Abstract
Older people constitute an increasingly greater proportion of patients with advanced CKD, including those patients undergoing maintenance dialysis treatment. Frailty is a biologic syndrome of decreased reserve and resistance to stressors that results from cumulative declines across multiple physiologic systems and causes vulnerability to adverse outcomes. Frailty is common in elderly CKD patients, and it may be associated with protein-energy wasting (PEW), sarcopenia, dynapenia, and other complications of CKD. Causes of frailty with or without PEW in the elderly with CKD can be classified into three categories: causes primarily caused by aging per se, advanced CKD per se, or a combination of both conditions. Frailty and PEW in elderly CKD patients are associated with impaired physical performance, disability, poorer quality of life, and reduced survival. Prevention and treatment of these conditions in the elderly CKD patients often require a multifaceted approach. Here, we examine the causes and consequences of these conditions and examine the interplay between frailty and PEW in elderly CKD patients.
Older patients comprise an increasing proportion of people with stage 5 CKD and those patients undergoing maintenance hemodialysis (MHD) or chronic peritoneal dialysis (CPD).1–4 Frailty and protein-energy wasting (PEW) are common complications in elderly patients with ESRD undergoing MHD or CPD.2,5–9 This phenomenon is clinically relevant, because many manifestations of frailty and PEW are strong risk factors for low quality of life (QOL), morbidity, and mortality.3,5,10,11 Frailty and PEW may be caused by aging, advanced kidney failure, or both conditions combined. Here, we review causes, consequences, and potential therapies for frailty and PEW in elderly ESRD patients.
Definitions
The US National Library of Medicine defines aged in humans as ages 65–79 years old. Individuals >79 years old are categorized as aged 80 years and over. Frailty can be defined as a biologic syndrome of decreased reserve and resistance to stressors that results from cumulative declines across multiple physiologic systems and causes vulnerability to adverse outcomes.11 Frailty implies decreased body energy and protein reserves and reduced strength. There are several excellent discussions of frailty in CKD patients.2,6,12,13 A simple criterion for frailty can be the presence of three or more of the following abnormalities: unintentional weight loss, self-reported exhaustion, measured weakness, slow walking speed, and low physical activity.11–13
PEW is defined as the loss of somatic and circulating body protein and energy reserves.14 The term PEW is used rather than protein-energy malnutrition, because some causes of PEW are unrelated to inadequate nutrient intake.9,14,15 Causes of PEW in ESRD patients include inadequate nutrient intake, losses of nutrients during dialysis, superimposed catabolic illnesses, nonspecific inflammation, acidemia, catabolic stress from the dialysis procedure, low levels of or resistance to such anabolic hormones as insulin, growth hormone, and IGF-1, increased levels of such catabolic hormones as parathyroid hormone and glucagon, blood losses from blood drawing or gastrointestinal bleeding,9,15 and possibly, oxidative and carbonyl stress.16–20
Two related concepts are sarcopenia and dynapenia. Sarcopenia is derived from the Greek words sarx (flesh) and penia (loss).21 Two common definitions for sarcopenia are progressive decline in muscle mass caused by aging, which results in decreased functional capacity of muscles,22 or simply, decreased muscle mass in the elderly.23 Dynapenia, derived from the Greek words dyn (power) and penia (loss), is defined as loss of strength with aging.23,24 These definitions may not be optimal, because reduced muscle mass and strength are not always present in people≥65 years old, and morbidity, malnutrition, or just physical inactivity can reduce muscle mass and strength in younger people.24 Skeletal muscle (SKM) mass size seems to be the most important predictor of muscle strength or physical performance25 and in maintenance dialysis patients, survival.26,27 However, SKM mass and strength can be disassociated.28 As normal people age, the rate of decline in muscle strength is greater than the rate of loss of muscle mass,29 and strength can diminish even while muscle mass is maintained or increases.30
Physical performance is defined as the capability to conduct normal daily physical activities. Physical performance is often measured by such activities as the time required to climb a defined number of stairs or the distance walked or number of rises from a chair during a given time period.31 Physical performance and mortality may be associated more with muscle strength than muscle mass.32–34 Another age-related change in body composition, sarcopenic obesity,35 refers to low muscle mass (sarcopenia) combined with increased body fat (obesity).36 Sarcopenic obesity may develop without weight changes if the decrease in muscle mass is similar to the gain in body fat.37
Increased Prevalence of Frailty and PEW in Elderly ESRD Patients
Frailty and PEW are well described in adult ESRD patients independent of age. PEW is found in 18%–75% of maintenance dialysis patients in different reports.9,13,38 There is less information concerning the prevalence and magnitude of these abnormalities in elderly ESRD patients. However, PEW (low serum albumin and subjective global assessment), sarcopenia (reduced mid-arm muscle circumference [MAMC]), and dynapenia (decreased hand grip strength) seem to be more common in older (>65 years) than younger maintenance dialysis patients.39 In MHD patients, decreased lean body mass40 and thigh muscle area41 are associated with aging. The prevalence of sarcopenia also increases with aging in CKD patients without ESRD.8 However, muscle wasting tends to be more severe in maintenance dialysis patients than dialysis-independent CKD patients.42 Sarcopenic obesity is more pronounced in aging nondiabetic MHD patients than aging controls.43 The volume of visceral fat, standardized by body mass index, is greater in nondiabetic MHD patients (mean age=57.5±1.3 years) compared with people with normal kidney function of similar age.44
Compared with the prevalence of frailty in elderly community-dwelling people (6.9% in the Cardiovascular Health Study11 and 16.3% in the Women’s Health Initiative45), frailty is substantially greater in elderly and near-elderly ESRD patients (67.7% in 2275 maintenance dialysis patients ages 58.2±15.5 years in the Dialysis Morbidity and Mortality Wave 2 Study).6 The prevalence of frailty increases with age in MHD patients.6 Moreover, elderly nondialyzed patients with primarily stage 3 CKD (mean age=76 years) had a greater prevalence of frailty (15% versus 6%; P<0.001) than elderly persons (mean age=72 years) with normal or mildly reduced kidney function.14
Causes of Frailty and PEW in Elderly ESRD Patients
Current thinking and scientific evidence regarding the many causes of frailty and PEW are well reviewed, and they are illustrated in Figure 1 and listed in Table 1 according to whether, in the authors’ opinion, the causes are kidney failure, aging, or both factors.9,46 The relative contributions of aging and ESRD to frailty and PEW may also be heavily influenced by such individual characteristics as the person’s genotype, phenotype, medical history, duration and severity of renal failure, psychosocial condition, and lifestyle.
Potential causes of frailty and protein-energy wasting in elderly patients with end stage kidney disease. 1,25(OH)2D3, 1,25-dihydroxycholecalciferol; ESKD, end stage kidney disease; PTH, parathyroid hormone; VDR, vitamin D receptor.
Clinical causes promoting frailty and PEW in elderly CKD patients
The causes of the aging process and its potential contributions to frailty are the foci of much research. These causes can be categorized into genetic and environmental exposure, including epigenetic factors.16,47,48 Hundreds of genetic variations have been identified that are associated with longevity in various species.16,47 Interestingly, a number of these genetic variations involve the insulin pathways including insulin, IGF, their receptors, and the signal transduction system that they induce.47,49,50 Alterations that suppress activity of this pathway seem to be particularly associated with increased longevity. The finding that, in many species, reducing intake of calories or other nutrients increases longevity might be related to the fact that carbohydrates and some amino acids stimulate release of insulin, IGF-1, or the major IGF binding protein in serum. The elderly may be growth hormone (GH)-deficient.51 IGF-1 exerts anabolic, anticatabolic, and antiapoptotic actions on SKM, and it helps to maintain SKM mass and enhance physical performance.52,53 There is an age-related decline in IGF-1 activity that stems from the decline of GH; this decline may result in loss of muscle mass and strength and reduced exercise capacity.54 Whether this decline promotes longevity is unknown.
Other environmental disorders that might contribute to aging include mitochondrial dysfunction and oxidative stress.55,56 The accumulation of free radicals48,57 may play a particular role in inducing age-related sarcopenia16 and DNA damage, protein crosslinking, nonenzymatic glycation or other carbonyl reactions with proteins, accumulation of partially or completely denatured proteins, and cellular inflammation, which is commonly present in the aged.58,59 Cellular apoptosis48 and autophagy,60,61 leading to loss of functional parenchymal cells, may increase along with failure of normal replacement by stem cells.62 In addition, the limits of cellular replication cycles because of telomere shortening48,63,64 as well as DNA damage and oncogene expression in aging lead to the accumulation of dysfunctional senescent cells, which may contribute to dysfunctional tissues and organ systems.48,65 Immune function also declines with aging.48,66 Chronic inflammation also plays an important role in the aging process.48,66–68
Hormonal dysfunction with low levels or resistance to many hormones, including sex hormones, testosterone, insulin, IGF-1, and thyroid hormone, may occur. Deficiency of 25-hydroxyvitamin D [25(OH)D] has become common in industrialized societies because of reduced time spent in sunlight and the frequent use of sunscreen or clothing that covers the skin.69 Increasing age does not alter intestinal absorption of dietary vitamin D, but it is associated with lower 25(OH)D levels, regardless of season.69 Decreased dietary vitamin D intake and reduced cutaneous synthesis of vitamin D, possibly related to decreased skin thickness, may contribute to lower serum 25(OH)D in the elderly.70 The normal elderly with low (<25 nmol/L) serum 25(OH)D levels are at higher risk for sarcopenia (assessed by dual-energy X-ray photon absorptiometry [DEXA]; odds ratio=2.14) and dynapenia (assessed by grip strength; odds ratio=2.57) compared with elderly persons with high serum levels (>50 nmol/L).71 Vitamin D supplementation in the elderly improves lower extremity muscle performance72 and increases the number and diameter of type II muscle fibers.73 ESRD patients are also likely to develop deficiency of both serum 1,25-dihydroxycholecalciferol, which is primarily synthesized in the kidney, and 25(OH)D. MHD patients receiving calcitriol (1,25-dihydroxyvitamin D) or paricalcitol (a 1,25-dihydroxyvitamin D analog) showed larger thigh muscle cross-sectional area measured by magnetic resonance imaging (P<0.05) and greater lower limb muscle strength (P<0.05) compared with MHD patients without either treatment.74 Because vitamin D deficiency has a direct association with type II muscle fiber atrophy and physical performance,75,76 vitamin D deficiency, particularly if advanced, may cause severe dynapenia, which may improve dramatically with supplements of 1,25-dihydroxyvitamin D.
Aging is associated with changes in central and peripheral nervous system activity, which affect SKM structure and function.77–79 Loss of lower motor neurons in the lumbospinal segments (L1–L3) is observed in people>60 years old.80 Doublet discharges from motor neuron axons are considered to increase both the rate and amount of force production in SKM and slow muscle fatigue development. The frequency of doublet discharges is lower in older individuals (74.1±8.8 years) than young subjects (21.9±3.6 years).81 The number and diameter of motor axons,80 peroneal nerve conduction velocity (a measure of nerve myelination), and compound muscle action potentials (a measure of axonal degeneration)82 all decrease with age. Compound muscle action potential is positively correlated with calf muscle density (a measure of fatty degeneration in muscle) assessed by computerized tomography.82
With aging, the loss of fast motor units (type II fibers) because of denervation is more pronounced than the loss of slow motor units (type I fibers).46 Denervated muscle fibers are recruited by surviving motor units and change their fiber type to the type of the surviving motor unit. Hence, there is a net conversion of type II fibers to type I fibers.46 Type II fiber-specific TNF-α signaling is another pathway that may account for the preferential loss and atrophy of type II muscle fibers with advancing age.83 Predominant atrophy of type II fibers is also observed in MHD patients (ages 44.1±17.2 years).84
Satellite cells (muscle stem cells) from older mice show reduced number and impaired myoblast generation and differentiation.85 In SKM of elderly men (76±1 years) compared with young men (20±1 years), the percent of type II fibers was lower (47±3% versus 57±3%; P<0.05), and the total cross-sectional area of the type II fibers was significantly reduced (P<0.05).86 The number of satellite cell per millimeter squared of type II muscle fibers was reduced in the elderly men compared with young men (9.7±1.0 versus 12.6±0.9, respectively; P<0.05).86 Aging is associated with decreased or delayed expression of myogenic regulatory factors, which regulate satellite cell proliferation and differentiation. These factors include myogenic determination factor, myogenic regulatory factor 5, and myogenin.87 The number of fibers in the vastus lateralis muscle and the motor units in the extensor digitorum brevis muscles begin to decline at approximately 50 and 60 years of age, respectively, in the general population.88,89 Possibly because of some of the foregoing neuromuscular disorders, muscle protein synthesis in the elderly in the general population (70±6 years) shows decreased sensitivity and responsiveness to essential amino acids compared with young men (28±6 years).90 Formerly, when access to dialysis was often delayed or not possible, severe neuropathy was often observed in patients with advanced CKD and ESRD. This uremic neuropathy, which often presents clinically with impaired sensation, could progress to hypoesthesia, reduced deep tendon reflexes, paresis, and ultimately, frank paralysis.
Tendons from older people (ages 69–80 years) are ∼15% more compliant than tendons from younger people (ages 20–26 years). This compliance may lead to force reduction and slower contractile force transmission from muscles to bones.91 In ESRD patients, calcium deposits may accumulate in tendons.92,93 Tendons in both elderly people and ESRD patients have an increased likelihood of rupturing or separating from their bony insertion when subjected to increased contractile force.93,94 ESRD patients may also fracture bones with intense muscle contraction.95,96 Scarring and loss of parenchymal function may occur from physical trauma, acute illnesses, and high prevalence of chronic diseases and other disorders, including hypertension, obesity, diabetes mellitus, atherosclerosis, osteoarthritis, physical deconditioning, and depression. Skeletal muscle mass within the lower 10th percentile of normal is observed in up to 62% of dialysis patients.97
Physical activity, in general, is decreased in dialysis patients and tends to decrease with age in both the general population98 and MHD patients.99 Decline in physical activity with advancing age, measured by accelerometry, is much greater for MHD patients than sedentary people without kidney disease.99 Dialysis patients are likely to describe a greater reduction in moderate or vigorous physical activity with aging.100 Physical inactivity in dialysis patients (ages 60±14 years) is associated with lower serum albumin and serum creatinine levels, which are indicative of PEW and small SKM mass.101 In contrast, increased levels of physical activity, measured by accelerometry, are associated with higher lean body mass, assessed by DEXA, in MHD patients (ages 47±2 years).102 In MHD patients (ages 64±11 years), physical activity for ≥50 min/d is associated with faster normal (P<0.001) and maximum (P<0.001) walking speed, greater leg strength (P=0.04), and better functional reach (P=0.02) compared with MHD patients with physical activity <50 min/d.103 In elderly dialysis patients, reduced frequency of daily physical activity is correlated with higher mortality risk (P<0.05).104
Reduced food intake in advanced CKD is often caused by anorexia, which may be caused by uremic toxins, inflammation, superimposed illnesses and depression, or other psychiatric disorders. In support of an anorexia-causing role for uremic toxicity in patients treated with conventional maintenance dialysis, quotidian MHD seems to be associated with increased energy and protein intake.105,106 Dietary protein intake is lower in normal elderly men (68.5±4.7 years) than normal younger men (25.6±3.7 years).107 The median age of incident ESRD patients was 64.2 years in 20084 in the United States; hence, aging per se may contribute to their reduced nutrient intake. Dementia is not uncommon in elderly ESRD patients and may reduce food intake. People with ESRD commonly are less affluent and may have inadequate funds to purchase food. Even an edentulous state may impair the ability of ESRD patients to eat. Vintage (duration) of MHD is negatively associated with intake of energy (r=−0.89, P<0.01) and protein (r=−0.05, P<0.05).108 Losses of amino acids, peptides, and water-soluble vitamins into dialysate may contribute to PEW and frailty.
Kidney failure intensifies and adds to many of the processes associated with aging. Kidney failure per se, like aging, engenders inflammation. In advanced CKD, there is impaired removal of proinflammatory cytokines (e.g., increased serum C-reactive protein, TNF-α, and IL-6) and exposure to inflammatory stimulants (e.g., uremic toxins), including those toxins engendered by the dialysis procedure itself (dialysis catheters, tubing, dialyzer membranes, and impure dialysate).9 Inflammation also may result from clinically apparent superimposed illnesses (Table 1). Inflammation not only stimulates protein degradation and SKM wasting109 but also suppresses appetite,110,111 stimulates resistance to insulin and GH,112 and enhances energy expenditure.113 Aging per se predisposes to chronic inflammation.114 A higher inflammatory state is associated with parenchymal fibrosis, less muscle mass and strength, and lower physical performance and functionality in the elderly.114
In chronic kidney failure as well as aging, there is also increased oxidant stress with enhanced generation of reactive oxygen species (ROSs), elevated serum oxidants, and reduced levels of antioxidants (Table 1).115,116 ROS-induced mitochondrial injury, where the ROSs are primarily generated, has been invoked as a key cause of the aging process, although this theory has recently been challenged.117,118 Both inflammatory cytokines and ROSs stimulate the ubiquitin–proteasome system. Oxidative stress caused by aging may cause atrophy and loss of muscle fibers17; oxidative stress may not be associated with muscle fiber atrophy in MHD patients.18 There are increased levels of protein carbonyls, such as58,119 advanced glycation endproducts120,121 and advanced lipid endproducts,121 which cause damage by reaction with endogenous proteins. Protein carbonyls, an indicator of oxidative damage to proteins, are directly associated with grip strength (β=−6.77, P<0.01) and decline in walking speed (P=0.002) in normal women≥65 years old.19,20
Genetic and epigenetic factors influence the propensity of individuals to develop CKD and the manifestations of the ESRD syndrome.122–124 As with aging, kidney failure engenders a cascade of changes in gene function, cell signaling, and metabolism that, ultimately, leads to expression of many of the phenotypic characteristics of the aged person.60,61,117,118,125
Serum levels of gluconeogenic hormones (glucagon and parathyroid hormone) are increased, and there is resistance to anabolic hormones (insulin, growth hormone, and IGF-1) in ESRD.126 Vitamin D deficiency, obesity, metabolic acidemia, inflammation, and accumulation of uremic toxins contribute to insulin resistance in advanced CKD.127 Insulin resistance in ESRD may activate caspase-3 and the ubiquitin–proteasome system, thereby enhancing muscle protein degradation.128,129 Insulin also stimulates protein synthesis. In nondiabetic MHD patients, insulin resistance is closely associated with SKM protein breakdown (R2=0.49, P=0.006).128 In diabetic compared with nondiabetic MHD and CPD patients, insulin resistance may contribute to greater loss of SKM during the first year of dialysis treatment130,131; diabetes mellitus was the strongest predictor of lean body mass loss in this study.130 Older adults, ages 70–79 years, with type 2 diabetes and without ESRD also show greater declines in leg muscle mass compared with nondiabetes.132 SKM from chronic renal failure rats shows reduced IGF-1 mRNA levels and IGF-1 protein, resistance to the IGF-1–induced suppression of protein degradation and stimulation of protein synthesis, increased IGF-1 receptor mRNA and IGF-1 receptor number, and impaired receptor tyrosine kinase activity. These findings suggest abnormal IGF-1 physiology and reduced sensitivity to IGF-1 in chronic renal failure.133 This pattern of skeletal muscle mRNA for IGF-1 and IGF-1 receptor is also observed in MHD patients.134,135
Male MHD patients not uncommonly have low serum testosterone.136 A progressive decline in serum testosterone occurs with aging in normal men.137 Low serum free testosterone is associated with frailty in elderly men.138 Treatment with supraphysiological doses of testosterone may increase muscle size and strength in otherwise normal men.139
Metabolic acidemia, which is common in CKD because of impaired ability of the kidney to excrete acid, promotes frailty and PEW in many ways. Acidemia enhances intracellular protein degradation by activating caspase-3 and the ubiquitin–proteasome system,129,140,141 reduces protein synthesis,142 causes growth hormone and insulin insensitivity, and engenders negative protein balance.143 Metabolic acidemia causes bone loss, more rapid progression of kidney failure in CKD patients, other endocrine disorders, systemic inflammation with increased proinflammatory cytokines, enhanced β2-microglobulin formation, and hypertriglyceridemia.143–145 Severe metabolic acidemia (e.g., arterial blood pH≤7.25) may be associated with anorexia, reduced food intake, malaise, and hypotension.
Clinical Consequences of Frailty and PEW in Elderly ESRD Patients
Frailty and PEW are associated with impaired physical performance, poorer quality of life, and reduced survival in elderly ESRD patients (Figure 2).7,27,146 In MHD patients ages 63±14 years, age-related decreases in SKM mass and increases in fat mass (intramuscular and intermuscular adipocytes) are associated with decreased isometric strength and impaired physical performance (6-minute walk test and gait speed).147 Reduced anterior tibialis muscle mass, which is more common in MHD patients than age- and sex-matched sedentary controls without advanced CKD, is significantly associated with reduced gait speed and isometric ankle dorsiflexor strength.148 MHD patients (ages 53±15 years) with lower MAMC had worse mental health scores, which was assessed by the Short Form 36-item health survey (SF-36) questionnaire, and poorer survival.26
Clinical consequences of frailty and protein-energy wasting in elderly patients with end stage kidney disease.
ESRD in adults of any age is associated with decreased physical performance. Scores of the Short Physical Performance Battery, an indicator of physical performance, are significantly lower in MHD patients compared with normal values for the elderly population in the Established Populations for Epidemiology Research in the Elderly, although the age of the MHD patients averaged 20 years younger than the elderly normals.149 The physical functioning subscale of the SF-36 questionnaire in these MHD patients was also reduced.149 In MHD patients>60 years (median age=75 years), both sit-to-stand scores and staircase climbing scores showed 50% and 54% fewer cycles, respectively, compared with age- and sex-matched control subjects without CKD.150
The foregoing findings mirror the effects of aging in the general population. In the elderly, the rate of decline in cognitive activity is positively correlated with increasing frailty151 and decreasing muscle strength.79 Moreover, the National Health and Nutrition Examination Survey Study indicates that normal adults≥55 years old (mean=70.1 years) with obesity and dynapenia have poorer physical function (walking speed) than adults without these two disorders.152 Increased fat mass rather than decreased fat-free mass is associated (P<0.01) with reduced physical capacity (walking speed) in normal people ages 68–82 years.153
Frailty and dynapenia are also associated with adverse clinical consequences. In adult maintenance dialysis patients in the Dialysis Morbidity and Mortality Wave 2 Study, frailty compared with no frailty is associated with greater hospitalization risk (adjusted hazard ratio [HR]=1.56, 95% confidence interval [CI]=1.36–1.79) and higher mortality (adjusted HR=2.24, 95% CI=1.60–3.15).6 In the general population, decreased whole-leg extension strength exposes the elderly to more falls.154 MHD patients≥65 years old commonly fall; in one study, 27% of patients fell in the previous 12 months, and another 16% of patients fell before the past year.155 Fall rates in elderly MHD patients (≥65 years) were higher than rates in community-dwelling elderly people without CKD (1.6 versus 0.6–0.8 falls/person-year).156 Impaired physical performance (10-m walking test) increases the risk of falls and fall-related fractures in elderly MHD patients.157 Falls are independently associated with increased mortality (adjusted HR=1.78, 95% CI=1.07–2.98, P=0.03) in elderly MHD patients.158
Impaired neuromuscular function, which was indicated by increased get-up-and-go time, reduced functional reach, and slower 6-minute walk test, is associated with an increased risk of bone fracture in MHD patients,146 roughly one-half of whom were elderly (mean age=66±9 years). The Dialysis Outcomes and Practice Patterns Study of MHD patients (mean age∼60 years), sampled from 12 countries, indicated that their yearly incidence of hip fracture was much higher than the general population (age∼60–65 years; 0.89% versus 0.07%–0.22%).95,96 Among maintenance dialysis patients from the Dialysis Morbidity and Mortality Study (age=61.7±15.5 years), those patients who sustained a hip, vertebral, or pelvic fracture had a 2.7 times greater mortality than those patients who did not sustain such fractures.159
In direct contrast to the general population, body mass index is inversely related to mortality in MHD and CPD patients.160–162 One hypothesis advanced to explain this observation is that obese MHD patients and CPD patients often have greater muscle mass than nonobese patients.163–166 Larger SKM mass, indicated by higher serum creatinine or MAMC, increased body fat mass, and gain in SKM mass or body fat are each independently associated with increased survival in nonelderly and elderly MHD and CPD patients,27,167,168 although it is still unclear why SKM mass or obesity should promote longer lifespan. Muscle mass may be more important than fat mass for survival.27 Obesity combined with sarcopenia may be considered a form of PEW, and it is associated with inflammation and increased mortality in MHD and CPD patients.169 In MHD patients, the location of the increased fat mass influences mortality. In MHD patients with a mean age of 65 years (range=51–74 years), such as in the general population, excess abdominal fat seems to be associated with higher mortality rate.170
Management Strategies for Frailty and PEW in Elderly ESRD Patients
Because frailty and PEW usually have multiple causes in elderly dialysis patients, prevention and treatment generally require a multifaceted approach. This subject is the focus of many studies and reviews.9,13,46,129 This section and Table 2 briefly summarize potential strategies for prevention and treatment.
Potential preventive and therapeutic strategies for frailty and PEW in elderly ESRD patients
Good Medical/Nephrology Care
We are unaware of any randomized prospective interventional trials that have assessed the effects of preventing or improving frailty or PEW on clinical outcomes of elderly ESRD patients. However, observational data indicate that, in general, the better the clinical status of the patient commencing dialysis, the better the prognosis for survival.171,172 PEW at the onset of dialysis is associated with poorer survival.171,172 Starting dialysis before patients develop PEW is associated with better long-term nutritional status and lower mortality.15,171,172 Indeed, commencement of dialysis is often associated with improvement in protein-energy status.173,174 Better control of uremia may lead to less frailty and PEW. Experience with quotidian hemodialysis suggests that more than two times per week MHD treatments and larger doses of dialysis may improve patients’ appetite, food intake, nutritional status, and QOL and reduce frailty and PEW.106,175
Intuitively, it would seem that advanced CKD and ESRD patients who have inflammatory catabolic illnesses and are treated promptly and aggressively with attention to their nutritional needs should have better clinical outcomes with less frailty and PEW. Moreover, given the high prevalence of oxidative, carbonyl, and inflammatory stress in ESRD patients, there should be a role for agents that correct these disorders. Anti-inflammatory and antioxidant drugs have been used in many trials of dialysis patients, most without apparent success.176–178 However, rather small-scale studies indicate that the antioxidants α-tocopherol and N-acetylcysteine may reduce adverse cardiovascular events in MHD patients.179,180 Hopefully, with further development, anti-inflammatory, antioxidant, or anticarbonyl drugs will be shown to reduce frailty and PEW and improve morbidity and mortality.
Nutrient Intake
Clearly, prevention and treatment of frailty and PEW require adequate intake of nutrients. Space does not allow for a detailed discussion of nutritional requirements in clinically stable and stressed ESRD patients, and reference is made to published reviews.38,181,182 Multivitamin and trace element supplements are commonly needed.181,183 Most expert groups recommend similar amounts of dietary protein intake (DPI) for adult MHD and CPD patients, ranging from 1.0 to 1.3 g/kg per day with at least 50% of the DPI of high biologic value.182 It has been suggested that a safe protein intake that maximizes the probability of good protein nutrition for clinically stable MHD and CPD patients is 1.2 g/kg per day and 1.2–1.3 g/kg per day, respectively.181 Current recommendations for DPI do not vary with age in adult MD patients, but this question has not been examined. The Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines for energy intake in MHD and CPD patients recommend 35 kcal/kg per day for patients<60 years and 30 kcal/kg per day for MHD patients≥60 years old.181 Energy prescription can be increased for patients who are underweight, have PEW, or engage in chronic heavy physical activity, and it can be reduced in patients who are very obese.
Most people undergoing standard maintenance dialysis treatment will not be able to ingest these quantities of protein and energy, and their food intake may need to be augmented to meet these goals. In these circumstances, oral nutritional supplements can be used. Oral supplements of protein or primarily essential amino acids, usually including additional calories, may improve protein balance and PEW, promote protein accrual in SKM of people with ESRD, or prevent or retard the development of sarcopenia in elderly persons without CKD.184–187 Tube feeding, intradialytic parenteral nutrition, or if necessary, total parenteral nutrition may be used for patients who are unable to take oral supplements.188,189 Tube feeding, intradialytic parenteral nutrition, and provision of amino acids through peritoneal dialysate may increase protein balance.182,190,191 Amino acids with or without glucose may be given through hemodialysate. The long-term nutritional or clinical benefits of all of these forms of nutritional support have not been well studied.191 Nutritional support for elderly ESRD patients apparently has not been examined.
Metabolic Acidemia
Although the KDOQI Nutrition and KDOQI Bone Mineral Disease Clinical Practice Guidelines recommended serum bicarbonate≥22 mEq/L,181,192 recent evidence suggests that higher pH values may be more anabolic. An arterial blood pH of 7.45–7.45 compared with 7.36–7.38 may engender more positive protein balance in CPD patients.142 CPD patients with plasma bicarbonate of 27.8±2.6 compared with 24.7±3.9 mmol/L (P=0.002) because of oral sodium bicarbonate treatment have a healthier higher subjective global assessment, increased nPNA (normalized total nitrogen appearance), and shorter hospitalizations.193 MHD patients with mean arterial pH=7.44 and predialysis plasma bicarbonate=26.1 mEq/L showed greater growth hormone sensitivity compared with MHD patients with arterial pH=7.32 and plasma bicarbonate=20.4 mEq/L.144 Moreover, a serum bicarbonate of about <23 mEq/L is associated with more rapid progression of CKD.143,194–197 We suggest that, pending additional information, serum bicarbonate should probably be maintained above 24 mEq/L, and arterial blood pH should probably be maintained above 7.38 and possibly closer to 7.44 in CKD and ESRD patients.
Anabolic Agents
Publications dating back >50 years indicate that testosterone and other androgenic steroids may increase nitrogen balance and/or decrease serum urea or net protein breakdown in advanced CKD or dialysis patients.198–201 More recent studies indicate that testosterone or other androgenic compounds may engender muscle hypertrophy and strength in dialysis patients.202–204 Nandrolone decanoate increases lean body mass (LBM), and it improves walking, stair-climbing,202 and quadriceps muscle cross-sectional area in maintenance dialysis patients.205 Androgens may increase anabolism and strength in the elderly without CKD. A meta-analysis of 11 randomized, double-blind trials in elderly men without known CKD ages 69.1±3.3 years reported that testosterone replacement significantly increased muscle strength.204 Carnitine also increases nitrogen balance in CPD patients (J.D. Kopple, unpublished observations).206
In MHD patients, GH increases muscle protein synthesis, reduces net protein catabolism,207 lowers serum urea and urea nitrogen appearance,208,209 induces positive protein balance,210,211 reduces fat mass, increases LBM,212–214 increases serum transferrin,212,214 decreases serum high-sensitivity C-reactive protein,214 improves SF-36 QOL,212 and seems to be safe.215 Not all studies report all of these positive results.216 In a small, randomized study focused on older MHD patients (mean age=73 years, range=53–92 years), GH increased muscle cross-sectional area, LBM, serum albumin, hand grip strength, and walking speed and reduced fat mass.217 Thus, GH also seems to be anabolic for elderly ESRD patients.
GH induces its anabolic effects primarily by stimulating IGF-1 production and release.218 IGF-1 may ameliorate some of the age-related derangements in neuromuscular innervation and changes in muscle fiber types,219 and it may improve excitation–contraction coupling in SKM.220 Administration of IGF-1 also reduces serum urea and urea nitrogen appearance, and it increases nitrogen balance in CPD patients.221 The side effect profile of IGF-1 is not as safe as GH, and IGF-1 has not been used in large clinical trials in CKD patients.222,223 A cautionary note in this regard, as indicated above, some genes associated with longevity may attenuate the insulin/IGF pathways.47,49,50 Whether chronic treatment with these anabolic hormones will reduce survival must be examined.
Exercise
Although many benefits are ascribed to exercise training of CKD and dialysis patients,224 the most universally observed improvement is in endurance exercise capacity. Increased strength and physical performance are probably the next most commonly reported improvements.31,205,225 Occasionally, exercise in nonelderly CKD or ESRD patients is reported to reduce inflammatory cytokines.226,227 Increased muscle mass with exercise training is described less commonly. This finding may caused by less frequent or lower intensity strength training regimens for dialysis patients or their antianabolic status.134 Muscle intracellular protein remodeling without hypertrophy seems to be common with exercise training.134 Several studies have examined exercise training in elderly CKD patients. Twelve weeks of strength training of the thigh in elderly (76±7 years) stage 4–5 CKD patients significantly increased (P<0.004) muscular strength and walking capacity to a similar extent as in elderly healthy subjects.228 MHD patients, ages 71±13 years, underwent low-intensity training of the leg and pelvic muscles.229 Patients, compared with nonexercising controls, displayed increased lower extremity strength and leg and whole-body lean mass (DEXA), reduced body fat mass, and increased activities of daily living scores.
Conclusions
This review suggests that many causes may contribute to frailty and PEW in ESRD patients, and many potential strategies may prevent or reduce the severity of these disorders. Few, if any, of these methods have been tested in large randomized clinical trials in elderly ESRD patients. Many of the mechanisms engendering these disorders (and on which prevention and treatment strategies must be based) are still not well defined. The importance of some preventive and therapeutic approaches is intuitively obvious, such as inauguratation of dialysis therapy in a timely manner before frailty or PEW develop, aggressive evidence-based treatment of superimposed illnesses, and assurance of adequate nutrient intake. However, the optimal methods for such treatments often are not well defined. For example, the indications for starting dialysis are still imprecise. Similarly, the optimal nutrient intakes for the various clinical disorders encountered by a dialysis patient are not conclusively defined. Even more relevant, the clinical benefits of most preventative and therapeutic approaches listed in the text and Table 2 have not been shown in large-scale clinical trials in which QOL, morbidity, and mortality are used as key outcomes. The large and growing numbers of elderly ESRD patients coupled with the strong association of frailty and PEW with poor QOL and high morbidity and mortality provide a strong justification for directing more research effort and resources into investigating these questions.
Disclosures
K.K.-Z. has received honoraria from Abbott Nutrition and BBraun, the manufacturers of oral nutritional supplements for dialysis patients. J.D.K. is a consultant for Nephroceuticals.
Acknowledgments
This manuscript was supported by National Institute of Diabetes, Digestive and Kidney Disease of the National Institutes of Health Research Grant R01-DK078106 and a philanthropist grant from Mr. Harold C. Simmons.
Footnotes
Published online ahead of print. Publication date available at www.jasn.org.
- Copyright © 2013 by the American Society of Nephrology
References
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- Increased Prevalence of Frailty and PEW in Elderly ESRD Patients
- Causes of Frailty and PEW in Elderly ESRD Patients
- Clinical Consequences of Frailty and PEW in Elderly ESRD Patients
- Management Strategies for Frailty and PEW in Elderly ESRD Patients
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- Functional and Cognitive Impairment, Frailty, and Adverse Health Outcomes in Older Patients Reaching ESRD--A Systematic Review
- Comparative Associations of Muscle Mass and Muscle Strength with Mortality in Dialysis Patients
- Association between Body Composition and Frailty among Prevalent Hemodialysis Patients: A US Renal Data System Special Study
- Physical Performance and All-Cause Mortality in CKD