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Multicenter, prospective, observational study to compare the relative bioavailability of once-daily tacrolimus formulations in de novo kidney transplant recipients. De novo kidney transplant recipients who started a tacrolimus-based regimen were included 14 days post-transplant and followed up for 6 months. Data from 218 participants were evaluated: 129 in the LCPT group (Envarsus) and 89 in the PR-Tac (Advagraf) group. Patients in the LCPT group exhibited higher relative bioavailability (C min /total daily dose [TDD]) vs. PR-Tac (61% increase; P < .001) with similar C min and 30% lower TDD levels (P < .0001). The incidence of treatment failure was 3.9% in the LCPT group and 9.0% in the PR-Tac group (P = .117). Study discontinuation rates were 6.2% in the LCPT group and 12.4% in the PR-Tac group (P = .113). Adverse events, renal function and other complications were comparable between groups. The median accumulated dose of tacrolimus in the LCPT group from day 14 to month 6 was 889 mg. Compared to PR-Tac, LCPT showed higher relative bioavailability, similar effectiveness at preventing allograft rejection, comparable effect on renal function, safety, adherence, treatment failure and premature discontinuation rates., (© 2021 The Authors. Clinical Transplantation published by John Wiley & Sons Ltd.)

Despite good long-term outcomes of kidney transplants from controlled donation after circulatory death (DCD) donors, there are few uncontrolled DCD (uDCD) programs. This longitudinal study compares outcomes for all uDCD (N = 774) and all donation after brain death (DBD) (N = 613) kidney transplants performed from 1996 to 2015 at our center. DBD transplants were divided into those from standard-criteria (SCD) (N = 366) and expanded-criteria (N = 247) brain-dead donors (ECD). One-, 5-, and 10-year graft survival rates were 91.7%, 85.7%, and 80.6% for SCD; 86.0%, 75.8%, and 61.4% for ECD; and 85.1%, 78.1%, and 72.2% for uDCD, respectively. Graft survival was worse in recipients of uDCD kidneys than of SCD (P = .004) but better than in transplants from ECD (P = .021). The main cause of graft loss in the uDCD transplants was primary nonfunction. Through logistic regression, donor death due to pulmonary embolism (OR 4.31, 95% CI 1.65-11.23), extrahospital CPR time ≥75 minutes (OR1.94, 95%CI 1.18-3.22), and in-hospital CPR time ≥50 minutes (OR 1.79, 95% CI 1.09-2.93) emerged as predictive factors of primary nonunction. According to the outcomes of our long-standing kidney transplantation program, uDCD could help expand the kidney donor pool., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: The aim of this study was to determine the distribution of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) promoter region T-275A and C-2152T single-nucleotide polymorphisms (SNPs) in stable transplant patients and to investigate the impact of these SNPs on the evolution of this population after 10 years of follow-up., Methods: White renal transplant recipients (n = 873) were studied. The median time of follow-up was 91.8 months (P25-75 46-146). Amplification with specific "primers" to delimit the study area was performed for each polymorphism. Amplification was performed with the use of real-time polymerase chain reaction., Results: T-275A promoter mutation was detected in 13% of patients and C-2152T in 12% of patients. Survival analysis was performed on 873 renal transplants, carried out between 2004 and 2013. We found a higher frequency of death from cancer among polymorphism carriers (P = .001)., Conclusions: It appears that carriers of T-275A and C-2152T SNPs of the UGT1A9 gene promoter region show a greater incidence of death from cancer, with a significantly higher cumulative incidence of death from gastrointestinal tumors., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Renal transplantation has been established as the treatment of choice for end-stage renal disease (ESRD) due to diabetic nephropathy. This study aimed to investigate the risk factors for recurrence of diabetic nephropathy (RDN) in renal allografts., Methods: We studied 1,011 renal transplant patients from 1986 to 2003, of which 95 had ESRD due to diabetic nephropathy. We retrospectively analyzed the clinical characteristics and outcomes of RDN after renal transplantation., Results: Of the 95 recipients with ESRD due to diabetic nephropathy, 41 developed RDN and 11 of those 41 underwent graft biopsy. The mean durations from transplantation to RDN and to renal replacement therapy was 81.58 months (range, 54-120 mo), and 109.66 months (range, 27-188.4 mo), respectively. At 5 years, treatment on statins and renin-angiotensin-aldosterone system (RAAS) blockers were associated with a higher survival free from RND (82.2% vs 63.2% [P = .070] and 100% vs 80% vs 0.6% [P = .013], respectively). Compared with cyclosporine, tacrolimus was associated with a higher risk for RND (odds ratio [OR], 4.27; 95% confidence interval [CI], 1.75-5.13; P = .047). High doses of prednisone (>0.06 mg/kg) were also associated with a higher risk of RDN (OR, 3.03; 95% CI, 1.19-8.30; P = .029). The combination of calcineurin inhibitor and mammalian target of rapamycin inhibitor (mTORi) demonstrated the highest risk of RDN (OR, 14.08; 95% CI, 3.72-53.29; P < .01)., Conclusions: Treatment with tacrolimus and mTORi is the most diabetogenic immunosuppressive regimen. Treatment with tacrolimus entails a greater risk of RDN than with cyclosporine. The administration of statins or RAAS blockers could delay the progression of RDN., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Although acute vascular rejection (AVR) is associated with a high risk of graft loss, it remains unclear whether AVR with accompanied cellular or humoral rejection (AHR) has dissimilar outcomes. The aim of this study was to examine the association between subtypes of AVR and graft loss., Methods: We assessed patients who provided biopsy samples for acute allograft rejection from 1998 to 2014. To investigate distinct rejection patterns, we retrospectively assessed rejection episodes with review of graft histology as well as donor-specific anti-HLA antibodies when available., Results: A total of 1,004 patients were biopsied and included in the main analyses, of which 259 (32.87%) had acute biopsy-proven rejection. We identified three patterns of graft rejection defined according to the presence of peritubular capillaritis (ptc): a) T-cell-mediated acute vascular rejection if ptc free; b) humoral-mediated acute vascular rejection if ptc >0; and c) T-cell-mediated rejection if vasculitis = 0 and ptc = 0 (148 [57%], 70 [27%], and 41 [16%], respectively). At 5 years, graft survival was lower among patients with ptc-vascular rejection than those with T-cell vascular rejection (72.3% vs 83.2%; P = .010). T-cell-mediated rejection without vasculitis had similar survival compared with rejection absence (89.3% vs 8 9.2%; P = .698). Multivariate analysis adjusted by age and sex showed that risk of graft loss was higher in biopsies with high scores of glomerulitis (g2-g3); vasculitis (v2-v3), capillaritis (ptc2-ptc3), or interstitial inflammation (i2-i3). However, tubulitis and C4d were not statically significant., Conclusions: We conclude that antibody-mediated AVR involves a poorer prognosis than T-cell-mediated AVR. The presence of tubulitis does not seem to determine a poor long-term renal graft prognosis., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Whooping cough is a respiratory infection with a severity that varies with age, immune status, and probably with other factors such as the degree of exposure and the virulence of the organism. The most frequent microorganism responsible for whooping cough is Bordetella pertussis. We present the case of a 62-year-old renal transplant recipient presenting with typical and severe manifestations of whooping cough caused by B. pertussis., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

In this study, we assessed the association between single-nucleotide polymorphisms (SNPs) in seven candidate genes involved in orchestrating the immune response against cytomegalovirus (CMV) and the 12-month incidence of CMV infection in 315 CMV-seropositive kidney transplant (KT) recipients. Patients were managed either by antiviral prophylaxis or preemptive therapy. CMV infection occurred in 140 patients (44.4%), including 13 episodes of disease. After adjusting for various clinical covariates, patients harboring T-allele genotypes of interleukin-28B (IL28B) (rs12979860) SNP had lower incidence of CMV infection (adjusted hazard ratio [aHR]: 0.66; 95% confidence interval [CI]: 0.46-0.96; p-value = 0.029). In the analysis restricted to patients not receiving prophylaxis, carriers of the TT genotype of toll-like receptor 9 (TLR9) (rs5743836) SNP had lower incidence of infection (aHR: 0.61; 95% CI: 0.38-0.96; p-value = 0.035), whereas the GG genotype of dendritic cell-specific ICAM 3-grabbing nonintegrin (DC-SIGN) (rs735240) SNP exerted the opposite effect (aHR: 1.86; 95% CI: 1.18-2.94; p-value = 0.008). An independent association was found between the number of unfavorable SNP genotypes carried by the patient and the incidence of CMV infection. In conclusion, specific SNPs in IL28B, TLR9 and DC-SIGN genes may play a role in modulating the susceptibility to CMV infection in CMV-seropositive KT recipients., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background and Objectives: The use of darbepoetin alfa in the first week of post-renal transplant (RT)., Methods: Retrospective observational study carried out in four hospitals, which included all adult patients that underwent RT for 9 months with haemoglobin data during the first 6 months of post-transplant (n=129). Darbepoetin alfa was administered in accordance with the clinical practice., Results: Darbepoetin alfa was administered in the first week to 60 individuals (46.5%), who had a mean baseline Hb (± standard deviation) of 12.7 g/dl ± 1.6g/dl. Anaemia incidence (Hb<11 g/dl) during the first month was higher in patients who did not receive darbepoetin alfa (40.6% vs. 25.0% in patients treated with darbepoetin alfa, P=.045). No anaemia incidence differences were observed during months +2 to +6. There was a tendency towards transfusion decrease in patients who received darbepoetin alfa (13.3% vs. 20.3%, P=.295). Renal recovery time was similar but in the subgroup which received grafts from donors with asystole there was a tendency towards a faster recovery with darbepoetin alfa (15.1 ± 7.7 vs. 20.1 ± 8.8 days, P=.157). The creatinine clearance rate at 3 and 6 months was similar. Fourteen patients (10.9%) suffered from cardiovascular events with no relation to darbepoetin alfa (P=.772)., Conclusions: Administering darbepoetin alfa in the first week following renal transplant reduces anaemia incidence during the first month without increase cardiovascular events.

Introduction: Persistence of inappropriately high serum levels of fibroblast growth factor-23 (FGF23), a recently discovered phosphaturic hormone, has been reported to play an important role in the pathogenesis of posttransplant hypophosphatemia. The aim of the present study was to evaluate FGF23 in the early posttransplant period and study the complex associations between FGF23, parathyroid hormone (PTH), 1,25(OH)(2) vitamin D, and phosphate in transplant patients., Materials and Methods: We performed a cross-sectional observational study of 42 adult kidney recipients in the early posttransplant period (<6 months). Fasting serum samples and 24-hour urine samples were collected during a routine follow-up outpatient visit. Serum creatinine, calcium, phosphate, magnesium and urinary creatinine, calcium, magnesium, and phosphate were measured using standard assays. We also studied concentrations of 25 hydroxyvitamin D, 1,25(OH)(2) vitamin D, intact PTH, and circulating FGF23., Results: Median values for the different parameters studied were as follows: 9.9 ± 0.6 mg/dL, phosphatemia 3.3 ± 0.7 mg/dL, estimated glomerular filtration rate (eGFR; 41.1 ± 14.0 mL/min, phosphate reabsorption rate 68.4% ± 10.7%, PTH 94.5 ng/L (53.8-199.5), calcitriol 33.0 pg/mL (24.0-44.1), calcidiol 27.3 ng/mL (17.0-38.0), FGF23 139 pg/mL (88-221), and calciuria 62.5 mg/d (40.3-101.3). The variables significantly associated with serum FGF23 levels were phosphate reabsorption rate (r = .493; P = .001), calcitriol (r = .399; P = .009), eGFR (r = .557; P < .001), PTH (0.349; P = .024)., Conclusions: Elevated serum levels of FGF23 could explain the deficiency of calcitriol and elevated renal phosphorus wasting in the early posttransplant period. All treatments that can lead to increased serum phosphate levels (eg, oral medication or calcitriol) should be carefully evaluated, since increased phosphatemia could further stimulate secretion of FGF23 and prolong high phosphorus loss., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: The discovery of fibroblast growth factor 23 (FGF23) provides a new conceptual framework that improves our understanding of the pathogenesis of post-transplant bone disease. Excess FGF23 is produced in the early post-transplant period; levels return to normal in the months following transplant. However, few manuscripts discuss FGF23 levels in stable long-term renal transplant recipients., Methods: We performed a cross-sectional observational study of 279 maintenance kidney recipients with chronic kidney disease (CKD) Stages 1-4 and stable allograft function who had received their transplant at least 12 months previously. We calculated the estimated GFR (eGFR) using the MDRD4 equation., Results: FGF23, parathyroid hormone (PTH) and phosphorus values were higher in more advanced stages, while the serum calcitriol levels and the phosphate reabsorption rate were lower. A significant inverse correlation was found between eGFR and FGF23 (r = -0.487; P < 0.001), PTH (r = -0.444; P < 0.001), serum phosphate levels (r = -0.315; P < 0.001) and fractional excretion of magnesium (r = -0.503; P < 0.001). Multivariable analysis showed that increased time on corticosteroids (P < 0.001), PTH (P < 0.001), serum phosphate (P = 0.003), decreased serum calcitriol (P = 0.049) and estimated glomerular filtration (P = 0.003) rate were associated with high FGF23 levels. In contrast with pre-transplant patients and first year post-transplant patients, higher FGF23 values were not correlated with increased phosphate excretion. An elevated phosphate reabsorption rate was associated with decreased PTH (P < 0.001) and calciuria (P = 0.028) and increased serum calcitriol (P = 0.009), plasma bicarbonate (P = 0.024) and estimated glomerular filtration (P = 0.003)., Conclusions: Serum FGF23 concentrations remain increased in long-term kidney graft recipients, even in the early stages of CKD. It remains to be seen whether measures aimed at reducing serum levels of PTH and phosphate and/or corticosteroid doses might help to lower serum FGF23 and whether this will improve kidney recipient outcomes.

Background: Substantial research has been conducted to develop limited-sampling strategies (LSS) to estimate the area under the curve (AUC(0-12h)) in patients treated with mycophenolate mofetil. However, no LSS has been validated for enteric-coated mycophenolate sodium (EC-MPS). Our aim was to develop an LSS to measure the AUC(0-12h) of mycophenolic acid in kidney recipients treated with tacrolimus and EC-MPS., Study Design: Thirteen serial blood samples were collected over 12 hours from 71 patients treated with tacrolimus and EC-MPS. Mycophenolic acid was measured in plasma using the enzyme-multiplied immunoassay. LSSs were developed and validated by multiple regression analysis using a 2-group method (test, n = 47; validation, n = 24)., Results: The best LSS obtained in the test group were for 3 and 4 time points AUC(0-12h) (mg·h(-1)·L(-1)) = 15.99 + 0.87C1 h + 0.68C2 h + 7.85C4 h and AUC(0-12h) (mg·h(-1)·L(-1)) =11.15 + 0.68C1 h + 0.45C1.5 h + 0.57C2 h + 8.16C4 h, respectively. When these LSS were tested in the validation group, the results were acceptable (adjusted r(2) = 0.71, bias =-0.214 [95% confidence interval (CI): -7.91 to 7.48], precision = 7.48 (95% CI: 3.69-19.39) for 3 time points and adjusted r(2) = 0.76, bias = -1.48 (95% CI: -8.23 to 5.27), precision = 7.68 (95% CI: 4.23-13.50) for 4 time points)., Conclusions: : An LSS using time points at C(1h)-C(2h)-C(4h) or C(1h)-C(1.5h)-C(2h)-C(4h) provides the most reliable and accurate estimation of the AUC(0-12h) of mycophenolic acid in stable renal transplant recipients treated with EC-MPS and tacrolimus.

Background: We analyzed our clinical experience with everolimus (EVL) and identified prognostic factors for a successful conversion., Methods: Retrospective study of 220 kidney recipients consecutively converted to EVL with calcineurin inhibitor elimination. We studied risk factors for proteinuria at 1 year after conversion, decline in renal function, and graft survival., Results: Baseline creatinine clearance was 52.4±17.8 mL/min vs. 53.4±20.1 mL/min 1 year after conversion (P=0.150). Median proteinuria increased from 304 mg/day (interquartile range 160-507) to 458 mg/day (interquartile range 238-892; P<0.001). Risk factors for development of proteinuria ≥900 mg/day (P75) at 1-year postconversion were creatinine clearance less than 60 mL/min (odds ratio [OR] 3.37; 95% confidence interval [CI]: 1.15-9.89), serum triglycerides ≥150 mg/day (OR 4.35; 95% CI: 1.70-11.17), no treatment with prednisone (OR 3.04; 95% CI: 1.22-7.59), baseline proteinuria ≥550 mg/day (OR 10.37; 95% CI: 3.99-26.99), and conversion ≥3 years after transplant (OR 5.77; 95% CI: 1.89-17.59). An interaction was observed between baseline proteinuria and time to conversion: in patients with baseline proteinuria ≥550 mg/day, the risk of developing proteinuria ≥900 mg/day was 77.1% if they were converted after ≥3 years posttransplant. However, this risk was 29.8% in the subgroup converted before (P=0.02). Actuarial graft survival at 1 and 4 years postconversion was 98.2% and 86.5%, respectively. Baseline proteinuria ≥550 mg/day was a risk factor for graft loss in patients converted after the third year but not in patients converted before this time. EVL discontinuation rate was 24% in the first year postconversion., Conclusions: Conversion to EVL and elimination of calcineurin inhibitors is safe. Success depends on not making late conversions and not converting patients with high baseline proteinuria.

Unlabelled: BK virus (BKV) nephropathy is a common viral infection in renal transplant patients, with a prevalence of 1-9% at approximately 12 months after surgery. While it is widely agreed that reduction of immunosuppression should be the first intervention after diagnosis of BKV infection, there is no consensus on whether calcineurin inhibitors or antiproliferative drugs should be reduced first. Furthermore, target levels of immunosuppressive drugs are poorly defined, as are criteria for replacing one immunosuppressive agent with another., Results: We report our series of 15 renal transplant patients who underwent surgery between September 2004 and March 2010 and who developed BKV infection. The first 8 patients were treated with reduction of immunosuppression; 7 of these patients received cidofovir and 6 received intravenous immunoglobulin. The remaining 7 renal transplant recipients received mammalian target of rapamycin inhibitors (imTOR). In this group, we observed faster and more efficacious BKV clearance in plasma and urine and a steady improvement in allograft function, with no episodes of acute allograft rejection during follow-up. The polymerase chain reaction assay for BKV in urine became positive in 2 patients in whom imTOR were stopped due to severe side effects., Conclusions: The use of imTOR should be considered a first step in the treatment of renal transplant recipients with BKV infection. In our experience, this change in treatment was safe and resulted in viral clearance., (© 2011 John Wiley & Sons A/S.)

Objectives: We investigated the incidence and risk factors for the metabolic syndrome (MS) and posttransplant diabetes mellitus (PTDM) among renal transplant recipients on tacrolimus-based immunosuppressive regimens during the first year posttransplant. In addition, we studied the relationship between MS and PTDM with transplant renal function at 1 year., Methods: We included the 100 patients who received a renal transplant in our unit between January 2007 and June 2008, collecting demographic, clinical and biochemical characteristics at 1, 6, and 12 months posttransplantation. We excluded 15% of patients with pretransplantation diabetes. MS was defined according to the National Cholesterol Education Program criteria and PTDM according to World Health Organization criteria. Insulin resistance at one year posttransplant was measured using the homeostasis model assessment (HOMA) index., Results: Insulin therapy was required in 46% of patients during the first hospitalization and hyperglycemia was present in 65% of the cases. The incidence of PTDM decreased throughout the first year posttransplant, namely, 44%, 24%, and 13% at 1, 6, and 12 months, respectively. The incidence of MS increased to 33%, 48% and 50% at 1, 6, and 12 months, respectively. Age, body mass index, plasma fasting glucose levels at 1 month posttransplant, and pretransplant fasting triglyceridemia predicted PTDM. Rejection and in-patient hyperglycemia predicted MS. PTDM and MS were closely correlated (P=.004). The HOMA index was higher among patients with MS than other subjects at 1 year posttransplant: 3.2 (1.2) versus 2.3 (0.9; P=.035). Neither PTDM nor MS was associated with impaired plasma creatinine levels at 1 year after kidney transplantation., Conclusion: There was an high incidence of PTDM and MS among kidney transplant recipients treated with tacrolimus as the main immunosuppressive agent. The HOMA index was a good test of insulin resistance in this population. Screening and treatment of risk factors may avoid the development of these entities, which are related to poor cardiovascular outcomes., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Introduction: The incidence of candiduria in renal transplant recipients is unknown. In clinical practice, the indications for antifungal therapy are not well established. Furthermore, there is the problem of the choice of the antifungal drug since some of them may select resistant Candida species, or interact with immunosuppressive agents or only be used intravenously., Aim: We sought to study the incidence, clinical repercussions and effectiveness of antifungal treatment to prevent recurrence of candiduria., Materials and Methods: We examined all episodes of Candida-positive urine cultures (>50,000 cfu/mL) in 996 recipients over 2 years. We considered the Candida species, administered treatment, presence of fever, requirement for hospital admission versus outpatient case, occurrence of simultaneous bacterial urinary tract infection (UTI), antibiotic use during the week before candiduria, and presence of an indwelling urinary catheter., Results: Among 996 subjects, 34 displayed 83 episodes of candiduria, yielding an accumulated incidence of 3.4% after 2 years. The frequency was higher among women (6.3% vs 1.7%, P<.001). Of the 45 outpatient episodes (54.2%), 17 were treated and one required hospitalization (5.9%). Of the 28 nontreated outpatients, two were hospitalized (7.1%, P=.68 vs treated patients). All cases of hospital admission presented simultaneous bacterial UTI, none developed candidemia, and two patients did not receive any antifungal therapy. With respect to the first episodes of each patient (n=34), 5/11 treated (45.5%) and 4/23 untreated (17.4%) patients developed recurrences (P=.095). Selection of more resistant Candida species was not observed. Fifty cases (60%) were associated with antibiotic therapy and 34 (41%) the presence of a urinary catheter., Conclusions: It does not seem necessary to treat candiduria in this setting. Antifungal therapy was not associated with either a reduction in recurrence or the appearance of more resistant species in this study. We observed no important clinical repercussions., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Mammalian target of rapamycin (mTOR) inhibitors induce pneumonitis, an unusual but potentially fatal side effect of this drug group. We retrospectively collected the cases of pneumonitis induced by sirolimus or everolimus among 1471 adult cadaveric renal transplant recipients who were grafted at our institution from 1980-2008. Due to chronic transplant dysfunction or tumor, 205 patients were switched from calcineurin inhibitors to sirolimus (n = 88) or to everolimus (n = 117). Six patients (2.9%) developed pneumonitis: 1 was associated with sirolimus and 5 with everolimus (5 males and 1 female; median age, 60 years [range, 47-73 years]). Median times from conversion to pneumonitis onset were 34 days in 4 patients (range, 24-46 days) and 491 days in 2 subjects (range, 454-528 days). The mean drug trough level at presentation was 8.2 microg/L (range, 5.5-13.8 microg/L). The most common symptoms were dry cough (n = 6), fever (n = 5), and dyspnea (n = 4). Imaging tests revealed lower lobe involvement in all patients. Bronchoalveolar lavage performed in 4 patients showed lymphocytic alveolitis. All patients completely recovered after drug withdrawal. Five patients received steroids, 5 were switched to a calcineurin inhibitor, and 1 was switched to the other mTOR inhibitor. In conclusion, mTOR inhibitor-associated pneumonitis is a rare disease. Sirolimus did not cause more cases of pneumonitis than everolimus. Pneumonitis development was not dependent upon the drug blood level. Lower lobe involvement and lymphocytic alveolitis were usually present. Discontinuation of the mTOR inhibitor with steroid prescription resulted in adequate outcomes. A change to the other mTOR inhibitor should be contemplated if patient circumstances require this type of immunosuppression.

Unlabelled: The aim of this study was to evaluate the distribution of UGT1A9 promoter region T-275A and C-2152T single nucleotide polymorphisms (SNPs) in stable transplant patients and to investigate the impact of these SNPs on mycophenolic acid (MPA) pharmacokinetics., Methods: In total, 133 Caucasian renal transplant recipients were studied. Also a complete 12-hour pharmacokinetic profile was recorded for 15 transplant patients who had the polymorphism and for 15 controls who were randomly chosen since they received the same type and dosage of mycophenolate, same posttransplant time and similar renal function., Results: The T-275A promoter mutation was detected in 12.03% of patients and the C-2152T in 9.77%. All patients with the mutation C-2152T had associated the mutation T-275A. Patients who carried either the T-275A or the C-2152T polymorphism (or both) experienced more admissions owing to gastrointestinal side effects (P < .05). The pharmacokinetics studies showed that carriers of T-275A and/or C-2152T displayed a smaller area under-concentration time curve (AUC): 57.8 +/- 4.3 vs 78.9 +/- 10.8 mg/L*h (P < .03)., Conclusion: It seemed that carriers of T-275A and C-2152T SNPs of the UGT1A9 gene promoter region in the late posttransplant recipient group, showed a greater incidence of gastrointestinal side effects and a lower MPA exposure.

Persistent hyperparathyroidism is observed in 17% to 50% of patients at 1 year after renal transplantation. In 10% of these patients, hypercalcemia is also present. This condition increases the risk of vascular calcification, correlating with inferior graft function among patients with interstitial calcification in the renal allograft. Hypertension is appears in 60% to 90% of patients after transplantation, favoring progressive graft dysfunction. Hypercalcemia per se causes hypertension. Parathyroid hormone can potentiate the pressor effects of hypercalcemia. Fourteen renal transplant recipients were included based upon: total serum calcium > 10.0 mg/dL, intact parathyroid hormone levels > 70 pg/mL, graft function > 6 months, creatinine clearance > 50 mL/min, and stable immunosuppressive therapy. We also examined blood pressure and antihypertensive treatment. Initially patients received 30 mg of cinacalcet once a day. The follow-up was up to 6 months. The mean cinacalcet dose was 40 mg/24 h. Five patients received 60 mg/24 h. Both serum calcium and iPTH decreased significantly from 10.6 (DE 0.4) to 9.8 (DE Both serum calcium and iPTH decreased significantly from 10.6 (DE 0.4)to 9.8 (DE 0.6) mg/dL (P < .001) and from 195.0 (DE 140.0) to 118.62 (DE 102.2; P < .0001). There were no significant changes in renal function, proteinuria, or tacrolimus levels. Mean blood pressure diminished from 94.1 (DE 12.0) to 88.0 (DE 7.5) mm Hg (P < .019) with no changes in antihypertensive treatment. Cinacalcet was suspended in one patient because of gastrointestinal discomfort and in another one because the iPTH was reduced to 51 pg/mL. Cinacalcet is an effective treatment for persistent hyperparathyroidism associated with hypercalcemia among renal transplant patients and may be helpful for hypertension control.

Defining absolute psychiatric or neurological contraindications among kidney transplantation candidates is controversial, especially taking into account that graft outcomes are similar to other groups of patients. The social support network should be exhaustively evaluated to ensure adherence to immunosuppressive therapy and minimization of complications resulting from the neuropsychiatric disorder. We reviewed transplants (n = 668) in our center between January 2001 and August 2008 searching for patients with a diagnosis of neurological or psychiatric disease before renal transplantation. We also reviewed demographic data, social support networks, patient and graft survivals as well as transplant complications. Twelve patients were transplanted with neurological or psychiatric disorders: seven with cognitive impairment and five with psychiatric diseases. Nine patients had good social support networks. The mean follow-up time was 2.65 +/- 2.42 years. The graft loss rate was 34% (n = 4), including only one attributed to a mental disorder, namely, nonadherence to immunosuppressive therapy. Regarding complications, four were related to the neuropsychiatric disorder: hypoglycemia due to insulin overdose, aspiration pneumonia because of altered pharynx-larynx motility, hyponatremia related to diuretic abuse, and malnutrition plus dehydration. Patient survival in this period was 91.7%. The one patient died due to multiple organ failure secondary to respiratory sepsis with a functioning graft. In summary, neuropsychiatric disorders should not be considered to be contraindications for kidney transplantation although a social support network is essential and must be carefully evaluated.

Introduction: The clinical utility of predose levels of mycophenolic acid (MPA) monitoring among patients treated with mycophenolate mofetil (MMF) has been questioned. The aim of this study was to evaluate the impact of adequate MPA levels in the incidence of acute rejection episodes among a cohort of kidney transplant recipients., Material and Methods: In this retrospective study of 314 consecutive cases treated with tacrolimus, MMF, and steroids, evaluated 12-hour trough MPA samples during the first week as well as at 1, 3, 6, and 12 months as median values., Results: During the first week, the median values of MPA were 1.6 microg/mL (p25-75 0.7-2.7 microg/mL) on mean doses of 1.84 +/- 0.38 g/d. The incidence of acute rejection was 28%. The mean MPA levels during the first week were significantly lower among patients who developed rejection than in nonrejectors (1.5 +/- 0.1 vs 2.1 +/- 0.1 microg/mL; P < .001). There were no significant differences in trough tacrolimus levels between rejectors and nonrejectors (11.2 +/- 0.4 vs 11.6 +/- 1.2 microg/mL; P < .78). Logistic regression analysis showed that one of the predictive factors of acute rejection was a 12-hour trough MPA <1.6 microg/mL (relative risk [RR] 2.6; CI [confidence interval] 95% 1.6-4.3; P < .001)., Conclusions: Adequate MPA exposure is important to prevent acute rejection. Taking into account that the routine measurement of the area under the curve of MPA is impractical, at least the follow-up of trough MPA levels may help in the management of renal transplant recipients.

Background: Large inter- and intrapatient variabilities have been observed in the pharmacokinetics of mycophenolic acid (MPA). As a consequence, the efficacy and safety of mycophenolate mofetil (MMF) may be optimized with individualized doses based on therapeutic drug monitoring., Materials and Methods: In this retrospective study we analyzed; 7536 12-hour trough MPA samples obtained during the first year posttransplantation among 314 kidney recipients treated with tacrolimus, MMF, and corticosteroids., Results: Despite taking similar MMF doses, patients with delayed graft function (DGF) showed lower 12-hour trough MPA levels than patients without DGF 1.4 +/- 0.1 vs 2.1 +/- 0.1 microg/mL; P = .001). There was a significant correlation between 12-hour trough MPA levels and creatinine clearance (r = .32; P < .001). Logistic regression analysis showed that creatinine clearance was a predictive factor of adequate 12-hour trough MPA levels (>1.6 microg/mL) at 7 days posttransplantation. Twelve-hour trough MPA levels at 7 days posttransplantation were lower among patients who developed an acute rejecton episode (1.5 +/- 0.1 vs 2.1 +/- 0.1 microg/mL; P < .001), whereas those with gastrointestinal side effects showed high levels (4.1 +/- 0.5 microg/mL)., Conclusions: In patients with delayed or poor graft function, MMF doses greater than 2 g/d may be necessary to achieve adequate MPA levels. Therapeutic drug monitoring of MPA may be useful to prevent acute rejection episodes or toxicity.

Objective: The immune monitoring of transplant patients may allow us to minimize adverse events of immunosuppression and predict risks of rejection. Herein we have evaluated the capacity of an immune cell function assay to predict episodes of rejection and infections as well as its correlation with immunosuppressive drug trough levels and CD4, CD8, CD25, and DR cell counts., Patients and Methods: This prospective study of 38 kidney transplant patients was performed from January to June 2008. Blood samples were obtained at several times posttransplantation until the sixth month. We measured intracellular adenosine triphosphate (iATP) levels following CD4 cell activation for comparison with the clinical courses., Results: Patients with >or=525 ng/mL levels of iATP in the first week posttransplantation were 6.6 times more likely to develop an acute rejection episode (ARE) than those with lower immune response values (P = .014). Those who had an ARE with iATP < 525 ng/mL were generally highly sensitized (4/5). Statistically significant variations in iATP levels were observed among patients who had an ARE (P = .006). There was a relationship between infections and iATP levels also. Infections were more frequent with iATP

Background: Preemptive living donor kidney transplantation is associated with better allograft and recipient survival. However, it remains unclear whether preemptive transplantation from deceased donors is beneficial too. An increased number of deceased donors has reduced the waiting list in our hospital in the last years allowing preemptive deceased donor kidney transplantation (PDDKT)., Aim: We compared our experience with preemptive transplantation with patients who underwent dialysis before transplantation., Patients and Methods: Thirty-three PDDKT, including 77.5% male patients of overall mean age of 48 +/- 14 years, were performed in our hospital between January 1999 and December 2004 (8% of transplantations). We compared the outcomes of these patients with those of renal transplants in subjects who had undergone dialysis. The donors for both groups had similar characteristic; they were paired donor kidneys in most cases., Results: The types of donors in both groups were: non-heart-beating (49%), heart-beating deceased (27%) or en bloc pediatric (24%). The serum creatinine of the recipients was 6.9 +/- 1.8 mg/dL prior to transplantation, and the creatinine clearance was 14.6 +/- 3.6 mL/min (estimated by the Cockroft-Gault formula). The Charlson comorbidity index adapted for patients with advanced chronic kidney disease (ACKD) was 0.8 +/- 0.2 in the preemptive group versus 1.7 +/- 0.4 in the dialysis group (P < .05). Delayed graft function rates were 0% versus 25% in preemptive vs dialysis groups, respectively. No differences in 1-month or 1-year renal function as determined by serum creatinine were observed between the groups. We did not observe differences in the incidence of acute rejection or 1- and 2-year graft and patient survivals., Conclusion: PDDKT is the treatment of choice for ACKD. It is associated with less delayed graft function and similar 2-year graft and patient survivals than kidney transplantation after dialysis. The Charlson index reflected less comorbidity among patients with PDDKT, a finding that must influence long-term outcomes.

Introduction: mTOR inhibitors (imTOR) are immunosuppressive drugs that have a concentration-related effects on hematopoiesis, potentially resulting in anemia. The reason is uncertain, but a pathogenic link between sirolimus-induced anemia and the appearance of an inflammatory state was recently suggested. Because inflammation-related anemia is characterized by a functional iron deficiency, we studied whether everolimus influenced iron homeostasis., Methods: We studied iron homeostasis in 43 patients after late introduction of everolimus into the immunosuppressive treatment. Thirty-seven patients (86%) were receiving mycophenolate. Hemoglobin concentration, red blood cell count, mean corpuscular volume, serum iron, ferritin, C-reactive protein levels, and transferrin saturation were evaluated 3 months before and 1, 3, and 6 months after the switch., Results: The percentage of anemic patients preconversion was 18.6% and it was 34.9% at 3 months and 18.6% at 6 months. We did not observe a significant reduction in hemoglobin, but there was increased red blood cell count after everolimus introduction, with a significant reduction in mean corpuscular volume. Serum iron and transferrin saturation levels were also markedly reduced after the switch, while ferritin serum concentrations remained stable. An improvement in renal function was observed., Conclusions: The anemia caused by everolimus--microcytosis, low serum iron, despite high ferritinemia, and elevated C-reactive protein levels--was consistent with the anemia of a chronic inflammatory state. This alteration occurred within the first months postconversion and disappeared at 6 months. The combination of mycophenolate and everolimus seemed to be useful without significant secondary effects.

Everolimus has recently been introduced into clinical practice with promising perspectives due to its efficacy, lack of nephrotoxicity, and antitumor effects. Experience in clinical trials associated with low-dose cyclosporine showed good results, but there is almost no experience in calcineurin inhibitor (CNI) elimination learning it as the primary immunosuppressant. We describe our experience in a series of 78 stable renal transplant patients who were switched to Everolimus with complete and quick elimination of the CNI: the procedure of conversion, pharmacokinetic results after conversion, evolution of renal parameters (renal function, proteinuria, and others), and safety data (acute rejection and adverse events). An initial dose of 3 mg/d was adequate to obtain the recommended trough levels between 5 and 10 ng/mL. Our results demonstrated that conversion to Everolimus was a simple, safe procedure that must be considered in patients CNI toxicity, especially those with malignant neoplasms and progressive deterioration of renal function due to chronic allograft nephropathy.

Introduction: Enteric-coated mycophenolate sodium (EC-MPS) is the enteric-coated salt form of mycophenolic acid (MPA), the active component of the prodrug mycophenolate mofetil. EC-MPS was developed to reduce the upper-gastrointestinal (GI) effects of mycophenolate mofetil. There are no studies available comparing trough plasma levels in patients with GI intolerance to MMF when they are converted to EC-MPS., Aim: To compare the GI tolerance and the MPA levels in patients previously treated with MMF in whom this drug was replaced by EC-MPS., Materials and Methods: A prospective study was conducted in 133 renal transplant patients after conversion from MMF to EC-MPS (median time posttransplant 42 months, range 1 to 240 months). The causes for EC-MPS switching were GI intolerance to MMF (51.9%; group A), low trough plasma levels with MMF (29.3%; group B), and others (18.8%; group C). These patients were converted to equipotent doses of EC-MPS., Results: The trough plasma MPA levels increased from 1.5 +/- 1.1 microg/mL at baseline to 2.5 +/- 2.0 microg/mL at 1 month postconversion despite the equipotent EC-MPS doses not being increased. These higher plasma levels were maintained throughout the study. In group A, this increase was from 1.8 +/- 1.0 to 2.7 +/- 2.1 microg/mL (P = .01) and in group B from 0.8 +/- 0.4 to 2.4 +/- 1.4 microg/mL (P < .001). The doses and levels of calcineurin inhibitor decreased from baseline. Creatinine clearance improved from 56.5 +/- 24.7 mg/dL at baseline to 61.9 +/- 28.6 at 6 months postconversion (P = .02). There was a statistically significant increase in hemoglobin levels. In group A, the GI tolerance improved in 78% of the patients., Conclusions: At equipotent doses, patients converted to EC-MPS have higher and more adequate levels of MPA. At 6 months postconversion, we observed an improvement of the renal function, probably due to a reduction of calcineurin inhibitor drugs. However, the possibility that a better immunosuppressive efficacy as demonstrated by more suitable trough plasma levels may have been a contributing factor cannot be discarded.

The introduction of mycophenolate mofetil (MMF) was an important advance in immunosuppressive therapy, although its use is limited by adverse gastrointestinal events. Enteric-coated mycophenolate sodium (EC-MPS; myfortic) has been developed to avoid these side effects. Recent clinical trials have demonstrated that EC-MPS is a safe drug in both de novo and maintenance renal transplant patients. In this prospective study, therapeutically equivalent doses of EC-MPS were administered to 39 stable kidney transplant patients receiving MMF. After 3 months of treatment with EC-MPS the incidence of adverse gastrointestinal events was lower (15.8% of the patients). There were higher levels of mycophenolic acid after conversion to EC-MPS, probably due to better absorption. These factors allowed decreased doses and levels of calcineurin inhibitors without increasing the risk of graft rejection. At 3 months postconversion, serum creatinine improved from the mean baseline value of 1.83 +/- 0.12 mg/dL to 1.70 +/- 0.10 mg/dL. In conclusion, EC-MPS was well tolerated in maintenance renal transplant patients with adverse gastrointestinal events secondary to MMF.

Disseminated varicella-zoster virus (VZV) infection in adult renal allograft recipients is a rare but potentially fatal illness. We retrospectively collected the cases of VZV infection that occurred in 812 adult renal transplant recipients, performed between 1995 and 2004 at our institution. Eight patients developed varicella (1%), seven men and one woman. The overall median age was 38 years (range = 31 to 64). The median time from transplantation to infection was 32 months (range = 2 to 92). Four cases were primary infections and four disseminated VZV reactivations. Immunosuppression consisted of prednisone (PDN) + cyclosporine (CSA) + mycophenolate (MF; n = 4); PDN + CSA + azathioprine (n = 1); PDN + tacrolimus (FK) + MF (n = 1); FK + MF (n = 1); PDN + rapamycin + MF (n = 1). Seven patients (87%) required hospital admission for a median duration of 11 days (range = 3 to 21). Four patients were previously diagnosed with chronic hepatitis virus infection: two type B (HBV) and two type C (HCV). The last cohort required longer admission than the negative patients (11.5 +/- 3 vs 7.5 +/- 9 days; P = .1). The only clinical manifestation in four patients was general malaise, fever, and a disseminated vesicular rash; the other four patients also showed visceral involvement: two pneumonitis, one hepatitis, and thrombotic microangiopathy, and one developed multiorgan failure and died due to a delayed diagnosis in a patient positive for HBVs. The diagnosis was established according to the symptoms, IgG-IgM seroconversion and VZV polymerase chain reaction quantification in vesicle contents. Treatment consisted of reduced immunosuppression, antiviral drugs (acyclovir or gancyclovir), and in six patients, a varicella-zoster immunoglobulin dose. We concluded that varicella infection in adult renal allograft recipients is unusual but highly morbid. A vaccination program in seronegative pretransplant candidates should be attempted. Early diagnosis and treatment may improve the prognosis. Although further studies are required, chronic HBV or HCV infection seemed to be a risk factor for the disease.

Background: Conversion from calcineurin inhibitors (CNI) to sirolimus (SRL) is an option for renal transplant patients who develop a tumor. This strategy, however, may be associated with an increased risk of rejection., Aim: We sought to evaluate a series of renal transplant patients who underwent conversion from CNI to SRL because they developed a tumor during the posttransplant period., Methods: This prospective study of 29 patients included 2 patients with skin cancer (1 melanoma and 1 squamous cell carcinoma) and 27 patients who developed other tumors: lung (n = 6), prostate (n = 4), lymphoma (n = 2), colon adenocarcinoma (n = 2), kidney (n = 2), Kaposi sarcoma (n = 2), urothelium (n = 1), parotid (n = 1), larynx (n = 1), gastric (n = 1), breast (n = 1), tongue (n = 1), liver (n = 1), xanthoastrocytoma (n = 1), and aggressive angiomyxoma of the perineum (n = 1)., Results: CNI were withdrawn in 28 patients and reduced in the remaining patient. Renal function was better when CNI were rapidly or abruptly suspended, with maintenance of cyclosporine (CsA) + SRL for more than 3 months being especially detrimental. Proteinuria worsened in patients whose preconversion levels were >0.5 g/d, particularly those treated with CsA. There was no episode of rejection., Conclusions: SRL is a promising option for the management of posttransplant tumors. The switch in immunosuppression should be undertaken quickly, especially in patients under treatment with CsA.

To date there is a substantial experience with rapamycin conversion in stable renal transplant recipients with respect to the procedure of conversion, initial doses, and target blood levels as well as adverse events, but in the case of Everolimus there is almost no experience with conversion and calcineurin inhibitor (CNI) withdrawal. We describe an initial experience among 32 renal transplant recipients who were converted to Everolimus with complete suspension of CNI in two Spanish transplant centers. Our results emphasised the procedure for conversion, the target levels, the adverse events, and the initial efficacy, over the first month after conversion. Our conclusions were that conversion from CNI to Everolimus was a simple, safe procedure with a predictable profile of adverse events, which were, in general, of mild intensity. There was a good correlation between initial dose and blood level. Initial doses of about 3 mg/d combined with rapid reduction in CNI exposure seemed to be adequate. The target range levels between 5 and 10 ng/mL seemed to be sufficient for complete CNI elimination, especially in patients also receiving antiproliferative drugs (such as mycophenolate mofetil or azathioprine) in whom levels near the lower end of the range might be adequate.

Background: The use of non-heart-beating donors could help shorten the list of patients who are waiting for a kidney transplant. Several reports describe acceptable results of transplantations from non-heart-beating donors who had in-hospital cardiac arrest, but few reports describe results of transplantations from non-heart-beating donors who had cardiac arrest that occurred outside of the hospital (Maastricht type I and type II donors)., Objective: To compare graft survival rates among patients receiving kidneys from heart-beating donors versus type I or type II non-heart-beating donors., Design: Retrospective cohort study of transplantations performed from January 1989 to December 2004., Setting: Kidney transplant program of a teaching hospital in Madrid, Spain., Patients: 320 patients who received a kidney transplant from non-heart-beating donors (273 type I donors and 47 type II donors) and 584 patients who received a kidney transplant from heart-beating donors divided into 2 groups according to donor age (age <60 years [n = 458] and age > or =60 years [n = 126])., Measurements: The primary outcome measure was graft survival. The median follow-up time was 68 months (range, 9 to 198 months)., Results: One- and 5-year graft survival rates were 90.7% and 85.5%, respectively, for transplants from heart-beating donors younger than 60 years of age; 79.8% and 73.3%, respectively, for transplants from heart-beating donors 60 years of age or older (P < 0.001); and 87.4% and 82.1%, respectively, for transplants from non-heart-beating donors (P = 0.22 [vs. those from heart-beating donors < 60 years of age] and P = 0.014 [vs. those from heart-beating donors >or = 60 years of age]). Graft survival did not differ between patients who received kidneys from heart-beating donors younger than 60 years of age and patients who received kidneys from non-heart-beating donors., Limitations: This single-site, observational study was retrospective, and immunosuppressive therapy regimens given to transplant recipients varied over time., Conclusions: Outcomes of transplants from non-heart-beating donors and younger heart-beating donors are similar, and results for transplants from non-heart-beating donors improved compared with those from older heart-beating donors. On the basis of these results, the authors encourage other transplant units to adopt the use of type I and type II non-heart-beating donors.

Recent studies have demonstrated some association between the renin-angiotensin system (RAS) activity and the development and progression of different entities as diabetes mellitus (DM) or chronic allograft nephropathy. To investigate these associations, we studied some gene polymorphisms of RAS in a group of renal transplant recipients. We retrospectively analyzed 42 patients who underwent a primary renal transplantation for 2 years. A subgroup of 23 patients (55%) was diagnosed with postransplant DM in accordance with American Diabetes Association 2001 criteria. We studied two RAS gene polymorphisms: the angiotensin-converting enzyme insertion/deletion (ACE I/D) and angiotensinogen (AGTM235T). Genotyping was performed by DNA purification and amplification with a polymerase chain reaction technique. The distributions of genotypes were ACE DD, ID, II: 33%, 48%, 19%; and AGT TT, MT, MM: 15%, 45%, 40%, respectively. We observed a progressive loss in renal function measured by creatinine clearance (Cockroft) in D-allele carriers (DD+ID) between the first and the second transplantation year: 65.3 +/- 4.3 vs 59.8 +/- 4.6 mL/min (P = 0.02); that was not seen in II patients: 68.8 +/- 4.6 vs 68.4 +/- 4 mL/min (P = 0.87). Fifty percent of D-allele carriers developed DM vs 25% of non-D-allele carriers (P = 0.19). Eighty-three percent of homozygous patients for the AGT-TT allele developed DM vs 35% of non TT patients (P = 0.04). There were no significant differences regarding recipient demographic characteristics, type of donor, number and severity of acute rejections, and immunosuppressant treatment between the groups. In conclusion, ACE D-allele seems to be associated with a poorer kidney graft long-term outcome. ACE D and AGT T alleles may be implicated in glucose metabolism disorders after transplantation.