A geriatric perspective on chronic kidney disease: The three M's

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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) A geriatric perspective on chronic kidney disease The three M’s. Harmke A. Polinder-Bos.

(3) Harmke A. Polinder-Bos A geriatric perspective on chronic kidney disease. The three M’s PhD dissertation University of Groningen, The Netherlands Financial support by the University of Groningen, Graduate School of Medical Sciences, Alzheimer Nederland, Beter Healthcare B.V., Chipsoft, Dialysis Center Groningen, Dutch Kidney Foundation, Fresenius Medical Care B.V., HMZ Fashiongroup B.V. (Lemon & Soda), and Nekst IT B.V. for the printing of this thesis is gratefully acknowledged.. ISBN: 978-94-034-1174-3 (printed version) ISBN: 978-94-034-1173-6 (digital version) Cover design: Ilse Modder, www.ilsemodder.nl Lay out and printed by: Gildeprint, Enschede © Copyright 2018 H.A. Polinder-Bos. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanically, by photocopying, recording or otherwise, without the permission of the author..

(4) A geriatric perspective on chronic kidney disease The three M’s Proefschrift A geriatric perspective onterchronic kidney disease verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen The three M’s op gezag van de rector magnificus prof. dr. E. Sterken en volgens besluit van het College voor Promoties. Proefschrift De openbare verdediging zal plaatsvinden op woensdag 9 januari 2019 om 12.45 uur ter verkrijging van de graad van doctor aan de door Rijksuniversiteit Groningen op gezag van de rector magnificus prof. dr. E. Sterken en Harmke Anthonia Bos volgens besluit van het College voor Promoties. geboren op 14 juni 1984 De openbare verdediging zal plaatsvinden op te Zeist woensdag 9 januari 2019 om 12.45 uur. door. Harmke Anthonia Bos geboren op 14 juni 1984 te Zeist.

(5) Promotores Prof. dr. C.A.J.M. Gaillard Prof. dr. R.T. Gansevoort Copromotor Dr. C.F.M. Franssen Beoordelingscommissie Prof. dr. S.E.J.A. de Rooij Prof. dr. S.J. Berger Prof. dr. P.M. ter Wee. Paranimfen E.A. Luitwieler-Blok, MSc Drs. A.C. Slotboom-Bosker.

(6) CONTENTS Chapter 1 Introduction PART I. 7. Muscle. Chapter 2 Lower body mass index and mortality risk in older adults. 31. starting dialysis Sci Rep 2018; 8(1):12858 Chapter 3 Low urinary creatinine excretion is associated with self-. 55. reported frailty in patients with advanced chronic kidney disease Kidney Int Rep 2017;2:676-685 Chapter 4 Creatinine synthesis rate and associations with muscle strength. 83. and self-reported physical health in dialysis patients Submitted PART II. Mobility. Chapter 5 High fall incidence and fracture rate in elderly dialysis patients Neth J of Med 2014;72(10):509-515 PART III. 107. Mind. Chapter 6 Hemodialysis induces an acute decline in cerebral blood flow. 125. in elderly patients J Am Soc Nephrol 2018;4:1317-1325 Chapter 7 Changes in cerebral oxygenation and cerebral blood. 155. flow during hemodialysis – a simultaneous near-infrared spectroscopy and positron emission tomography study Accepted for publication in J Cereb Blood Flow Metab Chapter 8 Summary, general discussion and future perspectives Nederlandse samenvatting - summary in Dutch Dankwoord - Acknowledgements About the author List of publications. 185 213 225 233 237.

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(8) Chapter 1 Introduction.

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(10) Introduction. General introduction Aging and CKD Worldwide, the population has aged markedly in the last decades and this process is expected to continue. At this point, 25% of the population in Europe is 60 years or older, and that proportion is projected to reach 35% in 2050 and to remain stable in the remainder of the century. 1 The other side of the coin is that the aging population has a high prevalence of comorbidities, because chronic and degenerative diseases are more common at older age. In this respect chronic kidney disease is a comorbidity of growing concern, since in older adults the prevalence of advanced stage chronic kidney disease has increased in the last decades, 2 as well as the incidence of initiation of dialysis therapy. 3, 4 In the Netherlands, the number of patients aged 65 years and older receiving dialysis therapy has increased from 2084 in 2001 to more than 4000 individuals in 2016. 5 Furthermore, 37% of all dialysis patients nowadays is 75 years or older. As a result, the advanced chronic kidney disease population has become largely a geriatric population. According the Oxford Dictionary, the definition of geriatric is ‘relating to old people, especially with regard to their healthcare’. 6 However, absolute age is not the only criterion to define a population as geriatric. Chronic kidney disease is also considered a model of accelerated aging. 7 More specifically, features of accelerated aging in chronic kidney disease include bone disease, vascular disease, arterial stiffness, chronic inflammation and oxidative stress. 8-10 These chronic kidney disease induced changes may result in a downward spiral of loss of muscle mass and function, functional decline and an accelerated loss of independence. 11, 12 As a result of aging and the aging-accelerating effects of chronic kidney disease, geriatric syndromes such as frailty, falls, sarcopenia, and cognitive impairment are common in the advanced chronic kidney disease population. The initiation of dialysis treatment might accelerate cognitive and functional decline (Figure 1). 13, 14 Patients who require skilled nursing facilities after dialysis initiation seem especially vulnerable to functional decline and early mortality. A study in these patients showed that 39% died within 6 months after dialysis initiation. Among those who survived the first six months of dialysis, a higher number of geriatric conditions, or so-called “non-disease specific problems” including cognitive impairment, depressive symptoms, exhaustion, falls, impaired mobility, and polypharmacy, was associated with a higher likelihood of functional impairment or transition to long-term care, and with a higher mortality risk. 15 Furthermore, for a substantial proportion of patients the initiation of dialysis therapy will also have a negative effect on their degree of independence. 16. 9.

(11) Chapter 1. Figure 1 Trajectory of functional status before and after the initiation of dialysis and cumulative mortality rate. Among United States nursing home residents with end-stage renal disease, the initiation of dialysis is associated with a steep decline in functional status. The dashed vertical line indicates the initiation of dialysis in a hypothetical 75-year-old person. MDS–ADL: Minimum Data Set–Activities of Daily Living. 13. Deteriorating cognitive function and the development of cognitive impairment in advanced chronic kidney disease patients has implications for their care and management. Cognitive impairment is associated with greater utilization of healthcare resources and decreased quality of life, and with poor outcomes including increased risk of disability, hospitalization, withdrawal from dialysis and death. 17, 18 It might also have a major impact on the adherence to medication and dietary prescription. Besides, cognitive dysfunction likely affects decisional capacity, which is a crucial consideration when the end-stage renal disease approaches and patients face choices regarding renal replacement therapy and treatment modalities. Therefore, assessment of cognitive function prior to deciding whether or not to start renal replacement therapy and to choose the optimal dialysis modality is necessary. In addition, follow-up on cognitive functioning after initiation of dialysis is warranted.. 10.

(12) Introduction. Where Geriatrics and Nephrology meet The term geriatrics is derived from the Greek γερων, meaning “old man”, and ’ιατρος meaning “healer”. Geriatricians are dedicated to treating the aging patient and focus on achieving the patient’s highest priorities in a context of multiple chronic conditions, and on preserving function. Geriatric medicine encompasses a holistic approach to the patient, and evaluates the physical, cognitive, affective, and social components that influence an older adult’s health. The term nephrology is derived from the Greek νεφρος meaning “kidney”, and -λογια meaning “the science or study of”. Nephrologists focus on the physiology and diseases of the kidneys, ranging from hypertension, electrolyte disturbances, to acute or chronic kidney injury and all forms of renal replacement therapy. Due to aging of the chronic kidney disease population, nephrologists increasingly have to make complex treatment decisions in older patients with comorbidities and functional and cognitive impairment. Therefore, nephrologists increasingly need to understand the unique issues of caring for an aging population. This is where geriatrics meets nephrology, and where merging the expertise of both specialties will be of added value to the patient. Providing adequate treatment for patients with advanced chronic kidney disease and geriatric syndromes requires unraveling the complex underlying mechanisms and processes. 19, 20 Sometimes it is difficult to discern whether problems and changes are age-related, disease-related, treatment-related, or are a combination of these factors, e.g. in older patients metabolic bone disease is complicated by age-related osteoporosis, and underweight might be the result of anorexia of aging, malnutrition, and, or protein energy wasting. The term ‘geriatric syndrome’ is used to capture those clinical conditions in older persons that do not ﬁt into one specific disease category. Geriatric syndromes have a substantial effect on quality of life and disability, and multiple risk factors and multiple organ systems are often involved. Geriatric syndromes often relate to Muscle (e.g. frailty and sarcopenia), to Mobility (e.g. falls), and/or to the Mind (e.g. delirium and cognitive impairment). Indeed, this thesis focuses on the three M’s, in patients with advanced chronic kidney disease.. PART I - Muscle Effects of aging and chronic kidney disease on muscle Both aging and chronic kidney disease have deteriorating effects on muscle. First, muscle inevitably undergoes remarkable changes with aging, characterized by a progressive loss of muscle mass from approximately 40 years of age onwards. Longitudinal studies showed muscle mass loss rates of 0.6–0.7% and 0.8-1.0% per year in 75 years and older aged women and men, respectively. 21 The loss of muscle strength with ag11.

(13) Chapter 1. ing occurs even at a 2-5 times faster rate than the loss of muscle mass. 22, 23 Notably, during periods of physical inactivity and immobilization, loss of skeletal muscle mass is substantially accelerated to 1 kg loss of muscle mass in 10 days, and accompanied by a major decline in strength of 0.3 to 4.2% per day. 24-27 Second, chronic kidney disease also have negative effects on muscle mass and strength. As a consequence, muscle wasting forms a hallmark in patients with chronic kidney disease. 28 Mechanisms that may predispose chronic kidney disease patients to loss of muscle mass include changes in amino acid and lipid metabolism, reduced physical activity, reduced food intake, endocrine dysfunction, defective myocyte regeneration, and upregulation of myostatin and inflammation in skeletal muscle. 29, 30 Third, the complications of chronic kidney disease (e.g., metabolic acidosis), and its therapies (e.g., dialysis) all contribute to the loss of skeletal muscle mass. 31, 32 Loss of muscle mass is also a criterion for the presence of protein energy wasting, referring to the losses of protein and energy stores in patients with chronic kidney disease. Besides loss of muscle mass, loss of muscle strength is a prevalent condition in chronic kidney disease as well. Loss of muscle strength is not solely dependent upon muscle wasting, but also on alterations in contractile quality, neural activation, and systemic inflammation. 33-36 Differences within the muscle of dialysis patients as compared to controls were already shown in hemodialysis patients with a mean age of 55 year. Hemodialysis patients had more non-contractile tissue in the muscle than controls, although the cross-sectional area of the muscle compartment in the lower leg was not significantly different. 37 Furthermore, hemodialysis patients demonstrated greater muscle fatigue as compared to controls, despite the performance of less work by about one-half of the dialysis subjects. 38 Among the consequences of accelerated muscle mass and muscle strength loss in chronic kidney disease are falls, frailty, depression, malnutrition, worse quality of life, higher risk of hospitalization, and an increased mortality (Figure 2). 39-44. Low body mass index in patients initiating dialysis An important indicator of protein energy wasting is the presence of low body weight. Low body weight could indicate a low fat mass, a low muscle mass, or both. Body weight usually is reported as body mass index (BMI), to correct for body size. Although BMI does not provide precise information about body composition, BMI can be useful for assessing protein energy wasting, especially in the low BMI spectrum where BMI is strongly correlated with lean body mass. 45 Another advantage of BMI is that it is easy to measure and requires no special equipment. In older adults, low BMI is a consistent predictor of an excess risk of mortality. 46-53 In chronic disease populations, the deleterious effect of low BMI on survival has extensively been documented, including in heart failure, chronic obstructive pulmonary disease, peripheral vascular disease, and rheumatoid arthritis. 54-58 Remarkably, a previous study failed to observe an association of BMI with 12.

(14) Introduction. long-term mortality risk in older adult patients starting dialysis. 59 This finding is striking, as it is inconsistent with the aforementioned effects of low BMI, both in the general older adult population and in chronic disease populations. Moreover, based on clinical experience an absent association of low BMI with survival in older adult dialysis patients seems counterintuitive. Mortality and cardiovascular event rates in dialysis patients are especially high in the first period after start of dialysis, and the effect of risk factors associated with mortality might therefore be different for the short versus longer-term of follow-up. 60, 61 Frailty. Physical inactivity. Sarcopenia. Impaired socialization Comorbidities. Falls. CKD. Depression. CKD Complications. Fractures. Dialysis Treatment . Hospitalization. Increasing functional dependence. Malnutrition/ PEW Earlier death. Declining quality of life. Figure 2 Clinical consequences of loss of muscle mass and function due to chronic kidney disease (CKD), CKD-associated comorbidities and inherent complications, and dialysis treatment. Clinical consequences will also influence each other negatively, e.g. a fall might lead to a fracture, increasing functional dependence and decreasing quality of life. PEW: protein energy wasting.. Measurement of muscle mass in chronic kidney disease As body weight is a crude measure of muscle mass, other methods are available to estimate muscle mass more precisely. Those muscle mass measurement methods vary from very precise -but costly- magnetic resonance imaging (MRI) to surrogate and more indirect measures including anthropometry. 31 Methods that are frequently used in research, are dual-energy X-ray absorptiometry and bioelectrical impedance, which measure lean body mass, the sum of total body water, skeletal muscle mass and the fatfree part of organs. However, important in advanced chronic kidney disease and dialysis patients, is that hydration status can affect the accuracy of those measurements. This is particularly important for dual-energy X-ray absorptiometry, because this method cannot distinguish between intracellular and extracellular (e.g. edema) fluid. 62 Besides, 13.

(15) Chapter 1. the estimation of lean body mass does not only include muscle mass but also connective tissue, nerves, and blood vessels. A proxy for muscle mass is creatinine synthesis rate and therefore skeletal muscle mass may be estimated by measuring 24h creatinine excretion.. Creatinine synthesis rate and frailty More than 98% of creatinine is derived from muscle, where it is produced and secreted at a continuous rate. 63 Creatinine in serum is excreted almost exclusively in the urine. When serum creatinine concentration is in steady state, regardless of its serum concentration, creatinine synthesis rate will equal creatinine excretion rate. Therefore, urinary creatinine excretion is an established marker of muscle mass in individuals in steady state. 63-69 Low urinary creatinine excretion has been associated with mortality in various populations including chronic kidney disease patients. 69-74 Yet, it is unclear why low creatinine excretion as a measure of muscle mass is associated with adverse health outcomes. An explanation of this association might be that a low creatinine excretion is related to frailty. Frailty is a clinical state marked by a loss of resilience and diminished capacity to respond to health stressors, and low muscle mass is an important component of frailty. 75 Frailty is common in patients with advanced chronic kidney disease and has been associated with earlier need for dialysis initiation, lower quality of life, and increased mortality risk. 43, 76-82 However, whether frailty is associated with a low urinary creatinine excretion in advanced chronic kidney disease has not yet been studied. Furthermore, reference values of urinary creatinine excretion are lacking.. Creatinine synthesis rate and muscle function Creatinine synthesis rate might not only be a measure of muscle mass, but also of muscle function. Grip strength, as a measure of muscle function, is a well-known and established predictor of all-cause and cardiovascular mortality in the general and many other populations. 83, 84 If creatinine synthesis rate would also reflect muscle function; e.g. as measured by grip strength, this might partly explain the association of creatinine synthesis rate with mortality, since muscle function has been reported to be a stronger predictor of death than muscle mass. 44, 85 In mice, a strong linear correlation between creatinine synthesis rate and myofibrillar protein mass was reported, suggesting that creatinine synthesis rate might capture information on functional and metabolic active muscle mass. 86 So far, no study has yet evaluated the relation between creatinine synthesis rate and muscle strength and physical performance. In addition, creatinine synthesis rate has hardly been studied in dialysis patients. Measuring creatinine synthesis rate in dialysis patients requires a different method compared to non-dialysis patients. Estimating creatinine synthesis rate in dialysis patients requires measurement of the creatinine removal in the dialysate, as well as the measurement of urinary creatinine 14.

(16) Introduction. excretion if the patient still produces urine. Contrary to clinical practice in peritoneal dialysis patients, dialysate is not routinely sampled in hemodialysis patients. Therefore, to accurately study creatinine synthesis rate in hemodialysis patients, the total volume of the dialysate needs to be collected during a hemodialysis session.. PART II - Mobility One of the possible consequences of loss of muscle mass and muscle strength is fall accidents (Figure 2). Falls result in a higher need for long-term institutional care, functional decline and hospitalizations. 87-90 In the Netherlands, the numbers of fall-related hospital admissions among older adults more than doubled between 1981 and 2008. 91 For community-dwelling adults aged ≥ 65 years the annual fall incidence is 30%, and 15% of them fall at least twice a year. 92-94 The elderly advanced chronic kidney disease population, and especially those receiving dialysis therapy form a high-risk population given the high prevalence of risk factors for falls, such as polypharmacy, multiple comorbidities including diabetes mellitus and cardiovascular disease, peripheral neuropathy, autonomic dysfunction, orthostatic hypotension, functional decline and cognitive impairment. 13, 95-99 Because of the adverse consequences of fall accidents, it is important to determine potential modifiable risk factors to define preventive strategies. Nevertheless, falls in older adult dialysis patients is a poorly studied topic.. PART III - Mind Cognitive impairment and dementia in advanced chronic kidney disease Evidence has accumulated that the processes leading to cognitive impairment and dementia begin in the early stages of chronic kidney disease and that there is a strong relationship between impaired cognition and decreasing kidney function. 100-107 The brain and the kidney are frequently affected by similar, commonly present risk factors such as diabetes and hypertension, and the aging process profoundly affects both. The link between decline of both kidney and brain function seems to be mediated through vascular mechanisms and vascular injury (Figure 3). 108-112 In addition, inflammation might be implicated in the cognitive decline in patients with chronic kidney disease. 113 Several studies even reported that the association between cognitive impairment and chronic kidney disease persisted after adjusting for vascular risk factors and markers of inflammation, thereby suggesting that other factors are also involved in the occurrence of cognitive impairment in chronic kidney disease. 102, 114 Besides a common shared (vascular) pathway, chronic kidney disease may be a potential accelerant of decline in 15.

(17) Chapter 1. cognitive functions. At first, associated anemia, inflammation, cerebral small vessel disease, oxidative stress, and endothelial dysfunction might have a negative effect on cognitive functioning. Besides, the biochemical and metabolic alterations associated with uremia might add to cognitive dysfunction. Studies in patient who have received kidney transplants and presumably corrected the metabolic derangements induced by chronic kidney disease showed a significant improvement in memory, psychomotor speed, and abstract reasoning immediately after a kidney transplant was reported, which persisted also after 1 year. 115, 116 A second component of cognitive impairment in chronic kidney disease is formed by associated comorbidities such as depression and obstructive sleep apnea syndrome, which are well known to affect cognitive abilities. 117-120 A third component is that chronic kidney disease therapies itself also have side effects (i.e. medication side effects, hypotension and, or low oxygenation during dialysis) that might contribute to a decline in cognitive function. In conclusion, because the underlying mechanisms are highly complex and yet partly unknown, there is a need for studies that further explore the complex pathophysiology of cognitive impairment in chronic kidney disease. Traditional risk factors: smoking, aging, hypertension, aging, diabetes mellitus, hyperlipidemia, albuminuria. Renal impairment. Vascular pathology: Strokes, lacunar infarctions, white matter lesions, atrophy, microbleeds.. Emerging risk factors: inflammation, oxidative stress, endothelial dysfunction . Dialysis treatment. Cognitive dysfunction . Abnormal calcium and phosphate metabolism Anemia Neural toxicity: uremic toxins, endogenous toxins, putative neurotoxins (e.g. parathyroid hormone) Figure 3 Potential causes of cognitive dysfunction in chronic kidney disease.. Effect of the hemodialysis procedure on the brain There is increasing evidence that the hemodialysis procedure itself might contribute to brain injury. First, it was reported that stroke incidence rose in the first month of 16.

(18) Introduction. hemodialysis in elderly patients and remained elevated afterward compared with the period before initiation of hemodialysis. 121 Second, a longer hemodialysis vintage is associated with reduced white matter integrity on MRI. 122-124 Finally, 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, providing indirect evidence that the hemodialysis procedure contributes to cerebral ischemia. 125 At present, the mechanism by which hemodialysis could contribute to brain damage is unknown. For the heart, it has been shown that hemodialysis induces a fall in myocardial blood flow resulting in subclinical myocardial ischemia. 126-128 Likewise, it can be hypothesized that a repetitive hemodialysis-induced cerebral blood flow decline may lead to (cumulative) ischemic brain lesions and thereby contribute to the accelerated cognitive decline after the initiation of hemodialysis. Although biological plausibility and a growing body of circumstantial evidence support an ischemic effect of hemodialysis on the brain, good quality mechanistic studies on the direct effect of hemodialysis on cerebral blood flow are lacking.. Cerebral oxygenation in dialysis patients The [15O]H2O positron emission tomography (PET) scan is the gold standard to quantitatively study cerebral blood flow. However, [15O]H2O PET-scanning involves radiation, requires an on-site cyclotron for nuclide generation, and is complicated to perform during a hemodialysis session. Therefore, there is a need for an alternative method that is easier to apply to monitor changes in cerebral perfusion during hemodialysis. 129, 130 A newer technique that has been proposed to monitor the adequacy of cerebral perfusion is near-infrared spectroscopy. Near infrared spectroscopy measures regional bifrontal cerebral oxygen saturation (rSO2), which is based on the difference of light absorption between oxygenated and deoxygenated hemoglobin. 131, 132 During hemodialysis, relative drops of more than 15% in rSO2 were associated with decreased executive cognitive function one year after start of hemodialysis. 133 Changes in rSO2 are commonly considered to reflect changes in cerebral blood flow, 134, 135 but whether intradialytic drops in rSO2 reflect simultaneous drops in cerebral blood flow is unknown. To our knowledge, the correlation between near infrared spectroscopy and PET has not yet been studied in chronic kidney disease patients or during hemodialysis. If near infrared spectroscopy forms a reliable noninvasive alternative to the PET-scan, this opens the door to future near infrared spectroscopy application for monitoring cerebral perfusion during hemodialysis in large cohort studies.. 17.

(19) Chapter 1. Aim and Outline of the thesis The population of patients with advanced chronic kidney disease is aging rapidly. Besides the aging process, chronic kidney disease itself is considered a model of accelerated aging. As a result, patients with advanced chronic kidney disease are more likely to develop different kinds of health problems that are non-disease specific and associated with substantial morbidity and poor outcomes. Geriatric medicine defined these health problems as ‘geriatric syndromes’, capturing those clinical conditions in older persons that do not fit into discrete disease categories and have a complex multifactorial pathophysiology. Merging the expertise of geriatricians and nephrologists might enhance the understanding of those health problems in advanced chronic kidney disease. Therefore, the general aim of this thesis is to provide a geriatric perspective on chronic kidney disease by focusing on the three M’s. Part one of this thesis focuses on muscle using several observational studies. Part two addresses mobility by studying falls in older adult dialysis patients. Part three focuses on the mind and evaluates effects of the hemodialysis procedure on brain perfusion and brain tissue oxygenation.. PART I Low BMI often not only mirrors a low fat mass, but also a low muscle mass. Although being not tissue specific, the advantage of BMI is that it requires no special equipment. Low BMI is a consistent predictor of an excess risk of mortality in elderly patients. In older adult incident dialysis patients, though, no effect of low BMI on mortality was reported. Therefore, in Chapter 2 we perform an in-depth analysis of the association of BMI with mortality risk in older incident dialysis patients to investigate whether the effect of baseline-measured BMI on mortality risk might change during follow-up time. Subsequently, in Chapter 3 we study muscle in more detail using creatinine excretion, an acknowledged marker of muscle mass. First, we define low and normal urinary creatinine excretion according a healthy population. Next, we evaluate whether low urinary creatinine excretion is increased in subjects with chronic kidney disease, and what the determinants are. In addition, we investigated whether low urinary creatinine excretion is associated with self-reported frailty in patients with advanced chronic kidney disease. Originally, the Fried frailty concept included physical measurement of handgrip strength. Therefore, in Chapter 4 we further investigate whether creatinine excretion is also associated with muscle strength, i.e. handgrip strength, and with self-reported physical health in a cohort of dialysis patients. For this study we not only collected urine but also dialysate to calculate creatinine synthesis rate as the sum of both urinary creatinine excretion and dialytic creatinine removal. 18.

(20) Introduction. PART II Fall incidents are a major problem in older people and often associated with significant morbidity and mortality. Older adult dialysis patients might especially at risk for falls given the high prevalence of risk factors for falls in this population. Nevertheless, fall accidents are a rarely studied topic in dialysis patients. Thus, Chapter 5 addresses the incidence and complications of fall incidents among older adult dialysis patients.. PART III Hemodialysis treatment might induce ischemic brain injury, but the underlying mechanisms are unclear. In Chapter 6 we study whether hemodialysis has an acute effect on cerebral blood flow by using [15O]H2O-PET scans. Because [15O]H2O-PET scanning involves radiation and is complicated to perform during hemodialysis, there is a need for an alternative method that is easier to apply during hemodialysis. 129 Near-infrared spectroscopy measures regional bifrontal cerebral oxygen saturation, and depends on cerebral blood flow, cerebral blood volume and blood oxygenation. In Chapter 7 we evaluate whether near infrared spectroscopy might be a valid alternative technique for detecting changes in cerebral blood flow during hemodialysis.. 19.

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(28) Introduction. 119. Sakaguchi Y, Shoji T, Kawabata H, Niihata K, Suzuki A, Kaneko T, Okada N, Isaka Y, Rakugi H, Tsubakihara Y: High prevalence of obstructive sleep apnea and its association with renal function among nondialysis chronic kidney disease patients in japan: A cross-sectional study. Clin J Am Soc Nephrol 6: 995-1000, 2011 120. Rock PL, Roiser JP, Riedel WJ, Blackwell AD: Cognitive impairment in depression: A systematic review and meta-analysis. Psychol Med 44: 2029-2040, 2014 121. 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 122. Zhang R, Liu K, Yang L, Zhou T, Qian S, Li B, Peng Z, Li M, Sang S, Jiang Q, Sun G: Reduced white matter integrity and cognitive deficits in maintenance hemodialysis ESRD patients: A diffusiontensor study. Eur Radiol 25: 661-668, 2015 123. Hsieh TJ, Chang JM, Chuang HY, Ko CH, Hsieh ML, Liu GC, Hsu JS: End-stage renal disease: In vivo diffusion-tensor imaging of silent white matter damage. Radiology 252: 518-525, 2009 124. Chou MC, Hsieh TJ, Lin YL, Hsieh YT, Li WZ, Chang JM, Ko CH, Kao EF, Jaw TS, Liu GC: Widespread white matter alterations in patients with end-stage renal disease: A voxelwise diffusion tensor imaging study. AJNR Am J Neuroradiol 34: 1945-1951, 2013 125. 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 126. Dasselaar JJ, Slart RH, Knip M, Pruim J, Tio RA, McIntyre CW, de Jong PE, Franssen CF: Haemodialysis is associated with a pronounced fall in myocardial perfusion. Nephrol Dial Transplant 24: 604-610, 2009 127. McIntyre CW, Burton JO, Selby NM, Leccisotti L, Korsheed S, Baker CS, Camici PG: Hemodialysisinduced cardiac dysfunction is associated with an acute reduction in global and segmental myocardial blood flow. Clin J Am Soc Nephrol 3: 19-26, 2008 128. Selby NM, Lambie SH, Camici PG, Baker CS, McIntyre CW: Occurrence of regional left ventricular dysfunction in patients undergoing standard and biofeedback dialysis. Am J Kidney Dis 47: 830841, 2006 129. MacEwen C, Watkinson P, Tarassenko L, Pugh C: Cerebral ischemia during hemodialysis-finding the signal in the noise. Semin Dial 2018 130. Wolfgram DF: Filtering the evidence: Is there a cognitive cost of hemodialysis? J Am Soc Nephrol 29: 1087-1089, 2018 131. Terborg C, Groschel K, Petrovitch A, Ringer T, Schnaudigel S, Witte OW, Kastrup A: Noninvasive assessment of cerebral perfusion and oxygenation in acute ischemic stroke by near-infrared spectroscopy. Eur Neurol 62: 338-343, 2009 132. Taussky P, O’Neal B, Daugherty WP, Luke S, Thorpe D, Pooley RA, Evans C, Hanel RA, Freeman WD: Validation of frontal near-infrared spectroscopy as noninvasive bedside monitoring for regional cerebral blood flow in brain-injured patients. Neurosurg Focus 32: E2, 2012 133. MacEwen C, Sutherland S, Daly J, Pugh C, Tarassenko L: Relationship between hypotension and cerebral ischemia during hemodialysis. J Am Soc Nephrol 2017 134. Murkin JM, & Arango M: Near-infrared spectroscopy as an index of brain and tissue oxygenation. Br J Anaesth 103 Suppl 1: i3-13, 2009 135. Holzschuh M, Woertgen C, Metz C, Brawanski A: Comparison of changes in cerebral blood flow and cerebral oxygen saturation measured by near infrared spectroscopy (NIRS) after acetazolamide. Acta Neurochir (Wien) 139: 58-62, 1997. 27.

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(30) PART I Muscle.

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(32) Chapter 2 Lower Body Mass Index and Mortality in Older Adults starting Dialysis Harmke A. Polinder-Bos1 Merel van Diepen2 Friedo W. Dekker2 Ellen K. Hoogeveen2,3 Casper F.M. Franssen1 Ron T. Gansevoort1 Carlo A.J.M Gaillard4 1 Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 2 Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. 3Department of Nephrology, Jeroen Bosch Hospital, Den Bosch, The Netherlands. 4Division of Internal Medicine and Dermatology, Department of Nephrology, University Medical Center Utrecht, University of Utrecht, The Netherlands. Sci Rep 2018; 8(1):12858.

(33) Chapter 2. ABSTRACT Lower body mass index (BMI) has consistently been associated with mortality in elderly in the general and chronic disease populations. Remarkably, in older incident dialysis patients no association of BMI with mortality was found. We performed an in-depth analysis and explored possible time-stratified effects of BMI. 908 incident dialysis patients aged ≥65 years of the NECOSAD study were included, and divided into tertiles by baseline BMI (<23.1 (lower), 23.1-26.0 (reference), ≥26.0 (higher) kg/m2). Because the hazards changed significantly during follow-up, the effect of BMI was modeled for the short-term (<1 year) and longer-term (≥1 year after dialysis initiation). During follow-up (median 3.8 years) 567 deaths occurred. Lower BMI was associated with higher short-term mortality risk (adjusted-HR 1.63 [1.14-2.32] P=0.007), and lower longer-term mortality risk (adjusted-HR 0.81 [0.63-1.04] P=0.1). 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. Thus, lower BMI is associated with increased 1-year mortality, but conditional on surviving the first year, lower BMI yielded a similar or lower mortality risk compared with the reference. Those patients with lower BMI, who had limited comorbidity and better physical functioning, had better survival.. 32.

(34) Lower body mass index and mortality in older adults starting dialysis. INTRODUCTION Underweight, defined as low body mass index (BMI), has been associated with an excess risk of mortality in older adults. 1-9 Besides in older adults, the deleterious effect of low BMI on survival has been documented in chronic disease populations, including heart failure, chronic obstructive pulmonary disease, peripheral vascular disease, and rheumatoid arthritis. 10-14 Remarkably, a previous study failed to observe an association of BMI with long-term mortality risk in elderly (≥ 65 years) patients starting dialysis. 15 This finding is striking, as it is inconsistent with the aforementioned effects of low BMI, both in the general older adult population and in chronic disease populations. Moreover, based on clinical experience an absent association of low BMI with survival in older adult dialysis patients seems counterintuitive. Mortality and cardiovascular event rate in dialysis patients are especially high in the first period after start of dialysis, and the effect of risk factors associated with mortality might therefore be different for the short versus longer-term of follow-up. 16, 17 Therefore, we conducted an in-depth exploratory analysis of the association of BMI with mortality risk in older incident dialysis patients to investigate whether the effect of baseline-measured BMI on mortality risk might change during follow-up time.. MATERIALS AND METHODS Study Design and Population For the present study data of the NECOSAD study were used. NECOSAD is an observational, prospective cohort study in which 2051 consecutive incident dialysis patients were enrolled between January 1997 and April 2004 in 38 participating dialysis centers across the Netherlands. Patients were followed from study inclusion at the start of dialysis until the end of follow-up on May 26 2009, kidney transplantation, death or until loss to follow-up. The institutional review board of the Academic Medical Hospital, Amsterdam, the Netherlands approved the study, and the institutional review boards of all participating hospitals confirmed this by an additional local approval. All patients gave written informed consent. The study was performed in accordance with the relevant guidelines and regulations. Detailed information on the design of the NECOSAD study has been published previously. 18 For this present study, we included participants who were aged ≥65 years at baseline, in whom height and weight were available. We focused on early mortality and therefore censored follow-up at four years after dialysis initiation.. 33.

(35) Chapter 2. Demographic and clinical data All demographic and clinical data were collected at start of dialysis treatment. Primary kidney disease was classified according to the codes of the European Renal Association–European Dialysis and Transplant Association (ERA-EDTA). 19 Patients were grouped into four classes of primary kidney disease: glomerulonephritis, diabetes mellitus, renal vascular disease, and other kidney diseases. Educational levels were categorized according to the International Standard Classification of Education as primary or below primary education (level 1), lower secondary education (level 2), upper secondary education (level 3), postsecondary, nontertiary or short-cycle tertiary education (level 4), bachelor master or doctorate graduate (level 5). 20 Current smokers included those who quitted smoking within the past 3 months. The subscales mobility and usual activities according the EuroQol 5-dimensional (EQ-5D) questionnaire were used as proxies of self-reported physical functioning. 21 Glomerular filtration rate (GFR) was calculated as the mean of urea and creatinine clearance, measured from 24-hour urine collections. The abbreviated modification of diet in renal disease equation was used to estimate GFR (eGFR). 24-hour urinary creatinine excretion (UCrE), as a measure for muscle mass, has previously been defined as low or normal, according the sex- and age-specific 5th percentile of a healthy population. 22. Outcome The main outcome of this study was all-cause mortality. For our analyses, we assessed time to death from the date of dialysis initiation onwards. Patient survival was censored at kidney transplantation, loss to follow-up, or at the end of follow-up. For the cause-specific analyses, cardiovascular mortality was defined as death attributable to myocardial ischemia and infarction, heart failure, cardiac arrest because of other or unknown cause, or cerebrovascular accident (ERA-EDTA codes 11, 14-16, 18, and 22). Noncardiovascular mortality was defined as all other known causes of death.. Statistical Analyses Variables are presented as mean ± SD, median (interquartile range), or number (percentage) where appropriate. Patients were stratified according baseline BMI tertiles, measured at start of dialysis. We used baseline BMI instead of repeated BMI measurements, because we were interested in the effect of pre-dialysis BMI rather than changes in BMI on mortality risk. Information on smoking, albumin, comorbidities, and dialysis modality was missing in 1-12% of cases, and missing values were imputed by multiple imputation using 10 repetitions.. 34.

(36) Lower body mass index and mortality in older adults starting dialysis. We used life tables to calculate cumulative proportions surviving during follow-up. Kaplan Meier curves were used to study the hazards for every BMI tertile. The proportional hazard (PH) assumption was tested using Schoenfeld residuals. Time-stratified Cox-regression analyses were performed to estimate the time-stratified hazard ratios (HR) and 95% confidence intervals for the mortality risks associated with BMI tertiles. Sequential models were developed to correct for different sets of confounding factors and are presented crude (model 1), and subsequently also adjusted for age, gender, race, primary kidney disease, and smoking (model 2), and additionally for albumin, systolic blood pressure, treatment modality at 3 months follow-up, and comorbidities (history of cardiovascular disease, malignancy, chronic lung disease, diabetes mellitus) (model 3). The middle BMI tertile was used as the reference. Because the hazard changed significantly over time, follow-up time was divided in the first year of follow up to model short-term mortality, and the follow-up thereafter, i.e. longer-term mortality. For the time-stratified Cox-regression analysis, we added two BMI time-stratified covariates (time <366 days * BMI tertile; time ≥366 days * BMI tertile) to the model. The different association of BMI with mortality risk according length of follow up was visualized by four-knot restricted cubic splines for the short-term and longer-term follow up separately. The knots were chosen at the 5th, 35th, 65th, and 95th percentiles of the BMI distribution. Several sensitivity analyses were performed. First, the time-stratified Cox-regression analyses were repeated without censoring for kidney transplantation, and follow-up time was extended to death after transplantation or censoring at 4 years of follow-up. Information on survival after kidney transplantation was available from the Dutch national renal data system (Renine). Secondly, the time-stratified Cox-regression analyses were repeated without adjustment for diabetes mellitus, systolic blood pressure and primary kidney disease, because those factors might be in the causal pathway between BMI and death. Thirdly, BMI was analyzed in categories according to the World Health Organization (WHO) guidelines in underweight (BMI <20 kg/m2), normal weight (BMI 20-25 kg/m2), overweight (BMI ≥25 kg/m2) or obesity (BMI ≥30), with normal weight as the reference category. Finally, we tested whether there was effect modification of dialysis modality by including an interaction term with BMI. In a post-hoc analysis, we explored characteristics of lower BMI patients who survived the first year compared with those who died, in order to identify correlates for future prognostic studies that potentially might have favored survival. Differences were tested for statistical significance using the Chi-square test, the T-test or Mann-Whitney test, as appropriate. In addition, we used logistic regression modeling (univariable and multivariable) to study potential risk factors for dying in the first year of dialysis treatment in lower BMI patients.. 35.

(37) Chapter 2. A P value <0.05 was considered statistically significant. The analyses were performed in SPSS version 23.0 (SPSS Inc, IBM company, USA), and in Stata/Se 14.2 (StataCorp LLC, USA).. RESULTS Study participants Of 2,051 patients included in NECOSAD, 925 were aged ≥65 years, and in 908 patients weight and height were available at baseline. Median age of these 908 patients was 73 years (IQR 69-77 years), and median BMI 24.5 kg/m2 (IQR 22.5-27.1 kg/m2). Three months after dialysis initiation 721 and 176 patients were receiving HD and PD treatment, respectively. Furthermore, 24-hour urinary creatinine excretion indexed by height (UCrE/ ht) as a measure of muscle mass, was lower with lower BMI both for men and women. Subjects in the middle and especially the lower BMI tertile had lower muscle mass, as measured by UCrE 22 (Table 1). Table 1 Baseline Characteristics of older incident dialysis patients according to tertiles of Body Mass Index Characteristics. Lower BMI < 23.1 kg/m2. Middle BMI 23.1-26.0 kg/m2. Higher BMI ≥26.0 kg/m2. Total N=908. N=302. N=303. N=303. Body mass index (kg/m2). 21.5 (20.3-22.3). 24.3 (23.7-25.1). 28.4 (27.1-30.6). Demographics Age (yr). 73.1 (69.2-77.4). 73.1 (69.0-76.9). 72.3 (69.1-76.5). Men (%). 195 (65). 196 (65). 172 (57). Non-Caucasian race (%). 18 (6). 17 (6). 14 (5). 17 (6). 24 (8). 20 (7). Primary kidney disease (%) Glomerulonephritis Diabetes mellitus. 24 (8). 35 (12). 71 (23). Renal vascular disease. 83 (28). 92 (30). 66 (22). Other. 178 (59). 152 (50). 146 (48). 8 (3). 9 (4). 6 (2). Educational level (%) (N=737) Level 1 Level 2. 19 (8). 18 (7). 14 (6). Level 3. 24 (10). 29 (12). 27 (11). Level 4. 91 (39). 99 (40). 96 (38). Level 5. 92 (39). 92 (37). 113 (44). Current smoking (%) (N=797). 75 (29). 51 (19). 35 (13). Systolic blood pressure (mmHg). 148 ± 25. 153 ± 35. 151 ± 23. Diastolic blood pressure (mmHg). 79 (70-85). 80 (70-86). 80 (70-86). 36.

(38) Lower body mass index and mortality in older adults starting dialysis. Table 1 Baseline Characteristics of older incident dialysis patients according to tertiles of Body Mass Index (continued) Characteristics. Lower BMI < 23.1 kg/m2. Middle BMI 23.1-26.0 kg/m2. Higher BMI ≥26.0 kg/m2. Total N=908. N=302. N=303. N=303. Mean arterial pressure (mmHg). 101 ± 14. 104 ± 15. 102 ± 14. Comorbidities (%) (N=800) Myocardial infarction. 51 (19). 63 (23). 45 (17). Heart failure. 59 (22). 60 (22). 41 (16). Diabetes mellitus. 45 (17). 62 (23). 103 (39). Peripheral vascular disease. 65 (25). 60 (22). 62 (24). Cerebrovascular accident. 32 (12). 28 (10). 35 (13). Malignancy. 49 (19). 42 (15). 34 (13). Chronic lung disease. 29 (11). 31 (11). 29 (11). Chronic infection. 6 (2). 7 (2). 3 (1). Self-reported physical functioning EQ5D mobility (%) (N=724) no limitations in walking. 62 (27). 58 (24). 48 (19). some limitations in walking. 154 (67). 174 (72). 195 (77). confined to bed. 13 (6). 10 (4). 10 (4). 52 (23). 63 (26). 39 (15). EQ5D usual activities (%) (UA) (N=721) no limitations in performing UA some limitations in performing UA. 112 (49). 112 (47). 132 (52). not able to perform UA. 65 (28). 64 (27). 82 (32). Laboratory results eGFR (ml/min) (N=699). 7.5 (5.7-9.5). 7.5 (5.9-9.7). 7.6 (6.1-9.3). Albumin (g/L) (N=829). 33.7 ± 5.9. 35.3 ± 5.6. 35.1 ± 6.0. Urea (mmol/L) (N=864). 33.7 ± 11.8. 31.1 ± 10.4. 31.4 ± 9.9. 4.2 ± 1.3. 4.5 ± 1.2. 5.0 ± 1.4. UCrE/height (mmol/24h/m) Men (N=267) Women (N=171) Low UCrE (%) (N=438) *. 3.3 ± 0.9. 3.7 ± 1.2. 3.8 ± 1.1. 81 (55). 59 (44). 56 (36). Data are expressed as mean ± SD or median (interquartile range). Educational level 1= university. *Low muscle mass was defined using a previously developed regression formula. 22 Abbreviations; eGFR, estimated glomerular filtration rate; EQ5D, EuroQol 5-dimensional questionnaire; MDRD, modification of diet in renal disease; UA, usual activities; UCrE, 24-hour urinary creatinine excretion.. 37.

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