The effect of regularly dosed paracetamol versus no paracetamol on renal function in Plasmodium knowlesi malaria (PACKNOW): study protocol for a randomised controlled trial

Daniel J Cooper, Katherine Plewes, Matthew J Grigg, Giri S Rajahram, Kim A Piera, Timothy William, Mark D Chatfield, Tsin Wen Yeo, Arjen M Dondorp, Nicholas M Anstey, Bridget E Barber, Daniel J Cooper, Katherine Plewes, Matthew J Grigg, Giri S Rajahram, Kim A Piera, Timothy William, Mark D Chatfield, Tsin Wen Yeo, Arjen M Dondorp, Nicholas M Anstey, Bridget E Barber

Abstract

Background: Plasmodium knowlesi is the most common cause of human malaria in Malaysia. Acute kidney injury (AKI) is a frequent complication. AKI of any cause can have long-term consequences, including increased risk of chronic kidney disease, adverse cardiovascular events and increased mortality. Additional management strategies are therefore needed to reduce the frequency and severity of AKI in malaria. In falciparum malaria, cell-free haemoglobin (CFHb)-mediated oxidative damage contributes to AKI. The inexpensive and widely available drug paracetamol inhibits CFHb-induced lipid peroxidation via reduction of ferryl haem to the less toxic Fe3+ state, and has been shown to reduce oxidative damage and improve renal function in patients with sepsis complicated by haemolysis as well as in falciparum malaria. This study aims to assess the ability of regularly dosed paracetamol to reduce the incidence and severity of AKI in knowlesi malaria by attenuating haemolysis-induced oxidative damage.

Methods: PACKNOW is a two-arm, open-label randomised controlled trial of adjunctive paracetamol versus no paracetamol in patients aged ≥ 5 years with knowlesi malaria, conducted over a 2-year period at four hospital sites in Sabah, Malaysia. The primary endpoint of change in creatinine from enrolment to 72 h will be evaluated by analysis of covariance (ANCOVA) using enrolment creatinine as a covariate. Secondary endpoints include longitudinal changes in markers of oxidative stress (plasma F2-isoprostanes and isofurans) and markers of endothelial activation/Weibel-Palade body release (angiopoietin-2, von Willebrand Factor, P-selectin, osteoprotegerin) over 72 h, as well as blood and urine biomarkers of AKI. This study will be powered to detect a difference between the two treatment arms in a clinically relevant population including adults and children with knowlesi malaria of any severity.

Discussion: Paracetamol is widely available and has an excellent safety profile; if a renoprotective effect is demonstrated, this trial will support the administration of regularly dosed paracetamol to all patients with knowlesi malaria. The secondary outcomes in this study will provide further insights into the pathophysiology of haemolysis-induced oxidative damage and acute kidney injury in knowlesi malaria and other haemolytic diseases.

Trial registration: Clinicaltrials.gov, NCT03056391 . Registered on 12 October 2016.

Keywords: Acute kidney injury; Malaria; Paracetamol; Plasmodium knowlesi.

Conflict of interest statement

Ethics approval and consent to participate

The study has been reviewed, and approved, by the Malaysian Research Ethics Committee (protocol number NMRR-16-356-29,088) and the Ethics Committee of Menzies School of Health Research, Darwin, Australia (reference number 2016-2544). The study is registered under www.clinicaltrials.gov (NCT03056391). First registered October 12, 2016; https://ichgcp.net/clinical-trials-registry/NCT03056391.

Consent for publication

Consent will be obtained by trained study staff nurses in Bahasa Malaysia or English. Parents or guardians of participants < 18 years old will be asked to provide consent, and assent will be sought from participants between 12 and 17 years old as per Malaysian Research Ethics Committee guidelines. If the patient is illiterate, a thumbprint will be obtained on the consent form in accordance with Malaysian GCP guidelines. Informed consent may be withdrawn at any time and will have no effect on the patient’s clinical management at the study site.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
PACKNOW trial design
Fig. 2
Fig. 2
Participant timeline (SPIRIT figure). (x) = Patients without parasite clearance. * Intensive paracetamol level sampling will be performed on a subset of patients at 0.5, 1.5, 2.5, 4.0, 72.5, 73.5, 74.5 and 76.0 h, in addition to 6-hourly as above. AE adverse event, BUSE blood urea and serum electrolytes, LFTs liver function tests (including bilirubin), CFHb cell-free haemoglobin, FBC full blood count, HCT haematocrit, F2-IsoP F2-isoprostanes, F2-IsoF F2-isofurans, WPB Weibel–Palade bodies, Ang-2 angiopoietin-2, vWF von-Willebrand factor, OPG osteoprotegerin, ACR albumin:creatinine ratio, NGAL neutrophil gelatinase-associated lipocalin

References

    1. Singh B, Kim Sung L, Matusop A, Radhakrishnan A, Shamsul SS, Cox-Singh J, et al. A large focus of naturally acquired Plasmodium knowlesi infections in human beings. Lancet. 2004;363(9414):1017–1024. doi: 10.1016/S0140-6736(04)15836-4.
    1. Daneshvar C, William T, Davis TME. Clinical features and management of Plasmodium knowlesi infections in humans. Parasitology. 2018;145(1):18-31.
    1. William T, Rahman HA, Jelip J, Ibrahim MY, Menon J, Grigg MJ, et al. Increasing incidence of Plasmodium knowlesi malaria following control of P. falciparum and P. vivax Malaria in Sabah, Malaysia. PLoS Negl Trop Dis. 2013;7(1):e2026. doi: 10.1371/journal.pntd.0002026.
    1. William T, Jelip J, Menon J, Anderios F, Mohammad R, Awang Mohammad TA, et al. Changing epidemiology of malaria in Sabah, Malaysia: increasing incidence of Plasmodium knowlesi. Malar J. 2014;13:390. doi: 10.1186/1475-2875-13-390.
    1. Yusof R, Lau YL, Mahmud R, Fong MY, Jelip J, Ngian HU, et al. High proportion of knowlesi malaria in recent malaria cases in Malaysia. Malar J. 2014;13:168. doi: 10.1186/1475-2875-13-168.
    1. Rajahram GS, Barber BE, William T, Grigg MJ, Menon J, Yeo TW, et al. Falling Plasmodium knowlesi Malaria Death Rate among Adults despite Rising Incidence, Sabah, Malaysia, 2010-2014. Emerg Infect Dis. 2016;22(1):41–48. doi: 10.3201/eid2201.151305.
    1. Lubis IND, Wijaya H, Lubis M, Lubis CP, Divis PCS, Beshir KB, et al. Contribution of Plasmodium knowlesi to Multispecies Human Malaria Infections in North Sumatera, Indonesia. J Infect Dis. 2017;215(7):1148–1155. doi: 10.1093/infdis/jix091.
    1. Herdiana H, Cotter C, Coutrier FN, Zarlinda I, Zelman BW, Tirta YK, et al. Malaria risk factor assessment using active and passive surveillance data from Aceh Besar, Indonesia, a low endemic, malaria elimination setting with Plasmodium knowlesi, Plasmodium vivax, and Plasmodium falciparum. Malar J. 2016;15:468. doi: 10.1186/s12936-016-1523-z.
    1. Barber BE, William T, Grigg MJ, Menon J, Auburn S, Marfurt J, et al. A prospective comparative study of knowlesi, falciparum, and vivax malaria in Sabah, Malaysia: high proportion with severe disease from Plasmodium knowlesi and Plasmodium vivax but no mortality with early referral and artesunate therapy. Clin Infect Dis. 2013;56(3):383–397. doi: 10.1093/cid/cis902.
    1. Rajahram GS, Barber BE, William T, Menon J, Anstey NM, Yeo TW. Deaths due to Plasmodium knowlesi malaria in Sabah, Malaysia: association with reporting as Plasmodium malariae and delayed parenteral artesunate. Malar J. 2012;11:284. doi: 10.1186/1475-2875-11-284.
    1. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl. 2012;2:1–138. doi: 10.1038/kisup.2012.1.
    1. Grigg MJ, William T, Barber BE, Rajahram GS, Menon J, Schimann E, et al. Age-related clinical spectrum of Plasmodium knowlesi malaria and predictors of severity. CID. 2018. In Press.
    1. Chawla LS, Eggers PW, Star RA, Kimmel PL. Acute kidney injury and chronic kidney disease as interconnected syndromes. N Engl J Med. 2014;371(1):58–66. doi: 10.1056/NEJMra1214243.
    1. Hsu RK, Hsu CY. The Role of Acute Kidney Injury in Chronic Kidney Disease. Semin Nephrol. 2016;36(4):283–292. doi: 10.1016/j.semnephrol.2016.05.005.
    1. Coca SG, Singanamala S, Parikh CR. Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int. 2012;81(5):442–448. doi: 10.1038/ki.2011.379.
    1. Chawla LS, Amdur RL, Shaw AD, Faselis C, Palant CE, Kimmel PL. Association between AKI and long-term renal and cardiovascular outcomes in United States veterans. Clin J Am Soc Nephrol. 2014;9(3):448–456. doi: 10.2215/CJN.02440213.
    1. Horkan CM, Purtle SW, Mendu ML, Moromizato T, Gibbons FK, Christopher KB. The association of acute kidney injury in the critically ill and postdischarge outcomes: a cohort study*. Crit Care Med. 2015;43(2):354–364. doi: 10.1097/CCM.0000000000000706.
    1. Mangano CM, Diamondstone LS, Ramsay JG, Aggarwal A, Herskowitz A, Mangano DT. Renal dysfunction after myocardial revascularization: risk factors, adverse outcomes, and hospital resource utilization. The Multicenter Study of Perioperative Ischemia Research Group. Ann Intern Med. 1998;128(3):194–203. doi: 10.7326/0003-4819-128-3-199802010-00005.
    1. Plewes K, Kingston HWF, Ghose A, Maude RJ, Herdman MT, Leopold SJ, et al. Cell-free hemoglobin mediated oxidative stress is associated with acute kidney injury and renal replacement therapy in severe falciparum malaria: an observational study. BMC Infect Dis. 2017;17(1):313. doi: 10.1186/s12879-017-2373-1.
    1. Boutaud O, Moore KP, Reeder BJ, Harry D, Howie AJ, Wang S, et al. Acetaminophen inhibits hemoprotein-catalyzed lipid peroxidation and attenuates rhabdomyolysis-induced renal failure. Proc Natl Acad Sci. 2010;107(6):2699–2704. doi: 10.1073/pnas.0910174107.
    1. Billings IF, Petracek MR, Roberts IL, Pretorius M. Perioperative Intravenous Acetaminophen Attenuates Lipid Peroxidation in Adults Undergoing Cardiopulmonary Bypass: A Randomized Clinical Trial. PLoS One. 2015;10(2):e0117625. doi: 10.1371/journal.pone.0117625.
    1. Moore KP, Holt SG, Patel RP, Svistunenko DA, Zackert W, Goodier D, et al. A causative role for redox cycling of myoglobin and its inhibition by alkalinization in the pathogenesis and treatment of rhabdomyolysis-induced renal failure. J Biol Chem. 1998;273(48):31731–31737. doi: 10.1074/jbc.273.48.31731.
    1. Simpson SA, Zaccagni H, Bichell DP, Christian KG, Mettler BA, Donahue BS, et al. Acetaminophen attenuates lipid peroxidation in children undergoing cardiopulmonary bypass. Pediatr Crit Care Med. 2014;15(6):503–510. doi: 10.1097/PCC.0000000000000149.
    1. Ware LB, Fessel JP, May AK, Roberts LJ., 2nd Plasma biomarkers of oxidant stress and development of organ failure in severe sepsis. Shock. 2011;36(1):12–17. doi: 10.1097/SHK.0b013e318217025a.
    1. Aronoff DM, Oates JA, Boutaud O. New insights into the mechanism of action of acetaminophen: Its clinical pharmacologic characteristics reflect its inhibition of the two prostaglandin H2 synthases. Clin Pharmacol Ther. 2006;79(1):9–19. doi: 10.1016/j.clpt.2005.09.009.
    1. Ouellet M, Percival MD. Mechanism of acetaminophen inhibition of cyclooxygenase isoforms. Arch Biochem Biophys. 2001;387(2):273–280. doi: 10.1006/abbi.2000.2232.
    1. Janz DR, Bastarache JA, Peterson JF, Sills G, Wickersham N, May AK, et al. Association between cell-free hemoglobin, acetaminophen, and mortality in patients with sepsis: an observational study. Crit Care Med. 2013;41(3):784. doi: 10.1097/CCM.0b013e3182741a54.
    1. Janz DR, Bastarache JA, Rice TW, Bernard GR, Warren MA, Wickersham N, et al. Randomized, Placebo-Controlled Trial of Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis: The Acetaminophen for the Reduction of Oxidative Injury in Severe Sepsis Trial*. Crit Care Med. 2015;43(3):534–541. doi: 10.1097/CCM.0000000000000718.
    1. Plewes K, Kingston HWF, Ghose A, Wattanakul T, Hassan MMU, Haider MS, et al. Acetaminophen as a Renoprotective Adjunctive Treatment in Patients with Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial. Clinical Infectious Diseases. 2018:ciy213-ciy
    1. Belcher JD, Chen C, Nguyen J, Milbauer L, Abdulla F, Alayash AI, et al. Heme triggers TLR4 signaling leading to endothelial cell activation and vaso-occlusion in murine sickle cell disease. Blood. 2014;123(3):377–390. doi: 10.1182/blood-2013-04-495887.
    1. Yeo TW, Lampah DA, Gitawati R, Tjitra E, Kenangalem E, Piera K, et al. Angiopoietin-2 is associated with decreased endothelial nitric oxide and poor clinical outcome in severe falciparum malaria. Proc Natl Acad Sci U S A. 2008;105(44):17097–17102. doi: 10.1073/pnas.0805782105.
    1. Barber BE, et al. Intravascular hemolysis in severe Plasmodium knowlesi malaria: association with endothelial activation, microvascular dysfunction, and acute kidney injury. Emerg Microbes Infect. 2018; In Press.
    1. Yeo TW, Lampah DA, Tjitra E, Gitawati R, Kenangalem E, Piera K, et al. Relationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavailability and perfusion in severe falciparum malaria. J Infect Dis. 2009;200(10):1522–1529. doi: 10.1086/644641.
    1. Elphinstone RE, Conroy AL, Hawkes M, Hermann L, Namasopo S, Warren HS, et al. Alterations in Systemic Extracellular Heme and Hemopexin Are Associated With Adverse Clinical Outcomes in Ugandan Children With Severe Malaria. J Infect Dis. 2016;214(8):1268–1275. doi: 10.1093/infdis/jiw357.
    1. Wang C, Blough ER, Arvapalli R, Dai X, Paturi S, Manne N, et al. Metabolic syndrome-induced tubulointerstitial injury: role of oxidative stress and preventive effects of acetaminophen. Free Radic Biol Med. 2013;65:1417–1426. doi: 10.1016/j.freeradbiomed.2013.10.005.
    1. Charunwatthana P, Abul Faiz M, Ruangveerayut R, Maude RJ, Rahman MR, Roberts LJ, 2nd, et al. N-acetylcysteine as adjunctive treatment in severe malaria: a randomized, double-blinded placebo-controlled clinical trial. Crit Care Med. 2009;37(2):516–522. doi: 10.1097/CCM.0b013e3181958dfd.
    1. WHO. World Malaria Report 2017. Available at: . Accessed 22 Jan 2018.
    1. WHO Malaria Policy Advisory Committee. Outcomes from the Evidence Review Group on Plasmodium knowlesi. Kota Kinabalu; 2017. Available at: . Accessed 22 Jan 2018.
    1. Barber BE, William T, Grigg MJ, Yeo TW, Anstey NM. Limitations of microscopy to differentiate Plasmodium species in a region co-endemic for Plasmodium falciparum, Plasmodium vivax and Plasmodium knowlesi. Malar J. 2013;12:8. doi: 10.1186/1475-2875-12-8.
    1. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–381. doi: 10.1016/j.jbi.2008.08.010.
    1. Ministry of Health Malaysia . Management Guidelines of Malaria in Malaysia. Malaysia: Ministry of Health; 2013.
    1. Milne GL, Yin H, Brooks JD, Sanchez S, Jackson Roberts L, 2nd, Morrow JD. Quantification of F2-isoprostanes in biological fluids and tissues as a measure of oxidant stress. Methods Enzymol. 2007;433:113–126. doi: 10.1016/S0076-6879(07)33006-1.
    1. Fessel JP, Porter NA, Moore KP, Sheller JR, Roberts LJ., 2nd Discovery of lipid peroxidation products formed in vivo with a substituted tetrahydrofuran ring (isofurans) that are favored by increased oxygen tension. Proc Natl Acad Sci U S A. 2002;99(26):16713–16718. doi: 10.1073/pnas.252649099.
    1. Hempel C, Pasini EM, Kurtzhals JA. Endothelial Glycocalyx: Shedding Light on Malaria Pathogenesis. Trends Mol Med. 2016;22(6):453–457. doi: 10.1016/j.molmed.2016.04.004.
    1. Imwong M, Tanomsing N, Pukrittayakamee S, Day NP, White NJ, Snounou G. Spurious amplification of a Plasmodium vivax small-subunit RNA gene by use of primers currently used to detect P. knowlesi. J Clin Microbiol. 2009;47(12):4173–4175. doi: 10.1128/JCM.00811-09.
    1. Padley D, Moody AH, Chiodini PL, Saldanha J. Use of a rapid, single-round, multiplex PCR to detect malarial parasites and identify the species present. Ann Trop Med Parasitol. 2003;97(2):131–137. doi: 10.1179/000349803125002977.
    1. Ismail S, Na Bangchang K, Karbwang J, Back DJ, Edwards G. Paracetamol disposition in Thai patients during and after treatment of falciparum malaria. Eur J Clin Pharmacol. 1995;48(1):65–69. doi: 10.1007/BF00202175.
    1. Macheras P, Parissi-Poulos M, Poulos L. Pharmacokinetics of acetaminophen after intramuscular administration. Biopharm Drug Dispos. 1989;10(1):101–105. doi: 10.1002/bdd.2510100111.
    1. WWARN. Methodology for the WWARN Parasite Clearance Estimator. Available from: . Accessed 15 Sept 2017.
    1. Chen S. Retooling the creatinine clearance equation to estimate kinetic GFR when the plasma creatinine is changing acutely. J Am Soc Nephrol. 2013;24(6):877–888. doi: 10.1681/ASN.2012070653.
    1. Krishna S, Pukrittayakamee S, Supanaranond W, ter Kuile F, Ruprah M, Sura T, et al. Fever in uncomplicated Plasmodium falciparum malaria: randomized double-‘blind’ comparison of ibuprofen and paracetamol treatment. Trans R Soc Trop Med Hyg. 1995;89(5):507–509. doi: 10.1016/0035-9203(95)90087-X.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다