Introduction
With the increase in the prevalence of end-stage renal disease (ESRD), the demand for kidney transplantation worldwide has also increased.[1] Kidney transplant (KT) candidates often present with multiple organ system impairments due to renal failure.[2] KT recipients can recover renal function after transplantation; however, they can still experience surgical injury, postoperative complications, and immune system instability.[3] Therefore, the general health status of KT recipients before and after transplantation is not optimistic. With the in-depth exploration of kidney transplantation, substantial research has demonstrated that KT candidates and recipients often experience frailty, which often results in an adverse outcome.[4–6] Accordingly, early intervention for frailty in KT candidates and recipients is crucial to improve their health and quality of life and to reduce the incidence of perioperative adverse events. In this study, we review the published literature to summarize the possible pathophysiological mechanisms underlying frailty and discuss the effective intervention strategies for frailty in KT candidates and recipients.
Definition of Frailty
Frailty refers to increased susceptibility and vulnerability of the body to stressors as well as the functional decline of various physiological systems. In this non-specific state, individuals are more prone to functional damage and adverse health outcomes due to the deterioration of various compensation mechanisms when attacked by external or internal risk factors. Negative outcomes include infection, disability, falls, mobility difficulties, hospitalization, and death.[7] Frailty has been widely studied in transplantation, cancer, and chronic kidney disease (CKD) as a tool to evaluate patients’ physiological reserve and system function.[8–10] Its meaning also extends from a single physical function assessment to a comprehensive evaluation of physical, psychological, and social functions.[11]
Epidemiology
To maximize the utility of kidney allocation, clinicians are more likely to select younger patients and those with better overall physical function as KT candidates.[12] Therefore, the prevalence of frailty in preoperative KT recipients is often lower than that in the general population with ESRD. However, the proportion of patients with frailty before KT is still high. Current studies have shown that the proportion of recipients with frailty before KT is approximately 20% whereas that of pre-frail recipients is approximately 30%.[13–16] The frailty of recipients is rarely assessed after KT, which is mainly because of the great variations in the frailty of recipients over time. After the surgical injury, immunosuppressive treatment, and possible acute rejection and infection, the recipients’ frailty usually worsens in the short term than before the operation.[17] However, the overall health status improves with the recovery of renal function. Consequently, frailty may also improve significantly compared with before the operation. A prospective cohort study of 349 KT recipients by McAdams-DeMarco et al[16] revealed that the prevalence of frailty before KT surgery was 19.8% whereas it was 33.3%, 27.7%, and 17.2% at 1, 2, and 3 months postoperatively, respectively. However, long-term frailty condition may not be significantly correlated with time after transplantation. A single-center cross-sectional study in Japan[18] indicated that at 6 months after KT surgery, frailty condition among KT recipients was no longer affected by the postoperative time. The proportion of recipients with frailty and pre-frailty was 11.2% and 26.8%, respectively. In the United States, a national epidemiological survey showed that, from 2000 to 2018, the prevalence of frailty in KT candidates and recipients was 16.4% and 14.3%, respectively.[19] It is also important to note that frailty can be related to region, race, and gender.[20]
Assessment Tools
Although a total of 67 tools have been applied to evaluate frailty,[21] there is still a lack of recognized and effective methods to assess the perioperative frailty of KT recipients. At present, two basic models are most widely used in kidney transplantation: the physical frailty phenotype (PFP) and the frailty index (FI). PFP was proposed by Fried et al[7] to evaluate the health status of the elderly and comprises the following five aspects: unexpected shrinking, slow walking speed, weakness, low physical activity, and exhaustion. Each item is given a score of 1; a score of 3 to 5 indicates the recipients’ condition as frail, a score of <3 indicates pre-frailty, and a score of 0 indicates non-frailty. FI is a new survey tool that is based on PFP and designed to refine and increase psychological and social function assessment. FI assesses health defects in five aspects: physical function, mental health, cognitive function, social function, and demographic characteristics.[22] Each variable is assigned a specific score according to its type to refine the proportion of each variable in frailty measurement. The degree of frailty as assessed by PFP and FI is more accurate in predicting kidney transplantation outcomes than other assessment tools. However, these two tools require subjective answers from the recipients, which inevitably leads to deviation. Completely objective testing, such as the short physical performance battery (SPPB),[23] avoids deviations and improves accuracy to predict postoperative outcomes. A multicenter prospective cohort study by Nastasi et al[24] pointed out that the SPPB has similar feasibility and ability to predict the outcomes of kidney transplantation as PFP. However, it is worth mentioning that frailty represents the overall functional status of multiple systems, so whether the simple measurement of lower extremity function can replace the assessment of frailty requires further discussion. In addition to clinical performance assessment, the American Transplantation Association believes that skeletal muscle imaging and serum biomarkers can provide a more comprehensive assessment of frailty.[25]
Relationship Between Frailty and Kidney Transplantation
Extensive studies have shown that frailty is closely related to KT-related perioperative adverse outcomes. Therefore, transplant accessibility for frail candidates will be affected.[12] Frailty also has adverse effects on the preoperative comorbidities and mortality of the candidates.[26–28] After transplantation, the incidence of hospital stay of >2 weeks in frail recipients was 1.6 times higher than that in non-frail recipients. In other respects, the risk of readmission of preoperative frail recipients was reported to increase by 60% within 1 month compared with non-frail recipients, the risk of delayed graft function (DGF) increased by 94%, and the incidence of DGF increased 6.20-fold when accompanied with depression.[14,29–31] Preoperative frailty is also strongly associated with poor long-term prognosis after kidney transplantation. In a single-center longitudinal cohort study, frail KT recipients were 1.29 times more likely to experience mycophenolate reduction (MDR) due to immunosuppressive intolerance compared with non-frail recipients. Significantly, MDR was associated with a 5.24-fold increased risk of graft loss.[32] In terms of cognitive impairment, short-term cognitive improvement after transplantation in frail and non-frail recipients has been reported.[33] However, in the middle and later stages, the cognitive function of non-frail recipients tended to improve, whereas that of frail recipients tended to decline.[33] Regarding predicting the risk of death, McAdams-DeMarco et al[13] tracked 537 KT candidates in a prospective cohort study. The results showed that the 5-year survival rates of non-frail, pre-frail, and frail candidates after kidney transplantation were 91.5%, 86.0%, and 77.5%, respectively, and frailty increased the risk of death by 117%. Moreover, frailty with depression further increased the risk of death in KT recipients.[30] Frailty can change the long-term prognosis of KT by affecting its short-term prognosis, such as DGF and MDR, or the length of stay and mortality.[32,34]
Although frailty is related to multiple undesirable consequences, it may also positively affect kidney transplantation. Frail recipients may be at a lower risk of acute rejection due to immunosenescence.[35] Immunosenescence is the activation of the regulatory immune network and inhibition of the positive immune activation network.[36] However, once rejection occurs in frail recipients, it is more likely to lead to severe consequences due to physiological reserve damage, such as graft loss and death.
Successful kidney transplantation can reverse the pathophysiology of ESRD and restore renal function to remove excess water and metabolites, which markedly improves the patient's health status and quality of life. A prospective cohort study in the United States confirmed that frailty in KT recipients worsened at 1 month after transplantation, returned to the pretransplant levels at 2 months, and improved significantly at 3 months.[17] Thus, successful kidney transplantation can improve the frailty condition of recipients and lead to gradual and long-term improvement.
Possible Pathogenesis of Frailty in KT Candidates and Recipients
The pathogenesis of frailty in KT candidates and recipients is based on the general pathogenesis of frailty. However, the respective specific pathological changes determine that the “pathways to frailty” of the two categories of patients are different from the general pathogenesis.
General pathogenesis of frailty
As previously recognized in other studies, frailty is a comprehensive reflection of the decline in overall health. Its occurrence and development involve changes in various organs and systems of the body.[37] Systems involved in the occurrence and development of frailty include the neuroendocrine, cardiovascular, respiratory, digestive, urinary, immune, blood, and skeletal muscle systems [Figure 1].[37–43] Changes in these systems play a specific role in promoting the occurrence and development of frailty; however, it is not clear which system plays a more crucial role.
;)
Figure 1: Changes in various systems and related manifestations in frailty.
It is worth noting that immune system changes have been considered the “original driving force” of the aging process.[44] Frailty essentially refers to biological aging, which is different from aging over time. The changes in the immune system in frail individuals are similar to those experienced during the aging process. Consequently, inflammaging and immunosenescence are also observed in frail individuals [Figure 2].[44,45] Inflammaging is a chronic state of low-grade inflammation under long-term endogenous or exogenous factors. In this state, the levels of inflammatory mediators and proinflammatory cytokines, such as interleukin-6 (IL-6), IL-1, C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α), increase. An increase in TNF-α, IL-6, and IL-1 levels is a sign of frailty. To avoid excessive inflammatory reactions, the immunosuppressive network is activated. Thus, the number of immunosuppressive cells, including myeloid-derived suppressors, regulatory B, and regulatory T cells, increases and the secretion of anti-inflammatory cytokines, such as IL-10, IL-4, and transforming growth factor-β also increases, whereas positive immune function decreases. Such long-term changes in the immune system will lead to immunosenescence.[44] Chronic low-grade inflammation and remodelling of the immune system are considered significant pathophysiological bases for frailty. For example, chronic low-grade inflammation affects the microenvironment of the bone marrow, thus weakening the cloning and differentiation ability of hematopoietic stem cells and affecting the renewal and regeneration of various tissues and organs.[46] Stem cell depletion is an important biological feature of frailty.[47] Cognitive decline is also associated with chronic low-grade inflammation. It has been reported that macrophages can increase the level of plasma cytokines by releasing proinflammatory cytokines, thereby increasing the risk of dementia.[48] Furthermore, chronic low-grade inflammation may also be related to intracellular telomere reduction. Kordinas et al[49] reported that the levels of inflammatory mediators, such as IL-6 and CRP, increased and telomerase activity decreased in patients with CKD. This decrease in telomerase activity accelerates telomere shortening, thus accelerating cell senescence, the basis of frailty and aging. Chronic inflammation and decreased telomerase activity are both significant pathophysiological changes in frailty and dementia. However, the available research has not yet revealed the mechanisms of inflammatory cells’ influence on telomerase activity.[50,51]
Figure 2: Alterations in the immune system in frailty. Bregs: Regulatory B cells; CRP: C-reactive protein; Mregs: Regulatory macrophages; TGF-β: Transforming growth factor-β; TNF-α: Tumor necrosis factor-α; Tregs: Regulatory T cells.
In addition to changes in the immune system, musculoskeletal system disorders are a characteristic pathophysiological change in frailty occurrence and development. One of the consequences of musculoskeletal system disorders is sarcopenia, which is considered an essential part of frailty syndrome.[52] Weight loss, poor grip strength, slow walking speed, and reduced daily activity are all associated with sarcopenia. Additionally, sarcopenia has a strong interaction with cognitive decline.[53] Sarcopenia is manifested in two aspects: muscle mass loss and muscle dysfunction [Figure 3].
Figure 3: General mechanisms of sarcopenia in frailty. ALS: Autophagy/lysosomal system; ATP: Adenosine triphosphate; MD: Muscle dysfunction; MML: Muscle mass loss; PC: Protein catabolism; PS: Protein synthesis; UPS: Ubiquitin–proteasome system.
Muscle mass loss includes three pathways: malnutrition, mechanical stress deficiency, and neuroendocrine disorder. In various chronic diseases, reduced food intake and insufficient exercise are often seen to coincide.[54,55] Inadequate nutritional intake is a crucial factor causing insufficient protein synthesis. Some older individuals are reluctant to exercise for fear of falling. Consequently, insufficient exercise leads to a loss in motor neurons, impaired capillary blood flow, and a decrease in the number of muscle satellite cells, which contributes to a deterioration in repair and regeneration.[56] Muscle protein catabolism then exceeds protein synthesis. A large cross-sectional study in Europe confirmed that a lack of exercise is an independent risk factor for overall frailty.[57] Additionally, a vast number of studies have also indicated that an effective exercise program can keep the overall body functioning well and even reverse frailty in older adults.[58,59] The effectiveness of exercise therapy further confirms that physical inactivity is a critically important and intervenable factor of frailty. Regarding neuroendocrine factors, the resistance of insulin-like growth factor 1 and insulin have been observed in animal models of muscle atrophy,[55] as well as increased levels of myostatin.[60] The cellular biological essence of muscle mass loss caused by the abovementioned three pathways is the imbalance between protein synthesis and catabolism in muscle cells; the latter is dominant. A study on patients with early lung cancer and chronic hemodialysis by Aniort et al[61] indicated a common increase in the gene expression levels of the ubiquitin–proteasome system (UPS) and autophagy-related enzymes in these two diseases. Thus, there may be two proteolytic pathways of UPS and autophagy/lysosomal system in the pathogenesis of sarcopenia. We can speculate from this that common pathways of sarcopenia exist in different diseases. Leitner et al[62] concluded that diseased organs, including the heart, lungs, kidneys, or tumors, secrete soluble factors, including angiotensin II, myostatin, and tumor growth factor-β, which induce the proteolysis system, including the UPS, in skeletal muscles.
Muscle dysfunction is associated with imbalances in muscle protein degradation and synthesis, mitochondrial dysfunction, oxidative stress, chronic inflammation, and motor neuron deficiency.[63,64] These factors influence each other and act in concert with the development of muscle dysfunction. As previously described, the predominance of muscle protein degradation is the cellular biological essence of muscle mass loss. The excessive loss of muscle proteins, including contractile proteins such as actin and myosin,[65,66] leads to decreased muscle contractile function. Mitochondrial dysfunction includes diminished respiratory function and increased production of reactive oxygen species (ROS).[67] Diminished respiratory function results in decreased adenosine triphosphate production, which results in insufficient energy supply and the inability to complete normal physiological activities. The absence or dysfunction of respiratory enzymes might be responsible for diminished respiratory function in myocyte respiration.[68] The increased production of ROS induces the activation of the UPS and enhances sarcolysis.[69] In addition, the increased ROS aggravate protein oxidative damage, and the accumulative oxidized protein in myocytes is difficult to remove, which causes a decrease in protein with contractile function.[70] Correspondingly, skeletal muscle contraction strength is severely reduced. Furthermore, ROS are involved in oxidative stress. The combined effects of oxidative stress and chronic inflammation contribute to mitochondrial dysfunction, forming an undesirable positive feedback pathway.[71] Moreover, oxidative stress plays a significant role in the promotion of muscle protein degradation and myocyte apoptosis.[72]
Inflammaging and sarcopenia are not independent processes. There is growing evidence that proinflammatory cytokines, such as TNF-α, IL-1, and IL-6, are involved in the development of sarcopenia.[73,74] Muscle catabolism also leads to an inflammatory state.[75] Other pathological changes related to frailty include stem cell depletion, telomere length shortening, autonomic nervous system dysfunction, and energy metabolism disorders. We speculate that there is a similar mechanism underlying the occurrence and development of frailty in patients with different diseases.
Pathogenesis of frailty in KT candidates
KT candidates are usually patients with ESRD. In addition to the general pathogenesis of frailty described above, there are also unique pathophysiological changes and the “disease-specific pathway” in the ESRD population. It is well known that renal excretion and metabolic function decrease in patients with ESRD, resulting in water, electrolyte, and acid–base balance disorders, such as water and sodium retention, hypertension, and metabolic acidosis. Simultaneously, uremic toxin accumulation, renal endocrine dysfunction, and persistent inflammation are also critical pathophysiological changes in ESRD. These pathophysiological changes not only directly promote the formation of frailty but also adversely affect the structure and function of multiple organ systems.
In patients with ESRD, the immune system has been in a low level of suppression for a long time. The renal tubular epithelial cells of patients with ESRD can induce the proinflammatory senescence-associated secretory phenotype, which causes chronic systemic inflammation and promotes frailness.[76] In addition, the composition of intestinal flora in patients with ESRD is different from that in healthy people. The specific pathological characteristics of ESRD result in the disbalance of intestinal flora, in which harmful flora increases and intestinal mucosal permeability increases.[77,78] Therefore, the possibility of bacterial-derived toxins and live bacteria entering the bloodstream increases. Under this condition, the immune system is constantly induced to activate, leading to immunosenescence and chronic low-grade inflammation.[79] Furthermore, the imbalance of the intestinal flora also leads to impaired antioxidant capacity, which will cause mitochondrial damage. The mitochondrial damage can activate the inflammatory pathway induced by mitochondrial DNA, which leads to the release of cytokines, chemokines, ROS, and monoxide by inflammatory cells.[80] This inflammatory pathway can change the homeostasis of muscles and play a role in promoting myocytes reduction. The imbalance of the intestinal flora and changes in the intestinal barrier can also lead to insulin resistance.[80] Taken together, harmful intestinal flora can promote the formation of frailty via these mechanisms. At the same time, the resistance of insulin-like growth factor-1 and growth hormone occurs in patients with ESRD, another characteristic of sarcopenia.[77]
Therefore, a series of factors lead to chronic low-grade inflammation and immune remodelling in the occurrence and development of ESRD. Various pathological conditions associated with ESRD, including chronic low-grade systemic inflammation, insulin resistance, and increased uremic toxins, have been shown to increase the risk of sarcopenia.[81] Additionally, a series of special pathophysiological changes in ESRD leads to multiple systemic dysfunctions of the body, thus worsening the overall health status, increasing the vulnerability to internal or external insult, and increasing the risk of adverse consequences [Figure 4].[43,82–84]
Figure 4: The possible pathogenesis of frailty in KT candidates. EPO: Erythropoietin; ESRD: End-stage renal disease; KT: Kidney transplant.
Pathogenesis of frailty in KT recipients
Few studies have been conducted on the frailty of KT recipients after surgery, especially ones related to the pathogenesis of frailty. Based on the current research progress, we will speculate on the recipients’ frailty condition change according to the special postoperative pathophysiological changes [Figure 5].[85,86]
Figure 5: Changes in frailty condition after kidney transplantation. KT: Kidney transplant.
Firstly, KT recipients’ postoperative frailty condition depends mainly on the preoperative frailty condition. Although there is a high probability that each recipient's frailty degree will change after surgery, it is a change that is based on the frailty condition before surgery. A prospective cohort study by McAdams-DeMarco et al[17] showed that most KT recipients’ frailty condition worsens in the first month after the operation and then gradually improves until it is better than before the operation. This increase in frailty degree in the first month is likely to be due to surgical blows and postoperative complications. The worsening of frailty condition in the first month might be due to risk factors such as surgical injury and postoperative complications. The surgical complications that may occur in the short term after kidney transplantation include bleeding, renal vascular thrombosis, urinary tract complications, wound complications, and ischemia–reperfusion injury.[3,87] Compared with non-frail KT recipients, preoperative frail recipients are more likely to suffer from surgical trauma, postoperative complications, and relatively excessive immunosuppressive therapy. The improvement in frailty in the medium term is due to the recovery of renal function and general health improvement. The long-term deterioration of postoperative frailty can be due to DGF, rejection, and uncorrected surgical complications.
Immunosuppressive therapy plays an anti-rejection role and has a significant impact on the recipient's immune system, which may accelerate the process of immunosenescence.[88] It is well known that suppression of the immune system increases the incidence of infection and malignant tumors, which is related to the long-term frailty of KT recipients. Besides, the adverse effects of various immunosuppressants also worsen the health of KT recipients. For instance, glucocorticoids can cause water and sodium retention and metabolic disorders. They also play a significant role in osteoporosis, which can result in bone disease after transplantation. Calcineurin inhibitors are nephrotoxic and reduce the activity of telomere-binding proteins, thus accelerating telomere length shortening and cell senescence.[89] In other respects, it has been reported that antibiotics and immunosuppressants can change the composition of the intestinal floras, thereby destroying the homeostasis of the intestinal system.[90] Once graft loss occurs, KT recipients will re-enter the ESRD stage and will require immunosuppressive therapy. Then, the possibility of developing frailty is stronger, and the mechanisms will be more complex. The current understanding of frailty's pathogenesis in KT recipients after surgery is insufficient and more clinical and basic research is needed in the future.
Interventions
Comprehensive intervention strategies include traditional interventions and emerging intervention methods aimed at the pathogenesis of frailty.
Traditional general interventions
The reversibility and dynamic process of frailty make pretransplant interventions accessible. More importantly, identifying frailty as early as possible provides sufficient time for preoperative interventions. At present, pretransplant interventions mainly include physical exercise, nutrition improvement, and drug therapy.[91–93] Additionally, compound prehabilitation (including nutritional supplements, physical exercise training, and lung function optimization) has been applied to frail patients with satisfactory effects in some clinical studies.[94] However, such compound methods are rarely reported for KT candidates and recipients. The treatment of basic diseases, control of ESRD complications, and dialectical therapy of traditional Chinese medicine also play positive roles in frailty intervention.[52,95] In the USA, the Society for Perioperative Assessment and Quality Improvement suggested that psychological interventions should be used as first-line interventions in the preoperative management of frailty.[96] Thus, medical staff can try to reduce anxiety in frail recipients before kidney transplantation, such as by employing deep breathing, music therapy, reading, and talking.
The rehabilitation of frail recipients after kidney transplantation is also worthy of attention. Based on existing studies, rehabilitation measures include early detection of high-risk groups, appropriate immunosuppressant adjustment, and cognitive impairment.[97]
Potential emerging interventions
The traditional methods for treating frailty have shown limited effects in some clinical studies, and they still lack support from large-sample, multicenter studies. In addition, the above interventions are not based on the specific pathogenesis of pre- and postoperative frailty in KT recipients. Consequently, the benefits of these interventions need to be further explored. In recent years, scholars have explored emerging treatment methods based on the mechanisms of occurrence and development of frailty. Although most of the studies are still in the initial stages of exploration, the results have shown bright clinical application prospects. Florea et al[47] summarized the feasibility and specific treatment method of mesenchymal stem cells (MSCs) in the treatment of frailty. The researchers injected allogeneic MSCs into the frail elderly to continuously inhibit chronic systemic inflammation and improve cardiopulmonary function and osteoporosis. Related clinical trials have indicated that intravenous injection of an appropriate dose of MSCs is safe and effective.[98] Researchers have also used microflora to treat gut microbiota dysbiosis in perioperative KT recipients.[99,100] Fecal microbiota transplantation has been demonstrated to be feasible and effective in improving intestinal flora's composition and metabolism in animal experiments.[101] DeJong et al[102] pointed out that dietary intervention can increase intestinal microbial diversity and short-chain fatty acids (a microbial metabolite that is beneficial to improving frailty), thus reducing systemic inflammation. This research also suggested that supplementation with microbial metabolites lost in frail patients might be a more effective and safer method than direct microbiota transplantation. Taken together, the specific intervention measures aimed at the pathophysiological mechanisms of frailty in KT candidates and recipients are worthy of further clinical research.
Discussion and Conclusions
Frailty is a non-specific state in which each system's physiological reserve is damaged, thus leading to an increase in vulnerability and susceptibility. This physical condition is intermediate between health and disability; therefore, it is often ignored by the public and medical staff. However, frailty has highly adverse effects on the health outcomes of patients.
Although many studies have demonstrated the significant application value of frailty in predicting the perioperative outcomes of KT, little is known about the pathogenesis of frailty in KT candidates and recipients. We believe that there are similar mechanisms of frailty in different diseases, but that the initial inducing factors vary. Chronic low-grade inflammation and musculoskeletal system disorders are the two most critical pathophysiological changes in the formation of frailty. These two changes are mutually reinforcing and promoting and are the “initial driving force” of each system's impaired function.
When it comes to KT candidates, they have lost the function of renal excretion, maintenance of water–electrolyte balance, and endocrine function. Moreover, the functions of multiple systems are impaired to varying degrees, and this dysfunction is accompanied by chronic systemic inflammation. The above changes result in a series of physiological and psychological disorders, including impaired cardiopulmonary function, muscle atrophy, osteoporosis, anemia, diabetes, anorexia, and depression. As a result, the ability to maintain the internal environment is weakened, which contributes to increased vulnerability and the formation of frailty.
For KT recipients, the occurrence and development of frailty after KT surgery are based on the preoperative frailty condition. Renal function will generally recover after kidney transplantation, which will fundamentally reverse the pathophysiological changes of ESRD; however, KT recipients may suffer surgical injury, postoperative complications, rejection, immunosuppressive therapy (which can aggravate systemic inflammation), muscle atrophy, and oxidative stress. Then, a decrease in telomere-binding protein activity and acceleration of telomere shortening might be observed. Therefore, the postoperative frailty of KT recipients is affected by the recovery of renal function and perioperative adverse factors based on the preoperative frailty condition. The results depend on the aspect that occupies the dominant position as well as the recipient's ability to withstand insults.
At present, interventions for the pathogenesis of frailty are being actively explored. Although these interventions have not been used in the clinical practice of kidney transplantation, they are worth exploring in deep due to their effectiveness and safety. We believe that new interventions for pathogenesis combined with traditional interventions will have more rapid and apparent effects.
In the future, more clinical and basic research is required to clarify the pathogenesis of frailty in KT candidates and recipients. To carry out further basic research, priority should be given to exploring animal models of frailty. Regarding interventions for frailty, it is necessary to find effective interventions based on the existing possible pathogenesis. For instance, we can search for cell signaling pathways that cause chronic low-grade inflammation to develop corresponding target-blocking drugs. Therapeutic strategies of the traditional interventions combined with specific interventions are also a potential direction for research. For example, we can increase skeletal muscle mass and improve muscle function through nutritional therapy, reasonable exercise, and anti-oxidative stress drugs. However, multicenter and large-sample prospective studies are required to confirm and improve these intervention strategies. In addition, an efficient and accurate evaluation system for frailty will help in the early detection of frail or pre-frail patients and enable early intervention. Thus, researchers can selectively combine clinical manifestations, serum markers, and imaging tests to construct a frailty evaluation system with high sensitivity and specificity.
Funding
None.
Conflicts of interest
None.
References
1. Hart A, Smith J, Skeans M, Gustafson S, Wilk A, Castro S, et al. OPTN/SRTR 2017 annual data report: kidney.
Am J Transplant 2019; 19: (Suppl 2): 19123. doi: 10.1111/ajt.15274.
2. Rapa S, Di Iorio B, Campiglia P, Heidland A, Marzocco S. Inflammation and oxidative stress in chronic kidney disease - potential therapeutic role of minerals, vitamins and plant-derived metabolites.
Int J Mol Sci 2019; 21:263doi: 10.3390/ijms21010263.
3. Afriansyah A, Rasyid N, Rodjani A, Wahyudi I, Mochtar CA, Susalit E, et al. Laparoscopic procurement of single versus multiple artery kidney allografts: meta-analysis of comparative studies.
Asian J Surg 2019; 42:6170. doi: 10.1016/j.asjsur.2018.06.001.
4. Pérez Fernández M, Martínez Miguel P, Ying H, Haugen C, Chu N, Rodríguez Puyol D, et al. Comorbidity,
frailty, and waitlist mortality among
kidney transplant candidates of all ages.
Am J Nephrol 2019; 49:103110. doi: 10.1159/000496061.
5. Haugen C, Thomas A, Chu N, Shaffer A, Norman S, Bingaman A, et al. Prevalence of
frailty among
kidney transplant candidates and recipients in the United States: estimates from a national registry and multicenter cohort study.
Am J Transplant 2020; 20:11701180. doi: 10.1111/ajt.15709.
6. Kobashigawa J, Dadhania D, Bhorade S, Adey D, Berger J, Bhat G, et al. Report from the American Society of Transplantation on
frailty in solid organ transplantation.
Am J Transplant 2019; 19:984994. doi: 10.1111/ajt.15198.
7. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al.
Frailty in older adults: evidence for a phenotype.
J Gerontol A Biol Sci Med Sci 2001; 56:M146M156. doi: 10.1093/gerona/56.3.m146.
8. Exterkate L, Slegtenhorst BR, Kelm M, Seyda M, Schuitenmaker JM, Quante M, et al.
Frailty and transplantation.
Transplantation 2016; 100:727733. doi: 10.1097/tp.0000000000001003.
9. Molina-Garrido MJ, Guillén-Ponce C. Where are we headed with research in frail elderly patients with cancer?
J Clin Oncol 2016; 34:40494050. doi: 10.1200/jco.2016.69.0487.
10. Roshanravan B, Khatri M, Robinson-Cohen C, Levin G, Patel KV, de Boer IH, et al. A prospective study of
frailty in nephrology-referred patients with CKD.
Am J Kidney Dis 2012; 60:912921. doi: 10.1053/j.ajkd.2012.05.017.
11. Turner G, Clegg A. British Geriatrics Society; Age UK; Royal College of General Practioners. Best practice guidelines for the management of
frailty: a British Geriatrics Society, Age UK and Royal College of General Practitioners report.
Age Ageing 2014; 43:744747. doi: 10.1093/ageing/afu138.
12. Haugen CE, Chu NM, Ying H, Warsame F, Holscher CM, Desai NM, et al.
Frailty and access to kidney transplantation.
Clin J Am Soc Nephrol 2019; 14:576582. doi: 10.2215/cjn.12921118.
13. McAdams-DeMarco MA, Law A, King E, Orandi B, Salter M, Gupta N, et al.
Frailty and mortality in
kidney transplant recipients.
Am J Transplant 2015; 15:149154. doi: 10.1111/ajt.12992.
14. Garonzik-Wang JM, Govindan P, Grinnan JW, Liu M, Ali HM, Chakraborty A, et al.
Frailty and delayed graft function in
kidney transplant recipients.
Arch Surg 2012; 147:190193. doi: 10.1001/archsurg.2011.1229.
15. McAdams-DeMarco MA, Chu NM, Segev DL.
Frailty and long-term post-kidney transplant outcomes.
Curr Transplant Rep 2019; 6:4551. doi: 10.1007/s40472-019-0231-3.
16. McAdams-DeMarco MA, Ying H, Olorundare I, King EA, Haugen C, Buta B, et al. Individual
frailty components and mortality in
kidney transplant recipients.
Transplantation 2017; 101:21262132. doi: 10.1097/tp.0000000000001546.
17. McAdams-DeMarco MA, Isaacs K, Darko L, Salter ML, Gupta N, King EA, et al. Changes in
frailty after kidney transplantation.
J Am Geriatr Soc 2015; 63:21522157. doi: 10.1111/jgs.13657.
18. Kosoku A, Uchida J, Iwai T, Shimada H, Kabei K, Nishide S, et al.
Frailty is associated with dialysis duration before transplantation in
kidney transplant recipients: a Japanese single-center cross-sectional study.
Int J Urol 2020; 27:408414. doi: 10.1111/iju.14208.
19. Haugen CE, Thomas AG, Chu NM, Shaffer AA, Norman SP, Bingaman AW, et al. Prevalence of
frailty among
kidney transplant candidates and recipients in the United States: estimates from a National Registry and Multicenter Cohort Study.
Am J Transplant 2020; 20:11701180. doi: 10.1111/ajt.15709.
20. Johansen KL, Chertow GM, Jin C, Kutner NG. Significance of
frailty among dialysis patients.
J Am Soc Nephrol 2007; 18:29602967. doi: 10.1681/asn.2007020221.
21. Buta BJ, Walston JD, Godino JG, Park M, Kalyani RR, Xue QL, et al.
Frailty assessment instruments: systematic characterization of the uses and contexts of highly-cited instruments.
Ageing Res Rev 2016; 26:5361. doi: 10.1016/j.arr.2015.12.003.
22. Searle SD, Mitnitski A, Gahbauer EA, Gill TM, Rockwood K. A standard procedure for creating a
frailty index.
BMC Geriatr 2008; 8:24doi: 10.1186/1471-2318-8-24.
23. Guralnik JM, Simonsick EM, Ferrucci L, Glynn RJ, Berkman LF, Blazer DG, et al. A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission.
J Gerontol 1994; 49:M85M94. doi: 10.1093/geronj/49.2.m85.
24. Nastasi AJ, McAdams-DeMarco MA, Schrack J, Ying H, Olorundare I, Warsame F, et al. Pre-kidney transplant lower extremity impairment and post-kidney transplant mortality.
Am J Transplant 2018; 18:189196. doi: 10.1111/ajt.14430.
25. Harhay MN, Rao MK, Woodside KJ, Johansen KL, Lentine KL, Tullius SG, et al. An overview of
frailty in kidney transplantation: measurement, management and future considerations.
Nephrol Dial Transplant 2020; 35:10991112. doi: 10.1093/ndt/gfaa016.
26. Lorenz EC, Cosio FG, Bernard SL, Bogard SD, Bjerke BR, Geissler EN, et al. The relationship between
frailty and decreased physical performance with death on the kidney transplant waiting list.
Prog Transplant 2019; 29:108114. doi: 10.1177/1526924819835803.
27. McAdams-DeMarco MA, Ying H, Thomas AG, Warsame F, Shaffer AA, Haugen CE, et al.
Frailty, inflammatory markers, and waitlist mortality among patients with end-stage renal disease in a prospective cohort study.
Transplantation 2018; 102:17401746. doi: 10.1097/tp.0000000000002213.
28. Locke JE, Carr JJ, Nair S, Terry JG, Reed RD, Smith GD, et al. Abdominal lean muscle is associated with lower mortality among kidney waitlist candidates.
Clin Transplant 2017; 3110.1111/ctr.12911. doi: 10.1111/ctr.12911.
29. McAdams-DeMarco MA, Law A, Salter ML, Chow E, Grams M, Walston J, et al.
Frailty and early hospital readmission after kidney transplantation.
Am J Transplant 2013; 13:20912095. doi: 10.1111/ajt.12300.
30. Konel JM, Warsame F, Ying H, Haugen CE, Mountford A, Chu NM, et al. Depressive symptoms,
frailty, and adverse outcomes among
kidney transplant recipients.
Clin Transplant 2018; 32:e13391doi: 10.1111/ctr.13391.
31. Schopmeyer L, El Moumni M, Nieuwenhuijs-Moeke GJ, Berger SP, Bakker SJL, Pol RA.
Frailty has a significant influence on postoperative complications after kidney transplantation - a prospective study on short-term outcomes.
Transpl Int 2019; 32:6674. doi: 10.1111/tri.13330.
32. McAdams-DeMarco MA, Law A, Tan J, Delp C, King EA, Orandi B, et al.
Frailty, mycophenolate reduction, and graft loss in
kidney transplant recipients.
Transplantation 2015; 99:805810. doi: 10.1097/tp.0000000000000444.
33. Chu NM, Gross AL, Shaffer AA, Haugen CE, Norman SP, Xue QL, et al.
Frailty and changes in cognitive function after kidney transplantation.
J Am Soc Nephrol 2019; 30:336345. doi: 10.1681/asn.2018070726.
34. McAdams-DeMarco MA, King EA, Luo X, Haugen C, DiBrito S, Shaffer A, et al.
Frailty, length of stay, and mortality in
kidney transplant recipients: a national registry and prospective cohort study.
Ann Surg 2017; 266:10841090. doi: 10.1097/sla.0000000000002025.
35. McAdams-DeMarco M, James N, Salter M, Walston J, Segev D. Trends in kidney transplant outcomes in older adults.
J Am Geriatr Soc 2014; 62:22352242. doi: 10.1111/jgs.13130.
36. Cossart AR, Cottrell WN, Campbell SB, Isbel NM, Staatz CE. Characterizing the pharmacokinetics and pharmacodynamics of immunosuppressant medicines and patient outcomes in elderly renal transplant patients.
Transl Androl Urol 2019; 8:S198S213. doi: 10.21037/tau.2018.10.16.
37. Khan KT, Hemati K, Donovan AL. Geriatric physiology and the
frailty syndrome.
Anesthesiol Clin 2019; 37:453474. doi: 10.1016/j.anclin.2019.04.006.
38. Tonner PH, Kampen J, Scholz J. Pathophysiological changes in the elderly.
Best Pract Res Clin Anaesthesiol 2003; 17:163177. doi: 10.1016/s1521-6896(03)00010-7.
39. Greco EA, Pietschmann P, Migliaccio S. Osteoporosis and sarcopenia increase
frailty syndrome in the elderly.
Front Endocrinol (Lausanne) 2019; 10:255doi: 10.3389/fendo.2019.00255.
40. Gea J, Pascual S, Casadevall C, Orozco-Levi M, Barreiro E. Muscle dysfunction in chronic obstructive pulmonary disease: update on causes and biological findings.
J Thorac Dis 2015; 7:E418E438. doi: 10.3978/j.issn.2072-1439.2015.08.04.
41. Bellumkonda L, Tyrrell D, Hummel SL, Goldstein DR. Pathophysiology of heart failure and
frailty: a common inflammatory origin?
Aging Cell 2017; 16:444450. doi: 10.1111/acel.12581.
42. Morley JE, Malmstrom TK.
Frailty, sarcopenia, and hormones.
Endocrinol Metab Clin North Am 2013; 42:391405. doi: 10.1016/j.ecl.2013.02.006.
43. Robertson DA, Savva GM, Kenny RA.
Frailty and cognitive impairment - a review of the evidence and causal mechanisms.
Ageing Res Rev 2013; 12:840851. doi: 10.1016/j.arr.2013.06.004.
44. Salminen A. Activation of immunosuppressive network in the aging process.
Ageing Res Rev 2020; 57:100998doi: 10.1016/j.arr.2019.100998.
45. Fulop T, McElhaney J, Pawelec G, Cohen AA, Morais JA, Dupuis G, et al.
Frailty, inflammation and immunosenescence.
Interdiscip Top Gerontol Geriatr 2015; 41:2640. doi: 10.1159/000381134.
46. Pang WW, Schrier SL, Weissman IL. Age-associated changes in human hematopoietic stem cells.
Semin Hematol 2017; 54:3942. doi: 10.1053/j.seminhematol.2016.10.004.
47. Golpanian S, DiFede DL, Khan A, Schulman IH, Landin AM, Tompkins BA, et al. Allogeneic human mesenchymal stem cell infusions for aging
frailty.
J Gerontol A Biol Sci Med Sci 2017; 72:15051512. doi: 10.1093/gerona/glx056.
48. Grant RW, Dixit VD. Adipose tissue as an immunological organ.
Obesity (Silver Spring) 2015; 23:512518. doi: 10.1002/oby.21003.
49. Kordinas V, Tsirpanlis G, Nicolaou C, Zoga M, Ioannidis A, Ioannidou V, et al. Is there a connection between inflammation, telomerase activity and the transcriptional status of telomerase reverse transcriptase in renal failure?
Cell Mol Biol Lett 2015; 20:222236. doi: 10.1515/cmble-2015-0016.
50. Rentoukas E, Tsarouhas K, Kaplanis I, Korou E, Nikolaou M, Marathonitis G, et al. Connection between telomerase activity in PBMC and markers of inflammation and endothelial dysfunction in patients with metabolic syndrome.
PLoS One 2012; 7:e35739doi: 10.1371/journal.pone.0035739.
51. Vaiserman A, Krasnienkov D. Telomere length as a marker of biological age: state-of-the-art, open issues, and future perspectives.
Front Genet 2020; 11:630186doi: 10.3389/fgene.2020.630186.
52. Gandolfini I, Regolisti G, Bazzocchi A, Maggiore U, Palmisano A, Piotti G, et al.
Frailty and sarcopenia in older patients receiving kidney transplantation.
Front Nutr 2019; 6:169doi: 10.3389/fnut.2019.00169.
53. Zhu H, Li H, Feng B, Zhang L, Zheng Z, Zhang Y, et al. Association between sarcopenia and cognitive impairment in community-dwelling population.
Chin Med J (Engl) 2020; 134:725727. doi: 10.1097/cm9.0000000000001310.
54. Bossola M, Tazza L, Giungi S, Luciani G. Anorexia in hemodialysis patients: an update.
Kidney Int 2006; 70:417422. doi: 10.1038/sj.ki.5001572.
55. Johansen KL, Chertow GM, Ng AV, Mulligan K, Carey S, Schoenfeld PY, et al. Physical activity levels in patients on hemodialysis and healthy sedentary controls.
Kidney Int 2000; 57:25642570. doi: 10.1046/j.1523-1755.2000.00116.x.
56. Nishikawa H, Fukunishi S, Asai A, Yokohama K, Nishiguchi S, Higuchi K. Pathophysiology and mechanisms of primary sarcopenia (Review).
Int J Mol Med 2021; 48:156doi: 10.3892/ijmm.2021.4989.
57. Ye L, Elstgeest L, Zhang X, Alhambra-Borrás T, Tan S, Raat H. Factors associated with physical, psychological and social
frailty among community-dwelling older persons in Europe: a cross-sectional study of Urban Health Centres Europe (UHCE).
BMC Geriatr 2021; 21:422doi: 10.1186/s12877-021-02364-x.
58. Courel-Ibáñez J, Buendía-Romero Á, Pallarés J, García-Conesa S, Martínez-Cava A, Izquierdo M. Impact of tailored multicomponent exercise for prevent weakness and falls on nursing home residents’ functional capacity.
J Am Med Dir Assoc 2022; 23:98104. e3. doi: 10.1016/j.jamda.2021.05.037.
59. Nixon A, Bampouras T, Gooch H, Young H, Finlayson K, Pendleton N, et al. Home-based exercise for people living with
frailty and chronic kidney disease: a mixed-methods pilot randomised controlled trial.
PLoS One 2021; 16:e0251652doi: 10.1371/journal.pone.0251652.
60. Zhang L, Rajan V, Lin E, Hu Z, Han HQ, Zhou X, et al. Pharmacological inhibition of myostatin suppresses systemic inflammation and muscle atrophy in mice with chronic kidney disease.
FASEB J 2011; 25:16531663. doi: 10.1096/fj.10-176917.
61. Aniort J, Stella A, Philipponnet C, Poyet A, Polge C, Claustre A, et al. Muscle wasting in patients with end-stage renal disease or early-stage lung cancer: common mechanisms at work.
J Cachexia Sarcopenia Muscle 2019; 10:323337. doi: 10.1002/jcsm.12376.
62. Leitner LM, Wilson RJ, Yan Z, Gödecke A. Reactive oxygen species/nitric oxide mediated inter-organ communication in skeletal muscle wasting diseases.
Antioxid Redox Signal 2017; 26:700717. doi: 10.1089/ars.2016.6942.
63. Cantó-Santos J, Grau-Junyent JM, Garrabou G. The impact of mitochondrial deficiencies in neuromuscular diseases.
Antioxidants (Basel) 2020; 9:964doi: 10.3390/antiox9100964.
64. Cruz-Jentoft A, Bahat G, Bauer J, Boirie Y, Bruyère O, Cederholm T, et al. Sarcopenia: revised European consensus on definition and diagnosis.
Age Ageing 2019; 48:1631. doi: 10.1093/ageing/afy169.
65. Salvadori L, Mandrone M, Manenti T, Ercolani C, Cornioli L, Lianza M, et al. Identification of Withania somnifera-Silybum marianum-Trigonella foenum-graecum formulation as a nutritional supplement to contrast muscle atrophy and sarcopenia.
Nutrients 2020; 13:49doi: 10.3390/nu13010049.
66. Brocca L, Longa E, Cannavino J, Seynnes O, de Vito G, McPhee J, et al. Human skeletal muscle fibre contractile properties and proteomic profile: adaptations to 3 weeks of unilateral lower limb suspension and active recovery.
J Physiol 2015; 593:53615385. doi: 10.1113/jp271188.
67. Yazdi P, Moradi H, Yang J, Wang P, Vaziri N. Skeletal muscle mitochondrial depletion and dysfunction in chronic kidney disease.
Int J Clin Exp Med 2013; 6:532539.
68. Xu C, Kasimumali A, Guo X, Lu R, Xie K, Zhu M, et al. Reduction of mitochondria and up regulation of pyruvate dehydrogenase kinase 4 of skeletal muscle in patients with chronic kidney disease.
Nephrology (Carlton) 2020; 25:230238. doi: 10.1111/nep.13606.
69. Uchida T, Sakashita Y, Kitahata K, Yamashita Y, Tomida C, Kimori Y, et al. Reactive oxygen species upregulate expression of muscle atrophy-associated ubiquitin ligase Cbl-b in rat L6 skeletal muscle cells.
Am J Physiol Cell Physiol 2018; 314:C721C731. doi: 10.1152/ajpcell.00184.2017.
70. Marcell T. Sarcopenia: causes, consequences, and preventions.
J 2003; M911M916. doi: 10.1093/gerona/58.10.m911.
71. Meng S, Yu L. Oxidative stress, molecular inflammation and sarcopenia.
Int J Mol Sci 2010; 11:15091526. doi: 10.3390/ijms11041509.
72. Andrianjafiniony T, Dupré-Aucouturier S, Letexier D, Couchoux H, Desplanches D. Oxidative stress, apoptosis, and proteolysis in skeletal muscle repair after unloading.
Am J Physiol Cell Physiol 2010; 299:C307C315. doi: 10.1152/ajpcell.00069.2010.
73. Saini A, Al-Shanti N, Stewart CE. Waste management - cytokines, growth factors and cachexia.
Cytokine Growth Factor Rev 2006; 17:475486. doi: 10.1016/j.cytogfr.2006.09.006.
74. Huang Z, Zhong L, Zhu J, Xu H, Ma W, Zhang L, et al. Inhibition of IL-6/JAK/STAT3 pathway rescues denervation-induced skeletal muscle atrophy.
Ann Transl Med 2020; 8:1681doi: 10.21037/atm-20-7269.
75. Webster JM, Kempen L, Hardy RS, Langen RCJ. Inflammation and skeletal muscle wasting during cachexia.
Front Physiol 2020; 11:597675doi: 10.3389/fphys.2020.597675.
76. Schroth J, Thiemermann C, Henson SM. Senescence and the aging immune system as major drivers of chronic kidney disease.
Front Cell Dev Biol 2020; 8:564461doi: 10.3389/fcell.2020.564461.
77. Casati M, Ferri E, Azzolino D, Cesari M, Arosio B. Gut microbiota and physical
frailty through the mediation of sarcopenia.
Exp Gerontol 2019; 124:110639doi: 10.1016/j.exger.2019.110639.
78. Ficek J, Wyskida K, Ficek R, Wajda J, Klein D, Witkowicz J, et al. Relationship between plasma levels of zonulin, bacterial lipopolysaccharides, D-lactate and markers of inflammation in haemodialysis patients.
Int Urol Nephrol 2017; 49:717725. doi: 10.1007/s11255-016-1495-5.
79. Margiotta E, Miragoli F, Callegari M, Vettoretti S, Caldiroli L, Meneghini M, et al. Gut microbiota composition and
frailty in elderly patients with chronic kidney disease.
PLoS One 2020; 15:e0228530doi: 10.1371/journal.pone.0228530.
80. Picca A, Fanelli F, Calvani R, Mulè G, Pesce V, Sisto A, et al. Gut dysbiosis and muscle aging: searching for novel targets against sarcopenia.
Mediators Inflamm 2018; 2018:7026198doi: 10.1155/2018/7026198.
81. Yabuuchi J, Ueda S, Yamagishi SI, Nohara N, Nagasawa H, Wakabayashi K, et al. Association of advanced glycation end products with sarcopenia and
frailty in chronic kidney disease.
Sci Rep 2020; 10:17647doi: 10.1038/s41598-020-74673-x.
82. Chen SI, Chiang CL, Chao CT, Chiang CK, Huang JW. Gustatory dysfunction is closely associated with
frailty in patients with chronic kidney disease.
J Ren Nutr 2021; 31:4956. doi: 10.1053/j.jrn.2020.06.006.
83. Yoong RK, Mooppil N, Khoo EY, Newman SP, Lee VY, Kang AW, et al. Prevalence and determinants of anxiety and depression in end stage renal disease (ESRD). A comparison between ESRD patients with and without coexisting diabetes mellitus.
J Psychosom Res 2017; 94:6872. doi: 10.1016/j.jpsychores.2017.01.009.
84. Van Pilsum Rasmussen S, Konel J, Warsame F, Ying H, Buta B, Haugen C, et al. Engaging clinicians and patients to assess and improve
frailty measurement in adults with end stage renal disease.
BMC Nephrol 2018; 19:8doi: 10.1186/s12882-017-0806-0.
85. Nafar M, Sahraei Z, Salamzadeh J, Samavat S, Vaziri ND. Oxidative stress in kidney transplantation: causes, consequences, and potential treatment.
Iran J Kidney Dis 2011; 5:357372. doi: NODOI.
86. Chan W, Chin SH, Whittaker AC, Jones D, Kaur O, Bosch JA, et al. The associations of muscle strength, muscle mass, and adiposity with clinical outcomes and quality of life in prevalent
kidney transplant recipients.
J Ren Nutr 2019; 29:536547. doi: 10.1053/j.jrn.2019.06.009.
87. Nieuwenhuijs-Moeke GJ, Pischke SE, Berger SP, Sanders JSF, Pol RA, Struys M, et al. Ischemia and reperfusion injury in kidney transplantation: relevant mechanisms in injury and repair.
J Clin Med 2020; 9:253doi: 10.3390/jcm9010253.
88. Lehner LJ, Staeck O, Halleck F, Liefeldt L, Bamoulid J, Budde K. Need for optimized immunosuppression in elderly
kidney transplant recipients.
Transplant Rev (Orlando) 2015; 29:237239. doi: 10.1016/j.trre.2015.08.001.
89. Endén K, Tainio J, Hou M, Suominen A, Pakarinen M, Huang T, et al. Telomere length regulators are activated in young men after pediatric kidney transplantation compared to healthy controls and survivors of childhood cancer - a cross-sectional study.
Pediatr Transplant 2019; 23:e13550doi: 10.1111/petr.13550.
90. Tabibian J, Kenderian S. The microbiome and immune regulation after transplantation.
Transplantation 2017; 101:5662. doi: 10.1097/tp.0000000000001444.
91. Nolte Fong JV, Moore LW. Nutrition trends in
kidney transplant recipients: the importance of dietary monitoring and need for evidence-based recommendations.
Front Med (Lausanne) 2018; 5:302doi: 10.3389/fmed.2018.00302.
92. Strollo F, Strollo G, Morè M, Magni P, Macchi C, Masini MA, et al. Low-intermediate dose testosterone replacement therapy by different pharmaceutical preparations improves
frailty score in elderly hypogonadal hyperglycaemic patients.
Aging Male 2013; 16:3337. doi: 10.3109/13685538.2013.773305.
93. Ma D, Chen C, Diao Y, Yang K, Li Y, Salerno S, et al. Efficacy of exercises in improving the quality of life for chronic kidney disease patients without dialysis.
Chin Med J (Engl) 2020; 133:17381740. doi: 10.1097/cm9.0000000000000941.
94. Hanna K, Ditillo M, Joseph B. The role of
frailty and prehabilitation in surgery.
Curr Opin Crit Care 2019; 25:717722. doi: 10.1097/mcc.0000000000000669.
95. Chan CWC, Chau PH, Leung AYM, Lo KC, Shi H, Yum TP, et al. Acupressure for frail older people in community dwellings - a randomised controlled trial.
Age Ageing 2017; 46:957964. doi: 10.1093/ageing/afx050.
96. Alvarez-Nebreda ML, Bentov N, Urman RD, Setia S, Huang JC, Pfeifer K, et al. Recommendations for preoperative management of
frailty from the society for perioperative
assessment and quality improvement (SPAQI).
J Clin Anesth 2018; 47:3342. doi: 10.1016/j.jclinane.2018.02.011.
97. Cheng XS, Lentine KL, Koraishy FM, Myers J, Tan JC. Implications of
frailty for peritransplant outcomes in
kidney transplant recipients.
Curr Transplant Rep 2019; 6:1625. doi: 10.1007/s40472-019-0227-z.
98. Zhu Y, Ge J, Huang C, Liu H, Jiang H. Application of mesenchymal stem cell therapy for aging
frailty: From mechanisms to therapeutics.
Theranostics 2021; 11:56755685. doi: 10.7150/thno.46436.
99. Ikee R, Sasaki N, Yasuda T, Fukazawa S. Chronic kidney disease, gut dysbiosis, and constipation: a burdensome triplet.
Microorganisms 2020; 8:1862doi: 10.3390/microorganisms8121862.
100. Lee JR, Magruder M, Zhang L, Westblade LF, Satlin MJ, Robertson A, et al. Gut microbiota dysbiosis and diarrhea in
kidney transplant recipients.
Am J Transplant 2019; 19:488500. doi: 10.1111/ajt.14974.
101. Ross CN, Reveles KR. Feasibility of fecal microbiota transplantation via oral gavage to safely alter gut microbiome composition in marmosets.
Am J Primatol 2020; 82:e23196doi: 10.1002/ajp.23196.
102. DeJong EN, Surette MG, Bowdish DME. The gut microbiota and unhealthy aging: disentangling cause from consequence.
Cell Host Microbe 2020; 28:180189. doi: 10.1016/j.chom.2020.07.013.
