How to use COVID-19 antiviral drugs in patients with chronic kidney disease

The paper addresses how to select and use COVID-19 antiviral drugs in patients with chronic kidney disease (CKD), a population at independently increased risk for severe and fatal COVID-19. CKD is associated with secondary immunodeficiency (SIDKD), higher susceptibility to severe disease, complications, hospitalization, mortality, and increased risk of COVID-19–related AKI. Many interventional COVID-19 trials excluded patients with impaired renal function, leaving gaps in pharmacokinetic/pharmacodynamic evidence and dosing guidance for this group. The review aims to synthesize available data on pharmacology, pharmacokinetics, efficacy, dosing, safety, and precautions for antivirals and monoclonal antibodies (mAbs) to guide use across CKD stages and dialysis.

The review compiles evidence from clinical trials, observational reports, regulatory fact sheets, and guidelines on antivirals and mAbs used in COVID-19 with attention to renal handling, safety profiles, and needed dose adjustments in CKD. It summarizes prior findings that: (1) remdesivir shortens recovery in hospitalized patients but concerns exist about its vehicle (SBECD) in renal failure; (2) molnupiravir reduces hospitalization/death in outpatients and is minimally renally cleared; (3) protease inhibitors (atazanavir, darunavir, lopinavir) have variable efficacy data and renal safety concerns; (4) nirmatrelvir/ritonavir reduces progression and death in high-risk patients but requires eGFR-based dose adjustments; (5) ribavirin and favipiravir carry renal clearance and toxicity concerns; (6) oseltamivir is largely renally eliminated yet can be safely dose-adjusted even in ESKD; (7) sofosbuvir involves predominant renal elimination of its metabolite with potential AKI in CKD; (8) dolutegravir has negligible renal elimination and is generally safe; (9) umifenovir shows mixed/negative clinical outcomes with AKI risk in severe COVID-19 cohorts; and (10) several mAbs are safe without renal dose adjustment and can be used in CKD and dialysis, whereas baricitinib requires renal dose modification and is not indicated in AKI/dialysis.

Narrative review of English-language clinical trials, clinical reports, official guidelines, and reviews (1993–2022) sourced from ClinicalTrials.gov, FDA, WHO, CDC, PubMed, IDSA, Web of Science, journal sites, and ScienceDirect. Articles were assessed for demographics and clinical outcomes. Pharmacokinetic and pharmacodynamic characteristics informed applicability, effectiveness, dosing, frequency, precautions, and limitations for CKD stages including dialysis.

- Remdesivir (RDV): Inhibits RdRp; recommended for hospitalized COVID-19. Standard dosing 200 mg IV day 1 then 100 mg daily (2–10 days per severity). Parent drug hepatically cleared; metabolite GS-441524 renally excreted (≈49% of dose in urine as metabolite). SBECD vehicle can accumulate in severe renal impairment; nephrotoxicity risk relates more to SBECD than RDV. Clinical trial data report renal adverse event risk <1%. Use acceptable in CKD with eGFR >30 ml/min; avoid in advanced CKD/ESKD or consider non-IV (e.g., nasal) routes to mitigate SBECD exposure. Monitor LFTs and coagulation. - Molnupiravir: Oral prodrug; active NHC triphosphate not significantly renally eliminated; minimal urinary excretion (<4%). No dose adjustment across mild–moderate renal impairment; limited data for eGFR <30 ml/min or dialysis but renal clearance is not significant. Reduced hospitalization/death in outpatients. Not recommended in pregnancy; avoid in patients <18 years due to cartilage/bone concerns; generally mild AEs. - Famciclovir: Oral prodrug to penciclovir; predominantly renally eliminated; requires dose adjustment based on creatinine clearance and hemodialysis timing (administer post-dialysis). Considered safe with adjusted dosing in CKD/ESKD; mild GI/CNS AEs. - Ribavirin: Primarily renally excreted (≈62%); exposure increases with reduced creatinine clearance; significant risk of hemolytic anemia; contraindicated in severe renal failure; dose reductions/avoidance recommended in CKD and RRT; teratogenic—pregnancy avoidance required. - Favipiravir: Hepatic metabolism to inactive M1 with renal excretion; M1 accumulates in renal impairment; limited PK data for eGFR <50; reports of AKI and uric acid elevation; insufficient efficacy in COVID-19 trials; not recommended in CKD or dialysis. - Atazanavir: Minimal renal elimination; mostly biliary excretion. Usable at standard doses in CKD; consider boosting after dialysis due to possible clearance during HD. Chronic exposure linked to interstitial nephritis/glomerulosclerosis; significant CYP-mediated drug interactions; use short-term with monitoring in CKD. - Darunavir (with booster): High protein binding; minimal renal elimination; no renal dose adjustment; avoid cobicistat when GFR <70 ml/min (can impede kidney clearance). Case reports of AKI and crystal nephropathy; monitor renal function and interactions. - Nirmatrelvir/ritonavir (Paxlovid): Protease inhibitor with ritonavir boosting; nirmatrelvir partly renally excreted (~35%), accumulates with reduced GFR. Dose by eGFR: ≥60 ml/min: 300/100 mg BID 5 days; 30–59 ml/min: 150/100 mg BID 5 days; not recommended at eGFR <30 ml/min (emerging modified regimens post-dialysis have been proposed but robust data pending). Reduced risk of hospitalization/death by up to 89% in high-risk outpatients; manage CYP3A interactions, common in CKD regimens. - Lopinavir/ritonavir: Did not improve mortality or hospital stay in large trials; associated with tubular damage and AKI with prolonged use; avoid in CKD, especially when GFR <90 ml/min; hepatotoxicity risk. - Oseltamivir: Renally cleared active metabolite; can be dose-adjusted and is generally safe/tolerated in CKD/ESKD including peritoneal dialysis; low-dose regimens suggested in CrCl <10 ml/min; efficacy in COVID-19 remains uncertain. - Azvudine: NRTI with activity against SARS-CoV-2; early trials show symptom improvement; limited data in GFR ≤60 ml/min; no reported renal adverse events; potentially usable with caution in CKD pending more data. - Dolutegravir (± rilpivirine): >99% protein bound; negligible renal excretion of parent; inhibits OCT2/MATE1 leading to benign creatinine increases without true GFR change. No renal dose adjustment; feasible in dialysis; monitor for drug–drug transporter interactions. - Sofosbuvir: Active metabolite GS-331007 renally eliminated (≈78%); half-life ~27 h; risk of AKI in moderate–severe CKD reported; dose reduction (e.g., 200 mg) considered in severe renal impairment for HCV; avoid in eGFR <30 ml/min or use with close monitoring; interactions with strong P-gp inducers; pregnancy precautions with combinations. - Umifenovir (arbidol): Predominantly fecal excretion; mixed clinical outcomes; in severe COVID-19 cohorts, associated with increased in-hospital mortality and AKI incidence; avoid in CKD and immunocompromised patients. - Monoclonal antibodies: Bamlanivimab/etesevimab, casirivimab/imdevimab, sotrovimab, and tocilizumab require no renal dose adjustment, are not renally cleared, and are considered safe in CKD, dialysis, and solid organ transplant patients; can be administered around dialysis without adjustment. Baricitinib is 75% renally eliminated; requires dose reduction for eGFR <60 ml/min and is not indicated in AKI or dialysis. - Overall recommendations: Safer options in CKD include azvudine, molnupiravir, Paxlovid (with eGFR-based dosing, avoiding severe CKD), remdesivir (avoid advanced CKD/ESKD and consider non-IV formulations), oseltamivir (dose-adjustable), famciclovir (dose-adjustable), and dolutegravir. Avoid or use with strong caution: sofosbuvir (especially in eGFR <30), umifenovir, favipiravir, and lopinavir/ritonavir. mAbs are preferred in CKD over nephrotoxic antivirals for eligible indications.

The review highlights that CKD substantially worsens COVID-19 outcomes and complicates antiviral therapy due to altered drug handling and drug–drug interactions common in nephrology. By aligning each agent’s pharmacokinetics with renal function, clinicians can better select, dose, and monitor therapies to maximize benefit and minimize nephrotoxicity in CKD. Findings suggest prioritizing agents with minimal renal clearance or established safety/dose-adjustment frameworks (molnupiravir, oseltamivir, dolutegravir, adjusted Paxlovid) and cautioning against drugs with problematic renal elimination or safety signals in CKD (sofosbuvir, favipiravir, umifenovir, lopinavir/ritonavir). For hospitalized or high-risk patients, mAbs offer effective, kidney-safe options. These recommendations directly address the initial problem of limited CKD-specific evidence by translating pharmacologic principles and available clinical data into practical guidance across CKD stages and dialysis.

Based on pharmacokinetic/pharmacodynamic profiles and available clinical evidence, the relative safety order in COVID-19–infected CKD patients (safest to least safe) is: among approved antivirals: azvudine, molnupiravir (Lagevrio), nirmatrelvir with ritonavir (Paxlovid), remdesivir (Veklury); among nonapproved/under evaluation: oseltamivir, famciclovir, dolutegravir/rilpivirine, darunavir, atazanavir, ribavirin, favipiravir, nirmatrelvir/ritonavir combination, sofosbuvir, umifenovir, lopinavir/ritonavir. The authors recommend not using sofosbuvir, umifenovir, favipiravir, and lopinavir/ritonavir in CKD. Preferred options for CKD and solid organ transplant patients include mAb combinations such as bamlanivimab/etesevimab, casirivimab/imdevimab, sotrovimab, and tocilizumab. Further large, CKD-inclusive clinical studies are needed to refine dosing, safety, and efficacy across CKD stages and dialysis.

- Many COVID-19 clinical trials excluded CKD patients, limiting direct evidence and generalizability to this population. - For several antivirals, pharmacokinetic and safety data in severe CKD (eGFR <30 ml/min), ESKD, and dialysis are sparse or absent. - Recommendations often rely on pharmacologic reasoning, small studies, observational data, or case reports rather than robust randomized trials in CKD. - Heterogeneity in dosing regimens, concomitant therapies, and evolving variants complicate efficacy assessments. - Drug–drug interaction data in typical CKD polypharmacy are incomplete for some agents.