Pharmacologic Treatment of COVID-19: What Nephrologists Need to Know
In This Article
- Patients with estimated glomerular filtration rate (eGRF) < 30 represent a large proportion of the patients who become critically ill from COVID-19
- Remdesivir can be used on a case-by-case basis in patients with eGFR < 30
- Because of the potential for cyclodextrin accumulation, patients at highest risk of nephrotoxicity with remdesivir are those who have pre-existing advanced chronic kidney disease and no plan for dialysis
- Plasma levels of favipiravir are two- to three-fold higher in patients with eGFR of 30 to 50, but that range is expected to be safe
- COVID-19 patients with acute kidney injury are generally eligible for monoclonal antibodies that target the hyperinflammatory phase of COVID-19
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Patients with estimated glomerular filtration rate (eGRF) < 30 represent a large proportion of the patients who become critically ill from COVID-19. On May 21, 2020, as part of a Massachusetts General Hospital Department of Medicine Grand Rounds, Meghan Sise, MD, of the Division of Nephrology at Mass General, reviewed what nephrologists should know about the experimental therapies being used to treat COVID-19.
Remdesivir
Patients with eGFR > 30 were excluded from reported clinical trials of remdesivir, which the FDA authorized for emergency use on May 1, 2020. The FDA has stated that patients with eGFR < 30 should not receive remdesivir unless the potential benefit outweighs the potential risk.
Thus, on a case-by-case basis, this medication could be used in patients with kidney failure, and nephrologists should try to help colleagues understand the risks.
Active metabolite
Patients most likely to benefit from remdesivir are those nearing intubation or recently intubated, in the early stage when the antiviral response is driving the illness. Remdesivir is metabolized to remdesivir triphosphate, a nucleotide analog that prevents the replication of SARS-CoV-2 by inhibiting RNA polymerase.
When nephrologists hear about a nucleotide analog they're likely to think of tenofovir, but nephrotoxicity is not a class effect. In addition, the nephrotoxicity associated with tenofovir occurs after months or years of dosing, whereas remdesivir is given for five to 10 days for COVID-19.
Both remdesivir and its active metabolite are renally eliminated. So far, though, clinical trials of remdesivir that include safety data have not shown a signal for kidney injury in patients with either COVID-19 or Ebola.
Cyclodextrin carrier
Remdesivir is administered intravenously and has limited water solubility, so it is given with a cyclodextrin carrier, the same one found in IV voriconazole. This carrier is filtered solely by the glomerulus, and patients with normal renal function eliminate it quickly. Conversely, patients with acute kidney injury (AKI) are at risk of cyclodextrin accumulation.
Each 100 mg of remdesivir powder contains 3 g cyclodextrin, and the solution contains 6 g, both well below the maximum recommended dose of 250 mg/kg/day. In addition, based on the experience with voriconazole, both dialysis and continuous renal replacement therapy should effectively remove cyclodextrin.
Risk–benefit ratio
Nephrologists should inform clinical teams and the patient or surrogate decision-maker that there are no safety data on remdesivir in patients with eGFR < 30 and help them weigh the risk in the context of the patient's AKI trajectory. If the patient is on continuous renal replacement therapy or is expected to begin it, the risk of cyclodextrin accumulation is low.
Patients at highest risk of cyclodextrin accumulation are those who have pre-existing advanced chronic kidney disease and no plan for dialysis.
Favipiravir
Favipiravir, another nucleotide analog that inhibits RNA polymerase, is approved for influenza in China and Japan and is being studied for COVID-19. It's given orally, so it doesn't have a carrier. No nephrotoxicity was seen in animal studies.
Favipiravir and its active metabolite are renally eliminated. Plasma levels are two- to three-fold higher in patients with eGFR of 30 to 50, but that range is expected to be safe. Still, trials are excluding patients with eGFR < 20.
Medications for Hyperinflammation
For patients in the hyperinflammatory phase of COVID-19, most medications being tried are monoclonal antibodies that target the interleukin-6 axis: tocilizumab, sarilumab, siltuximab and JAK inhibitors. These are not renally eliminated, so patients with AKI should generally be eligible. However, intravenous immunoglobulin, which is used in rare cases, is nephrotoxic.
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