The Mycophenolate-based Immunosuppressive Regimen Is Associated With Increased Mortality in Kidney Transplant Patients With COVID-19

Abstract

Background. The chronic use of immunosuppressive drugs is a key risk factor of death because of coronavirus disease 2019 in kidney transplant recipients (KTRs), although no evident association between the class of immunosuppressive and outcomes has been observed. Thus, we aimed to compare COVID-19-associated outcomes among KTRs receiving 3 different immunosuppressive maintenance regimes. Methods. This study included data from 1833 KTRs with COVID-19 diagnosed between March 20 and April 21 extracted from the national registry before immunization. All patients were taking calcineurin inhibitor associated with mycophenolate acid (MPA, n = 1258), azathioprine (AZA, n = 389), or mammalian targets of rapamycin inhibitors (mTORi, n = 186). Outcomes within 30 and 90 d were assessed. Results. Compared with patients receiving MPA, the 30-d (79.9% versus 87.9% versus 89.2%; P < 0.0001) and 90-d (75% versus 83.5% versus 88.2%; P < 0.0001) unadjusted patient survivals were higher in those receiving AZA or mTORi, respectively. Using adjusted multivariable Cox regression, compared with patients receiving AZA, the use of MPA was associated with a higher risk of death within 30 d (adjusted hazard ratio [aHR], 1.70; 95% confidence interval [CI], 1.21-2.40; P = 0.003), which was not observed in patients using mTORi (aHR, 0.78; 95% CI, 0.45-1.35; P = 0.365). At 90 d, although higher risk of death was confirmed in patients receiving MPA (aHR, 1.46; 95% CI, 1.09-1.98; P = 0.013), a reduced risk was observed in patients receiving mTORi (aHR, 0.59; 95% CI, 0.35-0.97; P = 0.04) compared with AZA. Conclusions. This national cohort data suggest that, in KTRs receiving calcineurin inhibitor and diagnosed with COVID-19, the use of MPA was associated with higher risk of death, whereas mTORi use was associated with lower risk of death.

A COVID-19 Overview from the Perspective of the Brazilian Kidney Transplantation Program

“…In the TANGO cohort, the withdrawal rates of tacrolimus and mycophenolate/everolimus were 23% and 65%, respectively [22]. Similarly, in a Brazilian multicenter study that was conducted before the vaccination era, it was observed that among KTRs diagnosed with COVID-19 and receiving an immunosuppressive regimen based on calcineurin inhibitors, patients treated with mycophenolate had a higher frequency of immunosuppression changes (61.6%, p < 0.001) than those treated with azathioprine (36.0%) or mTOR inhibitors (38.2%) [29]. Similar results were observed when immunosuppression was completely discontinued: mycophenolate (21.5%), azathioprine (19.3%), and mTOR inhibitors (12.9%, p = 0.02).…”

“…Similarly, the requirement for mechanical ventilation was higher for mycophenolate than for azathioprine (26.8% vs. 17.8%, p < 0.001); no difference was found for mTOR inhibitors. In a multivariate analysis, compared with azathioprine, the 90-day risk of death increased by 46% with mycophenolate and decreased by 41% with mTOR inhibitors [29].…”

“…An increased risk of death was observed with rituximab for rheumatological disease (RR = 1.72, 95% CI = 1.10-2.69) and for cancer (RR = 2.57, 95% CI = 1.86-3.56) [40]. A Brazilian multicenter study on COVID-19 in KTRs analyzed the data of 1833 patients who were using a regime based on a calcineurin inhibitor; the results showed that a higher hospitalization rate was observed among patients when the associated drug was mycophenolate (45.6% vs. 66.7%, p < 0.001) or mTOR inhibitor (45.6% vs. 61.1%, p = 0.001) than when the drug was azathioprine [29]. Similarly, the requirement for mechanical ventilation was higher for mycophenolate than for azathioprine (26.8% vs. 17.8%, p < 0.001); no difference was found for mTOR inhibitors.…”

A Head-to-head Comparison of De Novo Sirolimus or Everolimus Plus Reduced-dose Tacrolimus in Kidney Transplant Recipients: A Prospective and Randomized Trial

“…Whether MPAassociated impairment of CMV cell-mediated immunity, as observed after severe acute respiratory syndrome coronavirus 2 infection, in which patients receiving MPA demonstrated a higher COVID-19 associated lethality and poor vaccine response, outweighs mTORi-associated preservation of CMV cell-mediated immunity remains to be determined. 19,20 The other uncertainty regarding viral infection after kidney transplantation is whether mTORi show similar pharmacodynamic properties to control BKVPyV replication as observed with CMV. 21 The data of this study suggest that the use of mTORi is not associated with a lower proportion of patients developing BKVPyV viremia nor with the magnitude of individual viral load measurements.…”

“…Whether MPA-associated impairment of CMV cell–mediated immunity, as observed after severe acute respiratory syndrome coronavirus 2 infection, in which patients receiving MPA demonstrated a higher COVID-19 associated lethality and poor vaccine response, outweighs mTORi-associated preservation of CMV cell–mediated immunity remains to be determined. 19,20…”