Association between autonomic nervous dysfunction and cellular inflammation in end-stage renal disease

Eric Seibert, Kristina Zohles, Christof Ulrich, Alexander Kluttig, Sebastian Nuding, Jan A Kors, Cees A Swenne, Karl Werdan, Roman Fiedler, Matthias Girndt, Eric Seibert, Kristina Zohles, Christof Ulrich, Alexander Kluttig, Sebastian Nuding, Jan A Kors, Cees A Swenne, Karl Werdan, Roman Fiedler, Matthias Girndt

Abstract

Background: Alterations in autonomic nervous function are common in hemodialysis (HD) patients. Sympathetic as well as parasympathetic activation may be associated with immune and inflammatory responses. We intended to confirm a role of autonomous dysregulation for inflammation in HD patients.

Methods: 30 HD patients (including 15 diabetics) and 15 healthy controls were studied for heart rate variability (HRV) using 5 min ECG recordings. Heart rate variability was estimated by time-domain parameters (the standard deviation of the RR intervals (SDNN) and the percentage of pairs of adjacent RR intervals differing by >50 ms (pNN50)) and frequency-domain-analysis (high- and low-frequency variation of RR intervals, HF and LF). Inflammation was detected as serum C-reactive Protein (CRP), IL-6 and circulating monocyte subpopulation numbers. Immune cells were characterized by ACh receptor expression.

Results: Patients differed from controls in terms of age (68.0 [14.8] yrs vs. 58.0 [13.0] yrs, p < 0.001; Median [IQR]) and sex. However, HRV parameters were different in controls and HD patients (SDNN controls 34.0 [14.0] ms, HD patients 15.5 [14.8] ms, p < 0.01). This finding was not restricted to patients with diabetes mellitus (diab), although diabetes is an important cause of autonomous dysfunction (SDNN, diab 13.0 [14.0] ms, non-diab 18.0 [15.3] ms, p = 0.8). LF and HF were reduced by the same magnitude to 1/3 of those in controls. Patients suffered from chronic inflammation (CRP 9.4 [12.9] mg/l, controls 1.6 [2.4] mg/l, p < 0.001) and expanded proinflammatory monocyte subpopulations (CD14++/CD16+ cells: patients 41 [27]/μl, controls 24 [18]/μl, p < 0.01). ECG parameters did not correlate with inflammation in patients, but monocyte ACh receptor expression was enhanced, indicating potentially elevated responsiveness of this cell type to parasympathetic regulation.

Conclusions: HD patients have strongly impaired HRV. Chronic inflammation is not related to autonomous dysfunction, although monocytes express the ACh receptor at enhanced density making them potentially more sensitive to parasympathetic effects.

Trial registration: This study was listed with ClinicalTrials.gov ( NCT00878033 ).

Keywords: Autonomic nerves; Dialysis; Heart rate variability; Inflammation; Monocytes.

Figures

Fig. 1
Fig. 1
Monocyte subpopulations in a flow cytometry read-out. All cells showed monocyte characteristics, however, the populations differ in their expression density of CD14 and CD16. The Mo2 cell type is linked to enhanced inflammation and adverse clinical outcome in dialysis patients [4]
Fig. 2
Fig. 2
Flow cytometric gating strategy of CD3-positive T-cells expressing nicotinic acetylcholine receptor (AchR). After exclusion of doublets (a), lymphocytes were characterized by anti-CD3 staining (b) and by back-gating in a FSC/SSC plot (c). Plots d and e are representative of isotype control and the corresponding sample staining positive for CD3 + AchR+
Fig. 3
Fig. 3
Flow cytometric gating strategy of CD19-positive B-cells expressing nicotinic acetylcholine receptor (AchR). After exclusion of doublets (a), B-cells were characterized by anti-CD19 staining (b) and by back-gating in a FSC/SSC plot (c). Plots d and e are representative of isotype control and the corresponding sample staining positive for CD19 + AchR+
Fig. 4
Fig. 4
Flow cytometric gating strategy of CD14-positive monocytes expressing nicotinic acetylcholine receptor (AchR). After exclusion of doublets (a), CD15++ granulocytes and CD19+ B-cells were excluded (b). Monocytes were characterized by anti-CD86- (c) and by anti-CD14-staining (d). Plots e and f are representative of isotype control and the corresponding sample staining positive for CD14 + AchR+

References

    1. Cheung AK, Sarnak MJ, Yan G, Dwyer JT, Heyka RJ, Rocco MV, et al. Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients. Kidney Int. 2000;58:353–62. doi: 10.1046/j.1523-1755.2000.00173.x.
    1. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347:1557–65. doi: 10.1056/NEJMoa021993.
    1. Zimmermann J, Herrlinger S, Pruy A, Metzger T, Wanner C. Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int. 1999;55:648–58. doi: 10.1046/j.1523-1755.1999.00273.x.
    1. Heine GH, Ulrich C, Seibert E, Seiler S, Marell J, Reichart B, et al. CD14(++)CD16+ monocytes but not total monocyte numbers predict cardiovascular events in dialysis patients. Kidney Int. 2008;73:622–9. doi: 10.1038/sj.ki.5002744.
    1. Mizuno K, Takahashi HK, Iwagaki H, Katsuno G, Kamurul HASM, Ohtani S, et al. Beta2-adrenergic receptor stimulation inhibits LPS-induced IL-18 and IL-12 production in monocytes. Immunol Lett. 2005;101:168–72. doi: 10.1016/j.imlet.2005.05.008.
    1. Li C-Y, Chou T-C, Lee C-H, Tsai C-S, Loh S-H, Wong C-S. Adrenaline inhibits lipopolysaccharide-induced macrophage inflammatory protein-1 alpha in human monocytes: the role of beta-adrenergic receptors. Anesth Analg. 2003;96:518–23.
    1. Axelrod S, Lishner M, Oz O, Bernheim J, Ravid M. Spectral analysis of fluctuations in heart rate: an objective evaluation of autonomic nervous control in chronic renal failure. Nephron. 1987;45:202–6. doi: 10.1159/000184117.
    1. Kavelaars A, van de Pol M, Zijlstra J, Heijnen CJ. Beta 2-adrenergic activation enhances interleukin-8 production by human monocytes. J Neuroimmunol. 1997;77:211–6. doi: 10.1016/S0165-5728(97)00076-3.
    1. Speidl WS, Toller WG, Kaun C, Weiss TW, Pfaffenberger S, Kastl SP, et al. Catecholamines potentiate LPS-induced expression of MMP-1 and MMP-9 in human monocytes and in the human monocytic cell line U937: possible implications for peri-operative plaque instability. FASEB J. 2004;18:603–5.
    1. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458–62. doi: 10.1038/35013070.
    1. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature. 2003;421:384–8. doi: 10.1038/nature01339.
    1. Vonend O, Rump LC, Ritz E. Sympathetic overactivity--the Cinderella of cardiovascular risk factors in dialysis patients. Semin Dial. 2008;21:326–30. doi: 10.1111/j.1525-139X.2008.00456.x.
    1. Ferchland A, Rettkowski O, Pönicke K, Deuber HJ, Osten B, Brodde OE. Effects of uremic plasma on alpha- and beta-adrenoceptor subtypes. Nephron. 1998;80:46–50. doi: 10.1159/000045124.
    1. Malik S, Winney RJ, Ewing DJ. Chronic renal failure and cardiovascular autonomic function. Nephron. 1986;43:191–5. doi: 10.1159/000183828.
    1. Vita G, Bellinghieri G, Trusso A, Costantino G, Santoro D, Monteleone F, et al. Uremic autonomic neuropathy studied by spectral analysis of heart rate. Kidney Int. 1999;56:232–7. doi: 10.1046/j.1523-1755.1999.00511.x.
    1. Giordano M, Manzella D, Paolisso G, Caliendo A, Varricchio M, Giordano C. Differences in heart rate variability parameters during the post-dialytic period in type II diabetic and non-diabetic ESRD patients. Nephrol Dial Transplant. 2001;16:566–73. doi: 10.1093/ndt/16.3.566.
    1. Tong Y-Q, Hou H-M. Alteration of heart rate variability parameters in nondiabetic hemodialysis patients. Am J Nephrol. 2007;27:63–9. doi: 10.1159/000099013.
    1. Drawz PE, Babineau DC, Brecklin C, He J, Kallem RR, Soliman EZ, et al. Heart Rate Variability Is a Predictor of Mortality in Chronic Kidney Disease: A Report from the CRIC Study. Am J Nephrol. 2013;38:517–28. doi: 10.1159/000357200.
    1. Chandra P, Sands RL, Gillespie BW, Levin NW, Kotanko P, Kiser M, et al. Predictors of heart rate variability and its prognostic significance in chronic kidney disease. Nephrol Dial Transplant. 2012;27:700–9. doi: 10.1093/ndt/gfr340.
    1. Chan CT, Chertow GM, Daugirdas JT, Greene TH, Kotanko P, Larive B, et al. Effects of daily hemodialysis on heart rate variability: results from the Frequent Hemodialysis Network (FHN) Daily Trial. Nephrol Dial Transplant. 2014;29:168–78. doi: 10.1093/ndt/gft212.
    1. Chan CT, Levin NW, Chertow GM, Larive B, Schulman G, Kotanko P, et al. Determinants of cardiac autonomic dysfunction in ESRD. Clin J Am Soc Nephrol. 2010;5:1821–7. doi: 10.2215/CJN.03080410.
    1. Heart rate variability. Standards of measurement, physiological interpretation, and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Eur Heart J. 1996;17(3):354–81.
    1. Goldstein DS, Bentho O, Park M-Y, Sharabi Y. Low-frequency power of heart rate variability is not a measure of cardiac sympathetic tone but may be a measure of modulation of cardiac autonomic outflows by baroreflexes. Exp Physiol. 2011;96:1255–61. doi: 10.1113/expphysiol.2010.056259.
    1. Low PA, Benrud-Larson LM, Sletten DM, Opfer-Gehrking TL, Weigand SD, O'Brien PC, et al. Autonomic symptoms and diabetic neuropathy: a population-based study. Diabetes Care. 2004;27:2942–7. doi: 10.2337/diacare.27.12.2942.
    1. Valensi P, Pariès J, Attali JR. Cardiac autonomic neuropathy in diabetic patients: influence of diabetes duration, obesity, and microangiopathic complications—the french multicenter study. Metabolism. 2003;52:815–20. doi: 10.1016/S0026-0495(03)00095-7.
    1. Brück K, Stel VS, Gambaro G, Hallan S, Völzke H, Ärnlöv J, et al. CKD Prevalence Varies across the European General Population. J Am Soc Nephrol. 2015;27:ASN.2015050542–2147.
    1. Whiting PJ, Vincent A, Schluep M, Newsom-Davis J. Monoclonal antibodies that distinguish between normal and denervated human acetylcholine receptor. J Neuroimmunol. 1986;11:223–35. doi: 10.1016/0165-5728(86)90006-8.
    1. Roberts A, Lang B, Vincent A, Newsom-Davis J. Search for cross-reactive idiotypes on monoclonal and myasthenia gravis acetylcholine receptor antibodies. Autoimmunity. 1992;12:53–60. doi: 10.3109/08916939209146130.
    1. Heidenreich F, Vincent A, Newsom-Davis J. Differences in fine specificity of anti-acetylcholine receptor antibodies between subgroups of spontaneous myasthenia gravis of recent onset, and of penicillamine induced myasthenia. Autoimmunity. 1988;2:31–7. doi: 10.3109/08916938809019941.
    1. Dekker JM, Schouten EG, Klootwijk P, Pool J, Swenne CA, Kromhout D. Heart rate variability from short electrocardiographic recordings predicts mortality from all causes in middle-aged and elderly men. The Zutphen Study. Am J Epidemiol. 1997;145:899–908. doi: 10.1093/oxfordjournals.aje.a009049.
    1. de Bruyne MC, Kors JA, Hoes AW, Klootwijk P, Dekker JM, Hofman A, et al. Both decreased and increased heart rate variability on the standard 10-second electrocardiogram predict cardiac mortality in the elderly: the Rotterdam Study. Am J Epidemiol. 1999;150:1282–8. doi: 10.1093/oxfordjournals.aje.a009959.
    1. van Bemmel JH, Kors JA, van Herpen G. Methodology of the modular ECG analysis system MEANS. Methods Inf Med. 1990;29:346–53.
    1. Kurata C, Uehara A, Sugi T, Ishikawa A, Fujita K, Yonemura K, et al. Cardiac autonomic neuropathy in patients with chronic renal failure on hemodialysis. Nephron. 2000;84:312–9. doi: 10.1159/000045605.
    1. Faul F, Erdfelder E, Lang A-G, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39:175–91. doi: 10.3758/BF03193146.
    1. Faul F, Erdfelder E, Buchner A, Lang A-G. Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav Res Methods. 2009;41:1149–60. doi: 10.3758/BRM.41.4.1149.
    1. Stein PK, Domitrovich PP, Hui N, Rautaharju P, Gottdiener J. Sometimes higher heart rate variability is not better heart rate variability: results of graphical and nonlinear analyses. J Cardiovasc. 2005;16:954–9.
    1. Reyes del Paso GA, Langewitz W, Mulder LJM, van Roon A, Duschek S. The utility of low frequency heart rate variability as an index of sympathetic cardiac tone: a review with emphasis on a reanalysis of previous studies. Psychophysiology. 2013;50:477–87. doi: 10.1111/psyp.12027.
    1. Bootsma M, Swenne CA, Janssen MJA, Manger Cats V, Schalij MJ. Heart rate variability and sympathovagal balance: pharmacological validation. Neth Heart J. 2003;11:250–9.
    1. Kuss O, Schumann B, Kluttig A, Greiser KH, Haerting J. Time domain parameters can be estimated with less statistical error than frequency domain parameters in the analysis of heart rate variability. J Electrocardiol. 2008;41:287–91. doi: 10.1016/j.jelectrocard.2008.02.014.
    1. Fukuta H, Hayano J, Ishihara S, Sakata S, Mukai S, Ohte N, et al. Prognostic value of heart rate variability in patients with end-stage renal disease on chronic haemodialysis. Nephrol Dial Transplant. 2003;18:318–25. doi: 10.1093/ndt/18.2.318.
    1. Mylonopoulou M, Tentolouris N, Antonopoulos S, Mikros S, Katsaros K, Melidonis A, et al. Heart rate variability in advanced chronic kidney disease with or without diabetes: midterm effects of the initiation of chronic haemodialysis therapy. Nephrol Dial Transplant. 2010;25:3749–54. doi: 10.1093/ndt/gfq226.
    1. Racek J, Králová H, Trefil L, Rajdl D, Eiselt J. Brain natriuretic peptide and N-terminal proBNP in chronic haemodialysis patients. Nephron Clin Pract. 2006;103:c162–72. doi: 10.1159/000092914.
    1. Selim G, Stojceva-Taneva O, Spasovski G, Georgievska-Ismail L, Zafirovska-Ivanovska B, Gelev S, et al. Brain natriuretic peptide between traditional and nontraditional risk factors in hemodialysis patients: analysis of cardiovascular mortality in a two-year follow-up. Nephron Clin Pract. 2011;119:c162–70. doi: 10.1159/000327615.
    1. Psychari SN, Sinos L, Iatrou C, Liakos G, Apostolou TS. Relations of inflammatory markers to lipid levels and autonomic tone in patients with moderate and severe chronic kidney disease and in patients under maintenance hemodialysis. Clin Nephrol. 2005;64:419–27. doi: 10.5414/CNP64419.
    1. Kuroki K, Takahashi HK, Iwagaki H, Murakami T, Kuinose M, Hamanaka S, et al. beta2-adrenergic receptor stimulation-induced immunosuppressive effects possibly through down-regulation of co-stimulatory molecules, ICAM-1, CD40 and CD14 on monocytes. J Int Med Res. 2004;32:465–83. doi: 10.1177/147323000403200503.
    1. Girndt M, Sester U, Kaul H, Köhler H. Production of proinflammatory and regulatory monokines in hemodialysis patients shown at a single-cell level. J Am Soc Nephrol. 1998;9:1689–96.
    1. Sester U, Sester M, Heine G, Kaul H, Girndt M, Köhler H. Strong depletion of CD14(+)CD16(+) monocytes during haemodialysis treatment. Nephrol Dial Transplant. 2001;16:1402–8. doi: 10.1093/ndt/16.7.1402.
    1. Ulrich C, Heine GH, Garcia P, Reichart B, Georg T, Krause M, et al. Increased expression of monocytic angiotensin-converting enzyme in dialysis patients with cardiovascular disease. Nephrol Dial Transplant. 2006;21:1596–602. doi: 10.1093/ndt/gfl008.
    1. Ulrich C, Heine GH, Seibert E, Fliser D, Girndt M. Circulating monocyte subpopulations with high expression of angiotensin-converting enzyme predict mortality in patients with end-stage renal disease. Nephrol Dial Transplant. 2010;25:2265–72. doi: 10.1093/ndt/gfq012.
    1. Ulrich C, Seibert E, Heine GH, Fliser D, Girndt M. Monocyte angiotensin converting enzyme expression may be associated with atherosclerosis rather than arteriosclerosis in hemodialysis patients. Clin J Am Soc Nephrol. 2011;6:505–11. doi: 10.2215/CJN.06870810.
    1. Oduah EI, Linhardt RJ, Sharfstein ST. Heparin: Past, Present, and Future. Pharmaceuticals (Basel). 2016;9(3):38. doi:10.3390/ph9030038.
    1. Young E. The anti-inflammatory effects of heparin and related compounds. Thromb Res. 2008;122:743–52. doi: 10.1016/j.thromres.2006.10.026.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren