Therapy with lopinavir/ritonavir and hydroxychloroquine is associated with acute kidney injury in COVID-19 patients

Abstract

Background Acute kidney injury (AKI) is an independent risk factor for mortality, which affects about 5% of hospitalized coronavirus disease-2019 (COVID-19) patients and up to 25–29% of severely ill COVID-19 patients. Lopinavir/ritonavir and hydroxychloroquine show in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and have been used for the treatment of COVID-19. Both, lopinavir and hydroxychloroquine are metabolized by cytochrome P450 (CYP) 3A4. The impact of a triple therapy with lopinavir/ritonavir and hydroxychloroquine (triple therapy) on kidney function in COVID-19 is currently not known. Methods We retrospectively analyzed both non-ICU and ICU patients with COVID-19 receiving triple therapy for the incidence of AKI. Patients receiving standard therapy served as a control group. All patients were hospitalized at the University Hospital of Freiburg, Germany, between March and April 2020. A matched-pair analysis for the National Early Warning Score (NEWS) 2 was performed to control for the severity of illness among non-intensive care unit (ICU) patients. Results In non-ICU patients, the incidence of AKI was markedly increased following triple therapy (78.6% vs. 21.4% in controls, p = 0.002), while a high incidence of AKI was observed in both groups of ICU patients (triple therapy: 80.0%, control group: 90.5%). ICU patients treated with triple therapy showed a trend towards more oliguric or anuric kidney injury. We also observed a linear correlation between the duration of the triple therapy and the maximum serum creatinine level (p = 0.004, R2 = 0.276, R = 0.597). Conclusion Triple therapy is associated with an increase in the incidence of AKI in non-ICU COVID-19 patients. The underlying mechanisms may comprise a CYP3A4 enzyme interaction, and may be relevant for any future therapy combining hydroxychloroquine with antiviral agents.

Unsupervised clustering reveals phenotypes of AKI in ICU Covid19 patients

“…We first identified factors associated with AKI development. When considering Covid19 specific therapy, we found LPV/r and dexamethasone to be respectively positively and negatively related to AKI development, in accordance with other groups [33][34][35][36][37]. We also reported well described AKI risk factors, such as diabetes mellitus, use of norepinephrine and baseline eGFR [38,39].…”

“…Patients from clusters 1 and 2 also showed a distinct metabolic profile compared to cluster 3, expressing the impaired metabolism profile at a lower rate (22% [19-24] versus 29% [23-33] p=0.005, Figure 3d ). Among clusters 1 and 2, the expression of isolated hyperglycaemia was also higher in cluster 2 (13% [10-16] versus 25% [11-35], p=0.009, Figure 3d ).…”

Hydroxychloroquine/chloroquine and the risk of acute kidney injury in COVID-19 patients: a systematic review and meta-analysis

“…In addition, four studies [ 24 , 26 , 27 , 38 ] had a possible bias of deviation from the intended intervention, and five [ 29 , 39–42 ] presented some concerns regarding the bias of missing outcomes. For the nine NRSIs, six studies [ 30 , 31 , 34 , 35 , 37 , 43 ] showed a critical bias, three [ 32 , 33 , 36 ] showed moderate bias due to confounding, and four studies [ 31 , 34 , 35 , 37 ] showed moderate bias due to the selection of participants. In addition, three [ 31 , 32 , 36 ] showed critical bias, and three [ 32 , 34 , 43 ] showed moderate bias due to the measurement of outcomes, and one [ 43 ] showed moderate bias due to the selection of the reported result.…”

“…The results of the sensitivity analyses are presented in the Supplementary Appendix file (Figure S4 to S7 ), which showed that the effects remained stable in the random-effect model based on the evidence from RCTs. However, for evidence of NRSIs, the removal of the studies by Grimaldi [ 31 ] or Schneider [ 33 ] caused the pooled OR to no longer be significant ( p > .05) comparing hydroxychloroquine/chloroquine and active treatment. However, this did not alter the direction of the effects.…”

Clinical Efficacy and Safety of Antiviral Drugs in the Extended Use against COVID-19: What We Know So Far

“…A comparative randomized clinical trial between sofosbuvir/daclatasvir (SFV/DCV) and LPV/RTV was carried out where only the discharge rate was better in the LPV/RTV group; better survival rate and fewer complications were shown in the SFV/DCV group [125]. Similarly, Lepage et al [89] and Schneider et al [90] conducted retrospective studies and found several preliminary results that warrant well-designed and more extensive randomized controlled clinical trials.…”