EXECUTIVE IMPAIRMENT IN PATIENTS WITH CHRONIC KIDNEY DISEASE ON REPLACEMENT THERAPY: PRELIMINARY DATA.

Globally, there is an alarming and consistent increase in the number of patients suffering from Chronic Kidney Disease (CKD). Presently, this health issue has become a matter of worldwide concern due to its medical, social, and economic implications for both patients, their families, and healthcare systems. The Kidney Disease: Improving Global Outcomes (KDIGO) consortium (2012) defines CKD as a renal structural and functional alteration persisting for more than 3 months, relevant to health. Renal damage (determined by damage markers or renal biopsy) and reduced renal function (glomerular filtration rate below 60 ml/minute) for 3 months or more are key indicators. The disease's progression consists of five stages, determined by the presence of renal damage and glomerular filtration rate (GFR). According to international guidelines, the stages are: Stage 1 (GFR > 90), Stage 2 (GFR 60-89), Stage 3 A/B (GFR 30-59), Stage 4 (GFR 15-29), and Stage 5, representing end-stage renal failure or end-stage renal failure (ESRD) (GFR < 15). In the latter stage, renal replacement therapy is necessary (García-Maset et al., 2022). In Argentina, according to data from the National Institute of Central Unique Coordination of Ablation and Implant (INCUCAI) (2022), 14246 patients with CKD have been registered, of whom 29195 require dialysis. In the context of the province of San Juan, with an estimated population of 789489 inhabitants, 1384 people with CKD are registered, of which 678 are in the process of dialysis. Additionally, 145 patients are on the waiting list for a kidney transplant, and 556 are in the registration process INCUCAI (2022). CKD has been identified as a significant risk factor for decreased cognitive performance (Murtaza & Dasgupta, 2021), with a prevalence of cognitive decline that increases proportionally with patients' age (Portillo et al., 2020). White matter damage in the prefrontal cortex has been identified in brain images of CKD patients, along with impairments in subcortical monoaminergic and cholinergic systems in animal models, accompanied by widespread vascular damage (Viggiano, 2020). Among the clinical indicators of CKD, an association has been noted between decreased estimated glomerular filtration rate (eGFR) and cognitive dysfunction in individuals with CKD who do not yet require dialysis (Vanderlinden et al., 2019, Drew et al., 2019). It has been hypothesized that CKD affects brain morphology and function, which in turn impacts cognition. Cognitive changes manifest early in CKD (Pepín et al., 2021) and progress at different rates in various cognitive domains as glomerular filtration rate decreases, with a greater impact on dialysis patients with CKD (Berger et al., 2016). Patients with CKD perform worse in attention, memory, and executive functions compared to control groups (Viggiano et al., 2019). This cognitive impairment affects not only patients' daily lives but also their independence, treatment adherence, and medical decision-making (Van Zwieten et al., 2017). In a systematic review and meta-analysis of 148 articles on the subject, it is concluded that patients with CKD, especially those in pre-dialysis and on dialysis, are prone to show differences in cognition (Vanderlinden et al., 2019). However, there is controversy regarding cognitive deficits associated with different types of dialysis. Hemodialysis is attributed a significant role in cognitive impairment due to rapid changes in fluids and osmotic factors it causes, whereas peritoneal dialysis is associated with prolonged preservation of residual renal function (Van Sandwijk et al., 2016). However, cognitive performance begins to decline after two years of treatment (Zhang et al., 2018). The underlying processes for cognitive decline in renal failure include vascular disease, uremic neurotoxicity, chronic inflammation, oxidative stress, anemia, and risks associated with dialysis itself (Van Sandwijk et al., 2016). However, there is a lack of precise information on the specific timing in the disease's progression when cognitive difficulties arise. Mild cognitive impairment is considered an intermediate and transitional state, with a significant risk of progressing to dementia in the future. The study of cognitive changes in CKD patients has implications for patients, their families, clinicians, and public health policy makers (Drew et al., 2019). It has been found that staff in dialysis units spend 38% more time during treatment, especially at the end of dialysis, in patients with cognitive impairment (Castellano et al., 2020). For successful treatment follow-up in patients, not only is there a need for riskbenefit analysis, rule monitoring, and proper decision-making processes, but also the interaction of high-level processes such as self-monitoring, self-control, cognitive flexibility, and a highly motivational basis, processes related to executive functions. Therefore, the general objective of this study is to describe and compare the cognitive profile in people with chronic kidney failure undergoing hemodialysis and peritoneal dialysis and contrast it with a control group. As a secondary objective, the study sought to determine the presence of cognitive impairment and its severity in people with chronic kidney failure undergoing dialysis treatment

This research had a quasi-experimental design with a control group. An intentional nonprobabilistic sampling method was used for sample selection (Hernández-Sampieri, Fernández-Collado & Baptista-Lucio, 2017). The sample consists of 20 stage 5 Chronic Kidney Disease (CKD) patients undergoing renal replacement therapy (dialysis) in both types: peritoneal dialysis and hemodialysis. Of the participants, 31% are female and 69% are male. Regarding the renal replacement process, 69% are on hemodialysis, and the remaining 31% are on peritoneal dialysis. The control group comprised 20 individuals matched by sex and years of education. Participants in both groups reside in the Province of San Juan, Argentina. As inclusion criteria, they were required to have intact motor and sensory functions necessary to complete the neuropsychological assessment and provide informed consent to participate. Both the patient and control groups were evaluated using a neuropsychological battery including: INECO Frontal Screening (Torralva et al. 2009), WATBA-r (Sierra et al. 2010), WAIS-IV Vocabulary Subtest (Wechsler, 2012, Rosas et al. 2014), WAIS-IV Matrix Subtest (Wechsler, 2012), Rey Auditory Verbal Learning Test (RAVLT) (Strauss et al. 2006; Burin, et al. 2003), Rey-Osterrieth Complex Figure (Osterrieth, 1944, Rivera et al. 2015), Trail Making Test A and B (Partington et al. 1949, ArangoLasprilla et al. 2015), WAIS-IV Processing Speed Index (Wechsler, 2012), WAIS-IV Working Memory Index (Wechsler, 2012), Modified Wisconsin Card Sorting Test (Arango-Lasprilla et al. 2015), Hayling Test (Burguess & Shallice, 1997; Abusamra V, Miranda MA & Ferreres, 2007, Cartoceti, Abusamra, Sampedro & Ferreres, 2009), Córdoba Naming Test (Fernández, 2013), and Verbal Fluency (Labos et al. 2013). All subjects were evaluated by a single neuropsychologist for the first time as none had a prior cognitive assessment. The data were analyzed using descriptive and inferential statistics. To compare two variables with normal distribution between two different patient groups, the Student's ttest for unpaired data was utilized. The statistical software used was SPSS.

The mean age was 46.76 (SD = 12.26). Regarding the years of formal education, the mean was 10.76 (SD = 4.72). For the time of renal pathology evolution in months, the mean was 86.41 (SD = 72.98). Concerning the time that patients have undergone renal replacement therapy in months, the mean was 66.35 (SD = 73.19). The control group comprised 20 participants, 64.7% female and 35.3% male. The mean age was 45.30 (SD = 11.09). For years of formal education, the mean was 12.35 (SD = 2.90). In terms of the cognitive evaluation results, for tests assessing executive functions such as the INECO Frontal Screening (IFS), the Z-score mean was -1.31 (SD = 1.52). In the Wisconsin Sorting Card Test (WSCT), the Z-score mean was -1.61 (SD = 1.17). In attention tests, the WAIS IV Digit Span Subtest had a Z-score mean of -1.07 (SD = 0.79). Meanwhile, in the WAIS IV Symbol Search Subtest, the Z-score mean was -1.06 (SD = 0.74). Additionally, in the WAIS IV Processing Speed Index, the Z-score mean was -1.17 (SD = 0.84). In the Trail Making Test (TMT) part A, the Z-score mean was - 2.27 (SD = 2.58). In part B, the mean was -2.34 (SD = 2.21). From the analysis reported above, a decline in patients' performance in attention span, sustained and alternating attention, processing speed, working memory, and cognitive flexibility is observed. Thus, the found cognitive profile is attentional-dysexecutive. Of the evaluated patients, 52.9% presented mild cognitive impairment, 41.2% moderate severity impairment, and 5.9% severe cognitive impairment. The results obtained in the different tests for each of them were compared with normative values of their reference group (considering age and years of formal education), using Z-scores. To classify the severity, Z-scores of different tests were used, defining deficits for scores that were two deviations below the mean and low for scores that were more than one deviation below the mean. When comparing the performance of CKD patients in dialysis and the control groups, significant differences were observed between the groups in the WAIS IV Vocabulary Subtest (p<0.01), WAIS IV Matrix Subtest (p<0.01). Significant differences were also observed concerning the Estimated Intellectual Coefficient (p<0.01). In all cases, the dialysis patient group showed detriment. In attention tests, significant differences were observed between the groups in the WAIS IV Symbol Search Subtest (p<0.01) and in the WAIS IV Coding Subtest (p<0.01), as well as in the WAIS IV Processing Speed Index (p<0.01). Significant differences were also noted in the Trail Making Test (TMT) Part A (p<0.01) and in the Trail Making Test (TMT) Part B (p<0.05). In all cases, the dialysis patient group exhibited impaired performance. Regarding executive functions, significant differences were identified between the groups in the subtests of Conflicting Instructions (p<0.01), Visual Working Memory (p<0.01), and the Total Score of the INECO Frontal Screening (p<0.01). There were also significant differences in the Motor Inhibitory Control subtest (p<0.05), Backward Digit (p<0.05), Proverbs (p<0.05), and Verbal Inhibitory Control (p<0.05). In all cases, the dialysis patient group showed impaired performance. Significant differences between the groups were observed in the WAIS IV Digit Span Subtest (p<0.01) and WAIS IV Arithmetic Subtest (p<0.01). Moreover, significant differences were seen in the Hayling Test (p<0.05) and the Wisconsin Card Sorting Test (WSCT) (p<0.01). In all cases, the dialysis patient group displayed impaired performance. There were significant differences between the groups in the Rey Auditory Verbal Learning Test (RAVLT) (p<0.01), Initial List (p<0.01), Immediate Recall (p<0.01), Delayed Recall (p<0.01), and Recognition (p<0.01). In the visual episodic memory test, there were also significant differences in Recognition in the Rey Complex Figure (p<0.05). In all cases, the dialysis patient group exhibited impaired performance. Significant differences were observed between the groups in Phonological (p<0.01) and Semantic (p<0.01) Verbal Fluency, as well as in the Cordoba Naming Test (p<0.01). In all cases, the dialysis patient group showed impaired performance.

The present work aimed to describe and compare the cognitive profile in people with chronic kidney disease undergoing hemodialysis and peritoneal dialysis and contrast it with a control group. It also aimed to determine the presence of cognitive impairment and its severity in people with chronic kidney disease undergoing dialysis treatment. In this work, a dysexecutive-attentional cognitive profile could be described in patients with Chronic Kidney Disease (CKD), as the main difficulties were found in tests assessing processing speed, sustained and alternating attention, cognitive flexibility, working memory, among others. These results align with the findings reported by (Vanderlinden et al., 2019), who, in a systematic review and meta-analysis of 148 articles on the subject, concluded that patients with CKD, especially those on dialysis, are prone to exhibit differences in cognition. Upon comparing the means between both evaluated groups, significant differences were found in various domains. Patients showed poorer performance than control group participants in attention, memory, and executive function (Berger et al., 2016). Among the patients evaluated in the context of this project, impairments were also observed in functions such as language, particularly in conceptualization and visual confrontation naming skills. Subjects in the control group showed better performance in verbal and visual episodic memory tests, processing speed, sustained and alternating attention. One of the most relevant findings was the significant differences in the Estimated Intelligence Quotient, which represents the overall ability, to the detriment of the dialysis group. As noted, patients with CKD, with or without replacement therapy, are prone to experiencing cognitive difficulties due to their high vascular risk. The obtained results demonstrate that all evaluated patients showed difficulties in their cognitive performance; however, the severity varied. Hence, of the evaluated patients, 52.9% showed mild cognitive impairment, 41.2% moderate severity impairment, and 5.9% severe cognitive impairment. Identifying and describing the decline in cognitive abilities can be useful in assessing treatment adherence, identifying potential reversible causes of cognitive decline, adjusting medication treatment, instructing the patient and caregiver, and providing appropriate support to both. It should be acknowledged that this study has certain limitations. In terms of the sample, it is important to consider the size and disparity concerning renal replacement therapy. It is suggested that for future research, a more equitable search for participants should be conducted, making the sample representative of those undergoing hemodialysis as well as peritoneal dialysis. Comments to the Evaluation Committee: The presented results are preliminary and represent an initial approach to the subject since this is an ongoing investigation.