Long-term effects of melatonin on quality of life and sleep in haemodialysis patients (Melody study): a randomized controlled trial.

AIM: The disturbed circadian rhythm in haemodialysis patients results in perturbed sleep. Short term melatonin supplementation has alleviated these sleep problems. Our aim was to investigate the effects of long-term melatonin supplementation on quality of life and sleep. METHODS: In this randomized double-blind placebo-controlled trial haemodialysis patients suffering from subjective sleep problems received melatonin 3 mg day(-1) vs. placebo during 12 months. The primary endpoint quality of life parameter 'vitality' was measured with Medical Outcomes Study Short Form-36. Secondary outcomes were improvement of three sleep parameters measured by actigraphy and nighttime salivary melatonin concentrations. RESULTS: Sixty-seven patients were randomized. Forty-two patients completed the trial. With melatonin, no beneficial effect on vitality was seen. Other quality of life parameters showed both advantageous and disadvantageous effects of melatonin. Considering sleep, at 3 months sleep efficiency and actual sleep time had improved with melatonin compared with placebo on haemodialysis days (difference 7.6%, 95% CI 0.77, 14.4 and 49 min, 95% CI 2.1, 95.9, respectively). At 12 months none of the sleep parameters differed significantly from placebo. Melatonin salivary concentrations at 6 months had significantly increased in the melatonin group compared with the placebo group. CONCLUSIONS: The high drop-out rate limits the strength of our conclusions. However, although a previous study reported beneficial short term effects of melatonin on sleep in haemodialysis patients, in this long-term study the positive effects disappeared during follow up (6-12 months). Also the quality of life parameter, vitality, did not improve. Efforts should be made to elucidate the mechanism responsible for the loss of effect with chronic use.

The effects of melatonin on sleep-wake rhythm of daytime haemodialysis patients: a randomized, placebo-controlled, cross-over study (EMSCAP study).

AIM: The aim of this study was to investigate the effects of exogenous melatonin on sleep-wake rhythm in haemodialysis patients. METHODS: The study design is a randomized, double-blind, placebo-controlled, cross-over study of 3 x 6 weeks melatonin 3 mg at 22.00 h every night. Haemodialysis patients were asked to fill out a sleep questionnaire and to wear an actometer to record their sleep problems objectively. Furthermore, melatonin concentrations in saliva were sampled the night after daytime haemodialysis and the consecutive night. Actometers, the sleep questionnaire and melatonin concentrations were repeated during the study. RESULTS: In total, 20 patients (six female, median age 71 years) completed the investigation. On nights after daytime dialysis, objective sleep onset latency decreased significantly from a median of 44.5 (placebo) to a median of 15.5 min with melatonin (P < 0.01). Sleep efficiency increased from 67.3 to 73.1% with melatonin (P < 0.05). Actual sleep time increased from 376 min (placebo) to 388 min with melatonin (P < 0.01), and sleep fragmentation decreased from 4.5 to 3.1 (P < 0.01). Furthermore, subjective sleep parameters improved also. Patients reported less time needed to fall asleep (P < 0.05) and fewer wake periods (P < 0.05) on the nights with and without daytime dialysis and an increase in sleep time on the night of daytime dialysis (P < 0.05). Furthermore, the nocturnal melatonin rise was recovered. CONCLUSION: Treatment with melatonin resulted in an improvement of subjective and objective sleep parameters, as well as a recovered nocturnal melatonin rhythm.

Influence of different haemodialysis modalities on AGE peptide levels: intradialytic versus long-term results.

BACKGROUND: Peptide-linked degradation products of advanced glycation end products (AGE peptides) accumulate in chronic haemodialysis (HD) patients and may contribute to a number of HD-related long-term complications, such as accelerated atherosclerosis. METHODS: The influence of a single HD session versus long-term HD on serum AGE peptides was determined. The patients were randomized to HD with a low-flux polysulfone (PS; F 6HPS), a high-flux PS (F 60S), a superflux PS (F 500S), or a superflux cellulose triacetate (CTA; Tricea 150G) dialyzer. RESULTS: During a single HD session, both AGE peptides and reference peptides decreased significantly (AGE peptides: Tricea 150G -37.0 +/- 2.9%; F 6HPS -35.5 +/- 2.4%; F 60S -39.5 +/- 4.7%, and F 500S -43.3 +/- 2.1%, p = 0.005; reference peptides: Tricea 150G -73.2 +/- 8.8%; F 6HPS -73.2 +/- 7.9%; F 60S -72.5 +/- 8.2%, and F 500S -74.1 +/- 7.3%, p = 0.005). After 12 weeks of HD with the superflux CTA, the AGE peptide levels decreased significantly (week 1: 2.7 +/- 1.1 arbitrary units, week 12: 2.5 +/- 1.2 arbitrary units, decrease 7.4%; p = 0.01), whereas the AGE peptide levels remained unchanged after HD with each of the other three modalities. The reference peptide levels did not change after 12 weeks of HD. CONCLUSION: Although AGE peptides can be effectively removed during a single HD session, superflux CTA seems to be the only modality capable of reducing AGE peptides in the long term.

Improvement of a chronic rat model for peritoneal dialysis by using heparin-coated catheters.

The use of silicone peritoneal catheters, connected to implanted subcutaneous mini vascular access ports, was an essential step in the development of a widely used rat model for peritoneal dialysis (PD). Despite the model's many advantages, it has one major disadvantage: a high drop-out rate because of omental wrapping of the silicone catheter. To investigate whether heparinization of the peritoneal catheter reduces the high drop-out rate in the model, we infused rats with conventional PD fluid through either a regular silicone catheter (PDF, n = 14) or a heparin-coated catheter (PDF-h, n = 15) daily for 5 weeks. Untreated rats served as a control group (control, n = 7). We used various peritoneal tissues for cellular and morphologic analysis by light and electron microscopy. We found a statistically significant, lower rate of drop-out in rats implanted with heparin-coated catheters (20%) than in rats implanted with regular silicone catheters (57%, p < 0.05). No significant differences were seen between the two treated groups with regard to the PD fluid-induced angiogenic response in omentum and mesentery. Likewise, instillation of PD fluid resulted in a similar cellular response (increased numbers of mast cells and milky spots in the omentum and mesothelial regeneration on the liver) in both groups regardless of heparin coating. Based on our results, we recommend the use of heparin-coated catheters for instillation of dialysis solutions in the chronic PD model in the rat.

Peritoneal exposure model in the rat as a tool to unravel bio(in)compatibility of PDF.

Patients treated with peritoneal dialysis (PD) are at risk for development of ultrafiltration failure and peritonitis. The relative unphysiologic composition of the currently used peritoneal dialysis fluids (PDF) is a major cause for the development of morphologic changes of the peritoneal membrane such as fibrosis and new vessel formation, ultimately resulting in ultrafiltration failure. In recent years, a major research focus has become the development of new and improved PDF. Typically, the first phase of biocompatibility testing of new PDF involves in vitro testing, using cell culture systems such as primary mesothelial cells or peritoneal macrophages. In vivo studies using animal models permit the analysis of biocompatibility under conditions that allow for cell-to-cell interactions and dynamic changes in solution composition that more closely mimic the clinical situation. In this paper, we will review the applicability of a peritoneal exposure model in the rat to study PDF biocompatibility-related issues.

The management of xerostomia in patients on haemodialysis: comparison of artificial saliva and chewing gum.

Many patients on haemodialysis (HD) therapy suffer from a dry mouth and xerostomia. This can be relieved by mechanical and gustatory stimulation or palliative care. The aim of this crossover study was to investigate the effect and preferences of a sugar-free chewing gum (Freedent White) and a xanthan gum-based artificial saliva (Xialine) in the management of xerostomia in chronic HD patients. Sixty-five HD patients participated in a 6-week crossover trial. The artificial saliva was rated significantly lower than the chewing gum for effectiveness, taste and a global assessment. No preference differences were found for gender and age, although older subjects rated the artificial saliva with a higher mark. Thirty-nine subjects (60%) preferred chewing gum, 15% (n=10) preferred the artificial saliva. Therefore, both chewing gum and artificial saliva could play an important role in the palliative care of xerostomia in HD patients.

Chewing gum and a saliva substitute alleviate thirst and xerostomia in patients on haemodialysis.

BACKGROUND: Most patients on haemodialysis (HD) have to maintain a fluid-restricted diet to prevent a high interdialytic weight gain (IWG). The prevalence of xerostomia (the feeling of a dry mouth) is higher in HD patients than in controls. Recently, we demonstrated that xerostomia and thirst were positively correlated with IWG in HD patients. Thus, this may play a role as a stimulus for fluid intake between dialysis sessions. The aim of the present study was to investigate the effect of chewing gum or a saliva substitute on xerostomia, thirst and IWG. METHODS: This study was a randomized two-treatment crossover design with repeated measures. After the use of chewing gum or saliva substitute for 2 weeks, a wash-out period of 2 weeks was introduced and hereafter the other regimen was carried out. Xerostomia and thirst were assessed by validated questionnaires as xerostomia inventory (XI) and dialysis thirst inventory (DTI), at baseline and after each treatment period, as were IWG and salivary flow rates. RESULTS: Sixty-five HD patients (42 men, 54.6+/-14.1 years; 23 women, 54.7+/-16.3 years) participated in this study. Chewing gum decreased XI from 29.9+/-9.5 to 28.1+/-9.1 (P<0.05). Chewing gum as well as a saliva substitute reduced DTI significantly (P<0.05), but no differences occurred for the average IWG or salivary flow rates. CONCLUSIONS: The use of chewing gum and, to a lesser extent, a saliva substitute may alleviate thirst and xerostomia in some HD patients.

Enhanced long-term reduction of plasma leptin concentrations by super-flux polysulfone dialysers.

BACKGROUND: Hyperleptinaemia in chronic haemodialysis (CHD) patients has been associated with malnutrition, which is an independent predictor of morbidity and mortality in this patient group. METHODS: To assess the influence of HD on plasma leptin, 10 CHD patients were crossover randomized to low-flux polysulfone (PS: F 6HPS), high-flux PS (F 60S), super-flux PS (F 500S) or super-flux cellulose-tri-acetate (CTA: Tricea 150G) for 12 weeks each. Blood samples were collected at the start of the study and each 12-week period. In addition, the relationship between patient characteristics, inflammation and leptin was analysed. RESULTS: At baseline, all groups showed similar leptin concentrations (mean 33.6+/-21.7 ng/ml). After a single HD session, a significant (P<0.01) decrease was observed with all three high permeable devices (Tricea 150G -52.7+/-6.4%; F 60S -63.1+/-5.7%; F 500S -68.7+/-8.2%), whereas leptin remained stable with low-flux PS. After 12 weeks, a marked increase was observed with low-flux PS (week 1, 30.4+/-23.0; week 12, 40.5+/-5.4 ng/ml, P = 0.05), no change with super-flux CTA and high-flux PS (Tricea 150G week 1, 29.4+/-23.7; week 12, 32.0+/-27.9 ng/ml, P = ns; F 60S week 1, 36.0+/-31.8; week 12, 33.0+/-31.2 ng/ml, P = ns), and a significant decrease with super-flux PS (week 1, 38.3+/-33.0; week 12, 29.5+/-31.9 ng/ml, P = 0.02). The change in leptin after 12 weeks was significantly different between super-flux PS, and both low-flux PS (P = 0.009) and super-flux CTA (P = 0.01). Besides interleukin-6 (IL-6) at the start of the study (P = 0.006), no correlations were observed between patient characteristics, parameters of inflammation and plasma leptin levels. CONCLUSIONS: Apart from low-flux PS, plasma leptin decreased considerably with all three high permeable dialysers after a single HD session. In the long run, leptin levels were lower with high-flux PS than with low-flux PS. Moreover, after switching from high-flux PS to super-flux PS (but not super-flux CTA), an additional decrease in leptin was observed. Apart from IL-6 at the start of the study, neither patient characteristics nor inflammatory parameters correlated with plasma leptin levels in this patient group.

Interdialytic weight gain in patients on hemodialysis is associated with dry mouth and thirst.

BACKGROUND: Patients receiving hemodialysis (HD) have to maintain a fluid-restricted diet. Severe thirst can induce noncompliance to this diet, resulting in an increase of interdialytic weight gain (IWG = weight predialysis - postdialysis) associated with poor patient outcomes. Because oral dryness may contribute to experienced thirst, we investigated the possible relation between thirst, salivary flow rate, xerostomia, and IWG. METHODS: Unstimulated (UWS) and stimulated (CH-SWS) whole saliva were collected from 94 HD patients (64 men, 54.8 +/- 15.5 years; 30 women, 59.5 +/- 18.7 years). Secretion rates of saliva were determined gravimetrically. Xerostomia was assessed with a validated Xerostomia Inventory (XI), and thirst with a newly developed Dialysis Thirst Inventory (DTI). RESULTS: Before dialysis, 36.2% of the patients had hyposalivation (UWS < or =0.15 mL/min). The XI scores had a positive relation with IWG (r=.250, P < 0.001). Gender and age differences were observed for thirst, salivary flow rates, and xerostomia. The prevalence and severity of thirst and xerostomia were greater in younger subjects. Patients with urine output did not differ from those without urine output with respect to thirst, xerostomia, and IWG. Correlations were found between thirst (DTI) and both IWG and xerostomia (XI) (r=.329, P < 0.001, respectively; r=.740, P < 0.001). Other correlations were observed between xerostomia and both the salivary flow rate and total number of medications (r=-.252, P < 0.05, respectively; r=.235, P <.05). CONCLUSION: In HD patients, xerostomia (XI) and thirst (DTI) are associated with a higher IWG. Our data provide evidence that, in HD patients, xerostomia is related to both salivary flow rate and thirst (DTI).