LG3 fragment of endorepellin is a possible biomarker of severity in IgA nephropathy.

IgA nephropathy (IgAN), the most common primary glomerulonephritis, is characterized by deposition of IgA in the glomerular mesangium. The diagnosis of IgAN still requires a kidney biopsy that cannot easily be repeated in the same patient during follow-up. Therefore, identification of noninvasive urinary biomarkers would be very useful for monitoring patients with IgAN. We first used bidimensional electrophoresis (2DE) coupled to MALDI-TOF-TOF and Western blot to identify some urinary biomarkers associated with IgAN. Urine of IgAN patients showed an increase of albumin fragments, α-1-antitrypsin and α-1-ß-glycoprotein, along with a decrease of a single spot that was identified as the laminin G-like 3 (LG3) fragment of endorepellin. The urinary proteomes of 43 IgAN patients were compared to those of 30 healthy individuals by ELISA. Quantification of LG3 confirmed a significant decrease in the urine of IgAN patients compared to healthy controls, except in ten patients in whom LG3 was increased. These ten patients had a more severe disease with lower glomerular filtration rate values. We found a significant inverse correlation between LG3 levels and glomerular filtration rate in the 43 patients with IgAN, which was not observed in 65 patients with other glomerular diseases including membranous nephropathy (23), lupus nephropathy (13), focal segmental glomerulosclerosis (15), diabetic nephropathy (14), and six patients with nonglomerular diseases. Therefore, we suggest that the LG3 fragment of endorepellin could be associated with IgAN severity and might be related to pathogenesis of IgAN.

Renal biopsy practice in France: results of a nationwide study.

BACKGROUND: Although several risk factors associated with complications after renal biopsy (RB) have been identified, the gold standard for RB procedures remains to be defined. Practices vary widely among nephrologists, depending on personal experience and the availability of particular techniques. The purpose of our study was to depict the main aspects of the practice of RB in adults in France. METHODS: Members of the Société de Néphrologie in France were asked to participate in a questionnaire survey on RB procedures. RESULTS: Eighty-eight nephrologists from 74 units (27 in teaching hospitals, 35 in public general hospitals and 12 in private centres) participated in our study. Native kidney and graft biopsies were performed in 73 and 35 units, respectively. RB activity was highly variable among units, ranging from several hundred to <10 per year. Transjugular renal biopsy was judged to be smoothly accessible in 28 out of 73 units (38.4%). Significant variations in practices were observed regarding patient information before RB, assessment of haemorrhagic risk factors, management of patients with antiplatelet agents and haemorrhagic risk factors, and radiological guidance. Early discharge (<12 h) was the rule in 3 (4.1%) units for native kidney biopsies and in 10 (28.6%) units for graft biopsies. CONCLUSIONS: Our study is the first to provide a representative picture of 'everyday' RB practices in a country. Important variations in procedures were observed. Our study may represent a preliminary step for the elaboration of guidelines for all aspects of RB practices.

D-Penicillamine-induced ANCA-associated crescentic glomerulonephritis in Wilson disease.

Several drugs, including hydralazine and propylthiouracil, can induce antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. d-Penicillamine was implicated in a few patients with rheumatoid arthritis or systemic sclerosis, but in patients with both diseases, ANCA-associated vasculitides were described in the absence of the drug. Therefore, the role of d-penicillamine treatment could not be established. We report the first case of antimyeloperoxidase antibody-associated vasculitis in a patient treated with d-penicillamine for Wilson disease. Because Wilson disease was never associated with ANCA-related nephritis, this case strongly supports that d-penicillamine can induce ANCA-vasculitis. The presentation and rapidly progressive and potentially severe outcome of this complication dramatically contrast with those of membranous and minimal change glomerulopathy, also induced by the sulfhydryl compound.

Differentiated thyroid cancer cell invasion is regulated through epidermal growth factor receptor-dependent activation of matrix metalloproteinase (MMP)-2/gelatinase A.

Mechanisms of invasion in thyroid cancer remain poorly understood. We hypothesized that signaling via the epidermal growth factor receptor (EGFR) stimulates thyroid cancer cell invasion by altering the expression and cleavage of matrix metalloproteinases (MMPs). Papillary and follicular carcinoma cell lines were treated with EGF, the EGFR tyrosine kinase inhibitor AG1478, and the MMP inhibitors GM-6001 and Col-3. Flow cytometry was used to detect EGFR. In vitro invasion assays, gelatin zymography, and quantitative reverse transcription-PCR were used to assess the changes in invasive behavior and MMP expression and activation. All cell lines were found to overexpress functional EGFR. EGF stimulated invasion by thyroid cancer cells up to sevenfold (P<0.0001), a process that was antagonized completely by AG1478 and Col-3, partially by GM-6001, but not by the serine protease inhibitor aprotinin. EGF upregulated expression of MMP-9 (2.64- to 8.89-fold, P<0.0001) and membrane type-1 MMP (MT1-MMP, 1.97- to 2.67-fold, P<0.0001). This effect was blocked completely by AG1478 and partially by Col-3. The activation of MMP-2 paralleled MT1-MMP expression. We demonstrate that MMPs are critical effectors of invasion in the papillary and follicular thyroid cancer cell lines studied. Invasion is regulated by signaling through EGFR, an effect mediated by augmentation of gelatinase expression and activation. MMP inhibitors and growth factor antagonists may be effective tumoristatic agents for the treatment of aggressive thyroid carcinomas.

Stage-specific action of matrix metalloproteinases influences progressive hereditary kidney disease.

BACKGROUND: Glomerular basement membrane (GBM), a key component of the blood-filtration apparatus in the in the kidney, is formed through assembly of type IV collagen with laminins, nidogen, and sulfated proteoglycans. Mutations or deletions involving alpha3(IV), alpha4(IV), or alpha5(IV) chains of type IV collagen in the GBM have been identified as the cause for Alport syndrome in humans, a progressive hereditary kidney disease associated with deafness. The pathological mechanisms by which such mutations lead to eventual kidney failure are not completely understood. METHODS AND FINDINGS: We showed that increased susceptibility of defective human Alport GBM to proteolytic degradation is mediated by three different matrix metalloproteinases (MMPs)--MMP-2, MMP-3, and MMP-9--which influence the progression of renal dysfunction in alpha3(IV)-/- mice, a model for human Alport syndrome. Genetic ablation of either MMP-2 or MMP-9, or both MMP-2 and MMP-9, led to compensatory up-regulation of other MMPs in the kidney glomerulus. Pharmacological ablation of enzymatic activity associated with multiple GBM-degrading MMPs, before the onset of proteinuria or GBM structural defects in the alpha3(IV)-/- mice, led to significant attenuation in disease progression associated with delayed proteinuria and marked extension in survival. In contrast, inhibition of MMPs after induction of proteinuria led to acceleration of disease associated with extensive interstitial fibrosis and early death of alpha3(IV)-/- mice. CONCLUSIONS: These results suggest that preserving GBM/extracellular matrix integrity before the onset of proteinuria leads to significant disease protection, but if this window of opportunity is lost, MMP-inhibition at the later stages of Alport disease leads to accelerated glomerular and interstitial fibrosis. Our findings identify a crucial dual role for MMPs in the progression of Alport disease in alpha3(IV)-/- mice, with an early pathogenic function and a later protective action. Hence, we propose possible use of MMP-inhibitors as disease-preventive drugs for patients with Alport syndrome with identified genetic defects, before the onset of proteinuria.

[Pathogenesis of immune glomerulonephritis]. / Mécanismes des glomérulonéphrites immunes.

Immune glomerulonephritis (GN) initially develop as a result of inappropriate immune response, either inadequately directed to self-antigens, or unable to effectively eliminate a foreign antigen. This abnormal immune response leads to the formation of circulating immune complexes, auto-antibodies or self-reactive effector T cells that target glomerular antigens or to the inappropriate regulation of IgA producing lymphocytes (Berger disease) or helper T lymphocyte sub populations (minimal change nephrotic syndrome). In most of the cases, the initial immune injury induces an inflammatory response. However, it is the extent of the interstitial fibrosis which is genetically controlled, that conditioned the evolution of the initial glomerular injury to glomerular sclerosis and progressive renal failure. Recent data on the pathogenesis of the most frequent GN are reported: IgA nephropathy, membranous nephropathy and minimal change nephrotic syndrome. Recent significant advances in the pathophysiology of those glomerular diseases have shed considerable light on the understanding of the underlying disease even if they do not have immediate therapeutic implications.

[Renal biopsy practice: results of a French study and recommendations]. / Pratique de la biopsie rénale: résultat d'une enquête en France, revue de la littérature et recommandations.

BACKGROUND: Although several risk factors associated with complications after renal biopsy (RB) have been identified, recommendations for RB procedures are still lacking. Our working group, appointed by the scientific commission of the Société de néphrologie in France, aimed to depict the main aspects of the practice of RB in adults in France, before establishing some guidelines. METHODS: Members of the Société de néphrologie in France were asked to participate to a questionnaire survey on RB procedures. RESULTS: Eighty-eight nephrologists from 74 units (27 in teaching hospitals, 35 in public general hospitals, and 12 in private centers) participated in our study. Native kidney and graft biopsies were performed in 73 and 35 units, respectively. RB activity was highly variable among units, ranging from several hundred to less than ten per year. Transjugular RB was judged to be smoothly accessible in 28 out of 73 units (38.4%). Significant variations in practices were observed regarding patient information before RB, assessment of hemorrhagic risk factors, care of patients with antiplatelet agents and hemorrhagic risk factors, and radiological guidance. Early discharge (<12 hours) was the rule in three (4.1%) units for native kidney biopsies and in ten (28.6%) units for graft biopsies. CONCLUSIONS: Our study is the first to provide a representative picture of "everyday" RB practices in a country. Consensual recommendations on all points mentioned are provided here.

Patterns of noncryoglobulinemic glomerulonephritis with monoclonal Ig deposits: correlation with IgG subclass and response to rituximab.

BACKGROUND AND OBJECTIVES: Several different entities have recently been described among glomerular diseases associated with monoclonal IgG deposits. The aim of this study was to describe the distribution of the different pathologic subtypes of IgG-associated glomerulopathy and to evaluate the IgG isotype involved in these diseases. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a retrospective study including all patients with glomerular deposits of monoclonal IgG referred to three nephrology departments between 1980 and 2008. RESULTS: Twenty-six patients were included. Nephrotic syndrome was almost constantly associated with a renal dysfunction in 14 of 26 patients. The presence of M-spike was detected in only 30% of the patients, and an overt hematologic malignancy (myeloma, lymphoma) was identified in 9 of 26 patients. Patients were almost equally divided into two distinct histologic patterns: membranous nephropathy (MN) or membranoproliferative glomerulonephritis (MPGN). IgG3 deposits were identified in 80% of patients with MPGN, whereas IgG1 deposits were present in 64% of patients with MN. Ultrastructural study showed that immune deposits were nonorganized in most patients. Seven patients were treated with rituximab with excellent results: five of seven had a complete remission of the nephrotic syndrome and two of seven had a partial response. After a mean 24-month follow-up, only one patient experienced relapse of the nephropathy. CONCLUSIONS: GN with monoclonal Ig deposits can be associated with MPGN or MN, which are correlated with IgG3 and IgG1 isotypes, respectively. Rituximab appears to have a very favorable benefit-to-risk ratio for patients with no overt hematologic malignancy.

[High cardiovascular complications in systemic lupus erythematosus: physiopathology and risk management]. / Le risque cardiovasculaire accru du lupus: données physiopathologiques et thérapeutiques.

Today, cardiovascular mortality is the first cause of mortality in systemic lupus erythematosus (SLE). A 40-year-old woman with SLE is over 50 times more likely to have a myocardial infraction than a healthy woman of similar age. The high CV risk has a double origin: an early and progressive atherosclerosis and a prothrombotic propensity. Multiple factors are incriminated, including a higher prevalence of traditional CV risk factors in SLE population, as well as SLE-specific factors. Autoantibodies can modify lipid profile, induce tissue factor synthesis, favour clotting and endothelial apoptosis. Moreover, endothelial dysfunction and permanent chronic inflammation are present. Treatments are occasionally involved. To reduce more efficiently CV risk in SLE patients, we propose to consider SLE has a complete CV risk factor that should be implemented for CV risk management. This medical procedure of CV risk estimation is unusual in young patients. Its implementation in SLE patients requires a modification of medical practices. CV risk management in SLE patients include identification of optimal targets for each traditional risk factor and SLE specific treatments.

HAART-related nephropathies in HIV-infected patients.

There is no doubt that highly active antiretroviral therapy (HAART) has been the most important progress in the therapy of human immunodeficiency virus (HIV)-infected patients in the last decade. A growing number of observations suggest that the beneficial effects of HAART also include improvement of HIV-related renal complications. Consequently, the cohort of HIV-infected patients requiring HAART has increased and includes patients with preexisting nephropathies, whether related or unrelated to HIV infection. However, some antiretroviral drugs may have renal- and life-threatening side-effects, especially if underlying renal abnormalities exist. In this review, we focus on those aspects that require particular attention in preventing new health complications in HIV-infected patients.