Background
Little is known about antineutrophil cytoplasmic antibodies (ANCA)‐associated vasculitis (AAV) in older patients. We aim to study relapse risk of granulomatosis with polyangiitis (GPA) or ...microscopic polyangiitis (MPA) in patients diagnosed after 75 years and compare it with those of patients aged 65–75 years.
Methods
Data from AAV patients aged ≥65 years were extracted from the French Vasculitis Study Group (FVSG) database and from a call for observation to FVSG members. Cox and Fine–Gray models were used to assess relapse risk, taking death into account either as a censoring or a competing event, respectively.
Results
The analysis included 219 patients aged ≥75 years (median 79) and 80 patients aged 65–75 years (median 70), of those 155 had GPA (52%), 136 MPA (45%), with 95 (32%) anti‐proteinase 3 positivity and 179 (61%) anti‐myeloperoxidase. Patients aged ≥75 years had a lower relapse risk in multivariate analysis (cause‐specific hazards ratio CSHR 0.54, 95% CI 0.33–0.89, p = 0.016, Cox model; subdistribution hazard ratio SHR 0.46, 95% CI 0.29–0.74, p = 0.001, Fine–Gray model) after taking into account vasculitis type. Patients aged ≥75 years had a lower probability of being treated for remission maintenance with a combination of glucocorticoids and immunosuppressants (vs. glucocorticoids alone, HR 0.28, 95% CI 0.11–0.68, p = 0.005) after adjusting to Five Factor Score, although relapse‐free survival was significantly longer when receiving such combination (CSHR 0.40, 95% CI 0.24–0.67, p < 0.001).
Conclusions
AAV patients ≥75 years have a lower relapse risk than patients aged 65–75 years despite a lower probability of having received maintenance therapy with a combination of glucocorticoids and immunosuppressants, but they still benefit from such treatment regimen.
Uremic toxins have emerged as potential mediators of morbidity and mortality in patients with chronic kidney disease (CKD). Indole-3-acetic acid (IAA, a tryptophan-derived uremic toxin) might be a ...useful biomarker in patients with CKD. The objectives of the present study were to (i) describe IAA concentrations in a cohort of non-transplanted patients with CKD and a cohort of transplanted patients with CKD, and (ii) investigate the possible relationship between IAA levels and adverse outcomes in the two cohorts.
Levels of free and total IAA were assayed in the two prospective CKD cohorts (140 non-transplanted patients and 311 transplanted patients). Cox multivariate analyses were used to evaluate the association between IAA levels and outcomes (mortality, cardiovascular events, and graft loss).
In the non-transplanted CKD cohort, free and total IAA increased progressively with the CKD stage. In the transplanted CKD cohort, free and total IAA levels were elevated at the time of transplantation but had fallen substantially at one-month post-transplantation. Indole acetic acid concentrations were lower in transplanted patients than non-dialysis non-transplanted patients matched for estimated glomerular filtration rate (eGFR), age, and sex. After adjustment for multiple confounders, the free IAA level predicted overall mortality and cardiovascular events in the non-transplanted CKD cohort (hazard ratio 95% confidence interval: 2.5 1.2-5.1 and 2.5 1.3-4.8, respectively). In the transplanted CKD cohort, however, no associations were found between free or total IAA on one hand, and mortality, CV event, or graft survival on the other.
We demonstrated that levels of IAA increase with the CKD stage, and fall substantially, even normalizing, after kidney transplantation. Free IAA appears to be a valuable outcome-associated biomarker in non-transplanted patients, but-at least in our study setting-not in transplanted patients.
Cardiac output (CO) monitoring is a valuable tool for the diagnosis and management of critically ill patients. In the critical care setting, few studies have evaluated the level of agreement between ...CO estimated by transthoracic echocardiography (CO-TTE) and that measured by the reference method, pulmonary artery catheter (CO-PAC). The objective of the present study was to evaluate the precision and accuracy of CO-TTE relative to CO-PAC and the ability of transthoracic echocardiography to track variations in CO, in critically ill mechanically ventilated patients.
Thirty-eight mechanically ventilated patients fitted with a PAC were included in a prospective observational study performed in a 16-bed university hospital ICU. CO-PAC was measured via intermittent thermodilution. Simultaneously, a second investigator used standard-view TTE to estimate CO-TTE as the product of stroke volume and the heart rate obtained during the measurement of the subaortic velocity time integral.
Sixty-four pairs of CO-PAC and CO-TTE measurements were compared. The two measurements were significantly correlated (r = 0.95; p < 0.0001). The median bias was 0.2 L/min, the limits of agreement (LOAs) were -1.3 and 1.8 L/min, and the percentage error was 25%. The precision was 8% for CO-PAC and 9% for CO-TTE. Twenty-six pairs of ΔCO measurements were compared. There was a significant correlation between ΔCO-PAC and ΔCO-TTE (r = 0.92; p < 0.0001). The median bias was -0.1 L/min and the LOAs were -1.3 and +1.2 L/min. With a 15% exclusion zone, the four-quadrant plot had a concordance rate of 94%. With a 0.5 L/min exclusion zone, the polar plot had a mean polar angle of 1.0° and a percentage error LOAs of -26.8 to 28.8°. The concordance rate was 100% between 30 and -30°. When using CO-TTE to detect an increase in ΔCO-PAC of more than 10%, the area under the receiving operating characteristic curve (95% CI) was 0.82 (0.62-0.94) (p < 0.001). A ΔCO-TTE of more than 8% yielded a sensitivity of 88% and specificity of 66% for detecting a ΔCO-PAC of more than 10%.
In critically ill mechanically ventilated patients, CO-TTE is an accurate and precise method for estimating CO. Furthermore, CO-TTE can accurately track variations in CO.
Although kidney transplantation carries a survival benefit compared with dialysis, mortality, especially the first year after transplantation, is high in recipients older than 70. The aim of this ...study was to evaluate early death and graft failure, and to determine the risk factors associated with these events in this specific population.
All patients older than 70 years who received a kidney transplant between January 2000 and December 2014 in the North-West of France were included (
= 171). Baseline characteristics and outcomes after transplantation were studied. Kaplan-Meier analysis was performed to assess patient and graft survival, and Cox regression analysis to evaluate risk factors for graft failure and patient death.
The mean recipient age was 73.3 ± 2.5 years. Death-censored graft survival at 1, 3, and 5 years were 82.6%, 78.7%, and 75.4%, respectively. Patient survival at 1, 3, and 5 years was 90.1%, 82.5%, and 68.1%, respectively. One year after transplantation, 17 patients (9.9%) were dead, mainly from infectious (58.5%) or cardiovascular disease (29.4%). According to the Cox multivariate analysis, the independent risk factors for death or graft failure during the first year were arrhythmia (odds ratio OR 2.26; 95% confidence interval CI 1.08-4.8), left-ventricular ejection fraction (LVEF) under 56% (OR 2.38; 95% CI 1.18-4.83), human leucocyte antigen (HLA) antibodies (OR 2.1; 95% CI 1.04-4.2), deceased donor from cardiovascular cause (OR 5.18; 95% CI 1.22-6.3), and acute rejection (OR 2.77; 95% CI 1.2-6.3).
In kidney transplant recipients older than 70 years, cardiac evaluation and immunosuppression optimization seem to be crucial to improve short-term patient and graft survival.
Immunoreceptors can transduce either inhibitory or activatory signals depending on ligand avidity and phosphorylation status, which is modulated by the protein kinases Lyn and Fyn. Here we show that ...Lyn and Fyn control immune receptor signaling status. SHP-1 tyrosine 536 phosphorylation by Lyn activates the phosphatase promoting inhibitory signaling through the immunoreceptor. By contrast, Fyn-dependent phosphorylation of SHP-1 serine 591 inactivates the phosphatase, enabling activatory immunoreceptor signaling. These SHP-1 signatures are relevant in vivo, as Lyn deficiency exacerbates nephritis and arthritis in mice, whereas Fyn deficiency is protective. Similarly, Fyn-activating signature is detected in patients with lupus nephritis, underlining the importance of this Lyn-Fyn balance. These data show how receptors discriminate negative from positive signals that respectively result in homeostatic or inflammatory conditions.Src-family kinases Fyn and Lyn are signaling components downstream of ITAM-bearing antigen receptors. Here the authors show that by phosphorylating SHP-1 at different residues, Lyn and Fyn can have opposing regulatory effects on ITAM receptors.
Background:Indoxyl sulfate (IS) is a protein-bound uremic toxin that is known to be associated with the risk of cardiovascular (CV) disease and death in both predialysis and dialysis patients. Data ...on levels of protein-bound uremic toxins in kidney transplant patients are scarce. The study’s objective was to evaluate the levels of IS in kidney transplant patients and the relationship with hard outcomes.Methods and Results:In 311 kidney transplant patients, IS levels were measured immediately before transplantation (T0), and 1 month (M1) and 12 months (M12) afterwards. Over a mean±standard deviation follow-up period of 113±29 months, a total of 55 deaths, 70 CV events and 71 graft losses were recorded. We observed a rapid significant decrease (below or near the normal value) in IS levels after kidney transplantation. Total and free IS levels at M12 were significantly higher in non-transplant patients than in transplant patients (P=0.003 and <0.0001 respectively), despite having similar estimated glomerular filtration rates. Lastly, IS levels were not associated with overall mortality, CV events or graft loss at T0, M1 or M12.Conclusions:IS levels were significantly lower in kidney transplant receipts than in non-recipients suggesting that kidney transplantation protects against an increase in IS levels. IS levels were not associated with hard outcomes in kidney transplant patients. (Circ J 2016; 80: 722–730)
High serum levels of gut-derived uremic toxins, especially p-cresyl sulfate (pCS), indoxyl sulfate (IS) and indole acetic acid (IAA), have been linked to adverse outcomes in patients with chronic ...kidney disease (CKD). Sevelamer carbonate could represent an interesting option to limit the elevation of gut-derived uremic toxins. The aim of the present study was to evaluate the adsorptive effect of sevelamer carbonate on different gut-derived protein-bound uremic toxins or their precursors in vitro, and its impact on the serum levels of pCS, IS and IAA in patients with CKD stage 3b/4. For the in vitro experiments, IAA, p-cresol (precursor of pCS) and indole (precursor of IS), each at a final concentration of 1 or 10 µg/mL, were incubated in centrifugal 30 kDa filter devices with 3 or 15 mg/mL sevelamer carbonate in phosphate-buffered saline at a pH adjusted to 6 or 8. Then, samples were centrifuged and free uremic toxins in the filtrates were analyzed. As a control experiment, the adsorption of phosphate was also evaluated. Additionally, patients with stage 3b/4 CKD (defined as an eGFR between 15 and 45 mL/min per 1.73 m
) were included in a multicenter, double-blind, placebo-controlled, randomized clinical trial. The participants received either placebo or sevelamer carbonate (4.8 g) three times a day for 12 weeks. The concentrations of the toxins and their precursors were measured using a validated high-performance liquid chromatography method with a diode array detector. In vitro, regardless of the pH and concentration tested, sevelamer carbonate did not show adsorption of indole and p-cresol. Conversely, with 10 µg/mL IAA, use of a high concentration of sevelamer carbonate (15 mg/mL) resulted in a significant toxin adsorption both at pH 8 (mean reduction: 26.3 ± 3.4%) and pH 6 (mean reduction: 38.7 ± 1.7%). In patients with CKD stage 3b/4, a 12-week course of treatment with sevelamer carbonate was not associated with significant decreases in serum pCS, IS and IAA levels (median difference to baseline levels: -0.12, 0.26 and -0.06 µg/mL in the sevelamer group vs. 1.97, 0.38 and 0.05 µg/mL in the placebo group, respectively). Finally, in vitro, sevelamer carbonate was capable of chelating a gut-derived uremic toxin IAA but not p-cresol and indole, the precursors of pCS and IS in the gut. In a well-designed clinical study of patients with stage 3b/4 CKD, a 12-week course of treatment with sevelamer carbonate was not associated with significant changes in the serum concentrations of pCS, IS and IAA.
Summary
Multiple days assessments are frequent for the evaluation of candidates to living kidney donation, combined with an early GFR estimation (eGFR). Living kidney donation is questionable when ...eGFR is <90 ml/min/1.73 m2 (KDIGO guidelines) or 80 ml/min/1.73 m2 (most US centres). However, age‐related GFR decline results in a lower eGFR for older candidates. That may limit the number of older kidney donors. Yet, continuing the screening with a GFR measure increases the number of eligible donors. We hypothesized that in‐depth screening should be proposed to all candidates with a normal eGFR for age. We compared the evolution of eGFR after donation between three groups of predonation eGFR: normal for age (Sage) higher than 90 or 80 ml/min/1.73 m2 (S90 and S80, respectively); across three age groups (<45, 45–55, >55 years) in a population of 1825 French living kidney donors with a median follow‐up of 5.9 years. In donors younger than 45, postdonation eGFR, absolute‐ and relative‐eGFR variation were not different between the three groups. For older donors, postdonation eGFR was higher in S90 than in S80 or Sage but other comparators were identical. Postdonation eGFR slope was comparable between all groups. Our results are in favour of in‐depth screening for all candidates to donation with a normal eGFR for age.
The severity and course of sepsis-associated acute kidney injury (SA-AKI) are correlated with the mortality rate. Early detection of SA-AKI subphenotypes might facilitate the rapid provision of ...individualized care.
In this
analysis of a multicenter prospective study, we combined conventional kidney function variables with serial measurements of urine (tissue inhibitor of metalloproteinase-2 TIMP-2)* (insulin-like growth factor-binding protein IGFBP7) at 0, 6, 12, and 24 h) and then using an unsupervised hierarchical clustering of principal components (HCPC) approach to identify different phenotypes of SA-AKI. We then compared the subphenotypes with regard to a composite outcome of in-hospital death or the initiation of renal replacement therapy (RRT).
We included 184 patients presenting SA-AKI within 6 h of the initiation of catecholamines. Three distinct subphenotypes were identified: subphenotype A (99 patients) was characterized by a normal urine output (UO), a low SCr and a low TIMP-2*IGFBP7 level; subphenotype B (74 patients) was characterized by existing chronic kidney disease (CKD), a higher SCr, a low UO, and an intermediate TIMP-2*IGFBP7 level; and subphenotype C was characterized by very low UO, a very high TIMP-2*IGFBP7 level, and an intermediate SCr level. With subphenotype A as the reference, the adjusted hazard ratio (aHR) 95%CI for the composite outcome was 3.77 1.92-7.42 (
< 0.001) for subphenotype B and 4.80 1.67-13.82 (
= 0.004) for subphenotype C.
Combining conventional kidney function variables with urine measurements of TIMP-2*IGFBP7 might help to identify distinct SA-AKI subphenotypes with different short-term courses and survival rates.
Purpose
Data for ANCA-associated vasculitis (AAV) patients requiring intensive care are scarce.
Methods
We included 97 consecutive patients with acute AAV manifestations (new onset or relapsing ...disease), admitted to 18 intensive care units (ICUs) over a 10-year period (2002–2012). A group of 95 consecutive AAV patients with new onset or relapsing disease, admitted to two nephrology departments with acute vasculitis manifestations, constituted the control group.
Results
In the ICU group, patients predominantly showed granulomatosis with polyangiitis and proteinase-3 ANCAs. Compared with the non-ICU group, the ICU group showed comparable Birmingham vasculitis activity score and a higher frequency of heart, central nervous system and lungs involvements. Respiratory assistance, renal replacement therapy and vasopressors were required in 68.0, 56.7 and 26.8% of ICU patients, respectively. All but one patient (99%) received glucocorticoids, 85.6% received cyclophosphamide, and 49.5% had plasma exchanges as remission induction regimens. Fifteen (15.5%) patients died during the ICU stay. The following were significantly associated with ICU mortality in the univariate analysis: the need for respiratory assistance, the use of vasopressors, the occurrence of at least one infection event in ICU, cyclophosphamide treatment, sequential organ failure assessment at admission and simplified acute physiology score II. After adjustment on sequential organ failure assessment or infection, cyclophosphamide was no longer a risk factor for mortality. Despite a higher initial mortality rate of ICU patients within the first hospital stay (
p
< 0.0001), the long-term mortality of hospital survivors did not differ between ICU and non-ICU groups (18.6 and 20.4%, respectively,
p
= 0.36). Moreover, we observed no renal survival difference between groups after a 1-year follow-up (82.1 and 80.5%,
p
= 0.94).
Conclusion
This study supports the idea that experiencing an ICU challenge does not impact the long-term prognosis of AAV patients.
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