Nephrol Dial Transplant (2021) 37: ii23 –ii32 doi: 10.1093/ndt/gfab262 LEADING EUROPEAN NEPHROLOGY NEPHROLOGY DIALYSIS TRANSPLANTATION Cognitive disorders in patients with chronic kidney disease: specificities of clinical assessment REVIEW Marion Pépin1,2, Ana Carina Ferreira 3,4, Mustafa Arici5, Maie Bachman6, Michelangela Barbieri7, Inga Arune Bumblyte8, Sol Carriazo 9, Pilar Delgado10, Liliana Garneata11, Konstantinos Giannakou12, Olivier Godefroy13, Tomasz Grodzicki 14, Aleksandra Klimkowicz-Mrowiec14, Justina Kurganaite 8, Sophie Liabeuf 15,16, Carmen Antonia Mocanu11, Giuseppe Paolisso7,17, Goce Spasovski18, Evgueniy Stefanov Vazelov19, Davide Viggiano20, Carmine Zoccali 21,22, Ziad A. Massy1,23 and Andrzej WieR cek24; the CONNECT Action (Cognitive Decline in Nephro-Neurology European Cooperative Target) 1 Paris-Saclay University, UVSQ, Inserm, Clinical Epidemiology Team, Centre de Recherche en Epidémiologie et Santé des Populations (CESP), Villejuif, France, 2Department of Geriatrics, Ambroise Paré University Medical Center, APHP, Boulogne-Billancourt, France, 3Department of Nephrology, Centro Hospitalar e Universitário de Lisboa Central–Hospital Curry Cabral, Lisbon, Portugal, 4Department of Nephology, Universidade Nova de Lisboa–Faculdade de Ciências Médicas, Lisbon, Portugal, 5Department of Internal Medicine, Division of Nephrology, Faculty of Medicine, Hacetepe University, Ankara, Turkey, 6Department of Health Technologies, School of Information Technologies, Tallinn University of Technology, Tallinn, Estonia, 7Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy, 8Department of Nephrology, Lithuanian University of Health Sciences, Kaunas, Lithuania, 9Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, Madrid, Spain, 10Department of Neurology, Vall d’Hebron Hospital, Universitat Autonoma de Barcelona, Barcelona, Spain, 11Department of Internal Medicine and Nephrology, “Carol Davila” University of Medicine and Pharmacy, “Dr Carol Davila” Teaching Hospital of Nephrology, Bucharest, Romania, 12Department of Health Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus, 13Department of Neurology, Amiens University Hospital, and Laboratory of Functional Neurosciences (UR UPJV 4559), Jules Verne University of Picardie, Amiens, France, 14Department of Internal Medicine and Gerontology, Jagiellonian University Medical College, Cracow, Poland, 15Department of Pharmacology, Amiens University Medical Center, Amiens, France, 16MP3CV Laboratory, EA7517, University of Picardie Jules Verne, Amiens, France, 17Mediterranea Cardiocentro, Naples, Italy, 18Department of Nephrology, Clinical Centre “Mother Theresa”, Saints Cyril and Methodius University, Skopje, North Macedonia, 19Dialysis Clinic of UMHAT “Alexandrovska”, Sofia Medical University, Sofia, Bulgaria, 20Department of Nephrology, University of Campania “Luigi Vanvitelli”, Naples; BIOGEM, Ariano Irpino, Italy, 21Renal Research Institute, New York, NY, USA, 22Associazione Ipertensione Nefrologia Trapianto Renale, Reggio Calabria, Italy, 23 Department of Nephrology, Ambroise Paré University Medical Center, APHP, Paris, France and 24Department of Nephrology, Transplantation and Internal Medicine, Medical University of Silesia, Katowice, Poland, Correspondence to: Marion Pépin; E-mail: marion.pepin@aphp.fr ABSTRACT these patients. Here we review clinical warning signs that should Neurocognitive disorders are frequent among chronic kidney lead to cognitive screening; conditions frequent in CKD at risk disease (CKD) patients. Identifying and characterizing cognitive to interfere with cognitive testing or performance, including impairment (CI) can help to assess the ability of adherence to specificities of cognitive assessment in dialysis patients or after CKD risk reduction strategy, identify potentially reversible kidney transplantation; and available tests for screening and ob- causes of cognitive decline, modify pharmacotherapy, educate served cognitive patterns in CKD patients. the patient and caregiver and provide appropriate patient and caregiver support. Numerous factors are associated with the de- Keywords: chronic kidney disease, clinical assessment, cogni- velopment and progression of CI in CKD patients and various tive impairment, cognitive screening test, comprehensive conditions can influence the results of cognitive assessment in battery C The Author(s) 2021. Published by Oxford University Press on behalf of ERA. V This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re- use, please contact journals.permissions@oup.com ii23 GRAPHICAL ABSTRACT INTRODUCTION primarily cognitive disorders, acquired and progressive [5]. Chronic kidney disease (CKD) is a major public health problem Deterioration can affect one of the following six cognitive with a high global incidence and prevalence, with important domains: complex attention, executive function, learning and multisystemic complications leading to poor outcomes and memory, language, perceptual motor and social cognition. In high-cost treatments [1]. According to Kidney Disease: mild NCD [corresponding to the state usually called ‘mild cog- nitive impairment’ (MCI)], the individual remains functionally Improving Global Outcomes, CKD is defined as abnormalities independent, while in major NCD (subsumes the entity called of kidney structure or function present for >3 months with ‘dementia’), CI is severe enough to compromise social and/or implications for health. The following criteria determine the occupational functioning [6]. Cognitively impaired CKD diagnosis: decreased glomerular filtration rate (GFR; <60 mL/ patients often exhibit executive dysfunction that would be min/1.73 m2) or evidence of kidney damage such as albumin- expected in vascular NCD, but CKD patients are also at higher uria, tubular disorders, urine sediment abnormalities, structural risk of Alzheimer’s disease and mortality compared with the deviations detected by histology or by imaging methods or a general population [7]. CI is associated with adverse outcomes history of kidney transplantation. The reduction of GFR and and financial and social costs, including caregiver burden. CKD increased albuminuria have a crucial role in the development of patients [especially when under renal replacement therapy complications of CKD, and for this reason the disease is (RRT)] could benefit from cognitive screening. Identifying CI classified in five stages based on the GFR and risk levels are in patients with CKD can help to assess the ability to adhere to subclassified according to albuminuria levels [1]. CKD stages a CKD risk reduction strategy, identify potentially reversible are associated with all-cause death, cardiovascular death, anae- causes of dementia, modify pharmacotherapy, educate the pa- mia and bone and mineral disorders, among other complica- tient and caregiver and provide appropriate patient and care- tions [2]. The prevalence of CKD and cognitive impairment giver support. The potential benefits of screening likely (CI) both increase with age. Cognitive changes occur early in outweigh the possible risks associated with identification, such CKD, when GFR decreases to <60 mL/min/1.73 m2 or even be- as negative reaction to the diagnosis or stigma resulting from a fore [3, 4]. diagnosis of dementia. We aim to review the specificities of clin- The latest version of the Diagnostic and Statistical Manual of ical assessment for cognitive disorders in CKD patients: clinical Mental Disorders defined neurocognitive disorder (NCD) as warning signs that should lead to cognitive screening; ii24 M. Pépin et al. conditions frequent in CKD that may interfere with cognitive Demographic and psychosocial factors . Demographic fac- testing or performance, including specificities of cognitive as- tors such as lower education status, gender and age are key fac- sessment in dialysis patients or after kidney transplantation; tors affecting the results of cognitive testing in the general and available tests for cognitive screening and observed cogni- population. Advancing age, a lower educational level and fe- tive patterns in CKD patients. male gender are associated with poorer performance [15]. However, the impact of such factors on cognitive testing among Warning signs of cognitive decline in CKD patients CKD patients is limited [16]. Psychosocial factors including so- Neurological complications frequently become clinically evi- cial support, socio-economic care and access to healthcare were dent in advanced stages of the disease, therefore early detection also found to influence cognitive functioning in the general and management of these conditions could reduce their impact population. Similarly, data are limited regarding such factors at later stages [8]. Of interest, subjective cognitive complaints and CI in this patient population. Of note, marital status, reli- are not highly correlated with the presence of objective CI in gious activity and employment were found to influence psycho- end-stage renal disease (ESRD), highlighting the importance of social adjustment to dialysis treatment and the risk for periodic screening for early identification of CI that may lead to developing depression among dialysis patients [17]. targeted interventions and timely discussions with the patient and his/her family [4, 9, 10]. Nephrologists and other clinicians Drug-related factors, sleep and depression. Multiple med- may rely on their clinical judgement to obtain appropriate ications are required in CKD patients and the optimal dosing of diagnoses. Of note, a previous study reported that mental several medications is unclear, therefore these patients could be impairment among haemodialysis (HD) patients was poorly more susceptible to potential adverse drug effects and interac- recognized by healthcare providers/HD technicians, even tions between medications [18]. Some medications are associ- though they reported spending an average of 47 min with ated with CI in CKD patients, such as H1-receptor antagonists each patient during each of the twice- or thrice-weekly and opioids, probably because of their anticholinergic effect treatments [11]. [19]. If possible, unnecessary or ineffective medications with History taking and physical examination in conjunction central nervous system activity should be discontinued [19]. In with neuropsychological testing can accurately identify cogni- addition, sleep disturbances are often underdiagnosed and tive declines. Caregivers and family often notice cognitive defi- undertreated in CKD patients, which can impact cognitive cits before they are apparent to clinicians. Therefore history function (e.g. memory and concentration), leading to excessive taking from both the patient and caregiver/family is important daytime fatigue and sleepiness, impairing cognitive abilities di- for accurate reports on the onset, duration and severity of cog- rectly [20]. Sleep-disordered breathing (sleep apnoea) was also nitive and behavioural deficits, the presence of functional found to affect cognitive testing in CKD patients [21]. Lastly, impairments and other symptoms (e.g. sleep disturbance, depression was found to be highly prevalent in dialysis patients depression, etc.) or other events including unexplained falls or compared with the general population, with most studies esti- confusion about medication [10, 12]. Of note, caregiver- mating that 20–30% of such individuals are depressed [22, 23]. reported sleep disturbances are frequently associated with early Even though depression is relatively common in patients with stages of dementia and might be considered as warning signs of all stages of CKD, it remains significantly underdiagnosed [20, cognitive deterioration [13]. The examiner should look for focal 24]. Depression may influence the results of cognitive testing neurological deficits such as tremors, bradykinesia or rigidity and hence assessment of depression and anxiety should be part suggestive of previous stroke and signs of parkinsonism [10]. of all neuropsychological evaluations [25]. Assessment of functionality in everyday activities and mobil- Factors associated with impaired cognitive performance ity performance metrics such as the gait speed assessment could also offer hints of cognitive decline. For instance, mobility per- Biologic intrinsic-related factors. Anaemia has been linked formance metrics that involved multifaceted coordination be- with cognitive deficiency in both CKD and the elderly [26]. tween different parts of neuropsychology, such as cumulated This might be due to a decreased blood haemoglobin concen- posture duration and postural transition, could assist in dis- tration that leads to reduced oxygen delivery to the brain, with a criminating those with and without CI [14]. CI suspicion may detrimental effect on brain metabolism, or could be because lead to a global and comprehensive patient assessment, espe- once the blood haemoglobin concentration declines, cerebral cially screening for factors affecting cognitive performance. blood flow increases from normal to high levels, resulting in in- Older CKD patients might benefit from a nephrology-tailored creased distribution of uraemic toxins to the brain. Of interest, comprehensive geriatric assessment including a cognitive as- early small-scale studies have shown cognitive improvement sessment [15]. with the treatment of anaemia in CKD patients; however, it remains undetermined whether this is because of the improve- Conditions affecting cognitive assessment in CKD ment in the blood count or due to an independent effect of sup- patients plementation with erythropoiesis-stimulating agents (ESAs) Numerous factors can affect the results of cognitive assess- [27]. This observation was not confirmed in more recent large- ment and cause deviations from the ‘norm’ in the psychometric scale studies, where ESAs have not shown the expected benefi- definition. These factors should be considered when interpret- cial clinical cognitive effects in CKD patients. Also, putative ing results in patients with CKD. neurotoxins, including parathyroid hormone and by-products Cognitive disorders in patients with CKD ii25 of nitrogen metabolism, have also been mentioned as possible independent risk factor for future cerebral and vascular mor- mediating factors of CI in CKD, but the underlying mecha- bidity and incident dementia in both CKD/dialysis patients and nisms are not well understood [28]. Interestingly, recent find- the general population [39–41]. Previous magnetic resonance ings on the role of the glymphatic system, which clears the imaging studies have indicated that clinically silent white matter brain of protein waste products, primarily during sleep, offer hyperintensities of presumed vascular origin appear in 50% of pathophysiological hypotheses in CKD patients [13]. The link patients with CKD [41, 42] and relate to deficits in the cognitive between uraemic toxins and cognitive disorders is described in domains of executive function and processing speed, suggesting detail in a parallel article in this supplement (Liabeuf et al., a subcortical, vascular pattern of CI. Notably, established risk NDT 2021). Evidence data about albuminuria as a risk factor factors for white matter disease in CKD include advanced age, for CI and dementia are also detailed in another article in this hypertension and smoking [41]. Other lesions may be involved supplement (Hafez et al. NDT 2021). besides lacunar infarcts and white matter hyperintensities, such as brain microbleeds or atrophy related to cerebral small vessel Amino acids. Amino acids have a multifaceted physiological disease. significance in addition to being the main building material in protein synthesis. Plasma levels of homocysteine, cysteine Cardiac arrhythmias. CVDs frequently occur in CKD and cysteine sulfinic acid are elevated in uraemia and the patients [43]. CKD is combined with haemodynamic changes, percentages of protein-bound homocysteine and cysteine are which might further contribute to the negative changes in car- higher in uraemic dialysis patients than in conservatively diac structure. In particular, it has been reported that 50% of all treated patients. Elevated homocysteine levels have been associ- patients affected by CKD Stages 4 and 5 have CVD and cardio- ated with impairment and decline on tests of cognitive function. vascular mortality accounts for almost 50% of all deaths in Hyperhomocysteinaemia and low taurine levels are probably CKD patients (Stages 4 and 5) compared with 26% of age- involved in the pathogenesis of concomitant cardiovascular matched healthy control subjects [43]. Focusing on myocardial and cerebrovascular diseases in patients with CKD. alterations, left ventricular hypertrophy (LVH) is present in al- Supplementation with vitamin B (combinations containing B6, most 30% of CKD patients, a prevalence that increases up to B12 and folic acid) in the Homocysteine Study to some extent 70–80% in CKD Stage 5 patients [44]. LVH was associated with corrected hyperhomocysteinaemia but had no effect on cogni- incident dementia due to the strong association with increased tive function [29]. The lack of a positive effect can be attributed systemic blood pressure, followed by impaired ventricular fill- to comorbidities [29]. Increased amounts of aspartate may con- ing, left ventricular diastolic dysfunction, whole body hypoper- tribute to ageing-related CI by facilitating excitotoxicity [30]. fusion as well as myocardial structural changes such as a dilated atrial chamber, with an enhanced probability to develop AF Vascular-related factors. Large prospective studies have [45]. Such negative cardiac structural changes are often associ- indicated several vascular factors, including older age, hyperten- ated with a high ventricular rate [46], which again is responsible sion, diabetes mellitus and dyslipidaemia, as risk factors for dementia in the general population [31]. Dialysis and CKD for brain hypoperfusion and sudden death. Among the cardiac populations share most of these same risk factors for CI. arrhythmias, AF is most common, estimated to occur in 44% of Despite there is greater prevalence of traditional vascular risk CKD (Stages 3–5) patients [47]. AF is one of the treatable cogni- factors [e.g. hypertension, diabetes mellitus, hyperlipidaemia, tive risk factors in CKD. Direct evidence of the strong relation- cigarette smoking, atrial fibrillation (AF) and myocardial ship between AF and cognitive decline is also provided by the infarction] and cardiovascular disease (CVD) among CKD evidence that anticoagulation and ablation, but not anti- patients, studies to date have failed to establish a direct link be- aggregation, are helpful therapeutic tools for treating AF and tween any of these factors and the presence of cognitive dys- preventing cognitive decline [48]. function in patients with CKD [11, 28, 32, 33]. This implies that Pulse wave velocity. Arterial stiffness can cause microvascu- other factors may be implicated in the occurrence of CI. A possible role has been suggested for novel vascular risk lar damage in the brain due to an increased impact of pulsatility factors such as elevated levels of inflammatory mediators, which on the microvasculature, which possibly alters brain structure have been observed in CKD patients, highlighting the possibil- or cognitive functioning. Several studies in CKD patients have ity of an association between inflammatory markers and all- shown an association between increased pulse wave velocity cause dementia, as reported in the general population [34, 35]. and CI (global cognition or executive dysfunction), pointing to Likewise, elevated levels of prostaglandin D2 synthase, a media- the role of large artery damage in this complex process [49]. tor of inflammation, could induce neural apoptosis in dialysis Specificities of cognitive assessment for patients under patients [36]. Higher C-reactive protein levels were also RRT reported in dialysis patients [37] and have been linked to CI in the general population [38]. Dialysis. One important aspect for clinicians and researchers The significance of silent cerebrovascular disease is involved in cognitive testing of patients with CKD is the timing: highlighted by studies that showed an association between CI when, during the day, should a cognitive test be administered? and silent brain infarction, which was most commonly attribut- This question is especially crucial for HD patients. There is a able to subcortical lacunar infarcts in the general population theoretical risk that administering tests during the dialysis ses- [39]. Silent brain infarction has been shown to be an sion may lead to altered performance due to the lack of privacy, ii26 M. Pépin et al. the ongoing extracorporeal treatment (with modifications in Of note, in animal models, stress and corticosteroids are as- electrolyte and water content of the plasma), the forced immo- sociated with memory impairment and both reversible and irre- bilization, the psychologically stressful situation and the effect versible changes in the hippocampus. Clinical studies observed of accumulated toxins. Furthermore, these variables make com- that exposure to exogenous corticosteroids can change mood parisons with a control population more difficult, as non-HD and declarative memory, but a negative effect on cognition was control subjects are tested in completely different conditions. modest [59]. Psychopathological signs frequently observed in- To empirically test this problem, Murray et al. [50] observed dicate that corticosteroids may also induce functional disorder that the Mini–Mental State Examination (MMSE) score was re- of additional brain regions (e.g. frontal and temporal lobes), duced by 1 point (4%) when administered before HD compared which are important for cognitive and emotional processing with the score achieved 1 h after treatment or the day after [50]. [60]. In order to minimize the impact of high-dose steroids and This result has been known since the 1970s and confirmed sev- operative procedures on cognition, we recommend performing eral times [51]. Unsurprisingly, the lower MMSE scores do not an assessment at least 1 month after transplantation. improve during the first hour of HD [50, 52]. Likewise, imaging Perceived and measured cognition in KT patients differs. In studies [53] and electroencephalogram (EEG) records [54] have 157 KT patients assessed by trained medical personnel, per- shown variations in brain activity according to the timing of the ceived cognition scores weakly correlated with Montreal dialysis session. Cognitive Assessment (MoCA) scores [61]. Therefore, as in This timing parameter seems less problematic regarding other CKD patients, efficient cognitive screening in KT patients cognitive testing in peritoneal dialysis (PD), due to it being an relies on objective screening tests. However, it is still not fully at-home treatment and the frequent dialytic exchanges (often clear which screening tool should be used. Recent studies ob- on the order of two to three per day, every day). Indeed, one served discrepancies in the prevalence of CI in KT patients, major difference between HD and PD is the intermittent nature probably because the tests were different (MoCA, DemTect of the HD treatment compared with the almost continuous PD tool) [62]. treatment. An EEG study confirmed that PD brain activity is Calcineurin inhibitors (CNIs) have a known side effect of more stable compared with the great changes occurring before neurotoxicity [63]. A small study observed that attention and and after HD (with better EEG after HD) [54]. Therefore, stud- working memory were impaired in KT patients treated with ies adopt an off-dialysis timing (with an interval of at least 2 h sirolimus or tacrolimus, while performance of cyclosporine- from the last session) [55]. New methods of HD (such as noc- treated subjects was similar to healthy volunteer controls. Long- turnal HD or the use of a cooled dialysate) are expected to re- term effects of CNI on cognition and physiopathology are not duce the burden of sessions on neurocognitive function and well understood [63]. Further studies may establish the optimal quality of life. timing for cognitive assessment after KT and identify an opti- These data suggest that the cognitive performance in HD mal screening test in this specific population. patients is not stable and may constantly decrease as a function of the elapsed time from the last dialysis session. This may Screening tests greatly impinge on interpretation of the results. Therefore we Today, most scientific societies, including nephrology, rec- recommend testing patients at least 1 h after the HD session, ommend cognitive assessment in individuals with cognitive particularly if a control group without HD is used. The testing complaints and in individuals whose caregivers notice symp- time for PD should be the same as for the general population. toms that may indicate the presence of CI, especially when there We also recommend establishing appropriate timing in re- are difficulties in daily functioning. Various screening tests are search studies in case patients with CKD are included. commonly used in daily clinical practice to assess cognitive sta- tus [64] (see Table 1). Kidney transplantation. Cognitive function has been There is no consensus on which screening instrument shown to improve after kidney transplantation, specifically in should be used to identify NCD (major or mild) in people with psychomotor speed, attention, visual planning, learning and CKD. Rather, the screening methods used reflect the availability memory and abstract thinking [56]. Nevertheless, CI remains of tests in a given language or the habits of the examinees. more frequent in kidney transplant (KT) patients than in the In clinical practice, two main screening tests of CI are used, general population and is associated with frailty measured using the MMSE and, more recently, the MoCA. As in other diseases the physical frailty phenotype developed [57, 58]. Frail KT [65], the superiority of the MoCA, which also assesses executive recipients are at a higher risk of immunosuppression intoler- functions, and is especially sensitive to brain dysfunction com- ance and mortality than non-frail patients [58]. Post-KT frailty pared with the MMSE, has been examined in several studies in and cognitive performance are likely dynamic. On the one CKD patients. Focusing on the few studies using a comprehen- hand, frailty initially worsens in the first month post-KT, but sive neuropsychological battery as a gold standard and receiver then improves by 3 months post-KT; on the other hand, cogni- operating characteristics curve analysis, the area under the tive performance, assessed by the modified MMSE (3MSE), curve (AUC) did not significantly differ across tests [66, 67]. tends to improve in the first 3 months post-KT [57, 58]. More This indicates that the sensitivity of both screening tests does research is needed to differentiate if post-KT issues, like wound not differ greatly, although the small to moderate sample sizes healing, immunosuppression and infections, may affect the re- require careful conclusion. From our point of view, the impor- versal of frailty and CI after KT. tant conclusion from these studies is that the sensitivity of both Cognitive disorders in patients with CKD ii27 Table 1. Examples of psychometric tests used in CKD patients Examples of tests Details of test Function assessed Use in CKD Global cognition MMSE 30-point test (orientation, attention and calculation, mem- Screening of global CI Yes ory, language and visuospatial abilities) MoCA 30-point test (visuospatial abilities, executive functions, Screening of global CI (including Yes memory, attention, language, abstract reasoning and executive functions) orientation) CDT Non-verbal test. The patient is asked to draw a clock face Executive functions, visuospatial Yes and mark the hours and then draw the hands to indicate and visuoconstructional a particular time functioning Language Boston Naming Test Name objects shown in 60 black-and-white line drawings. Confrontation naming Yes Items are ordered according to their ability to be named, which is correlated with their frequency Visuospatial and constructive abilities Cancellation test Lines, circles, letters bells or stars are drawn in random Visual neglect, response inhibi- Yes positions on a sheet of paper (A4) and presented to pa- tion, motor perseveration and tient, who is asked to cancel or cross out the target attention Judgement of line orientation 30-item test in which the patient is asked to match two an- Visuospatial perception Yes gled lines to a set of 11 lines that are arranged in a semi- circle and separated 18 degrees from each other Rey–Osterrieth complex Patient is asked to copy a complex geometrical figure Complex visuospatial Yes figure test (copying) constructional ability Wechsler Adult Intelligence Scale (WAIS) Timed subtest of the WAIS. Identical blocks with surfaces Visuospatial and organizational Yes block design of solid red, surfaces of solid white and surfaces that are abilities and processing speed half-red and half-white are presented to the patient. The patient is asked, using an increasing number of blocks, to replicate a pattern that the test administrator presents to the patient Episodic memory Verbal memory Free and Cued Selective The test is based on 12 pictorial stimuli. The patient is Memory (includes assessment Yes Recall Test (FCRST) asked to identify pictured items (e.g. grapes and vest) in of retrieval processes) response to category cues (fruit and clothing). In the test phase, subjects are asked to recall the items they learned (free recall). The category cues are used to prompt recall of items not retrieved by free recall California Verbal Learning Test Patient is asked to recall List A (16 words) 5 times. List B Memory (includes assessment Yes (interference, 16 words) is administered after List A for of proactive interference) one trial. Short-delay free recall and cued recall are ad- ministrated after List B. A long delay follows the short- delay recalls, followed by non-verbal testing Visuospatial memory Baddeley Door Test The patient views photographs of 12 doors for 3 s each. Visual memory Yes Immediately thereafter, the patient tries to identify the door from the study list among 12 arrays of 4 doors each Rey-Osterrieth Complex Figure The patient is asked to reproduce from memory the com- Visual memory Yes Test (3 min recall) plex geometric figure he copied after a short delay (3 min) and then a long delay (30 min) Executive functions and action speed TMT Part A requires an individual to draw lines sequentially Visuomotor speed, visual Yes connecting 25 encircled numbers distributed on a sheet attention (TMT Part A) and of paper. In Part B the patient must alternate between task switching (TMT Part B) numbers and letters (1-A-2-B-3-C) The Stroop Colour and First, the subject is required to read names of colours Inhibition of cognitive Yes Word Test printed in black ink. Second, the subject names different interference colour patches. Third, he/she is required to name the col- our of the ink instead of reading the word (colour words are printed in an inconsistent colour ink) Semantic and literal fluency The patient is given 1 min to produce as many words as Lexico-semantic knowledge, Yes possible within a semantic category or starting with a lexical retrieval ability and given letter executive control ability Continued ii28 M. Pépin et al. Table 1. Continued Examples of tests Details of test Function assessed Use in CKD WAIS Digit Symbol Substitution Timed subtest of the WAIS. The test involves a key Processing speed, working Yes subtest consisting of numbers (1–9), each paired with a unique memory, visuospatial process- symbol. Below the key is a series of numbers (1–9) in ing and attention random order. The subject is then allowed 90 s to fill in the corresponding symbol for each number Wisconsin Card The subject is given a set of four stimulus cards, each differ- Abstract reasoning, mental Yes Sorting Test ent from the other in terms of colour, shape or number. flexibility and problem solving The participant is asked to accurately sort every response card with one of four stimulus cards but not how to match. The administrator provides simple feedback (right or wrong) based on a predetermined rule Inventory of the Behavioural Structured interview of an individual assessing changes Behavioural disorders (apathy, Yes Dysexecutive Syndrome relative to previous behaviour in 12 domains impulsivity, psychomotor instability, anosognosia etc.) Warning signs Etiological workup Patient or relatives’ complaints Clinical examination Functional impairment Global assessment Confusion about medication Brain imaging Unexplained falls, decreased mobility performance Age, educational level, Screening tests Factors associated with Timing Comprehensive gender, social support cognitive function in CKD MoCA cognitive battery Depression HD: 1h after Sleep disturbances MMSE session Executive functions Medications Other screening PD: Off-dialysis tests (CDT, 3MS, and action speed Drug neurotoxicity timing etc…) KT: > 1 month Language Self-reported after KT Visuospatial abilities Anemia methods Episodic memory PTH Amino acids Cognitive Uremic toxins Cardiovascular risk factors Inflammatory mediators pattern Silent cerebrovascular disease Atrial fibrillation Left ventricular hypertrophy Pulse wave velocity CDT: Clock drawing test HD: Hemodialysis KT: Kidney transplant Clinical therapeutic MMSE: Mini mental state examination management MoCA: Montreal cognitive assessment PTH: Parathyroid hormone PD: Peritoneal dialysis 3MS: Modified mini mental state examination Collaboration between nephrologists, neurologists, neuropsychologists, geriatricians, and general practitioners FIGURE 1: Integrating CKD in NCDs. screening tests is usually <80%, which appears to be moderate ability for severe CI (AUC 0.81). The score of 21/30 patients [66–68]. had a sensitivity of 86% and specificity of 55% for severe im- Regarding other screening tests, the Clock Drawing Test pairment, with a negative predictive value of 91%. The TMT (CDT), the digit span backward and the fist-edge-palm test Part B and Digit Symbol Substitution Test also performed rea- showed similar performance in identifying MCI in this popula- sonably well (AUCs 0.73 and 0.78, respectively). The other tests tion when compared with the MoCA (24/30 patients) [69]. In had lower predictive performances. a recently published study, Drew et al. [67] compared the pre- Self-reported cognitive assessment methods (e.g. MAC-Q) dictive ability of MMSE, 3MSE, MoCA, Trail Making Test are also available, but these are based primarily on observations (TMT) Part B, Mini-Cog Test and the Digit Symbol of memory deficits and may not have sufficient diagnostic sen- Substitution Test performance for identifying severe CI among sitivity in people with CKD. Despite some limitations, self- patients with HD. The MoCA had the highest overall predictive reported assessment of instrumental activities of daily living Cognitive disorders in patients with CKD ii29 remains useful in determining the cognitive function of a pa- functions. Anxiety and depression symptoms were also tient. In case it is not possible to examine the patient in person, common [66]. it is advisable to use tools that allow for assessment by the care- Cognitive decline occurs early in CKD and its frequency has giver. The AD8 scale or Informant Questionnaire on Cognitive been observed with different rates across cognitive domains Decline in the Elderly are recommended. Even if physicians do according to GFR decline in these cross-sectional studies [4]. not frequently use these modalities in daily practice, they can be Interestingly, in studies assessing cognitive function in HD useful for epidemiologic studies. It is worth noting that most of patients, the frequency of every cognitive domain measurement these cognitive tests were developed and validated in the ageing has the same ranges as in patients without RRT, from the most population, affected by physiological decline in both brain and frequent (with the most frequent test used): orientation and at- renal function. tention (with TMT Parts A and B), global cognition (MMSE), From a practical point of view, we propose using one of memory (Weschler Memory Scale), construction and motor the main screening tests (the MoCA or MMSE) with education- (Clock and Grooved Peg Board), executive function (Stroop (both tests) and age-adjusted (MoCA) cut-offs computed using test), concept and reasoning (progressive matrices), language normative data from the population of the country. Future (Hopkins Verbal Learning Test) and perception (Haltstead– studies are required to identify an optimal screening test and Reitan Neuropsychological Battery) [71]. Executive functions cut-off for CKD patients. and orientation and attention are the most frequently affected Cognitive pattern in CKD patients domains in HD patients, even if their performance is poorer than controls in other domains [51, 71]. The cognitive pattern The diagnosis of mild NCD and mild dementia (which is the seems to be different in PD patients, with less impaired execu- present targeted stage of diagnostics) requires comprehensive tive function [55]. neuropsychological assessment performed by a neuropsycholo- These studies converge towards a prominent impairment of gist. In addition to a positive diagnosis, comprehensive assess- three neuropsychological domains (action speed, cognitive and ment determines the cognitive pattern, which constitutes a behavioural executive functions) followed by impairment of central cue for the aetiological diagnosis. The choice of tests language and episodic memory [4, 51, 66, 71]. Such a cognitive composing the battery is determined by the clinical context in pattern is close to that of the two leading causes of CI, vascular order to improve sensitivity. It usually includes tests assessing CI and Alzheimer’s disease. Based on this review, future re- instrumental functions (language, visuospatial and constructive search may establish test sensitivity and cognitive patterns in a abilities), episodic memory, action speed and executive func- tions assessed both at the cognitive (i.e. tests) and behavioural large and representative population of CKD patients, including (i.e. semistructured heteroquestionnaires that include social full aetiological workup. cognition) levels. Such a battery is usually not used for diagnos- tic purposes in patients with clear impairment on screening CONCLUSION tests (e.g. MMSE <18 or MoCA <14); it should be interpreted Cognitive disorders are a frequent issue in patients with CKD. using country-related norms and specific procedures to im- Clinical assessment of CI in this population involves many spe- prove diagnostic accuracy [70]. cific conditions, as can be seen in Figure 1. Although much is The pattern of CI in CKD is not definitely established. known, gaps in knowledge remain in this area. Further research Berger et al. [4] systematically reviewed CI in CKD patients [es- needs to be done, including the establishment of cognitive test timated GFR (eGFR) <60 mL/min/1.73 m2] without RRT, in- sensitivity for the CKD and KT populations, a description of cluding 44 cross-sectional and cohort studies with 51 590 cognitive patterns and the establishment of optimal timing for participants in the final meta-analysis. Cognitive domains were cognitive assessment in dialysis patients and after KT, among not assessed with the same frequency in the studies: attention others. Further research may be useful to provide guidelines for and action speed (referred to as ‘orientation and attention’ in clinicians, as comprehensive clinical assessment and aetiological the article; 28 studies), global cognition (25 studies), memory workup will help to provide suitable therapeutic management (16 studies), executive functions (15 studies), construction and taking into consideration CKD specificities. motor praxis (11 studies), language (9 studies), concept forma- tion and reasoning (6 studies) and perception (1 study). CKD patients (eGFR <60 mL/min/1.73 m2) performed worse than ACKNOWLEDGEMENTS control groups in almost all cognitive domains except percep- The authors would like to thank Prof. Giovambattista tion, construction and motor praxis. The study of Puy et al. [66] Capasso, acting chair of Cognitive Decline in Nephro- formally assessed test sensitivity in 40 patients and showed that Neurology: European Cooperative Target (CONNECT) four of the tests had a Cohen’s d index 0.8: TMT Part B, Digit Action and members of COST Action for their support. Symbol Substitution Test, literal fluency and the groupe de re- flexion pour l’evaluation des fonctions eXécutives (GREFEX) inventory of the behavioural dysexecutive syndrome. This is FUNDING accounted for by the cognitive pattern with prominent impair- This article is published as part of a supplement financially sup- ment of action speed (also called psychomotor speed ported by the COST Action CA19127-Cognitive Decline in or processing speed) and cognitive and behavioural executive Nephro-Neurology: European Cooperative Target (CONNECT). ii30 M. Pépin et al. CONFLICT OF INTEREST STATEMENT 12. Viggiano D, Wagner CA, Blankestijn PJ et al. Mild cognitive impairment and kidney disease: clinical aspects. Nephrol Dial Transplant 2020; 35: None declared. The results presented in this article have not 10–17 been published previously in whole or part, except in abstract 13. Viggiano D, Wagner CA, Martino G et al. Mechanisms of cognitive dys- format. function in CKD. Nat Rev Nephrol 2020; 16: 452–469 14. Zhou H, Al-Ali F, Wang C et al. Harnessing digital health to objectively as- sess cognitive impairment in people undergoing hemodialysis process: the APPENDIX impact of cognitive impairment on mobility performance measured by wearables. PLoS One 2020; 15: e0225358 CONNECT collaborators are 15. Verghese J, Wang C, Lipton RB et al. Motoric cognitive risk syndrome and the risk of dementia. J Gerontol A Biol Sci Med Sci 2013; 68: 412–418 Giovambattista Capasso; Alexandre Andrade; Maie 16. Pereira AA, Weiner DE, Scott T et al. Cognitive function in dialysis patients. Bachmann; Inga Bumblyte; Adrian Constantin Covic; Pilar Am J Kidney Dis 2005; 45: 448–462 Delgado; Nicole Endlich; Andreas Engvig; Denis Fouque; 17. Kimmel PL. Depression in patients with chronic renal disease: what we know and what we need to know. J Psychosom Res 2002; 53: 951–956 Casper Franssen; Sebastian Frische; Liliana Garneata; Loreto 18. Liabeuf S, Laville M. Drug prescription in patients with chronic kidney dis- Gesualdo; Konstantinos Giannakou; Dimitrios Goumenos; ease: a true challenge. Nephrol Dial Transplant 2021; 36: 385–386 Ayşe Tugba Kartal; Laila-Yasmin Mani; Hans-Peter Marti; 19. Kurella Tamura M, Larive B, Unruh ML et al. Prevalence and correlates of Christopher Mayer; Rikke Nielsen; Vesna Psic; Merita Rroji cognitive impairment in hemodialysis patients: the Frequent Hemodialysis (Molla); Giorgos Sakkas; Goce Spasovski; Kate I. Stevens; Network trials. Clin J Am Soc Nephrol 2010; 5: 1429–1438 20. Iliescu EA, Coo H, McMurray MH et al. Quality of sleep and health-related Evgueniy Vazelov; Davide Viggiano; Lefteris Zacharia; Ana quality of life in haemodialysis patients. Nephrol Dial Transplant 2003; 18: Carina Ferreira; Jolanta Malyszko; Ewout Hoorn; Andreja 126–132 Figurek; Robert Unwin; Carsten A. Wagner; Christoph 21. Kang EW, Abdel-Kader K, Yabes J et al. Association of sleep-disordered Wanner; Annette Bruchfeld; Marion Pepin; Andrzej Wieçek; breathing with cognitive dysfunction in CKD stages 4–5. Am J Kidney Dis Dorothea Nitsch; Ivo Fridolin; Gaye Hafez; Maria José Soler; 2012; 60: 949–958 22. Finkelstein FO, Finkelstein SH. Depression in chronic dialysis patients: as- Michelangela Barbieri; Bojan Batinic; Laura Carrasco; Sol sessment and treatment. Nephrol Dial Transplant 2000; 15: 1911–1913 Carriazo; Ron Gansevoort; Gianvito Martino; Francesco 23. Wang WL, Liang S, Zhu FL et al. The prevalence of depression and the asso- Mattace Raso; Ionut Nistor; Alberto Ortiz; Giuseppe Paolisso; ciation between depression and kidney function and health-related quality Daiva Rastenyt_e; Gabriel Stefan; Gioacchino Tedeschi; Ziad of life in elderly patients with chronic kidney disease: a multicenter cross- A. Massy; Boris Bikbov; Karl Hans Endlich; Olivier Godefroy; sectional study. Clin Interv Aging 2019; 14: 905–913 24. Al-Hihi E, Awad A, Hagedorn A. Screening for depression in chronic he- Jean-Marc Chillon; Anastassia Kossioni; Justina Kurganaite; modialysis patients. Mo Med 2003; 100: 266–268 Norberto Perico; Giuseppe Remuzzi; Tomasz Grodzicki; 25. Agganis BT, Weiner DE, Giang LM et al. Depression and cognitive function Francesco Trepiccione; Carmine Zoccali; Mustafa Arici; Peter in maintenance hemodialysis patients. Am J Kidney Dis 2010; 56: 704–712 Blankestijn; Kai-Uwe Eckardt; Danilo Fliser; Eugenio 26. Eisenstaedt R, Penninx BW, Woodman RC. Anemia in the elderly: current understanding and emerging concepts. Blood Rev 2006; 20: 213–226 Gutiérrez Jiménez; Maximilian König; Ivan Rychlik; Michela 27. Cerami A, Brines M, Ghezzi P et al. Neuroprotective properties of epoetin Deleidi; George Reusz. alfa. Nephrol Dial Transplant 2002; 17(Suppl 1): 8–12 28. Kurella M, Chertow GM, Fried LF et al. Chronic kidney disease and cogni- REFERENCES tive impairment in the elderly: the health, aging, and body composition study. J Am Soc Nephrol 2005; 16: 2127–2133 1. Levey AS, Coresh J. Chronic kidney disease. Lancet 2012; 379: 165–180 29. Brady CB, Gaziano JM, Cxypoliski RA et al. Homocysteine lowering and 2. Quinn MP, Cardwell CR, Kee F et al. The finding of reduced estimated glo- cognition in CKD: the Veterans Affairs homocysteine study. Am J Kidney merular filtration rate is associated with increased mortality in a large UK Dis 2009; 54: 440–449 population. Nephrol Dial Transplant 2011; 26: 875–880 30. Hu R, Huang D, Tong J et al. Aspartic acid in the hippocampus: a bio- 3. Murray AM. Cognitive impairment in the aging dialysis and chronic kidney marker for postoperative cognitive dysfunction. Neural Regen Res 2014; 9: disease populations: an occult burden. Adv Chronic Kidney Dis 2008; 15: 143–152 123–132 31. DeCarli C. The role of cerebrovascular disease in dementia. Neurologist 4. Berger I, Wu S, Masson P et al. Cognition in chronic kidney disease: a sys- 2003; 9: 123–136 tematic review and meta-analysis. BMC Med 2016; 14: 206 32. Yaffe K, Ackerson L, Kurella Tamura M et al. Chronic kidney disease and 5. Sachdev PS, Mohan A, Taylor L et al. DSM-5 and mental disorders in older cognitive function in older adults: findings from the chronic renal insuffi- individuals: an overview. Harv Rev Psychiatry 2015; 23: 320–328 ciency cohort cognitive study. J Am Geriatr Soc 2010; 58: 338–345 6. Hugo J, Ganguli M. Dementia and cognitive impairment: epidemiology, di- 33. Stam F, van Guldener C, Becker A et al. Endothelial dysfunction contributes agnosis, and treatment. Clin Geriatr Med 2014; 30: 421–442 to renal function-associated cardiovascular mortality in a population with 7. McAdams-DeMarco MA, Daubresse M, Bae S et al. Dementia, Alzheimer’s mild renal insufficiency: the Hoorn study. J Am Soc Nephrol 2006; 17: disease, and mortality after hemodialysis initiation. Clin J Am Soc Nephrol 537–545 2018; 13: 1339–1347 34. Schmidt R, Schmidt H, Curb JD et al. Early inflammation and dementia: a 8. Arnold R, Issar T, Krishnan AV et al. Neurological complications in chronic 25-year follow-up of the Honolulu-Asia Aging Study. Ann Neurol 2002; 52: kidney disease. JRSM Cardiovasc Dis 2016; 5: 2048004016677687 168–174 9. Leinau L, Murphy TE, Bradley E et al. Relationship between conditions 35. Teunissen CE, van Boxtel MP, Bosma H et al. Inflammation markers in re- addressed by hemodialysis guidelines and non-ESRD-specific conditions af- lation to cognition in a healthy aging population. J Neuroimmunol 2003; fecting quality of life. Clin J Am Soc Nephrol 2009; 4: 572–578 134: 142–150 10. Kurella Tamura M, Yaffe K. Dementia and cognitive impairment in ESRD: 36. Maesaka JK, Palaia T, Fishbane S et al. Contribution of prostaglandin D2 diagnostic and therapeutic strategies. Kidney Int 2011; 79: 14–22 synthase to progression of renal failure and dialysis dementia. Semin 11. Sehgal AR, Grey SF, DeOreo PB et al. Prevalence, recognition, and implica- Nephrol 2002; 22: 407–414 tions of mental impairment among hemodialysis patients. Am J Kidney Dis 37. Fine A. Relevance of C-reactive protein levels in peritoneal dialysis patients. 1997; 30: 41–49 Kidney Int 2002; 61: 615–620 Cognitive disorders in patients with CKD ii31 38. Kurella Tamura M, Tam K, Vittinghoff E et al. Inflammatory markers and 55. Kalirao P, Pederson S, Foley RN et al. Cognitive impairment in peritoneal risk for cognitive decline in chronic kidney disease: the CRIC study. Kidney dialysis patients. Am J Kidney Dis 2011; 57: 612–620 Int Rep 2017; 2: 192–200 56. Gupta A, Lepping RJ, Yu AS et al. Cognitive function and white matter 39. Vermeer SE, Prins ND, den Heijer T et al. Silent brain infarcts and the risk changes associated with renal transplantation. Am J Nephrol 2016; 43: of dementia and cognitive decline. N Engl J Med 2003; 348: 1215–1222 50–57 40. Vermeer SE, Den Heijer T, Koudstaal PJ et al. Incidence and risk factors of 57. Chu NM, Gross AL, Shaffer AA et al. Frailty and changes in cognitive func- silent brain infarcts in the population-based Rotterdam Scan Study. Stroke tion after kidney transplantation. J Am Soc Nephrol 2019; 30: 336–345 2003; 34: 392–396 58. McAdams-DeMarco MA, Chu NM, Segev DL. Frailty and long-term post- 41. Nakatani T, Naganuma T, Uchida J et al. Silent cerebral infarction in hemo- kidney transplant outcomes. Curr Transplant Rep 2019; 6: 45–51 dialysis patients. Am J Nephrol 2003; 23: 86–90 59. Prado CE, Crowe SF. Corticosteroids and cognition: a meta-analysis. 42. Kim CD, Lee HJ, Kim DJ et al. High prevalence of leukoaraiosis in cerebral Neuropsychol Rev 2019; 29: 288–312 magnetic resonance images of patients on peritoneal dialysis. Am J Kidney 60. Brown ES, Vera E, Frol AB et al. Effects of chronic prednisone therapy on Dis 2007; 50: 98–107 mood and memory. J Affect Disord 2007; 99: 279–283 43. Jankowski J, Floege J, Fliser D et al. Cardiovascular disease in chronic kidney 61. Gupta A, Thomas TS, Klein JA et al. Discrepancies between perceived and disease: pathophysiological insights and therapeutic options. Circulation measured cognition in kidney transplant recipients: implications for clinical 2021; 143: 1157–1172 management. Nephron 2018; 138: 22–28 44. Di Lullo L, Gorini A, Russo D et al. Left ventricular hypertrophy in chronic 62. Nöhre M, Bauer-Hohmann M, Klewitz F et al. Prevalence and correlates of kidney disease patients: from pathophysiology to treatment. Cardiorenal cognitive impairment in kidney transplant patients using the DemTect— Med 2015; 5: 254–266 results of a KTx360 substudy. Front Psychiatry 2019; 10: 791 45. Norby FL, Chen LY, Soliman EZ et al. Association of left ventricular hyper- 63. Jurgensen A, Qannus AA, Gupta A. Cognitive function in kidney transplan- trophy with cognitive decline and dementia risk over 20 years: the tation. Curr Transplant Rep 2020; 7: 145–153 Atherosclerosis Risk in Communities-Neurocognitive Study (ARIC-NCS). 64. Patnode CD, Perdue LA, Rossom RC et al. Screening for cognitive impair- Am Heart J 2018; 204: 58–67 ment in older adults: updated evidence report and systematic review for the 46. Saglietto A, Scarsoglio S, Ridolfi L et al. Higher ventricular rate during atrial US Preventive Services Task Force. JAMA 2020; 323: 764–785 fibrillation relates to increased cerebral hypoperfusions and hypertensive 65. Siqueira GSA, Hagemann PMS, Coelho DS et al. Can MoCA and MMSE be events. Sci Rep 2019; 9: 3779 interchangeable cognitive screening tools? A systematic review. 47. Khouri Y, Stephens T, Ayuba G et al. Understanding and managing atrial fi- Gerontologist 2019; 59: e743–e763 brillation in patients with kidney disease. J Atr Fibrillation 2015; 7: 1069 66. Puy L, Bugnicourt JM, Liabeuf S et al. Cognitive impairments and dysexecu- 48. Diener HC, Hart RG, Koudstaal PJ et al. Atrial fibrillation and cognitive tive behavioral disorders in chronic kidney disease. J Neuropsychiatry Clin function: JACC review topic of the week. J Am Coll Cardiol 2019; 73: Neurosci 2018; 30: 310–317 612–619 67. Drew DA, Tighiouart H, Rollins J et al. Evaluation of screening tests for cog- 49. Zijlstra LE, Trompet S, Jukema JW et al. Association of cardiovascular struc- nitive impairment in patients receiving maintenance hemodialysis. J Am Soc ture and function with cerebrovascular changes and cognitive function in older Nephrol 2020; 31: 855–864 patients with end-stage renal disease. Aging (Albany NY) 2020; 12: 1496–1511 68. Tiffin-Richards FE, Costa AS, Holschbach B et al. The Montreal Cognitive 50. Murray AM, Pederson SL, Tupper DE et al. Acute variation in cognitive Assessment (MoCA) – a sensitive screening instrument for detecting cogni- function in hemodialysis patients: a cohort study with repeated measures. Am J Kidney Dis 2007; 50: 270–278 tive impairment in chronic hemodialysis patients. PLoS One 2014; 9: 51. Schneider SM, Malecki AK, Müller K et al. Effect of a single dialysis session e106700 on cognitive function in CKD5D patients: a prospective clinical study. 69. Paraizo MDA, Almeida ALM, Pires LA et al. Montreal Cognitive Nephrol Dial Transplant 2015; 30: 1551–1559 Assessment (MoCA) screening mild cognitive impairment in patients with 52. Drew DA, Tighiouart H, Scott TM et al. Cognitive performance before and chronic kidney disease (CKD) pre-dialysis. J Bras Nefrol 2016; 38: 31–41 during hemodialysis: a randomized cross-over trial. Nephron Clin Pract 70. Godefroy O, Gibbons L, Diouf M et al. Validation of an integrated method 2013; 124: 151–158 for determining cognitive ability: implications for routine assessments and 53. Schaier M, Wolf RC, Kubera K et al. Vasogenic brain edema during mainte- clinical trials. Cortex 2014; 54: 51–62 nance hemodialysis: preliminary results from tract-based spatial statistics 71. O’Lone E, Connors M, Masson P et al. Cognition in people with end-stage and voxel-based morphometry. Clin Neuroradiol 2021; 31: 217–224 kidney disease treated with hemodialysis: a systematic review and meta- 54. Buoncristiani U, Alberti A, Gubbiotti G et al. Better preservation of cogni- analysis. Am J Kidney Dis 2016; 67: 925–935 tive faculty in continuous ambulatory peritoneal dialysis. Perit Dial Int 1993; 13: 202– 205 Received: 15.5.2021; Editorial decision: 24.6.2021 ii32 M. Pépin et al.