University of Groningen A geriatric perspective on chronic kidney disease Bos, Harmke Anthonia

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(1)University of Groningen. A geriatric perspective on chronic kidney disease Bos, Harmke Anthonia. IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.. Document Version Publisher's PDF, also known as Version of record. Publication date: 2019 Link to publication in University of Groningen/UMCG research database. Citation for published version (APA): Bos, H. A. (2019). A geriatric perspective on chronic kidney disease: The three M's. Rijksuniversiteit Groningen.. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.. Download date: 27-06-2021.

(2) Chapter 8 Summary, general discussion and future perspectives.

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(4) Summary, general discussion and future perspectives. Summary The population of patients with advanced chronic kidney disease has largely become a geriatric population. Life expectancy has increased and chronic diseases including chronic kidney disease are more common in elderly individuals. Therefore, both the prevalence of advanced chronic kidney disease as well as the incidence of elderly starting dialysis therapy has grown the past years. In fact, chronic kidney disease itself is considered a model of accelerated aging. Geriatric syndromes are often present in older adults with advanced chronic kidney disease. The general aim of this thesis was to provide a geriatric perspective on chronic kidney disease. More specifically, we studied consequences of advanced chronic kidney disease on the three M’s: muscle, mobility and mind.. PART I - Muscle Low BMI could be an indicator of low muscle mass. Contrary to general and other chronic disease populations, low BMI was not associated with an excess risk of mortality in a study of incident dialysis patients. 1 Mortality and cardiovascular event rates in dialysis patients are especially high in the first period after the initiation of dialysis. Therefore, we hypothesized that the effect of low BMI on survival might be different for the short versus longer-term, and in Chapter 2 we studied possible time-dependent effects of low BMI in incident dialysis patients. Our main finding was that lower BMI conferred a higher mortality risk on the short-term (i.e. <1 year after dialysis initiation), whereas it was associated with a lower mortality on the long term, (i.e. >1 year after dialysis initiation). Furthermore, patients with lower BMI who died during the first year had significantly more comorbidity and worse self-reported physical functioning compared with those who survived the first year. Although we did not perform a prediction study, our results suggest that besides lower BMI, mobility and functional (in)dependence, low albumin levels, and comorbidities including diabetes mellitus, heart failure, and peripheral vascular disease should be included in prediction scores of short-term mortality. Next, we refined our research on body composition and outcomes in chronic kidney disease to a more specific muscle marker. To this end, we used creatinine synthesis rate, which was measured by determining the 24-hour urinary creatinine excretion, as a proxy of muscle mass. In Chapter 3, we first defined reference values of low urinary creatinine excretion using a large healthy subsample of the general-population based PREVEND study. Low urinary creatinine excretion, indexed for height, was defined as below the age- and sex-specific 5th percentile of the distribution in the healthy PREVEND sample. Subsequently, we applied this definition to a cohort of patients with advanced chronic kidney disease. For this cohort we included patients with chronic kidney disease stage 4 187.

(5) Chapter 8. (i.e. estimated glomerular filtration rate, eGFR <30ml/min/1.73m2) or stage 5 (eGFR <15 ml/min/1.73m2), not yet on dialysis, from the PREPARE-2 and NECOSAD cohorts. Applying this definition, we found that 38% of the advanced chronic kidney disease patients had a low urinary creatinine excretion. The strongest correlate of low urinary creatinine excretion was a lower kidney function. Second, we studied the association between low urinary creatinine excretion and self-reported frailty. We found that self-reported frailty was associated with low urinary creatinine excretion, independent of comorbidities. This was also true for all the individual components that define self-reported frailty, and the frailty-associated variables hemoglobin, albumin, and parathyroid hormone. As we expected, further adjusting of the models for glomerular filtration rate attenuated most associations with the individual frailty components. This finding suggests that reduced glomerular filtration rate, and thus chronic kidney disease and the complications of chronic kidney disease, might lead to muscle wasting, both directly and indirectly via weakness, slowness, physical inactivity, and exhaustion. The findings of our previous study led to the new hypothesis that urinary creatinine excretion might not only be a reflection of muscle mass, but also of muscle function and, more in general, of physical function. In Chapter 4 we investigated this hypothesis by studying associations between creatinine synthesis rate and muscle strength and selfreported measures of physical health in dialysis patients. For this study, total dialysate was collected to measure creatinine removal by the dialysis procedure, plus urinary creatinine excretion, in patients with residual renal function. Indeed, we found that higher creatinine synthesis rate was associated with higher handgrip strength in men and women. Furthermore, a higher creatinine synthesis rate was associated with better self-reported physical functioning, vitality, and physical activity, and with less fatigue and role limitation due to physical health. Thus, we concluded that creatinine synthesis rate reflects muscle function and self-reported physical health in dialysis patients. PART II - Mobility Geriatric syndromes or the so-called ‘Geriatric Giants’ are those clinical conditions in older persons that do not ﬁt into one specific disease category. In Chapter 5 we studied falls, a ‘Geriatric Giant’ that forms an important problem in older adults. We aimed to determine the incidence, complications and risk factors for falls in an elderly dialysis population. Our study showed that 55% of the patients aged ≥70 years fell at least once during a 1-year follow-up. Falls resulted in fractures in 15% of cases and in hospital admissions in 15% of patients. A lower systolic blood pressure before hemodialysis and a higher parathyroid hormone plasma concentration were identified as risk factors for falling. This study underscores that falls are an important health problem with adverse consequences in older adult dialysis patients, and therefore need the attention of ne188.

(6) Summary, general discussion and future perspectives. phrologists. Multifactorial fall prevention strategies can be applied to reduce the fall and thus complication risk. PART III - Mind Cognitive impairment is highly prevalent in patients with advanced chronic kidney disease. Interestingly, the transition to dialysis has been associated with an accelerated decline in cognitive functioning. Similar to myocardial perfusion, which declines during hemodialysis, we hypothesized that hemodialysis would also reduce brain perfusion. In Chapter 6 we reported the findings of our study on the acute effect of hemodialysis on cerebral blood flow, as measured by [15O]H2O positron emission tomography (PET) scanning. In agreement with our hypothesis, we found that hemodialysis led to a reduction in global and in regional cerebral blood flow as measured in the frontal, parietal, temporal, and occipital lobe, and the cerebellum and thalamus. Hemodialysis-related factors that were associated with a lower cerebral blood flow were a higher pH, a higher tympanic temperature, and a larger ultrafiltration volume and rate. These findings warrant followup research on the effects of modification of the dialysate bicarbonate concentration and of lowering the ultrafiltration rate by performing longer hemodialysis sessions on the preservation of cerebral blood flow during hemodialysis. In Chapter 7 we studied whether near-infrared spectroscopy would be an alternative method to detect changes in cerebral blood flow, because [15O]H2O PET-scanning involves radiation, requires an on-site cyclotron for nuclide generation, and is complicated to perform during a hemodialysis session. To this end, we estimated ΔrSO2 as the change in frontal regional oxygen saturation from before start of hemodialysis to the end of hemodialysis, as measured by near-infrared spectroscopy. Furthermore, we estimated ΔCBF as the change in frontal gray matter cerebral blood flow from before the start of hemodialysis to the end of hemodialysis, as measured by PET. In this study we found that the correlation between frontal ΔrSO2 and ΔCBF was moderate, although NIRS tended to underestimate ΔCBF. Furthermore, considerable differences were noted with regard to associations of hemodialysis- and oxygenation-related factors and markers of endothelial activation with rSO2 as compared to cerebral blood flow. Thus, near-infrared spectroscopy could be used to detect intradialytic CBF declines, although some correction factor may be needed. Furthermore, the different associations of hemodialysis- and oxygenation-related factors and markers of endothelial activation with rSO2 as compared to cerebral blood flow underscore that NIRS and PET capture different physiological parameters of the brain. Future studies are needed to evaluate the consequences of large intradialytic rSO2 declines on brain ischemia and cognitive functioning.. 189.

(7) Chapter 8. General discussion and future perspectives This thesis addresses consequences of advanced chronic kidney disease on muscle, mobility and mind. In the Discussion and Future perspectives, we will not only focus on the three individual M’s, but also speculate on how the three M’s are interconnected. Next, we will consider several interventions that might improve muscle, mobility and mind and, finally which future research is needed in patients with advanced chronic kidney disease.. Identifying low muscle mass and strength in chronic kidney disease Loss of muscle mass and of muscle strength are prevalent conditions in patients with chronic kidney disease. Consequences of loss of muscle mass and strength such as frailty, falls, immobility, loss of independence and quality of life, and ultimately mortality, that were reported in the general population 2-5 have also been demonstrated in the chronic kidney disease population. 6-11 With those consequences in mind, identification of patients with reduced muscle mass and strength is important. Although muscle strength could be easily measured, e.g. by using a hand dynamometer, this is rarely performed in clinical practice. Furthermore, consensus is lacking on the method to assess muscle mass in chronic kidney disease patients. This thesis provided an alternative definition of low muscle mass, by using a simple regression equation that defines low urinary creatinine excretion or low creatinine synthesis rate according a healthy population. The equation needs future validation in an external cohort and requires comparison with other techniques for low muscle mass identification (e.g. dual-energy X-ray absorptiometry).. Creatinine synthesis rate as a marker to monitor muscle and physical functioning Besides identifying patients with low muscle mass, creatinine synthesis rate might also be an easy applicable biomarker to detect declines in muscle mass and function, and physical functioning more in general, in patients with advanced chronic kidney disease. This thesis showed that creatinine synthesis rate was associated with self-reported frailty, and frailty-associated determinants in patients with advanced chronic kidney disease, and with muscle strength, and self-reported physical functioning, vitality, physical activity, fatigue, and role limitation due to physical health in dialysis patients. Creatinine synthesis rate is regularly estimated in non-dialysis chronic kidney disease patients, by measuring creatinine excretion in 24-hour urine samples. Nephrologists can take notice of the creatinine synthesis rate not only for the estimation of creatinine clearance by the kidney, but also as a proxy to assess (changes in) muscle mass and function. In peritoneal dialysis treatment, patients regularly collect all the spent dialysate during 24 hours, and, if applicable, also urine to estimate dialysis treatment adequacy. Thus, 190.

(8) Summary, general discussion and future perspectives. adding estimation of creatinine synthesis rate based on 24-hour dialysate and urine collections is relatively easy to perform. In hemodialysis patients, estimation of creatinine synthesis rate by measurement of creatinine excretion in the dialysate and, if applicable, also in the urine, is relatively easy to perform. Thus, due to its easy availability, creatinine synthesis rate estimation is a low-cost method, especially compared to dual-energy X-ray absorptiometry, computed tomography or MRI. Nevertheless, future research is needed to investigate the use of creatinine synthesis rate for monitoring muscle and physical health, and to study whether declines in creatinine synthesis rate are associated with adverse outcomes.. Falls in dialysis patients This thesis showed a high incidence of falls of 55% during 1-year follow-up in elderly dialysis patients, which is considerably higher than the one-year incidence of 32-41% that was reported in community-dwelling elderly aged ≥80 years. 12-15 In addition to the effects of chronic kidney disease on muscle and mobility, the dialysis procedure itself might have direct effects on muscle and mobility as well. It was reported that patients were slower to get out of their chair, had lower muscle strength, worse postural instability, and needed more time to perform the timed-up-and-go time test post-hemodialysis as compared to pre-hemodialysis. 16-18 Although it has often been hypothesized that hemodialysis patients would fall more frequently than peritoneal dialysis patients due to rapid fluid shifts during hemodialysis, recent studies showed that both have similar fall rates. 19, 20 Especially the period just after dialysis initiation, whether hemodialysis or peritoneal dialysis, might yield a large fall risk. A study among patients aged ≥67 years showed high rates of serious fall injuries both before and after hemodialysis therapy initiation. 21 Notably, the risk for a serious fall injury was 1.6-fold higher in the period after versus before hemodialysis initiation. Despite the overall lower monthly fall rates in peritoneal dialysis patients, the risk for a serious fall injury increased significantly after initiation of peritoneal dialysis and was even 4.1-fold higher in the period after versus before dialysis initiation.21. Mobility and falls in early chronic kidney disease It is more and more acknowledged that negative effects on physical ability and mobility are already present in the early stages of chronic kidney disease. Several large general population cohort studies reported associations between lower kidney function and gait impairment, slower gait speed, and lower muscle strength. 22-24 In addition, another study reported a strong and potentially causal relation between chronic kidney disease and declining mobility. In that study, metabolites of kidney function were associated with incident mobility disability. 25 Mobility disability, gait impairment and loss of muscle mass and function are all predisposing factors for falls. As a result, fall accidents in pa191.

(9) Chapter 8. tients with chronic kidney disease are not limited to those with advanced stage chronic kidney disease or those receiving dialysis therapy. In a cohort of community-dwelling older adults, the risk for serious fall injuries increased with higher levels of albuminuria. 26 Albuminuria, arising because of glomerular capillary leak and primarily caused by kidney microangiopathy, has been independently associated with cerebral small vessel disease, e.g. white matter hyperintensities, lacunar infarcts and microbleeds. 27 An extensive body of evidences suggests that white matter hyperintensities are associated with gait disturbances, mobility and falls, 28-32 thus potentially explaining the link between albuminuria and fall accidents.. Fall prevention strategies in dialysis patients A fall is often a life-changing event, the start of a downward spiral of decreasing physical functioning, dependency, and loss of quality of life. Given the complexity of falls and the interaction between many predisposing and precipitating factors, reduction of falls by applying a single intervention is an illusion. Fall prevention strategies need to be multifactorial, e.g. targeting balance and gait abnormalities, visual impairment, environmental factors, medication adverse effects, and patient and caregiver education. In independently living older adults, multifactorial and exercise interventions were shown to be effective in reducing the number of fallers, the frequency of falls, and, or fall-related injuries. 33-36 Yet, the evidence was reported to be most consistent across multiple fall-related outcomes for exercise. 33 Theoretically, fall prevention strategies in dialysis patients will be more effective if they also address specific dialysis-related fall risk factors, besides the traditional fall risk factors. Fall risk factors that were identified by this thesis and previous studies in dialysis patients include, but are not limited to, orthostatic hypotension, lower systolic blood pressure before dialysis, older age, frailty, antidepressants use, number of medications, comorbidities, ore specifically diabetes, a previous fall, malnutrition, higher parathyroid hormone, and (self-reported) frailty. 37-45 Currently, only one study examined fall prevention strategies in dialysis patients, limited to a dialysis center. 46 This study reported that after an interventional period, which included formal staff education, implementation of a fall risk assessment tool, active and passive patient education programs, and environmental modifications in the dialysis center, a remarkable reduction in falls was observed. Nevertheless, this thesis showed that only 2 (5%) of the 40 falls occurred in the dialysis center, whereas 23 (58%) falls occurred at home, and 14 (35%) outdoors. Therefore, fall prevention strategies should also focus on patient-related factors and the environment at home. By our knowledge, no such multifactorial intervention studies in dialysis patients have been reported. Similarly, exercise intervention studies to reduce fall incidents in dialysis patients have not been reported. Thus, future studies are needed to identify successful multifactorial and exercise interventions that reduce the number of fallers, fall frequency, and fall-related 192.

(10) Summary, general discussion and future perspectives. injuries in dialysis patients. Besides, caregivers should have attention for falls, especially in the period just after dialysis initiation.. Acute effects of hemodialysis on the brain The growing awareness that hemodialysis may carry significant physical costs, extends not only to muscle and mobility, but also to the mind. Especially the initiation of hemodialysis does not necessarily improve quality of life, 47 and has been associated with an increase in stroke incidence and a decline in cognitive function. 48, 49 This thesis showed that hemodialysis induced a decline in global and regional cerebral blood flow in elderly patients, which was symptomatic in one patient. This new direct evidence of an acute effect of the hemodialysis procedure on cerebral blood flow is an important step forwards in the understanding of how hemodialysis might induce brain injury. Further research is needed to explore whether (repetitive) cerebral blood flow decline are indeed associated with cognitive decline and cerebral ischemic injury in hemodialysis patients on the longer term. Furthermore, this thesis showed that a higher tympanic temperature, higher ultrafiltration volume and rate, and higher blood pH were associated with lower cerebral blood flow. These observations might form a point of departure to develop hemodialysis protocols that minimize or prevent cerebrovascular stress. It has already been shown that lowering the dialysate temperature resulted in an improvement in intradialytic hemodynamic stability and strongly attenuated the progression of white matter lesions during the first year of hemodialysis. 50 A secondary analysis of two dialysis trials, showed that more frequent hemodialysis schedules (i.e. 3 versus 6 times a week) with significantly lower ultrafiltration volumes in the 6-times group (2.2 vs. 3.1 L/session, and 2.0 vs. 2.5 L/ session) had no impact on cognitive function at 4 and 12 months follow-up. 51 However, the beneficial effects of lower ultrafiltration volumes might have been counteracted by the more frequent dialysis procedures. Furthermore, patients received cognitive testing two to three times within 1 year, which may have induced a learning effect. The presence of a learning effect is even likely since cognitive performance improved in both groups. Thus, a larger trial with as primary aim to study the effect of lower ultrafiltration volumes and, or rates on cognitive function is warranted. Finally, the role of pH in cerebral blood flow and cerebral function needs further attention, since this is a modifiable factor by changing the dialysate bicarbonate concentration.. Cerebral oxygenation monitoring during hemodialysis Cerebral oxygenation is dependent on cerebral blood flow, cerebral blood volume, and arterial oxygen content (i.e. the oxygen delivery), and on the cerebral metabolic rate (i.e. the oxygen demand). Therefore, the monitoring of cerebral oxygenation might serve as a proxy to detect declines in cerebral blood flow during hemodialysis. This thesis 193.

(11) Chapter 8. showed that the correlation between changes in rSO2, as measured by near-infrared spectroscopy, with changes in cerebral blood flow, as measured by PET, was moderate. Thus, NIRS could be used as a proxy of PET to detect intradialytic CBF changes, although some correction factor may be needed. Furthermore, the different associations of hemodialysis- and oxygenation-related factors and markers of endothelial activation with rSO2 as compared to cerebral blood flow underscore that NIRS and PET capture different physiological parameters of the brain. Apart from serving as a proxy to detect intradialytic CBF declines, intradialytic nearinfrared spectroscopy monitoring itself might provide clinically relevant information. Large rSO2 drops during hemodialysis may have clinical consequences. In our study, four patients experienced an rSO2 drop of >20% during hemodialysis. A 20% rSO2 decline has been proposed as predictor of cerebral ischemia in patients during carotid endarterectomy and cardiac surgery. 52, 53 Furthermore, a >15% drop in rSO2 during hemodialysis was shown to correlate with executive function decline at 1-year follow-up. 54 In future studies the long-term effects of a large fall in cerebral oxygenation (e.g. >15-20%) should be explored, especially in relation to incident ischemic brain lesions and the long-term course of cognitive function.. Merging the three M’s As parts of one body, muscle, mobility and mind are highly interconnected (Figure 1). The link between muscles and mobility is evident, and poor muscle strength has consistently been identified as one of the main contributors to falls. 55 Vice versa, a fall might lead to immobilization, hospitalization, fear of falling, and loss of functional independence, all factors that will promote the loss of muscle mass and strength. Without the brain there is no mobility. Yet, the influence of the mind on mobility & muscle is not limited to neuronal connections between brain and muscle. For example, cognitive impairment and dementia are established risk factors for falls. Additionally, white matter hyperintensities and loss of white matter integrity, both common in dialysis patients, are associated with gait disturbances, mobility and falls. 28-32, 56 Cerebral blood flow regulation may play an important role in the connection between mind and mobility. It has been suggested that impaired (regional) cerebral blood flow regulation, besides promoting cognitive impairment, 57-61 is also associated with alterations in gait and development of falls. 62, 63 Besides, endothelial dysfunction and microcirculatory damage may explain shared pathology of brain and muscle. Albuminuria, a marker of endothelial dysfunction and microcirculatory damage, 64 has been associated with cognitive impairment, dementia, 65 and cerebral small vessel disease. 27 Additionally, albuminuria has been associated with serious fall injuries, 26 and might even have a direct effect on muscle metabolism, 66 and physical performance. 67. 194.

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(27) Figure 1 Merging the three M’s. Connections between Muscle, Mobility and Mind: solid lines represent positive effects, whereas dotted lines represent negative effects. The beneficial effects of exercise might be mediated by myokines, improvement of endothelial dysfunction and cerebral blood flow regulation.. The opposite direction, namely an effect of mobility and muscle on mind is increasingly getting attention. Indirect evidence is provided by studies that indicate that regular physical exercise protects against cognitive decline, stroke, and the loss of cerebral volume. 68, 69 Furthermore, the benefit of physical activity in depression is generally accepted. 70 To understand this connection, it is important to acknowledge the endocrine and paracrine function of muscle. 71-73 Muscle-derived secretory proteins, so-called ‘myokines’, are released upon exercise to ‘communicate’ their energy demands to other organs. Several studies suggest myokine secretion as a mechanism behind the beneficial effects of exercise on mind. First, exercise led to elevated levels of myokine cathepsin-B, which promotes neuroplasticity and increases spatial memory abilities, and correlations were found between patient’s cathepsin-B levels and fitness, and hippocampusdependent memory functions. 74 Accordingly, another study indicated that exercise promotes neuroplasticity, 75 which is the brains’ ability to reorganize itself by forming new neuronal connections throughout life. Third, peroxisome-proliferator-activated receptor γ coactivator-1α (PGC-1α) proteins in skeletal muscle seem to play an important role in the favorable effects of exercise on depression. Exercise induces skeletal muscle 195.

(28) Chapter 8. expression of PCG-1α proteins, which are key regulators of mitochondrial biogenesis and energy metabolism. 76 A recent study showed that these exercise-induced changes in muscle PGC-1α1 favorably affected kynurenine metabolism and thereby protected from stress-induced depression. 77 As a consequence, when considering interventions to improve the three M’s in patients with advanced chronic kidney disease, it is essential to acknowledge the cross-talk between the three M’s and how they influence each other.. Future directions for improving the three M’s in patients with advanced chronic kidney disease A. Increasing physical activity Considering the aforementioned connections between the three M’s, increasing physical activity and, or physical exercise seems the most obvious intervention to improve the 3M’s in patients with chronic kidney disease. In the general population and in the chronic kidney disease population many health benefits of physical activity and exercise have been demonstrated. The health benefits include, but are not limited to, increases in muscle mass and strength, fall reduction, improvements in cognitive functioning, increased quality of life, and reduction of systemic inflammation. 78-93 Of note, studies even suggest that an increase in muscle mass, or physical activity might slow down the kidney disease progression.94-96 Thus, increasing physical activity will potentially yield very large health benefits for patients with chronic kidney disease. However, despite the robust evidence, most patients are highly inactive and regular physical activity is hardly emphasized, encouraged, or prescribed routinely by nephrologists 97, 98 or within dialysis clinics. 99-102 Changing lifestyle is probably one of the most challenging and complex processes. Doctors may try to motivate their patients by mentioning all the health benefits of e.g. smoking cessation. According Kurt Lewin (1890-1947), an influential psychologist, human behavior is an equilibrium: “a balance between driving forces that push for change and restraining forces that hold back change.” 103 He stated that if you want to achieve a change in behavior, it is more efficient to reduce restraining forces, than increase driving forces. Translated to medicine, it appears that doctors often try to motivate their patients by using the ‘driving forces’ (i.e. arguing all the health benefits), whereas addressing the ‘restraining forces’ (e.g. safety concerns, fatigue, comorbidities, or fear of pain or falling) might be more effective. Thus, knowledge of the ‘restraining forces’ is important. In hemodialysis patients several qualitative studies have been performed to explore the barriers to physical activity and exercise. 99, 101, 104-107 Patients mentioned that the availability of an individualized intradialytic exercise program that incorporates. 196.

(29) Summary, general discussion and future perspectives. education and motivation is an important facilitating factor. Besides, patients desired a culture of exercise in the dialysis unit. 104 B. Intradialytic exercise Since most hemodialysis patients visit the dialysis center three times a week for 4 hours, an intradialytic exercise program might be more feasible than participating in a training program on non-dialysis days. Besides an increase in muscle mass, muscle strength, and, or physical capacity, intradialytic exercise studies also suggested beneficial effects on intradialytic hypotension, bone mineral density, sleep quality, depression symptoms, and cognitive functioning. 108-118 Intradialytic exercise interventions that have been studied generally consist of aerobic exercise (cycling), or resistance training of some muscular groups against elastic bands, or a combination of both. Recently, studies reported on the favorable effects of intradialytic respiratory muscle training in hemodialysis patients, which were already proven in chronic obstructive pulmonary disease and heart failure patients. 119-121 Respiratory muscle training led to significant improvements in pulmonary function, respiratory muscle strength, functional capacity, and quality of life in hemodialysis patients, and showed even a greater positive effect on functional capacity than peripheral muscle training. 122-126 In conclusion, the three M’s could be improved by increasing physical activity in patients with chronic kidney disease. To achieve lifestyle changes, it might be more efficient to focus on the barriers to increase physical activity instead of pushing and arguing on all the potential health benefits. In hemodialysis patients, intradialytic exercise programs are proven to yield favorable effects on muscle, mobility and mind. Therefore, physical training during hemodialysis should be the rule, rather than the exception in dialysis clinics. C. Nutritional interventions Alongside increasing physical activity, optimization of nutritional status and decreasing protein energy wasting is warranted in chronic kidney disease patients. In general, protein supplementation has been shown to be effective for improving markers of protein energy wasting. 127 However, there is a paucity of nutritional intervention studies in chronic kidney disease, and specifically in dialysis patients. The few studies that were performed, among others by the Department of Nephrology in Groningen, showed contrasting results on the effect of nutritional supplementation, and protein supplementation in particular, on muscle mass. 128-133 Besides, it is unclear what the best source is of supplemental protein for chronic kidney disease patients with protein energy wasting. Thus, studies on nutritional interventions in chronic kidney disease are scarce and the evidence for reducing protein energy wasting is inconclusive. 197.

(30) Chapter 8. D. Bicarbonate supplementation Metabolic acidosis stimulates skeletal muscle breakdown, which may be reversed by correction of acidosis. 134-136 Studies of bicarbonate supplementation showed improvement of lower extremity muscle strength, and an increase in mid-arm muscle circumference in patients with chronic kidney disease. 137, 138 Furthermore, a number of trials are in progress that will prospectively measure the effect of bicarbonate therapy on muscle and physical function in chronic kidney disease patients.139 Bicarbonate supplementation might particularly be of interest to increase the benefits of exercise. In sports medicine, bicarbonate supplementation has been studied for many years as a way to enhance athletic performance by e.g. decreasing muscle fatigue. 140 In chronic kidney disease patients, exercise could result in transient worsening of acidosis through exercise-induced lactate generation, which in turn may reduce the benefits of exercise. Therefore, investigators evaluated muscle biopsies after a trial of combined walking exercise and standard (target plasma bicarbonate 24 mmol/L) or high bicarbonate (target plasma bicarbonate 29 mmol/L) supplementation in patients with chronic kidney disease stage 4-5, not receiving dialysis.141High dose bicarbonate supplementation resulted in an increase in the circulating bicarbonate concentration, and reduced the rise in lactate following acute exercise. Remarkably, muscle biopsies of exercise + standard bicarbonate patients showed a depletion of free amino acids after 6 months of exercise, whereas muscle biopsies of exercise + high bicarbonate patients did not. Since metabolic acidosis leads to neural networks overexcitation and is involved in cerebral autoregulation, researchers hypothesized that serum bicarbonate levels would associate with cognitive functioning. Indeed, in the Systolic BP Intervention Trial (SPRINT), a large cohort of hypertensive adults, higher serum bicarbonate concentration was independently associated with better global cognitive and executive performance. 142 Causality between low bicarbonate and cognitive impairment or whether they just share an underlying pathophysiology should be explored in a future longitudinal study. Of note, our finding of the association between a higher pH and lower cerebral blood flow is not in contrast with the findings of the SPRINT trial. Our study captured the effect of an intradialytic pH increase on cerebral blood flow, but this does not automatically imply that a higher pH would harm the brain or impair cognitive functioning. In conclusion, associations of serum bicarbonate with muscle, physical and cognitive functioning have been reported. Future trials should confirm whether bicarbonate supplementation or dietary modifications to correct metabolic acidosis consistently yield beneficial effects on muscle mass and function in patients with chronic kidney disease. Besides, bicarbonate supplementation might be needed to enhance the benefits of exercise in patients with chronic kidney disease. Insights from sports medicine in the effect of bicarbonate supplementation on muscle may be valuable for future research in chronic kidney disease. 198.

(31) Summary, general discussion and future perspectives. E. Improving endothelial function Endothelial dysfunction might explain the shared pathology of the brain and muscle in chronic kidney disease. The extremely fine-regulated endothelium is the gatekeeper of vascular health and has many roles, e.g. regulating the vessel tone. 143 Changes in the endothelium are believed to be of primary importance in atherogenesis, the underlying condition in most cardiovascular diseases. Aging, high BMI, smoking, hypertension, and metabolic diseases are known risk factors for endothelial dysfunction. 144, 145 Many interventions have been suggested or proven to improve endothelial dysfunction, which could be categorized into medication (e.g. allopurinol146-148), diet (e.g. magnesium supplementation149) or exercise. 150-152 In chronic kidney disease, the accumulation of uremic toxins contributes to oxidative stress and endothelial dysfunction. 153 Besides, hemodialysis is known to (further) induce endothelial dysfunction. 154, 155 Several interventions such as intradialytic exercise and nocturnal hemodialysis were suggested to attenuate the endothelial dysfunction. Intradialytic cycling led to an increase in serum endothelial progenitor cells, which play a role in the regeneration of vascular endothelium. 116 Furthermore, intradialytic respiratory muscle training led to a decrease in plasma syndecan-1 (a biomarker of endothelial glycocalyx derangement), and endothelin-1 (a potent vasoconstrictor) concentrations. 123 Therefore, improvement of endothelial function might be one of the mechanisms by which exercise exerts advantageous effects on the three M’s. Another option to improve endothelial function is to change the hemodialysis treatment. First, the transition from conventional hemodialysis to nocturnal hemodialysis is associated with a significant improvement in endothelial function. 156 Second, online hemodiafiltration improves endothelial function, both on the short and long-term, and reduces all-cause mortality as compared to conventional hemodialysis. 157-159 It would be interesting to study whether nocturnal hemodialysis and hemodiafiltration ultimately have relevant advantageous effects on the three M’s as compared to conventional hemodialysis. F. Closer cooperation between nephrologists and geriatricians in clinical care Finally, improvement of the three M’s and of the care for geriatric patients with advanced chronic kidney disease can be accomplished by a closer cooperation of nephrologists and geriatricians. The geriatrician can add specific knowledge and help the nephrologist when he or she is faced with patients with geriatric syndromes such as falls, frailty, and dementia. As previously mentioned, fall prevention is urgently needed in chronic kidney disease and especially in dialysis patient, and geriatricians can provide individualized fall prevention advices by a multidisciplinary approach. Furthermore, implementation of cognitive screening in advanced chronic kidney disease patients is highly recommended, 160, 161 since clinical awareness of the diagnosis of cognitive impairment was 199.

(32) Chapter 8. reported to be poor in the dialysis population. 162-164 Identification of cognitive impairment will have clinical implications, because it is associated with greater utilization of healthcare resources, decreased quality of life, and with poor outcomes. 165-168 Besides, cognitive impairment might also have a major impact on the adherence to medication and dietary instructions. Finally, a geriatric assessment can identify geriatric issues that nephrologists were not aware of. A comprehensive overview of the geriatric chronic kidney disease patient is crucial, especially when end-stage renal disease approaches and the patient face choices regarding renal replacement therapy and treatment modalities.. 200.

(33) Summary, general discussion and future perspectives. REFERENCES 1. Hoogeveen EK, Halbesma N, Rothman KJ, Stijnen T, van Dijk S, Dekker FW, Boeschoten EW, de Mutsert R, Netherlands Cooperative Study on the Adequacy of Dialysis-2 (NECOSAD) Study Group: Obesity and mortality risk among younger dialysis patients. Clin J Am Soc Nephrol 7: 280288, 2012 2. Manini TM, Visser M, Won-Park S, Patel KV, Strotmeyer ES, Chen H, Goodpaster B, De Rekeneire N, Newman AB, Simonsick EM, Kritchevsky SB, Ryder K, Schwartz AV, Harris TB: Knee extension strength cutpoints for maintaining mobility. J Am Geriatr Soc 55: 451-457, 2007 3. Visser M, Goodpaster BH, Kritchevsky SB, Newman AB, Nevitt M, Rubin SM, Simonsick EM, Harris TB: Muscle mass, muscle strength, and muscle fat infiltration as predictors of incident mobility limitations in well-functioning older persons. J Gerontol A Biol Sci Med Sci 60: 324-333, 2005 4. Newman AB, Kupelian V, Visser M, Simonsick EM, Goodpaster BH, Kritchevsky SB, Tylavsky FA, Rubin SM, Harris TB: Strength, but not muscle mass, is associated with mortality in the health, aging and body composition study cohort. J Gerontol A Biol Sci Med Sci 61: 72-77, 2006 5. Ruiz JR, Sui X, Lobelo F, Morrow JR,Jr, Jackson AW, Sjostrom M, Blair SN: Association between muscular strength and mortality in men: Prospective cohort study. Bmj 337: a439, 2008 6. Martinson M, Ikizler TA, Morrell G, Wei G, Almeida N, Marcus RL, Filipowicz R, Greene TH, Beddhu S: Associations of body size and body composition with functional ability and quality of life in hemodialysis patients. Clin J Am Soc Nephrol 9: 1082-1090, 2014 7. Carrero JJ, Chmielewski M, Axelsson J, Snaedal S, Heimburger O, Barany P, Suliman ME, Lindholm B, Stenvinkel P, Qureshi AR: Muscle atrophy, inflammation and clinical outcome in incident and prevalent dialysis patients. Clin Nutr 27: 557-564, 2008 8. Noori N, Kopple JD, Kovesdy CP, Feroze U, Sim JJ, Murali SB, Luna A, Gomez M, Luna C, Bross R, Nissenson AR, Kalantar-Zadeh K: Mid-arm muscle circumference and quality of life and survival in maintenance hemodialysis patients. Clin J Am Soc Nephrol 5: 2258-2268, 2010 9. Isoyama N, Qureshi AR, Avesani CM, Lindholm B, Barany P, Heimburger O, Cederholm T, Stenvinkel P, Carrero JJ: Comparative associations of muscle mass and muscle strength with mortality in dialysis patients. Clin J Am Soc Nephrol 9: 1720-1728, 2014 10. Beddhu S, Pappas LM, Ramkumar N, Samore M: Effects of body size and body composition on survival in hemodialysis patients. [Electronic version]. J Am Soc Nephrol 14: 2366-2372, 2003 11. Wang AY, Sherrington C, Toyama T, Gallagher MP, Cass A, Hirakawa Y, Li Q, Sukkar L, Snelling P, Jardine MJ: Muscle strength, mobility, quality of life and falls in patients on maintenance haemodialysis: A prospective study. Nephrology (Carlton) 22: 220-227, 2017 12. Tinetti ME, Speechley M, Ginter SF: Risk factors for falls among elderly persons living in the community. N Engl J Med 319: 1701-1707, 1988 13. Tromp AM, Smit JH, Deeg DJ, Bouter LM, Lips P: Predictors for falls and fractures in the longitudinal aging study amsterdam. J Bone Miner Res 13: 1932-1939, 1998 14. O’Loughlin JL, Robitaille Y, Boivin JF, Suissa S: Incidence of and risk factors for falls and injurious falls among the community-dwelling elderly. Am J Epidemiol 137: 342-354, 1993 15. Downton JH, & Andrews K: Prevalence, characteristics and factors associated with falls among the elderly living at home. Aging (Milano) 3: 219-228, 1991 16. Lockhart TE, Barth AT, Zhang X, Songra R, Abdel-Rahman E, Lach J: Portable, non-invasive fall risk assessment in end stage renal disease patients on hemodialysis. ACM Trans Comput Hum Interact : 84-93, 2010. 201.

(34) Chapter 8. 17. Soangra R, Lockhart TE, Lach J, Abdel-Rahman EM: Effects of hemodialysis therapy on sit-to-walk characteristics in end stage renal disease patients. Ann Biomed Eng 41: 795-805, 2013 18. Erken E, Ozelsancak R, Sahin S, Yilmaz EE, Torun D, Leblebici B, Kuyucu YE, Sezer S: The effect of hemodialysis on balance measurements and risk of fall. Int Urol Nephrol 48: 1705-1711, 2016 19. Farragher J, Rajan T, Chiu E, Ulutas O, Tomlinson G, Cook WL, Jassal SV: Equivalent fall risk in elderly patients on hemodialysis and peritoneal dialysis. Perit Dial Int 36: 67-70, 2016 20. Farragher J, Chiu E, Ulutas O, Tomlinson G, Cook WL, Jassal SV: Accidental falls and risk of mortality among older adults on chronic peritoneal dialysis. Clin J Am Soc Nephrol 9: 1248-1253, 2014 21. Plantinga LC, Patzer RE, Franch HA, Bowling CB: Serious fall injuries before and after initiation of hemodialysis among older ESRD patients in the united states: A retrospective cohort study. Am J Kidney Dis 70: 76-83, 2017 22. Konig M, Gollasch M, Spira D, Buchmann N, Hopfenmuller W, Steinhagen-Thiessen E, Demuth I: Mild-to-moderate chronic kidney disease and geriatric outcomes: Analysis of cross-sectional data from the berlin aging study II. Gerontology 64: 118-126, 2018 23. Odden MC, Chertow GM, Fried LF, Newman AB, Connelly S, Angleman S, Harris TB, Simonsick EM, Shlipak MG, HABC Study: Cystatin C and measures of physical function in elderly adults: The health, aging, and body composition (HABC) study. Am J Epidemiol 164: 1180-1189, 2006 24. Sedaghat S, Darweesh SKL, Verlinden VJA, van der Geest JN, Dehghan A, Franco OH, Hoorn EJ, Ikram MA: Kidney function, gait pattern and fall in the general population: A cohort study. Nephrol Dial Transplant 2018 25. Murphy RA, Moore S, Playdon M, Kritchevsky S, Newman AB, Satterfield S, Ayonayon H, Clish C, Gerszten R, Harris TB: Metabolites associated with risk of developing mobility disability in the health, aging and body composition study. J Gerontol A Biol Sci Med Sci 2017 26. Bowling CB, Bromfield SG, Colantonio LD, Gutierrez OM, Shimbo D, Reynolds K, Wright NC, Curtis JR, Judd SE, Franch H, Warnock DG, McClellan W, Muntner P: Association of reduced eGFR and albuminuria with serious fall injuries among older adults. Clin J Am Soc Nephrol 11: 1236-1243, 2016 27. Georgakis MK, Chatzopoulou D, Tsivgoulis G, Petridou ET: Albuminuria and cerebral small vessel disease: A systematic review and meta-analysis. J Am Geriatr Soc 66: 509-517, 2018 28. Annweiler C, & Montero-Odasso M: Vascular burden as a substrate for higher-level gait disorders in older adults. A review of brain mapping literature. Panminerva Med 54: 189-204, 2012 29. Holtzer R, Epstein N, Mahoney JR, Izzetoglu M, Blumen HM: Neuroimaging of mobility in aging: A targeted review. J Gerontol A Biol Sci Med Sci 69: 1375-1388, 2014 30. Zheng JJ, Delbaere K, Close JC, Sachdev PS, Lord SR: Impact of white matter lesions on physical functioning and fall risk in older people: A systematic review. Stroke 42: 2086-2090, 2011 31. Bolandzadeh N, Liu-Ambrose T, Aizenstein H, Harris T, Launer L, Yaffe K, Kritchevsky SB, Newman A, Rosano C: Pathways linking regional hyperintensities in the brain and slower gait. Neuroimage 99: 7-13, 2014 32. Rosario BL, Rosso AL, Aizenstein HJ, Harris T, Newman AB, Satterfield S, Studenski SA, Yaffe K, Rosano C, Health ABC Study: Cerebral white matter and slow gait: Contribution of hyperintensities and normal-appearing parenchyma. J Gerontol A Biol Sci Med Sci 71: 968-973, 2016 33. US Preventive Services Task F: Interventions to prevent falls in community-dwelling older adults: Us preventive services task force recommendation statement. JAMA Pages = {}, 2018 34. Gillespie LD, Robertson MC, Gillespie WJ, Sherrington C, Gates S, Clemson LM, Lamb SE: Interventions for preventing falls in older people living in the community. Cochrane Database Syst Rev (9):CD007146. doi: CD007146, 2012 202.

(35) Summary, general discussion and future perspectives. 35. Sherrington C, Michaleff ZA, Fairhall N, Paul SS, Tiedemann A, Whitney J, Cumming RG, Herbert RD, Close JCT, Lord SR: Exercise to prevent falls in older adults: An updated systematic review and meta-analysis. Br J Sports Med 51: 1750-1758, 2017 36. Tricco AC, Thomas SM, Veroniki AA, Hamid JS, Cogo E, Strifler L, Khan PA, Robson R, Sibley KM, MacDonald H, Riva JJ, Thavorn K, Wilson C, Holroyd-Leduc J, Kerr GD, Feldman F, Majumdar SR, Jaglal SB, Hui W, Straus SE: Comparisons of interventions for preventing falls in older adults: A systematic review and meta-analysis. Jama 318: 1687-1699, 2017 37. Cook WL, Tomlinson G, Donaldson M, Markowitz SN, Naglie G, Sobolev B, Jassal SV: Falls and fallrelated injuries in older dialysis patients. Clin J Am Soc Nephrol 1: 1197-1204, 2006 38. Roberts RG, Kenny RA, Brierley EJ: Are elderly haemodialysis patients at risk of falls and postural hypotension? Int Urol Nephrol 35: 415-421, 2003 39. Desmet C, Beguin C, Swine C, Jadoul M, Universite Catholique de Louvain Collaborative Group: Falls in hemodialysis patients: Prospective study of incidence, risk factors, and complications. Am J Kidney Dis 45: 148-153, 2005 40. Cook WL, & Jassal SV: Prevalence of falls among seniors maintained on hemodialysis. Int Urol Nephrol 37: 649-652, 2005 41. Li M, Tomlinson G, Naglie G, Cook WL, Jassal SV: Geriatric comorbidities, such as falls, confer an independent mortality risk to elderly dialysis patients. Nephrol Dial Transplant 23: 1396-1400, 2008 42. Abdel-Rahman EM, Yan G, Turgut F, Balogun RA: Long-term morbidity and mortality related to falls in hemodialysis patients: Role of age and gender - a pilot study. Nephron Clin Pract 118: c27884, 2011 43. Delgado C, Shieh S, Grimes B, Chertow GM, Dalrymple LS, Kaysen GA, Kornak J, Johansen KL: Association of self-reported frailty with falls and fractures among patients new to dialysis. Am J Nephrol 42: 134-140, 2015 44. Rossier A, Pruijm M, Hannane D, Burnier M, Teta D: Incidence, complications and risk factors for severe falls in patients on maintenance haemodialysis. Nephrol Dial Transplant 27: 352-357, 2012 45. McAdams-DeMarco MA, Suresh S, Law A, Salter ML, Gimenez LF, Jaar BG, Walston JD, Segev DL: Frailty and falls among adult patients undergoing chronic hemodialysis: A prospective cohort study. BMC Nephrol 14: 224-2369-14-224, 2013 46. Heung M, Adamowski T, Segal JH, Malani PN: A successful approach to fall prevention in an outpatient hemodialysis center. Clin J Am Soc Nephrol 5: 1775-1779, 2010 47. Cooper BA, Branley P, Bulfone L, Collins JF, Craig JC, Fraenkel MB, Harris A, Johnson DW, Kesselhut J, Li JJ, Luxton G, Pilmore A, Tiller DJ, Harris DC, Pollock CA, IDEAL Study: A randomized, controlled trial of early versus late initiation of dialysis. N Engl J Med 363: 609-619, 2010 48. Kurella Tamura M, Vittinghoff E, Hsu CY, Tam K, Seliger SL, Sozio S, Fischer M, Chen J, Lustigova E, Strauss L, Deo R, Go AS, Yaffe K, CRIC Study Investigators: Loss of executive function after dialysis initiation in adults with chronic kidney disease. Kidney Int 91: 948-953, 2017 49. Murray AM, Seliger S, Lakshminarayan K, Herzog CA, Solid CA: Incidence of stroke before and after dialysis initiation in older patients. J Am Soc Nephrol 24: 1166-1173, 2013 50. Eldehni MT, Odudu A, McIntyre CW: Randomized clinical trial of dialysate cooling and effects on brain white matter. J Am Soc Nephrol 26: 957-965, 2015 51. Kurella Tamura M, Unruh ML, Nissenson AR, Larive B, Eggers PW, Gassman J, Mehta RL, Kliger AS, Stokes JB, Frequent Hemodialysis Network (FHN) Trial Group: Effect of more frequent hemodialysis on cognitive function in the frequent hemodialysis network trials. Am J Kidney Dis 61: 228-237, 2013 203.

(36) Chapter 8. 52. Samra SK, Dy EA, Welch K, Dorje P, Zelenock GB, Stanley JC: Evaluation of a cerebral oximeter as a monitor of cerebral ischemia during carotid endarterectomy. Anesthesiology 93: 964-970, 2000 53. Murkin JM, Adams SJ, Novick RJ, Quantz M, Bainbridge D, Iglesias I, Cleland A, Schaefer B, Irwin B, Fox S: Monitoring brain oxygen saturation during coronary bypass surgery: A randomized, prospective study. Anesth Analg 104: 51-58, 2007 54. MacEwen C, Sutherland S, Daly J, Pugh C, Tarassenko L: Relationship between hypotension and cerebral ischemia during hemodialysis. J Am Soc Nephrol 2017 55. Guideline for the prevention of falls in older persons. american geriatrics society, british geriatrics society, and american academy of orthopaedic surgeons panel on falls prevention. J Am Geriatr Soc 49: 664-672, 2001 56. Callisaya ML, Beare R, Phan T, Blizzard L, Thrift AG, Chen J, Srikanth VK: Progression of white matter hyperintensities of presumed vascular origin increases the risk of falls in older people. J Gerontol A Biol Sci Med Sci 70: 360-366, 2015 57. Sorond FA, Hurwitz S, Salat DH, Greve DN, Fisher ND: Neurovascular coupling, cerebral white matter integrity, and response to cocoa in older people. Neurology 81: 904-909, 2013 58. Rosengarten B, Paulsen S, Burr O, Kaps M: Neurovascular coupling in alzheimer patients: Effect of acetylcholine-esterase inhibitors. Neurobiol Aging 30: 1918-1923, 2009 59. Toth P, Tarantini S, Csiszar A, Ungvari Z: Functional vascular contributions to cognitive impairment and dementia: Mechanisms and consequences of cerebral autoregulatory dysfunction, endothelial impairment, and neurovascular uncoupling in aging. Am J Physiol Heart Circ Physiol 312: H1-H20, 2017 60. Tarantini S, Hertelendy P, Tucsek Z, Valcarcel-Ares MN, Smith N, Menyhart A, Farkas E, Hodges EL, Towner R, Deak F, Sonntag WE, Csiszar A, Ungvari Z, Toth P: Pharmacologically-induced neurovascular uncoupling is associated with cognitive impairment in mice. J Cereb Blood Flow Metab 35: 1871-1881, 2015 61. Zlokovic BV: Neurovascular pathways to neurodegeneration in alzheimer’s disease and other disorders. Nat Rev Neurosci 12: 723-738, 2011 62. Sorond FA, Kiely DK, Galica A, Moscufo N, Serrador JM, Iloputaife I, Egorova S, Dell’Oglio E, Meier DS, Newton E, Milberg WP, Guttmann CR, Lipsitz LA: Neurovascular coupling is impaired in slow walkers: The MOBILIZE boston study. Ann Neurol 70: 213-220, 2011 63. Tarantini S, Yabluchanksiy A, Fulop GA, Hertelendy P, Valcarcel-Ares MN, Kiss T, Bagwell JM, O’Connor D, Farkas E, Sorond F, Csiszar A, Ungvari Z: Pharmacologically induced impairment of neurovascular coupling responses alters gait coordination in mice. Geroscience 39: 601-614, 2017 64. Stehouwer CD, & Smulders YM: Microalbuminuria and risk for cardiovascular disease: Analysis of potential mechanisms. J Am Soc Nephrol 17: 2106-2111, 2006 65. Georgakis MK, Dimitriou NG, Karalexi MA, Mihas C, Nasothimiou EG, Tousoulis D, Tsivgoulis G, Petridou ET: Albuminuria in association with cognitive function and dementia: A systematic review and meta-analysis. J Am Geriatr Soc 65: 1190-1198, 2017 66. Timmerman KL, & Volpi E: Endothelial function and the regulation of muscle protein anabolism in older adults. Nutr Metab Cardiovasc Dis 23 Suppl 1: S44-50, 2013 67. Kuo HK, Al Snih S, Kuo YF, Raji MA: Chronic inflammation, albuminuria, and functional disability in older adults with cardiovascular disease: The national health and nutrition examination survey, 1999-2008. Atherosclerosis 222: 502-508, 2012 68. Berra K, Rippe J, Manson JE: Making physical activity counseling a priority in clinical practice: The time for action is now. Jama 314: 2617-2618, 2015. 204.

(37) Summary, general discussion and future perspectives. 69. Colcombe SJ, Erickson KI, Scalf PE, Kim JS, Prakash R, McAuley E, Elavsky S, Marquez DX, Hu L, Kramer AF: Aerobic exercise training increases brain volume in aging humans. J Gerontol A Biol Sci Med Sci 61: 1166-1170, 2006 70. Lawlor DA, & Hopker SW: The effectiveness of exercise as an intervention in the management of depression: Systematic review and meta-regression analysis of randomised controlled trials. Bmj 322: 763-767, 2001 71. Giudice J, & Taylor JM: Muscle as a paracrine and endocrine organ. Curr Opin Pharmacol 34: 49-55, 2017 72. Di Raimondo D, Tuttolomondo A, Musiari G, Schimmenti C, D’Angelo A, Pinto A: Are the myokines the mediators of physical activity-induced health benefits? Curr Pharm Des 22: 3622-3647, 2016 73. Pedersen BK: Exercise-induced myokines and their role in chronic diseases. Brain Behav Immun 25: 811-816, 2011 74. Moon HY, Becke A, Berron D, Becker B, Sah N, Benoni G, Janke E, Lubejko ST, Greig NH, Mattison JA, Duzel E, van Praag H: Running-induced systemic cathepsin B secretion is associated with memory function. Cell Metab 24: 332-340, 2016 75. Zhou M, Liao H, Sreepada LP, Ladner JR, Balschi JA, Lin AP: Tai chi improves brain metabolism and muscle energetics in older adults. J Neuroimaging 2018 76. Lin J, Handschin C, Spiegelman BM: Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab 1: 361-370, 2005 77. Agudelo LZ, Femenia T, Orhan F, Porsmyr-Palmertz M, Goiny M, Martinez-Redondo V, Correia JC, Izadi M, Bhat M, Schuppe-Koistinen I, Pettersson AT, Ferreira DMS, Krook A, Barres R, Zierath JR, Erhardt S, Lindskog M, Ruas JL: Skeletal muscle PGC-1alpha1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell 159: 33-45, 2014 78. Manfredini F, Mallamaci F, D’Arrigo G, Baggetta R, Bolignano D, Torino C, Lamberti N, Bertoli S, Ciurlino D, Rocca-Rey L, Barilla A, Battaglia Y, Rapana RM, Zuccala A, Bonanno G, Fatuzzo P, Rapisarda F, Rastelli S, Fabrizi F, Messa P, De Paola L, Lombardi L, Cupisti A, Fuiano G, Lucisano G, Summaria C, Felisatti M, Pozzato E, Malagoni AM, Castellino P, Aucella F, ElHafeez SA, Provenzano PF, Tripepi G, Catizone L, Zoccali C: Exercise in patients on dialysis: A multicenter, randomized clinical trial. J Am Soc Nephrol 2016 79. Heiwe S, Tollback A, Clyne N: Twelve weeks of exercise training increases muscle function and walking capacity in elderly predialysis patients and healthy subjects. [Electronic version]. Nephron 88: 48-56, 2001 80. Barcellos FC, Santos IS, Umpierre D, Bohlke M, Hallal PC: Effects of exercise in the whole spectrum of chronic kidney disease: A systematic review. Clin Kidney J 8: 753-765, 2015 81. Castaneda C, Gordon PL, Parker RC, Uhlin KL, Roubenoff R, Levey AS: Resistance training to reduce the malnutrition-inflammation complex syndrome of chronic kidney disease. [Electronic version]. Am J Kidney Dis 43: 607-616, 2004 82. Castaneda C, Gordon PL, Uhlin KL, Levey AS, Kehayias JJ, Dwyer JT, Fielding RA, Roubenoff R, Singh MF: Resistance training to counteract the catabolism of a low-protein diet in patients with chronic renal insufficiency. A randomized, controlled trial. [Electronic version]. Ann Intern Med 135: 965-976, 2001 83. Heiwe S, & Jacobson SH: Exercise training in adults with CKD: A systematic review and metaanalysis. Am J Kidney Dis 64: 383-393, 2014 84. Cheema BS, & Singh MA: Exercise training in patients receiving maintenance hemodialysis: A systematic review of clinical trials. Am J Nephrol 25: 352-364, 2005. 205.

(38) Chapter 8. 85. Gould DW, Graham-Brown MP, Watson EL, Viana JL, Smith AC: Physiological benefits of exercise in pre-dialysis chronic kidney disease. Nephrology (Carlton) 19: 519-527, 2014 86. Moinuddin I, & Leehey DJ: A comparison of aerobic exercise and resistance training in patients with and without chronic kidney disease. Adv Chronic Kidney Dis 15: 83-96, 2008 87. Mustata S, Groeneveld S, Davidson W, Ford G, Kiland K, Manns B: Effects of exercise training on physical impairment, arterial stiffness and health-related quality of life in patients with chronic kidney disease: A pilot study. Int Urol Nephrol 43: 1133-1141, 2011 88. Kosmadakis GC, John SG, Clapp EL, Viana JL, Smith AC, Bishop NC, Bevington A, Owen PJ, McIntyre CW, Feehally J: Benefits of regular walking exercise in advanced pre-dialysis chronic kidney disease. Nephrol Dial Transplant 27: 997-1004, 2012 89. Baria F, Kamimura MA, Aoike DT, Ammirati A, Rocha ML, de Mello MT, Cuppari L: Randomized controlled trial to evaluate the impact of aerobic exercise on visceral fat in overweight chronic kidney disease patients. Nephrol Dial Transplant 29: 857-864, 2014 90. Viana JL, Kosmadakis GC, Watson EL, Bevington A, Feehally J, Bishop NC, Smith AC: Evidence for anti-inflammatory effects of exercise in CKD. J Am Soc Nephrol 25: 2121-2130, 2014 91. Greenwood SA, Koufaki P, Mercer TH, MacLaughlin HL, Rush R, Lindup H, O’Connor E, Jones C, Hendry BM, Macdougall IC, Cairns HS: Effect of exercise training on estimated GFR, vascular health, and cardiorespiratory fitness in patients with CKD: A pilot randomized controlled trial. Am J Kidney Dis 65: 425-434, 2015 92. Liu CK, Milton J, Hsu FC, Beavers KM, Yank V, Church T, Shegog JD, Kashaf S, Nayfield S, Newman A, Stafford RS, Nicklas B, Weiner DE, Fielding RA, LIFE-P Research Group: The effect of chronic kidney disease on a physical activity intervention: Impact on physical function, adherence, and safety. J Clin Nephrol Ren Care 3: 10.23937/2572-3286.1510021. Epub 2017 Feb 14, 2017 93. Watson EL, Gould DW, Wilkinson TJ, Xenophontos S, Clarke AL, Vogt BP, Viana JL, Smith AC: Twelve-week combined resistance and aerobic training confers greater benefits than aerobic training alone in nondialysis CKD. Am J Physiol Renal Physiol 314: F1188-F1196, 2018 94. Hanatani S, Izumiya Y, Araki S, Rokutanda T, Kimura Y, Walsh K, Ogawa H: Akt1-mediated fast/ glycolytic skeletal muscle growth attenuates renal damage in experimental kidney disease. [Electronic version]. J Am Soc Nephrol 25: 2800-2811, 2014 95. Robinson-Cohen C, Katz R, Mozaffarian D, Dalrymple LS, de Boer I, Sarnak M, Shlipak M, Siscovick D, Kestenbaum B: Physical activity and rapid decline in kidney function among older adults. Arch Intern Med 169: 2116-2123, 2009 96. Obermayr RP, Temml C, Knechtelsdorfer M, Gutjahr G, Kletzmayr J, Heiss S, Ponholzer A, Madersbacher S, Oberbauer R, Klauser-Braun R: Predictors of new-onset decline in kidney function in a general middle-european population. Nephrol Dial Transplant 23: 1265-1273, 2008 97. Delgado C, & Johansen KL: Deficient counseling on physical activity among nephrologists. Nephron Clin Pract 116: c330-6, 2010 98. Johansen KL, Sakkas GK, Doyle J, Shubert T, Dudley RA: Exercise counseling practices among nephrologists caring for patients on dialysis. Am J Kidney Dis 41: 171-178, 2003 99. Painter P, Clark L, Olausson J: Physical function and physical activity assessment and promotion in the hemodialysis clinic: A qualitative study. Am J Kidney Dis 64: 425-433, 2014 100. Curtin RB, Klag MJ, Bultman DC, Schatell D: Renal rehabilitation and improved patient outcomes in texas dialysis facilities. Am J Kidney Dis 40: 331-338, 2002 101. Kontos PC, Miller KL, Brooks D, Jassal SV, Spanjevic L, Devins GM, De Souza MJ, Heck C, Laprade J, Naglie G: Factors influencing exercise participation by older adults requiring chronic hemodialysis: A qualitative study. Int Urol Nephrol 39: 1303-1311, 2007 206.

(39) Summary, general discussion and future perspectives. 102. Painter P, Carlson L, Carey S, Myll J, Paul S: Determinants of exercise encouragement practices in hemodialysis staff. Nephrol Nurs J 31: 67-74, 2004 103. Lewin K: Field theory in social science: Selected theoretical papers by kurt lewin (edited by dorwin cartwright). New York: Harper & Row : 188-237, 1951 104. Jhamb M, McNulty ML, Ingalsbe G, Childers JW, Schell J, Conroy MB, Forman DE, Hergenroeder A, Dew MA: Knowledge, barriers and facilitators of exercise in dialysis patients: A qualitative study of patients, staff and nephrologists. BMC Nephrol 17: 192-016-0399-z, 2016 105. Delgado C, & Johansen KL: Barriers to exercise participation among dialysis patients. Nephrol Dial Transplant 27: 1152-1157, 2012 106. Goodman ED, & Ballou MB: Perceived barriers and motivators to exercise in hemodialysis patients. Nephrol Nurs J 31: 23-29, 2004 107. Heiwe S, & Tollin H: Patients’ perspectives on the implementation of intra-dialytic cycling--a phenomenographic study. Implement Sci 7: 68-5908-7-68, 2012 108. Rhee SY, Song JK, Hong SC, Choi JW, Jeon HJ, Shin DH, Ji EH, Choi EH, Lee J, Kim A, Choi SW, Oh J: Intradialytic exercise improves physical function and reduces intradialytic hypotension and depression in hemodialysis patients. Korean J Intern Med 2017 109. Johansen KL, Painter PL, Sakkas GK, Gordon P, Doyle J, Shubert T: Effects of resistance exercise training and nandrolone decanoate on body composition and muscle function among patients who receive hemodialysis: A randomized, controlled trial. J Am Soc Nephrol 17: 2307-2314, 2006 110. Kopple JD, Wang H, Casaburi R, Fournier M, Lewis MI, Taylor W, Storer TW: Exercise in maintenance hemodialysis patients induces transcriptional changes in genes favoring anabolic muscle. J Am Soc Nephrol 18: 2975-2986, 2007 111. Kirkman DL, Mullins P, Junglee NA, Kumwenda M, Jibani MM, Macdonald JH: Anabolic exercise in haemodialysis patients: A randomised controlled pilot study. J Cachexia Sarcopenia Muscle 5: 199-207, 2014 112. Cho JH, Lee JY, Lee S, Park H, Choi SW, Kim JC: Effect of intradialytic exercise on daily physical activity and sleep quality in maintenance hemodialysis patients. Int Urol Nephrol 50: 745-754, 2018 113. McAdams-DeMarco MA, Konel J, Warsame F, Ying H, Fernandez MG, Carlson MC, Fine DM, Appel LJ, Segev DL: Intradialytic cognitive and exercise training may preserve cognitive function. Kidney Int Rep 3: 81-88, 2017 114. Gomes Neto M, de Lacerda FFR, Lopes AA, Martinez BP, Saquetto MB: Intradialytic exercise training modalities on physical functioning and health-related quality of life in patients undergoing maintenance hemodialysis: Systematic review and meta-analysis. Clin Rehabil : 269215518760380, 2018 115. Afshar R, Emany A, Saremi A, Shavandi N, Sanavi S: Effects of intradialytic aerobic training on sleep quality in hemodialysis patients. Iran J Kidney Dis 5: 119-123, 2011 116. Liao MT, Liu WC, Lin FH, Huang CF, Chen SY, Liu CC, Lin SH, Lu KC, Wu CC: Intradialytic aerobic cycling exercise alleviates inflammation and improves endothelial progenitor cell count and bone density in hemodialysis patients. Medicine (Baltimore) 95: e4134, 2016 117. Bennett PN, Fraser S, Barnard R, Haines T, Ockerby C, Street M, Wang WC, Daly R: Effects of an intradialytic resistance training programme on physical function: A prospective stepped-wedge randomized controlled trial. Nephrol Dial Transplant 31: 1302-1309, 2016 118. DePaul V, Moreland J, Eager T, Clase CM: The effectiveness of aerobic and muscle strength training in patients receiving hemodialysis and EPO: A randomized controlled trial. Am J Kidney Dis 40: 1219-1229, 2002 207.

(40) Chapter 8. 119. Smart NA, Giallauria F, Dieberg G: Efficacy of inspiratory muscle training in chronic heart failure patients: A systematic review and meta-analysis. Int J Cardiol 167: 1502-1507, 2013 120. Gosselink R, De Vos J, van den Heuvel SP, Segers J, Decramer M, Kwakkel G: Impact of inspiratory muscle training in patients with COPD: What is the evidence? Eur Respir J 37: 416-425, 2011 121. Kawauchi TS, Umeda IIK, Braga LM, Mansur AP, Rossi-Neto JM, Guerra de Moraes Rego Sousa,A., Hirata MH, Cahalin LP, Nakagawa NK: Is there any benefit using low-intensity inspiratory and peripheral muscle training in heart failure? A randomized clinical trial. Clin Res Cardiol 106: 676-685, 2017 122. Pellizzaro CO, Thome FS, Veronese FV: Effect of peripheral and respiratory muscle training on the functional capacity of hemodialysis patients. Ren Fail 35: 189-197, 2013 123. Campos NG, Marizeiro DF, Florencio ACL, Silva IC, Meneses GC, Bezerra GF, Martins AMC, Liborio AB: Effects of respiratory muscle training on endothelium and oxidative stress biomarkers in hemodialysis patients: A randomized clinical trial. Respir Med 134: 103-109, 2018 124. de Medeiros AIC, Fuzari HKB, Rattesa C, Brandao DC, de Melo Marinho PE: Inspiratory muscle training improves respiratory muscle strength, functional capacity and quality of life in patients with chronic kidney disease: A systematic review. J Physiother 63: 76-83, 2017 125. El-Deen HAB, Alanazi FS, Ahmed KT: Effects of inspiratory muscle training on pulmonary functions and muscle strength in sedentary hemodialysis patients. J Phys Ther Sci 30: 424-427, 2018 126. Pomidori L, Lamberti N, Malagoni AM, Manfredini F, Pozzato E, Felisatti M, Catizone L, Barilla A, Zuccala A, Tripepi G, Mallamaci F, Zoccali C, Cogo A: Respiratory muscle impairment in dialysis patients: Can minimal dose of exercise limit the damage? A preliminary study in a sample of patients enrolled in the EXCITE trial. J Nephrol 29: 863-869, 2016 127. Kalantar-Zadeh K, Cano NJ, Budde K, Chazot C, Kovesdy CP, Mak RH, Mehrotra R, Raj DS, Sehgal AR, Stenvinkel P, Ikizler TA: Diets and enteral supplements for improving outcomes in chronic kidney disease. Nat Rev Nephrol 7: 369-384, 2011 128. Martin-Alemany G, Valdez-Ortiz R, Olvera-Soto G, Gomez-Guerrero I, Aguire-Esquivel G, Cantu-Quintanilla G, Lopez-Alvarenga JC, Miranda-Alatriste P, Espinosa-Cuevas A: The effects of resistance exercise and oral nutritional supplementation during hemodialysis on indicators of nutritional status and quality of life. Nephrol Dial Transplant 31: 1712-1720, 2016 129. Dong J, Sundell MB, Pupim LB, Wu P, Shintani A, Ikizler TA: The effect of resistance exercise to augment long-term benefits of intradialytic oral nutritional supplementation in chronic hemodialysis patients. J Ren Nutr 21: 149-159, 2011 130. Perez-Torres A, Gonzalez Garcia E, Garcia-Llana H, Del Peso G, Lopez-Sobaler AM, Selgas R: Improvement in nutritional status in patients with chronic kidney disease-4 by a nutrition education program with no impact on renal function and determined by male sex. J Ren Nutr 27: 303-310, 2017 131. Oguz Y, Bulucu F, Vural A: Oral and parenteral essential amino acid therapy in malnourished hemodialysis patients. Nephron 89: 224-227, 2001 132. Beddhu S, Filipowicz R, Chen X, Neilson JL, Wei G, Huang Y, Greene T: Supervised oral protein supplementation during dialysis in patients with elevated C-reactive protein levels: A two phase, longitudinal, single center, open labeled study. BMC Nephrol 16: 87-015-0070-0, 2015 133. Kloppenburg WD, Stegeman CA, Hovinga TK, Vastenburg G, Vos P, de Jong PE, Huisman RM: Effect of prescribing a high protein diet and increasing the dose of dialysis on nutrition in stable chronic haemodialysis patients: A randomized, controlled trial. Nephrol Dial Transplant 19: 1212-1223, 2004. 208.

(41) Summary, general discussion and future perspectives. 134. Mitch WE: Metabolic and clinical consequences of metabolic acidosis. J Nephrol 19 Suppl 9: S70-5, 2006 135. Graham KA, Reaich D, Channon SM, Downie S, Goodship TH: Correction of acidosis in hemodialysis decreases whole-body protein degradation. J Am Soc Nephrol 8: 632-637, 1997 136. Reaich D, Channon SM, Scrimgeour CM, Goodship TH: Ammonium chloride-induced acidosis increases protein breakdown and amino acid oxidation in humans. Am J Physiol 263: E735-9, 1992 137. de Brito-Ashurst I, Varagunam M, Raftery MJ, Yaqoob MM: Bicarbonate supplementation slows progression of CKD and improves nutritional status. J Am Soc Nephrol 20: 2075-2084, 2009 138. Abramowitz MK, Melamed ML, Bauer C, Raff AC, Hostetter TH: Effects of oral sodium bicarbonate in patients with CKD. Clin J Am Soc Nephrol 8: 714-720, 2013 139. Witham MD, & Lamb EJ: Should chronic metabolic acidosis be treated in older people with chronic kidney disease? Nephrol Dial Transplant 31: 1796-1802, 2016 140. Siegler JC, Marshall PW, Bishop D, Shaw G, Green S: Mechanistic insights into the efficacy of sodium bicarbonate supplementation to improve athletic performance. Sports Med Open 2: 41016-0065-9. Epub 2016 Oct 11, 2016 141. Watson EL, Kosmadakis GC, Smith AC, Viana JL, Brown JR, Molyneux K, Pawluczyk IZ, Mulheran M, Bishop NC, Shirreffs S, Maughan RJ, Owen PJ, John SG, McIntyre CW, Feehally J, Bevington A: Combined walking exercise and alkali therapy in patients with CKD4-5 regulates intramuscular free amino acid pools and ubiquitin E3 ligase expression. Eur J Appl Physiol 113: 2111-2124, 2013 142. Dobre M, Gaussoin SA, Bates JT, Chonchol MB, Cohen DL, Hostetter TH, Raphael KL, Taylor AA, Lerner AJ, Wright JT J, Rahman M, SPRINT Research Group: Serum bicarbonate concentration and cognitive function in hypertensive adults. Clin J Am Soc Nephrol 13: 596-603, 2018 143. Deanfield JE, Halcox JP, Rabelink TJ: Endothelial function and dysfunction: Testing and clinical relevance. Circulation 115: 1285-1295, 2007 144. Celermajer DS, Sorensen KE, Spiegelhalter DJ, Georgakopoulos D, Robinson J, Deanfield JE: Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women. J Am Coll Cardiol 24: 471-476, 1994 145. Benjamin EJ, Larson MG, Keyes MJ, Mitchell GF, Vasan RS, Keaney JF,Jr, Lehman BT, Fan S, Osypiuk E, Vita JA: Clinical correlates and heritability of flow-mediated dilation in the community: The framingham heart study. Circulation 109: 613-619, 2004 146. Cicero AFG, Pirro M, Watts GF, Mikhailidis DP, Banach M, Sahebkar A: Effects of allopurinol on endothelial function: A systematic review and meta-analysis of randomized placebo-controlled trials. Drugs 78: 99-109, 2018 147. Kanbay M, Huddam B, Azak A, Solak Y, Kadioglu GK, Kirbas I, Duranay M, Covic A, Johnson RJ: A randomized study of allopurinol on endothelial function and estimated glomular filtration rate in asymptomatic hyperuricemic subjects with normal renal function. Clin J Am Soc Nephrol 6: 18871894, 2011 148. Yelken B, Caliskan Y, Gorgulu N, Altun I, Yilmaz A, Yazici H, Oflaz H, Yildiz A: Reduction of uric acid levels with allopurinol treatment improves endothelial function in patients with chronic kidney disease. Clin Nephrol 77: 275-282, 2012 149. Darooghegi Mofrad M, Djafarian K, Mozaffari H, Shab-Bidar S: Effect of magnesium supplementation on endothelial function: A systematic review and meta-analysis of randomized controlled trials. Atherosclerosis 273: 98-105, 2018 150. Schmidt W, Endres M, Dimeo F, Jungehulsing GJ: Train the vessel, gain the brain: Physical activity and vessel function and the impact on stroke prevention and outcome in cerebrovascular disease. Cerebrovasc Dis 35: 303-312, 2013 209.

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