Remdesivir may exacerbate ischemic acute kidney injury through molecular alterations in PGC-1α and apoptosis pathways: An in vivo study

Why Remdesivir’s Kidney Impact Matters

Remdesivir (RDV) became the first antiviral approved for COVID‑19, but its rapid clearance through the kidneys raises a red flag for patients with compromised renal function. Acute kidney injury (AKI) is already a major complication of severe infections, major surgery, and organ transplantation. Adding a drug that may interfere with mitochondrial energy production could tip the balance from recovery to permanent damage.

Current Evidence: A Mixed Picture

Clinical studies report conflicting outcomes:

Some pharmacovigilance analyses link RDV to a higher incidence of AKI, especially in men over 65 with a glomerular filtration rate (GFR) < 30 mL/min.
Other cohort studies find no significant increase in creatinine or urea levels, even when eCrCl is below 30 mL/min.
A systematic review of 3,095 patients concluded that RDV is unlikely to raise AKI risk, suggesting that most renal events stem from the underlying disease rather than the drug itself.

These contradictions highlight the need for more precise biomarkers and controlled animal models.

Mitochondrial Health: The Hidden Battleground

Recent rat studies show that RDV can:

↓ PGC‑1α (a master regulator of mitochondrial biogenesis)
↑ Drp‑1, driving excessive mitochondrial fission
↑ caspase‑3, signaling heightened apoptosis
Elevate oxidative stress markers (MDA) whereas suppressing antioxidant enzymes (SOD, GPX, TAC)

In short, RDV may impair the kidney’s energy factories, making cells more vulnerable to ischemia‑reperfusion (I/R) injury.

Future Research Directions

1. Dual‑Model Approaches

Combining unilateral I/R injury with pre‑conditioning strategies could reveal whether RDV’s effects are amplified or mitigated under different stress levels.

2. Time‑Series Omics

Longitudinal proteomics, metabolomics, and transcriptomics from 0‑48 hours post‑reperfusion will map the exact windows when RDV‑induced mitochondrial dysfunction peaks.

3. Human‑Relevant Organoids

Kidney‑on‑a‑chip platforms allow real‑time monitoring of oxygen consumption, ROS production, and drug‑induced changes without the confounding influence of a contralateral kidney.

Emerging Technologies & Biomarkers

Traditional lab values (creatinine, urea) lag behind cellular injury. Newer markers gaining traction include:

Neutrophil gelatinase‑associated lipocalin (NGAL) – rises within 2 hours of tubular stress.
KIM‑1 (Kidney Injury Molecule‑1) – reflects proximal tubule damage.
Cell‑free mitochondrial DNA in plasma – a direct read‑out of mitochondrial injury.
Real‑time oxygen consumption rate (OCR) measured by Seahorse analyzers in renal organoids.

Did you know? The cyclodextrin carrier used in RDV formulations can accumulate in kidneys with GFR < 30 mL/min, potentially compounding any direct drug toxicity.

Clinical Implications for COVID‑19 and Beyond

For clinicians, the grab‑away is nuanced:

Screen early: Check baseline eGFR and consider NGAL or KIM‑1 if the patient is at risk.
Route matters: Sub‑cutaneous (SC) administration showed stronger mitochondrial disruption in rats compared with intraperitoneal (IP) injection, suggesting that formulation and delivery could influence renal safety.
Monitor trends, not single values: Serial creatinine, coupled with emerging biomarkers, provides a clearer picture of AKI progression.

What Patients and Physicians Can Do Now

Patients on RDV should stay hydrated, avoid concurrent nephrotoxic drugs (NSAIDs, high‑dose diuretics), and report any sudden changes in urine output. Physicians can:

Order baseline and follow‑up serum creatinine and eGFR.
Consider dose adjustments or alternative antivirals (e.g., molnupiravir) for GFR < 30 mL/min.
Enroll eligible patients in clinical trials investigating RDV‑sparing regimens or mitochondrial‑protective co‑therapies.

FAQ – Quick Answers

Is Remdesivir safe for patients with chronic kidney disease?: Most data suggest it can be used cautiously when eGFR > 30 mL/min; below that, benefits must be weighed against potential mitochondrial toxicity.
Can I prevent AKI while on Remdesivir?: Maintain adequate hydration, avoid nephrotoxic meds, and monitor renal biomarkers regularly.
What’s the most promising biomarker for early kidney injury?: NGAL has the fastest rise after tubular stress and is increasingly used in research settings.
Does the route of administration affect kidney risk?: Animal data indicate sub‑cutaneous delivery may cause more oxidative stress than intraperitoneal, but human data are still limited.
Are there any drugs that can protect mitochondria during Remdesivir therapy?: Compounds like coenzyme Q10, melatonin, and certain SIRT‑activators are under investigation for renal mitochondrial protection.

Pro tip: When prescribing Remdesivir, pair it with a low‑dose antioxidant regimen (e.g., vitamin C 500 mg BID) and re‑check oxidative markers if available.

Looking Ahead: The Next Wave of Renal Safety Research

Future trials will likely focus on:

Combining RDV with mitochondrial‑targeted antioxidants to offset potential toxicity.
Developing cyclodextrin‑free formulations that reduce carrier‑related kidney accumulation.
Leveraging AI‑driven predictive models that integrate patient genetics, comorbidities, and real‑time biomarker data to personalize antiviral dosing.

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