An Overview of Frailty in Kidney Transplantation

Measurement, Management and Future Considerations

Meera N. Harhay; Maya K. Rao; Kenneth J. Woodside; Kirsten L. Johansen; Krista L. Lentine; Stefan G. Tullius; Ronald F. Parsons; Tarek Alhamad; Joseph Berger; XingXing S. Cheng; Jaqueline Lappin; Raymond Lynch; Sandesh Parajuli; Jane C. Tan; Dorry L. Segev; Bruce Kaplan; Jon Kobashigawa; Darshana M. Dadhania; Mara A. McAdams-DeMarco


Nephrol Dial Transplant. 2020;35(7):1099-1112. 

In This Article

Frailty, Aging and Immune System

The Immunosenescence Phenotype of Aging and Chronic Disease

Akin to physiologic aging and chronic disease, frailty has been associated with alterations in the immune system[61,105–107] and these changes may have important implications for graft survival and immunosuppressive management for frail KT recipients. Immunosenescence, a state of deteriorating and compromised immune response, has been studied in the context of aging and among older KT recipients.[108] Notably, physiologic aging appears to be linked to an imbalance of innate and adaptive immunity, with innate immune responses gaining prominence (Figure 3, Panel A). Chronic disease processes such as CKD may also enhance the state of immunosenescence. Studies of immune function in pediatric patients with CKD have shown premature T-cell aging, including a reversal of the CD4:CD8 ratio, reduced portions of native T-cells with an evidence of T-cell exhaustion and loss of CD28 expression.[111] Immunosenescence, as defined by immunophenotyping or measurement of telomere length, has been linked to broad changes of the immune response, increasing the risk of infection and malignancy in older adults.[109,112,113] However, it should be noted that the state of immunosenescence does not equate to absence of inflammation. In fact, senescent cells have been characterized as secreting a number of proinflammatory cytokines, chemokines, growth factors and proteases locally and contribute to the 'inflammaging' phenotype of the elderly.[114] Therefore, given the aging KT populations,[7] research is needed to explore potential differences in the mode of action, dosing, metabolism and pharmacokinetics of immunosuppressants in the setting of immunosenescence.

Figure 3.

Physiology of immunosenescence: the aging immune system. (Panel A) Aging is associated with immunosenescence, resulting in alterations in the immune response. These alterations may require adjustment of immune therapy after KT [109] (Panel A redesigned with permission from Transplantation: November 2015-Volume 99-Issue 11- p 2258–2268, Copyright © 2015 Wolters Kluwer Health [110]). (Panel B) In addition to aging, frailty may also influence immune therapy risks after KT. Novel immune system biomarkers may permit individualization of immune therapy among vulnerable transplant recipients.

The Inflammatory Phenotype of Frailty

As frailty can occur across the lifespan in ESKD, it may not always be associated with a state of immunosensecence. However, relative to nonfrail individuals with ESKD, those with frailty exhibit increased inflammatory markers such as C-reactive protein and interleukin-6, findings that are independently associated with higher mortality risk among ESKD patients.[61] The implications of frailty-related inflammation on the response to immunosuppressive treatment are unclear. Importantly, there are no definitive data that would support reduced immunosuppression in the context of frailty alone. In contrast, a study of 525 KT recipients showed that mycophenolate mofetil dose reduction was associated with a 5-fold higher risk of death-censored graft loss and that this association was not modified by frailty status.[24] Research is needed to explore whether interventions to improve frailty can also impact systemic inflammation and how changes in inflammation might influence KT outcomes.

New Tools to Tailor Immunosuppressive Therapy for Frail KT Recipients

Given the complex interplay between frailty and physiologic aging, developing a better understanding of the role of biomarkers such as inflammatory markers, cytokines, T-cell phenotypes and markers of senescent cells in targeting immunosuppression may facilitate improved management of frail KT recipients.[105–107,115] A number of biomarkers have been associated with frailty, leading to interest in developing a biomarker-based frailty index.[116] However, studies of such an index in ESKD and KT populations have not yet been conducted. In addition, a number of noninvasive urine and blood biomarkers for acute rejection of kidney allografts have been studied and validated,[116–119] but these have not been examined in the context of frailty. Validation and implementation of noninvasive biomarkers, such as urine and blood messenger RNA/micro-RNA profiles, T- and B-cell phenotypes, blood cytokine levels and cell-free donor-derived DNA, in the frail KT population could lead to the development of a personalized approach to immunosuppression for vulnerable KT recipients. Striking the right balance between the risks of rejection and graft loss with the risks of infection and malignancy (Figure 3, Panel B) is critical to improving the quality of life for frail KT recipients.

The interaction between aging, frailty and the immune system is complex. Identification of frailty status prior to KT offers a window of opportunity to change one of the variables in the equation. Whether improvement in frailty status alters the immune phenotype of young and older frail KT candidates and improves posttransplant outcomes needs to be studied. Therefore it will be critical to define measures that can reduce frailty and mitigate the deleterious immune consequences of frailty prior to KT, which may include interventions such as physical therapy, cognitive training and novel therapeutics, including senolytic agents.[120]