Unbalanced circulating Humanin levels and cardiovascular risk in chronic hemodialysis patients: a pilot, prospective study.
Biomarker
Cardiovascular risk
End-stage kidney disease
Hemodialysis
Humanin
Journal
Journal of nephrology
ISSN: 1724-6059
Titre abrégé: J Nephrol
Pays: Italy
ID NLM: 9012268
Informations de publication
Date de publication:
05 Aug 2024
05 Aug 2024
Historique:
received:
07
05
2024
accepted:
10
07
2024
medline:
5
8
2024
pubmed:
5
8
2024
entrez:
5
8
2024
Statut:
aheadofprint
Résumé
Mortality and cardiovascular (CV) risk prediction in individuals with end-stage kidney disease (ESKD) on chronic hemodialysis (HD) remains challenging due to the multitude of implicated factors. In a multicenter ESKD-HD cohort, we tested the prognostic yield of the assessment of circulating Humanin, a small mitochondrial-derived peptide involved in CV protection, on CV events and mortality. We conducted a prospective, observational, pilot study on 94 prevalent HD patients. The prognostic capacity of circulating Humanin levels was tested on a primary composite (all-cause mortality + non-fatal CV events) and a secondary exploratory endpoint (all-cause mortality alone). Baseline Humanin level was comparable in patients reaching the primary or secondary endpoint as compared to others (p = 0.69 and 0.76, respectively). Unadjusted followed by multivariable Cox regression analyses adjusted for age, left ventricular mass index (LVMi), E/e', pulse pressure and diabetes mellitus indicated a non-linear relationship between Humanin levels and the composite outcome with the highest Hazard Ratio (HR) associated with very low (< 450.7 pg/mL; HR ranging from 4.25 to 2.49) and very high (> 759.5 pg/mL; HR ranging from 5.84 to 4.50) Humanin values. Restricted cubic splines fitting univariate and multivariate Cox regression analyses visually confirmed a curvilinear trend with an increasing risk observed for lower and higher Humanin values around the median, respectively. A similar, u-shaped association was also evidenced with the secondary endpoint. Altered Humanin levels may impart prognostic information in ESKD-HD patients at risk of death or CV events. Future investigations are needed to confirm whether Humanin measurement could improve CV and mortality risk prediction beyond traditional risk models.
Sections du résumé
BACKGROUND
BACKGROUND
Mortality and cardiovascular (CV) risk prediction in individuals with end-stage kidney disease (ESKD) on chronic hemodialysis (HD) remains challenging due to the multitude of implicated factors. In a multicenter ESKD-HD cohort, we tested the prognostic yield of the assessment of circulating Humanin, a small mitochondrial-derived peptide involved in CV protection, on CV events and mortality.
METHODS
METHODS
We conducted a prospective, observational, pilot study on 94 prevalent HD patients. The prognostic capacity of circulating Humanin levels was tested on a primary composite (all-cause mortality + non-fatal CV events) and a secondary exploratory endpoint (all-cause mortality alone).
RESULTS
RESULTS
Baseline Humanin level was comparable in patients reaching the primary or secondary endpoint as compared to others (p = 0.69 and 0.76, respectively). Unadjusted followed by multivariable Cox regression analyses adjusted for age, left ventricular mass index (LVMi), E/e', pulse pressure and diabetes mellitus indicated a non-linear relationship between Humanin levels and the composite outcome with the highest Hazard Ratio (HR) associated with very low (< 450.7 pg/mL; HR ranging from 4.25 to 2.49) and very high (> 759.5 pg/mL; HR ranging from 5.84 to 4.50) Humanin values. Restricted cubic splines fitting univariate and multivariate Cox regression analyses visually confirmed a curvilinear trend with an increasing risk observed for lower and higher Humanin values around the median, respectively. A similar, u-shaped association was also evidenced with the secondary endpoint.
CONCLUSIONS
CONCLUSIONS
Altered Humanin levels may impart prognostic information in ESKD-HD patients at risk of death or CV events. Future investigations are needed to confirm whether Humanin measurement could improve CV and mortality risk prediction beyond traditional risk models.
Identifiants
pubmed: 39102184
doi: 10.1007/s40620-024-02032-4
pii: 10.1007/s40620-024-02032-4
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024. The Author(s).
Références
Jankowski J, Floege J, Fliser D, Bohm M, Marx N (2021) Cardiovascular disease in chronic kidney disease: pathophysiological insights and therapeutic options. Circulation 143:1157–1172
doi: 10.1161/CIRCULATIONAHA.120.050686
pubmed: 33720773
pmcid: 7969169
Merry TL, Chan A, Woodhead JST, Reynolds JC, Kumagai H, Kim SJ et al (2020) Mitochondrial-derived peptides in energy metabolism. Am J Physiol Endocrinol Metab 319:E659–E666
doi: 10.1152/ajpendo.00249.2020
pubmed: 32776825
pmcid: 7750512
Kim SJ, Xiao J, Wan J, Cohen P, Yen K (2017) Mitochondrially derived peptides as novel regulators of metabolism. J Physiol 595:6613–6621
doi: 10.1113/JP274472
pubmed: 28574175
pmcid: 5663826
Coradduzza D, Congiargiu A, Chen Z, Cruciani S, Zinellu A, Carru C et al (2023) Humanin and its pathophysiological roles in aging: a systematic review. Biology (Basel). 12(4):558
pubmed: 37106758
pmcid: 10135985
Thiankhaw K, Chattipakorn K, Chattipakorn SC, Chattipakorn N (2022) Roles of humanin and derivatives on the pathology of neurodegenerative diseases and cognition. Biochim Biophys Acta Gen Subj 1866:130097
doi: 10.1016/j.bbagen.2022.130097
pubmed: 35104624
Conte M, Ostan R, Fabbri C, Santoro A, Guidarelli G, Vitale G et al (2019) Human aging and longevity are characterized by high levels of Mitokines. J Gerontol A Biol Sci Med Sci 74:600–607
doi: 10.1093/gerona/gly153
pubmed: 29955888
Yen K, Mehta HH, Kim SJ, Lue Y, Hoang J, Guerrero N et al (2020) The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan. Aging (Albany NY) 12:11185–11199
doi: 10.18632/aging.103534
pubmed: 32575074
Rochette L, Meloux A, Zeller M, Cottin Y, Vergely C (2020) Role of humanin, a mitochondrial-derived peptide, in cardiovascular disorders. Arch Cardiovasc Dis 113:564–571
doi: 10.1016/j.acvd.2020.03.020
pubmed: 32680738
Widmer RJ, Flammer AJ, Herrmann J, Rodriguez-Porcel M, Wan J, Cohen P et al (2013) Circulating humanin levels are associated with preserved coronary endothelial function. Am J Physiol Heart Circ Physiol 304:H393-397
doi: 10.1152/ajpheart.00765.2012
pubmed: 23220334
Cai H, Cao P, Sun W, Shao W, Li R, Wang L et al (2022) Circulating humanin is lower in coronary artery disease and is a prognostic biomarker for major cardiac events in humans. Biochim Biophys Acta Gen Subj 1866:130010
doi: 10.1016/j.bbagen.2021.130010
pubmed: 34525397
Liu C, Gidlund EK, Witasp A, Qureshi AR, Söderberg M, Thorell A et al (2019) Reduced skeletal muscle expression of mitochondrial-derived peptides humanin and MOTS-C and Nrf2 in chronic kidney disease. Am J Physiol Renal Physiol 317:F1122-f1131
doi: 10.1152/ajprenal.00202.2019
pubmed: 31432706
Harrell FE (2015) Springer Series in Statistics. In: Regression modeling strategies. Springer New York, NY. https://doi.org/10.1007/978-3-319-19425-7
Mendez-Barbero N, Oller J, Sanz AB, Ramos AM, Ortiz A, Ruiz-Ortega M et al (2023) Mitochondrial dysfunction in the Cardio-Renal Axis. Int J Mol Sci 24(9):8209
doi: 10.3390/ijms24098209
pubmed: 37175915
pmcid: 10179675
Li Y, Li Z, Ren Y, Lei Y, Yang S, Shi Y et al (2023) Mitochondrial-derived peptides in cardiovascular disease: novel insights and therapeutic opportunities. J Adv Res. https://doi.org/10.1016/j.jare.2023.11.018
doi: 10.1016/j.jare.2023.11.018
pubmed: 38123018
pmcid: 11258668
Cobb LJ, Lee C, Xiao J, Yen K, Wong RG, Nakamura HK et al (2016) Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers. Aging (Albany NY) 8:796–809
doi: 10.18632/aging.100943
pubmed: 27070352
Miller B, Kim SJ, Cao K, Mehta HH, Thumaty N, Kumagai H et al (2024) Humanin variant P3S is associated with longevity in APOE4 carriers and resists APOE4-induced brain pathology. Aging Cell 23:e14153
doi: 10.1111/acel.14153
pubmed: 38520065
pmcid: 11258485
Kim SJ, Devgan A, Miller B, Lee SM, Kumagai H, Wilson KA et al (2022) Humanin-induced autophagy plays important roles in skeletal muscle function and lifespan extension. Biochim Biophys Acta Gen Subj 1866:130017
doi: 10.1016/j.bbagen.2021.130017
pubmed: 34624450
Amado CA, Martín-Audera P, Agüero J, Ferrer-Pargada D, Josa Laorden B, Boucle D et al (2023) Alterations in circulating mitochondrial signals at hospital admission for COPD exacerbation. Chron Respir Dis 20:14799731231220058
doi: 10.1177/14799731231220058
pubmed: 38112134
pmcid: 10734331
Burtscher J, Soltany A, Visavadiya NP, Burtscher M, Millet GP, Khoramipour K et al (2023) Mitochondrial stress and mitokines in aging. Aging Cell 22:e13770
doi: 10.1111/acel.13770
pubmed: 36642986
pmcid: 9924952