Suphamai Bunnapradist

Background.: Older patients undergoing kidney transplantation are at risk of perioperative complications, underscoring the need for optimized care. The number of kidney transplants in older adults has increased in the past decade, with greater reliance on transplants from deceased donors. Methods.: The phase 3, randomized, double-blind, active-controlled P002 study evaluated 200 d of letermovir versus valganciclovir prophylaxis in cytomegalovirus-seronegative kidney transplant recipients who received kidneys from cytomegalovirus-seropositive donors. Outcomes among participants aged 65 y or older are reported. Results.: Forty-eight and 55 participants aged 65 y or older received letermovir or valganciclovir, respectively. A lower percentage of participants receiving letermovir versus valganciclovir had committee-confirmed cytomegalovirus disease through week 52 posttransplant (9% versus 22%; stratum-adjusted difference, –12% [95% confidence interval [CI], –27% to 2%]), without significant differences in cytomegalovirus disease or viremia between groups. A significantly higher percentage of participants receiving letermovir had ≥90% prophylaxis adherence (96% [95% CI, 86%-100%] versus 49% [95% CI, 35%-63%]). The letermovir group showed numerically lower incidences of drug-related adverse events (25% versus 49%) and study medication discontinuations due to adverse events (10% versus 20%). A significantly lower percentage of participants receiving letermovir had leukopenia or neutropenia events through week 28 posttransplant (31% [95% CI, 19%-46%] versus 62% [95% CI, 48%-75%]). Participants receiving letermovir had numerically lower rates of opportunistic infections (11% versus 25%) and rehospitalizations (51% versus 69%) through week 52 posttransplant. Conclusions.: Letermovir showed substantial advantages over valganciclovir in adherence, safety, and tolerability, supporting its use as an important option for cytomegalovirus disease prophylaxis for older patients undergoing kidney transplantation. Clinical trial registration number.: ClinicalTrials.gov, NCT03443869

Key Points: We assessed whether an initial donor-derived cell-free DNA elevation during routine surveillance was associated with allograft dysfunction and loss in kidney transplant recipients. Intermediate and high donor-derived cell-free DNA states were independently associated with 3.7-fold and 6.4-fold higher risks of allograft loss, respectively. Persistently low donor-derived cell-free DNA levels were associated with low rates of rejection and allograft loss, identifying a low-risk population. Background: Although donor-derived cell-free DNA (dd-cfDNA) correlates with histologic rejection and injury severity, its association with long-term graft outcomes has yet to be well established in kidney transplant recipients. We hypothesize that among patients monitored with dd-cfDNA, an initial elevation may be associated with subsequent allograft dysfunction and loss. Methods: The Kidney Allograft Outcomes AlloSure Registry is a prospective, multicenter cohort of 1743 adult kidney transplant recipients from 56 US centers; this analysis included 1258 patients who initiated dd-cfDNA surveillance 15–60 days post-transplant with up to 3-year follow-up. A multistate model was applied to characterize transitions from a low dd-cfDNA state (no elevations) to intermediate (0.5%–1.0% with ≥61% relative change value) or high (≥1.0%) dd-cfDNA states, and their unadjusted and covariate-adjusted associations with allograft loss or all-cause death were quantified using hazard regression models. Results: Within 3 years, 36% of patients transitioned to an elevated dd-cfDNA state (intermediate n =216; high n =233). Allograft dysfunction by 36 months occurred significantly more often in patients with dd-cfDNA elevations despite preserved allograft function at the time of elevation (eGFR ≥60 ml/min per 1.73 m ² in 42% of intermediate and 33% of high), consistent with subclinical injury. Transitions from low to elevated dd-cfDNA states were strongly associated with subsequent allograft loss (adjusted hazard ratios, 3.70 [95% confidence interval [CI], 1.38 to 9.90] for intermediate; 6.36 [95% CI, 2.80 to 14.42] for high), while mortality did not differ by dd-cfDNA state. Conclusions: Initial dd-cfDNA elevations exceeding established thresholds were independently associated with higher risks of allograft dysfunction and loss across both elevation categories, whereas patients who remained in the low dd-cfDNA state experienced favorable outcomes.

Background: LCPT (Envarsus XR (R)) is a common once-daily, extended-release oral tacrolimus formulation used in kidney transplantation. However, there are minimal evidence-based recommendations regarding optimal dosing and treatment in the de novo and conversion settings. Material/Methods: Using Delphi methodology, 12 kidney transplantation experts with LCPT experience reviewed available data to determine potential consensus topics. Key statements regarding LCPT use were generated and disseminated to the panel in an online Delphi survey. Statements were either accepted, revised, or rejected based on the level of consensus, perceived strength of evidence, and alignment with clinical practice. Consensus was defined a priori as 375% agreement. Results: Twenty-three statements were generated: 14 focused on de novo LCPT use and 9 on general administration or LCPT conversion use. After 2 rounds, consensus was achieved for 11/14 of the former and 7/9 of the latter statements. In a de novo setting, LCPT was recognized as a first -line option based on its safety and efficacy compared to immediate-release tacrolimus. In particular, African Americans and rapid metabolizer populations were identified as preferred for first -line LCPT therapy. In a conversion setting, full consensus was achieved for converting to LCPT to address neurological adverse effects related to immediate-release tacrolimus and for the time required (approximately 7 days) for steady-state LCPT trough levels to be reached. Conclusions: When randomized clinical trials do not replicate current utilization patterns, the Delphi process can successfully generate consensus statements by expert clinicians to inform clinical decision-making for the use of LCPT in kidney transplant recipients.

Background. A large number of procured kidneys continue not to be transplanted, while the waiting list remains high. Methods. We analyzed donor characteristics for unutilized kidneys in our large organ procurement organization (OPO) service area in a single year to determine the reasonableness of their nonuse and to identify how we might increase the transplant rate of these kidneys. Five experienced local transplant physicians independently reviewed unutilized kidneys to identify which kidneys they would consider transplanting in the future. Biopsy results, donor age, kidney donor profile index, positive serologies, diabetes, and hypertension were risk factors for nonuse. Results. Two-thirds of nonused kidneys had biopsies with high degree of glomerulosclerosis and interstitial fibrosis. Reviewers identified 33 kidneys as potentially transplantable (12%). Conclusions. Reducing the rate of unutilized kidneys in this OPO service area will be achieved by setting acceptable expanded donor characteristics, identifying suitable well-informed recipients, defining acceptable outcomes, and systematically evaluating the results of these transplants. Because the improvement opportunity will vary by region, to achieve a significant impact on improving the national nonuse rate, it would be useful for all OPOs, in collaboration with their transplant centers, to conduct a similar analysis.

CMV causes mostly asymptomatic but lifelong infection. Primary infection or reactivation in immunocompromised individuals can be life-threatening. CMV viremia often occurs in solid organ transplant recipients and associates with decreased graft survival and higher mortality. Furthering understanding of impaired immunity that allows CMV reactivation is critical to guiding antiviral therapy and examining the effect of CMV on solid organ transplant outcomes. This study characterized longitudinal immune responses to CMV in 31 kidney transplant recipients with CMV viremia and matched, nonviremic recipients. Recipients were sampled 3 and 12 months after transplant, with additional samples 1 week and 1 month after viremia. PBMCs were stained for NK and T cell markers. PBMC transcriptomes were characterized by RNA-Seq. Plasma proteins were quantified by Luminex. CD8 ⁺ T cell transcriptomes were characterized by single-cell RNA-Seq. Before viremia, patients had high levels of IL-15 with concurrent expansion of immature CD56 ^bright NK cells. After viremia, mature CD56 ^dim NK cells and CD28 ^– CD8 ⁺ T cells upregulating inhibitory and NK-associated receptors were expanded. Memory NK cells and NK-like CD28 ^– CD8 ⁺ T cells were associated with control of viremia. These findings suggest that signatures of innate activation may be prognostic for CMV reactivation after transplant, while CD8 ⁺ T cell functionality is critical for effective control of CMV.