Abstract Background and Aims The use of mTOR inhibitors (mTORi) is not usually considered in high immunological risk kidney transplant recipients (KTR) for a perceived increased risk of rejection. ...However, in most of the studies that examined the combination of mTORi with calcineurin inhibitors (CNI), hypersensitized patients have been excluded from enrollment. The aim of the present study is to analyze our clinical experience with the use of mTORi in association with calcineurin inhibitors (CNI) in this subset of patients. Method Analysis of 212 consecutive kidney transplant recipients with a baseline calculated panel reactive antibody (cPRA) ≥50% who received a graft from June 2013 to December 2019. Immunosuppression was based on tacrolimus, steroids and, alternatively, mycophenolic acid (MPA; n = 96) or mTORi (either sirolimus or everolimus, target trough levels 3-8 ng/ml, n = 116) depending on the active Institution's protocol at the time of transplantation. The outcomes chosen included rejection-free, graft and patient survival and were analyzed by means of Cox-regression analysis. Results Demographic and immunological characteristics were similar between groups, apart from the higher number of living donors in the MPA group (42.7% vs 14.7%%, P < 0.001). Baseline cPRA was 92.5 76-98% for the MPA and 94 77.25-98% for the mTORi group, respectively (P = 0.882). Induction therapy with lymphocyte-depleting agents was employed in the majority of patients (91.7% in the MPA group and 88.8% in the mTORi group, P = 0.898). Median follow-up time was 2.6 1.45-4.05 years. Biopsy-proven rejection (either cellular or humoral) occurred in 33.3% of the MPA and in 19.8% of the mTORi group, respectively. Cox-regression analysis of rejection-free survival revealed better rejection-free survival with mTORi versus MPA (HR 95% CI, 0.54 0.32-0.98, P = 0.028). The only other baseline factor associated with rejection was previous transplantation (HR 95% CI 1.96 1.07-3.60, P = 0.030). When entered into a bivariable Cox-regression analysis, both mTORi and previous transplantation maintained a statistical significant association with rejection (mTORi versus MPA HR 95% CI 0.53 0.31-0.91, P = 0.023, and previous transplantation HR 95% CI 2.01 1.09-3.69, P = 0.024). No differences between mTORi and MPA were noted for graft (HR 95% CI 0.90 0.40-2.02, P = 0.807) and patient survival (HR 95% CI 1.23 0.60-2.50, P = 0.606). Median creatinine 1 year after transplantation was 1.45 1.11-1.98mg/dl for the MPA group and 1.51 1.09-2.06mg/dl for the mTORi group (P = 0.917). Conclusion This retrospective study suggests that hypersensitized KTRs can receive safely a maintenance immunosuppression based on a combination of CNI with mTORi, without an increased risk of rejection.
Abstract
BACKGROUND AND AIMS
‘Stress hyperglycaemia’ is a condition characterized by elevated blood glucose levels during stress or illness. It is often multifactorial and leads to transient insulin ...resistance and/or insulin deficiency in critical ill patients. Patients with stress hyperglycaemia could be potential pancreas donors, although there is some concern about the influence of donor insulin use on pancreas graft survival. Studies have reported that stress hyperglycaemia increases the risk toward the development of type 2 diabetes (T2D) on the long term, but the patient profiles were of those not usually considered for pancreas donation. The objective of our study was to assess the impact of insulin requirements during intensive care unit (ICU) in surviving patients who otherwise would be potentially eligible for pancreas donation. The risk of T2D at 3 years after discharge was assessed to understand the pancreas function recovery after stress hyperglycaemia.
METHOD
we developed a retrospective study including patients admitted in the ICU between March 2011 and December 2017 due to severe neurological acute conditions subarachnoid haemorrhage (SAH), head trauma, non-SAH haemorrhage or stroke. Inclusion criteria were as follows: severe neurological condition requiring need for intubation, age <56 years and survival at discharge. Exclusion criteria included: obesity (BMI ≥30), diagnosis of diabetes prior to admission, HVB, HVC or HIV positive and lost to follow-up <3 years. Baseline characteristics, length of hospital and ICU stay, peak AST/ALT and amilase/lipase, insulin use during admission as well as variables associated with hyperglycaemia (use of parenteral nutrition, infections, use of corticosteroids or propofol sedation) were collected from patient's electronic medical records of our institution. Primary endpoint was diagnosis of T2D at 3 years after discharge (HbA1C ≥6.5% or fasting plasma glucose ≥126 mg/dL).
RESULTS
A total of 76 patients were included, with insulin requirement during ICU admission reported in only 5 (6.6%). Median age was 45 years (IQR 35–52), 50% were males, median Charlson index was 0, and 25 (32.9%) had present or past smoking habit. Hypertension was present in 11 (14.5%) and dyslipidaemia in 7 (9.2%). The main admission cause was SAH in 45 patients (59.2%) followed by head trauma in 21 (27.6%). As for hyperglycaemic factors, during admission, 6 (7.9%) received parenteral nutrition, 48 (63%) had an infectious complication, 51 (67%) received corticosteroids and 49 (64.5%) were under propofol sedation. A total of 55 (72.4%) received noradrenaline. Median amylase, lipase, AST and ALT peak were 115 U/L (69.5–233), 70 U/L (34–222), 51 U/L (33.25–101.5) and 94 U/L (35.5–165), respectively. Median ICU and hospital stay were 10 (5–17.75) and 29 (19–42.75) days, respectively. Those who required insulin had longer ICU stay compared with the median of the overall cohort (25 versus 10 days); all of them received corticosteroids and were diagnosed with SAH. At 3 years of follow-up, only three patients (3.9%) were diagnosed with T2D, but none of them had received insulin during admission. One patient was diagnosed 7 months after discharge and the other two were diagnosed 1 year after discharge. Three patients died during the follow-up, but any of them also required insulin during admission.
CONCLUSION
Insulin requirement in patients with severe neurological acute conditions who could meet criteria for pancreas donation was less common than expected, despite large use of corticoids, infectious complications and propofol sedation as hyperglycaemic factors. Remarkably, only three patients were diagnosed of T2D during the follow-up and none of them received insulin during admission. Prospective studies are needed in order to understand pancreas recovery after stress hyperglycaemia.
Abstract
Background and Aims
Biologically, the cellular activity of the mTOR complexes depends on the balance between the catabolic and the anabolic inputs. Hence, we hypothesized that the metabolic ...side effects of mTOR inhibitors (mTORi) in kidney transplantation depend on the baseline metabolic status of the patient.
Method
The analysis included all the patients that have been transplanted in our Center between June 2013 to December 2016, completed one year of follow-up and did not change medication during the first year after kidney transplantation (per-protocol population, n=298). Outcomes chosen include de novo diabetes, 1-year difference from baseline in glycated hemoglobin (HbA1c), triglycerides and total cholesterol. Kidney transplant recipients were treated either with an mTORi (either Sirolimus or Everolimus, n=134) or Mycophenolic Acid (MPA, n=164). Both drugs were always accompanied by tacrolimus and steroids. Patients were stratified according to the treatment received (mTORi versus MPA) and the baseline metabolic status (diabetes mellitus type 2 and obesity). Differences among groups were analyzed with exact Fisher test and ANOVA test with LSD post-hoc analysis.
Results
We observed a strong difference for 1-year change in HbA1c depending on the baseline metabolic status of the patients (P<0.001 between groups, Figure 1a). The worst results were observed for patients with baseline diabetes. Among these, obese patients treated with mTORi had the higher increase in HbA1c (3.04 ± 1.18% from baseline, P<0.01 with all groups at post-hoc analysis). De-novo diabetes was more frequent in patients taking mTORi (23.4 vs. 13.1%), albeit not significantly (P=0.100) and without differences taking into account obesity as a covariate. Triglycerides increased substantially in patients without baseline diabetes and treated with mTORi (P<0.05). Surprisingly, in diabetic patients no differences were observed in triglycerides between mTORi and MPA groups (Figure 1b). There were no differences in the increase in total cholesterol among groups (P=0.155) (Figure 1c).
Conclusion
We observed that the 1-year increase in HbA1c and triglycerides attributable to mTORi after kidney transplantation depends on the baseline metabolic status of the patients. We propose that the metabolic side effects of mTORi depend on the balance between anabolic and catabolic inputs of every kidney transplant recipient.
Figure: (below)
Cardiovascular disease is the major cause of death in patients with type 1 diabetes. Of the available risk predictors for this population, the Steno Type 1 Risk Engine (STENO T1) is the only one that ...includes kidney function as a risk factor, which is a well-described independent risk factor for cardiovascular disease.
We explore how simultaneous pancreas-kidney transplantation (SPKT) modifies the predicted cardiovascular risk by the STENO T1 through a retrospective study including recipients of a first SPKT between 2000 and 2016.
Two hundred sixty-eight SPKT recipients with a mean age of 40 y old and a median follow-up of 10 y were included. Before transplantation, the expected incidence of cardiovascular events (CVEs) at 5 and 10 y according to STENO T1 would have been 31% and 50%, respectively, contrasting with an actual incidence of 9.3% and 16% for the same timepoints, respectively (P < 0.05). These differences were attenuated when STENO T1 was recalculated assuming 12th-mo glomerular filtration rate (at 5 and 10 y predicted CVE incidence was 10.5% and 19.4%, respectively). Early pancreas graft failure (hazard ratio HR 3.00, 95% confidence interval CI, 1.14-7.88; P = 0.02) was an independent risk factor for post-SPKT CVE, alongside kidney graft failure (HR 2.90, 95% CI, 1.53-5.48; P = 0.001), and diabetes duration (HR 1.04, 95% CI, 1.00-1.09, P = 0.04).
SPKT decreases in more than two-thirds of the predicted cardiovascular risk by the STENO T1. A functioning pancreas graft further reduces CVE risk, independently of kidney graft function.
Liposomal iron in moderate chronic kidney disease Montagud-Marrahi, Enrique; Arrizabalaga, Pilar; Abellana, Rosa ...
Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia,
07/2020, Letnik:
40, Številka:
4
Journal Article
Recenzirano
Odprti dostop
The optimal iron supplementation route of administration (intravenous vs oral) in patients with chronic kidney disease (CKD) not on dialysis is a hot topic of debate. An oral preparation (liposomal ...iron, FeSu) has recently been developed with high bioavailability and low incidence of side effects. The objective was to evaluate the efficacy of FeSu in patients with stage 3 CKD and gastrointestinal intolerance to conventional oral iron therapy.
Prospective observational study of patients with stable stage 3 CKD and gastrointestinal intolerance to conventional oral iron therapy. An oral 30mg/day dose of FeSu was administered for 12 months. The primary outcome measure was haemoglobin increase at 6 and 12 months. Treatment adherence and adverse effects were also evaluated.
37 patients aged 72.6±14.7 years and with an estimated glomerular filtration rate (eGFR) of 42±10ml/min/1.73m
were included. 32 patients had received previous treatment with conventional oral formulations, 73% of which exhibited gastrointestinal intolerance with treatment adherence of 9.4%. After 6 months with FeSu, an increase in haemoglobin was observed versus baseline, which was sustained at 12 months (0.49±0.19 and 0.36±0.19g/dl, respectively, P<.05), despite a significant eGFR decrease of 3.16±1.16 and 4.20±1.28ml/min/1.73 m
at 6 and 12 months, respectively. None of the patients experienced adverse reactions that required the treatment to be suspended. Adherence was 100% at both 6 and 12 months.
FeSu is effective in a cohort of patients with stage 3 CKD with similar characteristics to the general population of moderate CKD patients, with a low rate of adverse reactions and excellent tolerability.
Abstract
Background and Aims
Early graft failure (EGL) is a devastating complication of kidney transplantation. Patients with EGL have an increased risk of mortality of up to twelve times compared to ...patients who received grafts that survive beyond 30 days. Moreover, they may have become sensitized to antigens from the failed graft and that human leukocyte antigen antibodies (anti-HLA), identified on single antigen bead assays, may not be reliable until several weeks after transplantation. Thus, if rapid re-transplantation occurs, there is no certainty regarding the recipient's immunological status. Hence, there could be an increased immunological risk with the consequent disturbance of the new graft's survival.
Method
We performed a retrospective single-center observational study in re-transplanted patients with EGL (defined as graft loss before 30 days from transplant) between January 1977 and November 2019 from our center to analyze the outcomes of rapid re-transplantation (occurred within 30 days of EGL) vs late re-transplantation (occurred beyond those 30 days).
Results: T
here were 82 re-transplants after EGL. The median overall patient survival after re-transplantation was 32 years. Eight patients died within the first year. Among the mortality causes, there were four septic shocks, one cardiogenic shock, one massive pulmonary thromboembolism, one myocardial infarction, and one unknown cause. When analyzed for periods, death censored graft survival was 89% at one and five years after re-transplantation. One graft was lost at eight days due to antibody-mediated rejection (AMR), while there was one death with a functioning graft three months after re-transplantation secondary to a pulmonary embolism. Seventy-three late re-transplants occurred. When analyzed for periods, death censored graft survival was 81% and 69% at one and five years after re-transplantation, respectively. The median patient survival after late re-transplantation was 32 years. There were fewer deaths after rapid re-transplantation than late re-transplantation, but given the small number of cases in the former, this difference did not reach statistical significance (p = 0.3). There was no association between the timing of re-transplantation and an increased risk of graft failure (HR 0.30 0.04 – 2.2). While four rapid re-transplants did not share any incompatibilities between donors, four did share at least one HLA type I incompatibility, and one shared an incompatibility of HLA class I and class II. There were no T-cell mediated rejections (TCMR), and there was only one AMR in the rapid rapid re-transplantation group, whereas there were six TCMRs and fifteen AMRs in the late re-transplantation group (p = 0.03 and p = 0.4, respectively).
Conclusion
Rapid re-transplantation appears to be safe and does not entail increased rejection risk, nor it diminishes long-term graft survival when compared to late re-transplantation.
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