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• W2750021728 abstract "Acquired thrombotic thrombocytopenic purpura (TTP) is a hematologic emergency associated with decreased thrombospondin motifs 13 (ADAMTS13, a disintegrin and metalloproteinase with thrombospondin motifs 13) activity, due to the presence of an inhibitor. Idiopathic membranous nephropathy related to the anti-phospholipase A2 receptor (anti-PLA2R) can coexist with other autoimmune diseases. Herein, we present a case of a 70-year-old man who presented with generalized anasarca and thrombocytopenia. A 70-year-old African American male patient was transferred to our hospital with a 3-day history of dyspnea and chest discomfort. He described nonradiant substernal chest pressure and progressive shortness of breath with exertion that improved with rest. He also reported new-onset edema in his legs and hands over the last 3 weeks. He denied hematuria or dysuria, but reported foamy urine. He also denied fever, chills, headache, vision problems, nausea, vomiting, abdominal pain, diarrhea, skin rash, or joint pain. His medical history was remarkable for untreated hepatitis C, type 2 diabetes mellitus, bladder cancer status postresection >5 years previously, Barrett's esophagus, and schizophrenia. He had no symptoms of retinopathy or neuropathy. He reported a long smoking history and a remote history of drug abuse, mostly methamphetamine and cocaine. His medications included finasteride, metformin, olanzapine, omeprazole, and simvastatin. He was afebrile; other vital signs included pulse in the 80s, blood pressure 180/100 mm Hg, and oxygen saturation of 97% (room air). Physical examination was remarkable for elevated jugular vein pressure, bilateral rales, and 2+ lower extremity edema. Initial laboratory workup is shown in Table 1. He was admitted for management of non−ST-segment elevation myocardial infarction. Heparin was not given because of thrombocytopenia. Hematologic findings were consistent with thrombotic thrombocytopenic purpura (TTP). von Willebrand factor protease (a disintegrin and metalloproteinase with thrombospondin motifs 13 [ADAMTS13]) activity level was assessed. An apheresis catheter was placed, and the patient was started on plasma exchange and prednisone 1 mg/kg. Renal ultrasound showed normal-sized kidneys. Ophthalmologic evaluation found minimal signs of diabetic retinopathy.Table 1Laboratory and radiographic investigation on initial presentationHGB7.4 mg/dl (was normal 5 months previously)WBC9.2 K/μl (ref range: 4−11)Platelets36 K/μl (was normal 5 months previously)Sodium143 mEq/lPotassium4.5 mEq/lChloride112 mEq/lBicarbonate25 mEq/lCreatinine1.43 mg/dl (1 mg/dl 5 months ago)Troponin I6.4 ng/ml (ref range < 0.03 ng/ml)BNP551 pg/mlCXRBilateral pleural effusionsECGNonspecific T-wave changesCoagulation labsINR 1.01, PTT 48,Hemolysis labsLDH 742 U/l (ref range: 171−308), haptoglobin undetectable, direct Coomb’s test negativePeripheral blood smearMany schistocytesUrine analysis (UA)UA shows 2+ blood, 3+ protein.Urine microscopyFew dark brown pigmented casts, oval fat bodies, many transitional cells, some RBCs, no RBC casts or WBC castsComplementNormalInfection serologyHIV negative. HCV positive (known)ANCANegativeLupus, antiphospholipid, serologyANA, negative. Lupus anticoagulant, Cardiolipin Ab, and β2-glycoprotein were absent.ElectrophoresisSerum and urine protein electropheresis were normalCryoglobulinsNegativeUrine protein/creatinine (Cr) ratio9 g/g CrSerum albumin2 mg/dlANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibodies; BNP, brain natriuretic peptide; CXR, chest X-ray; ECG, electrocardiogram; HCV, hepatitis C virus; HGB, hemoglobin; INR, international normalized ratio; LDH, lactate dehydrogenase; PTT, partial thromplastin time; RBC, red blood cell; WBC, white blood cell. Open table in a new tab ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibodies; BNP, brain natriuretic peptide; CXR, chest X-ray; ECG, electrocardiogram; HCV, hepatitis C virus; HGB, hemoglobin; INR, international normalized ratio; LDH, lactate dehydrogenase; PTT, partial thromplastin time; RBC, red blood cell; WBC, white blood cell. The renal team decided to proceed with renal biopsy because nephrotic-range proteinuria is unusual for TTP. Biopsy showed features of membranous nephropathy (MN). The deposits were immunoreactive for phospholipase A2 receptor (PLA2R) and IgG, which was restricted to the IgG1 subclass (Figure 1a and b). Many of the subepithelial deposits were flanked by new basement membrane material (“spikes”), which suggested some element of chronicity to this process (Figure 1c); and which were classified as stage II deposits according to the criteria by Ehrenreich and Churg.1Ehrenreich T. Churg J. Pathology of membranous nephropathy.Pathol Annu. 1968; 3: 145-186Google Scholar In addition, the patient had moderately severe arterial and arteriolar sclerosis and segmentally prominent double contour formation in the glomeruli that were not spatially associated with immune complex deposition. These vascular changes suggested a primary form of endothelial injury, consistent with chronic thrombotic microangiopathy. The platelet count of the patient normalized after 3 days of daily plasma exchanges; this rapidity of response was not expected. von Willebrand factor protease activity was <3% (reference range: 68−163%), and an ADAMTS13 inhibitor was present at a titer of 1.3 (reference range: <0.4 Bethesda equivalent units). Multimeric analysis of von Willebrand factor antigen was normal. Anti-PLA2R was detected in the serum at a titer of 40.3 RU/ml. Recombinant human ADAMTS13 was obtained as cell lysate from Dr. Evan Sadler, Washington University, St. Louis, Missouri. Equal amounts were electrophoresed under nonreducing conditions, transferred to nitrocellulose, and Western blotted using serum from the patient, control serum, or a commercial antibody against the StrepTag on the recombinant protein. Human IgG1 was detected with an IgG1 subclass specific sheep antibody (The Binding Site, Birmingham, UK). Serum from the patient was collected immediately after plasma exchange treatment, and at 1 and 2 months of follow-up. These sera, as well as serum from a normal control, were used to assess reactivity to recombinant human ADAMTS13, as well as the 2 known autoantigens in primary MN (PLA2R and thrombospondin type-1, domain-containing 7A [THSD7A]). Human glomerular extract (HGE), recombinant PLA2R, and recombinant human THSD7A were prepared as described2Tomas 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 (536) Google Scholar, 3Beck 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 (1504) Google Scholar and gel electrophoresed as previously described. In addition, a StrepTag- (IBA Lifesciences, Göttingen, Germany) and hexahistadine-tagged human PLA2R cysteine-rich (CysR) domain construct was expressed in HEK293 cells, and the secreted product was run by sodium dodecyl sulfate polyacrylamide gel electrophoresis under nonreducing conditions. After transfer to nitrocellulose, these products were Western blotted with patient or control serum, and assayed for the IgG1 or the IgG4 subclass of IgG. Immunoblot of rhADAMTS13 with a commercial antibody that recognized the StrepTag revealed the full-length product (1398 amino acids) and 3 smaller degradation products (Figure 2a). Notably, these 4 ADAMTS13 bands, when detected for IgG1, were found in the serum from the patient, both after plasma exchange and at 1-month follow-up. A control serum exhibited no reactivity. We next tested the serial serum samples from the patient by Western blot against a detergent extract of human glomerular proteins (HGE), as well as cell-expressed recombinant human PLA2R and THSD7A. The initial sample was reactive with native (in HGE) and recombinant (cell-expressed) PLA2R, mostly of the IgG1 subclass with a minor amount of IgG4 (Figure 2b). There was no reactivity with human THSD7A. The follow-up sample showed nearly equivalent amounts of IgG1 anti-PLA2R, although the IgG4 band had disappeared. Figure 2c demonstrates the continued presence of anti-PLA2R in the initial, and 1- and 2-month-follow up samples. We tested for reactivity to the CysR and the first C-type lectin-like (CTLD1) domains of PLA2R to assess whether any epitope spreading had occurred. The patient serum was only reactive with the immunodominant CysR domain. Acquired TTP is characterized by diminished ADAMTS13 activity due to acquired autoantibody inhibitors. Plasma ADAMTS13 normally cleaves von Willebrand factor after secretion and within thrombi. ADAMTS13 deficiency perturbs the regulation of the size of von Willebrand factor multimers, which leads to diffuse microthrombi, microangiopathic hemolysis, thrombocytopenia, and tissue ischemia.4Sadler J.E. Thrombotic thrombocytopenic purpura: a moving target.Hematology. 2006; : 415-420Crossref PubMed Scopus (47) Google Scholar More than 90% of patients with acquired TTP and severe ADAMTS13 deficiency have circulating anti-ADAMTS13 in the plasma.5Kremer Hovinga J.A. Lammle B. Role of ADAMTS13 in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura.Hematology. 2012; 2012: 610-616Crossref PubMed Google Scholar Most of these antibodies are inhibitory. Circulating antibodies are targeted against the primary epitope in the ADAMTS13 spacer domain (see Figure 3) in up to 97% to 100% of cases, with the amino acids Arg568, Phe592, Arg660, Tyr661, and Tyr665 as the primary antigenic targets.5Kremer Hovinga J.A. Lammle B. Role of ADAMTS13 in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura.Hematology. 2012; 2012: 610-616Crossref PubMed Google Scholar Moreover, antibodies that recognize epitopes in other ADAMTS13 domains are found in up to 64% of cases.5Kremer Hovinga J.A. Lammle B. Role of ADAMTS13 in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura.Hematology. 2012; 2012: 610-616Crossref PubMed Google Scholar, 6Klaus C. Plaimauer B. Studt J.D. et al.Epitope mapping of ADAMTS13 autoantibodies in acquired thrombotic thrombocytopenic purpura.Blood. 2004; 103: 4514-4519Crossref PubMed Scopus (184) Google Scholar, 7Luken B.M. Turenhout E.A. Hulstein J.J. et al.The spacer domain of ADAMTS13 contains a major binding site for antibodies in patients with thrombotic thrombocytopenic purpura.Thromb Haemost. 2005; 93: 267-274Crossref PubMed Scopus (103) Google Scholar, 8Zheng X.L. Wu H.M. Shang D. et al.Multiple domains of ADAMTS13 are targeted by autoantibodies against ADAMTS13 in patients with acquired idiopathic thrombotic thrombocytopenic purpura.Haematologica. 2010; 95: 1555-1562Crossref PubMed Scopus (102) Google Scholar Antibodies are predominantly of the IgG4 subclass (90%), followed by IgG1 (53%), IgG2 (50%), and IgG3 (33%).5Kremer Hovinga J.A. Lammle B. Role of ADAMTS13 in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura.Hematology. 2012; 2012: 610-616Crossref PubMed Google Scholar, 9Ferrari S. Mudde G.C. Rieger M. et al.IgG subclass distribution of anti-ADAMTS13 antibodies in patients with acquired thrombotic thrombocytopenic purpura.J Thromb Haemost. 2009; 7: 1703-1710Crossref PubMed Scopus (138) Google Scholar Titers of IgG4 and IgG1 subclasses are inversely correlated.10Berhe A. Bardsley W.G. Harkes A. et al.Molecular charge effects on the protein permeability of the guinea-pig placenta.Placenta. 1987; 8: 365-380Crossref PubMed Scopus (18) Google Scholar A subclass profile characterized by high levels of IgG4 seems to be predictive of a more responsive form of TTP compared with those with IgG1.10Berhe A. Bardsley W.G. Harkes A. et al.Molecular charge effects on the protein permeability of the guinea-pig placenta.Placenta. 1987; 8: 365-380Crossref PubMed Scopus (18) Google Scholar However, high titers of IgG4 have been associated with an increased risk of relapse,9Ferrari S. Mudde G.C. Rieger M. et al.IgG subclass distribution of anti-ADAMTS13 antibodies in patients with acquired thrombotic thrombocytopenic purpura.J Thromb Haemost. 2009; 7: 1703-1710Crossref PubMed Scopus (138) Google Scholar whereas the presence of IgA or IgG1 has been associated with poor and sometimes lethal outcome at the first episode.9Ferrari S. Mudde G.C. Rieger M. et al.IgG subclass distribution of anti-ADAMTS13 antibodies in patients with acquired thrombotic thrombocytopenic purpura.J Thromb Haemost. 2009; 7: 1703-1710Crossref PubMed Scopus (138) Google Scholar, 11Ferrari S. Scheiflinger F. Rieger M. et al.Prognostic value of anti-ADAMTS 13 antibody features (Ig isotype, titer, and inhibitory effect) in a cohort of 35 adult French patients undergoing a first episode of thrombotic microangiopathy with undetectable ADAMTS 13 activity.Blood. 2007; 109: 2815-2822Crossref PubMed Scopus (218) Google Scholar MN was attributed to formation of antibodies against podocyte antigens. Beck et al.3Beck 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 (1504) Google Scholar identified PLA2R as the major antigen in MN, associated with 70% of cases. PLA2R is a member of the mannose receptor family, which shares a common domain structure.12East L. Isacke C.M. The mannose receptor family.Biochim Biophys Acta. 2002; 1572: 364-386Crossref PubMed Scopus (497) Google Scholar Several studies using x-ray crystallography were performed on mannose receptor members to predict the structure and function of individual domains, particularly the N-terminal CysR domain.13Fresquet M. Jowitt T.A. Gummadova J. et al.Identification of a major epitope recognized by PLA2R autoantibodies in primary membranous nephropathy.J Am Soc Nephrol. 2015; 26: 302-313Crossref PubMed Scopus (138) Google Scholar It was suggested that the 3-dimensional conformational structure is an essential feature of PLA2R epitope, and that pH-dependent conformational changes could lead to certain epitope exposure.3Beck 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 (1504) Google Scholar The dominant epitope that interacts with human anti-PLA2R autoantibodies is located in the N-terminal CysR (ricin B) domain.13Fresquet M. Jowitt T.A. Gummadova J. et al.Identification of a major epitope recognized by PLA2R autoantibodies in primary membranous nephropathy.J Am Soc Nephrol. 2015; 26: 302-313Crossref PubMed Scopus (138) Google Scholar Although the pathogenicity of anti-PLA2R autoantibodies has not been conclusively confirmed, several observations support this hypothesis: the presence of PLA2R within immune deposits; the correlation of anti-PLA2R antibody titers and disease activity; and the elution of anti-PLA2R antibodies from glomerular extracts.14Beck Jr., L.H. Monoclonal anti-PLA2R and recurrent membranous nephropathy: another piece of the puzzle.J Am Soc Nephrol. 2012; 23: 1911-1913Crossref PubMed Scopus (10) Google Scholar In contrast, the absence of anti-PLA2R in secondary MN and other glomerular diseases argues against anti-PLA2R being a biomarker of the disease process or generally reflective of podocyte damage.14Beck Jr., L.H. Monoclonal anti-PLA2R and recurrent membranous nephropathy: another piece of the puzzle.J Am Soc Nephrol. 2012; 23: 1911-1913Crossref PubMed Scopus (10) Google Scholar In primary cases, IgG4 is the predominant IgG subclass within subepithelial deposits, which has been found in >75% of cases, whereas other subclasses predominate in secondary forms of the disease, such as those associated with autoimmune diseases or malignancy, in which IgG1 is predominant in approximately 60% of cases.15Huang C.C. Lehman A. Albawardi A. et al.IgG subclass staining in renal biopsies with membranous glomerulonephritis indicates subclass switch during disease progression.Mod Pathol. 2013; 26: 799-805Crossref PubMed Scopus (115) Google Scholar Consistent with the inability of IgG4 to activate the complement pathway, C1q staining is often absent or weak in biopsy specimens of primary MN. Conversely, it is prominent in other automimmune diseases (e.g., lupus). C4 has been demonstrated in immune deposits of primary MN, potentially implicating the lectin pathway.16Val-Bernal J.F. Garijo M.F. Val D. Rodrigo E. Arias M. C4d immunohistochemical staining is a sensitive method to confirm immunoreactant deposition in formalin-fixed paraffin-embedded tissue in membranous glomerulonephritis.Histol Histopathol. 2011; 26: 1391-1397PubMed Google Scholar, 17Espinosa-Hernández M. Ortega-Salas R. López-Andreu M. et al.C4d as a diagnostic tool in membranous nephropathy.Nefrologia. 2012; 32: 295-299PubMed Google Scholar There is some evidence that IgG4 anti-PLA2R autoantibodies can bind mannan-binding lectin and activate this pathway.18Yang Y. Wang C. Jin L. et al.IgG4 anti-phospholipase A2 receptor might activate lectin and alternative complement pathway meanwhile in idiopathic membranous nephropathy.Immunol Res. 2016; 64: 919-930Crossref PubMed Scopus (32) Google Scholar Anti-PLA2R is increasingly being used to monitor disease activity and predict response to treatment and relapse risk.19Kanigicherla D. Gummadova J. McKenzie E.A. et al.Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy.Kidney Int. 2013; 83: 940-948Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar Nephrotic range proteinuria in the setting of TTP was reported in patients with systemic lupus erythematosus (SLE). In a large series of patients with TTP, 23% of patients had some pathological findings that suggested SLE. In most cases, Libman-Sachs endocarditis was the only finding to indicate SLE. Only 4% had evidence of glomerular pathology.20Levine S. Shearn M.A. Thrombotic thrombocytopenic purpura and systemic lupus erythematosus.Arch Intern Med. 1964; 113: 826-836Crossref PubMed Scopus (59) Google Scholar Our case serology was completely negative for lupus, with no evidence of lupus nephritis on biopsy. IgG1 surprisingly consisted of most of the anti-PLA2R autoantibodies (accompanied by only minor amounts of IgG4) in both the subepithelial deposits on biopsy and by Western blot for PLA2R. This contrasted with reports that IgG4 was the predominant subclass for both TTP and MN. The presence of IgG1 against PLA2R in our case might have been crucial for disease development. There was the possibility that testing was confounded by the specimen being obtained after the initiation of the first plasma exchange. However, plasma exchange is not known to remove IgG subclasses differentially.21Ohkubo A. Okado T. Kurashima N. et al.Removal characteristics of immunoglobulin G subclasses by conventional plasma exchange and selective plasma exchange.Ther Apher Dial. 2015; 19: 361-366Crossref PubMed Scopus (22) Google Scholar An attractive hypothesis to explain the coexistence of these 2 disease entities is that a single pathogenic antibody might target a similar conformational epitope carried by both antigens. We interrogated whether any of the different epitopes known to be involved in the humoral response in MN exhibited any homology with domains within ADAMTS13. The presence of any potential homology could lead to epitope spreading, which was implicated in the pathogenesis of these 2 entities.22Seitz-Polski B. Dolla G. Payre C. et al.Epitope spreading of autoantibody response to PLA2R associates with poor prognosis in membranous nephropathy.J Am Soc Nephrol. 2016; 27: 1517-1533Crossref PubMed Scopus (120) Google Scholar, 23Grillberger R. Casina V.C. Turecek P.L. et al.Anti-ADAMTS13 IgG autoantibodies present in healthy individuals share linear epitopes with those in patients with thrombotic thrombocytopenic purpura.Haematologica. 2014; 99: e58-e60Crossref PubMed Scopus (26) Google Scholar ADAMTS13, similar to PLA2R, contains a region called a Cys-rich domain, which is located at the C-terminal to the first thrombospondin repeat and before the spacer region. When we compared that region of ADAMTS13 against all human proteins using Protein BLAST (National Center for Biotechnology Information, U.S. National Library of Medicine, Bethesda, MD), the only homologies found were with other ADAMTS proteins, and not PLA2R. We directly compared the ADAMTS13 CysR domain with the PLA2R CysR domain, and there was no homology. Therefore, it was unlikely that there was a common epitope in the respective CysR domains of the 2 autoantigens, despite the serum from this patient recognizing the CysR domain of PLA2R. The newly described antigen in MN, THSD7A,2Tomas 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 (536) Google Scholar is composed of repeating thrombospondin type-1 repeats that are similar to those in ADAMTS13. This raised the question whether our patient, in addition to possessing autoantibodies to PLA2R, might also carry anti-THSD7A antibodies, and that this shared epitope could explain the presence of the 2 autoimmune diseases. However, we did not find anti-THSD7A in this case. Despite the absence of autoantibodies targeting an epitope shared between the 2 molecules, these 2 autoimmune processes were also related because both autoantibodies were predominantly of the IgG1 subclass, instead of the more common IgG4 subclass. IgG1 might be dominant in the early phases of MN, because it is found in 64% of cases, and might possibly play a crucial role in early disease pathogenesis by activating the classical complement pathway.15Huang C.C. Lehman A. Albawardi A. et al.IgG subclass staining in renal biopsies with membranous glomerulonephritis indicates subclass switch during disease progression.Mod Pathol. 2013; 26: 799-805Crossref PubMed Scopus (115) Google Scholar The predominance of IgG1 against both ADAMTS13 and PLA2R might also have been directed by Th1 cytokines driven by an underlying inflammatory state or could instead represent an early, and perhaps, aggressive form of these 2 diseases. MN has been described in other autoimmune diseases like Grave’s disease, celiac disease, and others. One assumption is that patients with these diseases have a perturbed immune system and/or carry particular human leukocyte antigen haplotypes associated with autoimmune disease, which makes them more susceptible to also developing membranous disease. In contrast, it could be hypothesized that the immune process in one organ leads to exposures of certain antigens and possibly formation of antibodies for antigens in other organs.24Makker S.P. Tramontano A. Idiopathic membranous nephropathy: an autoimmune disease.Semin Nephrol. 2011; 31: 333-340Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar Other groups identified other antibodies that could be involved in disease pathogenicity or possibly develop subsequent to the primary insult.25Prunotto M. Carnevali M.L. Candiano G. et al.Autoimmunity in membranous nephropathy targets aldose reductase and SOD2.J Am Soc Nephrol. 2010; 21: 507-519Crossref PubMed Scopus (181) Google Scholar It seems that several antibodies can participate in the pathogenesis of MN.24Makker S.P. Tramontano A. Idiopathic membranous nephropathy: an autoimmune disease.Semin Nephrol. 2011; 31: 333-340Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar Plasma exchange has been an effective standard of care for the treatment of TTP. Because relapse of disease can be life threatening, preventing relapse is a critical component of management. Patients with low ADAMTS13 factor activity have a high risk of relapse, and thus ADAMTS13 factor activity and inhibitor level are useful markers in predicting relapse. Rituximab has been increasingly used to prevent relapses in TTP26Westwood J.P. Webster H. McGuckin S. et al.Rituximab for thrombotic thrombocytopenic purpura: benefit of early administration during acute episodes and use of prophylaxis to prevent relapse.J Thromb Haemost. 2013; 11: 481-490Crossref PubMed Scopus (122) Google Scholar and as an effective immunosuppressive agent in MN.27Ruggenenti P. Cravedi P. Chianca A. et al.Rituximab in idiopathic membranous nephropathy.J Am Soc Nephrol. 2012; 23: 1416-1425Crossref PubMed Scopus (200) Google Scholar, 28Bomback A.S. Derebail V.K. McGregor J.G. et al.Rituximab therapy for membranous nephropathy: a systematic review.Clin J Am Soc Nephrol. 2009; 4: 734-744Crossref PubMed Scopus (82) Google Scholar, 29Dahan K. Debiec H. Plaisier E. et al.Rituximab for severe membranous nephropathy: a 6-month trial with extended follow-up.J Am Soc Nephrol. 2017; 28: 348-358Crossref PubMed Scopus (201) Google Scholar There were 2 reported cases of successful treatment of TTP and MN with rituximab, before the era of PLA2R monitoring.30Kuppachi S. Chander P. Yoo J. Membranous nephropathy and thrombotic thrombocytopenic purpura treated with rituximab.J Nephrol. 2009; 22: 561-564PubMed Google Scholar, 31Golembiewska E. Dutkiewicz G. Stepniewska J. et al.Thrombotic thrombocytopenic purpura and membranous glomerulonephritis: a pregnancy-induced case.Case Rep Intern Med. 2014; 1: 60-64Google Scholar It is unfortunate that our patient was lost to follow-up, and that we could not assess any potential response to anti−B-cell therapy. Severe proteinuria in the setting of TTP should prompt a search for a secondary etiology. Although evidence to support a direct relationship between TTP and MN is lacking, it is possible that the same process that caused ADAMTS13 deficiency also resulted in immune complex deposition in the kidney. Presentations of concurrent autoimmune diseases continue to enrich our understanding of disease pathogenicity. Rituximab is a promising agent for targeting different autoimmune conditions that may share a primary etiology. Disease registries for uncommon conditions such as TTP and MN may be useful to enhance research into pathogenesis." @default.
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• W2750021728 title "Concurrent Presentation of Thrombotic Thrombocytopenic Purpura and Membranous Nephropathy" @default.
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