Profiling Sirolimus-Induced Inflammatory Syndrome: A Prospective Tricentric Observational Study

<div><h3>Background</h3><p>The use of the immunosuppressant sirolimus in kidney transplantation has been made problematic by the frequent occurrence of various side effects, including paradoxical inflammatory manifestations, the pathophysiology of which has remained elusive.</p> <h3>Methods</h3><p>30 kidney transplant recipients that required a switch from calcineurin inhibitor to sirolimus-based immunosuppression, were prospectively followed for 3 months. Inflammatory symptoms were quantified by the patients using visual analogue scales and serum samples were collected before, 15, 30, and 90 days after the switch.</p> <h3>Results</h3><p>66% of patients reported at least 1 inflammatory symptom, cutaneo-mucosal manifestations being the most frequent. Inflammatory symptoms were characterized by their lability and stochastic nature, each patient exhibiting a unique clinical presentation. The biochemical profile was more uniform with a drop of hemoglobin and a concomitant rise of inflammatory acute phase proteins, which peaked in the serum 1 month after the switch. Analyzing the impact of sirolimus introduction on cytokine microenvironment, we observed an increase of IL6 and TNFα without compensation of the negative feedback loops dependent on IL10 and soluble TNF receptors. IL6 and TNFα changes correlated with the intensity of biochemical and clinical inflammatory manifestations in a linear regression model.</p> <h3>Conclusions</h3><p>Sirolimus triggers a destabilization of the inflammatory cytokine balance in transplanted patients that promotes a paradoxical inflammatory response with mild stochastic clinical symptoms in the weeks following drug introduction. This pathophysiologic mechanism unifies the various individual inflammatory side effects recurrently reported with sirolimus suggesting that they should be considered as a single syndromic entity.</p> </div

Characteristics of the population.

<p>Data are given as mean ± SD or number (%).</p>*<p>Other initial nephropathies were: Wegener’s granulomatosis, diabetic nephropathy, CNI toxicity, posttraumatic loss of kidney.</p><p>eGFR was estimated at the time of inclusion by MDRD formula.</p>♦<p>Genotype of cytochrome 3A5: *1/*1 and *1/*3 are expressors, *3/*3 are non-expressors.</p

Profile of sirolimus-induced biological inflammatory syndrome.

<p>A) Heat map representing delta hemoglobin value at each time point for the population of the study. Black crosses indicate excluded patients (#6, 23, 25, 27) or excluded sera (patient #15, 17, 26, 30). The evolution of the levels of hemoglobin (B), reticulocyte count (C), mean corpuscular volume (D), ferritin (E), haptoglobin (F), fibrinogen (G), and CRP (H) are plotted (mean ± SEM). *p<0.05, **p<0.01, and ***p<0.001, as compared with baseline (d0) value.</p

Summary of the data available for analysis.

<p>A) Mean ± SEM of sirolimus trough levels are indicated at each time points for CYP3A5 expressors and non-expressors. Dashed lines indicate the target values. B) Flowchart of SIRILYGRE study summarizing data available for analysis. Among the 4 patients (Pt) excluded because of sirolimus discontinuation, 2 (#25 & #27, in bold) experienced severe inflammatory symptoms. Five sera were excluded from analysis because of the presence of a documented confounding inflammatory condition (sepsis). For one patient (#11) no analysis of cytokine dosage could be performed because time point of collection was not indicated on the tubes.</p

Changes in concomitant immunosuppressive drugs after sirolimus introduction.

<p>Results are expressed in number of patients (%).</p

Biological changes associated with sirolimus introduction.

<p>Results are expressed as mean ± SD.*Estimated glomerular filtration rate (MDRD formula).</p

Evolution of inflammatory cytokine levels correlates with clinical and biological manifestations of sirolimus-induced inflammatory syndrome.

<p>Pairwise correlation analysis was performed to determine how the changes of inflammatory cytokine levels are related to each other and with the changes of biological and clinical manifestations of sirolimus-induced inflammatory syndrome. The lower left half of the matrix is the color map of correlations. Bright colors indicate the pairs of variables closely correlated in the linear regression model (red for positive and blue for negative correlation). Faded colours encode for decreasing r values. The upper right half of the matrix is the colour map of p values. Decreasing p values are encoded from dark gray to dark green.</p

Comparison of machine perfusion versus cold storage in kidney transplant recipients from expanded criteria donors: a cohort-based study

International audienceBackground Most studies comparing the efficacy of hypothermic machine perfusion (HMP) versus static cold storage (SCS) are based on short-term outcomes. We aimed to better evaluate the mid-term impact of HMP in patients receiving expanded criteria donor (ECD) kidneys. Methods The analyses were based on the French Données Informatisées et VAlidées en Transplantation (DIVAT) observational cohort. Patients aged ≥45 years transplanted for the first or second times from an ECD donor since 2010 were studied. Our study reported the graft and/or patient survivals and the incidence of acute rejection episode. The Cox models and the Kaplan–Meier estimators, weighted on the propensity score, were used to study the times-to-events. Results Among the 2019 included patients, 1073 were in the SCS group versus 946 in the HMP group. The mean life expectancy with functioning graft was 5.7 years [95% confidence interval (CI) 5.4–6.1] for the HMP cohort followed-up for 8 years post-transplantation versus 6.0 years (95% CI 5.7–6.2) for the SCS group. These mid-term results were comparable in the patients receiving grafts from donors aged ≥70 years and in the transplantations with cold ischaemia time ≥18 h. Conclusions Our study challenges the utility of using HMP to improve mid-term patient and graft survival. Nevertheless, the improvement of the short-term outcomes is indisputable. It is necessary to continue technological innovations to obtain long-term results