Publications by authors named "Jacques Pourrat"

32 Publications

Microscopic polyangiitis: Clinical characteristics and long-term outcomes of 378 patients from the French Vasculitis Study Group Registry.

J Autoimmun 2020 08 25;112:102467. Epub 2020 Apr 25.

Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Hôpital Cochin, APHP, Université Paris Descartes, Paris, France. Electronic address:

Objective: To describe characteristics and long-term outcomes of patients with microscopic polyangiitis (MPA), an antineutrophil cytoplasm antibody (ANCA)-associated small-vessel necrotizing vasculitis.

Methods: MPA patients from the French Vasculitis Study Group Registry satisfying the European Medicines Agency algorithm were analyzed retrospectively. Characteristics at diagnosis, treatments, relapses and deaths were analyzed to identify factors predictive of death or relapse.

Results: Between 1966 and 2017, 378 MPA patients (median age 63.7 years) were diagnosed and followed for a mean of 5.5 years. At diagnosis, the main clinical manifestations included renal involvement (74%), arthralgias (45%), skin (41%), lung (40%) and mononeuritis multiplex (32%), with less frequent alveolar hemorrhage (16%), cardiomyopathy (5%) and severe gastrointestinal signs (4%); mean serum creatinine was 217 μmol/L. ANCA were detected in 298/347 (86%) patients by immunofluorescence and/or enzyme-linked immunosorbent assay (ELISA). Among the 293 patients with available ELISA specificities, 272 (92.8%) recognized myeloperoxidase and 13 (4.4%) proteinase-3. During follow-up, 131 (34.7%) patients relapsed and 78 (20.6%) died, mainly from infections. Respective 5-year overall and relapse-free survival rates were 84.2% and 60.4%. Multivariable analyses retained age >65 years, creatinine >130 μmol/L, severe gastrointestinal involvement and mononeuritis multiplex as independent risk factors for death. Renal impairment was associated with a lower risk of relapse.

Conclusion: Non-renal manifestations and several risk factors for death or relapse were frequent in this nationwide cohort. While mortality was low, and mainly due to treatment-related complications, relapses remained frequent, suggesting that MPA management can be further improved.
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http://dx.doi.org/10.1016/j.jaut.2020.102467DOI Listing
August 2020

Incidence and outcome of lupus nephritis in French Polynesia
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Clin Nephrol 2018 Jan;89 (2018)(1):41-49

Objective: Outcomes of systemic lupus erythematosus (SLE) and lupus nephritis (LN) are highly heterogeneous among some populations because of interactions between genetic, epigenetic, environmental, and socioeconomic factors. A better characterization of social and ethnic disparities in mixed populations may thus help to develop individualized treatment regimens.

Materials And Methods: Retrospective observational study including all patients with LN diagnosed between January 1993 and January 2014 in the only Nephrology Department of French Polynesia.

Results: The annual incidence of SLE and LN in French Polynesia was 3.6 and 0.96 per 100,000, respectively. Among the 45 patients with biopsy-proven LN (pediatric onset, 26.7%), LN occurred during the first SLE flare-up in 68.8%. At presentation, median eGFR was 72 mL/min/1.73m2 (31 - 105), 32 patients had class-III/IV active glomerulonephritis (GN), and 10 had pure or mixed class-V GN. During the follow-up, 5 patients died (11.1%) and 2 reached end-stage renal disease (4.4%). Cumulative incidences of complete and partial renal responses were 31.1% and 40% at 12 months. Complete renal response (CR) was only predicted by renal presentation (lack of leukocyturia, low proteinuria). Among the 36 patients with renal response, 18 relapsed. Maintenance treatment (mycophenolate mofetil) and place of residence (Windward Islands as compared to remote islands) were the only factors that protected from relapse.

Conclusion: Renal presentation was the main predictive factor for a renal response whereas geographical residence and maintenance-treatment regimen were predictive of LN relapses in patients from French Polynesia, an area characterized by a specific genetic background and including several isolated islands that have limited access to healthcare.
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http://dx.doi.org/10.5414/CN109194DOI Listing
January 2018

The clinicopathologic characteristics of kidney diseases related to monotypic IgA deposits.

Kidney Int 2017 03 6;91(3):720-728. Epub 2017 Jan 6.

Department of Nephrology, CHU Poitiers, Centre de référence maladies rares amylose AL et autres maladies par dépôts d'immunoglobulines monoclonales, Poitiers, France; Department of Immunology, National Center for Scientific Research, Joint Research Unit 7276, University of Limoges, Centre de référence maladies rares amylose AL et autres maladies par dépôts d'immunoglobulines monoclonales, Limoges, France.

Monoclonal gammopathy of renal significance (MGRS) regroups renal disorders caused by a monoclonal immunoglobulin without overt hematological malignancy. MGRS includes tubular disorders, glomerular disorders with organized deposits, and glomerular disorders with non-organized deposits, such as proliferative glomerulonephritis with monoclonal IgG deposits. Since glomerular involvement related to monotypic IgA deposits is poorly described we performed retrospective analysis and defined clinico-biological characteristics, renal pathology, and outcome in 19 referred patients. This analysis allowed distinction between 2 types of glomerulopathies, α-heavy chain deposition disease (5 patients) and glomerulonephritis with monotypic IgA deposits (14 patients) suggestive of IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits in 12 cases. Clinicopathologic characteristics of α-heavy chain deposition disease resemble those of the γ-heavy chain disease, except for a higher frequency of extra-capillary proliferation and extra-renal involvement. IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits should be differentiated from diseases with polytypic IgA deposits, given distinct clinical, histological, and pathophysiological features. Similarly to IgG-proliferative glomerulonephritis with monoclonal immunoglobulin deposits, overt hematological malignancy was infrequent, but sensitive serum and bone marrow studies revealed a subtle plasma cell proliferation in most patients with IgA-proliferative glomerulonephritis with monoclonal immunoglobulin deposits. Anti-myeloma agents appeared to favorably influence renal prognosis. Thus, potential progression towards symptomatic IgA multiple myeloma suggests that careful hematological follow-up is mandatory. This series expands the spectrum of renal disease in MGRS.
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http://dx.doi.org/10.1016/j.kint.2016.10.026DOI Listing
March 2017

Outcomes of patients with Goodpasture syndrome: A nationwide cohort-based study from the French Society of Hemapheresis.

J Autoimmun 2016 09 4;73:24-9. Epub 2016 Jun 4.

CHU de Toulouse, Département de Néphrologie et Transplantation d'Organes, Centre de Référence des maladies rénales rares, Hôpital Rangueil, Université Paul Sabatier - Toulouse III, Toulouse, France; INSERM U1048 (équipe 12), Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Toulouse, France. Electronic address:

The overall and renal outcomes of patients with Goodpasture syndrome (GS), a rare autoimmune disorder characterized by circulating anti-GBM antibodies and rapidly progressive glomerulonephritis and/or pulmonary hemorrhage, have mostly been reported in small-sized cohorts or by aggregating patients receiving a variety of therapies that include aggressive (i.e., combined plasma exchanges, corticosteroids, and cyclophosphamide) and less aggressive (i.e., either plasma exchanges or immunosuppressive drugs, or no treatment). To address the prognosis of GS patients with relatively homogeneous management including plasma exchanges, we conducted a multicenter retrospective study on GS patients included in the registry of the French Society of Hemapheresis. 122 patients were included (kidney alone (n = 28), lung alone (n = 5), or combined involvement (n = 89)). All 122 patients received plasma exchanges (median number of sessions: 13 [9-17]), either alone (n = 8) or associated with combined corticosteroids and oral or IV cyclophosphamide (n = 101) or with corticosteroids alone (n = 12) or cyclophosphamide alone (n = 2). One-year survival was 86.9%. 7/16 patients died from severe infection. In multivariate analyses (Cox's regression model), being aged <60 years, and number of plasma exchanges were correlated to overall survival. The use of alternative immunosuppressive drugs (because of refractory or relapsing GS) was correlated to mortality at one year. Superiority of oral cyclophosphamide compared to intravenous intake was close to significant. Using a logistic regression model, renal survival in patients alive at 1 year was only predicted by serum creatinine <500 μmol/L at presentation. This large series describes the predictive factors for overall and renal survival of GS patients treated by plasma exchanges. Interventional studies that compare oral and intravenous cyclophosphamide, as well as testing new immunosuppressive therapies, are warranted.
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http://dx.doi.org/10.1016/j.jaut.2016.05.015DOI Listing
September 2016

Glutathione S Transferases Polymorphisms Are Independent Prognostic Factors in Lupus Nephritis Treated with Cyclophosphamide.

PLoS One 2016 22;11(3):e0151696. Epub 2016 Mar 22.

Department of Internal Medicine, CHU Grenoble, Grenoble, France.

Objective: To investigate association between genetic polymorphisms of GST, CYP and renal outcome or occurrence of adverse drug reactions (ADRs) in lupus nephritis (LN) treated with cyclophosphamide (CYC). CYC, as a pro-drug, requires bioactivation through multiple hepatic cytochrome P450s and glutathione S transferases (GST).

Methods: We carried out a multicentric retrospective study including 70 patients with proliferative LN treated with CYC. Patients were genotyped for polymorphisms of the CYP2B6, CYP2C19, GSTP1, GSTM1 and GSTT1 genes. Complete remission (CR) was defined as proteinuria ≤0.33g/day and serum creatinine ≤124 µmol/l. Partial remission (PR) was defined as proteinuria ≤1.5g/day with a 50% decrease of the baseline proteinuria value and serum creatinine no greater than 25% above baseline.

Results: Most patients were women (84%) and 77% were Caucasian. The mean age at LN diagnosis was 41 ± 10 years. The frequency of patients carrying the GST null genotype GSTT1-, GSTM1-, and the Ile→105Val GSTP1 genotype were respectively 38%, 60% and 44%. In multivariate analysis, the Ile→105Val GSTP1 genotype was an independent factor of poor renal outcome (achievement of CR or PR) (OR = 5.01 95% CI [1.02-24.51]) and the sole factor that influenced occurrence of ADRs was the GSTM1 null genotype (OR = 3.34 95% CI [1.064-10.58]). No association between polymorphisms of cytochrome P450s gene and efficacy or ADRs was observed.

Conclusion: This study suggests that GST polymorphisms highly impact renal outcome and occurrence of ADRs related to CYC in LN patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151696PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4803192PMC
August 2016

Plasma exchanges for the treatment of severe systemic necrotizing vasculitides in clinical daily practice: Data from the French Vasculitis Study Group.

J Autoimmun 2015 Dec 29;65:49-55. Epub 2015 Aug 29.

Department of Internal Medicine, National Referral Center for Rare Autoimmune and Systemic Diseases, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Descartes, Paris, France. Electronic address:

The use of plasma exchanges (PLEX) in systemic necrotizing vasculitides (SNV) still need to be codified. To describe indications, efficacy and safety of PLEX for the treatment of SNV, we conducted a multicenter retrospective study on patients with ANCA-associated vasculitis (AAV) or non-viral polyarteritis nodosa (PAN) treated with PLEX. One hundred and fifty-two patients were included: GPA (n = 87), MPA (n = 56), EGPA (n = 4) and PAN (n = 5). PLEX were used for rapidly progressive glomerulonephritis (RPGN) in 126 cases (86%), alveolar hemorrhage in 64 cases (42%), and severe mononeuritis multiplex in 23 cases (15%). In patients with RPGN, there was a significant improvement in renal function compared to baseline value (P < 0.0001), the plateau being reached at month 3 after PLEX initiation, and estimated glomerular filtration rate improved especially as the number of PLEX increased. In patients with alveolar hemorrhage, mechanical ventilation was discontinued in all patients after a median time of 15 days. Patients treated for mononeuritis multiplex showed improvement of severe motor weakness. After a median follow of 22 months, 18 deaths (12%) were recorded, mainly in patients with RPGN and within the first 6 months. Incidence of end-stage renal disease and/or death was similar between groups of different baseline renal function, but was increased in MPO-ANCA compared to PR3-ANCA. Adverse events attributable to PLEX were recorded in 63%. No death occurred during PLEX. This large series describes indications, efficacy and safety of PLEX in daily practice. Randomized controlled studies are ongoing to define optimal indications, PLEX regimen and concomitant medications.
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http://dx.doi.org/10.1016/j.jaut.2015.08.003DOI Listing
December 2015

Cryofibrinogenemia: a marker of severity of cryoglobulinemic vasculitis.

Am J Med 2015 Aug 28;128(8):916-21. Epub 2015 Mar 28.

Toulouse University, Toulouse, France; Department of Internal Medicine, Toulouse University Hospital, France; INSERM UMR1027, Toulouse, France.

Background: Cryofibrinogenemia is frequently associated with cryoglobulinemia. The aim of this study was to determine the characteristics associated with the presence of cryofibrinogenemia in patients with cryoglobulinemic vasculitis.

Methods: This was a single-center retrospective study that included patients with cryoglobulinemic vasculitis who were tested for cryofibrinogen at a tertiary referral center between January 1, 2011 and December 31, 2012. Twenty-nine patients fulfilled the CryoVas (cryoglobulinemic vasculitis) Survey criteria for cryoglobulinemic vasculitis. Eighteen patients had a detectable cryofibrinogen (CF-positive) and 11 had no detectable cryofibrinogen (CF-negative). Median cryoglobulin levels were 89 ± 129 mg/L in the CF-positive group and 68 ± 82 mg/L in the CF-negative group (P = .32). Median cryofibrinogen level was 70 ± 174 mg/L. Clinical manifestations were similar in both groups. Cancers and hematological disorders were more frequent among CF-positive patients (39% vs 0%, P = .026). Levels of alpha-1 and alpha-2 globulinemia were higher in the CF-positive group. Cryofibrinogenemia ≥ 100 mg/L was associated with cryoglobulinemic vasculitis (odds ratio [OR] 2.86; 95% confidence interval [CI], 1.06-7.73) in cryoglobulinemic patients. Presence of cryofibrinogenemia was associated with use of corticosteroids, immunosuppressants, or plasmapheresis in cryoglobulinemic vasculitis patients (OR 22.7; 95% CI, 2.02-256.44).

Conclusions: Our results strongly suggest that presence of cryofibrinogenemia is associated with a more severe phenotype among patients with cryoglobulinemic vasculitis.
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http://dx.doi.org/10.1016/j.amjmed.2015.03.009DOI Listing
August 2015

Characteristics, prognosis, and outcomes of cutaneous ischemia and gangrene in systemic necrotizing vasculitides: a retrospective multicenter study.

Semin Arthritis Rheum 2014 Apr 9;43(5):681-8. Epub 2013 Oct 9.

Department of Internal Medicine, National Referral Center for Rare Systemic and Autoimmune Diseases, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris Descartes, Paris, France; Department of Rheumatology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.

Objectives: To describe the prevalence, characteristics, and outcome of cutaneous ischemia, and whether it can occur in systemic necrotizing vasculitides (SNVs), i.e., polyarteritis nodosa, granulomatosis with polyangiitis, and eosinophilic granulomatosis with polyangiitis and microscopic polyangiitis.

Methods: We conducted a retrospective analysis of all patients with SNV who were included in the French Vasculitis Study Group cohort database between March 1963 and September 2007. We compared characteristics and outcomes for patients with and without cutaneous ischemia (digital necrosis and/or isolated necrotic cutaneous ulcers).

Results: Among the 1304 patients with a diagnosis of SNVs, 40 (3.1%) had digital necrosis and 25 (1.9%) had isolated necrotic cutaneous ulcers, with an equal distribution among SNVs. Presence of cutaneous ischemia was associated with past and/or current smoking [odds ratio (OR), 1.73; 95% confidence interval (95% CI), 1.02-2.95] and history of coronary artery disease (2.40; 1.01-6.00), as well as with other cutaneous manifestations (6.54; 3.21-8.67), gastrointestinal tract perforations (4.29; 1.41-13.07), and arthralgias (1.84; 1.10-3.07) during diagnosis. Ten patients with digital necrosis underwent extremity amputation, but no patient with isolated necrotic cutaneous ulcers (p = 0.007) underwent it. Smoking was the main risk factor of amputation (OR, 9.1; 1.7-48.9). At a mean follow-up of 10 years, cutaneous ischemia was identified as an independent predictor of vasculitis relapse (hazard ratio, 1.47; 95% CI, 1.05-2.05) and all-cause death (1.66; 1.01-2.74).

Conclusions: Cutaneous ischemia is a rare manifestation of SNVs but is associated with an increased risk of relapse and mortality. Tobacco use is associated with amputation, which emphasizes the importance of managing conventional cardiovascular risk factors in SNV patients.
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http://dx.doi.org/10.1016/j.semarthrit.2013.09.001DOI Listing
April 2014

Study of anti-Müllerian hormone and its relation to the subsequent probability of pregnancy in 112 patients with systemic lupus erythematosus, exposed or not to cyclophosphamide.

J Clin Endocrinol Metab 2013 Sep 5;98(9):3785-92. Epub 2013 Jul 5.

University Pierre and Marie Curie (UPMC), Université Paris 6, Paris, France.

Context: Cyclophosphamide is used for renal and major extrarenal involvement in systemic lupus erythematosus (SLE) and is associated with a risk of premature ovarian failure. There are no data available about the relation between anti-Müllerian hormone (AMH) serum levels and the probability of subsequent pregnancy in SLE patients.

Objective: We analyzed AMH levels and the probability of pregnancy in SLE women exposed to cyclophosphamide.

Design And Setting: We conducted a matched cohort study in referral centers for SLE.

Patients: Fifty-six cyclophosphamide-exposed SLE women younger than 40 years of age and 56 control SLE women matched for age within 6 months participated in the study.

Main Outcome Measures: AMH was measured in samples from the PLUS study (ClinicalTrials.gov no. NCT00413361). All patients were interviewed in May 2012 regarding their obstetric status.

Results: The mean age ± SD of the 112 patients was 31.6 ± 5.8 years. The mean AMH level was low (1.21 ± 1.01 ng/mL) and was significantly lower in patients exposed to cyclophosphamide (P = .03) and in patients older than 30 years (P = .02). During a median follow-up (interval between sampling and the interview) period of 4.2 (range, 2.5-4.8) years, 38 patients sought to become pregnant, and 32 (84.2%) succeeded. In the univariate analysis, the risk of failure was associated with cumulative cyclophosphamide dose (P = .007) and older age (P = .02), but not with AMH.

Conclusion: We confirmed that AMH levels are low in SLE patients and decrease significantly with age and cyclophosphamide exposure. Nonetheless, the risk of failure to conceive was low and was predicted by cyclophosphamide exposure and age, but not by AMH levels.
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http://dx.doi.org/10.1210/jc.2013-1235DOI Listing
September 2013

High prevalence of infectious events in thrombotic thrombocytopenic purpura and genetic relationship with toll-like receptor 9 polymorphisms: experience of the French Thrombotic Microangiopathies Reference Center.

Transfusion 2014 Feb 27;54(2):389-97. Epub 2013 May 27.

Service d'Hématologie, Centre de Référence des Microangiopathies Thrombotiques, Hôpital Saint-Antoine, Université Pierre et Marie Curie, Paris, France; Service de Réanimation Polyvalente, Hôpitaux Universitaires de l'Est Parisien, AP-HP et UPMC Univ Paris 06, Paris, France; Inserm U1009, Institut Gustave Roussy, Villejuif, France; Laboratoire Jean Dausset d'Immunologie et d'Histocompatibilité & INSERM, AP-HP, UMRS 940, Paris, France; Service d'Immunopathologie, Service de Réanimation, Hôpital Saint-Louis, Université Paris 7 Denis Diderot, Paris, France; Service de Réanimation Médicale, Hôpital Charles Nicolle, Rouen, France; Service de Néphrologie, Hôpital Maison Blanche, Reims, France; Service de Néphrologie, Centre Hospitalier Universitaire, Lille, France; Service d'Hémaphérèse, Service de Médecine Interne, Hôpital de la Conception, Marseille, France; Service de Néphrologie, Centre Hospitalier de Valenciennes, Valenciennes, France; Service de Néphrologie- Médecine Interne, Hôpital Sud, Amiens, France; Service d'Hématologie Clinique et de Thérapie Cellulaire, CHU Dupuytren, Limoges, France; Service de Néphrologie, Hôpital Pellegrin, Bordeaux, France; Service Médecine Interne A, Hôpital Hôtel-Dieu, Nantes, France; Service de Néphrologie, Dijon, France; Service de Néphrologie, Hôpital Pontchaillou, Rennes, France; Service de Réanimation Médicale (7HO), Hôpital Gabriel Montpied, Clermont-Ferrand, France; Service de Néphrologie et Immunologie Clinique, CHU Rangueil, Toulouse, France; Service de Réanimation Polyvalente, AP-HP, Hôpital Cochin, Université Paris 5, Paris, France; Service de Réanimation Néphrologique, Hôpital Tenon, UPMC Université Paris 06, Paris, France; Service d'Hématologie, Hôpital Emile Muller, Mulhouse, France; Service d'Hématologie Biologique, Hôpital Antoine Béclère, AP-HP, Clamart et Université Paris-Sud 11, Le Kremlin-Bicêtre, France.

Background: Infectious events have been reported as major environmental triggers of thrombotic thrombocytopenic purpura (TTP). We detail here the potential association between infections and TTP.

Study Design And Methods: We recruited randomly and prospectively a cohort of 280 consecutive TTP patients during a 9-year period. Features of infection were systematically recorded.

Results: Features consistent with an infectious event were observed in 114 patients (41%) at time of TTP diagnosis. Infectious agents were documented in 34 cases and were mainly Gram-negative bacilli. At time of diagnosis infected patients more frequently had fever (p < 0.001). Infections at diagnosis did not impact prognosis and outcome. Thirty-six percent of patients experienced an infectious event during hospitalization, which resulted in more exacerbation of TTP (p = 0.02). Infections were not overrepresented during treatment in patients who received steroids and/or rituximab. Further genetic analysis of toll-like receptor (TLR)-9 functionally relevant polymorphisms revealed that TLR-9 +2848 G and TLR-9 +1174 A genotypes were more frequent in TTP patients than in controls (p = 0.04 and p = 0.026, respectively) and more particularly in patients negative for the Class II human leukocyte antigen system susceptibility allele DRB1*11 (p = 0.001 and p = 0.002, respectively). Haplotypes estimation showed that 1174A-2848G haplotype was significantly more frequent in TTP (p = 0.004), suggesting a primary role for this haplotype variation in conferring a predisposition for acquired TTP.

Conclusion: Infections should be considered as an aggravating factor during the course of TTP. Particular polymorphisms in TLR-9 gene may represent risk factors for TTP.
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http://dx.doi.org/10.1111/trf.12263DOI Listing
February 2014

Cryofibrinogenemia.

J Clin Rheumatol 2013 Apr;19(3):142-8

Departments of Internal Medicine, CHU Toulouse, France.

Cryofibrinogenemia is a cryoprotein that was first identified in 1955 by Korst and Kratochvil. Unlike cryoglobulin, the precipitate forms only in plasma and not in the serum. The presence of cryofibrinogen in plasma can be asymptomatic. Cryofibrinogenemia is considered a rare disorder: its prevalence varies from 0% to 7% in healthy subjects and from 8% to 13% in hospitalized patients. Nevertheless, cryofibrinogenemia, when a cryopathy is clinically suspected, has been reported in 12% to 51% of patients. Skin manifestations are usually the first signs and are usually moderate; in addition, cold intolerance, Raynaud phenomenon, purpura, or livedo reticularis often occurs. Skin necrosis, acral ulcers, and gangrene can lead to surgery and amputation. Systemic manifestations are common, and arterial or venous thrombotic events are frequent. Cryofibrinogenemia may be primary (essential) or secondary to other underlying disorders, such as carcinoma, infection, vasculitis, collagen disease, or associated with cryoglobulinemia. The histological features of cryofibrinogenemia can confirm the presence of cryofibrinogen within small and medium arteries, plus occlusive thrombotic diathesis composed of eosinophilic refractile deposits within vessel lumina. Cryofibrinogenemia is a treatable and potentially reversible disease.In moderate forms, it can be treated by simply avoiding cold temperatures. The use of corticosteroids in association with low-dose aspirin is the treatment of choice for moderate forms, although stanozolol is an alternative maintenance therapy. Immunosuppressive therapies, plasmapheresis, and/or intravenous fibrinolysis are useful at treating severe forms of cryofibrinogenemia. The use of anticoagulants is limited to the management of thrombotic events. Treatment of secondary cryofibrinogenemia involves the management of associated diseases. Regular follow-ups are needed because of the high risk of recurrence. Moreover, up to half of patients with cryofibrinogenemia considered as essential may develop lymphomas in the following years. Compared with cryoglobulinemia, less is known about cryofibrinogenemia. Its diagnosis should be considered when suggestive clinical manifestations are present and when there are specific biopsy findings. Although identification of cryofibrinogen in blood samples is simple and inexpensive, cryofibrinogenemia can be asymptomatic, and a lack of diagnosis criteria can make diagnosis difficult to confirm. This review describes the clinical manifestations and the biological and pathological features and discusses the criteria used to diagnose and manage cryofibrinogenemia.
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http://dx.doi.org/10.1097/RHU.0b013e318289e06eDOI Listing
April 2013

Population pharmacokinetics of rituximab with or without plasmapheresis in kidney patients with antibody-mediated disease.

Br J Clin Pharmacol 2013 Nov;76(5):734-40

Pharmacie, Centre Hospitalier Universitaire, Toulouse, France; EA4553, Université Paul Sabatier and Institut Claudius-Regaud, Toulouse, France.

Aims: Both rituximab and plasmapheresis can be associated in the treatment of immune-mediated kidney diseases. The real impact of plasmapheresis on rituximab pharmacokinetics is unknown. The aim of this study was to compare rituximab pharmacokinetics between patients requiring plasmapheresis and others without plasmapheresis.

Methods: The study included 20 patients receiving one or several infusions of rituximab. In 10 patients, plasmapheresis sessions were also performed (between two and six sessions per patient). Rituximab concentrations were measured in blood samples in all patients and in discarded plasma obtained by plasmapheresis using an enzyme-linked immunosorbent assay method. Data were analysed according to a population pharmacokinetic approach.

Results: The mean percentage of rituximab removed during the first plasmapheresis session ranged between 47 and 54% when plasmapheresis was performed between 24 and 72 h after rituximab infusion. Rituximab pharmacokinetics was adequately described by a two-compartment model with first-order elimination. Plasmapheresis had a significant impact on rituximab pharmacokinetics, with an increase of rituximab clearance by a factor of 261 (95% confidence interval 146-376), i.e. from 6.64 to 1733 ml h(-1) . Plasmapheresis performed 24 h after rituximab infusion decreased the rituximab area under the curve by 26%.

Conclusions: Plasmapheresis removed an important amount of rituximab when performed less than 3 days after infusion. The removal of rituximab led to a significant decrease of the area under the curve. This pharmacokinetic observation should be taken into account for rituximab dosing, e.g. an additional third rituximab infusion may be recommended when three plasmapheresis sessions are performed after the first rituximab infusion.
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http://dx.doi.org/10.1111/bcp.12098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3853532PMC
November 2013

Acute renal infarction: a case series.

Clin J Am Soc Nephrol 2013 Mar 30;8(3):392-8. Epub 2012 Nov 30.

Service de Néphrologie et Dialyse, Hôpital d'Instruction des Armées du Val de Grâce, Paris, France.

Background And Objectives: Renal infarction is an arterial vascular event that may cause irreversible damage to kidney tissues. This study describes the clinical characteristics of patients with renal infarction according to underlying mechanism of vascular injury.

Design, Setting, Participants, & Measurements: This study retrospectively identified 94 patients with renal infarction diagnosed between 1989 and 2011 with the aim of highlighting potential correlations between demographic, clinical, and biologic characteristics and the etiology of renal infarction. Four groups were identified: renal infarction of cardiac origin (cardiac group, n=23), renal infarction associated with renal artery injury (renal injury group, n=29), renal infarction associated with hypercoagulability disorders (hypercoagulable group, n=15), and apparently idiopathic renal infarction (idiopathic group, n=27).

Results: Clinical symptoms included abdominal and/or flank pain in 96.8% of cases; 46 patients had uncontrolled hypertension at diagnosis. Laboratory findings included increase of lactate dehydrogenase level (90.5%), increase in C-reactive protein level (77.6%), and renal impairment (40.4%). Compared with renal injury group patients, this study found that cardiac group patients were older (relative risk for 1 year increase=1.21, P=0.001) and displayed a lower diastolic BP (relative risk per 1 mmHg=0.94, P=0.05). Patients in the hypercoagulable group had a significantly lower diastolic BP (relative risk=0.86, P=0.005). Patients in the idiopathic group were older (relative risk=1.13, P=0.01) and less frequently men (relative risk=0.11, P=0.02). Seven patients required hemodialysis at the first evaluation, and zero patients died during the first 30 days.

Conclusions: This study suggests that the clinical and biologic characteristics of patients can provide valuable information about the causal mechanism involved in renal infarction occurrence.
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http://dx.doi.org/10.2215/CJN.05570612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586969PMC
March 2013

Hydroxychloroquine in systemic lupus erythematosus: results of a French multicentre controlled trial (PLUS Study).

Ann Rheum Dis 2013 Nov 10;72(11):1786-92. Epub 2012 Nov 10.

UPMC, Université Paris 6, , Paris, France.

Introduction: Hydroxychloroquine (HCQ) is an important medication for treating systemic lupus erythematosus (SLE). Its blood concentration ([HCQ]) varies widely between patients and is a marker and predictor of SLE flares. This prospective randomised, double-blind, placebo-controlled, multicentre study sought to compare standard and adjusted HCQ dosing schedules that target [HCQ] ≥1000 ng/ml to reduce SLE flares.

Patients And Methods: [HCQ] was measured in 573 patients with SLE (stable disease and SELENA-SLEDAI≤12) treated with HCQ for at least 6 months. Patients with [HCQ] from 100 to 750 ng/ml were randomised to one of two treatment groups: no daily dose change (group 1) or increased HCQ dose to achieve the target [HCQ] (group 2). The primary end point was the number of patients with flares during 7 months of follow-up.

Results: Overall, mean [HCQ] was 918±451 ng/ml. Active SLE was less prevalent in patients with higher [HCQ]. A total of 171 patients were randomised and followed for 7 months. SLE flare rates were similar in the two groups (25% in group 1 vs 27.6% in group 2; p=0.7), but a significant spontaneous increase in [HCQ] in both groups between inclusion and randomisation strongly suggested improved treatment adherence. Patients at the therapeutic target throughout follow-up tended to have fewer flares than those with low [HCQ] (20.5% vs 35.1%, p=0.12).

Conclusions: Although low [HCQ] is associated with higher SLE activity, adapting the HCQ dose did not reduce SLE flares over a 7-month follow-up.
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http://dx.doi.org/10.1136/annrheumdis-2012-202322DOI Listing
November 2013

Development and validation of a predictive model for death in acquired severe ADAMTS13 deficiency-associated idiopathic thrombotic thrombocytopenic purpura: the French TMA Reference Center experience.

Haematologica 2012 Aug 11;97(8):1181-6. Epub 2012 May 11.

Service de Médecine Interne, Hôpital Charles Nicolle, Rouen, France.

Background: Acquired thrombotic thrombocytopenic purpura is still associated with a 10-20% death rate. It has still not been possible to clearly identify early prognostic factors of death. This study involved thrombotic thrombocytopenic purpura patients with acquired severe (<10% of normal activity) ADAMTS13 deficiency and aimed to identify prognostic factors associated with 30-day death.

Design And Methods: The study involved a prospective cohort of patients and was carried out between October 2000 and August 2010. A validation cohort of patients was set up from September 2010 to August 2011. Altogether, 281 (analysis cohort) and 66 (validation cohort) consecutive adult thrombotic thrombocytopenic purpura patients with acquired severe ADAMTS13 deficiency were enrolled. The study evaluated 30-day mortality after treatment initiation according to characteristics at inclusion.

Results: Non-survivors (11%) were older (P=10(-6)) and more frequently presented arterial hypertension (P=5.10(-4)) and ischemic heart disease (P=0.013). Prognosis was increasingly poor with age (P=0.004). On presentation, cerebral manifestations were more frequent in non-survivors (P=0.018) and serum creatinine level was higher (P=0.008). The most significant independent variables determining death were age, severe cerebral involvement and LDH level 10 N or over. A 3-level risk score for early death was defined and confirmed in the validation cohort using these variables, with higher values corresponding to increased risk of early death.

Conclusions: A risk score for early death was defined in patients with thrombotic thrombocytopenic purpura and validated on an independent cohort. This score should help to stratify early treatment and identify patients with a worse prognosis.
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http://dx.doi.org/10.3324/haematol.2011.049676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3409815PMC
August 2012

Splenectomy and/or cyclophosphamide as salvage therapies in thrombotic thrombocytopenic purpura: the French TMA Reference Center experience.

Transfusion 2012 Nov 8;52(11):2436-44. Epub 2012 Mar 8.

Service de Néphrologie, Dialyse et Transplantation, Service des Maladies du Sang, Hôpital d'Angers, and Inserm U892 UMR S892, Université d'Angers, Angers, France.

Background: The objective was to assess the efficacy and safety of splenectomy and cyclophosphamide as salvage therapies in severe thrombotic thrombocytopenic purpura (TTP).

Study Design And Methods: During a 10-year period, patients who did not improve with plasma exchanges, steroids, vincristine, and/or rituximab were considered for splenectomy or cyclophosphamide. Patients with a documented severe (<10% of normal value) acquired ADAMTS13 deficiency are reported here.

Results: Eighteen patients with a severe acquired ADAMTS13 deficiency required a salvage therapy. Thirteen patients had a splenectomy 19 (interquartile range [IQR], 10-51) days after TTP diagnosis. One patient died the day after splenectomy. The remaining patients improved platelets (PLTs) until Day 6, along with a rapid and major lactate dehydrogenase improvement. Six patients, however, subsequently experienced a transient worsening. Durable PLT count recovery in survivors was observed within 13 (IQR, 11.5-25.5) days. Postoperative complications included thromboembolic events (two cases) and infections (five cases). Five patients received pulses of cyclophosphamide 12 (IQR, 12-15) days after TTP diagnosis. All patients recovered PLTs 10 (IQR, 9-24) days after the first pulse and two experienced a transient worsening. Three patients experienced infections. Three relapses occurred 5 months, 2.5 years, and 4.5 years after splenectomy and one relapse occurred 3.5 years after cyclophosphamide. After a 2.5 (IQR, 0.75-6.2)-year follow-up, the overall survival was 94%.

Conclusion: Cyclophosphamide and splenectomy provide comparable high remission rates in severe TTP with acceptable side effects and should be considered in the more severe patients who do not improve with other therapies.
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http://dx.doi.org/10.1111/j.1537-2995.2012.03578.xDOI Listing
November 2012

Scleroderma renal crisis: a retrospective multicentre study on 91 patients and 427 controls.

Rheumatology (Oxford) 2012 Mar 15;51(3):460-7. Epub 2011 Nov 15.

Department of Internal Medicine, Hôpital Cochin, Paris Cedex 14, France.

Objective: Scleroderma renal crisis (SRC) is a severe manifestation of SSc, whose prognosis remains severe, despite treatment with angiotensin-converting-enzyme inhibitor and dialysis. This study was undertaken to describe SRC characteristics, prognosis and outcome, and evaluate the responsibility of CSs in its occurrence.

Methods: Analysis concerned 91 SSc patients with SRC who were compared with 427 non-SRC-SSc patients taken as controls.

Results: Among the 91 SRC patients, 71 (78.0%) had high blood pressure, 53 (58.2%) hypertensive encephalopathy and 51 (56.0%) thrombotic microangiopathy; 64 (70.3%) had received CSs before or concomitantly with SRC vs 156 (36.5%) non-SRC-SSc patients (P < 0.001). Treated SRC patients also received more prednisone 29.3 (28.4) vs 3.6 (9.9) mg than controls (P < 0.001). SRC clinical outcomes were poor: 49 (53.8%) patients required dialysis, which was definitive for 38. Thirty-seven (40.7%) SRC patients died vs 10.8% of the controls (P < 0.001). Death was most frequent among dialysed patients who never recovered renal function (22 vs 2) and 13 never-dialysed SRC patients died.

Conclusions: Although SRC prognosis has improved markedly, SRC remains a severe manifestation of SSc, despite treatment with angiotensin-converting enzyme inhibitor and dialysis. CSs contributed significantly to SRC occurrence.
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http://dx.doi.org/10.1093/rheumatology/ker271DOI Listing
March 2012

Efficacy and safety of first-line rituximab in severe, acquired thrombotic thrombocytopenic purpura with a suboptimal response to plasma exchange. Experience of the French Thrombotic Microangiopathies Reference Center.

Crit Care Med 2012 Jan;40(1):104-11

Service d'Hématologie Clinique et de Thérapie Cellulaire, AP-HP, Groupe Hospitalier Pitié-Salpétrière, UPMC Univ Paris 6, Paris, France.

Objective: To assess the efficacy and safety of rituximab in adults responding poorly to standard treatment for severe autoimmune thrombotic thrombocytopenic purpura.

Design: Open-label prospective study. Outcomes in the survivors were compared to those of 53 historical survivors who were given therapeutic plasma exchange alone or with vincristine.

Setting: Hospitals belonging to the Reference Network for Thrombotic Microangiopathies in France.

Patients: Twenty-two adults with either no response or a disease exacerbation when treated with intensive therapeutic plasma exchange.

Intervention: Add-on rituximab therapy, four infusions over 15 days.

Measurements And Main Results: One patient died despite two rituximab infusions. In the rituximab-treated patients, the time to a durable remission was significantly shortened (p = .03), although the plasma volume required to achieve a durable remission was not significantly different compared to the controls. Platelet count recovery occurred within 35 days in all 21 survivors, compared to only 78% of the historical controls (p < .02). Of the rituximab-treated patients, none had a relapse within the first year but three relapsed later on. In patients treated with rituximab, a rapid and profound peripheral B-cell depletion was produced, lasting for 9 months and correlating with higher a disintegrin and metalloproteinase with thrombospondin-13 activity and lower anti-a disintegrin and metalloproteinase with thrombospondin-13 antibody titers. These differences were no longer significant after 12 months. No severe side effects occurred.

Conclusions: Adults with severe thrombocytopenic purpura who responded poorly to therapeutic plasma exchange and who were treated with rituximab had shorter overall treatment duration and reduced 1-yr relapses than historical controls.
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http://dx.doi.org/10.1097/CCM.0b013e31822e9d66DOI Listing
January 2012

Gammopathy with IgA mesangial deposition provides a monoclonal model of IgA nephritogenicity and offers new insights into its molecular mechanisms.

Nephrol Dial Transplant 2011 Dec 31;26(12):3930-7. Epub 2011 Mar 31.

Universite de Limoges, Limoges, France.

Background: Henoch-Schönlein purpura (HSP) and IgA nephropathy (IgAN) are characterized by mesangial deposition of polyclonal IgA eventually showing aberrant glycosylation, affinity for mesangial cells and/or co-precipitation with antigen, bacterial peptides, autoantibodies or soluble receptors. IgA were also suggested to be negatively charged and predominantly of λ type but rarely in a monoclonal form.

Methods: A gammopathy case with HSP provided us with a unique molecularly defined nephritogenic IgA1λ. Immunological analysis, biological activities, glycosylation analysis and finally IgA sequence were determined.

Results: Compared to IgA1 from healthy subjects or IgAN patients, IgA1 CAT showed hyposialylation but no hypogalactosylation, in agreement with underexpression of sialyltransferase genes by the plasma cell clone. IgA variable domains had low pIs with negatively charged complementarity-determining regions. Weak reactivity appeared against the cationic autoantigen lactoferrin, which was, however, absent from kidney deposits. Deposition also occurred in mice upon injection of only the polymeric form of IgA1 CAT, despite whether or not co-injected with lactoferrin.

Conclusions: This monoclonal model of IgA nephritogenicity strongly suggests that beside hinge region glycosylation, V domains play a role in IgA stability and pathogenicity and supports the hypothesis that responses against cationic epitopes from pathogens or autoantigens may select negatively charged complementarity-determining regions prone either to bind charged structures of the mesangium or to promote by themselves IgA aggregation and deposition.
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http://dx.doi.org/10.1093/ndt/gfr131DOI Listing
December 2011

Life-threatening drug-associated hyperkalemia: a retrospective study from laboratory signals.

Pharmacoepidemiol Drug Saf 2011 Jul 16;20(7):747-53. Epub 2011 Mar 16.

CHU de Toulouse, Service de Pharmacologie Clinique, Centre Midi-Pyrénées de Pharmacovigilance, de Pharmacoépidémiologie et d'Informations sur le Médicament, F-31000 Toulouse, France.

Purpose: Life-threatening hyperkalemia may be induced by drugs and preventable in at-risk patients. This study was designed to describe cases of 'serious' drug-associated hyperkalemia.

Methods: Adult subjects with a serum potassium concentration above 6.5 mmol/L detected at admission or during hospital stay in nephrology, cardiology, geriatric, emergency or intensive care units were identified by biology laboratories of hospitals and clinics located in Midi-Pyrenees (southwest France). Patients dialyzed for end-stage kidney disease were excluded. Data were collected from medical files. Hyperkalemia was defined as drug-associated if at least one drug known to increase serum potassium concentration was taken when hyperkalemia occurred (among drugs taken in outpatient care for hyperkalemia detected at admission and among drugs taken in outpatient care and continued at hospital and drugs introduced from admission for hyperkalemia detected during hospital stay).

Results: Of 168 hyperkalemia cases, 102 (60.7%) were classified as drug-associated. They concerned elderly patients (mean age: 76.1 years) often having arterial hypertension and/or cardiac diseases (88.2%). Risk factors, mainly acute kidney failure, were observed in almost all cases (98.0%). Drugs predominantly involved were angiotensin-converting enzyme inhibitors (47.1%), spironolactone (41.2%), angiotensin II receptor antagonists (23.5%) and potassium supplements (23.5%). In 10% of cases, death could be attributed to hyperkalemia.

Conclusions: Laboratory databases allowed an exhaustive identification of hyperkalemia cases. The frequency of drug-related hyperkalemia and their characteristics suggest that treatment with drugs known to increase serum potassium concentration can be inappropriate, especially regarding associations or indications, and is highly risky for predisposed patients.
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http://dx.doi.org/10.1002/pds.2128DOI Listing
July 2011

[Between the creation of the arteriovenous shunt and the dialysis: a convenient moment for patient education?].

Nephrol Ther 2011 Jul 8;7(4):207-10. Epub 2010 Dec 8.

Association d'aide aux insuffisants rénaux, 10, impasse de la Flambère, 31300 Toulouse, France.

The majority of the researchers having worked on the psychology-nephrology agree to say that the stake in dialysis patient is lived as a major traumatism. Do we consequently have to understand that the announcement of the renal insufficiency accompanied with a medical follow-up indeed upstream to the stake in dialysis cannot require a preventive value? To arrest various stages in the progress of the person reached by a renal pathology helps us to understand in what way the psychic temporality is different from the real time. Doctors, nursing, psychologists seem sometimes amazed to notice that the patient did not integrate certain elements of reality, cannot hear, accept his condition to be sick whereas he has a crowd of information or what it was "warned". In supporting us of clinical examples, we advance the hypothesis according to which the fistula arterio-venous as first physical burglary seems too to be traumatic. We wonder if between two of the creation of the arterio-venous fistula and the stake in dialysis is a convenient moment to inform the patient and watch that he welcomes as good as possible the treatment.
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http://dx.doi.org/10.1016/j.nephro.2010.11.001DOI Listing
July 2011

Predictive features of severe acquired ADAMTS13 deficiency in idiopathic thrombotic microangiopathies: the French TMA reference center experience.

PLoS One 2010 Apr 23;5(4):e10208. Epub 2010 Apr 23.

Service d'Hématologie et de Thérapie Cellulaire, AP-HP, Hôpital Saint-Antoine, Paris, France.

Severe ADAMTS13 deficiency occurs in 13% to 75% of thrombotic microangiopathies (TMA). In this context, the early identification of a severe, antibody-mediated, ADAMTS13 deficiency may allow to start targeted therapies such as B-lymphocytes-depleting monoclonal antibodies. To date, assays exploring ADAMTS13 activity require skill and are limited to only some specialized reference laboratories, given the very low incidence of the disease. To identify clinical features which may allow to predict rapidly an acquired ADAMTS13 deficiency, we performed a cross-sectional analysis of our national registry from 2000 to 2007. The clinical presentation of 160 patients with TMA and acquired ADAMTS13 deficiency was compared with that of 54 patients with detectable ADAMTS13 activity. ADAMTS13 deficiency was associated with more relapses during treatment and with a good renal prognosis. Patients with acquired ADAMTS13 deficiency had platelet count < 30 x 10(9)/L (adjusted odds ratio [OR] 9.1, 95% confidence interval [CI] 3.4-24.2, P<.001), serum creatinine level < or =200 micromol/L (OR 23.4, 95% CI 8.8-62.5, P<.001), and detectable antinuclear antibodies (OR 2.8, 95% CI 1.0-8.0, P<.05). When at least 1 criteria was met, patients with a severe acquired ADAMTS13 deficiency were identified with positive predictive value of 85%, negative predictive value of 93.3%, sensitivity of 98.8%, and specificity of 48.1%. Our criteria should be useful to identify rapidly newly diagnosed patients with an acquired ADAMTS13 deficiency to better tailor treatment for different pathophysiological groups.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0010208PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2859048PMC
April 2010

[An unusual retroperitoneal tumor].

Ann Pathol 2010 Feb 27;30(1):36-8. Epub 2009 Nov 27.

Service d'anatomie pathologique et histologie-cytologie Rangueil, 1 avenue Jean-Poulhès, Toulouse, France.

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http://dx.doi.org/10.1016/j.annpat.2009.10.018DOI Listing
February 2010

[Acute immuno-allergic interstitial nephritis after treatment with fluindione. Seven cases].

Nephrol Ther 2009 Jul 7;5(4):292-8. Epub 2009 Apr 7.

Centre hospitalier de Bigorre-Tarbes, service d'hémodialyse, boulevard de Maréchal-de-Lattre-de-Tassigny, 65013 Tarbes cedex 9, France.

We report seven cases of patients treated with fluindione, who presented with acute renal failure, associated with clinical features of allergy: poor status, fever, dyspnea, lymphadenopathy and erythroderma. All patients had elevated eosinophil counts. Renal biopsy disclosed in all cases a tubulo-interstitial nephritis with or without granuloma. The responsibility of fluindione, an oral anticoagulant widely used in France could be demonstrated. To our knowledge, there are only three reports of single cases of acute renal failure related to fluindione published so far to date. This serious side effect of fluindione should be recognized.
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http://dx.doi.org/10.1016/j.nephro.2009.01.008DOI Listing
July 2009

[Kidney involvement in systemic necrotizing vasculitis].

Rev Prat 2008 Mar;58(5):499-506

Service de néphrologie et immunologie clinique, hôpital de Rangueil, Toulouse.

Renal involvement occurs in 75% of the patients with systemic necrotizing small-vessel vasculitis ie microscopic polyangiitis, Wegener's granulomatosis or Churg-Strauss syndrome. Small-vessel vasculitis may also be limited to the kidney. The hallmark of small-vessel pauci-immune vasculitides consists of necrotizing glomerulonephritis and resultant crescent formation, without immune-complex deposits in vessel walls. The resulting renal manifestations consist of haematuria, proteinuria and rapidly progressive renal failure. ANCA testing has a 90% sensitivity for renal-associated pauci-immune small-vessel vasculitis. Kidney biopsy is required for demonstrating necrotizing vasculitis. Early identification and prompt treatment are mandatory to avoid early mortality and end-stage renal failure. Induction therapy combines corticosteroids and IV cyclophosphamide. Plasma exchange in indicated in the patients presenting with active renal lesions and serum creatinine > 500 micromol/L. Maintenance of immunosuppressive therapy is required for 18 months. Twenty to 50% of the patients relapse during follow-up, and close monitoring is warranted for early detection.
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March 2008

Blood concentrations of hydroxychloroquine and its desethyl derivative correlate negatively with the percentage of CD45RO+ cells among CD4+ lymphocytes in hydroxychloroquine-treated lupus patients.

Ann N Y Acad Sci 2007 Jun;1108:41-50

Service de Pharmacologie Clinique, Unité de Pharmacoépidémiologie EA3696, INSERM IFR 126, Faculte de Médecine, Université Paul Sabatier 31000 Toulouse, France.

The objective of the study was to investigate the influence of the blood concentrations of hydroxychloroquine ([HCQ]) and its derivative desethylhydroxychloroquine ([DHCQ]) on lymphocyte activation or differentiation in HCQ-treated lupus patients. We studied the correlations between [HCQ], [DHCQ], and the frequency of various lymphocyte subsets in 58 HCQ-treated lupus patients (mean HCQ dose: 4.93 +/- 1.58 mg/kg/day; mean duration of the disease: 122 +/- 64 months). [HCQ] and [DHCQ] were determined by high-performance liquid chromatography (HPLC). Lymphocyte markers were studied by flow cytometry using monoclonal anti-CD3, -CD4, -CD8, -CD25, -DR, -CD45RA, -CD45RO, -CD19, -CD38, and -CD86 antibodies. sIL2-R serum concentrations were measured by enzyme-linked immunosorbent assay (ELISA). [HCQ] and [DHCQ] were 599.9 ng/mL (median: 529.5; range: 55-1935) and 353.43 (median: 286 ng/mL; range: 118-1090). In a multiple regression analysis, [HCQ] and [DHCQ] were associated with the HCQ prescribed dose in mg/kg/day (P = 0.0002 and P = 0.03) and with compliance to the treatment (P = 0.004 and P = 0.03). We found a negative correlation between [HCQ], [DHCQ], and the CD45RO+ cell frequency among CD3+CD4+ cells (P = 0.03 and P = 0.007, respectively). Other lymphocyte subset markers (LSMs) and sIL2-R concentrations were not significantly associated with [HCQ] or [DHCQ]. In the multiple regression analysis, CD45RO+ expression was negatively influenced by [HCQ] (P = 0.005), and positively influenced by smoking habits (P = 0.005) and age (P = 0.005). Similar results were found in the multivariate model including [DHCQ]. Disease activity and taking more than 10 mg/day of corticosteroids or an immunosuppressive drug did not influence CD45RO+ expression. Lupus patients had less CD3+CD4+CD45RO+ cells than controls (P = 0.03). In lupus patients, HCQ and DHCQ may alter the generation or the blood circulation of CD4+CD45RO+ lymphocytes in a concentration-dependent pattern.
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http://dx.doi.org/10.1196/annals.1422.005DOI Listing
June 2007

Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome.

J Am Soc Nephrol 2006 Jul 8;17(7):2017-25. Epub 2006 Jun 8.

Assitance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d'Immunologie Biologique, Paris cedex 15, France.

Hemolytic uremic syndrome (HUS) is characterized by the triad of thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure. The non-Shiga toxin-associated HUS (atypical HUS [aHUS]) has been shown to be a disease of complement dysregulation. Mutations in the plasma complement regulators factor H and factor I and the widely expressed membrane cofactor protein (MCP; CD46) have been described recently. This study looked for MCP mutations in a panel of 120 patients with aHUS. In this cohort, approximately 10% of patients with aHUS (11 patients; nine pedigrees) have mutations in MCP. The onset typically was in early childhood. Unlike patients with factor I or factor H mutations, most of the patients do not develop end-stage renal failure after aHUS. The majority of patients have a mutation that causes reduced MCP surface expression. A small proportion expressed normal levels of a dysfunctional protein. As in other studies, incomplete penetrance is shown, suggesting that MCP is a predisposing factor rather than a direct causal factor. The low level of recurrence of aHUS in transplantation in patients with MCP mutations is confirmed, and the first MCP null individuals are described. This study confirms the association between MCP deficiency and aHUS and further establishes that a deficiency in complement regulation, specifically cofactor activity, predisposes to severe thrombotic microangiopathy in the renal vasculature.
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http://dx.doi.org/10.1681/ASN.2005101051DOI Listing
July 2006

Treatment of hepatorenal syndrome as defined by the international ascites club by albumin and furosemide infusion according to the central venous pressure: a prospective pilot study.

Am J Gastroenterol 2005 Dec;100(12):2702-7

Service d'Hépato-Gastro-Entérologie, Fédération Digestive, Hôpital Purpan, Toulouse, France.

Objective: Hepatorenal syndrome (HRS) is a functional renal failure that occurs late during cirrhosis. The prognosis is extremely poor with a mean survival of 1.7 wks from the time of diagnosis. The aim of the present study was to examine the effects of albumin and furosemide administration tailored to central venous pressure (CVP) on renal function and clinical outcome.

Methods: We treated 20 consecutive patients with HRS. Albumin was given to increase and/or maintain CVP above 3 cm H(2)O. If diuresis remained below 50 mL/h despite effective volume expansion, furosemide was administrated. Patients were considered responders and treatment was discontinued when creatinine clearance rose above 40 mL/min or serum creatinine fell under 132 mumol/L.

Results: The need for albumin varied from patient to patient (extremes 40-600 g) and in the same patient from day to day. All but one needed furosemide. Eleven patients (55%) responded to treatment. In this population, diuresis, serum creatinine, and creatinine clearance were all significantly improved. Creatinine clearance at baseline was predictive of treatment efficacy. Survival increased in these patients compared to nonresponders defined as patients with no improvement in renal function (259 days +/- 113 compared to 14 days +/- 3, p < 0.0005). Response to treatment and the type of HRS were the only variables with an independent prognostic value.

Conclusion: This study shows that HRS as defined by the International Ascites Club can be treated by albumin administration alone or with furosemide given according to the patient's specific need using CVP.
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http://dx.doi.org/10.1111/j.1572-0241.2005.00271.xDOI Listing
December 2005

Influence of antiviral therapy in hepatitis C virus-associated cryoglobulinemic MPGN.

Am J Kidney Dis 2004 Apr;43(4):617-23

Service de Médecine Interne, Pavillon Dieulafoy, CHU Purpan, Toulouse, France.

Background: The influence of hepatitis C virus (HCV) treatment on the course of HCV cryoglobulinemic membranoproliferative glomerulonephritis (MPGN) is controversial.

Methods: Twenty-five patients with nephrotic-range proteinuria, mixed cryoglobulinemia, MPGN proved by renal biopsy, and HCV infection were studied for their response to antiviral treatment.

Results: After first-line treatment with prednisone, furosemide, or plasmapheresis, antiviral therapy with standard or pegylated interferon alfa and ribavirin was introduced in 18 patients. These patients were compared with 7 patients who did not receive antiviral treatment. Mean duration of antiviral treatment was 18 +/- 10 months, with a follow-up of at least 6 months after treatment withdrawal. HCV RNA clearance (sustained virological response) was achieved in 12 of 18 patients. Compared with values before antiviral therapy, a decrease in proteinuria was observed in sustained virological responders at the end of combination therapy, as well as at the end of follow-up (mean, 2.85 +/- 2.2 [SD] versus 1 +/- 1.4 and 0.4 +/- 0.8 g/d, respectively; P < 0.05). In sustained virological responders, cryoglobulin levels at the end of treatment (0.29 +/- 0.4 g/L) and end of follow-up (0.25 +/- 0.4 g/L) were decreased (P < 0.05) compared with pretreatment values (1.38 +/- 2.2 g/L). Conversely, no changes in serum cryoglobulinemia levels were observed in nonresponders or controls. Serum creatinine levels remained stable in the 18 patients with antiviral therapy, regardless of response to treatment.

Conclusion: Anti-HCV treatment improved HCV-associated cryoglobulinemic glomerulonephritis.
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http://dx.doi.org/10.1053/j.ajkd.2003.11.020DOI Listing
April 2004