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In the past few years there has been increasing use of limited resection for pulmonary carcinoma, especially in patients with restricted cardiorespiratory function. Because there is frequently a choice as to the type of limited resection, it was considered worth while to review the safety and efficiency of the two principal types. In total, 212 wedge resections and 281 segmental resections are reported. Despite certain theoretical advantages to segmentectomy, wedge resection carried a lower complication rate. Seventy-one per cent of wedge resections were free of complications compared to 54% of segmental resections. Minor complications were defined as apical air space and apical haematoma. The incidence of minor complications was similar for each group, 22% for wedge resections and 27% for segmentectomies. However, there was a significantly higher major complication rate in the segmental resection group (19%) compared to the wedge group (7%). This is understandable, considering the amount of raw lung surface exposed after segmental resection. It appears that where it is surgically feasible, wedge resection should be practised. [ABSTRACT FROM PUBLISHER]

Background: The use Adrenocorticotropic hormone (ACTH) is rising since it received FDA approval as a treatment for proteinuria secondary to nephrotic syndrome. However, the frequency of adverse effects associated with the use of ACTH is unknown. Methods: A literature search was performed using MEDLINE, EMBASE, Google scholar and Cochrane Database from inception through July 18, 2015. Studies assessing safety of ACTH Treatment in adults with glomerular diseases were included. A meta-analysis was conducted to summarize the incidence of adverse effects in this population. We used a random-effects meta-analysis model to estimate the incident rate. Results: Our search strategy yielded 352 potentially relevant articles. There were 12 studies reported adverse effects of ACTH in 171 participants with membranous nephropathy (n = 87), FSGS (n = 30), minimal change disease (n = 8), Ig A nephropathy (n = 12), lupus nephritis (n = 4), diabetic nephropathy (n = 14) and other glomerular diseases (n = 16). Treatment duration ranged from 2 to 48 months. Edema was the most common side effect (incidence rate (IR) 0.10; 95% CI, 0.04-0.18) followed by insomnia (IR 0.08; 95% CI, 0.03-0.15), hyperglycemia (IR 0.07; 95% CI, 0.04-0.11) and mood swings (IR 0.07; 95% CI, 0.02-0.14) (table 1). The dropout rate due to adverse event was 7%, mostly due to edema and weight gain (5 out of 12 patients). No severe adverse reactions or death associated with ACTH injections were reported. Conclusions: ACTH therapy in glomerular diseases is overall well-tolerated and has a more favorable side effect profile than corticosteroids. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

SLE is a chronic multisystem autoimmune disease that affects the kidneys in approximately 50% of patients, with the prevalence rising to as high as 70% in certain populations, such as African American and Asian people. Antimalarials-and particularly hydroxychloroquine (HCQ)-are currently considered a mainstay of therapy, together with immunosuppressants. Over the past decades, several studies have extensively investigated the mechanisms of action of antimalarial agents and their potential beneficial properties in patients with SLE in general. However, the evidence for the therapeutic benefit of HCQ in patients with lupus nephritis (LN) derives mainly from observational studies, conducted in an era before the refinement of induction and maintenance protocols for immunosuppressive therapy. Despite the paucity of high-quality evidence on its efficacy in LN, the nephrology community widely supports the universal use of HCQ in patients with LN, and recommendations for its use are firmly entrenched in various clinical practice guidelines. Nonetheless, the use of antimalarials may also carry inherent risks, underscoring the importance of personalized approaches in these patients. Herein, we comprehensively review the available literature on antimalarials in LN, aiming to update the current evidence, limitations, and future perspectives for the use of antimalarials in adults., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

Objective: Avacopan, an activated complement factor 5 receptor antagonist, has been approved as adjunct therapy for severe active antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Current evidence supports the management of AAV presenting with diffuse alveolar hemorrhage (DAH) by administering glucocorticoids combined with either rituximab or cyclophosphamide in addition to supportive care. The role of avacopan in patients with DAH as a primary severe disease manifestation of AAV has not been well established. Furthermore, concerns remain regarding timely access to avacopan, the best glucocorticoid tapering regimen, and long-term efficacy and safety of the drug. We sought to identify clinical features and outcomes of patients presenting with DAH secondary to AAV who received avacopan in addition to glucocorticoids and rituximab or cyclophosphamide., Methods: We performed a retrospective cohort study of all consecutive patients presenting with DAH as part of active severe granulomatosis with polyangiitis or microscopic polyangiitis. Demographic and clinical characteristics were collected at presentation and follow-up., Results: Fifteen patients met inclusion criteria and were observed for a median time of 17 weeks (interquartile range [IQR] 6-37 weeks) after initiation of avacopan. Patients were predominantly female and White, had never smoked, and were a median age of 66 years (IQR 52-72 years) at diagnosis. The majority had newly diagnosed severe AAV with renal involvement. Three patients progressed to respiratory failure. The timing of avacopan introduction and patterns of glucocorticoid tapers varied widely in this cohort. Two serious adverse events related to infection were observed, including one opportunistic infection leading to the patient's death, although neither was directly attributed to avacopan administration., Conclusion: We describe the clinical course of patients who presented with the severe AAV disease manifestation of DAH and received avacopan as adjunct therapy. Most patients achieved remission during follow-up, and adverse events, including infection, were observed., (© 2024 The Author(s). ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: Nephritis is a common manifestation of IgA vasculitis and is morphologically indistinguishable from IgA nephropathy. While MEST-C scores are predictive of kidney outcomes in IgA nephropathy, their value in IgA vasculitis nephritis has not been investigated in large multiethnic cohorts., Methods: Biopsies from 262 children and 99 adults with IgA vasculitis nephritis ( N =361) from 23 centers in North America, Europe, and Asia were independently scored by three pathologists. MEST-C scores were assessed for correlation with eGFR/proteinuria at biopsy. Because most patients ( N =309, 86%) received immunosuppression, risk factors for outcomes were evaluated in this group using latent class mixed models to identify classes of eGFR trajectories over a median follow-up of 2.7 years (interquartile range, 1.2-5.1). Clinical and histologic parameters associated with each class were determined using logistic regression., Results: M, E, T, and C scores were correlated with either eGFR or proteinuria at biopsy. Two classes were identified by latent class mixed model, one with initial improvement in eGFR followed by a late decline (class 1, N =91) and another with stable eGFR (class 2, N =218). Class 1 was associated with a higher risk of an established kidney outcome (time to ≥30% decline in eGFR or kidney failure; hazard ratio, 5.84; 95% confidence interval, 2.37 to 14.4). Among MEST-C scores, only E1 was associated with class 1 by multivariable analysis. Other factors associated with class 1 were age 18 years and younger, male sex, lower eGFR at biopsy, and extrarenal noncutaneous disease. Fibrous crescents without active changes were associated with class 2., Conclusions: Kidney outcome in patients with biopsied IgA vasculitis nephritis treated with immunosuppression was determined by clinical risk factors and endocapillary hypercellularity (E1) and fibrous crescents, which are features that are not part of the International Study of Diseases of Children classification., (Copyright © 2024 by the American Society of Nephrology.)

Introduction: A significant number of patients with antineutrophil cytoplasmic antibodies (ANCA)- associated vasculitis (AAV) with glomerulonephritis (AAV-GN) still progress to end-stage kidney disease (ESKD, estimated glomerular filtration rate [eGFR] <15 ml/min per 1.73 m 2 ) despite advances in remission-induction treatment., Methods: This is a retrospective cohort study on myeloperoxidase (MPO)-ANCA or proteinase 3 (PR3)-ANCA positive patients with AAV (microscopic polyangiitis, MPA; or granulomatosis with polyangiitis, GPA) and eGFR <15 ml/min per 1.73 m 2 or ESKD at presentation. Renal recovery, dialysis discontinuation, and persistence of ESKD after standard remission-induction, with or without the use of plasma exchange (PLEX) were analyzed., Results: We analyzed 166 patients with biopsy-proven active AAV-GN and eGFR <15 ml/min per 1.73 m 2 at the time of diagnosis. Patients received glucocorticoids with cyclophosphamide (CYC) ( n  = 84) or with rituximab (RTX) ( n  = 72) for remission-induction, and 49 received PLEX. The predictors of renal recovery were erythrocyte sedimentation rate, serum creatinine (SCr) at diagnosis, and minimal or mild chronicity changes. We further analyzed 71 patients who started dialysis with or without PLEX within 4 weeks of AAV-GN diagnosis. The predictors of dialysis discontinuation were minimal chronicity changes in kidney biopsy at diagnosis (odds ratio = 6.138; 95% confidence interval [CI]: 1.389-27.118; P  = 0.017). Predictors of persistence of ESKD within 12 months included higher SCr at diagnosis (incidence rate ratio [IRR] = 1.086; 95% CI: 1.005-1.173; P  = 0.037), and moderate (IRR = 3.797; 95% CI: 1.090-13.225; P  = 0.036), or severe chronicity changes in kidney biopsy (IRR = 5.883; 95% CI: 1.542-22.439; P  =0.009)., Conclusion: In our cohort, kidney recovery, dialysis discontinuation, and persistence of ESKD in patients with AAV-GN and eGFR <15 ml/min per 1.73 m 2 depended on SCr and histologic findings on kidney biopsies at the time of diagnosis and was not affected by the addition of PLEX., (© 2024 International Society of Nephrology. Published by Elsevier Inc.)

Background: Little is known about the prognostic significance of monoclonal gammopathy of undetermined and renal significance (MGUS and MGRS) in patients with CKD. The objective of this study was to determine the clinical and kidney outcomes of patients with CKD with either MGUS or MGRS compared with those with CKD without MGUS or MGRS., Methods: We conducted a retrospective cohort study from 2013 to 2018. Patients who had both CKD diagnosis and monoclonal testing were identified. Patients were divided into MGRS, MGUS, and no monoclonal gammopathy groups. Cumulative incidence functions and Cox proportional hazards regression were used to model time to event data and to evaluate the association between monoclonal gammopathy status and risk of kidney failure, with death treated as a competing risk., Results: Among 1535 patients, 59 (4%) had MGRS, 648 (42%) had MGUS, and 828 (54%) had no monoclonal gammopathy. Unadjusted analysis showed that compared with no monoclonal gammopathy patients, patients with MGRS were at higher risk of kidney failure (hazard ratio [HR] [95% confidence interval]: 2.5 [1.5 to 4.2] but not patients with MGUS (HR [95% confidence interval]: 1.3 [0.97 to 1.6]), after taking death into account as a competing risk. However, in the multivariable analysis, after adjusting for age, sex, eGFR, proteinuria, and Charlson Comorbidity Index, the risk of progression to kidney failure (with death as competing risk) in the MGRS group was no longer statistically significant (HR: 0.9 [0.5 to 1.8]). The same was also true for the MGUS group compared with the group with no monoclonal gammopathy (HR: 1.3 [0.95 to 1.6]). When evaluating the association between MGUS/MGRS status and overall survival, MGRS was significantly associated with mortality in fully adjusted models compared with the group with no monoclonal gammopathy, while MGUS was not., Conclusions: After adjusting for traditional risk factors, MGUS/MGRS status was not associated with a greater risk of kidney failure, but MGRS was associated with a higher risk of mortality compared with patients with no monoclonal gammopathy., (Copyright © 2023 by the American Society of Nephrology.)

Membranous nephropathy (MN) is characterized by deposition of immune complexes leading to thickening of glomerular basement membranes. Over time, the understanding of MN has evolved, with the identification of specific autoantibodies against novel podocyte antigens and the unraveling of intricate pathogenic pathways. Although the anti-CD20 monoclonal antibody rituximab is favored as part of the initial therapy in MN, a subgroup of MN patients may be resistant to rituximab necessitating the use of alternative agents such as cytotoxic therapies. In addition, newer agents such as novel anti-CD20 monoclonal antibodies, therapies targeting the CD38-positive plasma cells and anti-complement therapy are being studied in patients who are resistant to traditional treatment strategies. This manuscript furnishes a review of the novel developments in the pathophysiology of MN including the identification of target antigens and current treatment standards for MN, concentrating on evidenced-based interventions designed to attain remission and to prevent disease progression., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Hematuria-either macroscopic hematuria or asymptomatic microscopic hematuria-is a clinical feature typical but not specific for immunoglobulin A nephropathy (IgAN). The only biomarker supported by the Kidney Disease: Improving Global Outcomes group as a predictor of progression, identifying patients needing treatment, is proteinuria >1 g/day persistent despite maximized supportive care. However, proteinuria can occur in the setting of active glomerulonephritis or secondary to sclerotic renal lesions. Microscopic hematuria is observed in experimental models of IgAN after IgA-IgG immunocomplex deposition, activation of inflammation and complement pathways. Oxidative damage, triggered by hemoglobin release, is thought to contribute to the development of proteinuria and progression. Despite being a clinical hallmark of IgAN and having a rational relationship with its pathophysiology, the value of microscopic hematuria in assessing activity and predicting outcomes in patients with IgAN is still debated. This was partly due to a lack of standardization and day-to-day variability of microhematuria, which discouraged the inclusion of microhematuria in large multicenter studies. More recently, several studies from Asia, Europe and the USA have highlighted the importance of microhematuria assessment over longitudinal follow-up, using a systematic approach with either experienced personnel or automated techniques. We report lights and shadows of microhematuria evaluation in IgAN, looking for evidence for a more consistent consensus on its value as a marker of clinical and histological activity, risk assessment and prediction of treatment response. We propose that hematuria should be included as part of the clinical decision-making process when considering when to use immunosuppressive therapy and as part of criteria for enrollment into clinical trials to test drugs targeting the inflammatory reaction elicited by immune pathway activation in IgAN., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Membranous nephropathy (MN) is a pattern of injury caused by autoantibodies binding to specific target antigens, with accumulation of immune complexes along the subepithelial region of glomerular basement membranes. The past 20 years have brought revolutionary advances in the understanding of MN, particularly via the discovery of novel target antigens and their respective autoantibodies. These discoveries have challenged the traditional classification of MN into primary and secondary forms. At least 14 target antigens have been identified, accounting for 80%-90% of cases of MN. Many of the forms of MN associated with these novel MN target antigens have distinctive clinical and pathologic phenotypes. The Mayo Clinic consensus report on MN proposes a 2-step classification of MN. The first step, when possible, is identification of the target antigen, based on a multistep algorithm and using a combination of serology, staining of the kidney biopsy tissue by immunofluorescence or immunohistochemistry, and/or mass spectrometry methodology. The second step is the search for a potential underlying disease or associated condition, which is particularly relevant when knowledge of the target antigen is available to direct it. The meeting acknowledges that the resources and equipment required to perform the proposed testing may not be generally available. However, the meeting consensus was that the time has come to adopt an antigen-based classification of MN because this approach will allow for accurate and specific MN diagnosis, with significant implications for patient management and targeted treatment., (Copyright © 2023 International Society of Nephrology and Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Background: The 2021 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend following anti-phospholipase A2 receptor (PLA2R) antibody levels as a marker of treatment response in membranous nephropathy; however, the optimal timing to evaluate antibody levels and how to combine them with other clinical variables are currently unknown., Methods: We used a cohort of 85 patients from the Membranous Nephropathy Trial Of Rituximab (MENTOR) with anti-PLA2R antibodies ≥14 RU/ml to identify risk factors for not experiencing proteinuria remission after 12 months of treatment with cyclosporine or rituximab. Three landmark times were considered: at baseline and after 3 and 6 months of treatment. Logistic regression model performance was evaluated using C-statistics and model fit (Akaike information criterion [AIC], R 2 )., Results: The model at baseline that best predicted no remission included anti-PLA2R antibodies >323 RU/ml and creatinine clearance; the best model after 3 months included the change from baseline in both antibody and albumin levels; and the best model after 6 months included antibody levels >14 RU/ml, creatinine clearance, and the change from baseline in albumin. Compared with the model at baseline, the model at 3 months had better model fit (AIC 70.9 versus 96.4, R 2 51.8% versus 30.1%) and higher C-statistic (0.93 versus 0.83, P = 0.008). The model at 6 months had no difference in performance compared with the model at 3 months (AIC 68.6, R 2 53.0%, C-statistic 0.94, P = 0.67)., Conclusions: In patients with membranous nephropathy treated with cyclosporine or rituximab in the MENTOR trial, we found that the optimal method to evaluate risk factors for the probability of treatment response was to use anti-PLA2R antibody levels combined with albumin levels after 3 months of treatment, which was significantly better than using antibody levels alone or risk factor evaluation at baseline, with no added benefit of waiting until 6 months of treatment., Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023&#95;10&#95;09&#95;CJN0000000000000237.mp3., (Copyright © 2023 by the American Society of Nephrology.)

COVID-19 is a systemic disease, and the kidney is one of the target organs of infection. Kidney injury is common and can occur in up to 40% of patients. Several glomerular diseases have been reported in association with COVID-19. Some are likely related to COVID-19 whereas many are likely coincidental. Glomerular diseases that are frequently reported in COVID-19 and have a plausible mechanistic explanation are likely to be related to COVID-19. In contrast, glomerular diseases that are seldom reported and have no known plausible mechanism, are likely to be unrelated. Collapsing glomerulopathy (CG) is by far the most prevalent. Its association with COVID-19, resembling HIV and CG, led to the newly proposed term "COVID-19 associated nephropathy" or "COVAN." High-risk APOL1 genotypes are the major risk factor in COVAN patients. Podocytopathy, membranous nephropathy (MN), pauci-immune crescentic glomerulonephritis (GN), and thrombotic microangiopathy (TMA) are also reported. In kidney allografts, CG remains the most common glomerular pathology. Patients typically present with acute kidney injury (AKI) or abnormal urinary findings at the time of or shortly after COVID-19 diagnosis. Treatment of glomerular disease in patients with COVID-19 is challenging. Providers should cautiously consider balancing risks and benefit of immunosuppression, particularly in patients with active diseases. Short-term outcomes vary but generally remain poor with high morbidity and mortality. Future study of long-term outcomes is needed to improve our understanding of glomerular disease associated with COVID-19., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

Membranous nephropathy (MN) is a common cause of nephrotic syndrome (NS) in adults and if untreated can progress to endstage kidney disease. Factors considered to place a patient at high or very high risk for progression include elevated serum creatinine at baseline, declining kidney function, persistent heavy proteinuria (>8 g/24 h), or persistent NS, presence of life-threatening complications related to NS (such as venous thromboembolic events), or very high anti-PLA2R antibody titers (>150 RU/ml). Patients who are at high or very high risk of progression should be treated with immunosuppression therapy to induce remission of proteinuria and to avoid progressive loss of kidney function. Traditional forms of immunosuppression for patients with MN have included the use of cyclic courses of corticosteroids with cyclophosphamide or calcineurin inhibitors. These forms of therapy are associated with significant toxicity, e.g. corticosteroids (infections, diabetes, weight gain), cyclophosphamide (infertility, severe leukopenia, malignancy), and calcineurin inhibitors (hypertension, nephrotoxicity). The introduction of anti-CD20 + B-cell therapies in the late 1990s has changed the landscape. In this article we will argue that anti-CD20 + B therapy should be the treatment of choice for patients at high/very high risk of progression when considering its efficacy and side-effect profile., Competing Interests: F.C.F. has received unrestricted research grants from Genentech, the maker of rituximab., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Objective: There is a paucity of population-based studies investigating the epidemiology of lupus nephritis (LN) in the US and long-term secular trends of the disease and its outcomes. We aimed to examine the epidemiology of LN in a well-defined 8-county region in the US., Methods: Patients with incident LN between 1976 and 2018 in Olmsted County, Minnesota (1976-2009) and an 8-county region in southeast Minnesota (2010-2018) were identified. Age- and sex-specific incidence rates and point prevalence over 4 decades, adjusted to the projected 2000 US population, were determined. Standardized mortality ratios (SMRs), survival rates, and time to end-stage renal disease (ESRD) were estimated., Results: There were 72 patients with incident LN between 1976 and 2018, of whom 76% were female and 69% were non-Hispanic White. Mean ± SD age at diagnosis was 38.4 ± 16.24 years. Average annual LN incidence per 100,000 population between 1976 and 2018 was 1.0 (95% CI 0.8-1.3) and was highest in patients ages 30-39 years. Between the 1976-1989 and 2000-2018 time periods, overall incidence of LN increased from 0.7 to 1.3 per 100,000, but this was not statistically significant. Estimated LN prevalence increased from 16.8 per 100,000 in 1985 to 21.2 per 100,000 in 2015. Patients with LN had an SMR of 6.33 (95% CI 3.81-9.89), with no improvement in the mortality gap in the last 4 decades. At 10 years, survival was 70%, and 13% of LN patients had ESRD., Conclusion: The incidence and prevalence of LN in this area increased in the last 4 decades. LN patients have poor outcomes, with high rates of ESRD and mortality rates 6 times that of the general population., (© 2022 American College of Rheumatology.)

Background: The optimal strategy for remission-maintenance therapy in patients with myeloperoxidase-ANCA (MPO-ANCA)-associated vasculitis is not established. Defining parameters to guide maintenance therapy is required., Methods: This was a retrospective cohort study of all patients with MPO-ANCA-associated vasculitis (microscopic with polyangiitis and granulomatosis with polyangiitis) and GN followed at the Mayo Clinic between 1996 and 2015. Relapse rate, MPO-ANCA status, and remission-maintenance therapies were reviewed. Logistic regression models, Kaplan-Meier method, and Cox proportional hazards regression models were applied., Results: We analyzed 159 patients with active MPO-ANCA-associated vasculitis with GN. Sixty-six (42%) patients had at least one relapse, and 52 (33%) relapsed before 60 months. Patients with MPO-ANCA who became persistently negative did not relapse (hazard ratio [HR], 0.03; 95% confidence interval [95% CI], 0.002 to 0.431; P =0.01). The reappearance of MPO-ANCA was associated with a higher risk of relapse (HR, 1.91; 95% CI, 1.109 to 3.293; P =0.02). Immunosuppression was withdrawn in 80 (50%) patients, and this was less likely in those who received cyclophosphamide for remission induction or in patients with persistently positive MPO-ANCA (odds ratio [OR], 0.44; 95% CI, 0.228 to 0.861; P =0.02 and OR, 0.42; 95% CI, 0.213 to 0.820; P =0.01, respectively). Relapse frequency was not different between patients with persistently positive MPO-ANCA and patients with MPO-ANCA reappearance (44% versus 39%, P =0.49), irrespective of remission-maintenance treatment. Ear, nose, and throat involvement (OR, 6.10; 95% CI, 1.280 to 29.010; P =0.02) and MPO-ANCA reappearance (OR, 9.25; 95% CI, 3.126 to 27.361; P <0.001) were independently associated with relapse after treatment withdrawal., Conclusions: Patients persistently MPO-ANCA negative are at low risk for relapse even without remission-maintenance therapy. Persistence or subsequent reappearance of MPO-ANCA is associated with a higher risk of relapse., Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast.aspx?p=CJASN&e=2023&#95;01&#95;10&#95;CJN06460622.mp3., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is the second most common monoclonal gammopathy of renal significance. Rates of progression to kidney failure as well as rates of recurrence after kidney transplantation are high, especially in the absence of treatment. Treatment is usually targeted toward the abnormal clone, but even in the absence of an identifiable clone, empiric treatment is still recommended to avoid worsening prognosis. In this report, we present an unusual course of a PGNMID case with a relapsing and remitting pattern of illness, likely triggered by infection and vaccination. The patient in this case showed subsequent improvement after each episode, with stable kidney function over the years. This case report highlights the importance of investigating possible recent infectious exposures or vaccinations as potential triggers for this disease. This association should be considered for future patients with PGNMID, especially when there is no identifiable clone to help guide therapy., (© 2022 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.)

The risk of progression to end-stage kidney disease (ESKD) in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and glomerulonephritis (AAV-GN) remains high. At 5 years of follow-up, 14-25% of patients will evolve to ESKD, suggesting that kidney survival is not optimized in patients with AAV. The addition of plasma exchange (PLEX) to standard remission induction has been the standard of care, particularly in patients with severe renal disease. However, there is still some debate regarding which patients benefit from PLEX. A recently published meta-analysis concluded that the addition of PLEX to standard remission induction in AAV probably reduced the risk of ESKD at 12 months and that PLEX was associated with an estimated absolute risk reduction for ESKD at 12 months of 16.0% for those at high risk or with a serum creatinine >5.7 mg/dl (high certainty of important effects). These findings were interpreted as supportive of offering PLEX to patients with AAV and a high risk of progression to ESKD or requiring dialysis and are making their way into societies recommendations. However, the results of the analysis can be debated. We provide an overview on the meta-analysis as an attempt to guide the audience through how the data were generated, to comment on our interpretation of the results and to explain why we feel uncertainty remains. In addition, we would like to provide insights in two questions that we believe are very relevant to consider when addressing the role of PLEX: the role of kidney biopsy findings in the decision making of whom might benefit from PLEX and the impact of novel treatments (i.e. complement factor 5a inhibitors) in avoiding progression to ESKD at 12 months. The treatment of patients with severe AAV-GN is complex and further studies that include only patients at high risk of progression to ESKD are needed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the ERA.)

Introduction: mRNA COVID-19 vaccine is more effective than traditional vaccines owing to superior immune activation. Nevertheless, the impact of mRNA COVID-19 vaccine on triggering de novo /relapsing glomerulonephritis (GN) is limited. We report a case series of patients who developed new or relapsing GN postvaccination., Methods: We evaluated baseline characteristics, vaccine type, and clinical outcomes of 13 patients from our institution who had a new diagnosis or relapse of their GN post-mRNA COVID-19 vaccination., Results: Of 13 patients, 8 patients were newly diagnosed with having GN and 5 patients had relapse. Median age was 62 years (range 19-83 years). Autoimmune disease (38%) was the most prevalent underlying disease followed by cancer (23%). Most patients were White males. IgA nephropathy (IgAN) was the most common GN in our series (5 patients, 38%) followed by membranous nephropathy (MN) (3 patients, 23%). There was 1 patient with IgAN who had evidence of IgA deposits before vaccination suggesting the immune activation after vaccination triggered a flare of the disease. Our case series also included the first case report of tip-variant focal segmental glomerulosclerosis (FSGS), NELL-1-associated MN, and atypical anti-glomerular basement membrane (GBM) nephritis. A total of 77% developed acute kidney injury (AKI) with most being Kidney Disease: Improving Global Outcomes stage 1 (67%). Outcomes are favorable with 80% responding to therapy., Conclusion: New cases and relapse of GN can present shortly after mRNA COVID-19 vaccination. New cases of IgAN may result from unmasking of undiagnosed IgAN owing to robust immune activation rather than development of new deposits., (© 2021 International Society of Nephrology. Published by Elsevier Inc.)

Background and Objectives: Kidney biopsy is the current gold standard to diagnose membranous nephropathy. Approximately 70%-80% of patients with primary membranous nephropathy have circulating anti-phospholipase A2 receptor antibodies. We previously demonstrated that in proteinuric patients with preserved eGFR and absence of associated conditions ( e.g., autoimmunity, malignancy, infection, drugs, and paraproteinemia), a positive anti-phospholipase A2 receptor antibody test by ELISA and immunofluorescence assay confirms the diagnosis of membranous nephropathy noninvasively. These data have not been externally validated., Design, Setting, Participants, & Measurements: The clinical and pathologic characteristics of patients with a positive anti-phospholipase A2 receptor antibody test at the Mayo Clinic, the University Hospital Vall D'Hebron (Barcelona), and the Columbia University Medical Center (New York) were retrospectively reviewed. Biopsy findings and presence or absence of a potential associated condition were assessed., Results: From a total of 276 patients with positive anti-phospholipase A2 receptor serology, previously reported patients ( n =33), kidney transplant recipients ( n =9), pediatric patients ( n =2), and patients without kidney biopsy ( n =69) were excluded. Among the 163 remaining patients, associated conditions were identified in 47 patients, and 15 patients had diabetes mellitus. All 101 patients of the final cohort had a primary diagnosis of membranous nephropathy on kidney biopsy. In the 79 patients with eGFR≥60 ml/min per 1.73 m 2 , none of the biopsy findings altered diagnosis or management. Among the 22 patients with decreased eGFR, additional findings included superimposed acute interstitial nephritis ( n =1)., Conclusions: In patients with preserved eGFR and absence of associated conditions or diabetes, a positive anti-phospholipase A2 receptor test by either ELISA >20 RU/ml or a positive immunofluorescence assay confirms the diagnosis of membranous nephropathy, precluding the requirement for a kidney biopsy., (Copyright © 2021 by the American Society of Nephrology.)

Background: Studies comparing all treatment options for frequently-relapsing/steroid-dependent (FR/SD) minimal change disease (MCD) in adults are lacking., Methods: Medical records of 76 adults with FR/SD MCD who were treated with corticosteroids as the first-line therapy were reviewed. Treatment options were compared for the time to relapse, change of therapy and progression (relapse on full-dose treatment)., Results: Second-line treatments included rituximab (RTX; n = 13), mycophenolate mofetil (MMF; n = 12), calcineurin inhibitors (CNI; n = 26) and cyclophosphamide (CTX; n = 16). During the second-line treatments, 48 (71.6%) patients relapsed at median 17 (range 2-100)  months. The majority of relapses occurred during dose tapering or off drug. Twenty of 65 (30.8%) changed therapy after the first relapse. The median time to relapse after the second line was 66 versus 28 months in RTX versus non-RTX groups (P = 0.170). The median time to change of treatment was 66 and 44 months, respectively (P = 0.060). Last-line treatment options included RTX (n = 8), MMF (n = 4), CNI (n = 3) and CTX (n = 2). Seven (41.2%) patients had a relapse during the last-line treatment at median 39 (range 5-112)  months. The median time to relapse was 48 versus 34 months in the RTX versus non-RTX groups (P = 0.727). One patient in the RTX group died presumably of heart failure. No major adverse event was observed. During the median follow-up of 81 (range 9-355)  months, no patients developed end-stage renal disease., Conclusions: Relapse is frequent in MCD in adults. Patients treated with RTX may be less likely to require a change of therapy and more likely to come off immunosuppressive drugs., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Objective: To increase the likelihood of finding a causative genetic variant in patients with a focal segmental glomerulosclerosis (FSGS) lesion, clinical and histologic characteristics were analyzed., Patients and Methods: Individuals 18 years and older with an FSGS lesion on kidney biopsy evaluated at Mayo Clinic from November 1, 1999, through October 31, 2019, were divided into 4 groups based on clinical and histologic characteristics: primary FSGS, secondary FSGS with known cause, secondary FSGS without known cause, and undetermined FSGS. A targeted gene panel and a customized gene panel retrieved from exome sequencing were performed., Results: The overall rate of detection of a monogenic cause was 42.9% (21/49). Individuals with undetermined FSGS had the highest rate of positivity (87.5%; 7/8) followed by secondary FSGS without an identifiable cause (61.5%; 8/13) and secondary FSGS with known cause (33.3%; 5/15). Four of 5 (80%) individuals in the latter group who had positive genetic testing results also had a family history of kidney disease. Univariate analysis showed that family history of kidney disease (odds ratio [OR], 13.8; 95% CI, 3.7 to 62.4; P<.001), absence of nephrotic syndrome (OR, 8.2; 95% CI, 1.9 to 58.1; P=.004), and female sex (OR, 5.1; 95% CI, 1.5 to 19.9; P=.01) were strong predictors of finding a causative genetic variant in the entire cohort. The most common variants were in the collagen genes (52.4%; 11/21), followed by the podocyte genes (38.1%; 8/21)., Conclusion: In adults with FSGS lesions, proper selection of patients increases the rate of positive genetic testing significantly. The majority of individuals with undetermined FSGS in whom the clinical presentation and histologic parameters are discordant had a genetic diagnosis., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: The etiology of kidney disease remains unknown in many individuals with chronic kidney disease (CKD). We created the Mayo Clinic Nephrology Genomics Clinic to improve our ability to integrate genomic and clinical data to identify the etiology of unexplained CKD., Study Design: Retrospective study., Setting & Participants: An essential component of our program is the Nephrology Genomics Board which consists of nephrologists, geneticists, pathologists, translational omics scientists, and trainees who interpret the patient's clinical and genetic data. Since September 2016, the Board has reviewed 163 cases (15 cystic, 100 glomerular, 6 congenital anomalies of kidney and urinary tract (CAKUT), 20 stones, 15 tubulointerstitial, and 13 other)., Analytical Approach: Testing was performed with targeted panels, single gene analysis, or analysis of kidney-related genes from exome sequencing. Variant classification was obtained based on the 2015 American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines., Results: A definitive genetic diagnosis was achieved for 50 families (30.7%). The highest diagnostic yield was obtained in individuals with tubulointerstitial diseases (53.3%), followed by congenital anomalies of the kidney and urological tract (33.3%), glomerular (31%), cysts (26.7%), stones (25%), and others (15.4%). A further 20 (12.3%) patients had variants of interest, and variant segregation, and research activities (exome, genome, or transcriptome sequencing) are ongoing for 44 (40%) unresolved families., Limitations: Possible overestimation of diagnostic rate due to inclusion of individuals with variants with evidence of pathogenicity but classified as of uncertain significance by the clinical laboratory., Conclusions: Integration of genomic and research testing and multidisciplinary evaluation in a nephrology cohort with CKD of unknown etiology or suspected monogenic disease provided a diagnosis in a third of families. These diagnoses had prognostic implications, and often changes in management were implemented., (© 2021 The Authors.)

Background: Treatment of proliferative GN with monoclonal Ig deposits (PGNMID) is not established. A monoclonal anti-CD38 antibody (daratumumab) is effective in treating multiple myeloma. Abnormal plasma cell clones may play a role in the pathogenesis of PGNMID., Methods: We evaluated daratumumab's safety and efficacy in an open-label, phase 2 trial in 11 adults with PGNMID and one with C3 glomerulopathy (C3G) with monoclonal gammopathy. Patients had an eGFR >20 ml/min per 1.73 m 2 and proteinuria >1 g/d. They received daratumumab intravenously (16 mg/kg) once weekly for 8 weeks, and then every other week for eight additional doses. Primary outcome was safety, defined as major infections, grade 3 or 4 anemia, leukopenia, or thrombocytopenia. Secondary outcomes were rate of complete remission (proteinuria <500 mg/d with <15% decline in baseline eGFR) or partial remission (>50% reduction in 24-hour proteinuria with <30% decline in eGFR) and proteinuria at 6 and 12 months., Results: One patient with C3G had GN unrelated to the monoclonal gammopathy, and one with PGNMID did not complete the first infusion. Five serious adverse events occurred. During the 12 months of the trial, six of the ten patients with PGNMID who received at least one dose of daratumumab had a partial response, and four had a complete response (an overall response rate of 100%). Three patients experienced relapse, two of whom re-entered partial remission after resuming daratumumab therapy. Proteinuria declined significantly, from a median of 4346 mg/d to 1264 mg/d by 12 months., Conclusions: Daratumumab demonstrated an acceptable safety profile and resulted in significant improvement in proteinuria while stabilizing kidney function in patients with PGNMID, suggesting the drug merits further investigation., Clinical Trial Registry Name and Registration Number: Daratumumab in Treatment of PGNMID and C3 GN, NCT03095118., (Copyright © 2021 by the American Society of Nephrology.)

Background: Microhematuria is common in immunoglobulin A nephropathy (IgAN). However, current prognostication is based on proteinuria and mesangial hypercellularity, endocapillary hypercellularity, segmental sclerosis, tubulointerstitial fibrosis and crescent (MEST-C) scores., Methods: In this retrospective study, we evaluated whether MEST-C score components are associated with the presence of microhematuria at biopsy and whether the degree of microhematuria during follow-up is associated with change in estimated glomerular filtration rate (eGFR), after adjusting for clinical and histological parameters. We identified 125 patients with biopsy-proven IgAN and MEST-C scoring who were not on immunosuppressive therapy at biopsy. Microhematuria was defined as ≥3 red blood cells (RBCs)/high-power field (hpf)., Results: Of the 125 patients, 97 had microhematuria at baseline and were more likely to have M1, E1 and C ≥ 1 lesions (P < 0.05 for all) compared with patients without microhematuria. Of the 125 patients, 72 had follow-up data available. An increase in the degree of microhematuria was significantly associated with an eGFR decline of -0.81 mL/min/1.73 m2 [95% confidence interval (CI) -1.44 to -0.19, P = 0.01], after adjusting for follow-up time, proteinuria and T score. Severe microhematuria (≥21 RBCs/hpf) was associated with an even larger decline in eGFR (-3.99 mL/min/1.73 m2; 95% CI -6.9411 to -1.0552, P = 0.008), after similar adjustments., Conclusion: Degree of microhematuria during follow-up is an independent predictor of eGFR decline after adjusting for clinical and histological parameters. Therefore, monitoring the degree of microhematuria as well as proteinuria is important when evaluating patients with IgAN. Additional studies using improvement in microhematuria as a primary surrogate outcome are needed., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Competing Interests: L. Zand reports research funding from Genentech, Janssen Pharmaceuticals, and Mallinckrodt. The remaining author has nothing to disclose.

Advances in the diagnosis and treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis have led to continued improvement in survival and prognosis over the course of the last 4 decades. Nevertheless, the most acute and severe disease manifestations, including severe kidney disease and alveolar hemorrhage, continue to be associated with increased early mortality from disease activity or treatment complications as well as risk for the development of end-stage kidney disease (ESKD), which in turn directly affects the overall prognosis of ANCA-associated vasculitis. Plasma exchange (PLEX) has long been proposed and used for these most severe disease manifestations under the assumption that its effects are swift and supported by our understanding of the pathogenic role of ANCA. Yet convincing evidence of a beneficial effect of PLEX in ANCA-associated vasculitis has been lacking, as early studies and small trials have generated conflicting results. The controversy regarding PLEX has been accentuated recently as the largest randomized controlled trial ever conducted in ANCA-associated vasculitis, the Plasma Exchange and Glucocorticoids in Severe ANCA-associated Vasculitis trial, which was specifically designed to evaluate the efficacy of PLEX in patients with severe renal disease or alveolar hemorrhage, failed to show a difference in the combined primary outcome measure of death or ESKD in patients who received PLEX versus those who did not. In light of these disappointing results, we herein review the currently available data on PLEX for ANCA-associated vasculitis and explain why we believe that these data no longer support the use of PLEX in ANCA-associated vasculitis., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Rational and Objective: Prognosis provides critical knowledge for shared decision making between patients and clinicians. While several prognostic indices for mortality in dialysis patients have been developed, their performance among elderly patients initiating dialysis is unknown, despite great need for reliable prognostication in that context. To assess the performance of 6 previously validated prognostic indices to predict 3 and/or 6 months mortality in a cohort of elderly incident dialysis patients., Study Design: Validation study of prognostic indices using retrospective cohort data. Indices were compared using the concordance ("c")-statistic, i.e. area under the receiver operating characteristic curve (ROC). Calibration, sensitivity, specificity, positive and negative predictive values were also calculated., Setting & Participants: Incident elderly (age ≥75 years; n = 349) dialysis patients at a tertiary referral center., Established Predictors: Variables for six validated prognostic indices for short term (3 and 6 month) mortality prediction (Foley, NCI, REIN, updated REIN, Thamer, and Wick) were extracted from the electronic medical record. The indices were individually applied as per each index specifications to predict 3- and/or 6-month mortality., Results: In our cohort of 349 patients, mean age was 81.5±4.4 years, 66% were male, and median survival was 351 days. The c-statistic for the risk prediction indices ranged from 0.57 to 0.73. Wick ROC 0.73 (0.68, 0.78) and Foley 0.67 (0.61, 0.73) indices performed best. The Foley index was weakly calibrated with poor overall model fit (p <0.01) and overestimated mortality risk, while the Wick index was relatively well-calibrated but underestimated mortality risk., Limitations: Small sample size, use of secondary data, need for imputation, homogeneous population., Conclusion: Most predictive indices for mortality performed moderately in our incident dialysis population. The Wick and Foley indices were the best performing, but had issues with under and over calibration. More accurate indices for predicting survival in older patients with kidney failure are needed., Competing Interests: Dr.Tangri reports grants and personal fees from AstraZeneca Inc., personal fees from Otsuka Inc., personal fees from Janssen, personal fees from Boehringer Ingelheim and Eli Lilly, grants, and personal fees, and other from Tricida Inc., outside the submitted work. Study contents are the sole responsibility of the authors and do not necessarily represent the official views of NIH or the US government. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Membranous nephropathy (MN) is the most common cause of primary nephrotic syndrome among adults. The identification of phospholipase A2 receptor (PLA2R) as target antigen in most patients changed the management of MN dramatically, and provided a rationale for B-cell depleting agents such as rituximab. The efficacy of rituximab in inducing remission has been investigated in several studies, including 3 randomized controlled trials, in which complete and partial remission of proteinuria was achieved in approximately two-thirds of treated patients. Due to its favorable safety profile, rituximab is now considered a first-line treatment option for MN, especially in patients at moderate and high risk of deterioration in kidney function. However, questions remain about how to best use rituximab, including the optimal dosing regimen, a potential need for maintenance therapy, and assessment of long-term safety and efficacy outcomes. In this review, we provide an overview of the current literature and discuss both strengths and limitations of "the new standard.", (© 2021 Published by Elsevier, Inc., on behalf of the International Society of Nephrology.)