The pineal hormone melatonin plays a major role in circadian sleep-wake rhythm. Patients with Chronic Kidney Disease (CKD), especially those who are on hemodialysis, frequently suffer from sleep disturbances. In this review an overview is given of the classification of stages of chronic kidney disease, followed by a presentation of the circadian rhythm disorders in renal disease involving sleep disturbances in relation to melatonin deficiency. The therapeutic benefit of melatonin treatment in sleep disorders related to chronic kidney disease including the controlled trials solving this topic, is described. Furthermore, the beneficial effect of melatonin on blood pressure alterations in CKD states and the protection of melatonin in oxidative stress and inflammation in renal disorders are explored. Finally a hypothetic model is described for the relation between circadian rhythm disorders and CKD.

AIMThe 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. METHODSIn 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. RESULTSSixty-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. CONCLUSIONSThe 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 quality of life of hemodialysis (HD) patients is hampered by reduced nocturnal sleep quality and excessive daytime sleepiness. In addition to the sleep/wake cycle, levels of circadian biomarkers (e.g. melatonin) are disturbed in end-stage renal disease (ESRD). This suggests impaired circadian clock performance in HD patients, but the underlying mechanism is unknown. In this observational study, diurnal rhythms of sleep, serum melatonin and cortisol concentrations and clock gene mRNA expression are compared between HD patients (n = 9) and healthy control subjects (n = 9). In addition, the presence of circulating factors that might affect circadian rhythmicity is tested in vitro with cell culture experiments. Reduced sleep quality (median sleep onset latency [interquartile range] of 23.9 [17.3] min for patients versus 5.0 [10] minutes for controls, p < 0.01; mean (± SD) sleep efficiency 70.2 ± 8.1% versus 82.9 ± 10.9%, p = 0.02 and mean awake minutes after sleep onset 104.8 ± 27.9 versus 54.6 ± 41.6 minutes, p =  0.01) and increased daytime sleepiness (mean Epworth Sleepiness Score of 10.0 ± 4.8 versus 3.9 ± 2.0, p < 0.01) were confirmed in HD patients. Reduced nocturnal melatonin concentrations (1 AM: 98.1 [122.9] pmol/L versus 12.5 [44.2] pmol/L, p =  0.019; 5 AM: 114.0 [131.6] pmol/L versus 11.8 [86.8] pmol/L, p =  0.031) and affected circadian control of cortisol rhythm and circadian expression of the clock gene REV-ERBα were found. HD patient serum had a higher capacity to synchronize cells in vitro, suggesting an accumulated level of clock resetting compounds in HD patients. These compounds were not cleared by hemodialysis treatment or related to frequently used medications. In conclusion, the abovementioned results strongly suggest a disturbance in circadian timekeeping in peripheral tissues of HD patients. Accumulation of clock resetting compounds possibly contributes to this. Future studies are needed for a better mechanistic understanding of the interaction between renal failure and perturbation of the circadian clock.

Background: Sleep disturbance is an important medical problem in patients with end-stage renal disease. It might be related to the disruption of the body's circadian clock since nocturnal levels of its key biomarker melatonin are markedly reduced. We aimed at investigating whether a change in renal function due to kidney transplantation or donation would modify sleep, melatonin levels, circadian rhythmicity, and quality of life in kidney transplant recipients (KTR) and living donors (LD). Methods: In KTR, we assessed saliva melatonin concentrations, sleep quality and daytime sleepiness prior to and at 2 weeks and 3 months after transplantation. In LD, we assessed these parameters prior to and at 3 months after donation. We additionally assessed 24-hour core body temperature (cBT), 24-hour blood pressure profile, and quality of life (QoL) prior to and 3 months after transplantation. Results: Twenty-three KTR and 23 LD completed the study. Regarding sleep, the amount of nighttime awake minutes tended to be reduced in recipients after transplantation (p = 0.05). Nocturnal melatonin concentrations did not change with transplantation or donation. Blood pressure dipping profile and the two circadian markers dim-light melatonin onset and time of core body temperature minimum did not change. Nevertheless, KTR reported that daytime sleepiness and QoL had improved. Conclusion: Objectively nocturnal sleep quality marginally improved after transplantation. Subjectively patients reported improved QoL and daytime sleepiness scores. Changes in renal function were not associated with modified melatonin secretion or circadian rhythmicity.

BackgroundLow-molecular-weight heparins (LMWHs) are frequently used to treat arterial and venous thrombo-embolic events. LMWHs accumulate with renal failure, but only limited clinical data regarding appropriate dosage adjustments are available. Nevertheless, LMWHs are routinely used in these patients worldwide. Although many clinics apply renal function-based dosage reductions, anti-factor Xa (anti-Xa) activity is not measured routinely.MethodsWe determined anti-Xa activity in 51 patients with MDRD-eGFR <60 mL/min/1.73 m2, treated with therapeutic doses of nadroparin according to a standard, renal function-based guideline.ResultsAn a priori dosage reduction resulted in anti-Xa activity within, below and above the reference range in 51, 30 and 19% of the measurements, respectively. Treatment resulted in different anti-Xa activities compared with dosages that were not given according to official advice (P < 0.001). Anti-Xa values increased with longer treatment duration (P = 0.038).ConclusionsA preemptive fixed reduction (25%) of the nadroparin dosage in all patients with renal failure seems appropriate. However, because target anti-Xa activities were reached in only half of the patients, we submit that the use of nadroparin, dosage reduction and monitoring of anti-Xa activity in combination with clinical outcome monitoring in this patient population urgently needs further investigation.