SLC27a2) 40-fold and increased FA transport 4-fold compared to resting (naïve) T cells (see Table). Donor T cells also increased levels of enzymes necessary for FA oxidation (e.g. CPT2) 100-fold and oxidized more FAs. Mitochondrial mass (required for FA oxidation) increased in donor T cells, as did the ratio of mitochondrial to nuclear DNA, and the expression of PGC-1a, a key regulator of mitochondrial biogenesis. Importantly, T cells proliferating during routine immune reconstitution (following syngeneic BMT) minimally increased FA transport (10% vs. 40% in GVHD T cells). Finally, inhibition of FA oxidation in vivo, through irreversible blockade of CPT1 with etomoxir, decreased the total number of well-divided donor T cells after a single dose. Furthermore, two weeks of etomoxir treatment, beginning on day +7, improved both GVHD clinical score (1.1 vs. 3.8 in untreated animals, P ¼ .02) and weight loss at day 40. In total, these data demonstrate that GVHD T cells up-regulate FA metabolism in vivo and that proliferating, donor cells can be selectively eliminated through inhibition of FA oxidation. Our data provide novel insights into the metabolism of lymphocytes activated in vivo and show that inhibition of FA oxidation may be a therapeutic target for the prevention and/ or treatment of GVHD.
Background and Aims Chronic kidney disease (CKD) is an important sequela of hematopoietic stem cell transplantation (HSCT), but data regarding CKD after pediatric HSCT are limited. Method In this single center cohort study, we evaluated eGFR dynamics, proteinuria and hypertension in the first decade after HSCT and assessed risk factors for chronic kidney disease in 216 pediatric long term HSCT survivors, transplanted between 2002 and 2012. Results The eGFR decreased from median 148 to 116 ml/min/1.73m2 between pre-HSCT and ten years after HSCT. CKD, defined as an eGFR <90 ml/min/1.73m2 and/or proteinuria (KDIGO stage ≥G2 or ≥A2) occurred in 21% of patients. In multivariate analysis, hematological malignancy as HSCT indication (HR 5.5, 95% CI 1.2-25) and cytomegalovirus reactivation (HR 2.4, 95% CI 1.1-5.4) were independent risk factors for CKD. One third of patients with CKD had both an eGFR <90 ml/min/1.73m2 as well as proteinuria, one third had isolated eGFR reduction and one third only had proteinuria. Hypertension was observed in 27% of patients with CKD compared to 4.4% of patients without CKD. Tubular proteinuria was present in 7% of the subgroup of patients (n=71) in which β2-microglobulinuria was measured. Conclusion In conclusion, a significant proportion of pediatric HSCT recipients developed chronic kidney disease within ten years after HSCT. Our data stress the importance of structural long term monitoring of eGFR, urine and blood pressure after HSCT to identify patients with beginning CKD who could benefit most from nephroprotective interventions.
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