Increased extracellular water measured by bioimpedance and by increased serum levels of atrial natriuretic peptide in RA patients—signs of volume overload


The aim of the study is to investigate water compartments in patients with rheumatoid arthritis (RA). Acute inflammatory episodes such as infection stimulate water retention, chiefly implemented by the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis. This is an important compensatory mechanism due to expected water loss (sweating etc.). Since SNS and HPA axis are activated in RA, inflammation might be accompanied by water retention. Using bioimpedance analysis, body composition was investigated in 429 controls and 156 treatment-naïve RA patients between January 2008 and December 2014. A group of 34 RA patients was tested before and after 10 days of intensified therapy. Levels of pro-atrial natriuretic peptide (proANP) and expression of atrial natriuretic peptide in synovial tissue were investigated in 15 controls and 14 RA patients. Extracellular water was higher in RA patients than controls (mean ± SEM: 49.5 ± 0.3 vs. 36.7 ± 0.1, % of total body water, p < 0.0001). Plasma levels of proANP were higher in RA than controls. RA patients expressed ANP in synovial tissue, but synovial fluid levels and synovial tissue superfusate levels were much lower than plasma levels indicating systemic origin. Systolic/diastolic blood pressure was higher in RA patients than controls. Extracellular water levels did not change in RA patients despite 10 days of intensified treatment. This study demonstrates signs of intravascular overload in RA patients. Short-term intensification of anti-inflammatory therapy induced no change of a longer-lasting imprinting of water retention indicating the requirement of additional treatment. The study can direct attention to the area of volume overload.

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  1. 1.

    Kuis W, Jong-de Vos V, Sinnema G, Kavelaars A, Prakken B, Helders PM et al (1996) The autonomic nervous system and the immune system in juvenile rheumatoid arthritis. Brain Behav Immun 10:387–398

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Perry F, Heller PH, Kamiya J, Levine JD (1989) Altered autonomic function in patients with arthritis or with chronic myofascial pain. Pain 39:77–84

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Dekkers JC, Geenen R, Godaert GL, Bijlsma JW, van Doornen LJ (2004) Elevated sympathetic nervous system activity in patients with recently diagnosed rheumatoid arthritis with active disease. Clin Exp Rheumatol 22:63–70

    CAS  PubMed  Google Scholar 

  4. 4.

    Dekkers JC, Geenen R, Godaert GL, van Doornen LJ, Bijlsma JW (2000) Diurnal rhythm of salivary cortisol levels in patients with recent-onset rheumatoid arthritis. Arthritis Rheum 43:465–467

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Catley D, Kaell AT, Kirschbaum C, Stone AA (2000) A naturalistic evaluation of cortisol secretion in persons with fibromyalgia and rheumatoid arthritis. Arthritis Care Res 13:51–61

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Schrier RW (2007) Decreased effective blood volume in edematous disorders: what does this mean? J Am Soc Nephrol 18:2028–2031

    Article  PubMed  Google Scholar 

  7. 7.

    DiBona GF (2003) Neural control of the kidney: past, present, and future. Hypertension 41:621–624

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Giordano R, Di VL, Lanfranco F, Broglio F, Benso A, Gianotti L et al (2001) Elderly subjects show severe impairment of dehydroepiandrosterone sulphate and reduced sensitivity of cortisol and aldosterone response to the stimulatory effect of ACTH(1–24). Clin Endocrinol (Oxf) 55:259–265

    CAS  Article  Google Scholar 

  9. 9.

    Lanfranco F, Gianotti L, Picu A, Fassino S, Abbate DG, Mondelli V et al (2004) The adrenal sensitivity to ACTH stimulation is preserved in anorexia nervosa. J Endocrinol Investig 27:436–441

    CAS  Article  Google Scholar 

  10. 10.

    Shichiri M, Miyasaka N, Hirata Y, Ando K, Marumo F (1991) Appearance of beta-human atrial natriuretic peptide in collagen disease. J Endocrinol 130:159–161

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Yasuda M, Yasuda D, Tomooka K, Nobunaga M (1993) Plasma concentration of human atrial natriuretic hormone in patients with connective tissue diseases. Clin Rheumatol 12:231–235

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Solus J, Chung CP, Oeser A, Avalos I, Gebretsadik T, Shintani A et al (2008) Amino-terminal fragment of the prohormone brain-type natriuretic peptide in rheumatoid arthritis. Arthritis Rheum 58:2662–2669

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Peters MJ, Welsh P, McInnes IB, Wolbink G, Dijkmans BA, Sattar N et al (2010) Tumour necrosis factor blockade reduces circulating N-terminal pro-brain natriuretic peptide levels in patients with active rheumatoid arthritis: results from a prospective cohort study. Ann Rheum Dis 69:1281–1285

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Francis GS, Felker GM, Tang WH (2016) A test in context: critical evaluation of natriuretic peptide testing in heart failure. J Am Coll Cardiol 67:330–337

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Palmer BF, Clegg DJ (2015) An emerging role of natriuretic peptides: igniting the fat furnace to fuel and warm the heart. Mayo Clin Proc 90:1666–1678

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Tan AC, Jansen TL, Termond EF, Russel FG, Thien T, Kloppenborg PW et al (1992) Kinetics of atrial natriuretic peptide in young and elderly subjects. Eur J Clin Pharmacol 42:449–452

    CAS  PubMed  Google Scholar 

  17. 17.

    Provan S, Angel K, Semb AG, Atar D, Kvien TK (2010) NT-proBNP predicts mortality in patients with rheumatoid arthritis: results from 10-year follow-up of the EURIDISS study. Ann Rheum Dis 69:1946–1950

    Article  PubMed  Google Scholar 

  18. 18.

    Mirjafari H, Welsh P, Verstappen SM, Wilson P, Marshall T, Edlin H et al (2014) N-terminal pro-brain-type natriuretic peptide (NT-pro-BNP) and mortality risk in early inflammatory polyarthritis: results from the Norfolk Arthritis Registry (NOAR). Ann Rheum Dis 73:684–690

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Tsigos C, Stefanaki C, Lambrou GI, Boschiero D, Chrousos GP (2015) Stress and inflammatory biomarkers and symptoms are associated with bio-impedance measures. Eur J Clin Investig 45:126–134

    CAS  Article  Google Scholar 

  20. 20.

    Ellis KJ (2000) Human body composition: in vivo methods. Physiol Rev 80:649–680

    CAS  PubMed  Google Scholar 

  21. 21.

    Lukaski HC, Bolonchuk WW, Hall CB, Siders WA (1986) Validation of tetrapolar bioelectrical impedance method to assess human body composition. J Appl Physiol 60:1327–1332

    CAS  PubMed  Google Scholar 

  22. 22.

    Heymsfield SB, Wang Z, Baumgartner RN, Ross R (1997) Human body composition: advances in models and methods. Annu Rev Nutr 17:527–558

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Wang Z, Heymsfield SB, Chen Z, Zhu S, Pierson RN (2010) Estimation of percentage body fat by dual-energy x-ray absorptiometry: evaluation by in vivo human elemental composition. Phys Med Biol 55:2619–2635

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Ott M, Fischer H, Polat H, Helm EB, Frenz M, Caspary WF et al (1995) Bioelectrical impedance analysis as a predictor of survival in patients with human immunodeficiency virus infection. J Acquir Immune Defic Syndr Hum Retrovirol 9:20–25

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Krause L, Becker MO, Brueckner CS, Bellinghausen CJ, Becker C, Schneider U et al (2010) Nutritional status as marker for disease activity and severity predicting mortality in patients with systemic sclerosis. Ann Rheum Dis 69:1951–1957

    Article  PubMed  Google Scholar 

  26. 26.

    Avila-Diaz M, Ventura MD, Valle D, Vicente-Martinez M, Garcia-Gonzalez Z, Cisneros A et al (2006) Inflammation and extracellular volume expansion are related to sodium and water removal in patients on peritoneal dialysis. Perit Dial Int 26:574–580

    PubMed  Google Scholar 

  27. 27.

    Kotanko P, Levin NW, Zhu F (2008) Current state of bioimpedance technologies in dialysis. Nephrol Dial Transplant 23:808–812

    Article  PubMed  Google Scholar 

  28. 28.

    Crepaldi C, Lamas EI, Martino FK, Rodighiero MP, Scalzotto E, Wojewodzka-Zelezniakowicz M et al (2012) Bioimpedance and brain natriuretic peptide in peritoneal dialysis patients. Contrib Nephrol 178:174–181

    Article  PubMed  Google Scholar 

  29. 29.

    Roubenoff R, Roubenoff RA, Ward LM, Holland SM, Hellmann DB (1992) Rheumatoid cachexia: depletion of lean body mass in rheumatoid arthritis. Possible association with tumor necrosis factor. J Rheumatol 19:1505–1510

    CAS  PubMed  Google Scholar 

  30. 30.

    Giles JT, Ling SM, Ferrucci L, Bartlett SJ, Andersen RE, Towns M et al (2008) Abnormal body composition phenotypes in older rheumatoid arthritis patients: association with disease characteristics and pharmacotherapies. Arthritis Rheum 59:807–815

    Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Bedogni G, Polito C, Severi S, Strano CG, Manzieri AM, Alessio M et al (1996) Altered body water distribution in subjects with juvenile rheumatoid arthritis and its effects on the measurement of water compartments from bioelectric impedance. Eur J Clin Nutr 50:335–339

    CAS  PubMed  Google Scholar 

  32. 32.

    Lofthouse CM, Azad F, Baildam EM, Akobeng AK (2002) Measuring the nutritional status of children with juvenile idiopathic arthritis using the bioelectrical impedance method. Rheumatology (Oxford) 41:1172–1177

    CAS  Article  Google Scholar 

  33. 33.

    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Fransen J, van Riel PL (2009) The disease activity score and the EULAR response criteria. Rheum Dis Clin N Am 35:745–viii

    Article  Google Scholar 

  35. 35.

    Straub RH, Rauch L, Fassold A, Lowin T, Pongratz G (2008) Neuronally released sympathetic neurotransmitters stimulate splenic interferon-gamma secretion from T cells in early type II collagen-induced arthritis. Arthritis Rheum 58:3450–3460

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Stobaus N, Pirlich M, Valentini L, Schulzke JD, Norman K (2012) Determinants of bioelectrical phase angle in disease. Br J Nutr 107:1217–1220

    Article  PubMed  Google Scholar 

  37. 37.

    Lauridsen BK, Iversen K, Hunter I, Bay M, Kirk V, Nielsen OW et al (2013) ProANP plasma measurement predicts all-cause mortality in acutely hospitalised patients: a cohort study. BMJ Open 3, e003288

    Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Kotyla PJ, Owczarek A, Rakoczy J, Lewicki M, Kucharz EJ, Emery P (2012) Infliximab treatment increases left ventricular ejection fraction in patients with rheumatoid arthritis: assessment of heart function by echocardiography, endothelin 1, interleukin 6, and NT-pro brain natriuretic peptide. J Rheumatol 39:701–706

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Vollmar AM, Schulz R (1994) Gene expression and secretion of atrial natriuretic peptide by murine macrophages. J Clin Invest 94:539–545

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Elkan AC, Engvall IL, Cederholm T, Hafstrom I (2009) Rheumatoid cachexia, central obesity and malnutrition in patients with low-active rheumatoid arthritis: feasibility of anthropometry, Mini Nutritional Assessment and body composition techniques. Eur J Nutr 48:315–322

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Giles JT, Bartlett SJ, Andersen RE, Fontaine KR, Bathon JM (2008) Association of body composition with disability in rheumatoid arthritis: impact of appendicular fat and lean tissue mass. Arthritis Rheum 59:1407–1415

    Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Straub RH (2012) Evolutionary medicine and chronic inflammatory state—known and new concepts in pathophysiology. J Mol Med 90:523–534

    Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Schlaich MP, Krum H, Sobotka PA (2010) Renal sympathetic nerve ablation: the new frontier in the treatment of hypertension. Curr Hypertens Rep 12:39–46

    Article  PubMed  Google Scholar 

  44. 44.

    Sacco M, Meschi M, Regolisti G, Detrenis S, Bianchi L, Bertorelli M et al (2013) The relationship between blood pressure and pain. J Clin Hypertens (Greenwich) 15:600–605

    Article  Google Scholar 

  45. 45.

    Struyf F, Meeus M (2014) Current evidence on physical therapy in patients with adhesive capsulitis: what are we missing? Clin Rheumatol 33:593–600

    Article  PubMed  Google Scholar 

  46. 46.

    Sarzi-Puttini P, Atzeni F, Diana A, Doria A, Furlan R (2006) Increased neural sympathetic activation in fibromyalgia syndrome. Ann N Y Acad Sci 1069:109–117:109–117

    Article  PubMed  Google Scholar 

  47. 47.

    Bomholt SF, Harbuz MS, Blackburn-Munro G, Blackburn-Munro RE (2004) Involvement and role of the hypothalamo-pituitary-adrenal (HPA) stress axis in animal models of chronic pain and inflammation. Stress 7:1–14

    CAS  Article  PubMed  Google Scholar 

  48. 48.

    Grossman E, Messerli FH (2012) Drug-induced hypertension: an unappreciated cause of secondary hypertension. Am J Med 125:14–22

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Titze J, Dahlmann A, Lerchl K, Kopp C, Rakova N, Schroder A et al (2014) Spooky sodium balance. Kidney Int 85:759–767

    CAS  Article  PubMed  Google Scholar 

  50. 50.

    Coderre TJ, Chan AK, Helms C, Basbaum AI, Levine JD (1991) Increasing sympathetic nerve terminal-dependent plasma extravasation correlates with decreased arthritic joint injury in rats. Neuroscience 40:185–189

    CAS  Article  PubMed  Google Scholar 

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Rainer H Straub contributed to the development of hypothesis and concept, analyses of data, generating draft figures, drafting the paper, and final approval; Boris Ehrenstein to the generation of data, revising the draft paper, and final approval; Florian Günther to the generation of data, revising the draft paper, and final approval; Luise Rauch to the generation of data, writing parts of the paper, revising the draft paper, and final approval; Nadezhda Trendafilova to the generation of data, revising the draft paper, and final approval; Dario Boschiero to the development of the BIA-ACC technique, coordinating patient recruitment in Italy (first study arm), writing the part on BIA methods, revising the draft paper, and final approval; Joachim Grifka to providing patient material, revising the draft paper, and final approval; and Martin Fleck to the generation of data, revising the draft paper, and final approval.

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Correspondence to Rainer H. Straub.

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The study was supported by the institutions. Dario Boschiero is the Director of the Research and Development at BioTekna Biomedical Technologies, Marcon, Italy. Dario Boschiero coordinated patient recruitment of the Italian patients (first study arm), but he was not involved in data analyses, and writing of the draft paper. All authors had access to the data and a role in writing the manuscript.



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Straub, R.H., Ehrenstein, B., Günther, F. et al. Increased extracellular water measured by bioimpedance and by increased serum levels of atrial natriuretic peptide in RA patients—signs of volume overload. Clin Rheumatol 36, 1041–1051 (2017).

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  • Hypertension
  • Inflammation
  • Rheumatoid arthritis
  • Volume overload