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For a long time, kidney biopsy was the only diagnostic means for membranous nephropathy (MN) and proteinuria and serum creatinine were the only markers of disease activity. The discovery of the phospholipase A2 receptor (PLA2R) antibody in 2009 has induced a paradigm shift in both the diagnosis and monitoring of patients. Two serological tests are routinely used: the enzyme-linked immunosorbent assay (ELISA), which is quantitative, and the immunofluorescence assay (IFA), which is more sensitive. In centres where the two assays are available, the recommendation is to use IFA for screening and diagnosis of immunological remission and ELISA for monitoring the effectiveness of therapy. In patients with positive PLA2R antibody serology, normal kidney function and no evidence of an underlying disease, a kidney biopsy is not mandatory given the almost 100% specificity of the assays. Because MN has different phases, one cannot base a clinical or therapeutic decision on a single measurement of PLA2R antibody at baseline. Risk evaluation of disease progression is a dynamic process that should be performed repeatedly to capture the trajectory of the disease based on both the traditional biomarkers (proteinuria and serum creatinine) and PLA2R antibody levels. The effectiveness of therapy is also evaluated on the PLA2R antibody trajectory, particularly during the first 6 months. Finally, PLA2R antibody monitoring has transformed the management of patients with kidney allografts. Future studies are needed to develop more subtle immunological tests, including monitoring of antigen-specific memory B cells.

Background The incidence of chronic kidney disease (CKD) is 10 times higher in human immunodeficiency virus (HIV)-infected patients than in the general population. We explored the prevalence and determinants of proximal tubular dysfunction (PTD) in HIV-infected individuals, and assessed the impact of the tubulopathy on the estimated glomerular filtration rate (eGFR) outcome. Methods A cohort study was performed on 694 outpatients followed in a French centre to analyse the prevalence of PTD, the diagnosis performance of screening tools and the associated factors. eGFR was prospectively evaluated to analyse the predictive value of the tubulopathy on eGFR decrease. Results At inclusion, 14% of the patients presented with PTD and 5% with CKD. No individual tubular marker, including non-glomerular proteinuria, glycosuria dipstick or hypophosphataemia, registered sufficient performance to identify PTD. We found a significant interaction between tenofovir disoproxil fumarate exposure and ethnicity (P = 0.03) for tubulopathy risk. Tenofovir disoproxil fumarate exposure was associated with PTD in non-Africans [adjusted odds ratio (aOR) = 4.71, P Conclusion PTD is not rare in HIV-infected individuals but is less frequent in sub-Saharan African patients and is associated with tenofovir disoproxil fumarate exposure only in non-Africans. Its diagnosis requires multiple biochemical testing and it is not associated with an accelerated eGFR decline.

etic risk is needed. The study of Sadowski et al., reporting that a single gene causes steroid-resistant nephrotic syndrome in 30% of children and young adults, owns its success to the fact that patients had an excellent ‘marker’ for a genetic disease: a positive family history. However, mutations in adult patients without family history are extremely rare and screening is not recommended. We agree with Doctors Mariani and Kretzler regarding the ‘paucity of robust data from RTC to support treatment recommendations’ in glomerular diseases. However, this is in great part due to the lack of interest from the funding agencies in conducting translational research. Instead, significant funding is invested in sophisticated research far away from the bedside, thus delaying clinician access to therapeutical approaches that could help patients today.

Of the glomerulonephritis associated with sarcoidosis, membranous nephropathy (MN) is the most prevalent. Coincidence or a causal relationship between these two diseases is unclear. Here, we present for the first time a high prevalence of PLA2R-related MN among patients with MN associated with active sarcoidosis. Our results suggest some causal link between sarcoidosis and PLA2R-related MN. Detection of anti-PLA2R antibodies in serum or PLA2R antigen in biopsy should not be taken as evidence against a secondary cause, particularly sarcoidosis. This important observation can affect treatment decision in these patients.

International audience; BACKGROUND: Treatment and co-morbidities of human immunodeficiency virus (HIV)-infected individuals have changed dramatically in the last 20 years with a potential impact on renal complications. Our objective was to assess the change in distribution of the glomerular diseases in HIV patients. METHODS: We retrospectively analysed demographic, clinical, laboratory and renal histopathological data of 88 HIV-infected patients presenting with a biopsy-proven glomerular disease between 1995 and 2007. RESULTS: In our study including 66% Black patients, HIV-associated nephropathy (HIVAN) was observed in 26 cases, classic focal segmental glomerulosclerosis (FSGS) in 23 cases, immune complex glomerulonephritis in 20 cases and other glomerulopathies in 19 patients. HIVAN decreased over time, while FSGS emerged as the most common cause of glomerular diseases (46.9%) in HIV-infected individuals undergoing kidney biopsy in the last 2004-07 period. Patients with HIVAN were usually Black (97%), with CD4

In this issue of Nephrology, Dialysis, Transplantation, Mirza et al. [1] present a very interesting but also puzzling case of membranous nephropathy (MN) transplanted in a patient with a history of long-term diabetes mellitus and severe atherosclerosis. Simultaneous heart and kidney transplantation were carried out at a time when the recipient’s estimated glomerular filtration rate was 28 mL/min and proteinuria 1+. His native kidney histology was unknown and although the aetiology of his nephropathy was multifactorial, it can be safely ascertained that the grafted kidney benefitted, in a broad sense, from a ‘non-immunologic’ environment. This case thus provides a unique opportunity to observe the outcome of immune deposits after cessation of the immunological aggression. The donor was a young woman who had died from a hypertensive subarachnoid haemorrhage. Prior to her death, she was not proteinuric. A pre-transplant biopsy of the donor’s kidney led to the discovery of lesions of Stages II, III and IV MN, a puzzling finding in the absence of proteinuria. The authors hypothesize that the preservation of the glomerular filtration barrier to proteins might be explained by the mild podocyte injury that was observed on the four serial biopsies that were performed up to Day 812. Each yielded a substantial number of glomeruli and showed by light microscopy, electron microscopy and immunofluorescence, a striking improvement of the initially severe membranous lesions. As in the donor, and despite persistence of Stages II and III glomerular basement membrane (GBM) lesions and immunoglobulin and complement staining, proteinuria was never significant and the kidney recipient maintained good function. This case is exceptional, although not the first one describing progressive wash-out of membranous immune deposits in kidneys transplanted into a non-immunologic environment. Parker et al. [2] reported the case of a patient with end-stage renal disease (ESRD) secondary to Type II diabetes mellitus who received a cadaveric renal transplant from a 37-year-old woman who died of cerebral infarction. A biopsy of the donor’s kidney performed at the time of transplantation showed MN by electron microscopy. There was immediate graft function and the recipient continued to have good kidney function 3 years post-transplantation. Nakazawa et al. [3] presented the case of a 41-year-old man grafted with a cadaver kidney. An allograft biopsy obtained during the operation showed spike formation on periodic acid-silver methenamine staining and deposition of IgG along the glomerular capillary loop on immunoperoxidase staining. Immunofluorescence staining for IgG persisted in the specimens obtained on Day 11 and after 4 weeks, but markedly decreased in the specimen obtained 7 weeks after transplantation. Electron-dense deposits also decreased in amount, but irregular thickening of the glomerular basement membrane with spikes, electron-lucent lesions and small amounts of electron-dense deposits remained 20 months after the transplantation. Akioka et al. [4] transplanted a kidney from a father, diagnosed with MN and mild proteinuria, to his son. At 39 months after transplantation, allograft biopsy showed a wash-out of electron-dense deposits and electron-lucent lesions. These reports are interesting but were not analyzed as meticulously as Mirza et al. did in their case. Their recipient’s kidney was studied by a pre-transplant histology followed by four biopsies up to 27 months post-transplantation. Along with light and electron microscopy, they used a wide panel of antibodies for immunofluorescence including staining for type-M phospholipase A2 receptor (PLA2R) that was negative. This is suggestive of a secondary aetiology of membranous glomerulonephritis (GN) but does not exclude a PLA2R-unrelated primary form [5]. PLA2R is a major target antigen in autoimmune idiopathic membranous GN. PLA2R is revealed in normal human glomeruli, and in idiopathic MN, PLA2R and IgG4 are shown to co-localize within subepithelial deposits. Early recurrence of MN in kidneys transplanted to recipients with circulating anti-PLA2R antibodies lends credit to a pathogenic role of these antibodies [6–8]. Their decrease IN F O C U S

Renal involvement is frequent in patients suffering from primary Sjögren’s syndrome (pSS). Tubulointerstitial infiltration is the most common renal lesion, while glomerular involvement is rare. We report the case of a 50-year-old woman with pSS who developed renal failure due to an unusual proliferative glomerulonephritis with humps and monotypic IgG1-kappa deposits. Searches for cryoglobulinaemia, anti-double-stranded DNA and anti-neutrophil cytoplasmic antibodies were negative. Serum protein electrophoresis and immunofixation revealed no monoclonal immunoglobulin. Extensive work-up excluded associated infectious, collagen or lymphoproliferative disease. This case adds to the spectrum of pSS-related glomerular disease which is reviewed in depth.

Membranous nephropathy (MN) is a non-proliferative glomerular disease characterized by accumulation of immune deposits on the outer aspect of the glomerular basement membrane (GBM) leading to complement activation and proteinuria. Eighty per cent of cases are referred to as ‘idiopathic MN’ (iMN), while ~20% are classified as ‘secondary’ because they occur in patients presenting with associated clinical conditions such as infection (hepatitis B, mostly in children), cancer, systemic lupus erythematosus (SLE) and related systemic autoimmune diseases and drug intoxication. For a long time, the target antigens have gone unrecognized. However, in the last 10 years, considerable progress has been achieved in the understanding of the pathophysiology of MN, with the identification of several target antigens from the neonatal period to adulthood, which makes it possible to discuss at the molecular level the mechanisms of association with other nephropathies. These advances started in 2002 with the identification by our group of neutral endopeptidase as the responsible antigen in a rare subset of patients with alloimmune antenatal MN [1, 2]. This finding provided evidence to support the concept that a human podocyte antigen could serve as a target for nephritogenic antibodies, which in turn laid the foundations for the identification of the M-type receptor for secretory phospholipase A2 (PLA2R1), the first podocyte antigen involved in autoimmune MN [3]. Our genome-wide association study (GWAS) further showed that single-nucleotide polymorphisms (SNPs) in the PLA2R1 gene were strongly associated with iMN [4], which confirmed the involvement of this antigen using an unbiased genetic approach. Other antigens such as aldose reductase, superoxide dismutase-2 and alpha-enolase have also been identified, pointing to immunological heterogeneity of MN [5, 6]. In addition to podocyte antigens, exogenous antigens such as cationic bovine serum albumin have been implicated in some patients with early-childhood MN, pointing to the role of environmental antigens as disease triggers [7]. These ground-breaking data have opened up a new era for the diagnosis and monitoring of MN from early infancy to adulthood. In this issue of the journal, Surindran et al. [8] report the interesting association of PLA2R1-positive MN with antineutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis (GN). Light microscopy showed cellular crescents with occasional necrosis of the glomerular tuft and mildly thickened GBM with numerous subepithelial electron deposits by electron microscopy. Granular deposits of C3 were seen by immunofluorescence while IgG could not be studied in the absence of glomeruli. Is this association a coincidence or are there common mechanisms or pathways involved? We will discuss this issue in MN associated with two different autoimmune diseases where target antigens are known, i.e. ANCA-associated vasculitis and anti-GBM disease.

International audience

We report the case of a young Caucasian man presenting with diffuse oedema and nephrotic syndrome. Clinical examination revealed multiple lymphadenopathies. Histological examination was consistent with the diagnosis of Kimura's disease. A renal biopsy showed focal segmental glomerulosclerosis. Immune thrombocytopenia and signs of humoral autoimmunity were discovered. Corticosteroid treatment induced remission of nephrotic syndrome but relapses occurred 12 and 18 months after onset of treatment while the patient was receiving 20 mg prednisone once a day. To our knowledge, this is the first case of Kimura's disease and nephrotic syndrome associated with B-cell autoreactivity.

Heymann's nephritis can be induced in rats by injection of antibodies (Ab) against the major nephritogenic antigen (Ag) (gp330). We previously reported on a 90-kD tubular-glomerular glycoprotein (gp90) having enzymatic activity (dipeptidyl-peptidase IV) which, after antibody interaction, induces a transient Heymann-like immunofluorescence pattern. In the present study we have analysed the ultrastructural features of the renal immune reaction occurring in rats after injection of a monoclonal antibody to gp90, revealed by a pre-embedding immunogold staining (5-nm particles). In the early stage (10-60 min) gold granules were found along the glomerular capillary walls mainly in the endothelial region. During the intermediate stage (24-48 h) the brush border microvilli were diffusely labelled. In the late stage (1-2 weeks) gold particles were still noticed at the tubular level. This work suggests that the immune reaction in Heymann's nephritis also occurs on the endothelial side of the glomerular capillary walls, thus facilitating the passage of epithelial-specific antibody. The tubular kinetics confirms that gp90 may play a role in the metabolic activity of tubular proximal cells. Because this antigen has been demonstrated in human kidney as well, it may be relevant to some membranous or other human nephropathies.

Sir, Drug-induced acute interstitial nephritis (AIN) can cause end stage renal failure. Withdrawal of imputable drugs is the best treatment, and requires early recognition. We report the first two biopsy-proven cases of fluindione-related AIN indicating that fluindione must be included in the list of imputable drugs.

Although it is generally considered that vasculitis of the polyarteritis nodosa (PAN) group and Wegener's granulomatosis (WG) is immune complex (IC) mediated, there are no simultaneous data on circulating IC, complement levels and deposits of Ig and complement in the kidney. Therefore we have performed a retrospective study of 43 patients suffering from PAN and WG. Ig glomerular deposits were uncommon and scanty, except in two patients with WG; C3 deposits were detected in 12 patients, whereas fibrinogen was constantly found when lesions were recent and active. Similar data were obtained for the renal vessel walls. Contrasting with these results, rheumatoid factors and cryoglobulins, suggestive of the presence of circulating IC, were detected respectively in nine of 39 and seven of 37 patients, and IC 'activity' assessed by the Raji cell assay and the Clq binding assay was found respectively in six of 17 and nine of 10 patients before treatment, and in none of 10 and five of seven patients in remission. Haemolytic complement activity and complement components were never decreased, but the C3d breakdown product of C3 was elevated in all the eight patients studied before treatment. Signs of persistent hepatitis B virus (HBV) infection were detected in five of 25 patients of the PAN group, whereas three of eight patients with WG had only anti-HBV antibodies. Furthermore, cytomegalovirus (CMV) could be isolated from the blood in a case of WG before the treatment was started. Persistent interferonaemia was detected in one of five patients. These results suggest either that renal deposition of CIC is transient, the paucity of Ig deposits being due to rapid clearance of IC by phagocytic cells; or alternatively that vascular and glomerular lesions are not caused by CIC, as in some cases of experimental vasculitis induced by infectious agents.