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Key Points Steroids and alkylating agents increase the rate of remission in patients with membranous nephropathy but can cause diabetes mellitus, myelotoxicity, infections, cancer, and other adverse events Calcineurin inhibitors can reduce proteinuria in patients with membranous nephropathy but are nephrotoxic, and these agents should be avoided in patients with abnormal kidney function The discovery of nephritogenic autoantibodies provided a clear rationale for interventions specifically aimed at preventing formation of antigen–antibody immunocomplexes with secondary complement activation, podocyte damage, and proteinuria B cell-targeted therapy with rituximab is at least as effective as steroids and alkylating agents in achieving remission in membranous nephropathy, and available evidence suggests that it is safer and better tolerated In patients with anti-PLA 2 R-related membranous nephropathy and overt nephrotic syndrome, evaluation of serum autoantibody titre and albumin levels, as well as assessment of proteinuria could guide tailored therapy Traditional immunosuppressive regimens will be replaced by specific, nontoxic agents such as B cell-targeting monoclonal antibodies; modulation of B-cell immunity could lead to a novel therapeutic paradigm in membranous nephropathy Membranous nephropathy is an immune-mediated disease and is the leading cause of nephrotic syndrome in adults. Here, the authors discuss the role of B cell-depleting regimens in the treatment of this disease and the potential use of rescue therapy with agents that target plasma cells, which might prevent antigen–antibody interactions and immune complex-mediated complement activation. In patients with membranous nephropathy, alkylating agents (cyclophosphamide or chlorambucil) alone or in combination with steroids achieve remission of nephrotic syndrome more effectively than conservative treatment or steroids alone, but can cause myelotoxicity, infections, and cancer. Calcineurin inhibitors can improve proteinuria, but are nephrotoxic. Most patients relapse after treatment withdrawal and can become treatment dependent, which increases the risk of nephrotoxicity. The discovery of nephritogenic autoantibodies against podocyte M-type phospholipase A2 receptor (PLA 2 R) and thrombospondin type-1 domain- containing protein 7A (THSD7A) antigens provides a clear pathophysiological rationale for interventions that specifically target B-cell lineages to prevent antibody production and subepithelial deposition. The anti-CD20 monoclonal antibody rituximab is safe and achieves remission of proteinuria in approximately two-thirds of patients with membranous nephropathy. In those with PLA 2 R-related disease, remission can be predicted by anti-PLA 2 R antibody depletion and relapse by antibody re-emergence into the circulation. Thus, integrated evaluation of serology and proteinuria could guide identification of affected patients and treatment with individually tailored protocols. Nonspecific and toxic immunosuppressive regimens will fall out of use. B-cell modulation by rituximab and second-generation anti-CD20 antibodies (or plasma cell-targeted therapy in anti-CD20 resistant forms of disease) will lead to a novel therapeutic paradigm for patients with membranous nephropathy.

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.

Key Points Anti-neutrophil cytoplasmic antibodies (ANCAs) specific for leukocyte proteinase 3 and myeloperoxidase — PR3-ANCAs and MPO-ANCAs, respectively — define distinct conditions among patients with ANCA-associated vasculitides (AAV) Classification of patients with small-vessel vasculitis based on ANCA specificity is feasible and could provide timely and clinically relevant diagnostic information more readily than clinical syndromes based on current classification systems Patients with PR3-AAV and MPO-AAV do not share the same genetic background and have only some pathophysiologic mechanisms in common ANCA specificity predicts response to induction therapies: rituximab is more effective than cyclophosphamide in patients with PR3-AAV (by contrast, both treatments are similarly effective in patients with MPO-AAV) ANCA specificity predicts differences in long-term prognosis: patients with PR3-ANCAs are at higher risk of relapse than patients with MPO-ANCAs Future studies should evaluate whether the duration of immunosuppressive maintenance therapy should be different for patients with PR3-AAV versus those with MPO-AAV after remission induction The type of anti-neutrophil cytoplasmic antibody (ANCA) seems to be a major determinant of clinical presentation in ANCA-associated vasculitides (AAV). The authors of this Review argue that ANCA specificity for PR3 or MPO provides clinically useful information and should be used in the classification of AAV. The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a heterogeneous group of rare syndromes characterized by necrotizing inflammation of small and medium-sized blood vessels and the presence of ANCAs. Several clinicopathological classification systems exist that aim to define homogeneous groups among patients with AAV, the main syndromes being microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic GPA (EGPA). Two main types of ANCA can be detected in patients with AAV. These ANCAs are defined according to their autoantigen target, namely leukocyte proteinase 3 (PR3) and myeloperoxidase (MPO). Patients with GPA are predominantly PR3-ANCA-positive, whereas those with MPA are predominantly MPO-ANCA-positive, although ANCA specificity overlaps only partially with these clinical syndromes. Accumulating evidence suggests that ANCA specificity could be better than clinical diagnosis for defining homogeneous groups of patients, as PR3-ANCA and MPO-ANCA are associated with different genetic backgrounds and epidemiology. ANCA specificity affects the phenotype of clinical disease, as well as the patient's initial response to remission-inducing therapy, relapse risk and long-term prognosis. Thus, the classification of AAV by ANCA specificity rather than by clinical diagnosis could convey clinically useful information at the time of diagnosis.

Monoclonal gammopathy of renal significance (MGRS) regroups all renal disorders caused by a monoclonal immunoglobulin (MIg) secreted by a nonmalignant B-cell clone. By definition, patients with MGRS do not meet the criteria for overt multiple myeloma/B-cell proliferation, and the hematologic disorder is generally consistent with monoclonal gammopathy of undetermined significance (MGUS). However, MGRS is associated with high morbidity due to the severity of renal and sometimes systemic lesions induced by the MIg. Early recognition is crucial, as suppression of MIg secretion by chemotherapy often improves outcomes. The spectrum of renal diseases in MGRS is wide, including old entities such as AL amyloidosis and newly described lesions, particularly proliferative glomerulonephritis with monoclonal Ig deposits and C3 glomerulopathy with monoclonal gammopathy. Kidney biopsy is indicated in most cases to determine the exact lesion associated with MGRS and evaluate its severity. Diagnosis requires integration of morphologic alterations by light microscopy, immunofluorescence (IF), electron microscopy, and in some cases by IF staining for Ig isotypes, immunoelectron microscopy, and proteomic analysis. Complete hematologic workup with serum and urine protein electrophoresis, immunofixation, and serum-free light-chain assay is required. This review addresses the pathologic and clinical features of MGRS lesions, indications of renal biopsy, and a proposed algorithm for the hematologic workup.

This study of ANCA-associated vasculitis compared a single course of rituximab with conventional immunosuppression with cyclophosphamide followed by azathioprine and showed similar results for the primary outcome of complete remission by 6 months, maintained through 18 months. Granulomatosis with polyangiitis (previously termed Wegener's granulomatosis) and microscopic polyangiitis are called antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides because they are frequently accompanied by autoantibodies against proteinase 3 or myeloperoxidase. 1 , 2 For nearly four decades, cyclophosphamide and glucocorticoids have been the standard therapy for the induction of remission. However, the primary results of the Rituximab in ANCA-Associated Vasculitis (RAVE) trial 3 and results from a European trial 4 showed that rituximab was as effective as cyclophosphamide for the induction of remission in patients with severe disease. Moreover, the rituximab-based regimen was superior in patients who had relapsing disease at 6 months. 3 Rituximab has . . .

C3 glomerulonephritis (C3GN) is a recently described disorder that typically results from abnormalities in the alternative pathway (AP) of complement. Here, we describe the clinical features, kidney biopsy findings, AP abnormalities, glomerular proteomic profile, and follow-up in 12 cases of C3GN. This disorder equally affected all ages, both genders, and typically presented with hematuria and proteinuria. In both the short and long term, renal function remained stable in the majority of patients with native kidney disease. In two patients, C3GN recurred within 1 year of transplantation and resulted in a decline in allograft function. Kidney biopsy mainly showed a membranoproliferative pattern, although both mesangial proliferative and diffuse endocapillary proliferative glomerulonephritis were noted. AP abnormalities were heterogeneous, both acquired and genetic. The most common acquired abnormality was the presence of C3 nephritic factors, while the most common genetic finding was the presence of H402 and V62 alleles of Factor H. In addition to these risk factors, other abnormalities included Factor H autoantibodies and mutations in CFH, CFI, and CFHR genes. Laser dissection and mass spectrometry of glomeruli from patients with C3GN showed accumulation of AP and terminal complement complex proteins. Thus, C3GN results from diverse abnormalities of the alternative complement pathway leading to subsequent glomerular injury.

This multicenter, randomized, double-blind, double-dummy, noninferiority trial compared rituximab with cyclophosphamide for remission induction in ANCA−associated vasculitis. Rituximab therapy was not inferior to daily cyclophosphamide treatment for remission induction in severe ANCA-associated vasculitis and may be superior in relapsing disease. Rituximab therapy was not inferior to daily cyclophosphamide treatment for remission induction in severe ANCA-associated vasculitis and may be superior in relapsing disease. Wegener's granulomatosis and microscopic polyangiitis are classified as antineutrophil cytoplasmic antibody (ANCA)−associated vasculitides because most patients with generalized disease have antibodies against proteinase 3 or myeloperoxidase. 1 , 2 The ANCA-associated vasculitides affect small-to-medium-size blood vessels, with a predilection for the respiratory tract and kidneys. 3 – 6 Cyclophosphamide and glucocorticoids have been the standard therapy for remission induction for nearly four decades. 7 , 8 This regimen transformed the usual treatment outcome of severe ANCA-associated vasculitis from death to a strong likelihood of disease control and temporary remission. 3 – 5 , 9 _ 11 However, not all patients have a remission with this combination of drugs, and those . . .

Abstract Focal segmental glomerulosclerosis (FSGS) is a histologic lesion resulting from a variety of pathogenic processes that cause injury to the podocytes. Recently, mutations in more than 50 genes expressed in podocyte or glomerular basement membrane were identified as causing genetic forms of FSGS, the majority of which are characterized by onset in childhood. The prevalence of adult-onset genetic FSGS is likely to be underestimated and its clinical and histological features have not been clearly described. A small number of studies of adult-onset genetic FSGS showed that there is heterogeneity in clinical and histological findings, with a presentation ranging from sub-nephrotic proteinuria to full nephrotic syndrome. A careful evaluation of adult-onset FSGS that do not have typical features of primary or secondary FSGS (familial cases, resistance to immunosuppression and absence of evident cause of secondary FSGS) should include a genetic evaluation. Indeed, recognizing genetic forms of adult-onset FSGS is of the utmost importance, given that this diagnosis will have major implications on treatment strategies, selecting of living-related kidney donor and renal transplantation success.

The Nephrotic Syndrome Study Network (NEPTUNE) is a North American multicenter collaborative consortium established to develop a translational research infrastructure for nephrotic syndrome. This includes a longitudinal observational cohort study, a pilot and ancillary study program, a training program, and a patient contact registry. NEPTUNE will enroll 450 adults and children with minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy for detailed clinical, histopathological, and molecular phenotyping at the time of clinically indicated renal biopsy. Initial visits will include an extensive clinical history, physical examination, collection of urine, blood and renal tissue samples, and assessments of quality of life and patient-reported outcomes. Follow-up history, physical measures, urine and blood samples, and questionnaires will be obtained every 4 months in the first year and biannually, thereafter. Molecular profiles and gene expression data will be linked to phenotypic, genetic, and digitalized histological data for comprehensive analyses using systems biology approaches. Analytical strategies were designed to transform descriptive information to mechanistic disease classification for nephrotic syndrome and to identify clinical, histological, and genomic disease predictors. Thus, understanding the complexity of the disease pathogenesis will guide further investigation for targeted therapeutic strategies.

To describe the change in the incidence rates of primary and secondary focal segmental glomerulosclerosis (FSGS) from 1994 through 2013 in Olmsted County, Minnesota, and to identify the clinical and biopsy characteristics that distinguish primary from secondary FSGS. Olmsted County adult residents with native kidney biopsy from January 1, 1994, through December 31, 2013, and FSGS as the only glomerulopathy were identified. The clinical and pathologic characterstics of primary and secondary FSGS were described and compared, and incidence rates were calculated. Of 370 adults biopsied, 281 had glomerular diseases, of which 46 (16%) had FSGS. From 1994-2003 to 2004-2013, there were significant increases in kidney biopsy rates (14.7 [95% CI, 12.1-17.3] vs 22.9 [95% CI, 20.0-25.7] per 100,000 person-years, 17% increase per 5 years; P<.001) and total FSGS rates (1.4 [95% CI, 0.6-2.2] vs 3.2 [95% CI, 2.1-4.3] per 100,000 person-years, 41% increase per 5 years; P=.02). Compared with patients with limited foot process effacement (<80%), patients with diffuse effacement (≥80%) without an identifiable cause had lower serum albumin levels (P<.001), had higher proteinuria (P<.001), and were more likely to have nephrotic syndrome (100% vs 4%; P<.001). Patients with diffuse effacement without an identifiable cause were classified as primary FSGS, which accounted for 3 of 12 patients (25%) during 1994-2003 and 9 of 34 (26%) during 2004-2013. Although the incidence of FSGS has increased, the proportions of primary and secondary FSGS have remained stable.