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Saudi Journal of Kidney Diseases and Transplantation
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REVIEW ARTICLE Table of Contents   
Year : 2010  |  Volume : 21  |  Issue : 6  |  Page : 1030-1037
New concepts to individualize calcineurin inhibitor therapy in renal allograft recipients

1 Department of Nephrology, University Hospital, INF 162, Heidelberg, Germany
2 Department of Immunology, University of Heidelberg, INF 400, Heidelberg, Germany

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Date of Web Publication4-Nov-2010


A maximum of efficacy with a minimum of toxicity is the ultimate goal of immuno­suppressive therapy. Calcineurin inhibitors are widely used as immunosuppressive drugs, and there is still a discussion about the optimal blood levels of cyclosporine A (CsA) and tacrolimus (Tac), balancing safety and efficacy. Monitoring of calcineurin inhibitor therapy is usually per­formed by blood trough levels, pharmacokinetics such as measurement of two-hour peak levels, or by various areas under the curve assessments (AUC, 4 to 12 hours). All these mentioned phar­macokinetic measurements cannot predict the individual biological effects of the immuno­suppressive drug. Several approaches have been undertaken to measure immunosuppression by calcineurin inhibitors. In this manuscript, general and specific immune monitoring strategies of calcineurin inhibitors and their clinical benefits are discussed.

How to cite this article:
Sommerer C, Giese T, Meuer S, Zeier M. New concepts to individualize calcineurin inhibitor therapy in renal allograft recipients. Saudi J Kidney Dis Transpl 2010;21:1030-7

How to cite this URL:
Sommerer C, Giese T, Meuer S, Zeier M. New concepts to individualize calcineurin inhibitor therapy in renal allograft recipients. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2021 Sep 28];21:1030-7. Available from: https://www.sjkdt.org/text.asp?2010/21/6/1030/72287

   Introduction Top

Since the introduction of calcineurin inhibitors (CNI) cyclosporine A (CsA) and tacrolimus (Tac), acute rejection rates have improved remarkably. [1] Unexpectedly, the overall renal allograft survival remained stable during the last decade. [2] With the expanding application of CNIs, undesirable side effects have come into focus. [3],[4],[5],[6] Especially in CNIs, the optimal moni­toring strategies are discussed in terms of safety and efficacy. [7] Pharmacokinetic (PK) monitoring of CNI (CsA, Tac) treatment by C0 levels is widely accepted. Certainly, the most reliable PK parameter for CNI dosing is the assess­ment of the CNI area under the concentration time curve (AUC) within 12 hours, a strategy hardly practicable in clinical routine. [8],[9],[10],[11] Never­theless, all PK monitoring strategies do not reflect the biological activity of the drug. [7],[12]

Recently, pharmacodynamic (PD) monitoring has been proposed as a new strategy to provide information about the biological effect of a specific drug.

   General Pharmacodynamic Assays for CNI Monitoring Top

Non-specific PD biomarkers are utilized to reflect the activity of the immune system. It is assumed that a combined effect of multiple immunosuppressive drugs can be anticipated. Several biomarkers are applied to detect occu­rring clinical events, such as acute rejection episodes, as early as possible.

The pharmacological effect on immune cells is quantified by PD assays, which measure immune functions responsible for graft rejec­tions. Most of the currently used immunosup­pressive drugs inhibit lymphocyte prolifera­tion. Several study groups investigated flow­cytometric or radio-nucleotide-based lympho­cyte proliferation in stimulated whole blood cultures or peripheral blood mononuclear cells (PBMCs). [13] Others assessed T-cell activation markers, such as CD25 and CD71 on CD4 + and CD8 + lymphocyte subsets or on natural killer cells. [14],[15] In various studies, the potential prediction of tolerance by natural regulatory T­ cells (CD4 + CD25 high FOXP3 + ) is evaluated. Pre­-clinical transplant models suggested their role in preventing allograft rejection and tolerance induction. [16] However, its clinical usefulness for guiding immunosuppressive drug weaning has not been verified so far.

Some of these suggested PD markers have already been evaluated in a substantial number of clinical studies. Two promising immune monitoring markers namely, the soluble CD30 molecule and T-cell adenosine triphosphate re­lease, are discussed in the following sections.

Soluble CD30 molecule

One of the key interesting immune monito­ring biomarkers is the soluble CD30 (sCD 30) molecule. sCD30 has been proposed as a T-cell activation marker with prognostic value regar­ding acute rejection episodes and renal allo­graft survival. [17] The sCD30 molecule is a member of the tumor necrosis factor/nerve growth factor receptor super family and pre­ferentially expressed on human CD4 + and CD8 + T cells that secrete Th2-type cytokines, whereas no or low CD30 expression is found on Th1-type cytokine-secreting T cells. [18] A so­luble form of CD30 is released into the blood­stream after activation of CD30 + T cells. [19] The five-year graft survival rate in 901 recipients with a high pre-transplant serum sCD30 ( - 100 U/mL) was 64 ± 2%, significantly lower than the 75 ± 1% rate in 2998 recipients with low sCD30 (< 100 U/mL) (P < 0.0001) including pa­tients on CsA and Tac treatment. [17] The sCD30 effect on graft survival was also evident in pre­sensitized patients with lymphocytotoxic anti­bodies and in patients who received grafts that were poorly HLA-matched. Recipients with a high pre-transplant sCD30 continued to lose grafts at a higher rate during the five-year fo­llow-up period, indicating that pre-transplant sCD30 is not only a predictor of acute rejec­tions but also a predictor of deterioration in chronic allograft nephropathy. [20] A more recent study confirmed a significant correlation bet­ween high levels of pre-transplant sCD30 and increased incidence of post-transplant viral and bacterial infections and increased serum crea­tinine. [21] Therefore, sCD30 is a marker for allo­reactive immune responses and identification of patients at high-risk of rejection-related complications. However, the predictive value for the post-transplant outcome at the indivi­dual level remains rather low.

Adenosine triphosphate (ATP) release of CD4 + T cells

A commercially available laboratory test mea­suring the concentration of adenosine triphos­phate (ATP) released after phytohemagglutinin (PHA) stimulation of CD4 + T cells (Immu­Know TM ; Cylex, Inc., Columbia, MD) was ap­proved by the US Food and Drug Adminis­tration (FDA) to measure global immune com­petence in solid organ transplant patients re­ceiving immunosuppressive therapy. [22] Although this is not a specific immunological response, previous reports in organ transplantation have shown that results of the ImmuKnow TM assay correlate with the clinical states of over- and under-immunosuppression in pediatric and adult allograft recipients independent of the type of immunosuppression. This immune monitoring assay has been proven clinically useful in identifying patients at risk of graft failure or infections, even prior to the development of clinical symptoms. [23] Low ImmuKnow TM ATP values seems to indicate a state of over­immunosuppression with an in creased risk of bacterial or viral infections such as cytomega­lovirus (CMV), Epstein-Barr virus (EBV) and polyoma virus (BKV), where-as a higher than normal ATP level is associated with rejection of the graft in organ transplantation. [24] Al­though many of the studies support the po­tential use of ImmuKnow TM assay in guiding immunosuppressive therapy after transplanta­tion, its contribution remains controversial and is not uniformly accepted. [25] There is a lack of large prospective interventional studies until now. Moreover, the adequacy of ATP release in PHA-stimulated CD4 + T-cells is discussed, since ATP reflects the over-all energy meta­bolism of cells and is not specific for immuno­suppressive drugs.

   Specific PD assays for CNI monitoring Top

A PD monitoring assay is only useful if it provides reliable and valid results, if it is easy to perform and if a clinical benefit has been proven. The principal action of CNIs, CsA and Tac, within the T-lymphocytes is the inhibition of the phosphatase calcineurin. Calcineurin is a key component of T-cell activation and acts as a target of the CsA-cyclophilin and Tac­FK506-binding protein 12 complexes. The in­hibition of calcineurin down-regulates the de­phosphorylation of the nuclear factor of acti­vated T-cells (NFAT) and consequently pre­vents the translocation of the transcription fac­tor NFAT into the nucleus of activated T­lymphocytes. Subsequently, the transcription of several central genes of the immune system, such as interleukin 2 (IL-2) or interferon-y (IFNγ) ) are blocked [Figure 1].
Figure 1 :A model of drug-specific pharmacodynamic monitoring of cyclosporine A and tacrolimus.

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T-cell immune monitoring reflects the inten­sity of specific CNI-induced immunosuppre­ssion in an individual patient and these new approaches are supposed to overcome the li­mitations of PK monitoring and guide optimal drug dosing. [26] A considerable number of ap­proaches have been undertaken to assess the PD consequences of CNI-based immunosup­pression and several PD parameters have been identified for the monitoring of immunosup­pressive therapy. These efforts resulted in the identification of promising biomarkers for spe­cific PD monitoring of calcineurin inhibitor dependent immunosuppression.

Calcineurin phosphatase activity

One of these specific T-cell immune monito­ring strategies quantified the individual immu­nosuppressive effect of CNIs on calcineurin phosphatase activity. [27],[28],[29] Different methods to assess calcineurin phosphatase activity have been evaluated: high performance liquid chro­matography (HPLC)-ultraviolet measurement of dephosphorylated peptide, [30] the radioactive measurement of [32] P-labeled phosphate [31] and a spectrophotometric method. [32] The calcineurin phosphatase activity is measured in various blood fractions as whole blood, [33] PBMCs, [34] and leukocyte subsets. [35] A cell-specific acti­vity has been recognized and, for this reason, inter- and intra-individual variations in leuko­cyte subset cell counts may influence mea­sured calcineurin phosphatase activity. [35] The activity of calcineurin phosphatase in lympho­cytes correlates inversely with blood CsA con­centrations. A high inter- and intra-individual variability in calcineurin phosphatase activity for CsA and Tac has been reported. Renal transplant patients exhibited an overall calci­neurin phosphatase activity of 50% of healthy volunteers and the peak CsA blood concen­trations resulted in a 70 to 96% reduction in calcineurin phosphatase activity. [27],[36] In Tac­treated patients, the maximum inhibitory effect on calcineurin phosphatase activity was about 60%. [27],[29] Calcineurin phosphatase activity cor­related inadequately with drug dosages or PK data in PK/PD studies. [33] These findings prove that immunosuppressive drugs induce a variety of inter-individual patient responses. Only li­mited data are available on PD monitoring of calcineurin phosphatase activity and clinical outcomes. Despite a poor but existing rela­tionship between drug concentration and calci­neurin phosphatase activity, no clear associa­tion between calcineurin phosphatase activity and clinical adverse events has been reported. [37] The clinical meaning has been maintained by the observation that a lower calcineurin phos­phatase activity results in a higher rate of graft-versus-host diseases in bone marrow re­cipients on CsA therapy. [38] This is confirmed by the clinical study of Sanquer et al [39] demons­trating that calcineurin activity predicts graft­ versus-host-disease in allogenic stem-cell trans­plantation. In organ transplant patients, calci­neurin phosphatase activity has been eva­luated in stable renal transplant patients with a higher baseline activity in low-dose CsA in comparison to standard-dose CsA, however, it is of note, that calcineurin phosphatase activity was similar at CsA C 2 . [40] High calcineurin phosphatase activity resulted in acute rejection episodes in liver transplant recipients on CsA and Tac therapy. [41]

T-cell specific cytokines

Some other studies have focused on T-cell specific cytokine production as PD parameters. With enzyme-linked immunosorbent assay (ELISA) and flow-cytometric techniques, the concentrations of cytokines or chemokines have been measured in whole blood, serum and in­tracellular in stimulated PBMCs derived from patients after transplantation. [15],[42],[43] Several interesting effector cytokine patterns of CD4 + T cells have been defined. For example, CD4 + T­cell effector cytokines such as IL-2, IFN-γ and TNF-α have been defined as predictor of acute rejection, and a decreased ratio of CD4 + T-cell to CD8 + T-cell cytokines has been confirmed as predictor of graft acceptance. IL-2 protein was measured in mitogen-activated whole blood. [44] The addition of mycophenolic acid to CsA or Tac-based immunosuppression reduced IL-2 production, demonstrating that it is not merely a CNI specific response of the T-cell effector cytokine IL-2. [34] Some study results confirmed an even tight co-rrelation between CsA C0 or C 2 levels and IL-2 production, [43],[44] while other studies failed to prove this strong association. [14] Concerning clinical outcome, only limited data are available. In a small study co­hort, an association between pre-transplant IL­2 production and the risk of acute rejection has been proposed. [45] Other study groups revealed the T-cell effector cytokine IFN-γ as a more specific marker of the CsA-induced immuno­suppressive effect. [40] However, monitoring of cytokine production is a problematic issue as a result of restrictions to certain cell cycle pha­ses, different half-lives for the circulation of cytokines and changes in the up- and down-regulation of cytokine expression. [46]

Cytokine mRNA expression

Detection of the messenger RNA (mRNA) level as a marker of the degree of calcineurin inhibition has been introduced to assess the degree of calcineurin inhibition. [44],[45] Hartel et al [47] described a human whole blood assay based on quantitative real-time cytokine reverse trans­cription polymerase chain reaction (rt-PCR) for PD monitoring. The authors observed a de­creased basal mRNA expression of TNFα in patients on CsA therapy and retarded cytokine mRNA expression kinetics during T-cell co­stimulation. These data suggested that distinct shifts in peak cytokine mRNA expression may represent a sensitive PD marker of individual CsA response. For prospective studies on cyto­kine mRNA concentrations, the parameter "area of cytokine mRNA expression over time" was suggested as PD monitoring tool, which should include absolute cytokine mRNA con­centrations measured at two different time points. The same study group investigated the potential PD effects of Tac on IL-2 mRNA expression in an in vitro human whole-blood assay. [45] IL-2 mRNA profiles revealed variable Tac sensitivity. Kinetic profiles of IL-2 mRNA expression demonstrated individually distinct degrees of CNI sensitivity in patients under­going Tac monotherapy before living-donor kidney transplantation. Individuals with un­affected IL-2 mRNA expression may be at in­creased risk of transplant rejection. Other stu­dies have investigated the expression of cyto­kines in kidney-transplant biopsies. [48] Recently, quantitative analysis of gene expression was employed to measure directly the functional effects of calcineurin inhibition: the transcrip­tional activities of NFAT-regulated genes in the peripheral blood. [49],[50],[51] This assay is based on the quantitative analysis of the gene ex­pression of the three NFAT-regulated cytokine genes IL-2, IFN-γ and granulocyte macrophage colony-stimulating factor (GM-CSF). Blood samples are taken at CNI trough, and the rela­tive inhibition of gene expression after oral drug intake is calculated at CNI peak level.

A short time ago, the assessment of NFAT­ regulated gene expression has been established to ameliorate CNI-specific PD monitoring. Se­veral clinical studies affirmed this approach as a useful tool with potential to individualize CNI therapy. The expression of NFAT-regu­lated genes correlated inversely with both CsA and Tac levels. [50] Similar to calcineurin phos­phatase activity, a high inter-individual varia­bility of NFAT-regulated gene expression in patients with corresponding CsA or Tac doses has been observed. Even in long-term renal transplant patients, there was a high variability in residual NFAT-regulated gene expression va­rying from 2 to 50%, which confirms various degrees of immunosuppression and T-cell acti­vation. On the other side, intra-individual va­riability of residual NFAT-regulated gene expre­ssion was low in repetitive measurements in one single patient with a stable CNI dose. [51] The monitoring of residual NFAT-regulated gene expression has been proven in clinical studies as a useful and safe tool to reduce CsA therapy. [52] CsA-treated patients with low resi­dual expression of NFAT-regulated genes were more likely to get recurrent infections or tu­mors, [51],[53] and patients with a low residual NFAT-regulated gene expression have an in­creased risk of non-melanoma skin cancer. [54] Elderly long-term renal transplant patients were at an increased risk for non-melanoma skin cancer if residual NFAT-regulated gene expre­ssion was below 15%. In a biopsy-controlled study, the stepwise reduction of CsA dose and the following increase of residual NFAT-regu­lated gene expression proceeded without ad­verse effects. [52] One patient had an acute cel­lular rejection with a residual NFAT-activity above 40% after the tapering of the CsA dose. In addition, the reduction of CsA dose resulted in a decrease of systolic and pulse pressure. An optimal range of residual NFAT-regulated gene expression has been proposed between 20 and 30% in long-term stable renal transplant patients. However, data on de novo renal trans­plant patients and recipients of other solid or­gans are not available.

   Conclusion Top

The optimal monitoring strategy of CNI the­rapy is still a controversial issue. Monitoring by traditional pharmacokinetic data is ham­pered by the fact of missing perfect association between drug exposure and PD effects. Seve­ral approaches have been undertaken to de­velop tools for pharmacodynamic monitoring of CNI therapy. General and drug-specific PD monitoring strategies which determine phar­macological efficacy constitute encouraging tools to assist clinical decisions on individual dosaging. Although the concept of PD moni­toring is attractive and although preliminary reports reveal associations between the diffe­rent PD markers and clinical outcomes, none of these methods is broadly validated or ac­cepted in clinical practice. Studies in larger pa­tient populations are desired to confirm indi­vidual benefits of these promising approaches.

   References Top

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51.Sommerer C, Konstandin M, Dengler T, et al. Pharmacodynamic monitoring of cyclosporine A in renal allograft recipients shows a quan­titative relationship between immunosuppre­ssion and the occurrence of recurrent infections and malignancies. Transplantation 2006;82: 1280-5.  Back to cited text no. 51
52.Sommerer C, Giese T, Schmidt J, Meuer S, Zeier M. Ciclosporin A Tapering monitored by NFAT­regulated gene expression: A new concept of individual immunosuppression. Transplantation 2008;85:15-21.  Back to cited text no. 52
53.Konstandin MH, Sommerer C, Doesch A, et al. Pharmacodynamic cyclosporine A-monitoring: relation of gene expression in lymphocytes to cyclosporine blood levels in cardiac allograft recipients. Transpl Int 2007;20:1036-43.  Back to cited text no. 53
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Correspondence Address:
Claudia Sommerer
Department of Nephrology, University of Heidelberg , Im Neuenheimer Feld 162 D-69120 Heidelberg
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3 Influence of poly (ethylene glycol) in cyclosporine a loaded PVM/MA nanoparticles and oral absorption of the drug
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