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Aims: Calcineurin inhibitors (CNI) have a small therapeutic window, and drug monitoring is required. Pharmacokinetic monitoring does not correlate sufficiently with clinical outcome. Therefore, the expression of nuclear factor of activated T cells (NFAT)-regulated genes in the peripheral blood has been suggested as a potentially useful immune monitoring tool to optimize CNI therapy. NFAT-regulated gene expression (RGE) was evaluated in renal allograft recipients as predictive biomarker to detect patients at risk of acute rejection or infections., Methods: NFAT-RGE (interleukin-2, interferon-γ, granular-macrophage colony-stimulating factor) was evaluated by quantitative real-time polymerase chain reaction in whole blood samples at day 7, day 14, month 1, 3, and 6 after transplantation in 64 de novo renal allograft recipients from 3 European centres. Immunosuppression consisted of tacrolimus (Tac), mycophenolic acid, and corticosteroids., Results: Tac concentrations (C0 and C1.5) correlated inversely with NFAT-RGE (P < .01). NFAT-RGE showed a high interindividual variability (1-61%). Patients with high residual gene expression (NFAT-RGE ≥30%) were at the increased risk of acute rejection in the following months (35 vs. 5%, P = .02), whereas patients with low residual gene expression (NFAT-RGE <30%) showed a higher incidence of viral complications, especially cytomegalovirus and BK virus replication (52.5 vs. 10%, P = .01)., Conclusions: NFAT-RGE was confirmed as a potential noninvasive early predictive biomarker in the immediate post-transplant period to detect patients at risk of acute rejection and infectious complications in Tac-treated renal allograft recipients. Monitoring of NFAT-RGE may provide additional useful information for physicians to achieve individualized Tac treatment., (© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

This study evaluate the potential of plasmatic CXCL-10 (pCXCL-10) as a pre&post transplantation prognostic and diagnostic biomarker of T-cell-mediated rejection (TCMR), antibody-mediated rejection (ABMR) and subclinical rejection (SCR) risk in adult kidney recipients considering BKV and CMV infections as possible clinical confounder factors. Twenty-eight of 100 patients included experienced rejection (TCMR:14; ABMR:14); 8 SCR; 13 and 16 were diagnosed with BKV and CMV infection, respectively. Pre-transplantation pCXCL-10 was significantly increased in TCMR and ABMR and post-transplantation in TCMR, ABMR and SCR compared with nonrejectors. All CMV + patients showed pCXCL-10 levels above the cutoff values established for rejection whereas the 80% of BKV + patients showed pCXCL-10 concentration < 100 pg/mL. pCXCL-10 could improve pre-transplantation patient stratification and immunosuppressive treatment selection according to rejection risk; and after kidney transplantation could be a potential early prognostic biomarker for rejection. Clinical confounding factor in BKV + and particularly in CMV + patients must be discarded., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Previous results from our group and others have shown that urinary pellet expression of miR155-5p and urinary CXCL-10 production could play a key role in the prognosis and diagnosis of acute rejection (AR) in kidney transplantation patients. Here, a logistic regression model was developed using NONMEM to quantify the relationships of miR155-5p urinary expression, CXCL-10 urinary concentration and tacrolimus and mycophenolic acid (MPA) exposure with the probability of AR in adult kidney transplant patients during the early post-transplant period. Owing to the contribution of therapeutic drug monitoring to achieving target exposure, neither tacrolimus nor MPA cumulative exposure was identified as a predictor of AR in the studied population. Even though CXCL-10 urinary concentration showed a trend, its effect on AR was not significant. In contrast, urinary miR155-5p expression was prognostic of clinical outcome. Monitoring miR155-5p urinary pellet expression together with immunosuppressive drug exposure could be very useful during routine clinical practice to identify patients with a potential high risk of rejection at the early stages of the post-transplant period. This early risk assessment would allow for the optimization of treatment and improved prevention of AR., Competing Interests: This work was funded by TEVA Pharmaceuticals, a commercial company. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, marketed products or products in development associated with this research. Fundació Clínic per la Recerca Biomèdica (FCRB) (Research Center of Hospital Clínic of Barcelona) acted as promoter of the study and was responsible for starting and managing of the study, but did not provide financial support.

Background: The progression from acute to chronic antibody-mediated rejection in kidney transplant recipients is usually not prevented by current therapeutic options. Here, we investigated whether the use of tofacitinib (TOFA), a Janus kinase 3 inhibitor, was capable of preventing the progression of allograft dysfunction in a Fisher-to-Lewis rat model of kidney transplantation., Methods: Rats were treated from the third week after transplantation to allow the development of rejection. Treatment was based on cyclosporin A, rapamycin or TOFA. Renal function was assessed at 1, 4, 8, and 12 weeks after transplantation, whereas rat survival, histological lesions, and infiltrating lymphocytes were analyzed at 12 weeks., Results: Tofacitinib prolonged graft survival, preserved tubular and glomerular structures and reduced humoral damage characterized by C4d deposition. Tofacitinib was able to reduce donor-specific antibodies. In addition, T and natural killer cell graft infiltration was reduced in TOFA-treated rats. Although rapamycin-treated rats also showed prolonged graft survival, glomerular structures were more affected. Moreover, only TOFA treatment reduced the presence of T, B and natural killer cells in splenic parenchyma., Conclusions: Tofacitinib is able to reduce the immune response generated in a rat model of kidney graft rejection, providing prolonged graft and recipient survival, better graft function, and less histological lesions.

Aims: MicroRNAs (miRNAs) may be useful biomarkers of rejection and allograft outcome in kidney transplantation. Elevated urinary CXCL10 levels have been associated with acute rejection (AR) and may predict allograft failure. We examined the correlation of miRNA, CXCL10 levels and immunosuppressive drug exposure with AR and graft function in kidney transplant recipients., Methods: Eighty de novo kidney transplant recipients were recruited from four European centres. All patients received tacrolimus, mycophenolate mofetil, and methylprednisolone. Urinary pellet expression of miR-142-3p, miR-210-3p and miR-155-5p was assessed by quantitative real-time polymerase chain reaction and urinary CXCL10 levels by enzyme-linked immunosorbent assay at the 1 st week and the 1 st , 2 nd , 3 rd and 6 th months post-transplantation., Results: Eight patients experienced AR. Before and during AR, patients showed a significant increase of urinary miR-142-3p, miR-155-5p and CXCL10 levels and a decrease of miR-210-3p levels. Receiver operating characteristic curve analysis showed that miR-155-5p (area under the curve = 0.875; P = 0.046) and CXCL10 (area under the curve = 0.865; P = 0.029) had excellent capacity to discriminate between rejectors and nonrejectors. The optimal cut-off values for the prognosis of AR were 0.51, with 85% sensitivity and 86% specificity for miR-155-5p and 84.73 pg ml -1 , with 84% sensitivity and 80% specificity for CXCL10. miR-155-5p and CXCL10 levels correlated with glomerular filtration rate. Levels of both biomarkers normalized after recovery of graft function., Conclusions: The regular early post-transplantation monitoring of urinary miR-155-5p and CXCL10 can help in the prognosis of AR and graft dysfunction. Large prospective randomized multicentre trials are warranted to refine our cut-off values and validate the clinical usefulness of these biomarkers., (© 2017 The British Pharmacological Society.)

The aim of this study was to find noninvasive T-cell markers able to predict rejection or infection risk after kidney transplantation. We prospectively examined T-lymphocyte subsets after cell culture stimulation (according to CD38, CD69, CD95, CD40L, and CD25 expression) in 79 first graft recipients from four centers, before and after transplantation. Patients were followed up for one year. Patients who rejected within month-1 (n=10) showed high pre-transplantation and week-1 post-transplantation percentages of CD95(+), in CD4(+) and CD8(+) T-cells (P<0.001 for all comparisons). These biomarkers conferred independent risk for early rejection (HR:5.05, P=0.061 and HR:75.31, P=0.004; respectively). The cut-off values were able to accurately discriminate between rejectors and non-rejectors and Kaplan-Meier curves showed significantly different free-of-rejection time rates (P<0.005). Patients who rejected after the month-1 (n=4) had a higher percentage of post-transplantation CD69(+) in CD8(+) T-cells than non-rejectors (P=0.002). Finally, patients with infection (n=41) previously showed higher percentage of CD38(+) in CD8(+) T-cells at all post-transplantation times evaluated, being this increase more marked in viral infections. A cut-off of 59% CD38(+) in CD8(+) T-cells at week-1, week-2 and month-2 reached 100% sensitivity for the detection of subsequent viral infections. In conclusion, predictive biomarkers of rejection and infection risk after transplantation were detected that could be useful for the personalized care of kidney recipients., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Transplant recipients are at risk of developing Legionnaires' disease (LD) because of impaired cellular immunity. Here, we describe a renal transplant recipient who developed LD at least 10 days after hospital admission and transplantation. The hospital water network was initially suspected, but further testing determined that the probable source was the patient's domestic water supply. Our report also suggests that the patient's immunosuppressed state may have switched potential colonization to pneumonia., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Prognostic biomarkers of acute rejection (AR) in solid organ transplantation have been addressed in multiple small retrospective studies, and there is a critical need for multicenter studies. Because of their tolerogenic properties, regulatory T cells (Tregs) play an important role in transplant outcome., Methods: In the present multicenter study, we have retrospectively examined different Treg subpopulations in an independent cohort of kidney transplant patients within first year after kidney transplantation. All participating centers used identical flow cytometry standard operating procedures., Results: Seventy-five renal transplant patients were included, and six of them experienced an AR episode. The activated Treg (aTreg) subpopulation (CD4CD25CD62LCD45RO) was increased in the AR group before transplantation, and an aTreg percentage higher than 1.46% before kidney transplantation conferred an increased risk of AR. The univariate logistic regression model achieved an area under the curve of 81.6%. By including recipient age and thymoglobulin induction as variables in a multivariate logistic regression model, the prediction of AR improved to 92.4%., Conclusion: The evaluation of CD4CD25CD62LCD45RO aTreg cells may be useful as pretransplantation predictive biomarker of AR in kidney transplant patients. Definitive confirmation of our results awaits tests in validation groups.

Acute rejection (AR) remains a major challenge in organ transplantation, and there is a need for predictive biomarkers. In the present multicenter study, we prospectively examined a series of biomarkers in liver and kidney recipients. Intracellular expression of IFN-γ, IL-17 and IL-2 and IL-17 soluble production were evaluated both pre-transplantation and post-transplantation (1st and 2nd week, 1st, 2nd and 3rd month). 142 transplant patients (63 liver/79 kidney) were included in the study. Twenty-eight recipients (14 liver/14 kidney) developed AR. Pre- and post-transplantation intracellular expression of %IFN-γ(+) in CD4(+)CD69(+) and in CD8(+)CD69(+) and soluble IL17 identified liver and kidney transplant patients at high risk of AR. Pre-transplantation, %IL-2(+) in CD8(+)CD69(+) also identified kidney patients at high risk. We constructed pre- and post-transplantation risk prediction models, based on a composite panel of biomarkers, which could provide the basis for future studies and will be a useful tool for the selection and adjustment of immunosuppressive treatments., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Several factors contribute to mycophenolic acid (MPA) between-patient variability. Here we characterize the metabolic pathways of MPA and quantify the effect of combining genetic polymorphism of multidrug-resistant-associated protein-2, demographics, biochemical covariates, co-medication (cyclosporine (CsA) vs. macrolides), and renal function on MPA, 7-O-MPA-glucuronide (MPAG), and acyl-glucuronide (AcMPAG) disposition, in renal transplant recipients, after mycophenolate mofetil. Complete pharmacokinetic profiles from 56 patients (five occasions) were analyzed. Enterohepatic circulation was modeled by transport of MPAG to the absorption site. This transport significantly decreased with increasing CsA trough concentrations (CtroughCsA). MPAG and AcMPAG plasma clearances significantly decreased with renal function. No significant influence of multidrug-resistant-associated protein-2 C24T single-nucleotide polymorphism was found. The model adequately predicted the increase in MPAG/AcMPAG exposures in CsA and macrolide patients with decreased renal function. This resulted in higher MPA exposures in macrolide patients versus CsA patients, and increased MPA exposures with renal function from 25 to 10 ml/min, in macrolide patients, owing to enhanced MPAG enterohepatic circulation. Lower-percentage enterohepatic circulation occurred with higher CtroughCsA and renal function values. The lack of MPA protein-binding modeling did not permit evaluation of the impact of renal function and CtroughCsA on MPA exposures in CsA patients. Thus, dose tailoring of covariates is recommended for target MPA exposure.

Adrenal insufficiency is a rare but life-threatening disease. Replacement therapy sometimes fails to prevent an acute adrenal crisis and most often does not lead to restoration of well-being. We report here the 1-year outcome of the first simultaneous kidney-adrenal gland-pancreas transplantation in a 33-year-old patient with type 1 diabetes and concomitant autoimmune adrenal insufficiency. En bloc left adrenal gland and kidney grafts were anastomosed on the left iliac vessels in normal vascular conditions and the pancreas graft was anastomosed on the right iliac vessels. The immunosuppressive regimen was not modified by the addition of the adrenal gland. We observed no additional morbidity due to the adrenal gland transplantation, as there were no surgical complications. One-year kidney and pancreas graft functions were satisfactory (estimated glomerular filtration rate: 55 mL/min/1.73 m(2) and HbA1c: 4.8%). The adrenal graft functioned well at 12 months with a normalization of cortisol and aldosterone baseline levels. Functional imaging at 3 months showed good uptake of [(123) I]-metaiodobenzylguanidine by the adrenal graft. Transplantation of the adrenal gland en bloc with the left kidney appears to be a good therapeutic option in patients with adrenal insufficiency awaiting kidney or kidney-pancreas transplantation., (© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: If pancreas transplantation is a validated alternative for type 1 diabetic patients with end-stage renal disease, the management of patients who have lost their primary graft is poorly defined. This study aims at evaluating pancreas retransplantation outcome., Methods: Between 1976 and 2008, 569 pancreas transplantations were performed in Lyon and Geneva, including 37 second transplantations. Second graft survival was compared with primary graft survival of the same patients and the whole population. Predictive factors of second graft survival were sought. Patient survival and impact on kidney graft function and survival were evaluated., Results: Second pancreas survival of the 17 patients transplanted from 1995 was close to primary graft survival of the whole population (71% vs. 79% at 1 year and 59% vs. 69% at 5 years; P=0.5075) and significantly better than their first pancreas survival (71% vs. 29% at 1 year and 59% vs. 7% at 5 years; P=0.0008) regardless of the cause of first pancreas loss. The same results were observed with all 37 retransplantations. Survival of second simultaneous pancreas and kidney transplantations was better than survival of second pancreas after kidney. Patient survival was excellent (89% at 5 years). Pancreas retransplantation had no impact on kidney graft function and survival (100% at 5 years)., Conclusion: Pancreas retransplantation is a safe procedure with acceptable graft survival that should be proposed to diabetic patients who have lost their primary graft.

Background: The use of the immunosuppressant sirolimus in kidney transplantation has been made problematic by the frequent occurrence of various side effects, including paradoxical inflammatory manifestations, the pathophysiology of which has remained elusive., Methods: 30 kidney transplant recipients that required a switch from calcineurin inhibitor to sirolimus-based immunosuppression, were prospectively followed for 3 months. Inflammatory symptoms were quantified by the patients using visual analogue scales and serum samples were collected before, 15, 30, and 90 days after the switch., Results: 66% of patients reported at least 1 inflammatory symptom, cutaneo-mucosal manifestations being the most frequent. Inflammatory symptoms were characterized by their lability and stochastic nature, each patient exhibiting a unique clinical presentation. The biochemical profile was more uniform with a drop of hemoglobin and a concomitant rise of inflammatory acute phase proteins, which peaked in the serum 1 month after the switch. Analyzing the impact of sirolimus introduction on cytokine microenvironment, we observed an increase of IL6 and TNFα without compensation of the negative feedback loops dependent on IL10 and soluble TNF receptors. IL6 and TNFα changes correlated with the intensity of biochemical and clinical inflammatory manifestations in a linear regression model., Conclusions: Sirolimus triggers a destabilization of the inflammatory cytokine balance in transplanted patients that promotes a paradoxical inflammatory response with mild stochastic clinical symptoms in the weeks following drug introduction. This pathophysiologic mechanism unifies the various individual inflammatory side effects recurrently reported with sirolimus suggesting that they should be considered as a single syndromic entity.

Background: It is unknown whether kidney transplant patients who receive rabbit antithymocyte globulin (rATG) become immunized against rabbit antibodies, leading to reduced efficacy, or are at higher risk of cytomegalovirus infection or post-transplant lymphoproliferative disorder (PTLD) on retreatment. The efficacy and tolerance of rATG when used as induction for the second time in patients undergoing retransplantation have not been evaluated., Methods: In a retrospective case-control study, 54 retransplanted patients who received rATG (Thymoglobulin) induction for the second time during 2004-2010 were compared to a matched cohort of 108 patients receiving rATG induction for a first kidney transplantation during the same period. Maintenance treatment was similar in both groups., Results: Median follow-up was 45.8 months and 47.3 months in the second and first treatment groups, respectively. No differences were observed between the two groups in terms of leukocyte, lymphocyte or platelet depletion. Dose and duration of rATG treatment were similar in both groups, suggesting a similar tolerance profile. Cytomegalovirus infection (including primoinfection and reactivation) occurred in 4/54 retreated patients versus 22/108 controls (p=0.108). Use of cytomegalovirus prophylaxis was similar between groups. PTLD occurred in one control patient and no retreated patients., Conclusion: A second course of rATG induction results in similar lymphocyte depletion and is as well tolerated as a first course. The incidence of cytomegalovirus infection and post-transplant lymphoproliferative disease was not increased during retreatment. Further studies are required to evaluate specific T cell subpopulation depletion and compare long-term outcome in patients receiving a second induction with rATG., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The use of uncontrolled deceased donors after cardiac arrest (uDDCA) has been developed in France to compensate for organ shortage. The quality of these kidneys remains unclear. We analyzed kidney graft function and histology from 27 uDDCA and compared them with kidneys from 30 extended criteria donors (ECD) and from 24 simultaneous pancreas kidney (SPK) donors as a control group of optimal deceased donors. Kidneys from ECD and SPK donors were preserved by static cold storage while kidneys from uDDCA were preserved by pulsatile perfusion. The uDDCA graft function at 3 years posttransplantation (estimated with MDRD and measured with inulin clearance) did not differ from that of the ECD group (eGFR 44.1 vs. 37.4 mL/min/1.73 m(2) , p = 0.13; mGFR 44.6 vs. 36.1 mL/min/1.73 m(2) , p = 0.07 in the uDDCA and ECD groups, respectively). The histological assessment of 3-month and 1-year protocol biopsies did not show differences for interstitial lesions between the uDDCA and ECD grafts (IF score at M3 was 30 vs. 28% and at M12 36 vs. 33%, p = NS). In conclusion, the results at 3 years with carefully selected and machine-perfused uDDCA kidneys have been comparable to ECD kidneys and encourage continuation of this program and development of similar programs., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: The aim of this study was to determine the relationship between single-nucleotide polymorphisms (SNPs) in MRP2 genes and mycophenolic acid (MPA) pharmacokinetics in renal transplant recipients of the Symphony Pharmacogenomic substudy., Methods: Sixty-six renal transplant recipients of eight Spanish centres were randomized into four branches of immunosuppressive regimen: low dose of cyclosporine, standard dose of cyclosporine, tacrolimus and sirolimus, all in addition to mycophenolate mofetil and steroids. Fifty-five patients were genotyped for SNPs in MRP2, C24T and C3972T. Pharmacokinetic sampling was done before MPA administration and up to 12 h post-dose at Day 7, 1 month and 3 months post-transplant. Relationships of area under the curve (AUC) of MPA and MPAG plasma sampling with the presence of MRP2 SNPs and with the immunosuppressive regimens were studied., Results: At steady-state conditions, MPA-reduced exposure was observed in C24T variant allele in MRP2 (CC: 68.73 ± 6.78; *T: 48.12 ± 4.90, P = 0.023); no significant differences linked to C3972T SNP were observed. Taking into account groups of treatment, lower MPA AUC in variant allele of C24T was only found under macrolides treatment with statistically significant differences at Month 3 (Tac and SRL, CC: 86.52 ± 10.98 versus *T: 41.99 ± 4.82, P = 0.001; CsA, CC: 52.31 ± 5.30 versus *T: 54.24 ± 8.30, P = 0.772); for C3972T, the same tendency was found but differences at steady state did not reach statistical significance., Conclusions: Renal transplant recipients T carriers of C24T MRP2 with macrolides treatment were associated with reduced MPA AUC in steady-state conditions. Patients treated with cyclosporine lost the effect of this polymorphism.

The prognosis of human immunodeficiency virus (HIV) infection has improved in recent years with the introduction of antiretroviral treatment. While the frequency of AIDS-defining events has decreased as a cause of death, mortality from non-AIDS-related events including end-stage renal diseases has increased. The etiology of chronic kidney disease is multifactorial: immune-mediated glomerulonephritis, HIV-associated nephropathy, thrombotic microangiopathies, and so on. HIV infection is no longer a contraindication to transplantation and is becoming standard therapy in most developed countries. The HIV criteria used to select patients for renal transplantation are similar in Europe and North America. Current criteria state that prior opportunistic infections are not a strict exclusion criterion, but patients must have a CD4+ count above 200 cells/mm(3) and a HIV-1 RNA viral load suppressible with treatment. In recent years, more than 200 renal transplants have been performed in HIV-infected patients worldwide, and mid-term patient and graft survival rates have been similar to that of HIV-negative patients. The main issues in post-transplant period are pharmacokinetic interactions between antiretrovirals and immunosuppressants, a high rate of acute rejection, the management of hepatitis C virus coinfection, and the high cardiovascular risk after transplantation. More studies are needed to determine the most appropriate antiretroviral and immunosuppressive regimens and the long-term outcome of HIV infection and kidney graft., (© 2011 International Society of Nephrology)

Background: HMG-CoA reductase inhibitors (statins) have effects beyond lipid lowering, including immunomodulatory and anti-inflammatory properties. Statins are frequently combined with immunosuppressive agents in transplant recipients to modulate the hyperlipidemic side effects of the immunosuppressants. However, the role of statins in the immunosuppressive response that is achieved in individual patients remains to be assessed., Objective: The aim of this study was to evaluate the immunomodulatory effect of atorvastatin given alone and in combined treatment with tacrolimus and mycophenolate mofetil., Study Design: Two patient groups were studied: renal transplant recipients receiving tacrolimus and mycophenolate mofetil therapy, and hypercholesterolemic patients (the control group). Fasting blood samples were taken from participants before and 1 month after atorvastatin treatment was started to study a small battery of biomarkers that are able to reflect the range of the effects of immunosuppressive therapy and atorvastatin., Setting: All patients in the study were enrolled at the Hospital Clinic of Barcelona., Patients: All patients enrolled in the study were candidates for treatment with atorvastatin because of high cholesterol levels. One group consisted of 25 stable renal transplant recipients with low-density lipoprotein (LDL) cholesterol levels above 100 mg/dL after 3 months of therapeutic lifestyle changes, according to the guidelines of the National Kidney Foundation - Kidney Disease Outcomes Quality Initiative. The other group included 25 hypercholesterolemic patients with LDL cholesterol levels above target values for the patients' overall risk, as derived from the National Cholesterol Education Program Adult Treatment Panel III criteria., Intervention: Atorvastatin (Lipitor®) treatment was started at a fixed dose of 20 mg daily., Main Outcome Measure: The studied biomarkers were lymphocyte proliferation, intracellular adenosine triphosphate (ATP) synthesis in CD4+ T cells, intralymphocytary cytokine expression (interleukin [IL]-2, interferon [IFN]-γ), soluble cytokine production (IL-2, IFN-γ, IL-10, IL-17, and transforming growth factor-β) and regulatory T (T(reg)) cells., Results: Atorvastatin proved to be an immunomodulatory agent, significantly decreasing lymphocyte proliferation by 15% (p = 0.001), increasing ATP levels by 16% (p = 0.0004), and showing a trend toward increasing T(reg) cells in hypercholesterolemic patients (p = 0.09). In the renal transplant recipients, atorvastatin therapy did not modify any of the biomarkers of immunosuppression that were studied., Conclusion: Atorvastatin showed immunoregulatory effects on T cells in hypercholesterolemic patients. These effects were absent in renal transplant recipients, suggesting that the beneficial effects of atorvastatin in this patient group do not relate to immunoregulation. Therefore, statin treatment cannot be considered as a means to reduce the dose of immunosuppressive agents.

Since the introduction of combined antiretroviral therapy (cART), solid organ transplantation (SOT) has become a therapeutic option for the HIV-positive population. In contrast with liver and kidney transplantation, only three simultaneous pancreas-kidney transplants (SPKT) have been reported among HIV-infected patients. Herein we have reported the first SPKT in an HIV-infected patient in Spain. The pancreas graft failed at 2 weeks and the patient died at 9 months because of a Pseudomonas aeruginosa infection. The three recipients reported in the literature lived, despite the failure of both the pancreas and kidney grafts in one subject. Despite the poor outcome of our case, HIV-1 infection was controlled after transplantation (stable CD4(+) cells and no AIDS-related events), and the kidney graft functioned with no episodes of rejection. The cART regimen used in the pretransplant period was switched at the time of transplantation to raltegravir and two nucleoside reverse transcriptase inhibitors (NRTI). Raltegravir has no interactions with immunosuppressive drugs. Target plasma levels of tacrolimus were achieved at a dose similar to that used in HIV-negative transplant recipients. The most adequate antiretroviral regimen for HIV-infected SOT recipients has not yet been established; however, one may consider switching protease inhibitors or non-NRTI-based regimens for a raltegravir-based regimen at the time of transplantation., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Clinical data are lacking concerning therapeutic action and systemic exposure of tacrolimus (TAC) and everolimus (EVL) in a combined regimen in renal transplantation., Methods: A prospective randomized phase II pharmacokinetic study was conducted comparing two fixed EVL dosages (0.75 mg two times per day (BID), group A, or 1.5 mg BID, group B) in combination with standard TAC dose. Complete 12-hr pharmacokinetic curves of both drugs were performed at days 4, 14, and 42 posttransplant., Results: A higher TAC Cmin was observed with EVL dose of 0.75 mg BID (TAC 11.1+/-6.4 group A vs. 9.4+/-5.0 ng/mL group B, P=0.03), with equivalent TAC area under the curves (162+/-61 vs. 171+/-75). The exposure to TAC was lower in group B despite higher TAC doses were required to maintain target concentrations (day 14: 9.5 vs. 12.5 mg and day 42: 6 vs. 9 mg, P<0.05). Cmin-TAC/dose and area under the curve-TAC/dose ratios were significantly lower, from day 4 to day 42, in group B. Both groups achieved good graft function and acute rejection rate was similar (20% and 15%, respectively)., Conclusions: We conclude that in adult renal transplant recipients, EVL significantly decreases TAC oral bioavailability in a dose-dependent manner. Doses higher than 1.5 mg BID would be probably needed for TAC-minimization strategies because 3 mg/day is not enough to achieve levels more than 3 ng/mL during the first 2 weeks. Therapeutic drug monitoring is mandatory to adjust the dose and prevent low TAC exposure. This regimen of low EVL exposure plus standard TAC exposure avoids wound healing problems with good efficacy.

Background: Intracellular ATP (iATP) production in CD4(+)-T cells has been proposed as a biomarker for routine personalized monitoring in transplant recipients. The aim of our study was to measure this biomarker in adult renal and liver transplant recipients receiving moderate immunosuppressive treatment (IST) during the maintenance period and to evaluate whether this biomarker can effectively predict clinical status (stability, rejection, or infection) and drug effect., Methods: iATP concentration and trough blood levels of IST were evaluated in 84 adult transplant recipients (50 renal and 34 liver) during the maintenance period. One hundred and fifty healthy donors were also recruited as a control group. In addition, 22 of 34 liver transplant recipients were included in a clinical study in which IST was withdrawn gradually until total elimination., Results: Most of the patients evaluated had iATP levels in the moderate immune response zone during a posttransplantation maintenance period with no relevant clinical events. iATP levels were significantly lower in transplant patients with infection (n=3) than in those free of infection. In the IST withdrawal study, 10 of 22 liver transplant recipients have achieved complete withdrawal and 12 receive 50% of IST. So far, there have been eight rejections once IST began to be withdrawn. None of these patients had iATP in the strong immune response zone (risk of rejection)., Conclusions: iATP seems to be more effective in identifying overimmunosuppressed patients with a high risk of adverse events (IST-safety) than in identifying those with a high risk of rejection (IST-efficacy) and should be used in combination with other biomarkers of immunosuppressive effect to improve the efficacy of IST.

Background: Exposure to mycophenolic acid (MPA), the primary active metabolite of mycophenolate mofetil (MMF), is correlated with therapeutic efficacy of MMF but varies depending on the concomitantly administered immunosuppressive drugs., Methods: A 3-month pharmacokinetic substudy of the prospective, randomized, multicentre, open-label Symphony study was performed. Eighty-three adult renal transplant patients received standard-dose cyclosporine, MMF 2 g/day and corticosteroids, or daclizumab induction, MMF 2 g/day and corticosteroids plus low-dose cyclosporine, low-dose tacrolimus or low-dose sirolimus. The area under the concentration-time curve (AUC(0-12)) of MPA and its metabolites between treatment groups was compared. Pharmacokinetic sampling was performed before MMF administration and at 20, 40, 75 min; 2, 3, 6, 8, 10 and 12 h post-dose on Day 7 and Months 1 and 3., Results: Compared with standard-dose cyclosporine, patients receiving low-dose tacrolimus or low-dose sirolimus had significantly higher AUC(0-12) values for MPA at Day 7 and Month 1 and for free MPA at Day 7, and significantly lower AUC(0-12) values for 7-O-MPA-glucuronide (MPAG) at Month 1 and for acyl-glucuronide at Months 1 and 3 (P < 0.05). AUC(0-12) of MPA and free MPA was significantly greater with low-dose tacrolimus and low-dose sirolimus than with low-dose cyclosporine in the first month (P < 0.05). The ratio of MPA to MPAG exposure was significantly higher in the three low-dose groups than in the standard-dose cyclosporine group (P < 0.05)., Conclusions: Standard- and low-dose cyclosporine reduces the exposure of MPA and free MPA compared to low-dose tacrolimus or low-dose sirolimus in patients given the same dose of MMF.

Introduction: In the current context of a high incidence end-stage kidney disease and a shortage of organs for kidney transplantation, the increasing use of transplants considered to be "borderline" represents a potential source of transplants. Over the last 10 years, some centers have developed a transplantation strategy, which consists of transplanting two borderline kidneys that cannot be proposed separately in a single recipient. The authors report their experience of dual kidney transplant., Materials and Methods: Since 2001, 15 dual kidney transplants have been performed in a single centre according to a local protocol based on the correspondence between the weight of the donor kidney and the recipient's weight, weighted by the number of fibrotic glomeruli observed on the initial biopsy. In this study, the authors analyze the postoperative complications and functional results observed in patients transplanted according to this protocol., Results: Dual kidney transplants represented less than 5% of all transplants performed during the study period concerned, which remained lower than the objectives initially announced by the ABM. The surgical technique was left to the surgeon's discretion. The mean follow-up was 26.3 months. Fourteen of the 15 recipients were alive with a functional graft. Surgical complications were globally more frequent when kidneys were transplanted on the same side (versus transplanted on both sides). Mean serum creatinine was 119.4 mol/l at six months (creatinine clearance according to MDRD formula: 57.3 ml/min per 1.73 m2), 118.8 mol/l at 12 months (creatinine clearance: 55.8) and 132.4 mol/l at 24 months (creatinine clearance: 44.2). One year post-transplant, mean renal function measured by inulin clearance was 55.5 ml/min per 1.73 m2. Four of the 15 patients had experienced an episode of acute rejection and three patients experienced delayed return of transplant function., Conclusion: In view of the results obtained, the authors consider that dual kidney transplant could be a reasonable and effective option for selected patients. Positioning of the transplants in each iliac fossa limited the surgical complication rate.

Introduction: Efficacious prophylaxis of acute rejection episodes (ARE) requires adequate exposure to each component of the immunosuppressive treatment from the first days after renal transplantation. The aim of the present study was to evaluate the correlation between cyclosporine (CsA) and mycophenolic acid (MPA) exposure based upon pharmacokinetics (PK) and pharmacodynamics (PD) and 6-month biopsy-proven acute rejection (BPAR) episodes and chronic allograft nephropathy on 6 month protocol biopsies., Patients and Methods: We examined twenty-two first or second de novo renal transplant recipients treated with steroids, Sandimmune Neoral (CsA) and Myfortic (720 mg twice a day). PK (C0, C2, and AUC(0-12h)) for both drugs were determined on days 7, 90, and 180. Calcineurin activity, interleukin-2 and interferon-gamma synthesis as well as %CEM were tested at days 7 and 180. CsA dosages were adjusted by C2 monitoring. Collected data included: BPAR during the first 6 months and Banff histological parameters on the 6-month protocol biopsies., Results: Eighteen of 22 patients completed 1 year follow-up under treatment. The 6-month BPAR was 18% (4/22). Six-month protocol biopsies in 50% of 14 recipients showed chronic allograft nephropathy 1. At day 7, CsA C2 and AUC median values were 138 ng/mL and 6377 ng x h/mL, while C0 MPA was 1.0 microg/mL and AUC = 23.9 microg x h/mL. CsA C2 medians at 3 and 6 months were 1468 and 1720 ng/mL. MPA-AUC reached therapeutic targets at 3 months (32.3 microg x h/mL) and was 48.3 microg x h/mL at 6 months. Patients with BPAR showed lower CsA AUC (P = .06) and a significantly lower baseline inhibition of calcineurin activity (P < .005) than patients with no BPAR. An increase in mesangial matrix in 6-month protocol biopsies correlated with higher CsA C2 (P = .01). All biomarkers evaluated were significantly inhibited compared with the standard population., Conclusions: When Myfortic is administered together with CsA, it is advisable to begin with higher doses (720 mg x 3 days) to reach adequate PK targets and improve BPAR rates. To prevent chronic allograft nephropathy, lower CsA C2 should be targeted from 3 months.

Background: Sirolimus is an agent with lymphocyte-specific features similar to those of calcineurin inhibitors but with a different mechanism of action and safety profile. To optimize the use of sirolimus-based immunosuppression, further investigation of appropriate pharmacokinetic (sirolimus exposure) and pharmacodynamic (sirolimus T-cell immunomodulator effect) monitoring is required to determine personalized target concentrations., Aim: The main objective of the study was to evaluate the feasibility and reproducibility of combined pharmacokinetic and pharmacodynamic monitoring and to apply biomarkers of immunosuppression in stable kidney transplant recipients receiving sirolimus monotherapy., Methods: Fourteen renal transplant patients treated with sirolimus monotherapy (median 2 years) were included in this study. Pharmacokinetic and pharmacodynamic parameters were evaluated in each patient three times: at inclusion in the study (day 1), then again at 3 and 6 months., Results: The median sirolimus concentration was 11.5 ng/mL. CD4+ T-cell adenosine triphosphate (ATP) concentrations (150 ng/mL) and interleukin (IL)-10 production (50.9 ng/mL) were significantly lower in treated patients than in healthy controls (n = 95) [301 ng/mL; 278 ng/mL, respectively]. Median inhibition of T-cell proliferation was 60% (31-96%) in treated patients. Interferon-gamma and transforming growth factor-beta production was found to be similar to those in the healthy controls. Our results suggest an association between low ATP and IL-10 concentrations and the presence of infection., Conclusions: The sequential measurement of these biomarkers in stable renal transplant recipients treated with monotherapy could be useful to evaluate the biological effect of sirolimus in each patient and to establish personalized therapy taking into account the individual response to the drug.

Mycophenolate mofetil (MMF) is an immunosuppressant that is widely used for prophylaxis of rejection in solid organ transplantation. In this study, we examined the effect of renal insufficiency on the pharmacokinetics of MMF, particularly on the free fraction of drug in renal transplant patients. Our study was performed on 10 patients with severe renal insufficiency (creatinine clearance [CrCl] <30 mL/min), and 10 control patients with preserved renal function (CrCl >90 mL/min). All the patients had received a cadaveric donor graft at least 1 year prior and were clinically stable under treatment with MMF and cyclosporine. For each patient, we determined 12-hour areas under the curve (AUC(0-12 h)) for the metabolites: mycophenolic acid (MPA), 7-O-mycophenolic acid glucuronide (MPAG), and the free non-protein-bound fraction of MPA (f-MPA). The two groups were matched for age, sex, and MMF dose. Mean AUC(0-12 h) values for MPA were similar in both groups. The renal insufficiency group showed a significantly increased AUC(0-12 h) for MPAG (1550 +/- 392 vs 3527 +/- 1130 microg.h/mL, P < .001) and increased trough and AUC(0-12 h) values for f-MPA (0.023 +/- 0.02 vs 0.094 +/- 0.07 microg/mL, P = .003, and 0.87 +/- 0.3 vs 1.52 +/- 0.8 microg . h/mL, P = .016, respectively). We proposed that these differences should be taken into account when deciding upon the dose of this drug for the subset of patients with impaired transplant function.

One strategy to minimize nephrotoxicity in maintenance immunosuppression in renal transplantation is reduction of cyclosporine (CsA) with addition of mycophenolate mofetil (MMF). This approach seems safe, but concern exists about whether it yields adequate immunosuppression in the long term. Thus, we investigated the pharmacodynamic response to CsA in stable renal allografts treated with standard CsA (n = 17, CsA-C0h > or = 125 ng/mL) and low CsA plus MMF (n = 18 CsA-C0h <100 ng/mL). Patients treated with MMF without CsA (n = 13) and healthy subjects (n = 7) were used as controls. We observed that inhibition of calcineurin (CN) activity in peripheral blood mononuclear cells (PBMC), as well as interleukin (IL)-2 and interferon (IFN)-gamma production were similar in Standard-CsA and Low-CsA+MMF groups. Moreover, addition of MMF to a low CsA dose regime improved the correlation between CsA-C2h and both CN activity and IL-2 production. Thus, our results suggest that MMF could be synergistic with the pharmacodynamic effect of low CsA in maintenance immunosuppression.

We performed a randomized trial to compare two regimens of low-risk kidney allograft recipients in the first year after transplantation. Both regimens initially included sirolimus, tacrolimus and steroids; one with long-term maintenance with these drugs vs. tacrolimus withdrawal. Group I: sirolimus levels of 4-8 ng/mL, plus tacrolimus 8-12 ng/mL for 3 months, and 5-10 ng/mL after month 3. Group II: sirolimus concentration of 8-16 ng/mL, plus tacrolimus 3-8 ng/mL with tacrolimus elimination from month 3 onwards. Owing to difficulties in achieving target levels, the protocol was amended to increase the doses. Eighty-seven patients were recruited. In the intention-to-treat analysis, glomerular filtration rate (GFR) at 12 months, adjusted to zero for graft loss, was similar in both groups (58.8 and 59.9 mL/min). Analysis of patients remaining on protocol showed that GFR was higher in group II only in the patients postamendment (58.4 and 72.9 mL/min, p = 0.03). Rates of biopsy-confirmed rejection (BCAR) were 9.3% and 22.7% in groups I and II, respectively (p = NS). After amendment, BCAR rates were 10.3% and 11.1% (p = NS). Diastolic blood pressure was significantly lower in patients who eliminated tacrolimus (80.4 vs. 75.6 mmHg) (p = 0.03). Combining sirolimus and tacrolimus with adequate loading doses was associated with a low incidence of BCAR, and allowed tacrolimus elimination in a high proportion of patients, which may be followed by amelioration in renal function and blood pressure.

Background: There is a correlation between cyclosporine (CsA) pharmacokinetics (PK) and pharmacodynamics (PD), especially 2 hours after drug administration., Aim: To evaluate the relationship between CsA PK and PD profiles in two groups of stable renal transplant patients treated with CsA alone or CsA plus mycophenolate mofetil (CsA+MMF), so as to define the best target for C2 and clarify the impact of concomitant immunosuppression., Methods: Thirty-eight stable renal transplant recipients were treated with CsA (n=20) or CsA+MMF (n=18). Twelve nontreated normal healthy controls (NHC) were also included. Calcineurin activity (CNa), IL-2 production, and CsA levels were measured at 0 and 2 hours postdose., Results: There were no significant differences in median CsA C2 values and CNa between the CsA alone and the CsA+MMF groups (388 microg/L and 497.5 microg/L and CNa 2h; 3.92% alkaline phosphatase [AP]; 3.94% AP, respectively). In vitro production of IL-2 was significantly lower in the CsA+MMF group than in the CsA group (median IL-2 2h: 280.52 ng/L, 169.48 ng/L, P<.001). The correlations (r) between C2 and CNa 2h were: CsA r=0.74; CsA+MMF r=0.84 (P<.001 in both cases)., Conclusions: In stable renal transplant patients, median CsA C2 values below 500 microg/L were associated with inhibition of CNa and IL-2 synthesis. CNa and IL-2 production may be good biological markers of CsA immunosuppression. The measurement of CNa depends mainly on CsA concentration, whereas in vitro IL-2 production reflects the effect of both CsA and MMF. Further studies are necessary to define the optimal C2 target concentration and the possible impact of concomitant immunosuppression.

Background: Graft survival depends on adequate immunosuppression. To evaluate the effect on the immune system of immunosuppressive therapies using calcineurin inhibitors (CNIs), several pharmacodynamic indices have been proposed to complement pharmacokinetic data. In this preliminary study we compared some of these parameters during combined immunosuppressant therapies., Methods: We treated 65 stable renal transplant recipients with cyclosporin A (CsA; n = 16), tacrolimus (TRL; n = 10); CsA + mycophenolate mofetil (MMF; n = 14); TRL + MMF (n = 13), and MMF (n = 12). Twelve nontreated healthy controls were also included. Calcineurin activity (CNA) in peripheral blood mononuclear cells was measured using (32)P-labeled peptide. Interleukin-2 (IL-2) and interferon-gamma production in phytohemagglutinin-activated whole blood were measured at 0 and 2 h postdose. The areas under the curves, c(min), c(max), and concentration at 2 h (c(2 h)) were also measured., Results: We found no differences in CNA between groups receiving CNIs alone or combined with MMF [median (25th-75th percentiles)]: CsA(2 h), 3.87 (3.00-6.85)% alkaline phosphatase (AP); CsA+MMF(2 h), 3.90 (1.78-5.19)% AP; TRL(2 h), 5.68 (3.02-16.00)% AP; TRL+MMF(2 h), 11.80 (4.05-14.63)% AP. In vitro IL-2 production was significantly lower in the groups receiving combined therapy than in groups receiving CNIs alone [median (25th-75th percentiles)]: CsA(2 h), 276.52 (190.41-385.25) ng/L; CsA+MMF(2 h), 166.48 (81.06-377.01) ng/L (P <0.001); TRL(2 h), 249.34 (127.48-363.50) ng/L; TRL+ MMF(2 h), 122.13 (51.02-180.00) ng/L (P <0.001). The correlations (r) between c(2 h) and CNA 2 h postdose were as follows: CsA, r = -0.74; CsA+MMF, r = -0.84; TRL, r = -0.70; TRL+ MMF, r = -0.70 (P <0.001 in all cases)., Conclusions: The measurement of CNA may be of help in following the effect on the immune system of CNI treatments, even in combined therapies, but does not reflect the additional effect of MMF. In contrast, IL-2 in vitro production reflects the effect of both MMF and CNIs.

We investigated the relationship between the pharmacokinetics and pharmacodynamics of cyclosporine in 15 stable renal transplant patients in order to define an effective and safe therapeutic range. The area under the curve of the first 4 h (AUC(0-4)), trough (C(0)) and 2 h (C(2)) levels showed median values of 1655 ng x h/ml, 114 ng/ml and 384 ng/ml, respectively. C(2) showed a strong correlation with AUC(0-4) (r=0.942, p=0.0005). C(0) correlated poorly with C(2) and AUC(0-4) (r=0.596, p=0.019 and r=0.538, p=0.031, respectively). Calcineurine activity (CNa) was 6.74% at 0 h and 3.90% at 2 h, representing significant reductions (82% and 89.6%, respectively; p<0.0005) compared with normal healthy controls (median basal value 37.4%). IL-2 production was 349 pg/ml at 0 h and 276.35 pg/ml at 2 h; both results were significantly lower (reductions of 44.5% and 56.1%, respectively; p=0.04 and 0.005) than the controls of 629.1 pg/ml. IFN-gamma at 2 h post-dose (8.16 UI/ml) was significantly lower (72.1% reduction, p=0.005) than in controls (29.2 UI/ml). There was a good correlation between CNa and IFN-gamma production, particularly at 2 h post-dose (r=0.537, p=0.007), and a fair correlation between CNa and IL-2 concentration (p=0.030, r=0.426). C(2) showed an inverse significant correlation with CNa (Spearman's p=0.000, r=-0.753), IL-2 (p=0.000, r=-0.725) and IFN-gamma (p=0.000, r=-0.701) production. In treated patients, the Emax inhibitory sigmoidal model showed that a C(2) of 279 ng/ml was needed to achieve a 50% inhibition (EC50) of IL-2 and INF-gamma production. The results demonstrated a significant inhibition of calcineurin activity and IL-2 and IFN-gamma production in patients receiving cyclosporine monotherapy compared to healthy controls. A median C(2) value of 384 ng/ml was associated with a good degree of inhibition of CNa and IL-2 and IFN-gamma synthesis, and the lack of rejection episodes and relevant toxicity.

Purpose: We assessed the cumulative incidence of transplant nephrectomy in our population of patients who underwent transplantation and those in whom the transplant failed due to immunological causes. Transplant nephrectomy indications, morbidity and mortality were analyzed to establish the most appropriate time for graft removal., Materials and Methods: We included all patients who underwent transplantation and graft removal at our institution from January 1, 1970 through January 1, 2000. We estimated the noncumulative incidence of transplant nephrectomy, morbidity and mortality. The cumulative incidence of transplant nephrectomy was estimated by Kaplan-Meier curves., Results: Of the 631 renal transplants performed in 598 patients we studied a total of 91 transplant nephrectomies in 85 patients. The cumulative incidence of transplant nephrectomy 15 years after the date of transplantation was 25% (95% CI 14 to 40). The cumulative incidence of transplant nephrectomy at 10 years after the date of return to dialysis was 74% (95% CI 49 to 90). The main indication for transplant nephrectomy was graft related complications associated with chronic rejection in 58.2% of cases. The morbidity rate was 48.3% (95% CI 37.7 to 59). Hemorrhagic events were the chief complication. In 7 patients there was a total of 10 reoperations (10.9%, 95% CI 5.3 to 19.2). The mortality rate was 7% (95% CI 2.6 to 14.7). These patients died of sepsis. Urgent transplant nephrectomies had statistically higher morbidity and mortality (p <0.01 and 0.002, respectively)., Conclusions: Most transplant nephrectomies were performed within 2 years of the transplant date and almost half were done within year 1 after the return to dialysis. The advent of cyclosporine significantly decreased the transplant nephrectomy rate at the expense of fewer graft failures but not at the expense of a lower amount of graft related symptoms after patients returned to dialysis. Bleeding was the leading cause of morbidity and infection was the main cause of mortality. Considering the high morbidity and mortality of transplant nephrectomy, and the potential benefits of leaving nonfunctioning grafts in situ our current policy is to remove the graft only in cases of failed transplants that cause intractable complications.

Suboptimal doses of mycophenolate mofetil (MMF) are frequently employed in renal transplant (Tx) patients, with drug-related side effects or low weight. The aim of this study was to compare the mycophenolic acid (MPA) pharmacokinetic profile and its pharmacodynamic effect on patients receiving either standard (2 g) or low (1.5 g or 1 g) MMF doses, in order to evaluate the therapeutic efficacy of such low doses in inhibiting IMPDH activity. Twenty-seven stable renal Tx recipients aged 18-65 years, with a post-Tx follow-up of 38.5 +/- 44.8 months (6-166 months), receiving 1 g (n = 10), 0.75 g (n = 7) and 0.5 g (n = 10) MMF twice a day in association with cyclosporine and prednisone, were included. The control group was made up of untreated healthy volunteers (n = 5). Plasma concentrations of MPA were analyzed by reverse-phase HPLC. IMPDH activity was determined in lymphocytes by the measurement of 3H release from [2,8-(3)H] hypoxantine. The mean value of areas under the concentration-time curves (AUC(0-12)) of MPA throughout the 12-h dosing interval in patients treated with 2 g was higher than the corresponding data in patients receiving 1.5 g or 1 g bid, but no statistical differences were observed between the three groups. There was no correlation between MPA-AUC(0-12) values and MMF dose (expressed in g/day or g/kg per day). Predose MPA concentrations correlated only weakly with the respective MPA-AUC(0-12) values (r2 from 0.385 to 0.655), whereas an acceptable correlation was observed between MPA Cmax and MPA-AUC(0-12) (r2 from 0.626 to 0.759) in 2 g, 1.5 g, and 1 g MMF groups. An inverse relationship between MPA concentrations and IMPDH activity was observed. In general, the maximum MPA concentration was achieved from 1 h to 2 h after dosing, and the maximum inhibition of IMPDH was also from 1 h to 2 h after dosing. The evaluation of IMPDH activity demonstrated that there was a significant statistical difference between samples from 0 to 1 h (P = 0.008) and 0 to 2 h (P = 0.04). In conclusion, concentration-time profiles of renal transplant recipients administered 0.75 g and 0.5 g twice a day are slightly lower than those from the 2 g group, but nor significantly. On the other hand, inhibition of IMPDH activity was comparable in the three groups, indicating considerable interindividual pharmacodynamic variability. Pharmacodynamic monitoring of the degree of immunosuppression and its correlation with MPA plasma concentrations will be assessed further in future studies.

Tacrolimus is a potent immunosuppressive drug successfully used for baseline and rescue immunosuppression in patients after liver and kidney transplantation. Data from several clinical trials have demonstrated the efficacy of tacrolimus in the prevention of allograft rejection, even at lower concentrations in the therapeutic range (5-15 microg/L). In fact, some patients with tacrolimus levels at less than 5 microg/L have excellent hepatic or kidney function. The limit of detection of the IMx Tacrolimus I assay (TAC I; Abbott Laboratories, IL) is only 5 microg/L and that of the lower tacrolimus calibrator is 10 microg/L. The second-generation assay uses the same monoclonal antibody and the same IMx technology but offers improved sensitivity, with a dynamic range from 0 microg/L to 30 microg/L (lower calibrator, 3 microg/L). The aim of this multicenter study was to evaluate the new IMx Tacrolimus II assay (TAC II) by assessing its precision, sensitivity, performance, and correlation degree relative to the IMx TAC I assay. The study was performed at three centers in Spain. The within-run coefficients of variation (CVs) obtained for the new assay, using each of the trilevel controls in replicates of 20 during 3 consecutive days, were 8.06%, 4.38% and 5.09% at 5 microg/L, 11 microg/L, and 22 microg/L, respectively. The corresponding between-run CVs obtained measuring each of the three controls in duplicate on 10 consecutive days were 9.54%, 6.38% and 5.75%. The limit of detection, with 97.5% confidence, was 1.22 microg/L. TAC II results (Y) were compared with those from the original TAC I assay (X) analyzing 293 whole blood samples from liver (n=145) and kidney (n=148) transplant recipients. The correlation study with patient samples (using the Passing-Bablock method) was y=1.056, x + 0.017, r=0.927. No statistically significant differences were observed between assays (TAC I versus TAC II) in the mean values obtained for total patients (9.89+/-5.42 microg/L versus 10.49+/-5.63 microg/L), liver patients (9.16+/-4.79 microg/L versus 10.00+/-5.20 microg/L), and kidney patients (10.62+/-5.87 micro g/L versus 10.98+/-5.99 microg/L). The new IMx TAC II assay demonstrated the same precision and accuracy that characterized the original assay but showed improved sensitivity to the demands of tacrolimus monitoring in the lower therapeutic range of drug concentrations.

Background In the developed world, kidney transplantation ( KT) in patients with human immunodeficiency virus ( HIV) infection is well established. Developing countries concentrate 90% of the people living with HIV, but their experience is underreported. Regional differences may affect outcomes. Objectives We compared the 3-year outcomes of patients with HIV infection receiving a KT in two different countries, in terms of incomes and development. Methods This was an observational, retrospective, double-center study, including all HIV-infected patients >18 years old undergoing KT. Results Between 2005 and 2015, 54 KTs were performed (39 in a Brazilian center, and 15 in a Spanish center). Brazilians had less hepatitis C virus co-infection (5% vs 27%, P=.024). Median cold ischemia time was higher in Brazil (25 vs 18 hours, P=.001). Biopsy-proven acute rejection ( AR) was higher in Brazil (33% vs 13%, P=.187), as were the number of AR episodes (22 vs 4, P=.063). Patient survival at 3 years was 91.3% in Brazil and 100% in Spain; P=.663. All three cases of death in Brazil were a result of bacterial infections within the first year post transplant. At 3 years, survival free from immunosuppressive changes was lower in Brazil (56% vs 90.9%, P=.036). Raltegravir-based treatment to avoid interaction with calcineurin inhibitor was more prevalent in Spain (80% vs 3%; P<.001). HIV infection remained under control in all patients, with undetectable viral load and no opportunistic infections. Conclusion Important regional differences exist in the demographics and management of immunosuppression and antiretroviral therapy. These details may influence AR and infectious complications. Non- AIDS infections leading to early mortality in Brazil deserve special attention. [ABSTRACT FROM AUTHOR]