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A Rationale for Age-Adapted Immunosuppression in Organ Transplantation

Krenzien, Felix MD1,2; ElKhal, Abdallah PhD1; Quante, Markus MD1,2; Rodriguez Cetina Biefer, Hector MD1; Hirofumi, Uehara MD1; Gabardi, Steven PharmD3; Tullius, Stefan G. MD, PhD1

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doi: 10.1097/TP.0000000000000842
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Increasing numbers of elderly patients with irreversible end organ damage are currently on the waitlist for organ transplantation. Indeed, the majority of transplant recipients and organ donors are older than 50 years, mainly as a consequence of demographic changes.1-3

The most frequent causes of death in older transplant recipients are linked to immunosuppressive therapies. At the same time, aging aspects are in general not integrated into clinical immunosuppressive trials. Bacterial infections and malignancies are more frequent in the elderly.4,5 Moreover, rates of pretransplant diabetes mellitus (PDM) and new-onset diabetes mellitus after transplantation (NODAT) are increasing with age. Of note, the use of immunosuppressive drugs has been shown to induce hyperglycemia and diabetes, both linked to inferior transplant outcomes, higher rates of acute rejections, and infections. Hence, older transplant recipients are more likely to suffer from adverse drug effects of their immunosuppression as reflected by higher rates of diabetes and de novo malignancies. Finally, older recipients are dying more frequently due to bacterial infections compared to younger transplant recipients and those patients remaining on the waitlist.6

In addition, compromised functional capacities of older livers are impacting first pass metabolism and consecutive blood concentrations of administered drugs. A recent prospective study demonstrated a 2-fold increase in serum troughs levels of calcineurin inhibitors (CNI) in older kidney transplant recipients (65-84 years) compared to young controls, even when adjusted for weight and dose.7 Aging is not only shaping drug metabolism but also impacting immune responses. In a large-scale study, we have recently shown that acute rejection rates decline in parallel to recipient age, a correlation which has also been confirmed for liver and heart transplant recipients.8-10 Thus, the selection of the immunosuppressive drug regime in the elderly is complex and not supported by broad clinical evidence thus far, but rather by few anecdotal observations. Here, we will highlight the critical importance of aging for immunosuppressive therapies and dissect the current literature of experimental science and clinical trials considering the aged patient.

INFECTIONS AND MALIGNANCIES IN TRANSPLANT RECIPIENTS

Major infections in transplant recipients are caused by bacteria and viruses. Of note, bacterial infection rates increase in older transplant recipients,5 whereas viral infections are decreasing with advanced age.11 The individual mortality risk caused by bacterial infections is multifactorial and relies on several contributing factors, such as donor and recipient demographics, incidence of diabetes, and advanced age.12 For instance, more than 20% of kidney transplant recipients (60-69 years) are dying because of severe infections. The incidence of bacterial infections with septic shock is 2-fold increased in graft recipients older than 50 years.13 In contrast, a comprehensive database analysis of more than 60,000 renal transplant recipients revealed that the incidence for active viral infection with varicella zoster is decreasing dramatically with advanced age.14 Patients younger than 18 years showed an infection rate of 14%, whereas patients older than 65 years presented an infection rate of less than 4%. When analyzing the serostatus, the median age of kidney transplant recipients being seropositive for cytomegalovirus and Epstein-Barr virus infection is significantly higher.15 Taken together, the prevalence of seropositivity is increasing with age, whereas the rate of active viral infection is decreasing. However, active viral infections in older patients are associated with inferior outcomes. The incidence of invasive fungal infection is in general very low in organ transplantation with a paucity of data from age-matched studies. In detail, Candida spp. and Aspergillus spp. count for most of the fungal infections16 and might be more frequent in the elderly.17,18

The incidence of cancer is known to be steadily increasing with age, reaching its highest numbers in graft recipients older than 50 years.19 Skin-related cancers and lymphoproliferative disorders are the most common malignancies among transplant recipients. In addition, de novo malignancies are one of the major causes of death, for example, accounting for one third of nonhepatic deaths of liver transplant recipients.4

DIABETES MELLITUS IN TRANSPLANT RECIPIENTS

The relevance of metabolic disorders increases with aging. Indeed, NODAT is more frequent in the elderly and linked to the immunosuppressive drug regime applied. For instance, the risk of NODAT after kidney transplantation increases 1.5-fold throughout every decade of life.20 The presence of NODAT is associated with increased rates of acute rejections, infections, late cardiovascular events, and inferior outcomes. Of note, frequencies of NODAT have been reported with a range of 4% to 25% in renal transplant recipients, 2% to 25% in liver transplant recipients, and 4% to 40% in heart transplant recipients.21 Pretransplant diabetes mellitus is increasing with age as well. The rate of PDM increased consecutively from 7% (age, 18-29 years) to 31% (age, 60-69 years) in a study of more than 12,000 liver transplant recipients.22

Overall, the likelihood of PDM and NODAT is increased in the elderly and of significant clinical relevance as diabetes is linked to higher rates of graft failure and inferior outcomes.

IMMUNOLOGY OF AGING

Immunosenescence is characterized by an impaired function of both adaptive and innate immunities (Figure 1), clinically evident by a compromised response to vaccination and an augmented risk of malignancies in the elderly, mostly linked to a compromised tumor surveillance.23,24 Thymic involution appears to play a critical role for compromised adaptive immune responses, although precise mechanisms remain unclear. Differentiation and emigration of T cells, as well as the total number of naive T cells decline with age.25 Hence, T-cell diversity is compromised, and the ability to recognize and eliminate pathogens declines remarkably in the elderly.26 Although the overall number of naive T cells decreases due to an involuted thymus, a shift toward CD8+ and CD4+ cells and a significant increase in memory and effector T cells is observed in the elderly.27,28 T-cell senescence is characterized by dysregulated immune functions accompanied with a loss of the costimulatory molecule, CD28, shorter telomeres, and altered production of proinflammatory cytokines.29,30 Of note, CTLA4 is upregulated, particularly on conventional and regulatory T cells.31 Clearly, the aging immune system may not only require less, but also specific immunosuppression as senescence affects some immune compartments more than others.

FIGURE 1
FIGURE 1:
Aging effects graft outcome. Immunosenescence is characterized by changes in both innate and adaptive immunity. Elderly organ transplant recipients have less acute rejections while the engraftment of old organs is linked to higher rejection rates associated to an augmented immunogenicity. Thus, both donor and recipient age need to be considered for a tailored immunosuppression.

Humoral immune responses are also impacted by aging as evidenced by a decline in the number of progenitor B cells.32 Moreover, T- and B-cell interactions are affected as CD4+ T cells, required for B-cell activation, show functional defects in the elderly.33 Humoral immune responses in the elderly are also characterized by a contracted B-cell repertoire. Clinically, it remains unclear if sensitization is age-dependent and if humoral rejections require a different therapeutic approach in the elderly.

In addition to changes of adaptive and humoral immune responses, the innate immune compartment undergoes age-associated changes. While some antigen-presenting cells, including macrophages, express less major histocompatability complex class II,34 older dendritic cells appear to have a more pronounced capacity to present antigens. In our own experimental study, we were able to show that organs containing older DCs elicit a more potent IL17 driven immune response in young recipient animals.35

ACUTE REJECTIONS IN OLDER RECIPIENTS

Although rejection rates appear less frequent in older recipients, the engraftment of older organs is linked to a higher frequency of acute rejections, potentially caused by an augmented immunogenicity and compromised repair mechanisms.8-10,36 Of note, acute rejections are most frequent when older organs are transplanted into younger recipients, whereas this effect appears blunted when older organs are transplanted into older recipients.8,37 The Eurotransplant Senior Program is applying principles of immunosenescence by allocating kidneys from old donors (≥65 years) to old recipients (≥65 years), whereas keeping ischemic times brief through a locoregional organ allocation.38 Clearly, immunosuppressive regimens must consider both donor and recipient age.

IMMUNOSUPPRESSION IN ELDERLY TRANSPLANT RECIPIENTS

In general, aging is associated with impaired organ function and impaired homeostasis affecting liberation, absorption, distribution, metabolism, and excretion of immunosuppressants (Table 1).39-41 In contrast, drugs approved for clinical use are mostly not studied in elderly patients who frequently have complex comorbidities, whereas receiving multidrug treatment.42 Recognizing complex medical conditions and addressing this issue, the Food and Drug Administration has endorsed clinical trials in the elderly.42,43 Of additional clinical relevance, if included into clinical studies, elderly patients had been picked selectively, thus not necessarily representing a general age-matched population.44 A recent meta-analysis revealed that kidney transplant recipients participating in clinical trials in the United States were significantly younger.45 Older age as an exclusion criterion was evident in 30% of studies. Obviously, clinical trials in transplant medicine do not consider the clinical reality of a steadily increasing volume of older transplant recipients.

TABLE 1
TABLE 1:
Pharmacokinetic changes in the elderly

Calcineurin Inhibitors

In a recent prospective study that included more than 2500 patients, tacrolimus and cyclosporine trough levels were 50% higher in older kidney transplant recipients (≥65 years) when normalized for dose and weight,7 linked to an altered first-pass metabolism of CNIs, facilitated by intestinal and hepatic enzymes. The metabolism of tacrolimus is mediated almost exclusively by the cytochrome P450 (CYP450) 3A subfamily in the liver and partly via the CYP3A subfamily and P-glycoprotein (P-gp) in the intestinal mucosa impacting both, oral bioavailability and clearance.46-48 Noticeably, clinical liver samples have shown an 8% decline of CYP3A with every decade of life.49 These findings are also supported by experimental data showing a remarkable age-related decline (up to 70%) of CYP3A activity and expression in the liver of old rats.50 Likewise, cyclosporine is mainly metabolized by CYP3A4 and to a minor extent by CYP3A5.51 Individuals expressing CYP3A5*1 have an approximately 2-fold higher clearance and need higher doses of CNIs to achieve comparable trough levels,7,52 but probably not in patients older 60 years old.53 CYP3A5 is predominantly expressed by whites but also present in other ethnic populations.54

Expression and activity of P-gp are important for the metabolism of CNIs; however, age-related changes are discussed controversially, and their influence on CNIs remains unclear.55,56 The transmembrane protein P-gp, encoded by the ABCB1 gene, is also present in lymphocytes. Cyclosporine has been shown to be both a substrate and inhibitor of P-gp, whereas tacrolimus inhibits P-gp.55 A study of cyclosporine in the elderly (>65 years) demonstrated higher cyclosporine concentrations within T cells.57 Moreover, CNI elimination was compromised with increasing age.

In liver transplant recipients, more than 80% of tacrolimus binds to erythrocytes with smaller amounts binding to plasma proteins (approximately 16%) and leukocytes (approximately 0.6%).58 This unbalanced distribution is the result of high concentrations of FK binding protein-12 in erythrocytes attracting tacrolimus. Interestingly, a study in renal transplant recipients correlated hematocrit with whole blood concentrations of tacrolimus.59 Indeed, hematocrit levels predicted the variability in tacrolimus whole blood concentrations but did not impact the unbound and therapeutically active fraction of tacrolimus. Thus, a higher hematocrit binds more tacrolimus and may overestimate the therapeutic dose of tacrolimus, whereas a low hematocrit may lead to an underestimation of the dosage. Those effects are of clinical relevance as hematocrit levels change with age, especially in the elderly and renal transplant recipients.

The pharmacokinetics of the CNIs in the elderly population may also be negatively impacted by the formulation of these agents (ie, brand versus generic). In 2015, the only generic tacrolimus study specifically evaluating generic tacrolimus in the elderly was published.60 This prospective, single-center, randomized, crossover trial evaluated the pharmacokinetic parameters of a generic tacrolimus (Tacni; Teva Pharmaceutical Industries, Petah Tikva, Israel) in 25 renal transplant recipients older than 60 years. Patients were randomized to receive either brand or generic tacrolimus at the time of transplantation. Pharmacokinetic parameters were assessed 6 and 8 weeks after transplantation. After the first assessment, the 2 groups crossed over; both the area under the curve (90% confidence interval, 1.10-1.23) and Cmax (90% confidence interval, 1.35-1.65) of generic tacrolimus did not meet bioequivalence standards. The authors urged caution in using this particular generic formulation in the elderly population due to the possibility for the higher drug exposure potentially increasing the risk of adverse events.

The diabetogenic effects of CNIs are linked to an impaired insulin secretion negatively regulating pancreatic β-cell growth and function.61 Several studies demonstrated higher incidences of NODAT in renal transplant recipients using tacrolimus compared to controls on cyclosporine.62,63 Thus, tacrolimus treatment is associated with an increased risk for the development of hyperglycemia and diabetes and cyclosporine might be favorable in patients in a prediabetic stage or with existing diabetes mellitus. However, long-term follow up of graft recipients maintained on tacrolimus showed superior graft function compared to patients on cyclosporine.64,65 Thus, the higher incidence of diabetes resulting from tacrolimus therapy might be blunted by an improved long-term patient survival and graft function.

T-cell aging may also affect pharmacodynamics. In an experimental study, calcineurin phosphatase activity had declined by more than 50% in old T cells.66 Moreover, IL2 production of older T cells had been impaired with aging while inducible nuclear factor of activated T cells had been reduced or absent in the elderly.67 Thus, although the impact of T-cell immunosenescence is recognized, CNI applications and dosages require more detailed assessment. Moreover, as significant portions of tacrolimus bind to plasma proteins, age-related changes of hepatic proteins will impact the distribution of the drug.68

Mechanistic Target of Rapamycin Inhibitors

Antitumor capacities of mechanistic target of rapamycin (mTOR) inhibitors seem of particular relevance in the design of immunosuppressive regimens in the elderly. In fact, de novo posttransplant malignancies were significantly lower with sirolimus/everolimus compared to CNI-based maintenance immunosuppression in a multivariate analysis of 30,000 primary renal transplant recipients.69 Additional prospective trials in nonrenal transplant recipients have been confirmatory.70

The oral bioavailability of both sirolimus and everolimus is low (<15%), related to their gastrointestinal (GI) and hepatic metabolism. Both drugs are metabolized by CYP450 (eg, CYP3A4 and CYP3A5) and transported by P-gp. Aging per se may alter both, enzymatic metabolization of mTOR inhibitors and the capacity of biliary transporters in the liver.71 Hence, age-related functional impairment of liver metabolism is linked to a compromised clearance of mTOR inhibitors that may require reduced dosages.72,73

The serine-threonine kinase mTOR plays a pivotal role in the insulin cascade, and inhibitors can alter glucose metabolism, insulin secretion, and sensitivity. Consequently, the risk to develop NODAT is increased in the transplant recipient under mTOR treatment. Numerous studies indicated an incidence of NODAT of 15% to 30%, whereas the exact mechanism remains vague.74 Moreover, the diabetogenic effect is enhanced by the combination mTOR inhibitors and CNIs.75

Antimetabolites

With a high percentage of mycophenolic acid (MPA) binding reversibly to serum albumin, age-related changes of albumin concentrations gain importance as only the unbound MPA is pharmacologically active. Low levels of albumin and impaired renal function are associated with an increased clearance of total MPA. During aging, levels of albumin decline, linked to liver impairment.76,77 For instance, liver transplant recipients with low serum albumin (35 g/L) required 2-fold higher mycophenolate mofetil (MMF) doses than patients with normal albumin levels due to an increase clearance of free drug.78 Those results were confirmed in a meta-analysis of more than 450 renal transplant patients.79 The MPA clearance decreases with higher albumin levels due to a smaller fraction of free unbound MPA. In conclusion, albumin levels and changes of renal function necessitate regular measurements of MPA trough levels and dose adaptations in particular in the elderly.

Mycophenolic acid is administered as the prodrug MMF or enteric-coated mycophenolate sodium (ECMPS). Those aspects might be of age-related clinical relevance as higher pH levels are present in the proximal GI tract. Mycophenolate mofetil is hydrolyzed to MPA in the GI tract, blood, liver and tissues, whereas ECMPS, the salt of MPA, is not getting hydrolyzed. After administration of MMF, higher pH levels reduce peak concentrations (Cmax), and the AUCs in healthy volunteers diminished significantly.80 In contrast, Cmax and AUC were not impacted by the acid-resistant ECMPS formulation.81

Corticosteroids

Prednisolone and prednisone are primarily metabolized in the liver and, to a smaller degree, in the kidneys.82 Adult liver transplant recipients have shown a broad intraindividual and interindividual variability in medication pharmacokinetics.83 At the same time, hepatic impairment has shown conflicting data on prednisolone and prednisone metabolism in nontransplant patients.84 Interestingly, CYP3A4 inhibitors decrease the clearance and increase the bioavailability of prednisolone and methylprednisolone.85,86 At the same time, high doses of steroids were able to increase P-gp and CYP3A concentrations in liver and intestine of rats leading to a decline in tacrolimus concentrations.87 In the plasma, prednisolone binds mainly to albumin, transcortin, and partly to α1-acid glycoprotein. Pharmacokinetic characteristics are furthermore complicated by a dose-dependent nonlinear plasma protein binding. When higher doses are applied, prednisolone protein binding capacity decreases from 95% to 60% to 70%.88 Compromised hepatic function in older patients is linked to changes in plasma protein levels, thus affecting plasma protein binding of glucocorticoids. Nevertheless clinical trials in the elderly are lacking.

The clearance of prednisolone89 and methylprednisolone90 declines in the elderly linked to an increased exposure and an augmented adrenal suppression. A decreased elimination of prednisolone is caused by a compromised renal clearance.84 The clearance of lipophilic corticosteroids is furthermore determined by body composition. As body weight is linked to aging, with a peak during the 5th and 6th decade of life and a decline thereafter,88 dose adjustment of corticosteroids should also be based on body weight.

Furthermore, glucocorticoids are also associated with a higher risk of developing NODAT in a dose-dependent manner. A dose of 0.01 mg/kg per day has been associated with a 5% risk for the development of NODAT.91 In contrast, steroid withdrawal has been shown to result in improved insulin sensitivity. A dose reduction of one third resulted in 24% increase of insulin sensitivity index.92

Belatacept

The receptor fusion protein belatacept is composed of the modified Fc domain of the human immunoglobulin IgG1 linked to the extracellular-binding domain CTLA4. Belatacept has shown a low variability (<30%) of pharmacokinetic parameters from phase I, II, and III trials. Drug exposure was not significantly affected by age or age-related parameters, such as renal function, albumin level (hepatic function), or diabetes.93

Differential effects of dendritic cells aging might influence effects of belatacept. Although the expression of CD80/CD86, the binding site of belatacept, appears age-independent, the ability of DCs to phagocytize antigens and to migrate to the antigen site declines with age.94 Moreover, CTLA4 is upregulated on old CD4+ T-cells.95 The altered capacity of DCs to present antigen and the enhanced expression of CTLA4 might increase the suppressive mechanism of belatacept in the elderly. Nevertheless, clinical trials that elucidate age-related mechanism of belatacept are lacking.

Of note, a comprehensive meta-analysis of randomized controlled trials showed a better metabolic profile of belatacept with lower incidences of NODAT, hypertension, and lower serum lipids levels compared to treatment with CNI.96 This is of particular interest as diabetes is a common comorbidity in the elderly associated with an increasing risk for infections, acute rejections, and graft failure.

Antibody-Based Therapies

The pharmacokinetics of antibodies are complex, as the tissue distribution is slow and the volume of distribution is low. Antibodies are metabolized to peptides and amino acids and can be recycled for de novo protein synthesis or used as an energy resource.

Antibodies are mainly catabolized through 2 major pathways. Nonspecific clearance is mediated by the interaction between the Fc region of the antibody and the Fc receptor. Alternatively, the Fab region of the antibody is binding specifically to its antigenic target. The specific clearance can be saturable linked to the amount of antigens; the nonspecific clearance, in contrast has large capacities. Subsequent to internalization antibodies into the cytoplasm, they are degraded by lysosomes.97,98 Interestingly, aging is linked to impaired macrophage polarization, making the elderly more susceptible to infections while slowing metabolism of monoclonal antibodies.99 In addition, the neonatal Fc receptor for IgG protects from degradation, thus explaining the long elimination half-life of antibodies (eg, basiliximab is 7.2 days).100 Possible changes in antibody pharmacokinetics seen with aging remain unknown, but may impact half-life and change their exposure.

BIOMARKERS AND THE DEVELOPMENT OF NEW IMMUNOSUPPRESSIVE PROTOCOLS

Shortcomings of current immunosuppressive drug therapies in the elderly are based on the complexity of aging and the use of trough levels as current “gold standard” to monitor immunosuppressive therapy. However, monitoring blood concentrations might not appropriately reflect effects of immunosenescence or age-related compromised organ function. Therefore, the diagnostic use of biomarkers may be a helpful tool to adjust drug therapies for age-specific changes. A number of promising candidates is available to serve as pharmacodynamic, pharmacogenetic, or immunological markers.101

Several pharmacodynamic assays are currently available assessing enzyme activities that may help to detect interindividual and age-dependent differences in pharmacokinetics (Table 2). Assessment of calcineurin phosphatase activity and its downstream product nuclear factor of activated T cell could serve as diagnostic tools to assess the intracellular effectivity of CNIs in the elderly.102 Along the same lines, the mTOR-dependent kinase p70S6103 and the inosin-monophosphate dehydrogenase for MPA104 can be used to assess the effectivity of corresponding target enzymes. Detailed assessment of T-cell subtypes and longitudinal tracking of T-cell depletion could help to avoid overimmunosuppression.105 Moreover, thymic function before transplantation is correlated to the rate of posttransplant malignancies. Thus, assessment of rearrangement excision circles may be a helpful in predicting posttransplant malignancies subsequent to rabbit ATG (rATG) treatment.106

TABLE 2
TABLE 2:
The Use of biomarkers can overcome age-related changes in pharmacokinetics and immunosenescence that may not be sufficiently recognized when using trough levels for drug monitoring

In addition, several soluble biomarkers detectable in urine and blood have been evaluated to monitor functional immune responses after transplantation.107,108 A meta-analysis concluded that the soluble CD30 marker showed only poor accuracy to predict acute rejection rates in the context of renal transplantation.109 Another approach to assess cell-mediated immune responses is the measurement of intracellular adenosine triphosphate production. Interestingly, individual levels of intracellular adenosine triphosphate production correlated with rates of infections and cellular rejections in a meta-analysis of more than 500 solid organ transplant recipients,110 independent of drug trough levels.111 Taken together, additional information about the individual immune response and monitoring the activity of the target enzymes may be of future relevance to adjust and maintain accurate levels of immunosuppression in the elderly.

AGE-ADAPTED IMMUNOSUPPRESSIVE PROTOCOLS

Experiences with immunosuppressive protocols in the elderly are limited because clinical trials have in general excluded elderly recipients or recipients of marginal organs, thus warranting prospective randomized immunosuppressive trials.

Induction Therapy

Randomized trials and meta-analyses have clearly demonstrated the superiority of induction therapy compared to conventional maintenance immunosuppression alone in the general renal transplant population. For example, the Kidney Disease: Improving Global Outcomes guidelines for kidney transplantation recommend interleukin-2 receptor antibodies (IL2-RA) as first line induction therapy. However, age-specific recommendations for organ transplantation are missing.112

A large retrospective registry analysis has evaluated effects of induction therapies in more than 14,000 patients older than 60 years.113 Interestingly, patients with higher immunological risk profile (peak panel reactive antibodies >20%, previous transplants or black race) receiving high-risk donors (expanded criteria donors, donation after cardiac death or prolonged ischemic time >24 hours) showed higher rates of rejections when treated with IL2-RA as compared to treatment with rATG. Of note, acute rejections in low-risk recipients that received low-risk organs (non–expanded criteria donors, non-DCD, living donor, short ischemic time <24 hours) were comparable after either IL2-RA or rATG induction. Thus, elderly high-risk recipients that receive high-risk donors (peak panel reactive antibodies >20% or previous transplant or black race) and possibly low-risk recipients with high-risk donors may benefit from an induction treatment with rATG, potentially with a dose reduction. A retrospective study evaluating age-dependent risk profiles linked to rATG therapy in elderly renal transplant recipients (>65 years) found no differences for death-censored graft survival, graft function, rejection rates, infections, malignancies, and hematologic adverse reactions when compared to nonelderly patients.114 Of note, another retrospective analysis of more than 300 older renal transplant recipients (≥60 years) treated with reduced cumulative rATG doses showed comparable renal graft function but lower rates of rejection when compared to younger patients (<60 years).115

These results are in part supported by a prospective multicenter trial nonadjusted for age in renal transplant recipients that had received deceased donor kidney transplants with high immunological risk.116 Patients with high risks for acute rejection or delayed graft function treated with rATG (1.5 mg/kg on days 0, 1, and 4) showed a lower incidence and less severity of acute rejections when compared to those that had received an induction treatment with basiliximab (20 mg on days 0 and 4). Both groups had similar incidences of delayed graft function, serious adverse events, cancer, and death. However, rATG-treated patients had more frequent infections. A Cochrane analysis of more than 10,000 kidney transplant recipients, not adjusted for age, evaluated the use of IL2-RA as induction therapy.117 Although acute rejection rates had been comparable in patients that received IL2-RA or rATG, less cytomegalovirus infections and malignancies were observed when IL2-RA was used. Taken together, rATG might be favorable in patients with high immunological risk due to a reduced lower incidence of acute rejections whereas IL2-RA seems to be superior in patients with a low immunological risk profile.

The use of alemtuzumab for induction therapy was associated with lower rates of NODAT in a large-scale clinical study of renal transplant recipients.62 Moreover, a randomized trial in kidney transplant recipients showed that an induction therapy with alemtuzumab followed by reduced CNI and MMF exposure had been superior to a standard basiliximab-based treatment (basiliximab followed by standard-dose tacrolimus, MPA, and prednisolone).118 However, a retrospective analysis showed that these superior effects might be blunted in older renal transplant recipients (>60 years) as reflected by a higher risk of acute rejection, graft loss and death.113 These findings were not consistent in a stratified analysis and the risk of acute rejections had been higher in low-risk recipients who had received high-risk donor organs. Taken together, the use of alemtuzumab in the elderly patient remains controversial due to a paucity of data and low evidence.

Maintenance Immunosuppression

At this time, only underpowered analyses and few studies of older recipients are available for evaluation. The mTOR inhibitors may be attractive as immunosuppressants in the elderly because these agents have been linked to antitumor capacities69,119,120 and an accumulation of regulatory T cells.121,122 At the same time, management of wound healing issues linked to mTOR inhibitors need to be addressed. Belatacept has recently been introduced as a maintenance immunosuppression. Meaningful clinical trials in older patients are not available. The BENEFIT-EXT study evaluated transplant recipients (mean recipient age, 55 years) that had received suboptimal kidneys (defined as DCD, cold ischemia time >24 hours, donors >60 years, or donors >50 years plus 2 of the following factors—serum creatinine >1.5 mg/dL, cerebrovascular disease, or hypertension). Belatacept-based maintenance immunosuppression sustained improvement in long-term renal function compared to a cyclosporine-based protocol.123 In addition, belatacept is associated with improved blood pressure, lipid profile, and a lower incidence of diabetes versus treatment with a CNI.96

The CNI-free protocols may be of interest in the elderly. A randomized trial of elderly renal transplant recipients (>65 years) evaluated if basiliximab induction and delayed tacrolimus combined with MMF and early steroid discontinuation could preserve renal function compared to standard tacrolimus, MMF, and steroids.124 Interestingly, delayed tacrolimus in combination with basiliximab induction did neither improve renal function nor reduce the incidence of delayed graft function.

The United Network for Organ Sharing data in patients older than 60 years revealed lower rates of acute rejections when tacrolimus had been used in high-immunological risk recipients.113 Likewise, tacrolimus maintenance immunosuppression reduced the risk of patient death independent of immunological risk, whereas there was no association between tacrolimus use and death-censored graft loss. In elderly patients (>60 years), MPA showed a significant decrease of graft loss and death in both, high- and low-immunological risk recipients. Interestingly, there was no clear effect of steroids in older patients on either graft loss or patient survival.113 Early steroid withdrawal or avoidance is of high relevance in older patients reducing age-prevalent side effects, including diabetes, osteoporosis, osteonecrosis, cognitive impairment, or impaired wound healing.125 Lower doses of MMF and lower tacrolimus levels in patients older than 60 years have been associated with improved graft and patient survival, whereas rates of acute rejection were not impacted.126

Acute Rejection Therapy

Clinical trials evaluating the treatment of acute cellular rejection (ACR) or antibody-mediated rejection in the elderly are lacking. Pulse steroids, usually 500 mg for three days followed by tapering for 6 days are the usual treatment for ACRs, although a number of protocols that use different doses ranging from 125 mg to 1000 mg per day have been reported. Recurrence of ACR warrants augmentation of immunosuppression with repeating pulse steroids or rATG with a subsequent switch to CNIs, or belatacept. The use of rATG might be favorable in steroid resistant rejection as it has shown its efficacy in the aged high immunological-risk patient for induction therapy.113

The development of de novo donor specific antibodies (dnDNS) is associated with higher frequencies of graft failure and graft loss.127,128 Of note, nonadherence is one of the most important factors in the development of dnDNS129 with an incidence peak in younger patients.130 Although these antibodies are linked to inferior outcomes, no randomized controlled trial has shown clinical efficacy of desensitization.131 Current therapeutic options include plasmapheresis, application of intravenous immunoglobulins, and rituximab in combination or as monotherapy. Taken together, the development of dnDNS is of critical relevance for both elderly and younger recipients, even though older patients have a lower risk for dnDNS development and acute rejection. Hence, fostering drug adherence and meticulous drug monitoring are critical to prevent in the development of dnDNS and antibody-mediated rejection.132 Although there are no reliable data available thus far demonstrating that elderly graft recipients need different treatments in case of acute rejections, there is clear evidence that acute rejections are less frequent in the elderly.8-10

RECOMMENDATIONS FOR IMMUNOSUPPRESSION IN ELDERLY TRANSPLANT RECIPIENTS

Immunosuppression and immune function in the elderly is in general characterized by less effective immune responses with lower acute rejection rates in addition to more frequent comorbidities. It is unclear, at this point, if recall mechanisms in sensitized patients will change with aging. Thus, not only an overall reduction of immunosuppression as currently practiced but also age-specific immunosuppressive regimens may be beneficial for elderly transplant recipients. This approach needs to consider an optimal protection of the graft with age-specific changes of metabolization linked to adverse effects such as infections, de novo malignancies, or nephrotoxicity. When conceptualizing age-dependent immunosuppression, effects of immunosenescence and graft immunogenicity need to be assessed. Those aspects are of importance as older recipients are frequently transplanted with older or marginal organs that have been associated with more frequent acute rejections.

Nonsensitized Older Patients Receiving High-Quality Organs

Older recipients receiving organs of reasonable quality from deceased donors (in the United States currently assessed with a Kidney Profile Donor Index <85%) or living donor may be candidates for an induction therapy with basiliximab. The IL2-RA are linked to lower rates of infections and malignancies, aspects of importance in the elderly recipient population.

In general, a dose minimization of existing immunosuppressive protocols appears reasonable. Triple immunosuppression with CNIs, MPA, and steroids could be applied with some modifications (Figure 2): a CNI dose reduction is supported by a highly reduced first-pass metabolism in the elderly and lower rejection rates reflected by initial trough level of 6 to 8 ng/dL, and levels of 4 to 6 ng/dl by month 6. The AUC of 30 to 60 mg h/L is the therapeutic level of MPA and can be assured by drug monitoring. The dose can be adjusted based on linear and nonlinear regression models or maximum Bayesian estimation.133 Independent of the model used, the need of dose adjustment is more likely in older patients with renal failure (creatinine clearance <20 mL/min per 1.73 m2) and albumin changes in parallel to compromised hepatic function. A rapid steroid withdrawal within 5 days is recommended particularly given a higher risk of NODAT and infections in the elderly. Although not based on evidence, a switch from CNIs to mTOR inhibitors after 3 to 6 months may help maintaining renal function while reducing risk for de novo malignancies. Moreover, implementing belatacept as a CNI replacement appears of interest with a good safety profile of the agent. Those latter approaches will hopefully be tested in future prospective clinical trials.

FIGURE 2
FIGURE 2:
Recommendations for an age-specific immunosuppression. Of note, clinical trials in the elderly remain rare and the proposed regimes are rather optional recommendations, not representing guidelines. The area under the curve (AUC) of 30 to 60 mg h/L is the therapeutic level of MPA and can be assured by drug monitoring. The dose should be based on linear and non-linear regression models or maximum Bayesian estimation.133

Nonsensitized Older Patients Receiving Marginal Organs

In older nonsensitized patients receiving an organ of marginal quality the use of rATG as induction appears preferable (Figure 2). At the same time, the cumulative dose of rATG may be reduced in the elderly (normal dose of 1.5 mg/kg per day for 4 days may be reduced to 0.75 mg/kg per day for 4 days), although further clinical trials are warranted to support this approach. A triple maintenance immunosuppression with CNIs, MPA, and steroids appears reasonable with an MPA (AUC of 30-60 mg h/L) dose adjustment based on linear and nonlinear regression models or maximum Bayesian estimation.133 Rapid steroid withdrawal within 3 months is recommended to prevent NODAT while keeping CNIs on a lower dose (trough level of 6-8 ng/dL, after 6 months 4-6 ng/dL). Again, CNI-free regimens including mTOR inhibitors or belatacept appear attractive in theory but warrant prospective trials.

Sensitized Older Recipients

Sensitized elderly patients have higher rates of rejections,134 although the immunobiology of sensitization and recall mechanisms in the elderly remain unclear. The rATG may be a favorable option for induction therapy (normal doses of 1.5 mg/kg per day for 4 days) considering the high immunological risk of the patients. Triple therapy (CNIs, MPA, and steroids) appears appropriate without an age-adapted dose reduction (Figure 2). Steroid withdrawal, CNI dose reduction, and a switch to CNI-free immunosuppression in this population remains to be studied prospectively. The MPA (AUC of 30-60 mg h/L) dose adjustment based on linear and nonlinear regression models or maximum Bayesian estimation may be relevant in this patient group with high immunological risk.133 In general, sensitized older patients may need to undergo separate trials to assure that maintenance immunosuppression can be safely reduced or switched as it remains unclear if sensitization in the elderly represents an effective allospecific or rather an unspecifically activated immune response.

CONCLUSIONS

Age is broadly impacting pharmacodynamics, pharmacokinetics, and immune responses. Yet, older patients have thus far been largely excluded from clinical immunosuppressive trials. In general, older recipients have less frequent acute rejections, whereas older organs have been linked to more potent immune responses and higher acute rejection rates.

Immunosuppressive protocols require an age adaption that goes beyond the current clinical practice of “as much as necessary and as little as possible.” Future clinical trials and the use of new biomarkers will need to include the elderly to define, beyond the current limit evidence, what agents are preferable in the elderly, and if a minimization of immunosuppression is safe in the elderly.

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