Elderly Transplant Recipients Research Articles

Assessment of Inpatient Mortality in the Peri-Transplant Period in Elderly Allogeneic Stem Cell Transplant Recipients with Co-Existing Mental Health Illnesses

Background Allogeneic hematopoietic stem cell transplant (alloHCT) is a potentially curative treatment for patients with hematological malignancies and nonmalignant conditions. AlloHCT involves invasive procedures, conditioning chemotherapy regimens, and prolonged isolation during hospitalization, which is physically and emotionally challenging. Transplant related mortality is higher in older individuals. Careful assessment of mortality risk before transplant is essential for optimal patient selection and informed decision-making, especially in elderly patients. Hematopoietic cell transplantation-specific comorbidity index (HCT-CI), an important prognostic scoring tool used in patients before alloHCT, includes psychiatric comorbidity as one of the scoring criteria. Patients with depression or anxiety disorders receive one point on the scoring scale, with the assumption that the two groups of patients are at an equivalent risk. However, there is literature showing decreased overall survival and worse inpatient outcomes in patients receiving alloHCT with co-morbid depression. Our primary objective was to evaluate the inpatient outcomes of elderly patients undergoing allogeneic stem cell transplant with a concurrent diagnosis of depression and patients with anxiety and adjustment disorders. Methods: Patients of ages ≥ 60 years, admitted with a principal procedure code of allogeneic stem cell transplant, were recruited from the 2016-2020 National Inpatient Sample. Three cohorts were created based on ICD-10 diagnostic codes for Depression and Anxiety and adjustment disorders: patients without depression and anxiety disorders, patients with depression only, and patients with anxiety and adjustment disorders only. Patients with diagnoses of other mental illnesses were excluded. The patient characteristics between the three cohorts were evaluated. Multiple Logistic Regression models were used to determine the impact of depression and anxiety disorders on inpatient mortality. Results: We evaluated 11655 hospital admissions with the primary procedure code for Allogeneic Stem Cell Transplant in patients aged 60 years and above. 8375 patients did not have any mental illness. 800 patients (9.5%) had a diagnosis of Depression, and 1640 patients (19.5%) had a diagnosis of Anxiety and adjustment disorders. Comparing the primary outcomes in patients with and without Depression, the length of stay was 31.3 days vs 28.2 days (p<0.01), the mean hospital charge was 558398.01 USD vs 498971.9 USD (p <0.01), and in-patient mortality was 8.1% vs 5.9% (aOR = 1.359, 95% CI 1.010-1.829, p=0.04). Utilization of mechanical ventilation was more prevalent in patients with depression (8.8 %vs 5.8 %, p <0.01). Out of different infectious complications, pneumonia was more common in patients with depression (14.4 % vs 9.8 %, p <0.01) (Table 1a). Baseline socio-demographic characteristics that were associated with having depression included: Female gender, White race, and Medicare insurance. Patients with depression had an increased prevalence of congestive heart failure, prior stroke, Obesity with BMI >= 35, chronic kidney disease, and COPD compared to patients without depression (p<0.01). For the primary outcomes in patients with and without anxiety and adjustment disorders, the length of stay was 29.15 days vs 28.2 days (p <0.01), the mean hospital charge was 474274.71 USD vs 498971.94 USD (p 0.612), and the in-patient mortality was 4% vs 5.9 % (aOR=0.61, 95% CI 0.45-0.83, p<0.01). Baseline socio-demographic characteristics that were prevalent in patients with anxiety and adjustment disorders were: female gender, white race, and Medicare as the most common insurance (P<0.01) (Table 1b). Conclusion We found that in elderly patients admitted for alloHCT, depression was independently associated with worse inpatient outcomes, while anxiety was not. Patients with depression were noted to have an increased incidence of infectious complications as compared to those without depression, possibly accounting for their increased mortality. Prognostic scoring systems like HCT-CI may need to be modified to assign more weight to depression as a psychiatric co-morbidity. Elderly transplant recipients with depressive disorders are a vulnerable group and multidisciplinary teams such as psychiatry and palliative care should be involved in their care.

Survival after kidney transplantation compared with ongoing dialysis for people over 70 years of age: A matched-pair analysis

Kidney transplantation offers improved survival and quality of life compared to dialysis for most recipients; however, benefits for elderly patients (>70 years) remain uncertain. Using the Australia and New Zealand Dialysis and Transplant Registry (2009-2019), elderly transplant recipients were matched to a waitlisted dialysis patient by age, cause of end-stage kidney disease, and dialysis duration (paired controls). We censored dialysis patients at the time of transplant. Survival was compared using stratified Cox regression. Elderly transplant recipients (KTRs) (n = 465) were matched to waitlisted pairs. Transplant group mortality initially exceeded dialysis due to excess infection-related deaths (1.9 transplant versus 0.3 dialysis/100 patient-years, P = .03). Beyond month 9, a progressive survival benefit in favor of transplantation was apparent. Over a median follow-up of 1.7 years, mortality was 38% lower for KTRs (95% confidence interval 0.41-0.94, P = .02), and 5-year survival was 80% KTRs vs 53% dialysis (P < .001). Recipients of living and standard criteria donor kidneys acquired immediate survival advantage compared with dialysis, while recipients of expanded criteria donor's kidneys experienced elevated risk of death for the first 17 months. Compared with remaining on dialysis, elderly KTRs incur an increased risk of early posttransplant mortality but thereafter may anticipate progressively superior survival rates.

A review of elderly transplantation regarding complications, outcomes, and survival

BackgroundRenal transplant adds survival benefits to end-stage renal disease patients over dialysis, and a similar concept applies to elderly patients. Some of the challenges of transplanting old patients may involve age-related cancers and comorbid conditions such as cardiovascular disease. Studies had shown that advanced age is associated with better outcomes compared to dialysis despite receiving poorer quality organs. AimThis extended literature review aims to identify the common complications, outcomes, and survival benefits of kidney transplantation in the elderly population. MethodsAn extended literature review was done to identify studies that compared elderly transplant recipients with the younger kidney transplant recipient population. The study population included elderly kidney recipients aged sixty and above and younger kidney recipients below the age of sixty. This literature review aims to discuss complications facing elderly kidney recipients and compare transplant outcomes to younger kidney recipients. PubMed, Midline, and google scholar databases were searched and papers meeting the pre-set inclusion criteria were identified. ResultsA total of 212 papers were identified. After screening the results, 12 papers met the inclusion criteria and were included for review. 10/12 papers included patients' age cutoff point, one paper had cut-off age between 60 and 80 years, while the last paper recruited patients with ages above 70. Most of the studies mentioned young group age as below 60, 2/12 papers divided the young group into further subgroups of age. Two studies used paired donor organs for both young and elderly groups to eliminate donor bias. While other studies used living, deceased, or both living and deceased donors for both elderly and young groups. One study matched donor type and gender in both groups. The studies looked at patient and graft survival and complications. Elderly transplant patients suffered more hospitalization, infections, cardiovascular complications, malignancy, and surgical complications. Post-transplant diabetes was higher in the young recipient group in one study. ConclusionIn the case of elderly renal transplant recipients, the cut-off point for age to perform renal transplant is not clear but studies showed better survival and cost-effectiveness in elderly patients compared to patients on the waiting list even in older patient cohorts

Kidney Transplant Outcomes in Recipients Over the Age of 70.

Patients older than 70 years are the fastest-growing age group of patients requiring renal replacement therapy. This has resulted in a corresponding increase in the number of elderly transplant recipients. We hypothesized that graft survival in this population would be comparable to that seen in the literature on kidney transplant recipients under 70 years of age. This was a retrospective, single-center review of outcomes of kidney transplant recipients aged ≥70 years. Patients were dichotomized based on whether their allograft originated from a living or deceased donor. A total of 59 recipients aged ≥70 years underwent kidney transplantation. Of these, five (8.5%) were lost to follow-up within the first year post transplant and excluded from the analysis. History of cerebrovascular accident (p = 0.003), coronary artery disease (p = 0.03), postoperative return to the operating room (p = 0.03), and readmission within one year of transplant were predictive of graft loss (p = 0.003). Overall graft survival in our cohort declined from 92.6% at one year to 53.8% at five years. Death-censored graft survival was 100% at one year and decreased to 80.8% at five years. There were no differences seen in patient, graft, or death-censored graft survival based on donor type. Kidney transplant patients over 70 years, as seen in our cohort, had good short-term outcomes. Graft survival is similar to rates seen in younger cohorts but the decline in this rate over time is steeper in the older age group, possibly due to decreased patient survival. These findings could be validated further in larger multi-center studies.

Nonalcoholic steatohepatitis is the most common indication for liver transplantation among the elderly: Data from the United States Scientific Registry of Transplant Recipients.

As the US population ages, more elderly patients may need liver transplantation. Our aim was to assess recent trends among elderly individuals requiring liver transplant in the United States. Scientific Registry of Transplant Recipients data (2002–2020) were used to select elderly (≥65 years) liver transplant candidates and assess on‐list and posttransplant outcomes. During the study period, 31,209 liver transplant candidates ≥65 years were wait listed. Common etiologies included nonalcoholic steatohepatitis (NASH; 31%), hepatitis C (23%), and alcoholic liver disease (18%); 30% also had hepatocellular carcinoma (HCC). Over time, the proportion of patients ≥65 years among all adult liver transplant candidates increased from 9% (2002–2005) to 23% (2018–2020) (trend, p < 0.0001). The proportion of NASH among elderly candidates increased from 13% (2002–2005) to 39% (2018–2020). Of the elderly candidates, 54% eventually received transplants. In multivariate analysis, independent predictors of a higher chance of receiving a transplant for the elderly included more recent years of listing, male sex, higher Model for End‐Stage Liver Disease (MELD) score, and HCC (all p < 0.01). Posttransplant mortality in elderly transplant recipients was higher than in younger patients but continued to decrease over time. In multivariate analysis, independent predictors of higher posttransplant mortality for elderly transplant recipients were earlier years of transplantation, older age, male sex, higher MELD score, history of diabetes, retransplantation, and having HCC (all p < 0.01). The proportion of elderly patients in need of liver transplantation in the United States is sharply increasing. NASH is the most common indication for liver transplantation among the elderly. The outcomes of these patients have been improving in the past 2 decades.

Ageing of Immune System and Response to a Live-Attenuated Herpes Zoster Vaccine in Lung Transplant Candidates.

The mean age of lung transplant recipients has significantly increased in recent decades. Elderly recipients have a higher risk of developing herpes zoster (HZ), and they have in general a worse response to vaccination than younger persons do. We investigated the relationship between the humoral and cellular immune response to a live-attenuated HZ vaccine (Zostavax®, Merck Sharp and Dohme) and the frequencies of T and B cell subsets, especially aged cell subsets (CD28−T cells and age associated B cells, ABCs). In total, 37 patients awaiting lung transplantation received one dose of Zostavax®, and peripheral blood was collected before and within 6 months after vaccination. We observed a robust immune response after vaccination. The frequencies of CD28−T cells before vaccination had no impact on the subsequent immune response to HZ vaccination. However, a higher frequency of ABCs before vaccination correlated with a lower immune response especially regarding the cellular immune response. Cytomegalovirus seropositivity was associated with increased frequencies of CD28−T cells but not with frequencies of ABCs in the patients. In conclusion, increased levels of ABCs might disturb the cellular immune response to HZ vaccination, which could lower the efficacy of such vaccination in elderly transplant recipients.

CTLA4-Ig prolongs graft survival specifically in young but not old mice.

Elderly organ transplant recipients have remained underrepresented in clinical trials, despite representing a rapidly growing population. Here, we assessed age-specific effects of CTLA4-Ig (cytotoxic T-lymphocyte antigen 4-Ig), a fusion protein blocking costimulatory signaling between antigen-presenting cells and T cells through CD28. Cardiac allografts in young mice (2-3months) treated with CTLA4-Ig survived indefinitely, whereas 80% of old recipients (18months) had lost their graft after 100days. CTLA4-Ig was also significantly less effective in older recipients of skin transplants. CTLA4-Ig reduced CD4+ central memory and effector memory T cells and diminished systemic interferon-gamma levels only in young recipients. These differences corresponded to a reduced expression of CD28 on antigen-experienced CD4+ T cells in old mice. In support, adoptive transfer of old CD4+ T cells that were transfected with a lentiviral vector inducing constant expression of CD28 accelerated the rejection of allogeneic skin grafts in young RAG2-/- recipient mice. Regulatory T cells (Tregs), in contrast, demonstrated an increased expression of CD28 with aging and CTLA4-Ig treatment in old recipients resulted in reduced frequencies, compromised proliferation, and diminished suppressive capacity of Tregs. These findings may prove to have unique clinical consequences for immunosuppression in the growing population of elderly transplant recipients.

Assessment of infectious complications in elderly kidney transplant recipients receiving induction with anti-thymocyte globulin vs basiliximab.

Elderly transplant recipients experience lower rates of acute rejection with higher rates of infectious complications compared to their younger counterparts. While less intensive immunosuppression may be preferable, there are no recommendations for depleting versus non-depleting induction strategies. We sought to compare infectious complications between anti-thymocyte globulin (ATG) and basiliximab (IL2RA) induction in elderly kidney transplant recipients (KTRs). We reviewed 146 KTRs ≥65years receiving ATG or IL2RA induction. Per institution protocol, ATG was administered to patients with the following characteristics, irrespective of age: African American (AA), PRA ≥20%, and/or re-transplantation. Infectious complications (bacterial, viral, and invasive fungal) at 1year were compared. There were significantly more AA, deceased donors, and sensitized KTRs in the ATG group, reflecting criteria for induction agent. ATG KTRs experienced higher rates of overall infectious complications (77% vs 56%, P=.01), driven by increased bacterial (54% vs 39%, P=.08) and viral infections (51% vs 35%, P=.05). Urinary tract infections (UTIs) and CMV in particular occurred at high rates among ATG patients (46% and 32%, respectively). In multivariate analysis, the only independent risk factor associated with increased risk for infection was induction with ATG (adjusted HR 1.71 [95% CI 1.04-2.83], P=.04). Overall rates of immunologic outcomes were low. Elderly KTRs receiving ATG are at an increased risk for infectious complications, largely attributed to high rates of UTIs and CMV. Additional strategies aimed at mitigating these complications in elderly patients requiring ATG may be beneficial.

When are you too old to get a kidney transplants?

With the increasing incidence and prevalence of ESRD in the elderly, we are now transplanting more elderly patients. Although we know from previous reports that transplantation provides increased survival advantage and/or quality of life when compared to being on dialysis, we also know that transplantation is not the best option for all patients. In this review, we try to identify the upper age limit (if any) for deceased donor renal transplantation, predictive factors that can identify the risks for transplant outcomes, frailty, and immunosenescence. Review of data over the last 5 years have identified certain risk predictors and outcomes that might be helpful in evaluation of the elderly transplant recipient, which we aim to summarize in this review. Identifying predictors to risk stratify elderly patients and promote transplantation is much needed. Modifiable risks should be addressed to ensure more candidates become transplantable. A combination of physical, medical, and immunological markers to better identify recipients is imperative for future research gearing towards precision medicine.

Some Aspects of Aging Are Advantageous: Elderly Organ Recipients May Get Away With Less Immunosuppression

Aging impacts health care broadly. In organ transplantation, most patients currently waiting for an organ transplant are older than 55 years, with >20% of transplant recipients being over the age of 65.1 Demographic changes are also relevant for the deceased donor population with approximately 20% of donors being older than 50 years and approximately 5% >65 years old.2 Markedly are geographic differences with close to 50% of donors being older than 60 years in Spain.3 Although relevance and necessity of age-specific aspects of immunosuppression in the elderly have been recognized, clinical immunosuppressive trials in organ transplantation have mostly excluded older patients. The aging immune system is characterized by reduced amounts of naïve T cells because of limited thymic outputs, an accumulation of less effective memory T cells, and a constricted T-cell receptor repertoire. Additional age specifics of T-cell metabolisms have started to be appreciated. The effects of immunosenescence on B-cell responses are less well understood. The efficacy of B cells may be influenced through compromised T cell function, with additional limitations in class switch recombinations playing a role.4 Clearly, understanding immunosuppression in the elderly is of clinical relevance. It is important to understand that an optimization of immunosuppression in aging may not be as simple as applying less of the same immunosuppression. Immunosuppressants that work effectively in young recipients may operate differently in the elderly. Tacrolimus, for example, has been more efficient at lower doses with age-specific effects based on lower calcineurin levels in older human CD-4 T cells. Moreover, mammalian target of rapamycin inhibition has been more effective in experimental models with reduced proinflammatory interferon-γ production and augmented amounts of interleukin (IL)-10 by old CD4+ T cells.5 Studying age-specific aspects of clinical immunosuppression appears, therefore, timely and relevant. While previous studies have compared the application of the polyclonal antibody Thymoglobulin (ATG) and Basiliximab (BSX) targeting the IL-2 receptor on activated T cells as induction treatments, those regimens have not been compared in the elderly. Masset et al6 from France showed that both ATG and BSX were effective in immunological low risk older (≥65 y) recipients. Three-year graft survival was different (74% for ATG- and 68% for BSX-treated recipients), however, not reaching statistical significant difference. BSX-treated patients also had higher rates of acute T-cell–mediated rejections. As the most prominent finding of this study, the occurrence of posttransplant diabetes (PTD) had been significantly higher in BSX compared to ATG-treated recipients (23% versus 15%, P = 0.04), potentially related to higher tacrolimus trough levels in the BSX group (BSX 9.48 versus ATG 7.30 ng/mL, P = 0.023). As T-cell–mediated rejections had been significantly higher in BSX-treated recipients, those patients may have also had an additional corticosteroid burden. A few additional aspects, including center-specific approaches of protocol versus for-cause biopsies and an overall small cohort, need to be contemplated. Moreover, conclusions of this study are based on a retrospective analysis with a broad center-specific variance of immunosuppressive treatments and only a small albeit significant difference for the incidence of PTD. Do those results confirm that less is more when it comes to immunosuppression in the elderly, or are there additional aspects to consider? We have come to understand that alloimmunity is determined by the sum of recipient’s alloimmune responses. The immunogenicity of the graft itself is playing an additional role. In aging, this constellation appears of particular relevance: older organs elicit more frequent acute rejections linked to activated intragraft dendritic cells.7-9 Remarkably, the frequency of acute rejections when transplanting older organs is blunted when older organs are transplanted into older recipients. Of additional clinical relevance, older recipients are more likely to receive an older organ that is, in turn, more likely to develop a delayed graft function,10 emphasizing the importance to postpone the initiation of calcineurin inhibitors. Immunosuppressive protocols for the elderly will thus need to have those complexities in mind. Although more frequent rates of PTD may very well be linked to increased tacrolimus trough levels, this finding may not necessarily make an argument for a BSX induction in elderly transplant recipients. A reduced Thymoglobulin dosage in parallel to a reduced tacrolimus dosage, initiated days after transplantation, may be a preferable alternative. Masset et al6 have helped us to focus on the elderly in transplantation with the goal to work toward an optimized immunosuppression in this growing transplant population. Future prospective immunosuppressive studies in the aging population with an additional detailed evaluation of alloimmune responses may provide further clarification for a clinically pressing problem in organ transplantation (Figure 1).FIGURE 1.: Future immunosuppressive trials in the elderly may address dosing of established immunosuppressants in addition to age-specific effects and alloimmune responses. ATG, antibody thymoglobulin.

Characterizing the pharmacokinetics and pharmacodynamics of immunosuppressant medicines and patient outcomes in elderly renal transplant patients.

This review examines what is currently known about the pharmacokinetics and pharmacodynamics of commonly prescribed immunosuppressant medicines, tacrolimus, cyclosporine, mycophenolate and prednisolone, in elderly renal transplant recipients, and reported patient outcomes in this cohort. Renal transplantation is increasing rapidly in the elderly, however, currently, long-term patient outcomes are relatively poor compared to younger adults. Some studies have suggested that elderly recipients may have higher dose-adjusted exposure and/or lower clearance of the calcineurin inhibitors tacrolimus and cyclosporine; with one study reporting up to 50% reduction in tacrolimus exposure in the elderly. Elderly transplant recipients do not appear to have higher dosage-adjusted exposure to mycophenolic acid (MPA). The effects of ageing on the pharmacokinetics of prednisolone are unknown. Only one study has examined how aging effects drug target enzymes, reporting no difference in baseline inosine 5'-monophosphate dehydrogenase (IMPDH) activity and MPA-induced IMPDH activity in elderly compared to younger adult renal transplant recipients. In elderly transplant recipients, immunosenescence likely lowers the risk of acute rejection, but increases the risk of drug-related adverse effects. Currently, the three main causes of death in elderly renal transplant recipients are cardiovascular disease, infection and malignancy. One study has showed that renal transplant recipients aged over 65 years are seven times more likely to die with a functioning graft compared with young adults (aged 18-29 years). This suggests that an optimal balance between immunosuppressant medicine efficacy and toxicity is not achieved in elderly recipients, and further studies are needed to foster long-term graft and patient survival. Lower maintenance immunosuppressant targets in elderly recipients may decrease patient susceptibility to drug side effects, however, further studies are required and appropriate targets need to be established.

Costimulatory Blockade with CTLA4-Ig Abrogates Prolonged Graft Survival in Old Recipients

Introduction Although they represent a rapidly growing population, elderly organ transplant recipients are underrepresented in clinical trials. Age-specific aspects of established immunosuppressants are therefore poorly understood. Methods Here, we assessed the impact of immunosuppressive treatment with CTLA4-Ig, a fusion protein blocking costimulatory signaling between APCs and T cells through CD28, on alloimmune responses in old and young recipients (2-3 months vs. 16 months) in a fully MHC-mismatched murine transplantation models. Results While treatment with CTLA4-Ig prolonged skin graft survival in young recipients, the same treatment was unable to prolong graft survival in old recipients. Conversely, cardiac allografts in young mice treated with CTLA4-Ig survived indefinitely, while 80% of old recipients treated with CTLA4-Ig had lost their graft after 100 days (log-rank test, p<0.001; n=5/group; Fig. 1).{{AbstractFigure.1}} CTLA4-Ig reduced the in-vivo proliferation of CD4+ and CD8+ T cells (as assessed by BrdU incorporation) uniformly in both young and old recipients; in contrast, CTLA4-Ig reduced CD4+ central-memory and effector-memory T cells only in young but not old recipients. Moreover, systemic frequencies of CD4+IFN-γ+ T cells and systemic levels of IFN-γ cytokine production were reduced in young recipients, but remained unchanged in old. CTLA4-Ig caused significant perturbation in the Treg compartments with reduced frequencies and compromised proliferation of CD4+CD25+Foxp3+ cells. These differences correlated with a significant reduction in expression of CD28 on T cells in old mice, while levels of CTLA4 remained stable.Conclusion Immunosuppressive effects of costimulatory blockade with CTLA4-Ig showed distinct age-dependent effects in both skin and cardiac transplantation. Reduced expression of CD28 with aging may represent an escape mechanism for old alloreactive T cells, with unique clinical consequences for immunosuppression in the growing population of elderly transplant recipients.

Reversible personality changes caused by brain nocardiosis in a 74-year old Caucasian male renal transplant recipient following disease-specific antimicrobial therapy

The management of potentially life-threatening brain nocardiosis in an elderly renal transplant recipient with the relevant specific antimicrobial agents while still continuing anti-rejection immunosuppressive therapy poses major clinical, pharmaceutical and logistical problems. This is a case of a 70-plus year old Caucasian male renal transplant recipient on maintenance immunosuppression, who developed a left flank abscess that was later complicated by the onset of personality changes from brain nocardiosis. The evolution of the diagnosis, treatment and recovery in this case presentation highlight the need for microbial susceptibility testing, the need for pharmacovigilance to monitor drug intolerance and drug resistance as well as other overarching treatment strategies including a close collaboration between Infectious Diseases and Transplant Medicine specialties in the management of this complicated case.

Lung transplantation in elderly patients.

Consensus statements on the selection of lung transplant candidates have consistently identified older age as a relative contraindication to transplantation. A combination of population-level demographic changes, revision of the lung allocation score (LAS), and clearer data on outcomes in elderly transplant recipients has, however, driven a steady increase in the threshold at which age is taken into consideration. This article reviews the current state of lung transplantation in elderly patients with an emphasis on the factors that have increased lung transplantation in older age groups, their expected outcomes including survival and health-related quality of life, and the factors that go in to appropriate candidate and procedure selection in this population.

Need for optimized immunosuppression in elderly kidney transplant recipients.

Accordingly, organ allocation policies in this population were adjusted in several countries. The European Senior Program is the most prominent example, where elderly patients (≥65years) receive elderly (≥65years) donor organs with acceptable results. Because of age-dependent changes in the immune response and higher susceptibility to immunosuppressant side effects, outcomes in elderly patients are different compared to younger kidney transplant recipients. However, elderly patients do reject, especially poorly matched elderly donor organs. This warrants tailored immunosuppressive regimes with regard to the age-related changes of the immune system. Rejection therapies may have detrimental side effects in the seniors and are frequently leading to over-immunosuppression (malignancy and infections) in long-term therapy. It is hypothesized that after initial graft adaptation elderly patients may benefit from less immunosuppression in order to lower cancer risk and reduce infection rates and cardiovascular comorbidities. Current evidence on recommended standard immunosuppressive therapy was mainly derived from trials, where elderly patients were excluded or only a minority. In order to improve immunosuppressive therapy in elderly transplant recipients, current immunosuppressive regimes have to be re-investigated in this growing population. Up to date, only a few well-designed prospective studies were performed in elderly populations and demonstrate the need for effective immunosuppression in the first months after transplantation. It is evident that novel treatment strategies and adequately powered prospective clinical trials are needed to establish time-adapted immunosuppressive regimens according to the needs of this vulnerable group of kidney transplant recipients.

Immunological characteristics of the elderly allograft recipient.

The increasing number of elderly people with a demand for organ transplantation poses an important medical challenge. The effect of aging on the immune system concerns wide modifications with a considerable influence on transplant outcomes. Aging causes significant changes in immune cells repertoire. Thymic involution impairs the production of new naïve cells. Immune remodeling induces important alterations in the activity of immunological molecules. Therefore, clinical implications in elderly transplant recipients should consider appropriate organ allocation with adequate individualization of immunosuppression.

Immunosenescence in renal transplantation: a changing balance of innate and adaptive immunity.

With global demographic changes and an overall improved healthcare, more older end-stage renal disease (ESRD) patients receive kidney transplants. At the same time, organs from older donors are utilized more frequently. Those developments have and will continue to impact allocation, immunosuppression and efforts improving organ quality. Findings mainly outside the field of transplantation have provided insights into mechanisms that drive immunosenescence and immunogenicity, thus providing a rationale for an age-adapted immunosuppression and relevant clinical trials in the elderly. With fewer rejections in the elderly, alloimmune responses appear to be characterized by a decline in effectiveness and an augmented unspecific immune response. Immunosenescence displays broad and ambivalent effects in elderly transplant recipients. Those changes appear to compensate a decline in allospecific effectiveness by a shift towards an augmented unspecific immune response. Immunosuppression needs to target those age-specific changes to optimize outcomes in elderly transplant recipients.

Pharmacokinetics and pharmacodynamics of immunosuppressive drugs in elderly kidney transplant recipients.

Elderly patients are a fast growing population among transplant recipients over the past decades. Both the innate and adaptive immune reactivity decrease with age, which is believed to contribute to the decreased incidence of acute rejection and increased infectious death rate in elderly transplant recipients. In contrast to recipient age, donor age is associated with a higher incidence of acute rejection. Pharmacokinetic studies in renal transplant recipients show that CNI troughs are >5% higher in elderly compared to younger patients given the same dose normalized by body weight. This may impact the starting dose of tacrolimus and cyclosporine. Possibly in elderly patients the intracellular (in lymphocyte) concentrations are relatively high in relation to the whole blood concentration, resulting in a stronger pharmacodynamic effect at the same whole blood trough concentration. For cyclosporine this has been shown, but it is not clear if the same is true for other immunosuppressive drugs. Pharmacodynamic studies have compared the inhibition of target enzymes, or more downstream effects of immunosuppressive drugs, in younger and older patients. Measurement of nuclear factor of activated T-cell (NFAT)-regulated gene expression (RGE), a pharmacodynamic read-out of CNI, is a promising biomarker of immunosuppression. Low levels of NFAT RGE are associated with increased risk of infection and non-melanoma skin cancer in elderly patients. Clinical trials to evaluate the safety and efficacy of immunosuppression regimens in this specific patient population, which is underrepresented in published trials, are lacking. More studies in elderly patients are needed to investigate the impact of age on the pharmacokinetics or pharmacodynamics of immunosuppressive drugs, and to decide on the optimal regimen and target levels for elderly transplant recipients.

Rates of renal transplantations in the elderly-data from Europe and the US.

The demography in most part of the world is changing with an increasing proportion of elderly persons. This is expected to reflect demography of patients accepted for renal replacement therapy both in the form of dialysis and transplantation. Based on this, the intention of the present review is to collect and describe available data on rates of transplantation with focus on the elderly patients in both Europe and the US. Data were collected from available sources including activity reports from national and supranational registries on uremia, organ procurement, waiting lists, and transplantations. Since 1990 both absolute numbers and proportions of elderly patients starting renal replacement therapy have increased dramatically in both Europe and the US. Although the pattern of changes is similar in Europe and the US, the incidence and prevalence rates for renal replacement therapy in the elderly are 3-4 times higher in the US. In the same period, the rates of renal transplantations in the elderly patient group have increased in both Europe and the US with increased access to the waiting list and to transplantation. Data from the United States Renal Data System on incidence of transplantation document a substantial increase in proportion of elderly transplant recipients (65+ years) from 4.2% in 1990 to 17.2% in 2012 and an increase in proportion of prevalent elderly renal transplant patients from 3.8% in 1992 to 23.3% in 2012. Similar changes have been seen in Europe. Due to these alterations in the demography of the transplant patients in both Europe and the US it is concluded that the elderly transplant patient from being a rare patient has now become a common patient necessitating increased focus on this group in order to optimize treatment results.

Clinical issues in renal transplantation in the elderly.

Kidney transplantation is the best renal replacement therapy option and is superior to dialysis in elderly end-stage renal disease (ESRD) patients. Furthermore, the outcome of transplantation in the elderly is comparable to younger patients in terms of allograft survival. The exact nature of this phenomenon is not completely clear. As the elderly population continues to grow, it becomes more important to identify specific issues associated with kidney transplantation. In particular, elderly transplant recipients might have a lower chance of acute rejection as their immune systems seem to be less reactive. This might predispose elderly recipients to greater risk of post-transplant infectious complications or malignancies. Furthermore, due to differences in pharmacokinetics, elderly recipients might require lower doses of immunosuppressive medication. As the main cause of graft failure in the elderly is death with a functioning graft and also considering the scarcity of donor organs, it might make sense to recommend transplanting elderly recipients with extended criteria donor kidneys. This approach would balance shorter patient survival compared to younger recipients. In conclusion, old age should not preclude ESRD patients from kidney transplantation. However, specific differences that have to do with immunosuppression and other aspects of managing elderly transplant recipients should be considered.