Tacrolimus Level Variability Is a Novel Measure Associated with Increased Acute Rejection in Lung Transplant (LTx) Recipients

Chiang, C.Y.; Schneider, Hans G.; Levvey, B.; Mitchell, L.; Snell, Greg

doi:10.1016/j.healun.2013.01.404

Cited by 16 publications

(12 citation statements)

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“…This would facilitate a closed feedback loop between the drug and the patient's response, which can then be adjusted to continuously deliver an optimal therapeutic dose in real-time. For example, optimal dosing of the immunosuppressant cyclosporine for patients undergoing organ transplantation is notoriously difficult because of inter- and intra-patient variability (36). Appropriate dosing is crucial because the effects of the drug are proportional to its concentration (37), but cyclosporine dose has also been correlated with levels of pro-inflammatory chemokines such as CXCL9 (38, 39), which are associated with nephropathy, acute graft rejection, and graft failure (40).…”

Section: Discussionmentioning

confidence: 99%

Real-Time, Aptamer-Based Tracking of Circulating Therapeutic Agents in Living Animals

et al. 2013

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A sensor capable of continuously measuring specific molecules in the bloodstream in vivo would give clinicians a valuable window into patients’ health and their response to therapeutics. Such technology would enable truly personalized medicine, wherein therapeutic agents could be tailored with optimal doses for each patient to maximize efficacy and minimize side effects. Unfortunately, continuous, real-time measurement is currently only possible for a handful of targets, such as glucose, lactose, and oxygen, and the few existing platforms for continuous measurement are not generalizable for the monitoring of other analytes, such as small-molecule therapeutics. In response, we have developed a real-time biosensor capable of continuously tracking a wide range of circulating drugs in living subjects. Our microfluidic electrochemical detector for in vivo continuous monitoring (MEDIC) requires no exogenous reagents, operates at room temperature, and can be reconfigured to measure different target molecules by exchanging probes in a modular manner. To demonstrate the system's versatility, we measured therapeutic in vivo concentrations of doxorubicin (a chemotherapeutic) and kanamycin (an antibiotic) in live rats and in human whole blood for several hours with high sensitivity and specificity at sub-minute temporal resolution. Importantly, we show that MEDIC can also obtain pharmacokineticparameters for individual animals in real-time. Accordingly, just as continuous glucose monitoring technology is currently revolutionizing diabetes care, we believe MEDIC could be a powerful enabler for personalized medicine by ensuring delivery of optimal drug doses for individual patients based on direct detection of physiological parameters.

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Section: Discussionmentioning

confidence: 99%

Real-Time, Aptamer-Based Tracking of Circulating Therapeutic Agents in Living Animals

et al. 2013

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“…We found no association between acute rejection and tacrolimus SD. Chiang et al, on the other hand, found a 23% increase risk of acute rejection for each 1 unit rise in tacrolimus trough level SD in the first 8-90 days post transplantation (23). In adult kidney transplant recipients, high within patient variability in tacrolimus clearance (estimated by correcting the blood trough level for the oral dose) in the 6-12 month period was found to increase the risk of graft failure and rejection after 12 months (24).…”

Section: Discussionmentioning

confidence: 99%

“…There are good reasons to believe that erratic exposure may be just as deleterious as sub-therapeutic tacrolimus exposure, but this possibility has been little explored. High tacrolimus trough level variability (assessed using standard deviation (SD)) increases the risk of acute rejection early post adult lung transplant but its affect on CLAD and survival are unknown (23). In the liver and kidney transplant literature, an association has been found between high intra-patient tacrolimus level variability and late graft failure (24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Erratic tacrolimus exposure, assessed using the standard deviation of trough blood levels, predicts chronic lung allograft dysfunction and survival

Gallagher

Sarwar

Tse

et al. 2015

The Journal of Heart and Lung Transplantation

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“…Only limited and inconclusive evidence is available for the association of native lung disease and ACR. Observational data indicate that among patients with higher grade ACR there is a higher prevalence of cystic fibrosis (CF), [27][28][29] but multivariate analysis does not allow definite conclusions in this regard. 6,29 Pulmonary hypertension (PH) is the only other native lung disease that has been found to be a risk factor for ACR, associated with early ACR (< 3 months after LTx) in one study 3 but not in another.…”

Section: Pretransplant Recipient Characteristicsmentioning

confidence: 99%

“…For cyclosporine, achieving and maintaining 2-hour post-dose levels has been associated with lower ACR rates, 67 whereas tacrolimus blood level variability was recognized as a risk factor for early ACR. 28 Pharmacogenetics focuses on polymorphisms of immunosuppressive drug targets, metabolizing enzymes or transporters and is another promising area of research that has the potential to complement TDM. 38,68 Alleles of CYP3A5 and ABCB-1 have been studied the most in association with tacrolimus pharmacokinetics and dose requirements.…”

Section: Post-transplant Factorsmentioning

confidence: 99%

Acute Cellular Rejection: Is It Still Relevant?

Koutsokera

Levy

Pal

et al. 2018

Semin Respir Crit Care Med

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Despite significant progress in the field of transplant immunology, acute cellular rejection (ACR) remains a very frequent complication after lung transplantation (LTx), with almost 30% of LTx recipients experiencing at least one episode of treated ACR during the first year of follow-up. Most episodes respond to the first-line immunosuppressive treatment and are rarely a direct cause of death. However, the association of ACR with later adverse outcomes, such as chronic lung allograft dysfunction, bronchial stricture, and infectious complications associated with the intensification of immunosuppression, negatively impacts long-term survival. The burden imposed on patients and health-care resources is even higher in cases of refractory or recurrent ACR, which accelerates lung function decline. Although important laboratory and clinical research conducted over the last two decades has improved our understanding of the mechanisms underlying ACR, there are still many uncertainties about the risk factors for ACR, the optimal monitoring strategies, and the prediction of long-term outcomes. These knowledge gaps contribute to the large variability in clinical practice among LTx centers, which renders multicenter studies of ACR challenging. In this review, we summarize current evidence on the epidemiology, pathogenesis, and risk factors of ACR. We describe diagnostic and therapeutic approaches that are currently used in the clinical practice and also review promising diagnostic tools that are under investigation. Associations between ACR and other adverse outcomes of LTx are examined. Finally, within each topic of discussion, we highlight the main areas of controversy and opportunities for future research.

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Tacrolimus Level Variability Is a Novel Measure Associated with Increased Acute Rejection in Lung Transplant (LTx) Recipients

Cited by 16 publications

References 0 publications

Real-Time, Aptamer-Based Tracking of Circulating Therapeutic Agents in Living Animals

Real-Time, Aptamer-Based Tracking of Circulating Therapeutic Agents in Living Animals

Erratic tacrolimus exposure, assessed using the standard deviation of trough blood levels, predicts chronic lung allograft dysfunction and survival

Acute Cellular Rejection: Is It Still Relevant?

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