ABSTRACT
Introduction: Paxlovid (nirmatrelvir+ ritonavir) is a promising new combination drug that can significantly reduce hospitalization and all-cause mortality in Covid-19 infection. Ritonavir is a potent inhibitor of cytochrome-P450 system CYP3A enzymes and concomitant use with calcineurin inhibitors (CNI) such as tacrolimus can dangerously increase CNI blood levels. We present a heart transplant recipient on tacrolimus who developed acute kidney injury (AKI) and refractory life-threatening hyperkalemia following Paxlovid use and successful treatment using P450 induction with phenytoin along with dialysis support. Case Description: A 43-year-old male with CKD stage III and previous heart transplant on tacrolimus was admitted with dyspnea, malaise, and oliguria. Few days earlier, he developed Covid-19 infection and received 5-day course of Paxlovid prescribed from elsewhere. On presentation, patient was hypervolemic, with the following serum values: K+ 7.1 mMol/L (peaking to 8.3 despite medical therapy), HCO3-17 mMol/L and creatinine 4.67 mg/dL (baseline 3.0). Patient required emergent hemodialysis. Tacrolimus trough level came back as >60 ng/mL Patient was started on IV phenytoin 100 mg every 12 hours. Tacrolimus levels remained extremely high over next few days with subsequent improvement (fig.). Patient required 4 dialysis sessions. Subsequently urine output improved, and serum creatinine returned to baseline. Discussion(s): Paxlovid use will likely increase with Covid-19 surge. This drug has important safety risks in organ transplant recipients and kidney disease as highlighted by our case, where supratherapeutic tacrolimus levels due to P450 inhibition resulted in AKI and hyperkalemia. Empiric dose reduction or withholding CNI agents when initiating Paxlovid with close CNI level monitoring is recommended. Risk mitigation strategies are also important such as interruptive alerts in electronic health records, educational outreach, and alerting pharmacies about Paxlovid-CNI interactions.
ABSTRACT
Introduction: Donor derived cell free DNA (dd-cfDNA) is a biomarker that helps to predict acute rejection in kidney allografts. Baseline dd-cfDNA levels are <1% in 96% of kidney transplant recipients (KTRs) and a value ≥ 1% suggests allograft injury usually from acute rejection. Adjuvants used to amplify vaccine immunogenicity could elicit non-specific inflammatory responses and thus could potentially incite immune mediated allograft injury. Here we present a KTR who developed elevated dd-cfDNA within one week of SARS-Cov-2 vaccination. Case Description: A 70-year old man who underwent pediatric en bloc deceased donor kidney transplantation 30 months earlier with peri-operative Thymoglobulin induction and tacrolimus/mycophenolic acid maintenance and excellent allograft function was found to have an elevation in surveillance dd-cfDNA (AlloSure, CareDx, Brisbane, CA) level at 3.0%. Patient had multiple negative dd-cfDNA values on all prior testing with a last level of 0.17% 3 months earlier. Serum creatinine was 0.8 mg/dl with no DSA and negative urinalysis. Serum BK virus and CMV PCR were negative. Patient did receive first dose of Pfizer/BioNTech Covid-19 vaccination (BNTb162b2) one week prior to the current dd-cfDNA measurement. Subsequent kidney allograft biopsy done due to elevated dd-cfDNA level did not show any evidence for rejection. Repeat dd-cfDNA 10 weeks later normalized to 0.15%. Discussion: We believe that elevation in dd-cfDNA in our patient with stable renal allograft function was triggered by SARS-Cov-2 vaccination. Pfizer/BioNTech utilizes an mRNA platform in which mRNA is encapsulated in lipid nanoparticles which act as delivery devices and possess natural adjuvant activity. Even though the allograft biopsy did not show clear evidence for rejection, we feel that the adjuvant lipid nanoparticles caused immune stimulation in the host thus triggering dd-cfDNA elevation. Since more and more KTRs will be receiving SARS-Cov-2 vaccination, temporal relationship between vaccination and dd-cfDNA elevations should be entertained. Post-marketing surveillance will be essential to delineate any potential association between SARS-CoV-2 vaccine components and allograft rejection.