Acetaminophen as a Renoprotective Adjunctive Treatment in Patients With Severe and Moderately Severe Falciparum Malaria: A Randomized, Controlled, Open-Label Trial

Katherine Plewes, Hugh W F Kingston, Aniruddha Ghose, Thanaporn Wattanakul, Md Mahtab Uddin Hassan, Md Shafiul Haider, Prodip K Dutta, Md Akhterul Islam, Shamsul Alam, Selim Md Jahangir, A S M Zahed, Md Abdus Sattar, M A Hassan Chowdhury, M Trent Herdman, Stije J Leopold, Haruhiko Ishioka, Kim A Piera, Prakaykaew Charunwatthana, Kamolrat Silamut, Tsin W Yeo, Sue J Lee, Mavuto Mukaka, Richard J Maude, Gareth D H Turner, Md Abul Faiz, Joel Tarning, John A Oates, Nicholas M Anstey, Nicholas J White, Nicholas P J Day, Md Amir Hossain, L Jackson Roberts Ii, Arjen M Dondorp, Katherine Plewes, Hugh W F Kingston, Aniruddha Ghose, Thanaporn Wattanakul, Md Mahtab Uddin Hassan, Md Shafiul Haider, Prodip K Dutta, Md Akhterul Islam, Shamsul Alam, Selim Md Jahangir, A S M Zahed, Md Abdus Sattar, M A Hassan Chowdhury, M Trent Herdman, Stije J Leopold, Haruhiko Ishioka, Kim A Piera, Prakaykaew Charunwatthana, Kamolrat Silamut, Tsin W Yeo, Sue J Lee, Mavuto Mukaka, Richard J Maude, Gareth D H Turner, Md Abul Faiz, Joel Tarning, John A Oates, Nicholas M Anstey, Nicholas J White, Nicholas P J Day, Md Amir Hossain, L Jackson Roberts Ii, Arjen M Dondorp

Abstract

Background: Acute kidney injury independently predicts mortality in falciparum malaria. It is unknown whether acetaminophen's capacity to inhibit plasma hemoglobin-mediated oxidation is renoprotective in severe malaria.

Methods: This phase 2, open-label, randomized controlled trial conducted at two hospitals in Bangladesh assessed effects on renal function, safety, pharmacokinetic (PK) properties and pharmacodynamic (PD) effects of acetaminophen. Febrile patients (>12 years) with severe falciparum malaria were randomly assigned to receive acetaminophen (1 g 6-hourly for 72 hours) or no acetaminophen, in addition to intravenous artesunate. Primary outcome was the proportional change in creatinine after 72 hours stratified by median plasma hemoglobin.

Results: Between 2012 and 2014, 62 patients were randomly assigned to receive acetaminophen (n = 31) or no acetaminophen (n = 31). Median (interquartile range) reduction in creatinine after 72 hours was 23% (37% to 18%) in patients assigned to acetaminophen, versus 14% (29% to 0%) in patients assigned to no acetaminophen (P = .043). This difference in reduction was 37% (48% to 22%) versus 14% (30% to -71%) in patients with hemoglobin ≥45000 ng/mL (P = .010). The proportion with progressing kidney injury was higher among controls (subdistribution hazard ratio, 3.0; 95% confidence interval, 1.1 to 8.5; P = .034). PK-PD analyses showed that higher exposure to acetaminophen increased the probability of creatinine improvement. No patient fulfilled Hy's law for hepatotoxicity.

Conclusions: In this proof-of-principle study, acetaminophen showed renoprotection without evidence of safety concerns in patients with severe falciparum malaria, particularly in those with prominent intravascular hemolysis.

Clinical trials registration: NCT01641289.

Figures

Figure 1.
Figure 1.
Flow chart for the “Acetaminophen as a Renoprotective Adjunctive Treatment in Patients With Severe and Moderately Severe Falciparum Malaria” study. *A total of 30 patients were recruited in Chittagong, Bangladesh, and 32 patients were recruited in Ramu, Bangladesh. Abbreviation: NG, nasogastric.
Figure 2.
Figure 2.
Effect of acetaminophen on creatinine stratified by intravascular hemolysis. Creatinine mean percent change from baseline at 12, 24, 36, 60, 48, and 72 hours of entire cohort (A) and patients stratified by level of intravascular hemolysis (B and C). Plasma cell-free hemoglobin (CFH) ≥45000 ng/mL (B); plasma CFH <45000 ng/mL (C); patients stratified by level of lipid peroxidation (D and E); plasma F2- isoprostanes (IsoPs) ≥22 pg/mL (D); plasma F2-IsoPs <22 pg/mL (E). A total of 35 of 434 (8%) creatinine sampling time points were missing and replaced by imputed values (for details see Supplementary Table 2). Frequencies in rows below figures represent number of patients (n) at each time point. P value represents overall treatment effect. Abbreviations: Cr, creatinine; CFH, cell-free hemoglobin; F2-IsoPs, F2-isoprostanes.
Figure 3.
Figure 3.
Kaplan–Meier plot comparing in-hospital acute kidney injury (AKI) development in patients with severe and moderately severe malaria treated with either acetaminophen or no acetaminophen (control). Patients were classified as developing AKI if they had a creatinine rise of ≥26.5 µmol/L after admission. A total of 17/62 (27%) patients had AKI during admission: 12/17 (38%) in the control group and 5/12 (16%) in the acetaminophen group. Competing risks regression adjusted by study site was used to assess subdistribution hazard ratio. Patients were censored at the time of creatinine rise meeting Kidney Disease: Improving Global Outcomes criteria and death censored as a competing risk preventing the primary event of interest (AKI) from occurring. Abbreviations: CI, confidence interval; KDIGO, Kidney Disease: Improving Global Outcomes; SHR, subdistribution hazard ratio.

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