Use of Pharmacogenetics to Optimize Immunosuppressant Therapy in Kidney-Transplanted Patients

Brancati, Valentina Urzì; Scarpignato, Carmelo; Minutoli, Letteria; Pallio, Giovanni

doi:10.3390/biomedicines10081798

Cited by 19 publications

(12 citation statements)

References 91 publications

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“…In order to optimize the immunosuppressant therapy in kidney-transplanted patients, pharmacogenetics studies have been considered. In this respect, Urzì Brancati et al proposed that the characterization of the polymorphisms in CYP3A5, CYP3A4, ABCB1, and UGT1A9 genes could be a strategy to select the ideal dosage for each patient [ 61 ].…”

Section: Rapamycin In Organ and Tissue Transplantationmentioning

confidence: 99%

The Long Scientific Journey of Sirolimus (Rapamycin): From the Soil of Easter Island (Rapa Nui) to Applied Research and Clinical Trials on β-Thalassemia and Other Hemoglobinopathies

Gambari,

Zuccato,

Cosenza

et al. 2023

Biology

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In this review article, we present the fascinating story of rapamycin (sirolimus), a drug able to induce γ-globin gene expression and increased production of fetal hemoglobin (HbF) in erythroid cells, including primary erythroid precursor cells (ErPCs) isolated from β-thalassemia patients. For this reason, rapamycin is considered of great interest for the treatment of β-thalassemia. In fact, high levels of HbF are known to be highly beneficial for β-thalassemia patients. The story of rapamycin discovery began in 1964, with METEI, the Medical Expedition to Easter Island (Rapa Nui). During this expedition, samples of the soil from different parts of the island were collected and, from this material, an antibiotic-producing microorganism (Streptomyces hygroscopicus) was identified. Rapamycin was extracted from the mycelium with organic solvents, isolated, and demonstrated to be very active as an anti-bacterial and anti-fungal agent. Later, rapamycin was demonstrated to inhibit the in vitro cell growth of tumor cell lines. More importantly, rapamycin was found to be an immunosuppressive agent applicable to prevent kidney rejection after transplantation. More recently, rapamycin was found to be a potent inducer of HbF both in vitro using ErPCs isolated from β-thalassemia patients, in vivo using experimental mice, and in patients treated with this compound. These studies were the basis for proposing clinical trials on β-thalassemia patients.

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Section: Rapamycin In Organ and Tissue Transplantationmentioning

confidence: 99%

The Long Scientific Journey of Sirolimus (Rapamycin): From the Soil of Easter Island (Rapa Nui) to Applied Research and Clinical Trials on β-Thalassemia and Other Hemoglobinopathies

Gambari,

Zuccato,

Cosenza

et al. 2023

Biology

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“…Here, we found that daily administration of 10 mg/Kg/day Tac (Tac-10) for 10 days was associated with high blood pressure, an increase in plasma creatinine, and renal damage, represented by the induction in IL-6 and NGAL, two mediators linked to the proinflammatory status [ 45 , 46 , 47 , 48 ]. The dose of Tac used was several times higher than the dose administered to transplant patients [ 49 , 50 ]. However, a study found that C57BL/6 mice might show differences in the resistance to nephrotoxicity induced by drug models (for example, cisplatin) [ 51 ] or to other acute kidney injury (AKI) experimental models driving to chronic kidney disease [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

The Mineralocorticoid Receptor on Smooth Muscle Cells Promotes Tacrolimus-Induced Renal Injury in Mice

et al. 2023

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Tacrolimus (Tac) is a calcineurin inhibitor commonly used as an immunosuppressor after solid organ transplantation. However, Tac may induce hypertension, nephrotoxicity, and an increase in aldosterone levels. The activation of the mineralocorticoid receptor (MR) is related to the proinflammatory status at the renal level. It modulates the vasoactive response as they are expressed on vascular smooth muscle cells (SMC). In this study, we investigated whether MR is involved in the renal damage generated by Tac and if the MR expressed in SMC is involved. Littermate control mice and mice with targeted deletion of the MR in SMC (SMC-MR-KO) were administered Tac (10 mg/Kg/d) for 10 days. Tac increased the blood pressure, plasma creatinine, expression of the renal induction of the interleukin (IL)-6 mRNA, and expression of neutrophil gelatinase-associated lipocalin (NGAL) protein, a marker of tubular damage (p < 0.05). Our study revealed that co-administration of spironolactone, an MR antagonist, or the absence of MR in SMC-MR-KO mice mitigated most of the unwanted effects of Tac. These results enhance our understanding of the involvement of MR in SMC during the adverse reactions of Tac treatment. Our findings provided an opportunity to design future studies considering the MR antagonism in transplanted subjects.

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“…Following the methodology described by Urzi Brancati et al [ 10 ], we considered all articles, written in English, where an analysis was made of the role of genetics in IS drug bioavailability and metabolization. We excluded redundant articles and when results showed also another kind of transplantation we privileged articles dealing with kidney transplantation.…”

Section: Methodsmentioning

confidence: 99%

Pharmacogenomics of Old and New Immunosuppressive Drugs for Precision Medicine in Kidney Transplantation

Turolo

Edefonti

Syrén

et al. 2023

JCM

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Kidney transplantation is the preferred therapeutic option for end-stage kidney disease, but, despite major therapeutic advancements, allograft rejection continues to endanger graft survival. Every patient is unique due to his or her clinical history, drug metabolism, genetic background, and epigenetics. For this reason, examples of “personalized medicine” and “precision medicine” have steadily increased in recent decades. The final target of precision medicine is to maximize drug efficacy and minimize toxicity for each individual patient. Immunosuppressive drugs, in the setting of kidney transplantation, require a precise dosage to avoid either adverse events (overdosage) or a lack of efficacy (underdosage). In this review, we will explore the knowledge regarding the pharmacogenomics of the main immunosuppressive medications currently utilized in kidney transplantation. We will focus on clinically relevant pharmacogenomic data, that is, the polymorphisms of the genes that metabolize immunosuppressive drugs.

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Use of Pharmacogenetics to Optimize Immunosuppressant Therapy in Kidney-Transplanted Patients

Cited by 19 publications

References 91 publications

The Long Scientific Journey of Sirolimus (Rapamycin): From the Soil of Easter Island (Rapa Nui) to Applied Research and Clinical Trials on β-Thalassemia and Other Hemoglobinopathies

The Long Scientific Journey of Sirolimus (Rapamycin): From the Soil of Easter Island (Rapa Nui) to Applied Research and Clinical Trials on β-Thalassemia and Other Hemoglobinopathies

The Mineralocorticoid Receptor on Smooth Muscle Cells Promotes Tacrolimus-Induced Renal Injury in Mice

Pharmacogenomics of Old and New Immunosuppressive Drugs for Precision Medicine in Kidney Transplantation

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