Urinary Excretion of the Main Metabolite of Melatonin Relates to All-Cause and Cardiovascular Mortality in Renal Transplant Recipients

A. van der Veen, I. Minovic, H.J.R. van Faassen, I.P. Kema, S.J.L. Bakker

Friday 16 march 2018

10:25 - 10:30h at Willem Burger Foyer

Categories: Clinical, Session (poster)

Parallel session: Poster session 6: Clinical

Objective

6-sulfatoxymelatonin (6-SM) is the major metabolite of melatonin, a multifaceted hormone that rises during the onset of darkness. Melatonin is rapidly hydroxylated in the liver and conjugated to 6-SM prior to excretion in urine. 24-hour urinary 6-SM (U6-SM) excretion is an integrated measurement of total melatonin production over a day. In patients with chronic kidney disease sleep is often disturbed. This could represent a risk factor for poor long-term outcome. In line with this, we hypothesized that low U6-SM is associated with excess mortality in renal transplant recipients (RTR).

Methods

U6-SM was measured using a newly developed isotope dilution liquid chromatography tandem mass spectrometry (LC-MS/MS) method. The study population consisted of 702 RTR with a functioning graft for at least one year, who visited the outpatient clinic between 2008 and 2010. All participants collected a 24-hour urine sample prior to their visit to the clinic. Baseline associations were explored by linear regression analyses. Kaplan-Meier and Cox regression analyses were employed to investigate the associations of U6-SM with all-cause mortality, cardiovascular mortality and graft-failure.

Results

Mean (±SD) age of the RTR was 53 (±13) years, with 57% males, a mean (±SD) eGFR of 45 (±19) ml/min/1.73m² and the median [IQR] of U6-SM was 13.2 [3.5 – 31.2] nmol/24h. U6-SM was associated among others with age, waist-circumference, eGFR and the use of antihypertensives (standardized ß respectively -0.35, -0.13, 0.17 and -0.20, all p<0.001). After median 5.4 [4.8-6.1] years follow-up 130 RTR died (19%), of whom 48 (37%) due to a cardiovascular cause, and 75 (11%) developed graft failure. U6-SM was significantly associated with all-cause mortality (HR [95%CI]=0.60 [0.44-0.81], p=<0.001) and cardiovascular mortality (HR [95%CI]=0.49 [0.29-0.84], p=0.009), independent of conventional risk factors and kidney function. There was no significant independent association with graft failure (HR [95%CI]= 1.16 [0.79-1.72], p=0.45).

Conclusion

In this study, we found that U6-SM, as a measure of total melatonin production, is inversely associated with all-cause mortality and cardiovascular mortality in RTR. Based on these results, evaluation and management of melatonin metabolism could be considered for improvement of long-term outcomes in RTR.