Faculty Bibliography

BACKGROUND:Physical frailty phenotype is characterized by decreased physiologic reserve to stressors and associated with poor outcomes, such as delirium and mortality, that may result from post-kidney transplant (KT) inflammation. Despite a hypothesized underlying pro-inflammatory state, conventional measures of frailty typically do not incorporate inflammatory biomarkers directly. Among KT candidates and recipients, we evaluated the inclusion of inflammatory biomarkers with traditional physical frailty phenotype components. METHODS:Among 1154 KT candidates and recipients with measures of physical frailty phenotype and inflammation (interleukin 6 [IL6], tumor necrosis factor alpha [TNFα], C-reactive protein [CRP]) at 2 transplant centers (2009-2017), we evaluated construct validity of inflammatory-frailty using latent class analysis. Inflammatory-frailty measures combined 5 physical frailty phenotype components plus the addition of an individual inflammatory biomarkers, separately (highest tertiles) as a sixth component. We then used Kaplan-Meier methods and adjusted Cox proportional hazards to assess post-KT mortality risk by inflammatory-frailty (n = 378); Harrell's C-statistics assessed risk prediction (discrimination). RESULTS:Based on fit criteria, a 2-class solution (frail vs nonfrail) for inflammatory-frailty was the best-fitting model. Five-year survival (frail vs nonfrail) was: 81% versus 93% (IL6-frailty), 87% versus 89% (CRP-frailty), and 83% versus 91% (TNFα-frailty). Mortality was 2.07-fold higher for IL6-frail recipients (95% CI: 1.03-4.19, p = .04); there were no associations between the mortality and the other inflammatory-frailty indices (TNFα-frail: 1.88, 95% CI: 0.95-3.74, p = .07; CRP-frail: 1.02, 95% CI: 0.52-2.03, p = .95). However, none of the frailty-inflammatory indices (all C-statistics = 0.71) improved post-KT mortality risk prediction over the physical frailty phenotype (C-statistics = 0.70). CONCLUSIONS:Measurement of IL6-frailty at transplantation can inform which patients should be targeted for pre-KT interventions. However, the traditional physical frailty phenotype is sufficient for post-KT mortality risk prediction.

Kidneys from older (age ≥50 years) donation after cardiac death (DCD50) donors are less likely to be transplanted due to inferior posttransplant outcomes. However, candidates who decline a DCD50 offer must wait for an uncertain future offer. To characterize the survival benefit of accepting DCD50 kidneys, we used 2010-2018 Scientific Registry for Transplant Recipients (SRTR) data to identify 92 081 adult kidney transplantation candidates who were offered a DCD50 kidney that was eventually accepted for transplantation. DCD50 kidneys offered to candidates increased from 590 in 2010 to 1441 in 2018. However, 34.6% of DCD50 kidneys were discarded. Candidates who accepted DCD50 offers had 49% decreased mortality risk (adjusted hazard ratio [aHR] _0.46 0.51_0.55 , cumulative mortality at 6-year 23.3% vs 34.0%, P < .001) compared with those who declined the same offer (decliners). Six years after their initial DCD50 offer decline, 43.0% of decliners received a deceased donor kidney transplant (DDKT), 6.3% received living donor kidney transplant (LDKT), 22.6% died, 22.0% were removed for other reasons, and 6.0% were still on the waitlist. Comparable survival benefit was observed even with DCD donors age ≥60 (aHR: _0.42 0.52_0.65 , P < .001). Accepting DCD50 kidneys was associated with a substantial survival benefit; providers and patients should consider these benefits when evaluating offers.

Kidney transplant (KT) outcomes for HIV-infected (HIV+) persons are excellent, yet acute rejection (AR) is common and optimal immunosuppressive regimens remain unclear. Early steroid withdrawal (ESW) is associated with AR in other populations, but its utilization and impact are unknown in HIV+ KT. Using SRTR, we identified 1225 HIV+ KT recipients between January 1, 2000, and December 31, 2017, without AR, graft failure, or mortality during KT admission, and compared those with ESW with those with steroid continuation (SC). We quantified associations between ESW and AR using multivariable logistic regression and interval-censored survival analysis, as well as with graft failure and mortality using Cox regression, adjusting for donor, recipient, and immunologic factors. ESW utilization was 20.4%, with more zero HLA mismatch (8% vs 4%), living donors (26% vs 20%), and lymphodepleting induction (64% vs 46%) compared to the SC group. ESW utilization varied widely across 129 centers, with less use at high- versus moderate-volume centers (6% vs 21%, P < .001). AR was more common with ESW by 1 year (18.4% vs 12.3%; aOR: _1.08 1.61_2.41 , P = .04) and over the study period (aHR: _1.02 1.39_1.90 , P = .03), without difference in death-censored graft failure (aHR _0.60 0.91_1.36 , P = .33) or mortality (aHR: _0.75 1.15_1.77 , P = .45). To reduce AR after HIV+ KT, tailoring of ESW utilization is reasonable.

Recently, the Organ Procurement and Transplant Network approved a plan to allocate kidneys within 250-nm circles around donor hospitals. These homogeneous circles might not substantially reduce geographic differences in transplant rates because deceased donor kidney supply and demand differ across the country. Using Scientific Registry of Transplant Recipients data from 2016-2019, we used an integer program to design unique, heterogeneous circles with sizes between 100 and 500 nm that reduced supply/demand ratio variation across transplant centers. We weighted demand according to wait time because candidates who have waited longer have higher priority. We compared supply/demand ratios and average travel distance of kidneys, using heterogeneous circles and 250 and 500-nm fixed-distance homogeneous circles. We found that 40% of circles could be 250 nm or smaller, while reducing supply/demand ratio variation more than homogeneous circles. Supply/demand ratios across centers for heterogeneous circles ranged from 0.06 to 0.13 kidneys per wait-year, compared to 0.04 to 0.47 and 0.05 to 0.15 kidneys per wait-year for 250-nm and 500-nm homogeneous circles, respectively. The average travel distance for kidneys using heterogeneous, and 250-nm and 500-nm fixed-distance circles was 173 nm, 134 nm, and 269 nm, respectively. Heterogeneous circles reduce geographic disparity compared to homogeneous circles, while maintaining reasonable travel distances.

BACKGROUND:In order to counter the lack of sufficient kidney donors, there has been interest in expanding the utilization of organs from increased infectious-risk donors. Negative nucleic acid testing of increased infectious-risk organs has been shown to increase their use as compared to only enzyme-linked immunosorbent assay negativity. However, it is not known how the expanded use of nucleic acid testing on a national scale might affect total donor utilization. OBJECTIVE:The objective of this paper was to determine if a national screening policy requiring the use of nucleic acid testing in both increased infectious-risk and non-increased infectious-risk renal transplant donors would increase the donor organ pool. METHODS:This study used decision-tree analysis to determine the cost-effectiveness of four US national screening policies based on an increasingly expansive use of nucleic acid testing for increased infectious-risk and non-increased infectious-risk kidneys. Parameters were taken from the literature. All costs were reported in 2020 US dollars using a Medicare payer perspective and a life-time horizon. RESULTS:The use of nucleic acid screening solely for increased infectious-risk organs was the dominant strategy. Our results were robust to deterministic and probabilistic sensitivity analyses. One of the main driving factors of cost-effectiveness was the false-positive rate of nucleic acid testing. CONCLUSION:Before implementing nucleic acid screening outside of increased infectious-risk organs, its false-positivity rate should be directly studied to ensure that its use does not detrimentally affect transplantation numbers, quality-adjusted life-years, and costs.

BACKGROUND:Approximately 30% of kidney transplant recipients undergo early steroid withdrawal (ESW) for maintenance immunosuppression. However, there is no consensus on which patients are suitable for ESW, and transplant centers may disagree on how various clinical factors characterize individual recipients' suitability for ESW. METHODS:To examine center-level variation in the association of clinical factors with the choice of ESW, we studied 206 544 kidney transplant recipients from 278 centers in 2002-2017 using SRTR data. We conducted multi-level logistic regressions to characterize the association of clinical factors with the choice of ESW at each transplant center. RESULTS:). When estimated at each center, this odds ratio was significantly lower than the population odds ratio at 48 (17.3%) centers and significantly higher at 28 (10.1%) centers. CONCLUSIONS:We have observed apparent inconsistencies across transplant centers in the practice of tailoring ESW to the recipient's risk profile. Standardized guidelines for ESW tailoring are needed.

BACKGROUND AND AIMS:In February 2020, the Organ Procurement and Transplantation Network replaced donor service area-based allocation of livers with acuity circles, a system based on three homogeneous circles around each donor hospital. This system has been criticized for neglecting to consider varying population density and proximity to coast and national borders. APPROACH AND RESULTS:Using Scientific Registry of Transplant Recipients data from July 2013 to June 2017, we designed heterogeneous circles to reduce both circle size and variation in liver supply/demand ratios across transplant centers. We weighted liver demand by Model for End-Stage Liver Disease (MELD)/Pediatric End-Stage Liver Disease (PELD) because higher MELD/PELD candidates are more likely to be transplanted. Transplant centers in the West had the largest circles; transplant centers in the Midwest and South had the smallest circles. Supply/demand ratios ranged from 0.471 to 0.655 livers per MELD-weighted incident candidate. Our heterogeneous circles had lower variation in supply/demand ratios than homogeneous circles of any radius between 150 and 1,000 nautical miles (nm). Homogeneous circles of 500 nm, the largest circle used in the acuity circles allocation system, had a variance in supply/demand ratios 16 times higher than our heterogeneous circles (0.0156 vs. 0.0009) and a range of supply/demand ratios 2.3 times higher than our heterogeneous circles (0.421 vs. 0.184). Our heterogeneous circles had a median (interquartile range) radius of only 326 (275-470) nm but reduced disparities in supply/demand ratios significantly by accounting for population density, national borders, and geographic variation of supply and demand. CONCLUSIONS:Large homogeneous circles create logistical burdens on transplant centers that do not need them, whereas small homogeneous circles increase geographic disparity. Using carefully designed heterogeneous circles can reduce geographic disparity in liver supply/demand ratios compared with homogeneous circles of radius ranging from 150 to 1,000 nm.

BACKGROUND:Although the population of older transplant recipients has increased dramatically, there are limited data describing the impact of immunosuppression regimen choice on outcomes in this recipient group. METHODS:National data for US Medicare-insured adult kidney recipients (N = 67 362; 2005-2016) were examined to determine early immunosuppression regimen and associations with acute rejection, death-censored graft failure, and mortality using multivariable regression analysis in younger (18-64 y) and older (>65 y) adults. RESULTS:The use of antithymocyte globulin (TMG) or alemtuzumab (ALEM) induction with triple maintenance immunosuppression (reference) was less common in older compared with younger (36.9% versus 47.0%) recipients, as was TMG/ALEM + steroid avoidance (19.2% versus 20.1%) and mammalian target of rapamycin inhibitor (mTORi)-based (6.7% versus 7.7%) treatments. Conversely, older patients were more likely to receive interleukin (IL)-2-receptor antibody (IL2rAb) + triple maintenance (21.1% versus 14.7%), IL2rAb + steroid avoidance (4.1% versus 1.8%), and cyclosporine-based (8.3% versus 6.6%) immunosuppression. Compared with older recipients treated with TMG/ALEM + triple maintenance (reference regimen), those managed with TMG/ALEM + steroid avoidance (adjusted odds ratio [aOR], 0.440.520.61) and IL2rAb + steroid avoidance (aOR, 0.390.550.79) had lower risk of acute rejection. Older patients experienced more death-censored graft failure when managed with Tac + antimetabolite avoidance (adjusted hazard [aHR], 1.411.782.25), mTORi-based (aHR, 1.702.142.71), and cyclosporine-based (aHR, 1.411.782.25) regimens, versus the reference regimen. mTORi-based and cyclosporine-based regimens were associated with increased mortality in both older and younger patients. CONCLUSIONS:Lower-intensity immunosuppression regimens (eg, steroid-sparing) appear beneficial for older kidney transplant recipients, while mTORi and cyclosporine-based maintenance immunosuppression are associated with higher risk of adverse outcomes.

BACKGROUND:The human immunodeficiency virus (HIV)-1 latent reservoir (LR) in resting CD4+ T cells is a barrier to cure. LR measurements are commonly performed on blood samples and therefore may miss latently infected cells residing in tissues, including lymph nodes. METHODS:We determined the frequency of intact HIV-1 proviruses and proviral inducibility in matched peripheral blood (PB) and lymph node (LN) samples from 10 HIV-1-infected patients on antiretroviral therapy (ART) using the intact proviral DNA assay and a novel quantitative viral induction assay. Prominent viral sequences from induced viral RNA were characterized using a next-generation sequencing assay. RESULTS:The frequencies of CD4+ T cells with intact proviruses were not significantly different in PB versus LN (61/106 vs 104/106 CD4+ cells), and they were substantially lower than frequencies of CD4+ T cells with defective proviruses. The frequencies of CD4+ T cells induced to produce high levels of viral RNA were not significantly different in PB versus LN (4.3/106 vs 7.9/106), but they were 14-fold lower than the frequencies of cells with intact proviruses. Sequencing of HIV-1 RNA from induced proviruses revealed comparable sequences in paired PB and LN samples. CONCLUSIONS:These results further support the use of PB as an appropriate proxy for the HIV-1 LR in secondary lymphoid organs.