Early calcineurin-inhibitor to belatacept conversion in steroid-free kidney transplant recipients.

Background: Belatacept (Bela) was developed to reduce nephrotoxicity and cardiovascular risk that are associated with the chronic use of Calcineurin inhibitors (CNIs) in kidney transplant recipients. The use of Bela with early steroid withdrawal (ESW) and simultaneous CNI avoidance has not been formally evaluated. Methods: At 3 months post-transplant, stable kidney transplant recipients with ESW on Tacrolimus (Tac) + mycophenolate (MPA) were randomized 1:1:1 to: 1) Bela+MPA, 2) Bela+low-dose Tac (trough goal <5 ng/mL), or 3) continue Tac+MPA. All patients underwent surveillance graft biopsies at enrollment and then at 12, and 24 months post-transplant. Twenty-seven recipients were included; 9 underwent conversion to Bela+MPA, 8 to Bela+low-dose Tac and 10 continued Tac+MPA. Serial blood samples were collected for immune phenotyping and gene expression analyses. Results: The Bela+MPA arm was closed early due to high rate of biopsy proven acute rejection (BPAR). The incidence of BPAR was 4/9 in Bela+MPA, 0/8 in Bela+low dose Tac and 2/10 in Tac+MPA, P= 0.087. The Bela+low-dose Tac regimen was associated with +8.8 mL/min/1.73 m2 increase in eGFR compared to -0.38 mL/min/1.73 m2 in Tac+MPA, P= 0.243. One graft loss occurred in the Bela+MPA group. Immunophenotyping of peripheral blood monocyte count (PBMC) showed that CD28+CD4+ and CD28+CD8+ T cells were higher in Bela+MPA patients with acute rejection compared to patients without rejection, although the difference did not reach statistical significance. Conclusions: Our data indicate that, in steroid free regimens, low-dose Tac maintenance is needed to prevent rejection when patients are converted to Bela, at least when the maneuver is done early after transplant.

The Role and Efficacy of Vitamin C in Sepsis: A Systematic Review and Meta-Analysis.

Clinical rationale for study: Despite advancements in critical care, the mortality rate of sepsis remains high, with an overall poor prognosis. There is a complex pathophysiology of a lethal cascade of cytokines and inflammatory proteins underlying sepsis. The use of vitamin C can theoretically suppress the inflammatory cascade but remains a questionable practice due to a lack of conclusive evidence. Aims of the study: To appraise the therapeutic role of vitamin C in sepsis. Materials and methods: A systematic review was conducted on PubMed, Embase, and the Central Cochrane Registry. The study included randomized clinical trials (RCTs) with vitamin C as an intervention arm in the septic patient population. For continuous variables, the difference in means (MD) and for discrete variables, the odds ratio (OR) was used. For effect sizes, a confidence interval of 95% was used. A p-value of less than 0.05 was used for statistical significance. The analysis was performed using a random-effects model irrespective of heterogeneity. Heterogeneity was evaluated using the I2 statistic. Results: 23 studies were included with the total sample size of 2712 patients. In patients treated with vitamin C, there was a statistically significant reduction in the mortality: OR = 0.778 (0.635 to 0.954), p = 0.016; the sequential organ failure assessment score (SOFA): MD = −0.749 (−1.115 to −0.383), p < 0.001; and the duration of vasopressor requirement: MD = −1.034 days (−1.622 to −0.445), p = 0.001. No significant difference was found in the hospital or ICU length of stay. Conclusions and clinical implications: Vitamin C treatment regimens were associated with reduced mortality, SOFA score, and vasopressor requirement compared to the control in sepsis. Given its low cost and minimal adverse effects, we strongly encourage further large, randomized trials to establish vitamin C as a standard of care in sepsis management.