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Background Although rapidly progressive glomerulonephritis is the main renal phenotype of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), slow renal disease progression is sometimes observed. These forms have been rarely discussed; we analysed their prevalence, clinico-pathological characteristics and outcome. Methods We screened patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis followed at seven referral centres and selected those with estimated glomerular filtration rate (eGFR) reduction Results Of 856 patients, 41 (5%) had slowly progressive renal AAV. All had MPA and all but one was P-ANCA/myeloperoxidase (MPO) ANCA-positive. At diagnosis, the median age was 70 years [interquartile range (IQR) 64–78] and extra-renal manifestations were absent or subclinical (interstitial lung lesions in 10, 24%). The median (IQR) eGFR was 23 mL/min/1.73 m2 (15–35); six patients (15%) had started renal replacement therapy (RRT). All had proteinuria (median 1180 mg/24 h, IQR 670–2600) and micro-haematuria. Main histologic findings were extracapillary proliferation at chronic stages and glomerulosclerosis; following Berden’s classification, 6/28 biopsies (21%) were ‘focal’, 1/28 (4%) ‘crescentic’, 9/28 (32%) ‘mixed’ and 12/28 (43%) ‘sclerotic’. At last follow-up (median 32 months, IQR 12–52), 20/34 patients (59%) treated with immunosuppression had eGFR improvement >25% as compared with diagnosis, while 4/34 (12%) had started RRT. Conclusions AAV may present with slow renal disease progression; this subset is hallmarked by advanced age at diagnosis, positive MPO-ANCA, subclinical interstitial lung lesions and chronic damage at kidney biopsy. Partial renal recovery may occur following immunosuppression.

Membranous nephropathy is a frequent cause of nephrotic syndrome in adults. In most patients, it appears as a primary renal disease but in about 20 % of cases membranous nephropathy is associated with systemic conditions such as systemic lupus erythematosus, infections or cancer, or with drug exposure. Reliable differentiation between primary and secondary membranous nephropathy has important implications for the patient, because of different therapeutic approaches between the different forms. The recent in vivo definition of glomerular targets of autoimmunity in idiopathic membranous nephropathy represented a real breakthrough and nowadays more than one podocyte antigen is considered in some way implicated in the pathogenesis of human membranous nephropathy. Specific antibodies against all these components have been detected in serum of patients and could become biomarkers of membranous nephropathy and/or of disease activity. In this brief review, we discuss the usefulness of newly described autoantibodies in the differential diagnosis of secondary membranous nephropathy. Histological clues for recognizing the two pathological entities are also analysed with regard to the available scientific evidence on this issue. Our evaluation shows that more research is needed to identify the best approach to reach a correct diagnosis of primary or secondary membranous nephropathy.

These proteins are expressed by humanpodocytes, and specific autoantibodies have beenshown to colocalize with IgG4 and C5b-9 in immunedeposits of MN biopsies.All these proteins are detectable at the surface ofpodocytes only in biopsy specimens from patientswith MN, suggesting that it is their aberrant localiza-tion to the cell surface that makes it possible for themto be targeted by autoantibodies in disease states. Invitro experiments implicate oxidant triggers in thisprocess. In a previously published cohort of 186patientswithMNevaluatedatthetimeofdiagnosis

The analysis of the urinary proteome is a potential source of information regarding the kidney's physiopathology. A clear knowledge of the protein composition of normal urine is an essential prerequisite to looking at its pathology. Technological evolution in the field of proteomics (2-dimensional [2D] electrophoresis, equalization, mass spectrometry and exosomes) has greatly expanded the power of analysis, allowing the detection of almost 2,000 spots in normal urine, only a minor part of which has been characterized as isoforms of known proteins. The identity of most spots (80%) remains to be determined. The analysis of urine composition in nephrotic syndrome (glomerulosclerosis and membranous nephropathy) and in lupus nephritis is in progress, but has not yet furnished any relevant material. The unique exception is the presence of acidic components that suggests alteration of the charge selectivity properties of the glomerular wall in cases of heavy proteinuria. In lupus nephritis, prostaglandin-H2-isomerase and hepcidin have also been identified as activity biomarkers. Several overexpressed or underexpressed proteins have also been found in urine IgA nephropathy, but their specificity needs validation. Decreased levels of aquaporin 2 and of inter-a-trypsin-inhibitor heavy chain 4 have been associated, respectively, with hypertension and with a different response to angiotensin-converting enzyme inhibition in IgA nephropathy patients. From the present stage, mainly characterized by discovery of new proteins in urine, we should now proceed to their validation as biomarkers of diseases and possibly to clinical trials. Participation by basic scientists and clinicians together in projects launched by worldwide organizations is of vital importance.

In children with idiopathic nephrotic syndrome, rituximab can maintain short-term remission with withdrawal of prednisone and calcineurin inhibitors. Long-term effects including the number of repeated infusions to maintain remission are unknown. To test this, we treated 46 consecutive children with idiopathic nephrotic syndrome lasting for at least 1 year (mean 6.3 years), maintained in remission with oral prednisone and calcineurin inhibitors. They received 1–5 rituximab courses during a median follow-up of 3 years. Oral agents were tapered after each infusion, and completely withdrawn within 45 days. Rituximab was well tolerated. Six-month probabilities of remission were 48% after the first infusion and 37% after subsequent infusions. One- and 2-year-remission probabilities were, respectively, 20 and 10%. Median time intervals between complete oral-agent withdrawal and relapse were 5.6 and 8.5 months, respectively, following the first and subsequent courses. The time to reconstitution of CD20 cells correlated with the duration of remission, but was not associated with variation in FcyR, CD20, or SMPDL-3B polymorphisms. Podocyte Src phosphorylation was normal. Thus, rituximab can be safely and repeatedly used as a prednisone and calcineurin inhibitor–sparing therapy in a considerable proportion of children with dependent forms of idiopathic nephrotic syndrome. Further study is needed to identify patients who will benefit most from rituximab therapy.

Idiopathic nephrotic syndrome resistant to standard treatments remains a therapeutic dilemma in pediatric nephrology. To test whether the anti-CD20 monoclonal antibody rituximab may benefit these patients, we conducted an open-label, randomized, controlled trial in 31 children with idiopathic nephrotic syndrome unresponsive to the combination of calcineurin inhibitors and prednisone. All children continued prednisone and calcineurin inhibitors at the doses prescribed before enrollment, and one treatment group received two doses of rituximab (375 mg/m(2) intravenously) as add-on therapy. The mean age was 8 years (range, 2-16 years). Rituximab did not reduce proteinuria at 3 months (change, -12% [95% confidence interval, -73% to 110%]; P=0.77 in analysis of covariance model adjusted for baseline proteinuria). Additional adjustment for previous remission and interaction terms (treatment by baseline proteinuria and treatment by previous remission) did not change the results. In conclusion, these data do not support the addition of rituximab to prednisone and calcineurin inhibitors in children with resistant idiopathic nephrotic syndrome.

Summary Background and objectives The discovery of different podocyte autoantibodies in membranous nephropathy (MN) raises questions about their pathogenetic and clinical meaning. This study sought to define antibody isotypes and correlations; to compare levels in MN, other glomerulonephritides, and controls; and to determine their association with clinical outcomes. Design, setting, participants, & measurements Serum IgG1 ,I gG3 ,a nd IgG4 against aldose reductase (AR), SOD2, and a-enolase (aENO) were measured at diagnosis in 186 consecutive MN patients, in 96 proteinuric controls (36 with FSGS, and 60 with IgA nephropathy), and in 92 healthy people recruited in four Italian nephrology units. Anti-phospholipase A2 receptor (PLA2r) and anti-neutral endopeptidase (NEP) IgG4 were titrated in the same specimens. Association with 1-year follow-up clinical parameters was studied in 120 patients. Results IgG4 was the most common isotype for all antibodies; IgG1 and IgG3 were nearly negligible. IgG4 levels werepositiveinasignificantproportionofMNpatients(AR,34%;SOD2,28%;aENO,43%).Antibodytiterswere higher in MN than in healthy and pathologic controls (P,0.005). Anti-NEP IgG4 did not differ from normal controls (P=0.12). Anti-PLA2r IgG4 was detected in 60% of patients and correlated with anti-AR, anti-SOD2, and anti-aENO IgG4 (P,0.001). In MN patients negative for the whole antibody panel (20%), 1-year proteinuria was lower compared with patients with at least one antibody positivity (P,0.05). Conclusions Our data suggest that IgG4 is the prevalent isotype for antibodies against cytoplasmic antigens of podocytes (AR, SOD2, aENO). Their levels were higher than in other proteinuric glomerulonephritides and in normal controls and were correlated with anti-PLA2r. Only baseline negativity for all known antibodies predicted lower 1-year proteinuria. Clin J Am Soc Nephrol 7: ccc–ccc, 2012. doi: 10.2215/CJN.02170312

Idiopathic membranous nephropathy (IMN) is responsible for most cases of nephrotic syndrome in adults [1]. Although spontaneous remission may occur in some cases and several therapeutic options are now available [2–4], in a significant number of patients the response to therapy is poor and the risk of cardiovascular events or kidney disease progression remains high. Prognostic markers in IMN would help clinicians identify potential candidates to early intervention and specific strategies. In general, the development of biomarkers largely depends on the understanding of the pathogenesis of the disease. Until recently, the mechanisms of IMN in humans were translated from animal models, mainly from Heymann nephritis. However, basic differences in autoantigens glomerular expression among mice, rabbits and humans represented the main roadblock to the understanding of mechanisms of IMN in humans [5]. In fact, megalin, the autoantigen of Heymann nephritis, is not expressed in human glomeruli. The finding that neutral endopeptidase (NEP) is the target antigen of the autoimmune response in neonatal forms of the disease represents a breakthrough in the identification of glomerular autoantigen in human IMN. Elegant works by Debiec et al. [6, 7] showed the presence of anti-NEP antibodies in a woman carrying a homozygous deletion in MME (the gene coding for NEP). After alloimmunization occurred during a former pregnancy, anti-NEP antibodies were transferred to the fetus during a successive pregnancy. This rare form of IMN first proved the role of circulating antibodies against a podocyte protein in determining human IMN. More recently, new podocyte autoantigens have been identified [8–10] and research is now focused on the development and validation of a panel of antibodies to risk stratify patients and assist clinical decision making. Direct analysis of antibodies eluted from human glomeruli are now possible thanks to advances in technologies of recent application to human pathology, such as laser capture microdissection and proteomics. Potential biomarkers are identified in a three-step process. Firstly, IgG4 eluted from laser-captured glomeruli of IMN patients are tested for binding to podocyte extracts. Proteins recognized by eluted antibodies become autoantigens candidates [11]. Secondly, these candidate molecules are considered autoantigens if 2428 Nephrol Dial Transphant (2011): Editorial Comments

Background and objectives: Mutations in nephrin (NPHS1) and podocin (NPHS2) genes represent a major cause of idiopathic nephrotic syndrome (NS) in children. It is not yet clear whether the presence of a single mutation acts as a modifier of the clinical course of NS. Design, setting, participants, & measurements: We reviewed the clinical features of 40 patients with NS associated with heterozygous mutations or variants in NPHS1 (n = 7) or NPHS2 (n = 33). Long-term renal survival probabilities were compared with those of a concurrent cohort with idiopathic NS. Results: Patients with a single mutation in NPHS1 received a diagnosis before those with potentially nongenetic NS and had a good response to therapies. Renal function was normal in all cases. For NPHS2, six patients had single heterozygous mutations, six had a p.P20L variant, and 21 had a p.R229Q variant. Age at diagnosis and the response to drugs were comparable in all NS subgroups. Overall, they had similar renal survival probabilities as non-NPHS1/NPHS2 cases (log-rank χ2 0.84, P = 0.656) that decreased in presence of resistance to therapy (P < 0.001) and in cases with renal lesions of glomerulosclerosis and IgM deposition (P < 0.001). Cox regression confirmed that the only significant predictor of dialysis was resistance to therapy. Conclusions: Our data indicate that single mutation or variant in NPHS1 and NPHS2 does not modify the outcome of primary NS. These patients should be treated following consolidated schemes and have good chances for a good long-term outcome.