Abstract
Purpose
Decreased heart rate variability (HRV) is closely related to abnormal cardiac autonomic nervous function, especially sympathetic hyperactivity, which intensifies the risk of cardiovascular events and sudden death. HRV parameters are lower in chronic kidney disease (CKD) and parathyroidectomy (PTX) can improve these abnormalities in severe secondary hyperparathyroidism (SHPT) patients. However, few studies have evaluated correlations between circulating bone markers and HRV in CKD patients.
Methods
We conducted a cross-sectional study including 134 stage 5 CKD patients with 100 controls and a prospective study of 29 PTX patients with follow-up. Circulating bone biomarkers included: (1) intact parathyroid hormone (iPTH) as bone remodeling regulator; (2) bone-specific alkaline phosphatase (BAP), representing bone formation; (3) tartrate-resistant acid phosphatase 5b (TRACP-5b), indicating bone resorption; and (4) bone-derived hormone, fibroblast growth factor 23 (FGF23).
Results
Stage 5 CKD patients had higher circulating iPTH, BAP, TRACP-5b, and FGF23 than controls and these bone markers were significantly elevated in SHPT patients. Baseline iPTH, BAP, and lnFGF23 were independently associated with HRV in CKD patients. After PTX with a follow-up (median interval: 6.7 months), high blood iPTH, BAP, TRACP-5b, FGF23, and attenuated HRV were ameliorated. Furthermore, improved HRV indices were associated with reduced iPTH, BAP, TRACP-5b, and FGF23.
Conclusions
Circulating bone markers are correlated with HRV in CKD 5 patients and PTX can improve decreased HRV, which are associated with corrected bone markers in severe SHPT patients. Thus, we propose that PTH increases sympathetic tone and both high circulating PTH levels and sympathetic hyperactivity increase bone turnover, and that the products of bone turnover influence HRV.
Similar content being viewed by others
References
Saran R, Robinson B, Abbott KC et al (2017) US renal data system 2016 annual data report: epidemiology of kidney disease in the United States. Am J Kidney Dis 69(3S1):A7–A8. https://doi.org/10.1053/j.ajkd.2016.12.004
Park J (2012) Cardiovascular risk in chronic kidney disease: role of the sympathetic nervous system. Cardiol Res Pract 2012:319432. https://doi.org/10.1155/2012/319432
Chandra P, Sands RL, Gillespie BW et al (2012) Predictors of heart rate variability and its prognostic significance in chronic kidney disease. Nephrol Dial Transpl 27(2):700–709. https://doi.org/10.1093/ndt/gfr340
Huang JC, Kuo IC, Tsai YC et al (2017) Heart rate variability predicts major adverse cardiovascular events and hospitalization in maintenance hemodialysis patients. Kidney Blood Press Res 42(1):76–88. https://doi.org/10.1159/000469716
Zhang J, Yu X, Sun B et al (2013) Parathyroidectomy and heart rate variability in patients with stage 5 CKD. Clin J Am Soc Nephrol 8(8):1378–1387. https://doi.org/10.2215/CJN.10381012
Zhang LN, Yang G, Cheng C et al (2015) Plasma FGF23 levels and heart rate variability in patients with stage 5 CKD. Osteoporos Int 26 (1):395–405. https://doi.org/10.1007/s00198-014-2862-7
Sardiwal S, Gardham C, Coleman AE et al (2012) Bone-specific alkaline phosphatase concentrations are less variable than those of parathyroid hormone in stable hemodialysis patients. Kidney Int 82(1):100–105. https://doi.org/10.1038/ki.2012.77
Henriksen K, Tanko LB, Qvist P et al (2007) Assessment of osteoclast number and function: application in the development of new and improved treatment modalities for bone diseases. Osteoporos Int 18 (5):681–685. https://doi.org/10.1007/s00198-006-0286-8
Yamada S, Inaba M, Kurajoh M et al (2008) Utility of serum tartrate-resistant acid phosphatase (TRACP5b) as a bone resorption marker in patients with chronic kidney disease: independence from renal dysfunction. Clin Endocrinol 69(2):189–196. https://doi.org/10.1111/j.1365-2265.2008.03187.x
Zhang L, Long J, Jiang W et al (2016) Trends in chronic kidney disease in China. New Engl J Med 375(9):905–906. https://doi.org/10.1056/NEJMc1602469
Paula FJ, Lanna CM, Shuhama T et al (2001) Effect of metabolic control on parathyroid hormone secretion in diabetic patients. Braz J Med Biol Res 34(9):1139–1145. https://doi.org/10.1590/S0100-879X2001000900006
Al Salmi I, AlRukhaimi M, AlSahow A et al (2016) Mineral bone disorder and its management among hemodialysis patients in the Gulf Cooperation Council: initial findings from the dialysis outcomes and practice patterns study (2012–2015). Saudi J Kidney Dis Transpl 27(Supplement):62–80. https://doi.org/10.4103/1319-2442.194902
Evenepoel P, Bover J, Urena Torres P (2016) Parathyroid hormone metabolism and signaling in health and chronic kidney disease. Kidney Int 90(6):1184–1190. https://doi.org/10.1016/j.kint.2016.06.041
Davina JJ, Priyadarssini M, Rajappa M et al (2017) Assessment of bone turnover markers to predict mineral and bone disorder in men with pre-dialysis non-diabetic chronic kidney disease. Clin Chim Acta 469:195–200. https://doi.org/10.1016/j.cca.2017.04.010
Kurajoh M, Inaba M, Okuno S et al (2011) Reduction of whole PTH/intact PTH ratio as a predictor of bone metabolism in cinacalcet treatment of hemodialysis patients with secondary hyperparathyroidism. Osteoporos Int 22 (3):923–930. https://doi.org/10.1007/s00198-010-1262-x
Tolouian R, Hernandez GT, Chiang WY et al (2010) A new approach for evaluating bone turnover in chronic kidney disease. Eur J Intern Med 21(3):230–232. https://doi.org/10.1016/j.ejim.2010.01.013
Zhang J, Wang N (2014) Prognostic significance and therapeutic option of heart rate variability in chronic kidney disease. Int Urol Nephrol 46(1):19–25. https://doi.org/10.1007/s11255-013-0421-3
Ferrario M, Raimann JG, Larive B et al (2015) Non-linear heart rate variability indices in the frequent hemodialysis network trials of chronic hemodialysis patients. Blood Purif 40(1):99–108. https://doi.org/10.1159/000381665
Oikawa K, Ishihara R, Maeda T et al (2009) Prognostic value of heart rate variability in patients with renal failure on hemodialysis. Int J Cardiol 131(3):370–377. https://doi.org/10.1016/j.ijcard.2007.10.033
Buonacera A, Boukhris M, Tomasello SD et al (2016) Impact of left ventricular remodeling and renal function on 24 h-ECG recordings and cardiovascular outcome in elderly hypertensive patients. Eur J Intern Med 29:71–77. https://doi.org/10.1016/j.ejim.2016.01.001
Roumelioti ME, Ranpuria R, Hall M et al (2010) Abnormal nocturnal heart rate variability response among chronic kidney disease and dialysis patients during wakefulness and sleep. Nephrol Dial Transpl 25(11):3733–3741. https://doi.org/10.1093/ndt/gfq234
Ussawawongaraya W, Spilles N, Nilwarangkoon S et al (2013) The correlation of parathyroid hormone and heart rate variability in CAPD patients. J Med Assoc Thai 96(5):595–602
Tentori F, Wang M, Bieber BA et al (2015) Recent changes in therapeutic approaches and association with outcomes among patients with secondary hyperparathyroidism on chronic hemodialysis: the DOPPS study. Clin J Am Soc Nephrol 10(1):98–109. https://doi.org/10.2215/CJN.12941213
Bliziotes M, McLoughlin S, Gunness M et al (2000) Bone histomorphometric and biomechanical abnormalities in mice homozygous for deletion of the dopamine transporter gene. Bone 26(1):15–19
Seger RL, Cross RA, Rosen CJ et al (2011) Investigating the mechanism for maintaining eucalcemia despite immobility and anuria in the hibernating American black bear (Ursus americanus). Bone 49(6):1205–1212. https://doi.org/10.1016/j.bone.2011.08.017
Fahrleitner-Pammer A, Herberth J, Browning SR et al (2008) Bone markers predict cardiovascular events in chronic kidney disease. J Bone Min Res 23(11):1850–1858. https://doi.org/10.1359/jbmr.080610
Faul C, Amaral AP, Oskouei B et al (2011) FGF23 induces left ventricular hypertrophy. J Clin Invest 121(11):4393–4408. https://doi.org/10.1172/jci46122
Longenecker JC, Zubaid M, Johny KV et al (2009) Association of low heart rate variability with atherosclerotic cardiovascular disease in hemodialysis patients. Med Principles Pract 18(2):85–92. https://doi.org/10.1159/000189804
Nishimura M, Hashimoto T, Kobayashi H et al (2004) Association between cardiovascular autonomic neuropathy and left ventricular hypertrophy in diabetic haemodialysis patients. Nephrol Dial Transpl 19(10):2532–2538. https://doi.org/10.1093/ndt/gfh361
Shimada T, Urakawa I, Isakova T et al (2010) Circulating fibroblast growth factor 23 in patients with end-stage renal disease treated by peritoneal dialysis is intact and biologically active. J Clin Endocrinol Metab 95(2):578–585. https://doi.org/10.1210/jc.2009-1603
Wesseling-Perry K (2011) FGF23: is it ready for prime time? Clin Chem 57(11):1476–1477. https://doi.org/10.1373/clinchem.2011.172890
Connelly K, Collister D, Tangri N (2018) Fracture risk and treatment in chronic kidney disease. Curr Opin Nephrol Hypertens 27(3):221–225
Benson T, Menezes T, Campbell J et al (2016) Mechanisms of vasodilation to PTH 1-84, PTH 1-34, and PTHrP 1-34 in rat bone resistance arteries. Osteoporos Int 27(5):1817–1826
Acknowledgements
The authors would like to thank Qing Ma and Yanyan Pan for the care and management of the patients; Yun Xia, Zhihui Song, Jing Tu and Saijun Yang for assistance with the analysis of heart rate variability. This work was funded by the National Natural Science Foundation of China (81270408, 81570666), International Society of Nephrology (ISN) Clinical Research Program (18-01-0247), Construction Program of Jiangsu Provincial Clinical Research Center Support System (BL2014084), Chinese Society of Nephrology (13030300415), Jiangsu Province Key Medical Personnel Project (RC201162, ZDRCA2016002), and Six Major Talents Summit of Jiangsu Province ([2010-WS-026]).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no competing interests.
Rights and permissions
About this article
Cite this article
Chen, H., Cui, Y., Xing, C. et al. Effects of parathyroidectomy on blood bone markers and heart rate variability in patients with stage 5 chronic kidney disease. Int Urol Nephrol 50, 2279–2288 (2018). https://doi.org/10.1007/s11255-018-1995-6
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11255-018-1995-6