Nephrotoxicity of immunosuppressive drugs: new insight and preventive strategies

Olyaei, Ali J.; Mattos, Angelo M. de; Bennett, William M.

doi:10.1097/00075198-200112000-00003

Cited by 263 publications

(165 citation statements)

References 36 publications

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“…Treatment with either inhibitor reduces immune-mediated rejection following organ transplantation. However, they also cause side effects, including nephrotoxicity, hypertension, and increased risk of cardiovascular events (52,53). The pathogenesis of nephrotoxicity and the other side effects induced by calcineurin inhibitors are complex and incompletely understood, but among the factors implicated are renal and systemic vasoconstriction, increased release of endothelin-1, and increased expression of TGF-␤1.…”

Section: Discussionmentioning

confidence: 99%

Calcineurin Negatively Regulates TLR-Mediated Activation Pathways

Kang

Kusler

Otsuka

et al. 2007

The Journal of Immunology

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In innate immunity, microbial components stimulate macrophages to produce antimicrobial substances, cytokines, other proinflammatory mediators, and IFNs via TLRs, which trigger signaling pathways activating NF-κB, MAPKs, and IFN response factors. We show in this study that, in contrast to its activating role in T cells, in macrophages the protein phosphatase calcineurin negatively regulates NF-κB, MAPKs, and IFN response factor activation by inhibiting the TLR-mediated signaling pathways. Evidence for this novel role for calcineurin was provided by the findings that these signaling pathways are activated when calcineurin is inhibited either by the inhibitors cyclosporin A or FK506 or by small interfering RNA-targeting calcineurin, and that activation of these pathways by TLR ligands is inhibited by the overexpression of a constitutively active form of calcineurin. We further found that IκB-α degradation, MAPK activation, and TNF-α production by FK506 were reduced in macrophages from mice deficient in MyD88, Toll/IL-1R domain-containing adaptor-inducing IFN-β (TRIF), TLR2, or TLR4, whereas macrophages from TLR3-deficient or TLR9 mutant mice showed the same responses to FK506 as those of wild-type cells. Biochemical studies indicate that calcineurin interacts with MyD88, TRIF, TLR2, and TLR4, but not with TLR3 or TLR9. Collectively, these results suggest that calcineurin negatively regulates TLR-mediated activation pathways in macrophages by inhibiting the adaptor proteins MyD88 and TRIF, and a subset of TLRs.

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Section: Discussionmentioning

confidence: 99%

Calcineurin Negatively Regulates TLR-Mediated Activation Pathways

Kang

Kusler

Otsuka

et al. 2007

The Journal of Immunology

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“…This effect was surprising since lack of nephrotoxicity is a well-known characteristic of sirolimus (21)(22)(23)(24). Sirolimus exerts its immunosuppressive effect by inhibiting the mammalian target of rapamycin, an enzyme required for T-and B-cell proliferation and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Sirolimus Prolongs Recovery from Delayed Graft Function After Cadaveric Renal Transplantation

McTaggart

Gottlieb

Brooks

et al. 2003

American Journal of Transplantation

163

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Sirolimus, lacking known nephrotoxicity, appeared to be an ideal immunosuppressive agent in the setting of delayed graft function (DGF) after renal transplantation. Coincident with our use of sirolimus however, we noticed prolongation of DGF. To investigate possible causes of prolonged DGF, extensive donor, recipient, transplant, and post-transplant data were collected on 132 consecutive cases of DGF at the University of California, San Francisco between 1/1/97 and 6/30/01. Cox proportional hazards analysis of time to graft function was used in univariate and multivariate models to identify factors that prolong DGF. Sirolimus had a large and highly significant effect on time to graft function (hazard ratio 0.48, p = 0.0007). The hazard ratio indicates that a recipient on sirolimus is half as likely to resolve DGF or twice as likely to remain on dialysis as a recipient without sirolimus. Two other factors had less potent but still significant association with DGF duration: recipient sensitization (hazard ratio 0.66, p = 0.037), and Novartis score (hazard ratio 0.93 per 1.0 increase; p = 0.034). Sirolimus retained its profound negative association with time to graft function in all multivariate models. Because sirolimus appears to prolong DGF, it may not be the optimal immunosuppressive choice in the DGF setting.

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“…Transforming growth factorbeta (TGF-b), which is increased by exposure to calcineurin inhibitor drugs (27), inhibits the proliferation of hematopoietic progenitor cells (28) by acting through its receptors TGFBR1, TGFBR2 and TGFBR3. The expression of TGFBR3 was increased by a mean of 1.6-fold in all rejecting anemic samples studied ( Figure 1); this may imply enhanced signaling activity leading to reduction in red blood cell production.…”

Section: Gene Profiling Of Anemia In Renal Transplantationmentioning

confidence: 99%

Molecular Profiling of Anemia in Acute Renal Allograft Rejection Using DNA Microarrays

Chua

Barry

Salvatierra

et al. 2003

American Journal of Transplantation

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Compromised renal function after renal allograft transplantation often results in anemia in the recipient. Molecular mechanisms leading to anemia during acute rejection are not fully understood; inadequate erythropoietin production and iron deficiency have been reported to be the main contributors. To increase our understanding of the molecular events underlying anemia in acute rejection, we analyzed the gene expression profiles of peripheral blood lymphocytes (PBL) from four pediatric renal allograft recipients with acute rejection and concurrent anemia, using DNA microarrays containing 9000 human cDNA clones (representing 7469 unique genes). In these anemic rejecting patients, an 'erythropoiesis cluster' of 11 down-regulated genes was identified, involved in hemoglobin transcription and synthesis, iron and folate binding and transport. Additionally, some alloimmune response genes were simultaneously down-regulated. An independent data set of 36 PBL samples, some with acute rejection and some with concurrence of acute rejection and anemia, were analyzed to support a possible association between acute rejection and anemia. In conclusion, analysis using DNA microarrays has identified a cluster of genes related to hemoglobin synthesis and/or erythropoeisis that was altered in kidneys with renal allograft rejection compared with normal kidneys. The possible relationship between alterations in the expression of this cluster, reduced renal function, the alloimmune process itself, and other influences on the renal transplant awaits further analysis.Key words: Anemia, gene expression, microarrays, rejection, renal transplantation Abbreviations: ALAS, delta-aminolevulinate synthase-2; CA1, carbonic anhydrase I; EPO, erythropoietin; MPP1, membrane protein, palmitoylated 1 55 kDa; NF-E2, nuclear factor (erythroid-derived 2); PBL, peripheral blood lymphocytes; rHuEPO, recombinant human EPO; TGF-b, transforming growth factor-beta

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Nephrotoxicity of immunosuppressive drugs: new insight and preventive strategies

Cited by 263 publications

References 36 publications

Calcineurin Negatively Regulates TLR-Mediated Activation Pathways

Calcineurin Negatively Regulates TLR-Mediated Activation Pathways

Sirolimus Prolongs Recovery from Delayed Graft Function After Cadaveric Renal Transplantation

Molecular Profiling of Anemia in Acute Renal Allograft Rejection Using DNA Microarrays

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