Long-term cardio-vascular risk assessment in chronic kidney disease and kidney transplanted patients following SARS-COV-2 disease: protocol for multi-center observational match controlled trial

Laura Tapoi, Mugurel Apetrii, Gianina Dodi, Ionut Nistor, Luminita Voroneanu, Lucian Siriteanu, Mihai Onofriescu, Mehmet Kanbay, Adrian Covic, Laura Tapoi, Mugurel Apetrii, Gianina Dodi, Ionut Nistor, Luminita Voroneanu, Lucian Siriteanu, Mihai Onofriescu, Mehmet Kanbay, Adrian Covic

Abstract

Background: The coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) produced a pandemic since March 2020 by affecting more than 243 million people with more than 5 million deaths globally. SARS-CoV-2 infection is produced by binding to angiotensin-converting enzyme, which among other sites is highly expressed in the endothelial cells of the blood vessels, pericytes and the heart, as well as in renal podocytes and proximal tubular epithelial cells. SARS-CoV-2 and cardiovascular disease (CVD) are interconnected by risk factors association with an increased incidence of the disease and by determining de novo cardiac complications. At the same time, COVID-19 disease can lead to acute kidney injury directly, or due to sepsis, multi-organ failure and shock. Therefore, the pre-existence of both CVD and chronic kidney disease (CKD) is linked with a higher risk of severe disease and worse prognosis.

Methods: The main aim of this study is to assess the CV risk in a CKD (stage 3 to 5), dialysis and kidney transplanted population, following SARS-CoV-2 infection, with focus on the endothelial dysfunction as compared to a control group of matched patients. By using clinical evaluation, flow-mediated dilatation, carotid-femoral pulse wave velocity, intima-media thickness, echocardiographic parameters, lung ultrasound, bioimpedance spectroscopy and a series of novel biomarkers, the investigators will determine the long-term impact of this disease on CV and renal outcomes.

Discussion: This study will address the challenges and implications in long-term CV sequeale of COVID-19 and focus on a better understanding of the underlying mechanisms and possible therapeutic options.

Trial registration: Patient enrolment in the trial started in January 2021 and is expected to finish at the end of 2022. The study can be found on ClinicalTrials.gov database with NCT05125913 identifier. Registered on 18 November 2021 - Retrospectively registered.

Keywords: Cardio-vascular risk; Cardiovascular disease; Chronic kidney disease; Kidney transplant; SARS-CoV-2; dialysis.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Protocol flowchart
Fig. 2
Fig. 2
Flow diagram of the study design

References

    1. Ghebreyesus TA. WHO director-General’s opening remarks at the media briefing on COVID-19-11 March 2020. Geneva: WHO; 2020.
    1. WHO Coronavirus (COVID-19) Dashboard. Available from: (Accessed 26 Oct 2020).
    1. Apetrii M, Enache S, Siriopol D, Burlacu A, Kanbay A, Kanbay M, et al. A brand-new cardiorenal syndrome in the COVID-19 setting. Clin Kidney J. 2020;13(3):291.
    1. Lindner D, Fitzek A, Bräuninger H, Aleshcheva G, Edler C, Meissner K, et al. Association of Cardiac Infection with SARS-CoV-2 in confirmed COVID-19 autopsy cases. JAMA Cardiol. 2020;5(11):1281–1285. doi: 10.1001/jamacardio.2020.3551.
    1. Su H, Yang M, Wan C, Yi LX, Tang F, Zhu HY, et al. Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China. Kidney Int. 2020;98(1):219–227. doi: 10.1016/j.kint.2020.04.003.
    1. Naser MN, Al-Ghatam R, Darwish AH, Alqahtani MM, Alahmadi HA, Mohamed KA, et al. Risk factors, predictions, and progression of acute kidney injury in hospitalized COVID-19 patients: an observational retrospective cohort study. PLoS One. 2021;16(9):e0257253. doi: 10.1371/journal.pone.0257253.
    1. Requião-Moura LR, Sandes-Freitas TV, Viana LA, Cristelli MP, Andrade LGM, Garcia VD, et al. High mortality among kidney transplant recipients diagnosed with coronavirus disease 2019: results from the Brazilian multicenter cohort study. PLoS One. 2021;16(7):e0254822. doi: 10.1371/journal.pone.0254822.
    1. Council E-E, Group EW Chronic kidney disease is a key risk factor for severe COVID-19: a call to action by the ERA-EDTA. Nephrol Dial Transplant. 2020;36(1):87–94. doi: 10.1093/ndt/gfaa314.
    1. Chibane S, Gibeau G, Poulin F, Tessier P, Goulet M, Carrier M, et al. Hyperacute multi-organ thromboembolic storm in COVID-19: a case report. J Thromb Thrombolysis. 2021;51(1):25–28. doi: 10.1007/s11239-020-02173-w.
    1. Rao A, Ranka S, Ayers C, Hendren N, Rosenblatt A, Alger HM, et al. Association of Kidney Disease with Outcomes in COVID-19: results from the American Heart Association COVID-19 cardiovascular disease registry. J Am Heart Assoc. 2021;10(12):e020910. doi: 10.1161/JAHA.121.020910.
    1. Cheng Y, Luo R, Wang K, Zhang M, Wang Z, Dong L, et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int. 2020;97(5):829–838. doi: 10.1016/j.kint.2020.03.005.
    1. Bansal M. Cardiovascular disease and COVID-19. Diabetes Metab Syndr. 2020;14(3):247–250. doi: 10.1016/j.dsx.2020.03.013.
    1. Sardu C, Gambardella J, Morelli MB, Wang X, Marfella R, Santulli G. Hypertension, thrombosis, kidney failure, and diabetes: is COVID-19 an endothelial disease? A comprehensive evaluation of clinical and Basic evidence. J Clin Med. 2020;9(5):1417. doi: 10.3390/jcm9051417.
    1. Tersalvi G, Vicenzi M, Calabretta D, Biasco L, Pedrazzini G, Winterton D. Elevated troponin in patients with coronavirus disease 2019: possible mechanisms. J Card Fail. 2020;26(6):470–475. doi: 10.1016/j.cardfail.2020.04.009.
    1. Gao L, Jiang D, Wen XS, Cheng XC, Sun M, He B, et al. Prognostic value of NT-proBNP in patients with severe COVID-19. Respir Res. 2020;21(1):83. doi: 10.1186/s12931-020-01352-w.
    1. Li Z, Wu M, Yao J, Guo J, Liao X, Song S, et al. Caution on Kidney Dysfunctions of COVID-19 Patients. MedRxiv. 2020. .
    1. Abdelrahman MM, Abd-Elrahman NM, Bakheet TM. Persistence of symptoms after improvement of acute COVID19 infection, a longitudinal study. J Med Virol. 2021;93(10):5942–5946. doi: 10.1002/jmv.27156.
    1. Bell ML, Catalfamo CJ, Farland LV, Ernst KC, Jacobs ET, Klimentidis YC, et al. Post-acute sequelae of COVID-19 in a non-hospitalized cohort: results from the Arizona CoVHORT. PLoS One. 2021;16(8):e0254347. doi: 10.1371/journal.pone.0254347.
    1. Tenforde MW, Kim SS, Lindsell CJ, Billig Rose E, Shapiro NI, Files DC, et al. Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network - United States, march-June 2020. MMWR Morb Mortal Wkly Rep. 2020;69(30):993–998. doi: 10.15585/mmwr.mm6930e1.
    1. Stavem K, Ghanima W, Olsen MK, Gilboe HM, Einvik G. Persistent symptoms 1.5–6 months after COVID-19 in non-hospitalised subjects: a population-based cohort study. Thorax. 2021;76(4):405–407. doi: 10.1136/thoraxjnl-2020-216377.
    1. Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27(4):601–615. doi: 10.1038/s41591-021-01283-z.
    1. Huang C, Huang L, Wang Y, Li X, Ren L, Gu X, et al. 6-month consequences of COVID-19 in patients discharged from hospital: a cohort study. Lancet. 2021;397(10270):220–232. doi: 10.1016/S0140-6736(20)32656-8.
    1. Yong SJ. Long COVID or post-COVID-19 syndrome: putative pathophysiology, risk factors, and treatments. Infect Dis (Lond) 2021;53(10):737–754. doi: 10.1080/23744235.2021.1924397.
    1. Basic-Jukic N, Juric I, Furic-Cunko V, Katalinic L, Radic J, Bosnjak Z, et al. Follow-up of renal transplant recipients after acute COVID-19-a prospective cohort single-center study. Immun Inflamm Dis. 2021;9(4):1563–1572. doi: 10.1002/iid3.509.
    1. Bowe B, Xie Y, Xu E, Al-Aly Z. Kidney outcomes in long COVID. J Am Soc Nephrol. 2021;32(11):2851–2862. doi: 10.1681/ASN.2021060734.
    1. Evans PC, Rainger GE, Mason JC, Guzik TJ, Osto E, Stamataki Z, et al. Endothelial dysfunction in COVID-19: a position paper of the ESC working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic cardiovascular science. Cardiovasc Res. 2020;116(14):2177–2184. doi: 10.1093/cvr/cvaa230.
    1. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395(10234):1417–1418. doi: 10.1016/S0140-6736(20)30937-5.
    1. World Health O . Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected: interim guidance, 13 March 2020. Geneva: WHO; 2020.
    1. Stefan G, Garneata L, Podgoreanu E, Mircescu G. Romanian Renal registry, 2019–2020, 39. . Accessed 25 Apr 2022.
    1. Jager KJ, Kramer A, Chesnaye NC, Couchoud C, Sánchez-Álvarez JE, Garneata L, Collart F, Hemmelder MH, Ambühl P, Kerschbaum J, Legeai C, Del Pino Y, Pino MD, Mircescu G, Mazzoleni L, Hoekstra T, Winzeler R, Mayer G, Stel VS, Wanner C, Zoccali C, Massy ZA. Results from the ERA-EDTA registry indicate a high mortality due to COVID-19 in dialysis patients and kidney transplant recipients across Europe. Kidney Int. 2020;98(6):1540–1548. doi: 10.1016/j.kint.2020.09.006.
    1. Hilbrands LB, Duivenvoorden R, Vart P, Franssen CFM, Hemmelder MH, Jager KJ, ERACODA Collaborators et al. COVID-19-related mortality in kidney transplant and dialysis patients: results of the ERACODA collaboration. Nephrol Dial Transplant. 2020;35(11):1973–1983. doi: 10.1093/ndt/gfaa261.
    1. Hemmelder MH, Noordzij M, Vart P, Hilbrands LB, Jager KJ, Abrahams AC, et al. Recovery of dialysis patients with COVID-19: health outcomes 3 months after diagnosis in ERACODA. Nephrol Dial Transplant. 2022:gfac008.
    1. Salerno S, Messana JM, Gremel GW, et al. COVID-19 risk factors and mortality outcomes among Medicare patients receiving long-term Dialysis. JAMA Netw Open. 2021;4(11):e2135379. doi: 10.1001/jamanetworkopen.2021.35379.
    1. Carriazo S, Mas-Fontao S, Seghers C, Cano J, Goma E, Avello A, Ortiz A, Gonzalez-Parra E. Increased 1-year mortality in haemodialysis patients with COVID-19: a prospective, observational study. Clin Kidney J. 2022;15(3):432–441. doi: 10.1093/ckj/sfab248.
    1. Puntmann VO, Carerj ML, Wieters I, Fahim M, Arendt C, Hoffmann J, et al. Outcomes of cardiovascular magnetic resonance imaging in patients recently recovered from coronavirus disease 2019 (COVID-19) JAMA Cardiol. 2020;5(11):1265–1273. doi: 10.1001/jamacardio.2020.3557.
    1. Rajpal S, Tong MS, Borchers J, Zareba KM, Obarski TP, Simonetti OP, et al. Cardiovascular magnetic resonance findings in competitive athletes recovering from COVID-19 infection. JAMA Cardiol. 2021;6(1):116–118.
    1. Fayol A, Livrozet M, Boutouyrie P, Khettab H, Betton M, Tea V, et al. Cardiac performance in patients hospitalized with COVID-19: a 6 month follow-up study. ESC Heart Fail. 2021;8(3):2232–2239. doi: 10.1002/ehf2.13315.
    1. Lassen MCH, Skaarup KG, Lind JN, Alhakak AS, Sengeløv M, Nielsen AB, et al. Echocardiographic abnormalities and predictors of mortality in hospitalized COVID-19 patients: the ECHOVID-19 study. ESC Heart Fail. 2020;7(6):4189–4197. doi: 10.1002/ehf2.13044.
    1. Pimentel SLG, Nascimento BR, Franco J, Oliveira KKB, Fraga CL, Macedo FVB, et al. Bedside echocardiography to predict mortality of COVID-19 patients beyond clinical data: data from the PROVAR-COVID study. Rev Soc Bras Med Trop. 2021;54:e03822021. doi: 10.1590/0037-8682-0382-2021.
    1. Karagodin I, Carvalho Singulane C, Woodward GM, Xie M, Tucay ES, Tude Rodrigues AC, et al. Echocardiographic correlates of in-hospital death in patients with acute COVID-19 infection: the World Alliance societies of echocardiography (WASE-COVID) study. J Am Soc Echocardiogr. 2021;34(8):819–830. doi: 10.1016/j.echo.2021.05.010.
    1. Khani M, Tavana S, Tabary M, Naseri Kivi Z, Khaheshi I. Prognostic implications of biventricular strain measurement in COVID-19 patients by speckle-tracking echocardiography. Clin Cardiol. 2021;44(10):1475–1481. doi: 10.1002/clc.23708.
    1. Barssoum K, Victor V, Salem A, Kumar A, Mubasher M, Hassib M, et al. Echocardiography, lung ultrasound, and cardiac magnetic resonance findings in COVID-19: a systematic review. Echocardiography. 2021;38(8):1365–1404.
    1. Saylik F, Akbulut T, Oguz M, Sipal A, Ormeci T. Association of echocardiographic parameters with chest computed tomography score in patients with COVID-19 disease. Adv Med Sci. 2021;66(2):403–410. doi: 10.1016/j.advms.2021.08.001.
    1. Lassen MCH, Skaarup KG, Lind JN, Alhakak AS, Sengeløv M, Nielsen AB, et al. Recovery of cardiac function following COVID-19 - ECHOVID-19: a prospective longitudinal cohort study. Eur J Heart Fail. 2021;23(11):1903–1912. doi: 10.1002/ejhf.2347.
    1. Erdoğan M, Kaya Kalem A, Öztürk S, Erdöl MA, Kayaaslan B, Özbebek YE, et al. Interleukin-6 level is an independent predictor of right ventricular systolic dysfunction in patients hospitalized with COVID-19. Anatol J Cardiol. 2021;25(8):555–564. doi: 10.5152/AnatolJCardiol.2021.24946.
    1. Kimura BJ, Shi R, Tran EM, Spierling Bagsic SR, Resnikoff PM. Outcomes of simplified lung ultrasound exam in COVID-19: implications for self-imaging. J Ultrasound Med. 2021;9999:1–8.
    1. Alharthy A, Abuhamdah M, Balhamar A, Faqihi F, Nasim N, Ahmad S, et al. Residual lung injury in patients recovering from COVID-19 critical illness: a prospective longitudinal point-of-care lung ultrasound study. J Ultrasound Med. 2021;40(9):1823–1838. doi: 10.1002/jum.15563.
    1. Thijssen DHJ, Bruno RM, van Mil ACCM, Holder SM, Faita F, Greyling A, et al. Expert consensus and evidence-based recommendations for the assessment of flow-mediated dilation in humans. Eur Heart J. 2019;40(30):2534–2547. doi: 10.1093/eurheartj/ehz350.
    1. Matsuzawa Y, Kwon TG, Lennon RJ, Lerman LO, Lerman A. Prognostic value of flow-mediated vasodilation in brachial artery and fingertip artery for cardiovascular events: a systematic review and meta-analysis. J Am Heart Assoc. 2015;4(11):e002270. doi: 10.1161/JAHA.115.002270.
    1. Ratchford SM, Stickford JL, Province VM, Stute N, Augenreich MA, Koontz LK, et al. Vascular alterations among young adults with SARS-CoV-2. Heart Circ Physiol. 2021;320(1):H404–HH10. doi: 10.1152/ajpheart.00897.2020.
    1. Oliveira MR, Back GD, da Luz GC, Domingos BC, Arena R, Borghi-Silva A. Endothelial function provides early prognostic information in patients with COVID-19: a cohort study. Respir Med. 2021;185:106469. doi: 10.1016/j.rmed.2021.106469.
    1. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the international brachial artery reactivity task force. J Am Coll Cardiol. 2002;39(2):257–265. doi: 10.1016/S0735-1097(01)01746-6.
    1. Riou M, Oulehri W, Momas C, Rouyer O, Lebourg F, Meyer A, et al. Reduced flow-mediated dilatation is not related to COVID-19 severity three months after hospitalization for SARS-CoV-2 infection. J Clin Med. 2021;10(6):1318. doi: 10.3390/jcm10061318.
    1. Ambrosino P, Calcaterra I, Molino A, Moretta P, Lupoli R, Spedicato GA, et al. Persistent endothelial dysfunction in post-acute COVID-19 syndrome: a case-control study. Biomedicines. 2021;9(8):957. doi: 10.3390/biomedicines9080957.
    1. Ergül E, Yılmaz AS, Öğütveren MM, Emlek N, Kostakoğlu U, Çetin M. COVID 19 disease independently predicted endothelial dysfunction measured by flow-mediated dilatation. Int J Card Imaging. 2022;38:25–32.
    1. Ambrosino P, Molino A, Calcaterra I, Formisano R, Stufano S, Spedicato GA, et al. Clinical assessment of endothelial function in convalescent COVID-19 patients undergoing multidisciplinary pulmonary rehabilitation. Biomedicines. 2021;9(6):614. doi: 10.3390/biomedicines9060614.
    1. Rodilla E, López-Carmona MD, Cortes X, Cobos-Palacios L, Canales S, Sáez MC, et al. Impact of Arterial Stiffness on All-Cause Mortality in Patients Hospitalized With COVID-19 in Spain. Hypertension. 2021;77(3):856–867. doi: 10.1161/HYPERTENSIONAHA.120.16563.
    1. Schnaubelt S, Oppenauer J, Tihanyi D, Mueller M, Maldonado-Gonzalez E, Zejnilovic S, et al. Arterial stiffness in acute COVID-19 and potential associations with clinical outcome. J Intern Med. 2021;290(2):437–443. doi: 10.1111/joim.13275.
    1. Lambadiari V, Mitrakou A, Kountouri A, Thymis J, Katogiannis K, Korakas E, et al. Association of COVID-19 with impaired endothelial glycocalyx, vascular function and myocardial deformation 4 months after infection. Eur J Heart Fail. 2021;23(11):1916–1926. doi: 10.1002/ejhf.2326.
    1. Szeghy RE, Province VM, Stute NL, Augenreich MA, Koontz LK, Stickford JL, et al. Carotid stiffness, intima-media thickness and aortic augmentation index among adults with SARS-CoV-2. Exp Physiol. 2021;1–14.
    1. Samprathi M, Jayashree M. Biomarkers in COVID-19: an up-to-date review. Front Pediatr. 2021;8(972):607647. doi: 10.3389/fped.2020.607647.
    1. Andrianto A-FMJ, Nugraha RA, Marsudi BA, Azmi Y. Biomarkers of endothelial dysfunction and outcomes in coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis. Microvasc Res. 2021;138:104224. doi: 10.1016/j.mvr.2021.104224.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe