Hepatotoxicity Associated With Cyclosporine Monitoring Using C2 Recommendations in Adults Renal Recipients Receiving Ketoconazole

Videla, C; Vega, Jorge; Borja, Hernán

doi:10.1016/j.transproceed.2004.09.011

Cited by 13 publications

(6 citation statements)

References 9 publications

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“…In this situation, the CsA AUC correlates better with C 0 than C 2 . Dose adjustments based on C 2 levels may lead to CsA toxicity (78). Trough concentration monitoring therefore should be used to adjust drug dosage.…”

Section: Rationalementioning

confidence: 99%

Special Issue: KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients

Eckardt¹,

Kasiske²,

Zeier³

2009

American Journal of Transplantation

1,205

294

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Journal compilation © 2009 The American Society of Transplantation and the American Society of Transplant Surgeons doi: 10.1111/j.1600-6143.2009.02834.x S2 American Journal of Transplantation 2009; 9 (Suppl 3): S2-S2Since the first successful kidney transplantation in 1954 It is our hope that this document will serve several useful purposes. Our primary goal is to improve patient care. We hope to accomplish this in the short term by helping clinicians know and better understand the evidence (or lack of evidence) that determines current practice. By making this guideline broadly applicable, our purpose is to also encourage and enable the establishment and development of transplant programs worldwide. Finally, by providing comprehensive evidence-based recommendations, this guideline will also help define areas where evidence is lacking and research is needed. Helping to define a research agenda is an often neglected, but very important function of clinical practice guideline development.We used the GRADE system to rate the strength of evidence and the strength of recommendations. In all, there were only 4 (2%) recommendations in this guideline for which the overall quality of evidence was graded 'A,' whereas 27 (13.6%) were graded 'B,' 77 (38.9%) were graded 'C,' and 90 (45.5%) ' and 148 (74.7%) graded '2.' There were 3 (1.5%) recommendations graded '1A,' 16 (8.1%) were '1B,' 18 (9.1%) were '1C, ' and 13 (6.6%) were '1D.' There was 1 (0.5%) graded '2A,' 11 (5.6%) were '2B,' 59 (29.8%) were '2C, ' and 77 (38.9%) BackgroundExcept perhaps for transplantation between identical twins, all kidney transplant recipients (KTRs) need immunosuppressive medications to prevent rejection. Induction therapy is treatment with a biologic agent, either a lymphocyte-depleting agent or an interleukin 2 receptor antagonist (IL2-RA), begun before, at the time of, or immediately after transplantation. The purpose of induction therapy is to deplete or modulate T-cell responses at the time of antigen presentation. Induction therapy is intended to improve the efficacy of immunosuppression by reducing acute rejection, or by allowing a reduction of other components of the regimen, such as calcineurin inhibitors (CNIs) or corticosteroids. Available lymphocytedepleting agents include antithymocyte globulin (ATG), antilymphocyte globulin (ALG) and monomurab-CD3. Basiliximab and daclizumab, the two IL2-RAs that are currently available in many parts of the world, bind the CD25 antigen (interleukin-2 [IL2] receptor a-chain) at the surface of activated T-lymphocytes and thereby competitively inhibit IL2-mediated lymphocyte activation, a crucial phase in cellular immune response of allograft rejection. Rationale• There is high-quality evidence that the benefits of IL2-RA vs. no IL2-RA (or placebo) outweigh harm in a broad range of KTRs with variable immunological risk and concomitant immunosuppressive medication regimens.• There is moderate-quality evidence that a lymphocytedepleting agent vs. no lymphocyte-depleting a...

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Section: Rationalementioning

confidence: 99%

Special Issue: KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients

Eckardt¹,

Kasiske²,

Zeier³

2009

American Journal of Transplantation

1,205

294

View full text Add to dashboard Cite

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“…In the ketoconazole group, the rejection rate was even lower than that in the control group in the first few months . This result may be explained by the following: (a) increased prednisolone exposure and immunosuppressive effects; (b) reduced toxicity of immunosuppressants at the low dose; (c) low immunocompetence; and (d) the addition of ketoconazole resulted in an inhibition of cyclosporine metabolism, resulting in more parent compounds, which are known to be more immunosuppressive than cyclosporine metabolites as postulated by First et al…”

Section: Discussionmentioning

confidence: 85%

“…the following: (a) increased prednisolone exposure and immunosuppressive effects16 ; (b) reduced toxicity of immunosuppressants at the low dose17 ; (c) low immunocompetence; and (d) the addition of ketoconazole resulted in an inhibition of cyclosporine metabolism, resulting in more parent compounds, which are known to be more immunosuppressive than cyclosporine metabolites as postulated byFirst et al 9 Graft function can be measured by SCr levels to some extent in kidney transplant patients. Our review found that there was no significant difference in the creatinine values between the two groups.…”

mentioning

confidence: 99%

Efficacy and safety of ketoconazole combined with calmodulin inhibitor in solid organ transplantation: A systematic review and meta‐analysis

et al. 2019

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What is known and objective Calcineurin inhibitors (CNIs) can significantly improve the results of solid organ transplantation regarding graft and patient survival. However, the high cost, chronic nephrotoxicity and other side effects are major challenges for the long‐term use of these drugs. Ketoconazole can significantly increase the plasma concentration of CNIs by inhibiting the activity of the cytochrome P450 enzyme. The combination of ketoconazole‐CNIs can reduce the cost of medication for patients by reducing the dosage of CNIs, but its safety is still controversial. Therefore, this study was designed to assess the safety and efficacy of this combination. Methods We performed a systematic literature search in PubMed, Embase, Cochrane Library and clinicaltrials.gov for randomized controlled trials on ketoconazole and CNI (cyclosporin or tacrolimus) co‐administration in solid organ transplantation. Two authors independently selected studies, assessed the risk of bias and extracted data. The meta‐analysis was performed in RevMan 5.3 provided by the Cochrane Collaboration. PROSPERO registration number: CRD42019118796. Results and discussion Five relevant trials with 326 patients were included. Compared with the controls, ketoconazole combined with CNIs can significantly reduce the dose of CNIs in patients receiving solid organ transplantation (WMD = −203.04 mg/day; 95% CI: −310.51 to −95.57, P = .0002). There was no significant difference in serum creatinine between the experimental group and the control group (WMD = −0.19 mg/mL; 95% CI: −0.52 to 0.14, P = .26). In addition, there was no significant difference in the number of rejections between the two groups (OR = 0.58; 95% CI: 0.27 to 1.22, P = .15). What's new and conclusion The co‐administration of ketoconazole and CNIs can significantly reduce the dose of CNIs. This combination may be safely used as a CNI‐sparing agent from the time of solid organ transplantation with low‐dose ketoconazole, based on the findings of this review.

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“…We had observed a rise in several liver function parameters in some of these C2‐patients, but realized that the only recent publication addressing this phenomenon is from Videla et al. [17] who reported a series of cases with severe, even ‘life‐threatening’ hepatotoxicity associated with CsA‐monitoring using C2‐recommendations. These renal transplant recipients, however, had also received ketoconazole.…”

Section: Introductionmentioning

confidence: 95%

Analysis of liver function in renal transplant recipients undergoing C2-monitoring for cyclosporine

et al. 2008

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Summary There exists no systematic evaluation of liver function in renal allograft recipients undergoing C2‐monitoring with Neoral® [cyclosporine A (CsA)‐microemulsion]. In the present cohort analysis, we compared the hepatic profiles of C2‐monitored (n = 80), C0‐monitored (n = 81), and non‐CsA‐treated renal allograft recipients (n = 29), transplanted between 1/1999 and 2/2004 in our institution. While the C2‐targets were set in accordance with (n = 72) or below (n = 8) the consensus on Neoral® (1500 ± 200 ng/ml), non‐CsA‐patients received FK506 (n = 29), partially in combination with rapamycin (n = 13) as primary immunosuppression. Analysis of maximum hepatic laboratory parameters and also repeated measures by anova within 30 days post‐transplant revealed highly significant elevations of direct, indirect and total bilirubin, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, and lactate dehydrogenase (P < 0.001) in the C2‐group, in comparison with the C0‐ and the non‐CsA‐group. Bilirubin‐levels were by far the most affected of all hepatic parameters, and correlated with C2‐levels (r2 = 0.62). Seventeen CsA‐patients had excessive bilirubin‐elevations (>4 mg/dl) and were therefore considered to be ‘CsA‐sensitive’ [14 C2‐patients (17% of all C2‐patients), 3 C0‐patients (4% of all C0‐patients)]. Bilirubin‐ and the other parameter elevations in these patients were reversible upon withdrawal or lowering of CsA. Most ‘CsA‐sensitive’ patients (n = 12, 70%) displayed pre‐transplant hepatic impairment, indicating a pre‐existing liver instability. Collectively, our data emphasize the need for increased awareness toward individual predispositions for CsA‐sensitivity.

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Hepatotoxicity Associated With Cyclosporine Monitoring Using C2 Recommendations in Adults Renal Recipients Receiving Ketoconazole

Cited by 13 publications

References 9 publications

Special Issue: KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients

Special Issue: KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients

Efficacy and safety of ketoconazole combined with calmodulin inhibitor in solid organ transplantation: A systematic review and meta‐analysis

Analysis of liver function in renal transplant recipients undergoing C2-monitoring for cyclosporine

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