Chronic kidney disease represents a public health problem worldwide. The prevalence of chronic kidney disease lies between 3 to 16% according to different epidemiological studies [1-5]. This high prevalence is observed in both developed and developing countries [1-5]. Chronic kidney disease is responsible for increased risk of cardiovascular diseases and end-stage renal failure. In the United States, for instance, the number of patients exhibiting end-stage renal failure was around 150 000 in 1995, 360 000 in 2003, and is estimated to reach 650 000 in 2015 . This exponential growth of the end-stage renal disease population has relevant implications for health care systems. The treatment option for these patients is dialysis or kidney transplantation. The number of end-stage renal failure patients treated by either dialysis or transplantation was around 209 000 in 1991 and 472 000 in 2004 (data from the US Renal Data System 2006, reported in ). The costs of Medicare for end-stage renal failure treatment represents 5% of total budget, while it serves only 0.7% of patients . The same observation is true for Europe with the proportion of the total health care budget dedicated to the end-stage renal disease population varying from 0.7% in the United Kingdom to 1.8% in Belgium in 1994, while this population is only 0.022% to 0.04% of the general population, respectively . In France, the REIN (for
The use of nonspecific immunosuppressive drugs has significantly reduced the incidence of acute kidney graft rejection . This led to a significant improvement in the first-year graft survival rates that are “almost close to perfect”, as mentioned in . However, the benefits of such immunosuppressive therapies on chronic rejection and overall long-term graft survival are uncertain [12, 13]. Long term graft survival remains unchanged over decades [13, 14]. Persistent excessive immunosuppression (also called over-immunosuppression) −related to these immunosuppressive drugs− exposes renal transplant recipients to long-term toxicities including: increased incidence of cancers, severe infectious complications and/or inflammatory “metabolic” diseases (for instance, diabetes, and accelerated atherosclerosis leading to cardiovascular diseases). The three major complications, cardiovascular diseases, infections and cancers, are reported to be the most common causes of patient death with functional graft. For instance, a recent study including 1 606 kidney transplant recipients reports that these three complications represent respectively 24%, 16%, and 12% of death with graft function . Preventing these complications is a way to limit the loss of functional kidney graft and to ameliorate patient quality of life.
An enhanced risk of cancer after renal transplantation has been observed in the last decades [16-21], as advances in medicine have extended the life of renal transplant recipients. A meta-analysis including five studies of cancer risks in organ transplant recipients, involving 31 977 organ transplant recipients −among whom 97% have received a kidney graft− from Denmark, Finland, Sweden, Australia, and Canada illustrates perfectly the importance of malignancy occurrence after kidney transplantation. This study shows an increase in the incidence of cancers related to viral infections implicating Epstein-Barr virus (EBV), human herpesvirus 8 (HHV8), hepatitis viruses B and C (HBV and HCV), or related to
The incidence of cardiovascular diseases related to accelerated atherosclerosis associated with kidney transplantation [8, 25] is at least 3 to 5 times higher than in the general population . Cardiovascular disease is reported to be the most common cause of death with functional graft ranging from 24% to 55% depending on the considered studies [8, 15, 26, 27]. Risk factors for cardiovascular diseases in renal transplant recipients are numerous including traditional and nontraditional factors. The main highly prevalent traditional risk factors of cardiovascular diseases are the following: tobacco use, physical inactivity, hypertension, diabetes, or dyslipidemia. Nontraditional cardiovascular risk factors related to a long history of end-stage renal failure, such as hyper-homocysteinemia, chronic inflammation or anemia, are also prevalent in renal transplant recipients [8, 15, 26, 28, 29]. Moreover, factors related to transplantation itself, including immunosuppression or rejection episodes as well as new-onset diabetes after transplant, impact on cardiovascular disease occurrence after kidney transplantation [8, 15, 26, 29, 30].
Altogether, it appears that over-immunosuppression is involved in both increased cancer occurrence and cardiovascular disease incidence observed after kidney transplantation. A greater understanding of risk factors leading to this excessive immunosuppression may help physicians in charge of end-stage renal failure patients to determine high-risk recipient profiles and optimize pre- and post-transplantation treatment strategies. In other words, identification of biomarkers predictive of immunosuppression-associated complications may improve late kidney transplantation outcome and patient selection. In this chapter, we will report the efforts of our laboratory to identify immunological factors that can predict the two main complications associated with kidney transplantation, namely cancer and accelerated atherosclerosis that leads to cardiovascular diseases. For many years, we had been focusing on CD4+ T cell lymphopenia −a consequence of anti-thymocyte globulin (ATG) administration− and T cell reconstitution after this severe T cell depletion. The analysis was performed on non-invasive blood samples (
2. Persistent CD4+ T cell lymphopenia, a biomarker for immunosuppression-associated complications
The first question to address is when CD4+ T cell lymphopenia is encountered in renal transplant recipients. CD4+ T cell lymphopenia in renal transplant recipients results mainly from ATG administration. CD4+ T cell lymphopenia persists for several years in some transplanted patients [31, 32] despite a limited treatment duration (until 4 days). In addition to ATG, Campath-1H, a humanized anti-CD52 monoclonal antibody called Alemtuzumab, can be used as induction immunosuppression causing T cell depletion [33, 34].
Our group previously reported that persistent CD4+ T cell lymphopenia after kidney transplantation is correlated with enhanced risks of cancers, including: skin cancers , monoclonal gammapathies , lymphomas as well as other non skin cancers, such as colon or lung cancers . This persistent CD4+ T cell depletion is also correlated with the increased incidence of opportunistic infections  and of atherosclerotic events . On the opposite, CD4+ T cell lymphopenia seems not to be associated with
However, the limitations of using persistent CD4+ T cell lymphopenia as a biomarker in clinical setting are the following: not all transplanted patients treated with ATG did develop a prolonged CD4+ T cell lymphopenia [39, 41, 42] and this is not a predictive biomarker. Indeed, when a patient exhibits a prolonged CD4+ T cell lymphopenia after ATG, how can physicians deal with it? Physicians can propose a more frequent clinical follow up in order, for instance, to detect earlier cancer occurrence. However, it will be difficult to prevent over-immunosuppression-associated complications. This is why the next step was to identify factors responsible for this prolonged severe CD4+ T cell lymphopenia allowing us to distinguish patients that will develop prolonged CD4+ T cell lymphopenia from patients that will not and to select the adequate immunosuppressive regimen. Indeed, ATG exerts a benefit over nondepleting induction therapy, especially for sensitized (high panel reactive antibodies, PRA) transplant patients. This is true not only for early acute graft rejection occurrence, but also for the preservation of allograft function [43, 44]. However, the ATG benefit is not similar for each patient [45, 46]. Thus, the choice of a complication risk level could vary according to the theoretical benefit of ATG. A high benefit of ATG may lead to accept a higher risk, whereas a slight benefit should lead to prefer a lower risk. Biomarkers, such as prolonged CD4+ T cell lymphopenia, but rather those allowing us to predict this lymphopenia, may help to select ATG as an appropriate induction therapy. We imagine that these biomarkers identified in the setting of ATG can be transposed to other depleting therapies, such as Campath-1H/Alemtuzumab. Indeed, clinical studies are available regarding the prolonged CD4+ T cell lymphopenia induced by Alemtuzumab administration , not always in the context of kidney transplantation [48, 49].
The identification of prolonged CD4+ T cell lymphopenia was a critical step in our search for biomarkers associated with over-immunosuppression. However, we need to go further and to identify factors present at the time of transplantation responsible for the persistent lymphopenia. This could limit the complications associated with kidney transplantation. We reasoned that factors that affect the duration, intensity or variability of CD4+ T cell reconstitution after ATG-induced T cell depletion can be useful biomarkers. Based on the literature, these factors can be the following: the thymic function/activity at time of transplantation and its capacity to regenerate, the capacity to respond to cytokines involved in homeostatic proliferation, and the variable sensitivity of CD4+ T cell subsets to ATG-induced lymphopenia. This will be discussed in the next paragraphs of this review, but before that we will quickly summarize the different steps involved in T cell reconstitution after profound depletion.
Based on studies performed in animal models (mainly mouse models), Mackall and colleagues proposed several years ago that T cell reconstitution after profound T cell depletion in Human arises from two main pathways: thymopoiesis (
3. The role of homeostatic proliferation expansion after CD4+ T cell depletion in the complications associated with over-immunosuppression
The first pathway of T cell reconstitution occurring after induction therapy-induced lymphopenia is the homeostatic proliferation of residual T cells, a compensatory process, also called lymphopenia-induced proliferation. We highly recommend a recent review on lymphodepletion and homeostatic proliferation . How does this step influence T cell reconstitution after CD4+ T cell depletion? First, it depends on the residual T cells that persist after ATG. In consequence, we will start with a paragraph dealing with data reporting sensitivity and resistance to ATG-induced T cell death. Second, the capacity of residual T cells to respond to homeostatic factors present in the microenvironment and competition for such factors may impact on T cell recovery. Here, we will restrict the discussion on CD4+ T cells. The CD4+ T cell pool is constituted by different CD4+ T cell subsets: naive CD4+ T cells expressing CD45RA that have not encountered their antigens called also T helper (Th) 0 cells and memory/activated CD4+ T cells expressing CD45RO+. These cells can be divided into effector memory and central memory according to CD62L/CCR7 or CD62L/CD44 expression. Depending on the cytokine microenvironment in which naive CD4+ T cells are primed, different Th subsets have been described: Th1, Th2, and Th17 (for a general scheme of Th cell differentiation, please refer to ). Moreover, this CD4+ T cell pool contains regulatory T cells (Treg) that play a key role in the control and maintenance of tolerance [55, 56]. FoxP3+ natural Treg (nTreg) are produced in the thymus while induced Treg (iTreg) are generated in the periphery from naive CD45RA+ CD4+ T cells in the presence of immunosuppressive cytokines: IL-10 for FoxP3neg T regulatory 1 (Tr1) cells  or TGF-β for FoxP3+ Th3 iTreg . This CD4+ T cell pool may vary after T cell depletion and reconstitution may affect this pool. Modifications of the CD4+ T cell pool may have consequences on late complications associated with renal transplantation (see below, §3.3).
3.1. CD4+ T cell subsets and sensitivity to anti-thymocyte globulin administration
Anti-thymocyte globulins are a complex mixture of antibodies with multiple specificities directed against different molecules expressed by T cells, but also non T cells [59, 60]. A thorough study in non human primates reported that ATG treatment induced a dose-dependent T cell depletion in the peripheral blood, as well as in the spleen and in the lymph nodes. Massive T cell apoptosis in secondary lymphoid organs was identified as the main mechanism implicated in T cell lymphopenia . This supports that lymphocyte depletion is the major mechanism by which ATG preparation exerts its immunosuppressive effect. However, when considering T cell reconstitution, one has to evoke other mechanisms:
It has been reported that CD4+ T cells are more sensitive to ATG-induced depletion than CD8+ T cells  and that the different CD4+ T cell subsets are not equally sensitive to ATG-induced depletion [63, 64]. For instance, in a mouse model, Treg were spared by anti-lymphocyte serum (ALS) −an equivalent of ATG in mice− treatment . This occurs by a mechanism dependent on OX40 signaling pathway present in Treg with a memory phenotype . However, another study in mice reported that all CD4+ T cell subsets are equally sensitive to mouse ATG, but that naive T cells expand very quickly after homeostatic proliferation with the acquisition of a memory phenotype . This may explain why initial studies reported that memory phenotype T cells are more resistant than naive T cells to ATG-induced death. The same is maybe true for CD8+ T cells that expand faster than CD4+ T cells (as discussed in ). The hypothesis of a different susceptibility to ATG-induced death or an imbalance in CD4+ T cell subset reconstitution is tantalizing to explain the relationship between CD4+ T cell lymphopenia and accelerated atherosclerosis after kidney transplantation, since some Th subsets are pro-atherogenic while other are anti-atherogenic (see §3.3). Whether ATG or immune recovery following ATG-induced lymphopenia may differently affect CD4+ Th subsets remains to be determined in renal transplant recipients. A study in renal transplant recipients suggested that Th2 subsets were less sensitive than Th1 subsets to ATG treatment . However, other Th subsets −such as Th17, or the putative Th9 [69, 70] or Th22 [71, 72] subsets− have not been explored yet.
What are the arguments in favor of depletion-independent mechanisms that may influence CD4+ T cell reconstitution after ATG-induced lymphopenia? The major mechanism is the induction of iTreg or the conversion of naive CD4+ T cells into iTreg. In
3.2. CD4+ T cell subsets and homeostatic proliferation after anti-thymocyte globulin administration
Lymphopenia-induced proliferation has been extensively studied in mice (for review ) and has been cleverly transposed to human setting . T cell dynamics −including T cell replenishment by homeostatic proliferation or after thymopoiesis− are usually extrapolated from mice to humans and
Homeostatic proliferation is the first pathway to be triggered when peripheral T cells decline acutely. It can follow a fast (~ one cell division per 6-8 hours) or a slow (~one division per 24-36 hours) kinetics . The fast kinetics is an antigen-specific process, and thus, only a smaller subset of T cells (
The kinetics of reconstitution after lymphopenia are dependent on the considered T cell subsets, with memory T cells expanding more rapidly than naive T cells and naive CD8+ T cells undergoing faster proliferation rates than naive CD4+ T cells [53, 62]. Furthermore, Th1 cell expansion is favored by homeostatic proliferation . This sustains that the subsets of T cells that resist to depleting therapy play a major role in reconstitution. Antigen persistence such as latent viruses may favor T cell exhaustion , and the loss of T cell specificity participating to immunodeficiency. The picture is more complicated for Treg . Initial works reported that in lymphopenic environment, Treg expand quickly and massively by homeostatic proliferation , as a mechanism to prevent unwanted autoimmune responses. “Spontaneous” conversion of naive CD4+ T cells into iTreg in the lymphopenic environment  may also participate to this increase of Treg. Moreover, the sites (gut
3.3. Clinical implications of altered homeostatic proliferation in the setting of CD4+ T cell lymphopenia
How can altered homeostatic proliferation after severe CD4+ T cell depletion participate in increased cancer occurrence or accelerated atherosclerosis? Several features with clinical consequences for lymphopenic patients are associated with the preferential homeostatic proliferation of limited T cells:
Homeostatic proliferation may also be implicated in accelerated atherosclerosis. Indeed, experiments performed in atherosclerosis prone apolipoprotein-E deficient or low density lipoprotein receptor deficient mice have distinguished pro-atherogenic from anti-atherogenic CD4+ T cell subsets (for reviews, [104, 105]). One may hypothesize that ATG-induced CD4+ T cell lymphopenia may favor a preferential expansion of pro-atherogenic Th1 cells in detriment of anti-atherogenic Treg (
4. The role of thymic activity after CD4+ T cell depletion in the complications associated with over-immunosuppression
The thymus participates more lately than homeostatic proliferation to immune reconstitution after profound T cell depletion. The role of the thymic function on immune reconstitution after profound T cell depletion has been studied in different clinical settings such as human immunodeficiency virus (HIV) infection or hematopoietic cell transplantation (for recent review ).
Different tools are available to discriminate recent thymic emigrants (RTE, reflecting thymic activity/output) from other lymphopenia-induced expanded T cells (
A last concern is that the thymus involutes with age and injury, but keeps its capacity for renewal. This is well illustrated in clinical settings associated with T cell recovery  where the thymus expands and may become greater than the normal size with intense cellular density, as attested by computerized tomography . Radiographic measurement of thymus by computer tomographs correlates with circulating TREC levels . However, thymus renewal capacity declines with age (for a review ). In consequence, circulating TREC levels are inversely correlated with age . Over the age of 45-50, thymic activity/output is reduced and naive T cell recovery may take until 5 years after severe iatrogenic lymphopenia . Overall, tools are available to study the part of thymic output in T cell reconstitution after ATG-induced lymphopenia.
4.1. Altered thymic activity, a predictive biomarker of persistent CD4+ T cell lymphopenia after anti-thymocyte globulins
Few data are available to date concerning the human thymic function and CD4+ T cell recovery after kidney transplantation. Several years ago, Monaco
We recently identified the thymic activity (as assessed by circulating TREC levels) at the time of kidney transplantation as a major factor predicting CD4+ T cell immune reconstitution after ATG administration [41, 117]. In a first patient cohort, we found a TREC value lower than 2 000 per 150 000 CD3+ cells at the time of transplantation to be the best threshold for prediction of persistent post-ATG CD4+ T cell lymphopenia . Renal transplant recipients with lower TREC levels at the time of transplantation exhibited a higher morbidity and mortality risk due to cancers as well as cardiovascular diseases. Determination of circulating TREC levels at the time of transplantation may help to identify patients at high risk of persistent ATG-induced CD4+ T cell lymphopenia and post-transplant cancer occurrence . Moreover, in a second cohort of patients, the levels of TREC at the time of transplantation is predictive of cancer occurrence in renal transplantation recipients and correlate with naive CD45RA+ CD4+ T cell recovery 1-5 years after transplantation . Thus, TREC analysis at the time of transplantation can be a useful predictive biomarker for over-immunosuppression-associated complications. This new biomarker could be a valuable tool to select induction treatment (ATG
The maintenance of naive T cell pool appears critical to avoid complications associated with over-immunosuppression after kidney transplantation. A recent interesting study challenges some “dogma” on the role of thymic output in the maintenance of human naive T cell pool . While thymic output is stable even with age in mice, in humans peripheral T cell proliferation may be the major mechanism contributing to the maintenance of naive T cell pool. Indeed, when the authors normalized the TREC content of peripheral CD4+ T cells by the TREC content of single positive CD4+ thymocytes (obtained from 45 children who underwent cardiac surgery), they observed that, in individuals older than 20, only around 10% of circulating naive T cells come from thymus while the majority are formed from peripheral naive T cell proliferation. The same data were obtained using
4.2. Clinical implications of altered thymic function in the setting of CD4+ T cell lymphopenia
How can altered thymic output after severe CD4+ T cell depletion participate in increased cancer occurrence or accelerated atherosclerosis? A major role of thymus during T cell recovery is the reconstitution of a most diverse polyclonal T cell repertoire. Thus, renal transplant recipients with an impaired thymic function exhibiting a skewed T cell repertoire and are less equipped to respond to pathogens (including oncogenic viruses) or even to control tumors than patients presenting an efficient T cell reconstitution with a fully diverse TCR repertoire (for a review ). This may explained the increased occurrence of cancers in renal transplant recipients.
In patients with altered thymic function, homeostatic proliferation becomes the main contributor to T cell recovery, and thus, duration of lymphopenia is extended with uncontrolled pro-atherogenic CD4+ T cell subset expansion leading to accelerated atherosclerosis (see above). Moreover, impaired thymic function and uncontrolled homeostatic proliferation may lead to immune exhaustion that aggravates immunodeficiency. In addition, impaired thymic output by limiting naive T cell production impacts highly on homeostatic proliferation. This explains why pre-transplant thymic function is a good and sensitive biomarker.
4.3. Perspectives: Toward a restoration of thymic function?
We recently identified impaired thymic function as a biomarker for increased occurrence of cancers and accelerated atherosclerosis related to persistent CD4+ T cell lymphopenia [41, 117]. It remains interesting to localize the defect more accurately in order to propose a therapeutic restoration of this function. One hypothesis is that the defect is localized before the thymus for instance, in CD34+ lymphoid precursors, as proposed for HIV . This is a possibility since ATG contains a mixture of antibodies with multiple specificities [59, 60], and thus, ATG may affect circulating thymic precursors. With this assumption in mind, we hypothesize that the capacity to regenerate hematopoiesis may impact thymic function. The
Significant advances have been performed in the comprehension of endogenous thymus regeneration and several factors have been shown to increase thymic activity (for a recent review , see also Ref. for IL-22). This is particularly interesting since recombinant human IL-7 has been used in clinical trials . Administration of IL-7 results in an expansion of both naive and memory CD4+ T cells and CD8+ T cells with a tendency toward enhanced CD8+ T cell expansion . Lymphopenic or normal older hosts receiving IL-7 develop an expanded circulating T cell pool with increased T cell repertoire diversity . Moreover, IL-7 administration exhibits a favorable toxicity profile , opening the perspective of potential future use in renal transplant recipients with severe prolonged CD4+ T cell lymphopenia in case that this IL7 pathway is altered. Furthermore, IL-7 treatment of human thymus −
We summarize in a Figure the different factors and critical steps involved in CD4+ T cell reconstitution after depletion by ATG (Figure 1). Overall, the aim of this review was to report our experience on the identification of biomarkers (CD4+ T cell lymphopenia after ATG and TREC levels at the time of transplantation) predicting transplantation-related complications (mainly atherosclerosis and cancer occurrence), and to propose to use these biomarkers in patient follow up and/or in immunosuppressive strategy design. Furthermore, we propose other “tracks” to improve the clinical relevance of these biomarkers, as well as to understand their implications in the occurrence of immunosuppression-associated complications. The efficacy of these identified biomarkers should be tested and validated in prospective clinical trials in order to select the appropriate immunosuppressive strategy. In the future, one could imagine that these biomarkers may help physicians to manage risks of cancers and cardiovascular diseases in renal transplant recipients.
We thank the Région de Franche-Comté for the LipSTIC grant (to P.S.)
AcknowledgmentsWe would like to thank Sarah Odrion for excellent editorial assistance and the Centre d’Investigation Clinique intégré en Biothérapies du CHU de Besançon (CBT-506) for its support. Our work in the fields was supported by grants from the Agence Nationale de la Recherche (Labex LipSTIC, ANR-11-LABX-0021 and ECellFrance consortium, ANR-11-INBS-0005), the Programme Hospitalier de Recherche Clinique 2011 (to D.D), the Fondation de France (Appel d’offre “Maladies cardiovasculaires” 2007, #2007 001859, to P.S.), the DHOS/INSERM/INCa (Appel d’offre Recherche Translationnelle 2008, to D.D. and P.S.), and the APICHU 2010 (SIGAL project to J.B.).
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