Frailty and Prehabilitation

Introduction

Frailty, a biological syndrome rendering an individual vulnerable to stressors, is highly prevalent in kidney transplant candidates.¹ Physical frailty phenotyping is typically determined by a combination of criteria that includes shrinking, exhaustion, slowness, weakness, and low physical activity levels.² Frail patients are more likely to be inactivated from the transplant waitlist and more likely to die while waiting for a kidney transplant.¹ Furthermore, for patients who receive a kidney transplant, frailty is associated with longer hospitalization after surgery, a two-fold higher risk of delayed graft function, a higher chance of early hospital readmission, a higher risk of cardiovascular disease, and a two-fold greater chance of mortality.¹ There are currently no pharmacological therapies to modify frailty. Unlike other comorbidities that are difficult to reverse in kidney failure, frailty is potentially modifiable with prehabilitation.

Prehabilitation to Mitigate Frailty before Transplant

Prehabilitation is a multimodal approach to improve the physiologic reserve to stressors and to optimize physical and psychological factors before surgery. In patients with kidney failure, exercise intervention has the potential to improve frailty by increasing physical activity levels, improving gait speed, increasing muscle mass and strength, reducing exertional fatigue, and increasing vitality. A combination of both resistance and aerobic exercise modalities is attractive for prehabilitation as aerobic exercise is a powerful stimulus for improvements in cardiopulmonary reserve, while resistance exercise is more efficacious for increasing strength and muscle mass. Small trials of prehabilitation in patients waitlisted for kidney transplant have shown exercise intervention to be feasible, safe, and efficacious at improving physical function.³ These trials have incorporated a combination of supervised and home-based resistance and aerobic exercise performed 1–3 times per week, over 2–3 months.³ Notably, promising preliminary evidence demonstrates participation in prehabilitation resulted in a 50% reduction in hospitalization days after surgery.⁴

Comprehensive prehabilitation should optimize exercise training with the synergistic integration of nutrition counseling, optimized pharmacological interventions, and behavioral support strategies to guarantee adoption and adherence. In frail patients referred to our center for prehabilitation (n=24; age, 65±10), a multipass 24-hour dietary recall revealed that total daily energy intake was only (mean±SD) 1565±605 kcal, equating to 48% of the recommended energy intake. In addition, protein intake was 0.79±0.37 g/kg, equivalent to 66% of the recommended intake for kidney failure. Exercise training without adequate nutrition intake could potentially exacerbate the catabolic status of this already vulnerable cohort, highlighting the importance of a synergistic, multidisciplinary approach to prehabilitation.

Cost-Effectiveness of Prehabilitation

A full economic analysis informed by large intervention trials to confirm whether prehabilitation is cost-effective is warranted. Nevertheless, preliminary evidence suggests such programs could prove to be cost-effective based on two value drivers. The first refers to the potential cost reduction in kidney transplant hospitalization. In 2020, the cost of transplant hospitalization averaged US $178,500, and the average length of stay was 6.7 days.⁵ A small pilot study has shown that prehabilitation interventions can help reduce length of stay (50% reduction compared with controls).⁴ Such interventions can potentially help reduce post-transplant hospitalization period and decrease readmission costs. The second driver of cost-effectiveness of prehabilitation programs could be through patient readiness for transplant. Compared with hemodialysis, kidney transplantation provides an estimated savings of $80,941 within the first 3 years of surgery and $60,749 for every subsequent year.⁶ Thus, accelerating patient eligibility to transplantation could provide meaningful opportunities to reduce the economic burden of kidney failure. The cost of establishing sustainable prehabilitation services should also be considered. This includes costs associated with access to outpatient clinic and rehabilitation space, purchase and maintenance of exercise equipment, and specialized personnel for supervised intervention.

Incorporating Prehabilitation into Clinical Care Models

There is consensus from the American Society of Transplantation Kidney Pancreas Community of Practice and the European Society for Organ Transplantation that prehabilitation is feasible, acceptable, and safe.^1,7 A recent European Society for Organ Transplantation consensus statement recommends that “evidence-based interventions are included in the prehabilitation of solid organ transplant candidates with the objective to improve cardiorespiratory fitness and/or muscular strength.”⁷ However, a considerable number of unanswered questions that need to be addressed before prehabilitation can be widely implemented. Table 1 highlights the need for evidence-based guidelines to identify which patients should be referred and when and which types of interventions and settings are most efficacious. Importantly, an interdisciplinary approach to pretransplant optimization is necessary. Toward successfully integrating prehabilitation into the clinical care model, exercise physiologists and dietitians should be established as part of the transplant team. The first step toward clinical incorporation is comprehensive education about the benefits of physical activity and nutrition in preparation for a transplant—for patients, care providers, and stakeholders.

Table 1.

Questions that need to be addressed before the widespread implementation of prehabilitation as standard of care

Who should be referred for prehabilitation?	• Research is needed to phenotype which patients are most responsive to prehabilitation • Tools to facilitate patient referral and clinical decision making in the workup include:  ○ Office-Based Frailty and Physical Performance Assessment: Fried Physical Frailty Phenotype (abridged version recently validated in kidney transplant candidates2). The Short Physical Performance Battery, 30-second sit-to-stand test, and the 6-minute walk test are also established surrogates of frailty and have been validated in the kidney transplant cohort1  ○ CPX: objective assessment of cardiopulmonary reserve may be a precise prognostic predictor for long-term post operative mortality. Perioperative risk stratification algorithms on the basis of CPX are available from the American Heart Association but not yet validated in kidney transplant candidates. If resources are unavailable, the 6-minute walk can be used as a crude surrogate for CPX and is widely adopted in the setting of heart and lung transplant  ○ Body Composition Assessment: myosteatosis, sarcopenia, and sarcopenic obesity can be identified through routine clinical abdominal computed tomography and have been positively associated with waitlist mortality in transplant candidates. May be limited by the need for additional sophistical analysis of radiologic images. Use of bioelectric impedance analysis as an easily accessible and pragmatic assessment tool could be an attractive option, but has not yet validated in kidney transplant candidates
When should patients be referred for prehabilitation?	• Research is needed to confirm the most efficacious timepoint for intervention. This will likely vary depending on the availability of living donors and local wait times for deceased donor transplant • The development of specialist programs that support sustained lifestyle changes as opposed to a stand-alone 8-week physical therapy referral may be important in the setting of unknown waitlist times • Early intervention in CKD for the prevention of frailty development is essential. This highlights a sentinel role for community nephrologists in the coordination of early physical activity and nutrition intervention
What type of intervention should be prescribed?	• ESOT recommendations entail interventions comprising exercise, nutrition, and psychological support; however, the consensus is that more evidence is needed to optimize each parameter • Majority of evidence is based on a combination of aerobic and resistance training. However, clinical trials are warranted to establish the most efficacious exercise prescription, including frequency, intensity, time, type, volume and progression • Ideal settings for prehabilitation should be defined (i.e., supervised outpatient, intradialytic, home-based, virtual)
How do I start set up prehabilitation at my center?	• Transplant-specific blueprints on the basis of currently established clinical programs such a cardiac rehabilitation need to be developed • Stakeholder and institutional support are essential to support the infrastructure of prehabilitation programs, including access to space, equipment, and personnel • ESOT recommendations suggest a need for specific assessments of feasibility in clinical trials • Medicare/Medicaid/commercial payer billing to support prehabilitation programs is necessary • The development and integration of virtual programs and culturally/ethnically conscious programs are warranted to support equal access to care and transplant

CPX, cardiopulmonary exercise testing; ESOT, European Society for Transplantation.

Overcoming Barriers to Prehabilitation

Despite consensus among nephrologists, patients, and health care professionals regarding the importance of physical activity in preparation for a transplant,¹ patient uptake of exercise is remarkably low. In a large Kidney Pancreas Community survey, 196 of 202 US transplant centers expressed a preference to refer frail patients to prehabilitation.⁸ However, in a brief survey delivered by us through the American Society of Transplantation Kidney/Pancreas listserv (57 center responses), only 41% of programs actively referred patients for prehabilitation. Therefore, developing strategies to address the current barriers is of critical importance.

Exercise Uptake and Adherence

Current evidence from solid organ transplant populations suggests high adherence to prehabilitation once patients are enrolled into a program. Medical appointments and family commitments are cited as the largest barriers to attendance.⁷ Efforts to establish exercise and nutrition as a long-term lifestyle change could yield the highest benefits, and this may be facilitated by behavior specialists or health coaches.

Access to Prehabilitation

Individuals who reside in neighborhoods with disadvantageous social determinants of health are less likely to be listed for a transplant before starting dialysis and have substantially lower rates of receiving a living donor transplant.⁹ These disparities are exacerbated in non-Hispanic Black patients, who typically wait for a transplant longer and who also have a significantly higher risk of being hospitalized while waiting for a transplant.⁹ Notably, the prevalence of frailty in Black transplant candidates is also higher, which may partially contribute to the health disparities associated with access to transplant.¹⁰ Prehabilitation could be particularly beneficial to these patients while simultaneously reducing inequities in access to transplant.

Billing and Reimbursement

Efforts to establish Medicare/Medicaid/commercial payer billing specifically for prehabilitation will help support dedicated programs for organ transplants. Stakeholders (transplant and nephrology societies) should also engage in leading these efforts on behalf of transplant centers and patients.

Evidence-Based Guidelines

Robust clinical trials that demonstrate the efficacy of prehabilitation on clinical end points are essential to successful and sustainable integration into clinical care. This is a call to action for the funding and implementation of such trials to support evidence-based guidelines.

Conclusions

Addressing frailty is essential for equitable and successful kidney transplant outcomes, and prehabilitation holds promise as a cost-effective and feasible therapeutic option. However, before prehabilitation is implemented widely, there are several clinical and logistical barriers and unanswered questions that need to be addressed. Importantly, support from key stakeholders and research funding bodies is critical to the sustainable establishment and implementation of clinical prehabilitation programs. Rigorous multicenter clinical trials are warranted to support appropriate integration of prehabilitation into clinical care.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/E813.

Funding

This work was supported by Virginia Commonwealth University Department of Internal Medicine Pilot Award and the Gupta-Levy Research Initiative.

Author Contributions

Conceptualization: Gaurav Gupta, Jason M. Kidd, Danielle L. Kirkman.

Data curation: Gaurav Gupta, Danielle L. Kirkman, Vasco M. Pontinha.

Formal analysis: Gaurav Gupta.

Methodology: Gaurav Gupta, Danielle L. Kirkman.

Writing – original draft: Gaurav Gupta, Jason M. Kidd, Danielle L. Kirkman, Dhiren Kumar, Vasco M. Pontinha.

Writing – review & editing: Salvatore Carbone, Gaurav Gupta, Jason M. Kidd, Danielle L. Kirkman, Dhiren Kumar, Vasco M. Pontinha, Bekir Tanriover.