ABSTRACT
Background
Chronic kidney disease is an important contributor to morbidity and mortality. 3-methylhistidine (3-MH) is the by-product of actin and myosin degradation reflecting skeletal ...muscle turnover. Markedly elevated 3-MH levels have been documented in uraemic patients, but the interpretation of high 3-MH concentration in maintenance haemodialysis (MHD) patients remains unclear. Indeed, it is not known whether elevated serum 3-MH levels are a marker of excessive muscle catabolism or a better lean tissue mass. Here, we evaluated the association between serum 3-MH levels and clinical outcomes in these patients.
Methods
Serum 3-MH concentration was measured by reverse-phase liquid chromatography/tandem mass spectrometry in a cohort of MHD patients. We analysed the relationships between various clinical/laboratory indices, lean tissue mass measured by bioimpedance spectroscopy, mortality and cardiovascular (CV) events.
Results
Serum 3-MH concentration was positively correlated with serum albumin, normalized protein catabolic rate (nPCR), simplified creatinine index (SCI) and lean tissue mass. Of 291 MHD patients, during a mean follow-up of 847 days, 91 patients died and 101 patients experienced a CV event. Survival was significantly better in patients with high 3-MH concentrations (P = .002). A higher level of 3-MH was also associated with a lower CV mortality and lower incidence of CV events (P = .015 and P < .001, respectively). Low serum 3-MH levels remained significantly associated with CV events but not with mortality after adjustment for demographic, metabolic and CV risk factors.
Conclusion
Elevated serum 3-MH concentration appears to be a marker of better lean tissue mass and nutritional status. Low serum 3-MH is a robust and independent predictor of CV events in the MHD population.
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.
In recent decades, the allocation policies of many countries have moved from center‐based to patient‐based approaches. The new French kidney allocation system (KAS) of donations after brain death for ...adult recipients, implemented in 2015, was principally designed to introduce a unified allocation score (UAS) to be applied locally for one kidney and nationally for the other and to replace regional borders by a new geographical model. The new KAS balances dialysis duration and waiting time to compensate for listing delays and provides more effective longevity matching between donors and recipients with better HLA and age matching. We report these changes, with their rationale and main results. Results show improved HLA matching for young recipients and more rapid access to transplant for older recipients. Young recipients also had better access to transplantation. Transplant access decreased for recipients aged 60–69 and required tuning of KAS parameters. In conclusion, our results strongly indicate that national or adequately broad geographic allocation areas, combined with multiplicative interactions between allocation criteria, permit multivariate optimization of organ allocation and thus improve national kidney sharing and balance HLA matching and age matching, at the price of longer cold ischemic times and more logistical constraints than with local allocation.
This study of the French Kidney Allocation Scheme strongly advocates for allocation areas of sufficient size, combined with multiplicative interactions among allocation criteria, to optimally balance competing considerations.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
End stage kidney disease increase the risk of COVID-19 related death but how the kidney replacement strategy should be adapted during the pandemic is unknown. Chronic hemodialysis makes social ...distancing difficult to achieve. Alternatively, kidney transplantation could increase the severity of COVID-19 due to therapeutic immunosuppression and contribute to saturation of intensive care units. For these reasons, kidney transplantation was suspended in France during the first epidemic wave. Here, we retrospectively evaluated this strategy by comparing the overall and COVID-19 related mortality in kidney transplant recipients and candidates over the last three years. Cross-interrogation of two national registries for the period 1 March and 1 June 2020, identified 275 deaths among the 42812 kidney transplant recipients and 144 deaths among the 16210 candidates. This represents an excess of deaths for both populations, as compared with the same period the two previous years (mean of two previous years: 253 in recipients and 112 in candidates). This difference was integrally explained by COVID-19, which accounted for 44% (122) and 42% (60) of the deaths in recipients and candidates, respectively. Taking into account the size of the two populations and the geographical heterogeneity of virus circulation, we found that the excess of risk of death due to COVID-19 was similar for recipients and candidates in high viral risk area but four-fold higher for candidates in the low viral risk area. Thus, in case of a second epidemic wave, kidney transplantation should be suspended in high viral risk areas but maintained outside those areas, both to reduce the excess of deaths of candidates and avoid wasting precious resources.
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Chronic kidney disease is an important contributor to morbidity and mortality. 3-methylhistidine (3-MH) is the by-product of actin and myosin degradation reflecting skeletal muscle turnover. Markedly ...elevated 3-MH levels have already been documented in uremic patients, but the interpretation of high 3-MH concentration in maintenance hemodialysis (MHD) patients remains unclear. Indeed, it is not known whether elevated serum 3-MH levels is a marker of excessive muscle catabolism or a better lean tissue mass. Here, we evaluated the association between serum-3-MH levels and clinical outcomes in these patients.
Serum 3-MH concentration was measured by reverse-phase liquid chromatography/tandem mass spectrometry in a cohort of MHD patients. We analyzed the relationships between various clinical/laboratory indices, lean tissue mass measured by bioimpedance spectroscopy, mortality and cardiovascular (CV) events.
Serum 3-MH concentration was positively correlated with serum albumin, normalized protein catabolic rate (nPCR), simplified creatinine index (SCI) and lean tissue mass. Out of 291 MHD patients, during a mean follow-up of 847 days, 91 patients died and 101 patients experienced a CV event. Survival was significantly better in patients with high 3-MH concentrations (p = 0.002). Higher level of 3-MH was also associated with a lower CV mortality and lower incidence of CV events (p = 0.015 and p < 0.001, respectively). Low serum 3-MH levels remained significantly associated with CV events but not with mortality after adjustment for demographic, metabolic and CV risk factors.
Elevated serum 3-MH concentration appears to be a marker of better lean tissue mass and nutritional status. Low serum 3-MH is a robust and independent predictor of CV events in the MHD population.
Abstract
BACKGROUND AND AIMS
Graft artery stenosis can have a significant short- and long-term negative impact on kidney graft function. We previously reported an unusual number of graft-arterial ...anomalies following kidney transplantation (KTx) in children during the first coronavirus disease (COVID-19) pandemic wave (Berteloot et al.) 1. We report herein the 1-year follow-up of these patients.
METHOD
In this retrospective study, we included all children who received a KTx at our centre from February to July 2020. We compared their outcome to that of paediatric recipients who were transplanted at our centre from 2015 to 2019 and presented an allograft vascular complication (‘Historic’ group) by querying our local data warehouse.
RESULTS
Among the 9 children who received a KTx at our centre between February and July 2020 8 boys, median age 10 years (3–17), 8 presented Doppler features suggesting arterial stenosis, with an unusual extensive pattern (Figure 1) after a median delay of 13 days (8–113). For comparison, persistent spectral Doppler arterial anomalies were observed in only 5% of children following KTx at our centre over the previous 5-year period and were all focal anastomotic stenoses. In addition, five children had lymphoceles, which required surgical management as compared to only one patient in the 5 previous years (1%). We retrospectively diagnosed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-20 infection in 6/8 children with arterial stenosis on serologies performed at D0, including one boy with a history of positive real time reverse transcription-polymerase chain reaction (RT-PCR) 120 days before KTx. None of the patients had reported any symptom suggestive of COVID-19. The remaining two patients had received a graft from an asymptomatic deceased adolescent donor with a positive serology at D0. These data led us to suspect immune post-viral graft vasculitis, triggered by SARS-CoV-2.
At 1-year post-transplantation, the outcome was favourable in the 8 isolated KTx recipients. A total of 4/8 children had normal blood pressure and 4 had controlled high blood pressure on mono or bi-therapy. Doppler anomalies had resolved in 5/8 and persisted in 3/8 with a trend for improvement of peak systolic velocities and no severe consequences on kidney function and histology. Indeed, the median glomerular filtration rate (GFR) was 91 mL/min/1.73 m² (65–129), with unspecific and mild lesions on 4/8 protocol kidney biopsies (IFTA 1 or Cpt 1). One liver-kidney graft recipient had persistent hypertension and diffuse irregular inflammatory parietal thickening of the whole vascular graft associated with a parietal thrombus upstream of the birth of the two hepatic arteries (Figure 2); treated with anti-aggregation and prednisone 10 mg/d.
CONCLUSION
Our case series suggests a risk of post-viral kidney graft vasculitis in children with recent SARS-CoV-2 infection in the recipient or donor. Pre-transplant vaccination against COVID-19 is mandatory in children > 5 years and their kidney donor candidates at our centre. We also strongly recommend vaccination of all people aged > 5 years in the household.
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.
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.
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.
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.
Protein 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 mitochondrial 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 to the browning of white adipose tissue and protein energy wasting.
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Graft 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.
Among children undergoing kidney transplantation during the COVID‐19 pandemic, the authors find a high incidence of arterial abnormalities attributed to SARS‐CoV‐2–triggered immune vasculitis that leads to recommendation for pretransplant virological and serological monitoring and posttransplant Doppler follow‐up.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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