Wirksamkeit der adjuvanten Strahlentherapie bei regionalen Lymphknotenmetastasen des malignen Melanoms

Bei unserer Untersuchung handelte es sich um eine retrospektive Studie, deren Ziel es war, den Nutzen der adjuvanten Strahlentherapie nach einer Lymphknotendissektion bei Patienten mit malignen Melanomen und Lymphknotenmetastasen zu evaluieren. Aus diesem Grund verglichen wir die Gruppe von 42 Patienten, die sich einer adjuvanten Bestrahlung nach der Lymphknotendissektion unterzogen haben, mit einer Kontrollgruppe, bei der nur eine Dissektion durchgeführt wurde (matched pairs). Vorraussetzung für die Aufnahme in unser Patientenkollektiv war eine positive Histologie der Dissektats, kein zweites Malignom, keine Fernmetastasen und die Durchführung der Operation und der Bestrahlung in unserer Universitätsklinik. Die Bestrahlung der 42 Patienten fand mit Einzeldosen von 1,8-3 Gy statt. Sie wurde 3-5 mal pro Woche bis zu einer Gesamtdosis von 46-55 Gy verabreicht, insgesamt über eine Zeitspanne von 2-6 Wochen. Zunächst untersuchten wir in unserer Kontrollgruppe den Einfluss von: Geschlecht, Alter, Lokalisation des Primärtumors, Dicke, Clark Level, Histologie, TNM Stadium, befallenen LK in dem Dissektat, Kapselperforation, Zeitspanne zwischen dem Primärtumor und dem Auftreten der Lymphknotenmetastasen auf die regionäre Rezidivrate und die Überlebenszeit. Statistisch konnte keine Abhängigkeit zwischen diesen Einflussfaktoren und den Zielgrößen (regionäre Rezidivrate und Überlebenszeit) nachgewiesen werden. Nur die Daten bezüglich der Anzahl der befallenen Lymphknoten waren nah an der Signifikanz (p=0,09). Als nächstes haben wir unseren beiden Gruppen bezüglich der regionären Lymphknotenrezidivraten, die Rezidivraten und die Überlebensraten verglichen. In den Gruppen wurden im Verlauf der Studie jeweils 9 Lymphknotenrezidive im OP-Bereich beobachtet. Die regionäre 2- bzw. 5-Jahres-Rezidivfreiheitsrate betrug in der Bestrahlungsgruppe 81% bzw. 70%. Ähnlich sahen die Zahlen in der Kontrollgruppe aus ( 76% bzw. 72%), so daß man bezüglich der regionären Lymphknotenrezidive keinen Unterschied feststellen konnte (p=0,75 ). Auch in der Frage nach der allgemeinen Rezidivfreiheit waren keine Unterschiede zu finden. In der Bestrahlungsgruppe lagen die 2- bzw. 5- Jahres-Rezidivfreiheitsraten bei 48% bzw. 37%, in der Kontrollgruppe lagen sie bei 44% bzw. 39% (p=0,74). Schließlich haben wir den Einfluss der Bestrahlung auf die Überlebensrate geprüft, aber auch hier waren die Therapiearme gleich wirksam (p=0,35). Die 2- bzw. 5-Jahres-Überlebensrate lag in der Bestrahlungsgruppe bei 58% bzw. 47% vs. 58% bzw. 38% in der Kontrollgruppe. Bezüglich der Nebenwirkungsrate stellte sich die Strahlentherapie als eine gut verträgliche Therapie dar, die Nebenwirkungen (Ödeme, Beweglichkeitseinschränkungen und Sensibilitätseinschränkungen) glichen den der alleinigen Dissektion. Strahlenbedingte Fibrosen kamen nur bei 3 Patienten von 42 vor. Aus unserer Studie geht hervor, daß die Strahlentherapie in unserer Klinik, so wie sie beim malignen Melanom durchgeführt wurde, keine besseren Ergebnisse im Vergleich zu der alleinigen Lymphknotendissektion aufwies. Weder die regionäre Rezidivfreiheit noch die Überlebensrate konnten durch die Bestrahlung verbessert werden. Möglicherweise wäre eine Bestrahlung mit höheren Einzeldosen wirksamer

Multi-population genome-wide association study implicates immune and non-immune factors in pediatric steroid-sensitive nephrotic syndrome

Genetics; Minimal change disease; Paediatric kidney diseaseGenética; Enfermedad de cambios mínimos; Enfermedad renal pediátricaGenètica; Malaltia de canvis mínims; Malaltia renal pediàtricaPediatric steroid-sensitive nephrotic syndrome (pSSNS) is the most common childhood glomerular disease. Previous genome-wide association studies (GWAS) identified a risk locus in the HLA Class II region and three additional independent risk loci. But the genetic architecture of pSSNS, and its genetically driven pathobiology, is largely unknown. Here, we conduct a multi-population GWAS meta-analysis in 38,463 participants (2440 cases). We then conduct conditional analyses and population specific GWAS. We discover twelve significant associations-eight from the multi-population meta-analysis (four novel), two from the multi-population conditional analysis (one novel), and two additional novel loci from the European meta-analysis. Fine-mapping implicates specific amino acid haplotypes in HLA-DQA1 and HLA-DQB1 driving the HLA Class II risk locus. Non-HLA loci colocalize with eQTLs of monocytes and numerous T-cell subsets in independent datasets. Colocalization with kidney eQTLs is lacking but overlap with kidney cell open chromatin suggests an uncharacterized disease mechanism in kidney cells. A polygenic risk score (PRS) associates with earlier disease onset. Altogether, these discoveries expand our knowledge of pSSNS genetic architecture across populations and provide cell-specific insights into its molecular drivers. Evaluating these associations in additional cohorts will refine our understanding of population specificity, heterogeneity, and clinical and molecular associations.K.I., K.N., and K.T. were supported by the Japan Agency for Medical Research and Development (AMED) under grant number JP17km0405108h0005. K.T. was supported by the Japan Agency for Medical Research and Development (AMED) under grants JP17km0405205h0002 and 18km0405205h0003. K.I., T.H., C.N., and K.N. were supported by the Japan Society for the Promotion of Science (JSPS) under Grant-in-Aid for Scientific Research fostering Joint International Research (B) 18KK0244. K.I., X.J., T.H., C.N., and K.N. were supported by the Japan Society for the Promotion of Science (JSPS) under Grant-in-Aid for Scientific Research fostering Joint International Research (B) 21KK0147. This work is supported by the Department of Defense (PR190746, PR212415) to S.S-C., by the National Center for Advancing Translational Sciences, National Institutes of Health (Grant Number UL1TR001873) to S.S-C., and by the National Institute of Health Grant RC2DK122397, M.Sam, S.S-C., M.R.P., and F.H. A.M. received support from the American Society of Nephrology KidneyCure Ben J. Lipps Research Fellowship. Y.G. received support from the NEPTUNE Career Development Award. P.R. and H.D. were funded by European Research Council grant ERC-2012- ADG_20120314 (grant agreement 322947) and Agence Nationale pour la Recherche “Genetransnephrose” grant ANR-16-CE17-004-01. M.Sam. was supported by NIH grants R01DK119380, 2U54DK083912, and a gift from The Pura Vida Kidney Foundation. The Nephrotic Syndrome Study Network (NEPTUNE) is part of the Rare Diseases Clinical Research Network (RDCRN), which is funded by the National Institutes of Health (NIH) and led by the National Center for Advancing Translational Sciences (NCATS) through its Division of Rare Diseases Research Innovation (DRDRI). NEPTUNE is funded under grant number U54DK083912 as a collaboration between NCATS and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Additional funding and/or programmatic support is provided by the University of Michigan, NephCure Kidney International, and the Halpin Foundation. RDCRN consortia are supported by the RDCRN Data Management and Coordinating Center (DMCC), funded by NCATS and the National Institute of Neurological Disorders and Stroke (NINDS) under U2CTR002818. The authors wish to thank Seong Kyu Han, Ph.D. (Boston Children’s Hospital and Harvard Medical School) for his assistance in creating figures

Serum Protein Signatures Using Aptamer-Based Proteomics for Minimal Change Disease and Membranous Nephropathy

Introduction: Minimal change disease (MCD) and membranous nephropathy (MN) are glomerular diseases (glomerulonephritis [GN]) that present with the nephrotic syndrome. Although circulating PLA2R antibodies have been validated as a biomarker for MN, the diagnosis of MCD and PLA2R-negative MN still relies on the results of kidney biopsy or empirical corticosteroids in children. We aimed to identify serum protein biomarker signatures associated with MCD and MN pathogenesis using aptamer-based proteomics. Methods: Quantitative SOMAscan proteomics was applied to the serum of adult patients with MCD (n = 15) and MN(n = 37) and healthy controls (n = 20). Associations between the 1305proteins detected with SOMAscan were assessed using multiple statistical tests, expression pattern analysis, and systems biology analysis. Results: A total of 208 and 244 proteins were identified that differentiated MCD and MN, respectively, with high statistical significance from the healthy controls (Benjamin-Hochberg [BH] P \u3c 0.0001). There were 157 proteins that discriminated MN from MCD (BH P \u3c 0.05). In MCD, 65 proteins were differentially expressed as compared with MN and healthy controls. When compared with MCD and healthy controls, 44 discriminatory proteins were specifically linked to MN. Systems biology analysis of these signatures identified cell death and inflammation as key pathways differentiating MN from MCD and healthy controls. Dysregulation of fatty acid metabolism pathways was confirmed in both MN and MCD as compared with the healthy subjects. Conclusion: SOMAscan represents a promising proteomic platform for biomarker development in GN. Validation of a greater number of discovery biomarkers in larger patient cohorts is needed before these data can be translated for clinical care

Pathophysiological lessons from rare associations of immunological disorders

Rare associations of immunological disorders can often tell more than mice and rats about the pathogenesis of immunologically mediated human kidney disease. Cases of glomerular disease with thyroiditis and Graves’ disease and of minimal change disease with lymphoepithelioma-like thymic carcinoma and lymphomatoid papulosis were recently reported in Pediatric Nephrology. These rare associations can contribute to the unraveling of the pathogenesis of membranous nephropathy (MN) and minimal change disease (MCD) and lead to the testing of novel research hypotheses. In MN, the target antigen may be thyroglobulin or another thyroid-released antigen that becomes planted in the glomerulus, but other scenarios can be envisaged, including epitope spreading, polyreactivity of pathogenic antibodies, and dysregulation of T regulatory cells, leading to the production of a variety of auto-antibodies with different specificities [immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX syndrome)]. The occurrence of MCD with hemopathies supports the role of T cells in the pathogenesis of proteinuria, although the characteristics of those T cells remain to be established and the glomerular permeability factor(s) identified

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10-12) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10-14), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10-103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10-49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10-93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10-23 and OR = 3.39, P = 5.2 × 10-82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk

Physiopathologie des glomérulopathies extramembraneuses

Les glomérulopathies extramembraneuses (GEM) sont des maladies rénales induites par le dépôt de complexes immuns et de complément sur le versant externe de la paroi des capillaires glomérulaires. Elles sont responsables de fuites de protéines dans les urines et d’insuffisance rénale. Dans les 10 dernières années, des progrès considérables ont été réalisés dans la compréhension de la maladie, conduisant à la description de trois mécanismes distincts. Dans la forme allo-immune du nouveau-né, les anticorps sont dirigés contre l’endopeptidase neutre (EPN), une protéine du podocyte, absente chez les mères qui s’immunisent pendant la grossesse contre cet antigène présenté par les cellules placentaires. Cette enzyme a été le premier antigène du podocyte décrit dans les GEM. Les formes de l’adulte les plus fréquentes sont des maladies auto-immunes sans cause identifiée, caractérisées par la production d’anticorps dirigés contre un autre antigène du podocyte, le récepteur de type M de la phospholipase A2 (PLA2R1). Les anticorps anti-PLA2R1 sont détectés chez 70 à 80 % des patients avant traitement immunosuppresseur, et occasionnellement dans les formes secondaires de GEM. Des variants des gènes PLA2R1 et HLA-DQA1 sont associés de façon très significative à la GEM primitive chez les patients caucasiens, répondant ainsi à la définition de gènes de prédisposition. Un troisième mécanisme implique l’immunisation contre une protéine étrangère, la sérum albumine bovine (BSA) cationique, qui est responsable de rares formes de GEM chez le jeune enfant. La maladie se développe car l’antigène qui porte des charges positives se plante dans la paroi du capillaire glomérulaire chargée négativement où il sert de cible aux anticorps anti-BSA circulants. Cette observation met en lumière un rôle possible des antigènes alimentaires et de l’environnement dans les GEM

[Idiopathic and secondary membranous nephropathies].

International audienceAntibodies to neutral endopeptidase, a podocyte protein, are responsible for rare alloimmune neonatal membranous nephropathy that develops in children from neutral endopeptidase-deficient mothers. Neutral endopeptidase was the first podocyte antigen described in human membranous nephropathy. PLA2R1, the type-M receptor of soluble phospholipase A2, is a major target antigen in so-called idiopathic membranous nephropathy in adults. Antibodies to PLA2R1 are detected in 60 to 80% of patients before immunosuppressive treatment, and are only occasionally found in secondary membranous nephropathy. To date, they have not been detected in other pathological conditions and in healthy individuals. PLA2R1 and HLA-DQA1 gene variants defined by single nucleotide polymorphisms are strongly associated with idiopathic membranous nephropathy in patients of white ancestry, and can thus be considered as predisposing genes. In addition to their diagnostic value, anti-PLA2R1 antibodies can be used to monitor treatment. Immunization against cationic bovine serum albumin is a cause of early childhood membranous nephropathy. This finding points to a possible role of food and environmental antigens in membranous nephropathy. The newly identified antigen-antibody systems should be considered as molecular signatures challenging the uniform histological definition and having a major impact on patient care in a near future

[Anti-CD 10 maternal-fetal allo-immunisation].

International audienceMaternal-fetal alloimmunisation with antenatal glomerulopathies (FMAIG) is a recently described allo-immune disorder that results from the production of maternal antibodies which cross the placenta, bind to fetal glomerular podocytes and thereby cause renal dysfunction. The pathogenic antibodies are directed against CD10/neutral endopeptidase (NEP). The infant's mother is apparently healthy but is genetically NEP-deficient, and thus becomes immunized against CD10/NEP expressed by placental cells during her first pregnancy. This disease, that we have now diagnosed in five families, is the first described organ-specific disorder due to maternal-fetal allo-immunisation. Because future pregnancies in CD10/NEP-immunized mothers are at high risk for the fetus, antigen-driven therapies aimed at eliminating pathogenic antibodies are urgently needed. This will require identification of the pathogenic epitopes born by the antigen

Pathophysiological advances in membranous nephropathy: time for a shift in patient's care

International audienceMembranous nephropathy is a major cause of nephrotic syndrome of non-diabetic origin in adults. It is the second or third leading cause of end-stage renal disease in patients with primary glomerulonephritis, and is the leading glomerulopathy that recurs after kidney transplantation (occurring in about 40% of patients). Treatment with costly and potentially toxic drugs remains controversial and challenging, partly because of insufficient insight into the pathogenesis of the disease and absence of sensitive biomarkers of disease activity. The disease is caused by the formation of immune deposits on the outer aspect of the glomerular basement membrane, which contain podocyte or planted antigens and circulating antibodies specific to those antigens, resulting in complement activation. In 2002, podocyte neutral endopeptidase was identified as an antigenic target of circulating antibodies in alloimmune neonatal nephropathy, and in 2009, podocyte phospholipase A2 receptor (PLA2R) was reported as an antigenic target in autoimmune adult membranous nephropathy. These major breakthroughs were translated to clinical practice very quickly. Measurement of anti-PLA2R antibodies in serum and detection of PLA2R antigen in glomerular deposits can now be done routinely. Anti-PLA2R antibodies have high specificity (close to 100%), sensitivity (70-80%), and predictive value. PLA2R detection in immune deposits allows for retrospective diagnosis of PLA2R-related membranous nephropathy in archival kidney biopsies. These tests already have a major effect on diagnosis and monitoring of treatment, including after transplantation