Publications by authors named "Moglie Le Quintrec"

53 Publications

Dynapenia and sarcopenia in chronic haemodialysis patients: do muscle weakness and atrophy similarly influence poor outcome?

Nephrol Dial Transplant 2020 Dec 11. Epub 2020 Dec 11.

Department of Biochemistry, University Hospital of Montpellier, University of Montpellier, Montpellier, France.

Background And Aims: Sarcopenia, defined as a decline in both muscle mass and function, has been recognized as a major determinant of poor outcome in hemodialysis patients. It is generally assumed that sarcopenia is driven by muscle atrophy related to protein energy wasting. However, dynapenia, defined as weakness without atrophy, has been characterized by a different disease phenotype from sarcopenia. The aim of this study was to compare the characteristics and prognosis of sarcopenic and dynapenic patients among a prospective cohort of chronic haemodialysis (CHD) patients.

Methods: Two hundred and thirty two chronic haemodialysis 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). Sarcopenia was defined as the association of weakness and atrophy (MVF and CI below the median) while dynapenia 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. Sarcopenia and dynapenia were observed in 33.7% and 16% of patients respectively. Compared to patients with sarcopenia, patients with dynapenia were younger and with a lower Charlson score. By contrast, mortality rate was similar in both groups (38 and 27% respectively). After adjustment for age, sex, LTI, serum albumin, hs-CRP, haemoglobin, nPCR, dialysis vintage and Charlson score, only patients with dynapenia were at increased risk of death (HR = 2.99 CI (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. By contrast to sarcopenia, dynapenia should appear as a phenotype induced by uremic milieu, characterized by young patients with low Charlson score and poor prognosis outcome independently of serum albumin, hs-CRP, haemoglobin, nPCR and dialysis vintage.
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http://dx.doi.org/10.1093/ndt/gfaa353DOI Listing
December 2020

Combined Liver-Kidney Transplantation With Preformed Anti-human Leukocyte Antigen Donor-Specific Antibodies.

Kidney Int Rep 2020 Dec 3;5(12):2202-2211. Epub 2020 Oct 3.

Department of Nephrology and Organ Transplantation, Toulouse University Hospital (Centre Hospitalier et Universitaire), Toulouse, France.

Introduction: The impact of preformed donor-specific anti-human leukocyte antigen (HLA) antibodies (pDSAs) after combined liver-kidney transplantation (CLKT) is still uncertain.

Methods: We conducted a retrospective study in 8 European high-volume transplant centers and investigated the outcome of 166 consecutive CLKTs, including 46 patients with pDSAs.

Results: Patient survival was lower in those with pDSAs (5-year patient survival rate of 63% and 78% with or without pDSA, respectively;  = 0.04). The presence of pDSAs with a mean fluorescence intensity (MFI) ≥ 5000 (hazard ratio 4.96; 95% confidence interval: 2.3-10.9;  < 0.001) and the presence of 3 or more pDSAs (hazard ratio 6.5; 95% confidence interval: 2.5-18.8;  = 0.05) were independently associated with death. The death-censored liver graft survival was similar in patients with or without pDSAs. Kidney graft survival was comparable in both groups. (The 1- and 5-year death-censored graft survival rates were 91.6% and 79.5%, respectively, in patients with pDSAs and 93% and 88%, respectively, in the donor-specific antibody [DSA]-negative group,  = not significant). Despite a higher rate of kidney graft rejection in patients with pDSAs (5-year kidney graft survival rate without rejection of 87% and 97% with or without pDSAs, respectively;  = 0.04), kidney function did not statistically differ between both groups at 5 years post-transplantation (estimated glomerular filtration rate 45 ± 17 vs. 57 ± 29 ml/min per 1.73 m, respectively, in patients with and without pDSAs). Five recipients with pDSAs (11.0%) experienced an antibody-mediated kidney rejection that led to graft loss in 1 patient.

Conclusion: Our results suggest that CLKT with pDSAs is associated with a lower patients' survival despite good recipients', liver and kidney grafts' outcome.
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http://dx.doi.org/10.1016/j.ekir.2020.09.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710847PMC
December 2020

Eculizumab discontinuation in children and adults with atypical haemolytic uremic syndrome: a prospective multicentric study.

Blood 2020 Dec 3. Epub 2020 Dec 3.

Assistance Publique - Hôpitaux de Paris, paris, France.

The optimal duration of eculizumab treatment in patients with atypical haemolytic uremic syndrome (aHUS) remains poorly defined. We conducted a prospective national multicentric open-label study in order to assess eculizumab discontinuation in children and adults with aHUS. Fifty-five patients (including 19 children) discontinued eculizumab (mean duration of treatment, 16.5 months). Twenty-eight (51%) patients had complement gene rare variants, mostly in MCP (n= 12, 22%), CFH (n= 6, 11%) and CFI (n=6, 10%) genes. At eculizumab discontinuation, 17 (30%) and 4 (7%) patients had chronic kidney disease stage 3 and 4, respectively. During follow-up, 13 (23%) patients (6 children and 7 adults) experienced aHUS relapse. In multivariable analysis, female gender and the presence of a rare complement gene variant were associated with an increased risk of aHUS relapse, whereas requirement for dialysis during previous episodes of acute aHUS was not. In addition, an increased soluble C5b-9 plasma level at eculizumab discontinuation was associated with a higher risk of aHUS relapse in all patients and in the subset of carriers of complement gene rare variants, in log rank test and in multivariable analysis. Among the 13 relapsing patients, who were all restarted on eculizumab, 11 regained their baseline renal function and two had a worsening of their pre-existing chronic kidney disease, including one patient who progressed to end-stage renal disease. A strategy of eculizumab discontinuation in aHUS patients based on complement genetics is reasonable and safe. It improves the management and quality of life of a sizeable proportion of aHUS patients while reducing the cost of treatment. Trail registration number: NCT02574403.
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http://dx.doi.org/10.1182/blood.2020009280DOI Listing
December 2020

Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis.

Kidney Int 2021 03 1;99(3):581-597. Epub 2020 Nov 1.

Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Université de Paris, Paris, France. Electronic address:

Rhabdomyolysis is a life-threatening condition caused by skeletal muscle damage with acute kidney injury being the main complication dramatically worsening the prognosis. Specific treatment for rhabdomyolysis-induced acute kidney injury is lacking and the mechanisms of the injury are unclear. To clarify this, we studied intra-kidney complement activation (C3d and C5b-9 deposits) in tubules and vessels of patients and mice with rhabdomyolysis-induced acute kidney injury. The lectin complement pathway was found to be activated in the kidney, likely via an abnormal pattern of Fut2-dependent cell fucosylation, recognized by the pattern recognition molecule collectin-11 and this proceeded in a C4-independent, bypass manner. Concomitantly, myoglobin-derived heme activated the alternative pathway. Complement deposition and acute kidney injury were attenuated by pre-treatment with the heme scavenger hemopexin. This indicates that complement was activated in a unique double-trigger mechanism, via the alternative and lectin pathways. The direct pathological role of complement was demonstrated by the preservation of kidney function in C3 knockout mice after the induction of rhabdomyolysis. The transcriptomic signature for rhabdomyolysis-induced acute kidney injury included a strong inflammatory and apoptotic component, which were C3/complement-dependent, as they were normalized in C3 knockout mice. The intra-kidney macrophage population expressed a complement-sensitive phenotype, overexpressing CD11b and C5aR1. Thus, our results demonstrate a direct pathological role of heme and complement in rhabdomyolysis-induced acute kidney injury. Hence, heme scavenging and complement inhibition represent promising therapeutic strategies.
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http://dx.doi.org/10.1016/j.kint.2020.09.033DOI Listing
March 2021

Trajectories of glomerular filtration rate and progression to end stage kidney disease after kidney transplantation.

Kidney Int 2021 01 8;99(1):186-197. Epub 2020 Aug 8.

Université de Paris, INSERM, PARCC, Paris Translational Research Centre for Organ Transplantation, Paris, France; Kidney Transplant Department, Necker Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France. Electronic address:

Although the gold standard of monitoring kidney transplant function relies on glomerular filtration rate (GFR), little is known about GFR trajectories after transplantation, their determinants, and their association with outcomes. To evaluate these parameters we examined kidney transplant recipients receiving care at 15 academic centers. Patients underwent prospective monitoring of estimated GFR (eGFR) measurements, with assessment of clinical, functional, histological and immunological parameters. Additional validation took place in seven randomized controlled trials that included a total of 14,132 patients with 403,497 eGFR measurements. After a median follow-up of 6.5 years, 1,688 patients developed end-stage kidney disease. Using unsupervised latent class mixed models, we identified eight distinct eGFR trajectories. Multinomial regression models identified seven significant determinants of eGFR trajectories including donor age, eGFR, proteinuria, and several significant histological features: graft scarring, graft interstitial inflammation and tubulitis, microcirculation inflammation, and circulating anti-HLA donor specific antibodies. The eGFR trajectories were associated with progression to end stage kidney disease. These trajectories, their determinants and respective associations with end stage kidney disease were similar across cohorts, as well as in diverse clinical scenarios, therapeutic eras and in the seven randomized control trials. Thus, our results provide the basis for a trajectory-based assessment of kidney transplant patients for risk stratification and monitoring.
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http://dx.doi.org/10.1016/j.kint.2020.07.025DOI Listing
January 2021

Distribution of Donor-Specific Antibody Subclasses Quantified by Mass Spectrometry: High IgG3 Proportion Is Associated With Antibody-Mediated Rejection Occurrence and Severity.

Front Immunol 2020 2;11:919. Epub 2020 Jun 2.

Department of Nephrology, Dialysis and Transplantation, Montpellier University Hospital, University of Montpellier, Montpellier, France.

Donor-specific antibodies (DSAs) are the main risk factor for antibody-mediated rejection (ABMR) and graft loss but could have variable pathogenicity according to their IgG subclass composition. Luminex-based test might lack sensitivity for the detection of IgG subclasses and this test does not allow quantifying the relative abundance of each IgG subclass. We investigated the precise repartition of each DSA subclass and their role in ABMR occurrence and severity, using an innovative mass spectrometry-based method. Between 2014 and 2018, we enrolled 69 patients who developed DSA ( = 29 without ABMR, and = 40 with ABMR) in two transplant centers. All IgG subclasses were detected in every samples tested: 62.7% were IgG1, 26.6% were IgG2, 6.6% were IgG3, and 4.2% were IgG4. The IgG3 proportion was significantly higher in the ABMR+ compared to the ABMR- group (8.4% vs. 5.6%, = 0.003). The proportion of IgG1, IgG2, and IgG4 of DSA was similar between the two groups. Higher IgG3 level was associated with higher C4d deposition, higher microvascular inflammation scores, and glomerular filtration rate decline >25%. IgG3 proportion was not correlated with DSA MFI. Multivariate analysis showed that proteinuria and high level of IgG3 DSA were the only two factors independently associated with ABMR. In conclusion, DSA are always composed of the four IgG subclasses, but in different proportions. High IgG3 proportion is associated with ABMR occurrence and severity and with poorer outcome, independently of DSA MFI.
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http://dx.doi.org/10.3389/fimmu.2020.00919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326073PMC
June 2020

Practical management of C3 glomerulopathy and Ig-mediated MPGN: facts and uncertainties.

Kidney Int 2020 11 3;98(5):1135-1148. Epub 2020 Jul 3.

Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d'Immunologie and Paris University, Paris, France.

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.
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http://dx.doi.org/10.1016/j.kint.2020.05.053DOI Listing
November 2020

Monitoring of patients with systemic lupus erythematosus during the COVID-19 outbreak.

Ann Rheum Dis 2020 Jun 8. Epub 2020 Jun 8.

Clinical Immunology and Osteoarticular Diseases Therapeutic Unit, CHRU Lapeyronie, Montpellier, France.

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http://dx.doi.org/10.1136/annrheumdis-2020-217919DOI Listing
June 2020

Estimation of residual renal function using beta-trace protein: Impact of dialysis procedures.

Artif Organs 2020 Jun 5;44(6):647-654. Epub 2020 Mar 5.

Département de Biochimie et Hormonologie, PhyMedExp, INSERM, CNRS, Université de Montpellier, CHU de Montpellier, Montpellier Cedex 5, France.

Beta-trace protein (BTP), a low molecular weight protein of 23-29 kDa, has been proposed as a promising biomarker to estimate residual renal function (RRF) in patients on maintenance hemodialysis (HD). Indeed, BTP is cleared by native kidney but not during conventional HD session. By contrast, the removal rate of BTP using convective processes (mainly hemodiafiltration [HDF]) and peritoneal dialysis (PD) has been little or not investigated. Therefore, an aim of this study was to evaluate the impact of dialysis procedures (high-flux HD, on-line post-dilution HDF and PD) on BTP removal in comparison with beta-2 microglobulin (B2M) and cystatin C (CYSC) removals after a single session. In addition, the ability of BTP to predict RRF in PD was assessed. This observational cross-sectional study included a total of 82 stable chronic kidney disease patients, 53 patients were on maintenance dialysis (with n = 26 in HD and n = 27 in HDF) and 29 were on PD. Serum concentrations of BTP, B2M, and CYSC were measured (a) before and after a single dialysis session in HD and HDF anuric patients to calculate reduction percentages, (b) in serum, 24-hour-dialysate and 24-hour-urine in PD patients to compute total, peritoneal, and urinary clearance. RRF was estimated using four equations developed for dialysis patients without urine collection and compared to the mean of the urea and creatinine clearances in PD. The concentrations of the three studied molecules were significantly reduced (P < .001) after dialysis session with significantly higher reduction ratio using HDF compared to HD modality (P < .001): BTP 49.3% vs 17.5%; B2M 82.3% vs 69.7%; CYSC 77.4% vs 66% in HDF and HD, respectively. In non-anuric PD patients, B2M and CYSC were partly removed by peritoneal clearance (72.3% and 57.6% for B2M and CYSC, respectively). By contrast, BTP removal by the peritoneum was negligible and a low bias for the BTP-based equation to estimate RRF (-1.4 mL/min/1.73 m ) was calculated. BTP is significantly removed by high-flux HD or HDF, thereby compromising its use to estimate RRF. By contrast, BTP appears as a promising biomarker to estimate RRF in PD patients since it is not affected by peritoneal clearance, unlike B2M and CYSC, and it is well correlated to RRF.
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http://dx.doi.org/10.1111/aor.13641DOI Listing
June 2020

Complement fragments are biomarkers of antibody-mediated endothelial injury.

Mol Immunol 2020 02 26;118:142-152. Epub 2019 Dec 26.

Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.molimm.2019.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192552PMC
February 2020

Temporal trends in living kidney donation in France between 2007 and 2017.

Nephrol Dial Transplant 2019 Nov 28. Epub 2019 Nov 28.

Nephrology and Renal Transplantation Department, Necker Hospital, Paris, France.

Background: Long-term studies have demonstrated a slight increased risk for end-stage renal disease (ESRD) for living kidney donors (LKD). In France, living kidney donation doubled within the past 10 years. We investigated the change in characteristics of LKD between 2007 and 2017 and the adequacy of follow-up.

Methods: Data were obtained from the national registry for LKD. We compared characteristics of LKD between two study periods: 2007-11 and 2012-17, and stratified donors by age and relation to recipient. We aggregated four characteristics associated with higher ESRD risk [young age, first-degree relation to recipient, obesity, low glomerular filtration rate (GFR) for age] in a single risk indicator ranging from 0 to 4.

Results: We included 3483 donors. The proportion of unrelated donors >56 years of age increased significantly. The proportion of related donors <56 years of age decreased significantly. The body mass index and proportion of obese donors did not change significantly. The proportion of donors with low estimated GFR for age decreased significantly from 5% to 2.2% (P < 0.001). The proportion of donors with adequate follow-up after donation increased from 19.6% to 42.5% (P < 0.001). No donor had a risk indicator equal to 4, and the proportion of donors with a risk indicator equal to 0 increased significantly from 19.2% to 24.9% (P < 0.001).

Conclusions: An increase in living kidney donation in France does not seem to be associated with the selection of donors at higher risk of ESRD and the proportion of donors with adequate annual follow-up significantly increased.
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http://dx.doi.org/10.1093/ndt/gfz229DOI Listing
November 2019

Use of Highly Individualized Complement Blockade Has Revolutionized Clinical Outcomes after Kidney Transplantation and Renal Epidemiology of Atypical Hemolytic Uremic Syndrome.

J Am Soc Nephrol 2019 12 1;30(12):2449-2463. Epub 2019 Oct 1.

French Study Group of Atypical Hemolytic Uremic Syndrome, France.

Background: Atypical hemolytic uremic syndrome (HUS) is associated with high recurrence rates after kidney transplant, with devastating outcomes. In late 2011, experts in France recommended the use of highly individualized complement blockade-based prophylaxis with eculizumab to prevent post-transplant atypical HUS recurrence throughout the country.

Methods: To evaluate this strategy's effect on kidney transplant prognosis, we conducted a retrospective multicenter study from a large French nationwide registry, enrolling all adult patients with atypical HUS who had undergone complement analysis and a kidney transplant since January 1, 2007. To assess how atypical HUS epidemiology in France in the eculizumab era evolved, we undertook a population-based cohort study that included all adult patients with atypical HUS (=397) between 2007 and 2016.

Results: The first study included 126 kidney transplants performed in 116 patients, 58.7% and 34.1% of which were considered to be at a high and moderate risk of atypical HUS recurrence, respectively. Eculizumab prophylaxis was used in 52 kidney transplants, including 39 at high risk of recurrence. Atypical HUS recurred after 43 (34.1%) of the transplants; in four cases, patients had received eculizumab prophylaxis and in 39 cases they did not. Use of prophylactic eculizumab was independently associated with a significantly reduced risk of recurrence and with significantly longer graft survival. In the second, population-based cohort study, the proportion of transplant recipients among patients with ESKD and atypical HUS sharply increased between 2012 and 2016, from 46.2% to 72.3%, and showed a close correlation with increasing eculizumab use among the transplant recipients.

Conclusions: Results from this observational study are consistent with benefit from eculizumab prophylaxis based on pretransplant risk stratification and support the need for a rigorous randomized trial.
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http://dx.doi.org/10.1681/ASN.2019040331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900783PMC
December 2019

The role of complement in antibody mediated transplant rejection.

Mol Immunol 2019 08 10;112:240-246. Epub 2019 Jun 10.

Department of Nephrology, Centre Hospitalier Universitaire de Montpellier, Montpellier, France.

Antibody mediated transplant rejection (AMR) is a major cause of long-term allograft failure, and currently available treatments are of limited efficacy for treating the disease. AMR is caused by donor specific antibodies (DSA) that bind to antigens within the transplanted organ. DSA usually activate the classical pathway of complement within the allograft, and complement activation is believed to be an important cause of tissue injury in AMR. Several new clinical assays may improve our ability to identify patients at risk of AMR. Complement inhibitory drugs have also been tested in selected patients and in small series. Better understanding of the role of complement activation in the pathogenesis of AMR will likely improve our ability to diagnose the disease and to develop novel treatments.
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http://dx.doi.org/10.1016/j.molimm.2019.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646053PMC
August 2019

Atypical and secondary hemolytic uremic syndromes have a distinct presentation and no common genetic risk factors.

Kidney Int 2019 06 15;95(6):1443-1452. Epub 2019 Mar 15.

Centre de Recherche en Transplantation et Immunologie, UMR 1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie, CHU Nantes, Nantes, France; Department of Nephrology and Immunology, Center Hospitalier Universitaire de Nantes, Nantes, France. Electronic address:

Secondary hemolytic uremic syndrome (HUS) is a heterogeneous group of thrombotic microangiopathies associated with various underlying conditions. Whether it belongs to the spectrum of complement-mediated HUS remains controversial. We analysed the presentation, outcome, and frequency of complement gene rare variants in a cohort of 110 patients with secondary HUS attributed to drugs (29%), autoimmune diseases (24%), infections (17%), malignancies (10%), glomerulopathies (9%), extra-renal organ transplantation (8%), and pancreatitis (3%). The frequency of complement gene rare variants was similar in patients with secondary HUS (5%) and in healthy individuals (6% and 8% in French and European controls, respectively). At diagnosis, 40% of patients required dialysis and 18% had neurological manifestations. Fifty percent of patients received plasmatherapy and 35% were treated with eculizumab. Haematological and complete renal remission was achieved in 80% and 24% of patients, respectively. Thirty-nine percent of patients progressed to chronic kidney disease (stages 3-4) and an additional 37% reached end-stage renal disease. Eleven percent of patients died, most often from complications of the underlying cause of HUS. Only one patient experienced an HUS relapse. Patients treated with eculizumab presented with more severe HUS and were more likely to require dialysis at the time of diagnosis as compared to patients not treated with eculizumab. Rates of hematological remission, chronic kidney disease (stages 3-4), and end-stage renal disease were similar in the two groups. Secondary HUS is an acute nonrelapsing form of HUS, not related to complement dysregulation. The efficacy of eculizumab in this setting is not yet established.
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http://dx.doi.org/10.1016/j.kint.2019.01.023DOI Listing
June 2019

C5b9 Deposition in Glomerular Capillaries Is Associated With Poor Kidney Allograft Survival in Antibody-Mediated Rejection.

Front Immunol 2019 8;10:235. Epub 2019 Mar 8.

University of Montpellier, Department of Nephrology, Dialysis and Transplantation, Lapeyronie Hospital, Montpellier University Hospital, Montpellier, France.

C4d deposition in peritubular capillaries (PTC) reflects complement activation in antibody-mediated rejection (ABMR) of kidney allograft. However, its association with allograft survival is controversial. We hypothesized that capillary deposition of C5b9-indicative of complement-mediated injury-is a severity marker of ABMR. This pilot study aimed to determine the frequency, location and prognostic impact of these deposits in ABMR. We retrospectively selected patients diagnosed with ABMR in two French transplantation centers from January 2005 to December 2014 and performed C4d and C5b9 staining by immunohistochemistry. Fifty-four patients were included. Median follow-up was 52.5 (34.25-73.5) months. Thirteen patients (24%) had C5b9 deposits along glomerular capillaries (GC). Among these, seven (54%) had a global and diffuse staining pattern. Twelve of the C5b9+ patients also had deposition of C4d in GC and PTC. C4d deposits along GC and PTC were not associated with death-censored allograft survival ( = 0.42 and 0.69, respectively). However, death-censored allograft survival was significantly lower in patients with global and diffuse deposition of C5b9 in GC than those with a segmental pattern or no deposition (median survival after ABMR diagnosis, 6 months, 40.5 months and 44 months, respectively; = 0.015). Double contour of glomerular basement membrane was diagnosed earlier after transplantation in C5b9+ ABMR than in C5b9- ABMR (median time after transplantation, 28 vs. 85 months; = 0.058). In conclusion, we identified a new pattern of C5b9+ ABMR, associated with early onset of glomerular basement membrane duplication and poor allograft survival. Complement inhibitors might be a therapeutic option for this subgroup of patients.
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http://dx.doi.org/10.3389/fimmu.2019.00235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6418012PMC
May 2020

Outcomes of Older Patients (≥60 years) with New-Onset Idiopathic Nephrotic Syndrome Receiving Immunosuppressive Regimen: A Multicentre Study of 116 Patients.

J Clin Med 2019 Mar 2;8(3). Epub 2019 Mar 2.

Département de Néphrologie et Transplantation d'Organes, Centre de Référence des Maladies Rénales Rares, Centre Hospitalier Universitaire de Toulouse, 31000 Toulouse, France.

Because of its rarity, renal presentation and outcomes of idiopathic nephrotic syndrome (INS; minimal changes disease or focal and segmental glomerulosclerosis) has poorly been described in elderly patients, precluding an individualized therapy procedure. Whether immunosuppressive regimens formerly designed in children and young adults are safe and efficient in elderly remains elusive. In a large multicentric retrospective study that included 116 patients with INS and onset ≥ 60 years of age, we showed that cumulative incidence of renal response was 95% after frontline therapy, with an age-dependent median time-to-response (60 days before 70 years of age at the onset vs. 120 days after; = 0.03). Cumulative incidence of relapse was 90% at 7 years, with relapse occurring continuously over time. After a median follow-up of 34 months (IQR (12; 57)), 7 patients had died (6%) and 5 reached end-stage renal disease. Complications were highly prevalent: diabetes mellitus (23.3%), hypertension (24.1%), infection requiring hospitalization (21.6%) and acute kidney injury (9.5%). Thus, in older patients with INS and receiving steroids, renal response is delayed and relapse is the rule. Alternative immunosuppressive regimens, including B-cells depleting agents as frontline therapy, should be tested in this subset of patients to improve the mid- to long-term outcomes.
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http://dx.doi.org/10.3390/jcm8030298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6463053PMC
March 2019

Successful treatment of a associated haemolytic uraemic syndrome by eculizumab.

Clin Kidney J 2019 Feb 20;12(1):106-109. Epub 2018 Mar 20.

Department of Nephrology and Kidney Transplantation, Centre Hospitalier Universitaire de Montpellier, Montpellier, France.

Haemolytic uraemic syndrome (HUS) is a rare complication of invasive infection by (SP-HUS), especially in adults. Here we report an unusual case of a 53-year-old man presenting SP-HUS with severe multivisceral involvement. After failure of supportive care and plasma exchanges, eculizumab (anti-C5 antibody) resulted in a favourable outcome.
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http://dx.doi.org/10.1093/ckj/sfy019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366139PMC
February 2019

Endothelium structure and function in kidney health and disease.

Nat Rev Nephrol 2019 02;15(2):87-108

INSERM, UMR_S 1138, Centre de Recherche des Cordeliers, F-75006, Paris, France.

The kidney harbours different types of endothelia, each with specific structural and functional characteristics. The glomerular endothelium, which is highly fenestrated and covered by a rich glycocalyx, participates in the sieving properties of the glomerular filtration barrier and in the maintenance of podocyte structure. The microvascular endothelium in peritubular capillaries, which is also fenestrated, transports reabsorbed components and participates in epithelial cell function. The endothelium of large and small vessels supports the renal vasculature. These renal endothelia are protected by regulators of thrombosis, inflammation and complement, but endothelial injury (for example, induced by toxins, antibodies, immune cells or inflammatory cytokines) or defects in factors that provide endothelial protection (for example, regulators of complement or angiogenesis) can lead to acute or chronic renal injury. Moreover, renal endothelial cells can transition towards a mesenchymal phenotype, favouring renal fibrosis and the development of chronic kidney disease. Thus, the renal endothelium is both a target and a driver of kidney and systemic cardiovascular complications. Emerging therapeutic strategies that target the renal endothelium may lead to improved outcomes for both rare and common renal diseases.
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http://dx.doi.org/10.1038/s41581-018-0098-zDOI Listing
February 2019

"Neuro-renal syndrome" related to anti-contactin-1 antibodies.

Muscle Nerve 2019 03 6;59(3):E19-E21. Epub 2019 Jan 6.

Institute for Neurosciences of Montpellier, INSERM U1051, Montpellier University, Hopital Gui de Chauliac, Montpellier, France.

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http://dx.doi.org/10.1002/mus.26392DOI Listing
March 2019

Both Monoclonal and Polyclonal Immunoglobulin Contingents Mediate Complement Activation in Monoclonal Gammopathy Associated-C3 Glomerulopathy.

Front Immunol 2018 2;9:2260. Epub 2018 Oct 2.

INSERM UMRS1138, Centre de Recherche des Cordeliers, Team "Complément et Maladies", Paris, France.

C3 glomerulopathy (C3G) results from acquired or genetic abnormalities in the complement alternative pathway (AP). C3G with monoclonal immunoglobulin (MIg-C3G) was recently included in the spectrum of "monoclonal gammopathy of renal significance." However, mechanisms of complement dysregulation in MIg-C3G are not described and the pathogenic effect of the monoclonal immunoglobulin is not understood. The purpose of this study was to investigate the mechanisms of complement dysregulation in a cohort of 41 patients with MIg-C3G. Low C3 level and elevated sC5b-9, both biomarkers of C3 and C5 convertase activation, were present in 44 and 78% of patients, respectively. Rare pathogenic variants were identified in 2/28 (7%) tested patients suggesting that the disease is acquired in a large majority of patients. Anti-complement auto-antibodies were found in 20/41 (49%) patients, including anti-FH (17%), anti-CR1 (27%), anti-FI (5%) auto-antibodies, and C3 Nephritic Factor (7%) and were polyclonal in 77% of patients. Using cofactor assay, the regulation of the AP was altered in presence of purified IgG from 3/9 and 4/7 patients with anti-FH or anti-CR1 antibodies respectively. By using fluid and solid phase AP activation, we showed that total purified IgG of 22/34 (65%) MIg-C3G patients were able to enhance C3 convertase activity. In five documented cases, we showed that the C3 convertase enhancement was mostly due to the monoclonal immunoglobulin, thus paving the way for a new mechanism of complement dysregulation in C3G. All together the results highlight the contribution of both polyclonal and monoclonal Ig in MIg-C3G. They provide direct insights to treatment approaches and opened up a potential way to a personalized therapeutic strategy based on chemotherapy adapted to the B cell clone or immunosuppressive therapy.
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http://dx.doi.org/10.3389/fimmu.2018.02260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175995PMC
September 2019

In Reply to 'Benefit of Eculizumab Compared to Standard of Care Still Unproven in C3 Glomerulopathy'.

Am J Kidney Dis 2018 12 17;72(6):906-907. Epub 2018 Sep 17.

Centre Hospitalier Universitaire de Nantes, Nantes, France.

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http://dx.doi.org/10.1053/j.ajkd.2018.08.005DOI Listing
December 2018

Physical inactivity and protein energy wasting play independent roles in muscle weakness in maintenance haemodialysis patients.

PLoS One 2018 1;13(8):e0200061. Epub 2018 Aug 1.

PhyMedExp, INSERM, CNRS, Univ Montpellier, Département de Biochimie et Hormonologie, CHU Montpellier, Montpellier, France.

Background: Muscle weakness is associated with increased mortality risk in chronic haemodialysis (CHD) patients. Protein energy wasting (PEW) and low physical activity could impair muscle quality and contribute to muscle weakness beyond muscle wasting in these patients. Aim of this study was to assess clinical and biological parameters involved in the reduction of muscle strength of CHD patients.

Methods: One hundred and twenty-three CHD patients (80 males, 43 females; 68,8 [57.9-78.8] y.o.) were included in this study. Maximal voluntary force (MVF) of quadriceps was assessed using a belt-stabilized hand-held dynamometer. Muscle quality was evaluated by muscle specific torque, defined as the strength per unit of muscle mass. Muscle mass was estimated using lean tissue index (LTI), skeletal muscle mass (SMM) assessed by bioelectrical impedance analysis and creatinine index (CI). Voorrips questionnaire was used to estimate physical activity. Criteria for the diagnosis of PEW were serum albumin, body mass index < 23 kg/m2, creatinine index < 18.82 mg/kg/d and low dietary protein intake estimated by nPCR < 0.80g/kg/d.

Results: MVF was 76.1 [58.2-111.7] N.m. and was associated with CI (β = 5.3 [2.2-8.4], p = 0.001), LTI (β = 2.8 [0.6-5.1], p = 0.013), Voorrips score (β = 17.4 [2.9-31.9], p = 0.02) and serum albumin (β = 1.9 [0.5-3.2], p = 0.006). Only serum albumin (β = 0.09 [0.03-0.15], p = 0.003), Voorrips score (β = 0.8 [0.2-1.5], p = 0.005) and CI (β = 0.2 [0.1-0.3], p<0.001) remained associated with muscle specific torque. Thirty patients have dynapenia defined as impaired MVF with maintained SMM and were younger with high hs-CRP (p = 0.001), PEW criteria (p<0.001) and low Voorrips score (p = 0.001), and reduced dialysis vintage (p<0.046).

Conclusions: Beyond atrophy, physical inactivity and PEW conspire to impair muscle strength and specific torque in CHD patients and could be related to muscle quality.

Trial Registration: ClinicalTrials.gov NCT02806089.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200061PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070183PMC
January 2019

Endothelial Microparticles and Systemic Complement Activation in Patients With Chronic Kidney Disease.

J Am Heart Assoc 2018 07 13;7(14). Epub 2018 Jul 13.

Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Center, Aurora, CO.

Background: Endothelial microparticles are associated with chronic kidney disease (CKD) and complement activation. We hypothesized that the complement pathway is activated in patients with CKD via endothelial microparticles and that complement activation correlates with endothelial dysfunction in CKD.

Methods And Results: We analyzed complement data of 30 healthy subjects, 30 patients with stage III/IV CKD, and 30 renal transplant recipients with stage III/IV CKD, evaluating the potential correlation of complement fragments with brachial artery flow-mediated dilation, Chronic Kidney Disease Epidemiology Collaboration glomerular filtration rate, and urinary albumin/creatinine ratio. Endothelial microparticles were characterized via proteomic analysis and compared between study groups. Complement fragment Ba was significantly increased in CKD and post-kidney transplant CKD. Plasma Ba levels correlated significantly with lower brachial artery flow-mediated dilation, lower Chronic Kidney Disease Epidemiology Collaboration glomerular filtration rate, and higher urinary albumin/creatinine ratio. Factor D levels were significantly higher in the plasma microparticles of patients with CKD versus healthy controls. Plasma microparticles isolated from patients with CKD and containing factor D activated the alternative pathway in vitro.

Conclusion: The alternative complement pathway is activated in CKD and correlates with endothelial dysfunction and markers of CKD. Future studies are needed to evaluate whether endothelial microparticles with increased factor D play a pathologic role in CKD-associated vascular disease.

Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02230202.
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http://dx.doi.org/10.1161/JAHA.117.007818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6064828PMC
July 2018

Eculizumab reversed severe distal ischemic syndrome and glomerulonephritis with isolated C3 deposits associated with anti-factor H autoantibodies: a case report.

Clin Rheumatol 2018 Apr 7;37(4):1119-1122. Epub 2018 Mar 7.

Department of Internal Medicine and Clinical Immunology, CHU Côte de Nacre-Université Basse Normandie, Avenue de la Côte de Nacre, 14000, Caen, France.

B-cell clones can produce a monoclonal immunoglobulin, which may be responsible for visceral involvements. Kidney involvement is frequent, affecting 20 to 50% of patients with multiple myeloma. One mechanism underlying this involvement is a dysregulation of the complement alternative pathway, leading to C3 glomerulopathies. We report a patient who had a multiple myeloma, C3 glomerulopathy related to factor H autoantibody, and digital ischemia, who was treated successfully with eculizumab, an anti-complement therapy, without any relapse in 2 years of follow-up.
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http://dx.doi.org/10.1007/s10067-018-4058-6DOI Listing
April 2018

Patterns of Clinical Response to Eculizumab in Patients With C3 Glomerulopathy.

Am J Kidney Dis 2018 07 9;72(1):84-92. Epub 2018 Feb 9.

Department of Nephrology and Immunology, Centre Hospitalier Universitaire de Nantes, Nantes, France. Electronic address:

Background: Cases reports and small series of patients with C3 glomerulopathy have reported variable efficacy of eculizumab.

Study Design: Case series of C3 glomerulopathy.

Setting & Participants: Pediatric and adult patients with C3 glomerulopathy treated with eculizumab between 2010 and 2016 were identified through the C3 glomerulopathy French registry database, and a questionnaire was sent to participating French pediatric and adult nephrology centers, as well as one pediatric referral center in Québec, Canada.

Outcomes: Global or partial clinical renal response.

Measurements: Evolution of serum creatinine and proteinuria values.

Results: 26 patients (13 children/adolescents) were included. 22 (85%) patients had received steroids, plasma exchange, or immunosuppressive therapy before eculizumab, and 3 of them had rapid progression of their kidney disease despite treatment. At the initiation of eculizumab therapy, 11 (42%) patients had chronic kidney disease, 7 (27%) had rapidly progressive disease, and 3 (12%) required dialysis. After eculizumab treatment (median duration, 14 months), 6 (23%) patients had a global clinical response; 6 (23%), a partial clinical response; and 14 (54%), no response. Compared with those who had a partial clinical or no response, patients who had a global clinical response had lower estimated glomerular filtration rates, a more rapidly progressive course, and more extracapillary proliferation on kidney biopsy. Age, extent of renal fibrosis, frequency of nephrotic syndrome, low serum C3 and C3 nephritic factor and elevated soluble C5b-9 concentrations, or complement gene variants did not differ between responders and nonresponders.

Limitations: Retrospective design without a control group, relatively small number of cases, inclusion of pediatric and adult cases.

Conclusions: Eculizumab appears to be a potential treatment for patients with crescentic rapidly progressive C3 glomerulopathy. Its benefit in patients with non-rapidly progressing forms seems to be limited.
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http://dx.doi.org/10.1053/j.ajkd.2017.11.019DOI Listing
July 2018

Stricturing Crohn's disease-like colitis in a patient treated with belatacept.

World J Gastroenterol 2017 Dec;23(48):8660-8665

Gastroenterology Department, Saint-Eloi Hospital, Montpellier University Hospital, Montpellier 34000, France

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) modifying agents have been involved in the development of intestinal inflammation, especially therapeutic monoclonal antibodies directed against CTLA-4. Here we report the appearance of a severe stricturing Crohn's disease-like colitis in a patient with a kidney allograft who was treated with belatacept, a recombinant CTLA-4-Ig fusion protein.
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http://dx.doi.org/10.3748/wjg.v23.i48.8660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752725PMC
December 2017

Prognostic Value of the Persistence of C1q-Binding Anti-HLA Antibodies in Acute Antibody-Mediated Rejection in Kidney Transplantation.

Transplantation 2018 04;102(4):688-698

Department of Nephrology and Kidney Transplantation, University Hospital of Tours, Tours, France.

Background: The differential pathogenicity of anti-HLA donor-specific antibodies (DSAs) is not fully understood. The presence of complement-binding DSAs helps in better defining the prognosis of acute antibody-mediated rejection (ABMR). The evolution of these antibodies after the treatment of ABMR is unknown.

Methods: We included patients from the French multicenter RITUX ERAH study diagnosed with acute ABMR within the first year of renal transplantation, with circulating anti-HLA DSAs and treated randomly by rituximab or placebo (and intravenous immunoglobulins, plasma exchange). We centrally analyzed serum samples at the time of ABMR, 3 and 6 months after ABMR, with anti-HLA DSAs specificities and C1q-binding capacity assessment.

Results: Twenty-five patients were included: 68% had C1q-binding DSAs at the time of ABMR. The presence of C1q-binding DSAs was associated with a poorer evolution of chronic glomerulopathy at 6 months (P = 0.036). The persistence of C1q-binding DSAs at 3 and/or 6 months after ABMR was associated with more severe chronic glomerulopathy (P = 0.006), greater C4d score deposition score at 6 months after ABMR (P = 0.008), and graft loss 5 years after ABMR (P = 0.029). C1q-binding capacity was associated with the DSA MFI but 5 C1q-binding DSAs in 4 patients had low MFI values without a prozone effect.

Conclusion: The presence and persistence of anti-HLA C1q-binding DSAs after ABMR is a detrimental marker, leading to transplant glomerulopathy and graft loss. Assessment of the complement-binding capacities of DSAs could help decide treatment intensification.
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http://dx.doi.org/10.1097/TP.0000000000002002DOI Listing
April 2018

A novel CFHR1-CFHR5 hybrid leads to a familial dominant C3 glomerulopathy.

Kidney Int 2017 10 18;92(4):876-887. Epub 2017 Jul 18.

Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche en Santé 1138, Team "Complement and Disease," Cordeliers Research Center, Paris, France; Paris Descartes University, Paris, France; Laboratoire d'Immunologie, Hôpital Européen Georges Pompidou, Assistance publique-Hôpitaux de Paris, Paris, France. Electronic address:

The intrinsic similarity shared between the members of the complement factor H family, which comprises complement factor H and five complement factor H-related (CFHR) genes, leads to various recombination events. In turn these events lead to deletions of some genes or abnormal proteins, which are found in patients with atypical hemolytic uremic syndrome or C3 glomerulopathies. Here we describe a novel genetic rearrangement generated from a heterozygous deletion spanning 146 Kbp involving multiple CFHR genes leading to a CFHR1-R5 hybrid protein. This deletion was found in four family members presenting with a familial dominant glomerulopathy histologically classified as an overlap of dense deposit disease and C3 glomerulonephritis. Affected patients exhibited permanently low C3 and factor B levels and high amounts of activation fragments sC5b9 and Bb, indicating a systemic alternative pathway dysregulation. The abnormal protein, characterized by Western blot and immunoprecipitation, was shown to circulate in association with CFHR1 and CFHR2, attributable to its two N-terminal dimerization motifs. The presence of this protein is associated with a perturbation of Factor H activity on the C3 convertase decay. Thus, our study highlights the role of CFHRs in the physiopathology of C3 glomerulopathies and stresses the importance of screening CFHRs in all familial C3 glomerulopathies. Such hybrids described till now were always associated with familial forms.
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http://dx.doi.org/10.1016/j.kint.2017.04.025DOI Listing
October 2017

C5 nephritic factors drive the biological phenotype of C3 glomerulopathies.

Kidney Int 2017 11 14;92(5):1232-1241. Epub 2017 Jul 14.

Assistance Publique - Hopitaux de Paris, Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, Paris, France; INSERM UMRS 1138, Cordeliers Research Center, Complement and Diseases team, Paris, France. Electronic address:

C3 Glomerulopathies, which include Dense Deposit Disease and C3 Glomerulonephritis, are associated with genetic and acquired dysregulation of the C3 convertase alternative pathway of complement. The potential role of the activation of the C5 convertase has not been studied extensively. Here we analyzed IgG samples from patients with C3 Glomerulopathies to identify circulating autoantibodies that stabilize the C3 alternative pathway (C3 Nephritic Factors) as well as C5 convertases (C5 Nephritic Factors), thus preventing decay of these enzyme complexes. Rare variants in alternative pathway genes were found in 28 of 120 tested patients. C3 and C5 Nephritic Factors were found in 76 of 101 (75%) and 29 of 59 (49%) of the patients, respectively. Therefore, we compared the results of the assays for the C3 and C5 nephritic factors functional activity: 29% were positive for C3 Nephritic Factors alone, 39% were positive for both C3 and C5 Nephritic Factors, and 10% were positive for C5 Nephritic Factors alone. We found that the addition of properdin-enhanced stabilization of C3 convertase in the presence of IgG doubly positive for both Nephritic Factors, while it did not modify the stabilization mediated by IgG solely positive for C3 Nephritic Factors. Both C3 and C5 Nephritic Factors correlated with C3 consumption, while only C5 Nephritic Factors correlated with sC5b9 levels. C5 Nephritic Factors-positive patients were more likely to have C3 Glomerulonephritis than Dense Deposit Disease. Thus, dysregulation of the C5 convertase contributes to C3 Glomerulopathies inter-disease differences and may have direct therapeutic implications.
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http://dx.doi.org/10.1016/j.kint.2017.04.017DOI Listing
November 2017