Maladies rénales fréquentes et rares : des mécanismes moléculaires à la médecine personnalisée

The worldwide burden of kidney disease is rising, but public awareness remains limited, underscoring the need for more effective communication by stakeholders in the kidney health community. Despite this need for clarity, the nomenclature for describing kidney function and disease lacks uniformity. In June 2019, Kidney Disease: Improving Global Outcomes (KDIGO) convened a Consensus Conference with the goal of standardizing and refining the nomenclature used in the English language to describe kidney function and disease, and of developing a glossary that could be used in scientific publications. Guiding principles of the conference were that the revised nomenclature should be patient-centered, precise, and consistent with nomenclature used in the KDIGO guidelines. Conference attendees reached general consensus on the following recommendations: (i) to use “kidney“ rather than “renal” or “nephro-” when referring to kidney disease and kidney function; (ii) to use “kidney failure” with appropriate descriptions of presence or absence of symptoms, signs, and treatment, rather than “end-stage kidney disease”; (iii) to use the KDIGO definition and classification of acute kidney diseases and disorders (AKD) and acute kidney injury (AKI), rather than alternative descriptions, to define and classify severity of AKD and AKI; (iv) to use the KDIGO definition and classification of chronic kidney disease (CKD) rather than alternative descriptions to define and classify severity of CKD; and (v) to use specific kidney measures, such as albuminuria or decreased glomerular filtration rate (GFR), rather than “abnormal” or “reduced” kidney function to describe alterations in kidney structure and function. A proposed 5-part glossary contains specific items for which there was general agreement. Conference attendees acknowledged limitations of the recommendations and glossary, but they considered standardization of scientific nomenclature to be essential for improving communication. The worldwide burden of kidney disease is rising, but public awareness remains limited, underscoring the need for more effective communication by stakeholders in the kidney health community. Despite this need for clarity, the nomenclature for describing kidney function and disease lacks uniformity. In June 2019, Kidney Disease: Improving Global Outcomes (KDIGO) convened a Consensus Conference with the goal of standardizing and refining the nomenclature used in the English language to describe kidney function and disease, and of developing a glossary that could be used in scientific publications. Guiding principles of the conference were that the revised nomenclature should be patient-centered, precise, and consistent with nomenclature used in the KDIGO guidelines. Conference attendees reached general consensus on the following recommendations: (i) to use “kidney“ rather than “renal” or “nephro-” when referring to kidney disease and kidney function; (ii) to use “kidney failure” with appropriate descriptions of presence or absence of symptoms, signs, and treatment, rather than “end-stage kidney disease”; (iii) to use the KDIGO definition and classification of acute kidney diseases and disorders (AKD) and acute kidney injury (AKI), rather than alternative descriptions, to define and classify severity of AKD and AKI; (iv) to use the KDIGO definition and classification of chronic kidney disease (CKD) rather than alternative descriptions to define and classify severity of CKD; and (v) to use specific kidney measures, such as albuminuria or decreased glomerular filtration rate (GFR), rather than “abnormal” or “reduced” kidney function to describe alterations in kidney structure and function. A proposed 5-part glossary contains specific items for which there was general agreement. Conference attendees acknowledged limitations of the recommendations and glossary, but they considered standardization of scientific nomenclature to be essential for improving communication. The worldwide burden of kidney disease is rising, but public awareness remains limited, underscoring the need for effective communication by stakeholders in the kidney health community.1Plantinga L.C. Boulware L.E. Coresh J. et al.Patient awareness of chronic kidney disease: trends and predictors.Arch Intern Med. 2008; 168: 2268-2275Crossref PubMed Scopus (227) Google Scholar, 2Saran R. Robinson B. Abbott K.C. et al.US Renal Data System 2018 Annual Data Report: Epidemiology of Kidney Disease in the United States.Am J Kidney Dis. 2019; 73: A7-A8Abstract Full Text Full Text PDF PubMed Scopus (513) Google Scholar, 3James S.L. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet. 2018; 392: 1789-1858Abstract Full Text Full Text PDF PubMed Scopus (6082) Google Scholar, 4Global Burden of Disease 2017 Causes of Death CollaboratorsGlobal, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017.Lancet. 2018; 392: 1736-1788Abstract Full Text Full Text PDF PubMed Scopus (3582) Google Scholar Despite this need for clarity, the nomenclature for describing kidney function and disease lacks uniformity. Two decades ago, a survey of hundreds of published articles and meeting abstracts reported a broad array of overlapping, confusing terms for chronic kidney disease (CKD) and advocated adoption of unambiguous terminology.5Hsu C.Y. Chertow G.M. Chronic renal confusion: insufficiency, failure, dysfunction, or disease.Am J Kidney Dis. 2000; 36: 415-418Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar Nevertheless, terms flagged by that analysis as problematic, such as “chronic renal failure” and “pre-dialysis,” still appear in current-day publications. A coherent, shared nomenclature could influence communication at all levels, including not only greater appreciation of the burden of disease, but also improved understanding about how patients feel about their disease, more effective communication between kidney disease specialists and other clinicians, more straightforward comparison and integration of datasets, better recognition of gaps in knowledge for future research, and more comprehensive public health policies for acute and chronic kidney disease. The international organization Kidney Disease: Improving Global Outcomes (KDIGO) has developed guidelines promulgating definitions and classifications for acute kidney injury (AKI), acute kidney diseases and disorders (AKD), and CKD, and guidelines for their evaluation and management.6Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work GroupKDIGO clinical practice guideline for acute kidney injury.Kidney Int Suppl. 2012; 2: 1-138Abstract Full Text Full Text PDF Scopus (2007) Google Scholar,7Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work GroupKDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.Kidney Int Suppl. 2013; 3: 1-150Abstract Full Text Full Text PDF Scopus (1596) Google Scholar Developing consistent, patient-centered, and precise descriptions of kidney function and disease in the scientific literature is an important objective that KDIGO is now pursuing to align communication in clinical practice, research, and public health. Although some terms have been in use for decades, the increased exchange of information among stakeholders makes it timely to revisit nomenclature in order to ensure consistency. The goal is to facilitate communication within and across disciplines and between practitioner and patient communities, to ultimately improve outcomes through clarity and precision. In June 2019, KDIGO convened a Consensus Conference with the goal of standardizing and refining the nomenclature used in English-language scientific articles to describe kidney function and disease, and developing a glossary that could be used by journals. Prior to the conference, KDIGO posted an announcement of the conference on its website, including the Scope of Work and requested public comment.8Kidney Disease: International Global OutcomesConsensus Conference on Nomenclature for Kidney Function & Disease.https://kdigo.org/conferences/nomenclature/Date Scholar at the conference of kidney kidney at general and other of clinical kidney health research, and Guiding principles of the conference were that the revised nomenclature should be patient-centered, precise, and consistent with nomenclature used in the KDIGO guidelines The on general of acute and chronic kidney disease and kidney measures, rather than specific kidney diseases and of function and The Scope of Work developed to the conference a of for of causes of kidney disease and measures, and for and were considered the of of the and and and the nomenclature to describe kidney function and on general of acute and chronic kidney disease and general kidney measures, rather than specific kidney diseases and specific of function and for “renal” or and definitions and other descriptions of disease and disease kidney and of “kidney with KDIGO guideline to that articles in the English-language literature should rather than “renal” or “nephro-” when referring to kidney disease and kidney failure” with appropriate descriptions of presence or absence of symptoms, signs, and rather than definition and classification of AKD and rather than alternative descriptions to define and classify severity of AKD and definition and classification of CKD rather than alternative descriptions to define and classify severity of kidney as albuminuria or decreased rather than “abnormal” or “reduced” kidney function to describe alterations in kidney structure and acute kidney diseases and acute kidney CKD, chronic kidney glomerular filtration Kidney Disease: Improving Global in a acute kidney diseases and acute kidney CKD, chronic kidney glomerular filtration Kidney Disease: Improving Global Prior KDIGO have been but is about the of terms used to describe kidney function and disease on have kidney disease. 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Conference attendees reached general consensus for of the a proposed glossary contains and specific items on which there was general among conference the glossary descriptions, and terms to with that which of the recommendations to and that when and how to terms to be consistent with nomenclature for other of the use of glossary terms in the at the conference and of Disease: Improving Global Outcomes (KDIGO) kidney function and disease terms to describe kidney function and kidney disease and and and when to to Kidney function and should be used when describing kidney disease and kidney with the “nephro-” in the of specific or Kidney the of acute kidney diseases and disorders and chronic kidney in the of specific Kidney the of and of the should not be with glomerular filtration rate function when describing specific renal renal kidney to of kidney which should be kidney to of kidney which should be insufficiency, kidney function in with kidney is Although it is used in the of this could be used to to kidney function in kidney renal function Kidney the of and of the by and of injury and structure when describing specific within the such as kidney to of kidney which should be kidney to of kidney which should be Causes of kidney of and CKD should be be or for and of should be should not be only presence of as and when to to Kidney or by is renal disease kidney disease renal insufficiency, kidney injury be revised by KDIGO guideline renal renal insufficiency, renal chronic renal chronic chronic insufficiency, kidney and or and with and be with of and with kidney not a for be revised by KDIGO AKD consensus is and by by to for CKD; 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2: 1-138Abstract Full Text Full Text PDF Scopus (2007) Google Scholar,7Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work GroupKDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.Kidney Int Suppl. 2013; 3: 1-150Abstract Full Text Full Text PDF Scopus (1596) Google Scholar In the acute conference attendees with disease severity by and treatment, but they not consensus on use of the “kidney failure” rather than or use of “kidney for all of it be appropriate for to be in with the of the KDIGO Disease: International Global Conference on Acute Kidney 2019; Scholar Conference attendees that and of kidney or the be and and there or to was as for research, with the that it be in the future to classify kidney by the presence or absence of and The KDIGO Conference in Chronic Kidney Disease use of the for not to but to for of kidney et of the KDIGO Conference on in Chronic Kidney Disease: developing a to improving Full Text Full Text PDF PubMed Scopus Google Scholar also an that could be used of with was considered to be consistent with the attendees the that of this in nomenclature not the to in the United and that the KDIGO definition and classification for should be used rather than the definitions to the classification and the Acute Kidney Injury which were by the 2012 KDIGO guideline Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work GroupKDIGO clinical practice guideline for acute kidney injury.Kidney Int Suppl. 2012; 2: 1-138Abstract Full Text Full Text PDF Scopus (2007) Google Scholar for a in by an in or within to with the severity of by the severity of in or for of kidney for as for CKD is that the for only in and of and its severity the of in is in other for AKD were proposed in the 2012 KDIGO they of kidney or for classification by AKD but it also disorders by of kidney such as and in which the rate of in is not as as in that AKD is more than et and of acute kidney diseases and disorders an to in a health 2019; PubMed Scopus Google Scholar definitions of and AKD were proposed by the Acute Conference in R. et kidney disease and renal consensus of the Acute Disease PubMed Scopus Google Scholar that the AKD definition to be consistent with the definitions of and CKD is a and this be the for a future KDIGO Consensus that the KDIGO definition and classification for CKD should be used rather than other definitions The for of kidney or for the CKD Kidney clinical practice guidelines for chronic kidney disease: and J Kidney Dis. 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Google Scholar The albuminuria and have been to their with for outcomes and kidney and CKD as a Disease: Improving Global Outcomes (KDIGO) CKD Work GroupKDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.Kidney Int Suppl. 2013; 3: 1-150Abstract Full Text Full Text PDF Scopus (1596) Google Scholar The guideline specific terms for of and of CKD, its and is not The terms and not and their use is not they should be in the of that specific kidney as albuminuria or and decreased rather than “abnormal” or “reduced” kidney should be used to describe alterations in kidney structure and function all measures, it is important to and of and their the 2012 CKD guideline Disease: Improving Global Outcomes (KDIGO) CKD Work GroupKDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.Kidney Int Suppl. 2013; 3: 1-150Abstract Full Text Full Text PDF Scopus (1596) Google Scholar of is to that of it be and is more in the but in albuminuria and it is important to describe the of for and and for and as as The terms and should not be used as it is important to the filtration and it is important to the filtration and and should be to of for and should be to such as and and the of filtration be by The albuminuria and in the 2012 CKD guideline be to with or CKD, but it is to be as to or not with albuminuria or and have that the of albuminuria or is but is on presence or absence of the The of the 2012 KDIGO guideline an alternative for J. et and of glomerular diseases a Kidney Disease: Improving Global Outcomes (KDIGO) 2019; Full Text Full Text PDF PubMed Scopus Google Scholar The 2012 and CKD KDIGO guidelines about of the definitions and classifications to Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work GroupKDIGO clinical practice guideline for acute kidney injury.Kidney Int Suppl. 2012; 2: 1-138Abstract Full Text Full Text PDF Scopus (2007) Google Scholar,7Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work GroupKDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.Kidney Int Suppl. 2013; 3: 1-150Abstract Full Text Full Text PDF Scopus (1596) Google Scholar not to with CKD to or and for and in to in is use of terms to describe acute and chronic kidney disease and kidney disease Conference attendees with the goal of standardizing and refining the nomenclature used in English to describe kidney function and disease, and of developing a glossary that could be used by for of scientific reached general consensus on the recommendations and on a glossary that the recommendations to be and by journals.

Randomized trials of rituximab in primary membranous nephropathy (PMN) have not been conducted. We undertook a multicenter, randomized, controlled trial at 31 French hospitals (NCT01508468). Patients with biopsy-proven PMN and nephrotic syndrome after 6 months of nonimmunosuppressive antiproteinuric treatment (NIAT) were randomly assigned to 6-month therapy with NIAT and 375 mg/m 2 intravenous rituximab on days 1 and 8 ( n =37) or NIAT alone ( n =38). Median times to last follow-up were 17.0 (interquartile range, 12.5–24.0) months and 17.0 (interquartile range, 13.0–23.0) months in NIAT-rituximab and NIAT groups, respectively. Primary outcome was a combined end point of complete or partial remission of proteinuria at 6 months. At month 6, 13 (35.1%; 95% confidence interval [95% CI], 19.7 to 50.5) patients in the NIAT-rituximab group and eight (21.1%; 95% CI, 8.1 to 34.0) patients in the NIAT group achieved remission ( P =0.21). Rates of antiphospholipase A2 receptor antibody (anti–PLA2R-Ab) depletion in NIAT-rituximab and NIAT groups were 14 of 25 (56%) and one of 23 (4.3%) patients at month 3 ( P <0.001) and 13 of 26 (50%) and three of 25 (12%) patients at month 6 ( P =0.004), respectively. Eight serious adverse events occurred in each group. During the observational phase, remission rates before change of assigned treatment were 24 of 37 (64.9%) and 13 of 38 (34.2%) patients in NIAT-rituximab and NIAT groups, respectively ( P <0.01). Positive effect of rituximab on proteinuria remission occurred after 6 months. These data suggest that PLA2R-Ab levels are early markers of rituximab effect and that addition of rituximab to NIAT does not affect safety.

The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.

A cyclical corticosteroid-cyclophosphamide regimen is recommended for patients with primary membranous nephropathy at high risk of progression. We hypothesized that sequential therapy with tacrolimus and rituximab is superior to cyclical alternating treatment with corticosteroids and cyclophosphamide in inducing persistent remission in these patients. This was tested in a randomized, open-label controlled trial of 86 patients with primary membranous nephropathy and persistent nephrotic syndrome after six-months observation and assigned 43 each to receive six-month cyclical treatment with corticosteroid and cyclophosphamide or sequential treatment with tacrolimus (full-dose for six months and tapering for another three months) and rituximab (one gram at month six). The primary outcome was complete or partial remission of nephrotic syndrome at 24 months. This composite outcome occurred in 36 patients (83.7%) in the corticosteroid-cyclophosphamide group and in 25 patients (58.1%) in the tacrolimus-rituximab group (relative risk 1.44; 95% confidence interval 1.08 to 1.92). Complete remission at 24 months occurred in 26 patients (60%) in the corticosteroid-cyclophosphamide group and in 11 patients (26%) in the tacrolimus-rituximab group (2.36; 1.34 to 4.16). Anti-PLA2R titers showed a significant decrease in both groups but the proportion of anti-PLA2R-positive patients who achieved immunological response (depletion of anti-PLA2R antibodies) was significantly higher at three and six months in the corticosteroid-cyclophosphamide group (77% and 92%, respectively), as compared to the tacrolimus-rituximab group (45% and 70%, respectively). Relapses occurred in one patient in the corticosteroid-cyclophosphamide group, and three patients in the tacrolimus-rituximab group. Serious adverse events were similar in both groups. Thus, treatment with corticosteroid-cyclophosphamide induced remission in a significantly greater number of patients with primary membranous nephropathy than tacrolimus-rituximab. A cyclical corticosteroid-cyclophosphamide regimen is recommended for patients with primary membranous nephropathy at high risk of progression. We hypothesized that sequential therapy with tacrolimus and rituximab is superior to cyclical alternating treatment with corticosteroids and cyclophosphamide in inducing persistent remission in these patients. This was tested in a randomized, open-label controlled trial of 86 patients with primary membranous nephropathy and persistent nephrotic syndrome after six-months observation and assigned 43 each to receive six-month cyclical treatment with corticosteroid and cyclophosphamide or sequential treatment with tacrolimus (full-dose for six months and tapering for another three months) and rituximab (one gram at month six). The primary outcome was complete or partial remission of nephrotic syndrome at 24 months. This composite outcome occurred in 36 patients (83.7%) in the corticosteroid-cyclophosphamide group and in 25 patients (58.1%) in the tacrolimus-rituximab group (relative risk 1.44; 95% confidence interval 1.08 to 1.92). Complete remission at 24 months occurred in 26 patients (60%) in the corticosteroid-cyclophosphamide group and in 11 patients (26%) in the tacrolimus-rituximab group (2.36; 1.34 to 4.16). Anti-PLA2R titers showed a significant decrease in both groups but the proportion of anti-PLA2R-positive patients who achieved immunological response (depletion of anti-PLA2R antibodies) was significantly higher at three and six months in the corticosteroid-cyclophosphamide group (77% and 92%, respectively), as compared to the tacrolimus-rituximab group (45% and 70%, respectively). Relapses occurred in one patient in the corticosteroid-cyclophosphamide group, and three patients in the tacrolimus-rituximab group. Serious adverse events were similar in both groups. Thus, treatment with corticosteroid-cyclophosphamide induced remission in a significantly greater number of patients with primary membranous nephropathy than tacrolimus-rituximab. Primary membranous nephropathy (PMN) is one of the most common causes of nephrotic syndrome in adults.1Couser W. Primary membranous nephropathy.Clin J Am Soc Nephrol. 2017; 12: 983-997Crossref PubMed Scopus (245) Google Scholar In 70%–80% of cases, the disease is mediated by autoantibodies targeting the phospholipase A2 receptor (PLA2R) expressed in podocytes and in 3%–5% by autoantibodies to thrombospondin type 1 domain–containing 7A (THSD7A).2Beck Jr., L.H. Bonegio R.G. Lambeau G. et al.M-Type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.N Engl J Med. 2009; 361: 11-21Crossref PubMed Scopus (1419) Google Scholar, 3Ronco P. Debiec H. Molecular pathogenesis of membranous nephropathy.Annu Rev Pathol. 2020; 15: 287-313Crossref PubMed Scopus (42) Google Scholar, 4Tomas N.M. Beck Jr., L.H. Meyer-Schwesinger C. et al.Thrombospondin type-1 domain–containing 7A in idiopathic membranous nephropathy.N Engl J Med. 2014; 371: 2277-2287Crossref PubMed Scopus (496) Google Scholar Spontaneous remission occurs in one-third of patients,5Polanco N. Gutiérrez E. Covarsí A. et al.Spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy.J Am Soc Nephrol. 2010; 21: 697-704Crossref PubMed Scopus (248) Google Scholar and therefore an observational period of at least 6 months is recommended.6Waldman M. Austin H.A. Treatment of idiopathic membranous nephropathy.J Am Soc Nephrol. 2012; 23: 1617-1630Crossref PubMed Scopus (62) Google Scholar, 7Hofstra J.M. Fervenza F.C. Wetzels J.F.M. Treatment of idiopathic membranous nephropathy.Nat Rev Nephrol. 2013; 9: 443-458Crossref PubMed Scopus (88) Google Scholar, 8Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work GroupKDIGO clinical practice guidelines for glomerulonephritis.Kidney Int Suppl. 2012; 2 (139–27)Google Scholar Conversely, about 50% of cases with persistent nephrotic syndrome eventually progress to end-stage kidney disease, and immunosuppressive therapy is recommended for these patients. Controversy persists about the most effective type of immunosuppressive regimen. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for glomerulonephritis recommended a 6-month cyclic regimen of alternating alkylating agents (usually cyclophosphamide) plus corticosteroids for patients at high risk of progression, since it was the only regimen that was shown to be effective in preventing end-stage kidney disease.8Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work GroupKDIGO clinical practice guidelines for glomerulonephritis.Kidney Int Suppl. 2012; 2 (139–27)Google Scholar, 9Ponticelli C. Zucchelli P. Passerini P. et al.A randomized trial of methylprednisolone and chlorambucil in idiopathic membranous nephropathy.N Engl J Med. 1989; 320: 8-13Crossref PubMed Scopus (240) Google Scholar, 10Ponticelli C. Zucchelli P. Passerini P. et al.A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy.Kidney Int. 1995; 48: 1600-1604Abstract Full Text PDF PubMed Scopus (336) Google Scholar, 11Ponticelli C. Altieri P. Scolari F. et al.A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy.J Am Soc Nephrol. 1998; 9: 444-450Crossref PubMed Google Scholar, 12Jha V. Ganguli A. Saha T.K. et al.A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy.J Am Soc Nephrol. 2007; 18: 1899-1904Crossref PubMed Scopus (215) Google Scholar However, given the important number of serious adverse events associated with cumulative doses of alkylating agents, treatment alternatives were introduced. Calcineurin inhibitors (both cyclosporine and tacrolimus) have shown efficacy in inducing remission of nephrotic syndrome in about 70% of patients.13Cattran D.C. Appel G.B. Hebert L.A. et al.Cyclosporine in patients with steroid-resistant membranous nephropathy: a randomized trial.Kidney Int. 2001; 59: 1484-1490Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar,14Praga M. Barrio V. Juárez G.F. Luño J. Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial.Kidney Int. 2007; 71: 924-930Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar However, the main limitation of these drugs is the high rate of relapse after discontinuation. An observational study found a reduction in relapse rates when rituximab was administered at the time of tapering off cyclosporine or tacrolimus,15Segarra A. Praga M. Ramos N. et al.Successful treatment of membranous glomerulonephritis with rituximab in calcineurin inhibitor-dependent patients.Clin J Am Soc Nephrol. 2009; 4: 1083-1088Crossref PubMed Scopus (82) Google Scholar and a pilot study reported encouraging results of a combined therapy with cyclosporine plus rituximab in high-risk PMN patients.16Waldman M. Beck Jr., L.H. Braun M. et al.Membranous nephropathy: pilot study of a novel regimen cyclosporine and Int Full Text Full Text PDF PubMed Scopus Google Scholar the efficacy of rituximab monotherapy P. P. A. et in idiopathic membranous nephropathy.J Am Soc Nephrol. 2012; 23: PubMed Scopus Google Scholar A of rituximab was to be effective for of remission in an observational P. P. G. rituximab to to therapy in idiopathic membranous nephropathy.Clin J Am Soc Nephrol. 2007; PubMed Scopus Google Scholar in clinical higher doses were for Debiec H. E. et for membranous nephropathy: a 6-month trial with Am Soc Nephrol. 2017; PubMed Scopus Google Scholar, F.C. Appel G.B. et or cyclosporine in the treatment of membranous nephropathy.N Engl J Med. PubMed Scopus Google Scholar, Debiec H. et rituximab and remission in membranous nephropathy.Clin J Am Soc Nephrol. PubMed Scopus Google Scholar the superior efficacy of rituximab versus cyclosporine in the of study was achieved a of F.C. Appel G.B. et or cyclosporine in the treatment of membranous nephropathy.N Engl J Med. PubMed Scopus Google Scholar The for comparing the 6-month cyclic alternating treatment with corticosteroids and cyclophosphamide with the alternatives was in a J. D.C. et and treatment of a Kidney Disease: Improving Global Outcomes (KDIGO) Int. Full Text Full Text PDF PubMed Scopus Google Scholar We the Treatment with Tacrolimus and and in study to cyclic alternating treatment of corticosteroids and cyclophosphamide with a sequential treatment of tacrolimus and rituximab in the and of nephrotic syndrome remission for 24 months. In the of after remission and the of anti-PLA2R autoantibodies the of the patients were for of were the for were the to in the study and of a of membranous nephropathy The 86 patients who the were assigned to the corticosteroid-cyclophosphamide group or to the tacrolimus-rituximab group in significant groups were at were in and anti-PLA2R was in showed at and patients patients with or anti-PLA2R at and patient was Kidney were months patients PMN and PMN to treatment patients was to the Kidney as of of 6 of 43 patients anti-PLA2R was at of 11 of 43 patients anti-PLA2R was at treatment of of 43 of 43 of of 43 of 43 A2 receptor receptor as or was to the Kidney Anti-PLA2R as In 6 of 43 patients anti-PLA2R was at In 11 of 43 patients anti-PLA2R was at in a A2 receptor receptor as or patients at least 1 month of the assigned patients in the corticosteroid-cyclophosphamide group and 6 in the tacrolimus-rituximab group the The in the corticosteroid-cyclophosphamide group and in the tacrolimus-rituximab the complete assigned to the corticosteroid-cyclophosphamide group a of methylprednisolone of in months and with a cumulative of The cumulative of methylprednisolone was The cumulative of cyclophosphamide was and of tacrolimus in the tacrolimus-rituximab group in patients in group a of rituximab in 2 1 in 1 at months and and 2 doses of tacrolimus month the follow-up period after the of the assigned patients in each group were to a to a of efficacy of the assigned In the corticosteroid-cyclophosphamide group, 2 patients were with rituximab at month 2 patients tacrolimus month and 1 patient cyclosporine month In the tacrolimus-rituximab group, the patients a 6-month cyclic treatment with corticosteroid and cyclophosphamide at month month or month the patients who were to a were to be was complete in of the 86 patients. patients (83.7%) in the corticosteroid-cyclophosphamide group and 25 patients (58.1%) in the tacrolimus-rituximab group a primary outcome of remission at 24 months (relative risk 95% confidence interval 1.08 to The significant in the primary outcome of in the corticosteroid-cyclophosphamide group and of in the tacrolimus-rituximab group 95% to The in the number of patients with complete or partial remission in both groups was significant at month and was the study outcome of complete or partial remission at to 24 cyclophosphamide risk of 43 of 43 of 43 of 43 of 43 of 43 of 43 of 43 of 43 of 43 cyclophosphamide risk of of of of of of of of of of confidence the patients who the the patients who the of trial In both the primary outcome was the composite of complete or partial remission at 24 or 95% in a confidence The the patients who the the patients who the of trial In both the primary outcome was the composite of complete or partial remission at 24 months. or 95% shown in and 26 patients (60%) in the corticosteroid-cyclophosphamide group achieved complete remission at 24 months. In the tacrolimus-rituximab group, 11 patients (26%) achieved complete remission at 24 months 95% 1.34 to remission at to 24 cyclophosphamide risk of 43 of 43 of 43 of 43 of 43 of 43 of 43 of 43 of 43 of 43 cyclophosphamide risk of of of of of of of of of of confidence the patients who the the patients who the of trial In both the primary outcome was the composite of complete or partial remission at 24 or 95% in a confidence The the patients who the the patients who the of trial In both the primary outcome was the composite of complete or partial remission at 24 months. or 95% A for a greater efficacy of the corticosteroid-cyclophosphamide treatment was found by of anti-PLA2R and were found in patients of patients were compared who achieved remission and with a significantly higher proportion of and a significantly higher were a at to at 24 months in the corticosteroid-cyclophosphamide group and at to 1 at 24 months in the tacrolimus-rituximab group a at to at 24 months in the corticosteroid-cyclophosphamide group and at to at 24 months in the tacrolimus-rituximab group was a for higher of rate in the corticosteroid-cyclophosphamide group than in the tacrolimus-rituximab group the follow-up 24 the of patients with a of were 1 in the corticosteroid-cyclophosphamide group and in the tacrolimus-rituximab group The of patients with at 24 months were in the corticosteroid-cyclophosphamide group and in the tacrolimus-rituximab group The only patient who end-stage kidney disease was a who assigned to the corticosteroid-cyclophosphamide group. months after treatment was the study of persistent and and to rituximab doses of 1 response was and was months after Anti-PLA2R showed a significant decrease in both groups The of patients who achieved response at and 6 months were significantly higher in the corticosteroid-cyclophosphamide group (77% and 92%, than in the tacrolimus-rituximab group (45% and 70%, patients who achieved response the study remission of nephrotic syndrome at 24 months. response at months and 6 months was associated with remission at 24 months. patients showed a in anti-PLA2R and a significantly proportion of compared with patients who achieved a complete or partial remission of nephrotic syndrome of anti-PLA2R and of response to treatment phospholipase A2 of were compared with the in a phospholipase A2 of were compared with the of the 36 patients in the corticosteroid-cyclophosphamide group, and of the 25 patients in the tacrolimus-rituximab group who achieved partial remission a relapse The in the tacrolimus-rituximab group occurred at month months after tacrolimus discontinuation. of occurred in patients who an response at month 6 and were by a of anti-PLA2R The relapse occurred in a patient in anti-PLA2R at Tacrolimus was in 2 patients and the one was with The relapse in the corticosteroid-cyclophosphamide group occurred at month in an patient who response at month In the relapse was by a of anti-PLA2R and the patient was with patients 6 the corticosteroid-cyclophosphamide group and the tacrolimus-rituximab at least 1 adverse adverse events were of or but were were adverse events and adverse events patient in the corticosteroid-cyclophosphamide group than in the tacrolimus-rituximab group patients in the corticosteroid-cyclophosphamide group and kidney and were common in the tacrolimus-rituximab group. was a significant the of and the of both in the trial and in each treatment group for the group and for the cyclophosphamide group, for the adverse events occurred the months of the trial of but only of the serious adverse events occurred events to treatment for the in number of events adverse adverse adverse events in at least of patients or serious adverse and kidney for patients as for events as for the in number of events groups. in a for patients as for events as were significant in the of serious adverse events groups. The only of serious kidney occurred in the tacrolimus-rituximab group, of the serious occurred in the corticosteroid-cyclophosphamide group. cases of were of was to be to the treatment occurred in the corticosteroid-cyclophosphamide group and at and 11 and 1 in the tacrolimus-rituximab group at 1 Anti-PLA2R was at in the patients with the time of the 2 patients in the corticosteroid-cyclophosphamide group were in clinical The study to the that sequential therapy with tacrolimus and rituximab was superior to cyclic alternating treatment with corticosteroids and cyclophosphamide in inducing persistent remission in patients with In found that treatment with corticosteroid and cyclophosphamide was effective than sequential treatment with tacrolimus and rituximab in inducing The of was in the corticosteroid-cyclophosphamide group, with a significant in the number of at months. most were complete in the corticosteroid-cyclophosphamide group, most were partial in the tacrolimus-rituximab group. with calcineurin inhibitors and rituximab have that these drugs effective at inducing remission in that the of calcineurin inhibitors in PMN be to in a C. M. et of kidney podocytes is a target of the of cyclosporine Med. PubMed Scopus Google Scholar However, found that tacrolimus induced a decrease in anti-PLA2R in with A. V. et follow-up study of membranous nephropathy with tacrolimus and corticosteroids versus cyclical corticosteroids and Int 2017; Full Text Full Text PDF PubMed Scopus Google Scholar The main limitation of calcineurin inhibitors is the high relapse rate after in of patients. In the F.C. Appel G.B. et or cyclosporine in the treatment of membranous nephropathy.N Engl J Med. PubMed Scopus Google Scholar rituximab at 1 and after and 2 at month 6 the patient complete was compared with cyclosporine given for months. were significant in the number of at months. However, a higher proportion of patients in the cyclosporine group after treatment and the number of patients in remission at 24 months was significantly higher in the rituximab group In the number of at 6 months was in the tacrolimus-rituximab group than in the corticosteroid-cyclophosphamide group. at month 6 the in remission the number of complete after rituximab An important was the number of after tacrolimus discontinuation. This with a observational study that reported a of at the of calcineurin to in PMN patients who to cyclosporine or A. Praga M. Ramos N. et al.Successful treatment of membranous glomerulonephritis with rituximab in calcineurin inhibitor-dependent patients.Clin J Am Soc Nephrol. 2009; 4: 1083-1088Crossref PubMed Scopus (82) Google Scholar The pathogenesis of after tacrolimus in PMN and the rituximab rituximab is effective in the number of nephrotic syndrome in kidney as disease and and M. et for nephrotic syndrome or nephrotic a 2014; Full Text Full Text PDF PubMed Scopus Google P. P. et in or idiopathic nephrotic Am Soc Nephrol. 2014; PubMed Scopus Google Scholar In the the number of for the than number of at 24 months. the response rate of in the tacrolimus-rituximab group was similar to that with in Debiec H. E. et for membranous nephropathy: a 6-month trial with Am Soc Nephrol. 2017; PubMed Scopus Google F.C. Appel G.B. et or cyclosporine in the treatment of membranous nephropathy.N Engl J Med. PubMed Scopus Google Scholar and than that after cyclosporine or tacrolimus the of rituximab D.C. Appel G.B. Hebert L.A. et al.Cyclosporine in patients with steroid-resistant membranous nephropathy: a randomized trial.Kidney Int. 2001; 59: 1484-1490Abstract Full Text Full Text PDF PubMed Scopus (297) Google Scholar,14Praga M. Barrio V. Juárez G.F. Luño J. Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial.Kidney Int. 2007; 71: 924-930Abstract Full Text Full Text PDF PubMed Scopus (216) Google A. V. et follow-up study of membranous nephropathy with tacrolimus and corticosteroids versus cyclical corticosteroids and Int 2017; Full Text Full Text PDF PubMed Scopus Google Scholar the it be that the tacrolimus-rituximab group in the corticosteroid-cyclophosphamide and were higher anti-PLA2R a higher of and a of in group. these at have the an outcome in the tacrolimus-rituximab group. the of anti-PLA2R autoantibodies as a of the disease in 70%–80% of patients with a cumulative number of have the of of anti-PLA2R to clinical to the and to the of immunosuppressive Jr., L.H. Bonegio R.G. Lambeau G. et al.M-Type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.N Engl J Med. 2009; 361: 11-21Crossref PubMed Scopus (1419) Google M. Wetzels P. The anti-PLA2R in membranous nephropathy: and a after Int. Full Text Full Text PDF PubMed Scopus Google Scholar, Fervenza F.C. A for a to membranous nephropathy.J Am Soc Nephrol. 2017; PubMed Scopus Google Scholar, E. G. A2 receptor autoantibodies and clinical outcome in patients with primary membranous nephropathy.J Am Soc Nephrol. 2014; PubMed Scopus Google Scholar, P. Debiec H. et receptor outcome of membranous nephropathy.J Am Soc Nephrol. PubMed Scopus Google Scholar, A2 receptor and treatment of membranous nephropathy: a J Am Soc Nephrol. 2014; 9: PubMed Scopus Google Scholar We found that both corticosteroid-cyclophosphamide and tacrolimus-rituximab induced a significant reduction in anti-PLA2R response occurred in the corticosteroid-cyclophosphamide group. and in a reduction in than drugs as rituximab or calcineurin and have the of alkylating agents in the most cases of A. et remission in membranous nephropathy: cyclophosphamide versus Int. Full Text Full Text PDF PubMed Scopus Google Scholar, et for membranous nephropathy: a controlled 2013; Full Text Full Text PDF PubMed Scopus Google Scholar, C. and in mediated kidney Rev Nephrol. 15: PubMed Scopus Google Scholar response was by clinical remission in the of the of anti-PLA2R for a treatment of the The rate of adverse was significantly higher patients with were in the number of serious adverse have shown that in PMN by serious J.M. Wetzels risk after cyclophosphamide treatment in idiopathic membranous nephropathy.Clin J Am Soc Nephrol. 2014; 9: PubMed Scopus Google P. A. et of rituximab compared with steroids and cyclophosphamide for idiopathic membranous nephropathy.J Am Soc Nephrol. 2017; PubMed Scopus Google Scholar However, cumulative doses of cyclophosphamide were higher than in have that of doses of the results in M. H. et of idiopathic membranous nephropathy in patients with cyclophosphamide and 2009; PubMed Scopus Google Scholar Anti-PLA2R to treatment in patients in a response is have reported encouraging results with the of of cyclophosphamide as a for cyclophosphamide in patients with the alternating cyclic regimen of corticosteroids and V. A. G. cyclophosphamide and is a and effective treatment for idiopathic membranous nephropathy.Clin Kidney J. 2017; PubMed Scopus Google P. cyclophosphamide and steroids immunological and clinical remission in and primary membranous 23: PubMed Scopus Google Scholar the it be important to the of doses of corticosteroids the of the of treatment with corticosteroids and cyclophosphamide be compared with calcineurin inhibitors and treatment with tacrolimus 6 months or higher and doses of rituximab the remission rates in patients with tacrolimus-rituximab be in The study important was of and outcome The by or of anti-PLA2R and anti-PLA2R were in a number of patients. were about the of rituximab was However, study was a controlled trial that compared the cyclic alternating treatment with corticosteroids and cyclophosphamide versus the alternatives treatment with tacrolimus and with a and follow-up period that to important about the treatment of PMN in clinical In treatment with corticosteroid-cyclophosphamide induced remission of nephrotic syndrome in a significantly greater number of patients than treatment with were in the group. This randomized, controlled trial with a was by the and at in 1 in the A complete of study and is in the of the and study for the trial in the The study was J. G. A. et al.A and open-label controlled randomized trial to the efficacy of sequential treatment with tacrolimus-rituximab versus steroids plus cyclophosphamide in patients with primary membranous nephropathy: the Kidney J. PubMed Scopus Google Scholar A and the of the and the of the the trial at The trial is at patients with PMN were patients were for an observational period of at least 6 months. were a decrease of the observational and the observational patients the of with receptor for at least 2 months and controlled for at least with in of or the In the of a was were causes of membranous nephropathy or disease, treatment with another or or to drugs treatment with corticosteroids months immunosuppressive months or to or with a risk for the patient and or Full as as and in We a in for with an to with corticosteroid-cyclophosphamide or tacrolimus-rituximab. The were assigned as each the In the corticosteroid-cyclophosphamide group, patients methylprednisolone at months and at and to months and patients cyclophosphamide for and for In the tacrolimus-rituximab group, patients tacrolimus to target of for 6 months. patients rituximab and tacrolimus was by with complete at the of month Tacrolimus was in of kidney with patients 1 and groups with a the treatment were to in of of and patients with a relapse of nephrotic syndrome were as The primary outcome was complete or partial remission at 24 months. the rate of complete and partial remission at and 24 relapse of nephrotic syndrome at and 24 response at to 24 and the of patients of of and with kidney at 24 and adverse were the proportion of patients with adverse events the study and cumulative of each study Complete remission was as a reduction of to a plus kidney partial remission as a reduction of and a plus response was as a reduction of Relapses were as a of and at least the in or in patients with partial or complete were to be for anti-PLA2R when were as with a C. 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Membranous nephropathy results from subepithelial antigen-antibody complex deposition along the glomerular basement membrane. Although PLA2R, THSD7A, and NELL-1 account for a majority (about 80%) of the target antigens, the target antigen in the remaining cases is not known. Using laser microdissection of PLA2R-negative glomeruli of patients with membranous nephropathy followed by mass spectrometry we identified a unique protein, Semaphorin 3B, in three cases. Mass spectrometry failed to detect Semaphorin-3B in 23 PLA2R-associated cases of membranous nephropathy and 88 controls. Semaphorin 3B in all three cases was localized to granular deposits along the glomerular basement membrane by immunohistochemistry. Next, an additional eight cases of Semaphorin 3B-associated membranous nephropathy were identified in three validation cohorts by immunofluorescence microscopy. In four of 11 cases, kidney biopsy also showed tubular basement membrane deposits of IgG on frozen sections. Confocal microscopy showed that both IgG and Semaphorin 3B co-localized to the glomerular basement membrane. Western blot analysis of five available sera showed reactivity to reduced Semaphorin 3B in four of four patients with active disease and no reactivity in one patient in clinical remission; there was also no reactivity in control sera. Eight of the 11 cases of Semaphorin 3B-associated membranous nephropathy were pediatric cases. Furthermore, in five cases, the disease started at or below the age of two. Thus, Semaphorin 3B-associated membranous nephropathy appears to be a distinct type of disease; more likely to be present in pediatric patients. Membranous nephropathy results from subepithelial antigen-antibody complex deposition along the glomerular basement membrane. Although PLA2R, THSD7A, and NELL-1 account for a majority (about 80%) of the target antigens, the target antigen in the remaining cases is not known. Using laser microdissection of PLA2R-negative glomeruli of patients with membranous nephropathy followed by mass spectrometry we identified a unique protein, Semaphorin 3B, in three cases. Mass spectrometry failed to detect Semaphorin-3B in 23 PLA2R-associated cases of membranous nephropathy and 88 controls. Semaphorin 3B in all three cases was localized to granular deposits along the glomerular basement membrane by immunohistochemistry. Next, an additional eight cases of Semaphorin 3B-associated membranous nephropathy were identified in three validation cohorts by immunofluorescence microscopy. In four of 11 cases, kidney biopsy also showed tubular basement membrane deposits of IgG on frozen sections. Confocal microscopy showed that both IgG and Semaphorin 3B co-localized to the glomerular basement membrane. Western blot analysis of five available sera showed reactivity to reduced Semaphorin 3B in four of four patients with active disease and no reactivity in one patient in clinical remission; there was also no reactivity in control sera. Eight of the 11 cases of Semaphorin 3B-associated membranous nephropathy were pediatric cases. Furthermore, in five cases, the disease started at or below the age of two. Thus, Semaphorin 3B-associated membranous nephropathy appears to be a distinct type of disease; more likely to be present in pediatric patients. Membranous nephropathy (MN) results from antibodies targeting an antigen in the glomerular basement membrane (GBM). MN is typically classified as primary MN, which has no identifiable underlying disease association, and secondary MN, where the MN may be associated with an autoimmune disease, infection, malignancy, and others.1Beck Jr., L.H. Salant D.J. Membranous nephropathy: from models to man.J Clin Invest. 2014; 124: 2307-2314Crossref PubMed Scopus (102) Google Scholar, 2Ronco P. Debiec H. Pathophysiological advances in membranous nephropathy: time for a shift in patient's care.Lancet. 2015; 385: 1983-1992Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar, 3Couser W.G. Primary membranous nephropathy.Clin J Am Soc Nephrol. 2017; 12: 983-997Crossref PubMed Scopus (165) Google Scholar The target antigen in primary MN has been identified as M-type phospholipase A2 receptor (PLA2R), thrombospondin type-1 domain-containing 7A (THSD7A), and the recently described neural epidermal growth factor like-1 protein (NELL-1), respectively.4Tomas N.M. Beck L.H. Meyer-Schwesinger C. et al.Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy.N Engl J Med. 2014; 371: 2277-2287Crossref PubMed Scopus (420) Google Scholar, 5Beck L.H. Bonegio R.G.B. Lambeau G.R. et al.M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.N Engl J Med. 2009; 361: 11-21Crossref PubMed Scopus (1288) Google Scholar, 6Sethi S. Debiec H. Madden B. et al.Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy.Kidney Int. 2020; 97: 163-174Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar Exostosin 1/exostosin 2 (EXT1/EXT2) have also recently been identified as the putative antigen(s) in secondary (autoimmune) MN.7Sethi S. Madden B.J. Debiec H. et al.Exostosin 1/exostosin 2–associated membranous nephropathy.J Am Soc Nephrol. 2019; 30: 1123-1136Crossref PubMed Scopus (69) Google Scholar NELL-1 and EXT1/EXT2 were identified using laser microdissection of PLA2R-negative MN glomeruli followed by mass spectrometry. Using a similar approach, we sought to identify other novel antigen(s) in MN. We detected a unique protein Semaphorin 3B (Sema3B) by tandem mass spectrometry (MS/MS) in the glomeruli of 3 cases (patients 1-3) of MN (Figure 1). The counts ranged from 10 to 42 with an average total spectral count of 23.7 (SD, ±16.5). The average spectral counts of Sema3B were lower than PLA2R (86.1; SD, ±27.5), NELL-1 (63.1; SD, ±21.6), and EXT1/EXT2 (EXT1, 65.3 [SD, ±34.6]; EXT2, 83.4 [SD, ±38.4]) in PLA2R-, NELL-1–, and EXT1/EXT2-associated MN, respectively.6Sethi S. Debiec H. Madden B. et al.Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy.Kidney Int. 2020; 97: 163-174Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar,7Sethi S. Madden B.J. Debiec H. et al.Exostosin 1/exostosin 2–associated membranous nephropathy.J Am Soc Nephrol. 2019; 30: 1123-1136Crossref PubMed Scopus (69) Google Scholar However, the presence of Sema3B was unique in this subset of MN, and importantly, all control cases including 15 time 0 kidney transplant biopsies, 73 other glomerulopathies, and 23 PLA2R-positive MN cases were negative for Sema3B. The spectral counts of Sema3B in the 3 cases, along with a representative sequence coverage map of Sema3B, are shown in Figure 2. The MS/MS match from 1 case is shown in Supplementary Figure S1. None of the cases showed any spectral counts for THSD7A or NELL-1. Subsequently, we screened over 2500 kidney biopsies, including pediatric cases, from our amyloid laboratory database (over 12,500 data files; both amyloid and nonamyloid cases) and did not find any kidney biopsy that showed any spectral counts for Sema3B. We included both adult and pediatric cases of C3 glomerulopathy. On analysis of other organs, we found trace amounts of Sema3B (1-3 spectral counts) in the heart and liver of 23 cases (over 2000 nonkidney cases were screened for Sema3B). All 4 classes of Igs were detected in Sema3B-associated MN, with average spectral counts of IgG1 25.0 (SD, ±4.0), IgG2 22.7 (SD, ±4.5), IgG3 25.0 (SD, ±9.5), and IgG4 17.0 (SD, ±5.3). We performed immunohistochemical (IHC) staining for Sema3B in all 3 cases positive on MS/MS studies. All cases showed positive (2–3+/3) granular staining for Sema3B along the GBM. Importantly, there was no significant mesangial staining (Figure 3a). There was no staining along Bowman’s capsule, tubular basement membranes, or in vessel walls. The positive Sema3B granular staining mirrored the granular IgG along the GBM seen in each case. All 45 control cases were negative for Sema3B, which included 3 pediatric cases of minimal change disease/focal segmental glomerulosclerosis. Representative negative staining for Sema3B in diabetes, focal segmental glomerulosclerosis, IgA nephropathy, minimal change disease, and PLA2R-associated MN is shown in Figure 3b. Given the results obtained in the Mayo cohort showing 2 adults (patients 1 and 2) and 1 pediatric patient (patient 3) of Sema3B-associated MN, we analyzed 3 validation cohorts, 1 adult (French cohort 1) and 2 pediatric (Italian cohort, French cohort 2) cohorts (Figure 1). Sema3B was detected using immunofluorescence microscopy (IF) studies on paraffin sections after antigen retrieval. Patient 4 of the validation cohort had both IHC and IF studies performed. Two adult cases (patients 4 and 5) of 59 PLA2R-, THSD7A-, EXT1/EXT2-, and NELL-1–negative primary MN were positive for Sema3B. One case (patient 4) was detected by IHC at the Mayo Clinic and was then confirmed by IF studies on paraffin sections at Tenon Hospital (Figure 4a and b). Patient 5 had 3 biopsies performed at the age of 1, 6, and 19 years, showing granular staining for Sema3B along the GBM (biopsy at age 1 and 19 shown in Figure 4c and d and Supplementary Figure S3E and F). It became clear that Sema3B-associated MN was enriched in pediatric patients. After this unique finding, we then screened for Sema3B in a larger cohort of MN in the pediatric age group (Italian cohort and French cohort 2). Four cases (patients 6, 7, 8, and 9) of 43 pediatric cases negative for PLA2R, THSD7A, EXT1/EXT2, and NELL-1 showed bright granular staining for Sema3B along the GBM (Figure 4e–h). Of note, patients 7 and 8 were siblings. Of the 43 cases, 6 had lupus class V MN, including 3 with class III + V, and were all negative for Sema3B. An additional 2 cases (patients 10 and 11) of 16 pediatric cases negative for PLA2R, THSD7A, EXT1/EXT2, and NELL-1 showed the bright granular deposits of Sema3B along the GBM (Figure 4i and j). Of the 16 cases, 9 had lupus class V MN and were all negative for Sema3B. Figure 4 shows the granular GBM staining and absence of mesangial or Bowman capsule staining in all cases. An adult and pediatric case of Sema3B-negative MN is also shown (Figure 4k and l). We performed confocal IF to determine whether Sema3B and IgG co-localized along the GBM (Figure 5). Bright granular staining for Sema3B (green) and IgG (red) was seen along the GBM (Figure 5a and b). Furthermore, superimposition of the 2 signals showed co-localization resulting in a yellow signal (Figures 5c). Laser quantitative analysis (Figure 5d and e) also confirmed the co-localization of Sema3B and IgG, further corroborating that the subepithelial deposits contained both Sema3B and IgG. A second case (patient 6, 2 years old) is shown in Supplementary Figure S2. Western blot analyses in nonreducing and reducing conditions were performed using human Sema3B full-length recombinant proteins to determine the presence of circulating anti-Sema3B antibodies in the available serum of 5 patients (patients 8, and 11) (Figure Four of the 5 patients showed reactivity Sema3B reducing not nonreducing A was seen at the full-length serum of patient was positive for anti-Sema3B were also available for analysis of with of antibodies after Patient was after a was negative by Western blot In sera from patients with conditions including PLA2R-, THSD7A-, and IgA focal segmental and minimal change disease and control did not reactivity with Sema3B analyzed We identified 11 cases of Sema3B-associated MN, 3 from the Mayo Clinic cohort, 2 from the French validation cohort 1, 4 from the validation cohort, and 2 from the French validation cohort 2 1). There were 7 and 4 patients. Of the 11 cases, 8 were pediatric patients years of and 3 were adult patients. Of the Mayo Clinic cohort (patients 1 was a pediatric patient of 4 pediatric PLA2R-negative MN cases for Sema3B, and 2 were adults of remaining primary and secondary PLA2R-negative MN including class V membranous lupus Of the validation cohorts and there were 8 pediatric patients of PLA2R-negative pediatric MN including case and 1 adult patient of PLA2R-negative adult MN patient In patient MN was at the age of 1 (biopsy performed of and biopsies performed 6 and years showed MN. of the pediatric cohorts included 9 patients with lupus MN class In 6 of pediatric cases were Sema3B in Semaphorin membranous protein nephropathy was at the age of 1 (biopsy performed of biopsy in and at age 19 1 and 9 2 to not Membranous nephropathy was at the age of 1 (biopsy performed of biopsy in and at age 19 in a not The average age of pediatric patients at disease was years (SD, and the average age of the 3 adult patients was years (SD, Two had of 1 in patient 10 and idiopathic with positive in patient The average serum was (SD, and was SD, biopsy in all cases showed of MN with microscopy showed granular IgG 2) and Sema3B deposits along the glomerular walls. 4 cases (patients 6, and all years of age at also showed tubular basement membrane staining for IgG in a granular (Figure 7, Supplementary Figure and In patient granular IgG deposits along tubular basement were in the biopsy 1 of However, the tubular basement membrane deposits were negative for Sema3B staining in all biopsies (Figure 7, Supplementary Figure and IgG in 4 cases in the Mayo Clinic cohort and 1 in French cohort 1) showed IgG1 in 3 cases and IgG1 and IgG4 in 1 case. IgG4 staining was in 4 cases of the cohort, and all 4 cases were negative for IgG4 microscopy was performed in all patients patients 4 and It showed glomerular subepithelial deposits in all cases that were as in cases. The deposits seen along tubular basement were confirmed or by microscopy in 3 cases (patients 6, and were in cases as biopsy in Semaphorin membranous basement membrane C3 C3 C3 C3 C3 C3 C3 C3 C3 IgA C3 and tubular in a and tubular 1 and 2 and with minimal at of and Patient 3 (Figures 6 and and and also the was Patient 4 was for 4 with of was 2 of at followed by a at 3 which is after 10 years no anti-Sema3B in Figure Patient 5 was at the age of 1 Figure and failed to to and from age 5 to 7 years was with that after a A second biopsy showed MN 2 with of granular tubular was and to 1 years of the of the patient was at the age of 19 years to of with a kidney biopsy (Figure 5 and Supplementary and was performed. The kidney biopsy showed MN 2 with deposits by IF and microscopy was then One the patient is in antibodies were not detected (Figure Patient 6 2 years of age with was at disease and and had MN. in 6 and to a with a of 7 and 8 are siblings. Patient 7 at age years with of 16 and was with of a after 2 a biopsy was that showed MN. The patient was started on an and was and at the of 4 The patient and has no at Patient 8 at age 2 years with and negative biopsy showed MN. the biopsy showed a IgA C3 of staining on the patient was with and followed by and was and after 2 The a 1) 2 years that showed MN on kidney biopsy that to The patient had a at 9 years of and kidney biopsy one in this confirmed MN. was with with on of and was to with years from was in with on and Patient 9 with of at 2 years of age and was with with after 4 of A biopsy was performed that showed MN. The patient after with and However, each time was and at age 7 years was with was in Patient 10 was to Patient 11 (Figure to kidney disease 3 years, to and MN is the of in On the other is a of in In the has to the of target MN including PLA2R, THSD7A, and putative N.M. Beck L.H. Meyer-Schwesinger C. et al.Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy.N Engl J Med. 2014; 371: 2277-2287Crossref PubMed Scopus (420) Google Scholar, 5Beck L.H. Bonegio R.G.B. Lambeau G.R. et al.M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.N Engl J Med. 2009; 361: 11-21Crossref PubMed Scopus (1288) Google Scholar, 6Sethi S. Debiec H. Madden B. et al.Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy.Kidney Int. 2020; 97: 163-174Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar, S. Madden B.J. Debiec H. et al.Exostosin 1/exostosin 2–associated membranous nephropathy.J Am Soc Nephrol. 2019; 30: 1123-1136Crossref PubMed Scopus (69) Google Scholar However, not account for all cases of MN, and in a significant of MN the target antigen is Using a of laser and IHC we a of PLA2R-negative MN to determine whether we identify novel target in this remaining group of MN. MS/MS studies confirmed spectral counts of NELL-1 and EXT1/EXT2 in a cohort of PLA2R-negative S. Debiec H. Madden B. et al.Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy.Kidney Int. 2020; 97: 163-174Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar,7Sethi S. Madden B.J. Debiec H. et al.Exostosin 1/exostosin 2–associated membranous nephropathy.J Am Soc Nephrol. 2019; 30: 1123-1136Crossref PubMed Scopus (69) Google Scholar Using the cohort, we then for other proteins that were unique to this group of PLA2R-negative MN. The to identify a putative from over to 2000 proteins detected on MS/MS were the of a unique protein and the absence spectral counts) of the protein in control cases and other cases of MN including both PLA2R-positive and MN. Using this approach, we found spectral counts of a unique protein, Sema3B, in 3 cases of MN. We confirmed the MS/MS by IHC and further our in 2 French cohorts and an Eight of 11 Sema3B-associated MN were pediatric of which 5 patients MN on or the age of 2 The remaining 3 patients MN at the of and Of the 3 adult cases the average age was years, which is lower than the primary MN age Thus, Sema3B-associated MN appears to pediatric patients and In the Mayo Clinic cohort 4 pediatric patients were of which 1 case was positive for Sema3B. However, the French and pediatric cohorts included a of patients and detected Sema3B in 6 of 59 pediatric MN patients 9 patients in each pediatric cohort had lupus class the of Sema3B-associated disease pediatric patients in and was 6 of It is that 5 of 8 patients with MN were years this Sema3B a target antigen in with the 2 patients had an autoimmune disease that included type 1 and One at disease had a immunofluorescence (patient 8 with no or of that was not present in kidney biopsies performed at The kidney biopsy of the glomeruli in Sema3B-associated MN were for MN. Sema3B was present along the subepithelial of the that Sema3B is from the than from the mesangial or there is no mesangial or staining for Sema3B. It is also likely that Sema3B not circulating antigen-antibody are more likely to be present in the of the GBM and have a along the the subepithelial Sema3B staining in our cases. IgG were in 4 cases and IgG1 in 3 cases and IgG4 along with IgG1 and IgG2 in 1 case. In IgG4 staining was in all 4 cases of the cohort, and all 4 cases were negative for to a IgG in Sema3B-associated MN, likely is from PLA2R-associated MN where IgG4 is the IgG tubular basement membrane deposits were present in 4 pediatric cases. All 4 cases had 2 years and showed tubular basement membrane deposits that for IgG. Of note, the tubular basement membrane deposits were negative for Sema3B glomerular deposits were for Sema3B in the sections (Figure 7, Supplementary Figure were and were negative in all cases. Thus, tubular basement membrane deposits in the of MN in a 2 years may a Sema3B-associated MN. The of Sema3B-associated MN in the pediatric age in in and the that in the cohort patients 7 and 8 are and patient 6 has a with MN the of a of the studies are to determine whether in the sequence of the protein or antigen are are a group of and proteins a Semaphorin of by et class 3 proteins and Int. Full Text Full Text PDF PubMed Scopus Google Scholar, and Semaphorin and Scopus Google Scholar, The PubMed Scopus Google Scholar The is the which The were identified as proteins that to then more than have been identified and are classified 8 and to are V, and are and is membrane classes and are In to the are also in other including and The primary are the and of 4 A and of 1 and 2. The of is in and in also have a in by H. for in the Full Text Full Text PDF PubMed Scopus Google Scholar Furthermore, the also a in disease including and and et and as of PubMed Scopus Google Scholar However, the and disease of Semaphorin 3 is a protein with a and a (Figure Semaphorin 3 and have been detected in and tubular et class 3 proteins and Int. Full Text Full Text PDF PubMed Scopus Google et Int. Full Text Full Text PDF PubMed Scopus Google Scholar In has been shown to proteins as and with protein and also et class 3 proteins and Int. Full Text Full Text PDF PubMed Scopus Google Scholar The and of Sema3B in the kidney is not and to the of our of Sema3B has not been in any kidney our results reactivity of Sema3B antibodies reducing that the is by of the Sema3B In conditions in of protein that as It be to determine the of Sema3B to the of change and to determine whether reduced conditions are for the antibodies to Sema3B the of the to It is to that the anti-Sema3B antibodies are to an on the or the detected sequence coverage of of the Sema3B protein (Figure this is a sera in 5 patients and IgG performed in 4 patients. There are also that studies to tubular basement membrane staining for IgG is present in the is the tubular basement membrane staining negative for the antigen in the tubular basement membrane deposits from Sema3B present in the MN the Sema3B-associated MN in pediatric patients with adult antibodies the recombinant protein were detected by Western blot in patients with active disease, and on clinical antibodies were present in MN patients were negative for and antibodies and not of a secondary et in membranous nephropathy and Am Soc Nephrol. PubMed Scopus (165) Google Scholar studies are to whether Sema3B is a antigen or a in Sema3B-associated MN. studies that the Sema3B on and studies that determine the of circulating antibodies to glomerular Sema3B. In Sema3B-associated MN a unique type of primary MN that is more likely to be present in pediatric in patients with years Sema3B-associated MN be to the of MN, including PLA2R-, THSD7A-, and MN. We performed MS/MS in kidney biopsies of cases of PLA2R-negative MN at the Mayo Clinic for analysis by MS/MS and detected the unique protein, Sema3B, in 2 cases. The cases included both primary and secondary membranous cases were also to detect recently novel EXT1/EXT2 and S. Debiec H. Madden B. et al.Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy.Kidney Int. 2020; 97: 163-174Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar,7Sethi S. Madden B.J. Debiec H. et al.Exostosin 1/exostosin 2–associated membranous nephropathy.J Am Soc Nephrol. 2019; 30: 1123-1136Crossref PubMed Scopus (69) Google Scholar IHC was then performed to the MS/MS In we screened PLA2R-negative MN cases the negative and 2 positive on by IHC for Sema3B. We detected 1 more positive which was confirmed by than 4 pediatric cases years of the remaining cases were all One biopsies were for Sema3B, of which 59 were from the French cohort 1, 43 from the pediatric cohort, and 16 from the French cohort 2. All cases were PLA2R-, THSD7A-, EXT1/EXT2-, and NELL-1–negative MN. pediatric cohort included 9 lupus class V cases. control cases, we performed MS/MS on cases that included 15 cases of time 0 transplant biopsies, cases of minimal change disease, cases of focal segmental glomerulosclerosis, 7 cases of glomerulosclerosis, 5 cases of IgA nephropathy, and 23 cases of PLA2R-positive MN. control IHC we 45 9 cases of minimal change disease, 9 cases of focal segmental glomerulosclerosis, 4 cases of IgA nephropathy, 7 cases of diabetes, 15 cases of PLA2R-positive MN, and 1 case of time 0 transplant biopsies were in the of and Mayo Clinic for and and IF including PLA2R and microscopy were performed in each case of MN. The clinical was obtained from the The was by the Mayo Clinic each case paraffin sections were obtained and on a membrane laser microdissection and using a the glomeruli were to to case. were with and for MS/MS The were identified by MS/MS using a mass to an All MS/MS were analyzed using and to a human was to and protein were at than by the with protein a and a using et for proteins by tandem mass PubMed Scopus Google Scholar and IHC staining was performed at the using the were at 5 and IHC staining was performed for Sema3B were for using 1 and in for 5 The Sema3B primary was to in and for 15 The was the primary and and was by 10 in and from the this were with were for 5 using and followed by in and is not the with the the was were from the and in for 5 were in of and in 3 of in staining was performed on sections for using target in The Sema3B primary was to in serum and and at with biopsy sections. Next, the were with secondary the IgG antibodies Next, IgG was with the after staining for Sema3B as described were in and with of Sema3B and IgG along the was by confocal microscopy using a and analyzed with Confocal Sema3B recombinant human protein was with nonreducing or reducing and for 10 were to and in were to to and then were with were at 4 with sera from control and antibodies Sema3B Subsequently, were and for 2 at with or IgG, proteins were with All the no We the Mayo Clinic of the Mayo Clinic of and and the Mayo is a of of the for in and the We are to of and of both in for patient We of and Mayo for amyloid database to for Sema3B. We are to the over the years, of the patients with primary MN in the of and and in the Hospital at Tenon and in the of and at and to from the of and to for in We and Confocal Hospital and Tenon Tenon and and all of the Tenon Hospital for in and data and the the and the kidney and and performed the laser microdissection and mass spectrometry. in clinical performed the and for the validation performed the confocal and Western blot and clinical The was and by the with as from the with Supplementary

Renal proximal tubular cells are the most energy-demanding cells in the body. The ATP that they use is mostly produced in their mitochondrial and peroxisomal compartments, by the oxidation of fatty acids. When those cells are placed under a biological stress, such as a transient hypoxia, fatty acid oxidation (FAO) is shut down for a period of time that outlasts injury, and carbohydrate oxidation does not take over. Facing those metabolic constraints, surviving tubular epithelial cells exhibit a phenotypic switch that includes cytoskeletal rearrangement and production of extracellular matrix proteins, most probably contributing to acute kidney injury-induced renal fibrogenesis, thence to the development of chronic kidney disease. Here, we review experimental evidence that dysregulation of FAO profoundly affects the fate of tubular epithelial cells, by promoting epithelial-to-mesenchymal transition, inflammation, and eventually interstitial fibrosis. Restoring physiological production of energy is undoubtedly a possible therapeutic approach to unlock the mesenchymal reprograming of tubular epithelial cells in the kidney. In this respect, the benefit of the use of fibrates is uncertain, but new drugs that could specifically target this metabolic pathway, and, hopefully, attenuate renal fibrosis merit future research.

In osteoarthritis (OA), interleukin-1 (IL-1) stimulates the expression of metalloproteinases and aggrecanases, which induce cartilage degradation. IL-1 is also capable of reducing the production of cartilage-specific macromolecules, including type II collagen, through modulation of the transcription factors Sp1 and Sp3. Conversely, Transforming growth factor-beta (TGF-beta) counteracts with most of the IL-1 deleterious effects and contributes to cartilage homeostasis. However, OA chondrocytes progressively loose the expression of TGF-beta type II receptor and become insensitive to the factor. This downregulation is also driven by IL-1. This review provides insights into the molecular mechanisms that underly the interplay between IL-1 and TGF-beta in OA cartilage metabolism and enlightens the central role of Sp1 and Sp3 transcription factors in the matrix pathological alterations.

The estimated lifetime risk of nephrolithiasis is growing nowadays, and the formation of kidney stones is frequently promoted by hypercalciuria. Vitamin D, and especially its active metabolite calcitriol, increase digestive calcium absorption-as urinary calcium excretion is directly correlated with digestive calcium absorption, vitamin D metabolites could theoretically increase calciuria and promote urinary stone formation. Nevertheless, there was, until recently, low evidence that 25-hydroxyvitamin D serum levels would be correlated with kidney stone formation, even if high calcitriol concentrations are frequently observed in hypercalciuric stone formers. Low 25-hydroxyvitamin D serum levels have been associated with a broad spectrum of diseases, leading to a huge increase in vitamin D prescription in the general population. In parallel, an increased frequency of kidney stone episodes has been observed in prospective studies evaluating vitamin D alone or in association with calcium supplements, and epidemiological studies have identified an association between high 25-hydroxyvitamin D serum levels and kidney stone formation in some groups of patients. Moreover, urinary calcium excretion has been shown to increase in response to vitamin D supplements, at least in some groups of kidney stone formers. It seems likely that predisposed individuals may develop hypercalciuria and kidney stones in response to vitamin D supplements.

Membranous nephropathy is a noninflammatory autoimmune disease of the kidney glomerulus, characterized by the formation of immune deposits, complement-mediated proteinuria, and risk of renal failure. Considerable advances in understanding the molecular pathogenesis have occurred with the identification of several antigens [neutral endopeptidase, phospholipase A2 receptor (PLA 2 R), thrombospondin domain-containing 7A (THSD7A)] in cases arising from the neonatal period to adulthood and the characterization of antibody-binding domains (that is, epitopes). Immunization against PLA2R occurs in 70% to 80% of adult cases. The development of highly specific and sensitive assays of circulating antibodies has induced a paradigm shift in diagnosis and treatment monitoring. In addition, several interacting loci in HLA-DQ, HLA-DR, and PLA2R1, as well as classical human leukocyte antigen (HLA)-D alleles have been identified as being risk factors, depending on a patient's ethnicity. Additionally, mechanisms of antibody pathogenicity and pathways of complement activation are now better understood. Further research is mandatory for designing new therapeutic strategies, including the identifying triggering events, the molecular bases of remission and progression, and the T cell epitopes involved.

The phospholipase A2 receptor (PLA2R1) is the major autoantigen in primary membranous nephropathy. Several PLA2R1 epitopes have been characterized, and a retrospective study identified PLA2R1 epitope spreading as a potential indicator of poor prognosis. Here, we analyzed the predictive value of anti-PLA2R1 antibody (PLA2R1-Ab) titers and epitope spreading in a prospective cohort of 58 patients positive for PLA2R1-Ab randomly allocated to rituximab (n=29) or antiproteinuric therapy alone (n=29). At baseline, the epitope profile (CysR, CysRC1, CysRC7, or CysRC1C7) did not correlate with age, sex, time from diagnosis, proteinuria, or serum albumin, but epitope spreading strongly correlated with PLA2R1-Ab titer (P<0.001). Ten (58.8%) of the 17 patients who had epitope spreading at baseline and were treated with rituximab showed reversal of epitope spreading at month 6. In adjusted analysis, epitope spreading at baseline was associated with a decreased remission rate at month 6 (odds ratio, 0.16; 95% confidence interval, 0.04 to 0.72; P=0.02) and last follow-up (median, 23 months; odds ratio, 0.14; 95% confidence interval, 0.03 to 0.64; P=0.01), independently from age, sex, baseline PLA2R1-Ab level, and treatment group. We propose that epitope spreading at baseline be considered in the decision for early therapeutic intervention in patients with primary membranous nephropathy. Export

BACKGROUND: The efficacy of high flow nasal canula oxygen therapy (HFNO) to prevent invasive mechanical ventilation (IMV) is not well established in severe coronavirus disease 2019 (COVID-19). The aim of this study was to compare the risk of IMV between two strategies of oxygenation (conventional oxygenation and HFNO) in critically ill COVID 19 patients. METHODS: This was a bicenter retrospective study which took place in two intensive care units (ICU) of tertiary hospitals in the Paris region from March 11, to May 3, 2020. We enrolled consecutive patients hospitalized for COVID-19 and acute respiratory failure (ARF) who did not receive IMV at ICU admission. The primary outcome was the rate of IMV after ICU admission. Secondary outcomes were death at day 28 and day 60, length of ICU stay and ventilator-free days at day 28. Data from the HFNO group were compared with those from the standard oxygen therapy (SOT) group using weighted propensity score. RESULTS: Among 138 patients who met the inclusion criteria, 62 (45%) were treated with SOT alone, and 76 (55%) with HFNO. In HFNO group, 39/76 (51%) patients received IMV and 46/62 (74%) in SOT group (OR 0.37 [95% CI, 0.18-0.76] p = 0.007). After weighted propensity score, HFNO was still associated with a lower rate of IMV (OR 0.31 [95% CI, 0.14-0.66] p = 0.002). Length of ICU stay and mortality at day 28 and day 60 did not significantly differ between HFNO and SOT groups after weighted propensity score. Ventilator-free days at days 28 was higher in HNFO group (21 days vs 10 days, p = 0.005). In the HFNO group, predictive factors associated with IMV were SAPS2 score (OR 1.13 [95%CI, 1.06-1.20] p = 0.0002) and ROX index > 4.88 (OR 0.23 [95%CI, 0.008-0.64] p = 0.006). CONCLUSIONS: High flow nasal canula oxygen for ARF due to COVID-19 is associated with a lower rate of invasive mechanical ventilation.

BACKGROUND: Intermittent hemodialysis (IHD) and continuous renal replacement therapy (CRRT) are the two main RRT modalities in patients with severe acute kidney injury (AKI). Meta-analyses conducted more than 10 years ago did not show survival difference between these two modalities. As the quality of RRT delivery has improved since then, we aimed to reassess whether the choice of IHD or CRRT as first modality affects survival of patients with severe AKI. METHODS: This is a secondary analysis of two multicenter randomized controlled trials (AKIKI and IDEAL-ICU) that compared an early RRT initiation strategy with a delayed one. We included patients allocated to the early strategy in order to emulate a trial where patients would have been randomized to receive either IHD or CRRT within twelve hours after the documentation of severe AKI. We determined each patient's modality group as the first RRT modality they received. The primary outcome was 60-day overall survival. We used two propensity score methods to balance the differences in baseline characteristics between groups and the primary analysis relied on inverse probability of treatment weighting. RESULTS: A total of 543 patients were included. Continuous RRT was the first modality in 269 patients and IHD in 274. Patients receiving CRRT had higher cardiovascular and total-SOFA scores. Inverse probability weighting allowed to adequately balance groups on all predefined confounders. The weighted Kaplan-Meier death rate at day 60 was 54·4% in the CRRT group and 46·5% in the IHD group (weighted HR 1·26, 95% CI 1·01-1·60). In a complementary analysis of less severely ill patients (SOFA score: 3-10), receiving IHD was associated with better day 60 survival compared to CRRT (weighted HR 1.82, 95% CI 1·01-3·28; p < 0.01). We found no evidence of a survival difference between the two RRT modalities in more severe patients. CONCLUSION: Compared to IHD, CRRT as first modality seemed to convey no benefit in terms of survival or of kidney recovery and might even have been associated with less favorable outcome in patients with lesser severity of disease. A prospective randomized non-inferiority trial should be implemented to solve the persistent conundrum of the optimal RRT technique.

OBJECTIVE: CADASIL is a genetic paradigm of cerebral small vessel disease caused by NOTCH3 mutations that stereotypically lead to the extracellular deposition of NOTCH3 ectodomain (Notch3(ECD) ) on the vessels. TIMP3 and vitronectin are 2 extracellular matrix proteins that abnormally accumulate in Notch3(ECD) -containing deposits on brain vessels of mice and patients with CADASIL. Herein, we investigated whether increased levels of TIMP3 and vitronectin are responsible for aspects of CADASIL disease phenotypes. METHODS: Timp3 and vitronectin expression were genetically reduced in TgNotch3(R169C) mice, a well-established preclinical model of CADASIL. A mouse overexpressing human TIMP3 (TgBAC-TIMP3) was developed. Disease-related phenotypes, including cerebral blood flow (CBF) deficits, white matter lesions, and Notch3(ECD) deposition, were evaluated between 6 and 20 months of age. RESULTS: CBF responses to neural activity (functional hyperemia), topical application of vasodilators, and decreases in blood pressure (CBF autoregulation) were similarly reduced in TgNotch3(R169C) and TgBAC-TIMP3 mice, and myogenic responses of brain arteries were likewise attenuated. These defects were rescued in TgNotch3(R169C) mice by haploinsufficiency of Timp3, although the number of white matter lesions was unaffected. In contrast, haploinsufficiency or loss of vitronectin in TgNotch3(R169C) mice ameliorated white matter lesions, although CBF responses were unchanged. Amelioration of cerebrovascular reactivity or white matter lesions in these mice was not associated with reduced Notch3(ECD) deposition in brain vessels. INTERPRETATION: Elevated levels of TIMP3 and vitronectin, acting downstream of Notch3(ECD) deposition, play a role in CADASIL, producing divergent influences on early CBF deficits and later white matter lesions.

Acute kidney injury can be accompanied by life-threatening electrolyte and metabolic abnormalities. Kidney-replacement therapy may be urgently needed to prevent death from uremia. This review considers treatment approaches, indications, and intensity in critically ill patients with AKI.

Abstract Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7 , with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10 −4 ) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10 −4 ). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10 −3 ), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10 −8 ). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10 −5 ). Conclusions Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

RATIONALE: The optimal strategy for initiation of renal replacement therapy (RRT) in patients with severe acute kidney injury in the context of septic shock and acute respiratory distress syndrome (ARDS) is unknown. OBJECTIVES: To examine the effect of an early compared with a delayed RRT initiation strategy on 60-day mortality according to baseline sepsis status, ARDS status, and severity. METHODS: Post hoc analysis of the AKIKI (Artificial Kidney Initiation in Kidney Injury) trial. MEASUREMENTS AND MAIN RESULTS: Subgroups were defined according to baseline characteristics: sepsis status (Sepsis-3 definition), ARDS status (Berlin definition), Simplified Acute Physiology Score 3 (SAPS 3), and Sepsis-related Organ Failure Assessment (SOFA). Of 619 patients, 348 (56%) had septic shock and 207 (33%) had ARDS. We found no significant influence of the baseline sepsis status (P = 0.28), baseline ARDS status (P = 0.94), and baseline severity scores (P = 0.77 and P = 0.46 for SAPS 3 and SOFA, respectively) on the comparison of 60-day mortality according to RRT initiation strategy. A delayed RRT initiation strategy allowed 45% of patients with septic shock and 46% of patients with ARDS to escape RRT. Urine output was higher in the delayed group. Renal function recovery occurred earlier with the delayed RRT strategy in patients with septic shock or ARDS (P < 0.001 and P = 0.003, respectively). Time to successful extubation in patients with ARDS was not affected by RRT strategy (P = 0.43). CONCLUSIONS: Early RRT initiation strategy was not associated with any improvement of 60-day mortality in patients with severe acute kidney injury and septic shock or ARDS. Unnecessary and potentially risky procedures might often be avoided in these fragile populations. Clinical trial registered with www.clinicaltrials.gov (NCT 01932190).

Idiopathic kidney stones originate mainly from calcium phosphate deposits at the tip of renal papillae, known as Randall's plaques (RPs), also detected in most human kidneys without stones. However, little is known about the mechanisms involved in RP formation. The localization and characterization of such nanosized objects in the kidney remain a real challenge, making their study arduous. This study provides a nanoscale analysis of the chemical composition and morphology of incipient RPs, characterizing in particular the interface between the mineral and the surrounding organic compounds. Relying on data gathered from a calculi collection, the morphology and chemical composition of incipient calcifications in renal tissue were determined using spatially resolved electron energy-loss spectroscopy. We detected microcalcifications and individual nanocalcifications found at some distance from the larger ones. Strikingly, concerning the smaller ones, we show that two types of nanocalcifications coexist: calcified organic vesicles and nanometric mineral granules mainly composed of calcium phosphate with carbonate in their core. Interestingly, some of these nanocalcifications present similarities with those reported in physiological bone or pathological cardiovascular biominerals, suggesting possible common formation mechanisms. However, the high diversity of these nanocalcifications suggests that several mechanisms may be involved (nucleation on a carbonate core or on organic compounds). In addition, incipient RPs also appear to present specific features at larger scales, revealing secondary calcified structures embedded in a fibrillar organic material. Our study proves that analogies exist between physiological and pathological biominerals and provides information to understand the physicochemical processes involved in pathological calcification formation.

A typical hemolytic uremic syndrome (aHUS) is a prototypic thrombotic microangiopathy attributable to complement dysregulation. Hypertensive emergency, characterized by elevation of systolic (>180 mmHg) or diastolic (>120 mmHg) blood pressure together with end-organ damage, can cause thrombotic microangiopathy which may mimic aHUS. We retrospectively evaluated the clinical, biological and complement genetic characteristics of 76 and 61 aHUS patients with and without hypertensive emergency, respectively. Patients with hypertensive emergency-aHUS were more frequently males, with neurological involvement, and a slightly higher hemoglobin level. At least one rare complement variant was identified in 51.3% (39/76) and 67% (41/61) patients with or without hypertensive emergency, respectively (P=0.06). In both groups, renal prognosis was severe with 23% and 40% of patients reaching end-stage renal disease after a 5-year follow-up (P=0.1). The 5-year renal survival was 77% in patients without hypertensive emergency or a complement variant, and below 25% in the three groups of patients with hypertensive emergency and/or a complement variant (P=0.02). Among patients without hypertensive emergency, the 5-year renal survival was 100% vs. 40% in those treated or not with eculizumab, respectively (P

Hereditary angiopathy, nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is an autosomal dominant syndrome caused by mutations in COL4A1 that encodes the α1 chain of collagen IV, a major component of basement membranes. Patients present with cerebral small vessel disease, retinal tortuosity, muscle cramps, and kidney disease consisting of multiple renal cysts, chronic kidney failure, and sometimes hematuria. Mutations producing HANAC syndrome localize within the integrin binding site containing CB3[IV] fragment of the COL4A1 protein. To investigate the pathophysiology of HANAC syndrome, we generated mice harboring the Col4a1 p.Gly498Val mutation identified in a family with the syndrome. Col4a1 G498V mutation resulted in delayed glomerulogenesis and podocyte differentiation without reduction of nephron number, causing albuminuria and hematuria in newborns. The glomerular defects resolved within the first month, but glomerular cysts developed in 3-month-old mutant mice. Abnormal structure of Bowman's capsule was associated with metalloproteinase induction and activation of the glomerular parietal epithelial cells that abnormally expressed CD44,α-SMA, ILK, and DDR1. Inflammatory infiltrates were observed around glomeruli and arterioles. Homozygous Col4a1 G498V mutant mice additionally showed dysmorphic papillae and urinary concentration defects. These results reveal a developmental role for the α1α1α2 collagen IV molecule in the embryonic glomerular basement membrane, affecting podocyte differentiation. The observed association between molecular alteration of the collagenous network in Bowman's capsule of the mature kidney and activation of parietal epithelial cells, matrix remodeling, and inflammation may account for glomerular cyst development and CKD in patients with COL4A1-related disorders.

Urinary stones can be readily disintegrated by Holmium:YAG laser (Holmium laser lithotripsy), resulting in a mixture of small stone dust particles, which will spontaneously evacuate with urine and larger residual fragments (RF) requiring mechanical retrieval. Differences between fragments and dust have not been well characterized. Also, it remains unknown how the recently introduced "Moses technology" may alter stone disintegration products. Three complementary analytical techniques have been used in this study to offer an in-depth characterization of disintegration products after in vitro Holmium laser lithotripsy: stereoscopic microscopy, scanning electron microscopy and Fourier-transform infrared spectroscopy. Dust was separated from fragments based on its floating ability in saline irrigation. Depending on initial crystalline constituents, stone dust either conserved attributes found in larger RFs or showed changes in crystalline organization. These included conversion of calcium oxalate dihydrate towards calcium oxalate monohydrate, changes in carbapatite spectra towards an amorphous phase, changes of magnesium ammonium phosphate towards a differing amorphous and crystalline phase and the appearance of hydroxyapatite on brushite fragments. Comparatively, "Moses technology" produced more pronounced changes. These findings provide new insights suggesting a photothermal effect occurring in Holmium laser lithotripsy. Figure: Appearance of hydroxyapatite hexagons on stone dust collected after Holmium laser lithotripsy of a brushite stone using "Moses technology."