Activation of browning in white adipose tissue during chronic kidney disease

International audienc

The uremic toxin 3 carboxy 4 methyl 5 propyl 2 furanpropanoic acid (cmpf): paradox of anew nutritional marker in haemodialysis

International audienc

Is 3-Carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) a clinically relevant uremic toxin in haemodialysis patients?

3-Carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) is a metabolite of furan fatty acid and a marker of fish oil intake. CMPF is described as a protein-bound uremic toxin and interacts with free oxygen radicals, which can induce cell damages. However, the clinical consequences of CMPF accumulation in haemodialysis patients remain poorly documented. The aims of this study are to investigate potential association between CMPF levels and (i) biochemical and nutritional parameters; (ii) cardiovascular events and (iii) mortality. Two hundred and fifty-two patients undergoing maintenance haemodialysis were included. Routine clinical biochemistry tests and assay for CMPF by HPLC technique were performed at the inclusion. Body composition parameters were measured using a bioimpedance spectroscopy method. The enrolled patients were prospectively monitored for cardiovascular events and mortality. CMPF level was positively correlated with nutritional parameters and lean mass and is significantly higher in patients without protein-energy wasting. However, the multivariate linear regression analysis indicated that CMPF level was not independently associated with albumin, prealbumin, creatinemia and body mass index. Elevated serum CMPF was not associated with mortality and cardiovascular morbidity. Our results indicate that CMPF is not a relevant uremic toxin in haemodialysis and in contrast could be a marker of healthy diet and omega 3 intakes

Serum levels of the adipokine zinc-alpha2-glycoprotein (ZAG) predict mortality in hemodialysis patients

Wasting has been associated with increased cardiovascular and all-cause mortality in chronic kidney disease (CKD). We investigated whether serum zinc-alpha2-glycoprotein (ZAG), a potent cachectic and lipid-mobilizing factor that is increased in patients with CKD, predicts clinical outcomes in patients on chronic hemodialysis. We quantified serum ZAG at baseline in a prospective cohort of 252 patients undergoing maintenance hemodialysis. Serum ZAG concentrations were inversely associated with serum albumin, creatinine, and triglycerides and, conversely, positively associated with age. Although ZAG is strongly linked to protein energy wasting (PEW) in patients with cancer, higher ZAG concentrations were not associated with PEW in our cohort. During a mean study follow-up of 954 days, 49 patients died and 62 patients experienced a cardiovascular event. Kaplan-Meier analysis revealed a significant correlation between serum ZAG concentrations and all-cause mortality and cardiovascular events. In separate multivariable Cox regression models, serum ZAG concentrations remained significantly associated with all-cause mortality and cardiovascular events after adjustment for demographic factors (age, sex, and dialysis vintage), metabolic parameters (serum albumin, prealbumin, triglycerides, cholesterol, normalized protein catabolic rate, and body mass index), and cardiovascular risk factors (diabetes, dyslipidemia, history of cardiovascular disease, smoking, and diuretic use as a proxy of residual renal function). Thus, serum ZAG appears to be a strong and independent predictor of mortality and cardiovascular events in patients with end-stage renal disease. Further studies are necessary to confirm this association and to elucidate the underlying mechanisms

Impact of the Kidney Transplantation Moratorium in France Because of the COVID-19 Pandemic: A Cohort-based Study

International audienceBackground. The COVID-19 pandemic has resulted in worldwide kidney transplantation (KT) moratoriums. The impacts of these moratoriums on the life expectancy of KT candidates remain unclear.Methods. We simulated the evolution of several French candidate populations for KT using a multistate semi-Markovian approach and according to moratorium durations ranging from 0 to 24 mo. The transition rates were modeled from the 63 927 French patients who began dialysis or were registered on the waiting list for KT between 2011 and 2019.Results. Among the 8350 patients active on the waiting list at the time of the French KT moratorium decided on March 16, 2020, for 2.5 mo, we predicted 4.0 additional months (confidence interval [CI], 2.8-5.0) on the waiting list and 42 additional deaths (CI, –70 to 150) up to March 16, 2030, compared with the scenario without moratorium. In this population, we reported a significant impact for a 9-mo moratorium duration: 135 attributable deaths (CI, 31-257) up to March 16, 2030. Patients who became active on the list after March 2020 were less impacted; there was a significant impact for an 18-mo moratorium (175 additional deaths [CI, 21-359]) in the 10 862 prevalent end-stage renal disease patients on March 16, 2020 and for a 24-mo moratorium (189 additional deaths [CI, 10-367]) in the 16 355 incident end-stage renal disease patients after this date.Conclusion. The temporary moratorium of KT during a COVID-19 peak represents a sustainable decision to free up hospitals’ resources if the moratorium does not exceed a prolonged period

Perspectives for future development of the kidney paired donation programme in France

International audienceAlmost one third of kidney donation candidates are incompatible (HLA and/or ABO) with their directed recipient. Kidney paired donation allows potential donors to be exchanged and gives access to a compatible kidney transplant. The Bioethics Law of 2011 authorised kidney paired donation in France with reciprocity between 2 incompatible “donor-recipient” pairs. A limited number of transplants have been performed due to a too restricted authorization compared to other European practices. This study presents the perspectives of the new Bioethics Law, enacted in 2021, which increases the authorised practices for kidney paired donation in France. The two simulated evolutions are the increase of the number of pairs involved in a kidney paired donation to 6 (against 2 currently) and the use of a deceased donor as a substitution to one of living donor. Different scenarios are simulated using data from the Agence de la Biomedecine; incompatible pairs registered in the kidney paired donation programme in France between December 2013 and February 2018 (78 incompatible pairs), incompatible transplants performed during the same period (476 incompatible pairs) and characteristics of deceased donors as well as proposals made over this period. Increasing the number of pairs has a limited effect on the number of transplants, which increases from 18 (23% of recipients) in the current system to 25 (32% of recipients) when 6 pairs can be involved. The use of a deceased donor significantly increases the number of transplants to 41 (52% of recipients). This study makes it possible to evaluate the increase in possibilities of kidney transplants by kidney paired donation following the new bioethics law. A working group and an information campaign for professionals and patients will be necessary for its implementation

Long-term survival benefit from dual kidney transplantation using kidneys from donors with very extended criteria-a French cohort between 2002 and 2014

International audienceBACKGROUND: This national multicentre retrospective cohort study aimed to assess the long-term outcomes of dual kidney transplantation (DKT) and compare them with those obtained from single kidney transplantation (SKT). METHODS: Our first analysis concerned all first transplants performed between May 2002 and December 2014, from marginal donors, defined as brain death donors older than 65 years, with an estimated glomerular filtration rate (eGFR) lower than 90 mL/min/1.73 m2. The second analysis was restricted to transplants adequately allocated according to the French DKT program based on donor eGFR: DKT for eGFR between 30 and 60, SKT for eGFR between 60 and 90 mL/min/1.73 m2. Recipients younger than 65 years or with a panel-reactive antibody percentage ≥25% were excluded. RESULTS: The first analysis included 461 DKT and 1131 SKT. DKT donors were significantly older (77.6 versus 74 years), had a more frequent history of hypertension and a lower eGFR (55.1 versus 63.6 mL/min/1.73 m2). While primary nonfunction and delayed graft function did not differ between SKT and DKT, 1-year eGFR was lower in SKT recipients (39 versus 49 mL/min/1.73 m2, P < 0.001). Graft survival was significantly better in DKT, even after adjustment for recipient and donor risk factors. Nevertheless, patient survival did not differ between these groups. The second analysis included 293 DKT and 687 SKT adequately allocated with donor eGFR and displayed similar results but with a smaller benefit in terms of graft survival. CONCLUSIONS: In a context of organ shortage, DKT is a good option for optimizing the use of kidneys from very expanded criteria donors

Aortic Stiffness of Kidney Transplant Recipients Correlates with Donor Age

Increased aortic stiffness is a major factor responsible for the high cardiovascular mortality in patients with end-stage renal disease, but the impact of kidney transplantation on recipient aortic stiffness remains poorly defined. The use of expanded-criteria kidney donors is associated with decreased recipient survival compared with the use of standard-criteria donors, although the underlying mechanisms are incompletely understood. It was hypothesized that donor characteristics may affect recipient aortic stiffness, which may contribute to cardiovascular mortality in these patients. Aortic stiffness was evaluated by measurement of carotid-femoral pulse wave velocity in 74 cadaveric kidney recipients at 3 and 12 mo after transplantation. At 3 mo, aortic stiffness was associated exclusively with recipient-related factors: Age, gender, and mean BP. At 12 mo, age of the donor kidney emerged as an additional determinant. The change in aortic stiffness between 3 and 12 mo strongly correlated with donor age; stiffness improved in recipients of young kidneys (first tertile of donor age) and worsened in recipients of older kidneys (upper tertile of donor age). At 12 mo, the carotid-femoral pulse wave velocity was >1 m/s higher in recipients of the oldest kidneys than in the recipients of younger kidneys. The association between donor age and aortic stiffness was independent of recipient age, gender, mean BP, pretransplantation dialysis duration, conventional cardiovascular risk factors, medication, posttransplantation events, and GFR. These results demonstrate that the impact of kidney transplantation on recipient aortic stiffness is dependent on donor age and suggest that ongoing damage to large arteries might contribute to the mechanism underlying the association of old-donor kidneys and increased cardiovascular mortality

Accumulation of natriuretic peptides is associated with protein energy wasting and activation of browning in white adipose tissue in chronic kidney disease

International audienceProtein energy wasting is a common feature of patients with chronic kidney disease (CKD) and is associated with poor outcomes. Protein energy wasting and cachexia, a severe form of protein energy wasting, are characterized by increased resting energy expenditure but the underlying mechanisms are unclear. Browning corresponds to the activation of inducible brown adipocytes in white adipose tissue and occurs in states of cachexia associated with hypermetabolic disease such as cancer. Here we tested the hypothesis that CKD-associated protein energy wasting could result from browning activation as a direct effect of the uremic environment on adipocytes. In a murine model of CKD (5/6 nephrectomy), there was increased resting energy expenditure, expression of uncoupling protein 1 (a thermogenic protein uncoupling oxidative phosphorylation in mitochondria) and citrate synthase activity (a proxy of mitochondria) density in white adipose tissue). Mice with CKD also exhibited increased levels of atrial natriuretic peptide, a well known activator of browning. The incubation of primary adipose cells with plasma from patients receiving dialysis treatment and having signs of protein energy wasting led to an increased synthesis of uncoupling protein 1. Similarly, primary adipose cells exposed to atrial natriuretic peptide at concentrations relevant of CKD led to a significant increase of uncoupling protein 1 content. Thus, accumulation of cardiac natriuretic peptides during CKD could contribute the browning of white adipose tissue and protein energy wasting

Arterial abnormalities identified in kidneys transplanted into children during the COVID‐19 pandemic

International audienceGraft artery stenosis can have a significant short- and long-term negative impact on renal graft function. From the beginning of the COVID-19 pandemic, we noticed an unusual number of graft arterial anomalies following kidney transplant (KTx) in children. Nine children received a KTx at our center between February and July 2020, eight boys and one girl, of median age of 10 years. Seven presented Doppler features suggesting arterial stenosis, with an unusual extensive pattern. For comparison, over the previous 5-year period, persistent spectral Doppler arterial anomalies (focal anastomotic stenoses) following KTx were seen in 5% of children at our center. We retrospectively evidenced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in five of seven children with arterial stenosis. The remaining two patients had received a graft from a deceased adolescent donor with a positive serology at D0. These data led us to suspect immune postviral graft vasculitis, triggered by SARS-CoV-2. Because the diagnosis of COVID-19 is challenging in children, we recommend pretransplant monitoring of graft recipients and their parents by monthly RT-PCR and serology. We suggest balancing the risk of postviral graft vasculitis against the risk of prolonged dialysis when considering transplantation in a child during the pandemic