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.

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.

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.

Peridialytic serum cytokine levels and their relationship with postdialysis fatigue and recovery in patients on chronic haemodialysis - A preliminary study.

BACKGROUND: The aetiology of postdialysis fatigue (PDF), an intermittent but debilitating fatigue occurring after haemodialysis (HD) treatment, is still unclear. In other inflammatory diseases, increasing evidence points toward the involvement of the immune system in the onset of fatigue symptoms. Altered serum levels of inflammatory cytokines have also been shown in HD patients. Therefore, we investigated whether pre- and postdialysis serum levels of pro- and anti-inflammatory cytokines (i.e. IL-1ß, IL-6, TNF-α and IL-10) or their intradialytic changes (if any) were related to PDF or the time HD patients reported needing to recover from HD treatment (TIRD). METHODS: Serum levels of IL-1ß, IL-6, TNF-α and IL-10 were measured immediately before and after HD in 45 patients using commercially available kits on an ELLA™ automated immunoassay system. The presence and severity of PDF as well as TIRD duration were assessed by self-report measures. KEY RESULTS: Seventy-four percent of patients reported PDF, with a median PDF severity index of 3.30 [IQR: 3.00-4.30] on a scale from 1 to 5. Median TIRD was 120 min [IQR: 60-480]. PDF severity correlated strongly with TIRD, rs = 0.85, p < 0.001. Only predialysis levels of IL-10 significantly and positively correlated with PDF severity (rs = 0.43, p = 0.003). CONCLUSION: Findings of the present study do not support the involvement of the immune system in the onset of PDF or the time patients needed to recover from HD treatment. A positive, but counterintuitive relationship was found between predialysis levels of anti-inflammatory IL-10 and PDF severity, which warrants further research.

Serum interleukin-6 and endotoxin levels and their relationship with fatigue and depressive symptoms in patients on chronic haemodialysis.

BACKGROUND: Little is known about the underlying aetiology of fatigue in haemodialysis (HD) patients apart from a significant association and overlapping symptomatology with depressive symptoms. Growing evidence exists for the involvement of the immune system, by pro-inflammatory cytokines, in the development of fatigue in other inflammatory diseases. In HD patients, increased exposure to bacterial endotoxins may contribute to an inflammatory response and may potentially lead to fatigue. We therefore aimed (i) to assess the interrelationship between serum endotoxin (EA) levels, interleukin-6 (IL-6) levels and fatigue in HD patients; (ii) to evaluate whether there is a relationship between depressive symptoms and inflammation as well and (iii) to what extent depressive symptoms and fatigue are related to each other. METHODS: Fatigue and depressive symptoms in daily life were assessed in 59 individuals using the SF-36 vitality subscale and the Geriatric Depression Scale. Blood samples were collected on a mid-week dialysis session to determine EA levels, through the Endotoxin Activity Assay (EAA™), and IL-6 concentrations, through the commercially available Abcam ELISA (Enzyme-Linked Immunosorbent Assay) kit. RESULTS: EA, IL-6 levels and depressive symptoms were significantly correlated with fatigue. EA levels and depressive symptoms were significant predictors of fatigue, explaining 31% of its variance. However, EA and IL-6 were not significantly associated with depression. CONCLUSIONS: Fatigue in HD patients may be related to endotoxemia and inflammation through IL-6. Furthermore, fatigue is significantly associated with depressive symptoms. Future research into the causal interrelationship of inflammation, fatigue and depression in HD patients might lead to potential targets for therapeutic strategies.

Comparison of the effects of hemodialysis and hemodiafiltration on left ventricular hypertrophy in end-stage renal disease patients: A systematic review and meta-analysis.

Whether hemodiafiltration (HDF) is better than conventional hemodialysis (HD) in improving left ventricular hypertrophy (LVH), defined as reduction of the left ventricular mass index (LVMi) and increasing the ejection fraction (EF), is unclear. A systematic literature search was performed. Primary outcome was the mean difference between pre- and post-procedural LVMi. Secondary outcome was the mean difference in EF. Seven studies with a total of 845 patients were included. The pooled mean difference between pre-and post-procedural LVMi was -8.0 g/m2 (95% confidence interval [CI] -13.1, -2.8). On subgroup analysis, the mean differences between pre- and post-procedural LVMi for HD and HDF were -6.7 g/m2 (95% CI -14.5, 1.1) and -9.3 g/m2 (95% CI -16.3, -2.3), respectively (P for subgroups = .62). Pooled mean difference between pre- and post-procedural EF was 2.4% (95% CI -1.8, 6.5). On subgroup analysis, the mean differences between pre- and post-procedural EF for HD and HDF were 3.6% (95% CI -2.7, 9.8) and 2.0% (95% CI 2.9, 6.8), respectively (P for subgroups = .68). On meta-regression, age (Beta -0.35 ± 0.05, P < .001) and longer dialysis duration (Beta -0.12 ± 0.02, P < .001) were associated with lower mean difference between pre-and post-procedural EF. No significant effects on changes in LVMi and EF were observed with HDF compared with conventional HD.

Reward (BIS/BAS) mechanisms and fatigue in patients on chronic hemodialysis.

Recently, it has been demonstrated that chronic inflammation could have a role on fatigue onset in chronic hemodialysis (HD). Research on neuro-immune interactions highlighted that an alteration of basal ganglia functioning, secondary to chronic inflammation, may translate in a reduced motivation and altered reward processes in chronic diseases. This study investigated a possible correlation between fatigue severity and reward mechanisms, that regulate motivational dispositions, in HD patients. Evaluation scales were administered to ninety-four patients on HD (54 Male, 40 Female; Mdage = 67±26.5; Dialytic Mdage in years = 4±6.3. Fatigue was assessed by using Fatigue Severity Scale (FSS). Behavioural Inhibition System (BIS) and Behavioural Activation System (BAS) Scale was administered to investigate approach/avoidance behaviours. Anxiety and depression were measured by State-Trait Anxiety Inventory (STAI-Y) and Beck Depression Inventory (BDI-II). Results show that the distribution of HD patients for FSS score did not show a normal pattern. FSS score was significantly higher in patients with high BIS Z-score than in patients with low and medium BIS Z-score. BDI score and STAI-Y scores were similar among BIS Z-score groups of patients. Findings suggest that in patients on chronic hemodialysis there is a correlation between fatigue severity symptoms and motivational disposition mechanisms that predispose to action inhibition.

Xerostomia in patients on chronic hemodialysis: An update.

Xerostomia, or dryness of oral cavity, is relatively common in patients on chronic hemodialysis and significantly impairs their quality of life. Xerostomia is often the consequence of reduced salivary flow resulting from atrophy and fibrosis of the salivary glands, an event that is of uncertain origin. Many medications commonly used in dialysis patients may also cause or exacerbate xerostomia. Its consequences may be serious and disturbing and include difficulties in chewing, swallowing, tasting, and speaking; increased risk of oral disease, including lesions of the mucosa, gingiva and tongue; bacterial and fungal infections, such as candidiasis, dental caries, and periodontal disease; interdialytic weight gain resulting from increased fluid intake; and a reduction in the quality of life. Therapeutically, stimulation of the salivary glands to increase the production of saliva mechanically by chewing-gum, mouthwash, acupressure, or transcutaneous electrical stimulation has had modest success. However, the long-term effectiveness of such treatments still needs to be investigated and defined. Xerostomia remains a frustrating and disturbing symptom for patients on hemodialysis. Further efforts should be made to find the causes and the mechanisms of the reduced salivary flow observed in patients on chronic hemodialysis.

Recovery Time after Hemodialysis Is Inversely Associated with the Ultrafiltration Rate.

INTRODUCTION: The present study aimed to determine the variables that are associated with a longer dialysis recovery time (DRT) and to define the relationship that exists between DRT and the ultrafiltration rate (UFR) in prevalent chronic hemodialysis (CHD) patients. METHODS: We studied 210 prevalent CHD of 5 hemodialysis units in Central Italy. Patients were invited to answer to the question: "How long does it take you to recover from a dialysis session?" Answers to this question were subsequently converted into minutes. Demographic, clinical and laboratory parameters were recorded for each patient as well as the UFR (mL/kg/h), the dialysate sodium concentration and temperature. RESULTS: Median DRT was 180 min (60-420). Ninety five (45%) patients had a DRT ≥ the median value. Mean UFR was 9.2 ± 3.0 mL/kg/h. Patients with a lower DRT had a less prevalent disability in the instrumental activities daily living, had a higher UFR, and a lower dialysate temperature, as compared with subjects with higher DRT. According to the logistic regression model, UFR was associated with a DRT below the median (i.e., 180) in the unadjusted model (OR 1.12; 95% CI 1.02-1.23; p = 0.019), after adjusting for age and sex (OR 1.11; 95% CI 1.01-1.22; p = 0.025), and in the fully adjusted model (OR 1.11; 95% CI 1.04-1.22; p = 0.040). UFR increase was associated with increasing probability of DRT below the median (p for trend = 0.035). The highest tertile of DRT was associated with UFR below the mean value (i.e., 9.2 mL/kg/h) in multinomial logistic regression having the lowest DRT tertile as reference. DRT was significantly lower in patients with UFR > 13 mL/kg/h than in patients with UFR 10-13 or < 10 mL/kg/h. CONCLUSION: DRT is inversely associated with UFR in CHD patients. Whether a high UFR should be recommended to reduce the DRT needs to be elucidated through an adequate prospective randomized study.

Update on mitochondria and muscle aging: all wrong roads lead to sarcopenia.

Sarcopenia is a well-known geriatric syndrome that has been endorsed over the years as a biomarker allowing for the discrimination, at a clinical level, of biological from chronological age. Multiple candidate mechanisms have been linked to muscle degeneration during sarcopenia. Among them, there is wide consensus on the central role played by the loss of mitochondrial integrity in myocytes, secondary to dysfunctional quality control mechanisms. Indeed, mitochondria establish direct or indirect contacts with other cellular components (e.g. endoplasmic reticulum, peroxisomes, lysosomes/vacuoles) as well as the extracellular environment through the release of several biomolecules. The functional implications of these interactions in the context of muscle physiology and sarcopenia are not yet fully appreciated and represent a promising area of investigation. Here, we present an overview of recent findings concerning the interrelation between mitochondrial quality control processes, inflammation and the metabolic regulation of muscle mass in the pathogenesis of sarcopenia highlighting those pathways that may be exploited for developing preventive and therapeutic interventions against muscle aging.

Prevalence and associated variables of post-dialysis fatigue: Results of a prospective multicentre study.

AIM: The study aims to determine prevalence and severity of PDF and to define its associated variables. METHODS: In five haemodialysis units of northern-centre Italy, patients were regarded to suffer from PDF if they spontaneously offered this complaint when asked the open-ended question: Do you feel better or worse after dialysis? If worse, please specify in which way. A complaint of fatigue would be probed further with questions directed at its duration, frequency and intensity, allowing creation of a fatigue index of severity (one third of the sum of these three parameters, each rated from 1 to 5). Patients were stratified into three groups according the severity of PDF: 1) score = 0; 2) score = 1-3; 3) score > 3. RESULTS: We studied 271 patients: 164 had PDF and 107 did not. PDF patients had significantly longer time of recovery after dialysis (TIRD). TIRD was significantly associated with PDF duration, intensity, and frequency. Patients with PDF were older and had a lower ADL score. At multivariate analysis, PDF was significantly associated with TIRD. In a multivariate model that did not include TIRD, PDF was independently associated with age and ADL. Sixty patients had moderate PDF and 104 had severe PDF. In patients with severe PDF, age and dialytic age were higher, ADL and IADL scores were lower, TIRD was longer and the ultrafiltration rate was lower. At multivariate analysis, PDF severity was independently associated with TIRD. In the model without TIRD, PDF severity was associated with ADL only. CONCLUSION: Post-dialysis fatigue is frequent and associated with age and ADL. Dialytic variables seem unrelated to PDF.

The Frustrating Attempt to Limit the Interdialytic Weight Gain in Patients on Chronic Hemodialysis: New Insights Into an Old Problem.

A significant percentage of patients on chronic hemodialysis have an interdialytic weight gain (IDWG) above the recommended values. High IDWG has detrimental effects on survival, cardiovascular outcomes, and quality of life. High IDWG is secondary to poor adherence to fluid restriction and to excessive intake of fluids, due to thirst and xerostomia. Various strategies have been proposed to limit IDWG such as the reduction of dietary salt intake, behavioral interventions aimed at improving the adherence to fluid restriction, the improvement of xerostomia, and the use of lower dialysate sodium concentration. The present narrative review aims to evaluate the efficacy of each of such strategies.

Health-related quality of life of patients on chronic dialysis: The need for a focused effort.

Health-related quality of life (HRQOL) in patients on chronic hemodialysis has not improved significantly in the last 20 years. This is largely due to their substantial symptom burden which is rarely assessed and treated in routine clinical practice. It also is a consequence of the lack of an appropriate armamentarium for the treatments of such symptoms. Adequate studies on the causes and pathogenesis of the symptoms of hemodialysis patients are needed followed by high quality studies on possible therapeutic pharmacological and nonpharmacological interventions.

Spatial distribution of kidney disease in the contaminated site of Taranto (Italy).

BACKGROUND: Exposure to heavy metals has been associated with kidney disease. We investigated the spatial distribution of kidney disease in the industrially contaminated site of Taranto. METHODS: Cases were subjects with a first hospital discharge diagnosis of kidney disease. Cases affected by specific comorbidities were excluded. Standardized Hospitalization Ratios (SHRs) were computed for low/high exposure area and for modeled spatial distribution of cadmium and fine particulate matter. RESULT: Using the high/low exposure approach, in subjects aged 20-59 years residing in the high exposure area a significant excess of hospitalization was observed in males and a non-significant excess in females. No excesses were observed in subjects aged 60 years and over. The analysis by the modeling approach did not show a significant association with the greatest pollution impact area. CONCLUSION: Due to the excesses of hospitalization observed in the high/low exposure approach, a continuing epidemiological surveillance of residents and occupational groups is warranted.

Fatigue in kidney transplant recipients.

Fatigue is still present in approximately 40%-50% of kidney transplant recipients (KTR), rates comparable to that of the hemodialysis population. Correlates of fatigue include inflammation, symptoms of depression, sleep disorders, and obesity. Fatigue in KTR determines a significant severe functional impairment, either when globally considered or when analyzed at the level of the single domains such as sleep and rest, homemaking, mobility, social interaction, ambulation, leisure activities, alertness behavior, and work limitations. In addition, fatigue in KTR is significantly associated with a severe deterioration of quality of life. Fatigue is very common among KTR poorly adherent to immunosuppressive therapy. Unfortunately, there is no evidence of studies about the treatments of this symptom in KTR. Efforts to detect and treat fatigue should be a priority in order to improve quality of life of KTR.

Parathyroid Ultrasonography in Renal Secondary Hyperparathyroidism: An Overlooked and Useful Procedure.

In secondary hyperparathyroidism (SHPT), ultrasonography (US) can accurately define the size and structure of parathyroid glands as well as differentiate diffuse and nodular hyperplasia. US may be also useful to predict the response of SHPT to vitamin D analogs and cinacalcet and to assess for regression of parathyroid glands hyperplasia by measurement of parathyroid gland volume. There is increasing evidence that US can potentially identify patients who will benefit from prompt surgical intervention. Therefore, US should be part of the diagnostic armamentarium in the treatment of SHPT in the daily clinical practice.

Postdialysis Fatigue: A Frequent and Debilitating Symptom.

Postdialysis fatigue (PDF) is a frequent and debilitating symptom of patients on chronic hemodialysis that affects their daily living and quality of life. Little is known about the mechanisms underlying this symptom and its severity. Only a few studies have investigated therapeutic interventions and with conflicting results. Given the major impact of PDF on the quality of life of hemodialysis patients, a larger effort is warranted to better understand, prevent, and treat PDF.

Skeletal muscle regeneration in cancer cachexia.

Muscle wasting is the most important phenotypic and clinical feature of cancer cachexia, and the principal cause of impaired physical function, fatigue, and respiratory complications. Muscle loss has been attributed to a variable combination of reduced nutritional intake and an imbalance between anabolic and catabolic processes. It has been suggested that defective skeletal muscle regeneration may also contribute to muscle wasting in cancer patients. However, there is little in vitro or in vivo data available, in either animals or in humans, regarding skeletal muscle regeneration in cancer wasting. The aim of the present review is to define the role of skeletal muscle regeneration in the muscle wasting of cancer patients and to determine possible therapeutic implications.

Serum Endotoxin Activity Measured with Endotoxin Activity Assay Is Associated with Serum Interleukin-6 Levels in Patients on Chronic Hemodialysis.

BACKGROUND: This study aims to evaluate, in patients on chronic hemodialysis (PHD), the levels of endotoxin through a chemiluminescent bioassay based on the oxidative burst reaction of activated neutrophils to complement coated LPS-IgM immune complexes and define the variables possibly correlated. METHODS: In 61 PHD, we measured serum endotoxin activity (EA) with the Endotoxin Activity Assay (EAA™) and we defined the possible association with demographic, clinical and laboratory variables. RESULTS: Mean serum EA was 0.43 ± 0.26 UI. EA was low (<0.40) in 29 patients (47.5%), intermediate (0.40-0.60) in 14 (23%) and high (>0.60) in 18 (29.5%). A significant exponential relationship was detected between EA and serum interleukin-6 (IL-6) levels (r = 0.871). At the multiple regression analysis, intermediate-high EA was directly associated only with serum IL-6 levels. In a second model of multiple regression analysis without the variable serum IL-6 levels, intermediate-high EA was directly associated with constipation and serum troponin levels and inversely associated with serum albumin and the monthly number of sevelamer tablets. CONCLUSIONS: A high percentage of PHD has intermediate or high EA. Intermediate-high EA is significantly associated with serum IL-6 levels.

Mortality in hospitalized chronic kidney disease patients starting unplanned urgent haemodialysis.

AIM: Data on the outcome of chronic kidney disease (CKD) patients who are hospitalized and start unplanned urgent haemodialysis (HD) are lacking. This prospective, longitudinal, observational study aimed to define the hospital mortality rate and associated factors in CKD patients who start unplanned urgent HD. METHODS: Between January 2003 and December 2009, all patients with CKD who were hospitalized, diagnosed with ESRD and started unplanned urgent haemodialysis at Haemodialysis Service of the Catholic University of Rome, Italy were recruited. Exclusion criteria were: acute renal failure, prior history of dialysis, multiple organ failure, coma, and dementia. Hospital mortality rate was the primary outcome. RESULTS: Three and hundred sixteen patients were studied: 99 died after 19.5 ± 27.3 days and 217 survived until discharge. Of these, 154 were prescribed chronic HD and 63 restored renal function. Patients who died were significantly older and had a higher Charlson Comorbidity Index score. The mortality rates were 51.1% in patients with 81-90 years, 37.8% with 71-80 years, 34.1% with 61-70 years and 13.9% with age ≤60 years. Logistic regression analysis showed that age only was an independent risk factor for all-cause mortality. CONCLUSIONS: In CKD patients who need hospitalization and start unplanned urgent haemodialysis the mortality is very high and significantly related to age.