Faculty Bibliography

A recent study concluded that SARS-CoV-2 mRNA vaccine responses were improved among transplant patients taking mTOR inhibitors (mTORi). This could have profound implications for vaccine strategies in transplant patients; however, limitations in the study design raise concerns about the conclusions. To address this issue more robustly, in a large cohort with appropriate adjustment for confounders, we conducted various regression- and machine learning-based analyses to compare antibody responses by immunosuppressive agents in a national cohort (n = 1037). MMF was associated with significantly lower odds of positive antibody response (aOR = _0.09 0.13_0.18 ). Consistent with the recent mTORi study, the odds tended to be higher with mTORi (aOR = _1.00 1.45_2.13 ); however, importantly, this seemingly protective tendency disappeared (aOR = _0.47 0.73_1.12 ) after adjusting for MMF. We repeated this comparison by combinations of immunosuppression agents. Compared to MMF + tacrolimus, MMF-free regimens were associated with higher odds of positive antibody response (aOR = _2.39 4.26_7.92 for mTORi+tacrolimus; _2.34 5.54_15.32 for mTORi-only; and _6.78 10.25_15.93 for tacrolimus-only), whereas MMF-including regimens were not, regardless of mTORi use (aOR = _0.81 1.54_2.98 for MMF + mTORi; and _0.81 1.51_2.87 for MMF-only). We repeated these analyses in an independent cohort (n = 512) and found similar results. Our study demonstrates that the recently reported findings were confounded by MMF, and that mTORi is not independently associated with improved vaccine responses.

BACKGROUND:Solid organ transplant recipients (SOTRs) are less likely to mount an antibody response to SARS-CoV-2 mRNA vaccines. Understanding risk factors for impaired vaccine response can guide strategies for antibody testing and additional vaccine dose recommendations. METHODS:Using a nationwide observational cohort of 1031 SOTRs, we created a machine learning model to explore, identify, rank, and quantify the association of 19 clinical factors with antibody responses to 2 doses of SARS-CoV-2 mRNA vaccines. External validation of the model was performed using a cohort of 512 SOTRs at Houston Methodist Hospital. RESULTS:Mycophenolate mofetil use, a shorter time since transplant, and older age were the strongest predictors of a negative antibody response, collectively contributing to 76% of the model's prediction performance. Other clinical factors, including transplanted organ, vaccine type (mRNA-1273 versus BNT162b2), sex, race, and other immunosuppressants, showed comparatively weaker associations with an antibody response. This model showed moderate prediction performance, with an area under the receiver operating characteristic curve of 0.79 in our cohort and 0.67 in the external validation cohort. An online calculator based on our prediction model is available at http://transplantmodels.com/covidvaccine/. CONCLUSIONS:Our machine learning model helps understand which transplant patients need closer follow-up and additional doses of vaccine to achieve protective immunity. The online calculator based on this model can be incorporated into transplant providers' practice to facilitate patient-centric, precision risk stratification and inform vaccination strategies among SOTRs.

RATIONALE & OBJECTIVE/UNASSIGNED:Disorders of bone and mineral metabolism frequently develop with advanced kidney disease, may be exacerbated by immunosuppression after kidney transplantation, and increase the risk of fractures. STUDY DESIGN/UNASSIGNED:Retrospective database study. SETTING & PARTICIPANTS/UNASSIGNED:Kidney-only transplant recipients aged ≥18 years from 2005 to 2016 in the United States captured in US Renal Data System records, which integrate Organ Procurement and Transplantation Network/United Network for Organ Sharing records with Medicare billing claims. EXPOSURES/UNASSIGNED:Various immunosuppression regimens in the first 3 months after kidney transplantation. OUTCOMES/UNASSIGNED:The development of fractures, as ascertained using diagnostic codes on Medicare billing claims. ANALYTICAL APPROACH/UNASSIGNED:We used multivariable Cox regression with inverse propensity weighting to compare the incidence of fractures >3 months-to-3 years after kidney transplantation associated with various immunosuppression regimens compared to a reference regimen of antithymocyte globulin (TMG) or alemtuzumab (ALEM) with tacrolimus + mycophenolic acid + prednisone using inverse probability treatment weighting. RESULTS/UNASSIGNED: < 0.001]). Induction with TMG or ALEM and the avoidance or early withdrawal of steroids significantly reduced the risk of fractures in younger (aHR, 0.63; 95% CI, 0.54-0.73) and older (aHR, 0.83; 95% CI, 0.74-0.94) patients. The avoidance or early withdrawal of steroids with any induction was associated with a reduced risk of fractures in women. LIMITATIONS/UNASSIGNED:This was a retrospective study which lacked data on immunosuppression levels. CONCLUSIONS/UNASSIGNED:Fractures after kidney transplantation are associated with significantly increased mortality risk and costs. The early avoidance or early withdrawal of steroids after induction with TMG or ALEM reduces the risk of fractures after kidney transplantation and should be considered for patients at high-risk of this complication, including older adults and women.

BACKGROUND:Early steroid withdrawal (ESW) is a viable maintenance immunosuppression strategy in low-risk kidney transplant recipients. A low panel reactive antibody (PRA) may indicate low-risk condition amenable to ESW. We aimed to identify the threshold value of PRA above which ESW may pose additional risk, and to compare the association of ESW with transplant outcomes across PRA strata. METHODS:We studied 121,699 deceased-donor kidney-only recipients in 2002-2017 from SRTR. Using natural splines and ESW-PRA interaction terms, we explored how the associations of ESW with transplant outcomes change with increasing PRA values, and identified a threshold value for PRA. Then, we assessed whether PRA exceeding the threshold modified the associations of ESW with 1-year acute rejection, death-censored graft failure, and death. RESULTS:The association of ESW with acute rejection exacerbated rapidly when PRA exceeded 60. Among PRA≤60 recipients, ESW was associated with a minor increase in rejection (aOR=1.001.051.10) and with a tendency of decreased graft failure (aHR=0.910.971.03). However, among PRA>60 recipients, ESW was associated with a substantial increase in rejection (aOR=1.191.271.36; interaction p<0.001) and with a tendency of increased graft failure (aHR=0.981.081.20; interaction p=0.028). The association of ESW with death was similar between PRA strata (PRA≤60, aHR=0.910.961.01; and PRA>60, aHR=0.900.991.09; interaction p=0.5). CONCLUSIONS:Our findings show that the association of ESW with transplant outcomes is less favorable in recipients with higher PRA, especially those with PRA>60, suggesting a possible role of PRA in the risk assessment for ESW.

Rationale & Objective/UNASSIGNED:Posttransplant diabetes mellitus (DM) after kidney transplantation increases morbidity and mortality, particularly in older and obese recipients. We aimed to examine the impact of immunosuppression selection on the risk of posttransplant DM among both older and obese kidney transplant recipients. Study Design/UNASSIGNED:Retrospective database study. Setting & Participants/UNASSIGNED:Kidney-only transplant recipients aged ≥18 years from 2005 to 2016 in the United States from US Renal Data System records, which integrate Organ Procurement and Transplantation Network/United Network for Organ Sharing records with Medicare billing claims. Exposures/UNASSIGNED:Various immunosuppression regimens in the first 3 months after transplant. Outcomes/UNASSIGNED:Development of DM >3 months-to-1 year posttransplant. Analytical Approach/UNASSIGNED:We used multivariable Cox regression to compare the incidence of posttransplant DM by immunosuppression regimen with the reference regimen of thymoglobulin (TMG) or alemtuzumab (ALEM) with tacrolimus + mycophenolic acid + prednisone using inverse propensity weighting. Results/UNASSIGNED:(aHR, 0.63; 95% CI, 0.46-0.87). Limitations/UNASSIGNED:Retrospective study and lacked data on immunosuppression levels. Conclusions/UNASSIGNED:The beneficial impact of steroid avoidance using tacrolimus on posttransplant DM appears to differ by patient age and induction regimen.

Background/UNASSIGNED:Posttransplant diabetes (PTD), a major complication after kidney transplantation (KT), is often attributable to immunosuppression. The risk of PTD may increase with more potent steroid maintenance and older recipient age. Methods/UNASSIGNED:Using United States Renal Data System data, we studied 12 488 adult first-time KT recipients (2010-2015) with no known pre-KT diabetes. We compared the risk of PTD among recipients who underwent early steroid withdrawal (ESW) versus continued steroid maintenance (CSM) using Cox regression with inverse probability weighting to adjust for confounding. We tested whether the risk of PTD resulting from ESW differed by recipient age (18-29, 30-54, and ≥55 y). Results/UNASSIGNED:). Conclusions/UNASSIGNED:The beneficial association of ESW with decreased PTD was more pronounced among recipients aged ≥55, supporting an age-specific assessment of the risk-benefit balance regarding ESW.

BACKGROUND:While several studies have observed that solid organ transplant recipients experience diminished antibody responses to SARS-CoV-2 mRNA vaccination, data specific to heart and lung transplant (HT/LT) recipients remains sparse. METHODS:US adult HT and LT recipients completed their vaccine series between January 7 and April 10, 2021. Reactogencity and SARS-CoV-2 anti-spike antibody were assessed after a priming dose (D1) and booster dose (D2). Modified Poisson regression with robust variance estimator was used to evaluate associations between participant characteristics and antibody development. RESULTS:Of 134 heart recipients, there were 38% non-responders (D1-/D2-), 48% booster responders (D1-/D2+), and 14% priming dose responders (D1+/D2+). Of 103 lung recipients, 64% were non-responders, 27% were booster responders, and 9% were priming dose responders. Lung recipients were less likely to develop antibodies (p < .001). Priming dose antibody response was associated with younger recipient age (p = .04), transplant-to-vaccination time ≥6 years (p < .01), and lack of anti-metabolite maintenance immunosuppression (p < .001). Pain at injection site was the most commonly reported reaction (85% after D1, 76% after D2). Serious reactions were rare, the most common being fatigue (2% after D1 and 3% after D2). No serious adverse events were reported. CONCLUSIONS:HT and LT recipients experienced diminished antibody response following vaccination; reactogenicity was comparable to that of the general population. LT recipients may exhibit a more impaired antibody response than HT recipients. While current recommendations are to vaccinate eligible candidates and recipients, further studies characterizing the cell-mediated immune response and clinical efficacy of these vaccines in this population are needed.