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International audience; 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.

International audience; The high frequency of monoclonal gammopathy in adult patients with C3 glomerulopathy (C3G) emphasizes the role of monoclonal immunoglobulin (MIg) in the occurrence of renal disease and raises the issue of the therapeutic management. The aim of the study was to evaluate the effect of chemotherapy in a large cohort of patients with MIg-associated C3G. Fifty adult patients with MIg and biopsy-proven C3G were extracted from the French national database of C3G. We retrospectively compared renal outcomes in patients who either received or did not receive chemotherapy targeting the underlying B-cell clone. At diagnosis, renal disease was severe, with nephrotic-range proteinuria in 20/46 (43%) patients and chronic kidney disease stage 3 or above in 42/49 (86%) patients. Monoclonal gammopathy was of IgG type in 47 (94%) patients. Hematological diagnosis was monoclonal gammopathy of renal significance in 30 (60%), multiple myeloma in 17 (34%), and chronic lymphocytic leukemia in 3 (6%) patients. Complement studies showed low C3 level in 22/50 (43%) and elevated soluble C5b-9 level in 27/34 (79%) patients. Twenty-nine patients received chemotherapy (including bortezomib in 22), whereas 8 and 13 patients received various immunosuppressive drugs or symptomatic measures alone, respectively. Patients who achieved hematological response after chemotherapy had higher renal response rates (P = .0001) and median renal survival (hazard ratio, 0.22; 95% confidence interval, 0.05-0.92; P = .009) than those receiving conservative/immunosuppressive therapy. In conclusion, our results suggest that chemotherapy adapted to the B-cell clone may constitute an efficient strategy for C3G in the setting of MIg, as rapid achievement of hematological response appears to result in improved renal survival.

Background Cardiac involvement in systemic light-chain amyloidosis (AL) imparts an adverse impact on outcome. The left atrium (LA), by virtue of its anatomical location and muscular wall, is commonly affected by the amyloid process. Although LA infiltration by amyloid fibrils leads to a reduction in its pump function, the infiltration of the left ventricular (LV) myocardium results in diastolic dysfunction with subsequent increase in filling pressures and LA enlargement. Even though left atrial volume (LAV) is an independent prognostic marker in many cardiomyopathies, its value in amyloid heart disease remains to be determined. In addition, few data are available as to the prognostic value of LA function in systemic AL. Using cardiac magnetic resonance (CMR), the current study aims to assess the prognostic significance of the maximal LAV and total LA emptying fraction (LAEF) in patients with AL. Methods and results Fifty-four consecutive patients (age 66 +/- 10 years, 59% males) with confirmed systemic AL and mean LV ejection fraction of 60 +/- 12% underwent CMR. As compared with patients with no or minimal cardiac involvement (Mayo Clinic [MC] stage I), those at moderate and high risk (MC stages II and III) had significantly larger indexed maximal LAV (36 +/- 15 vs. 46 +/- 13 vs. 52 +/- 19 mL/m(2), P = 0.03) and indexed minimal LAV (20 +/- 6 vs. 34 +/- 11 vs. 44 +/- 17 mL/m2, P < 0.001), lower LAEF (42 +/- 9 vs. 26 +/- 13 vs. 16 +/- 9%, P < 0.0001) but similar LVEF. Furthermore, myocardial late gadolinium enhancement (LGE) was more frequent and significantly associated with lower LAEF. LAEF was also significantly lower in symptomatic (NHYA >= II, 22 +/- 14%) as compared with asymptomatic patients (NYHA class I, 33 +/- 13%, P = 0.006). Two-year survival rate was lower in patients with LAEF 16% (37 +/- 11 vs. 94 +/- 4%, P = 0.001). In multivariate analysis, lower LAEF remained independently associated with a higher risk of 2-year mortality (HR = 1.08 per 1% decrease, 95%CI: 1.02-1.15, P = 0.003). Conclusion In patients with systemic AL, LAEF as assessed by CMR is associated with NYHA functional class, MC stage, myocardial LGE and 2-year mortality.

Monoclonal gammopathies are frequently complicated by kidney lesions that increase the disease morbidity and mortality. In particular, abnormal Ig free light chains (LCs) may accumulate within epithelial cells, causing proximal tubule (PT) dysfunction and renal Fanconi syndrome (RFS). To investigate the mechanisms linking LC accumulation and PT dysfunction, we used transgenic mice overexpressing human control or RFS-associated κLCs (RFS-κLCs) and primary cultures of mouse PT cells exposed to low doses of corresponding human κLCs (25 μg/ml). Before the onset of renal failure, mice overexpressing RFS-κLCs showed PT dysfunction related to loss of apical transporters and receptors and increased PT cell proliferation rates associated with lysosomal accumulation of κLCs. Exposure of PT cells to RFS-κLCs resulted in κLC accumulation within enlarged and dysfunctional lysosomes, alteration of cellular dynamics, defective proteolysis and hydrolase maturation, and impaired lysosomal acidification. These changes were specific to the RFS-κLC variable (V) sequence, because they did not occur with control LCs or the same RFS-κLC carrying a single substitution (Ala30→Ser) in the V domain. The lysosomal alterations induced by RFS-κLCs were reflected in increased cell proliferation, decreased apical expression of endocytic receptors, and defective endocytosis. These results reveal that specific κLCs accumulate within lysosomes, altering lysosome dynamics and proteolytic function through defective acidification, thereby causing dedifferentiation and loss of reabsorptive capacity of PT cells. The characterization of these early events, which are similar to those encountered in congenital lysosomal disorders, provides a basis for the reported differential LC toxicity and new perspectives on LC-induced RFS.

Monoclonal immunoglobulin (Ig) deposition disease (MIDD) is a rare complication of plasma cell disorders, defined by linear Congo red-negative deposits of monoclonal light chain (LCDD), heavy chain (HCDD) or both (LHCDD) along basement membranes. MIDD should be suspected in patients presenting with glomerular proteinuria and monoclonal gammopathy, but none of these criteria is necessary for the diagnosis although renal involvement is prominent. Since an abnormal serum κ/λ ratio is found in virtually all MIDD patients, including those with HCDD, serum free light chain assay should be included in the initial workup in patients older than 50 presenting with kidney disease. Bortezomib-based regimens are efficient and well tolerated, resulting in improvement in both renal and global survival, comparatively to historical series. High dose melphalan with autologous stem cell transplantation may be proposed as second line therapy in selected patients. The achievement of hematological response, based on the difference between involved and uninvolved serum free light chains (dFLC), is mandatory. In a recent series, post-treatment dFLC

We retrospectively reviewed 49 patients with light chain (LC) Fanconi syndrome (FS). Patients presented with chronic kidney disease (median estimated glomerular filtration rate (eGFR) of 33 ml/min/1.73 m2) and tubular proteinuria. All patients tested had elevated fractional excretion of phosphate, uric acid, generalized aminoaciduria and/or normoglycemic glycosuria. Thirty-eight patients had monoclonal gammopathy of renal significance and eleven patients had an overt hematological malignancy. The monoclonal LC isotype was kappa in 46/49 cases. Kidney biopsy in 39 patients showed various proximal tubular lesions and characteristic LC intracytoplasmic crystalline inclusions in 24 patients. Forty-two patients received chemotherapy. Patients with plasma cell proliferation (n=38) received bortezomib-based regimens (n=11), immunomodulatory agents (n=7) or alkylating agents (n=6). High-dose melphalan (HDM) followed by autologous stem cell transplantation was performed in 14 patients. Hematological response was obtained in 90% of evaluable patients, assessed on serum free light chains (FLC). GFR remained stable as long as hematological response was maintained and declined when serum FLC level rebounded. Improvement in proximal tubule function occurred in 13 patients. In patients with LC-associated FS, chemotherapy using HDM and/or new generation anti-myeloma agents can stabilize renal function and improve proximal tubule function. Serum FLC should be used to assess the hematological response, related to renal outcome.

Cryoglobulins are circulating immunoglobulins that precipitate with cold temperature and dissolve with rewarming. Type 1 cryoglobulinemia is composed of a single monoclonal immunoglobulin and is associated with renal involvement in up to 40% of cases. Type 1 cryoglobulinemia is related to an underlying B-cell haematological malignancy in 60% of patients. In the remaining cases, in the absence of criteria for malignancy, the diagnosis of monoclonal gammopathy of renal significance should be established. The clinical and biological setting and histological features of type 1 cryoglobulinemia are globally similar to those of mixed cryoglobulinemia. In case of haematological malignancy, the treatment is guided by the nature of the underlying disease, and aims at inducing haematological remission, which is necessary for the renal response. The management of monoclonal gammopathy of renal significance has been clarified by an international consensus group and is based on the nature of the underlying clone. In case of monoclonal cryoglobulinemia associated with a plasma-cell clone (IgG or IgA), the treatment is based on the combination of bortezomib, cyclophosphamide and dexamethasone. In case of IgM monoclonal cryoglobulinemia, the treatment is similar to that of Waldenström macroglobulinemia, and is based on rituximab. The clinical course of renal monoclonal cryoglobulinemia is intimately associated with the haematological response, and is usually favourable.

L’amylose systemique AL est une maladie grave. Son pronostic depend de l’extension des depots amyloides et de l’importance de l’atteinte cardiaque. Sans traitement efficace, la mediane de survie est d’environ 12 mois [1], mais l’ancienne notion que la formation des depots amyloides est un processus irreversible est fausse. Il existe un equilibre entre la formation et l’elimination des depots, tres variable suivant les malades et suivant les organes. La suppression ou la diminution de la concentration serique de la chaine legere (CL) monoclonale a l’origine des depots peut renverser l’equilibre et s’accompagner d’une elimination progressive des depots. Le degre de reduction de la production de la CL monoclonale necessaire pour l’elimination tissulaire varie entre les patients, et depend du turn-over des depots amyloides. Si le traitement est efficace, l’amelioration clinique peut quelquefois etre rapide et spectaculaire, ou plus souvent se manifester apres de nombreux mois.

The spectrum of glomerular disorders with organized immunoglobulin (Ig) deposits is heterogeneous. It encompasses 2 mains categories: glomerulopathies with fibrillary deposits are mostly represented by immunoglobulinic amyloidosis (most commonly AL amyloidosis, characterized by monoclonal light chain deposits often of the lambda isotype), and pseudo-amyloid fibrillary glomerulonephritis in which deposits predominantly contain polyclonal IgG4. Glomerulopathies with microtubular deposits include cryoglobulinemic glomerulonephritis (type I and type II, with or without detectable serum cryoglobulin) and glomerulonephritis with organized microtubular monoclonal Ig deposits (GOMMID) also referred to as immunotactoid glomerulopathy. Pathological diagnosis requires meticulous studies by light microscopy (with systematic Congo red staining), immunofluorescence with specific conjugates, and electron microscopy. Ultrastructural studies are required to differentiate amyloid fibrils (8 to 10 nm in external diameter), pseudo-amyloid fibrils (15-20 nm) and microtubules (10 to 50 nm in external diameter, with a central hollow core). Glomerular deposits in type I cryoglobulinemic glomerulonephritis are arranged into parallel straight microtubules similar to those observed in GOMMID, but with different topography that allows distinction between the two entities. Glomerular substructures composed of circulating Igs should be distinguished from collagen fibrils that are commonly observed in glomerular disorders with or without deposition of monoclonal or polyclonal Igs.

Introduction Le syndrome hemolytique et uremique atypique (SHUa) est associe a un defaut de regulation de la voie alterne (VA) du complement. La presence d’une immunoglobuline monoclonale (MIg) chez les sujets de plus de 50 ans souleve la question du lien physiopathologique entre la MIg et l’atteinte renale. Patients et methodes Nous rapportons la description clinicobiologique et immunologique de 20 patients ayant un SHUa associe a une MIg (MIg-SHUa) issus de la cohorte francaise. Les resultats ont ete compares aux patients SHUa de plus de 50 ans sans MIg. Resultats Dans la cohorte francaise de SHUa, 20/68 (29 %) des patients de plus de 50 ans ont une MIg. Au diagnostic, le tableau renal est plus severe compare aux patients sans MIg : 55 % des patients requierent une dialyse initiale et 50 % d’entre eux presentent des manifestations extrarenales. D’un point de vue immunologique, 35 % des patients MIg-SHUa ont un C3 bas, compare a 14 % dans le groupe sans MIg (p = 0,08). La recherche d’Ac anti-FH est positive chez 4/19 (22 %) des patients, frequence comparable a celle des patients sans MIg (5/41 [14 %], p = 0,44). De meme la frequence des variants genetiques des proteines de la VA est identique dans les 2 groupes (4/13 [33 %] versus 13/48 [27 %], p = 0,72). Apres exploration, 5/7 patients MIg-SHUa ont un C3 bas « inexplique » compare a 1/7 dans le groupe sans MIg (p = 0,04). La survie renale des patients MIg-SHUa est significativement moins bonne comparee aux patients sans MIg (p = 0,006), y compris en cas d’echanges plasmatiques (p = 0,04). Deux des trois patients MIg-SHUa ayant recu de l’eculizumab ont une fonction renale preservee au dernier recul. Une patiente a recu une chimiotherapie adaptee permettant l’obtention d’une remission renale. Discussion L’augmentation de la frequence des MIg chez les patients de plus de 50 ans comparee a la frequence attendue dans la population generale, la severite de l’atteinte renale avec une survie renale particulierement breve et l’existence de biomarqueurs d’activation de la C3 convertase sans anomalie identifiee chez ces patients suggerent que les mecanismes de deregulation different et souleve la question du role de la MIg. Conclusion Ce travail souleve la question du traitement du clone B sous-jacent dans les formes de SHUa associes aux MIg.

Les nephropathies associees aux gammapathies monoclonales sont variees. Elles sont liees majoritairement au depot ou a la precipitation d’une immunoglobuline (Ig) monoclonale entiere ou d’un fragment de celle-ci, (le plus souvent une chaine legere [CL] monoclonale), et exceptionnellement a l’activite anticorps de l’Ig monoclonale. Leur diagnostic repose sur la confrontation des donnees cliniques, immuno-hematologiques et histologiques. L’analyse de la biopsie renale permet de preciser la nature, la localisation et le caractere organise ou non des depots d’Ig monoclonale. Les nephropathies tubulaires sont toujours secondaires a la precipitation intracytoplasmique (syndrome de Fanconi [SF]) ou intratubulaire (nephropathie a cylindres myelomateux [NCM]) des CL monoclonales, souvent organisees en cristaux. La NCM est la principale cause d’insuffisance renale (IR) au cours du myelome multiple (MM), notamment des MM a CL et de forte masse tumorale. Elle se manifeste typiquement par une IR aigue avec proteinurie faite majoritairement de CL, souvent revelatrice du MM et precedee de facteurs favorisant la precipitation intratubulaire des CL : infections, deshydratation, hypercalcemie, medicaments nephrotoxiques. Son pronostic est sombre, avec une reponse renale dans environ 50 % des cas, chiffre encore abaisse en dessous de 20 % en cas d’IR severe necessitant la dialyse. La persistance d’une IR reduit considerablement la survie des malades. Le traitement repose sur des mesures symptomatiques urgentes et l’introduction rapide d’une chimiotherapie adaptee, reposant en premiere intention sur l’association bortezomib-dexamethasone (BD). En situation d’IR necessitant la dialyse, l’utilisation de nouvelles membranes de dialyse de tres haute permeabilite aux proteines, permettant une epuration efficace des CL, pourrait ameliorer le pronostic renal et vital. Les nephropathies glomerulaires sont surtout representees par l’amylose AL, caracterisee par des depots fibrillaires de CL (habituellement λ), positifs au rouge Congo, et la maladie de depots d’Ig monoclonale de type Randall, definie par des depots lineaires non organises le plus souvent de CLκ de topographie peritubulaire, glomerulaire et vasculaire, non colores par le rouge Congo. L’atteinte renale se manifeste par une proteinurie abondante, avec syndrome nephrotique et IR dans la moitie des cas. La presence d’une hypertension arterielle et d’une hematurie microscopique est rare dans l’amylose AL, mais les manifestations extrarenales sont frequentes, dominee par la cardiopathie hypertrophique et restrictive, facteur pronostique majeur. L’association melphalan-dexamethasone constitue le traitement de reference actuel, visant a l’obtention rapide d’une reponse evaluee par la mesure reguliere des CL libres seriques et des marqueurs d’atteinte cardiaque (Nt-proBNP). L’adjonction du bortezomib semble efficace dans les formes resistantes.

The term monoclonal gammopathy of renal significance (MGRS) was introduced by the International Kidney and Monoclonal Gammopathy Research Group (IKMG) in 2012. The IKMG met in April 2017 to refine the definition of MGRS and to update the diagnostic criteria for MGRS-related diseases. Accordingly, in this Expert Consensus Document, the IKMG redefines MGRS as a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined haematological criteria for treatment of a specific malignancy. The diagnosis of MGRS-related disease is established by kidney biopsy and immunofluorescence studies to identify the monotypic immunoglobulin deposits (although these deposits are minimal in patients with either C3 glomerulopathy or thrombotic microangiopathy). Accordingly, the IKMG recommends a kidney biopsy in patients suspected of having MGRS to maximize the chance of correct diagnosis. Serum and urine protein electrophoresis and immunofixation, as well as analyses of serum free light chains, should also be performed to identify the monoclonal immunoglobulin, which helps to establish the diagnosis of MGRS and might also be useful for assessing responses to treatment. Finally, bone marrow aspiration and biopsy should be conducted to identify the lymphoproliferative clone. Flow cytometry can be helpful in identifying small clones. Additional genetic tests and fluorescent in situ hybridization studies are helpful for clonal identification and for generating treatment recommendations. Treatment of MGRS was not addressed at the 2017 IKMG meeting; consequently, this Expert Consensus Document does not include any recommendations for the treatment of patients with MGRS.

Introduction Au cours des dernieres decennies, l’incidence des glomerulopathies associees aux infections a progressivement diminue dans les pays developpes. Par le passe, cette pathologie etait contractee dans l’enfance et etait principalement associee au streptocoque beta-hemolytique du groupe A implique. Sont maintenant concernes des patients de plus en plus âges, avec de nombreuses comorbidites, avec des infections aux agents infectieux varies. Patients/materiels et methodes Dix-sept adultes issus de quatre centres de nephrologie du Poitou-Charentes ont ete etudies retrospectivement de janvier 2000 a avril 2017. Nous avons examine les dossiers des patients et collecte les donnees cliniques, microbiologiques, anatomopathologiques et l’evolution apres traitement. Resultats Le ratio homme : femme etait de 2,4 :1 et l’âge median de 64 ans (22–76 ans). Cinquante-neuf pour cent (n = 10) des patients avaient un terrain immunodeprime, incluant neoplasies (23 %, n = 4), cirrhose (12 %, n = 2), toxicomanie intraveineuse (12 %, n = 2), et diabete (6 %, n = 1). Les principaux sites infectieux etaient : pulmonaire (29 %, n = 5), osseux (23 %, n = 4), cutane (18 %, n = 3) et abces dentaire (12 %, n = 2). Le plus frequent des agents infectieux retrouve etait Staphylococcus aureus (35 %, n = 6). Une hypocomplementemie etait observee chez 71 % (n = 12) des patients. L’histologie retrouvait un glomerulonephrite proliferative endocapillaire diffuse chez 87 % (n = 13) et focale chez 13 % (n = 2). Apres un suivi median de 14 mois (0,75–108), 65 % (n = 11) des patients avaient une reponse renale complete, 18 % (n = 3) avaient une reponse renale partielle, 18 % (n = 3) ont progresse vers l’insuffisance renale terminale et 17 % (n = 4) sont decedes. Discussion Contrairement a la classique glomerulonephrite post-streptococcique de l’enfant, Staphylococcus est le principal agent infectieux implique. L’heterogeneite des sites infectieux, la chronologie de l’apparition de la maladie renale (precedant parfois la decouverte de l’infection), et les nombreux diagnostics differentiels peuvent retarder diagnostic. Le pronostic est variable avec une part significative de patients evoluant vers l’insuffisance renale terminale, en lien avec des comorbidites sous-jacentes et de la rapidite du diagnostic. Parfois cette pathologie revele des anomalies innees ou acquises de la voie alterne du complement, qu’il convient de rechercher en cas de rechute ou persistance de la glomerulonephrite. Conclusion Cette etude confirme un tournant dans l’epidemiologie des glomerulopathies associees aux infections, affectant des patients plus âges avec un terrain immunodeprime.

Introduction La maladie de depots de chaines lourdes monoclonales (= heavy chain deposition disease ou HCDD) est une gammapathie monoclonale rare de signification renale (= monoclonal gammopathy of renal significance ou MGRS). Elle se caracterise par la presence de depots amorphes de chaines lourdes d’immunoglobulines monoclonales tronquees le long des membranes basales glomerulaires et tubulaires du rein mais aussi d’autres organes. La principale caracteristique moleculaire de ces chaines lourdes pathogenes est l’absence recurrente du premier exon du domaine constant CH1 permettant leur secretion en l’absence d’une chaine legere d’immunoglobuline. Cependant, les mecanismes moleculaires menant a la production d’une chaine lourde tronquee sont encore inconnus. Patients/materiels et methodes Dans la presente etude, nous avons effectue une caracterisation moleculaire complete des fragments d’immunoglobulines produits par le clone plasmocytaire d’un patient. Resultats En plus de la deletion genomique du domaine CH1 de la chaine lourde, nous avons montre que le meme clone plasmocytaire produisait une chaine legere monoclonale tronquee. Lorsqu’elle est exprimee dans la lignee plasmocytaire murine sp2/0, cette chaine legere tronquee ne peut s’associer ni avec la chaine lourde pathogene ni avec la chaine lourde reconstituee avec un domaine CH1. Dans ce modele cellulaire experimental, nous montrons que la deletion du CH1 reduit le stress du reticulum endoplasmique induit par la retention intracellulaire de la chaine lourde complete isolee. Conclusion Nous emettons ainsi l’hypothese que l’alteration de la chaine legere est l’evenement inaugural menant a la production d’une chaine lourde tronquee et finalement a l’apparition de la maladie de depots de chaines lourdes monoclonales.

8017Background: Triplet-based lenalidomide plus dexamethasone (Rd) combinations have become the new standard of care for early relapse and refractory multiple myeloma (RRMM), including carfilzomib ...

The spectrum of glomerular disorders with organized immunoglobulin (Ig) deposits is heterogeneous. It encompasses 2 mains categories: glomerulopathies with fibrillary deposits are mostly represented by immunoglobulinic amyloidosis (most commonly AL amyloidosis, characterized by monoclonal light chain deposits often of the lambda isotype), and pseudo-amyloid fibrillary glomerulonephritis in which deposits predominantly contain polyclonal IgG4. Glomerulopathies with microtubular deposits include cryoglobulinemic glomerulonephritis (type I and type II, with or without detectable serum cryoglobulin) and glomerulonephritis with organized microtubular monoclonal Ig deposits (GOMMID) also referred to as immunotactoid glomerulopathy. Pathological diagnosis requires meticulous studies by light microscopy (with systematic Congo red staining), immunofluorescence with specific conjugates, and electron microscopy. Ultrastructural studies are required to differentiate amyloid fibrils (8 to 10 nm in external diameter), pseudo-amyloid fibrils (15-20 nm) and microtubules (10 to 50 nm in external diameter, with a central hollow core). Glomerular deposits in type I cryoglobulinemic glomerulonephritis are arranged into parallel straight microtubules similar to those observed in GOMMID, but with different topography that allows distinction between the two entities. Glomerular substructures composed of circulating Igs should be distinguished from collagen fibrils that are commonly observed in glomerular disorders with or without deposition of monoclonal or polyclonal Igs.

International audience; C3 glomerulopathy is a recently described form of CKD. C3GN is a subtype of C3 glomerulopathy characterized by predominant C3 deposits in the glomeruli and is commonly the result of acquired or genetic abnormalities in the alternative pathway (AP) of the complement system. We identified and characterized the first mutation of the C3 gene (p. I734T) in two related individuals diagnosed with C3GN. Immunofluorescence and electron microscopy studies showed C3 deposits in the subendothelial space, associated with unusual deposits located near the complement receptor 1 (CR1)-expressing podocytes. In vitro, this C3 mutation exhibited decreased binding to CR1, resulting in less CR1-dependent cleavage of C3b by factor 1. Both patients had normal plasma C3 levels, and the mutant C3 interacted with factor B comparably to wild-type (WT) C3 to form a C3 convertase. Binding of mutant C3 to factor H was normal, but mutant C3 was less efficiently cleaved by factor I in the presence of factor H, leading to enhanced C3 fragment deposition on glomerular cells. In conclusion, our results reveal that a CR1 functional deficiency is a mechanism of intraglomerular AP dysregu-lation and could influence the localization of the glomerular C3 deposits.

Long-term outcomes in renal transplant recipients withdrawn from steroid and submitted to further minimization of immunosuppressive regimen after 1 year are lacking. In this multicenter study, 204 low immunological risk kidney transplant recipients were randomized 14.2 ± 3.7 months post-transplantation to receive either cyclosporine A (CsA) + azathioprine (AZA; n = 53), CsA + mycophenolate mofetil (MMF; n = 53), or CsA monotherapy (n = 98). At 3 years postrandomization, the occurrence of biopsy for graft dysfunction was similar in bitherapy and monotherapy groups (21/106 vs. 26/98; P = 0.25). At 10 years postrandomization, patients' survival was 100%, 94.2%, and 95.8% (P = 0.25), and death-censored graft survival was 94.9%, 94.7%, and 95.2% (P = 0.34) in AZA, MMF, and CsA groups, respectively. Mean estimated glomerular filtration rate was 70.4 ± 31.1, 60.1 ± 22.2, and 60.1 ± 19.0 ml/min/1.73 m(2), respectively (P = 0.16). The incidence of biopsy-proven acute rejection was 1.4%/year in the whole cohort. None of the patients developed polyomavirus-associated nephropathy. The main cause of graft loss (n = 12) was chronic antibody-mediated rejection (n = 6). De novo donor-specific antibodies were detected in 13% of AZA-, 21% of MMF-, and 14% of CsA-treated patients (P = 0.29). CsA monotherapy after 1 year is safe and associated with prolonged graft survival in well-selected renal transplant recipient (ClinicalTrials.gov number: 980654).

Monoclonal immunoglobulin (Ig) deposition disease (MIDD) is a rare complication of plasma cell disorders, defined by linear Congo red-negative deposits of monoclonal light chain (LCDD), heavy chain (HCDD) or both (LHCDD) along basement membranes. MIDD should be suspected in patients presenting with glomerular proteinuria and monoclonal gammopathy, but none of these criteria is necessary for the diagnosis although renal involvement is prominent. Since an abnormal serum κ/λ ratio is found in virtually all MIDD patients, including those with HCDD, serum free light chain assay should be included in the initial workup in patients older than 50 presenting with kidney disease. Bortezomib-based regimens are efficient and well tolerated, resulting in improvement in both renal and global survival, comparatively to historical series. High dose melphalan with autologous stem cell transplantation may be proposed as second line therapy in selected patients. The achievement of hematological response, based on the difference between involved and uninvolved serum free light chains (dFLC), is mandatory. In a recent series, post-treatment dFLC40mg/L was the major predictive factor of renal response and was associated with improvement of both renal and global survival. In MIDD, bortezomib-based therapy is safe and efficient when introduced early after diagnosis. dFLC response is a favorable prognostic factor for renal survival.

International audience; BACKGROUND:Kidney diseases associated with immunoglobulin M (IgM) monoclonal gammopathy are poorly described, with few data for patient outcomes and renal response.STUDY DESIGN:Case series.SETTING & PARTICIPANTS:35 patients from 8 French departments of nephrology were retrospectively studied. Inclusion criteria were: (1) detectable serum monoclonal IgM, (2) estimated glomerular filtration rate (eGFR) < 60mL/min/1.73m2 and/or proteinuria with protein excretion > 0.5g/d and/or microscopic hematuria, and (3) kidney biopsy showing monoclonal immunoglobulin deposits and/or lymphomatous B-cell renal infiltration. All patients received chemotherapy, including rituximab-based regimens in 8 cases.PREDICTORS:Patients were classified into 3 groups according to renal pathology: glomerular AL amyloidosis (group 1; n=11), nonamyloid glomerulopathies (group 2; n=15, including 9 patients with membranoproliferative glomerulonephritis), and tubulointerstitial nephropathies (group 3; n=9, including cast nephropathy in 5, light-chain Fanconi syndrome in 3, and isolated tumor infiltration in 1).OUTCOMES:Posttreatment hematologic response (≥50% reduction in serum monoclonal IgM and/or free light chain level) and renal response (≥50% reduction in 24-hour proteinuria or eGFR≥30mL/min/1.73m2 in patients with glomerular and tubulointerstitial disorders, respectively).RESULTS:Nephrotic syndrome was observed in 11 and 6 patients in groups 1 and 2, respectively. Patients in group 3 presented with acute kidney injury (n=7) and/or proximal tubular dysfunction (n=3). Waldenström macroglobulinemia was present in 26 patients (8, 12, and 6 in groups 1, 2, and 3, respectively). Significant lymphomatous interstitial infiltration was observed in 18 patients (4, 9, and 5 patients, respectively). Only 9 of 29 evaluable patients had systemic signs of symptomatic hematologic disease (2, 5, and 2, respectively). In groups 1, 2, and 3, respectively, hematologic response was achieved after first-line treatment in 3 of 9, 9 of 10, and 5 of 6 evaluable patients, while renal response occurred in 5 of 10, 9 of 15, and 5 of 8 evaluable patients.LIMITATIONS:Retrospective study; insufficient population to establish the impact of chemotherapy.CONCLUSIONS:IgM monoclonal gammopathy is associated with a wide spectrum of renal manifestations, with an under-recognized frequency of tubulointerstitial disorders.

Monoclonal immunoglobulin deposition disease (MIDD) is a rare complication of plasma cell disorders, defined by linear Congo red-negative deposits of monoclonal light chain, heavy chain, or both along basement membranes. While renal involvement is prominent, treatment strategies, such as the impact of novel anti-myeloma agents, remain poorly defined. Here we retrospectively studied 49 patients with MIDD who received a median of 4.5 cycles of intravenous bortezomib plus dexamethasone. Of these, 25 received no additional treatment, 18 also received cyclophosphamide, while 6 also received thalidomide or lenalidomide. The hematological diagnoses identified 38 patients with monoclonal gammopathy of renal significance, 10 with symptomatic multiple myeloma, and 1 with Waldenstrom macroglobulinemia. The overall hematologic response rate, based on the difference between involved and uninvolved serum-free light chains (dFLCs), was 91%. After median follow-up of 54 months, 5 patients died and 10 had reached end-stage renal disease. Renal response was achieved in 26 patients, with a 35% increase in median eGFR and an 86% decrease in median 24-h proteinuria. Predictive factors were pre-treatment eGFR over 30 ml/min per 1.73 m(2) and post-treatment dFLC under 40 mg/l; the latter was the sole predictive factor of renal response by multivariable analysis. Thus, bortezomib-based therapy is a promising treatment strategy in MIDD, mainly when used early in the disease course. dFLC response is a favorable prognostic factor for renal survival.

International audience; Noninfectious mixed cryoglobulinemic GN (MCGN) has been poorly investigated. We analyzed presentation and outcome of 80 patients with biopsy-proven MCGN, which were identified in the retrospective French CryoVas survey. MCGN was related to primary Sjögren's syndrome in 22.5% of patients and to lymphoproliferative disorders in 28.7% of patients, and was defined as essential in 48.8% of patients. At presentation, hematuria, proteinuria ≥1 g/d, hypertension, and renal failure were observed in 97.4%, 84.8%, 85.3%, and 82.3% of cases, respectively. Mean±eGFR was 39.5±20.4 ml/min per 1.73 m2. Membranoproliferative GN was the predominant histologic pattern, observed in 89.6% of cases. Renal interstitium inflammatory infiltrates were observed in 50% of cases. First-line treatment consisted of steroids alone (27.6%) or in association with rituximab (21.1%), alkylating agents (36.8%) or a combination of cyclophosphamide and rituximab (10.5%). After a mean follow-up of 49.9±45.5 months, 42.7% of patients relapsed with a renal flare in 75% of cases. At last follow-up, mean eGFR was 50.2±26.1 ml/min per 1.73 m2 with 9% of patients having reached ESRD; 59% and 50% of patients achieved complete clinical and renal remission, respectively. A rituximab+steroids regimen prevented relapses more effectively than steroids alone or a cyclophosphamide+steroids combination did, but was associated with a higher rate of early death when used as first-line therapy. Severe infections and new-onset B-cell lymphoma occurred in 29.1% and 8.9% of cases, respectively; 24% of patients died. In conclusion, noninfectious MCGN has a poor long-term outcome with severe infections as the main cause of death

Resume Les glomerulonephrites a depots organises d'immunoglobulines sont heterogenes. Elles comprennent les glomerulopathies a depots fibrillaires amyloides AL constituees de chaines legeres d'immunoglobulines monoclonales le plus souvent lambda, les glomerulonephrites a depots fibrillaires pseudoamyloides constituees d'immunoglobulines Ig4 polyclonales predominantes, les glomerulonephrites a depots organises microtubulaires d'immunoglobulines tres frequemment monoclonales, les glomerulonephrites des cryoglobulines de type I et II avec ou sans cryoglobulinemie detectable. Le diagnostic de ces differents depots organises necessite d'une part, une coloration par le rouge Congo couplee a une etude soigneuse en immunofluorescence avec des conjugues specifiques, et d'autre part, l'etude ultrastructurale permettant de differencier les fibrilles amyloides de 8 a 10 nm de diametre, les fibrilles pseudoamyloides de 15 a 20 nm de diametre externe et les microtubules dont le diametre externe varie de 10 a 50 nm. Les depots des cryoglobulines de type I sont constitues de microtubules rectilignes analogues a ceux rencontres dans les glomerulonephrites a depots organises microtubulaires d'immunoglobuline monoclonale (glomerulonephritis with organized microtubular monoclonal immunoglobulin deposits [GOMMID]), mais, la topographie des depots permet de differencier ces deux types d'atteinte glomerulaire. Les depots des cryoglobulines de type II presentent une composition et une organisation tres differentes permettant facilement leur diagnostic. Ces substructures constituees de proteines circulantes doivent etre distinguees des fibrilles d'origine collagene qui sont frequemment observees dans les nephropathies glomerulaires avec ou sans depots d'immunoglobulines monoclonales ou polyclonales.

Fanconi's syndrome (FS) is a disorder of sodium-dependent proximal tubule reabsorption, which may complicate plasma cell disorders producing a free monoclonal light chain (LC). FS often occurs in the setting of smoldering myeloma and features cytoplasmic crystalline inclusions of monoclonal kappa LC in proximal tubular cells and malignant plasma cells. Although the clinical and pathological presentation may vary, including lack of crystal formation, monoclonal kappa LCs that underlie FS show a striking genetic and biochemical homogeneity: they almost always belong to the Vkappa1 subgroup of variability and originate from 2 germline genes, O2/O12 or O8/O18. Their variable domain sequences present unusual hydrophobic residues, responsible for the resistance to proteolysis, which leads to LC accumulation in the endocytic compartment of proximal tubule cells. We report a patient with slowly progressive Waldenstrom's macroglobulinemia and full-blown FS with accumulation of a monoclonal kappa LC within proximal tubules, but no detectable crystalline organization. This LC, which belonged to the unusual Vkappa3 subgroup and derived from the L2/L16 germline gene, showed no common substitution with previously described FS kappaI LC and was sensitive to trypsin digestion. These data show that molecular and biochemical characteristics of kappa LCs in patients with FS are more heterogeneous than initially suspected. Mechanisms other than resistance of LCs to endosomal proteolysis probably are involved in the pathogenesis of FS-associated plasma cell dyscrasias.

Introduction La frequence elevee des gammapathies monoclonales au cours de la glomerulopathie a depots de C3 (GPC3) chez les sujets de plus de 50 ans souleve la question de l’implication de l’Ig monoclonale dans l’activation de la voie alterne (VA). Materiels et methodes L’objectif de ce travail etait d’etudier les mecanismes d’activation de la VA chez 41 patients ayant une GPC3 et une Ig monoclonale. La recherche d’anticorps (Ac) diriges contre les proteines du complement a ete realisee par Elisa. L’activation de la C3 convertase en presence d’Ig totales (purification par proteine G) et/ou des fractions monoclonales et polyclonales (purification par chromatographie) a ete etudiee par WB et Elisa. Resultats Trente pour cent des patients ont un C3 diminue et 79 %, une augmentation du sC5b-9 temoins d’une activation de la C3/C5 convertase. La recherche d’anticorps diriges contre les proteines du complement (anti-CR1, anti-FH, anti-FI, anti-properdine et anti-C5) est positive chez 50 % des patients. Seuls 4 % des patients ont un C3Nef. Les Ac anti-FH et anti-CR1 sont associes a une diminution de l’activite cofacteur du FH et de CR1 chez 40 % des patients. Ces Ac sont polyclonaux et ne sont pas de la meme sous-classe que l’Ig monoclonale chez 75 % des patients testes. En presence de C3, FB et FD, les Ig totales jouent le role de « plateforme » et sont associees a un clivage plus important du C3 en C3b temoignant d’une augmentation de la formation de la C3 convertase, en phase fluide (12/32 patients) et/ou lorsqu’elles sont immobilisees (12/34 patients). Apres purification des Ig, la formation de la C3 convertase est plus importante en presence de la fraction monoclonale qu’en presence des Ig polyclonales chez 50 % des patients testes. En presence de serum humain normal (NHS), les Ig totales des patients sont associees a la formation accrue de C3a dans 30 % des cas. Un effet pro C5 convertase est observe en presence de properdine en exces chez les patients ayant des Ac anti-proteines regulatrices. Discussion Au cours de GPC3 associees aux Ig monoclonales, l’activation de la VA n’est pas liee, le plus souvent, a une activite Ac de l’Ig monoclonale. Conclusion L’activation non regulee de la VA resulte a la fois de mecanismes impliquant le composant monoclonal mais aussi les Ig polyclonales.

Introduction L’amylose AL systemique associee a une gammapathie monoclonale de type IgM est exceptionnelle, souvent secondaire a une proliferation lympho-plasmocytaire. De nouvelles strategies therapeutiques emergent ciblant cette proliferation. Nous avons etudie retrospectivement l’efficacite et la tolerance du traitement par rituximab bendamustine (R-Benda). Patients et methodes Les caracteristiques cliniques, biologiques, la tolerance, la reponse hematologique (RH) et d’organes de 10 patients atteints d’une amylose AL associee a une gammapathie monoclonale IgM ayant recu une chimiotherapie par R-Benda entre 2013 et 2015 ont ete extraites de la base de donnees du centre de reference francais des amyloses AL. Resultats L’âge median au diagnostic est de 68 ans (58–77), le diagnostique hematologique est : maladie de Waldenstrom (n = 4), lymphome malin B non hodgkinien (n = 4), et MGRS (n = 2). La mediane du pic IgM est de 9 g/L (8–28), et celle des chaines legeres libres (CL) de 52 mg/L (29–327) avec un rapport anormal chez 8 patients. Le nombre d’organes atteints est de 1,5 (1–2,75) avec atteintes renale (n = 8) et cardiaque (n = 5) predominantes. R-Benda est administre en premiere, deuxieme ou troisieme ligne respectivement chez 6, 3 et 1 patients pendant 6 cycles en mediane. Une RH a ete obtenue chez 7 patients (reponse complete n = 2 ; tres bonne reponse partielle [TBRP] n = 2 et reponse partielle n = 3). Une reponse renale et cardiaque est observee respectivement chez 2 et 4 patients. Les effets indesirables sont : neutropenie grade ≥ 3 (n = 2), pneumopathie infectieuse (n = 3), et une reaction allergique. Discussion Deux etudes recentes des centres de Pavia [1] et de Boston [2] , utilisant notamment l’association rituximab bortezomib dexamethasone ou melphalan haute dose et autogreffe, ont permis un taux de RH respectivement de 78 % et 74 % comparables au notre de 70 %. Conclusion R-Benda semble etre un traitement efficace et bien tolere dans ce type d’amylose AL.

Introduction Le benefice du sevrage en steroides en transplantation renale chez le receveur a faible risque immunologique reste debattu. Chez le receveur âge, l’impact d’une strategie immunosuppressive avec sevrage precoce (Cs–) n’a pas ete evalue. Patients et methodes Etude observationnelle de cohorte, incluant des receveurs âges de 65 ans ou plus, beneficiant d’une premiere transplantation renale entre mai 2008 et decembre 2014. Le groupe Cs– est defini par l’absence de Cs apres j8, et l’absence d’anticorps anti-HLA preforme specifique du donneur (DSA) ; le groupe Cs+ recoit une corticotherapie au long cours ou est sevre dans les premiers mois post-greffe. Le debit de filtration glomerulaire (DFG) est estime selon le MDRD. Les donnees sont issues de la base ASTRE du groupe Spiesser. Resultats Au total, 278 patients transplantes ont ete inclus : 36 patients Cs–et 242 patients Cs+. L’âge moyen des donneurs et des receveurs est de 67 ± 11 et de 70 ± 3 ans respectivement, sans difference entre les 2 groupes. Avec un suivi moyen de 32,0 ± 20,8 mois, la survie des patients est de 93,9 % dans le groupe Cs– et de 94,6 % dans le groupe Cs+ ( p = 0,26). La survie des greffons est de 90,6 % dans le groupe Cs– versus 95,0 % ( p = 0,58). A 3 mois post-greffe, le DFG est inferieur dans le groupe Cs– compare au groupe Cs + : 36,0 ± 12,8 versus 42,9 ± 15,2 mL/min/1,73 m 2 ( p p p = 0,28). Enfin, la prevalence du diabete de novo est de 19 % (7/36) pour les patients Cs– versus 25 % (39/242) ( p = 0,46). Discussion Le sevrage precoce en steroides est associe a une moins bonne fonction du greffon a 3 mois post-greffe et a une augmentation du nombre de rejets aigus, sans impact sur la survie du greffon. Le benefice de l’epargne en steroides, notamment dans la prevention du diabete de type 2, est difficile a evaluer compte tenu de l’effectif et de la duree de l’etude. Conclusion Le sevrage precoce en steroides dans une population âgee recevant un premier greffon renal ne semble pas pertinent.

Introduction Le myelome multiple est frequemment responsable d’une atteinte renale, dont le mecanisme peut etre divers. Parmi ceux-ci, la glomerulonephrite a depots isoles de C3 (GP-C3) est secondaire a une dysregulation de la voie alterne du complement (AP). Cette dysregulation peut etre liee a un auto-anticorps anti-facteur H (FH), une activite cofacteur du facteur I et est un inhibiteur competitif pour la liaison du C3b avec le facteur B. Observation Une patiente de 68 ans etait hospitalisee pour un acrosyndrome vasculaire douloureux. Ses antecedents comprenaient un diabete de type II, une hypertension arterielle et une dyslipidemie. Depuis 8 mois, elle avait une anemie normocytaire aregenerative et une deterioration progressive de sa fonction renale (creatininemie passant de 113 a 247 μmol/L et hemoglobinemie de 9,2 a 7,6 g/dL). L’examen etait sans particularite, en dehors de l’acrosyndrome. L’electrophorese des proteines plasmatiques, confirmee par l’immunofixation, revelait une immunoglobuline monoclonale G kappa (IgG κ) a 10,4 g/L. Le myelogramme confirmait le diagnostic de myelome a caryotype normal, avec 15 % de cellules plasmocytaires dystrophiques. Il n’existait pas d’hypercalcemie ni de lesions osteolytiques. La proteinurie etait non selective a 2 g/jour, avec des traces d’IgG κ. La biopsie renale etait en faveur d’une GP-C3. Les taux de C3, C4, CH50, facteurs H et I, CD46 etaient normaux, mais il existait une augmentation des taux du facteur Bb et du C5b-9 soluble. Il n’etait pas retrouve de C3nef et le Western Blot du CHFR1 etait normal. Des auto-anticorps anti-FH etaient mis en evidence (950 UA/mL, N Discussion L’originalite de ce cas est liee a l’association d’une GP-C3 avec des ischemies digitales sans stigmate de microangiopathie thrombotique, liee a des auto-anticorps anti-FH. La chimiotherapie du myelome n’a pas permis d’ameliorer les differentes atteintes malgre une reponse hematologique, alors que le blocage de l’AP a permis une amelioration rapide des lesions ischemiques et renales. Le FH a un effet inhibiteur sur l’activation du facteur XII, comparable a celui de β2-GP1. Des anticorps anti-FH ont ainsi ete detectes dans le syndrome des antiphospholipides. Le FH possede aussi une activite reductase du facteur von Willebrand sur les multimeres de haut poids moleculaire. Ces multimeres pourraient favoriser des thromboses microvasculaires. L’eculizumab a ete utilise avec succes dans les GP-C3, particulierement en cas de progression rapide avec des depots glomerulaires importants de C5b-9, ainsi que dans des cas de gangrenes ischemiques distales associees a des auto-anticorps anti-FH, mais uniquement au cours de SHU atypiques. Conclusion Une dysregulation de l’AP peut etre suspectee en cas d’angiopathie distale sans etiologie retrouvee, particulierement en cas d’association avec une gammapathie monoclonale. Dans ce cas, l’eculizumab, en association avec le traitement etiologique de la dyscrasie plasmocytaire, peut trouver sa place pour controler de facon plus rapide les manifestations thrombotiques et renales liees aux anticorps anti-FH.

International audience; Hepatocyte growth factor (HGF) is a pro-angiogenic cytokine activated by tissue-type plasminogen activator (tPA) that might play a role in the progression of multiple myeloma (MM). Preliminary studies indicated that serum HGF levels were higher in patients with AL amyloidosis (AL) compared to those with MM. The aim of the present study was to determine whether HGF is a relevant marker of diagnosis and prognosis in AL. HGF serum levels were measured at diagnosis in patients with monoclonal gammopathy (MG) without AL (76 controls), or with biopsy-proven systemic AL (69 patients). HGF serum levels were significantly higher in patients with AL compared to controls, respectively, 11.2 ng/mL [min: 0.95-max: 200.4] versus 1.4 ng/mL [min: 0.82-max: 6.2] (p

International audience; Randall-type heavy chain deposition disease (HCDD) is a rare disorder characterized by glomerular and peritubular amorphous deposits of a truncated monoclonal immunoglobulin heavy chain (HC) bearing a deletion of the first constant domain (CH1). We created a transgenic mouse model of HCDD using targeted insertion in the immunoglobulin κ locus of a human HC extracted from a HCDD patient. Our strategy allows the efficient expression of the human HC in mouse B and plasma cells, and conditional deletion of the CH1 domain reproduces the major event underlying HCDD. We show that the deletion of the CH1 domain dramatically reduced serum HC levels. Strikingly, even with very low serum level of truncated monoclonal HC, histologic studies revealed typical Randall-type renal lesions that were absent in mice expressing the complete human HC. Bortezomib-based treatment resulted in a strong decrease of renal deposits. We further demonstrated that this efficient response to proteasome inhibitors mostly relies on the presence of the isolated truncated HC that sensitizes plasma cells to bortezomib through an elevated unfolded protein response (UPR). This new transgenic model of HCDD efficiently recapitulates the pathophysiologic features of the disease and demonstrates that the renal damage in HCDD relies on the production of an isolated truncated HC, which, in the absence of a LC partner, displays a high propensity to aggregate even at very low concentration. It also brings new insights into the efficacy of proteasome inhibitor-based therapy in this pathology.

Acute graft rejection remains a major problem in renal transplant recipients, and there is no consensus on the optimal immunosuppressive strategy. Immunoprophylaxis with Thymoglobulin or basiliximab has significantly reduced the incidence of acute rejection episodes and graft loss following kidney transplantation. This open, randomized, multicenter study investigated the efficacy and tolerability of basiliximab (20mg day 0-day 4) plus early cyclosporine from day 0 (n = 50) compared with Thymoglobulin plus delayed cyclosporine (n = 50) in adult kidney transplant patients. In addition, all patients received steroids and mycophenolate mofetil (MMF) at standard doses from day 0. Patient and graft survival rates at 12 months were 98 and 94% in the basiliximab group, respectively, compared with 100 and 96% in the Thymoglobulin' group. The incidences of biopsy-confirmed acute rejection (8.0% in each group) and treatment failure (14% in the basiliximab group vs. 8% in the Thymoglobulin group) were comparable in the two groups. There was a non-significant tendency to more dialysis (14 vs. 6%), and fewer cytomegalovirus (CMV) infections (p = 0.005) in the basiliximab group, but the percentage of clinical CMV was not different between the two groups (6 vs. 12%). Both strategies give excellent results, despite the differences in patterns, in nonhyperimmunized patients receiving their first cadaveric renal allograft.

Introduction La reponse hematologique dans l’amylose AL est evaluee par la difference entre la chaine legere impliquee et celle non impliquee (dFLC). Pour les patients ayant une dFLC Patients et methodes Quatre-vingt-dix-sept patients atteints d’amylose AL systemique avec dFLC 50 mg/L (gp2) pendant la meme periode. Resultats Au moment du diagnostic, l’âge moyen etait de 65 ans, avec 68 % d’hommes. L’hemopathie causale etait une MGUS dans 68 % et la chaine legere (CL) impliquee le plus souvent etait de type Lambda (56 %). L’immunofixation serique etait positive pour 84 % des patients. L’atteinte d’organe la plus frequente etait l’atteinte renale (69 %), isolee dans 24 % des cas ; puis l’atteinte cardiaque (42 %), avec une predominance de stade I (45 %). Apres une ligne de traitement, 50 % des patients avaient normalise leurs CL, mais l’immunofixation n’etait pas realisee pour la plupart d’entre eux ; 22 % progressaient sur le plan renal et 22 % avaient une reponse cardiaque. Discussion Cette etude confirme la predominance de l’atteinte renale : 69 % gp1 vs 61 % gp2, moins marquee que dans la serie de Merlini (77 % vs 63 %) ou dans l’etude de Sanchorawala (77 %). La frequence moindre d’atteinte cardiaque (42 % gp1 vs 68 % gp2) est comparable a celle decrite par Merlini (43 % vs 83 %) et Sanchorawala (26 %) ; de meme que son stade moins avance 15 % de stade III dans le groupe DFLC 50 mg/L. Dans notre serie, la courbe de survie des patients du gp1 est comparable a celle du gp2 en reponse hematologique ce qui est comparable aux 2 etudes suscitees. Conclusion Les patients atteints d’amylose AL a dFLC

Introduction L’introduction de concentre de dialyse au citrate, en place de l’acetate, a permis d’ameliorer la biocompatibilite et de prevenir, en partie, la coagulation dans le dialyseur. Le but de notre etude retrospective en hemodialyse conventionnelle, est d’evaluer l’impact de l’utilisation d’un concentre citrate a 1 mmol/L comparativement au concentre acetate a 3 mmol/L sur le bilan calcique et acido-basique, l’equilibre hemodynamique, et l’adequation de la dialyse. Patients et methodes Au total, 66 patients en hemodialyse conventionnelle depuis plus de 6 mois ont ete inclus. Chaque patient etait son propre temoin. La balance calcique, le statut acido-basique, l’equilibre hemodynamique, et le Kt/V par la dialysance ionique ont ete evalues sur trois periodes de plus de 2 mois : periode 1 : dialyse a l’acetate avec [Ca 2+ ] a 1,5 ou 1,75 mmol/L ; periode 2 : dialyse au citrate avec [Ca 2+ ] a 1,5 ou 1,75 mmol/L ; periode 3 : dialyse au citrate avec [Ca 2+ ] a 1,65 ou 1,75 mmol/L. Les parametres ont ete compares entre la periode 1 versus periode 2, et periode 1 versus periode 3 ; puis en realisant une approche stratifiee selon le taux de calcium du concentre. Resultats Les calcemies pre- et post-dialytiques ainsi que les bicarbonatemies pre- et post-dialytiques sont significativement plus basses ( p Discussion La baisse des calcemies semble liee a la chute du calcium ionise dans le bain citrate ou son taux est divise par 2 par rapport au bain acetate par formation de citrate tricalcique favorisant aussi la baisse tensionnelle per-dialytique. La tendance a l’acidose peut etre en rapport avec un metabolisme hepatique insuffisant du citrate. Conclusion Ces resultats suggerent que le bain citrate en hemodialyse conventionnelle necessite des ajustements des prescriptions de calcium et de bicarbonate. Des etudes supplementaires sont necessaires afin de confirmer nos observations et d’evaluer le benefice des bains au citrate sans acetate sur la survie globale et la survenue d’evenements cardiovasculaires.

Introduction La maladie de depots de chaines legeres d’immunoglobulines (Ig) monoclonales (LCDD) est une complication rare des dyscrasies plasmocytaires caracterisee par des depots amorphes d’une Ig monoclonale le long des membranes basales tubulaires et glomerulaires. Elle se manifeste par une insuffisance renale progressive frequemment associees a un syndrome nephrotique et une glomerulosclerose nodulaire. Materiels et methodes Nous avons developpe un modele transgenique par insertion genique dirigee d’un domaine variable d’Ig humaine pathogene dans le locus des Ig kappa de souris. Un haut niveau de production seriques de chaines legeres est atteint (> 500 mg/L) grâce a un croisement avec des souris LMP2A qui presentent une hyperplasmocytose en absence de chaines lourdes d’Ig. Resultats Notre modele murin reproduit les principales caracteristiques de la LCDD, dont les depots peritubulaires et glomerulaires visibles des le 2e mois mais aussi a partir du 6e mois, la glomerulosclerose, le syndrome nephrotique et finalement l’insuffisance renale terminale avec une survie mediane des animaux de 8 mois. Un traitement hematologique a base d’inhibiteurs du proteasome permet de faire diminuer le taux d’Ig pathogenes et ainsi de preserver les fonctions renales et d’augmenter la survie des animaux. Discussion Nous demontrons que le domaine variable de l’Ig porte a lui-seul la pathogenicite de la proteine monoclonale. Contrairement a l’amylose AL qui reste difficile a modeliser chez la souris, le LCDD est parfaitement transposable aux rongeurs. Notre modele permet de reproduire l’ensemble des caracteristiques de la LCDD et va ainsi permettre de mieux comprendre la physiopathologie de cette maladie. Des etudes de transcriptomiques sont en cours afin de mettre en evidence les voies moleculaires impliquees dans la modification de la matrice extracellulaire au cours de la glomerulosclerose nodulaire. Conclusion Nous avons developpe le premier modele murin de LCDD recapitulant l’ensemble des caracteristiques de la maladie. Ce modele represente un outil important pour l’etude de la pathologie mais aussi pour mener des tests precliniques de nouvelles strategies therapeutiques.

Introduction La glomerulonephrite a depots non organises non Randall d’immunoglobuline monoclonale (PGNMID) est une entite maintenant bien individualisee au sein des gammapathies monoclonales de signification renale. Les depots sont le plus souvent constitues d’une immunoglobuline entiere, principalement IgG3 kappa. Nous rapportons une serie de 7 cas de PGNMID a chaine legere monoclonale. Patients et methodes Etude retrospective multicentrique incluant les patients presentant des depots granulaires, discontinus, de localisation glomerulaire exclusive, rouge Congo negatifs, marques en immunofluorescence par un seul isotype de chaine legere sans chaine lourde associee. Resultats L’âge median au diagnostic etait de 63 ans. Tous les patients presentaient une insuffisance renale chronique avec proteinurie et hematurie. Aucun cas n’avait de manifestations extrarenales. Un composant monoclonal circulant etait detectable dans 6/7 cas (myelome symptomatique, n = 1). L’aspect en microscopie optique etait une glomerulonephrite membrano-proliferative (n = 5), mesangiale (n = 1) ou extramembraneuse atypique (n = 1). En immunofluorescence, les depots etaient constitues de chaines legeres kappa (n = 5) ou lambda (n = 2), toujours associes a des depots de C3. Trois patients avaient un C3 serique bas sans anomalies des proteines regulatrices de la voie alterne. Dans 1 cas, nous avons montre que la chaine legere lambda purifiee activait la voie alterne du complement. Le sequencage de cette chaine legere Vλ3 a revele plusieurs mutations dans les regions hypervariables (principalement CDR1). Six patients ont recu une chimiotherapie a base d’alkylant ± bortezomib. Une reponse hematologique, suivie dans tous les cas d’une reponse renale, a ete obtenue chez les 3/3 patients traites par bortezomib. Tous les patients en bonne reponse hematologique ont normalise leur taux circulant de C3. Discussion Nous rapportons la premiere serie de PGNMID a chaine legere monoclonale. L’association constante avec des depots de C3 suggere une activation de la voie alterne du complement par la chaine legere monoclonale. Un traitement ciblant le clone B sous-jacent, parfois non detectable par les techniques usuelles, est indispensable pour preserver le pronostic renal. Conclusion Le sequencage des chaines legeres monoclonales pourrait permettre de mieux comprendre les mecanismes physiopathologiques impliques dans cette forme rare de PGNMID.

AL amyloidosis is a severe complication of plasma-cell disorders, secondary to monoclonal immunoglobulin light chain (LC) deposition in the kidney and other organs. Though the physicochemical properties of amyloid-forming monoclonal LCs have been demonstrated to be involved in their propensity to aggregate, it remains unclear where, when, and finally why amyloid fibrils are formed in vivo. Teng et al. shed light on this long-standing issue thanks to a new animal model.

BACKGROUND Renal involvement in light chain (LC) deposition disease (LCDD) is typically characterized by nodular glomerulosclerosis and nephrotic range proteinuria. Rare cases of LCDD without glomerular symptoms have been reported, but clinical and pathological characteristics of this entity remain poorly described. METHODS This multi-centre retrospective study included 14 patients with biopsy-proven renal LCDD and proteinuria

The use of cyclosporin monotherapy as maintenance immunosuppression in primary cadaveric renal transplant recipients is not popular except in a few European centres. Corticosteroid withdrawal is becoming more popular, and is usually attempted with the newer immunosuppressants which have a more corticosteroid-sparing effect than cyclosporin. The adverse effects and morbidity associated with maintenance regimens consisting of 2 or 3 immunosuppressive drugs are well known, but the potential benefits of cyclosporin monotherapy must be balanced against an increased risk of graft loss by rejection. We selected patients for a trial of corticosteroid withdrawal and subsequent cyclosporin monotherapy. These patients received an individually designed immunosuppressive regimen with careful control of cyclosporin trough concentrations. The cyclosporin formulations used were its original oil-based solution or gelatin capsule (Sandimmun, Sandimmune )until mid-1996 and then the microemulsion formulation (Neoral). Corticosteroid withdrawal was attempted in 89% of patients with a graft functioning at 3 months after transplantation and was effective in 88% of them. At a mean follow-up time of 98 +/- 23 months, 69% of grafts were functioning and 92% of patients were alive. 50% of patients with a functioning graft were receiving long term cyclosporin monotherapy. Mild rejection episodes occurred in 6% of patients receiving cyclosporin monotherapy per year of treatment, and chronic rejection caused graft loss in 1.4% of patients per year of treatment. Comparison of successful and unsuccessful outcomes allows us to define favourable predictive factors. For corticosteroid withdrawal these are: older recipient age, lower creatininaemia at months 6 and 8 and higher trough cyclosporin concentrations at month 6. For cyclosporin monotherapy these are: later timing of azathioprine withdrawal, recipient age25 years, donor ageor=40 years, creatininaemiaor=125 micromol/L at initiation of monotherapy and no rejection episode before initiation of monotherapy. We have observed a low incidence of nonmelanoma skin cancers and of squamous-cell carcinoma in our series. This is perhaps the result of the azathioprine-sparing effects of the regimen (7 azathioprine-free years per patient with successful cyclosporin monotherapy, and 4 azathioprine-free years per patient with unsuccessful monotherapy). This important point will need further studies but is encouraging. Maintenance cyclosporin monotherapy is feasible and probably useful in selected primary graft recipients without deleterious effects on overall results in terms of graft and patient survival. Careful patient selection using the predictive factors we have defined should make cyclosporin monotherapy more effective, allowing the present 57% success rate at 5 years post-transplantation to be increased by 15 or 20%.

Background Renal thrombotic microangiopathy (TMA) is an uncommon vascular complication of systemic lupus erythematosus (SLE). Its clinical symptoms and impact on renal survival remain unclear. Methods Eight patients aged 25 +/- 6 years with biopsy-proven renal TMA and at least four ARA criteria for the diagnosis of SLE were retrospectively studied over a 7-year period. Results All patients presented with renal failure (creatinine 3.3 +/- 2.1 mg/dl), six had proteinuria (2.5 +/- 1.3 g/day) with microscopic haematuria in four cases. Six patients had hypertension, which was severe in five cases. Renal histology disclosed arterial and/or arteriolar thrombosis with parietal thickening without angeitis (8 patients), glomerular microthrombi (3 patients), and vascular fibrin deposits (5/6 patients). In two cases, vascular lesions were associated with a mesangial or a proliferative glomerulonephritis. Thrombocytopenia was present in four patients with haemolytic microangiopathic anaemia in one case. Lupus anticoagulant (LA) was detected in five of eight patients, who also had anticardiolipin antibodies (3/7 patients) and/or were positive for VDRL (3/6 patients). Four patients with LA experienced arterial thrombosis and/or repeated spontaneous abortions. Treatment consisted of corticosteroids (8 patients), cytotoxic drugs (4 patients), plasma exchanges and/or intravenous immunoglobulins (4 patients) and antiplatelet and/or anticoagulant therapy (3 patients). Two patients recovered normal renal function and five had persistent renal insufficiency. One patient started haemodialysis on admission and died of sepsis 2 months later. Conclusions TMA may be the sole renal complication in SLE and is not usually associated with haemolytic microangiopathic anaemia. In our series renal survival was influenced by the extent and severity of vascular lesions. Despite a frequent association with antiphospholipid antibodies, pathophysiological mechanisms of renal TMA in SLE remain unknown. Renal histology is mandatory for the diagnosis and the prognostic evaluation of renal vasculopathy in SLE.

Autoreactive anti–MHC class II T cells are found in Brown Norway (BN) and Lewis (LEW) rats that receive either HgCl2 or gold salts. These T cells have a T helper cell 2 (Th2) phenotype in the former strain and are responsible for Th2-mediated autoimmunity. In contrast, T cells that expand in LEW rats produce IL-2 and prevent experimental autoimmune encephalomyelitis, a cell-mediated autoimmune disease. The aim of this work was to investigate, using T cell lines derived from HgCl2-injected LEW rats (LEWHg), the effect of these autoreactive T cells on the development of Th2-mediated autoimmunity. The five LEWHg T cell lines obtained protect against Th2-mediated autoimmunity induced by HgCl2 in (LEW × BN)F1 hybrids. The lines produce, in addition to IL-2, IFN-γ and TGF-β, and the protective effect is TGF-β dependent since protection is abrogated by anti-TGF-β treatment. These results identify regulatory, TGF-β–producing, autoreactive T cells that are distinct from classical Th1 or Th2 and inhibit both Th1- and Th2-mediated autoimmune diseases.

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Background: Renal failure is a common complication for patients (pts) with MM. The incidence of renal failure increases during the course of the disease. Renal insufficiency is associated with poor prognosis in MM; however, the introduction of novel agents has led to improved survival. This trial evaluates safety, efficacy, and pharmacokinetics of pomalidomide (POM) plus dexamethasone (DEX) in pts with myeloma-related renal impairment and an eGFR < 45 mL/min/1.73m2as well as in pts on hemodialysis. Aims:The aim of this analysis is to summarize the safety profile of POM and DEX in pts with RRMM and renal impairment, including pts on hemodialysis. Methods: This interventional phase 2, open-label, multicenter study enrolled 3 cohorts of pts with RRMM and differing degrees of renal impairment. Cohort A included pts with moderate renal impairment (eGFR between 30 and 45 mL/min/1.73m2), cohort B included pts with severe renal impairment (eGFR ≤ 30 mL/min/1.73m2) not requiring hemodialysis, and cohort C included pts with severe renal impairment requiring hemodialysis. Enrollment occurred in parallel, and all pts received treatment with starting doses of POM 4 mg and DEX 40 mg (20 mg for pts aged > 75 years). All pts continued study treatment until disease progression or unacceptable toxicity. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for AEs v4.0. Supportive care, such as hematopoietic growth factors, was allowed; thromboembolic prophylaxis was required for all pts not on hemodialysis. Results: As of June 2016, 78 pts (30 in cohort A, 34 in cohort B, 14 in cohort C) across 19 institutions in 8 European countries were enrolled in the trial. At the time of this abstract, there were 28 pts still on treatment (15, 11, and 2 in cohorts A, B, and C, respectively). During the study, 27 pts (34.6%) discontinued treatment due to progressive disease (33.3% [n = 10/30], 41.2% [n = 14/34], and 21.4% [n = 3/14] in cohorts A, B, and C, respectively), 8 pts (10.3%) due to AEs (6.7% [n = 2/30], 8.8% [n = 3/34], and 21.4% [n = 3/14]), and 15 pts (19.2%) due to other reasons. The safety population consisted of 76 pts (29, 34, and 13 in cohorts A, B, and C, respectively). Median treatment duration was 3.8 months (range, 0.5-17.5 months) overall (4.1 months [range, 0.9-17.5 months], 4.1 months [range, 0.5-13.4 months], and 2.1 months [range, 0.5-9.2 months] in cohorts A, B, and C, respectively), and the median average daily POM dose was 4 mg/day for all cohorts. Dose reductions occurred in 12 pts (15.8%) overall (13.8% [n = 4/29], 17.6% [n = 6/34], and 15.4% [n = 2/13] in cohorts A, B, and C, respectively). Occurrence of ≥ 1 grade 3/4 AE was similar between cohorts (75.9%, 76.5%, and 76.9% in cohorts A, B, and C, respectively). In cohorts A, B, and C, the occurrence of serious AEs was 48.3%, 52.9%, and 76.9%, respectively. Overall, the most frequently reported AEs of any grade were neutropenia in 46 (60.5%) pts (69.0%, 52.9%, and 61.5% in cohorts A, B, and C, respectively) and thrombocytopenia in 32 (42.1%) pts, (48.3%, 35.3%, and 46.2% in cohorts A, B, and C, respectively). Neutropenia did not translate into febrile neutropenia, which occurred in only 1 pt each in cohorts A and B. Overall, infections were reported in 41 (53.9%) pts (55.2%, 58.8%, and 38.5% in cohorts A, B, and C, respectively), including 11 pts (14.5%) who had pneumonia (20.7%, 5.9%, and 23.1%). Rates of asthenia (20.7%, 11.8%, and 30.8% in cohorts A, B, and C, respectively) and fatigue (20.7%, 17.6%, and 30.8%) were slightly higher in pts on hemodialysis compared with pts with moderate renal impairment or severe renal impairment without hemodialysis, representative of the poor performance status and anemia (at baseline, 41.4%, 41.2%, and 61.5% in cohorts A, B, and C, respectively) noted in these pts. Conclusions: Results of this study investigating POM in combination with DEX in pts with RRMM and renal impairment show a similar AE profile as previously reported in pts without renal insufficiency. Compared with pts not on hemodialysis, slightly more non-hematologic AEs were reported in pts on hemodialysis, who have a poor performance status in comparison with other cohorts. Updated data will be presented at the meeting. Disclosures Weisel: Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Onyx: Consultancy; Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Honoraria. Dimopoulos:Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. van de Donk:Celgene: Research Funding; BMS: Research Funding; Janssen: Research Funding; Amgen: Research Funding. Ramasamy:Celgene: Honoraria, Research Funding. Streetly:Guys and St. Thomas' NHS Trust: Honoraria. Offidani:Celgene: Honoraria, Research Funding; Janssen: Honoraria. Bridoux:Celgene, Roche, Amgen, Janssen, Baxte: Honoraria, Research Funding. de la Rubia:Janssen: Consultancy; Amgen,: Consultancy; Celgene: Consultancy; Bristol Myers: Consultancy. Kueenburg:Celgene International Sarl: Consultancy, Honoraria. Lersch:Celgene: Employment. Bacon:Celgene: Employment, Equity Ownership. Sonneveld:Celgene: Other: Advisory board, Research Funding; Onyx: Other: Advisory board, Research Funding; Millennium: Other: Advisory board, Research Funding; Janssen-Cilag: Other: Advisory board, Research Funding.

Multiple myeloma (MM) is often revealed by acute kidney injury (AKI) usually related to MCN. Recovery of renal function is a key prognostic factor. With novel anti-myeloma agents, HD-independence occurs in about 30% of pts with severe AKI, advocating for the use of additional strategies to rapidly remove circulating monoclonal free light chains (FLC). We designed a prospective randomized trial to compare the HD-independence rate in pts with inaugural severe AKI secondary to biopsy-proven MCN, treated by intensive HD (8 sessions over the first 10 days, then thrice a week) using either a HCO dialyzer or a conventional high-flux dialyzer. In both groups, pts received 21-day courses of Bortezomib and dexamethasone (BD), reinforced by cyclophosphamide after 3 cycles in the absence of haematological response (HR). Between 2011 and 2015, 98 pts were randomised. One pt withdrew consent, and 3 had main exclusion criteria. Baseline characteristics in the control arm (n=48) and HCO arm (n=46) were close, including similarly high serum FLC levels (median 6,015mg/L). HD independence was achieved in 33% and 43% (p= 0.31) at 3 and in 37.5% and 60 % (p=0.03) at 6 mo, in the control and HCO arms, respectively. HR rate of very good partial response or above at 3 mo based on FLC was 48% in control and 59% in HCO groups (p=0.29). Tolerance of HD schedule and of chemotherapy was acceptable in both arms. At 12 mo, 17 pts have died (10 vs 7). This randomized trial demonstrates that in MM patients with MCN and severe AKI treated with a bortezomib-based regimen, intensive HCO-HD results in higher renal recovery rate than HD with conventional high-flux dialyzers. Disclosures Augeul-Meunier: janssen: Consultancy; gilead: Consultancy. Benboubker:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.