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and individualisation of immunosuppression&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Renal transplant success largely resides in the use of potent immunosuppressive drugs that limit the ability of the immune system to reject allografts&#46; During the early post-transplant period&#44; recipients usually receive drugs whose dose is measured in mg&#47;kg body weight until the target blood levels are achieved&#44; which show great variability between individuals&#46;<span class="elsevierStyleSup">1</span> In clinical practice the difficult balance between over-immunosuppression with its adverse effects and under-immunosuppression and the risk of rejection should be achieved&#46;<span class="elsevierStyleSup">2</span> The survival rate of long-term graft has not changed significantly over the last 20 years&#44; mainly due to lifelong use of immunosuppressant drugs&#46;<span class="elsevierStyleSup">3&#44;4</span> The ability to minimise and monitor immunosuppressive therapy individually in each patient would improve the long-term prognosis of renal transplantation and reduce the associated costs&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">IMMUNE MONITORING</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">It is impossible to monitor the overall clinical immunosuppression state of a patient by measuring only one parameter&#46;<span class="elsevierStyleSup">2</span> To date&#44; the biomarkers most used in clinical practice have been pharmacokinetics&#46; However&#44; it is the biomarkers related to the pharmacodynamic effects of immunosuppressants which are becoming more important&#46;<span class="elsevierStyleSup">5</span> In theory&#44; the routine study of &#40;an&#41; ideal biomarker&#40;s&#41; would identify those patients at risk of acute rejection&#44; infection or cancer&#44; and those patients susceptible to minimising immunosuppression&#46; It would also serve as a fundamental tool in the individual monitoring of patients with under or over-immunisation and could even complement and&#47;or replace pharmacokinetic monitoring&#46; Since the immune system responds quickly and is constantly changing&#44; regular and repeated monitoring of patients seems fundamental to understanding any immune response&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">BASICS OF ImmuKnow<span class="elsevierStyleSup">&#174;</span></span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The application of the assay was approved in 2010 by the Food and Drug Administration &#40;FDA&#41; for detection of cellular immune response in patients undergoing organ transplantation and receiving immunosuppressant treatment&#46;<span class="elsevierStyleSup">6&#44;7</span> Recently&#44; the assay also exceeded the requirements of the European directive for <span class="elsevierStyleItalic">in vitro</span> diagnosis&#46; Specifically&#44; it measures the ability of CD4&#43; T cells from a whole blood sample to react to polyclonal stimulus with phytohaemagglutinin &#40;PHA&#41; mitogen &#40;Figure 1&#41;&#46; As with immunosuppressive agents used in clinical practice&#44; PHA is not specific to any T cell&#44; and as such&#44; it reflects the ability of any of its subtypes to respond&#46; The method quantifies the amount of ATP produced by CD4&#43; T cells after overnight incubation with PHA&#46;<span class="elsevierStyleSup">8</span> ATP production is an early event in the cell activation process and reflects the response to mitogen stimulation&#46;<span class="elsevierStyleSup">9</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">In the case of solid organ transplantation&#44; acute rejection primarily presents in cell activation&#59; however&#44; every day there is increasing evidence of the importance of rejection mediated by antibodies&#46;<span class="elsevierStyleSup">10</span> CD4&#43; T Helper &#40;Th&#41; cells guide the immune response towards a type of cellular response &#40;Th1&#44; Th2&#44; Th17&#44; Tregs&#44; etc&#46;&#41; through the synthesis and secretion of various cytokine combinations&#44; depending on the type of antigen that it finds&#46; Although the purpose of this review is not to investigate multiple immunological mechanisms involved in acute rejection&#44; we must not forget that CD4&#43; T cells participate in all of them&#46; The importance of this assay is that it provides a functional overall measurement of Th cells and not only the measurement of a metabolite&#44; cell or a drug level&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Furthermore&#44; it is a reproducible method that minimises the variability that exists with other cellular assays&#44; detection through flow cytometry of the intracellular cytokine production or cell proliferation measured by the incorporation of tritiated thymidine&#46;<span class="elsevierStyleSup">11&#44;12</span> This is achieved because it adjusts the controls to blood volume and not to the number of cells in the assay&#46; It is considered that this situation more reliably reproduces the situation in the bloodstream than the use of a fixed and artificial number of cells&#46; The expected variability of intracellular ATP levels produced between transplant recipients is 11&#46;7&#37;&#46;<span class="elsevierStyleSup">8</span> Figure 2A shows the differences in the concentration of ATP produced based on blood volume according to the number of CD4&#43;&#47;ul blood cells in a group of renal transplant recipients undergoing induction treatment with thymoglobulin&#44; followed by triple standard maintenance immunosuppressive therapy&#46;<span class="elsevierStyleSup">13</span> Figure 2B also shows the lack of correlation between ATP assay values and tacrolimus<span class="elsevierStyleSup">13</span> trough levels&#46; That is&#44; the results of ImmuKnow<span class="elsevierStyleSup">&#174;</span> are unrelated to the number of CD4&#43; T cells and blood levels of immunosuppressants&#46; Furthermore&#44; the cellular immunity specific to each patient and therefore&#44; the changes that occur over time provide an individual immune profile that may be a prognosis of phenomena mediated by cellular immunity in relation to excessive or deficient immunosuppression&#46;<span class="elsevierStyleSup">2&#44;5&#44;14</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">ImmuKnow</span><span class="elsevierStyleBold"><span class="elsevierStyleSup">&#174;</span></span><span class="elsevierStyleBold"> AND ASSOCIATION WITH CLINICAL EVENTS</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">A retrospective multicentre study that included 10 American hospitals compared ImmuKnow<span class="elsevierStyleSup">&#174;</span> values with the clinical situation of more than 500 recipients of solid organ transplants &#40;kidney&#44; liver&#44; intestine and heart&#41;&#46; Table 1 shows how recipients with ImmuKnow<span class="elsevierStyleSup">&#174;</span> values between 130 and 450ng&#47;ml of ATP had a lower risk of infection or rejection than recipients with values above or below this range&#44; respectively&#46;<span class="elsevierStyleSup">15</span> Recipients with an output of 280ng&#47;ml of ATP had a negative predictive value of 96&#37; for both infection and rejection&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">These data have been replicated in other single centre studies in renal transplant patients&#46;<span class="elsevierStyleSup">13&#44;16-22</span> The areas under the ROC curve ranged between 0&#46;671 and 0&#46;845 for ATP values of 180ng&#47;ml&#46; The study by Berglund et al&#46;<span class="elsevierStyleSup">22</span> on renal&#44; renal pancreas or liver transplant patients showed that severe infections and mortality increased with ATP values below 175ng&#47;ml&#46; The absolute values of the assay are specific to each centre and depend on the specific characteristics of the patients and the immunosuppressive treatment load supplied by each centre&#46; The correlation between intracellular ATP production and clinical episodes shown by most studies is that the latter take place on diagnosis or about 30 days after the episode&#46; The statistical significance of the correlation is lost when the assay is carried out 90 days before the episode&#46;<span class="elsevierStyleSup">23</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Each type of allograft has its own characteristics according to the immune response that it induces&#46; The main risk of renal transplant in particular is infection by the BK virus&#46;<span class="elsevierStyleSup">23&#44;24</span> This virus latently infects 95&#37; of the adult kidneys&#44; but can lead to the development of BK nephropathy in immunocompromised patients&#46; It has been estimated that 20-40&#37; of transplant recipients develop viruria with only 12&#37; of viraemia&#46;<span class="elsevierStyleSup">23</span> Many centres periodically monitor the presence of viruria and BK viraemia by C-reactive protein &#40;CRP&#41;&#46;<span class="elsevierStyleSup">5&#44;26</span> Once BK virus is detected in the blood&#44; immunosuppression is reduced empirically or one or more immunosuppressants are eliminated&#46; The risk of rejection is increased if immunosuppression is reduced abruptly or is not restored in time&#46;<span class="elsevierStyleSup">27</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The study by Batal et al&#46;<span class="elsevierStyleSup">20</span> showed how measuring with ImmuKnow<span class="elsevierStyleSup">&#174;</span> in renal transplant patients identified those patients at increased risk of BK nephropathy&#46; BK viraemia patients showed mean ATP levels of 103ng&#47;ml&#44; while those with viruria or negatives had higher figures&#46; Within the viruria group&#44; patients with lower ImmuKnow<span class="elsevierStyleSup">&#174;</span> levels were associated with higher viral load in urine and&#44; furthermore&#44; these low levels correlating with viral replication eventually resulted in the development of viraemia&#46; In the abovementioned study&#44; of the three patients who developed BK nephropathy&#44; two had low ATP levels &#40;50 and 178ng&#47;ml&#41; 3 and 5 weeks before the development of nephropathy&#44; respectively&#46; The third patient was&#44; in principle&#44; negative for BK&#44; with ATP figures of 206ng&#47;ml&#46; Ten weeks later&#44; the values fell to 106ng&#47;ml and the patient developed BK viraemia&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The usefulness of reducing the risk of immunosuppressive infection with ImmuKnow<span class="elsevierStyleSup">&#174;</span> has also been described in the post-transplant lymphoproliferative disease caused by the Epstein Barr virus and cytomegalovirus &#40;CMV&#41; infection&#46;<span class="elsevierStyleSup">19&#44;28-30 </span>A series of 12 renal transplant recipients&#44; admitted due to infections&#44; had very low levels of ATP &#40;range 3-178ng&#47;ml&#41;&#46;<span class="elsevierStyleSup">29</span> Patients were treated with various maintenance immunosuppression regimens at the time of infection&#46; Treatment consisted of reducing or eliminating one or more of the immunosuppressants that they were receiving&#44; together with antiviral use in some cases&#46; ATP values in the weeks following this treatment increased while viral loads disappeared or were reduced to acceptable levels&#46; There were no episodes of rejection&#46; These results suggest that ImmuKnow<span class="elsevierStyleSup">&#174;</span> titration could be used to monitor an increase in immunosuppression in order to prevent rejection&#44; once the infection is resolved&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">A prospective observational study of 49 renal transplant patients who received induction therapy with basiliximab and maintenance with tacrolimus&#44; mycophenolate mofetil &#40;MMF&#41; and steroids&#44; without selection criteria&#44; determined the production of ATP by ImmuKnow<span class="elsevierStyleSup">&#174;</span> after 7&#44; 14&#44; 21 and 42 days&#44; and after 3&#44; 6 and 12 months after transplant&#46;<span class="elsevierStyleSup">19</span> Seventeen &#40;34&#46;6&#37;&#41; of recipients had infections including&#58; 11 with CMV infection&#44; 2 stomach invasive disease and colitis&#44; 2 with viruria and BK viraemia and two with bacterial infection&#46; All infectious episodes were accompanied by low levels of ATP&#46; CMV replication was predicted from low levels of ATP in 57&#46;1&#37; before the onset of clinical manifestations&#46; Reducing immunosuppression significantly decreased BK replication&#46; Three transplant patients showed clinical and laboratory signs of rejection&#44; which were confirmed by biopsy&#44; but only one showed high levels of ATP&#46; Therefore&#44; the study demonstrated the usefulness of ImmuKnow<span class="elsevierStyleSup">&#174;</span> in detecting infections and modifying immunosuppression&#44; without involving a risk of cell rejection&#46; The usefulness of ImmuKnow<span class="elsevierStyleSup">&#174;</span> for predicting the risk of infection was recently demonstrated in two meta-analyses in renal<span class="elsevierStyleSup">31</span> and liver<span class="elsevierStyleSup">32</span> transplant&#44; and is outlined in Figure 3&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">As well as helping predict the risk of infection associated with excessive immunosuppression&#44; ImmuKnow<span class="elsevierStyleSup">&#174;</span> has also been assessed as an intervention method for preventing toxicities associated with immunosuppression in transplant patients&#44; as with corticosteroids&#44; which can cause high morbidity&#46;<span class="elsevierStyleSup">33-37</span> Experimental protocols designed to reduce&#44; avoid or eliminate the use of steroids in transplants have incorporated the ImmuKnow<span class="elsevierStyleSup">&#174;</span> assay as a monitoring tool&#46; Thus&#44; a clinical trial involving 57 renal transplant patients&#44; of whom 27 were randomised for rapid reduction of the dose of corticosteroids&#44; assessed the utility of ImmuKnow<span class="elsevierStyleSup">&#174;</span>&#46;<span class="elsevierStyleSup">38</span> During the assay&#44; 53&#37; of the control patients were diagnosed with infection and 56&#37; of the latter also had several infections&#46; In contrast&#44; only 22&#37; of randomised patients developed infections and none had repeated infections &#40;<span class="elsevierStyleItalic">p</span>&#60;&#46;05&#41;&#46; There was no difference in the rate of rejection between the two groups&#46; In this assay&#44; employing ImmuKnow<span class="elsevierStyleSup">&#174;</span> to monitor the immune response helped reduce episodes of infection&#44; their duration and the elimination of steroids&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">In renal transplantation&#44; but also in other solid organ transplants&#44; it can be useful to reduce&#44; limit or eliminate anti-calcineurin &#40;ACN&#41; immunosuppression drugs&#46;<span class="elsevierStyleSup">36&#44;39-42</span> Two macrolides&#44; sirolimus and everolimus and mammalian target of rapamycin &#40;mTOR&#41; inhibitors are used as an alternative to ACN in maintenance immunosuppressive therapy&#46; One study compared ATP levels in stable renal transplant recipients maintained on sirolimus monotherapy with healthy control subjects and it showed how sirolimus treatment induced a significantly lower number of ATP&#44; together with a greater degree of proliferation inhibition in mixed lymphocyte culture and decreased production of interleukin 10 &#40;IL-10&#41;&#46;<span class="elsevierStyleSup">43</span> Other studies have also shown that very low values of ATP were accompanied by decreased production of IL-10 and increased risk of bacterial infection&#46;<span class="elsevierStyleSup">44</span> These results are similar to those of another study in 18 renal transplant patients which analysed the numbers of regulatory T cells and ATP production after conversion to mTOR inhibitors from ACN&#46;<span class="elsevierStyleSup">41</span> The regulatory T cell number increased in more than 80&#37; of converted patients and directly correlated with a mean decrease in the production of ATP from 328 to 248ng&#47;ml&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">A two-branch assay with 25 kidney-pancreas transplant patients converted from a maintenance treatment with sirolimus&#44; cyclosporine and corticosteroids to another with sirolimus and mycophenolic acid &#40;MPA&#41; used ImmuKnow<span class="elsevierStyleSup">&#174;</span> to prospectively monitor the immune response&#46;<span class="elsevierStyleSup">37&#44;40</span> ATP figures fell slightly and progressively in the 6 conversion months&#46; Subsequently&#44; the numbers gradually stabilised during the remainder of post-conversion follow-up year&#46; In this assay&#44; two patients showed permanent ATP values below 100ng&#47;ml and one patient developed CMV disease&#46; In these patients&#44; the MPA dose was reduced approximately by half and ATP values increased&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">A multicentre trial of steroid elimination&#44; randomised in 3 branches with 126 kidney transplant patients&#44; evaluated ImmuKnow<span class="elsevierStyleSup">&#174;</span> as a biomarker of cellular immunity with other methods&#44; such as ELISPOT&#44; flow cytometry&#44; donor-specific antibodies and HLA compatibility&#46;<span class="elsevierStyleSup">38</span> The three branches received thymoglobulin and prednisone as induction therapy until 5 days after transplant&#46; ATP levels were quantified before and after this induction treatment&#46; On average&#44; ATP values decreased from 322 to 172ng&#47;ml of ATP prior to randomisation&#46; Multivariate analysis of the data showed that a value of ATP&#62;375ng&#47;ml was the only variable that correlated &#40;<span class="elsevierStyleItalic">p</span>&#61;&#46;04&#41; with acute cellular rejection and unstable creatinine levels after transplantation&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Our group<span class="elsevierStyleSup">21</span> prospectively analysed InmuKnow<span class="elsevierStyleSup">&#174;</span> in renal transplant recipients in different clinical situations&#46; The assay was used to identify patients at risk of rejection or infection and the information obtained was useful for monitoring immunosuppression&#46; The study concluded that&#44; in stable or infected renal transplant patients with low levels of ATP&#44; the dose of immunosuppression can be reduced safely without increasing the risk of rejection&#46; In stable patients or those with rejection and high ATP figures&#44; the immunosuppression dose may be increased or other immunosuppressants added to prevent immunological damage to the graft&#44; but it seems to provide more useful information in cases of low ATP levels&#44; over-immunosuppression&#44; than in the contrary case&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Another retrospective study monitored the production of ATP before and after renal transplantation in 64 recipients<span class="elsevierStyleSup">16</span> and compared it to the type of immunosuppression&#44; doses&#44; blood levels&#44; serum creatinine concentration&#44; white blood cell count&#44; HLA typing&#44; preformed antibodies&#44; adverse effects&#44; infections and rejections&#46; There was no association of the assay with any clinical test&#44; but there were high levels of pretransplant ATP in those with more rejection episodes &#40;8&#47;10&#41;&#44; while patients with low ATP numbers had more infections &#40;6&#47;10 <span class="elsevierStyleItalic">P</span>&#60;&#46;001&#41;&#46; Patients treated for rejection showed a decrease in ATP figures&#44; 5 days after treatment was begun &#40;<span class="elsevierStyleItalic">P</span>&#61;&#46;002&#41;&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The management of immunosuppression has acquired a more complex factor with the appearance of generic ACN and MMF preparations&#46; The narrow therapeutic window of these drugs and the high degree of variability in patients increases the difficulty&#44; since the problem is not just about changing an innovative commercial drug to the generic formula&#46; It is likely that the use of the revised assay here before and during the change to the generic preparation &#40;similar to studies from ACN to imTOR&#41; may serve as a security tool for the clinician and yield results in terms of overall action on cellular immunity in relation to changes in immunosuppressants&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">Table 2 summarises the clinical situations in renal transplant where the measurement of intracellular ATP production may be of interest&#46; It should be considered that InmuKnow<span class="elsevierStyleSup">&#174;</span> is an expensive laboratory method&#44; largely because it is new and because it has not been made available on the market&#46; However&#44; the price of the method is comparable to that of many genetic tests in clinical practice and less than many imaging tests &#40;CT&#44; MRI&#44; etc&#46;&#46;&#41; that are requested every day in a hospital&#46; In any case&#44; it should not be considered an open test of the catalogue&#44; but its request must be well established and have clear involvement in the management of renal transplant patient&#44; which will improve the efficiency of the test&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Acknowledgements</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">We would like to thank Dr&#46; Kowalski for the suggestions and comments he contributed to the drafting of the manuscript&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Conflicts of interest</span></p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara">The authors declare that they have no conflicts of interest related to the contents of this article&#46;</p><p class="elsevierStylePara">&#160;</p><p class="elsevierStylePara"><span class="elsevierStyleBold">Key concepts</span></p><p class="elsevierStylePara">&#160;</p><li>The decrease of intracellular ATP levels in patients has a clear predictive risk of infection value in renal and liver transplantation&#44; especially with values &#60;100ng&#47;ml&#46;</li><li>A single measurement of ATP in a patient has no predictive or diagnostic utility&#46;</li><li>The value of the intracellular ATP measurement produced by CD4&#43; T cells in blood as a biomarker of the effect of immunosuppressant drugs on the immune system is checked when serially used for individual monitoring&#46;</li><li>The measurement cycle of renal monitoring after transplantation remains to be defined&#44; although measurement should be more frequent in the first 6 months after transplantation&#44; and carried out annually thereafter&#46;</li><li>The essay should be requested before any changes in immunosuppressive therapy and periodically after said changes&#46;</li><p class="elsevierStylePara"><a href="grande&#47;11540&#95;16025&#95;43324&#95;en&#95;t111540i&#46;jpg" class="elsevierStyleCrossRefs"><img src="11540_16025_43324_en_t111540i.jpg" alt="Summary of the number of rejections and infections per transplanted organ and their relationship with detected ATP"></img></a></p><p class="elsevierStylePara">Table 1&#46; Summary of the number of rejections and infections per transplanted organ and their relationship with detected ATP</p><p class="elsevierStylePara"><a href="grande&#47;11540&#95;16025&#95;43325&#95;en&#95;t211540i&#46;jpg" class="elsevierStyleCrossRefs"><img src="11540_16025_43325_en_t211540i.jpg" alt="Possible indications of intracellular ATP measurement in renal transplant patients"></img></a></p><p class="elsevierStylePara">Table 2&#46; Possible indications of intracellular ATP measurement in renal transplant patients</p><p class="elsevierStylePara"><a href="grande&#47;11540&#95;16025&#95;43326&#95;en&#95;f111540i&#46;jpg" class="elsevierStyleCrossRefs"><img src="11540_16025_43326_en_f111540i.jpg" alt="Explanatory diagram of assay for measuring in vitro the overall function of CD4&#43; T blood cells"></img></a></p><p class="elsevierStylePara">Figure 1&#46; Explanatory diagram of assay for measuring in vitro the overall function of CD4&#43; T blood cells</p><p class="elsevierStylePara"><a href="grande&#47;11540&#95;16025&#95;43327&#95;en&#95;f211540i&#46;jpg" class="elsevierStyleCrossRefs"><img src="11540_16025_43327_en_f211540i.jpg" alt="Effect of the number of CD4&#43; T blood cells and tacrolimus blood levels on intracellular ATP production&#46;"></img></a></p><p class="elsevierStylePara">Figure 2&#46; Effect of the number of CD4&#43; T blood cells and tacrolimus blood levels on intracellular ATP production&#46;</p><p class="elsevierStylePara"><a href="grande&#47;11540&#95;16025&#95;43328&#95;en&#95;f311540i&#46;jpg" class="elsevierStyleCrossRefs"><img src="11540_16025_43328_en_f311540i.jpg" alt="Proposal of intracellular ATP production level ranges associated with risk of infection in renal transplant in literature published to date"></img></a></p><p class="elsevierStylePara">Figure 3&#46; Proposal of intracellular ATP production level ranges associated with risk of infection in renal transplant in literature published to date</p>"
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        "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleItalic">ImmuKnow<span class="elsevierStyleSup">&#174;</span> is an in vitro diagnosis method that uses patient samples of whole blood polyclonally stimulated with phytohaemagglutinin&#46; It also measures adenosine-5&#8217;-triphosphate &#40;ATP&#41; production by CD4&#43; T cells&#46; The test aims to offer an objective and overall measurement of each individual&#8217;s cellular immune response&#46; The assay was designed with the idea of individually monitoring the immunosuppression administered to transplant patients&#46; At the same time&#44; it aims to help achieve a balance as a way of avoiding immunosuppression excess and the associated adverse effects &#40;infections&#44; cancer&#44; etc&#46;&#41; or an immunosuppression defect and the subsequent risk of allograft rejection&#46; The majority of studies that have evaluated its clinical usefulness display great diversity in terms of patient recruitment&#44; the immunosuppressant treatment received&#44; the clinical variables analysed and&#44; above all&#44; the time between performing ImmuKnow<span class="elsevierStyleSup">&#174; </span>and the evaluated clinical event&#46; The most consistent data show that this assay on CD4&#43; T cell functioning is useful for predicting the risk of infection in renal transplant patients&#46; However&#44; its use as a rejection risk indicator is unclear&#46; Lastly&#44; given the great variability of immune response amongst individuals and that of existing publications&#44; it can be deduced that the isolated ImmuKnow<span class="elsevierStyleSup">&#174;</span> value does not have diagnostic capacity and only individual serial monitoring could provide definitive assistance in clinical decision making and immunosuppressant treatment changes&#46; Other aspects of ImmuKnow<span class="elsevierStyleSup">&#174; </span>application in the clinical routine&#44; such as assay cycles&#44; require randomised prospective studies for more comprehensive information&#46;</span></p>"
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      "titulo" => "Bibliography"
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