Early cytomegalovirus DNAemia and antiviral dose adjustment in high vs intermediate risk kidney transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) infection continues to negatively affect outcomes for solid organ transplant recipients, despite the advent of strategies for preemptive surveillance and prophylaxis. The impact is especially great for CMV seronegative recipients of donor seropositive organs, who typically lack the ability to control CMV infection at the time of transplantation. METHODS: We reviewed episodes of CMV DNAemia in a modern cohort of kidney transplant recipients over a 3-year period at a high-volume transplant center to investigate the frequency of DNAemia during antiviral prophylaxis. RESULTS: Despite receipt of antiviral prophylaxis per current guidelines, 75 cases of CMV DNAemia were observed in the first 100 days after transplantation. For high risk patients, median time to DNAemia was 75 days after transplantation, and the majority of patients had experienced dose-reduction of valganciclovir due to renal insufficiency. Review of CMV seropositive intermediate risk patients demonstrated DNAemia occurring earlier after transplantation compared with high risk patients with a median time of 64 days (P = .029). The impact of valganciclovir dose adjustment was less notable in the intermediate risk group. CONCLUSIONS: Guidelines recommend beginning routine surveillance for CMV after the completion of antiviral prophylaxis. Our findings suggest that closer monitoring may be beneficial, especially for high risk patients at risk for DNAemia. Patients requiring dose adjustment of valganciclovir due to renal insufficiency may be at increased risk for CMV DNAemia. Improved methods for CMV prophylaxis and evaluation of immunologic risk for CMV DNAemia and disease are needed to improve patient outcomes after kidney transplantation.

Time to second kidney transplantation in young adults after failed pediatric kidney transplant.

BACKGROUND: Under the current kidney allocation system, pediatric candidates listed prior to age 18 receive priority for high-quality deceased donor organs. This has resulted in a decline in living donor transplantation in pediatrics, despite superior outcomes of living donor transplantation. Due to a young age at transplantation, most pediatric kidney transplant recipients require re-transplantation. The effects of a previously failed deceased donor vs a previously failed living donor on re-transplant candidates are unknown. METHODS: Using the United Network for Organ Sharing database, we examined 2772 re-transplant recipients aged 18-30 years at time of relisting for second KT from 2000 to 2018 with history of prior pediatric KT (age ≤ 18 years). RESULTS: PFLDKT recipients compared to those with PFDDKT had shorter median waiting times and dialysis time regardless of their second donor type (14.0 vs 20.3 months, and 19.1 vs 34.5 months, respectively). PFLDKT recipients had higher re-transplant rates (adjusted HR 1.17, 95% CI 1.09-1.27, and adjusted HR 1.05, 95% CI 0.95-1.15 when calculating from time of relisting and time of returning to dialysis, respectively). PFDDKT recipients were more likely to have higher median PRA levels (90% vs 73%). CONCLUSIONS: Re-transplant candidates who received a previous deceased donor as a child had a higher level of sensitization, longer waiting time, and dialysis exposure compared to those with PFLDKT. Among primary pediatric kidney transplant candidates, consideration should be considered for living donor transplantation, despite the priority for deceased donor organs, to avoid increased sensitization and longer waiting times for with re-transplantation.

Screening Coccidioides serology in kidney transplant recipients: A 10-year cross-sectional analysis.

BACKGROUND: Kidney transplant recipients (KTRs) are at risk for reactivation and complicated infection due to Coccidioides. Pre-transplant serological screening should provide benefit for patients from endemic areas. We evaluated Coccidioides seroprevalence by area of residence in KTRs at a major transplant program in Los Angeles. METHODS: We performed cross-sectional analyses of adult KTRs who underwent transplantation at UCLA between 2007-2016. Patients with Coccidioides serology by enzyme immunoassay (EIA) before or within 14 days from transplantation were included. Patients were classified as living in highly, established, suspected, or not endemic areas by their residential zip code. RESULTS: Overall prevalence of Coccidioides IgG and IgM were 1.4% and 2.8%, respectively. Of patients with positive serology, 31.4% had isolated IgG and 66.3% isolated IgM. Patients from established and highly endemic areas had IgG seropositivity of 3.7% versus 1.3% for patients living in suspected endemic areas(P < .01). Rates of IgM seropositivity were 3.7% compared to 2.8% respectively (P = .28). No patients from non-endemic areas had positive screening serology. CONCLUSIONS: Pre-transplant serological screening for Coccidioides is recommended in kidney transplant candidates from endemic areas. We observed high seroprevalence among patients from highly and established endemic areas, for whom universal prophylaxis is recommended. For residents from less well-established areas of endemicity, serological screening showed benefit in identifying patients at risk. In patients with isolated EIA IgM, performing repeat and confirmatory tests is recommended. Patients from non-endemic areas had low risk of infection, however, a thorough social history is necessary to evaluate risk.

Etomoxir Inhibits Macrophage Polarization by Disrupting CoA Homeostasis.

Long-chain fatty acid (LCFA) oxidation has been shown to play an important role in interleukin-4 (IL-4)-mediated macrophage polarization (M(IL-4)). However, many of these conclusions are based on the inhibition of carnitine palmitoyltransferase-1 with high concentrations of etomoxir that far exceed what is required to inhibit enzyme activity (EC90 < 3 µM). We employ genetic and pharmacologic models to demonstrate that LCFA oxidation is largely dispensable for IL-4-driven polarization. Unexpectedly, high concentrations of etomoxir retained the ability to disrupt M(IL-4) polarization in the absence of Cpt1a or Cpt2 expression. Although excess etomoxir inhibits the adenine nucleotide translocase, oxidative phosphorylation is surprisingly dispensable for M(IL-4). Instead, the block in polarization was traced to depletion of intracellular free coenzyme A (CoA), likely resulting from conversion of the pro-drug etomoxir into active etomoxiryl CoA. These studies help explain the effect(s) of excess etomoxir on immune cells and reveal an unappreciated role for CoA metabolism in macrophage polarization.