatitis C, and delayed graft function) and emergent comorbidity within the first posttransplant year (diabetes, proteinuria, renal function, and immunosuppressants) were used to weigh each variable in the calculation of the score and allocated into risk quartiles. RESULTS: The probability of death at 3 years, estimated by baseline cumulative hazard function from the Cox model [P (death)=1-0.993592764 (exp(score/100)], increased from 0.9% in the lowest-risk quartile (score=40) to 4.7% in the highest risk-quartile (score=200). The observed incidence of death increased with increasing risk quartiles in testing population (log-rank analysis, P<0.0001). The overall C-index was 0.75 (95% confidence interval: 0.72-0.78) and 0.74 (95% confidence interval: 0.70-0.77) in both populations, respectively. CONCLUSION: This new index is an accurate tool to identify high-risk patients for mortality after KT.

Predicting delayed graft function and mortality in kidney transplantation.

Kidney transplantation (KT) is the treatment of choice for end-stage renal failure, but such patients are increasingly older and have additional comorbid conditions leading to high mortality rates after transplantation. Delayed graft function is a common complication after KT, especially in recipients who receive expanded criteria donor, and these complications are associated with a poorer graft survival in the long term. Taken together, an appropriate assessment of comorbidity grouped in prognostic indexes could be a useful tool to make crucial therapeutic decisions at the time of transplant. Allocation systems based upon a recipient risk score, as well as identification of risk factors for delayed graft function, may improve outcomes after KT. The aim of this review is to assess the contribution and utility of comorbid conditions, grouped in prognostic indexes to predict and improve kidney transplant outcomes.

Impact of cold ischemia time on renal allograft outcome using kidneys from young donors.

Prolonged cold ischemia time (CIT) is associated with delayed graft function and worse kidney transplant (KT) outcome, but the effect of CIT on long-term allograft survival in KT from younger donors has not been well established. We investigated the predictive value of CIT exposure on long-term death-censored graft loss in 829 KT recipients from younger donors (<50 years) that were performed in our center between 1991 and 2005. Overall death-censored graft failure rate was significantly higher in CIT>or=19 h group versus CIT<19 h group (26 vs. 16.5%; P = 0.002). Significant differences were also observed when patients with primary nonfunctioning graft were excluded (21 vs. 14%; P = 0.020) and in patients who received tacrolimus plus mycophenolate mofetil (12 vs. 4%; P = 0.05). By multivariate Cox analysis, CIT was found to be independently associated with death-censored graft loss with a 20% increase for every 5 h of CIT [relative risk (RR) 1.04; 95% Confidence Interval (CI): 1.01-1.1; P = 0.021]. Likewise, graft loss risk significantly increased in CIT>or=19 h group versus CIT<19 h group (RR 1.5; 95%CI: 1.1-2.1; P = 0.023). Prolonged CIT is an independent predictor of graft survival in KT from younger donors. Efforts at minimizing CIT (<19 h) should improve transplant outcome significantly in this population.

Surgical complications and renal function after kidney alone or simultaneous pancreas-kidney transplantation: a matched comparative study.

BACKGROUND: In selected type 1 diabetic (T1DM) patients with end-stage renal disease (ESRD), simultaneous pancreas-kidney transplantation (SPKT) offers higher long-term graft and patient survival, but also higher initial morbidity and mortality than cadaveric kidney transplantation alone (CKTA). The development of new immunosuppressive regimens and surgical approach has improved this initial outcome, but little is known about their effect on short-term renal function and surgical complications related to the renal graft. METHODS: We analysed retrospectively the short-term follow-up of 45 T1DM patients consecutively transplanted during 42 months (20 SPKT and 25 CKTA) in order to compare short-term (6 months) renal allograft function and surgical complications related to the renal allograft in both groups. RESULTS: There were no differences in donor characteristics. SPKT recipients had a significantly shorter time on dialysis and cold ischaemia time, with a higher number of HLA mismatches. There was no difference in acute rejection incidence, but delayed kidney graft function was less frequent in SPKT (5% vs 32%; P<0.05). Plasma creatinine level at discharge and 6 months was significantly lower in SPKT (1.1+/-0.3 vs 1.6+/-0.7; P<0.005 and 1.1+/-0.3 vs 1.5+/-0.6; P<0.05, respectively). There were no differences in surgical renal complications (haemorrhage, thrombosis or arterial stenosis, ureter leaks or stricture, lymphoceles or dehiscences). Two SPKT patients needed reintervention on the renal allograft and only one CKTA patient. CONCLUSIONS: In the modern transplant era, SPKT in ESRD diabetic patients, offers a slightly better short-term kidney allograft function without significant increase in surgical morbidity, compared with CKTA.

Glycated haemoglobin levels are related to chronic subclinical inflammation in renal transplant recipients without pre-existing or new onset diabetes.

BACKGROUND: C-reactive protein (CRP), a marker of chronic subclinical inflammation (CSI), is related to cardiovascular mortality in the general and renal transplant populations. In the general population, high CRP levels are associated with pre-diabetic glucose homeostasis alterations which may contribute to the proatherogenic effect of CSI. METHODS: We studied 134 consecutive renal transplant recipients without pre-existing or new onset diabetes. CRP, oral glucose tolerance test, insulin sensitivity and HbA1c were measured. RESULTS: Among CRP tertiles, fasting glucose and glucose after 120 min were not different. However, HbA1c was higher (4.9+/-0.6; 5.2+/-0.5; 5.4+/-0.5; P=0.005] and insulin sensitivity lower (McAuley index: 7.2+/-2; 6.8+/-2; 6.2+/-1.3; P=0.042) in the third CRP tertile. In addition, HDL-cholesterol was lower and triglycerides and body mass index (BMI) higher in the third tertile. Consequently, metabolic syndrome was more prevalent in the upper CRP tertiles [11 (25%); 19 (43%); 22 (50%); P=0.01). In multivariate analyses, HbA1c was related to higher CRP levels (standardized beta coefficient=0.21, P=0.013), independently of BMI (standardized beta coefficient=0.24, P=0.005) and triglycerides (standardized beta coefficient=0.18; P=0.03). CONCLUSIONS: Subclinical glucose homeostasis alterations are related to chronic inflammation in renal transplant recipients without pre-existing or new onset diabetes and may contribute to their high cardiovascular mortality.

Increased cardiovascular risk profile and mortality in kidney allograft recipients with post-transplant diabetes mellitus in Spain.

BACKGROUND: Post-transplant diabetes mellitus (PTDM) is associated with poorer outcomes in kidney transplantation (KT) but little information exists about the evolution of traditional cardiovascular risk (CVR) factors under this disorder. METHODS: We retrospectively analysed CVR factors at 3, 12 and 24 months of follow-up and mortality at three yr in 3365 KT performed in Spain during the years 1990, 1994 and 1998 with a functioning graft after the first year. Three groups were considered: (i) (PTDM, n, 251), (ii) diabetes mellitus as primary disease (DM, n = 156) and (iii) the remaining patients (controls, n = 2958). RESULTS: Recipient age, weight and body mass index (BMI) were higher in PTDM than in the other groups (p < 0.0001), with a lower increase of body weight during follow-up (p < 0.003). PTDM patients showed higher total-cholesterol levels than controls at one (p < 0.01) and two yr (p < 0.0009), and higher triglyceride levels than the other groups during follow-up (p < 0.002). Compared with Controls, PTDM patients had significantly higher systolic blood pressure at one (p < 0.001) and two yr (p < 0.005). Diastolic blood pressure was higher in PTDM and controls (p < 0.001), while pulse pressure was higher in PTDM and DM patients (p < 0.0001) during follow-up. Using Cox proportional hazards analysis, PTDM correlated with total mortality (RR = 1.55; range 1.05-2.3; p < 0.02) but not with cardiovascular mortality. CONCLUSIONS: In Spanish KT recipients with graft function after one yr, PTDM is associated with a worse traditional CVR profile and a higher overall mortality. Although short-term cardiovascular mortality remains similar, better control of CVR factors is mandatory to prevent long-term cardiovascular mortality inherent to this population.

Impact of diabetes mellitus on kidney transplant recipients in Spain.

BACKGROUND: The increasing prevalence of pre-existing diabetes mellitus (DM) and especially the incidence of post-transplant diabetes mellitus (PTDM) is a disturbing tendency with far-reaching health and cost implications. We assessed the factors associated with PTDM and the impact of either condition on death-censored graft and patient survival. METHODS: We studied 3365 adult kidney allograft recipients transplanted in 1990, 1994 and 1998, whose graft was functioning after 1 year of follow-up. Three groups were considered: Group I (DM; N = 156), Group II (PTDM; N = 251) and Group III (non-diabetic; N = 2958). RESULTS: Group I patients had been dialysed for shorter periods and received angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-receptor blockers (ARB) therapy more frequently during follow-up than the other groups (P<0.001). Mean age, body weight and body mass index (BMI) were greater in Group II patients than the other groups (P<0.001). Group II showed lower rejection rates than Group III (P<0.01). Risk factors for developing PTDM were recipient age > 60 years (OR = 2.24; P<0.001), female recipient (OR = 1.5; P<0.005), recipient weight > 65 kg (OR = 1.77; P<0.002), BMI > 25 kg/m(2) (OR = 1.6; P<0.04) or > 30 kg/m(2) (OR = 2.92; P<0.005), and tacrolimus-based therapy (OR = 1.48; P<0.05). Of note, the use of Sandimmune vs Neoral had a protective effect (OR = 0.7; P<0.01). Using Cox's proportional hazards analysis, DM correlated with reduced death-censored graft survival (RR = 1.68; 95% CI = 1.14-2.47; P<0.008), while PTDM correlated with reduced patient survival (RR = 1.55; 95% CI = 1.05-2.27; P<0.02). CONCLUSIONS: One year after transplantation, DM was associated with a decrease in death-censored graft survival, while PTDM was an independent negative predictor of patient survival after kidney transplantation. New strategies to improve outcome are needed.