Serum Tacrolimus Levels Research Articles

The Efficacy of Intensive Monitoring of Serum Tacrolimus Level Post Itraconazole Cessation in Preventing Rejection after Heart Transplant

Purpose Prior research in our institution has demonstrated that cessation of itraconazole fungal prophylaxis in the heart transplant population results in marked individual variations of serum tacrolimus levels despite initial dose escalation, leaving a proportion of individuals at increased risk of acute rejection due to subtherapeutic serum tacrolimus levels. Here, we report the efficacy of intensive monitoring of tacrolimus levels post itraconazole cessation in preventing acute rejection. Methods This retrospective, single centre analysis included all heart transplant patients at our institution from January 2017 to March 2018 who underwent itraconazole cessation at 3-8 months post-transplant whilst receiving a stable regimen of tacrolimus-based immunosuppression. Patients were classified into the intensive monitoring group if tacrolimus levels and dose titration were performed at least once a week for 6 weeks post cessation of itraconazole; or the control group, where tacrolimus levels measurements and dose titration were performed less frequently on clinic follow-ups only (up to monthly). Primary outcome included clinically significant rejection defined as biopsy proven ISHLT 2R rejection or left ventricular dysfunction on echocardiography requiring glucocorticoid pulsing, and infections requiring hospitalisation. Statistical calculations were performed using Fisher's exact test. Results A total of 40 patients were included in this study, with 18 patients in the control group and 23 patients in the intensive group (one patient underwent itraconazole cessation twice). Within 2 months of itraconazole cessation, 7 patients in the control group and 2 patients in the intensive group had clinically significant rejection (P = 0.028). In the same timeframe, 0 patients in the control group and 5 patients in the intensive group developed bacterial infections requiring hospitalisation (P = 0.056). No fungal infection had been observed in any patient post itraconazole cessation. Conclusion Intensive monitoring of tacrolimus levels post cessation of itraconazole on a weekly basis is effective in preventing clinically significant rejection, although there is a non-significant trend towards an increased risk in non-fungal infections.

Evaluation of Tacrolimus Levels and Risk of Acute Graft-Versus-Host Disease in Allogeneic Hematopoietic Stem Cell Transplant

Background Achieving therapeutic tacrolimus blood concentrations is crucial for decreasing the risk of developing acute graft-versus-host-disease (aGvHD) in allogeneic hematopoietic stem cell transplant (aHSCT) patients. Studies have suggested that tacrolimus levels in the first 1-2 weeks may affect the risk of aGVHD but therapeutic goals are not well established. This study explores tacrolimus levels and risk of GVHD during that time frame. Methods This study is a retrospective cohort single center chart review performed with 348 consecutive adult patients who received an aHSCT and were followed for at least 100 days post-transplant for aGvHD development. Patients that received a transplant from a cord blood or participated in aGvHD prophylaxis clinical trials were excluded. The primary endpoint was aGvHD grades II - IV incidence. Serum tacrolimus levels were evaluated from days -1 to +100 post-transplant. Serum tacrolimus levels were divided into time intervals of days 0 - 7 and days 0 - 14 post-transplant. Receiver operator characteristic curves (ROC) were used to quantify serum tacrolimus levels as predictors of aGvHD grades II-IV. Using the ROC analysis and Youden's Index, optimal cutpoints in the tacrolimus level distribution for the individual time intervals were assessed. From this, patients were analyzed based on whether they achieved mean tacrolimus serum levels below the cutpoint (low group) or if they achieved a mean tacrolimus level above the cutpoint (high group). Results Within the URD group during days 0-7 post-transplant, the low group and high group demonstrated a mean tacrolimus level of 11.3 and 14.5 respectively, with significantly less aGVHD observed in the high group (38% vs 57.2%, p = 0.021). In respect to days 0-14, the low group and high group demonstrated a mean tacrolimus level of 10.4 and 13 respectively, again with significantly less aGVHD in the high group (35.6% vs 57.3%, p = 0.012). Within the RD group during days 0-7 post-transplant, the low group and high group demonstrated a mean tacrolimus level of 10.9 and 13.7 respectively, also with significantly less aGVHD in the high group (21.7% vs 38.7%, p = 0.042). In respect to days 0-14, the low and high group demonstrated a mean tacrolimus level of 10.2 and 13.1 respectively. However, there was not a significant difference in aGVHD (25.7% vs 35.9%, p = 0.272). Conclusion Higher levels of tacrolimus in the first 2 weeks after allogeneic stem cell transplant appear to correlate with a lower incidence of grade II-IV aGVHD. Higher levels in both weeks 1 and 2 were associated with a 37% reduction in the URD group while higher levels in week 1 were associated with a 44% in the RD group. While larger studies would help to clarify more specific ranges, this data suggests that target tacrolimus levels should be 14-15 ng/ml in the first 2 weeks post allogeneic transplant to decrease rates of grade II-IV aGVHD.

Post-Renal Transplant Metabolic Acidosis: A Neglected Entity.

Metabolic acidosis is a prevalent yet overlooked entity among renal transplant recipients (RTRs) and incurs adverse effects on graft function. Although graft dysfunction and calcineurin inhibitor usage have been linked with renal tubular acidosis (RTA), there is no Indian data on prevalence or risk factors of post-transplant acidosis. A cross-sectional study was conducted on 106 adult RTRs, with a transplant duration of >6 months and an estimated glomerular filtration rate (GFR) >40 ml/min/1.73 m2. Acidosis was diagnosed on basis of plasma bicarbonate and arterial pH. Serum and urine electrolytes with anion gap were determined to diagnose and type RTA. Acidosis was diagnosed in 44 of 106 patients (41.5%) with 23 (52.27%) having severe acidosis. Type I RTA was the most common subtype (52.5%) followed by type IV (30.9%) and type II RTA (7.5%). The correlation between estimated glomerular filtration rate and acidosis was minimally linear (r = 0.1088), with multivariate analysis revealing previous acute rejection episodes, current serum tacrolimus levels, cotrimoxazole usage and intake of animal proteins to be independent risk factors. The serum albumin levels were low in the acidosis group and showed linear correlation with bicarbonate levels (r = 0.298). There is a high prevalence of metabolic acidosis in RTRs with type I RTA being most common subtype. Screening of RTRs on a regular basis is a feasible approach for early diagnosis and intervention. However, prospective studies are needed to demonstrate the effect of acidosis on graft survival and benefit of bicarbonate therapy in RTRs.

Low early posttransplant serum tacrolimus levels are associated with poor patient survival in lung transplant patients.

BACKGROUND:Low-dose tacrolimus-based immunosuppression is a standard therapy in kidney and liver transplantation; however, the optimal therapeutic level of tacrolimus has not been established in lung transplantation. We aimed to identify the tacrolimus level associated with better outcomes in lung transplant patients.METHODS:This retrospective study included patients who underwent lung transplantation at Seoul National University Hospital between 2006 and 2016. Kaplan–Meier survival analysis and Cox regression were performed according to tacrolimus levels at several time-points within 1-year posttransplantation.RESULTS:A total of 43 patients received bilateral lung transplantation. The median age was 53 years and the median follow-up was 20.5 months. Overall and 1-year patient survival rates were 55.8% and 74.4%, respectively. Infection was the most common cause of death (78.9%). Chronic lung allograft dysfunction was observed in 16.3%. A tacrolimus level <9 ng/ml at 1 month was associated with lower rejection-free survival (P = 0.009). A time-averaged tacrolimus level <10 ng/ml within 1 month posttransplantation was an independent risk factor for poor patient survival (hazard ratio: 4.904; 95% confidence interval: 1.930–12.459; P= 0.001). Furthermore, higher tacrolimus levels did not increase infectious complications.CONCLUSIONS:These finding suggest that tacrolimus levels ≥10 ng/ml within 1 month after lung transplantation appear to be associated with better patient survival.

Clinical use of an immune monitoring panel in liver transplant recipients: A prospective, observational study

Immunosuppressive therapy greatly contributed to making liver transplantation the standard treatment for end-stage liver diseases. However, it remains difficult to predict and measure the efficacy of pharmacological immunosuppression. Therefore, we used a panel of standardized, commonly available, biomarkers with the aim to describe their changes in the first 3 weeks after the transplant procedure and assess if they may help therapeutic drug monitoring in better tailoring the dose of the immunosuppressive drugs.We prospectively studied 72 consecutive patients from the day of liver transplant (post-operative day #0) until the post-operative day #21. Leukocytes, neutrophils, lymphocytes (CD4+, CD8+), natural killer cells, monocytes, immunoglobulins and tacrolimus serum levels were measured on peripheral blood (at day 0, 3, 7, 14, 21 after surgery). Patients who developed infections showed significantly higher CD64+ monocytes on post operative day #7. IgG levels were lower on post operative day #3 among patients who later developed infections. We also found that a sharp decrease in IgA from post operative day #0 to 3 (−226 mg/dL in the ROC curve analysis) strongly correlates with the onset of infections among HCV− patients. No specific markers of rejection emerged from the tested panel of markers. Our results show that some early changes in peripheral blood white cells and immunoglobulins may predict the onset of infections and may be useful in modulating the immunosuppressive therapy. However, a panel of commonly available, standardized biomarkers do not support in improving therapeutic drug monitoring ability to individualize immunosuppressive drugs dosing.

Early Clinical Predictors of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Myeloablative Stem Cell Transplantation

Hepatic veno-occlusive disease (VOD), or sinusoidal obstruction syndrome (SOS), is a serious complication of hematopoietic stem cell transplantation (HSCT) with mortality in its severe form exceeding 80%. Although the incidence of VOD/SOS has fallen with contemporary transplantation practices, the increasing use of inotuzumab, the return of gemtuzumab, and the popularity of pharmacokinetic-guided high-dose busulfan may impact incidence. Early intervention with defibrotide improves survival, but prompt diagnosis can be difficult. We aimed to identify clinical parameters that could aid in early detection of VOD/SOS in a large, retrospective, cohort study. Of the 1823 adult patients who underwent myeloablative HSCT between 1996 and 2015 in our center, 205 (11%) developed VOD/SOS, with a median onset of day +14. We compared parameters in the 7 days preceding VOD/SOS onset for cases to 447 randomly selected control subjects in an analogous time frame to determine those with predictive value. Between 7 days before and the day of diagnosis, VOD/SOS patients had higher serum creatinine levels and were more likely to develop acute kidney injury (61% versus 33%, P < .0001), more commonly experienced refractoriness to platelet transfusion (48% versus 24%, P < .0001), and had higher trough serum tacrolimus levels (7 days before VOD/SOS onset: median 8.8 versus 7.3, P = .0002; day of onset: median 9.3 versus 7.2, P < .0001) compared with control subjects. Acute renal dysfunction, platelet refractoriness, and elevated or abnormal tacrolimus levels are dynamic clinical markers that should alert clinicians to the development of VOD/SOS before the presence of classical diagnostic criteria. Using these clinical features to recognize VOD/SOS earlier in its clinical course could promote earlier treatment and lead to improved outcomes of this potentially serious complication.

Cyclosporine Versus Tacrolimus: Which Calcineurin Inhibitor Has Influence on Cytomegalovirus Infection in Cardiac Transplantation?

IntroductionCytomegalovirus (CMV) infection is a relevant cause of morbidity and mortality in transplantation patients. Its major incidence is in the first year and viral replication is related to acute rejection, survival reduction, and graft vascular disease. ObjectiveThis study aims to evaluate retrospectively whether a high dose of calcineurin inhibitors correlates with CMV-positive polymerase chain reaction (PCR), need for treatment, and death in cardiac transplantation patients. MethodsThis is a case-control study including patients who underwent transplantation between 2014 and 2016. They were separated into two groups (positive or negative PCR) and evaluated for dosage serum levels of cyclosporine and tacrolimus. Patients were classified with adequate dose of immunosuppressant or high dose, and was analyzed that there was any association with those and positive CMV-PCR, need for treatment for CMV, and deaths. For statistical analysis, the Student t test was used for the quantitative variables and the Fisher’s Exact Test for qualitative variables. To show CMV-free survival, the Kaplan-Meier curve was used. The level of significance was set at 5%. ResultsCMV-positive PCR in the sample was 72% for a total of 50 individuals. Positive PCR correlated with a high dose of calcineurin inhibitors in a statistically significant way (P = .002), as did a high dose of cyclosporine (P = .004); however, a high dose of tacrolimus had no such association (P = .17). When a high dose was assessed with a need for treatment, the chance of needing treatment increased more than eight times (P = .024; odds ratio = 8.25; 95% CI = 1.33 to 51.26), which was different from results found with high-dose tacrolimus (P = 1.0). However, no significant association was found in relation to deaths. ConclusionsTacrolimus serum levels showed no association with CMV-PCR, which was different from serum cyclosporine, which showed association with CMV-PCR positivity, increasing the need for treatment approximately 8-fold, without association with death.

Polymorphisms of CYP3A5 Affect Serum Levels and Maintenance Doses of Tacrolimus in Myasthenia Gravis Patients

Objectives: To evaluate the influences of polymorphisms of cytochrome P450 (CYP) 3A5 (A6986G, CYP3A5*3) on serum levels of tacrolimus and cyclosporine (CyA) in patients with myasthenia gravis (MG). Methods: This study included 74 MG patients treated with tacrolimus (n=65) or CyA (n=22). Genomic DNA was extracted and amplified with specific primers, and CYP3A5 alleles were confirmed by direct sequencing of PCR products on an automated AB13100 DNA sequencer. We measured blood trough level (C0) of tacrolimus and CyA. Clinical disabilities were evaluated with the MG-ADL scale. Results: For tacrolimus C0, the CYP3A5*3/*3 genotype was associated with higher levels than the CYP3A5*1/*3 genotypes (7.1 ng/ml versus 2.9 ng/ml; P<0.0001) and CYP3A*1/*1 (7.1 ng/ml versus 1.3 ng/ml; P<0.0004). The improvement in the mean MG-ADL scores tended to be better in MG patients with the CYP3A5*3/*3 or CYP3A5*1/*3 than those with CYP3A5*1/*1. For the CyA concentrations, CYP3A5 genotypes did not have significant effects. Conclusion: In MG patients, CYP3A5 polymorphism significantly affects serum levels of tacrolimus and thereby treatment effects, but not those of CyA. The maintenance dose of tacrolimus should be determined considering CYP3A5 polymorphism.

Variability index of tacrolimus serum levels in pediatric liver transplant recipients younger than 12years: Non-adherence or risk of non-adherence?

MLVI has been used to assess adherence. To determine the MLVI in children <12years of age at transplantation and to identify demographic correlates and consequences for the graft. This is a retrospective study of 50 outpatients (4.0±3.5years), at least 13-month post-liver transplantation. The outcomes evaluated were MLVI, ALT>60IU/L, ACR, death, and graft loss. We analyzed demographic and socioeconomic characteristics, indication for transplantation, and type of donor. Student's t test and the chi-square test were used. Statistical significance was set at P≤.05. Seventy-two percent were infants or preschoolers, 62% biliary atresia. Seventy-four percent of the mothers had middle-school education, and 54% of the families had an income ≤3632.4US$/y. Twenty-two (44%) patients had a MLVI≥2 SD; this was more prevalent in families with higher incomes (P=.045). ALT levels>60IU/L were more common in MLVI≥2 SD group (P=.035). ACR episodes were similar between groups (P=1.000). No patient died or lost the graft. MLVI≥2 SD may be an indicator of the risk of medication non-adherence.

Conversion from twice-daily to once-daily tacrolimus formulation in pediatric liver transplant recipients - a long-term prospective study.

To assess the safety and efficacy of conversion from twice-daily tacrolimus to once-daily tacrolimus in pediatric liver transplant recipients. Conversion from twice-daily to once-daily tacrolimus was made in stable pediatric liver transplant recipients. Doses and serum levels of tacrolimus, liver, and renal function were recorded on the day before the conversion and at days 5, 30, 90, and 180 postconversion. Patients were controlled every 2-3 months thereafter. Fifty-five patients were enrolled in the study. The mean age at conversion was 10.2 ± 3.6 years. The mean tacrolimus trough level was 4.7 ± 1.9 ng/dl preconversion, followed by a significant decline to 4.2 ± 1.7 30 days after the switch (P < 0.004). Mean daily tacrolimus dose was 0.09 ± 0.046 mg/Kg preconversion with a significant increase to 0.11 ± 0.060 3 months postconversion (P < 0.001). Fifteen patients with calculated glomerular filtration rate between 60 to 80 ml/min/m2 preconversion showed a significant improvement one and 3 years after the switch (73 ± 4.1, 83 ± 4.3 and 90.3 ± 7.3 ml/min/m2 , respectively (P < 0.001). The mean follow-up was 5.2 ± 2.4 years. Conversion to once-daily tacrolimus is safe and effective in a cohort of stable pediatric liver transplant patients.

The Effects of Tacrolimus on T-Cell Proliferation Are Short-Lived: A Pilot Analysis of Immune Function Testing.

BackgroundOptimal immunosuppression after organ transplant should balance the risks of rejection, infection, and malignancy while minimizing barriers to adherence including frequent or time-sensitive dosing. There is currently no reliable immune function assay to directly measure the degree of immunosuppression after transplantation.MethodsWe developed an immune function assay to mea//sure T-cell proliferation after exposure to immunosuppression in vivo. We tested the assay in mice, and then piloted the approach using single time point samples, 11 pediatric kidney transplant recipients prescribed tacrolimus, mycophenolate, and prednisone 6 months to 5 years posttransplant, with no history of rejection, opportunistic infection, or cancer. Twelve healthy adults were controls.ResultsWe demonstrated that our assay can quantify suppression of murine T-cell proliferation after tacrolimus treatment in vivo. In humans, we found a mean 25% reduction in CD4 and CD8 T-cell proliferation in pediatric renal transplant recipients on triple immunosuppression compared with adult healthy controls, but the pilot results were not statistically significant nor correlated with serum tacrolimus levels. We observed that cell processing and washing reduced the effects of tacrolimus on T-cell proliferation, as did discontinuation of tacrolimus treatment shortly before sampling.ConclusionsT-cell proliferation is currently not suitable to measure immunosuppression because sample processing diminishes observable effects. Future immune function testing should focus on fresh samples with minimal washing steps. Our results also emphasize the importance of adherence to immunosuppressive treatment, because T-cell proliferation recovered substantially after even brief discontinuation of tacrolimus.

Postoperative acute kidney injury in living donor liver transplantation recipients.

There are many risk factors for postoperative acute kidney injury in liver transplantation. The aim of this study is to investigate the risk factors for postoperative acute kidney injury in living donor liver transplantation recipients. 220 living donor liver transplantation recipients were retrospectively evaluated in the study. According to the Kidney Disease Improving Global Outcomes Guidelines, acute kidney injury in postoperative day 7 was investigated for all patients. The patient's demographic data, preoperative and intraoperative parameters, and outcomes were recorded. Acute kidney injury was found in 27 (12.3%) recipients. In recipients with acute kidney injury, female population, model for end-stage liver disease score, norepinephrine requirement, duration of mean arterial pressure less than 60 mmHg, the usage of gelatin and erythrocyte suspension and blood loss were significantly higher than recipients with nonacute kidney injury (for all p<0.05). In multivariate analyses, the likelihood of acute kidney injury on postoperative day 7 were increased 2.8-fold (1.1-7.0), 2.7-fold (1.02-7.3), 3.4-fold (1.2-9.9) and 5.1-fold (1.7-15.0) by postoperative day 7, serum tacrolimus level ≥10.2 ng dL-1, intraoperative blood loss ≥14.5 mL kg-1, the usage of gelatin >5 mL kg-1 and duration of MAP less than 60 mmHg ≥5.5 minutes respectively (for all p<0.05). In living donor liver transplantation recipients, serum tacrolimus levels, intraoperative blood loss, hypotension period and the usage of gelatin may be risk factors for acute kidney injury in the early postoperative period.

Post-transplant lymphoproliferative disorder after liver transplantation: Incidence, long-term survival and impact of serum tacrolimus level.

AIMTo investigate incidence and survival of post-transplant lymphoproliferative disorder (PTLD) patients after liver transplantation.METHODSA cross-sectional survey was conducted among patients who underwent liver transplantation at Shiraz Transplant Center (Shiraz, Iran) between August 2004 and March 2015. Clinical and laboratory data of patients were collected using a data gathering form.RESULTSThere were 40 cases of PTLD in the pediatric age group and 13 cases in the adult group. The incidence of PTLD was 6.25% in pediatric patients and 1.18% in adult liver transplant recipients. The post-PTLD survival of patients at 6 mo was 75.1% ± 6%, at 1 year was 68.9% ± 6.5% and at 5 years was 39.2% ± 14.2%. Higher serum tacrolimus level was associated with lower post-PTLD survival in pediatric patients (OR = 1.07, 95%CI: 1.006-1.15, P = 0.032). A serum tacrolimus level over 11.1 ng/mL was predictive of post PTLD survival (sensitivity = 90%, specificity = 52%, area under the curve = 0.738, P = 0.035).CONCLUSIONIncidence of PTLD in our liver transplant patients is comparable to other centers. Transplant physicians may consider adjustment of tacrolimus dose to maintain its serum level below this cutoff point.

Immunosuppressive serum levels in allogeneic hematopoietic stem cell transplantation: pharmaceutical care contribution.

Background:Cyclosporine and tacrolimus are limited by a narrow therapeutic window. Maintaining immunosuppressive drugs at desired levels may be difficult. Pharmaceutical care emerges as a philosophy of practice that enhances medication use and leads to a better control of serum concentration.Objective:This study aims to evaluate the impact of pharmaceutical care in the maintaining of proper serum levels of immunosuppressive medications in patients who have undergone allo-HSCT.Methods:The study had a quasi-experimental design that included a comparison group. The service model used was pharmacotherapy follow-up, according to an adaptation of the Dader method. The pharmacist consultation was carried out at a day-hospital or at the outpatient hematology clinic as needed. The intervention group consisted of 22 patients seen by a clinical pharmacist. The control group consisted of 44 patients that received standard care. This study aims to evaluate the impact of pharmaceutical care on keeping patient serum levels of cyclosporine and tacrolimus within the desired range.Results:Control group displayed 65% of the proper serum levels of immunosuppressive agents. While In intervention group, the figure was 82% (p = 0.004).Conclusion:The role of the pharmacist in the multidisciplinary team may contribute to a greater success in attaining the patients’ therapeutic targets with regard to the use of immunosuppressant.

Hypomagnesemia in Pediatric Heart Transplant Patients Treated with Tacrolimus.

We aimed to investigate the frequency of hypomagnesemia and urinary magnesium excretion in pediatric heart transplant recipients. In this study, 22 pediatric patients who underwent heart transplanted at a single center between March 2014 and April 2015 and who were treated with oral tacrolimus were analyzed prospectively. Serum magnesium, creatinine, and tacrolimus levels and total amount of urinary magnesium excretion were measured. Serum tacrolimus levels were measured 12 hours after the last dose of tacrolimus. Our patient group included 11 boys (50%) and 11 girls (50%) with a mean age of 16.72 ± 4.78 years. Serum tacrolimus levels were in the therapeutic range, with a mean of 1.48 ± 0.13 ng/mL (range, 1.2-1.69 ng /mL), mean fractional magnesium excretion was 8.59 ± 5.9% (range, 3%-22%), and 24-hour urinary magnesium excretion was 90.2 ± 62.95 mg/d. Hypermagnesuria was assessed in 80% of patients. We found 24-hour urinary magnesium excretion to be higher than normal in 27% of patients. There was no association between serum tacrolimus levels and serum magnesium levels or urinary magnesium excretion. Serum magnesium levels should be periodically measured in pediatric heart transplant patients treated with tacrolimus.

One-Year Follow-up of the Changes in Renal Function After Liver Transplantation in Patients Without Chronic Kidney Disease

BackgroundImpaired renal function is a strong risk factor for morbidity and mortality after liver transplantation (LT). There is clearly a progressive deterioration in renal function after LT. The greatest loss of renal function occurs within the 1st year after LT. Several factors, including calcineurin inhibitors, are associated with decreased renal function. The aims of the present study were to identify changes in renal function before and after LT and to determine the risk factors related to decreased renal function after LT. MethodsWe reviewed medical records of 106 LT recipients without moderate to severe chronic kidney disease (estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m2). We investigated eGFR changes from before to 1 year after LT with the use of propensity score matching. Statistical significance of differences between clinical parameters and 1-year eGFR changes was assessed with the use of univariate and multivariate analyses. ResultsMean age was 49.5 ± 10.9 years, and 66% of the patients were male. Mean differences in 1-year eGFR and serum creatinine were −32.0 ± 29.2 mL/min/1.73 m2 and 0.3 ± 0.3 mg/dL, respectively. Variables significantly associated with renal dysfunction 1 year after LT were old age, low pre-LT eGFR, low post-LT hemoglobin, and perioperative acute kidney injury. Multivariate analysis showed that pre-LT renal function was an independent risk factor for decreased renal function after LT. However, there was no significant correlation between 1-year eGFR change and serum tacrolimus level. ConclusionsRenal function significantly decreased the 1st year after LT, and baseline renal function was an independent risk factor for worsening renal function in LT recipients.

Targeted Delivery of Immunomodulators to Lymph Nodes.

SUMMARYActive-targeted delivery to lymph nodes represents a major advance toward more effective treatment of immune-mediated disease. The MECA79 antibody recognizes peripheral node address in molecules expressed by high endothelial venules of lymph nodes. By mimicking lymphocyte trafficking to the lymph nodes, we have engineered MECA79-coated microparticles containing an immunosuppressive medication, tacrolimus. Following intravenous administration, MECA79-bearing particles showed marked accumulation in the draining lymph nodes of transplanted animals. Using an allograft heart transplant model, we show that targeted lymph node delivery of microparticles containing tacrolimus can prolong heart allograft survival with negligible changes in tacrolimus serum level. Using MECA79 conjugation, we have demonstrated targeted delivery of tacrolimus to the lymph nodes following systemic administration, with the capacity for immune modulation in vivo.

Curing Hepatitis C in Liver Transplant Recipients Is Associated with Changes in Immunosuppressant Use.

Background and Aims: All-oral interferon-free antivirals are highly effective in treating recurrent hepatitis C (HCV) infection in liver transplant (LT) recipients. The aim of the study was to assess immunosuppression needs after achieving a sustained viral response (SVR). Methods: We compared immunosuppression needs before and after achieving a SVR in adult LT recipients treated for recurrent HCV infection with all-oral direct acting agents. Results: We identified 52 liver LT treated recipients who achieved a SVR. The median (25th and 75th percentile interquartile range [IQR]) age was 62 years (57.75, 65). Most recipients received tacrolimus (TAC) for their immunosuppressant regimen. After achieving SVR, there was no statistically significant difference in daily dose of TAC unadjusted per weight (p > 0.05). However, there was a statistically significant decrease in daily dose of TAC adjusted per weight, serum levels of TAC, and the product of glomerular filtration rate and TAC. No statistically significant differences in cyclosporine unadjusted/adjusted per weight daily dose or serum levels were noted. Conclusions: Immunosuppression needs were increased for those patients treated with TAC but not cyclosporine. LT recipients prescribed TAC require close monitoring after treatment completion to avoid potential risk of acute rejection.

Pharmacogenomics: personalizing pediatric heart transplantation.

In recent years, outcomes for pediatric cardiac transplantation (PCTx) have steadily improved, with current 5-year overall survival rates estimated at 83%.1 This progress may be attributed to improvements in pretransplantation management, selection of donor hearts, surgical technique, prevention and treatment of rejection, and minimization of treatment-related adverse events. Despite these advances, children who receive cardiac transplants experience significant morbidity and mortality, and there is considerable variability in outcomes, much of which cannot be explained by known clinical risk factors. One source of interindividual variability is genetic variation in the host. There is growing evidence that genomic variation leads to differences in immune response, response to therapies, and susceptibility to adverse outcomes such as malignancy and infection.2–4 This review will focus on the effect of variation in genes that encode enzymes, transporters, and drug target molecules that influence drug response. After review of the foundational principles of pharmacogenomics, evidence for the pharmacogenomic effects on cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil (MMF), and the mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus will be reviewed and clinical implications of these findings discussed. Given the limited nature of evidence from studies of PCTx patients, support will also be drawn from non-PCTx research and pediatric renal transplantation. Genetic studies of nonpharmacogenes such as those in immunomodulatory pathways and variation in the donor genotype may contribute to risk prediction but are beyond the scope of this review. ### Genetic Variation DNA variation can alter biological function through several mechanisms (Figure 1). Variation within the coding sequence or in intron/exon borders can change the protein product through changes in start codons, stop codons, splice sites, or within the coding sequence, leading to nonsense-mediated decay or altered protein function. Other variants associated with pharmacogenomic outcomes are not predicted to change the encoded protein. These synonymous and …

Proximal Tubular Injury in Medullary Rays Is an Early Sign of Acute Tacrolimus Nephrotoxicity.

Tacrolimus (FK506) is one of the principal immunosuppressive agents used after solid organ transplantations to prevent allograft rejection. Chronic renal injury induced by tacrolimus is characterized by linear fibrosis in the medullary rays; however, the early morphologic findings of acute tacrolimus nephrotoxicity are not well characterized. Kidney injury molecule-1 (KIM-1) is a specific injury biomarker that has been proven to be useful in the diagnosis of mild to severe acute tubular injury on renal biopsies. This study was motivated by a patient with acute kidney injury associated with elevated serum tacrolimus levels in whom KIM-1 staining was present only in proximal tubules located in the medullary rays in the setting of otherwise normal light, immunofluorescent, and electron microscopy. We subsequently evaluated KIM-1 expression in 45 protocol and 39 indicated renal transplant biopsies to determine whether higher serum levels of tacrolimus were associated with acute segment specific injury to the proximal tubule, as reflected by KIM-1 staining in the proximal tubules of the cortical medullary rays. The data suggest that tacrolimus toxicity preferentially affects proximal tubules in medullary rays and that this targeted injury is a precursor lesion for the linear fibrosis seen in chronic tacrolimus toxicity.