Pathologic thrombosis is a major cause of mortality. Hemolytic-uremic syndrome (HUS) features episodes of small-vessel thrombosis resulting in microangiopathic hemolytic anemia, thrombocytopenia and ...renal failure. Atypical HUS (aHUS) can result from genetic or autoimmune factors that lead to pathologic complement cascade activation. Using exome sequencing, we identified recessive mutations in DGKE (encoding diacylglycerol kinase ɛ) that co-segregated with aHUS in nine unrelated kindreds, defining a distinctive Mendelian disease. Affected individuals present with aHUS before age 1 year, have persistent hypertension, hematuria and proteinuria (sometimes in the nephrotic range), and develop chronic kidney disease with age. DGKE is found in endothelium, platelets and podocytes. Arachidonic acid-containing diacylglycerols (DAG) activate protein kinase C (PKC), which promotes thrombosis, and DGKE normally inactivates DAG signaling. We infer that loss of DGKE function results in a prothrombotic state. These findings identify a new mechanism of pathologic thrombosis and kidney failure and have immediate implications for treating individuals with aHUS.
Abstract
Background
Sarcopaenia, defined as a decline in both muscle mass and function, has been recognized as a major determinant of poor outcome in haemodialysis (HD) patients. It is generally ...assumed that sarcopaenia is driven by muscle atrophy related to protein-energy wasting. However, dynapaenia, defined as weakness without atrophy, has been characterized by a different disease phenotype from sarcopaenia. The aim of this study was to compare the characteristics and prognosis of sarcopaenic and dynapaenic patients among a prospective cohort of chronic HD (CHD) patients.
Methods
Two hundred and thirty-two CHD patients were enrolled from January to July 2016 and then followed prospectively until December 2018. At inclusion, weakness and atrophy were, respectively, evaluated by maximal voluntary force (MVF) and creatinine index (CI). Sarcopaenia was defined as the association of weakness and atrophy (MVF and CI below the median) while dynapaenia was defined as weakness not related to atrophy (MVF below the median, and CI above the median).
Results
From a total of 187 prevalent CHD patients 65% of men, age 65.3 (49.7–82.0) years, 44 died during the follow-up period of 23.7 (12.4–34.9) months. Sarcopaenia and dynapaenia were observed in 33.7 and 16% of the patients, respectively. Compared with patients with sarcopaenia, patients with dynapaenia were younger and with a lower Charlson score. In contrast, mortality rate was similar in both groups (38 and 27%, respectively). After adjustment for age, sex, lean tissue index, serum albumin, high-sensitivity C-reactive protein (hs-CRP), haemoglobin (Hb), normalized protein catabolic rate (nPCR), dialysis vintage and Charlson score, only patients with dynapaenia were at increased risk of death hazard ratio (HR) = 2.99, confidence interval 1.18–7.61; P = 0.02.
Conclusions
Screening for muscle functionality is highly warranted to identify patients with muscle functional impairment without muscle atrophy. In contrast to sarcopaenia, dynapaenia should appear as a phenotype induced by uraemic milieu, characterized by young patients with low Charlson score and poor prognosis outcome independently of serum albumin, hs-CRP, Hb, nPCR and dialysis vintage.
Graphical Abstract
In recent years, a substantial body of experimental and clinical work has been devoted to C3 glomerulopathy and Ig-mediated membranoproliferative glomerulonephritis. Despite the rapid accumulation of ...data, several uncertainties about these 2 rare forms of nephropathies persist. They concern their pathophysiology, classification, clinical course, relevance of biomarkers and of pathology findings, and assessment of the efficacy of the available therapies. The present review discusses the impact of these uncertainties on the clinical management of patients.
•Complement activation on endothelial cells generates complement fragments.•Complement activation on endothelial cells generates microvesicles.•Complement fragments are increased in antibody-mediated ...rejection.•Plasma endothelial microparticles decreased in antibody-mediated rejection.
Antibody-mediated rejection (AbMR) adversely affects long-term graft survival in kidney transplantation. Currently, the diagnosis of AbMR requires a kidney biopsy, and detection of complement C4d deposition in the allograft is one of the diagnostic criteria. Complement activation also generates several soluble fragments which could potentially provide non-invasive biomarkers of the process. Furthermore, microvesicles released into the plasma from injured cells can serve as biomarkers of vascular injury. To explore whether soluble complement fragments or complement fragments bound to endothelial microvesicles can be used to non-invasively detect AbMR, we developed an in vitro model in which human endothelial cells were exposed to anti-HLA antibodies and complement sufficient serum. We found that complement fragments C4a and sC5b-9 were increased in the supernatants of cells exposed to complement-sufficient serum compared to cells treated complement-deficient serum. Furthermore, complement activation on the cell surface was associated with the release of microvesicles bearing C4 and C3 fragments. We next measured these analytes in plasma from kidney transplant recipients with biopsy-proven acute AbMR (n = 9) and compared the results with those from transplant recipients who also had impaired allograft function but who did not have AbMR (n = 30). Consistent with the in vitro results, complement fragments C4a and Ba were increased in plasma from patients with AbMR compared to control subjects (P < 0.001 and P < 0.01, respectively). Endothelial microvesicle counts were not increased in patients with AbMR, however, and the number of microvesicles with C4 and C3 bound to the surface was actually lower compared to control subjects (both P < 0.05). Our results suggest that plasma complement activation fragments may be useful as non-invasive biomarkers of antibody-mediated complement activation within the allograft. Complement-opsonized endothelial microvesicles are decreased in patients with AbMR, possibly due to enhanced clearance of microvesicles opsonized with C3 and C4 fragments.
Abstract
Objectives
This study aimed to estimate the prevalence of ANCA-associated vasculitis (AAV). That is, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic ...granulomatosis with polyangiitis (EGPA), in Southern France in 2018, and evaluate differences among Europeans and non-Europeans.
Methods
This population-based, cross-sectional study used four sources (hospitals, community-based physicians, laboratories, National Health Insurance) to identify adults ≥15 years diagnosed with GPA, MPA or EGPA, living in Hérault and Gard in 2018. Cases were defined using the ACR/EULAR classification criteria, and if necessary, the European Medicines Agency algorithm. Prevalence estimates were standardised to the world population and capture-recapture analysis was used to assess the comprehensiveness of the estimation. The influence of geographical origin was evaluated.
Results
A total of 202 patients were selected, with 86 cases of GPA (42.6%), 85 cases of MPA (42.1%) and 31 cases of EGPA (15.3%). The standardised prevalence estimates per million inhabitants for 2018 were: 103 (95%CI 84–125) for AAV, 48 (95%CI 35–64) for GPA, 39 (95%CI 28–53) for MPA and 16 (95%CI 9–26) for EGPA, 36 (95%CI 25–50) for anti-PR3 positive AAV, 46 (95%CI 34–61) for anti-MPO positive AAV, and 16 (95%CI 9–26) for ANCA-negative AAV. The global estimation of comprehensiveness by capture-recapture analysis was 80.5%. The number of AAV cases was higher for non-European residents (P = 0.001), particularly for MPA (P < 0.0001).
Conclusion
We provide a new estimate of AAV prevalence in France and show a higher prevalence of MPA in non-European patients.
After renal transplantation, hemolytic uremic syndrome (HUS) may occur either as a recurrent or de novo form. Over the past decade, much effort has been devoted to elucidating the pathogenesis of ...atypical HUS (aHUS). Approximately 60-70% patients with aHUS have mutations in regulatory factors of the complement system or antibodies against complement factor H. The risk of post-transplant recurrence of aHUS depends on the genetic abnormality involved, and ranges from 15% to 20% in patients with mutations in the gene that encodes membrane cofactor protein and from 50% to 100% in patients with mutations in the genes that encode circulating regulators of complement. Given the poor outcomes associated with recurrence, isolated renal transplantation had been contraindicated in patients at high risk of aHUS recurrence. However, emerging therapies, including pre-emptive plasma therapy and anti-C5 component monoclonal antibody (eculizumab) treatment have provided promising results and should further limit indications for the risky procedure of combined liver-kidney transplantation. Studies from the past 2 years have demonstrated genetic abnormalities in complement regulators in 30% of renal transplant recipients who experienced de novo HUS after renal transplantation. This finding suggests that the burden of endothelial injury in a post-transplantation setting may trigger de novo HUS in the presence of mild genetic susceptibility to HUS.
Age and comorbidity-related sarcopenia represent a main cause of muscle dysfunction in patients on long-term hemodialysis. However, recent findings suggest muscle abnormalities that are not ...associated with sarcopenia. The aim of this study was to isolate functional and cellular muscle abnormalities independently of other major confounding factors, including malnutrition, age, comorbidity, or sedentary lifestyle, which are common in patients on maintenance hemodialysis. To overcome these confounding factors, alterations in skeletal muscle were analyzed in highly selected patients on long-term hemodialysis undergoing kidney transplantation.
In total, 22 patients on long-term hemodialysis scheduled for kidney transplantation with few comorbidities, but with a long-term uremic milieu exposure, and 22 age, sex, and physical activity level frequency-matched control participants were recruited. We compared biochemical, functional, and molecular characteristics of the skeletal muscle using maximal voluntary force and endurance of the quadriceps, 6-minute walking test, and muscle biopsy of
. For statistical analysis, mean comparison and multiple regression tests were used.
In patients on long-term hemodialysis, muscle endurance was lower, whereas maximal voluntary force was not significantly different. We observed a transition from type I (oxidative) to type II (glycolytic) muscle fibers, and an alteration of mitochondrial structure (swelling) without changes in DNA content, genome replication (peroxisome proliferator activator receptor
coactivator-1
and mitochondrial transcription factor A), regulation of fusion (mitofusin and optic atrophy 1), or fission (dynamin-related protein 1). Notably, there were autophagosome structures containing glycogen along with mitochondrial debris, with a higher expression of light chain 3 (LC3) protein, indicating phagophore formation. This was associated with a greater conversion of LC3-I to LC3-II and the expression of
and
genes involved in mitophagy.
In this highly selected long-term hemodialysis population, a low oxidative phenotype could be defined by a poor endurance, a fiber-type switch, and an alteration of mitochondria structure, without evidence of sarcopenia. This phenotype could be related to uremia through the activation of autophagy/mitophagy.
NCT02794142 and NCT02040363.
C3 glomerulopathy (C3G) is a prototypic complement-mediated kidney disease. Rapidly progressive forms of C3G usually respond poorly to conventional treatments. We report on the efficacy of the ...terminal complement inhibitor eculizumab in 3 adult patients with rapidly progressive C3G. In all 3 patients, serum creatinine levels had increased by >50% in the 2 months preceding initiation of eculizumab treatment despite the use of conventional immunosuppressive drugs and/or plasma exchanges in 2 of these individuals. Of note, 2 patients had long-standing nephrotic syndrome. Kidney biopsy performed prior to eculizumab treatment disclosed marked glomerular inflammatory changes and increased C5b-9 deposition in all patients. Eculizumab use was associated with significant improvement in kidney function, with estimated glomerular filtration rates of patients increasing 22 to 38 mL/min/1.73 m2 . Eculizumab use also was associated with remission of nephrotic syndrome in the 2 affected patients, an effect observed as early as one week after treatment initiation. Repeat kidney biopsy disclosed regression of glomerular inflammatory changes and decreases in glomerular staining for C5b-9 in all patients. These results warrant further assessment of eculizumab for treatment of rapidly progressive forms of C3G with markedly increased glomerular C5b-9 deposits.
Background and aim
Incisional hernia (IH) after Kidney Transplantation (KT) is a challenging complication due to both technical reasons and patients’ complexity. Data regarding outcomes of hernia ...repair in KT recipients are uncertain, since the biggest part of previous papers focused on risk factors for incisional hernia occurrence and not on its outcomes. Aim of the study was to focus on risk factors for incisional hernia recurrence after surgical repair in KT recipients.
Methods
Data regarding all consecutive patients undergoing kidney transplantations from January 2011 until September 2020 in Montpellier University Hospital were retrospectively collected from a single institutional database.
Results
After a median follow-up of 48 months (IQR
25-75
31–59), data from 1546 consecutive KT were collected. 83 patients underwent 99 incisional hernia surgeries after KT, with 14 patients that had one recurrence (14.4%) and 2 patients that experienced two recurrences (2.4%). Total recurrence rate was 16.8%. At univariate analysis, the only factor associated with an incisional hernia recurrence was having undergone to at least one previous abdominal surgery other than KT (
p
value 0.002). Overall morbidity was 15% (
n
= 15), with most of complications classified as mild (59%). No mortality related to incisional hernia repair occurred.
Conclusion
IHs after KT represent an important condition. Its surgical management is challenging due to its anatomical complexity and patient’s status. This is the largest sample size in the literature of patients treated for IH after KT and it shows that a previous surgery other than the KT is a risk factor for hernia recurrence after surgical repair, without regarding surgical technique or other comorbidity and therapeutical factors.
Complement activation is an important cause of tissue injury in patients with Ab-mediated rejection (AMR) of transplanted organs. Complement activation triggers a strong inflammatory response, and it ...also generates tissue-bound and soluble fragments that are clinically useful markers of inflammation. The detection of complement proteins deposited within transplanted tissues has become an indispensible biomarker of AMR, and several assays have recently been developed to measure complement activation by Abs reactive to specific donor HLA expressed within the transplant. Complement inhibitors have entered clinical use and have shown efficacy for the treatment of AMR. New methods of detecting complement activation within transplanted organs will improve our ability to diagnose and monitor AMR, and they will also help guide the use of complement inhibitory drugs.
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