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Sleep and Breathing

, Volume 23, Issue 1, pp 161–169 | Cite as

Serum levels of NGAL and cystatin C as markers of early kidney dysfunction in patients with obstructive sleep apnea syndrome

  • Athanasios Voulgaris
  • Kostas Archontogeorgis
  • Evangelia Nena
  • Christina Tsigalou
  • Maria Xanthoudaki
  • Maria Kouratzi
  • Grigorios Tripsianis
  • Marios Froudarakis
  • Paschalis SteiropoulosEmail author
Sleep Breathing Physiology and Disorders • Original Article
  • 128 Downloads

Abstract

Purpose

Obstructive sleep apnea syndrome (OSAS) has been recently proposed as an independent risk factor for chronic kidney disease. Cystatin C (Cyst C) and neutrophil gelatinase-associated lipocalin (NGAL) are novel biomarkers for the earlier detection of latent kidney disease. The aim of the study was to assess serum Cyst C and NGAL levels in otherwise healthy OSAS patients and to explore possible associations with sleep parameters.

Methods

Consecutive subjects (n = 96, 79.2% males), without known comorbidities, with symptoms suggestive of OSAS were included. All of them underwent polysomnography (PSG) and blood examination for the measurement of serum Cyst C and NGAL levels.

Results

Based on apnea-hypopnea index (AHI), subjects were classified into two groups: 32 controls and 64 OSAS patients, with no significant differences in terms of age (50.1 ± 11.7 vs 51 ± 12.2 years, p = 0.747) and BMI (33.9 ± 8.8 vs 35.9 ± 13.1 kg/m2, p = 0.449). Serum Cyst C and NGAL mean levels were higher in OSAS patients compared to those in controls (1155.2 ± 319.3 vs 966.8 ± 173 ng/ml, p = 0.001, and 43.7 ± 23.2 vs 35.6 ± 13.8 ng/ml, p = 0.035, respectively). After adjustment for age and BMI in OSAS patients, serum NGAL levels were associated with AHI (β = 0.341, p = 0.015) and minimum oxyhemoglobin saturation during sleep (β = − 0.275, p = 0.032), while serum Cyst C levels were associated with percentage of time with oxyhemoglobin saturation < 90% (β = 0.270, p = 0.043), average (β = − 0.308, p = 0.018), and minimum (β = − 0.410, p = 0.001) oxyhemoglobin saturation during sleep.

Conclusions

Higher risk for latent kidney disease in otherwise healthy OSAS patients is indicated. Sleep hypoxia seems to be a significant contributor in the pathogenetic process of renal dysfunction in OSAS.

Keywords

Cystatin C NGAL Kidney injury Kidney dysfunction Obstructive sleep apnea syndrome 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

References

  1. 1.
    Flemons WW, Buysse D, Redline S et al (1999) Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. Sleep 22:667–689CrossRefGoogle Scholar
  2. 2.
    Senaratna CV, Perret JL, Lodge CJ, Lowe AJ, Campbell BE, Matheson MC, Hamilton GS, Dharmage SC (2017) Prevalence of obstructive sleep apnea in the general population: a systematic review. Sleep Med Rev 34:70–81.  https://doi.org/10.1016/j.smrv.2016.07.002 CrossRefGoogle Scholar
  3. 3.
    Gottlieb DJ, Yenokyan G, Newman AB, O'Connor GT, Punjabi NM, Quan SF, Redline S, Resnick HE, Tong EK, Diener-West M, Shahar E (2010) Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation 122:352–360.  https://doi.org/10.1161/CIRCULATIONAHA.109.901801 CrossRefGoogle Scholar
  4. 4.
    Redline S, Yenokyan G, Gottlieb DJ, Shahar E, O’Connor GT, Resnick HE, Diener-West M, Sanders MH, Wolf PA, Geraghty EM, Ali T, Lebowitz M, Punjabi NM (2010) Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study. Am J Respir Crit Care Med 182:269–277.  https://doi.org/10.1164/rccm.200911-1746OC CrossRefGoogle Scholar
  5. 5.
    Abuyassin B, Sharma K, Ayas NT, Laher I (2015) Obstructive sleep apnea and kidney disease: a potential bidirectional relationship? J Clin Sleep Med 11:915–924.  https://doi.org/10.5664/jcsm.4946 Google Scholar
  6. 6.
    Nicholl DDM, Ahmed SB, Loewen AHS, Hemmelgarn BR, Sola DY, Beecroft JM, Turin TC, Hanly PJ (2012) Declining kidney function increases the prevalence of sleep apnea and nocturnal hypoxia. Chest 141:1422–1430.  https://doi.org/10.1378/chest.11-1809 CrossRefGoogle Scholar
  7. 7.
    Molnar MZ, Mucsi I, Novak M, Szabo Z, Freire AX, Huch KM, Arah OA, Ma JZ, Lu JL, Sim JJ, Streja E, Kalantar-Zadeh K, Kovesdy CP (2015) Association of incident obstructive sleep apnoea with outcomes in a large cohort of US veterans. Thorax 70:888–895.  https://doi.org/10.1136/thoraxjnl-2015-206970 CrossRefGoogle Scholar
  8. 8.
    Lee Y-C, Hung S-Y, Wang H-K, Lin CW, Wang HH, Chen SW, Chang MY, Ho LC, Chen YT, Liou HH, Tsai TC, Tseng SH, Wang WM, Lin SH, Chiou YY (2015) Sleep apnea and the risk of chronic kidney disease: a nationwide population-based cohort study. Sleep 38:213–221.  https://doi.org/10.5665/sleep.4400 CrossRefGoogle Scholar
  9. 9.
    Marrone O, Battaglia S, Steiropoulos P, Basoglu OK, Kvamme JA, Ryan S, Pepin JL, Verbraecken J, Grote L, Hedner J, Bonsignore MR, the ESADA study group (2016) Chronic kidney disease in European patients with obstructive sleep apnea: the ESADA cohort study. J Sleep Res 25:739–745.  https://doi.org/10.1111/jsr.12426 CrossRefGoogle Scholar
  10. 10.
    Lopez-Giacoman S, Madero M (2015) Biomarkers in chronic kidney disease, from kidney function to kidney damage. World J Nephrol 4:57–73.  https://doi.org/10.5527/wjn.v4.i1.57 CrossRefGoogle Scholar
  11. 11.
    Mussap M, Plebani M (2004) Biochemistry and clinical role of human cystatin C. Crit Rev Clin Lab Sci 41:467–550.  https://doi.org/10.1080/10408360490504934 CrossRefGoogle Scholar
  12. 12.
    Shlipak MG, Mattes MD, Peralta CA (2013) Update on cystatin C: incorporation into clinical practice. Am J Kidney Dis 62:595–603.  https://doi.org/10.1053/j.ajkd.2013.03.027 CrossRefGoogle Scholar
  13. 13.
    Archontogeorgis K, Nena E, Tsigalou C, Voulgaris A, Xanthoudaki M, Froudarakis M, Steiropoulos P (2016) Cystatin C levels in middle-aged patients with obstructive sleep apnea syndrome. Pulm Med 2016:1–8.  https://doi.org/10.1155/2016/8081723 CrossRefGoogle Scholar
  14. 14.
    Kjeldsen L, Johnsen AH, Sengeløv H, Borregaard N (1993) Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem 268:10425–10432Google Scholar
  15. 15.
    Flo TH, Smith KD, Sato S, Rodriguez DJ, Holmes MA, Strong RK, Akira S, Aderem A (2004) Lipocalin 2 mediates an innate immune response to bacterial infection by sequestrating iron. Nature 432:917–921.  https://doi.org/10.1038/nature03104 CrossRefGoogle Scholar
  16. 16.
    Mishra J, Mori K, Ma Q, Kelly C, Yang J, Mitsnefes M, Barasch J, Devarajan P (2004) Amelioration of ischemic acute renal injury by neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol 15:3073–3082.  https://doi.org/10.1097/01.ASN.0000145013.44578.45 CrossRefGoogle Scholar
  17. 17.
    Bolignano D, Lacquaniti A, Coppolino G, Donato V, Campo S, Fazio MR, Nicocia G, Buemi M (2009) Neutrophil gelatinase-associated lipocalin (NGAL) and progression of chronic kidney disease. Clin J Am Soc Nephrol 4:337–344.  https://doi.org/10.2215/CJN.03530708 CrossRefGoogle Scholar
  18. 18.
    Murase K, Mori K, Yoshimura C, Aihara K, Chihara Y, Azuma M, Harada Y, Toyama Y, Tanizawa K, Handa T, Hitomi T, Oga T, Mishima M, Chin K (2013) Association between plasma neutrophil gelatinase associated lipocalin level and obstructive sleep apnea or nocturnal intermittent hypoxia. PLoS One 8:e54184.  https://doi.org/10.1371/journal.pone.0054184 CrossRefGoogle Scholar
  19. 19.
    Maski MR, Thomas RJ, Karumanchi SA, Parikh SM (2016) Urinary neutrophil gelatinase-associated lipocalin (NGAL) in patients with obstructive sleep apnea. PLoS One 11:e0154503.  https://doi.org/10.1371/journal.pone.0154503 CrossRefGoogle Scholar
  20. 20.
    Tsara V, Serasli E, Amfilochiou A, Constantinidis T, Christaki P (2004) Greek version of the Epworth Sleepiness Scale. Sleep Breath 8:91–95.  https://doi.org/10.1007/s11325-004-0091-6 CrossRefGoogle Scholar
  21. 21.
    James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC Jr, Svetkey LP, Taler SJ, Townsend RR, Wright JT Jr, Narva AS, Ortiz E (2014) Evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 311:507–520.  https://doi.org/10.1001/jama.2013.284427 CrossRefGoogle Scholar
  22. 22.
    Marathe PH, Gao HX, Close KL (2017) American Diabetes Association standards of medical care in diabetes 2017. J Diabetes 9:320–324.  https://doi.org/10.1111/1753-0407.12524 CrossRefGoogle Scholar
  23. 23.
    Levey AS, Coresh J, Greene T, Stevens LA, Zhang Y(L), Hendriksen S, Kusek JW, van Lente F, for the Chronic Kidney Disease Epidemiology Collaboration* (2006) Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 145:247–254CrossRefGoogle Scholar
  24. 24.
    IBER C (2007) Respiratory rules. AASM Man Scoring Sleep Assoc Events Rules Terminol Tech Specif 45–50Google Scholar
  25. 25.
    Kiskac M, Zorlu M, Akkoyunlu ME, Kilic E, Karatoprak C, Cakirca M, Yavuz E, Ardic C, Camli AA, Cikrikcioglu M, Kart L (2014) Vaspin and lipocalin-2 levels in severe obsructive sleep apnea. J Thorac Dis 6:720–725.  https://doi.org/10.3978/j.issn.2072-1439.2014.06.17 Google Scholar
  26. 26.
    Kato K, Takata Y, Usui Y, Shiina K, Asano K, Hashimura Y, Saruhara H, Nishihata Y, Tomiyama H, Yamashina A (2011) Severe obstructive sleep apnea increases cystatin C in clinically latent renal dysfunction. Respir Med 105:643–649.  https://doi.org/10.1016/j.rmed.2010.11.024 CrossRefGoogle Scholar
  27. 27.
    Chen Y, Li Y, Jiang Q, Xu X, Zhang X, Simayi Z, Ye H (2015) Analysis of early kidney injury-related factors in patients with hypertension and obstructive sleep apnea hypopnea syndrome (OSAHS). Arch Iran Med 18:827–833Google Scholar
  28. 28.
    Zhang X-B, Jiang X-T, Lin Q-C, Chen X, Zeng HQ (2014) Effect of continuous positive airway pressure on serum cystatin C among obstructive sleep apnea syndrome patients. Int Urol Nephrol 46:1997–2002.  https://doi.org/10.1007/s11255-014-0779-x CrossRefGoogle Scholar
  29. 29.
    Zhang X-B, Lin Q-C, Deng C-S, Chen GP, Cai ZM, Chen H (2013) Elevated serum cystatin C in severe OSA younger men without complications. Sleep Breath 17:235–241.  https://doi.org/10.1007/s11325-012-0678-2 CrossRefGoogle Scholar
  30. 30.
    Ahmed SB, Ronksley PE, Hemmelgarn BR, Tsai WH, Manns BJ, Tonelli M, Klarenbach SW, Chin R, Clement FM, Hanly PJ (2011) Nocturnal hypoxia and loss of kidney function. PLoS One 6:e19029.  https://doi.org/10.1371/journal.pone.0019029 CrossRefGoogle Scholar
  31. 31.
    Sharma S, Kavuru M (2010) Sleep and metabolism: an overview. Int J Endocrinol 2010:1–12.  https://doi.org/10.1155/2010/270832 CrossRefGoogle Scholar
  32. 32.
    Dharnidharka VR, Kwon C, Stevens G (2002) Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis 40:221–226.  https://doi.org/10.1053/ajkd.2002.34487 CrossRefGoogle Scholar
  33. 33.
    Marin JM, Carrizo SJ, Vicente E, Agusti AGN (2005) Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 365:1046–1053.  https://doi.org/10.1016/S0140-6736(05)71141-7 CrossRefGoogle Scholar
  34. 34.
    Zhao YY, Wang R, Gleason KJ, Lewis EF, Quan SF, Toth CM, Morrical M, Rueschman M, Weng J, Ware JH, Mittleman MA, Redline S, on behalf of the BestAIR Investigators (2017) Effect of continuous positive airway pressure treatment on health-related quality of life and sleepiness in high cardiovascular risk individuals with sleep apnea: Best Apnea Interventions for Research (BestAIR) trial. Sleep 40.  https://doi.org/10.1093/sleep/zsx040
  35. 35.
    Nicholl DDM, Hanly PJ, Poulin MJ, Handley GB, Hemmelgarn BR, Sola DY, Ahmed SB (2014) Evaluation of continuous positive airway pressure therapy on renin-angiotensin system activity in obstructive sleep apnea. Am J Respir Crit Care Med 190:572–580.  https://doi.org/10.1164/rccm.201403-0526OC CrossRefGoogle Scholar
  36. 36.
    Puckrin R, Iqbal S, Zidulka A, Vasilevsky M, Barre P (2015) Renoprotective effects of continuous positive airway pressure in chronic kidney disease patients with sleep apnea. Int Urol Nephrol 47:1839–1845.  https://doi.org/10.1007/s11255-015-1113-y CrossRefGoogle Scholar
  37. 37.
    Marrone O, Cibella F, Pépin J-L, Grote L, Verbraecken J, Saaresranta T, Kvamme JA, Basoglu OK, Lombardi C, McNicholas WT, Hedner J, Bonsignore MR (2018) Fixed but not autoadjusting positive airway pressure attenuates the time-dependent decline in glomerular filtration rate in patients with obstructive sleep apnea. Chest.  https://doi.org/10.1016/j.chest.2018.04.020
  38. 38.
    Nicholl DDM, Ahmed SB, Loewen AHS, Hemmelgarn BR, Sola DY, Beecroft JM, Turin TC, Hanly PJ (2012) Clinical presentation of obstructive sleep apnea in patients with chronic kidney disease. J Clin Sleep Med JCSM Off Publ Am Acad Sleep Med 8:381–387.  https://doi.org/10.5664/jcsm.2028 Google Scholar
  39. 39.
    Nicholl DDM, Ahmed SB, Loewen AHS, Hemmelgarn BR, Sola DY, Beecroft JM, Turin TC, Hanly PJ (2013) Diagnostic value of screening instruments for identifying obstructive sleep apnea in kidney failure. J Clin Sleep Med 9:31–38.  https://doi.org/10.5664/jcsm.2334 Google Scholar
  40. 40.
    Adams RJ, Appleton SL, Vakulin A et al (2017) Chronic Kidney Disease and Sleep Apnea Association of Kidney Disease With Obstructive Sleep Apnea in a population study of men. Sleep 40.  https://doi.org/10.1093/sleep/zsw015
  41. 41.
    López Gómez JM, Sacristán Enciso B, Micó M et al (2011) Serum cystatin C and microalbuminuria in the detection of vascular and renal damage in early stages. Nefrol 31:560–566.  https://doi.org/10.3265/Nefrologia.pre2011.Jul.10834 Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Athanasios Voulgaris
    • 1
    • 2
  • Kostas Archontogeorgis
    • 1
  • Evangelia Nena
    • 1
    • 3
  • Christina Tsigalou
    • 4
  • Maria Xanthoudaki
    • 2
  • Maria Kouratzi
    • 2
  • Grigorios Tripsianis
    • 5
  • Marios Froudarakis
    • 2
  • Paschalis Steiropoulos
    • 1
    • 2
    Email author
  1. 1.MSc Programme in Sleep Medicine, Medical SchoolDemocritus University of ThraceAlexandroupolisGreece
  2. 2.Department of Pneumonology, Medical SchoolDemocritus University of Thrace and University General HospitalAlexandroupolisGreece
  3. 3.Laboratory of Hygiene and Environmental Protection, Medical SchoolDemocritus University of ThraceAlexandroupolisGreece
  4. 4.Laboratory of Microbiology, Medical SchoolDemocritus University of ThraceAlexandroupolisGreece
  5. 5.Laboratory of Medical Statistics, Medical SchoolDemocritus University of ThraceAlexandroupolisGreece

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