The Pharmacogenetics of Calcineurin Inhibitor–Related Nephrotoxicity

Hesselink, Dennis A.; Bouamar, Rachida; Gelder, Teun van

doi:10.1097/ftd.0b013e3181e44244

Cited by 60 publications

(42 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In randomized trials [31,32,33], the high-CNI exposure group did not have significantly lower graft function, which refutes the chronic nephrotoxic effects. The role of drug transporters and drug metabolizing enzymes in causing interindividual variability in CNI pharmacokinetics has recently been reviewed by Hesselink et al [34]. The drug transporter adenosine triphosphate-binding cassette protein B1 (ABCB1), which is responsible for transporting drugs from the cytoplasm to the cell surface and then into the extracellular space, is found most prominently in the brush border of proximal tubular epithelial cells of human kidneys.…”

Section: Cni Pharmacokinetics and Pharmacogenetics: How Tight Is The mentioning

confidence: 99%

Calcineurin Inhibitor Nephrotoxicity: A Review and Perspective of the Evidence

2013

View full text Add to dashboard Cite

Background: There is no doubt that acute calcineurin inhibitor (CNI) nephrotoxicity exists; however, chronic CNI nephrotoxicity is questionable at best. Methods: We reviewed the literature to identify original articles related to the use of CNIs in renal and nonrenal solid organ transplantation in order to examine the available evidence about their chronic nephrotoxicity and contribution to graft failure. Results: Early clinical experience and animal studies support the evidence of CNI nephrotoxicity. These findings evolved into the dogma that CNI nephrotoxicity is the major cause of late renal allograft failure. However, in transplanted kidneys the specific role of chronic CNI nephrotoxicity has been questioned. The emerging literature clearly highlights the lack of solid evidence for the role of CNIs as the sole and major injurious agents that cause chronic renal dysfunction and subsequent graft failure. Most of the evidence available to date is against complete CNI avoidance, and minimization appears to be a more viable strategy. It is becoming increasingly clear that the typical pathological lesions linked to chronic CNI use are highly nonspecific, and most of the chronic changes that have been attributed to chronic CNI nephrotoxicity are the consequences of previously unrecognized immunologic injuries. One needs to keep in mind that the potential risk of side effects of CNI use should be balanced against the risk of rejection. Conclusions: More research should focus on addressing the true causes of chronic graft dysfunction rather than focusing on the overexaggerated contribution of CNIs to late graft loss.

show abstract

Section: Cni Pharmacokinetics and Pharmacogenetics: How Tight Is The mentioning

confidence: 99%

Calcineurin Inhibitor Nephrotoxicity: A Review and Perspective of the Evidence

2013

View full text Add to dashboard Cite

show abstract

“…It may seem counter-intuitive that ciclosporin therapy results in oral tissues that are primarily inflamed with little fibrosis, while kidney fibrosis is a severe complication of ciclosporin therapy. (For reviews, see Busauschina et al [2004], Hesselink et al [2010], and López-Hernández and López-Novoa [2012].) The innate immune system is particularly important in the oral environment, due to microbial and physical insults which are not as relevant to internal organs such as the kidney.…”

Section: Are All Drug-induced Forms Of Gingival Overgrowth Fibrotic?mentioning

confidence: 99%

Molecular and Clinical Aspects of Drug-induced Gingival Overgrowth

Trackman

Kantarcı²

2015

J Dent Res

125

109

View full text Add to dashboard Cite

Drug-induced gingival overgrowth is a tissue-specific condition and is estimated to affect approximately one million North Americans. Lesions occur principally as side-effects from phenytoin, nifedipine, or ciclosporin therapy in approximately half of the people who take these agents. Due to new indications for these drugs, their use continues to grow. Here, we review the molecular and cellular characteristics of human gingival overgrowth lesions and highlight how they differ considerably as a function of the causative drug. Analyses of molecular signaling pathways in cultured human gingival fibroblasts have provided evidence for their unique aspects compared with fibroblasts from the lung and kidney. These findings provide insights into both the basis for tissue specificity and into possible therapeutic opportunities which are reviewed here. Although ciclosporin-induced gingival overgrowth lesions exhibit principally the presence of inflammation and little fibrosis, nifedipine-and especially phenytoin-induced lesions are highly fibrotic. The increased expression of markers of gingival fibrosis, particularly CCN2 [also known as connective tissue growth factor (CTGF)], markers of epithelial to mesenchymal transition, and more recently periostin and members of the lysyl oxidase family of enzymes have been documented in phenytoin or nifedipine lesions. Some oral fibrotic conditions such as leukoplakia and oral submucous fibrosis, after subsequent additional genetic damage, can develop into oral cancer. Since many pathways are shared, the study of gingival fibrosis and comparisons with characteristics and molecular drivers of oral cancer would likely enhance understandings and functional roles of molecular drivers of these oral pathologies.

show abstract

“…2 Yet, in thiopurine-refractory patients with preferential 6-MMP metabolism, thiopurine-allopurinol combination therapy might prove to be beneficial over the more costly and nephrotoxic calcineurin inhibitors. 20,21 In conclusion, allopurinol in combination with low-dose thiopurine might be an effective and relatively safe alternative immunosuppressive strategy for AIH patients failing standard thiopurine therapy due to preferential 6-MMP metabolism. The present report is limited by its small and heterogeneous patient group and therefore larger and controlled studies are needed to confirm the promising outcomes of this combination therapy.…”

mentioning

confidence: 99%

Allopurinol safely and effectively optimises thiopurine metabolites in patients with autoimmune hepatitis

Boer

Gerven

Boer

et al. 2013

Aliment Pharmacol Ther

View full text Add to dashboard Cite

SUMMARY BackgroundTen percent of patients with autoimmune hepatitis (AIH) are nonresponsive or intolerant to thiopurine therapy. A skewed metabolism, leading to the preferential generation of (hepato)toxic thiopurine metabolites (6-MMPs) instead of the metabolic active 6-tioguanine (thioguanine) nucleotides (6-TGNs), may explain this unfavourable outcome. Co-administration of allopurinol to low-dose thiopurine therapy may effectively revert this deviant metabolism, as has been shown in inflammatory bowel disease.

show abstract

The Pharmacogenetics of Calcineurin Inhibitor–Related Nephrotoxicity

Cited by 60 publications

References 79 publications

Calcineurin Inhibitor Nephrotoxicity: A Review and Perspective of the Evidence

Calcineurin Inhibitor Nephrotoxicity: A Review and Perspective of the Evidence

Molecular and Clinical Aspects of Drug-induced Gingival Overgrowth

Allopurinol safely and effectively optimises thiopurine metabolites in patients with autoimmune hepatitis

Contact Info

Product

Resources

About