Monitoring of gene expression in tacrolimus-treated de novo renal allograft recipients facilitates individualized immunosuppression: Results of the IMAGEN study.

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.

Multimorbidity and medication complexity: New challenges in heart transplantation.

INTRODUCTION: Multimorbidity and therapeutic complexity are a recognized problem in the heart transplant (HTx) population. However, little is known about how best to quantify this complexity or the strategies that could reduce its burden. METHODS: This single-center, observational study included adult heart transplant recipients (HTxR) >1.5 years from transplant. We assessed multimorbidity (>2 comorbidities) and the patient-level Medication Regimen Complexity Index Spanish version (pMRCI-S) score. We also analyzed the independent predictors of pMRCI-S and the impact of the index score on specific clinical variables. RESULTS: We included 135 chronic-stage HTxR. Comorbidities significantly increased after HTx (6 ± 3 vs 2 ± 2, P-value < .001). Patients took 12 ± 3 chronic drugs/d, 58% of them to treat comorbidities. The mean total pMRCI-S score was 42 ± 11, higher than in several other chronic diseases. The medication category drugs to treat comorbidities predicted a higher total pMRCI-S score (OR = 3.12, 95% CI 2.8-3.43, P-value < .001). Therapeutic complexity after HTx had an impact on solid malignancies (OR = 1.1, 95% CI 1.02-1.18, P-value = .02) and renal function (OR=-0.81, 95% CI -1.21-(-0.42), P-value < .001). CONCLUSIONS: The multimorbidity and pMRCI-S scores obtained in HTx population were worrisomely high. The pMRCI score is a sensitive method that allows identification of the factors determining therapeutic complexity after HTx and selection of strategies to reduce pMRCI-S values.

Assessment of Tacrolimus Neurotoxicity Measured by Retinal OCT.

BACKGROUND: Neurotoxicity secondary to anticalcineurinics is a prevalent side effect in transplant recipients. Optical coherence tomography (OCT) scans the central nervous system by direct access to the retina. OCT assesses central nervous system involvement by measuring the thickness of the retinal layers, especially the ganglion cell layer (GCL). The retinal scan divides the scanned area into affected and unaffected segments, which can be quantified for each eye. The aim of this study was to determine retinal GCL thickness by means of OCT, analyzing the proportion of affected segments in individuals exposed to tacrolimus compared with a control group. MATERIALS AND METHODS: We evaluated 20 renal transplant recipients exposed to tacrolimus for ≥6 months. The number of affected segments in the GCL of the retina was quantified by OCT. The control group was drawn from the general population attending routine ophthalmologic checkups. RESULTS: Patients exposed to tacrolimus had a pathologic examination in 50% of cases compared with 20% in the control group (P < .044). Furthermore, among patients with an exposure time to tacrolimus >5 years, the examination was pathologic in 80% (P < .005). Linear regression analysis showed the presence of GCL segments with decreased thickness to be associated with the duration of exposure to tacrolimus (P = .036) and the time in dialysis before kidney transplant (P = .030). CONCLUSION: Although this is a preliminary study, OCT scanning could serve to detect the neurotoxic effect of tacrolimus on the retinal GCL and central nervous system in renal transplant recipients.