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 (COVID-19) 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.

FIGURE 1.

Detailed patient flowchart. AZA, azathioprine; CNi, calcineurin inhibitor; COVID-19, coronavirus disease 2019; KT, kidney transplant; MPA, mycophenolic acid; MPAA, MPA analogs; mTORi, mammalian target of rapamycin inhibitor; RT-PCR, reverse-transcription polymerase chain reaction.

FIGURE 2.

Patients’ survival after the coronavirus disease 2019 diagnosis stratified by groups. AZA, azathioprine; CNi, calcineurin inhibitor; MPA, mycophenolate acid; mTORi, mammalian target of rapamycin inhibitor.

FIGURE 3.

Intermediate outcomes stratified by groups. Overall differences among the 3 groups for hospitalization, admission to the ICU, and MV requirement: P < 0.001. For hospitalization: CNi-AZA vs CNi-MPA, P < 0.001; CNi-AZA vs CNi-mTORi, P = 0.001; CNi-MPA vs CNi-mTORi, P = 0.13. For admission to the ICU: CNi-AZA vs CNi-MPA, P < 0.001; CNi-AZA vs CNi-mTORi, P = 0.40; CNi-MPA vs CNi-mTORi, P < 0.001. For mechanical ventilation requirement: CNi-AZA vs CNi-MPA, P < 0.001; CNi-AZA vs CNi-mTORi, P = 0.19; CNi-MPA vs CNi-mTORi, P < 0.001. AZA, azathioprine; CNi, calcineurin inhibitor; ICU, intensive care unit; MPA, mycophenolate acid; mTORi, mammalian target of rapamycin inhibitor; MV, mechanical ventilation.

FIGURE 4.

Patients’ survival stratified by immunosuppression change after the coronavirus disease 2019 diagnosis in the MPA group. Thirty- and ninety-day survival in patients who continued the MPA on their usual dose: 78% and 72%, respectively; 30- and 90-d survival in patients with MPA dose reduced or discontinued: 83% and 81%, respectively (P < 0.001). MPA, mycophenolate acid.

FIGURE 5.

Sensitivity analyses for death within 30 and 90 d after coronavirus disease 2019 diagnosis stratified by hospitalization, ICU, and mechanical ventilation requirement status. AZA, azathioprine; CI, confidence interval; CNi, calcineurin inhibitor; ICU, intensive care unit; MPA, mycophenolate acid; mTORi, mammalian target of rapamycin inhibitor.