Kidney Disease, Kidney Transplant, and Frailty
Frailty is highly prevalent among those with chronic kidney disease (CKD) and end-stage kidney disease (ESKD). In patients treated with hemodialysis (the most common form of treatment for those with ESKD), two studies have reported physical frailty in 68%-73% of patients (Johansen et al., 2007; Bao et al., 2012). A study of kidney transplant candidates and recipients, in contrast, reported 20% of patients were frail based on the physical frailty phenotype. The difference in these two sets of estimates suggests a potential effect of selection for surgical intervention, including a younger age (see below; Chu et al., 2020).
Both CKD and aging are risk factors for the physical frailty phenotype. Kidney disease is associated with physical and cognitive declines that are similar to those seen during aging, and is therefore considered to cause accelerated aging (McAdams-DeMarco. et al., 2015). Even among patients at early stages of CKD (stage<4), frailty prevalence is increased compared to healthy age-matched controls (Smyth et al., 2013). Similarly, there is a substantial burden of frailty even in younger patients when CKD is severe, such as among kidney transplant candidates and recipients (Chu, et al., 2020).
Kidney transplant (KT) is the optimal treatment for ESKD, yet many individuals are not considered for this because of decreased pre-transplant physical function, and specifically frailty (Haugen et al., 2019). The interdependence of frailty and ESKD makes this even more challenging to navigate clinically, as not undergoing transplant to improve renal function may then contribute to worsening physical function. Therefore, in order to improve care for ESKD, research is needed to improve our understanding of the differences and similarities in ESKD outcomes and KT in frail and non-frail patients, and whether treatments directed at one of these two conditions can to be leveraged to ameliorate the other, in order to optimize treatment decisions and develop effective interventions.
Impact of Frailty on Kidney Disease
In the interplay between aging, frailty, and kidney disease, CKD accelerates aging and aging hastens the progression of kidney disease. This latter phenomenon has been described as “senescent nephropathy” (Worthen & Tennankore, 2019). The combination leads to a vicious cycle with worse outcomes. Frailty is associated with higher mortality and hospitalizations in patients with ESKD (Bao et al., 2012; McAdams-DeMarco et al., 2013). Patients with ESKD awaiting transplant who are physically frail experience worse health-related quality of life (McAdams-Demarco et al., 2016) as well as increased mortality (McAdams-Demarco et al., 2018; Lai et al., 2014).
Frailty has been associated with a higher estimated glomerular filtration rate (eGFR) at dialysis initiation, which might suggest better renal function in this population. However, sarcopenia can partially explain this association, since eGFR overestimates true GFR among people with muscular atrophy. This patient population is also likely to have a higher symptom burden at a given eGFR, leading to what appears to be an “earlier” dialysis start in the hope of ameliorating such impacts. Improving the measures of renal function by incorporating an understanding of the impact of muscle mass, frailty and age on the traditional serum markers, is an active area of research (Pavkov & Nelson, 2019).
Kidney transplant itself, although the preferred treatment for ESKD overall, is less well tolerated in frail ESKD patients. After transplant surgery, frailty is associated with increased risk of many post-transplant complications. In a series of papers on a well-established 10-year prospective cohort study of aging and kidney transplantation at Johns Hopkins, increased risk has been documented for immediate poor outcomes such as delirium, longer length of stay, early hospital readmission as well as longer term problems with immunosuppression, intolerance, poor quality of life, cognitive decline and mortality. (See the list of references from this cohort below.)
The vast majority of kidney transplant programs in the US recognize frailty as an important variable to be considered in transplant candidates. However, the inclusion of this concept in practice has been challenging due to the diversity of available tools (see instruments page) and a lack of a validated single kidney-specific version to measure frailty (McAdams-DeMarco et al., 2020). It is important to note that the method used will influence the prevalence of frailty. A systematic review on frailty and CKD showed a lack of correlation between performance-based tests compared to questionnaires, which means that the relationships between frailty and CKD will be different in studies with different methods (Chowdhury et al., 2017).
Impact of Kidney Disease on Frailty
As with other conditions that accelerate aging (see HIV section), kidney disease predisposes to frailty through a variety of direct and indirect effects including elevated inflammation, low levels of physical activity, a substantial burden of comorbidity, and years of dialysis treatment. For example, the pro-inflammatory cytokines interleukin-6 and tumor necrosis factor alpha, which may play a role in loss of muscle mass and sarcopenia, have been shown to be elevated in patients with CKD (Chowdhury et al., 2017). In fact, such markers of inflammation can be used to improve waitlist mortality prediction, consistent with a causal role in the declining health associated with CKD (McAdams-DeMarco et al., 2018).
The prevalence of frailty increases as eGFR declines, and is highest in patients receiving dialysis even at younger ages, suggesting a correlation between kidney disease and accelerated biological aging. In addition, advanced age, female sex, and hemodialysis (compared to peritoneal dialysis) have been independently associated with frailty (Johansen, JASN, 2007).
Applying Knowledge of Frailty in Kidney Disease and Kidney Transplant
Although the presence of frailty is clearly a risk factor for adverse outcomes in patients with CKD, it is not known yet whether intervention along the path from early CKD to ESKD would render frailty a reversible risk factor. Also, screening and better identifying frail patients, as well as flagging those at risk of progressing to frailty, may help inform discussions on the different therapeutic options in advanced kidney disease. Considering frailty will allow a more patient-centered approach including options like active medical management of kidney disease, palliative care, dialysis and/or transplantation (Crews et al., 2019).
Significant work is needed to identify interventions which will reduce the burden of frailty in ESKD and improve the tolerability of transplant in this population. It also is needed to rigorously evidence the efficacy of targeting treatment plans by frailty status. Doing so also requires a better research consensus on measuring frailty in patients with kidney disease. The American Society of Transplantation held a Consensus Conference in 2018 to address the measurement and use of frailty in transplantation (Kobashigawa et al., 2019). The Conference recommended identifying an optimal method to measure frailty for KT recipients, which can support efforts to develop novel interventions to reduce the risk of adverse post-KT outcomes among frail recipients.
References from a prospective cohort study of aging and kidney transplantation at Johns Hopkins:
Haugen CE, Mountford A, Warsame F, Berkowitz R, Bae S, A GT, Brown CHt, Brennan DC, Neufeld KJ, Carlson MC, Segev DL, McAdams-DeMarco M. Incidence, Risk Factors, and Sequelae of Post-kidney Transplant Delirium. J Am Soc Nephrol. 2018. Epub 2018/04/25. doi: 10.1681/ASN.2018010064. PubMed PMID: 29685884.
McAdams-DeMarco MA, King EA, Luo X, Haugen C, DiBrito S, Shaffer A, Kucirka LM, Desai NM, Dagher NN, Lonze BE, Montgomery RA, Walston J, Segev DL. Frailty, Length of Stay, and Mortality in Kidney Transplant Recipients: A National Registry and Prospective Cohort Study. Annals of surgery. 2016b. doi: 10.1097/SLA.0000000000002025. PubMed PMID: 27655240.
McAdams-DeMarco MA, Law A, Salter ML, Chow E, Grams M, Walston J, Segev DL. Frailty and early hospital readmission after kidney transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2013;13(8):2091-5. Epub 2013/06/05. doi: 10.1111/ajt.12300. PubMed PMID: 23731461; PMCID: 4000567.
McAdams-DeMarco MA, Law A, Tan J, Delp C, King EA, Orandi B, Salter M, Alachkar N, Desai N, Grams M, Walston J, Segev DL. Frailty, mycophenolate reduction, and graft loss in kidney transplant recipients. Transplantation. 2015a;99(4):805-10. doi: 10.1097/TP.0000000000000444. PubMed PMID: 25393156; PMCID: PMC4382409.
McAdams-DeMarco MA, Olorundare IO, Ying H, Warsame F, Haugen CE, Hall R, Garonzik-Wang JM, Desai NM, Walston JD, Norman SP, Segev DL. Frailty and Postkidney Transplant Health-Related Quality of Life. Transplantation. 2018b;102(2):291-9. Epub 2017/09/09. doi: 10.1097/TP.0000000000001943. PubMed PMID: 28885489; PMCID: PMC5790611.
Chu NM, Gross AL, Shaffer AA, Haugen CE, Norman SP, Xue QL, Sharrett AR, Carlson MC, Bandeen-Roche K, Segev DL, McAdams-DeMarco MA. Frailty and Changes in Cognitive Function after Kidney Transplantation. J Am Soc Nephrol. 2019;30(2):336-45. Epub 2019/01/27. doi: 10.1681/ASN.2018070726. PubMed PMID: 30679381; PMCID: PMC6362628.
McAdams-DeMarco MA, Law A, King E, Orandi B, Salter M, Gupta N, Chow E, Alachkar N, Desai N, Varadhan R, Walston J, Segev DL. Frailty and mortality in kidney transplant recipients. American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2015b;15(1):149-54. doi: 10.1111/ajt.12992. PubMed PMID: 25359393; PMCID: PMC4332809.