Relevance of IL10, TGFβ1, TNFα, and IL4Rα Gene Polymorphisms in Kidney Transplantation: A Collaborative Transplant Study Report

Mytilineos, Joannis; Laux, Gunter; Opelz, Gerhard

doi:10.1111/j.1600-6143.2004.00561.x

Cited by 41 publications

(33 citation statements)

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“…It was demonstrated that a TGF-␤ polymorphism in codon 10 was associated with renal function in both adult and pediatric heart transplant recipients (333)(334)(335), although a study in liver transplant recipients could not confirm this association (336). In renal transplantation, TGF-␤ variants in the recipient were not associated with renal allograft outcome in a very large study (337), but this could be explained by the possibility that local TGF-␤ production could depend more on donor genotype than on recipient genotype. Angiotensin converting enzyme (ACE) gene polymorphisms have been associated with serum ACE levels (338).…”

Section: Local Renal Susceptibility Factors For Cni Nephrotoxicitymentioning

confidence: 98%

Calcineurin Inhibitor Nephrotoxicity

Naesens

Kuypers²,

Sarwal³

2009

Clinical Journal of the American Society of Nephrology

1,241

1,000

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The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis. The authors also review the available literature on the physiologic and molecular mechanisms underlying acute and chronic calcineurin inhibitor nephrotoxicity, and demonstrate that its development is related to both reversible alterations and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. The main question-whether nephrotoxicity is secondary to the actions of cyclosporine and tacrolimus on the calcineurin-NFAT pathway-remains largely unanswered. The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cyclosporine or tacrolimus could be more important than systemic exposure. Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-␤ and ACE. Better insight into the mechanisms underlying calcineurin inhibitor nephrotoxicity might pave the way toward more targeted therapy or prevention of calcineurin inhibitor nephrotoxicity.Clin J Am Soc Nephrol 4: 481-508, 2009. doi: 10.2215/CJN.04800908 T he introduction of the calcineurin inhibitor (CNI) cyclosporine in human kidney transplantation in the late 1970s revolutionized transplantation medicine, and made transplantation a preferable therapeutic intervention for end-stage renal diseases (1,2). In 1984, the potent immunosuppressive properties of another CNI, tacrolimus, were discovered, and tacrolimus was used successfully in human liver, kidney, and heart allograft recipients (3,4). Currently, 94% of kidney transplant recipients are discharged after transplantation with a CNI-based immunosuppressive regimen (5).The immunosuppressive properties of cyclosporine and tacrolimus result from inhibition of calcineurin, a calcium-and calmodulin-dependent phosphatase (protein phosphatase 3 [PPP3C], formerly PP2B). Intracellularly, these completely different molecules bind to cyclophylin and FKBP12 for cyclosporine and tacrolimus, respectively (6 -9). The competitive binding of cyclosporine-cyclophylin and tacrolimus-FKBP12 complexes to calcineurin inhibits phosphatase activity of calcineurin. This inhibition then suppresses the transcription of IL-2 via inhibition of the dephosphorylation and impaired translocation of the nucl...

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Section: Local Renal Susceptibility Factors For Cni Nephrotoxicitymentioning

confidence: 98%

Calcineurin Inhibitor Nephrotoxicity

Naesens

Kuypers²,

Sarwal³

2009

Clinical Journal of the American Society of Nephrology

1,241

1,000

View full text Add to dashboard Cite

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“…No associations between the different presumed phenotypes and graft survival were found in first transplant recipients for the loci tested ( [27] in Tables 2 and 3). Repeat transplant recipients with the TNFA rs1800629 (− 308) A/A "high producer" genotype presented lower graft survival.…”

Section: Positive Associations In Kidney Transplant Recipientsmentioning

confidence: 50%

“…Perhaps the largest cohort in a single publication to-date involved 2298 primary transplant recipients and 1901 repeat transplants [27].…”

Section: Positive Associations In Kidney Transplant Recipientsmentioning

confidence: 99%

Genetic polymorphisms in the immune response: A focus on kidney transplantation

Stojanova

Pouché

Picard

2016

Clinical Biochemistry

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“…The most interesting -308 variant of the gene has a potential functional effect, being associated with elevated TNF levels (Elahi et al, 2009). One of the first large genetic association studies containing cytokine gene polymorphisms was done by Mytilineos et al (2004). A total of 2,298 first and 1,901 repeat kidney recipients were included in the study involving 73 transplant centres.…”

Section: Cytokine Genes Associate With Poor Outcome Of Kidney Transplmentioning

confidence: 99%

“…A total of 2,298 first and 1,901 repeat kidney recipients were included in the study involving 73 transplant centres. An association was found between the high TNF producer genotype -308A and lower graft survival (P=0.0116 after Bonferroni correction) in retransplant patients (Mytilineos et al, 2004). Other parameters than graft survival were not analysed due to difficulties in getting standardized clinical variables from different centres in the retrospective study.…”

Section: Cytokine Genes Associate With Poor Outcome Of Kidney Transplmentioning

confidence: 99%