Uremic toxins and the brain in chronic kidney disease.

Chronic kidney disease (CKD) patients have an increased risk for cognitive impairment compared to the general population. The risk is much higher in CKD patients who progress to end-stage kidney disease (ESKD) and require hemodialysis or peritoneal dialysis. Multiple factors may contribute to cognitive impairment in CKD patients and in patients on chronic dialysis. However, the observation that, after kidney transplantation, there is an improvement in several cognitive performance markers and that some structural and functional brain abnormalities may improve suggests that cognitive deficits in patients on dialysis may be at least partially reversible. Recent evidence supports the hypothesis that uremic toxins may disrupt the blood brain barrier and damage the brain cells. Such brain toxicity should prompt efforts to lower the burden of uremic toxins through dialytic and non-dialytic strategies.

Interdialytic weight gain and low dialysate sodium concentration in patients on chronic hemodialysis: a systematic review and meta-analysis.

PURPOSE: The present systematic review and meta-analysis aimed at evaluating the effect of low dialysate sodium concentration on interdialytic weight gain (IDWG) in chronic hemodialysis patients. METHODS: Studies were eligible for inclusion if they were English language papers published in a peer-reviewed journal and met the following inclusion criteria: (1) studies in adult patients (over 18 years of age), (2) included patients on chronic hemodialysis since at least 6 months; (3) compared standard (138-140 mmol/l) or high (> 140 mmol/l) dialysate sodium concentration with low (< 138 mmol/l) dialysate sodium concentration; (4) Included one outcome of interest: interdialytic weight gain. Medline, PubMed, Web of Science, and the Cochrane Library were searched for the quality of reporting for each study was performed using the Quality Assessment Tool of Controlled Intervention Studies of the National Institutes of Health. The quality of reporting of each cross-over study was performed using the Revised Cochrane Risk of Bias (RoB) tool for cross-over trials as proposed by Ding et al. RESULTS: Nineteen studies (710 patients) were included in the analysis: 15 were cross-over and 4 parallel randomized controlled studies. In cross-over studies, pooled analysis revealed that dialysate sodium concentration reduced IDWG with a pooled MD of - 0.40 kg (95% CI - 0.50 to - 0.30; p < 0.001). The systematic review of four parallel, randomized, studies revealed that the use of a low dialysate sodium concentration was associated with a significant reduction of the IDWG in two studies, sustained and almost significant (p = 0.05) reduction in one study, and not significant reduction in one study. CONCLUSION: Low dialysate sodium concentration reduces the IDWG in prevalent patients on chronic hemodialysis.

Geriatric Depression Scale predicts mortality in elderly patients on chronic hemodialysis.

INTRODUCTION: The aim of this study was to determine if the Geriatric Depression Scale (GDS) was predictor of mortality in elderly patients on chronic hemodialysis (HD). METHODS: A total of 140 HD patients ≥65 years were studied. Symptoms of depression were assessed through GDS and cognitive function through the Mini Mental State Examination (MMSE). GDS scores 0-9 are considered normal (Group 1); scores of 10-20 (Group 2) and 21-30 (Group 3) indicate mild and severe depression. RESULTS: Median GDS was 13 (11-15): 54 patients in Group 1, 49 in Group 2, and 37 in Group 3. After a follow-up of 58.85 ± 38.8 months, 94 patients died and 46 were alive. Kaplan-Meier survival was significantly lower in patients of Groups 2 and 3 than in Group 1 (log-rank χ2 : 101.9; DF: 2; p < 0.0001). According to Cox regression analysis, mortality was associated with age and GDS, and inversely associated with MMSE and Kt/V. CONCLUSION: GDS predicts mortality in elderly HD patients.

Fatigue in Patients Receiving Maintenance Hemodialysis: A Review.

Fatigue surrounding hemodialysis treatments is a common and often debilitating symptom that impacts patients' quality of life. Intradialytic fatigue develops or worsens immediately before hemodialysis and persists through the dialysis treatment. Little is known about associated risk factors or pathophysiology, although it may relate to a classic conditioning response. Postdialysis fatigue (PDF) develops or worsens after hemodialysis and may persist for hours. There is no consensus on how to measure PDF. Estimates for the prevalence of PDF range from 20%-86%, likely due to variation in methods of ascertainment and participant characteristics. Several hypotheses seek to explain the pathophysiology of PDF, including inflammation, hypothalamic-pituitary-adrenal axis dysregulation, and osmotic and fluid shifts, but none is currently supported by compelling or consistent data. PDF is associated with several clinical factors, including cardiovascular and hemodynamic effects of the dialysis procedure, laboratory abnormalities, depression, and physical inactivity. Clinical trials have reported hypothesis-generating data about the utility of cold dialysate, frequent dialysis, clearance of large middle molecules, treatment of depression, and exercise as potential treatments. Existing studies are often limited by sample size, lack of a control group, observational design, or short intervention duration. Robust studies are needed to establish the pathophysiology and management of this important symptom.

Trend and determinants of mortality in incident hemodialysis patients of the Lazio region.

BACKGROUND: . In the last decades some studies observed a moderate progressive decrease in short-term mortality in incident hemodialysis patients. The aim of the study is to analyse the mortality trends in patients starting hemodialysis using the Lazio Regional Dialysis and Transplant Registry. METHODS: . Patients who started chronic hemodialysis between 2008 and 2016 were included. Annual 1-year and 3-year Crude Mortality Rate*100 Person Years (CMR*100PY) overall, by gender and age classes were calculated. Cumulative survival estimates at 1 year and 3 years since the date of starting hemodialysis were presented as Kaplan-Meier curves for the three periods and compared using the log-rank test. The association between periods of incidence in hemodialysis and 1-year and 3-year mortality were investigated by means of unadjusted and adjusted Cox regression models. Potential determinants of both mortality outcomes were also investigated. RESULTS: . Among 6,997 hemodialysis patients (64.5% males, 66.1% over 65 years old) 923 died within 1 year and 2,253 within 3 years form incidence; CMR*100PY were 14.1 (95%CI: 13.2-15.0) and 13.7 (95%CI: 13.2-14.3), respectively; both remained unchanged over the years. Even after stratification by gender and age classes no significant changes emerged. Kaplan-Meier mortality curves did not show any statistically significant differences in survival at 1 year and 3 years from hemodialysis incidence across periods. No statistically significant associations were found between periods and 1-year and 3-year mortality. Factors associated with a greater increase in mortality are: being over 65 years, born in Italy, not being self-sufficient, having systemic versus undetermined nephropathy, having heart disease, peripheral vascular disease, cancer, liver disease, dementia and psychiatric illness, and receiving dialysis by catheter rather than fistula. CONCLUSIONS: . The study shows that the mortality rate in patients with end-stage renal disease starting hemodialysis in the Lazio region was stable over 9 years.

Interdialytic weight gain is not associated with symptoms of depression or apathy in patients on chronic hemodialysis.

PURPOSE: Little is known about the relationships between apathy, depressive symptoms and interdialytic weight gain (IDWG) in patients on chronic hemodialysis. Aim of the present study is to investigate the association between IDWG and symptoms of depression and apathy in hemodialysis patients. METHODS: A total of 139 chronic patients of the HD units between January 2020 and December 2021 were included in the present cross-sectional study. IDWG was calculated as the difference between the pre-HD weight and the weight registered after the previous session; the average of the sessions in a month was registered. Apathy Evaluation Scale (AES) was adopted to evaluate apathy. Depression was assessed by Beck Depression Inventory (BDI). RESULTS: Ninety-three patients had IDWG% ≤ 4 and 46 had an IDWG% > 4. Correlation between IDWG% and BDI as well that between IDWG% and AES were not statistically significant. Median BDI and mean AES did not differ significantly between the groups. In addition, 104 patients had a BDI < 16 and 35 had a BDI ≥ 6. Seventy-five patients had an AES score ≤ 35 and 63 had a AES score > 35. The IDWG (kg) and the IDWG% did not differ significantly between the two groups. CONCLUSION: IDWG is not associated with symptoms of depression or apathy in hemodialysis patients. Thus, these results may question if the use of behavioral intervention aimed at improving motivation is warranted in the hemodialysis population to reduce the IDWG.

Post-dialysis fatigue: Comparison of bicarbonate hemodialysis and online hemodiafiltration.

INTRODUCTION: The present cross-sectional study aimed to compare the prevalence, the characteristics of post-dialysis fatigue and the length of recovery time after hemodialysis in prevalent end-stage renal disease patients (ESRD) receiving bicarbonate hemodialysis (HD) or hemodiafiltration (HDF). METHODS: Patients were suffering from post-dialysis fatigue if they spontaneously offered this complaint when asked the open-ended question: "Do you feel fatigued after dialysis?". Moreover, each patient was invited to rate the intensity, duration, and frequency of post-dialysis fatigue from 1 to 5. In order to assess RECOVERY TIME AFTER DIALYSIS, patients were invited to answer to the following single open-ended question: "How long does it take you to recover from a dialysis session?" FINDINGS: We included 335 patients: 252 received HD and 83 received HDF. Post-dialysis fatigue was present in 204 patients (60.9%). Prevalence of post-dialysis fatigue did not differ significantly between patients on HD (62.3%) and on HDF (56.6%; p = 0.430). Median recovery time after dialysis was 180 min [180-240] and did not differ significantly between the two subgroups (180 min [130-240] and 240 min [120-332] p = 0.671, respectively). Median post-dialysis fatigue intensity, duration, and frequency were 3 [1-5], 3 [1-5], and 4 [1-5] and did not differ significantly between patients on HD and on HDF. At the multivariate analysis, age, ADL and hemoglobin levels were the independent predictors of the HDF treatment. DISCUSSION: Prevalence and characteristics of post-dialysis fatigue do not differ significantly between patients receiving bicarbonate HD or HDF.

Post-dialysis fatigue and serum S100B protein in patients on chronic hemodialysis. A pilot study.

BACKGROUND: Aim of the present study was to assess whether post-dialysis fatigue (PDF) may be related to pre- or post-dialysis levels of serum S100B protein. Hemodialysis patients (HD) who answered to be fatigued after their hemodialysis sessions when asked: "Do you feel worse after dialysis? if they answered yes" were considered to suffer from PDF. Serum Interleukins (IL-1ß, IL-6, IL-10), TNF-α and S100B were assessed by ELISA kit. RESULTS: Thirty HD patients were studied: 22 (73.4%) reported to suffer from PDF. Serum S100B post-dialysis levels (median [IQR] = 17.4 µg [7.1 to 30.9]) were significantly higher than serum S100B pre-dialysis levels (median [IQR] = 5 µg [1.4 to 22.1]; p = 0.0001). S100B post-dialysis was significantly higher than S100B pre-dialysis either in patients with PDF or without PDF. CONCLUSIONS: Pre- and post-dialysis values of serum S100B and its delta did not differ significantly between patients with and without PDF and were not associated with the length of the TIRD in patients on chronic hemodialysis.

Mini-Mental State Examination predicts mortality in patients on chronic hemodialysis.

BACKGROUND: No available and easy to administer cognitive test has been evaluated for the prediction of mortality in prevalent patients on chronic hemodialysis. The aim of the present study was to determine if the Mini-Mental State Examination (MMSE) was predictor of mortality in patients on chronic hemodialysis. METHODS: One hundred twenty-seven prevalent patients on chronic hemodialysis were studied. All patients underwent assessment of cognitive function through the MMSE. The MMSE was administered during a midweek hemodialysis session, avoiding the beginning and the end of each treatment to minimize the effects of fluctuations in uremic syndrome or blood pressure in accordance with a previous study. An MMSE score ≤23 was used as indicative of cognitive impairment. Demographic, clinical, and laboratory parameters were recorded for each patient. RESULTS: Mean (SD) MMSE was 23.2 ± 4.1. Median MMSE was 24 (min-max: 2-30). MMSE was ≤23 in 72 patients and >23 in 55. With data updated in March 2021, after a mean follow-up of 58.8 ± 41 months (range: 2-156 months), 75 patients died, and 17 were transplanted. None was lost to follow-up or was transferred to another unit. Dead participants, as compared with alive ones, were significantly older, had a higher Charlson Index score, had lower Activities daily living and Instrumental activities daily living, and had a lower MMSE score and lower serum albumin levels. Kaplan-Meier analysis showed that survival was significantly lower in patients with MMSE ≤23 than in those with MMSE >23 (log-rank χ2 : 8.825, p = 0.003). According to Cox regression analysis, mortality was associated with age and inversely associated with MMSE. CONCLUSION: We show that the MMSE predicts mortality in prevalent patients on chronic hemodialysis.

Interdialytic weight gain and educational/cognitive, counseling/behavioral and psychological/affective interventions in patients on chronic hemodialysis: a systematic review and meta-analysis.

BACKGROUND: This work aimed to shed light on the notorious debate over the role of an educational/cognitive/behavioral or psychological approach in the reduction of interdialytic weight gain (IDWG) in patients on chronic hemodialysis. METHODS: Searches were run from 1975 to January 2022 on Medline, PubMed, Web of Science, and the Cochrane Library. The search terms included "hemodialysis/haemodialysis" AND "adherence" AND ("fluid intake" OR "water intake") AND ("weight gain" OR "interdialytic weight gain" OR "IDWG") AND "patient-level interventions. Randomized controlled studies were eligible if they were in English, published in a peer-reviewed journal and regarded adults patients with on chronic hemodialysis for at least 6 months; compared educational/cognitive and/or counseling/behavioral or psychological interventions to no intervention on interdialytic weight gain. Outcome of interest was interdialytic weight gain. The review was registered on the International Prospective Register of Systematic Reviews in Health and Social Care (PROSPERO, ID number CRD42022332401). RESULTS: Eighteen studies (1759 patients) were included in the analysis. Compared to the untreated group, educational/cognitive and/or counseling/behavioral interventions significantly reduced interdialytic weight gain with a pooled mean difference of - 0.15 kg (95% CI - 0.26, 30-0.05; P = 0.004). On the other hand, psychological/affective interventions reduced interdialytic weight gain with a pooled mean difference of - 0.26 kg (95% CI - 0.48, - 0.04; P = 0.020). CONCLUSIONS: Educational/cognitive, counseling/behavioral or psychological/affective interventions significantly reduced the interdialytic weight gain in patients on chronic hemodialysis, although such reduction did not appear to be clinically relevant on hard outcomes.

Tube feeding in patients with head and neck cancer undergoing chemoradiotherapy: A systematic review.

Patients with head and neck cancer (HNC) are frequently malnourished at the time of diagnosis and before beginning treatment. In addition, chemoradiotherapy causes or exacerbates symptoms such as alteration or loss of taste, mucositis, xerostomia, fatigue, nausea, and vomiting, with consequent worsening of malnutrition. If obstructing cancer and/or mucositis interferes with swallowing, enteral nutrition should be delivered by a nasogastric tube (NGT) or percutaneous endoscopic gastrostomy (PEG). To review studies comparing NGT's and PEG's nutrition outcomes, survival, hospitalizations, radiotherapy interruptions, quality of life, and swallowing function. Two hundred fifty publications were identified via electronic databases. 26 manuscripts that met the inclusion criteria were included for analysis. We divided the analysis in two sections: (1) comparison of enteral nutrition through NGT or PEG and (2) comparison of reactive PEG (R-PEG) and prophylactic PEG (P-PEG). They have comparable nutrition outcomes, number of radiotherapy interruptions, survival, and quality of life, whereas swallow function seems better with NGT. PEG may be associated with major complications such as exit-site infection, malfunction, leakage, pain, pulmonary infection, and higher costs. Nevertheless, NGTs dislodged more often; patients find NGTs more inconvenient; NGTs may cause aspiration pneumonia; P-PEG and R-PEG have similar nutrition outcomes, number of radiotherapy interruptions, and survival. PEG does not have better nutrition, oncologic, and quality-of-life outcomes than NGT. Prophylactic feeding through NGT or PEG, compared with reactive feeding, does not offer significant advantages in nutrition outcomes, radiotherapy interruptions, and survival. However, the number of prospective randomized studies on this topic is limited; consequently, definitive conclusions cannot be drawn. Further adequate, prospective randomized studies are needed.

Fatigue and apathy in patients on chronic hemodialysis.

INTRODUCTION: This study explores the link between fatigue and apathy in patients on chronic hemodialysis (HD). METHODS: One hundred thirty-nine chronic HD patients underwent the assessment of fatigue, apathy, depression, and their functional status, with the fatigue severity scale (FSS), the Apathy Evaluation Scale (AES), the beck depression inventory (BDI), the activity of daily living (ADL), and instrumental activity of daily living (IADL). RESULTS: Patients with high FSS had a significantly lower ADL and IADL score, higher BDI, Charlson Comorbidity Index, and AES score, and lower serum levels of creatinine, compared to low FSS patients. FSS was highly correlated with the AES, as well as with the BDI and the AES correlates with the BDI. At multiple regression analyses, only apathy and IADL were independent predictor variables of fatigue in HD population. CONCLUSION: Future longitudinal studies could determine if apathy is a causative factor for fatigue manifestation and development in HD patients.

Gender Disparities in Vascular Access and One-Year Mortality among Incident Hemodialysis Patients: An Epidemiological Study in Lazio Region, Italy.

(1) Background: Interest in gender disparities in epidemiology, clinical features, prognosis and health care in chronic kidney disease patients is increasing. Aims of the study were to evaluate the association between gender and vascular access (arteriovenous fistula (AVF) or central venous catheter (CVC)) used at the start of hemodialysis (HD) and to investigate the association between gender and 1-year mortality. (2) Methods: The study includes 9068 adult chronic HD patients (64.7% males) registered in the Lazio Regional Dialysis Register (January 2008-December 2018). Multivariable logistic regression models were used to investigate the associations between gender and type of vascular access (AVF vs. CVC) and between gender and 1-year mortality. Interactions between gender and socio-demographic and clinical variables were tested adding the interaction terms in the final model. (3) Results: Females were older, had lower educational level and lower rate of self-sufficiency compared to males. Overall, CVC was used in 51.2% of patients. Females were less likely to use AVF for HD initiation than males. 1354 out of 8215 (16.5%) individuals died at the end of the follow-up period. Interaction term between gender and vascular access was significant in the adjusted model. From stratified analyses by vascular access, OR female vs. male (AVF) = 0.65; 95% CI 0.48-0.87 and OR female vs. male (CVC) = 0.88; 95% CI 0.75-1.04 were found. (4) Conclusions: This prospective population-based cohort study in a large Italian Region showed that in females starting chronic HD AVF was less common respect to men. The better 1-year survival of females is more evident among those women with AVF. Reducing gender disparity in access to AVF represents a key point in the management of HD patients.

Effects of uremic toxins on hippocampal synaptic transmission: implication for neurodegeneration in chronic kidney disease.

Patients affected by chronic kidney disease (CKD) have an increased risk of developing cognitive impairment. The cause of mental health disorders in CKD and in chronic hemodialysis patients is multifactorial, due to the interaction of classical cardiovascular disease risk factors, kidney- and dialysis-related risk factors with depression, and multiple drugs overuse. A large number of compounds, defined as uremic toxins that normally are excreted by healthy kidneys, accumulate in the circulations, in the tissues, and in the organs of CKD patients. Among the candidate uremic toxins are several guanidino compounds, such as Guanidine. Uremic toxins may also accumulate in the brain and may have detrimental effects on cerebral resident cells (neurons, astrocytes, microglia) and microcirculation. The present study aims to analyze the effect of Guanidine on hippocampal excitatory postsynaptic field potentials (fEPSPs) and in CA1 pyramidal neurons recorded intracellularly. Moreover, we compared these effects with the alterations induced in vitro by CKD patients derived serum samples. Our results show an increased, dose-dependent, synaptic activity in the CA1 area in response to both synthetic Guanidine and patient's serum, through a mechanism involving glutamatergic transmission. In particular, the concomitant increase of both NMDA and AMPA component of the excitatory postsynaptic currents (EPSCs) suggests a presynaptic mechanism. Interestingly, in presence of the lower dose of guanidine, we measure a significant reduction of EPSCs, in fact the compound does not inhibit GABA receptors allowing their inhibitory effect of glutamate release. These findings suggest that cognitive symptoms induced by the increase of uremic compounds in the serum of CKD patients are caused, at least in part, by an increased glutamatergic transmission in the hippocampus.

Fatigue in Kidney Transplantation: A Systematic Review and Meta-Analysis.

Fatigue is still present in up to 40-50% of kidney transplant recipients (KTR), the results of studies comparing the prevalence among patients on hemodialysis (HD) and KTR led to conflicting results. Fatigue correlates include inflammation, symptoms of depression, sleep disorders and obesity. Fatigue in KTR leads to significant functional impairment, it is common among KTR poorly adherent to immunosuppressive therapy and is associated with a serious deterioration of quality of life. The following databases were searched for relevant studies up to November 2020: Medline, PubMed, Web of Science and the Cochrane Library. Several studies have compared the prevalence and severity of fatigue between KTR and hemodialysis or healthy patients. They have shown that fatigue determines a significant functional deterioration with less chance of having a paid job and a significant change in quality of life. The aim of the review is to report methods to assess fatigue and its prevalence in KTR patients, compared to HD subjects and define the effects of fatigue on health status and daily life. There is no evidence of studies on the treatment of this symptom in KTR. Efforts to identify and treat fatigue should be a priority to improve the quality of life of KTR.

Fatigue in CKD: Epidemiology, Pathophysiology, and Treatment.

Fatigue is a commonly reported and debilitating symptom among patients with CKD, yet little is known about its epidemiology, pathogenesis, and treatment. Various measurement tools have been used in published studies to identify and quantify fatigue. These include several single-item measures embedded in longer questionnaires for assessing depression, quality of life, or symptom burden in patients with kidney disease. Approximately 70% of patients with CKD report fatigue, with up to 25% reporting severe symptoms. Patient-reported fatigue is associated with death, dialysis initiation, and hospitalization among individuals with CKD. The pathophysiology is multifactorial and likely includes decreased oxygen delivery and increased reliance on anaerobic metabolism, thus generating lactic acidosis in response to exertion; the effects of chronic metabolic acidosis and hyperphosphatemia on skeletal muscle myocytes; protein-energy wasting and sarcopenia; and depression. Physical activity has been shown to improve fatigue in some small but promising trials, and so should be recommended, given the additional benefits of exercise. Targeting higher hemoglobin levels with erythropoiesis-stimulating agents may improve fatigue, but potential adverse cardiovascular effects preclude their use to solely treat fatigue without the presence of another indication. Current guidelines recommend cautious individualization of hemoglobin targets for those at low cardiovascular risk who still experience fatigue or functional limitation despite a hemoglobin level of 10 g/dl. Sodium bicarbonate supplementation for the treatment of metabolic acidosis may also improve functional status. Selective serotonin reuptake inhibitors have not been consistently shown to improve fatigue in patients with kidney disease, but an ongoing trial will evaluate the effect of alternative antidepressant drug and behavioral activation therapy on fatigue in patients with CKD. Overall, more research is needed to further clarify underlying mechanisms of fatigue and identify effective, targeted treatments for patients with CKD.

mHealth-based experience sampling method to identify fatigue in the context of daily life in haemodialysis patients.

Background: Fatigue in haemodialysis (HD) patients is a prevalent but complex symptom impacted by biological, behavioural, psychological and social variables. Conventional retrospective fatigue questionnaires cannot provide detailed insights into symptom variability in daily life and related factors. The experience sampling methodology (ESM) overcomes these limitations through repeated momentary assessments in patients' natural environments using digital questionnaires. This study aimed to gain in-depth understanding of HD patients' diurnal fatigue patterns and related variables using a mobile Health (mHealth) ESM application and sought to better understand the nature of their interrelationships. Methods: Forty HD patients used the mHealth ESM application for 7 days to assess momentary fatigue and potentially related variables, including daily activities, self-reported physical activity, social company, location and mood. Results: Multilevel regression analyses of momentary observations (n = 1777) revealed that fatigue varied between and within individuals. Fatigue was significantly related to HD treatment days, type of daily activity, mood and sleep quality. Time-lagged analyses showed that HD predicted higher fatigue scores at a later time point (ß = 0.22, P = 0.013). Interestingly, higher momentary fatigue also significantly predicted more depressed feelings at a later time point (ß = 0.05, P = 0.019) but not the other way around. Conclusions: ESM offers novel insights into fatigue in chronic HD patients by capturing informative symptom variability in the flow of daily life. Electronic ESM as a clinical application may help us better understand fatigue in HD patients by providing personalized information about its course and relationship with other variables in daily life, paving the way towards personalized interventions.